Schizophrenia and Psychotic Disorders

Non-modifiable — genetic

• Polygenic inheritance: heritability is high (twin and family studies place it among the most heritable psychiatric disorders). Risk rises steeply with genetic proximity — roughly 1% general population, ~10% in a first-degree relative, and approaching 50% in monozygotic twins. Common variants of small effect (including the MHC/complement C4 locus, implicating excessive synaptic pruning) plus rare copy-number variants explain the pattern.
• 22q11.2 deletion syndrome (DiGeorge/velocardiofacial): the single strongest identifiable genetic risk factor; a stem with conotruncal cardiac anomaly, hypocalcemia, cleft palate, and adolescent psychosis is testing this.
• Advanced paternal age: de novo mutations in paternal germline.

Non-modifiable — neurodevelopmental

• Prenatal and perinatal insults: maternal infection (influenza, Toxoplasma), malnutrition/famine exposure, Rh incompatibility, obstetric complications with fetal hypoxia. These converge on the two-hit model — early neurodevelopmental vulnerability unmasked by late-adolescent synaptic pruning and stress.
• Late winter/early spring birth: small but reproducible epidemiologic association, consistent with the infection hypothesis.
• Age and sex: onset in late teens–20s in men, late 20s with a second peri-/postmenopausal peak in women (estrogen is thought to be protective).

Modifiable / environmental

• Cannabis: high-potency, high-THC use beginning in adolescence is dose-dependently associated with earlier onset and increased incidence; the most commonly planted modifiable exposure. Stimulants, hallucinogens, and PCP produce phenocopies.
• Childhood adversity and trauma, urban upbringing, migrant/minority status with social defeat, and social isolation.
• Duration of untreated psychosis: the most actionable modifiable prognostic variable — the APA Practice Guideline for the Treatment of Patients With Schizophrenia endorses coordinated specialty care for first-episode psychosis specifically to shorten it.

• Distractor: parenting style and "schizophrenogenic mother" theories are historical and are never the answer.

• Dopamine hypothesis (primary mechanism): Hyperactivity of dopamine in mesolimbic pathways drives positive symptoms (hallucinations, delusions), while hypodopaminergia in mesocortical pathways contributes to negative and cognitive symptoms. This explains why dopamine antagonists (antipsychotics) reduce positive but may worsen negative symptoms.

• Glutamatergic dysfunction: Hypofunction of NMDA receptors on GABAergic interneurons leads to reduced GABAergic inhibition of glutamate neurons, resulting in excessive glutamate activity. This "glutamate excitotoxicity" contributes to cognitive deficits and psychotic symptoms. Phencyclidine (PCP) blocks NMDA receptors and produces schizophrenia-like psychosis, supporting this model.

• Structural brain abnormalities: Progressive gray matter loss (particularly in prefrontal cortex and temporal lobes), ventricular enlargement, and reduced hippocampal volume. White matter abnormalities affect connectivity between brain regions, contributing to disorganized thinking and cognitive dysfunction.

• Neurotrophic factors and inflammation: Reduced brain-derived neurotrophic factor (BDNF), elevated cytokines (IL-6, TNF-α), and microglial activation suggest an inflammatory component. Prenatal/perinatal infections increase risk, supporting immune-mediated mechanisms.

• Neurotransmitter imbalances: Alterations in serotonin (5-HT2A hyperactivity), acetylcholine, and GABA systems also contribute. Atypical antipsychotics' efficacy partly derives from serotonin antagonism.

• Genetic vulnerability with environmental triggers: Polygenic inheritance (multiple genes including DISC1, NRG1, COMT) with environmental stressors (cannabis use, urban living, childhood trauma, prenatal infections) determine phenotypic expression.

• Positive symptoms (additions to normal experience): Hallucinations (typically auditory—often commanding or derogatory voices), delusions (persecutory, grandiose, referential, somatic, or nihilistic), disorganized speech (tangentiality, circumstantiality, word salad), and disorganized/catatonic behavior. Auditory hallucinations are most common and nearly pathognomonic when running commentary or multiple voices conversing.

• Negative symptoms (diminishment of normal functions): Alogia (poverty of speech), avolition (lack of motivation/goal-directed activity), anhedonia (inability to experience pleasure), affective flattening (restricted emotional expression), and social withdrawal. These are often more disabling long-term than positive symptoms and respond less robustly to antipsychotics.

