Industrial Psychiatry Journal

REVIEW ARTICLE
Year
: 2021  |  Volume : 30  |  Issue : 2  |  Page : 198--206

First-episode psychosis: How long does it last? A review of evolution and trajectory


Jyoti Prakash, K Chatterjee, K Srivastava, VS Chauhan 
 Department of Psychiatry, Armed Forces Medical College, Pune, Maharashtra, India

Correspondence Address:
Prof. Jyoti Prakash
Department of Psychiatry, Armed Forces Medical College, Pune - 441 040, Maharashtra
India

Abstract

Study of first-episode psychosis (FEP), an episode of psychotic nature which manifests for the first time in an individual in the longitudinal continuum of his/her illness, has been study matter of research interest in recent years. A comprehensive review of the literature will help us understand the evolution and trajectory of this concept better. A literature review of available articles addressing the concept, phenomenology, evolution, identification, course, and outcome of FEP was done; the same was subsequently divided into broad topics for better clarity and analyzed. FEP constituted a clinical psychotic phenomenon with underlying significant heterogeneity in diagnosis, stability, course, and outcome. The study has attempted to view FEP both as horizontal spectrum across various diagnoses and longitudinally ranging from asymptomatic individual with unknown risk status to attenuated psychosis to multiple relapses/unremitting illness. Many risk and protective factors have been brought out with varying certainty ranging bio-psycho-social spectrum. Efforts have been made to calculate polygenic risk score based on genes involvement/sharing between various psychotic spectrum disorders; as well as biomarker panels to identify people at risk. FEP may prove to be an important concept to understand psychosis in general; without putting things into the diagnostic rubric. It may help understand multiple risk and protective factors for the course and outcome of psychotic illness and may clear the cloud to sharpen the evidence toward commonality and distinctiveness between various psychotic diagnoses in vogue for more comprehensive concept.



How to cite this article:
Prakash J, Chatterjee K, Srivastava K, Chauhan V S. First-episode psychosis: How long does it last? A review of evolution and trajectory.Ind Psychiatry J 2021;30:198-206


How to cite this URL:
Prakash J, Chatterjee K, Srivastava K, Chauhan V S. First-episode psychosis: How long does it last? A review of evolution and trajectory. Ind Psychiatry J [serial online] 2021 [cited 2021 Dec 8 ];30:198-206
Available from: https://www.industrialpsychiatry.org/text.asp?2021/30/2/198/321972


Full Text



First-episode psychosis (FEP) is an episode of mental illness where symptoms qualify for a psychosis and there has not been a psychotic episode before the index episode.[1]

The concept of FEP is important as the nature of the presentation of psychosis and the associated biopsychosocial correlates has lot of bearings on the overall outcome and course of the illness. FEP may have varied and transient presentation of symptoms at the outset which may become clearer and stable as the illness further evolves over time or during the subsequent occurrence of the episode.[2] The FEP therefore may be considered as a “psychotic spectrum disorder.” The evolving and changing nature of the episode cautions us from jumping to diagnostic conclusion based on our symptomatology-driven classificatory system. The expanse of horizontal assessment needs to be complimented with the depth of longitudinal assessment to conjecture course of illness and response to intervention.

Researchers over the years have found various demographic, biological, psychological, cultural, and illness-related factors affecting the course and outcome of illness and treatment response variably. Life cycle of psychosis has been charged with various predispositional and situational factors implicated; the scientific evidence, however, lacked the replication of the result in the subsequent research or in its clinical utility.[3] The factors studied were not found enough to justify the outcome merely by itself or the proposed combination. The complex interaction of the stress and vulnerabilities spun more yarn of possibility than what science could comprehend by its reductionist approach to unravel the disease by the study of associated genes and related molecules. The same environment given the intensity and duration of interaction or associated variables can be favorable to the course and outcome of illness at one instance and adverse at another. Intervention while on one hand was found to improve the morbidity; but one the other hand, was fraught with adverse effects, comorbidities, and increased mortality.[4],[5] Researchers have also put together a combination of factors to predict the possibility of psychosis in at-risk population or to predict the outcome of a FEP, the same has not given a result as it promised to yield.[6],[7]

Regardless of the complexity of the illness and inconsistencies in results, some findings were consistent, glaring, replicated often and had a significant bearing on the course of the illness. Duration of untreated psychosis (DUP) was found related to the poor outcome of the illness; while an early intervention and reduced DUP was associated with significant improvement in clinical and functional outcome. Established guidelines on psychosis today lay adequate emphasis on reducing DUP to enhance remission and recovery. Involvement of patient's social network in therapy has also been found beneficial.[8],[9]

The clinical picture may be evolving one and be the initial presentation of any of the specific psychotic syndrome like schizophrenia, delusional disorder, depression with psychotic features, mania with psychotic symptoms, acute and transient psychotic disorders, substance-induced psychotic disorder, organic psychotic disorder or an unspecified or other nonorganic psychotic illness.[10]

Therefore, understanding the longitudinal course of a FEP from the outset and monitoring various biopsychosocial parameters as they come into play, during the course of observation, may help us understand the construct of FEP as it evolves. It will help the clinicians in taking course correction early, thereby avoiding exacerbation of illness, chronicity, or poor outcome. With the above premise in mind, we reviewed the available literature in this direction to understand the evolution and trajectory of “FEP.” As we go through a comprehensive review of available literature with reference to FEP, we will bring out nuances of the construct as under:

Life span perspective of FEPStability of diagnosis in a FEPPositive modifiers of course and outcome of FEPNegative modifiers of course and outcome of FEPEfforts at the prediction of psychosis.

