Early Intervention for Schizophrenia on the Horizon: Implications for Clinicians and Patients

eyetronic/AdobeStock

SPECIAL REPORT: SCHIZOPHRENIA

Schizophrenia is one of the most recognized yet least understood chronic brain disorders. The estimates of the international prevalence of schizophrenia among noninstitutionalized individuals are 0.33% to 0.75%.^1,2 Schizophrenia is complex and characterized by substantial biological and clinical heterogeneity³ that varies significantly from person to person, leading to missed diagnosis and conflation with other diseases or drug use.

For instance, psychosis is a hallmark trait of schizophrenia but it may also be present in other clinical conditions, such as posttraumatic stress disorder, bipolar disorder, major depression, certain personality disorders, and delusional disorders.⁴ Furthermore, stimulant and cannabis use⁵ as well as psychedelics⁶ can cause individuals to have temporary psychosis-like symptoms.

Schizophrenia is often associated with delusions and hallucinations⁷ but also with marked cognitive impairment⁸ and less recognized negative symptoms, such as social withdrawal and diminished emotional expression.⁹ Additionally, clinicians may interview and care for patients who may suffer from anosognosia¹⁰ or are unaware they are ill. This “lack of insight” may lead to difficulty obtaining an accurate history or to conflicting reports between patients and their family members advocating for them to get help. Moreover, some research has shown a disparate diagnosis of schizophrenia among minoritized groups that fail to reflect an increased prevalence,¹¹ highlighting racial disparities in mental health care.

All this is to say that diagnosing schizophrenia, and intervening early, presents challenges for clinicians and health care providers who care for this population. As a result, diagnosing schizophrenia is often unnecessarily delayed until late in the course of the illness, after a crisis, or when symptoms have become more severe and debilitating. Caregivers and families can be left with complex, high-burden care situations, resulting in significant stress,¹² and patients face an increased risk for poverty, homelessness, and criminal justice involvement.¹³ Early intervention can improve health and social outcomes and alter the development of chronic symptoms, but this can be achieved only if the condition is identified and treated promptly.

The Challenges of the Clinical High-Risk State

Many of the challenges found in diagnosing schizophrenia are compounded when diagnosing youths and young adults in the clinical high-risk (CHR) state, also known as the psychosis prodrome phase. During this prodrome period, individuals are at elevated risk for developing a psychotic disorder¹⁴ such as schizophrenia; still, many of the symptoms of the prodrome, such as anxiety and paranoia, are often subtle, subjective, and difficult to quantify.

Additionally, individuals may experience symptoms that are not specific to any 1 disorder, making it challenging to differentiate the condition. The lack of specific and objective markers for the prodromal phase of psychosis can lead to a high rate of false positives,¹⁵ in which individuals unnecessarily receive a diagnosis of psychosis, and conversely, false negatives, in which individuals receive delayed or insufficient care.

To date, the natural course of the prodrome is not fully understood, making it difficult to predict who will develop a psychotic disorder and who will not. Research indicates that at a 2-year follow-up of young people with signs of clinical high risk, approximately 20% transition to psychosis,¹⁶ some experience some symptoms and problems in functioning, and 41% undergo remission.¹⁷

Research also shows that untreated psychosis is associated with worse outcomes¹⁸ yet no diagnostic tools exist to help identify individuals at high risk of developing schizophrenia. Consequently, a diagnosis is typically not made until clear symptoms of psychosis emerge and all other possible causes have been excluded. Understanding these outcomes better, developing treatments to mitigate or even prevent symptoms, and finding better ways to identify and connect young people to effective care as early as possible are urgently needed.

Intervening Earlier Requires Better Tools to Measure the Illness

Table 1. Types of Objective Biomarkers²⁰

Objective biomarkers are the key to unlocking new possibilities for identifying and treating young people at risk for schizophrenia. Detection and intervention before psychosis develops, when individuals are in the CHR state, could attenuate, postpone, or even prevent the transition to psychosis and improve individuals’ clinical and functional outcomes.¹⁹ Objective biomarkers (Table 1) related to inflammatory, stress-related, metabolic, neurotrophic, or neurotransmission processes²⁰ would help identify physiological changes associated with schizophrenia, providing evidence of the disorder and informing treatment decisions.

Once identified and validated, objective biomarkers could be used for early diagnosis before psychosis develops, to monitor and predict the likelihood of progression to psychosis and other health outcomes, to show pharmacological response, and to help study how treatments work for different groups of people. Objective biomarkers could provide more reliable and accurate information than current subjective methods, such as patient interviews. Thus, they may reduce the impact of bias, help standardize the diagnostic process, and lead to better monitoring of patient progress.