• Cognitive symptoms: Deficits in attention, working memory, executive function, and processing speed. These may precede psychotic symptoms and persist despite treatment, directly impacting functional recovery.

• First-episode psychosis (FEP): Acute onset of hallucinations, delusions, or disorganized speech/behavior, often with prominent anxiety, agitation, and mood disturbance. Duration of untreated psychosis (DUP) should be minimized—each month of delay worsens prognosis.

• Catatonia (when present): Waxy flexibility, mutism, negativism, posturing, or excessive purposeless motor activity. Requires urgent evaluation for medical causes (neuroleptic malignant syndrome, encephalitis, etc.) before attributing to psychosis alone.

• Affective features: Depressive symptoms occur in up to 50% and increase suicide risk; mood-incongruent delusions distinguish primary psychosis from psychotic mood disorders.

• Important clinical pearl: Premorbid personality changes (social withdrawal, declining grades/work performance, magical thinking) often precede overt psychosis by months to years (prodromal phase).

• DSM-5 criteria: Two or more psychotic symptoms present for ≥1 month (or ≥1 week if rapidly progressive), with at least one being delusions, hallucinations, or disorganized speech. Continuous signs of illness must persist for ≥6 months total (including prodromal/residual phases). Must exclude substance use, medical conditions, and other psychiatric disorders.

• Structured clinical interviews: SCID (Structured Clinical Interview for DSM-5), PANSS (Positive and Negative Syndrome Scale), or BPRS (Brief Psychiatric Rating Scale) help standardize symptom assessment and severity quantification. Critical for establishing baseline and monitoring treatment response.

• Neuroimaging (MRI/CT): Not diagnostic but used to rule out organic causes (brain tumors, stroke, abscess, hydrocephalus). Indicated in first episode, atypical presentations, rapid onset, focal neurologic signs, or age >40 at first psychosis onset (suggests secondary psychosis).

• Laboratory and toxicology screening: Comprehensive metabolic panel, CBC, urine drug screen, pregnancy test, syphilis serology (RPR), and HIV testing. Screen for medical mimics: thyroid dysfunction, electrolyte abnormalities, hepatic encephalopathy, HIV/neurosyphilis, lupus (CNS vasculitis).

• Electroencephalography (EEG): Consider if catatonia present, risk of seizures, or altered consciousness. Helps differentiate seizure activity from psychotic symptoms.

• Exclude other disorders: Psychotic depression/bipolar disorder (psychotic features mood-congruent, present only during mood episodes), brief psychotic disorder (<1 month), substance-induced psychosis, psychotic disorder due to medical condition, delusional disorder (non-bizarre delusions without other prominent hallucinations).

• Prodromal symptoms assessment: At-Risk Mental State (ARMS) criteria or Structured Interview for Prodromal Syndromes (SIPS) identify individuals at ultra-high risk who may benefit from early intervention before threshold psychosis develops.

• Antipsychotic medications (first-line for psychosis): Dopamine D2 antagonists form the cornerstone of treatment. Typical (first-generation) antipsychotics (haloperidol, chlorpromazine) are potent but carry high risk of extrapyramidal side effects (EPS) and tardive dyskinesia; rarely used as monotherapy now. Atypical (second-generation) antipsychotics are preferred: risperidone (2–6 mg/day; 63% risk of EPS at higher doses), olanzapine (5–20 mg/day; good efficacy but significant weight gain/metabolic effects), quetiapine (400–800 mg/day; sedating, lower EPS risk), aripiprazole (10–20 mg/day; D2 partial agonist, minimal weight gain), paliperidone (3–12 mg/day; active metabolite of risperidone). Long-acting injectables (LAI) like paliperidone palmitate monthly or aripiprazole monohydrate improve adherence in maintenance phase. Dose titration over days to weeks; response onset 2–4 weeks, full effect often by 8–12 weeks.

• Antipsychotic selection principles: Response rate ~70% to any given agent; if one fails, try different class. Monitor weight, glucose, prolactin, lipids, and EKG (QTc prolongation risk with some agents). Clozapine (100–900 mg/day divided) reserved for treatment-resistant schizophrenia (TRS; failure of ≥2 antipsychotics at adequate doses/duration). Requires baseline WBC and biweekly monitoring initially due to agranulocytosis risk (0.8%), but most effective antipsychotic overall and only agent clearly reducing suicide risk.

