At risk mental state

Diagnostic criteria

Individuals who meet criteria for CHR often experience both positive symptoms (i.e., symptoms that reflect a loss of contact with reality, including delusions, hallucinations, and disorganized thoughts/behavior) and negative symptoms (i.e., symptoms that represent a deficit in experiences, such as blunted affect, anhedonia, avolition, and asociality) that do not meet the threshold for a chronic psychotic disorder. As the conceptualization of psychosis has evolved towards understanding psychotic experiences on a spectrum, the task of defining the cutoffs for thresholds of what meets criteria for a disorder vs. a state of enhanced risk vs. normative experience, has been a topic of active debate.

Within a spectrum-model of psychosis, the CHR state has been demonstrated to be specific for the development of chronic psychosis, as individuals who meet criteria for CHR are not at enhanced risk for developing other mental health disorders, such as bipolar or other mood disorders and anxiety disorders. Despite this specificity of CHR criteria, the CHR population is quite heterogeneous, such that only approximately 20-30% of individuals who meet criteria will transition to a chronic psychotic disorder. Due to this heterogeneity, defining diagnostic criteria that maintain specificity while improving accuracy of predicting conversion has proven to be challenging.

Assessment for CHR

A variety of different instruments have been developed to identify individuals meeting CHR criteria, with the most popular being the Structured Interview for Psychosis-Risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS), which were harmonized into a single instrument in 2024, the Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS). Symptoms are described with respect to their severity, frequency, and attribution (i.e., symptoms cannot be attributed to another disorder). However, in spite of the harmonization efforts, the persisting differences in the CHR criteria between these instruments, such as the length of time during which symptoms are present (e.g., SIPS requires symptoms to be present within the last month, whereas CAARMS considers symptoms over the past year), reflect the heterogeneous nature of the population and the challenges of identifying the salient features of the high risk state.

Risk syndromes

Within the framework of the SIPS and CAARMS, there are three distinct risk syndromes. While there is considerable overlap between the criteria between the two instruments for each of the three risk subgroups, meta-analyses have revealed cross-instrument divergence in predicting conversion for each subgroup.

Brief (Limited) Intermittent Psychotic Syndrome is characterized by the presence of brief, time-limited intermittent positive symptoms that are fully psychotic in severity. In the framework of the SIPS, this subgroup is referred to as BIPS, and fully psychotic experiences (e.g., delusions, hallucinations, unusual thoughts, disorganized behavior) must be present for at least several minutes in the past month, but symptoms cannot be experienced on a daily basis, nor last over an hour if they are experienced between 3 and 6 days a week. In the framework of the CAARMS, this risk syndrome is described as BLIPS and similarly requires the presence of fully psychotic symptoms at any point in the past year, with symptoms having resolved within one week without use of antipsychotic medication. Evidence from meta-analyses suggests that although inter-rater agreement between the BIPS and BLIPS is poorer than that of other risk syndromes, this subgroup nonetheless presents with a greater risk of conversion, which has led some to argue that BIPS/BLIPS should be removed from CHR and that its prognosis does not differ significantly from that of brief psychotic disorder. The enhanced conversion risk in BIPS aligns with findings that have identified the severity of symptoms as being one of the most influential predictors of conversion.

Attenuated Positive Symptoms Syndrome is characterized by the presence of positive symptoms that are not fully psychotic in their severity (e.g., lower degree of conviction endorsed in unusual beliefs, such that individual is able to generate doubt about beliefs). The framework of the SIPS requires that these attenuated positive symptoms must occur at least once per week for a month to meet criteria for the APSS subgroup, while the CAARMS defines this risk syndrome as APS and requires symptoms to have been experienced in the past year at a frequency of at least once per month and up to 2 days a week for greater than an hour during each occurrence, or between 3 and 6 days a week for less than an hour. Within the APS subgroup, the CAARMS also includes individuals who have experienced positive symptoms at fully psychotic intensity, but at similar subthreshold frequency. The most prevalent subgroup within CHR populations is those who meet criteria for attenuated positive symptoms, and meta-analyses reveal good between-instrument agreement between the SIPS and the CAARMS in terms of predicting conversion within this subgroup.