 Life Span Perspective of First-Episode Psychosis



Based on available research a psychosis can be viewed on a continuum for the understanding of risk to transition and implementation of relevant prevention or intervention. The continuum tends to address populations ranging from asymptomatic individuals with ambiguous risk status to multiple relapses/chronicity. The spectrum gives a lot of scope of intervention at various stages in the life span of a psychosis.

Clinical staging model in first-episode psychosis

The clinical staging model view psychosis as the transition of illness from one stage to another with each stage having its own relative risk of progression into another. The first stage of interest is prepsychotic clinical stage of ultra-high risk followed by stage 2 (First acute episode), stage 3 (phase of relapse with remissions), and stage 4 (chronic treatment-refractory unremitting stage). The study suggest the transition from stage 1–2 in 18% of the individual within 6 months (increasing to 36% within 3 years), stage 2–4 in 6% within 1st year rising to 23% within 10 years.[11]

Clinically high risk for psychosis

Erstwhile known as At-Risk Mental State, this construct developed in the dawn of the last century to address those heterogeneous group of subjects, who were at higher risk of “imminent development of a first-episode psychotic disorder.” Studies have found three different clinically high risk for psychosis (CHR-P) groups called Attenuated Psychotic Symptoms, Brief (and limited) Intermittent Psychotic Symptoms , and Genetic Risk and Deterioration Syndrome. There was significantly higher risk of transitioning to psychosis in CHR-P.[12]

Revised clinical staging for psychosis

Researchers have attempted to combine a revised staging model with targeted intervention in high-risk groups to change the trajectory of the disorder in the early stages. The revised staging framework was seen in the light of available research evidence of preempted intervention. It ranges anywhere from asymptomatic individuals with unknown risk status to attenuated psychosis to the first episode of psychosis to multiple relapses/unremitting illness.[13] From this staging it was evident that:

FEP is preceded by various stages and is followed by course ranging from relapses to unremitting chronic illness and outcome ranging from complete recovery to persistence of illness. These factors may affect the course and outcome of FEP variablyEarly mental health literacy and family psychoeducation may prevent or reduce risk of FEPIdentification and targeted prevention to the individual having CHR-P may reduce chances of FEPIntervention may differ depending on the future course and outcome of FEP.

The multidimensional profile of risk factors responsible for transitioning of illness dimension from one stage to another highlights the complexity of the process and difficulty in specificity in research findings.

Duration of untreated psychosis

DUP refers to the duration between the first appearance of psychotic symptoms to the initiation of treatment. Some studies also consider the prodromal period also to be part of the period, but most of the prodrome need not be psychotic in nature and many need not convert in psychosis.[14] The average time of initiation of treatment following onset of psychosis was seen to be 1–2 years. Increased DUP has been associated with inadequate remission, poor response to treatment, and worse outcomes in terms of total symptoms, overall functioning, and quality of life. Whereas early treatment has been associated with a better prognosis and less functional deficit.[8],[15] Few studies have found the importance of early psychosocial intervention to be therapeutic in nature and consider delay in intensive psychosocial treatment to be more sensitive marker of response than DUP. The early phase of psychosis has been suggested to be a critical period for plasticity and a good window for the opportunity in treatment.[16] For this very reason first 3–5 years of FEP is taken as critical period.[17] Thus, the DUP has far-reaching implication in the course and outcome of psychosis. Studies, however, suggest that DUP by itself does not determine the poor outcome and there is an important role of psychopathological heterogeneity too.[18]

 Stability of Diagnosis in First-Episode Psychosis



Around 32 per lakh adults have the onset of psychosis each year. The onset is mostly in the 15–25 years of age.[19] About 70% of FEP comes to psychiatric emergency.[20] Around a half of FEP comes with 4 weeks of onset.[21] Of all diagnosis in FEP the diagnosis which was most stable across time was Bipolar disorder (96.5%) followed by schizophrenia (75%), delusional disorder (72.7%), major depressive disorder with psychotic symptoms (70.1%), brief psychotic disorder (61.1%), and schizophreniform (10.5%).[10] Schizophreniform was least stable of all. In this group, only a half, maintained stability at 1 year follow-up. There was a high relapse transition to the schizophrenia group and a third was relocated to mood disorder at 6 year follow-up.[22],[23] Brief psychotic disorder had a change of diagnosis in half of the cases at 1 year follow-up, mostly to mood disorder, followed by schizophrenia. In acute polymorphic psychotic disorder, similar to the diagnosis of brief psychotic disorder in the Diagnostic and Statistical Manual of Mental Disorders V, around three fourth maintained diagnosis at 3 years. Most crossed over to mood disorder.[24] In substance-induced psychotic disorder mostly cannabis had an add-on psychotic episode at 3 years follow-up.[25],[26] Half of these were of schizophrenia spectrum. The clinical features suggesting psychosis due to general medical condition was the presence of physical symptoms, atypical nature of symptoms, onset at later age, and poor response to treatment. Neuroimaging in FEP was mostly normal or accidental in findings.[27] Some studies have found that in 2 years follow-up of FEP, around one-third is in the rubric of affective psychosis and two-third in the spectrum of schizophrenia. Majority of these recover, 10%–15% becomes treatment-resistant and a subgroup has multiple relapses.[28],[29]

