Version July 2025
INTRODUCTION —
Psychosis is a condition of the mind broadly defined as a loss of contact with reality as evidenced by symptoms such as hallucinations, delusions, thought disorganization and grossly disorganized behavior. Psychosis is seen in several psychiatric disorders including schizophrenia, brief psychotic disorder, delusional disorder, schizophreniform disorder, mood disorders, substance use disorders, and personality disorders. Psychosis can also result from medical or neurologic conditions.
Attenuated psychosis syndrome (APS; also referred to as clinical high-risk state, at-risk mental state, or ultra-high-risk state) refers to symptoms that are psychotic in nature but below the threshold for consideration as counting towards the diagnosis of a psychotic disorder. Typically, they are less severe and more transient. Individuals with APS may later meet diagnostic criteria for schizophrenia, bipolar disorder, or another disorder with psychosis [1]. Premorbid signs may also be present in childhood.
APS operationalizes the symptoms typically described as having been present during the prodromal phase of psychiatric illness. Individuals who meet the APS criteria have an increased risk of developing a psychotic disorder and those who do not later convert to psychosis may continue to have poor psychosocial functioning and develop other nonpsychotic Axis I disorders or personality disorders [2]. APS is included in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM 5-TR) Section III as one of the conditions for further study [3].
This topic describes the clinical manifestations, diagnostic criteria, course, predictors of future psychosis, and treatment of APS. The epidemiology, pathogenesis, clinical features, course, and diagnosis of psychosis are discussed separately.
●(See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation".)
●(See "Psychosis in adults: Initial management".)
●(See "Schizophrenia in adults: Clinical features, assessment, and diagnosis".)
●(See "Schizophrenia in adults: Maintenance therapy and side effect management".)
●(See "Bipolar disorder in adults: Clinical features", section on 'Psychosis'.)
EPIDEMIOLOGY
Prevalence — Attenuated psychosis syndrome (APS) typically presents in mid to late adolescence or early adulthood, affecting males and females equally. Attenuated psychotic symptoms are present in up to 7 percent of the general population. However, the prevalence of APS in help seeking individuals between 16 and 40 years is 0.3 percent. Fewer individuals meet the full criteria for APS because the symptoms are not distressing or of recent onset [3,4].
The epidemiology of psychosis due to schizophrenia, mood disorders, and other disorders are discussed separately. (See "Schizophrenia in adults: Epidemiology and pathogenesis" and "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation" and "Postpartum psychosis: Epidemiology, clinical features, and diagnosis" and "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)
Comorbidity — Individuals with APS appear to have a high prevalence of comorbid disorders. In a meta-analysis of 7834 subjects from 312 publications, over 75 percent of participants with APS had a comorbid mental disorder (0.78, 95% CI 0.73-0.82) [5].
The comorbid conditions with the greatest prevalence were (see 'Differential diagnosis' below):
●Any anxiety or mood disorder (60 percent)
●Any mood disorder (44 percent)
●Any depressive disorder (38 percent)
●Any anxiety disorder (34 percent)
●Major depression (30 percent)
●Trauma-related disorder (29 percent)
●Personality disorder (23 percent)
In another study of 710 individuals meeting APS criteria, over 50 percent met criteria for a current or past major depression, over 30 percent had a current or lifetime anxiety disorder and over 20 percent met criteria for ADHD prior to meeting the APS criteria [6].
PATHOGENESIS —
The pathogenesis of attenuated psychosis syndrome (APS), like other emerging mental disorders in adolescence, is multifactorial and likely includes genetic, neurodevelopmental, and environmental factors. Increasing evidence suggests that the neuropathologic changes in the prodrome and first episode of psychosis are dynamic and different than what is observed in the more chronic forms of mental illness. This neuroplasticity in early psychosis offers a window of opportunity to alter the course of the illness.
●Brain morphology – Neuroimaging studies have reported that decreased cortical thickness and accelerated cortical thinning [7,8], white matter alterations [9-11], thalamo-cortical and cerebello-thalamo-cortical connectivity alterations [12,13] and neurometabolic changes [14-18] are associated with conversion to psychosis in individuals meeting APS criteria. The neuroanatomical changes in the early stages of psychosis appear to be progressive changes beyond those associated with normal development [19]. (See "Schizophrenia in adults: Epidemiology and pathogenesis", section on 'Brain morphology and neuropathology'.)
●Neurodevelopmental abnormalities – Like schizophrenia, some individuals who meet the APS criteria also show evidence of neurodevelopmental abnormalities that fully emerge during late adolescence or early adulthood and most likely begin to develop in utero [20]. Theoretically, pre- or perinatal neurodevelopmental abnormalities lead to a vulnerability to postpubertal insults that contribute to the accelerated loss of gray matter and aberrant connectivity in individuals with APS.
