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DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e

Chapter 87: Schizophrenia

M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley

KEY CONCEPTS

KEY CONCEPTS

Although dysfunction in multiple neurotransmitters are involved in schizophrenia, the etiology is likely mediated by multiple subcellular processes that are influenced by different genetic polymorphisms.

The clinical presentation of schizophrenia is characterized by positive symptoms, negative symptoms, and impairment in cognitive functioning.

Comprehensive care for individuals with schizophrenia must occur in the context of a multidisciplinary mental healthcare environment that offers comprehensive psychosocial services in addition to
psychotropic medication management.

A thorough patient evaluation (eg, history, mental status examination, physical examination, psychiatric diagnostic interview, and laboratory analysis) should occur to establish a diagnosis of
schizophrenia and to identify potential co­occurring disorders, including substance use disorders and general medical disorders.

Given that it is challenging to differentiate among antipsychotics based on efficacy, adverse medication reaction profiles become important in choosing an antipsychotic for an individual patient.

Pharmacotherapy guidelines should emphasize antipsychotic monotherapies that optimize benefit­to­risk ratios before progressing to medications with greater adverse reaction risks. Combination
regimens should only be used in the most treatment­resistant patients.

Adequate time on a given medication at a therapeutic dose is the most important variable in predicting medication response.

Long­term maintenance antipsychotic treatment is necessary for most patients with schizophrenia in order to prevent relapse.

Thorough patient and family psychoeducation should be implemented, utilizing motivational interviewing methods that focus on patient­driven outcomes in an effort to allow patients to achieve life goals.

Pharmacotherapy decisions should be guided by systematic monitoring of patient symptoms, preferably with the use of brief symptom rating scales and systematic assessment of potential adverse effects.

PATIENT CARE PROCESS

Patient Care Process for Schizophrenia

Collect

Patient characteristics (eg, age, race, sex, gender identity, pregnancy status)

Patient history (past mental and medical, medication adherence, family, social—diet, alcohol and substance use, tobacco use)

Mental status exam

Medications (current and past)

Objective data

Brief Positive and Negative Symptom Scales (see Table 87­11)

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Chapter 87: Schizophrenia,
Blood pressure M.height,
(BP), heart rate (HR), Lynn Crismon;
weight, and bodyTawny L.(BMI)
mass index Smith; Peter
(see Table F. Buckley
87­12) Page 1 / 48
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Labs: Hemoglobin A1c (HgA1c), lipids, other tests if indicated (see Table 87­12)

Assess
 Patient history (past mental and medical, medication adherence, family, social—diet, alcohol and substance use, tobacco use)
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Mental status exam
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Medications (current and past)

Objective data

Brief Positive and Negative Symptom Scales (see Table 87­11)

Blood pressure (BP), heart rate (HR), height, weight, and body mass index (BMI) (see Table 87­12)

Labs: Hemoglobin A1c (HgA1c), lipids, other tests if indicated (see Table 87­12)

Assess

Patient’s concerns and attitudes toward treatment, medication adherence (see Table 87­5)

Symptom severity and the extent that treatment goals have been met

Do any co­occurring disorders (mental, substance use disorder, medical) need to be addressed?

Are patient’s psychosocial needs being met? (see Table 87­2)

Adverse medication reactions (see Tables 87­7 and 87­12)

Potential for medication interactions (see Tables 87­9 and 87­10)

Appropriateness and effectiveness of current psychotropic regimen

Plan*

Actively engage patient in care plan

Medication therapy regimen (egspecify the continuation and discontinuation of existing therapies) (see Fig. 87­1 and Tables 87­3, 87­4, and 87­6)

Monitoring parameters including efficacy and time frame (see Tables 87­11 and 87­12)

Patient education (eg, medication, life style management)

Referrals to other providers as appropriate (eg, physician, psychologist, social worker)

Implement*

Provide patient education regarding all elements of treatment plan

Use motivational interviewing and coaching strategies to maximize adherence

Schedule follow­up

Follow­up: Monitor and Evaluate*

Determine symptom attainment (see Table 87­11)

Presence of adverse effects (see Table 87­12)

Presence of medication interactions (see Tables 87­9 and 87­10)

Need for psychosocial interventions

Patient adherence to treatment plan using multiple sources of information

* Collaborate with patient, caregivers, and other healthcare professionals.

BEYOND THE BOOK

BEYOND THE BOOK

Watch the approximately 9­minute video on YouTube, “Four Patients with Schizophrenia.”

For each of the patients, list the symptoms that are associated with schizophrenia. Use Table 87­11 as a reference, and for each patient list those symptoms that are present on the Brief Positive and Negative
Symptom Scales. The intent of this learning activity is to help you identify symptoms associated with schizophrenia and identify symptoms that can be used to monitor response to pharmacotherapy.

INTRODUCTION
Schizophrenia is one of the most complex and challenging psychiatric disorders as it represents a heterogeneous syndrome of disorganized and bizarre thoughts, delusions, hallucinations, inappropriate affect, and
impaired psychosocial functioning. From the time that Kraepelin first described dementia praecox in 1896 until publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM­5) in 2013,
the description of this illness has continuously evolved.1 Scientific advances that increase our knowledge of central nervous system (CNS) physiology, pathophysiology, and genetics will likely improve our
understanding of schizophrenia in the future.

EPIDEMIOLOGY

The lifetime prevalence of schizophrenia ranges from 0.28% to 0.6%2 with the worldwide prevalence being similar among most cultures. Schizophrenia most commonly has its onset in late adolescence or early
adulthood and rarely occurs before adolescence or after the age of 40 years. Although the prevalence of schizophrenia is equal between the sexes, the onset of illness tends to be earlier in males as they typically have
their first episode during their early 20s, whereas with females it is usually during their late 20s.1
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ETIOLOGY
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Although the etiology of schizophrenia is unknown, research has demonstrated various abnormalities in brain structure and function.3 However, these changes are not consistent among all individuals with
schizophrenia. The cause of schizophrenia is likely multifactorial, that is, multiple pathophysiologic abnormalities can play a role in producing the similar but varying clinical phenotypes we refer to as schizophrenia.
the description of this illness has continuously evolved.1 Scientific advances that increase our knowledge of central nervous system (CNS) physiology, pathophysiology, and genetics will likely improve our
understanding of schizophrenia in the future.
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EPIDEMIOLOGY Access Provided by:

The lifetime prevalence of schizophrenia ranges from 0.28% to 0.6%2 with the worldwide prevalence being similar among most cultures. Schizophrenia most commonly has its onset in late adolescence or early
adulthood and rarely occurs before adolescence or after the age of 40 years. Although the prevalence of schizophrenia is equal between the sexes, the onset of illness tends to be earlier in males as they typically have
their first episode during their early 20s, whereas with females it is usually during their late 20s.1

ETIOLOGY

Although the etiology of schizophrenia is unknown, research has demonstrated various abnormalities in brain structure and function.3 However, these changes are not consistent among all individuals with
schizophrenia. The cause of schizophrenia is likely multifactorial, that is, multiple pathophysiologic abnormalities can play a role in producing the similar but varying clinical phenotypes we refer to as schizophrenia.

A neurodevelopmental model, formed from the study of brains from individuals diagnosed with schizophrenia, has been evoked as one possible explanation for its etiology.3,4 Although many different avenues of
research have been undertaken, most find that biological and functional abnormalities in cell shape, position, symmetry, and connectivity have been associated with development of abnormal brain circuits that lead
to the symptoms seen in schizophrenia.4 The changes seen as part of this research are consistent with a cell migration abnormality during the second trimester of pregnancy, and some studies associate upper
respiratory infections during the second trimester of pregnancy with a higher incidence of schizophrenia.4 Other studies associate low birth weight (LBW; less than 2.5 kg [5.5 lb]), obstetric complications, or neonatal
hypoxia with schizophrenia.4 Theories of maternal stress have been developed which may be related to aberrations in circulating glucocorticoids in utero as a risk factor for schizophrenia.4 Although imaging studies
show decreased cortical thickness and increased ventricular size in the brains of many patients with schizophrenia, this occurs in the absence of widespread changes in the glial cells (or gliosis).4 One hypothesis for
these changes is that obstetric complications and hypoxia, in combination with a genetic predisposition, could activate a glutamatergic cascade resulting in increased neuronal pruning. Genes controlling N­methyl­D­
aspartate (NMDA) receptor activity are hypothesized to be part of this process, as dendrite pruning, which is part of normal neurodevelopmental process, is higher in individuals with schizophrenia. As synaptic
pruning predominantly involves glutamatergic dendrites, hypoxia or other prenatal insults can result in fewer basal neurons overall, and glutamatergic activation can exaggerate the pruning process.3,4 Furthermore,
a relationship has been documented between autoimmune encephalitis and psychosis, which is based upon glutamate receptor autoantibodies. This is important as studies have shown an increased susceptibility to
immune/autoimmune disorders in schizophrenia, as well as abnormalities of autoantibodies and cytokine functioning.5 Although this etiology is felt to be uncommon, it serves as a model for the heuristic immune
hypothesis of schizophrenia, which also emphasizes integration of mental and physical well­being.5 A plethora of diverse findings point to immune dysfunction in schizophrenia.

Numerous studies have shown neuropsychological abnormalities, impairment in reaching normal motor milestones and abnormal movements, in young children who later develop schizophrenia.4 These
abnormalities in brain function occur long before the onset of psychotic symptomatology and provide empirical evidence for schizophrenia being a neurodevelopmental disorder.2 Furthermore, brain imaging
studies show deteriorative brain changes in patients with frequent relapses,4,6 with these changes being most pronounced among adolescents with early onset schizophrenia.4,7 Therefore, continued
pathophysiological changes, secondary to the original neurodevelopmental insult, may lead to the first psychotic episode, and brain morphology resembling neurodegeneration.3,4,7

Although the risk of developing schizophrenia is estimated as 0.28% to 0.6% worldwide, the risk is approximately 3% if a second­degree relative has the illness and 10% if there is a first­degree relative.4 If both
parents have schizophrenia, the risk of schizophrenia, to the offspring, increases to approximately 40%. Dizygotic twins report a 12% to 14% risk if one twin has the illness, with this increasing to 48% for monozygotic
twins.4 Furthermore, in siblings the onset of illness tends to occur at the same age in each, and adoption studies indicate that environmental changes during the child’s developmental stages do not alter their genetic
risk, both of which give less credence to the possibility of an environmental precipitant.

Numerous approaches have been utilized to study the genetics of neurodevelopment and schizophrenia risk, but one single genetic risk factor has not been found.7 Genome­wide association studies (GWAS)
have identified over 120 genetic small­effect loci that account for a small percent of the risk.3,7 Of major interest is the finding that polymorphisms of the complement component 4 (C4) genes on chromosome 6 may
be implicated in the abnormal dendritic pruning seen in individuals with schizophrenia.8 Additionally, schizophrenia risk has been increasingly linked to about a dozen recurrent copy number variants (CNV) that have
high penetrance; however, cumulatively they likely account for no more than 1% to 2% of all cases.3,7 Genetic risk has also been attributed to the synaptic protein neurexin 1 (NRXN1) and neuregulin 1 (NRG1) which, in
particular, may increase the risk of developing the first psychotic episode for those who are already at high risk.3 MicroRNAs (mRNA), which are small noncoding RNAs critical to neurodevelopment and regulation of
adult neuronal processes, have also been linked to schizophrenia risk and are being actively explored.3

There is an overlap—both clinically and biologically—between schizophrenia and mood disorders with single nucleotide polymorphisms (SNPs) from chromosomes 3, 10, and 12 being common across schizophrenia,
bipolar disorder, and major depression. Two of these SNPs were at loci related to the pathophysiology of calcium­channels.3,7 Some of the CMVs identified for schizophrenia risk have also been associated with
autism spectrum disorder, intellectual disability, and attention­deficit hyperactivity disorder.7 Thus, several genetic and biological studies now suggest a greater shared genetic—and neurobiological—basis across
psychiatric disorders so that the idea of schizophrenia being a distinct “condition” is increasingly being challenged.

PATHOPHYSIOLOGY
Studies have found consistent decreases in gray matter in multiple brain areas, including the frontal lobes, cingulate gyri, and medial temporal regions among others. A longitudinal study of high­risk youth showed a
substantially greater decrease in gray matter in high­risk youth who progressed to psychosis than in high­risk youth who did not progress to psychosis or in normal controls.9 Additionally, increases in ventricular
size, as well as decreased white matter in the corpus callosum, have been observed.9 Changes in hippocampal volume may correspond with impairment in neuropsychological testing.4,6 It is felt then, that rather than
a decrease in the number of neurons in affected brain areas, a decrease in axonal and dendritic communications between cells can result in a loss of connectivity impacting neuronal adaptivity and CNS
homeostasis,4,6 which are likely consistent with the evidence for abnormal neuronal pruning.2 Intense research efforts have been made to explore and link brain imaging and other biomarkers to disease expression
and progression, in an effort to arrive at clinically relevant biomarkers that could aid treatment of schizophrenia—just as has occurred in cancer and other medical conditions.

Historically, schizophrenia has been attributed to dopamine (DA) receptor defects, but increasingly subcortical dopaminergic dysregulation, including increased DA synthesis and release have been observed.10
While presynaptic changes in dopaminergic neurons occur and are consistent with the neurodevelopmental model that has been proposed,3,6 numerous positron emission tomography (PET) studies have shown
brain abnormalities including increased glucose metabolism in the caudate nucleus and decreased blood flow and glucose metabolism in the frontal lobe and left temporal lobe.4 These findings may indicate
dopaminergic hyperactivity in the head of the caudate nucleus and dopaminergic hypofunction in the frontotemporal regions, which may be confirmed by alterations in dopamine­2 (D2) receptors densities.4,6

However, increases in presynaptic DA synthesis and release into the striatum may only translate into a small increase in D2/3 receptor availability.11

Additionally, PET studies assessing dopamine­1 (D1) receptor function suggest that subpopulations of patients with schizophrenia may have decreased densities of D1 receptors in the caudate nucleus and the
prefrontal cortex, in addition to the D2 receptors. Clinically this may lead to hypofrontality within the prefrontal cortex, which can be associated with a lack of volition and cognitive dysfunction, core features of
schizophrenia. It is unknown whether these changes represent a primary event or secondary processes related to other pathophysiologic abnormalities in schizophrenia. Because of the heterogeneity in the clinical
presentation of schizophrenia, the DA hypothesis may be more applicable to individuals who respond to antipsychotic treatment, with multiple different etiologies possibly being responsible for causing
schizophrenia.4,6 While attempts have been made to develop relationships between these abnormal findings and behavioral symptoms present in patients with schizophrenia, the positive symptoms of schizophrenia
are possibly more closely associated with DA­receptor hyperactivity in the mesocaudate, whereas negative symptoms and cognitive impairment are most closely related to DA­receptor hypofunction in the prefrontal
cortex. As the presynaptic D1 receptors in the prefrontal cortex are thought to be involved in modulating glutamatergic activity, this hypofunctionality can impact working memory in individuals with schizophrenia.4,6

One can examine different neurotransmitter alterations in the context of different proposed phases of schizophrenia.12 The Predrome phase typically occurs before an individual is diagnosed with schizophrenia.
This phase can last weeks to years where clinically high­risk individuals are thought to exhibit glutamategic synaptic dysfunction that results in a glutamate signaling defect, leading to some affective and/or psychotic
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symptoms. Partial compensation by gamma­aminobutyric acid (GABA) downregulation and synaptic proliferation are associated with the Prodromal Phase. This deficit in GABA is felt to result in less inhibition of
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 3 / 48
excitatory circuits, producing dopaminergic dysfunction, the onset of psychosis, and the Syndrome Phase, with the degree of dopamine dysfunction associated with more severe disease.6 During the Syndrome
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Phase, most individuals are officially diagnosed with schizophrenia. In the last phase, the Chronic Phase, years of chronic schizophrenia symptoms and treatments are thought to be associated with the loss of gray
matter compounding the synaptic deficits.12

12
schizophrenia. It is unknown whether these changes represent a primary event or secondary processes related to other pathophysiologic abnormalities in schizophrenia. Because of the heterogeneity in the clinical
presentation of schizophrenia, the DA hypothesis may be more applicable to individuals who respond to antipsychotic treatment, with multiple different etiologies possibly being responsible for causing
Birzeit University
schizophrenia.4,6 While attempts have been made to develop relationships between these abnormal findings and behavioral symptoms present in patients with schizophrenia, the positive symptoms of schizophrenia
Access in
are possibly more closely associated with DA­receptor hyperactivity in the mesocaudate, whereas negative symptoms and cognitive impairment are most closely related to DA­receptor hypofunction Provided by:
the prefrontal
cortex. As the presynaptic D1 receptors in the prefrontal cortex are thought to be involved in modulating glutamatergic activity, this hypofunctionality can impact working memory in individuals with schizophrenia.4,6

One can examine different neurotransmitter alterations in the context of different proposed phases of schizophrenia.12 The Predrome phase typically occurs before an individual is diagnosed with schizophrenia.
This phase can last weeks to years where clinically high­risk individuals are thought to exhibit glutamategic synaptic dysfunction that results in a glutamate signaling defect, leading to some affective and/or psychotic
symptoms. Partial compensation by gamma­aminobutyric acid (GABA) downregulation and synaptic proliferation are associated with the Prodromal Phase. This deficit in GABA is felt to result in less inhibition of
excitatory circuits, producing dopaminergic dysfunction, the onset of psychosis, and the Syndrome Phase, with the degree of dopamine dysfunction associated with more severe disease.6 During the Syndrome
Phase, most individuals are officially diagnosed with schizophrenia. In the last phase, the Chronic Phase, years of chronic schizophrenia symptoms and treatments are thought to be associated with the loss of gray
matter compounding the synaptic deficits.12

As the glutamatergic system is one of the most widespread excitatory neurotransmitter systems in the brain, hypo­ or hyperactive alterations in function can result in toxic neuronal reactions.12 Dopaminergic
innervation from glutamate in the ventral striatum decreases the limbic system’s inhibitory activity (perhaps through GABA interneurons) and thus increases arousal. The corticostriatal glutamate pathways have the
opposite effect, whereas inhibiting dopaminergic function from the ventral striatum allows increased inhibitory activity in the limbic system. Due to the interaction between glutamatergic and dopaminergic tracts, as
well as through GABA interneurons, glutamatergic deficiency produces symptoms similar to those of dopaminergic hyperactivity and possibly those seen in schizophrenia. Therefore, alterations in the interactions
between dopamine and glutamate due to NMDA hypofunction have been associated with the latent clinical expression of psychotic symptoms in late adolescence or early adulthood.

Schizophrenia is a complex disorder, and multiple etiologies likely exist. Based on current knowledge, it is naïve to think that any one proposed etiology or one dysfunction in neurotransmission can adequately
explain the genesis of this complex disease. Moreover, ongoing research into distinct biomarkers for schizophrenia, as well as the promise of stem cell research to disentangle the pathobiology of this enigmatic
disorder, will also help identify phenotypes and help to determine the boundaries between psychosis and mood disorders.3,7,11,13

CLINICAL PRESENTATION
The clinical presentation of functional psychosis seen with schizophrenia is highly variable. Despite numerous attempts to portray a stereotype in movies and on television, the stereotypic person with schizophrenia
essentially does not exist, and schizophrenia is not a “split personality.” It is a chronic disorder of thought and affect with the individual having a significant disturbance in interpersonal relationships and ability to
function in society.

The first psychotic episode can be sudden in onset with few premorbid symptoms, or more commonly is preceded by withdrawn, suspicious, peculiar behavior, termed schizoid. During acute psychotic episodes,
the patient loses touch with reality, and in a sense, the brain creates a false reality to replace it. Acute psychotic symptoms can include hallucinations (especially hearing voices), delusions (fixed false beliefs), and
ideas of influence (beliefs that one’s actions are controlled by external influences). Thought processes are disconnected (loose associations), the patient may not be able to carry on logical conversation (alogia), and
can have simultaneous contradictory thoughts (ambivalence). The patient’s affect can be flat (no emotional expression), or it can be inappropriate and labile. The patient is often withdrawn and inwardly directed
(autism). Uncooperativeness, hostility, and verbal or physical aggression can be seen because of the patient’s misperception of reality. Self­care skills are impaired, and patients may be dirty and unkempt with
generally poor hygiene during acute episodes. Sleep and appetite are often disturbed. When the acute psychotic episode remits, the patient typically has residual features, which is an important point in
differentiating schizophrenia from other psychotic disorders. Although residual symptoms and their severity vary, patients can have difficulty with anxiety management, suspiciousness, and lack of volition,
motivation, insight, and judgment. They often have difficulty living independently, and because of poor anxiety management and suspiciousness, they are frequently withdrawn socially, and have difficulty forming
close relationships with others. Impaired volition and motivation contribute to poor self­care skills and make it difficult for the patient with schizophrenia to maintain employment.

Patients with schizophrenia frequently experience a lack of historicity, or difficulty in learning from their experiences, resulting in them repeatedly making the same mistakes in social conduct and situations requiring
judgment. They have difficulty understanding the importance of treatment, including medications, in maintaining their ability to function. Therefore, they tend to discontinue treatments, increasing the risk of relapse
and rehospitalization.

The co­occurrence of substance use disorder (SUD) (predominantly alcohol or polysubstance—alcohol, cannabis, and cocaine) in patients with schizophrenia is very common and is another frequent reason for
relapse and hospitalization.1 This effect can be caused by direct toxic effects of these substances on the brain,14 but is also caused by the medication nonadherence that is associated with substance use. Some
substances—most notably heavy cannabis use during adolescence—have been associated with a higher prevalence of schizophrenia, as cannabis use raises the risk of schizophrenia four­ to sixfold.15

Although the course of schizophrenia is variable, the long­term prognosis for many patients is poor. It is marked by intermittent acute psychotic episodes and impaired psychosocial functioning between acute
episodes, with most of the deterioration in psychosocial functioning occurring within 5 years after the first psychotic episode.16 By late life, the patient can appear “burned out,” that is, they cease to have acute
psychotic episodes, but residual symptoms persist (the chronic phase). In a subpopulation of patients, probably 5% to 15%, psychotic symptoms are nearly continuous, and response to antipsychotics is poor.16

Schizophrenia is a chronic disorder, and the patient’s history must be carefully assessed for dysfunction that has persisted for longer than 6 months. After their first episode, patients with schizophrenia rarely have a
level of adaptive functioning as high as before the onset of the disorder. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM­5) should be consulted for the complete criteria for a diagnosis
of schizophrenia.1 The DSM­5 also asks the clinician to specify the episode severity for schizophrenia after having the diagnosis for at least 1 year and whether the patient is presenting with catatonia.1

The DSM­5 classifies the symptoms of schizophrenia into two categories: positive and negative; however, greater emphasis is now being placed on a third symptom category, cognitive dysfunction.1,16 The areas of
cognition found to be abnormal in schizophrenia include attention, working memory, and executive function. Positive symptoms have traditionally attracted the most attention and are the ones most improved by
antipsychotics. However, negative symptoms and impairment in cognition are more closely associated with poor psychosocial function.

CLINICAL PRESENTATION: Schizophrenia and Symptoms Clusters

Positive Symptoms

Suspiciousness

Unusual thought content (delusions)

Hallucinations

Conceptual disorganization

Negative Symptoms

Affective flattening

Alogia

Anhedonia

Avolition

Cognitive Symptoms
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Impaired executive function

level of adaptive functioning as high as before the onset of the disorder. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM­5) should be consulted for the complete criteria for a diagnosis
Birzeit1
of schizophrenia.1 The DSM­5 also asks the clinician to specify the episode severity for schizophrenia after having the diagnosis for at least 1 year and whether the patient is presenting with catatonia. University
Access
1,16Provided by:
The DSM­5 classifies the symptoms of schizophrenia into two categories: positive and negative; however, greater emphasis is now being placed on a third symptom category, cognitive dysfunction. The areas of
cognition found to be abnormal in schizophrenia include attention, working memory, and executive function. Positive symptoms have traditionally attracted the most attention and are the ones most improved by
antipsychotics. However, negative symptoms and impairment in cognition are more closely associated with poor psychosocial function.

CLINICAL PRESENTATION: Schizophrenia and Symptoms Clusters

Positive Symptoms

Suspiciousness

Unusual thought content (delusions)

Hallucinations

Conceptual disorganization

Negative Symptoms

Affective flattening

Alogia

Anhedonia

Avolition

Cognitive Symptoms

Impaired attention

Impaired working memory

Impaired executive function

Along with these characteristic features of schizophrenia, many patients also have comorbid psychiatric and general medical disorders.2,16 These include depression, anxiety disorders, SUD, and general medical
disorders such as respiratory disorders, cardiovascular disorders, and metabolic disturbances. These comorbidities substantially complicate the clinical presentation and course of schizophrenia.

Symptom complexes are correlated with prognosis, cognitive functioning, structural abnormalities in the brain, and response to antipsychotic medications. Negative symptoms and cognitive impairment are more
closely associated with prefrontal lobe dysfunction and positive symptoms with temporolimbic abnormalities. As many patients demonstrate both positive and negative symptoms, those with negative symptoms
frequently have more antecedent cognitive dysfunction, poor premorbid adjustment, low level of educational achievement, and a poorer overall prognosis.1,16

TREATMENT
Desired Outcome

Pharmacotherapy is a mainstay of treatment in schizophrenia, as it is impossible to effectively implement psychosocial rehabilitation programs without antipsychotic treatment in most patients.14 The most
current treatment guidelines for schizophrenia espouse 24 recommendations, three of which relate to overall assessment and treatment planning, 11 of which cover medication treatments, and the remaining 10
focus on psychosocial approaches to care (Table 87­1). A pharmacotherapeutic treatment plan should be developed that delineates medication­related aspects of therapy. Most deterioration in psychosocial
functioning occurs during the first 5 years after the initial psychotic episode, and treatment should be particularly assertive during this period.16 The individualized treatment plan created for each patient should have
explicit end points defined, including realistic goals for the target symptoms most likely to respond, and the relative time course for response.17 Other desired outcomes include avoiding unwanted adverse
medication reactions, integrating the patient back into the community, increasing adaptive functioning to the extent possible, and preventing relapse.

TABLE 87­1
Guidelines for the Care of Patients with Schizophrenia

Patients have a comprehensive initial assessment

Initial education includes a quantitative measure of symptoms—functioning

Treatment planning includes evidence based pharmacologic and nonpharmacologic treatments

Patients receive antipsychotic medications for treatment, evaluating both efficacy and safety

Patients whose illness has improved with medication receive continued antipsychotic treatment

Patients with treatment resistant schizophrenia receive clozapine

Patients with persistent suicidality/risk of suicidality despite other treatments, receive clozapine

*Patients with aggression that persists despite other treatments receive clozapine

*Patients with preference and/or history of inadequate medication noncompliance receive long­acting injectable antipsychotic medication

Patients with antipsychotic­induced dystonia receive an anticholinergic medicine

*Patients with antipsychotic­induced parkinson symptoms have their medication dosage reduced or switched to another antipsychotic or receive an anticholinergic medication

*Patients with antipsychotic induced akathisia have their medication dosage reduced, switch to another antipsychotic, or receive either a benzodiazepine or beta blocker

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that is antipsychotic induced receive a vesicular monoamine transporter 2 (VMAT2) reversible inhibitor
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Patients receive cognitive behavioral therapy
 Pharmacotherapy is a mainstay of treatment in schizophrenia, as it is impossible to effectively implement psychosocial rehabilitation programs without antipsychotic treatment in most patients.14 The most
current treatment guidelines for schizophrenia espouse 24 recommendations, three of which relate to overall assessment and treatment planning, 11 of which cover medication treatments, and the remaining
Birzeit 10
University
focus on psychosocial approaches to care (Table 87­1). A pharmacotherapeutic treatment plan should be developed that delineates medication­related aspects of therapy. Most deterioration in psychosocial
Access Provided by:
functioning occurs during the first 5 years after the initial psychotic episode, and treatment should be particularly assertive during this period.16 The individualized treatment plan created for each patient should have
explicit end points defined, including realistic goals for the target symptoms most likely to respond, and the relative time course for response.17 Other desired outcomes include avoiding unwanted adverse
medication reactions, integrating the patient back into the community, increasing adaptive functioning to the extent possible, and preventing relapse.

