Psychiatry/Behavioral · PANCE / PANRE

Schizophrenia

Chronic psychotic disorder with positive, negative, and cognitive symptoms persisting >=6 months.

Also known as: schizophrenia, psychotic disorder, primary psychosis

Overview

A chronic primary psychotic disorder defined by >=1 month of active-phase symptoms (>=2 of delusions, hallucinations, disorganized speech, grossly disorganized/catatonic behavior, negative symptoms — including at least one of the first three) with total disturbance >=6 months including prodromal/residual phases, and significant functional decline.

Epidemiology

Lifetime prevalence ~0.7-1%. Onset typically late teens to mid-20s in males, slightly later in females. Slight male predominance with earlier onset and worse outcomes.

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Risk factors

Family history (first-degree relative ~10% risk; monozygotic twin ~50%)
Advanced paternal age at conception
Obstetric complications, perinatal hypoxia, maternal infection (influenza in second trimester)
Urban upbringing, migration
Cannabis use in adolescence (especially high-potency THC)
Childhood adversity

Pathophysiology

Polygenic disorder with disruption of cortical development and synaptic pruning. Dopaminergic hyperactivity in mesolimbic pathways (positive symptoms) and hypoactivity in mesocortical pathways (negative/cognitive symptoms). NMDA receptor hypofunction, GABAergic interneuron deficits, neuroinflammation. Ventriculomegaly and reduced gray matter volume on imaging.

Clinical presentation

Symptoms

Positive: delusions (often persecutory or referential), hallucinations (auditory most common), disorganized speech (derailment, tangentiality, word salad), grossly disorganized/catatonic behavior
Negative: avolition, alogia, anhedonia, asociality, blunted/flat affect
Cognitive: deficits in attention, working memory, executive function, processing speed
Prodromal phase: social withdrawal, declining function, attenuated psychotic symptoms preceding overt psychosis by months to years

Signs / physical exam

Flat affect, poor eye contact, internal preoccupation
Thought disorder evident in speech
Catatonia: stupor, mutism, posturing, waxy flexibility, echolalia, echopraxia (now its own DSM specifier)
Neurological soft signs

Differential diagnosis

Schizophreniform disorder — Same symptoms 1-6 months without the social/occupational decline requirement
Brief psychotic disorder — Symptoms 1 day to 1 month with return to premorbid function
Schizoaffective disorder — Mood episode concurrent with psychosis, plus >=2 weeks of psychosis without mood symptoms
Bipolar I with psychotic features — Psychosis confined to mood episodes
MDD with psychotic features — Mood-congruent psychosis during depressive episode only
Substance/medication-induced psychosis — Stimulants, cannabis, hallucinogens, corticosteroids, anticholinergics; resolves with abstinence
Psychosis due to medical condition — Delirium, autoimmune encephalitis (anti-NMDA), temporal lobe epilepsy, Huntington, B12 deficiency, neurosyphilis
Delusional disorder — >=1 month of non-bizarre delusions without other psychotic symptoms; function otherwise preserved

Diagnostic workup

Diagnostic criteria

DSM-5-TR: (A) >=2 of delusions, hallucinations, disorganized speech, grossly disorganized/catatonic behavior, negative symptoms — each for a significant portion of 1 month (or less if treated), with at least one being delusions, hallucinations, or disorganized speech; (B) Marked decline in functioning; (C) Continuous signs >=6 months including >=1 month of active symptoms; (D) Schizoaffective and mood disorders with psychosis excluded; (E) Not attributable to substance or medical condition.

Labs

CBC, BMP, LFTs, TSH, vitamin B12, syphilis serology, HIV
Urine drug screen — essential to exclude substance-induced psychosis
Baseline metabolic labs and ECG (QTc) before antipsychotic
Pregnancy test in women of reproductive age
Consider autoimmune encephalitis workup (anti-NMDA, paraneoplastic panel) for atypical presentations

Imaging

MRI brain in first-episode psychosis to exclude structural lesion, demyelination, encephalitis
EEG if temporal lobe epilepsy or encephalopathy suspected

Diagnostic algorithm

Disorder	Active sx duration	Total duration	Mood overlap
Brief psychotic	1 day - 1 month	<1 month	No
Schizophreniform	1-6 months	<6 months	No
Schizophrenia	>=1 month active	>=6 months	No (or brief)
Schizoaffective	>=1 month	>=2 wks psychosis w/o mood	Major mood episode concurrent
Mood d/o w/ psychosis	Variable	Limited to mood episode	Always

Primary psychotic disorder differentials by duration and mood overlap.

Treatment

First-line

Atypical (second-generation) antipsychotic — risperidone, olanzapine, aripiprazole, quetiapine, paliperidone, lurasidone (titrate to lowest effective dose)
Long-acting injectable (LAI) antipsychotics for adherence problems — paliperidone palmitate, aripiprazole monohydrate, risperidone microspheres
Coordinated specialty care for first-episode psychosis — early intervention improves long-term outcomes
Psychosocial: family psychoeducation, cognitive remediation, supported employment, social skills training, assertive community treatment
Smoking cessation, metabolic monitoring, cardiovascular risk reduction

Treatment-resistant (>=2 adequate antipsychotic trials)

Clozapine — uniquely effective; reduces suicide risk
REMS monitoring: weekly ANC for 6 months, then every 2 weeks, then monthly
Monitor for agranulocytosis, myocarditis, seizures, ileus, metabolic syndrome, sialorrhea

Acute agitation

Verbal de-escalation first; offer PO medication
IM olanzapine, haloperidol with benzodiazepine, or aripiprazole IM if needed
Avoid combining IM olanzapine + IM benzodiazepine (respiratory depression)

Catatonic features

Lorazepam challenge (1-2 mg IV/IM)
ECT for benzodiazepine non-response
Hold antipsychotics initially if NMS risk

Second-line / adjunct

First-generation (typical) antipsychotic — haloperidol, fluphenazine, perphenazine (cost-effective; higher EPS risk)
Adjunctive antidepressant for comorbid depression (NOT during active psychosis)
Mood stabilizers for aggression or affective lability

Complications

Suicide — lifetime risk ~5%; highest early in illness
Premature mortality 15-20 years shorter than general population — cardiovascular and metabolic disease
Substance use disorders, especially tobacco and cannabis
Tardive dyskinesia (especially first-generation), neuroleptic malignant syndrome, metabolic syndrome with atypicals
Homelessness, unemployment, social isolation
Victimization (more often victims than perpetrators of violence)

PANCE pearls

Duration of untreated psychosis predicts outcome — early intervention with coordinated specialty care improves trajectory.
Clozapine is the only antipsychotic with demonstrated efficacy in treatment-resistant schizophrenia and reduces suicide risk; underutilized due to monitoring burden.
NMS: fever, rigidity, autonomic instability, elevated CK, altered mental status — stop antipsychotic, supportive care, consider dantrolene or bromocriptine.
Tardive dyskinesia: late-onset involuntary movements; treat with VMAT2 inhibitors (valbenazine, deutetrabenazine).
Monitor metabolic parameters at baseline, 12 weeks, then annually (weight/BMI, BP, fasting glucose, lipids); olanzapine and clozapine have highest metabolic burden.

References

APA 2020 — American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd ed. (2020)
CATIE — Lieberman JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005
RAISE — Kane JM et al. Comprehensive Versus Usual Community Care for First-Episode Psychosis. Am J Psychiatry 2016
DSM-5-TR — American Psychiatric Association. DSM-5-TR (2022)

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