●Epigenetic factors – Substance misuse, stress, and maternal infection may contribute to a later neurodegenerative process [19,21,22]. While disturbances of neurodevelopment early in life may be necessary for the future emergence of psychosis, environmental influences during the late adolescent period may contribute to the emergence of first episode of psychosis via a range of possible interconnected neuropathologic mechanisms.
●Neurotransmitters and other pathologic mechanisms – Hypothalamic pituitary axis hyperactivity, neuroinflammation, N-methyl-D-aspartate receptor hypofunction, glutamatergic or dopaminergic transmission abnormalities and reduced neuroplasticity are possible changes that are associated with the development of psychosis. All of these are potential targets for early intervention in the prodrome or first episode of psychosis. (See "Schizophrenia in adults: Epidemiology and pathogenesis", section on 'Neurodevelopment, neuropathology, and vulnerabilities'.)
●Genetic factors – There are limited genetic studies in APS, but one study found that polygenic risk scores for schizophrenia are higher in individuals of European descent meeting APS criteria who go on to develop psychosis compared with those who do not [23].
CLINICAL PRESENTATION —
The onset of attenuated psychosis syndrome (APS) is typically mid to late adolescence or early adulthood.
Symptoms of APS include:
●Attenuated delusions – These are delusional symptoms that are mild or less disturbing. They may manifest as mild suspiciousness, persecutory ideas of reference, or grandiose beliefs. Insight is typically maintained.
●Attenuated hallucinations – Altered sensory perceptions that typically present as unformed sounds or images. The individual demonstrates skepticism about their reality.
●Attenuated disorganized speech – Disorganized communication can present as vague, overelaborate, or circumstantial speech, but the individual can be refocused.
While distressing, the attenuated symptoms are described as less severe or more transient than psychotic symptoms that are seen in schizophrenia or other psychotic disorders; they do not have a fixed nature and are less intrusive. The individual often has some insight about the symptoms (ie, they appreciate that their perceptions are altered, they question if they are real). (See "Schizophrenia in adults: Clinical features, assessment, and diagnosis", section on 'Clinical manifestations'.)
The symptoms must have been present at least once per week over the past month and have begun or worsened over the past year. The time specifications for the diagnosis are used to identify individuals with recently emerging symptoms rather than more chronic subsyndromal symptoms that are seen in schizotypal personality disorder.
The onset of illness is often, but not always, preceded by premorbid signs or symptoms including neurocognitive impairments, developmental delays, neuromotor abnormalities, minor physical anomalies (eg, facial dysmorphia, wide skull base), mood changes, functional decline, slower reaction time, and social isolation [24-28].
COURSE OF ILLNESS
Risk of developing psychosis — Help-seeking individuals who meet the attenuated psychosis syndrome (APS) criteria have a 22 percent risk of developing psychosis over a three-year period [24]. The highest risk for transition to psychosis appears to be within the first two years; however, the risk is present for up to 10 years [29]. Among individuals who do not progress to full psychosis, one-third have a full remission of symptoms while the remaining two-thirds continue to have a variety of outcomes including poor functioning, persistent attenuated psychotic symptoms or comorbid conditions [30].
While 73 percent of APS cases who convert to psychosis develop a nonaffective schizophrenia spectrum disorder (eg, schizophrenia), 11 percent progress to an affective psychosis (eg, bipolar disorder, with psychosis, or major depression with psychotic features) [31].
Predictors of future psychosis
Clinical and environmental predictors — A variety of clinical and environmental predictors of conversion to psychosis have been identified in individuals who meet the APS criteria in research settings [32-34]. Studies of clinical and environmental risk factors for later conversion to psychosis in youth meeting the APS criteria have identified stressful life experiences [35], bullying [35], decline in social functioning [36], neurocognitive deficits [24], and substance use disorder [36] as risk factors that, along with the clinical symptom criteria, may contribute to the development of an algorithm of psychosis risk. While no single factor is sufficiently predictive, research is focusing on and combining these into a calculator that may help identify those at risk for psychosis with greater prognostic accuracy than any one alone [37].
Among the attenuated psychotic symptoms, it is the attenuated delusional symptoms (eg, suspiciousness, ideas of reference, grandiosity), rather than attenuated hallucinations or perceptual changes, that are most predictive of a later psychotic conversion [36]. In the development of an Individualized Risk Calculator for Psychosis in 596 individuals meeting APS criteria (diagnosed with the Structured Interview for Prodromal Syndromes [SIPS]), it was the attenuated delusional symptoms, a decline in social functioning (Global Functioning: Social Scale), and verbal learning and memory (Hopkins Verbal Learning Test) that contributed most to psychosis risk among an already high-risk population [38].