TABLE 87­1
Guidelines for the Care of Patients with Schizophrenia

Patients have a comprehensive initial assessment

Initial education includes a quantitative measure of symptoms—functioning

Treatment planning includes evidence based pharmacologic and nonpharmacologic treatments

Patients receive antipsychotic medications for treatment, evaluating both efficacy and safety

Patients whose illness has improved with medication receive continued antipsychotic treatment

Patients with treatment resistant schizophrenia receive clozapine

Patients with persistent suicidality/risk of suicidality despite other treatments, receive clozapine

*Patients with aggression that persists despite other treatments receive clozapine

*Patients with preference and/or history of inadequate medication noncompliance receive long­acting injectable antipsychotic medication

Patients with antipsychotic­induced dystonia receive an anticholinergic medicine

*Patients with antipsychotic­induced parkinson symptoms have their medication dosage reduced or switched to another antipsychotic or receive an anticholinergic medication

*Patients with antipsychotic induced akathisia have their medication dosage reduced, switch to another antipsychotic, or receive either a benzodiazepine or beta blocker

Patients with at least moderate tardive dyskinesia that is antipsychotic induced receive a vesicular monoamine transporter 2 (VMAT2) reversible inhibitor

Patients with first episode psychosis are treated in a comprehensive program

Patients receive cognitive behavioral therapy

Patients receive psychoeducation

Patients receive supported employment opportunities

Patients with social complications contributing to recurrent relapses receive assertive community treatment

*Patients with family contact receive family supportive activities

*Patients receive recovery­based activities

*Patients receive cognitive remediation

*Patients with focus on social performances receive social skills training

*Patients receive supportive psychotherapy

* Recommended or suggested by the American Psychiatric Association (APA). Data from References 18 and 20­22.

Nonpharmacologic Therapy

Psychosocial rehabilitation programs focused on improving patients’ adaptive functioning are the mainstay of non­medication treatment for schizophrenia. These programs include case management,
psychoeducation, targeted cognitive therapy, basic living skills, social skills training, basic education, work programs, supported housing, and financial support. In particular, programs aimed at supportive
employment and housing are effective and considered “best practices.” Those that involve families in the care and life of the patient have been shown to decrease rehospitalization and improve functioning in the
community. For particularly low­functioning patients, assertive intervention programs, referred to as active community treatment (ACT), are effective in improving patients’ functional outcomes. These ACT teams are
available on a 24­hour basis and work in the patient’s home and/or place of employment to provide comprehensive treatment, including medication, crisis intervention, daily living skills, and supported employment
and housing.18 Pharmacotherapy cannot be successful without proper attention to these other aspects of care, as people with schizophrenia need comprehensive care, with coordination of services across
psychiatric, SUD, medical, social, and rehabilitative services. In the United States, care coordination is often insufficient, putting patients at risk to “fall through the cracks.” Some countries have implemented more
robust primary and secondary preventative approaches, highlighting early identification, ease of access to care, and staging of disease management.19 The National Institute of Mental Health (NIMH) Recovery After
Initial Schizophrenia Episode (RAISE) study found that four core interventions (“personalized medication management, family psychoeducation, resilience­focused individual therapy, and supported employment
and education”) significantly improved the quality of life over a 24­month period for individuals with early schizophrenia as compared to usual community care.20

The patient­centered approach to the recovery­based system of care is growing, where the person’s lifetime aspirations and goals become the center of care, rather than symptom reduction being the primary focus.
This recovery­based approach recognizes the strengths and resilience of people with schizophrenia, and acknowledges how people with schizophrenia can be a support to others who are living with the illness.20 It is
important to frame clinical decision making in the context of a mutual process involving patient and clinician. Psychosocial/cognitive behavioral strategies can help some patients, and emerging computer­based
therapies and social media–related approaches may be helpful. Cognitive remediation—which uses computer­based cognitive retraining techniques—has been shown to be of benefit.21 Social media and mobile
technology strategies may be harnessed to improve communications, medication adherence, and potentially detect early warning signs of impending relapse in patients with schizophrenia.

Pharmacologic Therapy

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The importance of an initial accurate diagnostic assessment cannot be overemphasized. A thorough mental status examination (MSE), psychiatric diagnostic interview, physical and neurologic examination,
Chapter 87: Schizophrenia, M. Lynnworkup
complete family and social history, and laboratory Crismon;
must beTawny
performedL.to Smith; Peter
confirm the F. Buckley
diagnosis
Page 6 / 48
and exclude general medical or substance­induced causes of psychosis. Laboratory tests, biologic markers, and
©2022 McGraw
commonly Hill.
available brain All techniques
imaging Rights Reserved. Terms
do not assist in the of ofUse
diagnosis • Privacy
schizophrenia Policyof•medication.
or selection Notice •AAccessibility
pretreatment patient workup not only is important in excluding other pathology but also
serves as a baseline for monitoring potential adverse medication reactions, and should include vital signs, complete blood count, electrolytes, hepatic function, renal function, electrocardiogram (ECG), fasting serum
glucose, hemoglobin A1c, serum lipids, thyroid function, and urine drug screen.
The patient­centered approach to the recovery­based system of care is growing, where the person’s lifetime aspirations and goals become the center of care, rather than symptom reduction being the primary focus.
Birzeit
This recovery­based approach recognizes the strengths and resilience of people with schizophrenia, and acknowledges how people with schizophrenia can be a support to others who are living illness.20 It is
with theUniversity
important to frame clinical decision making in the context of a mutual process involving patient and clinician. Psychosocial/cognitive behavioral strategies can help some patients, and emerging computer­based
Access Provided by:
therapies and social media–related approaches may be helpful. Cognitive remediation—which uses computer­based cognitive retraining techniques—has been shown to be of benefit.21 Social media and mobile
technology strategies may be harnessed to improve communications, medication adherence, and potentially detect early warning signs of impending relapse in patients with schizophrenia.

Pharmacologic Therapy

The importance of an initial accurate diagnostic assessment cannot be overemphasized. A thorough mental status examination (MSE), psychiatric diagnostic interview, physical and neurologic examination,
complete family and social history, and laboratory workup must be performed to confirm the diagnosis and exclude general medical or substance­induced causes of psychosis. Laboratory tests, biologic markers, and
commonly available brain imaging techniques do not assist in the diagnosis of schizophrenia or selection of medication. A pretreatment patient workup not only is important in excluding other pathology but also
serves as a baseline for monitoring potential adverse medication reactions, and should include vital signs, complete blood count, electrolytes, hepatic function, renal function, electrocardiogram (ECG), fasting serum
glucose, hemoglobin A1c, serum lipids, thyroid function, and urine drug screen.

Both first­generation antipsychotics (FGAs, also known as traditional) and second­generation antipsychotics (SGAs, also known as atypical) are used in the treatment of schizophrenia,14,23 with no absolute
criterion distinguishing between the two. As compared with FGAs, SGAs appear to have the ability to produce antipsychotic response with fewer occurring extrapyramidal symptoms (EPS). Other attributes that have
been ascribed to some SGAs include enhanced efficacy (particularly for negative symptoms and cognition), near absence of propensity to cause tardive dyskinesia, and lack of effect on serum prolactin.24 To date,
only clozapine truly fulfills all of these criteria, with other SGAs having some of these attributes.24 Therefore, the major factor used in practice when distinguishing among antipsychotics is adverse effects.22­24 While
the SGAs have a lower risk of neurologic adverse reactions, particularly effects on movement, this is offset by increased risk of metabolic syndrome with some SGAs, including weight gain, hyperlipidemias, and
diabetes mellitus. Adverse medication reaction profiles differ among antipsychotics, and this information should be used in combination with individual patient characteristics when choosing a medication for an
individual patient.

Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, primarily in patients with chronic schizophrenia, indicate that olanzapine, compared with quetiapine, risperidone,
ziprasidone, and the FGA perphenazine, had modest but not statistically significant superiority in maintenance therapy with treatment persistence as the primary clinical outcome.17 However, increased metabolic
effects occurred with olanzapine, and additional studies of patients early on in their illness highlight the high rate of cardiometabolic disturbances with olanzapine and the need to tailor treatment.25

Previous patient or family history of response to an antipsychotic is helpful in the selection of an agent. Acquisition cost varies significantly among different antipsychotics and dosage forms, and should be
considered in context of any potential advantages of an agent. Table 87­2 lists antipsychotics and their usual dosage ranges.

TABLE 87­2
Available Antipsychotics and Dosage Ranges

Generic Name Trade Name Starting Dose (mg/day) Usual Dosage Range (mg/day) Comments

First­Generation Antipsychotics

Chlorpromazine Thorazine 50­150 300­1,000 Most weight gain among FGAs

Fluphenazine Prolixin 5 5­20

Haloperidol Haldol 2­5 2­20 Higher dropout rate in first episode

Loxapine Loxitane 20 50­150

Loxapine inhaled Adasuve 10 10 Maximum 10 mg per 24 hours Approved REMS program only

Perphenazine Trilafon 4­24 16­64

Thioridazine Mellaril 50­150 100­800 Significant QTc prolongation

Thiothixene Navane 4­10 4­50

Trifluoperazine Stelazine 2­5 5­40

Second­Generation Antipsychotics

Aripiprazole Abilify 5­15 15­30

Asenapine Saphris 5 10­20 Sublingual only, no food or drink for 10 minutes after administration

Brexpiprazole Rexulti 1 2­4

Cariprazine Vraylar 1.5 1.5­6 Due to long half­life, steady state is not reached for several weeks

Clozapine Clozaril 25 100­800 REMS program; Check plasma level before exceeding 600 mg

Iloperidone Fanapt 1­2 6­24 Care with dosing in CYP2D6 slow metabolizers

Lumateperone Caplyta 42 42 Bioavailability increased by 9% when administered with high fat meal

Lurasidone Latuda 20­40 40­120 Take with food; ≥350 calories (1,460 Joules)

Olanzapine Zyprexa 5­10 10­20 Avoid in first episode because of weight gain

Paliperidone Invega 3­6 3­12 Bioavailability increased when administered with food

Quetiapine Seroquel 50 300­800

Quetiapine XR Seroquel XR 300 mg 400­800

Risperidone Risperdal 1­2 2­8

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Chapter 87: Schizophrenia,
Ziprasidone Geodon M. Lynn
40 Crismon; Tawny L. Smith;
80­160 Peter F. Buckley Take with food, ≥500 calories (2,100 Joules) Page 7 / 48
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REMS: Risk Evaluation and Mitigation Strategy. XR: extended release.
Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, primarily in patients with chronic schizophrenia, indicate that olanzapine, compared with quetiapine, risperidone,
ziprasidone, and the FGA perphenazine, had modest but not statistically significant superiority in maintenance therapy with treatment persistence as the primary clinical outcome.17 However,Birzeit
increasedUniversity
metabolic
effects occurred with olanzapine, and additional studies of patients early on in their illness highlight the high rate of cardiometabolic disturbances with olanzapine and the need to tailor treatment.
Access25 Provided by:

Previous patient or family history of response to an antipsychotic is helpful in the selection of an agent. Acquisition cost varies significantly among different antipsychotics and dosage forms, and should be
considered in context of any potential advantages of an agent. Table 87­2 lists antipsychotics and their usual dosage ranges.

TABLE 87­2
Available Antipsychotics and Dosage Ranges

Generic Name Trade Name Starting Dose (mg/day) Usual Dosage Range (mg/day) Comments

First­Generation Antipsychotics

Chlorpromazine Thorazine 50­150 300­1,000 Most weight gain among FGAs

Fluphenazine Prolixin 5 5­20

Haloperidol Haldol 2­5 2­20 Higher dropout rate in first episode

Loxapine Loxitane 20 50­150

Loxapine inhaled Adasuve 10 10 Maximum 10 mg per 24 hours Approved REMS program only

Perphenazine Trilafon 4­24 16­64

Thioridazine Mellaril 50­150 100­800 Significant QTc prolongation

Thiothixene Navane 4­10 4­50

Trifluoperazine Stelazine 2­5 5­40

Second­Generation Antipsychotics

Aripiprazole Abilify 5­15 15­30

Asenapine Saphris 5 10­20 Sublingual only, no food or drink for 10 minutes after administration

Brexpiprazole Rexulti 1 2­4

Cariprazine Vraylar 1.5 1.5­6 Due to long half­life, steady state is not reached for several weeks

Clozapine Clozaril 25 100­800 REMS program; Check plasma level before exceeding 600 mg

Iloperidone Fanapt 1­2 6­24 Care with dosing in CYP2D6 slow metabolizers

Lumateperone Caplyta 42 42 Bioavailability increased by 9% when administered with high fat meal

Lurasidone Latuda 20­40 40­120 Take with food; ≥350 calories (1,460 Joules)

Olanzapine Zyprexa 5­10 10­20 Avoid in first episode because of weight gain

Paliperidone Invega 3­6 3­12 Bioavailability increased when administered with food

Quetiapine Seroquel 50 300­800

Quetiapine XR Seroquel XR 300 mg 400­800

Risperidone Risperdal 1­2 2­8

Ziprasidone Geodon 40 80­160 Take with food, ≥500 calories (2,100 Joules)

REMS: Risk Evaluation and Mitigation Strategy. XR: extended release.

Note: In first­episode patients, starting dose and target dose should generally be 50% of the usual dose range. See Long­Acting Injectable Antipsychotics in text for dosing of these agents.

Data from References 24,26­33.

Published Guidelines and an Algorithm Example

Figure 87­1 outlines a suggested pharmacotherapeutic algorithm for schizophrenia, based on information from four published guidelines, the Psychopharmacology Algorithm Project at the Harvard Medical
School Department of Psychiatry South Shore Program,23 the Canadian Schizophrenia Guidelines,22 the guidelines from the World Federation of Biological Psychiatry, and the APA Guidelines.14,22,24

FIGURE 87­1

Suggested pharmacotherapy algorithm for treatment of schizophrenia. Schizophrenia should be treated in the context of an interprofessional model that addresses the psychosocial needs of the patient, necessary
psychiatric pharmacotherapy, psychiatric co­occurring mental disorders, treatment adherence, and any medical problems the patient may have. (See the text for a description of the algorithm stages.)

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Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 8 / 48
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 Figure 87­1 outlines a suggested pharmacotherapeutic algorithm for schizophrenia, based on information from four published guidelines, the Psychopharmacology Algorithm Project at the Harvard Medical
School Department of Psychiatry South Shore Program,23 the Canadian Schizophrenia Guidelines,22 the guidelines from the World Federation of Biological Psychiatry, and the APA Guidelines.14,22,24
Birzeit University
FIGURE 87­1
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Suggested pharmacotherapy algorithm for treatment of schizophrenia. Schizophrenia should be treated in the context of an interprofessional model that addresses the psychosocial needs of the patient, necessary
psychiatric pharmacotherapy, psychiatric co­occurring mental disorders, treatment adherence, and any medical problems the patient may have. (See the text for a description of the algorithm stages.)

Stage 1A of the treatment algorithm applies to those patients experiencing their first acute episode of schizophrenia. Use of SGAs during the first acute episode may result in greater treatment retention and
effectiveness in preventing a second psychotic episode compared to FGAs. In addition, SGAs carry a reduced risk of EPS.24 Among the SGAs, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone have
evidence of efficacy in first­episode patients, with lurasidone showing efficacy in adolescents with schizophrenia, but most were not treatment naive.23,34 Despite its efficacy, olanzapine is not recommended in first
episode because of weight gain and adverse metabolic effects.23,24

Since quetiapine is associated with less time to rehospitalization compared to other SGAs and causes greater weight gain, some guidelines do not recommend it in stage 1A.23 This leaves aripiprazole, risperidone,
and ziprasidone as the evidence­based options in first­episode patients (stage 1A).23 Of these, aripiprazole and ziprasidone produce the least weight gain. However, few head­to­head clinical trials have been
conducted, and the level of evidence is not sufficiently high to recommend these as the only preferred agents in first episode.14,22 The 2021 APA Guidelines do not provide any preference among initial antipsychotic
selection. Because first­episode patients demonstrate greater sensitivity to adverse medication reactions, antipsychotic dosing should be initiated at the lower end of the dose range.20,22,23

In first­episode patients, long­acting risperidone injectable was more effective than oral risperidone in preventing relapse over a one­year period.35 The relapse rate was six times higher in the oral risperidone group
than with the long­acting injectable (LAI); therefore, risperidone LAI can be considered as a treatment option for first­episode patients. If this medication is used, patients should first be stabilized on oral risperidone.
It is critical that enriched psychosocial programs be implemented along with appropriate pharmacotherapy.

Stage 1B addresses pharmacotherapy for a patient who was previously treated with an antipsychotic, and treatment is being restarted because the patient stopped taking the medication. If during the initial
antipsychotic trial, the patient experienced a robust improvement in symptoms, good tolerability, and is positive about taking this antipsychotic again, then that medication can be restarted. If a different medication
is needed, one from stage 2 should be used. Stage 2 addresses pharmacotherapy in a patient who had inadequate clinical improvement with the antipsychotic used in stage 1A or 1B, or the patient responded but
subsequently had a relapse while taking the medication. Stage 2 recommends antipsychotic monotherapy with an FGA or SGA not used in stage 1 or stage 1B.14,22­24 Because of safety concerns and the need for white
blood cell (WBC) monitoring, clozapine is not generally recommended at stage 2.14,22,23 However, clozapine has superior efficacy in decreasing suicidal behavior, and it should be considered at stage 2 for the patient
with suicidal thoughts.22,23 Clozapine can also be considered at stage 2 in patients with a history of violence or comorbid substance use disorder.22,23,36 If a patient has an unacceptable adverse medication reaction
with the antipsychotic used during stage 1A, stage 1B, or stage 2, then an alternate antipsychotic for that stage should be chosen.

Long­acting injectable antipsychotics (LAIAs) should be considered as an option at stage 2. The use of LAIAs should be discussed with the patient as a life style choice, and their use should not be reserved for patients
with poor medication adherence. In fact, if a patient prefers receiving a LAIA, it should be considered as an option at Stages 1A, 1B, and 2.22­24 If there is good documentation of poor symptom improvement with two
different antipsychotic trials at appropriate dose and duration, then pharmacotherapy should be initiated with the stage 3 recommended treatment clozapine.22­24 In stage 4, minimal evidence exists for any treatment
option for patients who do not have adequate symptom improvement with clozapine. The Harvard Department of Psychiatry South Shore algorithms present various treatment options for such patients, however,
none of these options have conclusive evidence.23 It is important to note that the use of antipsychotic combinations is controversial, as limited evidence supports increased efficacy for antipsychotic polypharmacy,
despite this practice being somewhat common.22,23 The APA Guidelines state that electroconvulsive therapy (ECT) combined with an antipsychotic may be useful in some patients with treatment resistance.22

Predictors of Response

Obtaining a thorough medication history is important, and previous treatment response should help guide antipsychotic selection, in that either a good prior response favors the use of the same agent or a negative
prior response suggests the selection of a dissimilar medication. Substance use can influence psychiatric presentation and needs to be considered when making decisions regarding a patient’s diagnosis or
antipsychotic response. Amphetamines and other CNS stimulants, cocaine, corticosteroids, digitalis glycosides, indomethacin, cannabis, pentazocine, phencyclidine, other medications, and substances can induce
psychosis in susceptible individuals or exacerbate psychosis in patients with preexisting psychiatric illness.1,16,22,23 Patients with schizophrenia who use alcohol or other substances usually have a poor response to
medications and a poor overall prognosis. Furthermore, alcohol, cannabis, caffeine, and nicotine use may potentially interact with antipsychotics.

Individual predictors of patient response have been either proposed or identified. Acute onset of symptoms and short duration of illness, presence of acute stressors or precipitating factors, later age of onset, family
history of affective illness, and good premorbid adjustment as reflected in stable interpersonal relationships or employment are all predictors of good response.14
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Chapter
Although 87: Schizophrenia,
controversial, M.can
affective symptoms Lynn Crismon;
correlate Tawny
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negative symptoms and neuropsychological deficits related to cognition and neurologic soft signs can Page
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/ 48
©2022
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Subjective Terms
positive patient ofwithin
response Usethe• Privacy Policy
first 48 hours • administration
after FGA can be associated with medication responsiveness,37 whereas an initial dysphoric
Notice • Accessibility
response, demonstrated by stating a dislike of the medication, feeling worse or “zombie­like,” anxiety or akathisia­like symptoms, is associated with poor medication response, adverse effects, and nonadherence.

The importance of developing a therapeutic alliance between the patient and the clinician cannot be underestimated (see Chapter e81, “Evaluation of Psychiatric Illness”). Patients who form positive therapeutic
Obtaining a thorough medication history is important, and previous treatment response should help guide antipsychotic selection, in that either a good prior response favors the use of the same agent or a negative
prior response suggests the selection of a dissimilar medication. Substance use can influence psychiatric presentation and needs to be considered when making decisions regarding a patient’s diagnosis
Birzeit or
University
antipsychotic response. Amphetamines and other CNS stimulants, cocaine, corticosteroids, digitalis glycosides, indomethacin, cannabis, pentazocine, phencyclidine, other medications, and substances can induce
Access Provided by:
psychosis in susceptible individuals or exacerbate psychosis in patients with preexisting psychiatric illness.1,16,22,23 Patients with schizophrenia who use alcohol or other substances usually have a poor response to
medications and a poor overall prognosis. Furthermore, alcohol, cannabis, caffeine, and nicotine use may potentially interact with antipsychotics.

Individual predictors of patient response have been either proposed or identified. Acute onset of symptoms and short duration of illness, presence of acute stressors or precipitating factors, later age of onset, family
history of affective illness, and good premorbid adjustment as reflected in stable interpersonal relationships or employment are all predictors of good response.14

Although controversial, affective symptoms can correlate with an overall good response, while negative symptoms and neuropsychological deficits related to cognition and neurologic soft signs can correlate with
poor antipsychotic response.14,16,22,23 Subjective positive patient response within the first 48 hours after FGA administration can be associated with medication responsiveness,37 whereas an initial dysphoric
response, demonstrated by stating a dislike of the medication, feeling worse or “zombie­like,” anxiety or akathisia­like symptoms, is associated with poor medication response, adverse effects, and nonadherence.

The importance of developing a therapeutic alliance between the patient and the clinician cannot be underestimated (see Chapter e81, “Evaluation of Psychiatric Illness”). Patients who form positive therapeutic
alliances are more likely to be adherent with all aspects of therapy, experience a better outcome at 2 years, and require lower antipsychotic doses.20 However, a certain minority of patients fail to benefit from
antipsychotic therapy, and their psychosocial functioning can worsen with antipsychotic continuation.

Initial Treatment in an Acute Psychotic Episode

The goals during the first 7 days of treatment should be decreased agitation, hostility, combativeness, anxiety, tension, and aggression, and normalization of sleep and eating patterns. The usual recommendation is
to initiate therapy and to titrate the dose over the first few days to an average effective dose, unless the patient’s physiologic status or history indicates that this dose can result in unacceptable adverse medication
reactions. Because of strong alpha­1 (α1) receptor antagonism and resulting risk of hypotension, iloperidone and clozapine should be titrated more slowly than other SGAs. Rapid titration to high doses is not

recommended. Table 87­2 lists the usual dosage range, with an average dose typically being midrange.14,22­24 Because patients with first­episode psychosis have an increased sensitivity to adverse medication
reactions, particularly EPS, typical dosing ranges are approximately 50% of the doses used in chronically ill individuals.22,23 If “cheeking” of medication is suspected (where the patient places the medication in their
cheek and then spits it out later), liquid formulations and orally disintegrating tablets are available for some antipsychotics. If a patient has no improvement after 2 weeks at a therapeutic dose, then later clinical
response is unlikely, and moving to the next treatment stage of the algorithm is recommended.38

Although some clinicians believe that larger daily doses are necessary in patients with more severe symptoms, data do not support this practice. Some symptoms, such as agitation, tension, aggression, and increased
motor activity, may respond more quickly, but adverse medication reactions can be more common with higher doses. However, interindividual differences in dosage and response do occur. In patients with partial
response who are tolerating the chosen antipsychotic, it may be reasonable to titrate above the usual dose range. However, this tactic should be time­limited (ie, 2­4 weeks), and if the patient does not achieve further
improvement, either the dose should be decreased or an alternative treatment strategy should be tried. As previously stated, rapid titration of antipsychotic dosage is not indicated14,22­24; however, intramuscular (IM)
antipsychotic administration (eg, haloperidol 2­5 mg IM, olanzapine 2.5­10 mg IM, or ziprasidone 10­20 mg IM) can be used to assist in calming a patient with severe agitation. Clinically, agitation can manifest as loud,
physically or verbally threatening behavior, motor hyperactivity, or physical aggression. Although use of IM antipsychotics can assist in calming a patient with acute agitation due to psychosis, it does not improve the
rate of remission, time to remission, or the length of hospitalization. Haloperidol (an FGA) given IM for treatment of acute aggression is associated with a higher incidence of EPS than IM SGAs. If the patient is receiving
an antipsychotic within the usual therapeutic range, the use of lorazepam 2 mg IM as needed in combination with the maintenance antipsychotic is a rational alternative for treatment of aggression. Hypotension,
respiratory depression, CNS depression, and death have been reported with injectable lorazepam in combination with either olanzapine or clozapine; thus, injectable lorazepam is not recommended in combination
with either of these medications.24

Inhaled loxapine powder is Food and Drug Administration (FDA) approved for treatment of acute agitation associated with schizophrenia or bipolar disorder. Because of the risk of bronchospasm, pulmonary
distress, and pulmonary arrest, the medication can only be administered in a healthcare facility through the FDA­approved Risk Evaluation and Mitigation Strategy (REMS). Before administration, patients must be
screened for a history of asthma, chronic obstructive pulmonary disease, or other lung disease associated with bronchospasm, and use is limited to one 10 mg inhaled dose per 24­hour period.26 Whether inhaled
loxapine offers any therapeutic advantages in acute agitation compared with other antipsychotics is unknown, and patients must be sufficiently cooperative to inhale it appropriately.

Stabilization Therapy

Symptom improvement may occur over 6 to 12 weeks with appropriate medication therapy and comprehensive treatment. During the first 2 to 3 weeks, goals should include increased socialization and
improvement in self­care habits and mood. Improvement in any formal thought disorder should follow and may take an additional 6 to 8 weeks. Patients who are early in the course of their illness tend to experience a
more rapid resolution of symptoms than individuals who are more chronically ill. In general, if a patient has shown no improvement after 2 weeks of treatment at therapeutic doses, or has achieved only a partial
decrease in positive symptoms within 8 to 12 weeks at adequate doses, then the next algorithm stage should be considered. In more chronically ill patients, symptoms may continue to improve over 3 to 4 months.
Quantifying symptom change using a brief symptom rating scale can be helpful in monitoring treatment and making decisions. An optimum target medication dose should be estimated in the initial treatment plan. If
the patient begins to show adequate response at a dose, then the patient should remain at this dosage if symptoms continue to improve. In general, adequate time on a therapeutic antipsychotic dose is the most
important factor in predicting medication response. However, if necessary, dose titration can continue within the therapeutic range every 1 or 2 weeks if the patient has no adverse medication reactions.

Before changing medications in a patient with poor response, the following should be considered: Were the initial target symptoms indicative of schizophrenia or did they represent manifestations of a different
diagnosis, a long­standing behavioral problem, a substance use disorder, or a general medical condition? Is the patient adherent with pharmacotherapy? Are the persistent symptoms poorly responsive to
antipsychotics (eg, impaired insight or judgment, or fixed delusions)? How does the patient’s current status compare with response during previous exacerbations? Would this patient potentially benefit from
advancing to a different treatment stage (Fig. 87­1)? Does this patient have treatment­resistant schizophrenia?

The conclusion that the patient with a partial response has achieved as much symptomatic improvement as possible is one that must be made with great care as treatment goals must be realistic. Medications are
effective in decreasing many of the symptoms of schizophrenia (and are thus referred to as palliative), but they are not curative, and not all symptoms may abate. Although one should aim to achieve full remission to
minimal residual positive symptoms, it is still unclear what a realistic goal is regarding maximum improvement in negative symptoms.