 Positive Modifiers of Course And Outcome of First-Episode Psychosis



Multicomponent treatment package,[30],[31],[32],[33],[34] technological enhancement of psychosocial treatment,[35],[36],[37] personalized psychosocial intervention,[38],[39],[40],[41] improvement of quality of health care, and reducing DUP were found associated with improved outcome in a psychosis spectrum disorder.[42]

AESOP study found that being female, employed, in relation, short DUP and diagnosis of mania or brief psychotic disorders was associated with early sustained remission.[43]

Living independently, working or studying, having absent or stable mild symptoms for 2 years and having social contact or participation in social activities was found associated with increased resilience at 4 years in a study.[44],[45]

Self-reflection was associated with symptom remission and improved insight.[46] Good cognitive reserve led to better to better coping and improved clinical and functional outcomes.[47],[48]

Course has been found to be better in developing countries than the developed countries.[49]

Old age, female gender, and diagnosis of brief psychotic disorder was associated positively with quality of life.[50],[51],[52],[53],[54]

Living with spouse and children and affective symptoms on Postive and Negative Syndrome Scale (PANSS) was found to be a positive predictor for symptom remission.[55]

Good premorbid intelligence quotient was associated with better outcome at 3 years follow-up.[47]

Antipsychotic medication was found to be associated with improvement in symptoms but debatable impact on the outcome of the illness.[56] Psychotherapies found useful are cognitive behavior therapy, dialectical behavior therapy, cognitive behavior social skill training, motivational interviewing, acceptance commitment therapy, mindfulness meditation, and cognitive adaptation training.[1],[57]

 Negative Modifiers of Course and Outcome of First-Episode Psychosis



Following were associated with poor outcome:

Hospitalization at onset and frequent hospitalization[32],[58]Substance abuse especially tobacco[30]Poor physical health[59]Decreased rate of participation in competitive employment[31]Male gender[60]Ethnic minority[60]Decreased premorbid adjustment[60]Low cognitive function or intelligence quotient[60]Poor socio-economic status[60]Personality disorder[60]Negative symptoms[60]Low education[60]Younger age at onset[60]Schizophrenia spectrum disorder, nonaffective psychosis[60]Long DUP and prodromal symptoms[61]Discontinuation of treatment[62]Deprived area[63]Unemployment[64]Past depression[64]Suicidality[64]Unmet social needs[64]Functional deficits[64]Poor social network[65]Decreased global function at admission[65]Single[65]Insidious onset[65]

aa. Expressed emotion.[65]

Following were associated with increased risk of relapse:

Expressed emotion[61],[66]Negative affective style[61]Stigma and self-stigma[61]Communication deviance[61]Social isolation[61]Medication non adherence[66]Persistent substance use disorder[66]Poor premorbid adjustment[66]Prior cannabis use[67]Poor insight.[67]

Following were associated with increased mortality:

Discontinuation of treatment[68]Increased C-reactive protein (CRP) and leukocyte count[69],[70]Suicidality[71]Cardiovascular disease (CVD) with antipsychotic use[5]Substance abuse, smoking.[72]

Brain imaging[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89] – Alterations in rhythmic activity on electroencephalography, prefrontal Magnetic Resonance Spectroscopy (MRS) markers of neuronal loss, striatal D2 receptor-binding potential, integrating frontotemporal white matter tract, abnormal gyrification of the cerebral cortex, white matter network organization, volume of the ventricle, temporal lobe, hippocampal gyrus, superior temporal gyrus, and lack of elevated dopamine synthesis capacity are associated with antipsychotic treatment resistance.

Genetics[90],[91],[92],[93],[94],[95],[96],[97],[98] – Heritability in schizophrenia and bipolar disorder ranged from 65% to 85%. Increased polygenic risk score (PRS) in a genome-wide association study was associated with reduced treatment response, increase the possibility of clozapine treatment, increased hospital admission and increased severity of negative symptoms in schizophrenia. Increased schizophrenia PRS is associated with increased psychotic risk in bipolar disorder. Bipolar PRS is associated with severe manic symptoms in schizophrenia and psychotic symptoms in bipolar disorder. Shared PRS (Schizophrenia and bipolar) was associated with psychotic symptoms in bipolar disorders and more negative symptoms in schizophrenia. Schizophrenia PRS was also associated with reduced hippocampal volume in FEP. Copy number variations and rare mutation was associated with neurodevelopmental issues which in associated schizophrenia and other psychotic disorders can lead to reduced cognitive function.

Blood-based marker[99],[100],[101],[102],[103],[104],[105],[106],[107],[108] – Several proinflammatory markers were found to be raised in FEP. CRP was associated with increased mortality. Schizophrenia with anti-N-methyl-D-aspartate receptor antibodies were associated with more severe symptoms. Increased cortisol in patients with CHR-P was associated with more transitioning to psychosis, the severity of symptoms, and aggression. Increased plasma homovanillic acid, the principal dopamine metabolite, and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol was associated with increase in treatment response.

Physical comorbidity[109],[110],[111],[112],[113],[114],[115] – young age, low body mass index before treatment, female sex, non-white, negative symptoms, poor social function, co-medications were risk factors for antipsychotic-induced weight gain. Increased smoking was associated with less weight gain. Early weight gain predicted further weight gain. SNP (ADRA2A, DRD2, HTR2C, MC4R) were also found associated with antipsychotic-induced weight gain.

Antipsychotic medication[4],[5] – Antipsychotic medication in the recommended dosage was associated with better outcome and reduced mortality but more than the recommended dosage of antipsychotic medication was found associated with increased CVD mortality.

