Schizophrenia

Clinical picture

• Positive symptoms dominate acute episodes: persecutory or referential delusions, auditory hallucinations that comment or command, and disorganized speech.
• Negative symptoms drive long-term disability: blunted affect, alogia, avolition, anhedonia, and asociality that persist between psychotic episodes.
• Cognitive deficits of 1-2 standard deviations in working memory, processing speed, and executive function predict vocational outcome better than delusions.
• A prodrome of social withdrawal, declining grades, odd beliefs, and attenuated perceptual disturbance typically precedes frank psychosis by 1-3 years.
• Insight is frequently absent; anosognosia rather than defiance underlies much nonadherence and shapes engagement, capacity, and treatment planning.
• Grossly disorganized or catatonic behavior, poor grooming, and inappropriate affect emerge in severe presentations and raise the risk of self-neglect.

Criteria snapshot

• Two or more of delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms for much of one month.
• At least one of the required symptoms must be delusions, hallucinations, or disorganized speech, anchoring the diagnosis in positive psychotic phenomena.
• Continuous signs of disturbance persist at least 6 months, including prodromal or residual periods where only negative or attenuated symptoms appear.
• Functioning in work, relationships, or self-care falls markedly below the prior level, or fails to reach expected milestones in youth-onset cases.
• Schizoaffective disorder and mood disorders with psychosis are excluded, and the picture is not attributable to a substance or medical condition.

Neurobiology

• Mesolimbic dopamine hyperactivity generates positive symptoms, while mesocortical D1 hypofunction in dorsolateral prefrontal cortex tracks negative and cognitive deficits.
• NMDA receptor hypofunction on parvalbumin interneurons disrupts gamma oscillations, a model supported by ketamine and phencyclidine psychotomimetic effects.
• Heritability approaches 80%; risk is highly polygenic with the strongest signal at the MHC locus, implicating complement C4-mediated synaptic pruning.
• Imaging shows lateral ventricular enlargement, reduced hippocampal and superior temporal gray matter, and accelerated cortical thinning after onset.
• Obstetric complications, winter birth, urban rearing, migration, and adolescent cannabis use interact with polygenic load in a neurodevelopmental model.
• Life expectancy is shortened 15-20 years, driven by cardiovascular disease, smoking, and antipsychotic-related metabolic syndrome more than by suicide.

Psychology

• Aberrant salience attribution assigns motivational significance to neutral stimuli, and delusions form as explanatory frameworks that resolve that dysphoric ambiguity.
• Jumping-to-conclusions reasoning and an externalizing attributional bias sustain persecutory beliefs and are direct targets of cognitive therapy for psychosis.
• Source-monitoring failure misattributes inner speech to external agents, producing the phenomenology of voices experienced as originating outside the head.
• Social cognition deficits in theory of mind and emotion recognition predict community functioning independent of positive symptom severity.
• High expressed emotion in the family, meaning criticism, hostility, and emotional overinvolvement, roughly doubles relapse risk over 9-12 months.

Differential & comorbidity

• Distinguish from schizoaffective disorder, where mood episodes occupy most of the illness, and from bipolar or depressive disorders with psychotic features.
• Substance-induced psychosis from methamphetamine, cannabis, or synthetic cannabinoids resolves within days to weeks of abstinence; obtain urine toxicology.
• Rule out autoimmune encephalitis, temporal lobe epilepsy, neurosyphilis, HIV, Huntington disease, and steroid or anticholinergic effects in atypical onset.
• Tobacco use disorder affects 60-80% and substance use disorder roughly 50%; depression, obsessive-compulsive symptoms, and social anxiety worsen outcome.
• Lifetime suicide risk is roughly 5%, highest early in the illness with preserved insight; command hallucinations and violence risk require direct assessment.

Pharmacologic treatment

• Second-generation antipsychotics are first line: risperidone 2-6 mg/day, aripiprazole 10-30 mg/day, or olanzapine 10-20 mg/day for 2-6 weeks before judging response.
• Clozapine 300-450 mg/day is the only agent proven in treatment resistance after two adequate trials; monitor ANC for agranulocytosis and screen for myocarditis.
• Long-acting injectables such as paliperidone palmitate or aripiprazole monohydrate cut relapse and rehospitalization and are reasonable after a first episode.
• Monitor weight, waist circumference, fasting glucose, and lipids at baseline, 3 months, then annually; olanzapine carries the heaviest metabolic burden.
• Watch for akathisia, parkinsonism, hyperprolactinemia, and QTc prolongation; valbenazine or deutetrabenazine treat established tardive dyskinesia.

Psychotherapy

• CBT for psychosis over 16-24 sessions produces small to moderate reductions in positive symptom distress and is recommended when symptoms persist on medication.
• Family psychoeducation lasting 9 months or longer lowers relapse rates by roughly 20 percentage points by reducing expressed emotion and improving crisis planning.
• Cognitive remediation paired with a real work or school placement improves processing speed and functional outcome far more than isolated drill practice.
• Social skills training in structured, role-played modules improves conversational and self-care performance, though transfer to community settings is modest.
• Coordinated specialty care in first-episode psychosis integrates therapy, medication, employment support, and family work with better 2-year outcomes than usual care.

Adjunct options

• Supported employment using the individual placement and support model places 55-60% into competitive jobs versus about 20% with prevocational training.
• ECT augments clozapine in refractory psychosis and is first-line for catatonia, typically delivered as 8-12 bilateral treatments over several weeks.
• Assertive community treatment, clubhouse programs, and supported housing reduce hospital days among high utilizers with poor outpatient engagement.
• Track severity with the PANSS or the briefer BPRS, and screen for abnormal movements with the AIMS every 6 to 12 months on any antipsychotic.
• Smoking cessation with varenicline, metformin for antipsychotic weight gain, and annual metabolic labs directly address the excess mortality gap.

Clinical pearls

• Duration of untreated psychosis is the strongest modifiable predictor of long-term outcome.
• Two failed antipsychotic trials means clozapine, not a third me-too agent.
• Negative symptoms, not delusions, decide whether the patient ever works again.