It is important to screen patients for co­occurring psychiatric disorders, and their presence can become more apparent during the stabilization or maintenance phases of treatment. Examples include substance use
disorders, depression, obsessive­compulsive disorder, and panic disorder. As co­occurring disorders will limit symptom and functional improvement and increase the risk of relapse. It is critical that treatment for the
co­occurring disorder be implemented in combination with evidence­based treatment for schizophrenia.

Maintenance Treatment

Maintenance medication therapy prevents relapse, as shown in numerous double­blind studies, which is a major goal of treatment.14,22­24 The average relapse rate after 1 year is 18% to 32% with active medication
(including some patients with nonadherence) versus 60% to 80% for placebo.14,22­24

After treatment of the first psychotic episode in a patient with schizophrenia, medication should be continued for at least 18 months after remission.14,22­24 Many experts recommend that patients with robust
medication response be treated for at least 5 years; however, in chronically ill individuals, continuous or lifetime pharmacotherapy is necessary in most patients to prevent relapse. This practice should be
approached with the lowest effective antipsychotic dose that is tolerated by the patient.14,22­24

Antipsychotics should be tapered slowly before discontinuation as abrupt discontinuation, especially with clozapine, can result in withdrawal symptoms, felt to be a manifestation of rebound cholinergic outflow.
Insomnia, nightmares, headaches, gastrointestinal symptoms (eg, abdominal cramps, stomach pain, nausea, vomiting, and diarrhea), restlessness, increased salivation, and sweating are reported. Although available
evidence does not indicate a best way to switch from one antipsychotic to another, it is often recommended to taper and discontinue the first antipsychotic over at least 1 to 2 weeks while the second antipsychotic is
initiated and the dose titrated.24 Tapering needs to occur more slowly with clozapine.38

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Long­Acting Injectable Antipsychotics
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 10 / 48
©2022
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studies Hill. Alldemonstrate
did not consistently Rights Reserved.
an advantage of Terms
LAIAs overof Use
oral • Privacy
agents. Policydesigned
However, studies, • Notice • Accessibility
to reflect real­world practices, have more consistently demonstrated an advantage in reduced
hospitalizations and relapse prevention in patients with schizophrenia, findings that were confirmed in a meta­analysis.39,40 Despite the potential advantages, the use of LAIAs is relatively low compared with oral
antipsychotics, and in most Western countries use falls below 20%.41 Barriers to LAIA use may be clinician or patient driven and include: biases and attitudes, limited insurance coverage, or lack of experience with
42
 After treatment of the first psychotic episode in a patient with schizophrenia, medication should be continued for at least 18 months after remission.14,22­24 Many experts recommend that patients with robust
medication response be treated for at least 5 years; however, in chronically ill individuals, continuous or lifetime pharmacotherapy is necessary in most patients to prevent relapse. This practice should University
Birzeit be
approached with the lowest effective antipsychotic dose that is tolerated by the patient.14,22­24
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Antipsychotics should be tapered slowly before discontinuation as abrupt discontinuation, especially with clozapine, can result in withdrawal symptoms, felt to be a manifestation of rebound cholinergic outflow.
Insomnia, nightmares, headaches, gastrointestinal symptoms (eg, abdominal cramps, stomach pain, nausea, vomiting, and diarrhea), restlessness, increased salivation, and sweating are reported. Although available
evidence does not indicate a best way to switch from one antipsychotic to another, it is often recommended to taper and discontinue the first antipsychotic over at least 1 to 2 weeks while the second antipsychotic is
initiated and the dose titrated.24 Tapering needs to occur more slowly with clozapine.38

Long­Acting Injectable Antipsychotics

Early studies did not consistently demonstrate an advantage of LAIAs over oral agents. However, studies, designed to reflect real­world practices, have more consistently demonstrated an advantage in reduced
hospitalizations and relapse prevention in patients with schizophrenia, findings that were confirmed in a meta­analysis.39,40 Despite the potential advantages, the use of LAIAs is relatively low compared with oral
antipsychotics, and in most Western countries use falls below 20%.41 Barriers to LAIA use may be clinician or patient driven and include: biases and attitudes, limited insurance coverage, or lack of experience with
LAIAs.42 Traditionally, LAIAs have been primarily used later in the course of treatment and in patients who are unreliable in taking oral medication. It has been suggested to offer LAIAs to patients as a treatment option
earlier in their disease before they develop a pattern of nonadherence.41,42 For example, they can be presented to a patient as a life style option, in which the patient does not need to take a medication daily.22
Normalizing the use of LAIAs, providing appropriate education to families and patients on LAIAs, utilizing motivational interview techniques, and offering it as an early treatment option may aid in improving LAIA
acceptability with patients.39

Treatment nonadherence rates as high as 60% in patients with schizophrenia can lead to negative clinical outcomes.41 Nonadherence can be due to several factors including cognitive impairment, persistent
symptoms, substance use, or lack of insight. However, before declaring a patient as nonadherent, it should be determined whether the patient is experiencing adverse medication reactions. If so, an alternative
medication with better tolerability should be considered before initiating a LAIA. The patient’s motivation for treatment is a major factor influencing outcome.

There are ten LAIAs available for use in the United States: risperidone (two different formulations), paliperidone palmitate (three formulations), aripiprazole (monohydrate and lauroxil), olanzapine pamoate,
haloperidol decanoate, and fluphenazine decanoate. Conversion from an oral antipsychotic to a LAIA should start with stabilization on an oral dosage form of the same agent for a short trial (4­14 days) to determine
whether the patient tolerates the medication without significant adverse medication reactions, especially if the patient has no previous exposure to the oral agent.39

With risperidone microspheres (Consta®), measurable serum concentrations are not seen until approximately 3 weeks after single­dose administration. Thus, it is important that the oral antipsychotic be
administered for at least 3 weeks after the first injection. The recommended starting dose with risperidone microspheres is 25 mg. Clinical experience suggests that titration to doses greater than or equal to 37.5 mg
per injection may be necessary for maintenance treatment; however, efficacy was demonstrated with doses of 25 to 50 mg IM every 2 weeks. Dose adjustments are recommended to be made no more often than once
every 4 weeks.43 Doses above 50 mg every 2 weeks are not recommended, as research indicates no greater clinical efficacy but more EPS.25 With risperidone extended­release injectable suspension (PERSERIS®),
dosing is 90 or 120 mg once monthly, no oral overlap or loading dose is necessary, and it is the only LAIA that is administered subcutaneously in the abdomen.44

Paliperidone palmitate (Invega Sustenna®) has the advantage of easy conversion from oral paliperidone to IM treatment, as there is no need for oral overlap, and this formulation offers once­monthly injections with
the option to convert to 3­month or 6­month formulations.43 It is initiated with 234 mg on day 1 and 156 mg a week later (+/− 4 days) with deltoid administration for the first two doses as gluteal absorption results in
28% lower Cmax. The 1­month paliperidone palmitate (1MPP) IM doses are then titrated according to response within a range of 39 to 234 mg and can be injected into either the deltoid or gluteal muscle.43 If a patient’s

oral paliperidone is established prior to converting to the 1MPP, the maintenance dose required for similar paliperidone exposure is outlined in Table 87­5.45

A 3­month paliperidone palmitate (3MPP, Invega Trinza®) and 6­month paliperidone palmitate (6MPP, Invega Hafyera) LAIA are approved for the management of schizophrenia, with both formulations being found to
significantly delay time to relapse compared with placebo. The 3MPP and 6MPP provide the longest dosing interval available, but require patients to be treated for at least 4 months with 1MPP prior to 3MPP initiation.
Those who have received at least one dose of the 3MPP may be converted to the 6MPP. The first 3MPP dose is based on the previous 1 month injection dose, and the first 6MPP dose is based on either the 1­ or 3­
month injection dose, as shown in Table 87­3.46

TABLE 87­3
Summary of Available Long­Acting Injectable Antipsychotics (LAIAs)

Medication Fluphenazine Haloperidol Risperidone Risperidone Paliperidone Paliperidone Paliperidone Olanzapine Aripiprazole Aripiprazole
Name Decanoate Decanoate (Risperdal (PERSERIS) Palmitate Palmitate (Invega Palmitate (Invega Pamoate Monohydrate (Lauroxil
Consta) (Invega Trinza) (3MPP) Hafyera)(6MPP) (Zyprexa (Abilify Maintena) Aristada®)
Sustenna) Relprevv)
(1MPP)

Dose Range (mg) 12.5­100 20­450 12.5­50 90­120 39­234 273­819 1,092­1,560 150­405 300­400 441­882b

PO Overlap None 4 weeks 3 weeks after None None None None None 2 weeks PO dose ranges 21 days PO
(none if first injection: from 10 to 20 mg/day overlap after
loading); use use PO dose first injection
PO dose patient was
patient was taking prior to
taking prior injection
to injection

Recommended 100 mg every 2­ 450 mg every 50 mg every 2 120 mg 234 mg every 819 mg every 3 1,560 mg every 6 months 300 mg 400 mg monthly 882 mg
maximum dose 3 weeks 4 weeks weeks monthly 4 weeks months every 2 monthly
weeks or 405
mg every 4
weeks

Initiation or Can Load Can Load None None Initiation None required, dose None required, dose used Initiation None None
Loading required based on last Invega depends on last Invega required required,
Sustenna dose: Sustenna or Trinza dose dose based
If 78 mg give 273 mg For Invega Sustenna: on PO dose:
If 117 mg give 410 mg If 156 mg give 1,092 mg If 10 mg/day
If 156 mg give 546 mg If 234 mg give 1,560 mg give 441 mg
If 234 mg give 819 mg For Invega Trinza: If 15 mg/day
If 546 mg give 1,092 mg give 662 mg
If 819 mg give 1,560 mg If 20 mg give
Downloaded 2022­10­24 3:41 P Your IP is 41.233.255.202 882 mg
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 11 / 48
Time to peak 8­24 hours
©2022 McGraw Hill. All Rights4­11 days
Reserved.4­5 weeks
Terms of4­6
Usehr 13 days
• Privacy Policy •30­33 days
Notice 29­32 days
• Accessibility <1 week 5­7 days 5­6 days

T ss 2­3 months 2­3 months 6­8 weeks 60 days 7­11 months Continues steady­ Continues steady­state 3 months 3­4 months 4 months
state
A 3­month paliperidone palmitate (3MPP, Invega Trinza®) and 6­month paliperidone palmitate (6MPP, Invega Hafyera) LAIA are approved for the management of schizophrenia, with both formulations being found to
significantly delay time to relapse compared with placebo. The 3MPP and 6MPP provide the longest dosing interval available, but require patients to be treated for at least 4 months with 1MPP prior to 3MPP initiation.
Those who have received at least one dose of the 3MPP may be converted to the 6MPP. The first 3MPP dose is based on the previous 1 month injection dose, and the first 6MPP dose is based on either the 1­ or 3­
Birzeit University
month injection dose, as shown in Table 87­3.46 Access Provided by:

TABLE 87­3
Summary of Available Long­Acting Injectable Antipsychotics (LAIAs)

Medication Fluphenazine Haloperidol Risperidone Risperidone Paliperidone Paliperidone Paliperidone Olanzapine Aripiprazole Aripiprazole
Name Decanoate Decanoate (Risperdal (PERSERIS) Palmitate Palmitate (Invega Palmitate (Invega Pamoate Monohydrate (Lauroxil
Consta) (Invega Trinza) (3MPP) Hafyera)(6MPP) (Zyprexa (Abilify Maintena) Aristada®)
Sustenna) Relprevv)
(1MPP)

Dose Range (mg) 12.5­100 20­450 12.5­50 90­120 39­234 273­819 1,092­1,560 150­405 300­400 441­882b

PO Overlap None 4 weeks 3 weeks after None None None None None 2 weeks PO dose ranges 21 days PO
(none if first injection: from 10 to 20 mg/day overlap after
loading); use use PO dose first injection
PO dose patient was
patient was taking prior to
taking prior injection
to injection

Recommended 100 mg every 2­ 450 mg every 50 mg every 2 120 mg 234 mg every 819 mg every 3 1,560 mg every 6 months 300 mg 400 mg monthly 882 mg
maximum dose 3 weeks 4 weeks weeks monthly 4 weeks months every 2 monthly
weeks or 405
mg every 4
weeks

Initiation or Can Load Can Load None None Initiation None required, dose None required, dose used Initiation None None
Loading required based on last Invega depends on last Invega required required,
Sustenna dose: Sustenna or Trinza dose dose based
If 78 mg give 273 mg For Invega Sustenna: on PO dose:
If 117 mg give 410 mg If 156 mg give 1,092 mg If 10 mg/day
If 156 mg give 546 mg If 234 mg give 1,560 mg give 441 mg
If 234 mg give 819 mg For Invega Trinza: If 15 mg/day
If 546 mg give 1,092 mg give 662 mg
If 819 mg give 1,560 mg If 20 mg give
882 mg

Time to peak 8­24 hours 4­11 days 4­5 weeks 4­6 hr 13 days 30­33 days 29­32 days <1 week 5­7 days 5­6 days

T ss 2­3 months 2­3 months 6­8 weeks 60 days 7­11 months Continues steady­ Continues steady­state 3 months 3­4 months 4 months
state

Half­life 14 ± 2a days 21 days 3­6 days 9­11 days 25­49 days 84­89 days (deltoid) 148­159 days 30 days 30­47 days 29­35 days
118­139 days (gluteal)

Injection Gluteal Yes Yes Yes Abdominal Yes after 2nd Yes Yes Yes Yes Yes
Site only dose

Deltoid Yes Yes Yes Yes Yes No No No Yes, but only

441 mg dose

Injection Z­Track Z­Track Subcutaneous

Method/Technique Injection

Notes A starting 90 mg = 3 mg Avoid use in Requires at least a 4­ Requires at least a 4 Monitor for Maintenance dose May require 2
dose of 12.5 PO patients with month trial with month trial with 1MPP or PDSS reduced to 300 mg if week PO trial
mg is Risperidone moderate­to­ 1MPP. Not at least 1 cycle of 3MPP. Subject to patient experiences to establish
recommended 120 mg = 4 severe renal recommended in Not recommended in REMS adverse events. Dose efficacy
in patients mg PO impairment patients with patients with moderate or adjustment needed in before
with hepatic Risperidone (CrCl <50 moderate or severe severe renal impairment CYP2D6 slow initiating LAIA
or renal mL/min [0.83 renal impairment (CrCl <50 mL/min [0.83 metabolizers. Avoid use Avoid use of
impairment mL/s]) (CrCl <50 mL/min mL/s]) in patients taking CYP strong
[0.83 mL/s]) 3A4 inhibitors >14 days CYP2D6 and
3A4 inhibitors
for 662 and
882 mg dose,
no
adjustment
needed for
441 mg dose

CrCl, creatine clearance; IM, intramuscular; LAIA, long­acting injectable; PO, oral; Tss, time to steady state.

aBased on multiple­dose data. Single­dose data indicate a β­half­life of 6­10 days.

Downloaded 2022­10­24
bAdditional dosing regimens 3:41 P Your IP is 41.233.255.202
include extended intervals up to 1,064 mg every 8 weeks; loading protocol with Aristada Initio 675 mg + maintenance Aristada dose + PO 30 mg x1 dose does not require PO overlap
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 12 / 48
©2022
Data fromMcGraw
References 38,Hill. All45,Rights
43, 47­49, Reserved.
46, 50­52, and 48. Terms of Use • Privacy Policy • Notice • Accessibility
Olanzapine pamoate monohydrate is a LAIA administered every 2 or 4 weeks that does not require oral overlap. It is recommended for deep gluteal injection, and the initial injectable dose varies from 210 to 405 mg
depending on the oral olanzapine daily maintenance dose and the frequency of injectable administration.43,50 A disadvantage to olanzapine pamoate is its association with post­injection delirium/sedation syndrome
 no
adjustment
Birzeit University
needed for

Access441 mg doseby:
Provided

CrCl, creatine clearance; IM, intramuscular; LAIA, long­acting injectable; PO, oral; Tss, time to steady state.

aBased on multiple­dose data. Single­dose data indicate a β­half­life of 6­10 days.

bAdditional dosing regimens include extended intervals up to 1,064 mg every 8 weeks; loading protocol with Aristada Initio 675 mg + maintenance Aristada dose + PO 30 mg x1 dose does not require PO overlap

Data from References 38, 43, 47­49, 45, 46, 50­52, and 48.

Olanzapine pamoate monohydrate is a LAIA administered every 2 or 4 weeks that does not require oral overlap. It is recommended for deep gluteal injection, and the initial injectable dose varies from 210 to 405 mg
depending on the oral olanzapine daily maintenance dose and the frequency of injectable administration.43,50 A disadvantage to olanzapine pamoate is its association with post­injection delirium/sedation syndrome
(PDSS) occurring in <2% of patients.50 The symptoms of PDSS are similar to those of an oral olanzapine overdose and include delirium, ataxia, confusion, heavy sedation, or altered levels of consciousness. Although
PDSS can occur with any dose and at any time during treatment, most cases have occurred within the first three injections.51 The most likely explanation for the occurrence of PDSS is an accidental intravascular
injection resulting in the medication dissolving more rapidly and sharp increases in plasma levels.51,52 The product labeling contains an FDA­boxed warning regarding PDSS, and olanzapine pamoate is subject to a
REMS with the FDA labeling limiting the availability of olanzapine LAIA to a restricted distribution program. The injection must be administered in a registered healthcare facility, and the patient must be observed by a
health professional for at least 3 hours after administration and must not drive or operate machinery that day.50

Aripiprazole monohydrate LAIA (Abilify Maintena) is administered as a single intramuscular injection in the gluteal or deltoid muscle once a month at a starting and maintenance dose of 400 mg. If the patient does not
tolerate the 400 mg dose, the next injection can be reduced to 300 mg. After the first injection of aripiprazole monohydrate LAIA, a 14­day overlap with oral aripiprazole (10­20 mg/day) or any other antipsychotic is
recommended.43 Aripiprazole lauroxil LAIA (Aristada) is administered as a single intramuscular injection in the deltoid (441 mg only) or gluteal (441, 662, or 882 mg, once a month). The 882 mg dose can be
administered every 6 weeks and the 1,084 mg every 2 months. Aripiprazole lauroxil has the advantage of having initiation dosing available (Aristada Initio)47; however, if Aristada Initio is not utilized, oral overlap is
required for 3 weeks with this LAIA formulation.52

For the FGA fluphenazine decanoate, the simplest dosing conversion method recommends 1.25 times the oral fluphenazine daily dose for stabilized patients, rounding to the nearest 12.5 mg interval, which is
administered in weekly doses for the first 4 to 6 weeks; or 1.6 times the oral daily dose given weekly for the first 4 weeks for more acutely ill patients.48 Subsequently, fluphenazine decanoate can be administered once
every 2 to 3 weeks. Although oral fluphenazine can be overlapped for 1 week, the dose should be reduced by half with the first injection to reduce the risk of EPS.48 For haloperidol decanoate, the first dose should be
10 to 20 times the oral haloperidol daily dose. In patients who are at high risk of relapse, and are tolerant to oral haloperidol, a loading dose of 20 times the oral dose can be considered.48 In patients naïve to
haloperidol decanoate, the initial injection is limited to 100 mg followed by the remaining balance of the first monthly dose given 3 to 7 days later.43 Overlap with oral haloperidol overlap is not necessary if the patient
receives a loading dose, but is recommended for the first month if a loading dose strategy is not utilized. The maintenance dose is typically 10 to 15 times the oral dose once monthly. Table 87­3 provides a summary of
the LAIAs.

Methods to Enhance Patient Adherence

Treatment nonadherence rates are as high as 60% in patients with schizophrenia, which can lead to negative clinical outcomes.41 If nonadherence is suspected, the clinician should ask in a nonjudgmental manner if
the patient is having any difficulty taking their medication and then the reason for nonadherence should be determined. If nonadherence is occurring because of adverse effects, then a medication with a more
favorable tolerability profile should be considered. Suspected nonadherence can also be assessed by obtaining an antipsychotic serum concentration.53

Maintaining appropriate medication adherence is often challenging for individuals with chronic illnesses and partial adherence is a reality and should be expected to be the norm.24 Individuals with serious
psychiatric disorders have higher nonadherence rates than those with general medical disorders, with the following explanations provided: denial of illness, lack of insight, grandiosity or paranoia, no perceived need
for medication, perceived lack of input into choice of medication or dosage, adverse medication reactions, misperceived “allergies,” too many medications prescribed, or too many doses prescribed daily (see Table
87­4). It is estimated that half of patients with schizophrenia or schizoaffective disorder take their medication less than 70% of the time.24 Discussions regarding this topic should be approached in a positive,
nonjudgmental manner, with the clinician actively engaging the patient in care and using motivational interviewing techniques as mechanisms to enhance therapeutic alliance and patient adherence.

TABLE 87­4
Nonadherence with Antipsychotic Medications Is a Multidimensional Dilemma

Patient factors Medication Factors Other factors

Lack of insight Efficacy Family perspectives

Paranoia Adverse medication reactions Cultural influences
Attitude to medications Mode of delivery/ingestion Clinician perspectives and influences
Prior experiences Cost Insurance coverage
Perception of efficacy of medication Availability Cost of care
Comorbid substance use disorder Medication access and support
Mental illness stigma

Data from References 54 and 55.

Numerous different methods have been used to improve treatment adherence of patients with schizophrenia. Interventions that provide continuous focus on adherence and that are of long duration have shown
benefit. These should incorporate problem­solving techniques and be accompanied by technical learning aids. As previously noted, programs need to include a focus on patient­driven outcomes, and not just
medication adherence, and interventions should include efforts to allow patients to achieve life goals and function. This requires that programs be tailored to the needs of individual patients.54 Psychoeducation
strategies should include motivational interviewing techniques in individual counseling as well as group activities.

Compliance therapy, targeted cognitive behavioral therapy focusing on medication adherence, can improve patient adherence, but the success seen in early studies has not been consistently replicated.54

Groups facilitated by trained individuals who have the illness are thought to be more effective in enhancing awareness and acceptance of schizophrenia and necessary treatment, than groups led only by
professionals. Active involvement of family members further increases the likelihood of patient adherence with treatment. In addition to programs provided by community mental health centers, support groups
operated by consumer groups such as the National Alliance on Mental Illness (NAMI) are available for patients and their families in most urban areas. In the hospital, self­medication administration can reinforce the
patient’s perception of his or her active role in treatment. When patients miss outpatient appointments, active outreach interventions must be implemented to enhance patient engagement in treatment.54

The LAIAs have been a mainstay of treatment for people who are nonadherent with taking oral medications. However, for various reasons, they are used in only a relatively small subset of patients, and many patients
simply do not like getting injections. Abilify MyCite, an FDA­approved technology, includes a biosensor inside the aripiprazole tablet; after the medication is ingested, the coating is degraded and a specific patch worn
by the patient picks up a biosensor signal from the formulation.49 Data are then transferred to a smart phone application and can be shared by the patient with the treating clinician via the internet. It is not clear
Downloaded
whether 2022­10­24
this technology 3:41
improves patient P Your
adherence in a IP is 41.233.255.202
population that is often suspicious and paranoid. Regardless, a great deal of education is necessary to make sure that the patient knows how to use the
technology
Chapterand87:to Schizophrenia,
assure that the patientM.
wears the patch
Lynn and uses Tawny
Crismon; the smart phone application
L. Smith; Petercorrectly.
F. Buckley Page 13 / 48
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Management of Treatment­Resistant Schizophrenia

In general, “treatment resistant” describes a patient who has had inadequate symptom response from multiple antipsychotic trials.22­24,53 The clinical definition of treatment resistance requires persistent symptoms
53
Groups facilitated by trained individuals who have the illness are thought to be more effective in enhancing awareness and acceptance of schizophrenia and necessary treatment, than groups led only by
professionals. Active involvement of family members further increases the likelihood of patient adherence with treatment. In addition to programs provided by community mental health centers, support
Birzeit groups
University
operated by consumer groups such as the National Alliance on Mental Illness (NAMI) are available for patients and their families in most urban areas. In the hospital, self­medication administration can reinforce the
Access Provided by:
patient’s perception of his or her active role in treatment. When patients miss outpatient appointments, active outreach interventions must be implemented to enhance patient engagement in treatment.54

The LAIAs have been a mainstay of treatment for people who are nonadherent with taking oral medications. However, for various reasons, they are used in only a relatively small subset of patients, and many patients
simply do not like getting injections. Abilify MyCite, an FDA­approved technology, includes a biosensor inside the aripiprazole tablet; after the medication is ingested, the coating is degraded and a specific patch worn
by the patient picks up a biosensor signal from the formulation.49 Data are then transferred to a smart phone application and can be shared by the patient with the treating clinician via the internet. It is not clear
whether this technology improves patient adherence in a population that is often suspicious and paranoid. Regardless, a great deal of education is necessary to make sure that the patient knows how to use the
technology and to assure that the patient wears the patch and uses the smart phone application correctly.

Management of Treatment­Resistant Schizophrenia

In general, “treatment resistant” describes a patient who has had inadequate symptom response from multiple antipsychotic trials.22­24,53 The clinical definition of treatment resistance requires persistent symptoms
of at least moderate severity, despite treatment with two different antipsychotics at adequate dosage for at least 6 weeks each with good treatment adherence.53 Between 10% and 30% of patients receive minimal
symptomatic improvement after multiple antipsychotic monotherapy trials.22­24 An additional 30% to 60% of patients have partial but inadequate improvement in symptoms or unacceptable adverse medication
reactions associated with antipsychotic use. In patients not responding to two or more pharmacotherapy trials, a treatment­refractory evaluation should be performed to reexamine diagnosis, substance use,
medication adherence, and psychosocial stressors. Targeted cognitive behavioral therapy or other psychosocial augmentation strategies should be considered.22,23 While clozapine remains the treatment of choice
for treatment­resistant schizophrenia, its use has declined over time in favor of sequential treatment trials of SGAs. This is problematic and trainees need exposure to initiating clozapine therapy, given the low
likelihood of later use in clinical practice without this experience.

Clozapine

Only clozapine has shown superiority over other antipsychotics in randomized clinical trials for the management of treatment­resistant schizophrenia as most other SGAs have either not been studied in this patient
population, or have been evaluated in small open trials. In a seminal study, clozapine was effective in approximately 30% of patients with treatment­resistant schizophrenia, compared with only 4% treated with a
combination of chlorpromazine and the anticholinergic benztropine.56 Other candidates for clozapine include those patients with severe suicidality, aggressive behavior, or those who cannot tolerate neurologic
adverse medication reactions from conservative doses of other antipsychotics.

Symptomatic improvement with clozapine in the treatment­refractory patient often occurs slowly, and as many as 60% of patients continue to improve if clozapine is used for up to 6 months. This, in combination with
clozapine’s tolerability profile, provides sufficient information to conclude that clozapine is not a panacea for schizophrenia. Polydipsia and hyponatremia (psychogenic water drinking) is a frequent problem among
treatment­refractory patients, and clozapine reportedly decreases water drinking and increases serum sodium in such patients.23,24

Because of the risk of orthostatic hypotension, clozapine is usually titrated more slowly than other antipsychotics, particularly on an outpatient basis. If a 12.5­mg test dose does not produce hypotension, then
clozapine 25 mg at bedtime is recommended, increased to 25 mg twice a day after 3 days, and then increased in 25 to 50 mg/day increments every 3 days until a dose of at least 300 mg/day is reached. If tolerated, a
minimum trial should be 3 months with a clozapine serum concentration of at least 350 ng/mL (mcg/L; 1.07 µmol/L). Because high doses are associated with significantly increased adverse medication reactions,
including seizures, a clozapine serum concentration is recommended before exceeding 600 mg/day.24 If the clozapine serum concentration is greater than 350 ng/mL (mcg/L; 1.07 µmol/L), then further dosage
increases are not indicated.53

Augmentation and Combination Strategies

Limited empirical evidence exists to guide treatment decisions for patients who do not respond to clozapine.22–24 Current strategies include augmentation with a non­antipsychotic medication in patients with poor or
partial response, or combination treatment using two antipsychotics simultaneously.

