Contents

1 Introduction 3

2 Understanding Psychosis 4
2.1 Definition and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Historical Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2.1 Early Theories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2.2 Evolution of Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3 Symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3.1 Positive Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3.2 Negative Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.3.3 Cognitive Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.4 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.4.1 Prevalence and Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.4.2 Demographic Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3 Etiology of Psychosis 10
3.1 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.1.1 Heritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.1.2 Specific Genetic Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2 Neurobiological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2.1 Brain Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2.2 Neurotransmitter Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.3 Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.3.1 Substance Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.3.2 Stress and Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.3.3 Socioeconomic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.4 Interaction of Genetic and Environmental Factors . . . . . . . . . . . . . . . . . . . . . . 15

4 Diagnosis and Assessment 16

4.1 Clinical Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.1.1 Interviews and History Taking . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.1.2 Use of Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.2 Psychometric Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.2.1 Symptom Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.2.2 Cognitive Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.3 Challenges in Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.3.1 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.3.2 Subclinical and Prodromal States . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5 Treatment and Management 20

5.1 Pharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.1.1 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.1.2 Adjunctive Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2 Psychosocial Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.2.1 Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.2.2 Social Support and Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.3 Emerging Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.3.1 Neuromodulation Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.3.2 Digital and Mobile Health Interventions . . . . . . . . . . . . . . . . . . . . . . . 24
5.4 Treatment Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.4.1 Treatment Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.4.2 Side Effects and Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

1
6 Impact of Psychosis 27
6.1 On Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.1.1 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.1.2 Functional Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.2 On Society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.2.1 Economic Impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.2.2 Stigma and Discrimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

7 Special Populations 29
7.1 Child and Adolescent Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
7.1.1 Early Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
7.1.2 Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
7.2 Elderly Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
7.2.1 Late-Onset Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
7.2.2 Differential Diagnosis with Dementia . . . . . . . . . . . . . . . . . . . . . . . . . 32
7.3 Cultural and Ethnic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
7.3.1 Cultural Competence in Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . 32
7.3.2 Variations in Symptom Expression . . . . . . . . . . . . . . . . . . . . . . . . . . 33

8 Research Directions 34
8.1 Biomarkers and Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
8.1.1 Genetic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
8.1.2 Imaging and Neurophysiological Markers . . . . . . . . . . . . . . . . . . . . . . . 35
8.2 Longitudinal and Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.2.1 Natural History of Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.2.2 Predictors of Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
8.3 Interventional Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.3.1 Novel Pharmacological Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.3.2 Innovative Psychosocial Approaches . . . . . . . . . . . . . . . . . . . . . . . . . 38

9 Conclusion 38

2
 Investigating the Complex Landscape of Psychosis: Etiology,
Symptoms, and Treatment Innovations
John Doe
noreply@thesisai.io
April 21, 2024

Abstract
This study investigates the complex interplay between oxidative stress and psychosis, with a
particular focus on the manifestation of psychosis and mania symptoms, and their progression over
a two-year follow-up period in adolescents at the threshold of psychosis. It delves into the role
of oxidative stress in the development and treatment of psychosis, highlighting the necessity for
further research to elucidate its impact. The research also scrutinizes demographic and clinical
characteristics, such as illness duration, onset, and symptom severity, to pinpoint predictors of psy-
chosis outcomes. Emphasizing the significance of self-rated mental health and factors like gender,
relationship status, education, and duration of untreated psychosis in forecasting these outcomes,
the study employs longitudinal analyses to trace the evolution of psychosis in patients over time,
despite the inherent challenges of such research endeavors. Moreover, it examines the influence of
social determinants, including deprivation and social fragmentation, on the prognosis of psychosis,
advocating for a comprehensive approach that integrates biological, psychological, and social di-
mensions. Through this extensive exploration, the study aims to enhance the understanding of
psychosis and foster the development of targeted interventions to improve the long-term well-being
of individuals experiencing this condition.

1 Introduction
Introduction to the study of psychosis encompasses a multifaceted exploration of its symptoms, causes,
treatment options, and the overall impact on individuals and society. Psychosis is characterized by a
disconnection from reality, where individuals may experience hallucinations, delusions, and impaired
thought processes. Understanding the etiology of psychosis is crucial for developing effective treatments
and interventions. The complexity of psychosis symptoms and their causes necessitates a comprehen-
sive approach, integrating insights from various research studies and clinical observations.
The social reconnection hypothesis suggests that certain patterns observed in psychosis might be
understood through the lens of individuals’ attempts to reconnect socially [Sho+23]. This perspective
underscores the importance of considering the social dimensions of psychosis, which can offer novel
insights into its underlying mechanisms and potential avenues for intervention. Additionally, the inclu-
sion of diverse perspectives, such as those from Indigenous communities, enriches our understanding
of psychosis. For instance, research involving Māori youth and adults with First Episode Psychosis
(FEP) highlights the value of incorporating culturally sensitive methodologies and recognizing the
unique experiences and needs of Indigenous populations [Man+24]. Such approaches not only enhance
the relevance and applicability of research findings but also contribute to more holistic and effective
care practices.
The demographic characteristics of research participants, such as gender, age, and ethnicity, play
a significant role in the study of psychosis. For example, a study with a majority of male participants
with an average age of 38.4 years, predominantly identifying as Black, White, or Asian, emphasizes
the need to consider demographic factors in research and clinical practice [Cel+24]. These factors can
influence the presentation of psychosis symptoms, the accessibility and effectiveness of treatment, and
the overall impact of the disorder on individuals’ lives.
Moreover, the limitations of existing research, such as the predominance of studies conducted in
developed countries with mostly White participants, highlight the challenges of generalizing findings

3
across different cultural and socio-economic groups [Gra+24]. This underscores the necessity of con-
ducting more inclusive research that can address the diverse experiences and needs of individuals with
psychosis across various contexts.
The growing caseness for Autism Spectrum Disorder (ASD) reported in recent decades, attributed
to diagnostic accretion and better case finding, alongside potential environmental and biological causes,
points to the complexity of understanding psychiatric disorders, including psychosis [Ges+24]. This
complexity is further compounded by the multifaceted roles of researchers in the field, encompassing
responsibilities such as writing, reviewing, editing, supervision, methodology development, and project
administration [Vel+24]. Such roles reflect the collaborative and interdisciplinary nature of psychosis
research, which is essential for advancing our knowledge and improving outcomes for individuals af-
fected by the disorder.
In conclusion, the introduction to the study of psychosis sets the stage for a comprehensive explo-
ration of its symptoms, causes, treatment options, and impact. By integrating diverse perspectives,
considering the demographic characteristics of research participants, acknowledging the limitations of
existing studies, and recognizing the complexity of psychiatric disorders, this research aims to con-
tribute to a deeper understanding of psychosis and enhance the effectiveness of interventions and
support for affected individuals.

2 Understanding Psychosis
2.1 Definition and Overview
Psychosis represents a complex mental health condition characterized by an impaired relationship with
reality, often manifesting through hallucinations, delusions, and disordered thinking. Understanding
the multifaceted nature of psychosis involves exploring its symptoms, underlying causes, treatment
options, and the overall impact on individuals’ lives. The symptoms of psychosis, such as hearing voices
or experiencing beliefs that have no basis in reality, significantly affect a person’s perception, thoughts,
and behaviors, leading to substantial distress and functional impairments [Far+24; Vel+24]. These
symptoms can be episodic or persistent, varying greatly in intensity and duration among individuals.
The causes of psychosis are diverse, involving a combination of genetic, biological, environmental,
and psychological factors. Research has identified childhood trauma as a significant risk factor for the
development of psychosis later in life, suggesting a complex interplay between early life experiences and
neurobiological vulnerabilities. Additionally, substance use, particularly cannabis, has been associated
with an increased risk of psychosis, though the causal mechanisms remain a subject of ongoing investi-
gation [Gro+24]. The neurobiological mechanisms underlying psychosis are still being elucidated, with
studies recommending further investigation to understand these complex interactions fully [Vel+24].
Treatment for psychosis typically involves a combination of pharmacological and psychosocial inter-
ventions. Antipsychotic medications are commonly used to manage symptoms, while psychotherapies,
such as cognitive-behavioral therapy (CBT), aim to address the psychological aspects of the condi-
tion [Far+24]. The effectiveness of trauma-focused interventions for psychosis further highlights the
importance of integrating psychological and pharmacological approaches in treatment. Moreover, the
consideration of cultural differences in the diagnosis and treatment of psychosis underscores the need
for a transcultural approach, particularly for populations such as refugees who may have unique mental
health needs [SSE23].
The impact of psychosis on individuals and society is profound, affecting personal, social, and
occupational functioning. Early intervention in psychosis has been emphasized in research, focusing
on clinician-reported outcome measures primarily in high-income, Western contexts [Nai+24]. This
highlights the need for comprehensive and culturally sensitive assessment and intervention strategies
to mitigate the adverse effects of psychosis on individuals’ lives.
In summary, psychosis is a complex condition characterized by a disconnection from reality, with
symptoms that can significantly impair an individual’s functioning. Its causes are multifaceted, involv-
ing genetic, environmental, and psychological factors. Treatment approaches are diverse, emphasizing
the need for personalized and culturally sensitive interventions. The impact of psychosis is far-reaching,
affecting not only the individuals experiencing the condition but also their families and communities,
thereby necessitating ongoing research and innovation in care and treatment strategies.

4
2.2 Historical Perspectives
2.2.1 Early Theories
Early theories on the etiology and manifestation of psychosis have evolved significantly over time,
reflecting broader shifts in the understanding of mental health disorders. Initially, psychosis was often
viewed through a supernatural lens, with symptoms attributed to possession or witchcraft. However,
as medical science advanced, these explanations gave way to more empirical investigations into the
brain and its functions.
The 19th century marked a pivotal shift towards a more medicalized view of psychosis, with early
psychiatrists like Emil Kraepelin distinguishing between different types of mental disorders, includ-
ing what he termed dementia praecox (later known as schizophrenia) and manic depression (bipolar
disorder). Kraepelin’s work laid the groundwork for the modern diagnostic system, emphasizing the
importance of symptom clusters and disease courses in understanding mental disorders [Sav+24].
Concurrently, Sigmund Freud and his followers proposed that psychosis could arise from uncon-
scious conflicts, particularly those rooted in early developmental stages. This psychoanalytic perspec-
tive suggested that unresolved psychological conflicts could manifest as psychotic symptoms, such as
hallucinations or delusions. While the Freudian model has been critiqued and evolved over time, it
underscored the potential role of psychological factors in psychosis, paving the way for therapeutic
interventions aimed at resolving these underlying conflicts [Tay+24].
The discovery of the first antipsychotic medication in the 1950s further transformed the landscape
of psychosis treatment and theory. The effectiveness of these drugs in alleviating psychotic symptoms
suggested a biological underpinning to the disorder, leading to increased interest in the neurochemical
and structural abnormalities associated with psychosis. This biological perspective has been bolstered
by modern imaging and genetic studies, which have identified specific brain regions and genetic variants
associated with an increased risk of psychosis [Far+24; RM24].
However, the recognition that not all patients respond to medication, combined with the obser-
vation of psychosis-like symptoms in various cultural and social contexts, has led to a more nuanced
understanding of the disorder. Contemporary theories often adopt a biopsychosocial model, acknowl-
edging the interplay between biological vulnerabilities, psychological stressors, and social factors in the
development and manifestation of psychosis [Bon+24; Vel+24].
Moreover, recent research has emphasized the importance of early intervention and the identification
of prodromal symptoms, reflecting a shift towards a more preventative approach to psychosis. This
perspective is informed by studies demonstrating that early treatment can improve long-term outcomes,
challenging traditional diagnostic boundaries and underscoring the continuum of psychotic experiences
[Nom+24].
In summary, early theories of psychosis have evolved from supernatural explanations to complex,
multifaceted models that integrate biological, psychological, and social factors. This evolution reflects
broader changes in the understanding of mental health disorders and underscores the importance of a
comprehensive approach to treatment and prevention.

2.2.2 Evolution of Diagnostic Criteria

The evolution of diagnostic criteria for psychosis has been a complex journey, reflecting the multi-
faceted nature of the condition itself. Initially, the diagnosis of psychosis was largely based on clinical
observation, with a significant emphasis on the presentation of symptoms such as delusions, hallucina-
tions, and disorganized thinking. However, as our understanding of psychosis has deepened, there has
been a concerted effort to refine and standardize these criteria to improve diagnosis, treatment, and
research outcomes.
One pivotal moment in this evolution was the introduction of the Diagnostic and Statistical Man-
ual of Mental Disorders (DSM) by the American Psychiatric Association, which has undergone several
revisions to incorporate the latest research findings. Similarly, the International Classification of Dis-
eases (ICD) by the World Health Organization has played a crucial role in standardizing the diagnostic
criteria for psychosis on a global scale. These classification systems have evolved to include specific
criteria for diagnosing schizophrenia and other psychotic disorders, emphasizing the importance of
symptom duration, the exclusion of substance-induced psychosis, and the differentiation from mood
disorders with psychotic features.

5
 The concept of First Episode Psychosis (FEP) illustrates the refinement in understanding and
diagnosing psychosis. FEP refers to the first time an individual experiences psychotic symptoms,
which can be challenging to pinpoint accurately due to the gradual onset of symptoms. The literature
suggests defining FEP as symptom onset within the last six months to five years, with two years being
a common benchmark [Tay+24]. This highlights the shift towards recognizing the importance of early
intervention and the need for criteria that can identify psychosis at its nascent stages.
Moreover, the exclusion criteria have become more sophisticated, excluding individuals who have
previously been treated with antipsychotics to ensure that studies and clinical assessments are exam-
ining untreated psychosis. This is crucial for understanding the natural course of the disorder and the
effects of interventions [Tay+24; Cas+24]. Additionally, the recognition of the impact of substance
use, particularly cannabis, on psychosis has led to more nuanced diagnostic criteria that consider the
role of substance-induced psychosis. This is particularly relevant given the changing legal and societal
attitudes towards cannabis use [Gro+24].
The heterogeneity in how studies conceptualize and measure affective mediators and psychosis
symptomatology has been noted as a challenge in the field [Gra+24]. This underscores the ongoing
need to refine diagnostic criteria to ensure they are capturing the complexity of psychosis and its diverse
manifestations. Furthermore, the acknowledgment of the role of trauma and other environmental
factors in the development of psychosis has led to a broader perspective on diagnosis, considering not
just the symptoms but also the context in which they occur [SSE23].
In summary, the evolution of diagnostic criteria for psychosis reflects a growing understanding of
the disorder’s complexity. It underscores a shift towards early identification and intervention, the
importance of excluding other causes of psychosis, and the need for criteria that can accommodate the
diverse presentations of psychosis. This evolution is critical for improving the outcomes for individuals
with psychosis, guiding research, and informing clinical practice.

2.3 Symptomatology
2.3.1 Positive Symptoms
Positive symptoms in psychosis represent a class of symptoms that include hallucinations and delusions,
which are among the most recognizable and distressing aspects of psychotic disorders. These symptoms
are termed "positive" because they denote the presence of abnormal perceptions or beliefs that are not
typically experienced by individuals without psychosis. Hallucinations are sensory experiences without
a real external stimulus, whereas delusions are strongly held false beliefs that are not amenable to
change in light of conflicting evidence.
The etiology of positive symptoms is multifaceted, involving a complex interplay of genetic, neu-
robiological, and environmental factors. Research has shown that alterations in the dopaminergic
pathways, particularly in the mesolimbic pathway, play a crucial role in the development of positive
symptoms. This is supported by the effectiveness of antipsychotic medications, which primarily act by
blocking dopamine receptors, in alleviating these symptoms [Jen+24; Vel+24]. Furthermore, structural
and functional abnormalities in brain regions such as the prefrontal cortex, thalamus, and cerebellum
have been associated with the manifestation of positive symptoms, suggesting that disruptions in
cortical-subcortical-cerebellar circuitry may underlie these phenomena [Jen+24].
Environmental factors, such as exposure to childhood trauma (CT), have also been identified as
significant risk factors for the development of psychosis and its positive symptoms. Studies have
consistently found that individuals with psychosis have greater exposure to CT compared to controls,
indicating that early adverse experiences can contribute to the vulnerability to psychosis later in
life. This relationship underscores the importance of considering both biological and environmental
contributions to the pathogenesis of positive symptoms.
The impact of positive symptoms on individuals with psychosis is profound, affecting their quality
of life, social functioning, and overall well-being. Hallucinations and delusions can be highly distressing,
leading to significant distress and impairment. The subjective experience of these symptoms, including
their content and perceived control over them, can vary widely among individuals, influencing their
impact on daily functioning and the effectiveness of treatment interventions [Nai+24].
Treatment of positive symptoms primarily involves the use of antipsychotic medications, which can
significantly reduce the severity of hallucinations and delusions. However, the response to treatment
can be variable, and some individuals may experience persistent symptoms despite medication ad-

6
herence. Additionally, antipsychotics can have side effects that may affect treatment compliance and
quality of life [Vel+24]. Therefore, a comprehensive treatment approach that includes psychosocial
interventions, such as cognitive-behavioral therapy, is essential for addressing the complex needs of
individuals with psychosis and improving their outcomes.
In summary, positive symptoms are a central feature of psychosis, with significant implications
for diagnosis, treatment, and prognosis. Understanding the underlying mechanisms and factors con-
tributing to these symptoms is crucial for developing effective interventions and supporting individuals
affected by psychosis in achieving recovery and improving their quality of life.

