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 |
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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