• Adjunctive medications: Benzodiazepines (lorazepam

Disease-related

• Suicide — emergency. Lifetime risk is several-fold that of the general population, highest early in illness, in young men, with preserved insight and comorbid depression. Command hallucinations to self-harm mandate acute safety assessment and often involuntary hospitalization.
• Premature cardiovascular mortality: life expectancy is shortened by roughly one to two decades, driven mainly by cardiometabolic disease and very high smoking rates — not by psychosis itself.
• Comorbid substance use disorder, homelessness, incarceration, victimization, medication non-adherence, and progressive functional/cognitive decline.
• Catatonia — emergency when malignant (fever, autonomic instability). Diagnose with a lorazepam challenge; ECT is definitive for refractory or malignant cases.
• Polydipsia with hyponatremia: psychogenic water intoxication causing seizures.

Treatment-related

• Acute dystonia: D2 blockade in nigrostriatum within hours–days; oculogyric crisis, torticollis. Laryngeal dystonia is an airway emergency. Treat with anticholinergic (benztropine) or diphenhydramine.
• Akathisia: inner restlessness, pacing; frequently misread as worsening psychosis. Associated with suicidality. Reduce dose; beta blocker (propranolol) is standard.
• Parkinsonism and tardive dyskinesia: TD reflects chronic D2 blockade with receptor supersensitivity — choreoathetoid orofacial movements, often irreversible. Treat with a VMAT2 inhibitor (valbenazine, deutetrabenazine).
• Neuroleptic malignant syndrome — emergency: lead-pipe rigidity, hyperthermia, autonomic instability, altered mentation, markedly elevated CK, leukocytosis. Stop the antipsychotic, cool aggressively, supportive care; dantrolene and bromocriptine are adjuncts.
• Metabolic syndrome: 5-HT2C/H1 antagonism drives weight gain, dyslipidemia, and diabetes (worst with olanzapine and clozapine). The ADA/APA consensus on antipsychotic drugs and metabolic risk directs baseline and serial weight, BP, glucose/HbA1c, and lipids.
• Hyperprolactinemia (risperidone, paliperidone, haloperidol): tuberoinfundibular D2 blockade → galactorrhea, amenorrhea, sexual dysfunction, bone loss.
• QTc prolongation → torsades (ziprasidone, IV haloperidol).
• Clozapine-specific: severe neutropenia/agranulocytosis (mandated ANC monitoring), myocarditis in the first weeks (fever, tachycardia, eosinophilia, rising troponin/CRP), dose-dependent seizures, and anticholinergic ileus, which can be fatal.

• Duration defines the diagnosis: <1 month = brief psychotic disorder; 1–6 months = schizophreniform disorder; ≥6 months = schizophrenia. Psychosis plus a mood episode where delusions/hallucinations persist ≥2 weeks without prominent mood symptoms = schizoaffective disorder; if psychosis occurs only during mood episodes, it is a mood disorder with psychotic features.
• Single best next step in first-episode psychosis: exclude secondary causes before committing to the diagnosis — urine toxicology, metabolic panel, TSH, HIV/RPR, and neuroimaging if the onset is after age 40, focal signs are present, or the course is atypical. New psychosis with seizures, orofacial dyskinesias, and autonomic instability in a young woman = anti-NMDA receptor encephalitis (check for ovarian teratoma), not schizophrenia.
• The association examiners love: clozapine is the only antipsychotic with demonstrated benefit for treatment-resistant schizophrenia and for reducing suicidality. Fever or flu-like illness in the first weeks of clozapine → check ANC and troponin/CRP (myocarditis), not just reassurance.
• Smoking induces CYP1A2; abrupt smoking cessation raises clozapine and olanzapine levels and can precipitate toxicity or seizures.
• Distractor to avoid: giving benztropine for tardive dyskinesia — anticholinergics worsen TD. They treat acute dystonia and parkinsonism. Use a VMAT2 inhibitor for TD.
• Distractor to avoid: escalating the antipsychotic dose for a restless, pacing patient — that is akathisia, and more D2 blockade makes it worse.
• Rigidity + hyperthermia: NMS is lead-pipe rigidity with hyporeflexia, days-to-weeks after a dopamine blocker; serotonin syndrome is clonus and hyperreflexia, lower-extremity predominant, hours after a serotonergic agent.
• Prognosis: better with later onset, acute onset, female sex, good premorbid function, prominent mood symptoms, and short duration of untreated psychosis; worse with insidious onset and prominent negative symptoms. Negative and cognitive symptoms — not hallucinations — drive long-term disability.