Biomarkers of psychosis risk — At the present time, the biomarkers are still being validated in studies of APS in academic research settings and are not yet developed for clinical use.
Multisite studies have identified biomarkers associated with conversion to psychosis. Potential biomarkers may include neuroimaging, electrophysiologic, neurocognitive, inflammatory, genetic, and neurohormonal biomarkers [39]. The identification of biomarkers linked to psychotic conversion may help to:
●Identify individuals at greatest risk of psychotic conversion
●Understand the underlying pathology
●Develop individualized treatment
Early evidence suggests that adding biomarkers to the Individualized Risk Calculator for Psychosis shows promise in improving the predictive algorithm [39]. Next steps include development of protocols (imaging, electrophysiologic, genetic) that can be easily used in community settings with high reliability.
ASSESSMENT —
We advocate early identification and subsequent management for all individuals with suspected attenuated psychosis syndrome (APS). These are suggested to reduce what has been, on average, years-long delays from psychosis onset to detection and treatment [40]. Such delays have been associated with poorer treatment responses in analyses of patients ultimately diagnosed with schizophrenia or other psychotic disorders [41-43].
Our goal is to intervene to reduce symptoms, improve functioning and prevent the emergence or improve the clinical course of a DSM-5-TR psychotic disorder [3]. (See 'Management' below.)
For all individuals with symptoms of APS, we rule out underlying acute and chronic medical etiologies, substance use-related etiologies before considering primary psychiatric illness. Our diagnostic evaluation of symptoms of APS is similar to that of frank psychosis. The specific information to be gleaned from the initial interview, mental status examination and laboratory assessment are described separately. (See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation", section on 'Diagnostic evaluation'.)
In assessing individuals with APS, in addition to complete evaluation, we find it useful to use the Structured Interview for Prodromal Syndromes (SIPS) or the Mini-SIPS [44,45] for supporting data regarding the diagnosis of APS. The SIPS requires training to administer and score.
DIAGNOSIS —
The proposed attenuated psychosis syndrome (APS) criteria in DSM-5-TR were developed based on research diagnostic criteria used over the last 25 years to identify individuals at clinical high risk for the development of a future psychotic illness [46]. APS, included in the DSM-5-TR under “Conditions for Further Study,” describes an attenuated form of psychotic symptoms that do not meet the full threshold for psychosis, are less severe, more transient and the individual maintains some level of insight into their experiences [3]:
A. At least one of the following symptoms is present and is of sufficient severity or frequency to warrant clinical attention (see 'Clinical presentation' above):
●Attenuated delusions
●Attenuated hallucinations
●Attenuated disorganized speech
B. Symptom(s) must have been present at least once per week for the past month.
C. Symptom(s) must have begun or worsened in the past year.
D. Symptom(s) is sufficiently distressing and disabling to the individual to warrant clinical attention.
E. Symptom(s) is not better explained by another mental disorder, including a depressive or bipolar disorder with psychotic features, and is not attributable to the physiologic effects of a substance or another medical condition.
F. Criteria for any psychotic disorder have never been met.
DIFFERENTIAL DIAGNOSIS —
Symptoms of attenuated psychosis syndrome (APS) may be similar to those seen in other disorders that often begin in adolescence or young adulthood [47,48]. Further discussion of the diagnostic workup for psychosis is discussed elsewhere. (See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation", section on 'Determining the etiology'.)
We differentiate APS from the following other disorders. In most cases, the disorders are differentiated from each other over time (eg, by the change in the nature of symptoms or the emergence of new symptoms).
●Primary psychiatric causes
•Affective disorders (eg, bipolar disorders, major depressive disorder, dysthymic disorder, schizoaffective disorder) – We differentiate affective disorders with psychosis (eg, major depression with psychosis, schizoaffective disorder) from APS by presence of prominent mood symptoms (eg, depression, mania) that are present in affective disorders and are often a focus of the treatment. While mood symptoms may be present in APS, they are not typically as pervasive or intense.
Furthermore, in individuals with mood disorders with psychosis, the psychosis is typically fixed as compared with APS where the symptoms may be transient, and the patient may have insight.
•Psychotic disorders – In schizophrenia and other schizophrenia spectrum disorders, the psychotic symptoms are described as fixed and pervasive. However, in individuals with APS, the psychotic symptoms are less pervasive, less fixed, and the individual may have a degree of insight.