2.3.2 Negative Symptoms

Negative symptoms in psychosis represent a significant challenge in both understanding and treating
this complex condition. These symptoms are characterized by a reduction or absence of normal be-
haviors and functions, which can profoundly impact the quality of life for individuals experiencing
psychosis. Unlike positive symptoms that include hallucinations and delusions, negative symptoms
are often more persistent and less responsive to treatment. They encompass a range of experiences
such as blunted affect, where individuals show reduced emotional expression; alogia, or poverty of
speech; anhedonia, which is the inability to experience pleasure; asociality, the lack of interest in social
interactions; and avolition, a lack of motivation to engage in purposeful activities [Jen+24; Gra+24].
The etiology of negative symptoms is multifaceted, involving complex interactions between genetic,
neurobiological, and environmental factors. Research has indicated that negative symptoms may be
linked to dysfunction in specific brain circuits, particularly those involving the prefrontal cortex and
basal ganglia, areas known to be crucial for motivation, emotional regulation, and social behavior. This
neurobiological perspective is supported by findings of aberrant functional connectivity (FNC) patterns
in individuals with psychosis, suggesting that disruptions in the coordination between different brain
regions may underlie the manifestation of negative symptoms [Jen+24].
Treatment approaches for negative symptoms are diverse, yet they present considerable challenges.
Pharmacological interventions, particularly those targeting the dopaminergic and serotonergic systems,
have shown some efficacy in managing these symptoms. However, the effectiveness of antipsychotic
medications is often limited and can vary significantly between individuals [Wil+24]. This variability
underscores the need for personalized treatment strategies that consider the unique neurobiological
and psychosocial context of each patient.
Psychological interventions, including cognitive-behavioral therapy (CBT) for psychosis, have emerged
as important components of a comprehensive treatment plan for negative symptoms. These inter-
ventions aim to improve social functioning, motivation, and emotional regulation through targeted
cognitive and behavioral techniques. The emphasis on individualized client formulations and the
incorporation of trauma-focused CBT highlight the importance of addressing the broader range of
potential mechanisms contributing to negative symptoms.
Despite these advances, the treatment of negative symptoms remains a critical area of unmet
need. The persistent and debilitating nature of these symptoms emphasizes the importance of ongoing
research to elucidate their underlying mechanisms and to develop more effective interventions. Future
studies should continue to explore the complex interplay between neurobiological, psychological, and
environmental factors in the genesis and maintenance of negative symptoms. Additionally, there is
a growing recognition of the need to broaden the scope of research and treatment approaches to
encompass the full spectrum of affective processes and their role in psychosis, beyond the traditional
focus on anxiety and mood-related difficulties [Gra+24].
In summary, negative symptoms significantly contribute to the burden of psychosis, affecting indi-
viduals’ ability to function and engage in meaningful life activities. Understanding the multifaceted
nature of these symptoms and developing effective treatments require a multidisciplinary approach
that integrates insights from neurobiology, psychology, and clinical practice. As the field advances, it
is hoped that more precise and personalized interventions will become available, improving outcomes
for individuals experiencing negative symptoms of psychosis.

2.3.3 Cognitive Symptoms

Cognitive symptoms in psychosis encompass a broad range of deficits that significantly impact the func-
tioning and quality of life of individuals diagnosed with schizophrenia and related disorders. These

7
symptoms are characterized by difficulties in attention, memory, executive functions, and social cogni-
tion. Understanding the nature and treatment of cognitive symptoms is crucial for improving outcomes
in psychosis.
Research has consistently shown that cognitive deficits are a core feature of schizophrenia, affecting
various domains of cognition. Cognitive remediation (CR) has emerged as a promising intervention
aimed at reducing these cognitive difficulties and supporting functional recovery. The effectiveness of
CR interventions has been substantiated by a substantial body of evidence, leading to the inclusion of
CR in clinical guidelines internationally [Cel+24]. These guidelines recommend CR for individuals with
schizophrenia to address cognitive impairments and facilitate recovery, highlighting the importance of
targeting cognitive symptoms in treatment plans.
Pharmacotherapy remains a cornerstone in the stabilization of early psychosis, with current guide-
lines acknowledging its necessity, especially in the initial stages of the clinical course. However, to
achieve additional benefits in the medium to longer term, augmentation with psychosocial interventions
is recommended [Wil+24]. This approach underscores the multifaceted nature of psychosis treatment,
where addressing cognitive symptoms requires a combination of pharmacological and psychosocial
strategies.
The impact of external factors, such as substance use, on cognitive symptoms in psychosis has also
been a focus of research. Cannabis use, in particular, has been associated with an earlier age of onset
of psychosis and may contribute to the progression of psychosis illness to schizophrenia in high-risk
individuals. This suggests that cannabis may not only exacerbate positive and negative symptoms
but could also potentially influence cognitive outcomes in psychosis. However, the causal relationship
between cannabis use and cognitive symptoms remains a complex issue, with observational studies
providing limited insight into causality [Gro+24].
Furthermore, the COVID-19 pandemic has introduced new considerations for the management of
psychosis, with clinicians advised to be prepared for possible increases in psychotic presentations or
deterioration of psychosis in affected patients [Bon+24]. This highlights the need for ongoing vigilance
and adaptability in the treatment of cognitive symptoms amidst evolving external challenges.
In summary, cognitive symptoms in psychosis represent a critical target for intervention, with
cognitive remediation and pharmacotherapy playing key roles in treatment strategies. The influence of
external factors, such as substance use and global health crises, further complicates the management
of cognitive symptoms, emphasizing the need for comprehensive and flexible treatment approaches.

2.4 Epidemiology
2.4.1 Prevalence and Incidence
The prevalence and incidence of psychosis represent critical epidemiological measures that illumi-
nate the burden of psychotic disorders within populations. Understanding these metrics is essential
for allocating healthcare resources, designing public health strategies, and identifying at-risk pop-
ulations. The prevalence of psychosis varies significantly across different geographical regions and is
influenced by a myriad of factors including socio-demographic characteristics, environmental exposures,
and genetic predispositions. Congdon et al. highlighted the importance of considering spatial varia-
tions in psychosis, suggesting that the prevalence of psychotic disorders is not uniformly distributed
across populations. Factors such as area deprivation, social fragmentation, ethnic mix, and access to
greenspace have been implicated in the prevalence variations observed across 983 neighborhoods in
London [Con24]. This spatial heterogeneity underscores the complexity of psychosis epidemiology and
the need for localized public health interventions.
Moreover, the incidence of psychosis, which refers to the rate of new cases identified within a specific
time period, provides insights into the dynamic nature of the disorder’s emergence in the population.
The role of environmental risk factors becomes increasingly apparent at various stages in the devel-
opment of psychosis, raising questions about the timing and mechanisms through which these factors
exert their influence. Rejek and Misiak pointed out the uncertainty surrounding the Environmental
Sensitivity (ES) hypothesis in predicting the emergence of clinically relevant psychotic disorders and
psychotic-like experiences (PLEs) within the general non-help-seeking population [RM24]. This high-
lights the challenges in understanding the etiological pathways leading to psychosis and the potential
for early intervention strategies.
The incidence and prevalence of psychosis are also influenced by the heterogeneity of psychotic

8
disorders and the spectrum of psychotic experiences. For instance, cognitive behavioral approaches to
psychosis aim to develop psychological ’distance’ from psychotic experiences, which might be expected
to yield early improvements in negative symptoms, with more gradual improvement in social function-
ing [Wil+24]. This suggests that the clinical presentation and course of psychotic disorders can vary
widely among individuals, further complicating efforts to accurately measure and interpret prevalence
and incidence rates.
Furthermore, the methodological quality of systematic reviews and primary studies on psychosis-
related outcomes, such as those examining the relationship between cannabis use and psychosis, has
been critically evaluated. Groening et al. noted that the vast majority of existing systematic reviews
on cannabis use and psychosis-related outcomes have critically low methodological quality, limiting
confidence in their conclusions [Gro+24]. This points to the need for high-quality longitudinal studies
that can provide more reliable data on the incidence and prevalence of psychosis, as well as the factors
that influence these epidemiological measures.
In summary, the prevalence and incidence of psychosis are influenced by a complex interplay of
genetic, environmental, and socio-demographic factors. The spatial heterogeneity in the prevalence
of psychosis underscores the importance of localized public health strategies, while the variability in
the incidence of new cases highlights the dynamic nature of the disorder’s emergence in populations.
High-quality epidemiological research is essential for advancing our understanding of psychosis and
informing effective prevention and intervention strategies.

2.4.2 Demographic Variations

Demographic variations play a crucial role in understanding the epidemiology of psychosis, with sev-
eral factors such as ethnicity, urbanicity, and migration status significantly impacting the prevalence
and manifestation of psychosis symptoms. The ethnic density effect, as highlighted by Congdon et
al., suggests that the impact of non-white ethnicity on psychosis rates is significant, with both linear
and quadratic terms being considered to model this relationship. This indicates a complex interplay
between ethnicity and psychosis risk, potentially mediated by factors such as social cohesion, discrim-
ination, and access to healthcare services.
Urbanicity has been established as a significant factor in the epidemiology of psychosis, with individ-
uals in urban areas showing higher psychosis risk compared to those in rural settings. This urban-rural
divide in psychosis risk could be attributed to a variety of stressors prevalent in urban environments,
including but not limited to, higher levels of social fragmentation, deprivation, and reduced access
to green spaces. The protective role of green spaces against psychosis risk further emphasizes the
importance of environmental factors in the epidemiology of psychosis [Con24].
Migration status and the experience of being a refugee or migrant have also been identified as signif-
icant demographic variables affecting psychosis prevalence. Studies have shown that individuals within
migrant populations, particularly those diagnosed with schizophrenia, face unique challenges and stres-
sors that may elevate their risk of developing psychosis. However, the literature often lacks a clear
definition and distinction between ’refugees’ and ’migrants,’ which could lead to an underestimation
of the nuanced differences in psychosis risk within these groups [SSE23].
The heterogeneity of psychosis as a condition, coupled with the diverse nature of the popula-
tions studied, poses challenges in drawing definitive conclusions about the demographic variations in
psychosis risk [Jen+24]. For instance, studies investigating microstate dynamics in clinical high-risk
(CHR) and first-episode psychosis (FEP) patients have been limited by small sample sizes and the
absence of clinical control subjects, making it difficult to ascertain the specificity of psychosis-related
effects [Lie+24]. This underscores the need for larger, more comprehensive studies that include diverse
demographic groups and control for potential confounding factors.
Furthermore, the pathophysiology of psychosis remains incompletely understood, with evidence
pointing towards a multifactorial etiology involving both genetic and environmental contributors
[Tay+24]. This complexity is mirrored in the demographic variations observed in psychosis epidemiol-
ogy, suggesting that a multitude of factors, including but not limited to genetic predisposition, environ-
mental exposures, and individual demographic characteristics, interact in complex ways to influence
psychosis risk.
In light of these findings, future research should aim to disentangle the effects of various demo-
graphic factors on psychosis risk and outcomes. Longitudinal studies following cohorts from before the
onset of subclinical psychosis symptoms, particularly focusing on high-risk groups such as migrants

9
and individuals living in urban environments, could provide valuable insights into the causal pathways
linking demographic variations to psychosis [Gro+24]. Additionally, incorporating trauma-informed
treatment modalities that attend to the multiple potential mechanisms linking trauma and psychosis
could offer avenues for more effective interventions tailored to specific demographic groups [Gra+24].
Overall, the demographic variations in psychosis epidemiology highlight the importance of consid-
ering a wide range of factors, including ethnicity, urbanicity, and migration status, in understanding
and addressing the complex pathways leading to psychosis.

3 Etiology of Psychosis
3.1 Genetic Factors
3.1.1 Heritability
Heritability plays a crucial role in the etiology of psychosis, indicating that genetic factors signifi-
cantly contribute to the risk of developing psychotic symptoms. The investigation into the genetic
underpinnings of psychosis has been propelled by advancements in genetic methodologies, including
genome-wide association studies (GWAS) and Mendelian randomization studies. These approaches
have elucidated the complex genetic architecture of psychosis, revealing that both common and rare
genetic variants contribute to its pathogenesis.
The concept of heritability, defined as the proportion of variance in a trait attributable to genetic
factors within a given population, underscores the importance of genetics in psychosis. However, it
is essential to recognize that heritability estimates do not apply to individuals but to populations,
and they vary depending on the environmental context and the population studied. This complexity
is further compounded by the polygenic nature of psychosis, where numerous genetic variants each
contribute a small effect to the overall risk.
Mendelian randomization studies have provided insights into the causal relationships between ge-
netic predispositions and psychosis. By using genetic variants as instrumental variables, these studies
have begun to disentangle the intricate web of causality, suggesting that certain genetic profiles may
increase the susceptibility to psychosis. This approach has also been instrumental in exploring the
genetic overlap between psychosis and other psychiatric or neurological conditions, highlighting the
shared genetic etiology among different disorders.
Furthermore, the exploration of gene-environment interactions has emerged as a pivotal area of
research. It is increasingly recognized that the impact of genetic predispositions on psychosis risk is
modulated by environmental factors. For instance, exposure to adverse life events, substance use, and
other environmental stressors can interact with genetic vulnerabilities to trigger the onset of psychotic
symptoms. This interaction underscores the complexity of psychosis etiology, where both genetic and
environmental factors are intricately interwoven [Man+24].
In addition to common genetic variants, rare genetic mutations and copy number variations (CNVs)
have been implicated in the risk of psychosis. These rare genetic alterations often have a more sub-
stantial effect on risk compared to common variants but are less frequent in the population. The
identification of these rare variants has provided valuable insights into the biological pathways in-
volved in psychosis, offering potential targets for therapeutic intervention [Gro+24].
The study of heritability in psychosis also highlights the importance of considering population
diversity. Research has often been limited by a lack of racial and ethnic diversity, which can obscure the
understanding of genetic risk factors across different populations. Addressing these gaps by including
diverse populations in genetic studies is crucial for developing a more comprehensive understanding
of psychosis etiology and for ensuring that genetic research benefits all individuals, regardless of their
background [Tay+24].
In summary, the heritability of psychosis underscores the significant role of genetic factors in its
etiology. Through the combined efforts of GWAS, Mendelian randomization studies, and investigations
into gene-environment interactions, the field is moving towards a more nuanced understanding of how
genetic predispositions interact with environmental factors to influence the risk of psychosis. This
knowledge not only advances our understanding of the disorder’s pathogenesis but also opens avenues
for personalized interventions and treatments tailored to an individual’s genetic profile.

10
3.1.2 Specific Genetic Markers
Specific genetic markers play a crucial role in the etiology of psychosis, offering insights into the
underlying biological mechanisms and potential pathways for targeted interventions. The identification
and analysis of these markers have been instrumental in understanding the genetic predisposition to
psychosis, including both the onset and progression of the condition. Genetic studies have consistently
highlighted the complex interplay between multiple genes and environmental factors in the development
of psychosis, underscoring the importance of a multifaceted approach to research and treatment.
One of the key findings in the field is the association between certain genetic variations and an
increased risk of developing psychosis. These variations, often referred to as single nucleotide polymor-
phisms (SNPs), can influence the function of neurotransmitter systems, brain development, and neural
connectivity, all of which are critical in the pathophysiology of psychosis. For instance, variations in
genes related to the dopamine and glutamate neurotransmitter systems have been implicated in the
susceptibility to psychosis, reflecting the significance of these pathways in the disorder.
Moreover, the advent of genome-wide association studies (GWAS) has revolutionized our under-
standing of the genetic architecture of psychosis. GWAS have identified numerous risk loci associated
with schizophrenia, a major form of psychosis, providing valuable insights into the genetic underpin-
nings of the disorder. These studies have highlighted the polygenic nature of psychosis, with many
genetic variants each contributing a small effect to the overall risk. This complexity underscores the
challenge of pinpointing specific genetic markers for psychosis but also opens up new avenues for
research and potential therapeutic targets.
In addition to identifying risk loci, genetic research has also focused on understanding how these ge-
netic factors interact with environmental influences to trigger the onset of psychosis. Epigenetic mech-
anisms, such as DNA methylation and histone modification, have emerged as key processes through
which environmental factors can influence gene expression and, consequently, an individual’s risk of de-
veloping psychosis. This area of research holds promise for unraveling the intricate gene-environment
interactions that contribute to the etiology of psychosis and for identifying individuals at high risk
based on their genetic and epigenetic profiles.
Furthermore, the study of genetic markers has implications for the development of personalized
medicine approaches to the treatment of psychosis. By identifying individuals with specific genetic risk
profiles, clinicians may be able to tailor interventions to target the underlying biological mechanisms
more effectively. This precision medicine approach could lead to more effective and individualized
treatment strategies, ultimately improving outcomes for people with psychosis.
In summary, the investigation of specific genetic markers has provided valuable insights into the
genetic basis of psychosis, highlighting the complex interplay between genetic and environmental fac-
tors in the etiology of the disorder. Continued research in this area is essential for advancing our
understanding of psychosis and for developing more effective prevention and treatment strategies.

3.2 Neurobiological Factors

3.2.1 Brain Structure and Function
Brain structure and function play a pivotal role in the etiology of psychosis, with numerous studies
highlighting alterations in various brain regions and their connections as key factors in the development
and manifestation of psychotic symptoms. The neurobiological underpinnings of psychosis encompass
a complex interplay between genetic, environmental, and neurochemical factors, which ultimately
manifest in structural and functional brain abnormalities.
Research has consistently shown that individuals across the psychosis continuum exhibit differences
in brain structure when compared to healthy controls. These differences are particularly pronounced in
regions such as the prefrontal cortex, which is crucial for executive functions, and the temporal lobes,
which are involved in auditory processing and memory. Such structural abnormalities may underlie
the cognitive deficits and characteristic symptoms observed in psychosis, such as hallucinations and
delusions. Furthermore, the hippocampus, a region integral to memory formation and emotional
regulation, has also been implicated in psychosis, with studies reporting both volume reduction and
functional alterations in this area.
Functional brain imaging studies have further elucidated the role of altered brain connectivity in
psychosis. Abnormalities in functional connectivity, particularly within the default mode network
(DMN), the salience network, and the central executive network, have been observed. These networks

11
are critical for self-referential thinking, the detection of salient stimuli, and executive function, re-
spectively. Disruptions in the connectivity within and between these networks may contribute to the
disorganized thought and impaired reality testing characteristic of psychosis.
The impact of antipsychotic medication on brain structure and function is another area of significant
interest. While these medications are effective in managing symptoms for many individuals, their
influence on brain morphology and the potential for contributing to certain structural changes remains
a topic of ongoing research. Future studies are encouraged to explore the effects of antipsychotic
use with a nuanced approach, considering factors such as medication type, dosage, and duration of
treatment [Jen+24].
Moreover, the exploration of biomarkers related to immune and oxidative stress pathways offers
promising insights into the neurobiological mechanisms underlying psychosis. Elevated levels of certain
biomarkers, such as C-reactive protein (CRP) and homocysteine, have been associated with psychosis
and psychosis-risk states, suggesting that inflammation and oxidative stress may play a role in the
pathophysiology of the disorder [Tay+24].
In summary, the study of brain structure and function in psychosis reveals a complex picture of
widespread neural alterations that contribute to the onset and progression of the disorder. Understand-
ing these neurobiological factors is crucial for developing more effective treatments and interventions
aimed at mitigating the impact of psychosis on individuals’ lives. Further research in this area, partic-
ularly studies employing longitudinal designs and advanced neuroimaging techniques, will be essential
for unraveling the intricate relationships between brain abnormalities and psychotic symptoms.