In a small, single blind, randomized trial, 50% of patients demonstrated clinically significant improvement in symptoms with electroconvulsive therapy (ECT) augmentation of clozapine, compared with no responders
in the clozapine monotherapy group. When the patients in the clozapine monotherapy group received ECT, 47% demonstrated clinically significant improvement.23

Mood stabilizers are frequently used as an augmentation strategy, and while lithium does not enhance the antipsychotic effect, it may improve labile affect and agitated behavior in select patients.23 Enzyme induction
with carbamazepine can cause a decrease in antipsychotic serum concentrations and potentially worsen psychotic symptoms in some patients.23,57

Only limited data are available to support antidepressant augmentation of antipsychotics.22­24 However, consistently positive results have been reported when using selective serotonin reuptake inhibitors (SSRIs) to
treat obsessive­compulsive symptoms that worsen or arise during clozapine treatment.

Combining an FGA with an SGA and combining different SGAs have been suggested as intervention strategies for treatment­resistant patients. Pharmacodynamically, there is limited rationale to explain how
combinations of antipsychotics would produce enhanced efficacy, but increased adverse medication reactions, particularly increased EPS, metabolic effects, and hyperprolactinemia, are possible results.22 The
evidence to support antipsychotic combinations is scant. However, a large Finnish database study, using patients as their own controls, found that clozapine plus aripiprazole had a lower rehospitalization rate than
any other monotherapy or combination antipsychotic treatment.58 This observational study was not in patients identified as treatment resistant. Regardless, this topic remains highly contentious, and clinicians’
practice is often not aligned with available evidence. Moreover, the availability of new treatment options can result in combination therapies being tried with antipsychotics with insufficient scientific evidence. This
approach further complicates the application of systematic, evidence­based treatments for schizophrenia. In general, a series of antipsychotic monotherapy courses, including clozapine, are preferred over
antipsychotic combinations.22 However, when clozapine fails to produce desired outcomes, a time­limited combination trial is sometimes considered (eg, maximum 12 weeks) with the patient carefully evaluated
using standardized rating scales to assess symptomatology.23 If no apparent improvement is observed, then one of the medications should be tapered and discontinued. However, if the patient has a partial response
(greater than or equal to 20% improvement in positive symptoms) after 12 weeks with combination treatment, medications should be titrated to doses at the upper end of the therapeutic range, and treatment should
continue for an additional 12 weeks before a change in treatment is considered.

Violence in Schizophrenia

Most people with schizophrenia do not exhibit violent behavior; however, they are more likely to be violent than the general population. The rate of violence in people with schizophrenia is 9.9% compared with 1.6%
in the general population.36 Risk factors for violence include those associated with violence in the general population (eg, childhood trauma and exposure to violence, alcohol and substance use disorders,
psychopathy, and access to firearms) and (to lesser extent) psychotic symptoms.36 Most of the risk of violence is associated with co­occurring substance use disorders.36 Patients are at risk to become violent when
they relapse and so keeping patients clinically stable is a major consideration. Clozapine has been found to be superior to other antipsychotics in decreasing aggressive and violent behavior.36 Some states have
outpatient commitment laws where patients at risk of violence are “forced” to get ongoing care, and if they default, they are sent back to the hospital. Patients who are dangerous are invariably managed either in the
legal system itself or legally as “forensic” patients where they are held by court order in a psychiatric facility.

Antipsychotic Mechanism of Action

The exact mechanism of actions of antipsychotics are unknown. Antipsychotics is classified into three different categories: (a) typical (traditional or FGAs) (high D2 antagonism and low serotonin­2 receptor [5­HT2A]

antagonism); (b) atypical (SGAs) (moderate­to­high D2 antagonism and high 5­HT2A antagonism); and (c) atypical clozapine­like (low D2 antagonism and high 5­HT2A antagonism).59 With the exception of aripiprazole

and brexpiprazole, all current SGAs have a greater affinity for 5­HT2A receptors than D2 receptors, and brexpiprazole shows stronger antagonism of the 5­HT2A receptor than aripiprazole.59,60 Brexpiprazole also

Downloaded
demonstrates higher2022­10­24 3:41 P Your
affinity for the serotonin­1A (5­HT1AIP compared to aripiprazole but with less intrinsic D2 activity than aripiprazole.60
is 41.233.255.202
) receptor
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 14 / 48
Prospective studies of antipsychotic receptor binding in humans have used PET scans to examine neurotransmitter receptor binding 12 hours post­dose in small numbers of individuals at steady­state
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
concentrations. It has been proposed that at least 60% to 65% D2 receptor occupation is necessary to decrease positive psychotic symptoms, whereas blockade of approximately 77% or more of D2 receptors is

associated with EPS.59 Table 87­5 outlines the relative differences in receptor binding for various agents. In general, all FGAs are DA receptor antagonists with high affinity for D2 receptors, and during chronic
treatment, between 70% and 90% of D receptors in the striatum are usually occupied. In contrast, during clozapine treatment only 38% to 47% of D receptors are occupied, even with high doses. Newer SGAs have
outpatient commitment laws where patients at risk of violence are “forced” to get ongoing care, and if they default, they are sent back to the hospital. Patients who are dangerous are invariably managed either in the
legal system itself or legally as “forensic” patients where they are held by court order in a psychiatric facility.
Birzeit University
Antipsychotic Mechanism of Action
Access Provided by:

The exact mechanism of actions of antipsychotics are unknown. Antipsychotics is classified into three different categories: (a) typical (traditional or FGAs) (high D2 antagonism and low serotonin­2 receptor [5­HT2A]

antagonism); (b) atypical (SGAs) (moderate­to­high D2 antagonism and high 5­HT2A antagonism); and (c) atypical clozapine­like (low D2 antagonism and high 5­HT2A antagonism).59 With the exception of aripiprazole

and brexpiprazole, all current SGAs have a greater affinity for 5­HT2A receptors than D2 receptors, and brexpiprazole shows stronger antagonism of the 5­HT2A receptor than aripiprazole.59,60 Brexpiprazole also

demonstrates higher affinity for the serotonin­1A (5­HT1A) receptor compared to aripiprazole but with less intrinsic D2 activity than aripiprazole.60

Prospective studies of antipsychotic receptor binding in humans have used PET scans to examine neurotransmitter receptor binding 12 hours post­dose in small numbers of individuals at steady­state
concentrations. It has been proposed that at least 60% to 65% D2 receptor occupation is necessary to decrease positive psychotic symptoms, whereas blockade of approximately 77% or more of D2 receptors is

associated with EPS.59 Table 87­5 outlines the relative differences in receptor binding for various agents. In general, all FGAs are DA receptor antagonists with high affinity for D2 receptors, and during chronic
treatment, between 70% and 90% of D2 receptors in the striatum are usually occupied. In contrast, during clozapine treatment only 38% to 47% of D2 receptors are occupied, even with high doses. Newer SGAs have

variable D2 binding. Low D2 binding seen with the SGAs, can be directly associated with how rapidly the antipsychotic disassociates from the D2 receptor.59 This transient blockade of DA receptors may be adequate to
produce antipsychotic effect, but longer term D2 blockade is required for production of EPS and sustained hyperprolactinemia. Aripiprazole and brexpiprazole are partial agonists at D2 receptors, and represent a

further elaboration of the DA hypothesis of antipsychotic action.59,60

TABLE 87­5
Relative Neuroreceptor Binding Affinities of Select Antipsychotics

Aripiprazole Asenapine Chlorpromazine Clozapine Haloperidol Iloperidone Lumateperone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone

D1 ­ ++ + + + ++ + ­ + +

D2 ++++ +++ +++ + ++++ +++ ++ +++ ++ +++ + +++ +++

D3 ++ +++ +++ + +++ +++ ++ + ++ ­ ++ ++

D4 + +++ +++ ++ +++ ++ ++ ­ ­ ­ ++

5­ ++ ++ ­ ­ ­ ++ + ­ ­ ­ ­ +++
HT1A

5­ + ­ ­ ­ + ­ + +++
HT1D

5­ +++ +++ ++ +++ + ++++ ++++ +++ +++ +++ ++ ++++ ++++
HT2A

5­ + ++++ ++ ++ ­ ++ + ++ + ­ ++ ++++
HT2C

5­HT6 + +++ ++ ++ ­ ++ ++ ­ ­ ­ +

5­HT7 ++ +++ ++ ++ ­ ++++ ­ ++ ­ +++ ++

α + +++ ++++ +++ +++ ++++ ++ + ++ +++ +++ +++ ++

α + ++ + + ­ ++ + + ++ ­ ++ ­

H1 + ++ ++++ +++ ­ ++ ­ ­ +++ ­ ++ ­ ­

m1 ++ ­ ++++ ­ ­ +/­ ­ +++ ­ ++ ­ ­

Relative neuroreceptor binding affinities of select antipsychotics.

(­) = minimal or none; (+) = low; (++) = moderate; (+++) = high; (++++) = very high

Data from References 61 and 62.

Iloperidone’s pharmacology is different in that it has high affinity for D2, dopamine­3 (D3), and 5­HT2A receptors, and moderate affinity for dopamine­4 (D4), serotonin­6 (5­HT6), serotonin­7 (5­HT7), and α1­

receptors.27 Asenapine has high affinity for 5­HT2A and D2 receptors as well as for α1­ and histamine­1 receptors with D2 occupancy approximating 80% with a sublingual dose of 5 to 10 mg twice daily.28 Cariprazine
has high affinity for D2 and D3 receptors as a partial agonist, with the D3 potency being significantly greater than D2. It is also a partial agonist at 5­HT1A receptors and an antagonist at serotonin­1B (5­HT1B)

receptors.29 Therefore, given all of these different mechanisms of action, our understanding of the manner in which they produce a clinical profile is still in its infancy.

With low­dose risperidone (2­5 mg/day), D2 binding ranges from 60% to 79%, but with doses greater than 6 mg daily, binding commonly exceeds the 77% threshold associated with the development of EPS.

Risperidone 2 mg/day produces 5­HT2A binding greater than 70%, and with 4 mg/day it is nearly 100%.59 Olanzapine 10 to 20 mg/day produces D2 binding ranging from 71% to 80%, whereas at 30 to 40 mg/day, it

ranges from 83% to 88%. At 5 mg/day, 5­HT2A receptors are near saturation of binding.59 Ziprasidone has the highest 5­HT2A­to­D2 affinity ratio of any of the currently available antipsychotics. It is also a potent

serotonin­1A (5­HT1A) agonist.59

Quetiapine has the lowest D2 binding. At doses of 300 to 600 mg/day, 12­hour post­dose D2 binding ranges from 0% to 27%. Even at quetiapine 800 mg/day, only 30% of D2 receptors are occupied. At these same daily
doses, 45% to 90% of 5­HT2A receptors are occupied. However, when quetiapine D2 binding is examined 2 to 3 hours post­dose, 58% and 64% of receptors were occupied with 400 and 450 mg, respectively.

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2 receptors. It is
Lumateperone is a moderate antagonist at both D1 and D2 receptors and a potent antagonist at 5­HT2A receptors. In individuals with schizophrenia, lumateperone occupied approximately 42% of DPage
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley 15 / 48
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DA agonist AllaRights Reserved.
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in increased

The primary therapeutic effects of antipsychotics are thought to occur in the limbic system, including the ventral striatum, whereas EPS are thought to be related to DA blockade in the dorsal striatum. For SGAs, 5­
HT2A antagonism in combination with modest D2 blockade leads to release of DA in the prefrontal cortex, and this is one explanation for the decrease in negative symptoms and improvement in cognition reported
With low­dose risperidone (2­5 mg/day), D2 binding ranges from 60% to 79%, but with doses greater than 6 mg daily, binding commonly exceeds the 77% threshold associated with the development of EPS.

Risperidone 2 mg/day produces 5­HT2A binding greater than 70%, and with 4 mg/day it is nearly 100%.59 Olanzapine 10 to 20 mg/day produces D2 binding ranging from 71% to 80%, whereas at 30 to 40 mg/day, it
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ranges from 83% to 88%. At 5 mg/day, 5­HT2A receptors are near saturation of binding.59 Ziprasidone has the highest 5­HT2A­to­D2 affinity ratio of any of the currently available antipsychotics. It is also a potent
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serotonin­1A (5­HT1A) agonist.59

Quetiapine has the lowest D2 binding. At doses of 300 to 600 mg/day, 12­hour post­dose D2 binding ranges from 0% to 27%. Even at quetiapine 800 mg/day, only 30% of D2 receptors are occupied. At these same daily
doses, 45% to 90% of 5­HT2A receptors are occupied. However, when quetiapine D2 binding is examined 2 to 3 hours post­dose, 58% and 64% of receptors were occupied with 400 and 450 mg, respectively.

Lumateperone is a moderate antagonist at both D1 and D2 receptors and a potent antagonist at 5­HT2A receptors. In individuals with schizophrenia, lumateperone occupied approximately 42% of D2 receptors. It is

also a presynaptic DA agonist and a 5­HT reuptake inhibitor. It indirectly modulates glutamatergic activity resulting in increased NMDA and AMPA activity.33,62

The primary therapeutic effects of antipsychotics are thought to occur in the limbic system, including the ventral striatum, whereas EPS are thought to be related to DA blockade in the dorsal striatum. For SGAs, 5­
HT2A antagonism in combination with modest D2 blockade leads to release of DA in the prefrontal cortex, and this is one explanation for the decrease in negative symptoms and improvement in cognition reported

with these antipsychotics.48 Medications that are not D2 antagonists are currently in clinical trials for the treatment of schizophrenia. If these medications are approved by the FDA, they may have a significant effect on
how we look at antipsychotic mechanisms of action and efficacy.

As discussed, antipsychotics vary in their effects on other neurotransmitter receptor systems.59 Although the significance of these different mechanisms on efficacy is unclear, they do potentially explain differences in
adverse medication reaction profiles. These differences in pharmacodynamics profiles point out that the SGAs are not alike, and patients obtaining an inadequate clinical response (either efficacy or adverse
medication reactions) with one antipsychotic may have a superior response/tolerability on an alternate medication. Thus, serial SGA monotherapy trials should be tried in patients receiving a suboptimal clinical
response (see Fig. 87­1).

Pharmacokinetics

As a class, antipsychotics are highly lipophilic and highly bound to membranes and plasma proteins. They distribute readily into most tissues with a high blood supply and can accumulate in tissues; therefore, they
have large volumes of distribution.63 Most antipsychotics are largely metabolized, primarily through the cytochrome P450 (CYP) pathways in the liver, except for ziprasidone, which is largely metabolized by aldehyde
oxidase. Fluphenazine and perphenazine are metabolized through CYP2D6, and thus are susceptible to pharmacogenetically regulated metabolism.64 This is also one of the major pathways for the metabolism of
aripiprazole, brexpiprazole, haloperidol, iloperidone, and risperidone.64 Thirty percent to 35% of people of African and Asian descent are slow to intermediate CYP2D6 metabolizers, and approximately 0% to 5% of
African American, 1% of Asian, and 5% to 10% of White populations are poor metabolizers.65 In addition, some people of Swedish descent and up to 30% of those from Northern Africa may be ultra­rapid CYP2D6
metabolizers.66 Genetic variation within CYP1A2 can potentially result in a decrease in the metabolic rate of clozapine, whereas, smoking may increase clozapine and olanzapine metabolism due to the effect of
cigarette smoke inducing CYP1A2 linked to a specific genotype.64,65 Pharmacogenomics should be considered when dosing and monitoring the clinical effects of antipsychotics.64­66 Additional resources related to
specific gene and drug pairs for pharmacogenomics information can be obtained at the Clinical Pharmacogenomics Implementation Consortium (CPIC) Website (www.cipicpgx.org). Table 87­6 outlines the prominent
metabolic pathways of selected antipsychotics.

TABLE 87­6
Pharmacokinetic Parameters of Selected Antipsychotics

Medication Bioavailability (%) Half­Life Major Metabolic Pathways Active Metabolites

Selected First­Generation Antipsychotics (FGAs)

Chlorpromazine 10­30 8­35 hr FMO3, CYP3A4 7­Hydroxy, others

Haloperidol 40­70 12­36 hr CYP2D6, CYP1A2, CYP3A4 Reduced haloperidol

Perphenazine 20­25 8.1­12.3 hr CYP2D6 7­OH­perphenazine

Second­Generation Antipsychotics (SGAs)

Aripiprazole 87 48­68 hr CYP2D6, CYP3A4 Dehydroaripiprazole

Asenapine <2 orally 13­39 hr CYP1A2, UGT1A4, CYP2D6, CYP3A4 None known

35 SL

Nonlinear

Brexpiprazole 95 91 hr CYP2D6, CYP3A4 DM­3411

Cariprazine 2­4 days, DDCAR 1­3 weeks CYP3A4, CYP2D6 Desmethyl cariprazine (DCAR),

Didesmethyl cariprazine (DDCAR)

Clozapine 12­81 11­105 hr CYP1A2, CYPD6, CYP3A4 Desmethylclozapine

Iloperidone 96 18­33 hr CYP2D6, CYP3A4 P88

Lumateperone 4.4 13­21 hr CYP3A4, CYP1A2, CYP2C8, Aldoketoreductase 1C1, UGT1A1, UGT1A4, UGT 2B15 IC200131, IC200161, IC200565

Lurasidone 10­20 18 hr CYP3A4, CYP1A2 ID­14233 and ID­14326

Olanzapine 80 20­70 hr CYP1A2, CYP3A4, FMO3 N­Glucuronide; 2­OH­methyl; 4­N­oxide

Paliperidone ER 28 23 hr Renal unchanged (59%) None known

CYP3A4 and multiple pathways

Quetiapine 9±4 6.88 hr CYP3A4, CYP3A5 N­desalkylquetiapine

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CYP3A4, CYP3A5 N­desalkylquetiapine
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 16 / 48
Risperidone 68 3­24 hr
©2022 McGraw Hill. All Rights Reserved. Terms of Use CYP2D6, CYP3A4
• Privacy Policy • Notice • Accessibility 9­OH­risperidone

Ziprasidone 59 4­10 hr Aldehyde oxidase, CYP3A4, CYP1A2 None

aripiprazole, brexpiprazole, haloperidol, iloperidone, and risperidone.64 Thirty percent to 35% of people of African and Asian descent are slow to intermediate CYP2D6 metabolizers, and approximately 0% to 5% of
African American, 1% of Asian, and 5% to 10% of White populations are poor metabolizers.65 In addition, some people of Swedish descent and up to 30% of those from Northern Africa may beBirzeit
ultra­rapid CYP2D6
University
metabolizers.66 Genetic variation within CYP1A2 can potentially result in a decrease in the metabolic rate of clozapine, whereas, smoking may increase clozapine and olanzapine metabolism due to the effect of
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cigarette smoke inducing CYP1A2 linked to a specific genotype.64,65 Pharmacogenomics should be considered when dosing and monitoring the clinical effects of antipsychotics.64­66 Additional resources related to
specific gene and drug pairs for pharmacogenomics information can be obtained at the Clinical Pharmacogenomics Implementation Consortium (CPIC) Website (www.cipicpgx.org). Table 87­6 outlines the prominent
metabolic pathways of selected antipsychotics.

TABLE 87­6
Pharmacokinetic Parameters of Selected Antipsychotics

Medication Bioavailability (%) Half­Life Major Metabolic Pathways Active Metabolites

Selected First­Generation Antipsychotics (FGAs)

Chlorpromazine 10­30 8­35 hr FMO3, CYP3A4 7­Hydroxy, others

Haloperidol 40­70 12­36 hr CYP2D6, CYP1A2, CYP3A4 Reduced haloperidol

Perphenazine 20­25 8.1­12.3 hr CYP2D6 7­OH­perphenazine

Second­Generation Antipsychotics (SGAs)

Aripiprazole 87 48­68 hr CYP2D6, CYP3A4 Dehydroaripiprazole

Asenapine <2 orally 13­39 hr CYP1A2, UGT1A4, CYP2D6, CYP3A4 None known

35 SL

Nonlinear

Brexpiprazole 95 91 hr CYP2D6, CYP3A4 DM­3411

Cariprazine 2­4 days, DDCAR 1­3 weeks CYP3A4, CYP2D6 Desmethyl cariprazine (DCAR),

Didesmethyl cariprazine (DDCAR)

Clozapine 12­81 11­105 hr CYP1A2, CYPD6, CYP3A4 Desmethylclozapine

Iloperidone 96 18­33 hr CYP2D6, CYP3A4 P88

Lumateperone 4.4 13­21 hr CYP3A4, CYP1A2, CYP2C8, Aldoketoreductase 1C1, UGT1A1, UGT1A4, UGT 2B15 IC200131, IC200161, IC200565

Lurasidone 10­20 18 hr CYP3A4, CYP1A2 ID­14233 and ID­14326

Olanzapine 80 20­70 hr CYP1A2, CYP3A4, FMO3 N­Glucuronide; 2­OH­methyl; 4­N­oxide

Paliperidone ER 28 23 hr Renal unchanged (59%) None known

CYP3A4 and multiple pathways

Quetiapine 9±4 6.88 hr CYP3A4, CYP3A5 N­desalkylquetiapine

Quetiapine XR 7 hr CYP3A4, CYP3A5 N­desalkylquetiapine

Risperidone 68 3­24 hr CYP2D6, CYP3A4 9­OH­risperidone

Ziprasidone 59 4­10 hr Aldehyde oxidase, CYP3A4, CYP1A2 None

UGT, UDP glucuronosyltransferases genes; FMO3, flavin containing monooxygenase 3 gene; SL, sublingual.

aB o l d print indicates major pathway.

Data from References 27­29, 60, 63­66, and 33,67.

Asenapine is unique in that it has less than 2% bioavailability after oral administration, but has a bioavailability of approximately 35% sublingually—the FDA­approved route of administration. Eating and drinking
within 10 minutes after sublingual administration will reduce bioavailability, and bioavailability decreases with single doses above 10 mg.28,66

Most antipsychotics have long elimination half­lives, generally 24 hours or more, with the exception of quetiapine and ziprasidone, which have short half­lives.63,66 Among the SGAs, only clozapine has an established
therapeutic serum concentration, with efficacy being associated with a clozapine plasma concentration greater than 350 ng/mL (mcg/L; 1.07 µmol/L).63 Whether a potential maximum therapeutic clozapine serum
concentration exists is unknown. Clozapine serum concentration should be obtained before exceeding 600 mg daily, in patients who develop unusual or severe adverse medication reactions, in patients who are
taking concomitant medications that can cause medication interactions, in patients who have age or pathophysiologic changes suggesting a change in pharmacokinetics, or for assessment of patient adherence.63,66

Adverse Medication Reactions

Table 87­7 presents the relative risk of common categories of antipsychotic adverse medication reactions, which are discussed below with respect to organ system affected. A general approach to monitoring and
assessing adverse medication reactions requires prospective monitoring by clinicians, preferably using a thorough review of systems approach. Patient­oriented self­rated scales can be helpful, as many patients with
schizophrenia do not readily endorse adverse medication reactions.

TABLE 87­7

Relative Incidence of Adverse Medication Reactions from Commonly Used Antipsychoticsa,b

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Aripiprazole + +c + + + ±

Asenapine ++ +/++ + + ++ +
taking concomitant medications that can cause medication interactions, in patients who have age or pathophysiologic changes suggesting a change in pharmacokinetics, or for assessment of patient adherence.63,66

Adverse Medication Reactions Birzeit University

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Table 87­7 presents the relative risk of common categories of antipsychotic adverse medication reactions, which are discussed below with respect to organ system affected. A general approach to monitoring and
assessing adverse medication reactions requires prospective monitoring by clinicians, preferably using a thorough review of systems approach. Patient­oriented self­rated scales can be helpful, as many patients with
schizophrenia do not readily endorse adverse medication reactions.

TABLE 87­7

Relative Incidence of Adverse Medication Reactions from Commonly Used Antipsychoticsa,b

Sedation EPS Anticholinergic Orthostasis Weight Gain Prolactin

Aripiprazole + +c + + + ±

Asenapine ++ +/++ + + ++ +

Brexpiprazole + + ± + + +

Cariprazine ± +/++c + + + +

Chlorpromazine +++ +++ ++++ ++++ ++ ++

Clozapine ++++ + +++ ++++ ++++ ±

Fluphenazine + ++++ + + + +++

Haloperidol ++ ++++ + + + +++

Iloperidone + ± +++ +++ +++ +

Lumateperone + ± + + + +

Lurasidone ++ +/++c + + + ++

Olanzapine ++ ++ +++ ++ ++++ +

Paliperidone + ++ + + ++ ++++

Perphenazine + ++++ + + + +++

Quetiapine +++ + ++++ ++ +++ +

Risperidone ++ ++ + ++ ++ ++++

Thioridazine ++ +++ ++++ ++++ + +++

Thiothixene ++ ++++ + + + +++

Ziprasidone ++ ++ + + + +

EPS, extrapyramidal side effects—includes dystonias, parkinsonism, akathisia, and tardive dyskinesia.

Relative side effect risk: ±, negligible; +, low; ++, moderate; +++, moderately high; ++++, high.

aAdverse medication reactions shown are relative risk based on doses within the recommended therapeutic range.

b Individual patient risk varies depending on patient­specific factors.

cPrimarily akathisia

As mentioned previously, adverse medication reactions are one of the primary predictors of patient nonadherence. With the variety of antipsychotics available, using an alternative should be considered to improve
patient outcomes in those who endorse poorly tolerated adverse medication reactions. As we learn more about relative risks (eg, metabolic, QTc prolongation, and EPS), it will be necessary to regularly reconsider
which antipsychotics should be considered first­line treatment alternatives.

Endocrine System

Within the hypothalamic tuberoinfundibular tract, DA blockade results in increased prolactin levels with hyperprolactinemia occurring in up to 71% of patients diagnosed with schizophrenia and treated with
antipsychotics.68 While US­based studies show no sex difference in the incidence of antipsychotic­induced hyperprolactinemia, UK­based studies suggest females are twice as likely to experience antipsychotic­
induced hyperprolactinemia than males (52% vs 26%, respectively).68,69 The major symptoms associated with hyperprolactinemia are gynecomastia, galactorrhea, menstrual irregularities, infertility, and sexual
dysfunction. Although the clinical significance is unclear, chronic hyperprolactinemia has been associated with decreased bone mineral density, which may put patients at higher risk of osteoporosis.70 Tolerance
does not appear to develop to antipsychotic­induced hyperprolactinemia.71 In general, FGAs are associated with higher rates of hyperprolactinemia than SGAs, the exceptions being risperidone and paliperidone
which have reported rates exceeding 70%.68,69,71 As they have poor penetration of the blood­brain barrier, their greater presence at D2 receptors in the pituitary gland may be contributing to this adverse effect.68,69,71
On the other hand, a D2 partial agonist, aripiprazole is more prolactin sparing and other newer antipsychotics including asenapine, iloperidone, lurasidone, brexpiprazole, cariprazine, and lumateprone have not

been shown to induce clinically meaningful changes in prolactin levels.27,28,30,68,72,73

If a patient experiences symptomatic hyperprolactinemia, switching to an agent that has minimal sustained effect on prolactin is a reasonable treatment option, as is attempting to lower the antipsychotic dose.
However, both interventions run the risk of relapse. Augmentation with aripiprazole 5 to 30 mg daily may help reduce risperidone­induced hyperprolactinemia.74 However, there have also been case series reporting
symptom exacerbation with the addition of aripiprazole and, in general, antipsychotic polypharmacy is discouraged.68 Dopamine agonists, bromocriptine, cabergoline, and pramipexole have been shown to decrease
prolactin, but this approach is not recommended due to the lack of controlled trials, as well as reports of psychosis exacerbation.68 For females with schizophrenia who suffer from amenorrhea due to antipsychotic­
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induced hyperprolactinemia, metformin 750 to 1,500 mg/day has been shown to restore menstrual function, with associated reduction in prolactin level.75 While this is a potentially appealing intervention, especially
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 18 / 48
in patients who are gaining weight and at risk for Type 2 diabetes mellitus (T2DM), additional evidence is needed before recommending metformin as a first­line intervention for females with antipsychotic­induced
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hyperprolactinemia.

