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

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. Copyright:

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.[45] 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.[67]

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.[89]

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 FEP

Stability of diagnosis in a FEP

Positive modifiers of course and outcome of FEP

Negative modifiers of course and outcome of FEP

Efforts 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 variably

Early mental health literacy and family psychoeducation may prevent or reduce risk of FEP

Identification and targeted prevention to the individual having CHR-P may reduce chances of FEP

Intervention 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.[815] 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.[2223] 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.[2526] 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.[2829]

POSITIVE MODIFIERS OF COURSE AND OUTCOME OF FIRST-EPISODE PSYCHOSIS

Multicomponent treatment package,[3031323334] technological enhancement of psychosocial treatment,[353637] personalized psychosocial intervention,[38394041] 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.[4445]

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.[4748]

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.[5051525354]

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.[157]

NEGATIVE MODIFIERS OF COURSE AND OUTCOME OF FIRST-EPISODE PSYCHOSIS

Following were associated with poor outcome:

Hospitalization at onset and frequent hospitalization[3258]

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[6166]

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[6970]

Suicidality[71]

Cardiovascular disease (CVD) with antipsychotic use[5]

Substance abuse, smoking.[72]

Brain imaging[7374757677787980818283848586878889] – 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[909192939495969798] – 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[99100101102103104105106107108] – 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[109110111112113114115] – 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[45] – 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[116117118119120121] – 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[122123124125126] – 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.