3.2.2 Neurotransmitter Systems

Neurotransmitter systems play a pivotal role in the etiology of psychosis, influencing various neurobio-
logical pathways and contributing to the manifestation of symptoms. The complexity of these systems,
including their interactions and the balance between excitatory and inhibitory neurotransmitters, un-
derscores the multifaceted nature of psychosis. Among the neurotransmitters implicated in psychosis,
dopamine has been the most extensively studied, primarily due to its association with the positive
symptoms of psychosis, such as hallucinations and delusions. However, recent research has expanded
our understanding to include the role of other neurotransmitters, such as glutamate, serotonin, and
gamma-aminobutyric acid (GABA), in contributing to both the positive and negative symptoms of
psychosis.
Dopamine dysregulation, particularly in the mesolimbic and mesocortical pathways, has been a cor-
nerstone of psychosis research. The dopamine hypothesis suggests that hyperactivity of dopaminergic
transmission in the mesolimbic pathway contributes to positive symptoms, while hypofunctionality in
the mesocortical pathway leads to negative symptoms and cognitive deficits. This hypothesis is sup-
ported by the efficacy of antipsychotic drugs, which primarily act by blocking dopamine D2 receptors,
thereby reducing dopamine activity and alleviating positive symptoms.
Glutamate, the primary excitatory neurotransmitter in the brain, has also been implicated in the
pathophysiology of psychosis. The glutamate hypothesis posits that N-methyl-D-aspartate (NMDA)
receptor hypofunction leads to disrupted glutamatergic transmission, contributing to both positive and
negative symptoms of psychosis. This hypothesis is supported by observations that NMDA receptor
antagonists can induce psychotic symptoms in healthy individuals and exacerbate symptoms in those
with psychosis. Furthermore, recent studies have focused on the potential of targeting the glutamater-
gic system for novel therapeutic approaches, highlighting the importance of glutamate in psychosis
etiology.
Serotonin, another key neurotransmitter, interacts with dopamine and glutamate systems and
has been implicated in the pathophysiology of psychosis. The serotonergic system’s involvement is
evidenced by the effectiveness of second-generation antipsychotics, which not only block dopamine D2
receptors but also target serotonin 5-HT2A receptors. This dual action suggests that serotonin plays
a role in modulating dopamine and glutamate activity, contributing to the complex neurochemical
landscape of psychosis [Gro+24].
GABA, the primary inhibitory neurotransmitter in the brain, has also been associated with psy-
chosis. GABAergic dysfunction, particularly in the prefrontal cortex, has been linked to cognitive
deficits and negative symptoms in psychosis. The interplay between GABAergic and glutamatergic
neurotransmission is crucial for maintaining neural circuitry balance, and disruptions in this balance
may contribute to the pathophysiology of psychosis [Jen+24].

12
 In summary, the neurotransmitter systems involved in psychosis are intricate and interrelated,
with dopamine, glutamate, serotonin, and GABA playing significant roles in the manifestation of
symptoms. Understanding these systems’ interactions and dysregulations provides insight into the
neurobiological underpinnings of psychosis and opens avenues for developing targeted treatments. The
ongoing research into these neurotransmitter systems underscores the complexity of psychosis and the
need for a multifaceted approach to understanding and treating this condition.

3.3 Environmental Factors

3.3.1 Substance Use
Substance use, particularly cannabis, has been extensively studied for its association with psychosis,
revealing complex interactions that suggest a significant environmental factor in the etiology of psy-
chosis. The relationship between cannabis use and psychosis is multifaceted, with evidence suggesting
that cannabis use may increase the risk of developing psychosis among individuals, especially those
with a pre-existing vulnerability. This association is further complicated by factors such as the fre-
quency and quantity of cannabis use, indicating that heavier use may have a more pronounced effect
on the risk of transitioning to psychosis.
Research has also highlighted the potential confounding effects of alcohol use, which may influence
the observed association between cannabis use and psychosis. This underscores the importance of con-
sidering other substance use when examining the impact of cannabis on psychosis outcomes. Moreover,
the role of genetic predisposition in conjunction with cannabis use has been suggested, with studies
indicating that the interaction between genetic risk and cannabis use could influence psychosis-related
outcomes [Gro+24]. This points to a gene-environment interaction where both genetic susceptibility
and environmental factors such as cannabis use contribute to the risk of psychosis.
The diagnostic challenges associated with mental disorders, including psychosis, are significant,
with current practices relying heavily on clinical consensus and symptom clusters without incorporating
more objective biological measures [Pel+24]. This highlights a gap in the diagnostic process that could
potentially be addressed by considering the impact of substance use, including cannabis, on psychosis.
Furthermore, the effects of antipsychotic use in individuals with psychosis have been considered,
with some studies suggesting that the impact of these medications may be reduced in samples with a
relatively short duration of illness [Jen+24]. This indicates the complexity of treating psychosis and
the potential influence of substance use on treatment outcomes.
In light of these findings, there is a call for more transdiagnostic approaches to study the impact of
environmental factors such as substance use on psychosis [Gra+24]. This approach would allow for a
more comprehensive understanding of the interplay between various factors, including substance use,
genetic predisposition, and treatment effects, in the development and management of psychosis.
The cumulative effects of substance use within the extended psychosis phenotype have not been
fully explored, suggesting an area for future research [RM24]. This could provide valuable insights
into how substance use, particularly cannabis, impacts various aspects of psychosis and its broader
phenotype, including prodromal symptoms and schizotypy.
In summary, the relationship between substance use and psychosis is complex and influenced by
multiple factors, including the type and amount of substance used, genetic predisposition, and other
environmental factors. Understanding this relationship is crucial for developing effective prevention
and treatment strategies for psychosis, highlighting the need for further research in this area.

3.3.2 Stress and Trauma

Stress and trauma have been identified as significant environmental factors contributing to the etiol-
ogy of psychosis. The relationship between childhood interpersonal trauma and the development of
psychosis symptoms has been extensively studied, revealing a complex interplay that mediates this
association. For instance, loneliness has been found to mediate the relationship between childhood
interpersonal trauma and positive symptoms of psychosis. This suggests that the social isolation
experienced as a result of trauma can exacerbate or contribute to the emergence of psychosis symp-
toms. Furthermore, within-person fluctuations in depressive and anxious symptomatology have been
observed to mediate the relationship between loneliness and psychosis, indicating that the emotional

13
disturbances stemming from trauma and social isolation can further influence the development of
psychosis.
The role of disrupted brain connectivity, particularly within the corpus callosum (CC), in the
etiology of psychosis has also been highlighted. Psychosis is characterized as a neurodevelopmental
disorder involving disrupted cortico-cortical connectivity. This disruption is believed to play a crucial
role in the manifestation of psychosis symptoms, with early psychosis (EP) being associated with
altered white matter connectivity specifically within the CC [Mog+24]. These findings underscore the
importance of understanding the neurobiological underpinnings of psychosis, as they provide insight
into how stress and trauma may lead to alterations in brain structure and function that contribute to
the development of the disorder.
Moreover, the use of validated measures of interpersonal trauma, symptoms/diagnoses, and medi-
ators in research has facilitated a more nuanced understanding of the psychosis spectrum. Psychotic
experiences have been shown to exist on a continuum, ranging from subclinical psychotic-like experi-
ences to full-blown psychotic disorders [Gra+24]. This continuum perspective allows for the exploration
of how varying degrees of stress and trauma exposure may differentially impact the severity and type
of psychosis symptoms experienced by individuals.
The heterogeneity in terms used to describe psychosis-related outcomes in the literature, such as
"psychotic-like experiences," "psychotic symptoms," and "psychotic experiences," reflects the complex-
ity of the disorder and the challenges in delineating its etiology. Despite this variability in terminology,
the consensus is that stress and trauma are pivotal environmental factors that significantly influence
the risk of developing psychosis. The evidence map of genetic moderators of the association between
cannabis use and psychosis-related outcomes further illustrates the multifaceted nature of psychosis
etiology, highlighting the interplay between environmental factors, such as stress and trauma, and
genetic predispositions [Gro+24].
In the context of treatment and impact, understanding the role of stress and trauma in the devel-
opment of psychosis is crucial for the formulation of effective interventions. Services that address the
social and environmental conditions maintaining exposure to psychosis risk are essential for improving
outcomes for individuals affected by the disorder. This includes recognizing and meeting the needs
of vulnerable populations, such as Indigenous youth, whose experiences of stress and trauma may go
unrecognized or unmet by health systems focused on other family members [Man+24].
In summary, the relationship between stress, trauma, and psychosis is complex and multifaceted,
involving a combination of neurobiological alterations, emotional disturbances, and social isolation.
Research efforts continue to unravel the mechanisms underlying this association, with the ultimate
goal of informing more targeted and effective interventions for individuals at risk of or experiencing
psychosis.

3.3.3 Socioeconomic Factors

Socioeconomic factors play a significant role in the etiology of psychosis, influencing both the onset
and the trajectory of the disorder. The interplay between socioeconomic status (SES) and psychosis
is complex, with various elements such as poverty, education, employment status, and social support
systems contributing to the risk and outcomes associated with psychotic disorders. Research has
consistently shown that lower socioeconomic status is associated with a higher risk of developing
psychosis, suggesting that environmental stressors related to SES can act as significant triggers or
exacerbating factors in the development of psychotic symptoms [Mog+24; RM24; Man+24; Ges+24].
One of the critical aspects of socioeconomic influence on psychosis is the concept of social drift,
which posits that individuals with psychotic disorders may experience a decline in their socioeconomic
status due to the debilitating nature of the illness. This decline can lead to worsening symptoms, cre-
ating a vicious cycle where the socioeconomic decline exacerbates the psychosis, which in turn leads to
further socioeconomic deterioration. Additionally, individuals from lower socioeconomic backgrounds
may have less access to mental health services, leading to delays in diagnosis and treatment, which
can worsen the prognosis [Mog+24].
Furthermore, the stress-vulnerability model suggests that individuals with a predisposition to psy-
chosis may be more vulnerable to the effects of socioeconomic stressors. These stressors can include
financial instability, living in deprived neighborhoods, and experiencing social isolation, all of which
can contribute to the onset of psychotic symptoms [Ges+24]. The cumulative effect of these stres-
sors can overwhelm an individual’s coping mechanisms, leading to the emergence or exacerbation of

14
psychosis.
Moreover, socioeconomic factors also intersect with other environmental factors, such as exposure
to trauma, substance abuse, and adverse childhood experiences, which are known to increase the risk of
psychosis. Individuals from lower socioeconomic backgrounds are more likely to experience these risk
factors, further compounding their vulnerability to developing psychotic disorders [Mog+24; RM24].
This highlights the importance of considering the broader social and environmental context when
examining the etiology of psychosis.
The impact of socioeconomic factors on psychosis is not only limited to the individual level but
also extends to the community and societal levels. Communities with higher levels of socioeconomic
deprivation are often characterized by higher rates of psychosis, indicating that the social environ-
ment plays a crucial role in the epidemiology of psychotic disorders. This underscores the need for
cross-sectoral approaches that address the structural determinants of health, including socioeconomic
inequalities, to mitigate the risk of psychosis at the population level.
Addressing the socioeconomic determinants of psychosis requires a multifaceted approach that
includes improving access to education, creating employment opportunities, enhancing social support
networks, and ensuring equitable access to mental health services. Interventions aimed at alleviating
poverty and reducing social inequalities can play a crucial role in preventing the onset of psychosis and
improving outcomes for those affected by the disorder [Man+24].
In summary, socioeconomic factors are integral to understanding the etiology and progression of
psychosis. The interplay between socioeconomic status and psychosis highlights the need for com-
prehensive strategies that address the social determinants of health to effectively prevent and treat
psychotic disorders.

3.4 Interaction of Genetic and Environmental Factors

The interaction of genetic and environmental factors plays a crucial role in the etiology of psychosis,
a complex mental health condition characterized by symptoms such as delusions, hallucinations, and
impaired thought processes. This interaction, often referred to as the gene-environment interplay,
suggests that the development of psychosis is neither solely the result of genetic predisposition nor
purely due to environmental influences, but rather a combination of both.
Genetic predisposition to psychosis is supported by studies indicating a higher risk of developing
psychotic disorders among individuals with a family history of these conditions. However, not all
individuals with a genetic predisposition will develop psychosis, which underscores the significant role
of environmental factors in the manifestation of the disorder. Environmental factors such as childhood
trauma, substance abuse, and social defeat have been identified as significant contributors to the onset
and progression of psychosis.
Childhood trauma, including physical, emotional, and sexual abuse, has been linked to an increased
risk of developing psychosis later in life. The relationship between childhood interpersonal trauma and
positive symptoms of psychosis in adulthood has been demonstrated, with affect being identified as
a small but statistically significant mediator in this relationship [Gra+24]. This suggests that the
emotional response to trauma may play a role in the development of psychotic symptoms.
Substance abuse, particularly cannabis use, has been shown to exacerbate psychotic outcomes in
clinical populations. The adverse effects of cannabis are not limited to the general population but may
further worsen psychosis-related outcomes, indicating a significant environmental risk factor for the
development of psychosis [Gro+24].
Social defeat, characterized by experiences of failure, rejection, and isolation, has also been asso-
ciated with psychotic disorders. The robust connection between various forms of social defeat and
psychotic experiences highlights the impact of social environmental factors on the risk of developing
psychosis. Chronic social defeat, in particular, has been found to have large magnitude associations
with delusion-proneness, suggesting its significant role in the etiology of psychosis [Sho+23].
The interaction between genetic predisposition and environmental factors is further complicated by
the presence of various moderators and mediators. For instance, the psychosis polyrisk score, which
includes factors such as a history of childhood trauma, ethnicity, immigration status, and urbanicity,
aims to improve the detection of individuals at risk for psychosis by considering both genetic and
environmental influences [RM24].
In summary, the etiology of psychosis involves a complex interplay between genetic predisposition
and environmental factors. Understanding this interaction is crucial for identifying individuals at

15
risk, developing preventive strategies, and tailoring treatment approaches to address both genetic and
environmental influences on psychosis. Further research focusing on elucidating the precise mechanisms
of this interaction will enhance our understanding of psychosis and improve outcomes for individuals
affected by this condition.

4 Diagnosis and Assessment

4.1 Clinical Assessment
4.1.1 Interviews and History Taking
Interviews and history taking are pivotal components in the clinical assessment of individuals presenting
with symptoms suggestive of psychosis. This process is not only fundamental in establishing a diagnosis
but also in formulating a comprehensive treatment plan that addresses the unique needs of each patient.
The nuanced nature of psychosis, with its diverse symptomatology and complex etiologies, necessitates
a thorough and empathetic approach to history taking and interviewing.
The initial step in this process involves the collection of a detailed psychiatric history, which
is crucial for distinguishing between primary psychotic disorders and symptoms secondary to other
conditions, such as substance-induced psychosis or organic brain disorders. This differentiation is
essential, as it significantly influences the subsequent management and treatment strategies. For
instance, patients with substance-induced psychosis or organic brain disorders were excluded from
certain studies to ensure a homogeneous study population, underscoring the importance of accurate
diagnosis.
Moreover, the inclusion criteria for studies often require that participants have had limited prior
exposure to antipsychotic medications, highlighting the significance of understanding the patient’s
treatment history. This information not only aids in the assessment of the current episode but also
provides insights into the patient’s response to previous interventions, which can guide future treatment
choices.
The use of structured clinical interviews, such as the Structured Clinical Interview for DSM-IV-TR
criteria, is a common practice in the assessment of psychosis. These interviews allow for a systematic
evaluation of symptoms and have been instrumental in the diagnosis of affective and non-affective psy-
chosis. The structured approach ensures that all relevant clinical information is gathered, facilitating
a comprehensive understanding of the patient’s condition.
In addition to structured interviews, the assessment process often incorporates patient-reported
outcome measures (PROMs) and clinician-rated outcome measures (CROMs), which are administered
in the patient’s preferred language to ensure accurate communication and understanding. These tools
provide valuable quantitative data on the patient’s symptoms, functioning, and overall well-being,
further enriching the clinical assessment.
The distress total score, rather than individual item scores, has been adopted in some settings
to improve the specificity of the assessment, particularly in the context of screening for psychosis or
psychosis spectrum disorders [Sav+24]. This approach reflects the ongoing efforts to refine assessment
methodologies to achieve greater accuracy and reliability in the diagnosis of psychosis.
Furthermore, the integration of time-varying covariates in the assessment process allows for the
dynamic nature of clinical symptoms to be considered throughout the course of treatment. This ap-
proach acknowledges the fluctuating course of psychosis and the impact of various factors on symptom
severity over time, enabling a more personalized and responsive treatment plan.
The role of intersubjectivity, or the ability to share in another’s lived experience, in the co-
construction of the patient narrative is also recognized as a critical aspect of the assessment process
[Nai+24]. This concept emphasizes the importance of a collaborative relationship between the patient
and clinician, where both perspectives are valued and integrated to enhance the therapeutic alliance
and ultimately improve treatment outcomes.
In summary, interviews and history taking in the context of psychosis assessment are multifaceted
processes that require a careful and empathetic approach. The use of structured interviews, along with
PROMs and CROMs, facilitates a thorough evaluation of the patient’s symptoms and history. The
incorporation of time-varying covariates and an emphasis on intersubjectivity further enrich the assess-
ment, enabling a more nuanced understanding of the patient’s condition and guiding the development
of a tailored treatment plan.