Within the framework of the SIPS, Genetic Risk and Deterioration Syndrome (GRDS) is characterized by family history of a first-degree relative with psychosis or schizotypal personality disorder, accompanied by a significant decline (i.e., a 30% drop) in social or occupational functioning over any month in the past year. This subgroup is referred to as a Vulnerability Group in the CAARMS, and also includes those who experience a sustained level of poor functioning for at least the past year. This subgroup has been identified as being the least common in CHR populations. Its relative rarity have posed a challenge for the accurate prediction of conversion rates, particularly since many individuals who meet criteria for GRDS and transition to chronic psychosis also meet criteria for either APSS or BIPS.

Prognosis

There has been some considerable development of how the concept can be applied clinically. In the revision of the DSM-5, attenuated psychosis syndrome was included as a diagnosis as an Other Specified Schizophrenia Spectrum and Other Psychotic Disorder. However, there has been debate over its inclusion, particularly regarding the benefit-to-harm ratio of intervening with antipsychotic medication for false positives (i.e., individuals who meet criteria for CHR, but do not transition to chronic psychosis). As psychosis research moves beyond a model where schizophrenia is the de facto prototypical psychotic disorder and towards a conceptualization of a psychosis spectrum, it has been argued that goals of clinical intervention should shift accordingly to emphasize treatment of persistent, non-specific psychopathology that affects CHR individuals, even those who do not convert.

For converters

CHR criteria are sensitive to risk for imminent onset of psychosis, such that the incidence rate of conversion decelerates substantially after 2.5 to 3 years, and most CHR individuals who transition to chronic psychosis will do so within the first year upon identification, with approximately 80% of conversions occurring within the first two years.

Risk factors

For those who go on to transition to chronic psychosis, severity of positive symptoms is among the strongest risk factors associated with conversion, with more mixed evidence in support of the duration of symptoms being a significant predictor of transition. Other important risk factors include greater psychosocial stress, level of baseline global functioning (including broad cognitive functioning, and intensity of negative symptoms.

Mechanisms of conversion

The mechanisms that underlie how different risk factors contribute to conversion in CHR remain unclear. Evidence from literature examining the etiology of schizophrenia and other chronic psychotic disorders has implicated disruptions in neuroinflammatory processes and brain function as potential significant mechanisms underpinning the development of psychosis. This is supported by research in CHR populations that reveals elevated peripheral levels of proinflammatory cytokines may predict conversion, as well as accelerated thinning of cortical grey matter and disrupted functional connectivity in brain networks (e.g., between the thalamus and cortex).

For non-converters

A large portion of those who meet criteria for CHR do not go on to transition to a chronic psychotic disorder. Outcomes for non-converters reflect the heterogeneity within the CHR population itself. Meta-analyses suggest that approximately half of non-converters will go on to experience remission from CHR symptoms, whereas others may continue to experience a consistent level or even worsening of psychotic symptoms. Even among individuals whose psychotic symptoms remit, this remission is not necessarily accompanied by improvements in cognitive or social functioning, and comorbidity with depression and anxiety often remains elevated. Evidence from meta-analyses suggest that CHR individuals with comorbid depressive disorders often experience greater deficits in social and role functioning. While comorbid depression often predicts worse functional outcomes, it has not been identified as a risk factor for conversion. Persistent negative symptoms are also associated with poorer outcomes in general functioning and overall quality of life for non-converters, even when controlling for persistent depressive symptoms.

Treatment options

There are a variety of treatments that have been studied in CHR individuals, with the two most common types of interventions being psychosocial (i.e., psychotherapy) or pharmacological.

The most widely studied psychosocial treatment option is cognitive behavioral therapy (CBT), with evidence from several randomized controlled trials demonstrating that CBT may reduce the frequency and intensity of attenuated positive symptoms. However, meta-analyses do not support CBT being more effective in reducing transition risk compared to other interventions, and CBT was not associated with significant improvements in negative symptoms or social functioning. Other randomized controlled trials have been performed to explore the potential of other therapeutic modalities, including family focused therapy and integrative psychological therapy.

