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Schizophrenia

BASICS

  • Definition: Severe, persistent mental illness with delusions, hallucinations, disorganized thought/behavior, cognitive dysfunction, and impaired reality testing.
  • Course: Prodromal, active, and residual phases with variable symptomatology and progression.
  • DSM-5: No longer includes subcategories (paranoid, disorganized, catatonic).
  • Systems Affected: Central nervous system.

EPIDEMIOLOGY

  • Prevalence: 0.3–0.7% (adults >18 years).
  • Onset: Typically <30 years; earlier in males (late teens to mid-20s) than females (early 20s to early 30s).

ETIOLOGY & PATHOPHYSIOLOGY

  • Multifactorial: Genetic and environmental interaction.
  • Neurobiology: Overstimulation of mesolimbic D2 dopamine receptors, deficient prefrontal dopamine, abnormal glutamate (NMDA) activity.
  • Genetics: 8–10% risk if a first-degree relative is affected.

RISK FACTORS

  • Antenatal: Prenatal infection/malnutrition, obstetric hypoxia, winter birth, postnatal infection.
  • Lifetime: Cannabis use (adolescence), childhood trauma, urban residence, autoimmune disorders, stress, low SES, minority/immigrant status, poor social support, advanced paternal age.

PREVENTION

  • Patient education about cannabis and family history risk.
  • Early identification of at-risk individuals.

ASSOCIATED CONDITIONS

  • Substance Use: Nicotine dependence (>50%), other substance use disorders.
  • Medical: Metabolic syndrome, diabetes, obesity.

DIAGNOSIS

  • Chronic decline in social/functional performance over ≥6 months.
  • Core Symptoms (≥2 for ≥1 month; at least 1 must be delusions, hallucinations, or disorganized speech):
  • Delusions (fixed, false beliefs)
  • Hallucinations (auditory > visual)
  • Disorganized speech (derailment/incoherence)
  • Grossly disorganized/catatonic behavior
  • Negative symptoms (flat affect, poverty of speech/thought, amotivation, social withdrawal)

Physical Exam

  • No pathognomonic findings.
  • Long-term neuroleptic treatment: Extrapyramidal symptoms (dystonia, akathisia, parkinsonism, tardive dyskinesia).

Differential Diagnosis

  • Substance-induced psychosis (25% may transition to schizophrenia; high with cannabis use)
  • Personality disorders (paranoid, schizotypal, borderline, schizoid)
  • Mood disorders (bipolar, MDD with psychosis/catatonia)
  • PTSD, autism spectrum, neurodevelopmental disorders

Diagnostic Tests

Rule Out Medical Causes:

  • Labs: TSH, CBC, chemistries, vitamin B12, folate, thiamine, vitamin D, drug/alcohol screen, HIV, syphilis, heavy metals, ceruloplasmin, urine porphobilinogen, ESR, ANA, hepatitis panels
  • Imaging: MRI (to exclude structural causes; often shows ventriculomegaly, brain volume loss)
  • EEG/LP: As indicated
  • Other: ECG (QTc), metabolic panels, pregnancy test, AIMS for extrapyramidal symptoms

Before Antipsychotic Initiation:

  • ECG (QTc), CBC, chemistries, HbA1c, lipids, TSH, pregnancy test, prolactin (if indicated)

Monitoring (at least annually):

  • Weight, waist circumference, BP, CBC, HbA1c, lipids, ECG (QTc), AIMS for movement disorders

Neuropsychological Testing

  • Not routine but helpful for functional assessment and need for support.

TREATMENT

General

  • Pharmacologic: Mainstay; antipsychotics.
  • Psychosocial: Therapy, vocational support, psychoeducation, CBT (especially for negative symptoms), family support.

Antipsychotic Medications

First-Line

  • Atypical (2nd generation): risperidone, olanzapine, aripiprazole, quetiapine, ziprasidone, paliperidone, lurasidone, asenapine, iloperidone, clozapine (for refractory cases), brexpiprazole, cariprazine, pimavanserin.
  • Typical (1st generation): haloperidol, chlorpromazine, fluphenazine, trifluoperazine, perphenazine, thioridazine, thiothixene, loxapine.

Drug Selection Considerations

  • Extrapyramidal risk: Lower with atypicals.
  • Tardive dyskinesia risk: Lowest with quetiapine, clozapine.
  • Metabolic syndrome risk: Lower with aripiprazole, ziprasidone, lurasidone, perphenazine.
  • QTc prolongation risk: Lowest with aripiprazole; avoid thioridazine/ziprasidone if prolonged QT.
  • Poor compliance: Use long-acting injectables (haloperidol, fluphenazine, risperidone, olanzapine, aripiprazole, paliperidone).

Dosing Ranges (common initiation/maintenance)

  • See full drug list in source for typical dosing.

Special Considerations

  • Clozapine: Gold-standard for refractory schizophrenia; effective for suicidality; risk of agranulocytosis (requires registry, weekly–monthly CBC), seizures (dose-dependent), myocarditis, severe constipation, sialorrhea, DVT, tachycardia, orthostasis, weight gain.
  • All antipsychotics: Weight gain and tardive dyskinesia risk.
  • Elderly: Black box warning—all antipsychotics increase mortality in dementia-related psychosis.

Managing Antipsychotic Side Effects

  • Dystonia: Diphenhydramine or benztropine IM
  • Akathisia: Propranolol or lorazepam
  • Parkinsonism: Trihexyphenidyl, benztropine, amantadine
  • Tardive dyskinesia: Switch to clozapine; otherwise deutetrabenazine, valbenazine, tetrabenazine
  • Neuroleptic malignant syndrome: Hospitalization, IV fluids, stop antipsychotic
  • Weight gain: Metformin up to 2000 mg/day may help attenuate

Adjuncts

  • Benzodiazepines: Short-term for agitation, catatonia (risk of dependence, cognitive impairment)
  • Mood stabilizers: Valproic acid for agitation/violence, lithium for affective symptoms/suicidality
  • Antidepressants: For comorbid depression/anxiety (prefer over polypharmacy with second antipsychotic)

Nonpharmacologic

  • CBT (esp. for persistent symptoms/negative symptoms)
  • Vocational/rehabilitative support
  • Psychoeducation for patients/families
  • Family support organizations: e.g., NAMI

Electroconvulsive Therapy (ECT)

  • Consider for catatonia, severe depression, aggression, or suicidality.

Admission Criteria

  • Risk of harm to self/others; inability to care for self.

ONGOING CARE

  • Regular follow-up to monitor symptoms, safety, comorbidities, and side effects.

PROGNOSIS

  • Chronic, relapsing-remitting course.
  • ~20% attempt suicide, 5–6% die by suicide.
  • Reduced life expectancy due to medical comorbidities.

COMPLICATIONS

  • Tardive dyskinesia, orthostatic hypotension, QTc prolongation, metabolic syndrome.
  • Comorbid substance use.

ICD-10

  • F20.3 Undifferentiated schizophrenia
  • F20.5 Residual schizophrenia
  • F20.2 Catatonic schizophrenia

CLINICAL PEARLS

  • Multidisciplinary team approach is key for management and recovery.
  • Positive symptoms: hallucinations, delusions.
  • Negative symptoms: flat affect, anhedonia, social withdrawal, amotivation.
  • Tobacco, diabetes, dyslipidemia, and obesity are common and reduce life expectancy.
  • Comprehensive care should address medical as well as mental health needs.