16
4.1.2 Use of Diagnostic Criteria
The use of diagnostic criteria in the clinical assessment of psychosis is a cornerstone in ensuring accu-
rate diagnosis, which is critical for effective treatment planning and understanding the impact of the
disorder. Diagnostic criteria serve as a standardized framework for clinicians to identify and catego-
rize symptoms of psychosis, which can vary widely among individuals. The Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5), provides one such set of criteria, emphasizing the
importance of specific symptoms such as delusions, hallucinations, disorganized thinking, and negative
symptoms for the diagnosis of psychotic disorders.
In the context of early intervention services for psychosis, the utilization of patient-reported mea-
sures alongside clinical assessments has been highlighted as a valuable approach. This method allows
for the collection of data directly from patients regarding their symptoms, quality of life, and experi-
ences with care without clinician interference or bias. Such an approach not only aids in the diagnostic
process but also helps in addressing power imbalances and improving communication between patients
and clinicians [Nai+24]. This is particularly relevant in the assessment of subthreshold psychosis,
where symptoms may not fully meet the criteria for a psychotic disorder as defined by the DSM-5 but
still significantly impact the individual’s functioning and quality of life.
Furthermore, the inclusion of specific scales and outcome measures, such as the Positive And
Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF), in the diagnostic
process allows for a more nuanced understanding of the severity and impact of psychosis symptoms
on an individual’s daily life [Pel+24]. These tools provide a quantitative measure of symptoms and
functioning, which can be invaluable in both diagnosis and monitoring treatment outcomes.
However, the diagnostic process is not without its challenges. For instance, the generalizability of
findings from diagnostic assessments can be limited by factors such as the setting in which screening
is implemented and the prevalence of psychotic spectrum disorders in the population being studied
[Sav+24]. This highlights the need for careful consideration of the context in which diagnostic criteria
and screening tools are applied.
Moreover, the heterogeneity in study variables and analyses across research on psychosis necessitates
a narrative approach to synthesize findings from included studies, as opposed to a more straightforward
quantitative synthesis [Gra+24]. This underscores the complexity of diagnosing psychosis, which
cannot be fully captured by a single set of criteria or measure.
In addressing these challenges, the development and validation of diagnostic criteria and assessment
tools that are sensitive to the diverse presentations of psychosis are crucial. This includes considering
the methodological differences in biospecimen type, scales used for assessing psychotic-like experiences
(PLEs), and the age at which PLE assessment and biomarker measurements are conducted, as these
factors can contribute to the heterogeneity of study findings [Tay+24].
In summary, the use of diagnostic criteria in the clinical assessment of psychosis is a multifaceted
process that requires a combination of standardized diagnostic tools, patient-reported measures, and
consideration of the specific context in which the assessment is conducted. By adhering to these
principles, clinicians can enhance the accuracy of psychosis diagnoses, thereby facilitating more effective
treatment and ultimately improving outcomes for individuals affected by this complex disorder.

4.2 Psychometric Assessments

4.2.1 Symptom Scales
Symptom scales play a pivotal role in the psychometric assessment of psychosis, facilitating the quan-
tification and evaluation of symptoms that are otherwise qualitative and subjective in nature. These
scales are instrumental in diagnosing and assessing the severity of psychotic disorders, thereby guid-
ing treatment decisions and monitoring the impact of interventions over time. The development and
validation of reliable and valid symptom scales are therefore critical for advancing our understanding
of psychosis and improving patient care.
One of the fundamental challenges in the field of psychosis research and clinical practice is the
heterogeneity of symptoms among individuals. Psychotic symptoms can range from hallucinations
and delusions to disorganized thinking and negative symptoms such as apathy or lack of motivation.
This diversity necessitates the use of comprehensive symptom scales that can capture the wide array
of symptoms associated with psychosis. The Positive and Negative Syndrome Scale (PANSS) and the
Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative

17
Symptoms (SANS) are examples of such comprehensive tools that have been widely used in both
research and clinical settings [Nai+24].
The accuracy of symptom scales in identifying psychosis and the spectrum of psychotic disorders
is of paramount importance. For instance, the Prodromal Questionnaire – Brief Version (PQ-B) has
been utilized to detect early signs of psychosis, demonstrating the potential for early intervention and
prevention strategies. However, the challenge of low sample sizes in studies assessing the effectiveness
of these tools underscores the need for caution in interpreting their results. The discrepancies observed
in symptom identification, even with additional training provided to healthcare providers, highlight
the complexity of accurately diagnosing psychosis and the necessity for further refinement of these
scales [Sav+24].
Moreover, the role of symptom scales extends beyond diagnosis to include the assessment of risk
and prognosis. For example, the identification of individuals at clinical high risk for psychosis (CHR-
P) relies on specific symptom criteria that can be quantified using structured assessment tools. This
approach not only aids in the early detection of psychosis but also in the stratification of risk levels
among individuals presenting with subthreshold symptoms [Cor+24].
The integration of symptom scales with biological markers represents a promising avenue for en-
hancing the precision of psychosis diagnosis and assessment. The complexity of psychosis, influenced
by a myriad of genetic, neurobiological, and environmental factors, necessitates a multimodal approach
to its assessment. The exploration of biological criteria, in conjunction with psychometric assessments,
holds the potential to improve the early detection of psychosis and tailor interventions to individual
needs [Jen+24].
In summary, symptom scales are indispensable tools in the psychometric assessment of psychosis,
enabling the quantification of diverse symptoms, guiding clinical decision-making, and facilitating
research into the underlying mechanisms of psychotic disorders. The ongoing development and refine-
ment of these scales, coupled with advances in our understanding of the biological underpinnings of
psychosis, are essential for improving the diagnosis, treatment, and prognosis of individuals affected
by these complex disorders.

4.2.2 Cognitive Assessments

Cognitive assessments play a crucial role in the diagnosis and evaluation of psychosis, providing insights
into the cognitive deficits that often accompany this condition. The Montreal Cognitive Assessment
(MoCA) has been highlighted for its utility in detecting cognitive deficits in individuals with early
stages of schizophrenia, including those experiencing First Episode Psychosis (FEP), Clinical High
Risk (CHR), and Psychosis-Like Experiences (PLE). This tool is praised for its ease of use and brief
administration time, making it an efficient option for clinicians.
Research has demonstrated a significant trend towards lower MoCA scores across various cognitive
domains in individuals with psychosis, following the order from healthy controls (HC) to those with
PLE, CHR, and FEP, indicating a gradation of cognitive impairment that correlates with the severity
of psychotic symptoms [Cor+24]. This gradation underscores the importance of early detection and
intervention, as cognitive deficits can severely impact the quality of life and functional outcomes for
individuals with psychosis.
Furthermore, the inclusion of patient-reported measures in mental healthcare has gained traction,
emphasizing the importance of integrating subjective experiences with objective assessments to form
a comprehensive understanding of the patient’s condition [Nai+24]. This approach aligns with the
broader movement towards measurement-based care, which advocates for the use of both clinician-
administered and patient-reported measures to guide treatment planning and monitor progress.
The significance of cognitive assessments extends beyond diagnosis and treatment planning. Studies
have explored the association between traumatic stress load, psychopathology, and cognition, suggest-
ing that cognitive impairments in psychosis may also be influenced by environmental factors such
as trauma [Tay+24]. This highlights the complex interplay between biological, psychological, and
environmental factors in the manifestation of cognitive deficits in psychosis.
In the context of research, the consistent use of updated diagnostic tools like the DSM-5 and
PSYRATS, along with rigorous methodological approaches, has been recommended to improve the
accuracy of psychosis prevalence data and, by extension, the understanding of cognitive impairments
associated with the condition [SSE23]. This call for greater methodological rigor underscores the

18
need for standardized assessment protocols to ensure the reliability and validity of findings related to
cognitive deficits in psychosis.
The exploration of cognitive assessments in psychosis is further enriched by studies investigating
neurophysiological patterns of dysconnectivity in individuals with FEP and EP. These studies aim to
uncover the neural mechanisms underlying psychosis and identify reliable and sensitive biomarkers for
early detection [Jen+24]. Such biomarkers could revolutionize the approach to diagnosing and treating
psychosis, enabling interventions to be tailored more precisely to the individual’s neurocognitive profile.
In summary, cognitive assessments are indispensable in the context of psychosis, offering valuable
insights into the cognitive impairments that characterize the condition. Tools like the MoCA facilitate
the early detection of cognitive deficits, while the integration of patient-reported measures and the
pursuit of biomarkers for psychosis underscore the evolving landscape of psychosis diagnosis and treat-
ment. The ongoing refinement of assessment tools and methodologies promises to enhance the accuracy
and efficacy of interventions for individuals with psychosis, ultimately improving their prognosis and
quality of life.

4.3 Challenges in Diagnosis

4.3.1 Differential Diagnosis
Differential diagnosis in the context of psychosis spectrum disorders presents a significant challenge
due to the heterogeneity of symptoms and their overlap with other psychiatric conditions. The process
of distinguishing between various psychosis spectrum disorders and other mental health issues requires
careful consideration of symptomatology, patient history, and, in some cases, the response to initial
treatment interventions. This complexity is further compounded by the need to identify care pathways
for individuals who may not meet the full criteria for early psychosis care but still require mental health
services.
One of the primary challenges in differential diagnosis lies in the accurate identification of psychosis
spectrum disorders. A study highlighted the use of a threshold of ≥ 27 to identify psychosis spectrum
disorder, which resulted in a mix of true positives, true negatives, false positives, and false negatives
[Sav+24]. This underscores the difficulty in setting a clear diagnostic threshold that can reliably dis-
tinguish between those with and without the disorder. The implications of misdiagnosis are profound,
affecting treatment decisions and ultimately patient outcomes.
Moreover, the persistence of psychosis spectrum symptoms over time adds another layer of com-
plexity to differential diagnosis. A prospective two-year follow-up study demonstrated the enduring
nature of these symptoms in a cohort, suggesting that the diagnostic process cannot rely solely on a
cross-sectional assessment but must also consider the longitudinal course of symptoms [Tay+24]. This
longitudinal perspective is crucial for distinguishing between transient psychotic experiences and those
indicative of a more persistent psychosis spectrum disorder.
The intervention strategies for psychosis spectrum disorders often involve a combination of psy-
choeducation, cognitive-behavioral therapy, and medication management, tailored to the individual’s
specific symptoms and diagnostic profile [Far+24]. This personalized approach underscores the impor-
tance of accurate differential diagnosis in informing treatment planning. Without a clear understanding
of the underlying disorder, clinicians may struggle to select the most appropriate and effective inter-
ventions.
Furthermore, the diagnostic process must navigate the challenge of diagnostic neutrality and mini-
mize the medicalization of symptoms. Prioritizing a patient-centered approach that allows individuals
to express their subjective experiences without immediately categorizing them into diagnostic boxes
has been shown to improve care. This approach emphasizes the importance of self-reported measures
and a careful clinical encounter that respects the complexity of the patient’s experience.
In addition, the consideration of comorbidities and the patient’s preferred language of assessment
are critical factors that can influence the diagnostic process. Acknowledging the potential biases
introduced by language barriers and the presence of physical health comorbidities is essential for a
comprehensive and accurate assessment [Nai+24]. These factors highlight the multifaceted nature of
differential diagnosis, requiring clinicians to consider a wide range of influences on the patient’s mental
health.
In summary, the differential diagnosis of psychosis spectrum disorders is a complex and nuanced
process that demands a careful and comprehensive evaluation of symptoms, patient history, and the

19
longitudinal course of the disorder. The challenges inherent in this process underscore the need for
a patient-centered approach that prioritizes diagnostic accuracy and the minimization of biases. By
addressing these challenges, clinicians can improve the precision of their diagnoses, thereby enhancing
the effectiveness of treatment interventions and ultimately improving patient outcomes.

4.3.2 Subclinical and Prodromal States

Subclinical and prodromal states represent critical phases in the continuum of psychotic disorders,
where symptoms may not yet meet the full criteria for a clinical diagnosis but indicate a heightened
risk for developing a psychotic disorder such as schizophrenia. These early stages, including the Clinical
High Risk (CHR) state for psychosis, are characterized by mild or transient psychotic symptoms and
other nonspecific symptoms. Identifying and understanding these states are paramount for early
intervention strategies, which aim to delay or prevent the transition to full-blown psychosis.
The CHR state encompasses a heterogeneous group, with only a subset of individuals eventually
transitioning to a psychotic disorder. Studies suggest that about 25% of individuals in the CHR state
transition to psychosis within the first four years, with the rate increasing to 35% within ten years.
This variability underscores the challenge in diagnosing and treating individuals in these early stages,
as the CHR state represents a broader range of psychopathology than solely the prodromal stages of
psychosis.
Microstate analysis, a method that examines the brain’s electrical activity, has been explored as
a potential tool for understanding the neurobiological underpinnings of these subclinical and prodro-
mal states. Microstates are brief, stable patterns of brain activity that are thought to represent the
building blocks of human thought processes. Alterations in microstate parameters have been observed
in individuals with psychosis and those at high risk, suggesting their potential as biomarkers for early
detection. However, findings regarding microstate dynamics in CHR individuals compared to those
with manifest psychosis have been inconsistent. Some studies have found no significant differences in
microstate parameters between these groups, indicating that these neurophysiological signatures may
not depend on disease progression.
Furthermore, the impact of antipsychotic medication on microstate dynamics adds another layer of
complexity. Medications commonly used to treat psychosis symptoms can alter microstate parameters,
potentially confounding the interpretation of these measures in clinical and research settings [Lie+24].
This highlights the importance of considering medication status when evaluating microstate analyses
in the context of psychosis and its prodromal states.
In addition to neurophysiological approaches, the role of biomarkers of immunity and oxidative
stress has been investigated in relation to pediatric psychosis and psychosis-risk states. Elevated levels
of proinflammatory markers have been found in youth with threshold psychosis compared to those
without, suggesting that inflammation may play a role in the pathophysiology of early psychotic states
[Tay+24]. However, the specificity of these biomarkers to psychosis, as opposed to other psychiatric
conditions, remains to be fully elucidated.
The challenges in diagnosing subclinical and prodromal states of psychosis are further compounded
by the heterogeneity of symptoms and the influence of external factors such as medication and comorbid
conditions. Despite these challenges, the identification of reliable biomarkers and neurophysiological
signatures holds promise for improving the early detection and intervention of psychotic disorders.
Continued research in this area is crucial for developing targeted therapies that can potentially alter
the trajectory of these conditions, ultimately improving outcomes for individuals at risk for psychosis.

5 Treatment and Management

5.1 Pharmacological Interventions
5.1.1 Antipsychotics
Antipsychotics play a pivotal role in the pharmacological intervention of psychotic disorders, offering
symptomatic relief and stabilization for patients. These medications are fundamental in managing both
acute psychotic episodes and long-term maintenance to prevent relapse. The efficacy of antipsychotics
in alleviating psychotic symptoms, such as hallucinations and delusions, is well-documented, although
their impact on negative symptoms and cognitive deficits remains more ambiguous [Nom+24; Vel+24].

20
 The treatment landscape of psychosis has been significantly shaped by the advent of antipsychotic
medications. Initially, the discovery of chlorpromazine marked the beginning of the modern era of
antipsychotic treatment, leading to the development of a wide range of first-generation antipsychotics.
Despite their effectiveness in treating positive symptoms, these medications are associated with a
high incidence of extrapyramidal side effects, including tardive dyskinesia and parkinsonism, which
significantly impact patients’ quality of life.
In response to these challenges, second-generation antipsychotics were developed, offering a more
favorable side effect profile, particularly regarding motor side effects. These medications are thought
to provide better management of negative symptoms and cognitive impairments, which are critical
determinants of functional outcomes in patients with schizophrenia and related disorders. However,
concerns regarding metabolic side effects, such as weight gain and increased risk of diabetes, have been
raised with some of these newer agents, necessitating careful consideration in treatment planning.
The heterogeneity in response to antipsychotic treatment among patients underscores the complex-
ity of psychotic disorders and the need for personalized treatment approaches. Factors such as the
inflammatory subtypes of schizophrenia have been associated with altered brain morphology and may
influence treatment response, suggesting that biomarkers could play a role in guiding antipsychotic
selection in the future [Vel+24]. Additionally, the duration of untreated psychosis (DUP) has been
identified as a critical factor in treatment outcomes, with longer DUP associated with poorer prog-
nosis. This highlights the importance of early intervention and the timely initiation of antipsychotic
treatment to optimize outcomes [Pel+24].
Despite the effectiveness of antipsychotics in managing psychosis, the challenge of treatment re-
sistance remains, with a significant proportion of patients not achieving satisfactory response to con-
ventional antipsychotic therapy. This has led to the exploration of adjunctive treatments and the use
of clozapine for treatment-resistant schizophrenia, which, despite its potential for serious side effects,
remains the most effective medication for this patient group [Nom+24].
The impact of antipsychotics extends beyond symptom control, influencing the overall trajectory
of psychotic disorders. While these medications are a cornerstone of treatment, their use must be
balanced with the management of side effects and the pursuit of comprehensive care approaches that
include psychosocial interventions. The ongoing research into the mechanisms underlying psychosis
and the development of novel therapeutic targets promises to further refine the role of antipsychotics
in the treatment landscape [Wil+24].
In summary, antipsychotics are a critical component of the pharmacological management of psy-
chotic disorders, offering relief from the most distressing symptoms and enabling better functional
outcomes. The evolution of these medications has significantly improved the quality of life for many
patients, although challenges in treatment response and side effect management persist. Future ad-
vancements in understanding the pathophysiology of psychotic disorders and the development of tar-
geted treatments hold the promise of further enhancing the efficacy and tolerability of antipsychotic
medications.