Weight gain is frequently reported in both adults and children receiving antipsychotics,76,77 and is often seen within the first 12 weeks of antipsychotic initiation, with the rate of weight gain decreasing over time.76,77
 2

On the other hand, a D2 partial agonist, aripiprazole is more prolactin sparing and other newer antipsychotics including asenapine, iloperidone, lurasidone, brexpiprazole, cariprazine, and lumateprone have not
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been shown to induce clinically meaningful changes in prolactin levels.27,28,30,68,72,73
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If a patient experiences symptomatic hyperprolactinemia, switching to an agent that has minimal sustained effect on prolactin is a reasonable treatment option, as is attempting to lower the antipsychotic dose.
However, both interventions run the risk of relapse. Augmentation with aripiprazole 5 to 30 mg daily may help reduce risperidone­induced hyperprolactinemia.74 However, there have also been case series reporting
symptom exacerbation with the addition of aripiprazole and, in general, antipsychotic polypharmacy is discouraged.68 Dopamine agonists, bromocriptine, cabergoline, and pramipexole have been shown to decrease
prolactin, but this approach is not recommended due to the lack of controlled trials, as well as reports of psychosis exacerbation.68 For females with schizophrenia who suffer from amenorrhea due to antipsychotic­
induced hyperprolactinemia, metformin 750 to 1,500 mg/day has been shown to restore menstrual function, with associated reduction in prolactin level.75 While this is a potentially appealing intervention, especially
in patients who are gaining weight and at risk for Type 2 diabetes mellitus (T2DM), additional evidence is needed before recommending metformin as a first­line intervention for females with antipsychotic­induced
hyperprolactinemia.75

Weight gain is frequently reported in both adults and children receiving antipsychotics,76,77 and is often seen within the first 12 weeks of antipsychotic initiation, with the rate of weight gain decreasing over time.76,77
The risk of cardiovascular­related mortality is higher in individuals with schizophrenia,78 and this is further aggravated by medication­related weight gain and the high prevalence of smoking. Additionally, obesity is a
risk factor for diabetes mellitus.78,79 Weight gain during treatment is concerning for patients and a reason for poor medication adherence.55 Clozapine and olanzapine have the highest rates of antipsychotic­induced
weight gain (AIWG), with olanzapine being the most studied and likely producing the highest risk. Mid­risk antipsychotics include asenapine, iloperidone, paliperidone, quetiapine, and risperidone. Aripiprazole,
lurasidone, and ziprasidone are associated with the lowest risk of AIWG.28,30,72,76 Newer agents, brexpiprazole, cariprazine and lumateperone, also appear to have low risk of AIWG, similar to aripiprazole.31,33,73

Although the exact mechanism for AWIG uncertain, it has been associated with antihistaminic effects, antimuscarinic effects, adrenaline alpha­1, and blockade of 5­HT2C receptors.77 However, dietary factors and
activity levels can play a significant role in this population, as well as nourishment after a period of poor self­care. The risk of weight gain may be greater in patients with their first psychotic episode and those who are
underweight at baseline.

Several different genetic variations have been associated with predisposition for AIWG. The 5­HT2c gene and its relationship to AIWG is the most extensively studied polymorphism.64,80 A meta­analysis of all genetic
studies looking at the C–759T promoter region polymorphism of the 5­HT2C receptor gene confirmed the relationship with AIWG. While the C allele is the major allele in the population, the meta­analysis found that T

allele is protective against AIWG.80 In this same meta­analysis, polymorphisms of dopamine receptor D2 (D2), alpha­2 adrenergic receptor (α2), and melanocortin­4 receptor (MC4R) genes were also found to be
associated with AIWG. Insulin­induced gene 2 (INSIG2) and Guanine Nucleotide Binding Protein (GNB3) had smaller effect sizes, but were also found to be associated with AIWG. Polymorphisms in leptin and leptin
receptor genes, methylenetetrahydrofolate reductase (MTHFR), and brain­derived neurotrophic factor (BDNF) gene have been genetic targets; however, results are inconsistent regarding a potential relationship
between these polymorphisms and AIWG.64,80,81 In general, AIWG is most likely polygenic and impacted by environmental factors.

The combination of olanzapine and samidorphan was FDA approved for use in schizophrenia and bipolar disorder in May 2021. The addition of samidorphan, a functional opioid antagonist, to olanzapine is a novel
approach to attenuate olanzapine­induced weight gain. In a 24­week Phase 3 trial, the olanzapine/samidorphan combination resulted in significantly less weight gain compared to olanzapine monotherapy, with the
mean increase in weight of 3.18 kg (7.01 lb) and 5.08 kg (11.2 lb), respectively.82 Additionally, significantly fewer subjects in the combination group had >7% weight gain as compared to olanzapine monotherapy
(27.5% vs 42.7%, respectively). Unfortunately, the olanzapine/samidorphan combination did not result in any metabolic benefit when compared to olanzapine monotherapy.82

Several other approaches have been recommended to address weight gain. Switching the antipsychotic to another agent with less weight gain liability is one choice, and an American Diabetes Association consensus
task force recommends consideration of a change in antipsychotic if a patient gains more than 5% of baseline body weight after starting the medication.83 Metformin is effective in treating AIWG with a meta­analysis
indicating an average of a 3.17 kg (6.99 lb) weight loss compared with placebo.84 Dietary restriction, exercise, and behavior modification programs are reported to be successful. Both the Reducing Weight and
Diabetes Risk in an Underserved Population (STRIDE) and the Randomized Trial of Achieving Healthy Lifestyles in Psychiatric Rehabilitation (ACHIEVE) clinical trials showed behavioral weight loss interventions
resulted in significant weight loss in patients with mental illness receiving antipsychotics. The STRIDE study also showed reductions in fasting glucose over 6­ and 12­month periods using such interventions.80,85,86

The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) trial is the only randomized trial to compare different strategies to address overweight/obese youth who had experienced significant
weight gain on antipsychotics.87 All groups received health lifestyle education and were randomized to either the addition of metformin, a switch to aripiprazole, or continued their baseline antipsychotic. In this 24­
week trial, the additional of metformin or a switch to aripiprazole resulted in a decrease in BMI z­score where continued antipsychotic resulted in an increase.87

Patients with schizophrenia have a twofold higher prevalence of T2DM compared with the general population.78 While the illness itself contributes to elevated risk, antipsychotics are a major contributing factor, with
individuals exposed to antipsychotics having higher rates of T2DM than those unexposed.78,79 The exact mechanism by which antipsychotics elevate the risk of T2DM is unknown. While weight gain seen with
antipsychotics can lead to insulin resistance and elevated risk of T2DM, a systematic review of antipsychotic­associated diabetic ketoacidosis (DKA) found that weight gain was only associated with roughly half of the
included cases, and DKA was often the first indicator of a diabetes diagnosis. The SGAs can rapidly and directly influence glucose metabolism independent of AIWG and adiposity.88 Antipsychotics also may directly
cause T2DM through increased insulin resistance or impaired β­cell function or a combination of the two.79 The greatest increase in glucose impairment typically occurs during the first 14 weeks of treatment,85 and
for clozapine, olanzapine, quetiapine, and risperidone nearly 60% of new­onset diabetes occurred within the first 6 months of treatment initiation.83,85

The FDA­approved product labeling for all SGAs reflects the increased risk of diabetes mellitus in patients taking these medications, but risk varies based on the antipsychotic. Clozapine and olanzapine have the
highest risk of new­onset diabetes followed by quetiapine and risperidone, while the risk appears lowest with ziprasidone and aripiprazole.83,85 Although inadequate data are available for asenapine, iloperidone,
lurasidone, brexpiprazole, cariprazine, and lumateperone, their risk also appears low.33,89 Olanzapine is not recommended as a first­line antipsychotic option due to its metabolic risks14,22,23; therefore, designing
care models and standards for managing diabetes in patients with schizophrenia is important in addressing this major health problem.

Cardiovascular System

Orthostatic Hypotension
Orthostatic hypotension, thought to be caused by α­adrenergic blockade, is a common adverse reaction of antipsychotics.90 Clozapine and quetiapine had the highest incidence of orthostatic hypotension in the
CATIE study, and iloperidone appears to have the highest risk among newer SGAs.90 Orthostatic hypotension can occur in any patient, but patients with diabetes and pre­existing cardiovascular disease and older
adults are particularly predisposed. Other risk factors may include dehydration, presence of alcohol associated neuropathy and antipsychotic combination treatment.90,91 Patients should be advised to avoid sudden
positional changes to allow for adaptation. Tolerance to orthostatic hypotension may occur within 2 to 3 months. If not, lower doses or a change to an antipsychotic with less α­blockade can be attempted. Fluid
resuscitation or increasing salt intake may also help minimize orthostatic blood pressure changes.90,91

Electrocardiographic Changes
The electrocardiographic (ECG) changes seen with antipsychotics include increased heart rate (through sinus tachycardia from anticholinergic effects, or reflex tachycardia from α­adrenergic blockade), flattened T
waves, ST segment depression, and prolongation of QT and PR intervals. The most clinically important of these potential changes is prolongation of the QTc interval, which has been associated with ventricular
arrhythmias, including torsade de pointes syndrome. This is thought to occur as a result of blockade of the cardiac delayed potassium rectifier channel as well as impairment in autonomic function.89,91 Among the
antipsychotics, thioridazine is most likely to cause these changes and has been shown to prolong the QTc an average of about 30 msec, which is over 20 msec longer than haloperidol, risperidone, olanzapine, or
quetiapine, and 15 msec longer than ziprasidone.92 Thioridazine’s effect on QTc prolongation is dose related, and has led to a boxed warning in the FDA­approved product labeling. A comprehensive review was not
able to stratify the degree of QTc prolongation of nine different SGAs.93 Iloperidone, however, is subject to pharmacogenomic differences in metabolism, and there may be an increased risk of QTc prolongation in
CYP2D6 poor metabolizers.27 High IV doses of haloperidol elevate the risk for QTc prolongation, resulting in a boxed warning in the FDA­approved labeling.94 Although the precise point at which QTc prolongation
becomes clinically dangerous is unclear, the risk for arrhythmia escalates when the QTc interval exceeds 500 msec, or is 60 msec above the baseline QTc.93,94 Accordingly, it has been recommended to discontinue a
medication associated with QTc prolongation if the interval consistently exceeds 500 msec. QTc intervals greater than or equal to 450 msec and/or a 30 msec increase in QTc interval from baseline may be predictors
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of a medication’s risk to cause torsades.93
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 19 / 48
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QTc prolongation Hill.predict
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torsade de pointes, it rarelyTerms
happensof Use
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risks factors, including•patients
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greater than 60 years, female gender, those with preexisting cardiac or
cerebrovascular disease (including bradycardia, second­ or third­degree AV block, and congenital long QTc syndrome), hepatic impairment, hypokalemia, hypomagnesemia, concomitant medications that prolong
the QTc interval, metabolic inhibition by another medication, or preexisting QTc prolongation.93,94 For patients over the age of 50 years of age, a pretreatment ECG is recommended, as are baseline serum potassium
and magnesium levels.
arrhythmias, including torsade de pointes syndrome. This is thought to occur as a result of blockade of the cardiac delayed potassium rectifier channel as well as impairment in autonomic function.89,91 Among the
Birzeit
antipsychotics, thioridazine is most likely to cause these changes and has been shown to prolong the QTc an average of about 30 msec, which is over 20 msec longer than haloperidol, risperidone, University
olanzapine, or
quetiapine, and 15 msec longer than ziprasidone.92 Thioridazine’s effect on QTc prolongation is dose related, and has led to a boxed warning in the FDA­approved product labeling. A comprehensive review was
Access Provided by:not
able to stratify the degree of QTc prolongation of nine different SGAs.93 Iloperidone, however, is subject to pharmacogenomic differences in metabolism, and there may be an increased risk of QTc prolongation in
CYP2D6 poor metabolizers.27 High IV doses of haloperidol elevate the risk for QTc prolongation, resulting in a boxed warning in the FDA­approved labeling.94 Although the precise point at which QTc prolongation
becomes clinically dangerous is unclear, the risk for arrhythmia escalates when the QTc interval exceeds 500 msec, or is 60 msec above the baseline QTc.93,94 Accordingly, it has been recommended to discontinue a
medication associated with QTc prolongation if the interval consistently exceeds 500 msec. QTc intervals greater than or equal to 450 msec and/or a 30 msec increase in QTc interval from baseline may be predictors
of a medication’s risk to cause torsades.93

While QTc prolongation may predict torsade de pointes, it rarely happens in the absence of other risks factors, including patients greater than 60 years, female gender, those with preexisting cardiac or
cerebrovascular disease (including bradycardia, second­ or third­degree AV block, and congenital long QTc syndrome), hepatic impairment, hypokalemia, hypomagnesemia, concomitant medications that prolong
the QTc interval, metabolic inhibition by another medication, or preexisting QTc prolongation.93,94 For patients over the age of 50 years of age, a pretreatment ECG is recommended, as are baseline serum potassium
and magnesium levels.

Myocarditis and Cardiomyopathy

Myocarditis is an infrequent and dose independent adverse effect that is most likely to occur with clozapine, but has been reported with quetiapine,90 and possibly with olanzapine.95 Eighty­seven percent of
clozapine­induced myocarditis cases occur within the first 4 weeks of treatment, but cases as late as 22 weeks have been reported.89,96 Symptoms of clozapine­induced myocarditis can be nonspecific and include: flu­
like symptoms (eg, fever, myalgias), respiratory (eg, dyspnea, cough, orthopnea), and cardiac (persistent tachycardia, chest pain, syncope) symptoms. Myocarditis is considered a life­threatening event and therefore
early detection is essential. While the incidence of clozapine­induced myocarditis may be as high as 3%, and the mortality rate upwards of 10% to 30%, there are no mandatory monitoring parameters.96
Recommended laboratory monitoring has been proposed with baseline and weekly monitoring of C­Reactive Protein (CRP) for the first 4 weeks, while troponin (I or T) and B­type natriuretic peptide monitoring has
also been suggested. A baseline echocardiogram (ECHO) is recommended and repeated if myocarditis is suspected. Both CRP elevations above 100 mg/L and troponin greater than two times the upper limit of normal
have been shown to be highly sensitive in detecting clozapine­induced myocarditis. Clozapine rechallenge after the occurrence of myocarditis is debated, and only a few cases have been reported. The decision to
rechallenge should only be made in patients where the clinical value greatly outweighs the potential risk, and only after full resolution of the myocarditis and no signs of permanent cardiac damage. A rechallenge
should be conducted in a hospital where close monitoring can occur, as myocarditis recurrence during rechallenge has been reported.96

Cardiomyopathy, a potentially life­threatening adverse effect, can also be seen with clozapine, which typically presents later during treatment than myocarditis, with an average time of onset of 14 months.96,97 The
current incidence of cardiomyopathy is estimated to be 0.02% to 0.1%, but this adverse effect may be under­reported,97 as shortness of breath, palpitations, and fatigue are the most frequently reported symptoms.
The diagnosis of cardiomyopathy is typically made with an ECHO with a reduction in ejection fraction (EF) being the most consistent finding. For patients with an EF less than 25%, lower recovery and higher mortality
rates have been seen, whereas those with an EF greater than 40% typically fully recover.97 In suspected cases of clozapine­induced cardiomyopathy, clozapine should be discontinued, and a rechallenge is not
recommended.98

Sudden Cardiac Death

The risk of sudden cardiac death (SCD) with use of FGAs and SGAs is reported to be twice that of nonusers, with risk increasing with escalated dose.89,90 Fifteen cases of SCD may occur per 10,000 years of
antipsychotic exposure.89,90 There is insufficient evidence to confer a greater risk with one class of antipsychotics over another.89,90 A case­crossover study involving over 17,000 patients showed that antipsychotic
use was associated with a 1.53­fold increase in ventricular arrhythmia or SCD. The magnitude of effect was greatest among patients who received antipsychotics for a short term (less than 28 days).99 Nonetheless,
prospectively designed studies are needed to confirm dose­dependency with antipsychotic­associated cardiovascular sudden death, and whether risk is different among antipsychotics.

Lipid Changes
Treatment with at least some SGAs and phenothiazines is associated with elevated serum triglycerides and cholesterol. Among the SGAs, olanzapine, clozapine, and quetiapine have the highest risk for dyslipidemia,
with elevations in serum triglycerides being the most frequently reported abnormality.28,30 Increased appetite and subsequent weight increase can negatively affect lipids. Independent of weight gain, antipsychotic
effects on apolipoprotein B, lipoprotein oxidation, and elevations in sterol regulatory element binding protein­controlled gene expression are among possible mechanisms by which lipid changes may occur with
antipsychotics.100 As previously discussed, olanzapine is associated with greater and significant adverse effects on metabolic parameters, including lipids, blood glucose, and body weight as compared with other
antipsychotics in the CATIE trial.17

The occurrence of weight gain, diabetes, and lipid abnormalities during antipsychotic therapy is consistent with the development of metabolic syndrome, and cohorts of patients with schizophrenia have shown
elevated prevalence of metabolic syndrome as compared with general population cohorts. Prevalence rates of metabolic syndrome in US populations treated with antipsychotics range from 28% to 60%, with 40.9%
reported in the prospectively designed CATIE trial.101

Metabolic syndrome consists of raised triglycerides (greater than or equal to 150 mg/dL [1.70 mmol/L]), low HDL cholesterol (less than or equal to 40 mg/dL [1.03 mmol/L] for males, less than or equal to 50 mg/dL
[1.29 mmol/L] for females), elevated fasting glucose (greater than or equal to 100 mg/dL [5.6 mmol/L]), blood pressure elevation (greater than or equal to 130/85 mm Hg), and weight gain (abdominal circumference
greater than 102 cm [40 in.] for males, greater than 89 cm [35 in.] in females).102 A diagnosis of metabolic syndrome can be made in individuals who meet at least three of these criteria. Therefore, these abnormalities
dictate an important role for general health screening and monitoring in patients with schizophrenia, and prompt intervention when such abnormalities occur. The propensity of individual antipsychotics to produce
metabolic disturbances should be considered in the context of individual patient risk factors at the time of medication selection.

Thromboembolism
Compared to the general population, the risk of venous thromboembolism (VTE) is twofold higher in individuals with schizophrenia. Sedentary lifestyle, smoking, and metabolic syndrome are all potential
explanations for the higher incidence. Increased rates have also been reported in stuporous catatonia and prolonged physical restraints. Additionally, both FGAs and SGAs have been associated with elevating the risk
of VTE. The risk may be highest within the first 30 days of antipsychotic exposure and with higher doses. Although the mechanism for increased VTE risk is unknown, increased sedative adverse medication reactions,
metabolic effects, antipsychotic effect on platelet aggregation, and hyperprolactinemia indirectly increasing venous stasis have been proposed.103 The QThrombosis (https://qthrombosis.org/) is a validated VTE risk
calculator that includes antipsychotics in the risk assessment model.104 This tool may be helpful in identifying patients at elevated risk for VTE and can easily be implemented in clinic practice.

Anticholinergic Effects

Patients receiving antipsychotics or antipsychotics in combination with anticholinergics can experience anticholinergic adverse reactions (eg, dry mouth, constipation, tachycardia, blurred vision, inhibition or
impairment of ejaculation, urinary retention, or impaired memory). These adverse medication reactions are particularly seen with low­potency FGAs, and in older adult patients who are especially sensitive to these
effects. Of the SGAs, clozapine and olanzapine have moderately high rates of anticholinergic effects. Constipation, caused by slowed peristaltic movement and decreased intestinal fluid content, should be closely
monitored and treated, especially in older adults. Paralytic ileus and necrotizing enterocolitis can also occur.89,90

Central Nervous System

Extrapyramidal System
Extrapyramidal symptoms (EPS) is an umbrella term used to describe antipsychotic­induced movement symptoms due to excess dopamine blockade in the nigrostriatal pathway. These symptoms include: dystonia,
akathisia, parkinsonism, and tardive dyskinesia, which are explained in detail below.

Dystonia
Dystonia is a state of abnormal tonicity, sometimes described simplistically as a severe “muscle spasm.105 More accurately, dystonias are prolonged tonic contractions, with a rapid onset, usually within 24 to 96 hours
of initiating or increasing the dose of an antipsychotic.106 Types of dystonic reactions include trismus, glossospasm, tongue protrusion, pharyngeal–laryngeal spasms, blepharospasm, oculogyric crisis, torticollis,
and retrocollis, but can occur with any skeletal muscle group. They can be life threatening, as in the case of pharyngeal–laryngeal dystonias, and can contribute significantly to patient medication nonadherence.
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Dystonic reactions occur primarily with high potency FGAs and are greatly reduced with SGAs. Risk factors for dystonia include younger patients, male sex, the use of high­potency agents, rapid titration and high
Chapter
dosage. 87: Schizophrenia,
The overall M. Lynn
incidence from the 1960s Crismon;
to the mid­1970s Tawny
ranged L. to
from 2.3% Smith;
10%, butPeter F. Buckley
as higher­potency traditional antipsychotics became more widely used, the rate increased to as high asPage
64%. 20 / 48
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Intramuscular or IV anticholinergics (Table 87­8) are the treatment of choice for dystonias, with benzodiazepines being a second­line option.106 Benztropine 2 mg or diphenhydramine 50 mg can be given IM or IV,
whereas diazepam 5 to 10 mg by slow IV push or lorazepam 1 to 2 mg intramuscularly are treatment alternatives. Relief from the dystonia is typically seen within 15 to 20 minutes of an IM injection or within 5 minutes
of IV administration. The antipsychotic can be continued, with concomitant short­term use of an oral anticholinergic, which is then subsequently tapered and stopped. In general, prophylactic anticholinergic
Extrapyramidal System
Birzeit
Extrapyramidal symptoms (EPS) is an umbrella term used to describe antipsychotic­induced movement symptoms due to excess dopamine blockade in the nigrostriatal pathway. These symptoms University
include: dystonia,
akathisia, parkinsonism, and tardive dyskinesia, which are explained in detail below.
Access Provided by:
Dystonia
Dystonia is a state of abnormal tonicity, sometimes described simplistically as a severe “muscle spasm.105 More accurately, dystonias are prolonged tonic contractions, with a rapid onset, usually within 24 to 96 hours
of initiating or increasing the dose of an antipsychotic.106 Types of dystonic reactions include trismus, glossospasm, tongue protrusion, pharyngeal–laryngeal spasms, blepharospasm, oculogyric crisis, torticollis,
and retrocollis, but can occur with any skeletal muscle group. They can be life threatening, as in the case of pharyngeal–laryngeal dystonias, and can contribute significantly to patient medication nonadherence.
Dystonic reactions occur primarily with high potency FGAs and are greatly reduced with SGAs. Risk factors for dystonia include younger patients, male sex, the use of high­potency agents, rapid titration and high
dosage. The overall incidence from the 1960s to the mid­1970s ranged from 2.3% to 10%, but as higher­potency traditional antipsychotics became more widely used, the rate increased to as high as 64%.

Intramuscular or IV anticholinergics (Table 87­8) are the treatment of choice for dystonias, with benzodiazepines being a second­line option.106 Benztropine 2 mg or diphenhydramine 50 mg can be given IM or IV,
whereas diazepam 5 to 10 mg by slow IV push or lorazepam 1 to 2 mg intramuscularly are treatment alternatives. Relief from the dystonia is typically seen within 15 to 20 minutes of an IM injection or within 5 minutes
of IV administration. The antipsychotic can be continued, with concomitant short­term use of an oral anticholinergic, which is then subsequently tapered and stopped. In general, prophylactic anticholinergic
medications are not recommended routinely. However, prophylaxis is reasonable when using high­potency FGAs (eg, haloperidol or fluphenazine) in young males and in patients with a history of dystonia.105
Dystonias can also be minimized by the use of lower initial FGA doses or the use of SGAs. Anticholinergics are good choices for prophylaxis, whereas amantadine has not been proven effective for this purpose.

TABLE 87­8
Agents Used to Treat Extrapyramidal Symptoms

Generic Name Equivalent Dose (mg) Daily Dosage Range (mg)

Antimuscarinic

Benztropinea 1 1­8b

Biperidena 2 2­8

Trihexyphenidyl 2 2­15

Antihistamine

Diphenhydraminea 50 50­400

Dopamine Agonist

Amantadine NA 100­400

Benzodiazepine

Lorazepama NA 1­8

Diazepam NA 2­20

Clonazepam NA 2­8

β­Blocker

Propranolol NA 20­160

NA, Not applicable.

aInjectable dosage form can be given intramuscularly for relief of acute dystonia.

bIn treatment­refractory cases, dosage can be titrated to 12 mg/day with careful monitoring; nonlinear pharmacokinetics have been reported.

Akathisia
Akathisia is defined as the inability to sit still and having functional motor restlessness. The most accurate diagnosis is made by combining subjective patient reports with objective observations (pacing, shifting,
shuffling, or tapping feet). Subjectively, patients may describe a feeling of inner restlessness or disquiet or a compulsion to move or remain in constant motion that provides some relief. Akathisia occurs in 20% to
40% of patients treated with high­potency FGAs105,107 and is frequently accompanied by dysphoria. In severe cases, akathisia may be mistaken for aggression and if left untreated, has been linked to insomnia,
increased suicidality, and development of tardive dyskinesia.107

Akathisia generally appears early in antipsychotic treatment, but can be chronic if not appropriately addressed.107 Risk of akathisia is greater when the antipsychotic dose is increased rapidly or multiple
antipsychotics are used, as well as in antipsychotic naïve individuals.107 Traditionally, a reduction in antipsychotic dosage has been considered the best intervention; however, this might not be a realistic goal in a
patient with acute psychosis. A logical alternative is to switch to an antipsychotic with a lower risk of akathisia, or an antipsychotic the patient previously tolerated. Akathisia can occasionally occur with SGAs,
particularly aripiprazole, cariprazine, lurasidone, or risperidone. Iloperidone, quetiapine and clozapine appear to have the lowest risk of producing akathisia.72,107

Unlike acute dystonias, akathisia responds poorly to anticholinergics;107 therefore, benzodiazepines have been used for treatment of akathisia, but the high prevalence of co­occurring substance use disorders in
schizophrenia discourages their use.107 The β­blockers (eg, propranolol in doses up to 160 mg daily) are effective and have the most evidence.105,107 Additionally, 5­HT2 receptor antagonists may be protective against

akathisia and may be used for its management. Examples of such agents include mirtazapine, trazodone, and cyproheptadine, with mirtazapine having the most data to support its use.105,107

Parkinson Symptoms
Antipsychotic­induced parkinson symptoms resembles idiopathic Parkinson disease with symptom onset typically within 1 to 2 weeks after antipsychotic initiation or a dose increase. For some it may be delayed with
50% to 75% of cases occurring within a month and 90% within 3 months.105,106 A patient with antipsychotic­induced parkinson symptoms can present with any of four cardinal symptoms: (a) akinesia, bradykinesia, or
decreased motor activity including difficulty initiating movement, as well as extreme slowness, mask­like facial expression, micrographia, slowed speech, and decreased arm swing; (b) tremor that is predominant at
rest and decreases with movement, and known as the pill­rolling type, usually involves the fingers and hands, although tremors can also be seen in the arms, legs, neck, head, and chin; (c) cogwheel rigidity, seen as
the patient’s limbs yielding in jerky, ratchet­like fashion when passively moved by the examiner; and (d) postural abnormalities and instability manifested as stooped posture, difficulty in maintaining stability when
changing body position, and a gait that ranges from slow and shuffling to festinating. Fatigue and weakness can be noted, as well as oral abnormalities including dysphagia, dysarthria, and abnormal palmomental
and glabellar reflexes.
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2022­10­24 3:41ofPFGA­induced
Your IPparkinson symptoms ranges from 15.4% to 36%, depending on the medication and dose, and akinesia alone can be seen in 59% of patients on high­
is 41.233.255.202
potency FGAs. The risk of parkinson symptoms with SGAs is low. A secondary data analysis from the CATIE study did not find marked differences in rates of EPS between perphenazine and SGAs, suggesting that a less
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 21 / 48
potent FGA at modest doses may present a similar risk of parkinson symptoms as SGAs.108 Other risk factors for the development of parkinson symptoms include increasing age and possibly female sex.
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
The efficacy of anticholinergic medications in treating symptoms of antipsychotic­induced parkinson symptoms is well established,105,106 although diphenhydramine produces more sedation than the other agents.
Table 87­7 outlines the dosing of these medications. Symptoms typically begin to resolve within 3 to 4 days after initiation of treatment, but a minimum of at least 2 weeks of treatment is normally required for full
Parkinson Symptoms
Birzeit University
Antipsychotic­induced parkinson symptoms resembles idiopathic Parkinson disease with symptom onset typically within 1 to 2 weeks after antipsychotic initiation or a dose increase. For some it may be delayed with
50% to 75% of cases occurring within a month and 90% within 3 months.105,106 A patient with antipsychotic­induced parkinson symptoms can present with any of four cardinal symptoms: (a) akinesia,Access Provided by: or
bradykinesia,
decreased motor activity including difficulty initiating movement, as well as extreme slowness, mask­like facial expression, micrographia, slowed speech, and decreased arm swing; (b) tremor that is predominant at
rest and decreases with movement, and known as the pill­rolling type, usually involves the fingers and hands, although tremors can also be seen in the arms, legs, neck, head, and chin; (c) cogwheel rigidity, seen as
the patient’s limbs yielding in jerky, ratchet­like fashion when passively moved by the examiner; and (d) postural abnormalities and instability manifested as stooped posture, difficulty in maintaining stability when
changing body position, and a gait that ranges from slow and shuffling to festinating. Fatigue and weakness can be noted, as well as oral abnormalities including dysphagia, dysarthria, and abnormal palmomental
and glabellar reflexes. The overall incidence of FGA­induced parkinson symptoms ranges from 15.4% to 36%, depending on the medication and dose, and akinesia alone can be seen in 59% of patients on high­
potency FGAs. The risk of parkinson symptoms with SGAs is low. A secondary data analysis from the CATIE study did not find marked differences in rates of EPS between perphenazine and SGAs, suggesting that a less
potent FGA at modest doses may present a similar risk of parkinson symptoms as SGAs.108 Other risk factors for the development of parkinson symptoms include increasing age and possibly female sex.

