DRUG TREATMENT OF
PSYCHOSIS
Psychiatric illness
Psychosis Neurosis
OCD
Schizophrenia
Phobia
Anxiety
Mania Depression Bipolar
PTSD
Psychosis: Pt is not aware of illness and refers to treatment
Neurosis: Less serious and insight present
(Obsessive compulsive disorder, Post traumatic stress disorder)
Psychosis
• Psychosis is a thought disorder
characterized by :
• Disturbances of reality and perception
• Impaired cognitive functioning
• Inappropriate or diminished affect (mood)
• Psychosis denotes many mental disorders.
Schizophrenia is a type of functional
psychosis in which severe personality changes
and thought disorders
• Earlier: termed as major tranquilizers
• USA: Antipsychotics
• Europe: Neuroleptics (both antipsyo + EPS)
Schizophrenia
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens early
twenties.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.
Schizophrenia
• It is a thought disorder.
• The disorder is characterized by a divorcement from
reality in the mind of the person (psychosis).
• Symptoms positive or negative.
• Positive:
– visual and auditory hallucinations
– Delusions
– Thought disorders
– Irrational conclusions
– Control by external forces (paranoia),
• Negative
– Poor socialization
– Emotional blunting
– Introvert behaviour
– Lack of motivation
– Congnitive deficits (lack of attention and loss of memory)
Psychosis Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
Role of DA in psychosis
• Positron emission tomographic (PES) DA receptor density
• Postmortem DA density
• Inc DA by L Dopa , Amphetamine, Apomorphin precipitate
the symptoms
• Most antipsychotic drugs blocking D2 in CNS Mesolimbic,
frontal
• Inc Homovalinic acid (HVA)
• Drug should absolutely rather then partially, ineffective
Central Dopaminergic pathway
• Ultra short Periglomular cells in olfactory bulb
• Intermediate Ventral hypothalamus role in
prolactin release, Hypothalamic-hypophyseal functions
• Long : most IMP. Cover SN, Ventral Tegmental areas to
Limbic system, amygdala, Caudate, Putamen
Parkinson’s dec. DA in
basal ganglia
Scizopherenia Over activity
of DA in Mesolimbic
Mesocortical Mesofrontal
There are four major pathways for the dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway: Voluntary movements
II. The Mesolimbic Pathway.: Behaviour
III. The Mesocortical Pathway: Behaviour
IV. The Tuberoinfundibular Pathway: Prolactin release
• 5HT2 agonist visual hallucinations and
sensory disturbance , which are similar to
psychosis
• 5HT has a modulator role on DA pathway
• After has fall off because
• 5HT Visual
• Schizo Auditory predominate
Glutamate
• Glutamate exerts excitatory, while DA exerts inhibitory role
over GABA ergic striatal neurons which projects to thalamus
and serves as sensory gate.
• Inc Glu, or Dec DA disturbed the Gate t allow uninhibited
sensory inputs to cortex.
• Hallucination and thought disorders.
Tyrosine
Dopamine Synapse
Tyrosine
L-DOPA
DA
Antipsychotic treatments
In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly
were adopted by psychiatrists to calm down their
mental patients.
In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhone-Pauline Laboratories
in France.
In-patients at Mental Hospitals dropped by 1/3.
Antipsychotic/Neuroleptics
OLDER DRUGS
Three major groups :
1. Phenothiazines
2. Thioxanthine
3. Butyrophenones
Antipsychotic/Neuroleptics
1) Phenothiazines
• Aliphatic Piperidine Piperazine*
Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine
Acetophenazine
Carphenazine
Prochlorperazine
* Most likely to cause extrapyramidal effects.
Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines
Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed
Atypical Antipsychotic
Pimozide
Atypical Antipsychoitcs Indolones
Loxapine Sertindole
Clozapine Ziprasidone
Olanzapine Olindone
Quetiapine Molindone
Risperidone
Classification of antipsychotic drugs:
Atypical Antipsychotic Drugs:
Clozapine, Typical Antipsychotic Drugs:
Olanzapine, Phenothiazines:
Risperidone, Chlorpromazine,
Ziprasidone Thioridazine ,
Trifluperazine,
Fluphenazine.
Butyrophenones:
Haloperidol
Benperidol.
Thioxanthenes:
Thiothixene
Others:
Pimozide
Loxapine
Antipsychotics/Neuroleptics
Tyrosine
Dopamine Synapse
• The affinities of
most older
Tyrosine
L-DOPA
“classical” “Typical”
DA
dopamine agents for the D2
receptor
antagonist
receptors correlate
with their clinical
potencies as
D2 antipsychotics
Typical Atypical
• 1st generation • 2nd generation
• Agitation, Acute mania • Depression, bipolar, mania
• More extrapyramidal • Less extrapyramidal
symptom symptom
• Less efficacy • Efficacy is more
• addicitive • Less addicitive
• Difficulty to discontinue • Easier discontinue
• Slow excret • Fast excret (relapse)
Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their therapeutic effects are not
evident until 4-8 weeks of treatment.