The Accelerated Medicines Partnership Program—Schizophrenia

The Accelerated Medicines Partnership program—Schizophrenia (AMP SCZ) is a public-private research collaboration working to improve our understanding of the underlying biology of schizophrenia and accelerate the development of new and innovative treatments for individuals who are at risk of developing the disorder. The Foundation for the National Institutes of Health manages the partnership between the National Institute of Mental Health (NIMH), the US Food and Drug Administration (FDA), the European Medicines Agency, and multiple public and private organizations, including the American Psychiatric Association Foundation, Boehringer Ingelheim, Janssen Research & Development LLC, National Alliance on Mental Illness, One Mind, Otsuka Pharmaceutical Development & Commercialization, Inc, Schizophrenia & Psychosis Action Alliance, and Wellcome.

Table 2. The 4 Goals of the AMP SCZ Program²²

The goal of AMP SCZ is to generate tools that will fast-track the development of effective, early-stage treatments for individuals at risk for schizophrenia as well as to develop and validate biomarkers and other objective measures that can aid in diagnosis and assessing treatment response²¹ (Table 2²²). As such, the program uses various cutting-edge techniques such as genomics, digital measures, speech analysis, and imaging to study the biology of CHR. The program has established a research network with US and international sites focused on CHR populations to accelerate clinical research and the development of new pharmacologic interventions. A critical component of AMP SCZ is the rapid dissemination of research data to the scientific community using the NIMH Data Archive platform, allowing faster translation of findings into key tools and therapies.

The hope is that the findings from this program will lead to the development of novel, effective medicines for earlier intervention in schizophrenia and in the CHR state to improve the lives of those affected by the disorder. Although there are some FDA-approved treatments for schizophrenia, it continues to be challenging for many patients to find a tolerable, beneficial treatment regimen because of the heterogeneity and complex biology underpinning the disease.²³

Optimal treatment regimens differ from person to person so many individuals living with the illness must withstand a course of trial and error with multiple treatment regimens to find what works best for them.²⁴ Medications also commonly cause adverse effects associated with nonadherence²⁵ and not all patients will respond to treatment,²⁶ leaving many patients with symptoms resulting in functional impairment.

Consequently, an urgent, unmet need exists to develop novel therapeutics that are more effective for a broader swath of individuals, contain more favorable safety profiles than existing medicines, and treat symptoms that current medications fail to address, such as negative and cognitive symptoms. The AMP SCZ program is working to address these needs by developing the scientific tools necessary to discover better treatments for individuals at risk for schizophrenia.

The results from the AMP SCZ program may one day have several significant implications for clinicians and health care providers. Developing new biomarkers and objective measures will improve diagnostic accuracy and reliability, reducing the risk of misdiagnosis and mistreatment. Additionally, the results of AMP SCZ may ultimately inform clinical practice and help guide treatment decisions, leading to better outcomes for the CHR population and those who develop psychosis.

What Does This Mean for Clinicians and Patients Today?

Early identification and intervention for patients with schizophrenia remain elusive, yet ongoing research may change this reality for millions of patients, families, and clinicians. Clinicians can help raise awareness of the AMP SCZ initiative among their patients and the wider community and encourage participation in this program and related studies (ampscz.org/participate). By working with patients and other partners such as researchers, clinicians can help bring new, more effective treatments to individuals with schizophrenia and improve the lives of those affected by this debilitating condition. Any clinicians working with young people who are experiencing symptoms of the CHR state should share this information with these patients and invite them to participate at 1 of the active study sites. Helping enroll participants can make a difference in moving the science forward.

Table 3. Signs That Individuals May Be at CHR for Psychosis²⁷

Young people experiencing signs of CHR for psychosis may have difficulty describing their symptoms, or their symptoms may sound vague or confusing. Some signs that someone may be at clinical high risk for psychosis are listed in Table 3.²⁷ Individuals who show these signs may be at increased risk for developing schizophrenia or a related disorder and should talk with a clinician.

Encouraging participation in the AMP SCZ study will allow researchers to understand better what happens to young people at CHR for psychosis. Further, it may lead to improved mental health treatments and support, facilitating the developmental, functional, and social outcomes that matter to patients and their families. To learn more about the active research AMP SCZ is working toward, visit www.ampscz.org.

Mr Larrauri is a member of the National Alliance on Mental Illness Board of Directors in Arlington, Virginia. Dr Brady is the director of the Division of Neuroscience and Basic Behavioral Science at the National Institute of Mental Health, National Institutes of Health, in Bethesda, Maryland. Dr Travaglia is the director of Neuroscience at the Foundation for the National Institutes of Health in Bethesda, Maryland.

Disclosures: Mr Larrauri reports that he occasionally receives remuneration from the pharmaceutical industry for presentations on his lived experience and nonbranded disease awareness campaigns. Drs Brady and Travaglia have no conflicts of interest to disclose.