The efficacy of anticholinergic medications in treating symptoms of antipsychotic­induced parkinson symptoms is well established,105,106 although diphenhydramine produces more sedation than the other agents.
Table 87­7 outlines the dosing of these medications. Symptoms typically begin to resolve within 3 to 4 days after initiation of treatment, but a minimum of at least 2 weeks of treatment is normally required for full
response. Amantadine may be as efficacious for parkinson symptoms as anticholinergics, but with significantly less impact on cognition.105,106 Prophylactic use of these agents against parkinson symptoms is less
convincing compared with dystonias, and is unnecessary when using SGAs.105,106 The long­term treatment of parkinson symptoms with antiparkinson medication is somewhat controversial. An attempt should be
made to taper and discontinue these agents in 6 weeks to 3 months after symptom resolution. If symptoms reappear, then switching to an SGA should be considered. Quetiapine, aripiprazole, brexpiprazole,
iloperidone, asenapine, lumateperone, and clozapine are reasonable alternatives in a patient experiencing EPS with other SGAs.33,72,109

Tardive Dyskinesia
Tardive dyskinesia (TD) is a syndrome characterized by abnormal involuntary hyperkinetic movements occurring late in onset in relation to initiation of antipsychotic therapy. The classic description of tardive
dyskinesia is an insidious onset of oral or orofacial movements often associated with lip smacking or tongue thrusting as the disorder progresses, which can interfere with the patient’s ability to chew, speak, or
swallow. Other facial movements include frequent blinking, brow arching, grimacing, and upward deviation of the eyes. Involvement of the extremities sometimes occurs, and may involve any skeletal muscle group.
Orofacial movements are more common in older patients, whereas the truncal axial movements are classically reported in young adults. Movements can worsen with stress, decrease with sedation, and disappear
during sleep. Concentration on motor tasks or attempts to suppress the movements can increase them.110

Early signs of tardive dyskinesia can be reversible but if allowed to persist, can become irreversible, even with medication discontinuation. The exact time point in which TD becomes irreversible is unknown, which
underscores the importance of early detection.106 When the antipsychotic dose is decreased or tapered and discontinued, worsening of abnormal movements may occur, followed by possible slow improvement after
months or years if the patient remains on lower doses or discontinues treatment. Younger age correlates with a greater chance of reversing TD.106 No standardized diagnostic criteria for tardive dyskinesia are
available. Abnormal involuntary movements can be detected early through physical assessment and the use of rating scales. Available rating scales include the Abnormal Involuntary Movement Scale (AIMS) and the
Dyskinesia Identification System: Condensed User Scale (DISCUS).109 Neither scale is diagnostic (see Chapter e81).

One of the greatest risk factors for TD is older age, with patients over 65 having a two­to­fivefold higher incidence of TD than younger adults.111 Other possible risk factors include history of acute EPS, poor
antipsychotic medication response, diagnosis of organic mental disorder, diabetes mellitus, mood disorders, female sex, use of anticholinergics, current and cumulative antipsychotic doses, and duration of
antipsychotic exposure.110 Additionally, genetic variation within CYP2D6, vesicular monoamine transporter­2 (VMAT2) gene, and D2 receptor gene have been suggested as being associated with increased risk.112 A

systematic review of 12 studies lasting 1 year or more found the overall risk of TD with SGAs to be approximately 2.9% per year in adults under 65 years of age as compared with 7.7% for FGAs.113 These results were
confirmed with a meta­analysis which indicated that olanzapine and aripiprazole may have a small advantage over other non­clozapine SGAs.114 Tardive dyskinesia is not always permanent, with spontaneous
remission of symptoms observed in 25% of patients after 5 years of continued treatment;24 however, overall morbidity and mortality are greater in tardive dyskinesia patients.

Prevention of TD is important, as treatment of the movements once they occur is difficult. One of the more compelling arguments for the first­line use of SGAs is their lower risk of TD.24 Therefore, regular neurologic
examinations (AIMS or other scales) should be performed at baseline, and APA guidelines recommend TD monitoring at least every 6 months for those at high risk and every 12 months for all others.22 At the first sign
of TD, the need for continuing antipsychotic treatment should be assessed, and if the patient is taking an FGA and continuing treatment is indicated, the medication should be switched to an SGA.

The VMAT2 inhibitors deutetrabenazine and valbenazine are FDA­approved medications for the treatment of TD. Both are considered first­line interventions, as they produced clinically significant decreases in AIMS
scores in both short­ and long­term trials.115 However, when valbenazine treatment is discontinued, TD symptoms can rapidly return toward pretreatment levels within 4 weeks after discontinuation.116

Deutetrabenzine should be initiated at 6 mg twice daily with food, with weekly dose increases of 6 mg up to a maximum dose of 48 mg per day. It is primarily metabolized via CYP2D6 and a maximum daily dose of 36
mg is recommended with concomitant strong CYP2D6 inhibitors or in CYP2D6 poor metabolizers.103 It is contraindicated in individuals with severe hepatic impairment or those taking a monoamine oxidase inhibitor.
Valbenazine is initiated at 40 mg once daily and increased to 80 mg after 1 week. This medication is not recommended for use in combination with strong CYP3A4 inducers, and a maximum daily dose of 40 mg is
recommended when used with CYP3A4 strong inhibitors. Use in individuals with severe renal impairment is not recommended. Labeling for both deutetrabenzine and valbenazine includes warnings about suicidality,
depression, and QTc prolongation.115,116

Numerous other medications have been used to treat tardive dyskinesia. In two controlled trials lasting 22 to 52 weeks, clozapine decreased abnormal involuntary movement,24 therefore switching to clozapine has
been recommended as a treatment for moderate­to­severe TD.14,22­24 A 2013 guideline developed by the American Academy of Neurology (AAN) recommended short­term treatment of TD with either clonazepam (up
to 4.5 mg daily) or ginkgo biloba extract 240 mg daily based upon randomized clinical trial data. However, long­term treatment data are lacking.117 The AAN guideline was developed before the availability of the two
VMAT2 inhibitors. However, in patients who do not have access to these agents, or do not tolerate or respond with their use, clonazepam or ginkgo biloba can be considered.115

Seizures
An increased risk of medication­induced seizures can occur in patients receiving antipsychotics as these agents decrease the seizure threshold. However, this risk is greater if the following predisposing factors are
present: preexisting seizure disorder, history of medication­induced seizure, abnormal electroencephalogram (EEG), and preexisting CNS pathology or head trauma. Seizures are more closely associated with high
plasma concentrations, rapid dosage titration, and treatment initiation. The exact mechanism is unknown, but involvement of D2 and Ds receptors has been proposed.90 When an isolated seizure occurs, a dosage
reduction of the antipsychotic is first recommended, and routine prophylactic use of antiseizure medication is not recommended. Although spontaneously occurring seizures have been reported with most
antipsychotics, the highest potential risk for an antipsychotic­related seizure is with clozapine or chlorpromazine. If a change in antipsychotic therapy is required because of a medication­induced seizure,
aripiprazole, risperidone, thioridazine, haloperidol, pimozide, trifluoperazine, and fluphenazine are associated with the lowest potential.90

Thermoregulation
Poikilothermia, the body temperature adjusting to the ambient temperature, can be a serious adverse reaction in temperature extremes.118 Hyperpyrexia can be a danger in hot weather or during exercise.
Additionally, inhibition of sweating, a result of anticholinergic properties impairing the peripheral mechanisms of heat dissipation can contribute to this problem, which in its severest form can lead to heat stroke.
Hypothermia is a risk in cold temperatures, particularly in older adults. All patients receiving antipsychotics should be educated about these potential problems. Thermoregulatory problems are reportedly more
common with the use of low­potency FGAs, but can occur with the more anticholinergic SGAs.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) occurs in <1% of patients and is reported with both FGAs and SGAs, with the highest incidence occurring with high­potency FGAs.90 High antipsychotic doses, rapid parenteral
administration, use of multiple antipsychotics, previous history of NMS, dehydration, physical restraints, and older age all increase the risk.90 Symptoms are most likely to occur within the first week of antipsychotic
initiation and develop rapidly over the course of 24 to 72 hours. The mortality rates associated with NMS is high at approximately 10%, with premorbid dehydration elevating the risk of mortality.

Possible mechanisms of NMS include disruption of the central thermoregulatory processes or excess production of heat secondary to skeletal muscle contractions, including the involvement of proinflammatory
cytokines.
Downloaded Regardless of the mechanism,
2022­10­24 the differential
3:41 P Yourdiagnoses for NMS include: heat stroke, lethal catatonia, malignant hyperthermia, anticholinergic toxicity, and serotonin toxicity. The cardinal signs and
IP is 41.233.255.202
symptoms of NMS are body temperature exceeding 38°C (100.4°F) on at least two occasions, mental status changes, autonomic instability (tachycardia, blood pressure, diaphoresis, tachypnea, or urinary or fecal
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 22 / 48
incontinence), and rigidity.119 Laboratory evaluation, although nonspecific, frequently shows leukocytosis with or without a left shift, and increases in creatine kinase, aspartate aminotransferase, alanine
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
aminotransferase, lactate dehydrogenase, and myoglobinuria.118,119 Importantly, NMS treatment should begin with antipsychotic discontinuation and supportive care (eg, IV fluid hydration and benzodiazepines).
Dantrolene, bromocriptine, or amantadine may be useful in severe cases as all three agents have reports of reduced time to clinical improvement and reduction in mortality rates.118
 Birzeit University
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initiation and develop rapidly over the course of 24 to 72 hours. The mortality rates associated with NMS is high at approximately 10%, with premorbid dehydration elevating the risk of mortality.

Possible mechanisms of NMS include disruption of the central thermoregulatory processes or excess production of heat secondary to skeletal muscle contractions, including the involvement of proinflammatory
cytokines. Regardless of the mechanism, the differential diagnoses for NMS include: heat stroke, lethal catatonia, malignant hyperthermia, anticholinergic toxicity, and serotonin toxicity. The cardinal signs and
symptoms of NMS are body temperature exceeding 38°C (100.4°F) on at least two occasions, mental status changes, autonomic instability (tachycardia, blood pressure, diaphoresis, tachypnea, or urinary or fecal
incontinence), and rigidity.119 Laboratory evaluation, although nonspecific, frequently shows leukocytosis with or without a left shift, and increases in creatine kinase, aspartate aminotransferase, alanine
aminotransferase, lactate dehydrogenase, and myoglobinuria.118,119 Importantly, NMS treatment should begin with antipsychotic discontinuation and supportive care (eg, IV fluid hydration and benzodiazepines).
Dantrolene, bromocriptine, or amantadine may be useful in severe cases as all three agents have reports of reduced time to clinical improvement and reduction in mortality rates.118

Many patients with schizophrenia, despite having had NMS, will require future antipsychotic pharmacotherapy. The literature suggests that the risk of rechallenge is acceptable in most patients, provided that the
patient is observed for an extended period of time (2 weeks or more is suggested) without antipsychotics, that there is careful monitoring, slow dose titration, and that the patient is maintained on the lowest possible
dose.118,119 A different antipsychotic, an SGA or a low­potency FGA, should be used for rechallenge following an episode of NMS.

Psychiatric Adverse Medication Reactions

Aripiprazole has been associated with impulse control disorders, including pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating and other intense urges. This led to
an FDA safety announcement in 2016 and subsequent update to the warnings in the package labeling for all aripiprazole products.120 Mechanistically the D2 partial agonist activity and possible D3 receptor activity

seen with aripiprazole have been implicated as potential pathways for these reactions.120 Clinicians are encouraged to monitor for changes in impulse control behaviors and reduce the dose or stop aripiprazole
should urges develop or worsen.

Ophthalmologic Effects

Anticholinergic effects of antipsychotics or concomitant antiparkinson medications can exacerbate narrow­angle (angle­closure) glaucoma. Therefore, antipsychotics with low anticholinergic effects should be used
in such individuals, and they should be appropriately monitored.121

Opaque deposits in the cornea and lens can occur with chronic phenothiazine treatment, with this adverse event occurring most frequently with chlorpromazine. Although visual acuity is not usually affected, periodic
ophthalmologic examinations are frequently recommended in patients receiving long­term treatment with phenothiazines, as fully formed cataracts are possible.121

Because of cataract development and lenticular changes in animals, baseline and periodic eye examinations are recommended in quetiapine product labeling. However, effect of quetiapine on lens opacity was found
to be no different than risperidone in a 2­year comparative trial.122 Lastly, retinitis pigmentosa can result from use of thioridazine doses greater than 800 mg daily, due to melanin deposits that can result in
permanent visual impairment or blindness.

Genitourinary System

Urinary hesitancy and retention, secondary to antipsychotic anticholinergic effects are reported with low­potency FGAs and with clozapine; those with benign prostatic hypertrophy are especially prone to this
effect.90 Reducing the antipsychotic dose or switching to an antipsychotic with less anticholinergic activity may help. Alternatively, bethanecol can be used to treat antipsychotic­induced urinary hesitancy and
retention.

Urinary incontinence is thought to be caused by α­blockade, and among the SGAs, it appears to be particularly problematic with clozapine.90 The incidence has been reported to be as high as 44%, and it can be
persistent in 25% of patients. Female sex and previous urinary incontinence can be risk factors for developing incontinence.90

Although inadequately studied, multiple mechanisms are likely responsible for sexual dysfunction seen with antipsychotic use, including dopaminergic blockade, hyperprolactinemia, histaminergic blockade,
anticholinergic effects, and α­adrenergic blockade. However, unmedicated individuals with schizophrenia also report decreased libido. Most, but not all, studies show a relationship between hyperprolactinemia and
sexual dysfunction, including decreased libido, erectile dysfunction, difficulty achieving orgasm, and ejaculatory abnormalities. Risperidone and paliperidone produce at least as much sexual dysfunction as FGAs,
while other SGAs, with weak effects on prolactin, produce less sexual dysfunction. Patients experiencing sexual dysfunction with FGAs or risperidone or paliperidone should be switched to an SGA with less effect on
prolactin.123

Priapism, a sustained and painful erection that is unprovoked and persists for longer than an hour, is increasingly reported with antipsychotic medication use. This is believed to occur because of α1­adrenergic

receptor blockade, leading to intracavernosal blood stasis.124 This can evolve into a urologic emergency, due to the ischemic nature of the priapism, and as such patients experiencing this adverse event require
emergency treatment. If left untreated, priapism may lead to permanent impotence.

Hematologic System

Transient leukopenia can occur during initial treatment with antipsychotics; however, it typically does not progress to be clinically significant.125 Agranulocytosis reportedly occurs in 0.01% of patients receiving FGAs,
and more frequently with chlorpromazine and thioridazine. The three antipsychotics with the highest relative risk for neutropenia in rank order are clozapine, chlorpromazine, and olanzapine.125 The onset is usually
within the first 8 weeks of therapy. If the absolute neutrophil count (ANC) is less than 500/µL (0.5 × 109/L), the antipsychotic should be discontinued and the ANC monitored closely until it returns to normal and the
patient monitored for the development of secondary infections. Agranulocytosis can initially manifest as a local infection, with sore throat, leukoplakia, erythema, and ulcerations of the pharynx. These symptoms in
any patient receiving antipsychotics should signal the immediate need for an ANC. Additionally, isolated rare cases of thrombocytopenia and eosinophilia have been reported.

Agranulocytosis with clozapine has significantly inhibited use of this agent, and it is only available in the United States through the Clozapine REMS Program.32 The risk of developing neutropenia or agranulocytosis
with clozapine is approximately 3% and 0.8%, respectively,124 and most cases occur between 6 weeks and 6 months. The baseline ANC must be at least 1,500/µL (1.5 × 109/L) to start clozapine, and weekly ANC
monitoring for the first 6 months of therapy is mandated in the FDA­approved product labeling. After this time, if the patient’s ANC remains greater than 1,500/µL (1.5 × 109/L), the labeling allows monitoring to be
decreased to every 2 weeks for the next 6 months. After this, monitoring can be decreased to monthly if all ANCs remain greater than 1,500/µL (1.5 × 109/L). If at any time the ANC drops to less than 500/µL (0.5 × 109/L),
clozapine must be discontinued and the ANC monitored daily until it is greater than 1,500/µL (1.5 × 109/L). The FDA­approved product labeling should be consulted for more detailed information regarding ANC
monitoring, including monitoring for mild and moderate leukopenia and recommendations for patients with benign ethnic neutropenia.32

Dermatologic System

Allergic reactions are rare and usually occur within 8 weeks of initiating therapy, manifesting as maculopapular, erythematous, pruritic rashes that are evident on the face, neck, trunk, or extremities. Contact
dermatitis, including the oral mucosa, has been reported in patients and medical personnel exposed to FGA liquid formulations. The risk of oral mucosal reactions can be decreased by mixing the FGA concentrate in
a sufficient quantity of a nonacidic liquid and swallowing it quickly. Care should be taken in the handling and preparation of liquid FGAs. Ziprasidone’s FDA­approved label contains a warning regarding the risk of a
rare but fatal skin reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).126

Phenothiazines can absorb ultraviolet light, resulting in the formation of free radicals, which can have damaging effects on the skin. All antipsychotics can cause photosensitivity resulting in erythema and sunburn;
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therefore, exposure to sunlight should be limited, and patients should be educated about the use of a maximally blocking sunscreen, hats, protective clothing, and sunglasses.125
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 23 / 48
Blue­gray
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purplish skin coloration
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Use •receiving
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• Notice phenothiazines during long­term administration, especially with chlorpromazine. This
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adverse event commonly occurs with concurrent corneal or lens pigmentation.

Miscellaneous Adverse Effects

Dermatologic System

Birzeit University
Allergic reactions are rare and usually occur within 8 weeks of initiating therapy, manifesting as maculopapular, erythematous, pruritic rashes that are evident on the face, neck, trunk, or extremities. Contact
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dermatitis, including the oral mucosa, has been reported in patients and medical personnel exposed to FGA liquid formulations. The risk of oral mucosal reactions can be decreased by mixing the FGA concentrate in
a sufficient quantity of a nonacidic liquid and swallowing it quickly. Care should be taken in the handling and preparation of liquid FGAs. Ziprasidone’s FDA­approved label contains a warning regarding the risk of a
rare but fatal skin reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).126

Phenothiazines can absorb ultraviolet light, resulting in the formation of free radicals, which can have damaging effects on the skin. All antipsychotics can cause photosensitivity resulting in erythema and sunburn;
therefore, exposure to sunlight should be limited, and patients should be educated about the use of a maximally blocking sunscreen, hats, protective clothing, and sunglasses.125

Blue­gray or purplish skin coloration in areas exposed to sunlight occurs in patients receiving higher doses of low­potency phenothiazines during long­term administration, especially with chlorpromazine. This
adverse event commonly occurs with concurrent corneal or lens pigmentation.

Miscellaneous Adverse Effects

Clozapine­induced sialorrhea (drooling), which is typically prominent at night,125 affects up to 54% of patients receiving clozapine. The mechanism behind this drooling is unclear; however, two theories exist. The
first involves muscarinic receptor activity and clozapine’s imbalanced binding affinity to this receptor. The other involves clozapine’s α­antagonist activity at the salivary glands leaving unopposed beta­receptor
stimulation and hence hyper­salivation.125 Anticholinergics such as benztropine and atropine, and α­agonists such as clonidine have been used to treat clozapine­related sialorrhea.127

Use in Pregnancy and Lactation

The reproductive health of females with schizophrenia has historically received little attention from clinicians or researchers, partly due to reports of lower fertility rates in individuals with schizophrenia. However,
with the introduction of more prolactin sparing SGAs (exceptions being risperidone and paliperidone), fertility rates in schizophrenia are increasing.128 While data on the safety of antipsychotic medication use during
pregnancy and lactation are limited, greater than 50% of individuals with schizophrenia who discontinue their medication will experience relapse.129 Additionally, pregnant individuals with untreated schizophrenia
are more likely to use alcohol, tobacco and other substances and are less likely to engage in prenatal care visits.127 Therefore, these factors may put pregnant individuals and their offspring at greater risk,
outweighing any potential risks associated with antipsychotic use.

The risk of teratogenesis with FGAs has not been sufficiently studied, and a specific pattern of teratogenicity has not been found.130,131 The use of phenothiazines and low dose haloperidol to treat hyperemesis
gravidarum provide additional reassurance that FGAs are not major teratogens.132 Haloperidol is the best studied FGA with approximately 400 reported exposures.127 With regard to labor and delivery complications,
one small study found greater than a two­fold elevated risk of preterm birth in pregnant individuals with schizophrenia taking FGAs as compared with those not taking antipsychotics, but did not find an association
between FGA exposure and low birth weight or small for gestational age.133 A major limitation in interpreting this study are the confounding variables such as disease severity, concurrent substance use or other
concurrent medications that were not addressed.

Data regarding the safety of SGAs in pregnancy are rapidly increasing but also limited. All SGAs cross the blood­placenta barrier, but to varying degrees. In one study sample, the highest rates of transfer were for
olanzapine (72.1%), followed by haloperidol (65.5%) and risperidone (49.2%), with quetiapine being the lowest (24.1%).134 Among the SGAs, safety data are most abundant for olanzapine, quetiapine, aripiprazole,
and risperidone. As a class, SGAs are not thought to be major teratogens. Results from the largest database study to date (9,258 pregnant females with SGA exposure in the first trimester) suggest that the SGAs
aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone collectively do not increase the risk of congenital malformations or cardiac malformation. This finding held true when evaluating each agent
individually, except for a small, but statistically significant increase of congenital malformations with risperidone (RR, 1.26; 95% CI, 1.02­1.56).135­138 A meta­analysis of 12 studies (which did not include the previous
study) found a greater risk of congenital malformations with SGA exposure in early pregnancy, but no specific abnormality was identified. In this same study, an increased risk of preterm birth was present in the SGA­
treated group. However, healthy females composed the control group in these studies, and the underlying disease state being treated with an SGA is an important confounder.139 Data on pregnancy exposure with the
newer SGAs (eg, asenapine, lurasidone, brexpiprazole, lumateperone, and cariprazine) are minimal or absent. While large, well­controlled studies are still needed to determine the safety of all SGAs during
pregnancy, the British Association for Psychopharmacology Consensus Guidelines do not currently consider them major teratogens.127

The potential for antipsychotic related postnatal and gestational complications is of interest. Weight gain associated with SGAs and the potential risk of gestational diabetes should be considered in medication
selection. A systematic review that included 10 studies did not find an association between SGAs collectively and gestational diabetes.140 A retrospective cohort study reported an increased risk of gestational diabetes
in individuals who continued quetiapine or olanzapine during the first 20 weeks of pregnancy versus those who discontinued those agents.141 An increase risk was not observed with risperidone, aripiprazole, or
ziprasidone which indicates that risk may differ among SGAs.127 An increased risk of hypertension in individuals taking antipsychotics during pregnancy as well as venous thromboembolism have also been
reported.128

Risk of neonatal EPS is increased with in utero exposure to FGAs, with effects in the infant lasting for 3 to 12 months after birth. In 2011, the FDA issued a safety announcement informing healthcare professionals that
the pregnancy section of medication labels had been updated for the entire antipsychotic class, highlighting the potential risk for EPS and withdrawal symptoms in newborns exposed to antipsychotics in utero during
the third trimester.142 Symptoms of neonatal withdrawal reported to the FDA included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.

To date, little is known about in utero exposure to antipsychotics and neurodevelopmental teratology with most data being derived from case reports and case­series. One case­control study (n=76) reported a
transient delay in cognitive, motor, social­emotional, and adaptive behavior in SGA­exposed infants at 2 months of age that resolved by 12 months.143 One prospective study reported in utero exposure to
antipsychotics (n=22) was associated with lower neuromotor screening measures at 6 months of age compared to either antidepressant exposed infants or no psychotropic exposure.144 A population­based cohort
study of 411,251 children did not find an elevated risk of autism spectrum disorder or attention deficit hyperactivity disorder with in utero exposure to SGAs.145

For many individuals with schizophrenia, discontinuing the antipsychotic during pregnancy may not be recommended, despite the lack of safety data. The risk of antipsychotic use must be weighed against the
benefits of pharmacotherapy in pregnant individuals experiencing disorganized thoughts, delusions about change in body image or pregnancy, or who are unable to engage in prenatal care.133 A national pregnancy
exposure registry monitors pregnancy outcomes in those exposed to SGAs during pregnancy. Clinicians are encouraged to report SGA use in pregnancy through the registry to assist in gathering safety information.
This registry can be accessed at: http://womensmentalhealth.org/clinical­and­research­programs/pregnancyregistry/atypicalantipsychotic.

Data regarding the antipsychotics and human milk are even more limited than their use during pregnancy. Olanzapine is the most studied antipsychotic in lactation (n = 170 exposures), followed by quetiapine (n =
14), risperidone (n = 8), and aripiprazole (n = 4). Overall, olanzapine and quetiapine have reported relative infant doses (RIDs) of less than 2%, meaning that with continued exposure to human milk, infants would only
be exposed to 2% of maternal dosage overall.146 Risperidone (+ 9­OH­risperidone) and aripiprazole have reports of slightly higher RID ranges (2.8­9.1 and 0.7­8.3, respectively).146 Of note, treatment with aripiprazole
may lead to reduced milk production as a result of reduced prolactin release.147 Breastfeeding while on clozapine is not recommended due to the risk of severe neutropenia and seizures in the infant.127 For all of the
FGAs, the overall RID is thought to be less than 10%, which is a common threshold indicating that these medications are safe when feeding infants human milk.

Data evaluating long­term outcomes in infants exposed to antipsychotics through human milk are minimal to absent. The co­administration of chlorpromazine and haloperidol is reported to result in developmental
delays at 12 to 18 months of age; however, these were not controlled studies.127 Although most antipsychotics are not contraindicated in lactation, the lowest dosage for antipsychotics should be used, and the infant
carefully monitored for antipsychotic adverse events such as EPS, sedation, seizures, and developmental delays.127,146,147 Additional studies evaluating short­ and long­term adverse effects, including developmental
outcomes, of infants exposed to antipsychotics via human milk are warranted.