5.1.2 Adjunctive Treatments

Adjunctive treatments in the management of psychosis play a crucial role in enhancing the efficacy
of primary pharmacological interventions. These treatments, which include psychoeducation, family
engagement, and the use of partial agonists, are designed to address the multifaceted nature of psy-
chosis, targeting not only the symptoms but also the broader psychosocial and environmental factors
that influence patient outcomes.
Psychoeducation emerges as a significant adjunctive treatment, providing patients and their fam-
ilies with essential information about the disorder, its management, and strategies for coping with
its impact. This educational approach fosters a better understanding of psychosis, which can lead to
improved treatment adherence and outcomes. The incorporation of family-based psychoeducational
methods has been shown to significantly enhance the prognosis of patients with psychotic disorders,
particularly when initiated early in the treatment process. This underscores the importance of involv-
ing the patient’s support system in the therapeutic journey, facilitating a collaborative approach to
management.
Family engagement, facilitated through psychoeducational methods, not only educates the family
about the disorder but also integrates them into the care and support framework. This approach
has been identified as a key factor in improving patient outcomes, as it addresses the social and

21
environmental aspects of the disorder. The use of "cultural brokers," such as interpreters or religious
counselors, can further bridge communication and cultural gaps, ensuring that the treatment plan
is culturally sensitive and more likely to be accepted and followed by the patient and their family
[Bon+24].
The exploration of partial agonists as an option in the pharmacological management of psychosis
represents another facet of adjunctive treatments. These agents, characterized by their ability to act
as agonists at some receptors and antagonists at others, have been hypothesized to offer benefits in
terms of fewer motor side effects, affective regulation, and improvement in depressive symptoms, while
also sparing prolactin levels [Nom+24]. Although specific clinical guidelines for the management of
psychosis with partial agonists are yet to be established, their potential for a more favorable side effect
profile makes them an area of interest for further research.
In conclusion, adjunctive treatments in the management of psychosis encompass a range of strate-
gies aimed at enhancing the effectiveness of primary pharmacological interventions. Through the
integration of psychoeducation, family engagement, and the potential use of partial agonists, these
treatments address the complex interplay of biological, psychological, and social factors in psychosis.
The ongoing exploration of these adjunctive strategies highlights the evolving nature of psychosis
management, emphasizing the need for a holistic approach that considers the diverse needs of patients.

5.2 Psychosocial Interventions

5.2.1 Psychotherapy
Psychotherapy stands as a cornerstone in the treatment and management of psychosis, offering a
multifaceted approach to address both the symptoms and underlying causes of the condition. The
efficacy of psychotherapy in psychosis is underscored by its ability to improve social functioning and
alleviate depressive symptoms, as evidenced by the use of continuous validated rating scales in assessing
outcomes. This highlights the critical role of psychotherapy not only in symptom management but
also in enhancing the quality of life for individuals with psychosis.
The initiation of Early Intervention in Psychosis (EIP) interventions, which often include psy-
chotherapy, has shown preliminary evidence of effectiveness. However, the specific components that
contribute most significantly to their success, such as particular medications, modalities of psycho-
logical therapy, or social interventions, require further investigation to fully understand their impact
[Wil+24]. This underscores the necessity for more research to refine psychotherapy approaches within
EIP frameworks to maximize their benefits.
Augmentation strategies, such as the use of estrogens and selective estrogen-receptor modulators
(SERMs), have been suggested to enhance antipsychotic treatment, particularly in postmenopausal
women with psychosis. These strategies not only aim to reduce side effects but also seek to improve
menopause-related and cognitive symptoms, indicating a nuanced approach to psychotherapy that con-
siders the biological underpinnings of psychosis [Nom+24]. This approach exemplifies the personalized
nature of psychotherapy, where treatments are tailored to meet the unique needs of each individual,
taking into account factors such as gender and physiological changes.
The relationship between trauma, particularly that involving intentional harm, and psychosis fur-
ther emphasizes the importance of psychotherapy. Research indicates that trauma, especially when it
results in Complex PTSD, is strongly associated with psychosis [Gra+24]. This association highlights
the need for psychotherapy interventions that are sensitive to the trauma histories of individuals with
psychosis, aiming to address not only the psychotic symptoms but also the underlying trauma that
may contribute to the condition.
Moreover, the implementation of Cognitive Remediation (CR) as a form of psychotherapy for
psychosis presents challenges in clinical services, despite clear evidence of its effectiveness. Studies
evaluating different methods of CR delivery, including group and one-to-one sessions with a therapist,
have found them to be equivalent in benefit and cost-effectiveness compared to independent CR with
minimal therapist support [Cel+24]. This suggests that while CR is a valuable psychotherapeutic
intervention for psychosis, the mode of delivery can be flexible, allowing for adaptation to the needs
and preferences of the individual.
Participants in psychotherapy interventions have reported the desire for longer engagement in
therapy to address not only depersonalisation but also additional issues such as self-esteem and trauma,
indicating the complex and interconnected nature of psychosis symptoms and causes [Far+24]. This

22
feedback underscores the necessity for psychotherapy to be adaptable and responsive to the evolving
needs of individuals with psychosis, ensuring that treatment is not only effective in addressing specific
symptoms but also in facilitating overall mental health and well-being.
In summary, psychotherapy for psychosis encompasses a broad spectrum of interventions, from tra-
ditional psychotherapeutic techniques to innovative augmentation strategies and trauma-informed care.
The effectiveness of psychotherapy in improving social functioning, alleviating depressive symptoms,
and addressing the underlying causes of psychosis underscores its indispensable role in the comprehen-
sive treatment and management of the condition. As research continues to elucidate the most effective
components and delivery methods of psychotherapy for psychosis, it is imperative that interventions
remain personalized, trauma-informed, and adaptable to the needs of individuals, thereby ensuring the
right care, first time [Jen+24].

5.2.2 Social Support and Rehabilitation

Social Support and Rehabilitation play a crucial role in the treatment and management of psychosis,
offering a complementary approach to pharmacological interventions. The importance of integrating so-
cial support mechanisms and rehabilitation services into the care of individuals experiencing psychosis
cannot be overstated, as these psychosocial interventions are associated with sustained reductions in
psychotic symptoms and improvements in patients’ overall well-being [Wil+24].
The concept of social support encompasses a broad range of services and interactions that can
provide emotional, informational, and practical assistance. These services are designed to address the
social and emotional aspects of living with psychosis, helping individuals to rebuild their confidence,
regain social skills, and foster a sense of belonging within their communities. Rehabilitation services,
on the other hand, focus on helping individuals to develop the skills and strategies needed to manage
their symptoms, improve their functioning, and achieve their personal recovery goals. This can include
vocational training, educational support, and cognitive-behavioral therapies aimed at improving coping
mechanisms.
One of the key aspects of effective social support and rehabilitation is the emphasis on personalized
care, which acknowledges the unique needs and preferences of each individual. Collaborative care
models, where medical and behavioral health staff work closely together, have been shown to be
particularly effective in providing comprehensive support to individuals with psychosis. These models
facilitate coordination between different services, ensuring that care is seamless and that individuals
receive the most appropriate interventions for their specific circumstances [Sav+24].
Moreover, the integration of family-oriented responses into social support and rehabilitation efforts
has been identified as a valuable strategy for enhancing the effectiveness of psychosocial interventions.
By involving family members in the care process, interventions can be more closely aligned with the
individual’s social context, providing a more supportive environment for recovery. External evaluations
for social accountability have also been suggested as a means to ensure that interventions are responsive
and tailored to the needs of the community, further emphasizing the importance of a holistic approach
to care.
However, the implementation of social support and rehabilitation services faces several challenges,
including barriers related to socio-cultural priorities within institutions. These barriers can hinder the
successful integration of psychosocial interventions into standard care practices, underscoring the need
for systemic changes that prioritize social responsiveness over traditional, output-focused models of
service delivery [Man+24]. Addressing these challenges requires a concerted effort from all stakeholders
involved in mental health care, including policymakers, healthcare providers, and the community at
large.
In summary, social support and rehabilitation are essential components of a comprehensive ap-
proach to the treatment and management of psychosis. By focusing on the social and emotional needs
of individuals, these interventions can significantly enhance the quality of care and contribute to better
outcomes for those affected by psychosis. As research and practice in this area continue to evolve, it
is crucial to remain committed to developing and implementing strategies that are person-centered,
inclusive, and responsive to the diverse needs of individuals living with psychosis.

23
5.3 Emerging Treatments
5.3.1 Neuromodulation Techniques
Neuromodulation techniques have emerged as a promising avenue for the treatment and management
of psychosis, particularly given the limitations of traditional pharmacotherapy and psychotherapy in
fully addressing the complex symptomatology and underlying neurobiological alterations associated
with psychotic disorders. These techniques, which include both invasive and non-invasive methods,
aim to directly modulate neural activity in specific brain circuits implicated in psychosis, thereby
offering a novel approach to treatment that could potentially ameliorate symptoms or even alter the
disease trajectory.
One of the key targets for neuromodulation in psychosis is the fronto-striatal circuit, abnormali-
ties within which have been consistently implicated in the pathophysiology of first-episode psychosis
(FEP). This circuit, integral to cognitive and emotional processing, has shown dysconnectivity and
aberrant activity patterns in individuals with psychosis, as evidenced by resting-state functional mag-
netic resonance imaging (rs-fMRI) studies. Specifically, increased spontaneous neural activity in the
striatum and widespread dysconnectivity between the caudate and several other brain regions have
been observed [Jen+24]. These findings underscore the potential of targeting the fronto-striatal circuit
through neuromodulation techniques to address core pathophysiological processes in psychosis.
Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) rep-
resent two non-invasive neuromodulation strategies that have garnered attention for their potential
in treating psychosis. TMS utilizes magnetic fields to induce electrical currents in the brain, thereby
modulating neuronal activity, while tDCS applies a constant, low electrical current to the scalp to
achieve a similar effect. Both techniques have the advantage of being relatively well-tolerated and
offering the possibility of targeting specific brain regions implicated in psychosis, such as those within
the fronto-striatal circuit. However, the precise mechanisms through which these interventions exert
their therapeutic effects, as well as their optimal parameters (e.g., frequency, intensity, and duration
of stimulation), remain areas of active investigation.
Deep brain stimulation (DBS), an invasive form of neuromodulation, involves the surgical implan-
tation of electrodes in specific brain areas, with the electrodes connected to a pulse generator that
delivers electrical impulses to modulate neural activity. While DBS has been extensively studied and
applied in the treatment of movement disorders, its application in psychosis is still experimental. The
potential of DBS lies in its ability to provide continuous, targeted modulation of brain circuits im-
plicated in psychosis, such as the fronto-striatal circuit, with the possibility of adjusting stimulation
parameters to optimize therapeutic outcomes. However, the invasive nature of DBS, along with the
associated risks and ethical considerations, necessitates careful patient selection and rigorous clinical
trials to fully evaluate its efficacy and safety in the context of psychosis.
In conclusion, neuromodulation techniques offer a promising complement to existing treatment
modalities for psychosis, with the potential to address some of the limitations of current pharmaco-
logical and psychotherapeutic approaches. By directly targeting the neural circuits implicated in the
pathophysiology of psychosis, these techniques open new avenues for intervention that could lead to
improved outcomes for individuals affected by this challenging condition. Further research is needed to
elucidate the mechanisms underlying the therapeutic effects of neuromodulation, optimize treatment
parameters, and evaluate the long-term efficacy and safety of these interventions in diverse populations
with psychosis.

5.3.2 Digital and Mobile Health Interventions

Digital and Mobile Health Interventions (DMHIs) have emerged as a promising avenue for enhancing
the accessibility and effectiveness of treatments for psychosis. These interventions leverage technology
to deliver therapeutic content, monitor symptoms, and provide support, thereby addressing some of
the barriers associated with traditional face-to-face therapies. The integration of DMHIs into the
treatment landscape for psychosis is informed by a growing body of research that underscores their
potential to facilitate early intervention, support ongoing management, and improve outcomes for
individuals experiencing psychosis.
One of the key advantages of DMHIs is their ability to provide continuous monitoring and sup-
port in real-time, which is particularly valuable for managing a condition characterized by fluctuating
symptoms and the need for timely intervention. For instance, the use of mobile applications equipped

24
with symptom tracking functionalities enables individuals to monitor their mental health status, rec-
ognize early signs of relapse, and seek appropriate support promptly. This proactive approach to
symptom management can significantly enhance the effectiveness of treatment strategies by ensuring
that interventions are administered at the optimal time.
Furthermore, DMHIs offer the potential to deliver personalized treatment experiences. Through
the collection and analysis of data on an individual’s symptoms, behaviors, and preferences, these in-
terventions can tailor therapeutic content and recommendations to meet the specific needs of each user.
This level of personalization is difficult to achieve in traditional treatment settings but is facilitated
by the sophisticated algorithms and data processing capabilities of digital platforms [Sav+24].
The accessibility of DMHIs also addresses a critical barrier to treatment for many individuals with
psychosis: the stigma associated with seeking mental health services. By providing a discreet and
convenient way to access support, DMHIs can encourage more individuals to engage with treatment
services, thereby reducing the impact of stigma on treatment uptake [Bon+24]. Additionally, the
flexibility of digital platforms, which can be accessed at any time and from any location, ensures that
support is available when it is most needed, overcoming logistical barriers such as transportation and
scheduling conflicts that often hinder access to traditional services.
Despite these advantages, the implementation of DMHIs in the treatment of psychosis is not without
challenges. Ensuring the clinical efficacy and safety of these interventions requires rigorous evaluation
through well-designed studies. The variability in the duration of treatment and the degree of exposure
to intervention components across different studies highlights the need for standardized protocols to
assess the effectiveness of DMHIs [Wil+24]. Moreover, ethical considerations related to privacy and
data security must be addressed to protect the sensitive information collected through digital platforms
[Man+24].
In summary, Digital and Mobile Health Interventions represent a significant advancement in the
treatment and management of psychosis. By leveraging technology to enhance accessibility, person-
alization, and continuous support, DMHIs have the potential to improve outcomes for individuals
experiencing psychosis. However, the successful integration of these interventions into clinical prac-
tice requires careful consideration of their clinical efficacy, ethical implications, and the challenges
associated with their implementation.

5.4 Treatment Challenges

5.4.1 Treatment Resistance
Treatment resistance in the context of psychosis presents a significant challenge in the management and
therapeutic intervention of affected individuals. The phenomenon of treatment resistance is character-
ized by a patient’s lack of substantial clinical improvement despite the administration of adequate doses
of antipsychotic medications over a sufficient period. This condition not only complicates the clinical
management of psychosis but also impacts the prognosis and overall quality of life of the patients.
The primary outcomes of interest in evaluating the effectiveness of interventions for psychosis
include changes in the severity of positive and negative psychotic symptoms and the rate of discon-
tinuation from treatment for any reason, which may encompass recovery or other factors not neces-
sarily indicative of a poor outcome. However, the presence of treatment resistance complicates these
outcomes, as traditional pharmacotherapy may not yield the expected clinical improvements. This
necessitates a broader exploration of treatment modalities beyond conventional pharmacotherapy.
In addressing treatment resistance, the classification of interventions into combinations of pre-
specified components of care, such as case management, pharmacotherapy, psychological interventions,
family interventions, and social interventions, provides a structured approach to treatment. Despite
this comprehensive framework, the incremental benefits observed by adding specific components to
pharmacotherapy were generally modest, highlighting the challenge of overcoming treatment resistance.
This finding underscores the complexity of treatment resistance and the need for innovative strategies
that go beyond standard pharmacological approaches.
The exploration of psychological interventions, in addition to pharmacotherapy, has shown prelimi-
nary evidence of varying effects, from no clinically relevant impact to significant improvements in social
functioning one year after treatment delivery [Wil+24]. This suggests that psychological interventions
may offer a valuable adjunctive treatment modality for addressing treatment resistance, although the
evidence remains preliminary and further research is needed to establish their efficacy conclusively.

25
 Moreover, the assessment of therapist competence and fidelity in delivering interventions, as well
as the feasibility of trial procedures and acceptability of therapy, are critical components in evaluating
the effectiveness of treatment modalities for psychosis [Far+24]. These factors play a significant role
in ensuring the quality and consistency of care provided to patients, which is particularly important
in the context of treatment resistance where tailored and high-quality interventions are essential.
The inclusion of patients with substance use problems in research studies, without considering it as
part of any exclusion criteria, reflects the real-world complexity of treating psychosis and the overlap-
ping challenges that may contribute to treatment resistance [Pel+24]. This approach acknowledges the
multifaceted nature of psychosis and the importance of addressing co-occurring conditions to enhance
treatment outcomes.
In summary, treatment resistance in psychosis represents a multifaceted challenge that necessi-
tates a comprehensive and innovative approach to treatment. The modest benefits observed with the
addition of specific components to pharmacotherapy highlight the need for further research and the
development of tailored interventions that address the unique needs of treatment-resistant patients.
The exploration of psychological interventions, alongside the assessment of therapist competence and
the feasibility of trial procedures, underscores the importance of a holistic approach to treatment that
encompasses both pharmacological and non-pharmacological strategies.

5.4.2 Side Effects and Compliance

Side effects and compliance are critical factors that significantly influence the treatment outcomes
for individuals with psychosis. The management of psychosis often involves pharmacotherapy, among
other interventions, to mitigate the symptoms and improve the quality of life for patients. However,
the efficacy of these treatments can be substantially compromised by the side effects associated with
antipsychotic medications and the challenges related to patient compliance.
Antipsychotic medications, while central to the treatment of psychosis, are known to be associ-
ated with a range of side effects that can affect patients’ physical and mental health. Long-term
antipsychotic treatment has been linked to changes in brain volumes, highlighting the importance
of considering the potential adverse effects of these medications on brain structure. Moreover, the
side effects of antipsychotics are not limited to neurocognitive changes but also include metabolic and
cardiovascular risks, which necessitate careful monitoring and management [Jen+24]. These side ef-
fects can significantly impact patients’ willingness to adhere to prescribed treatment regimens, thereby
affecting the overall effectiveness of the treatment.
Compliance, or adherence to treatment, is another pivotal aspect in the management of psychosis.
Factors influencing compliance can range from the patient’s understanding and acceptance of the ill-
ness, the perceived benefits versus the drawbacks of the treatment, to the quality of the therapeutic
relationship between the patient and healthcare providers [Cel+24; Pel+24]. For instance, the dura-
tion of untreated psychosis (DUP) is a critical factor in the effectiveness of early intervention programs
(EIP), with a shorter DUP being associated with better outcomes. This underscores the importance
of timely treatment initiation and adherence to the treatment plan [Pel+24]. Furthermore, the en-
gagement of patients in their treatment, as evidenced by the number of therapy sessions attended and
the total hours spent in therapy, is positively correlated with familiarity with technology, suggesting
that leveraging technology could enhance treatment engagement and compliance [Cel+24].
The challenges of side effects and compliance are not insurmountable but require a multifaceted
approach to address effectively. This includes the development of personalized treatment plans that
consider the patient’s unique profile, preferences, and needs. It also involves ongoing education for
patients and their families about the illness and the treatment options available, including the potential
side effects and how they can be managed. Additionally, fostering a strong therapeutic alliance is
crucial for enhancing compliance, as it can help patients feel more supported and understood, thereby
increasing their willingness to adhere to the treatment regimen [Far+24].
In summary, the management of psychosis is complex and requires careful consideration of the side
effects associated with antipsychotic medications and strategies to improve compliance. By addressing
these challenges through personalized care, patient education, and strong therapeutic relationships,
healthcare providers can enhance treatment outcomes for individuals with psychosis.