Presynaptic Effects
Blockade of D2 receptors
Compensatory Effects
Ý Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
Ý DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Receptor Supersensitivity
Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
Thioridazine
• Least incidence of EPS
• Low D2 blocking preset central anticholinergic
activity
– Interferes male sexual by inhibiting ejaculation
– It can cause cardical arry. (Prolong QT interval)
– Retinal damage limits long term admnistration
Trifluperazine, fluphenazine, Haloperidol
• High potency drugs and have least α blocking,
anticholinergic , sedative, Cause jaundice,
• Penfluridol: long acting anti psychotic
• Pimozidine : Selective D2, long duration, inc QT
A typical antipsychotics
• Unique receptor profile
• Effective against the negative as well as
positive schizophrenia
• Lesser liability for inducing Extra pyramidal
• Effectiveness in patient refractoru to typical
neuroleptics
• 5HT2, and D4 high affinity
• Besides α1, M1, H1, D2
• No singal receptor action best predict
Clozapine 5-HT2 >H1=M1= 1 =D4>D2=D1
olanzapine 5-HT2 >H1=M1=D4> 1 =D2=D1
Risperidone 5-HT2 > 1 = D2>D4>H1>D1
Quetiapine 1 =H1>D2=5-HT2 =M1>D1
Clozapine:
• weak D2 blocking action
• 5HT2, α, D4
• Positive and negative schizophrenia
• Dyskinesia rare
• Reserve drug,(Risk of precipitation of seizures and agranulocytosis)
• Risk of EPS
• Risks of intestinal dysfunction, weight gain,
uncontrol BP, hyperlipidemia,
Risperidone: 5HT2, α, D2
• EPS at high dose , less precipitation of seizures
Olanzapine: 5HT2, α, D2, M more action
• Anti cholinergic side effects
• Can cause seizures, weight gain,
• Mania, bipolar disorder
Ziprasidone: Inc QT, arrhythmias
Quetiapine : Cataract formation , short half life
Aripiprazole: partial agonist 5HT1a, D2, antagonist at
5HT2a/. DA, 5HT stabilizer
PK
• Oral BV vary largely
• IM inj 10 fold inc BV
• IM Oil depot longer acting
• Highly lipophilic
• Highly protein binding
• Metab cyto p-450
Non psychotics Uses
• Antiemetics:D2 block in CTZ
• Preanaesthetic (Promethazine) Anti H, Anti
Choli, Antiemetic
• Huntington’s disease (Haloperidol)
Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Neurological effects
b) Autonomic effects
c) Endocrine effects
d) Cardiac effects
3) Poor Concentration
Neurological effects
• Acute dystonia- Spasms of muscles of tongue, neck
and face (ACh)IM anticholinergic
• Akasthisia – Uncontrolled motor restlessness
• Parkinsonism
• Neuroleptic Mallignant Syndrome dantrolene, Diazepam
• Rabbit syndrome (perioral tremors)Anti choliner
• Tardive dyskinesia
Piperazines
Butyrophenones
Tardive Dyskinesia (TD)
• Repetitive involuntary movements, lips, jaw,
and tongue
• Choreiform quick movements of the extremities
• As with Parkinson’s, movements stop during
sleep
• May get worse when medications
discontinued, No effective treatment
ADR/Anticholinergic
Some antipsychotics have effects at
muscarinic acetylcholine receptors:
• Dry mouth
• Blurred vision
• Urinary retention
• Constipation
Clozapine
Chlorpromazine
Thioridazine
ADR/CVS
Some antipsychotics have effects at a-
adrenergic receptors:
Chlorpromazine
Thioridazine
Postural hypotension, Palpitation,
Inhibition of ejaculations, Q-T prolongation ( Tiori)
Excess cardiovascular mortality
Phenothiazine
ADR/CNS
Drowsiness, Lethargy, confusion (typical)
Other side effects are increased appetite
Sedation (RAS)
Weight gain
Aggravation of seizures
ADR/ Endocrinal
Blockade of D2 receptors in lactotrophs in
breast increase prolactin concentration
Galactorrhea in females
Males Gynaeocmastia
Dec FSH, LH amenorrhoea
Riseridone
ADR/ Metabolic
Elevation of blood sugar (insulin resistance)
Triglyceride levels
Low potency drug high risk
Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors
(increased locomotion and stereotyped behaviour).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of
prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
• Postural hypotension (α blocking)
• Weight again ( except haloperidol)
• Retinal damage ( Thioridazine)
• Agranulocytosis ( Clozapine)
• Cataract formation ( Quetiapine)
• Cholestatic jaundice ( Chlorpormazine)
• Dryness mouth, blurred vision(max thioridazine )
THANK Q
Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.