The use of antipsychotic medications in the CHR population has been controversial, particularly as there is mixed evidence for their efficacy. Randomized controlled trials of olanzapine, amisulpride, and ziprasidone suggest that although antipsychotics may be effective in improving attenuated psychotic symptoms, they do not necessarily reduce transition risk. Other pharmacological treatments that have been studied include omega-3 fatty acids and N-methyl-D-aspartate receptor (NMDAR) modulators, with mixed results across different studies in terms of their impact on reducing conversion risk. One randomized controlled trial of D-serine demonstrated that administration of D-serine was associated with improvement in negative symptoms, but further research into NMDAR modulators is needed.

Overall, meta-analyses suggest that there is not one particular treatment that is superior to the others in terms of reducing transition risk, attenuated psychotic symptoms, or negative symptoms, and CHR individuals may benefit from any kind of treatment.

References

References

1. (April 2006). "Prospective investigations of the prodromal state of schizophrenia: review of studies". Acta Psychiatrica Scandinavica.
2. (1996). "Monitoring and care of young people at incipient risk of psychosis". Schizophr Bull.
3. (2003-01-01). "The Schizophrenia Prodrome Revisited: A Neurodevelopmental Perspective". Schizophrenia Bulletin.
4. (1996-01-01). "The Prodromal Phase of First-episode Psychosis: Past and Current Conceptualizations". Schizophrenia Bulletin.
5. "ORYGEN Youth Health".
6. (1996). "Monitoring and care of young people at incipient risk of psychosis". Schizophr Bull.
7. (August 2005). "Outreach and support in south London (OASIS): implementation of a clinical service for prodromal psychosis and the at risk mental state". Eur. Psychiatry.
8. [http://info.med.yale.edu/psych/clinics/prime/pintro.html PRIME]
9. [http://www.copeclinic.org/The_COPE_Clinic_at_Columbia_Psychiatry.html (COPE)]
10. "Emory University".
11. (2013-01-01). "The Psychosis High-Risk State: A Comprehensive State-of-the-Art Review". JAMA Psychiatry.
12. (Jan 2018). "The slow death of the concept of schizophrenia and the painful birth of the psychosis spectrum". Psychological Medicine.
13. Murray, Robin M.. (2016-12-21). "Mistakes I Have Made in My Research Career". Schizophrenia Bulletin.
14. Fusar-Poli, Paolo. (Jan 2017). "The Clinical High-Risk State for Psychosis (CHR-P), Version II". Schizophrenia Bulletin.
15. (2016-10-01). "An Individualized Risk Calculator for Research in Prodromal Psychosis". American Journal of Psychiatry.
16. (Dec 1999). "Symptom Assessment in Schizophrenic Prodromal States". Psychiatric Quarterly.
17. (2005). "Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States". Aust N Z J Psychiatry.
18. (April 2024). "Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS". Early Intervention in Psychiatry.
19. (2018). "Meta-analytical prognostic accuracy of the Comprehensive Assessment of at Risk Mental States (CAARMS): The need for refined prediction". European Psychiatry.
20. (Oct 2015). "At risk or not at risk? A meta-analysis of the prognostic accuracy of psychometric interviews for psychosis prediction". World Psychiatry.
21. (2016-02-01). "Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk: A Meta-analytical Stratification". JAMA Psychiatry.
22. (2014-03-28). "Attenuated Psychosis Syndrome: Ready for DSM-5.1?". Annual Review of Clinical Psychology.
23. (2016-03-01). "Prognosis of Brief Psychotic Episodes: A Meta-analysis". JAMA Psychiatry.
24. (Jan 2017). "A Severity-Based Clinical Staging Model for the Psychosis Prodrome: Longitudinal Findings From the New York Recognition and Prevention Program". Schizophrenia Bulletin.
25. (2022). "North American Prodrome Longitudinal Study (NAPLS 3): Methods and baseline description". Schizophrenia Research.
26. (March 2003). "Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group". Schizophr. Res..
27. (October 2002). "Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms". Arch. Gen. Psychiatry.
28. (May 2007). "Three-year follow-up of a randomized controlled trial of cognitive therapy for the prevention of psychosis in people at ultrahigh risk". Schizophr Bull.