Suicide risk[116],[117],[118],[119],[120],[121] – 90% of CHR-P reports suicidal ideation. Most suicides are during first 2 years of FEP. Risk is highest preceding and 2 months following treatment. Suicide in early course is associated with increased lethality. Predictors for increased suicidal risk are early age of onset, history of previous suicide attempt, increased severity of anxiety, depression or psychosis, substance abuse, male, higher education, higher IQ, high socioeconomic status, poor premorbid adjustment, living alone, longer DUP, insight, and family history of suicide.

Substance abuse[122],[123],[124],[125],[126] – Substance abuse in FEP is associated with increased relapse rate, longer hospital admission, greater violence, frequent hospitalization, reduced life expectancy and more severe positive symptoms. It is associated with increased risk of relapse and poor outcome.

Quality of life[54] – Being separated or divorced, poor education, unemployment, longer DUP, male gender, depression, comorbid personality disorder, increased positive and negative symptoms, higher caregiver burden, and deteriorated psychosis/well-being were associated with reduced quality of life leading to decreased response to treatment and recovery.

Life stress[1] – physical, environmental, emotional, chronic stress and acute life events may trigger psychotic episodes. Stress bucket hypothesis suggests that overflow of accumulated stress in a vulnerable individual is associated with an increased risk of psychosis.

 Efforts at Prediction of Psychosis



Sabine Bahn group marker bio-panel consisting of 26 analytes predicted 0.82–0.90 of who later developed psychosis.[125] North America Prodrome longitudinal study tested the prediction of psychosis conversion using 15 analytes (0.90). The studies need further replication for its utility.[126] Risk calculation at psychotic conversion ib CHR-P and outcome prediction for FEP is till at its infancy.[127]