Medication Interactions

Most medication interactions occur because of pharmacodynamic or pharmacokinetic interactions (Tables 87­9 and 87­10). Common examples of pharmacodynamic interactions resulting in enhanced effect include
the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative adverse effects. Additive antimuscarinic effects can also be seen when antipsychotics are
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used with other medications possessing antimuscarinic effects, potentially resulting in urinary retention, constipation, blurred vision, or other anticholinergic adverse effects.148 Both combined sedative and
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 24 / 48
anticholinergic effects from multiple medications can result in impaired cognition or delirium, particularly in older adults and other patients predisposed to such problems.148 Patients are more likely to experience
©2022 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
symptomatic orthostatic hypotension when an antipsychotic is used with other medications that cause orthostasis. Metoclopramide, a DA antagonist, is prescribed for treating esophageal reflux or gastroparesis, and
patients may be more likely to experience akathisia and other EPS (including TD) if it is used concomitantly with antipsychotics.149 Although some selective serotonin reuptake inhibitors (SSRIs) can interact with
antipsychotics through enzyme inhibition, they can also interact through pharmacodynamic mechanisms. Since 5­HT2 receptors are present on the presynaptic dopaminergic neuron, their activation leads to
delays at 12 to 18 months of age; however, these were not controlled studies.127 Although most antipsychotics are not contraindicated in lactation, the lowest dosage for antipsychotics should be used, and the infant
Birzeitdevelopmental
carefully monitored for antipsychotic adverse events such as EPS, sedation, seizures, and developmental delays.127,146,147 Additional studies evaluating short­ and long­term adverse effects, including University
outcomes, of infants exposed to antipsychotics via human milk are warranted.
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Medication Interactions

Most medication interactions occur because of pharmacodynamic or pharmacokinetic interactions (Tables 87­9 and 87­10). Common examples of pharmacodynamic interactions resulting in enhanced effect include
the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative adverse effects. Additive antimuscarinic effects can also be seen when antipsychotics are
used with other medications possessing antimuscarinic effects, potentially resulting in urinary retention, constipation, blurred vision, or other anticholinergic adverse effects.148 Both combined sedative and
anticholinergic effects from multiple medications can result in impaired cognition or delirium, particularly in older adults and other patients predisposed to such problems.148 Patients are more likely to experience
symptomatic orthostatic hypotension when an antipsychotic is used with other medications that cause orthostasis. Metoclopramide, a DA antagonist, is prescribed for treating esophageal reflux or gastroparesis, and
patients may be more likely to experience akathisia and other EPS (including TD) if it is used concomitantly with antipsychotics.149 Although some selective serotonin reuptake inhibitors (SSRIs) can interact with
antipsychotics through enzyme inhibition, they can also interact through pharmacodynamic mechanisms. Since 5­HT2 receptors are present on the presynaptic dopaminergic neuron, their activation leads to
decreased DA release from the presynaptic terminal. Increased availability of 5­HT through the SSRI’s effect can activate these receptors, which in turn results in decreased DA release, and adds to the dopaminolytic
effects of antipsychotics.57 In the absence of enzyme inhibition, SSRIs can still precipitate akathisia or EPS when added to a patient stabilized on an antipsychotic. Several cases of serotonin syndrome have been
reported with SGAs used in combination with serotonergic agents, such as SSRIs or tramadol.57 Another potentially dangerous interaction can occur when medications that slow myocardial conduction, and thus
prolong the QTc interval, are used in combination with antipsychotics having the same effect.57 Careful monitoring should occur with medications that prolong the QTc interval, as well as when antipsychotics with
this effect are combined with diuretics.57

Food enhances the absorption of both ziprasidone and lurasidone, with the product labels noting a greater than twofold increase in bioavailability when the agents are given with food (Table 87­10). The exact
mechanism for the impact of food on absorption is not fully understood30,150 but simply doubling the dose in a fasted state will not necessarily double the level.150 Therefore, ziprasidone requires administration with
a 500 kcal (2,100 kJ) meal and 350 kcals (1,460 kJ) with lurasidone.30,150 Asenapine, on the other hand, requires that food and drink be avoided for at least 10 minutes after administration to reduce the chance of the
patient swallowing the medication instead of allowing for sublingual absorption, which as previously discussed, impacts bioavailability.28,66

TABLE 87­9
Common Potential Pharmacodynamic Interactions with Antipsychotic Medications

Mechanism of Interaction Examples of Interacting Drugs or Other Substances Clinical Effect

Muscarinic receptor blockade Anticholinergics Increased risk of anticholinergic adverse reactions

Benztropine
Diphenhydramine
Trihexyphenidyl

Additive or synergistic sedation Sedatives Anticholinergics Increased risk of sedation

Benzodiazepines Benztropine Lethargy
Concomitant AP Diphenhydramine Impaired cognition
Diphenhydramine Trihexyphenidyl Impaired psychomotor activity
Melatonin and melatonin agonists Mirtazapine Risk of accidents
Mirtazapine
Trazodone
TCAs
Hypnotics
Opiates

DA antagonist use for different indication Metoclopramide Increased risk of EPS

Cardiovascular interactions

QTc prolongation Amitriptyline Procainamide Increased risk of ECG changes and dysrhythmias
Clomipramine Quinidine
Imipramine
Citalopram
Fluorquinolone antibiotics

Electrolyte changes Diuretics Increased risk of ECG changes and dysrhythmias

Stimulation of presynaptic 5­HT receptors on DA neuron SSRIs Increased EPS

Sympatholytics: α­blockade decreases NE release Clonidine Increased hypotension

Methyldopa
Prazosin
Nitric oxide containing products

Increased DA receptor binding Antipsychotics Increased adverse medication reactions particularly EPS

DA, dopamine; ECG, electrocardiogram; EPS, extrapyramidal symptoms; 5­HT, serotonin; SSRI, serotonin selective reuptake inhibitor; TCAs, tricyclic antidepressants; NE, norepinephrine.

Data from References 27­30, 32, 37, 148, and 149.

TABLE 87­10
Common Potential Pharmacokinetic Interactions with Antipsychotic Medications

Substrate Antipsychotic and Mechanism of Interaction Interacting Medication or Substance Clinical Effect

Aripiprazole, brexpiprazole, cariprazine, and iloperidone

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Inhibition of AP 3:41
metabolism (CYP2D6, P Your IP is 41.233.255.202
CYP3A4) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley
Bupropion Ciprofloxacin Chlorpheniramine Page 25 / 48
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Clomipramine • Accessibility
Clarithromycin Cimetidine
Doxepin Erythromycin Cocaine
Duloxetine Fluconazole Diltiazem
Fluoxetine Ketoconazole Diphenhydramine
 TABLE 87­10
Common Potential Pharmacokinetic Interactions with Antipsychotic Medications Birzeit University
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Substrate Antipsychotic and Mechanism of Interaction Interacting Medication or Substance Clinical Effect

Aripiprazole, brexpiprazole, cariprazine, and iloperidone

Inhibition of AP metabolism (CYP2D6, CYP3A4) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Bupropion Ciprofloxacin Chlorpheniramine
Clomipramine Clarithromycin Cimetidine
Doxepin Erythromycin Cocaine
Duloxetine Fluconazole Diltiazem
Fluoxetine Ketoconazole Diphenhydramine
Fluvoxamine Itraconazole Cimetidine
Paroxetine Antipsychotics Grapefruit juice
Sertraline Asenapine Haloperidol
HIV protease inhibitors Chlorpromazine Hydroxyzine
Indinavir Haloperidol Methadone
Nelfinavir Perphenazine Quinidine
Ritonavir Thioridazine Ticlopidine
Verapamil

Induction of AP metabolism Antiseizure Medications Anti­infectives Herbals Decreased AP effect

Carbamazepine Rifampin St. John’s wort
Oxcarbazepine Miscellaneous
Phenobarbital Glucocorticoids
Phenytoin Modafinil

Asenapine

Inhibition of AP metabolism (CYP1A2) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Fluvoxamine Ciprofloxacin Amidarone
Fluroquinolones Cimetidine

Induction of AP metabolism Anti­infectives Miscellaneous Miscellaneous Decreased AP effect

Nafcillin Broccoli Insulin
Brussels sprouts Modafinil
Chargrilled meat Omeprazole
Smoking tobacco

NOTE: Eating food or drinking liquids within 10 minutes of asenapine sublingual administration will decrease bioavailability

Clozapine

Inhibition of AP metabolism (CYP3A4, CYP1A2, CYP2D6) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Fluoxetine Ciprofloxacin Amidarone
Fluvoxamine Clarithromycin Cimetidine
HIV protease inhibitors Erythromycin Diltiazem
Indinavir Fluconazole Grapefruit juice
Nelfinavir Fluroquinolones Haloperidol
Ritonavir Ketoconazole Ticlopidine
Itraconazole Verapamil
Nafcillin Cimetidine

Induction of AP metabolism Antiseizure Medications Miscellaneous Herbals Decreased AP effect

Carbamazepine Glucocorticoids St. John’s wort
Phenobarbital Insulin Anti­infectives
Phenytoin Modafinil Rifampin
Omeprazole
Smoking tobacco

Haloperidol

Inhibition of AP metabolism (CYP2D6, CYP3A4, CYP1A2) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Bupropion Ciprofloxacin Amiodarone
Doxepin Clarithromycin Chlorpheniramine
Duloxetine Erythromycin Cimetidine
Fluoxetine Fluoconazole Diltiazem
Fluvoxamine Fluoroquinolones Diphenhydramine
Paroxetine Ketoconazole Quinidine
Sertraline Itraconazole Diphenhydramine
HIV protease inhibitors Antipsychotics Cimetidine
Indinavir Chlorpromazine Grapefruit juice
Nelfinavir Perphenazine Hydroxyzine
Ritonavir Methadone
Sequinavir Quinidine
Verapamil

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Induction of AP metabolism Antiseizure Medications
3:41 P Your IP is 41.233.255.202 Anti­infectives Herbals Decreased AP effect
Carbamazepine Nafcillin St. John’s wort
Chapter 87: Schizophrenia, M. Lynn Crismon; Tawny L. Smith; Peter F. Buckley Page 26 / 48
Oxcarbazepine Rifampin Tobacco smoking
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Phenobarbital Miscellaneous
Phenytoin Broccoli
Brussels sprouts
 Sertraline Itraconazole Diphenhydramine
HIV protease inhibitors Antipsychotics Cimetidine
Indinavir Chlorpromazine Grapefruit juice Birzeit University
Nelfinavir Perphenazine Hydroxyzine Access Provided by:
Ritonavir Methadone
Sequinavir Quinidine
Verapamil

Induction of AP metabolism Antiseizure Medications Anti­infectives Herbals Decreased AP effect

Carbamazepine Nafcillin St. John’s wort
Oxcarbazepine Rifampin Tobacco smoking
Phenobarbital Miscellaneous
Phenytoin Broccoli
Brussels sprouts
Chargrilled meat
Glucocorticoids
Insulin
Modafinil
Omeprazole

Olanzapine

Inhibition of AP metabolism (CYP3A4 and CYP1A2) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Fluoxetine (norfluoxetine) Ciprofloxacin Amiodarone
Fluvoxamine Clarithromycin Cimetidine
HIV protease inhibitors Erythromycin Diltiazem
Indinavir Fluoconazole Cimetidine
Nelfinavir Fluoroquinolones Grapefruit juice
Ritonavir Ketoconazole Verapamil
Itraconazole

Induction of AP metabolism Antiseizure Medications Miscellaneous Herbals Decreased AP effect

Carbamazepine Broccoli St. John’s wort
Oxcarbazepine Brussels sprouts Smoking tobacco
Phenobarbital Chargrilled meat HIV protease inhibitors
Phenytoin Glucocorticoids Efavirenz
Anti­infectives Insulin Nevirapine
Nafcillin Modafinil
Rifampin Omeprazole

Paliperidone

The bioavailability of paliperidone is significantly increased when it is taken with food. Although this could increase paliperidone effect, including adverse effects, the clinical significance is undetermined. Only potent CYP3A4 (eg,
carbamazepine, rifampin, St. John’s wort) inducers appear to increase paliperidone metabolism and affect dose requirements.

Lurasidone, lumateperone, and quetiapine

Inhibition of AP metabolism (CYP3A4) Antidepressants Anti­infectives Miscellaneous Increased AP effect and risk of adverse medication reactions
Fluoxetine (norfluoxetine) Ciprofloxacin Amiodarone
Fluvoxamine Clarithromycin Cimetidine
Nefazodone Erythromycin Diltiazem
HIV protease inhibitors Fluoconazole Grapefruit juice
Indinavir Ketoconazole Verapamil
Nelfinavir Itraconazole
Ritonavir
Sequinavir

Induction of AP metabolism Antiseizure Medications Anti­infectives Herbals Decreased AP effect

Carbamazepine Rifampin St. John’s wort
Oxcarbazepine Miscellaneous HIV protease inhibitors
Phenobarbital Glucocorticoids Efavirenz
Phenytoin Modafinil Nevirapine

NOTE: Lurasidone AUC and Cmax increase by two­ and threefold when given with at least 350 calories (1,460 J) of food regardless of fat content.
NOTE: Lumateperone is metabolized through multiple different pathways, but interactions have been found with moderate to potent CYP3A4 inhibitors and a CYP3A4 inducer.

Perphenazine and risperidone

Inhibition of AP metabolism (CYP2D6) Antidepressants Miscellaneous Increased AP effect and risk of adverse medication reactions
Bupropion Amiodarone
Clomipramine Cimetidine
Doxepin Chlorpheniramine
Duloxetine Cocaine
Fluoxetine Diphenhydramine
Paroxetine Cimetidine
Sertraline Haloperidol
Antipsychotics Hydroxyzine
Chlorpromazine Methadone
Haloperidol (reduced haloperidol) Quinidine
Perphenazine
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Chapter 87:ofSchizophrenia,
Induction M. Lynn
AP metabolism (via CYP3A34, Crismon;
a minor pathway Tawny L.
for risperidone) Smith; Peter F. Buckley
Miscellaneous Anti­infectives Decreased AP effect Page 27 / 48
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Dexamethasone Rifampin• Accessibility

NOTE: Because risperidone’s metabolite formed through CYP2D6 metabolism is active (paliperidone), the clinical significance of pharmacokinetic interactions with risperidone is unclear.
 Duloxetine Cocaine
Fluoxetine Diphenhydramine
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Paroxetine Cimetidine
Sertraline Haloperidol Access Provided by:

Antipsychotics Hydroxyzine
Chlorpromazine Methadone
Haloperidol (reduced haloperidol) Quinidine
Perphenazine

Induction of AP metabolism (via CYP3A34, a minor pathway for risperidone) Miscellaneous Anti­infectives Decreased AP effect
Dexamethasone Rifampin

NOTE: Because risperidone’s metabolite formed through CYP2D6 metabolism is active (paliperidone), the clinical significance of pharmacokinetic interactions with risperidone is unclear.

Ziprasidone

The bioavailability of ziprasidone is increased twofold when it is taken with food. Consistent administration with food is recommended.

AP, antipsychotic; AUC, Area Under the Curve; Cmax, maximum plasma concentration.

Data from References 27­33, 57, and 148­150.

Asenapine inhibits CYP2D6, and is the only SGA that has been shown to significantly affect the pharmacokinetics of other medications.28 Table 87­6 lists the known major pathways involved in the metabolism of SGAs.
Risperidone is largely metabolized by CYP2D6 to its active metabolite, 9­OH­risperidone (paliperidone), which is thought to have a similar pharmacodynamic profile.57 Although paliperidone is primarily eliminated
renally unchanged, potent inducers of CYP3A4 can cause a potential need for dosage adjustment.57,66 For asenapine, CYP1A2 is the primary isoenzyme responsible for metabolism with CYP3A4 also being a significant
pathway.57,66

Based on current information, inhibitors of CYP1A2 have the greatest potential for causing interactions with clozapine and olanzapine, and some concern with asenapine.57 Examples include cimetidine, fluvoxamine,
and fluoroquinolone antibiotics (ie, ciprofloxacin) to varying degrees. To date, however, no serious inhibition interactions have been reported with olanzapine, which may be a result of olanzapine’s wide therapeutic
index; however, carbamazepine has been reported to increase olanzapine elimination by as much as 50%.57 Cigarette smoking is a potent inducer of CYP1A2, and one would expect lower mean olanzapine serum
concentrations in smokers compared with those in nonsmokers.

Because of the risk of seizures with higher clozapine tissue concentrations, interactions that inhibit clozapine’s metabolism are potentially significant. In particular, fluvoxamine increases clozapine serum
concentrations by an average of two­ to threefold and up to fivefold.57 Ciprofloxacin, other fluroquinolones, fluoxetine, and erythromycin can also increase clozapine serum concentrations.57 As smoking has been
associated with a 33% to 55% increase in clozapine clearance,57 smoking cessation can result in increased clozapine serum concentration that may increase the risk of seizures.66 Carbamazepine can also induce
clozapine metabolism and lead to lower serum concentrations.57

A study with the potent CYP3A4 inhibitor ketoconazole showed minimal effects on ziprasidone single­dose pharmacokinetics, with only a 33% mean increase in the ziprasidone area under the time­versus­
concentration curve.57 These results are consistent with data suggesting that aldehyde oxidase is the major metabolic pathway for ziprasidone, with only 30% to 35% being metabolized by CYP3A4.57

Modest elevations of aripiprazole serum concentrations occur in the presence of ketoconazole or quinidine, which inhibit CYP3A4 and 2D6, respectively. Ketoconazole has a profound effect on decreasing lurasidone
metabolism, and it is recommended that they not be used concomitantly.30,57 Carbamazepine has been reported to decrease aripiprazole serum concentrations.57

Since iloperidone is metabolized through CYP2D6 and 3A4, its clearance can be impaired by inhibitors of these pathways. These types of interactions have the potential to be clinically significant. For example, it is
recommended that the iloperidone dose be decreased by 50% when used with CYP2D6 inhibitors such as fluoxetine or paroxetine.27,57

Multiple enzymes are responsible for the metabolism of lumateperone. AKR1C1 is the predominant enzyme metabolizing lumateperone to the alcohol metabolite IC200131.151 Multiple other enzymes are involved in
its metabolism including CYP3A4. Dosage adjustments should occur in patients taking moderate to strong CYP3A4 inhibitors or inducers.33

Personalized Pharmacotherapy

Pharmacotherapy must be individualized for each person with schizophrenia. Apart from iloperidone, no laboratory tests are generally available that will predict a patient’s response to treatment. Past response to
treatment, potential adverse effects, patient personal preference, and medication price are the primary variables that should be used in selecting an antipsychotic that is included in stages 1A, 1B, or 2 of the treatment
algorithm. In the CATIE study, the number one reason for medication discontinuation was the patient not wanting to take that medication any more, and the second most common reason was adverse effects.17 These
two factors should be carefully considered in antipsychotic selection and medication dosage must be individualized within the usual dose ranges. Careful consideration must also be given to concomitant
medications that may interact with the antipsychotic and necessitate a change in dosage.

Preliminary data suggest a relationship between different genetic markers and clinical improvement as well as QTc prolongation in patients treated with iloperidone.27,64 Substantial interest exists regarding the
potential utility of pharmacogenetic monitoring in the pharmacotherapy of schizophrenia. Increasing relationships are being identified between specific genetic variation in relation to both the pharmacodynamics
and pharmacokinetics of different antipsychotics. However, no convincing data have demonstrated that clinical outcomes are superior when using routine pharmacogenetic monitoring in the pharmacotherapy of
schizophrenia, nor have cost­effectiveness studies of its use been performed.64,65 Although promising for the future, routine pharmacogenetic monitoring in all patients with schizophrenia is not currently
recommended. However, it may be useful in select patients. For example, if a patient appears particularly sensitive to developing EPS when treated with antipsychotics metabolized through CYP2D6, it might be useful
to perform pharmacogenetic testing to determine whether the patient is a poor CYP2D6 metabolizer. If so, antipsychotics metabolized through CYP2D6 should be used at lower doses, or the patient switched to an
antipsychotic not metabolized by CYP2D6.64 Clinicians should consult accepted guidelines, such as those by the Clinical Pharmacogenetics Implementation Consortium (https://cpicpgx.org/), before utilizing
pharmacogenetic data.67

Given that no antipsychotic has proven superiority regarding efficacy in the treatment of schizophrenia (with the exception of clozapine in treatment resistance), cost should be a factor in antipsychotic selection.
Many antipsychotics have generic equivalents available, and this should be a factor in selecting an antipsychotic (Table 87­9).

Evaluation of Therapeutic Outcomes

Assessment of response has traditionally been done subjectively or empirically (a relative sense of how the clinician feels the patient is doing). A formal mental status exam (MSE) is used to structure the patient
interview and focus on items related to appearance, mood, sensorium, intellectual functioning, and thought processes. However, the MSE is neither specific nor quantitative for the measurement of medication
response. Clinicians should be trained to use simple, standardized psychiatric rating scales to assist in objectively rating patient medication responses.152 The Brief Psychiatric Rating Scale (BPRS) and the Positive and
Negative Syndrome Scale (PANSS) were developed for use in clinical trials as research tools to quantify symptom improvement seen with antipsychotic treatment (see Chapter e81). Objectively, a numeric indicator
(eg, 20%, 30%, or 40% reduction in BPRS score) has been used to quantify overall symptom reduction and classify patients according to different degrees of response. However, these types of rating scales are too
long and unwieldy to be routinely used within the time constraints of most clinical practices. Symptom scales used in clinical practice must be sufficiently brief to be used during an ordinary clinic visit (eg, 15­30
minutes) while measuring both positive and negative symptoms, and being sufficiently representative of overall symptomatology. The four­item Positive Symptom Rating Scale (PSRS) and the four­item Brief Negative
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scales P
thatYour IP criteria
meet such (Table 87­11).152 A brief rating scale of positive symptoms, such as the PSRS, should be used at baseline before starting pharmacotherapy, and at
is 41.233.255.202
each time response
Chapter to pharmacotherapyM.
87: Schizophrenia, is assessed.
Lynn Crismon;
Tawny L. Smith; Peter F. Buckley Page 28 / 48
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TABLE 87­11
Brief Clinical Assessments for Monitoring Antipsychotic Response in Schizophrenia
 Assessment of response has traditionally been done subjectively or empirically (a relative sense of how the clinician feels the patient is doing). A formal mental status exam (MSE) is used to structure the patient
Birzeit University
interview and focus on items related to appearance, mood, sensorium, intellectual functioning, and thought processes. However, the MSE is neither specific nor quantitative for the measurement of medication
Access
response. Clinicians should be trained to use simple, standardized psychiatric rating scales to assist in objectively rating patient medication responses.152 The Brief Psychiatric Rating Scale (BPRS) andProvided by: and
the Positive
Negative Syndrome Scale (PANSS) were developed for use in clinical trials as research tools to quantify symptom improvement seen with antipsychotic treatment (see Chapter e81). Objectively, a numeric indicator
(eg, 20%, 30%, or 40% reduction in BPRS score) has been used to quantify overall symptom reduction and classify patients according to different degrees of response. However, these types of rating scales are too
long and unwieldy to be routinely used within the time constraints of most clinical practices. Symptom scales used in clinical practice must be sufficiently brief to be used during an ordinary clinic visit (eg, 15­30
minutes) while measuring both positive and negative symptoms, and being sufficiently representative of overall symptomatology. The four­item Positive Symptom Rating Scale (PSRS) and the four­item Brief Negative
Symptom Assessment (BNSA) are brief scales that meet such criteria (Table 87­11).152 A brief rating scale of positive symptoms, such as the PSRS, should be used at baseline before starting pharmacotherapy, and at
each time response to pharmacotherapy is assessed.

TABLE 87­11
Brief Clinical Assessments for Monitoring Antipsychotic Response in Schizophrenia

Four­Item Positive Symptom Rating Scale (PSRS)

Use each item’s anchor points to rate the patient

1. Suspiciousness NA 1 2 3 4 5 6 7

2. Unusual thought content NA 1 2 3 4 5 6 7

3. Hallucinations NA 1 2 3 4 5 6 7

4. Conceptual disorganization NA 1 2 3 4 5 6 7

Each item is scored from 1 (not present) to 7 (extremely severe) SCORE:

Brief Negative Symptom Assessment (BNSA)

Use each item’s anchor points to rate the patient

1. Prolonged time to respond 1 2 3 4 5 6

2. Emotion: Unchanging facial expression, blank, expressionless face 1 2 3 4 5 6

3. Reduced social drive 1 2 3 4 5 6

4. Poor grooming and hygiene 1 2 3 4 5 6

Each item is scored from 1 (normal) to 6 (severe) SCORE:

aNA, not able to be assessed.

Data from Reference 152.

Similarly, the pharmacotherapeutic plan should include specific monitoring parameters for adverse medication reactions (Table 87­12). The plan should include how the potential reactions will be evaluated, and the
frequency of assessment. Given the risk of weight gain, diabetes, and lipid abnormalities associated with many of the SGAs, a consensus task force led by the American Diabetes Association recommends the following
baseline parameters before beginning antipsychotics: family history, weight, height, BMI, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.83 They also recommend follow­up
monitoring of these parameters after beginning or changing SGAs. Weight should be monitored monthly for the first 3 months and quarterly thereafter. The other parameters should be assessed at the end of 3
months, and if normal, then at least annually. Self­assessments can be a useful adjunct in treating the patient. Although the patient with schizophrenia may not always be accurate in evaluating symptom severity, the
use of patient self­assessments increases patient engagement in care, enhances therapeutic alliance, and gives the clinician an opportunity to identify misconceptions the patient may have regarding symptoms
associated with the illness, adverse medication reactions, and the like.55 Traditionally, clinicians have often accepted partial symptom response in schizophrenia as success, and have not been aggressive in
attempting to achieve greater symptomatic remission. The advent of multiple different SGAs with varying tolerability profiles should encourage clinicians to be more assertive in attempting to achieve symptom
remission. This is consistent with an increasing focus on remission as a goal of treatment and the evolving emphasis on consumerism in the care of patients with severe mental illness.54

TABLE 87­12
Antipsychotic Adverse Reactions and Monitoring Parameters

Adverse Reaction Monitoring Parameter Frequency Comments

Adverse Reaction Monitoring Parameters for All Antipsychotic Medications

Akathisia Ask about restlessness or anxiety. Observe patient for restlessness. Barnes Akathisia Scale can also be used Every visit

Anticholinergic Ask patient about constipation, blurry vision, urinary retention, or unusual dry mouth Every visit
adverse effects

Glucose intolerance FBS or HbA1c At baseline, after 3

months, and if normal,
then annually

Hyperlipidemia Lipid profile At baseline, after 3

months, and if normal,
then annually

Orthostatic Ask patient about dizziness on standing. If present, check BP and HR in sitting and standing positions Every visit The degree of orthostatic change in BP to
hypotension produce symptoms varies. In general, a BP
change of 20 mm Hg or more is significant
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Chapter 87: Schizophrenia,
Hyperprolactinemia M.about
In females, ask Lynn Crismon;
expression Tawny
of milk from L.and
the breast Smith; Peter
menstrual F. Buckley
irregularities. In males, ask about breast Every visit In the absence of symptoms,Page
there is 29
no / 48
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All Rights Reserved.
or expression Terms
of milk from nipples. of Use • present,
If symptoms Privacy checkPolicy • Notice
serum prolactin level • Accessibility need to monitor serum prolactin

Sedation Ask patient about unusual sedation or sleepiness Every visit

monitoring of these parameters after beginning or changing SGAs. Weight should be monitored monthly for the first 3 months and quarterly thereafter. The other parameters should be assessed at the end of 3
months, and if normal, then at least annually. Self­assessments can be a useful adjunct in treating the patient. Although the patient with schizophrenia may not always be accurate in evaluatingBirzeit
symptomUniversity
severity, the
use of patient self­assessments increases patient engagement in care, enhances therapeutic alliance, and gives the clinician an opportunity to identify misconceptions the patient may have regarding symptoms
Access Provided by:
associated with the illness, adverse medication reactions, and the like.55 Traditionally, clinicians have often accepted partial symptom response in schizophrenia as success, and have not been aggressive in
attempting to achieve greater symptomatic remission. The advent of multiple different SGAs with varying tolerability profiles should encourage clinicians to be more assertive in attempting to achieve symptom
remission. This is consistent with an increasing focus on remission as a goal of treatment and the evolving emphasis on consumerism in the care of patients with severe mental illness.54

TABLE 87­12
Antipsychotic Adverse Reactions and Monitoring Parameters

Adverse Reaction Monitoring Parameter Frequency Comments

Adverse Reaction Monitoring Parameters for All Antipsychotic Medications

Akathisia Ask about restlessness or anxiety. Observe patient for restlessness. Barnes Akathisia Scale can also be used Every visit

Anticholinergic Ask patient about constipation, blurry vision, urinary retention, or unusual dry mouth Every visit
adverse effects

Glucose intolerance FBS or HbA1c At baseline, after 3

months, and if normal,
then annually

Hyperlipidemia Lipid profile At baseline, after 3

months, and if normal,
then annually

Orthostatic Ask patient about dizziness on standing. If present, check BP and HR in sitting and standing positions Every visit The degree of orthostatic change in BP to
hypotension produce symptoms varies. In general, a BP
change of 20 mm Hg or more is significant

Hyperprolactinemia In females, ask about expression of milk from the breast and menstrual irregularities. In males, ask about breast Every visit In the absence of symptoms, there is no
enlargement or expression of milk from nipples. If symptoms present, check serum prolactin level need to monitor serum prolactin

Sedation Ask patient about unusual sedation or sleepiness Every visit

Sexual dysfunction Ask patient about decreased sexual desire, difficulty being aroused, or problems with orgasm Every visit Patients with schizophrenia have more
sexual dysfunction than the normal
population. Compare symptoms with
medication­free state

Tardive dyskinesia Standardized rating scale such as the AIMS or the DISCUS At baseline, and then
every 6 months for FGAs
and every 12 months for
SGAs

Weight gain Measure body weight, BMI, and waist circumference BMI every visit for 6 Waist circumference is the single best
months and at least predictor of cardiac morbidity
quarterly thereafter

Adverse Reaction Monitoring Parameters for Specific Antipsychotics

Agranulocytosis Absolute neutrophil counts (ANC) At baseline, weekly for 6 Clozapine only
months, then every 2
weeks for 6 months, and
then monthly

Sialorrhea or excess Ask patient about problems with excess drooling, waking in the morning with a wet ring on his or her pillow. Visual Every visit Clozapine only
drooling observation of the patient for drooling

Bronchospasm, Before administration, patients must be screened for a history of asthma, chronic obstructive pulmonary disease, or other Every dose Inhaled loxapine only. Can only be
respiratory distress, lung disease associated with bronchospasm. Monitor patient every 15 minutes for a minimum of 1 hour after medication administration administered in approved healthcare
respiratory administration for signs and symptoms of bronchospasm (ie, vital signs and chest auscultation). Only one 10­mg dose can be facilities registered in REMS program
depression, given every 24 hours
respiratory arrest

Post injection Observation of the patient for at least 3 hours after medication administration. Monitor for possible sedation, altered level of Every dose Long­acting olanzapine pamoate
sedation/delirium consciousness, coma, delirium, confusion, disorientation, agitation, anxiety, or other cognitive impairment administration monohydrate only. Can only be
syndrome administered in approved healthcare
facilities registered in REMS program

FBS, fasting blood sugar; AIMS, abnormal involuntary movement scale; DISCUS, dyskinesia identification system condensed user scale; FGA, first­generation antipsychotic; SGA, second­generation antipsychotic.