29. Schäfer Amminger. (2008). "Indicated Prevention of Psychotic Disorders with Long-Chainomega-3 Fatty Acids: A Randomized, Placebo-Controlled Trial". Schizophrenia Research.
30. "Schizophrenia Spectrum and Other Psychotic Disorders". Diagnostic and statistical manual of mental disorders: DSM-5 (fifth ed.). Washington, D.C: American Psychiatric Association. 2013. p. 122. ISBN 978-0-89042-554-1.
31. (July 2010). "Should a "Risk Syndrome for Psychosis" be included in the DSMV?". Schizophrenia Research.
32. (April 2020). "The DSM-5 proposal for attenuated psychosis syndrome: a history". Psychological Medicine.
33. (August 2004). "Is our concept of schizophrenia influenced by Berkson's bias?". Social Psychiatry and Psychiatric Epidemiology.
34. (June 2016). "Psychosis as a transdiagnostic and extended phenotype in the general population". World Psychiatry.
35. (2020-07-01). "Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention". JAMA Psychiatry.
36. (2015-06-01). "Speed of Psychosis Progression in People at Ultra-High Clinical Risk: A Complementary Meta-analysis". JAMA Psychiatry.
37. (2021-09-01). "Probability of Transition to Psychosis in Individuals at Clinical High Risk: An Updated Meta-analysis". JAMA Psychiatry.
38. (October 2016). "Duration of attenuated positive and negative symptoms in individuals at clinical high risk: Associations with risk of conversion to psychosis and functional outcome". Journal of Psychiatric Research.
39. (April 2023). "Characteristics and clinical correlates of risk symptoms in individuals at clinical high-risk for psychosis: A systematic review and meta-analysis". Schizophrenia Research.
40. (November 2023). "Recent Updates on Predicting Conversion in Youth at Clinical High Risk for Psychosis". Current Psychiatry Reports.
41. (2023-06-17). "Psychosocial stress, interpersonal sensitivity, and social withdrawal in clinical high risk for psychosis: a systematic review". Schizophrenia.
42. (2021-10-21). "The Independent Effects of Psychosocial Stressors on Subclinical Psychosis: Findings From the Multinational EU-GEI Study". Schizophrenia Bulletin.
43. (2020-01-04). "What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors". Schizophrenia Bulletin.
44. (2017-01-01). "The Role of Cognition and Social Functioning as Predictors in the Transition to Psychosis for Youth With Attenuated Psychotic Symptoms". Schizophrenia Bulletin.
45. (April 2012). "Negative symptoms in individuals at clinical high risk of psychosis". Psychiatry Research.
46. (June 2019). "Predictors of Transition to Psychosis in Individuals at Clinical High Risk". Current Psychiatry Reports.
47. Buckley, Peter F.. (August 2019). "Neuroinflammation and Schizophrenia". Current Psychiatry Reports.
48. (2024-02-08). "Neuroinflammation and schizophrenia – is there a link?". [[Frontiers in Psychiatry]].
49. (2022-10-29). "Impaired dynamic functional brain properties and their relationship to symptoms in never treated first-episode patients with schizophrenia". Schizophrenia.
50. (2022-11-08). "Disrupted local functional connectivity in schizophrenia: An updated and extended meta-analysis". Schizophrenia.
51. Ramsay, Ian S.. (October 2019). "An Activation Likelihood Estimate Meta-analysis of Thalamocortical Dysconnectivity in Psychosis". Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
52. (December 2020). "Meta-analysis of cytokine and C-reactive protein levels in high-risk psychosis". Schizophrenia Research.
53. (March 2015). "Towards a Psychosis Risk Blood Diagnostic for Persons Experiencing High-Risk Symptoms: Preliminary Results From the NAPLS Project". Schizophrenia Bulletin.
54. (December 2016). "Differential expression of the inflammation marker IL12p40 in the at-risk mental state for psychosis: a predictor of transition to psychotic disorder?". BMC Psychiatry.
55. (March 2023). "Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk". Molecular Psychiatry.
56. (2021-03-16). "Baseline Cortical Thickness Reductions in Clinical High Risk for Psychosis: Brain Regions Associated with Conversion to Psychosis Versus Non-Conversion as Assessed at One-Year Follow-Up in the Shanghai-At-Risk-for-Psychosis (SHARP) Study". Schizophrenia Bulletin.
57. (January 2015). "Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk". Biological Psychiatry.
58. (2018-09-21). "Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization". Nature Communications.