26
6 Impact of Psychosis
6.1 On Individuals
6.1.1 Quality of Life
Quality of life (QoL) in individuals with psychosis is a critical area of concern, as the impact of psychosis
extends beyond the clinical symptoms to affect various aspects of personal and social functioning. The
EuroQol-5D scale, a widely recognized measure for assessing overall quality of life, considers five key
areas: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [Cel+24]. This
multidimensional approach underscores the complex interplay between physical health, mental health,
and daily living activities in determining the QoL for individuals experiencing psychosis.
Research has shown that negative and positive psychotic symptoms significantly influence QoL.
A study highlighted the beneficial effects of case management in reducing rates of both negative and
positive psychotic symptoms, which in turn could imply an improvement in the QoL for individuals
with psychosis [Wil+24]. This suggests that interventions targeting symptom reduction can have a
meaningful impact on improving the day-to-day experiences of those affected.
Furthermore, the relationship between psychosis and quality of life is not isolated to the direct
effects of symptoms. The broader context of an individual’s life, including experiences of trauma and
social defeat, also plays a crucial role. For instance, childhood interpersonal trauma has been linked to
both positive and negative symptom domains of psychosis, with anxiety identified as a strong connector
between such trauma and psychosis [Gra+24]. This indicates that the adverse effects of trauma on
QoL may be mediated through its impact on psychosis symptomatology.
Additionally, the concept of psychosis-proneness and its association with chronic social defeat pro-
vides insight into how prolonged exposure to adverse social conditions can exacerbate the decline in
QoL among those predisposed to psychosis [Sho+23]. This highlights the importance of considering
environmental and social factors when addressing the QoL in psychosis, suggesting that interventions
should not only focus on symptom management but also on improving the social determinants of
health.
The PQ-B tool has been effective in identifying individuals meeting criteria for a psychosis spectrum
disorder, which includes both clinical high risk (CHR) and threshold psychosis. By facilitating early
identification of those at risk, it opens the door for early intervention strategies that can potentially
mitigate the impact of psychosis on QoL. This is particularly relevant given the evidence suggesting
that early intervention in psychosis can lead to better outcomes in terms of symptom severity and
functional recovery [Sav+24].
In summary, improving the quality of life for individuals with psychosis requires a multifaceted
approach that addresses not only the clinical symptoms but also the broader psychosocial context.
This includes interventions aimed at symptom reduction, trauma-informed care, social support, and
early identification and intervention. By adopting such a comprehensive approach, it is possible to
make significant strides in enhancing the QoL for those affected by psychosis.

6.1.2 Functional Outcomes

Functional outcomes in individuals with psychosis are significantly influenced by a variety of factors,
including the severity of symptoms, the effectiveness of treatment, and the presence of supportive
interventions. Psychosis, characterized by symptoms such as delusions, hallucinations, and disorga-
nized thinking, can profoundly impact an individual’s ability to function in daily life. The relationship
between psychosis and functional outcomes is complex, necessitating a multifaceted approach to treat-
ment and support.
The impact of psychosis on functional outcomes is evident in the challenges individuals face in
areas such as employment, education, and social relationships. For instance, cognitive impairments, a
common feature of schizophrenia and related disorders, can hinder an individual’s ability to perform
tasks that require concentration, memory, and executive functioning [Jen+24]. These cognitive deficits
contribute to difficulties in maintaining employment and achieving educational goals, underscoring the
importance of addressing cognitive dysfunction in treatment strategies.
Moreover, the transition from schizophreniform disorder to more chronic conditions such as schizophre-
nia or schizoaffective disorder is associated with poorer premorbid functioning and higher baseline
clinical severity. These findings highlight the need for early intervention and the potential benefits of

27
identifying and treating psychosis at the earliest possible stage. Early intervention programs, which
combine pharmacological treatment with psychoeducation, family support, and case management, have
been shown to improve outcomes in individuals with first-episode psychosis [Pel+24].
Social interventions aimed at addressing the adverse social conditions resulting from psychotic
symptoms also play a crucial role in improving functional outcomes. These interventions may include
support for education, employment, housing, and finances, which are areas significantly affected by the
debilitating nature of psychosis [Wil+24]. By providing targeted support in these areas, individuals
with psychosis can achieve better social integration and an improved quality of life.
The relationship between trauma and psychosis further complicates the functional outcomes of af-
fected individuals. Evidence suggests that affective dysfunction, such as insecure attachment resulting
from trauma, may contribute to the development of psychosis [Gra+24]. Understanding the affective
pathways between trauma and psychosis is crucial for developing interventions that address the un-
derlying emotional and psychological needs of individuals, thereby potentially improving functional
outcomes.
In summary, improving functional outcomes in individuals with psychosis requires a comprehensive
approach that addresses the multifaceted nature of the disorder. Cognitive impairments, the severity
of symptoms at onset, and the impact of trauma are all factors that influence the ability of individuals
with psychosis to function effectively in daily life. Early intervention, combined with pharmacological
treatment, psychoeducation, family support, and targeted social interventions, offers the best hope for
enhancing functional outcomes and improving the overall quality of life for those affected by psychosis.

6.2 On Society
6.2.1 Economic Impact
The economic impact of psychosis on society is substantial and multifaceted, encompassing direct costs
related to healthcare provision, as well as indirect costs through lost productivity and societal con-
tributions. Patients with schizophrenia, a severe form of psychosis, often require long-term treatment
and support, which incurs significant healthcare costs. The European SOHO (Schizophrenia Outpa-
tient Health Outcomes) study highlighted the financial burden associated with the relapse of patients
with schizophrenia, indicating that preventing relapse can be a cost-effective strategy for managing
the economic impact of the disorder [Gro+24].
Direct healthcare costs include expenses for hospital admissions, medications, outpatient services,
and long-term care facilities. These costs are significantly higher for individuals with psychosis com-
pared to the general population, primarily due to the chronic nature of the disorder and the need
for comprehensive treatment approaches. Indirect costs, on the other hand, are related to the loss
of productivity among individuals with psychosis who are unable to work or achieve full employment
due to their symptoms. Additionally, there is a societal cost associated with caregiving, where family
members or friends may need to reduce their working hours or leave employment altogether to care
for someone with psychosis.
The economic impact is not limited to direct and indirect costs alone. There are also opportunity
costs to consider, which represent the loss of potential gain from other alternatives when one alternative
is chosen. For individuals with psychosis, this could mean the loss of educational opportunities, career
advancement, and contributions to society through employment or volunteer work. Furthermore,
the stigma associated with psychosis can exacerbate these economic impacts by hindering access to
employment and social support, thereby increasing the reliance on social welfare systems.
To mitigate the economic impact of psychosis on society, it is crucial to invest in early intervention
and prevention strategies. Early detection and treatment of psychosis can reduce the severity and
duration of the disorder, leading to better long-term outcomes for individuals and lower healthcare
costs. Additionally, integrating mental health services with employment and educational support can
help individuals with psychosis to achieve better social integration and economic independence.
Moreover, public health policies aimed at reducing the stigma associated with psychosis can facili-
tate access to care and support, thereby improving outcomes and reducing the overall economic burden
on society. By addressing the economic impact of psychosis through comprehensive care, support, and
policy measures, society can improve the quality of life for individuals with psychosis and reduce the
financial strain on healthcare systems and the economy at large.

28
6.2.2 Stigma and Discrimination
Stigma and discrimination are pervasive issues that significantly impact individuals with psychosis, af-
fecting their social interactions, access to healthcare, and overall quality of life. The societal perception
of psychosis often carries negative connotations, leading to prejudicial attitudes and behaviors towards
those diagnosed with psychotic disorders. This societal stigma can manifest in various forms, including
social ostracism, bullying, and discrimination, which exacerbate the challenges faced by individuals
with psychosis.
Research has shown that individuals at clinical high risk of psychosis or those with established psy-
chosis experience higher rates of substance use compared to healthy controls, which may be partly at-
tributed to attempts at self-medication or coping with the negative effects of stigma and discrimination
[Gro+24]. The stigma associated with psychosis not only affects the individuals directly experiencing
symptoms but also influences the attitudes and behaviors of healthcare providers, potentially lead-
ing to diagnostic overshadowing. This phenomenon occurs when a patient’s primary diagnosis, such
as Autism Spectrum Disorder (ASD), overshadows the recognition of comorbid conditions, including
psychosis, thereby complicating the diagnostic process and access to appropriate treatment [Ges+24].
The impact of stigma and discrimination on trust and social relationships is profound. Studies have
found that experiences of chronic social defeat, such as ostracism and bullying, are negatively associated
with trust, particularly among individuals with low delusion-proneness or those who have not been
socially excluded in controlled environments [Sho+23]. This suggests that the social consequences of
psychosis-related stigma extend beyond immediate psychological distress, impairing the ability to form
and maintain trusting relationships, which are crucial for social support and recovery.
Furthermore, the intersectionality of racism and social determinants of health exacerbates the
stigma and discrimination faced by individuals with psychosis. Indigenous populations, for example,
encounter unique challenges that include racism and inadequate responses from institutions to their
social and mental health needs, both prior to and following the diagnosis of psychosis [Man+24]. These
experiences highlight the need for a more nuanced understanding of how societal factors contribute
to the stigmatization of psychosis and the importance of addressing these issues within healthcare
systems and broader social policies.
Efforts to combat stigma and discrimination against individuals with psychosis require a multi-
faceted approach that includes public education to dispel myths and misconceptions about psychosis,
training for healthcare providers to recognize and address their own biases, and the implementation
of policies that promote social inclusion and equitable access to healthcare. By addressing the root
causes of stigma and discrimination, society can move towards a more compassionate and supportive
environment for individuals with psychosis, ultimately improving their quality of life and outcomes.

7 Special Populations
7.1 Child and Adolescent Onset
7.1.1 Early Identification
Early identification of psychosis, particularly in child and adolescent populations, is a critical area of fo-
cus that can significantly influence the trajectory of the disorder and the effectiveness of interventions.
The identification of individuals at an ultra-high risk (UHR) of psychosis has been facilitated by struc-
tured interviews such as the Comprehensive Assessment of At Risk Mental States (CAARMS), which
assesses sub-threshold psychosis symptoms [Kan+24]. This approach underscores the importance of
recognizing early signs and symptoms that may precede the full onset of psychotic disorders.
In the context of early-course psychosis (EP), demographic studies reveal that participants typically
present with an average illness onset in late adolescence, around 17.2 years of age, with a duration of
illness averaging less than one year. This demographic information is crucial as it highlights a window
of opportunity for early intervention during the initial stages of psychosis, potentially altering the
course of the disorder.
The inclusion criteria for studies focusing on non-affective psychosis further emphasize the need
for a stable clinical condition and sufficient understanding and command of English to consent to the
study and participate in therapy [Cel+24]. This criterion ensures that participants can effectively

29
engage with the interventions, which is particularly important in early identification and treatment
efforts.
Moreover, the recruitment process in community public mental health services targeting youth
and young adults who self-identify as belonging to specific demographic groups, such as Māori in
New Zealand, and have a diagnosis of First Episode Psychosis (FEP) within the previous five years,
highlights the targeted approach to early identification within specific populations [Man+24]. This
targeted recruitment is essential for understanding the unique needs and treatment responses of diverse
groups.
Exclusion criteria for studies often include individuals with substance use disorders, intellectual
disabilities, major ophthalmologic issues, or significant head injuries, among others. These criteria are
designed to isolate the effects of psychosis from those of other conditions or factors, thereby providing
clearer insights into the nature and treatment of psychosis itself.
The role of childhood trauma in the development and manifestation of psychosis has also been
explored, with findings indicating that childhood trauma, as measured by the Childhood Trauma
Questionnaire (CTQ), influences certain conditions in psychosis, particularly in the context of interac-
tion with inflammatory responses [Vel+24]. This suggests that early life experiences can significantly
impact the development and trajectory of psychosis, further emphasizing the importance of early
identification and intervention.
Inflammatory cytokines have been studied in relation to cognitive function in adolescents with
first-episode schizophrenia, bipolar disorder, or major depressive disorder, indicating a biological un-
derpinning that could potentially serve as a biomarker for early identification [Tay+24]. Understanding
the biological mechanisms underlying psychosis can aid in the development of more targeted and ef-
fective treatments.
In conclusion, early identification of psychosis, especially in child and adolescent populations, is
a multifaceted process that involves recognizing early symptoms, understanding demographic and
biological factors, and considering the impact of early life experiences. Through targeted assessment
and intervention strategies, it is possible to improve outcomes for individuals at risk of or experiencing
early-course psychosis.

7.1.2 Treatment Considerations

Treatment considerations for child and adolescent onset psychosis necessitate a multifaceted approach,
integrating pharmacological interventions with psychological and social support to address the com-
plex needs of this population. The early intervention in psychosis (EIP) services model, which includes
case management and psychological interventions alongside pharmacotherapy, has been supported by
evidence to provide sustained benefits. This model underscores the importance of a comprehensive
treatment strategy that goes beyond medication to include support for the individual’s broader psy-
chological and social needs.
Pharmacotherapy, as a cornerstone of treatment, must be carefully considered, especially in younger
populations. The inclusion criteria for first episode psychosis (FEP) programs typically encompass a
wide range of psychotic disorders, necessitating a nuanced approach to medication management that
is tailored to the individual’s specific diagnosis and symptoms [Cas+24]. The potential for oxidative
stress reduction in adolescents with FEP indicates that biological markers could play a role in guiding
treatment decisions, particularly in relation to symptom management over time [Tay+24]. This sug-
gests that ongoing monitoring of biological markers could inform adjustments in treatment to optimize
outcomes.
Psychological interventions, as part of the EIP model, are crucial for addressing the complex psy-
chological needs of young individuals experiencing psychosis. The evidence supports the integration of
these interventions with pharmacotherapy to achieve the best outcomes [Wil+24]. This approach aligns
with the understanding that psychosis in children and adolescents is not only a biological condition
but also one that affects the individual’s psychological and social functioning.
Social support and case management are integral components of a comprehensive treatment plan.
The socio-economic disadvantages and the potential for attrition bias highlight the importance of
addressing the broader social determinants of health in treatment planning [Kis+24]. This includes
ensuring that treatment plans are sensitive to the socio-economic contexts of individuals, which can
significantly impact treatment engagement and outcomes.

30
 Furthermore, the impact of substance use, particularly cannabis, on the onset and progression of
psychosis underscores the need for interventions that address substance use as part of the treatment
plan. The association between earlier age of onset of cannabis use and increased risk of psychosis
outcomes necessitates a focus on substance use interventions to mitigate this risk [Gro+24]. This
highlights the importance of integrating substance use treatment with psychosis treatment to address
all factors contributing to the individual’s condition.
In summary, treatment considerations for child and adolescent onset psychosis require a comprehen-
sive approach that integrates pharmacological, psychological, and social interventions. The evidence
supports the EIP services model as a framework for treatment, emphasizing the need for a holistic
approach that addresses the biological, psychological, and social aspects of psychosis. The role of
substance use, particularly cannabis, in the onset and progression of psychosis further highlights the
need for integrated treatment strategies that address all contributing factors to optimize outcomes for
young individuals experiencing psychosis.

7.2 Elderly Populations

7.2.1 Late-Onset Psychosis
Late-Onset Psychosis (LOP) emerges as a significant clinical concern, particularly within elderly pop-
ulations, where it presents unique diagnostic and therapeutic challenges. Unlike early-onset psychosis,
which typically manifests in adolescence or early adulthood, LOP often occurs after the age of 60
and can significantly impact the quality of life, not only for those directly affected but also for their
caregivers and the broader healthcare system. The etiology of LOP is multifaceted, involving a com-
plex interplay of neurobiological, genetic, and environmental factors, which may differ from those
contributing to early-onset cases.
One critical aspect of understanding LOP is recognizing the role of neurobiological changes as-
sociated with aging, which can predispose individuals to psychosis. Age-related neurodegenerative
processes, such as those seen in Alzheimer’s disease and Parkinson’s disease, often manifest with psy-
chotic symptoms, including hallucinations and delusions. This suggests a potential overlap between
the pathophysiological mechanisms underlying these neurodegenerative diseases and LOP, highlighting
the importance of thorough neurological assessment in this population.
Furthermore, the impact of LOP extends beyond the individual to affect societal and healthcare
systems. The onset of psychosis in later life can lead to significant functional decline, increased depen-
dency, and a higher burden on caregivers and healthcare services. This necessitates a multidisciplinary
approach to management, incorporating medical, psychological, and social support interventions tai-
lored to the unique needs of the elderly.
In terms of treatment, the management of LOP poses distinct challenges. Pharmacological inter-
ventions, while essential, must be approached with caution due to the increased sensitivity of older
adults to side effects and the potential for interactions with medications prescribed for comorbid con-
ditions. Therefore, treatment plans for LOP must be highly individualized, balancing the benefits of
symptom control against the risks of adverse effects.
Moreover, the diagnostic process for LOP requires careful consideration of the broader differential
diagnosis, including delirium, dementia, and mood disorders, which can also present with psychotic
symptoms in the elderly. This underscores the importance of comprehensive assessment strategies
that integrate clinical history, physical examination, and appropriate diagnostic testing to accurately
identify the underlying cause of psychosis and guide treatment planning.
In addressing LOP within elderly populations, it is also crucial to consider the role of psychosocial
factors. Social isolation, bereavement, and physical health problems are common in later life and can
contribute to the onset or exacerbation of psychotic symptoms. Interventions aimed at enhancing
social support, improving physical health, and addressing specific psychological needs are therefore an
integral part of the management of LOP, alongside pharmacological treatments [Wil+24].
In summary, Late-Onset Psychosis represents a complex clinical entity that demands a nuanced
understanding of its etiology, impact, and management. The challenges associated with diagnosing
and treating LOP in elderly populations underscore the need for a comprehensive, multidisciplinary
approach that addresses the biological, psychological, and social dimensions of this condition. Through
such an approach, it is possible to improve outcomes for individuals affected by LOP and reduce the
broader societal and healthcare impacts of this condition.