•Anxiety-related disorders disorder – Social anxiety disorder, generalized anxiety disorder, panic disorder, can present with referential thoughts, derealization, depersonalization or magical thinking related to anxiety. The anxiety is provoked by anticipation of specific situations, avoidance of situations, fear of panic attacks. or repetitive thoughts or behaviors that are time consuming. In individuals with APS, the focus of attention is not on panic attacks or fear of specific situations.
•Posttraumatic stress disorder (PTSD) – PTSD commonly presents with perceptual changes related to flashbacks, derealization, depersonalization, and suspiciousness. However, in PTSD they are typically triggered by a reminder of a past traumatic event.
•Obsessive-compulsive disorder (OCD) – OCD may present with intrusive thoughts that may be similar to APS symptoms. However, in OCD the response to the thoughts (eg, compulsive behaviors) are time consuming and cause significant distress or psychosocial impairment.
•Schizotypal personality disorder – Schizotypal personality disorder may present with attenuated psychotic symptoms. However, in schizotypal personality disorder the symptoms represent an enduring pattern of behavior or inner experience whereas in APS the attenuated symptoms have started or been present for up to one year.
●Substance use disorders – Cannabis use disorder, alcohol use disorder, stimulant use disorder, and opioid use disorder can present with substance-induced psychosis similar to that seen in APS.
We differentiate the disorders by noting that in individuals with substance induced psychosis, the psychotic symptoms are generally limited to the time period during or soon after intoxication, withdrawal or exposure to the substance [49,50]. (See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation", section on 'Rule out substance-induced psychosis'.)
●Medical causes or delirium (eg, neurologic, infectious, head injury) – Evaluation of medical causes are discussed in detail elsewhere. (See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation", section on 'Medical and substance/medication-related causes'.)
MANAGEMENT —
We prefer that all patients with suspected attenuated psychosis syndrome (APS) have an evaluation by a provider with expertise in the evaluation, diagnosis, and treatment of mental health disorders (eg, specialty clinic, psychiatric provider). Studies examining efficacy of early intervention services (eg, case management, family support, supported employment, education) show that these services may lead to better clinical outcomes (eg, global psychopathology, symptom severity) than treatment as usual; however, trials have not consistently supported one intervention over another. Our preference for management is found below and is based on developed international guidelines, and our clinical experience [41-43,51,52]. (See 'Assessment' above.)
Address comorbid conditions — Assess for and treat comorbid conditions such as depression, anxiety, personality disorders, substance use disorders with the evidence-based treatments, including psychosocial and pharmacologic, for the individual condition. (See 'Comorbidity' above and "Approach to the adult patient with suspected depression" and "Major depressive disorder in adults: Approach to initial management".)
Psychosocial interventions — Provide appropriate psychosocial intervention such as cognitive-behavioral therapy (CBT) or other family-focused therapy to establish a collaborative process involving the patient, family, and other supports. CBT and family therapy as psychosocial interventions for schizophrenia are discussed elsewhere. (See "Schizophrenia in adults: Psychosocial management", section on 'Cognitive-behavioral therapy' and "Schizophrenia in adults: Psychosocial management", section on 'Family-based Interventions'.)
●CBT – CBT appears to be effective in some but not all studies [53-61]:
•A meta-analysis of CBT treatment for psychosis (10 studies, n = 1128) found low-quality evidence that CBT was superior to needs-based intervention (ie, treatment as usual or nonspecific control treatment) in reducing rate of transition to psychosis for over 24 months (relative risk 0.58, 95% CI 0.35-0.95) [60]. Additionally, low-quality evidence supports greater improvement of symptoms with CBT as compared with nonspecific treatment at 24 months treatment (standardized mean difference -0.24, 95% CI -0.43 to -0.06); however, differences in effect on overall functioning, depression or quality of life were not reported.
•In a meta-analysis investigating interventions to prevent transition of APS to psychosis (26 trials, n = 2351) the pooled effect of CBT was found to be greater than that of other interventions (eg, pharmacologic management, family intervention, cognitive remediation) [59]. CBT was associated with a reduced incidence of psychosis, as compared with control, at 12 months and 18 to 48 months (relative risk 0.52, 95% CI 0.33-0.82 and relative risk 0.6, 95% CI 0.42-0.84, respectively). Interpretation is limited by heterogeneity of methods and outcomes.
•In a meta-analyses examining interventions for social functioning (19 studies, n = 1513), there was no evidence that CBT, omega-3, or cognitive remediation improved social functioning [61].
●Family-focused therapy – Family-focused therapy appears to improve communication between youth with high risk of psychosis and their family members [62]. Improvement in communication is an important treatment outcome for youth with APS and their families.