 Conclusion



FEP constituted a clinical psychotic phenomenon with underlying significant heterogeneity in diagnosis, stability, course, and outcome. FEP spans the spectrum horizontally across various diagnoses and longitudinally ranging from asymptomatic individuals with unknown risk status to attenuated psychosis to multiple relapses/unremitting illness. Many risk and protective factors are there of varying impact across the biopsychosocial paradigm. Efforts are in progress to calculate PRS based on genes involvement/sharing between various psychotic spectrum disorders; as well as biomarker panels to identify people at risk. Thus, FEP may prove to be an important concept to understand psychosis in general.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Bromley S, Choi M, Faruqui S. First Episode Psychosis – An Information Guide. Revise Edition. Canada: Centre for Addiction and Mental Health; 2015.
2Keshavan MS, Clementz BA, Pearlson GD, Sweeney JA, Tamminga CA. Reimagining psychoses: An agnostic approach to diagnosis. Schizophr Res 2013;146:10-6.
3Malla AK, Norman RM, Joober R. First-episode psychosis, early intervention, and outcome: What have we learned? Can J Psychiatry 2005;50:881-91.
4Crump C, Winkleby MA, Sundquist K, Sundquist J. Comorbidities and mortality in persons with schizophrenia: A Swedish national cohort study. Am J Psychiatry 2013;170:324-33.
5Torniainen M, Mittendorfer-Rutz E, Tanskanen A, Björkenstam C, Suvisaari J, Alexanderson K, et al. Antipsychotic treatment and mortality in schizophrenia. Schizophr Bull 2015;41:656-63.
6Cannon TD, Yu C, Addington J, Bearden CE, Cadenhead KS, Cornblatt BA, et al. An individualized risk calculator for research in prodromal psychosis. Am J Psychiatry 2016;173:980-8.
7Deo RC. Machine learning in medicine. Circulation 2015;132:1920-30.
8Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: A systematic review. Arch Gen Psychiatry 2005;62:975-83.
9Mihalopoulos C, Chatterton ML. Economic evaluations of interventions designed to prevent mental disorders: A systematic review. Early Interv Psychiatry 2015;9:85-92.
10Salvatore P, Baldessarini RJ, Tohen M, Khalsa HM, Sanchez-Toledo JP, Zarate CA Jr., et al. McLean-harvard international first-episode project: Two-year stability of DSM-IV diagnoses in 500 first-episode psychotic disorder patients. J Clin Psychiatry 2009;70:458-66.
11Demjaha A, Lappin JM, Stahl D, Patel MX, MacCabe JH, Howes OD, et al. Antipsychotic treatment resistance in first-episode psychosis: Prevalence, subtypes and predictors. Psychol Med 2017;47:1981-9.
12Fusar-Poli P, Sullivan SA, Shah JL, Uhlhaas PJ. Improving the detection of individuals at clinical risk for psychosis in the community, primary and secondary care: An integrated evidence-based approach. Front Psychiatry 2019;10:774.
13Fusar-Poli P, McGorry PD, Kane JM. Improvinf outcome in first episode psychosis: An overview. World Psychiatry 2017;16:251-65.
14Schwartz JE, Fennig S, Tanenberg-Karant M, Carlson G, Craig T, Galambos N, et al. Congruence of diagnoses 2 years after a first-admission diagnosis of psychosis. Arch Gen Psychiatry 2000;57:593-600.
15McGorry PD, Killackey E, Yung A. Early intervention in psychosis: Concepts, evidence and future directions. World Psychiatry 2008;7:148-56.
16de Haan L, Linszen DH, Lenior ME, de Win ED, Gorsira R. Duration of untreated psychosis and outcome of schizophrenia: Delay in intensive psychosocial treatment versus delay in treatment with antipsychotic medication. Schizophr Bull 2003;29:341-8.
17Power P. Outcome and recovery in first-episode psychosis. Br J Psychiatry 2017;211:331-3.
18Addington J, Van Mastrigt S, Addington D. Duration of untreated psychosis: Impact on 2-year outcome. Psychol Med 2004;34:277-84.
19Kirkbride JB, Errazuriz A, Croudace TJ, Morgan C, Jackson D, Boydell J, et al. Incidence of schizophrenia and other psychoses in England, 1950-2009: A systematic review and meta-analyses. PLoS One 2012;7:e31660.
20Menezes PR, Scazufca M, Busatto G, Coutinho LM, McGuire PK, Murray RM. Incidence of first-contact psychosis in São Paulo, Brazil. Br J Psychiatry Suppl 2007;51:s102-6.
21Oliveira AM, Menezes PR, Busatto GF, McGuire PK, Murray RM, Scazufca M. Family context and duration of untreated psychosis (DUP): Results from the Sao Paulo Study. Schizophr Res 2010;119:124-30.
22Iancu I, Dannon PN, Ziv R, Lepkifker E. A follow-up study of patients with DSM-IV schizophreniform disorder. Can J Psychiatry 2002;47:56-60.
23Zarate CA Jr., Tohen M, Land ML. First-episode schizophreniform disorder: Comparisons with first-episode schizophrenia. Schizophr Res 2000;46:31-4.
24Sajith SG, Chandrasekaran R, Sadanandan Unni KE, Sahai A. Acute polymorphic psychotic disorder: Diagnostic stability over 3 years. Acta Psychiatr Scand 2002;105:104-9.
25Crebbin K, Mitford E, Paxton R, Turkington D. First-episode drug-induced psychosis: A medium term follow up study reveals a high-risk group. Soc Psychiatry Psychiatr Epidemiol 2009;44:710-5.
26Arendt M, Rosenberg R, Foldager L, Perto G, Munk-Jørgensen P. Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: Follow-up study of 535 incident cases. Br J Psychiatry 2005;187:510-5.
27Goulet K, Deschamps B, Evoy F, Trudel JF. Use of brain imaging (computed tomography and magnetic resonance imaging) in first-episode psychosis: Review and retrospective study. Can J Psychiatry 2009;54:493-501.
28Verma S, Subramaniam M, Abdin E, Poon LY, Chong SA. Symptomatic and functional remission in patients with first-episode psychosis. Acta Psychiatr Scand 2012;126:282-9.
29Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161:1-56.
30Breitborde NJ, Bell EK, Dawley D, Woolverton C, Ceaser A, Waters AC, et al. The Early Psychosis Intervention Center (EPICENTER): Development and six-month outcomes of an American first-episode psychosis clinical service. BMC Psychiatry 2015;15:266.