31
7.2.2 Differential Diagnosis with Dementia
Differential diagnosis with dementia, particularly in elderly populations, necessitates a nuanced un-
derstanding of the symptomatology and underlying pathophysiological mechanisms that distinguish
it from other psychiatric disorders, such as psychosis. The complexity of this task is underscored
by the overlapping symptoms between dementia and psychotic disorders, including cognitive deficits,
behavioral changes, and at times, hallucinations or delusions. However, distinguishing between these
conditions is crucial for effective treatment and management.
One of the primary considerations in differential diagnosis is the temporal progression and onset
of symptoms. Dementia typically presents with a gradual decline in cognitive function, affecting
memory, executive function, and language skills. In contrast, psychotic disorders may present more
acutely, with symptoms such as hallucinations and delusions not typically seen in the early stages of
dementia. Furthermore, cognitive deficits in psychosis, when present, often do not exhibit the pervasive
and progressive nature characteristic of dementia [RM24].
The role of biomarkers and neuroimaging in differential diagnosis cannot be overstated. While cur-
rently no definitive biomarkers exist for either condition, research efforts continue to identify potential
candidates that could aid in distinguishing between dementia and psychosis. For instance, neuroimag-
ing studies have shown distinct patterns of brain atrophy in dementia, particularly in Alzheimer’s
disease, which is characterized by significant loss in temporal and parietal lobes. On the other hand,
structural changes in psychosis are more subtle and often involve different brain regions, such as the
frontal and temporal lobes [Tay+24; Lie+24].
Another critical aspect is the examination of functional impairment. Dementia’s hallmark is the
progressive impairment in daily functioning, directly attributable to cognitive decline. In psychosis,
while social and occupational functioning may be impaired, it is primarily due to the psychotic symp-
toms themselves rather than an underlying cognitive decline. This distinction is crucial for treatment
planning, as interventions for dementia often focus on managing symptoms and slowing cognitive
decline, whereas treatment for psychosis may involve antipsychotic medications and psychosocial in-
terventions [RM24; Pel+24].
The diagnostic shift observed in longitudinal studies further complicates the differential diagnosis.
For example, a diagnostic shift from schizoaffective disorder to schizophrenia or affective psychosis
has been noted, underscoring the fluidity and complexity of psychiatric diagnoses over time. This
highlights the importance of continuous assessment and reevaluation in elderly patients presenting
with psychotic symptoms, to accurately diagnose and differentiate from dementia [Pel+24].
In conclusion, the differential diagnosis between dementia and psychosis in elderly populations re-
quires a comprehensive approach that considers the onset and progression of symptoms, the presence of
cognitive deficits, functional impairment, and potential biomarkers. Understanding the distinct patho-
physiological mechanisms underlying these conditions is essential for developing targeted interventions
that address the specific needs of this population.

7.3 Cultural and Ethnic Considerations

7.3.1 Cultural Competence in Treatment
Cultural competence in treatment is paramount for addressing the diverse needs of individuals ex-
periencing psychosis symptoms. The effectiveness of psychological interventions, such as cognitive-
behavioral therapy for psychosis (CBTp), cognitive remediation, and other forms of psychotherapy,
is significantly influenced by the cultural context of the patient [Wil+24]. These interventions must
be adaptable to the cultural and ethnic backgrounds of individuals to ensure their acceptability and
effectiveness. The integration of cultural competence into treatment plans not only respects the indi-
vidual’s cultural background but also enhances the therapeutic alliance between the patient and the
healthcare provider.
The impact of structural racism and colonization has been identified as a significant factor con-
tributing to disparities in mental health outcomes among ethnic minority and Indigenous populations
[Man+24]. These systemic issues have led to discrepancies in exposure to risk and protective factors,
which in turn affect the prevalence and manifestation of psychosis symptoms in these communities.
Therefore, it is crucial for mental health professionals to acknowledge and address these broader social
determinants of health when developing and implementing treatment plans.

32
 Furthermore, the perception and understanding of mental health and illness vary significantly across
cultures. For instance, in Nigeria, mental health symptoms are often attributed to supernatural causes
such as divine punishment or witchcraft [Bon+24]. These cultural beliefs can significantly influence
an individual’s willingness to seek and engage in conventional mental health treatments. Therefore,
mental health professionals must be aware of these cultural nuances and incorporate this understanding
into their treatment approach to improve engagement and outcomes.
Cross-cultural studies have shown that outcomes in psychosis can vary significantly between low and
middle-income countries (LMICs) and high-income countries, with better clinician-reported outcomes
observed in LMICs [Nai+24]. This suggests that cultural factors play a crucial role in the treatment
and recovery process. Adapting treatment approaches to align with the cultural context and values of
the patient can lead to more effective care and better outcomes.
The concept of ethnic density, which refers to the proportion of a specific ethnic group within a
given area, has also been shown to impact psychosis risk and outcomes [Con24]. Studies have found
that being part of a larger ethnic community can have protective effects against psychosis symptoms.
This highlights the importance of considering the social and community context of individuals when
planning and delivering treatment.
In summary, cultural competence in the treatment of psychosis is essential for providing effective
and personalized care. By understanding and integrating cultural, social, and systemic factors into
treatment plans, mental health professionals can improve the accessibility, acceptability, and outcomes
of mental health interventions for diverse populations. This approach not only addresses the symptoms
of psychosis but also contributes to the broader goal of reducing health disparities among ethnic
minority and Indigenous populations.

7.3.2 Variations in Symptom Expression

Variations in symptom expression among individuals with psychosis can be significantly influenced by
cultural and ethnic considerations. This is particularly evident when examining the prevalence and
manifestation of psychotic disorders across different populations. For instance, research has highlighted
that the risk of non-affective psychosis, such as schizophrenia, is notably higher in refugee populations
compared to non-refugee migrants, suggesting that the traumatic experiences associated with forced
displacement may contribute to this increased vulnerability. This underscores the importance of con-
sidering the unique socio-cultural and environmental contexts in which individuals experience and
express symptoms of psychosis.
Moreover, the classification and diagnosis of psychotic disorders often vary, with studies examining a
range of conditions from individual psychotic symptoms to schizophrenia and mixed psychotic disorders
[SSE23]. This diversity in classification reflects the complexity of psychotic symptomatology and the
need for a nuanced understanding of its expression across different cultural and ethnic groups. The
concept of the exposome score (ES), or the polyenviromic risk score (PERS), has been proposed as a
comprehensive measure to capture all environmental exposures that may contribute to the development
of psychosis, emphasizing the multifactorial nature of these disorders [RM24].
The assessment of psychotic symptoms also reveals variations in expression, with tools such as
the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of
Negative Symptoms (SANS) being utilized to evaluate the presence and severity of symptoms. These
assessment tools highlight the distinction between positive and negative symptoms, which can manifest
differently among individuals and be influenced by cultural factors. For example, a study reported
that patients in Chennai exhibited significantly better outcomes for negative symptoms compared to
positive symptoms, suggesting that cultural factors may play a role in the manifestation and perception
of these symptoms [Nai+24].
Furthermore, the generalizability of findings from studies on psychosis is often limited by the lack of
equitable representation concerning race, ethnicity, and geographical location [Vel+24]. This limitation
highlights the need for more inclusive research that can capture the diverse experiences and expressions
of psychosis across different populations. Additionally, the presence of shorter durations of untreated
psychosis (DUP) and past contact with child and adolescent mental health services (CAMHS) have
been associated with categorical diagnoses outside the psychosis spectrum, indicating that variations in
the healthcare system and professional practices can also influence symptom expression and diagnosis
[Pel+24].

33
 In summary, the expression of psychotic symptoms exhibits considerable variation across different
cultural and ethnic groups, influenced by factors such as trauma, environmental exposures, and socio-
cultural contexts. Understanding these variations is crucial for the development of culturally sensitive
diagnostic tools and treatment approaches, ensuring that individuals from diverse backgrounds receive
appropriate and effective care.

8 Research Directions
8.1 Biomarkers and Precision Medicine
8.1.1 Genetic Biomarkers
Genetic biomarkers play a pivotal role in the understanding and management of psychosis, offering
insights into its causes, potential treatment pathways, and the overall impact on affected individuals.
The identification and analysis of these biomarkers are crucial for the advancement of precision medicine
in psychiatry, particularly for conditions characterized by complex symptoms such as psychosis. Recent
studies have shed light on the genetic underpinnings of psychosis, highlighting the significance of genetic
polymorphisms in the manifestation and progression of this condition. For instance, research has
demonstrated that cannabis-induced psychosis may be influenced by specific genetic polymorphisms,
suggesting a genetic predisposition that could interact with environmental factors like cannabis use to
trigger psychotic episodes [Gro+24]. This finding underscores the importance of considering genetic
factors when evaluating the risk and treatment strategies for psychosis.
Moreover, the study of cardiometabolic disorders and their genetic links to psychosis provides
further evidence of the intricate relationship between genetic factors and the development of psychotic
symptoms. It has been found that certain genetic predispositions not only contribute to the risk
of cardiometabolic disorders but also impact brain structure, functional connectivity, and cognitive
processes in individuals at various stages of psychosis, including those at high risk, early psychosis,
and chronic psychosis stages [Vel+24]. This highlights the multifaceted role of genetic biomarkers in
understanding the pathophysiology of psychosis and the interconnectedness of physical and mental
health conditions.
The exploration of immune biomarkers in youth with clinical high risk for psychosis (CHR-P) and
first-degree relatives with a history of psychosis (FHR-P) further illustrates the potential of genetic
and biological markers in predicting the onset and course of psychotic disorders. The absence of
studies comparing immune biomarkers in these populations points to a significant gap in the current
research landscape and emphasizes the need for comprehensive studies that could lead to the identifi-
cation of reliable predictors for psychosis. Such biomarkers could revolutionize the early detection and
intervention strategies for psychosis, potentially mitigating its impact on individuals and society.
In addition to genetic and immune biomarkers, the investigation of neuroinflammation biomarkers,
such as the p40 subunit of IL-12 and IL-23, has revealed their predictive value in the transition
to psychosis. This specific biomarker was identified as a significant predictor of psychosis onset in
a placebo-controlled study, marking a significant step forward in the quest for biomarkers that can
accurately identify individuals at risk of developing psychosis [Tay+24]. The ability to predict psychosis
onset with such biomarkers opens new avenues for preventive measures and targeted therapies, aligning
with the goals of precision medicine.
The collective findings from these studies underscore the critical role of genetic biomarkers in the
field of psychiatry, particularly in the context of psychosis. By unraveling the genetic factors associated
with psychosis, researchers can pave the way for personalized treatment approaches that consider the
unique genetic makeup of each individual. This approach not only promises more effective management
of psychosis but also contributes to the broader objectives of precision medicine, which seeks to tailor
healthcare interventions to individual characteristics, needs, and preferences. As research in this area
continues to evolve, the integration of genetic biomarkers into clinical practice holds the potential to
transform the diagnosis, treatment, and prevention of psychosis, ultimately improving outcomes for
affected individuals and their families.

34
8.1.2 Imaging and Neurophysiological Markers
Imaging and neurophysiological markers have emerged as pivotal tools in the understanding and man-
agement of psychosis, offering insights into its underlying mechanisms and potential pathways for
targeted treatments. The integration of neuroimaging techniques, such as magnetic resonance imag-
ing (MRI) and electroencephalography (EEG), with clinical assessments, provides a comprehensive
approach to elucidate the neurobiological alterations associated with psychosis. This approach not
only aids in the diagnosis and prognosis of psychotic disorders but also facilitates the development of
precision medicine strategies for individualized treatment.
Neuroimaging studies have identified structural and functional abnormalities in various brain re-
gions implicated in psychosis. For instance, alterations in the connectivity between intrinsic connectiv-
ity networks (ICNs), specifically between the superior temporal gyrus (STG) and the anterior middle
temporal gyrus (A. MTG) with the posterior hippocampus, have been observed in individuals with
psychosis. These findings underscore the importance of examining the intricate network dynamics
within the brain to understand the pathophysiology of psychosis. Furthermore, longitudinal MRI
studies have differentiated the effects of antipsychotic medication and illness progression on brain vol-
ume reductions in first-episode psychosis, highlighting the potential of neuroimaging to disentangle the
complex interactions between treatment effects and disease processes.
The application of multimodal MRI techniques has further refined our understanding of psychosis,
revealing significant changes in the thalamus and enabling the efficient stratification of subgroups within
first episode psychosis [Jen+24]. This stratification is crucial for tailoring treatment approaches to the
specific neurobiological profiles of patients, thereby enhancing the efficacy of interventions. Addition-
ally, the examination of retinal layer abnormalities through neuroimaging has provided preliminary
evidence of their association with clinical and brain measures in psychotic disorders [Vel+24]. This
novel avenue of research suggests that peripheral biomarkers could complement central neuroimaging
findings, offering a more holistic view of the neurophysiological underpinnings of psychosis.
Neurophysiological markers, such as elevated neurofilament light (NfL) levels, have also shown
promise in distinguishing between neurological and neurodegenerative disorders and psychiatric con-
ditions, including psychosis [Kan+24]. The potential of NfL as a blood-based biomarker to ’rule
out’ neurodegenerative disorders underscores the importance of identifying specific neurophysiological
markers that can aid in the differential diagnosis of psychosis. This is particularly relevant in the con-
text of precision medicine, where the accurate characterization of the disorder is essential for selecting
the most appropriate treatment strategy.
The detection of psychotic-like experiences (PLEs) and their association with the risk of developing
mental disorders further emphasizes the need for a nuanced understanding of the neurobiological
markers of psychosis [RM24]. While the clinical relevance of PLEs without functional impairment
remains a topic of debate, their identification could serve as an early indicator of susceptibility to
psychosis, thereby enabling preemptive interventions.
In summary, the integration of imaging and neurophysiological markers provides a comprehensive
framework for understanding the neurobiological alterations associated with psychosis. This approach
not only enhances our ability to diagnose and prognosticate psychotic disorders but also paves the way
for the development of targeted treatments based on the individual neurobiological profiles of patients.
As research in this field continues to evolve, it holds the promise of transforming the management of
psychosis through the principles of precision medicine, ultimately improving outcomes for individuals
affected by this complex condition [Bon+24; Gro+24; Jen+24].

8.2 Longitudinal and Cohort Studies

8.2.1 Natural History of Psychosis
The natural history of psychosis encompasses the progression and changes in the condition over time,
including the onset of symptoms, their development, and the potential for recovery or chronicity.
Understanding this trajectory is crucial for developing effective interventions and support mechanisms
for individuals experiencing psychosis. A pivotal aspect of this understanding comes from longitudinal
and cohort studies, which provide insights into the patterns and predictors of psychosis outcomes.
One significant finding from these studies is the identification of early psychosis and schizophrenia as
conditions marked by aberrant connectivity patterns in the brain. Jensen et al. [Jen+24] observed these
patterns within one and two years of the first clinical contact for psychosis, highlighting the potential

35
for establishing stable biomarkers for psychosis during this critical period. This early identification is
crucial for intervention strategies aiming to mitigate the progression of psychosis.
Furthermore, the role of environmental and genetic factors in the etiology of psychosis has been
increasingly recognized. Rejek and Misiak [RM24] demonstrated that environmental exposures could
predict the transition to psychosis in individuals with a high familial risk, suggesting that the cumula-
tive impact of these exposures plays a significant role in the development of the condition. This finding
underscores the importance of considering both genetic predispositions and environmental factors in
understanding the natural history of psychosis.
Ethnicity and cultural factors also influence the pathways to care during the first episode of psy-
chosis, as evidenced by the work of Manuel et al. [Man+24]. Their study on ethnicity and pathways to
care highlights the impact of cultural illness attributions on the treatment-seeking behavior of individ-
uals experiencing psychosis. This suggests that cultural competence in mental health care is essential
for effectively addressing the needs of diverse populations.
The lifetime prevalence of non-affective psychosis, as discussed by Smyth et al. [SSE23], further
contributes to our understanding of the natural history of psychosis by indicating that the condition’s
prevalence is influenced by the duration of time examined. This highlights the chronic nature of
psychosis for many individuals and the need for long-term support and treatment strategies.
In addition to these factors, Kang et al. [Kan+24] provided insights into the diagnostic process
for first-episode psychosis, emphasizing the importance of accurate diagnosis for effective treatment
planning. Their study recruited individuals with first-episode psychosis, individuals at ultra-high risk
of psychosis, and healthy controls, underscoring the diversity within the psychosis spectrum and the
need for tailored interventions.
Collectively, these studies contribute to a nuanced understanding of the natural history of psychosis.
They underscore the importance of early identification, the role of environmental and genetic factors,
the impact of cultural and ethnic considerations, and the need for accurate diagnosis and tailored
interventions. This comprehensive approach is essential for advancing research and improving outcomes
for individuals experiencing psychosis.