CONCLUSION
Schizophrenia is a neurodevelopmental disorder whose etiology is currently unknown. A multitude of medications, primarily working through dopamine, serotonin, and glutamatergic antagonism, have been
developed to treat symptoms associated with this syndrome. Although there is no cure for schizophrenia, lifelong antipsychotic use combined with comprehensive psychosocial services can allow many of these
individuals to function. However, medication adherence can be challenging, and the use of long­acting injectable antipsychotics combined with psychosocial services designed to address engagement with treatment
Downloaded
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medications have IP is 41.233.255.202
a multitude of potential adverse reactions, and prudent monitoring is necessary. As the common core symptoms associated with schizophrenia (positive,
Chapter
negative, and87: Schizophrenia,
cognitive) M.toLynn
vary among person Crismon;
person, TawnyofL.
continual evaluation Smith; outcomes
therapeutic Peter F.focusing
Buckleyon overall functioning and quality of life is necessary. Page 30 / 48
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ABBREVIATIONS
 FBS, fasting blood sugar; AIMS, abnormal involuntary movement scale; DISCUS, dyskinesia identification system condensed user scale; FGA, first­generation antipsychotic; SGA, second­generation antipsychotic.
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Access Provided by:
CONCLUSION
Schizophrenia is a neurodevelopmental disorder whose etiology is currently unknown. A multitude of medications, primarily working through dopamine, serotonin, and glutamatergic antagonism, have been
developed to treat symptoms associated with this syndrome. Although there is no cure for schizophrenia, lifelong antipsychotic use combined with comprehensive psychosocial services can allow many of these
individuals to function. However, medication adherence can be challenging, and the use of long­acting injectable antipsychotics combined with psychosocial services designed to address engagement with treatment
can promote adherence. Antipsychotic medications have a multitude of potential adverse reactions, and prudent monitoring is necessary. As the common core symptoms associated with schizophrenia (positive,
negative, and cognitive) vary among person to person, continual evaluation of therapeutic outcomes focusing on overall functioning and quality of life is necessary.

ABBREVIATIONS

α1 alpha one adrenergic receptor

α2 alpha two adrenergic receptor

AAN American Academy of Neurology

ACHIEVE Randomized Trial of Achieving Healthy Lifestyles in Psychiatric Rehabilitation

ACT active community treatment

ADTA2A adrenoreceptor alpha­2a

AIMS Abnormal Involuntary Movement Scale

AIWG antipsychotic­induced weight gain

ANC absolute neutrophil count

AP antipsychotic

APA American Psychiatric Association

ASP autism spectrum disorder

AUC area under the curve

β2 beta­2 adrenergic receptor

BDNF brain­derived neurotrophic factor

BLM buccal–lingual–masticatory

BMI body mass index

BP blood pressure

BNSA Brief Negative Symptom Assessment

BPRS Brief Psychiatric Rating Scale

C4 complement component 4 genes

CACN1A2 voltage­dependent calcium channel 1A2

CATIE Clinical Antipsychotic Trials of Intervention Effectiveness

CK creatine kinase

CNS central nervous system

CNV copy number variant

Cmax maximum plasma concentration

CRP C­reactive protein

CYP cytochrome P450

D1 dopamine­1 receptor

D2 dopamine­2 receptor

D3 dopamine­3 receptor

D4 dopamine­4 receptor

DA dopamine
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DISCUS87: Schizophrenia, M.Identification
Dyskinesia Lynn Crismon; Tawny
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User Smith; Peter F. Buckley Page 31 / 48
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DKA diabetic ketoacidosis

DRESS Drug Reaction with Eosinophilia and Systemic Symptoms

 D2 dopamine­2 receptor
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D4 dopamine­4 receptor

DA dopamine

DISCUS Dyskinesia Identification System: Condensed User Scale

DKA diabetic ketoacidosis

DRESS Drug Reaction with Eosinophilia and Systemic Symptoms

DSM­5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

ECG electrocardiogram or electrocardiographic

ECHO echocardiogram

ECT electroconvulsive therapy

EEG electroencephalogram

EF ejection fraction

EPS extrapyramidal side effect

FBS fasting blood sugar

FDA Food and Drug Administration

FGA first­generation antipsychotic

FMO3 flavin containing monooxygenase 3 gene

GABA gamma­aminobutyric acid

GNB3 guanine nucleotide binding protein

GWAS genome­wide association studies

HgA1c hemoglobin A1c

5­HT serotonin or 5­hydroxytryptamine

5­HT1A serotonin­1A receptor

5­HT2 serotonin­2 receptor

5­HT2A serotonin­2A receptor

5­HT2C serotonin­2C receptor

5­HT6 serotonin­6 receptor

5­HT7 serotonin­7 receptor

HR heart rate

ICD impulse control disorder

IM intramuscular

INSIG2 insulin­induced gene 2

IV intravenous

LAIA long­acting injectable antipsychotic

LBW low birth weight

MC4R melanocortin­4­receptor

1MPP 1­month paliperidone palmitate (Invega Sustenna®)

3MPP 3­month paliperidone palmitate (Invega Trinza®)

mRNA microribonucleic acid

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MSE mental status examination
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NAMI National Alliance on Mental Illness

NE norepinephrine
 MC4R melanocortin­4­receptor

1MPP
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1­month paliperidone palmitate (Invega Sustenna®)
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3MPP 3­month paliperidone palmitate (Invega Trinza®)

mRNA microribonucleic acid

MTHFR methylenetetrahydrofolate reductase

MSE mental status examination

NAMI National Alliance on Mental Illness

NE norepinephrine

NIMH National Institute of Mental Health

NMDA N­methyl­D­aspartate

NMS neuroleptic malignant syndrome

NRG1 neuregulin 1

NRXN1 synaptic protein neurexin 1

PANSS Positive and Negative Symptom Scale

PDSS post injection delirium/sedation syndrome

PET positron emission tomography

PORT Patient Outcomes Research Team

PSRS Positive Symptom Rating Scale

RAISE Recovery After Initial Schizophrenia Episode

REMS Risk Evaluation and Mitigation Strategy

RID relative infant dose

RNA ribonucleic acid

SCD sudden cardiac death

SEs side effects

SGA second­generation antipsychotic

SNP single nucleotide polymorphism

SSRI selective serotonin reuptake inhibitor

STRIDE Reducing Weight and Diabetes Risk in an Underserved Population

T2DM type 2 diabetes mellitus

TCA tricyclic antidepressant

TD tardive dyskinesia

UK United Kingdom

VMAT2 vesicular monoamine transporter­2

VTE venous thromboembolism

WBC white blood cell

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122.

2. Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull . 2018;44:1195–1203. [PubMed: 29762765]

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4. Price AJ, Jaffe AE, Weinberger DR. Cortical cellular diversity and development in schizophrenia. Mol Psychiatry . 2021;26(1):203–217. 10.1038/s41380­020­0775­8
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7. Arsalan A, Kowalec K. Genetic architecture of schizophrenia: a review of major advancements. Psychol Med. 2021;51(13):2168–2177. 10.1017/S0033291720005334
1. American Psychiatric Association. Schizophrenia spectrum and other psychotic disorders. In: Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA: American Psychiatric Association; 2013:87–
122. Birzeit University
Access Provided by:
2. Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull . 2018;44:1195–1203. [PubMed: 29762765]

3. Milan ML, Andrieux A, Bartzokis G, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov. 2016;15:485–515. [PubMed: 26939910]

4. Price AJ, Jaffe AE, Weinberger DR. Cortical cellular diversity and development in schizophrenia. Mol Psychiatry . 2021;26(1):203–217. 10.1038/s41380­020­0775­8
[PubMed: 32404946] .

5. Dalmau J, Graus F. Antibody­mediated encephalitis. N Engl J Med. 2018;378:840–851. [PubMed: 29490181]

6. Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental cognitive model. Lancet . 2014;383:1677–1687. [PubMed: 24315522]

7. Arsalan A, Kowalec K. Genetic architecture of schizophrenia: a review of major advancements. Psychol Med. 2021;51(13):2168–2177. 10.1017/S0033291720005334
[PubMed: 33550997] .

8. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature . 2016;530:177–183. doi: 10.1038/nature16549.

9. Cannon TD, Chung Y, He G, et al. North American Prodrome Longitudinal Study Consortium. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth
at elevated clinical risk. Biol Psychiatry . 2015;77(2):147–157. [PubMed: 25034946]

10. McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—an overview. JAMA Psychiatry . 2020;77(2):201–210. 10.1001/jamapsychiatry.2019.3360
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122. Laties AM, Flach AJ, Baldycheva I, et al. Cataractogenic potential of quetiapine versus risperidone in long­term treatment of patients with schizophrenia or schizoaffective disorder: a randomized open­label,
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125. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long­term treatment of
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127. Ben­Sheetrit J, Huller­Harari L, Rasner M, et al. Psychiatric disorders and compliance with prenatal care: a 10­year retrospective cohort compared to controls. Eur Psychiatry . 2018;49:23–29.
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129. Damkier P, Videnbech P. The safety of second­generation antipsychotics during pregnancy: a clinically focused review. CNS Drugs . 2018;32:351–366. [PubMed: 29637530]

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131. Huybrechts KF, Hernández­Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry . 2016;73(9):938–46. 10.1001/jamapsychiatry.2016.1520
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132. Arsenault MY, Lane CA, MacKinnon CJ, et al. 2002. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can , 24, 817­31; quiz 832­3

133. Lin HC, Chen IJ, Chen YH, et al. Maternal schizophrenia and pregnancy outcome: does the use of antipsychotics make a difference? Schizophr Res. 2010;116(1):55–60. [PubMed: 19896335]

134. Newport DJ, Calamaras MR, DeVane CL, et al. Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes. Am J Psychiatry . 2007;164(8):1214–20.
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135. Huybrechts KF, Hernandez­Diaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry . 2016;73:938–946. doi: 10.1001/jamapsychiatry.2016.1520.

136. Coughlin CG, Blackwell KA, Bartley C, et al. Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy. Obstet Gynecol. 2015;125(5):1224–1235. 10.1097/AOG.0000000000000759
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137. Ellfolk M, Leinonen MK, Gissler M, et al. Second­generation antipsychotic use during pregnancy and risk of congenital malformations. Eur J Clin Pharmacol. 2021;77(11):1737–1745. 10.1007/s00228­021­03169­y
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138. Viguera AC, Freeman MP, Góez­Mogollón L, et al. Reproductive safety of second­generation antipsychotics: updated data from the Massachusetts General Hospital National Pregnancy Registry for Atypical
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142. FDA Drug Safety Communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. U.S. Food and Drug
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143. Peng M, Gao K, Ding Y, et al. Effects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case­controlled, prospective study. Psychopharmacology (Berl) .
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146. Uguz F. Second generation antipsychotics during the lactation period. A comparative systematic review on infant safety. J Clin Psychopharmcol. 2016;36:244–252.
143. Peng M, Gao K, Ding Y, et al. Effects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case­controlled, prospective study. Psychopharmacology (Berl) .
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SELF­ASSESSMENT QUESTIONS
1. Which of the following is the most accurate statement regarding the potential etiology of schizophrenia?

A. Schizophrenia is likely caused by the affected individual having an oppressive mother during early childhood development.

B. Genetics studies suggest a Mendelian genetic relationship for developing schizophrenia.

C. PET studies indicate that schizophrenia is a degenerative brain disorder.

D. Schizophrenia may be caused by variety of genetic polymorphisms in combination with an environmental assault in utero.

2. A theory regarding the pathophysiology of schizophrenia suggests that the predrome phase of the illness is associated with

A. Excessive synthesis and release of serotonin from presynaptic receptors

B. Decreased density of D2 receptors in the mesocaudate

C. Glutamatergic synaptic dysfunction resulting in a glutamatergic signaling defect

D. Hyperactivity of gamma­amino­butyric acid (GABA) pathways

3. Symptom domains that are characteristic of a diagnosis of schizophrenia include all of the following except:

A. Cognitive impairment

B. Depression

C. Negative symptoms

D. Positive symptoms

4. The four core interventions that have been shown to improve the quality of life in individuals with early schizophrenia include all of the following except:

A. Family psychoeducation

B. Psychoanalysis

C. Resilience­focused individual therapy

D. Supported employment and education

5. Which of the following most accurately reflects the initial workup (ie, evaluation) of a patient suspected of having schizophrenia?

A. Mental status exam, physical exam, neurological exam, social history, laboratory workup, and PET scan

B. Mental status exam, physical exam, neurological exam, social history, laboratory workup, and MRI scan

C. Mental status exam, physical exam, neurological exam, social history, family history, and a CSF homovanillic acid (HVA) level

D. Mental status exam, physical exam, neurological exam, family history, social history, and laboratory workup

6. Based upon both efficacy and safety, which of the following are evidence­based first­line pharmacotherapy options in a patient experiencing the first psychotic episode associated with schizophrenia?

A. Aripiprazole, risperidone, and ziprasidone

B. Perphenazine, quetiapine, and risperidone

C. Haloperidol, olanzapine, and quetiapine

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D. Aripiprazole, lurasidone, and ziprasidone
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7. O.Y. is aMcGraw Hill.schizophrenia
27­year­old with All Rightsadmitted
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for their second of Use
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risperidone, the patient presents in an acute psychotic episode with fulminate suicidal ideation and a
serious suicide attempt prior to hospitalization. Based on this information, which of the following antipsychotics would be the best choice for this patient at the present time?

A. Clozapine
 D. Mental status exam, physical exam, neurological exam, family history, social history, and laboratory workup
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6. Based upon both efficacy and safety, which of the following are evidence­based first­line pharmacotherapy options in a patient experiencing the first psychotic episode associated with schizophrenia?
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A. Aripiprazole, risperidone, and ziprasidone

B. Perphenazine, quetiapine, and risperidone

C. Haloperidol, olanzapine, and quetiapine

D. Aripiprazole, lurasidone, and ziprasidone

7. O.Y. is a 27­year­old with schizophrenia admitted for their second psychiatric hospitalization. Treated with risperidone, the patient presents in an acute psychotic episode with fulminate suicidal ideation and a
serious suicide attempt prior to hospitalization. Based on this information, which of the following antipsychotics would be the best choice for this patient at the present time?

A. Clozapine

B. Haloperidol

C. Lurasidone

D. Risperidone

8. Which of the following are interventions that may increase the treatment adherence of individuals with schizophrenia?

A. Cognitive behavioral therapy

B. Involvement of families

C. Patient information about the disorder and treatment

D. All of the above may be helpful

9. B.W. is a 33­year­old with schizophrenia in an acute exacerbation who has had previous unsuccessful medication courses with risperidone and olanzapine. The risperidone was at a maximum dose of 6 mg/day for
6 months, and olanzapine was for a maximum dose of 20 mg daily for 9 months. Patient adherence with treatment was deemed to be adequate during the previous medication trials. Based on the available
information, which of the following is the most appropriate medication intervention at the present time?

A. Asenapine

B. Cariprazine

C. Clozapine

D. Lumateperone

10. The rapid on, rapid off theory of atypicality is best associated with which of the following antipsychotics?

A. Aripiprazole

B. Olanzapine

C. Quetiapine

D. Risperidone

11. C.H. is a 25­year­old with a diagnosis of schizophrenia previously treated with haloperidol and risperidone. Since starting risperidone, the patient has gained about 8 pounds and inquires about a change in
medication to an antipsychotic that is less likely to cause weight gain. Based on this request, which of the following would be the best choice?

A. Ziprasidone

B. Chlorpromazine

C. Clozapine

D. Olanzapine

12. J.B. is a 34­year­old with a diagnosis of schizophrenia previously treated with monotherapy trials of haloperidol, perphenazine, and fluphenazine decanoate. J.B. has had persistent difficulty with extrapyramidal
side effects, including parkinsonian symptoms and dystonic reactions. These symptoms have been treated with benztropine and diphenhydramine, but breakthrough EPS symptoms still occur. Which of the
following would be the poorest antipsychotic treatment option for this patient?

A. Risperidone

B. Olanzapine

C. Quetiapine

D. Brexpiprazole

13. B.C. is a 35­year­old with a diagnosis of schizophrenia. In the past, B.C. has taken haloperidol and risperidone and experienced parkinsonian symptoms on both of these medications. After taking olanzapine 15
mg daily for the past 6 months, B.C. presented to primary care for complaints of fatigue, excessive thirst, and frequent urination. Fasting blood glucose is 180 mg/dL (10.0 mmol/L). Although psychotic symptoms
are reasonably well controlled, the clinician deems that it is best to change antipsychotic medication. Based on the information above, which of the following would be the best choice?

A. Aripiprazole

B. Clozapine

C. Haloperidol

D. Quetiapine

14. D.D. is a 66­year­old with a diagnosis of schizophrenia, hypertension, and gastroesophageal reflux disorder (GERD) and medication regimen includes quetiapine, hydrochlorothiazide, metoclopramide, and
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D.D. hasPdeveloped
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a shuffling gait, drooling, and a resting tremor. In screening the patient’s profile, which of the following might represent a drug interaction?
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A. Ranitidine is inhibiting the metabolism of quetiapine, causing the patient to develop Parkinson’s symptoms.
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B. Hydrochlorothiazide alteration of quetiapine elimination in the kidneys is resulting in Parkinson’s symptoms.

C. Metoclopramide’s dopaminergic blockade in combination with quetiapine is producing Parkinson’s symptoms.

 A. Aripiprazole
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B. Clozapine
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C. Haloperidol

D. Quetiapine

14. D.D. is a 66­year­old with a diagnosis of schizophrenia, hypertension, and gastroesophageal reflux disorder (GERD) and medication regimen includes quetiapine, hydrochlorothiazide, metoclopramide, and
ranitidine. Over the past 3 months, D.D. has developed a shuffling gait, drooling, and a resting tremor. In screening the patient’s profile, which of the following might represent a drug interaction?

A. Ranitidine is inhibiting the metabolism of quetiapine, causing the patient to develop Parkinson’s symptoms.

B. Hydrochlorothiazide alteration of quetiapine elimination in the kidneys is resulting in Parkinson’s symptoms.

C. Metoclopramide’s dopaminergic blockade in combination with quetiapine is producing Parkinson’s symptoms.

D. Metoclopramide alteration of quetiapine metabolism is causing Parkinson’s symptoms.

15. After initiating a new antipsychotic in a patient with schizophrenia, appropriate routine monitoring parameters are best reflected by:

A. Brief standardized clinical rating scales, weight, blood pressure, waist circumference, blood glucose, serum lipids

B. Positive and Negative Symptom Rating Scale, weight, antipsychotic serum concentration, waist circumference, blood glucose, serum lipids

C. Brief standardized clinical rating scales, weight, blood pressure, blood glucose, serum lipids, electrocardiogram

D. Positive and Negative Symptom Rating Scale, weight, blood pressure, blood glucose, serum lipids, white blood cell count, electrocardiogram

SELF­ASSESSMENT QUESTION­ANSWERS
1. D . Schizophrenia is a neurodevelopmental disorder that is associated with genetic polymorphism of multiple different genes combined with an unknown environmental risk factor. The environmental risk likely
occurs in utero or in the perinatal period (see “Etiology” section).

2. C . The predrome phase is a high­risk period for the development of schizophrenia. Glutamatergic dysfunction may precede abnormalities in dopaminergic dysfunction. Glutamatergic dysfunction results in
decreased GABA activity (prodrome phase), and this results in decreased inhibition of dopaminergic transmission. The actual increase in dopaminergic transmission may be associated with onset of the first psychotic
episode (see “Pathophysiology” section).

3. B . Although depression is commonly seen in individuals with schizophrenia, it is not one of the core symptoms required for the diagnosis of the syndrome (see “Clinical Presentation” section).

4. B . Effective psychosocial interventions focus on improving the individuals’ ability to function on a daily basis, including methods to promote adherence with medication and other treatment regimens. Therapy is
typically focused on improving the person’s resilience, daily psychosocial functioning, and treatment adherence. However, cognitive therapy that focuses on the needs of a person with schizophrenia may be of
benefit. Classic psychoanalysis has no evidence to support its use in individuals with schizophrenia (see Table 87­4).

5. D . The initial workup for an individual suspected of having schizophrenia is focused on eliminating other potential causes of psychosis (eg, medical disorder, substance use), and establishing a baseline for medical
monitoring of the patient. The mental status and history focus on making sure that the clinical features are consistent with the DSM­5 criteria for schizophrenia. There are no laboratory tests or imagining studies that
are diagnostic for schizophrenia.

6. A . Aripiprazole, risperidone, and ziprasidone have all been studied during the initial or first episode of schizophrenia, and all have similar efficacy. The one study with quetiapine during the first episode showed a
higher relapse rate than in the studies with the other three medications. While olanzapine has good efficacy during the first episode, it has the highest incidence of weight gain and other metabolic side effects and is
not recommended for first episode. The other medications listed have not been studied during first episode (see Fig. 87­1).

7. A . The general recommendation is to use clozapine in a patient who has failed to have adequate improvement in symptoms after two adequate monotherapy trials (dose and duration) with other antipsychotics.
However, clozapine is the only antipsychotic that has evidence of decreasing suicide in highly suicidal patients, and its use is indicated earlier in treatment for treating suicidality associated with schizophrenia.
Clozapine would be the best choice for this particular patient (see Fig. 87­1).

8. D . All of the listed psychosocial interventions have evidence for improving treatment adherence in individuals with schizophrenia, and outcomes are thought to be better when they are used in combination.
Comprehensive psychosocial services in combination with appropriate medication are necessary to achieve the best clinical outcomes in persons with schizophrenia (see Table 87­4).

9. C . Clozapine is the only antipsychotic that has evidence for efficacy in individuals with “treatment­resistant schizophrenia.” Treatment resistance is most commonly defined as inadequate improvement in clinical
symptoms with adequate monotherapy trials (dose and duration) with two different antipsychotics.

10. C . All available antipsychotics bind to D2 receptors rapidly (rapid on). However, of available antipsychotics only clozapine and quetiapine have evidence for rapid disassociation from the D2 receptor (rapid off).
Based on this theory, only relatively brief binding to dopaminergic D2 receptors is necessary for antipsychotic effect while longer binding (slow off) is thought to be associated with greater risk of extrapyramidal side
effects. While there is some evidence in humans, utilizing PET scan technology, to support this theory, it is important to emphasize that it is still largely theoretical (see Table 87­5).

11. A . Of the listed antipsychotics, ziprasidone is associated with the least weight gain. Olanzapine causes the most weight gain, and both chlorpromazine and quetiapine are associated with more weight gain than
ziprasidone (see Table 87­7).

12. A . Of the second­generation antipsychotics listed, risperidone has the greatest risk of extrapyramidal side effects. The risk of EPS with risperidone is dose related, and at doses greater than 6 mg daily, risperidone
loses most of its atypical antipsychotic profile (see Table 87­7).

13. A . Patient B.C. is experiencing glucose intolerance, possibly associated with olanzapine. With a history of EPS with the use of haloperidol and risperidone, both of those medications would be a poor choice of
antipsychotics. B.C. does not appear to have treatment­resistant symptoms, and clozapine is also associated with significant weight gain and metabolic disturbances. Of the antipsychotics listed, aripiprazole has the
least risk of both causing EPS and producing metabolic disturbances.

14. E. Metoclopramide is a D2 receptor antagonist and can cause EPS, including pseudoparkinsonism. The risk of this is higher in older individuals. Since both metoclopramide and quetiapine have D2 receptor
antagonist properties, the two medications could have a pharmacodynamic additive effect increasing the risk for Parkinson’s symptoms. Given that there are a number of therapeutic alternatives available for treating
GERD, the use of metoclopramide should be avoided in older individuals and in combination with antipsychotics

15. A . The use of brief objective rating scales helps in evaluating clinical response to antipsychotics. In particular, brief rating scales can be useful in monitoring partial response and changes in symptoms with
changes in the pharmacological regimen. The other rating scales listed are longer rating scales primarily used in clinical research. Because of the effects of antipsychotics on weight and other metabolic parameters, it
is important to monitor weight, blood pressure, waist circumference, blood glucose, serum lipids. These parameters need to be monitored at baseline before starting medications, as well as periodically after
medications are started. If base line monitoring parameters are not obtained, it is challenging to determine whether changes are drug related (see Table 87­11).

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GERD, the use of metoclopramide should be avoided in older individuals and in combination with antipsychotics
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15. A . The use of brief objective rating scales helps in evaluating clinical response to antipsychotics. In particular, brief rating scales can be useful in monitoring partial response and changes in symptoms with
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changes in the pharmacological regimen. The other rating scales listed are longer rating scales primarily used in clinical research. Because of the effects of antipsychotics on weight and other metabolic by: it
parameters,
is important to monitor weight, blood pressure, waist circumference, blood glucose, serum lipids. These parameters need to be monitored at baseline before starting medications, as well as periodically after
medications are started. If base line monitoring parameters are not obtained, it is challenging to determine whether changes are drug related (see Table 87­11).

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