59. (November 2020). "Structural and functional imaging markers for susceptibility to psychosis". Molecular Psychiatry.
60. (2015-09-01). "Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk". JAMA Psychiatry.
61. (2019-08-01). "Clinical and functional long-term outcome of patients at clinical high risk (CHR) for psychosis without transition to psychosis: A systematic review". Schizophrenia Research.
62. (2022). "Clinical outcomes in individuals at clinical high risk of psychosis who do not transition to psychosis: a meta-analysis". Epidemiology and Psychiatric Sciences.
63. (July 2014). "Symptomatic and functional remission of subjects at clinical high risk for psychosis: A 2-year naturalistic observational study". Schizophrenia Research.
64. (November 2020). "Real-world long-term outcomes in individuals at clinical risk for psychosis: The case for extending duration of care". [[eClinicalMedicine]].
65. (March 2015). "EPA guidance on the early intervention in clinical high risk states of psychoses". European Psychiatry.
66. (2014-01-01). "Comorbid Depressive and Anxiety Disorders in 509 Individuals With an At-Risk Mental State: Impact on Psychopathology and Transition to Psychosis". Schizophrenia Bulletin.
67. (October 2016). "Persistence or recurrence of non-psychotic comorbid mental disorders associated with 6-year poor functional outcomes in patients at ultra high risk for psychosis". Journal of Affective Disorders.
68. (2018-02-15). "Lack of Diagnostic Pluripotentiality in Patients at Clinical High Risk for Psychosis: Specificity of Comorbidity Persistence and Search for Pluripotential Subgroups". Schizophrenia Bulletin.
69. (August 2011). "At Clinical High Risk for Psychosis: Outcome for Nonconverters". American Journal of Psychiatry.
70. (March 2019). "Multidisciplinary Treatment for Individuals at Clinical High Risk of Developing Psychosis". Current Treatment Options in Psychiatry.
71. (June 2018). "Lack of evidence to favor specific preventive interventions in psychosis: a network meta-analysis". World Psychiatry.
72. (2020-10-05). "Progression from being at-risk to psychosis: next steps". npj Schizophrenia.
73. (2012-04-05). "Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial". BMJ.
74. (January 2011). "A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis". Schizophrenia Research.
75. (2012-11-01). "Cognitive Behavioral Therapy for Subjects at Ultrahigh Risk for Developing Psychosis: A Randomized Controlled Clinical Trial". Schizophrenia Bulletin.
76. (February 2019). "Attenuated psychotic symptom interventions in youth at risk of psychosis: A systematic review and meta-analysis". Early Intervention in Psychiatry.
77. (2018-06-06). "Negative Symptom Interventions in Youth at Risk of Psychosis: A Systematic Review and Network Meta-analysis". Schizophrenia Bulletin.
78. (April 2019). "Interventions and social functioning in youth at risk of psychosis: A systematic review and meta-analysis". Early Intervention in Psychiatry.
79. (August 2014). "Family-Focused Treatment for Adolescents and Young Adults at High Risk for Psychosis: Results of a Randomized Trial". Journal of the American Academy of Child & Adolescent Psychiatry.
80. (January 2012). "Preventing progression to first-episode psychosis in early initial prodromal states". British Journal of Psychiatry.
81. (May 2006). "Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis". American Journal of Psychiatry.
82. (December 2007). "Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis". British Journal of Psychiatry.
83. (2017-03-01). "112. Effects of Ziprasidone Versus Placebo in Patients at Clinical High Risk for Psychosis". Schizophrenia Bulletin.
84. (2017-03-01). "23. Omega-3 Fatty Acid Versus Placebo in a Clinical High-Risk Sample From the North American Prodrome Longitudinal Studies (NAPLS) Consortium". Schizophrenia Bulletin.
85. (2010-02-01). "Long-Chain ω-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial". Archives of General Psychiatry.
86. (2017-01-01). "Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial". JAMA Psychiatry.
87. (May 2015). "D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial". The Lancet Psychiatry.
88. (August 2013). "Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies". European Neuropsychopharmacology.