31Srihari VH, Tek C, Kucukgoncu S, Phutane VH, Breitborde NJ, Pollard J, et al. First-episode services for psychotic disorders in the U.S. public sector: A pragmatic randomized controlled trial. Psychiatr Serv 2015;66:705-12.
32Kane JM, Robinson DG, Schooler NR, Mueser KT, Penn DL, Rosenheck RA, et al. Comprehensive versus usual community care for first-episode psychosis: 2-Year outcomes from the NIMH RAISE early treatment program. Am J Psychiatry 2016;173:362-72.
33Rosenheck R, Mueser KT, Sint K, Lin H, Lynde DW, Glynn SM, et al. Supported employment and education in comprehensive, integrated care for first episode psychosis: Effects on work, school, and disability income. Schizophr Res 2017;182:120-8.
34Ruggeri M, Bonetto C, Lasalvia A, Fioritti A, de Girolamo G, Santonastaso P, et al. Feasibility and effectiveness of a multi-element psychosocial intervention for first-episode psychosis: Results from the cluster-randomized controlled GET UP PIANO trial in a catchment area of 10 million inhabitants. Schizophr Bull 2015;41:1192-203.
35Brunette MF, Rotondi AJ, Ben-Zeev D, Gottlieb JD, Mueser KT, Robinson DG, et al. Coordinated technology-delivered treatment to prevent rehospitalization in schizophrenia: A novel model of care. Psychiatr Serv 2016;67:444-7.
36Niendam T, Iosif AM, Tully LM, Burch K, Carter C. Preliminary longitudinal study examining the clinical correlates of medication adherence assessed via a mobile health application in early psychosis care. Neuropsychopharmacology 2015;40:S576.
37Breitborde NJ, Dawley D, Bell EK, Vanuk JR, Allen JJ, Lane RD. A personalized paced-breathing intervention to increase heart rate variability among individuals with first-episode psychosis following stress exposure. Schizophr Res 2015;169:496-7.
38McGorry P, Bates T, Birchwood M. Designing youth mental health services for the 21st century: Examples from Australia, Ireland and the UK. Br J Psychiatry Suppl 2013;54:s30-5.
39McGorry PD, Goldstone SD, Parker AG, Rickwood DJ, Hickie IB. Cultures for mental health care of young people: An Australian blueprint for reform. Lancet Psychiatry 2014;1:559-68.
40Patulny R, Muir K, Powell A, Flaxman S, Oprea I. Are we reaching them yet? Service access patterns among attendees at the headspace youth mental health initiative. Child Adolesc Ment Health 2013;18:95-102.
41Rickwood DJ, Telford NR, Parker AG, Tanti CJ, McGorry PD. Headspace - Australia's innovation in youth mental health: Who are the clients and why are they presenting? Med J Aust 2014;200:108-11.
42Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: A critical review and meta-analysis. Am J Psychiatry 2005;162:1785-804.
43Lappin JM, Heslin M, Lomas B, Jones PB, Doody GA, Reininghaus UA, et al. Early sustained recovery following first episode psychosis: Evidence from the AESOP10 follow-up study. Schizophr Res 2018;199:341-5.
44Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: Long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013;70:913-20.
45Torgalsbøen AK, Fu S, Czajkowski N. Resilience trajectories to full recovery in first-episode schizophrenia. Eur Psychiatry 2018;52:54-60.
46O'Connor JA, Ellett L, Ajnakina O, Schoeler T, Kollliakou A, Trotta A, et al. Can cognitive insight predict symptom remission in a first episode psychosis cohort? BMC Psychiatry 2017;17:54.
47Leeson VC, Sharma P, Harrison M, Ron MA, Barnes TR, Joyce EM. IQ trajectory, cognitive reserve, and clinical outcome following a first episode of psychosis: A 3-year longitudinal study. Schizophr Bull 2011;37:768-77.
48Amoretti S, Bernardo M, Bonnin CM, Bioque M, Cabrera B, Mezquida G, et al. The impact of cognitive reserve in the outcome of first-episode psychoses: 2-year follow-up study. Eur Neuropsychopharmacol 2016;26:1638-48.
49Hopper K, Wanderling J. Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: Results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. Schizophr Bull 2000;26:835-46.
50Schulz SC. Brief Psychotic Disorder. Minneapolis, MN, USA: University of Minnesota Medical School; 2019.
51Hasson-Ohayon I, Kravetz S, Roe D, David AS, Weiser M. Insight into psychosis and quality of life. Compr Psychiatry 2006;47:265-9.
52Carpiniello B, Pinna F, Tusconi M, Zaccheddu E, Fatteri F. Gender differences in remission and recovery of schizophrenic and schizoaffective patients: preliminary results of a prospective cohort study. Schizophr Res Treatment. 2012;2012:576369. doi: 10.1155/2012/576369. Epub 2012 Jan 16. PMID: 22966440; PMCID: PMC3420715.
53Pang S, Subramaniam M, Abdin E, Poon LY, Chong SA, Verma S. Gender differences in patients with first-episode psychosis in the Singapore Early Psychosis Intervention Programme. Early Interv Psychiatry 2016;10:528-34.
54Satghare P, Abdin E, Shahwan S, Chua BY, Poon LY, Chong SA, et al. Subjective quality of life and its associations among first episode psychosis patients in Singapore. Int J Environ Res Public Health 2019;17:260.
55Rosen K, Garety P. Predicting recovery from schizophrenia: A retrospective comparison of characteristics at onset of people with single and multiple episodes. Schizophr Bull 2005;31:735-50.
56Dixon LB, Holoshitz Y, Nossel I. Treatment engagement of individuals experiencing mental illness: Review and update. World Psychiatry 2016;15:13-20.
57Kabat-Zinn J. Mindfulness-based interventions in context: Past, present, and future. Clin Psychol 2003;10:144-56.
58Chang WC, Chu AO, Kwong VW, Wong CS, Hui CL, Chan SK, et al. Patterns and predictors of trajectories for social and occupational functioning in patients presenting with first-episode non-affective psychosis: A three-year follow-up study. Schizophr Res 2018;197:131-7.
59Srihari VH, Phutane VH, Ozkan B, Chwastiak L, Ratliff JC, Woods SW, et al. Cardiovascular mortality in schizophrenia: Defining a critical period for prevention. Schizophr Res 2013;146:64-8.
60Hall MH, Holton KM, Öngür D, Montrose D, Keshavan MS. Longitudinal trajectory of early functional recovery in patients with first episode psychosis. Schizophr Res 2019;209:234-44.