In a six-month multisite trial, 66 adolescents and young adults with clinically high risk of psychosis were randomly assigned to family-focused therapy (an 18-session family treatment that includes psychoeducation, communication training, and problem solving training) versus enhanced care treatment (ie, three sessions of psychoeducation) [62]. Participants in the family-focused therapy, as compared with those in the enhanced care treatment, showed improvements from baseline to follow-up measures of constructive communication during problem solving interactions.
●Social skills training and cognitive remediation – We introduce treatment to address functional impairment. (See "Schizophrenia in adults: Psychosocial management", section on 'Social skills training' and "Schizophrenia in adults: Psychosocial management", section on 'Cognitive remediation'.)
Pharmacologic management — Clinical trials do not consistently support the use of any medication as effective in reducing the risk of future psychosis in individuals with APS [53,57,58,63-68]. Furthermore, some data suggest that in individuals with clinically high-risk or attenuated psychosis, treatment with higher dose of medication as compared with treatment with lower dose of medication appears to be associated with increased risk of transition to psychosis at up to two-year follow-up [69]. However, a higher dose of medication may also indicate more severe positive symptoms and a greater chance of transition to psychosis.
We consider pharmacologic management only in select cases in which symptoms may be impairing the individual’s ability to engage in or benefit from psychosocial interventions. Our choice is based on medication profile, past history and patient preference. (See "Psychosis in adults: Initial management", section on 'Antipsychotic therapy'.)
●A meta-analysis and other trials investigating the use of medication to reduce the risk of psychosis in individuals at high risk of psychosis (eg, prodromal symptoms, attenuated psychosis) have not consistently supported any medication as effective. As an example, in an observational study involving 300 individuals with clinical high-risk for psychosis antipsychotic treatment as compared with no antipsychotic treatment led to similar rates of conversion to psychosis at three years (27 versus 25 percent) [64]. Furthermore, individuals’ treatment with antipsychotics as compared with those who were not treated with antipsychotics, were more likely to suffer functional declines as measured by global assessment of function scale.
●In a meta-analysis including 290 subjects with APS who were treated with antipsychotics, those who converted to psychosis over two-year follow-up had a higher mean baseline chlorpromazine equivalent dose than individuals that did not convert to psychosis (162 mg/d versus 116 mg/day, respectively [69].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psychotic disorders".)
SUMMARY AND RECOMMENDATIONS
●Attenuated psychosis syndrome (APS) – APS refers to the clinical symptoms that have been retrospectively described as the prodromal phase in individuals diagnosed with schizophrenia and other psychotic disorders. This syndrome, also referred to as clinical high-risk state, at-risk mental state, or ultra-high-risk state refers to symptoms that are psychotic in nature but below the threshold for consideration as psychosis. (See 'Introduction' above.)
●Presentation and course – APS typically presents in mid- to late adolescence or early adulthood with attenuated delusions, attenuated hallucination, and/or attenuated disorganized speech. Help seeking individuals who meet the APS criteria have a 20 percent risk of developing psychosis over a three-year period. Most patient who convert to psychosis develop schizophrenia; however, affective psychosis such as bipolar disorder with psychosis are also described. (See 'Clinical presentation' above.)
Among individuals who do not progress to full psychosis, one-third have a full remission of symptoms while the remaining two-thirds continue to have a variety of outcomes including poor functioning, persistent attenuated psychotic symptoms, or comorbid conditions. (See 'Course of illness' above.)
●Predictors of future psychosis – A variety of clinical and environmental predictors of conversion to psychosis have been identified in individuals who meet the APS criteria in research settings. While no single factor is sufficiently predictive, research is focusing on and combining these into a calculator that may help identify those at risk for psychosis with greater prognostic accuracy than any one alone. Additionally, biomarkers of future conversion to psychosis are being validated but are not yet available for clinical use. (See 'Predictors of future psychosis' above.)
●Comorbidity – Individuals with APS appear to have a high prevalence of comorbid disorders including anxiety disorders, depression, and substance use disorders. (See 'Comorbidity' above.)
●Early identification – We advocate early identification in all individuals with APS. For all individuals with suspected APS, we rule out underlying acute and chronic medical etiologies, and etiologies related to substance use before considering primary psychiatric illness. The differential diagnosis for psychosis is reviewed in detail separately. (See 'Assessment' above.)
●Management – Our goal is to intervene to prevent the development of a full psychotic syndrome. While some evidence supports cognitive-behavioral therapy, no intervention has been consistently supported as compared with another. (See 'Management' above.)