References

1. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141.

2. Moreno-Küstner B, Martín C, Pastor L. Prevalence of psychotic disorders and its association with methodological issues. a systematic review and meta-analyses. PLoS One. 2018;13(4):e0195687.

3. Wolfers T, Doan NT, Kaufmann T, et al. Mapping the heterogeneous phenotype of schizophrenia and bipolar disorder using normative models. JAMA Psychiatry. 2018;75(11):1146-1155.

4. Dubovsky SL, Ghosh BM, Serotte JC, Cranwell V. Psychotic depression: diagnosis, differential diagnosis, and treatment. Psychother Psychosom. 2021;90(3):160-177.

5. Alharbi FF, el-Guebaly N. Cannabis and amphetamine-type stimulant-induced psychoses: a systematic overview. Addict Disord Their Treat. 2016;15(4):190-200.

6. Andersen KAA, Carhart-Harris R, Nutt DJ, Erritzoe D. Therapeutic effects of classic serotonergic psychedelics: a systematic review of modern-era clinical studies. Acta Psychiatr Scand. 2021;143(2):101-118.

7. Picchioni MM, Murray RM. Schizophrenia. BMJ. 2007;335(7610):91-95.

8. Zanelli J, Mollon J, Sandin S, et al. Cognitive change in schizophrenia and other psychoses in the decade following the first episode. Am J Psychiatry. 2019;176(10):811-819.

9. Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16:519-534.

10. Little JD. In schizophrenia, are lack of capacity and lack of insight more usefully understood as anosognosia? Australas Psychiatry. 2021;29(3):346-348.

11. Schwartz RC, Blankenship DM. Racial disparities in psychotic disorder diagnosis: a review of empirical literature. World J Psychiatry. 2014;4(4):133-140.

12. On pins & needles: caregivers of adults with mental illness. National Alliance for Caregiving. February 2016. Accessed February 5, 2023. https://www.caregiving.org/wp-content/uploads/2020/05/NAC_Mental_Illness_Study_2016_FINAL_WEB.pdf

13. Peterson J, Heinz K. Understanding offenders with serious mental illness in the criminal justice system. Mitchell Hamline Law Review. 2016;42(2).

14. Fusar-Poli P, Borgwardt S, Bechdolf A, et al. The psychosis high-risk state: a comprehensive state-of-the-art review. JAMA Psychiatry. 2013;70(1):107-120.

15. Herrera S, Fietzer AW. What’s the risk? The frequency of false positives in psychosis risk screening instruments. Psychol Serv. 2021;18(2):137-146.

16. Salazar de Pablo G, Radua J, Pereira J, et al. Probability of transition to psychosis in individuals at clinical high risk: an updated meta-analysis. JAMA Psychiatry. 2021;78(9):970-978.

17. Salazar de Pablo G, Besana F, Arienti V, et al. Longitudinal outcome of attenuated positive symptoms, negative symptoms, functioning and remission in people at clinical high risk for psychosis: a meta-analysis. EClinicalMedicine. 2021;36:100909.

18. Penttilä M, Jääskeläinen E, Hirvonen N, et al. Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2014;205(2):88-94.

19. Worthington MA, Cannon TD. Prediction and prevention in the clinical high-risk for psychosis paradigm: a review of the current status and recommendations for future directions of inquiry. Front Psychiatry. 2021;12:770774.

20. Perkovic MN, Erjavec GN, Strac DS, et al. Theranostic biomarkers for schizophrenia. Int J Mol Sci. 2017;18(4):733.

21. Brady LS, Larrauri CA; AMP SCZ Steering Committee. Accelerating Medicines Partnership Schizophrenia (AMP SCZ): developing tools to enable early intervention in the psychosis high risk state. World Psychiatry. 2023;22(1):42-43.

22. Goals. Accelerating Medicines Partnership—Schizophrenia. Reviewed May 2, 2022. Accessed February 5, 2023. https://www.ampscz.org/about/goals/

23. Insel TR. Rethinking schizophrenia. Nature. 2010;468(7321):187-193.

24. Geils H, Riley A, Lavelle TA. Incentivizing drug development in serious mental illness. Clin Ther. 2022;44(9):1258-1267.

25. Velligan DI, Sajatovic M, Hatch A, et al. Why do psychiatric patients stop antipsychotic medication? a systematic review of reasons for nonadherence to medication in patients with serious mental illness. Patient Prefer Adherence. 2017;11:449-468.

26. Samara MT, Nikolakopoulou A, Salanti G, Leucht S. How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr Bull. 2019;45(3):639-646.

27. Hua LL; Committee on Adolescence. Collaborative care in the identification and management of psychosis in adolescents and young adults. Pediatrics. 2021;147(6):e2021051486.