61McFarlane WR. Prevention of the first episode of psychosis. Psychiatr Clin North Am 2011;34:95-107.
62Thompson A, Winsper C, Marwaha S, Haynes J, Alvarez-Jimenez M, Hetrick S, et al. Maintenance antipsychotic treatment versus discontinuation strategies following remission from first episode psychosis: Systematic review. BJPsych Open 2018;4:215-25.
63Morgan C, Lappin J, Heslin M, Donoghue K, Lomas B, Reininghaus U, et al. Reappraising the long-term course and outcome of psychotic disorders: The AESOP-10 study. Psychol Med 2014;44:2713-26.
64Koutsouleris N, Kahn RS, Chekroud AM, Leucht S, Falkai P, Wobrock T, et al. Multisite prediction of 4-week and 52-week treatment outcomes in patients with first-episode psychosis: A machine learning approach. Lancet Psychiatry 2016;3:935-46.
65Kalla O. Characteristics, Course & Outcome in First Episode Psychosis: A Cross Cultural Comparison of Finnish and Spanish Group. Jyvskala Studied in Education, Psychology and Social Research. Jyvskala University Printing House; 2005.
66Alvarez-Jimenez M, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, et al. Risk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies. Schizophr Res 2012;139:116-28.
67Bergé D, Mané A, Salgado P, Cortizo R, Garnier C, Gomez L, et al. Predictors of relapse and functioning in first-episode psychosis: A two-year follow-up study. Psychiatr Serv 2016;67:227-33.
68Tiihonen J, Tanskanen A, Taipale H. 20-Year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry 2018;175:765-73.
69Horsdal HT, Köhler-Forsberg O, Benros ME, Gasse C. C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression – Associations with mortality and psychiatric outcomes: A population-based study. Eur Psychiatry 2017;44:164-72.
70Miller BJ, Kandhal P, Rapaport MH, Mellor A, Buckley P. Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses. Brain Behav Immun 2015;45:28-35.
71Simon GE, Stewart C, Yarborough BJ, Lynch F, Coleman KJ, Beck A, et al. Mortality rates after the first diagnosis of psychotic disorder in adolescents and young adults. JAMA Psychiatry 2018;75:254-60.
72Dickerson F, Origoni A, Schroeder J, Adamos M, Katsafanas E, Khushalani S, et al. Natural cause mortality in persons with serious mental illness. Acta Psychiatr Scand 2018;137:371-9.
73Keinänen J, Mantere O, Markkula N, Partti K, Perälä J, Saarni SI, et al. Mortality in people with psychotic disorders in Finland: A population-based 13-year follow-up study. Schizophr Res 2018;192:113-8.
74Manchanda R, Norman R, Malla A, Harricharan R, Northcott S, Richard J. Electroencephalographic abnormalities and 5-year outcome in first-episode psychosis. Can J Psychiatry 2014;59:285-8.
75Wood SJ, Berger GE, Lambert M, Conus P, Velakoulis D, Stuart GW, et al. Prediction of functional outcome 18 months after a first psychotic episode: A proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 2006;63:969-76.
76Corripio I, Pérez V, Catafau AM, Mena E, Carrió I, Alvarez E. Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis. Neuroimage 2006;29:662-6.
77Luck D, Buchy L, Czechowska Y, Bodnar M, Pike GB, Campbell JS, et al. Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: A DTI-tractography study. J Psychiatr Res 2011;45:369-77.
78Palaniyappan L, Marques TR, Taylor H, Handley R, Mondelli V, Bonaccorso S, et al. Cortical folding defects as markers of poor treatment response in first-episode psychosis. JAMA Psychiatry 2013;70:1031-40.
79Palaniyappan L, Marques TR, Taylor H, Mondelli V, Reinders AA, Bonaccorso S, et al. Globally efficient brain organization and treatment response in psychosis: A connectomic study of gyrification. Schizophr Bull 2016;42:1446-56.
80Crossley NA, Marques TR, Taylor H, Chaddock C, Dell'Acqua F, Reinders AA, et al. Connectomic correlates of response to treatment in first-episode psychosis. Brain 2017;140:487-96.
81Lieberman J, Chakos M, Wu H, Alvir J, Hoffman E, Robinson D, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001;49:487-99.
82Milev P, Ho BC, Arndt S, Nopoulos P, Andreasen NC. Initial magnetic resonance imaging volumetric brain measurements and outcome in schizophrenia: A prospective longitudinal study with 5-year follow-up. Biol Psychiatry 2003;54:608-15.
83de Castro-Manglano P, Mechelli A, Soutullo C, Landecho I, Gimenez-Amaya JM, Ortuño F, et al. Structural brain abnormalities in first-episode psychosis: Differences between affective psychoses and schizophrenia and relationship to clinical outcome. Bipolar Disord 2011;13:545-55.
84Sauras R, Keymer A, Alonso-Solis A, Díaz A, Molins C, Nuñez F, et al. Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis. Eur Psychiatry 2017;45:1-5.
85Takahashi T, Wood SJ, Yung AR, Soulsby B, McGorry PD, Suzuki M, et al. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Arch Gen Psychiatry 2009;66:366-76.
86Dazzan P, Arango C, Fleischacker W, Galderisi S, Glenthøj B, Leucht S, et al. Magnetic resonance imaging and the prediction of outcome in first-episode schizophrenia: A review of current evidence and directions for future research. Schizophr Bull 2015;41:574-83.
87Fusar-Poli P, Meyer-Lindenberg A. Forty years of structural imaging in psychosis: Promises and truth. Acta Psychiatr Scand 2016;134:207-24.
88Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 2012;169:1203-10.
89Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, et al. Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: An 18FDOPA PET Study. Neuropsychopharmacology 2017;42:941-50.
90Li J, Yoshikawa A, Brennan MD, Ramsey TL, Meltzer HY. Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes. Schizophr Res 2018;192:194-204.
91Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, et al. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry 2015;20:913.
92Meier SM, Agerbo E, Maier R, Pedersen CB, Lang M, Grove J, et al. High loading of polygenic risk in cases with chronic schizophrenia. Mol Psychiatry 2016;21:969-74.
93Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 2018;173:1705-15.
94Wimberley T, Gasse C, Meier SM, Agerbo E, MacCabe JH, Horsdal HT. Polygenic risk score for schizophrenia and treatment-resistant schizophrenia. Schizophr Bull 2017;43:1064-9.
95Allardyce J, Leonenko G, Hamshere M, Pardiñas AF, Forty L, Knott S, et al. Association between schizophrenia-related polygenic liability and the occurrence and level of mood-incongruent psychotic symptoms in bipolar disorder. JAMA Psychiatry 2018;75:28-35.
96Vassos E, Di Forti M, Coleman J, Iyegbe C, Prata D, Euesden J, et al. An examination of polygenic score risk prediction in individuals with first-episode psychosis. Biol Psychiatry 2017;81:470-7.
97Harrisberger F, Smieskova R, Vogler C, Egli T, Schmidt A, Lenz C, et al. Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis. Transl Psychiatry 2016;6:e868.
98Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 2017;49:27-35.
99Fond G, d'Albis MA, Jamain S, Tamouza R, Arango C, Fleischhacker WW, et al. The promise of biological markers for treatment response in first-episode psychosis: A systematic review. Schizophr Bull 2015;41:559-73.
100Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016;21:1696-709.
101Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663-71.
102Wang AK, Miller BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder, and depression. Schizophr Bull 2018;44:75-83.
103Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis. Schizophr Res 2014;155:101-8.
104Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry 2013;73:993-9.
105Kayser MS, Dalmau J. Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res 2016;176:36-40.
106Pollak TA, Rogers JP, Nagele RG, Peakman M, Stone JM, David AS, et al. Antibodies in the diagnosis, prognosis, and prediction of psychotic disorders. Schizophr Bull 2019;45:233-46.
107Jézéquel J, Johansson EM, Dupuis JP, Rogemond V, Gréa H, Kellermayer B, et al. Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nat Commun 2017;8:1791.
108Walker EF, Trotman HD, Pearce BD, Addington J, Cadenhead KS, Cornblatt BA, et al. Cortisol levels and risk for psychosis: Initial findings from the North American prodrome longitudinal study. Biol Psychiatry 2013;74:410-7.
109Zhang JP, Lencz T, Zhang RX, Nitta M, Maayan L, John M, et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: A systematic review and meta-analysis. Schizophr Bull 2016;42:1418-37.
110Basson BR, Kinon BJ, Taylor CC, Szymanski KA, Gilmore JA, Tollefson GD. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 2001;62:231-8.
111Strassnig M, Miewald J, Keshavan M, Ganguli R. Weight gain in newly diagnosed first-episode psychosis patients and healthy comparisons: One-year analysis. Schizophr Res 2007;93:90-8.
112Saddichha S, Ameen S, Akhtar S. Predictors of antipsychotic-induced weight gain in first-episode psychosis: Conclusions from a randomized, double-blind, controlled prospective study of olanzapine, risperidone, and haloperidol. J Clin Psychopharmacol 2008;28:27-31.
113Pérez-Iglesias R, Martínez-García O, Pardo-Garcia G, Amado JA, Garcia-Unzueta MT, Tabares-Seisdedos R, et al. Course of weight gain and metabolic abnormalities in first treated episode of psychosis: The first year is a critical period for development of cardiovascular risk factors. Int J Neuropsychopharmacol 2014;17:41-51.
114Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg JC, et al. Antipsychotic-induced body weight gain: Predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 2009;43:620-6.
115Scheffler F, Kilian S, Chiliza B, Asmal L, Phahladira L, du Plessis S, et al. Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders. Schizophr Res 2018;199:90-5.
116Ventriglio A, Gentile A, Bonfitto I, Stella E, Mari M, Steardo L, et al. Suicide in the Early Stage of Schizophrenia. Front Psychiatry 2016;7:116.
117Ayesa-Arriola R, Alcaraz EG, Hernández BV, Pérez-Iglesias R, López Moríñigo JD, Duta R, et al. Suicidal behaviour in first-episode non-affective psychosis: Specific risk periods and stage-related factors. Eur Neuropsychopharmacol 2015;25:2278-88.
118Dutta R, Murray RM, Hotopf M, Allardyce J, Jones PB, Boydell J. Reassessing the long-term risk of suicide after a first episode of psychosis. Arch Gen Psychiatry 2010;67:1230-7.
119Nordentoft M, Madsen T, Fedyszyn I. Suicidal behavior and mortality in first-episode psychosis. J Nerv Ment Dis 2015;203:387-92.
120Pompili M, Serafini G, Innamorati M, Lester D, Shrivastava A, Girardi P, et al. Suicide risk in first episode psychosis: A selective review of the current literature. Schizophr Res 2011;129:1-1.
121Robinson J, Harris MG, Harrigan SM, Henry LP, Farrelly S, Prosser A, et al. Suicide attempt in first-episode psychosis: A 7.4 year follow-up study. Schizophr Res 2010;116:1-8.
122Weibell MA, Hegelstad WT, Auestad B, Bramness J, Evensen J, Haahr U, et al. The effect of substance use on 10-year outcome in first-episode psychosis. Schizophr Bull 2017;43:843-51.
123Schoeler T, Monk A, Sami MB, Klamerus E, Foglia E, Brown R, et al. Continued versus discontinued cannabis use in patients with psychosis: A systematic review and meta-analysis. Lancet Psychiatry 2016;3:215-25.
124Bowtell M, Eaton S, Thien K, Bardell-Williams M, Downey L, Ratheesh A, et al. Rates and predictors of relapse following discontinuation of antipsychotic medication after a first episode of psychosis. Schizophr Res 2018;195:231-6.
125Chan MK, Krebs MO, Cox D, Guest PC, Yolken RH, Rahmoune H, et al. Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset. Transl Psychiatry 2015;5:e601.
126Perkins DO, Jeffries CD, Addington J, Bearden CE, Cadenhead KS, Cannon TD, et al. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: Preliminary results from the NAPLS project. Schizophr Bull 2015;41:419-28.
127Suvisaari J, Mantere O, Keinänen J, Mäntylä T, Rikandi E, Lindgren M, et al. Is it possible to predict the future in first-episode psychosis? Front Psychiatry 2018;9:580.