8.2.2 Predictors of Outcome

Predictors of outcome in the context of psychosis symptoms, their causes, treatment, and impact
have been a focal point of longitudinal and cohort studies. These studies aim to unravel the complex
interplay between various factors that influence the prognosis of individuals experiencing psychosis. A
significant body of research has been dedicated to understanding how different variables, ranging from
biological markers to social determinants, contribute to the outcomes of psychosis.
One intriguing area of research has been the exploration of oxidative stress levels and their associa-
tion with psychosis symptoms and outcomes. Taylor et al. [Tay+24] found that lower oxidative stress
was linked with more severe psychosis and mania symptoms, as well as poorer outcomes in adolescents
with threshold psychosis over a two-year follow-up period. This counterintuitive finding suggests that
the relationship between oxidative stress and psychosis is complex and warrants further investigation
to elucidate its role in the progression and treatment of psychosis.
Another critical aspect of predicting outcomes in psychosis involves the analysis of demographic
and clinical characteristics. Velez-Perez et al. [Vel+24] utilized descriptive and bivariate analyses to
assess the demographic characteristics of participants, alongside illness duration, onset, and symptom
severity scores. Such analyses are fundamental in identifying patterns and correlations that could
serve as predictors of outcome, thereby enhancing our understanding of the factors that influence the
trajectory of psychosis.
Furthermore, the role of self-rated mental health in predicting outcomes cannot be overlooked.
Naira et al. [Nai+24] highlighted the significance of considering gender, relationship status, years of
education, and duration of untreated psychosis, along with symptoms of anxiety and depression, as
potential confounders in the final model for self-rated mental health. This comprehensive approach
underscores the importance of a multifaceted assessment in predicting outcomes, taking into account
both clinical and personal factors.
The longitudinal analysis of data plays a pivotal role in identifying predictors of outcome. Liebranda
et al. [Lie+24] emphasized the need for further work to understand the longitudinal evolution of pa-
tients, acknowledging the challenges inherent in such studies. Their discussion on the interdependence

36
of microstate parameters in reflecting aspects of neuronal dynamics points to the complexity of iden-
tifying clear predictors in the constantly evolving landscape of psychosis research.
In addition to biological and personal factors, social determinants of health have also been examined
as potential predictors of outcome. Congdon [Con24] explored the influence of deprivation and social
fragmentation on outcomes, revealing the intricate ways in which social and environmental factors can
impact the prognosis of psychosis. This line of research highlights the necessity of adopting a holistic
view that encompasses not only the biological and psychological aspects but also the social context in
which individuals with psychosis live.
The exploration of predictors of outcome in psychosis through longitudinal and cohort studies is a
testament to the multifaceted nature of this condition. By integrating findings from various domains,
including oxidative stress levels, demographic and clinical characteristics, self-rated mental health, and
social determinants, researchers are paving the way for a more nuanced understanding of psychosis.
This comprehensive approach is crucial in developing targeted interventions and support mechanisms
that address the diverse needs of individuals experiencing psychosis, ultimately aiming to improve their
long-term outcomes.

8.3 Interventional Studies

8.3.1 Novel Pharmacological Targets
Novel pharmacological targets in the treatment of psychosis represent a critical frontier in the quest to
improve outcomes for individuals experiencing symptoms of this complex condition. The identification
and exploration of these targets are essential for developing more effective and personalized treatment
strategies. Recent research has highlighted the potential of various novel targets, including the mod-
ulation of specific neurotransmitter systems, the use of anti-inflammatory agents, and the exploration
of neuroprotective strategies.
One promising area of investigation is the role of glutamate, a key neurotransmitter in the brain, in
psychosis. Traditional antipsychotic medications primarily target the dopamine system; however, the
glutamatergic system’s involvement suggests that modulating this pathway could offer new therapeutic
avenues. Agents that modulate glutamatergic neurotransmission, such as the use of NMDA receptor
modulators, have shown potential in early-phase clinical trials [Jen+24]. This approach is based on
the hypothesis that dysregulation of glutamate signaling may contribute to the pathophysiology of
psychosis, particularly in the context of schizophrenia.
Another novel target is the endocannabinoid system, which has been implicated in the modulation
of various physiological processes, including mood, cognition, and perception. Research indicates that
alterations in endocannabinoid signaling may be associated with psychosis. Cannabinoid receptor (CB1
and CB2) agonists and antagonists, as well as enzymes that modulate the levels of endocannabinoids,
are being explored for their therapeutic potential. The rationale behind targeting the endocannabinoid
system stems from observations of cannabis-induced psychosis and the role of endocannabinoids in
neurodevelopmental processes [Gro+24].
Inflammation has also been identified as a potential contributor to the pathophysiology of psy-
chosis, with several studies suggesting that immune dysregulation may play a role in the development
and progression of the condition. Anti-inflammatory agents, therefore, represent another novel phar-
macological target. Specific anti-inflammatory drugs, including those that inhibit cytokine production
or action, are currently under investigation for their efficacy in treating psychosis symptoms. This
approach is supported by evidence linking elevated levels of pro-inflammatory cytokines with acute
psychotic episodes and the observation that some anti-inflammatory treatments can ameliorate psy-
chotic symptoms [Tay+24; Man+24].
Neuroprotection is an emerging focus in the search for novel pharmacological targets for psychosis.
The neurodegenerative hypothesis of schizophrenia, for instance, posits that the progression of the
disorder may be partly due to neurodegenerative processes. Agents that offer neuroprotective effects,
such as antioxidants or those that modulate neurotrophic factors, are being explored for their potential
to halt or reverse these processes. This strategy aims to protect neuronal integrity and function,
potentially addressing both the symptoms and the underlying neurobiological changes associated with
psychosis [Wil+24].
The exploration of novel pharmacological targets in psychosis is a rapidly evolving field, driven by
advances in our understanding of the neurobiological underpinnings of the condition. While traditional

37
treatments have focused on the modulation of the dopamine system, the recognition of the role of other
neurotransmitter systems, inflammatory processes, and neurodegenerative mechanisms has broadened
the scope of potential therapeutic targets. Ongoing research into these areas is essential for the
development of more effective, personalized, and mechanistically informed treatments for psychosis.

8.3.2 Innovative Psychosocial Approaches

Innovative psychosocial approaches in the treatment and management of psychosis symptoms have
garnered significant attention in recent years, particularly in the context of early intervention and the
development of treatment strategies that go beyond pharmacological interventions. The emphasis on
understanding and addressing the broader socio-environmental context in which individuals experience
psychosis is crucial for developing effective interventions. Manuel et al. highlighted the inadequacy
of current institutional responses that focus on individuals outside of their family context, suggesting
that such approaches fail to address the complex socio-environmental factors contributing to psychosis
vulnerability in Indigenous youth. This underscores the need for interventions that are not only respon-
sive to immediate social needs but also capable of addressing the underlying family and community
dynamics.
Further complicating the treatment landscape is the variability in psychosis prognoses, with a
significant portion of individuals experiencing treatment-resistant symptoms, which necessitates a more
nuanced approach to care. Early Intervention for Psychosis (EIP) services, which provide specialized,
intensive treatment and support during the early stages of a psychotic disorder, represent a critical
step forward in this regard [Wil+24]. However, the effectiveness of these services can be enhanced
through the integration of innovative psychosocial approaches that address the individual’s broader
life context.
One promising direction is the exploration of multiscale integrative approaches, such as leveraging
brain dynamics to identify unique biomarkers of First Episode Psychosis (FEP). This approach not
only has the potential to improve diagnostic precision but also to tailor interventions more closely to
the individual’s specific condition. Additionally, understanding the effects of medication within these
broader treatment frameworks is essential for optimizing outcomes [Jen+24].
The reductive service delivery models currently in place, which prioritize short-term needs and cri-
sis management over the creation of conditions conducive to long-term wellbeing, further highlight the
necessity for a shift towards more holistic and family-oriented approaches [Man+24]. Such approaches
would not only address immediate health needs but also work towards establishing a supportive envi-
ronment that can mitigate the impact of psychosis and potentially prevent its onset.
Moreover, the methodological limitations identified in current research, including the heterogeneity
of findings and the need for more rigorous study designs, point to the importance of advancing the
scientific basis for psychosocial interventions [Gra+24; SSE23]. Future research should aim to employ
longitudinal designs and systematic sampling methods to better understand the causal interplays
between various factors influencing psychosis outcomes [Gra+24]. This would provide a more solid
foundation for the development of psychosocial interventions that are both effective and scientifically
grounded.
In conclusion, the integration of innovative psychosocial approaches within the broader framework
of psychosis treatment and management represents a critical area of development. By focusing on the
individual within their socio-environmental context, leveraging advanced scientific methodologies, and
addressing the limitations of current research, it is possible to enhance the effectiveness of interventions
and improve outcomes for individuals experiencing psychosis.

9 Conclusion
The investigation into psychosis, a profoundly disruptive condition that affects an individual’s percep-
tion of reality, has significantly advanced our comprehension of its complex nature. This condition
encompasses a broad range of symptoms, arises from a variety of causes, and has a considerable impact
on society. Through comprehensive research, we have integrated various perspectives, highlighting the
importance of demographic factors, the challenges of current research methodologies, and the intricate
dynamics of psychiatric disorders. Such thorough exploration has notably enhanced our understanding
of psychosis, leading to the development of better support and treatment options for those affected.

38
 Delving into psychosis, which severely hampers an individual’s ability to function, unveils a disorder
deeply intertwined with genetic, environmental, and psychological factors. The diversity in treatment
approaches underscores the urgent need for personalized care that addresses the cultural and individ-
ual needs of those impacted. The repercussions of psychosis extend beyond the individuals directly
experiencing its symptoms, affecting their families and communities, thus underscoring the importance
of continued advancements in therapeutic strategies and care.
Our evolving comprehension of psychosis, transitioning from interpretations steeped in supernatural
beliefs to sophisticated, integrated models, mirrors broader shifts in the understanding of mental health
disorders. This evolution emphasizes the necessity for a comprehensive strategy in managing and
preventing psychosis. Efforts to refine the diagnostic criteria for psychosis reflect its complex nature,
moving from clinical observations to a concerted effort towards standardization, thereby improving
diagnostic accuracy, therapeutic interventions, and research efficacy.
Psychosis manifests a spectrum of symptoms—positive, negative, and cognitive—each presenting
distinct challenges in understanding and treating this multifaceted disorder. Positive symptoms, such
as hallucinations and delusions, are particularly distressing and noticeable. Negative symptoms, indi-
cating a reduction or loss of normal behaviors and functions, tend to persist and pose greater treatment
challenges. Cognitive symptoms cover a wide range of deficits that significantly impair the functioning
and quality of life of individuals diagnosed with schizophrenia and related conditions.
Epidemiological studies on psychosis offer vital insights into its prevalence, incidence, and demo-
graphic variations, illuminating the societal burden of psychotic disorders and the factors contributing
to their emergence. These insights are critical for allocating healthcare resources, formulating public
health policies, and identifying at-risk populations.
Genetic research has underscored the significant role of heredity in psychosis, uncovering a complex
genetic landscape that underpins the disorder. This research has identified both common and rare
genetic variants that elevate the risk of psychosis, enhancing our understanding of its origins.
This extensive investigation lays the groundwork for future research and discussions in the field of
psychosis. By continuously integrating diverse perspectives, refining diagnostic standards, and evolving
treatment methodologies, we anticipate a future enriched with deeper insights and improved outcomes
for those affected by psychosis. The collaborative and interdisciplinary nature of research into psychosis
is crucial for advancing our knowledge and enhancing the lives of individuals living with this complex
condition.

39
References
[Bon+24] L. Bond et al. “Comorbidities and COVID-19 —A case study of an adolescent’s tumultuous
journey through psychosis”. In: Psychiatry Research Case Reports 3.0 ( 2024). doi: 10.
1016/j.psycr.2023.100200. url: https://doi.org/10.1016/j.psycr.2023.100200.
[Cas+24] Ana Viejo Casas et al. “Individuals with psychosis present a reduced lung diffusion capacity
and early spirometry alterations: Results from a cross-sectional study”. In: Journal of
Psychosomatic Research 176 ( 2024). doi: 10.1016/j.jpsychores.2023.111554. url:
https://doi.org/10.1016/j.jpsychores.2023.111554.
[Cel+24] Matteo Cella et al. “Evaluating remote delivery of cognitive remediation in people with
psychosis”. In: Schizophrenia Research 267 (Apr. 2024), pp. 367–372. url: https://doi.
org/10.1016/j.schres.2024.04.001.
[Con24] Peter Congdon. “Spatial and Spatio-temporal Epidemiology”. In: Spatial and Spatio-temporal
Epidemiology 48 (2024). doi: 10.1016/j.sste.2023.100631. url: https://doi.org/
10.1016/j.sste.2023.100631.
[Cor+24] Sebastian Corral et al. “Montreal Cognitive Assessment (MoCA) as a screening tool for
cognitive impairment in early stages of psychosis”. In: Schizophrenia Research: Cognition
36 (Jan. 2024). doi: https://doi.org/10.1016/j.scog.2024.100302.
[Far+24] Simone Farrelly et al. “A brief CBT intervention for depersonalisation-derealisation dis-
order in psychosis: Results from a feasibility randomised controlled trial”. In: Journal of
Behavior Therapy and Experimental Psychiatry 82 (2024). url: https://doi.org/10.
1016/j.jbtep.2023.101911.
[Ges+24] Camilla Gesia et al. “Beyond imagination: Sorting out and treating psychosis in the context
of autism spectrum disorder”. In: Journal of Psychiatric Research 173 (Mar. 2024). url:
https://doi.org/10.1016/j.jpsychires.2024.03.043.
[Gra+24] Shelley Grady et al. “Does affect mediate the relationship between interpersonal trauma
and psychosis? A systematic review and meta-analysis”. In: Schizophrenia Research 264
(Jan. 2024). doi: 10.1016/j.schres.2024.01.008. url: https://doi.org/10.1016/j.
schres.2024.01.008.
[Gro+24] Johanna Manja Groening et al. “A systematic evidence map of the association between
cannabis use and psychosis-related outcomes across the psychosis continuum: An umbrella
review of systematic reviews and meta-analyses”. In: Psychiatry Research 331 (2024). doi:
10.1016/j.psychres.2023.115626. url: https://doi.org/10.1016/j.psychres.
2023.115626.
[Jen+24] Kyle M. Jensen et al. “A whole-brain neuromark resting-state fMRI analysis of first-
episode and early psychosis: Evidence of aberrant cortical-subcortical-cerebellar functional
circuitry”. In: NeuroImage: Clinical 41 (Feb. 2024). doi: 10.1016/j.nicl.2024.103584.
url: https://doi.org/10.1016/j.nicl.2024.103584.
[Kan+24] Matthew J.Y. Kang et al. “Plasma neurofilament light chain is not elevated in people with
first-episode psychosis or those at ultra-high risk for psychosis”. In: Schizophrenia Research
267 (Apr. 2024), pp. 269–272. url: https://doi.org/10.1016/j.schres.2024.04.003.
[Kis+24] Steve Kisely et al. “Admissions for psychosis following agency-notified child maltreat-
ment at 40-year-follow-up: Results from the Childhood Adversity and Lifetime Morbidity
(CALM) cohort”. In: Schizophrenia Research 267 (Apr. 2024). doi: 10.1016/j.schres.
2024.03.040. url: https://doi.org/10.1016/j.schres.2024.03.040.
[Lie+24] Matthias Liebranda et al. “EEG microstate D as psychosis-specific correlate in adolescents
and young adults with clinical high risk for psychosis and first-episode psychosis”. In:
Schizophrenia Research 264 ( 2024). url: https://doi.org/10.1016/j.schres.2023.
11.014.
[Man+24] Jenni Manuel et al. “Institutional pathways to psychosis for Indigenous Māori: A quali-
tative exploration of experiences”. In: SSM – Qualitative Research in Health (Apr. 2024).
doi: 10.1016/j.ssmqr.2024.100435. url: https://doi.org/10.1016/j.ssmqr.2024.
100435.

40
[Mog+24] Hossein Sanjari Moghaddam et al. “White matter alterations in affective and non-affective
early psychosis: A diffusion MRI study”. In: Journal of Affective Disorders 351 (Jan. 2024).
url: https://doi.org/10.1016/j.jad.2024.01.238.
[Nai+24] Neha Naira et al. “Patient-reported outcome measures in early psychosis: A cross-cultural,
longitudinal examination of the self-reported health and self-reported mental health mea-
sures in Chennai, India and Montreal, Canada”. In: Schizophrenia Research 267 (Mar.
2024). doi: 10.1016/j.schres.2024.03.006. url: https://doi.org/10.1016/j.
schres.2024.03.006.
[Nom+24] Odete Nombora et al. “Menopause-associated psychosis: A case report and literature re-
view”. In: Psychiatry Research Case Reports 3 (Feb. 2024). doi: 10.1016/j.psycr.2024.
100210. url: https://doi.org/10.1016/j.psycr.2024.100210.
[Pel+24] Lorenzo Pelizza et al. “Diagnostic shift in first episode psychosis: Results from the 2-year
follow-up of the "Parma Early Psychosis" program”. In: Schizophrenia Research 267 (Mar.
2024), pp. 99–106. url: https://doi.org/10.1016/j.schres.2024.03.010.
[RM24] Maksymilian Rejek and Błalzej Misiak. “Modelling the effects of the exposome score within
the extended psychosis phenotype”. In: Journal of Psychiatric Research 169 ( 2024).
doi: 10 . 1016 / j . jpsychires . 2023 . 11 . 022. url: https : / / doi . org / 10 . 1016 / j .
jpsychires.2023.11.022.
[Sav+24] Mark Savilla et al. “The diagnostic accuracy of screening for psychosis spectrum disorders
in behavioral health clinics integrated into primary care”. In: Schizophrenia Research 266
(Feb. 2024). url: https://doi.org/10.1016/j.schres.2024.02.007.
[Sho+23] Bridget Shovestula et al. “Social defeat and psychosis-related outcomes: Associative and
experimental tests related to the nature of defeat, specificity of outcomes, and psychosis-
proneness”. In: Psychiatry Research Communications 3 (Oct. 2023). doi: 10 . 1016 / j .
psycom.2023.100149. url: https://doi.org/10.1016/j.psycom.2023.100149.
[SSE23] Emily Smyth, Craig Steel, and Lyn Ellett. “The prevalence of non-affective psychosis in
refugee populations: A systematic review”. In: Schizophrenia Research 260 (Aug. 2023).
url: https://doi.org/10.1016/j.schres.2023.08.011.
[Tay+24] Jerome Henry Taylor et al. “Immune and oxidative stress biomarkers in pediatric psy-
chosis and psychosis-risk: Meta-analyses and systematic review”. In: Brain, Behavior, and
Immunity 117 (Jan. 2024). doi: 10.1016/j.bbi.2023.12.019. url: https://doi.org/
10.1016/j.bbi.2023.12.019.
[Vel+24] Erik Velez-Perez et al. “Electroretinographic dysfunction, insulin resistance, and childhood
trauma in early-course psychosis: A case-control exploratory study”. In: Biomarkers in
Neuropsychiatry 10 (Mar. 2024). url: https://doi.org/10.1016/j.bionps.2024.
100088.
[Wil+24] Ryan Williams et al. “Comparing interventions for early psychosis: a systematic review and
component network meta-analysis”. In: eClinicalMedicine 70 (Apr. 2024). doi: 10.1016/
j.eclinm.2024.102537. url: https://doi.org/10.1016/j.eclinm.2024.102537.

41