Schizophrenia Study Guide

📖 Core Concepts Schizophrenia – chronic neurodevelopmental disorder marked by positive (hallucinations, delusions), negative (avolition, blunted affect), and cognitive (memory, attention) deficits plus functional impairment. Positive vs. Negative vs. Cognitive Symptoms – Positive = added experiences; Negative = loss of normal function; Cognitive = neuro‑ and social‑cognitive deficits that are relatively stable. Dopamine Hypothesis – Hyper‑dopaminergic activity (especially in striatum) drives positive symptoms; antipsychotics block D2 receptors to reduce this excess. Glutamate (NMDA) Hypothesis – NMDA‑receptor hypofunction contributes to both positive and cognitive symptoms; NMDA antagonists can mimic schizophrenia. Treatment‑Resistant Schizophrenia (TRS) – Failure of ≥2 adequate antipsychotic trials; clozapine is the only proven effective agent. Duration of Untreated Psychosis (DUP) – Longer DUP predicts poorer short‑ and long‑term outcomes. Polygenic Risk & CNVs – High heritability (70‑80 %); common variants (polygenic scores) + rare copy‑number variations (e.g., 22q11.2 deletion) raise risk. Prodrome / Ultra‑High‑Risk – Subtle negative/cognitive changes preceding full psychosis; 20‑30 % convert within 2 yr. 📌 Must Remember Diagnostic threshold: ≥2 core symptoms (delusions, hallucinations, disorganized speech, grossly disorganized/catatonic behavior, negative symptoms) ≥1 mo, functional decline ≥6 mo. Lifetime prevalence: 0.3 %–0.7 % (≈1 % globally). Male‑female pattern: Males ≈1.4× more common, earlier onset (early‑20s vs. late‑20s). Clozapine risks: Agranulocytosis < 4 %; also thromboembolism, myocarditis, cardiomyopathy. Extrapyramidal symptoms (EPS): All antipsychotics can cause EPS; risk highest with typical agents. Metabolic side‑effects: Second‑generation antipsychotics → weight gain, dyslipidemia, diabetes → ↑ cardiovascular mortality. Suicide rate: 5 % (20‑40 % attempt); clozapine reduces suicide risk. Long‑acting injectables (LAIs): Improve adherence, lower relapse vs. oral meds. Negative symptom domains: avolition, anhedonia, asociality, alogia, blunted affect. 🔄 Key Processes Diagnosing Schizophrenia Conduct Structured Clinical Interview (SCID‑5) → confirm ≥2 core symptoms ≥1 mo. Verify functional impairment ≥6 mo. Exclude brief psychotic disorder (<1 mo), schizophreniform (1‑6 mo), mood disorder with psychosis, substance‑induced psychosis, medical mimics. Antipsychotic Initiation Start low, titrate to therapeutic dose (typical: haloperidol 5‑10 mg PO; atypical: risperidone 1‑2 mg PO). Monitor for EPS (use rating scales) and metabolic parameters (weight, fasting glucose, lipids). Re‑assess at 4‑6 wk; if inadequate response, consider dose increase or switch. Identifying TRS & Starting Clozapine Verify ≥2 failed trials (≥6 wk each, adequate dose). Baseline CBC, weekly CBC × 18 wk, then bi‑weekly/monthly. Counsel on agranulocytosis signs (fever, sore throat). Implementing LAI Choose depot after ≥1 yr stable oral regimen or documented non‑adherence. Administer loading dose (if needed), then maintenance (e.g., risperidone 25 mg IM q 2 wk). 🔍 Key Comparisons Typical vs. Atypical Antipsychotics Typical: Strong D2 antagonism → high EPS, lower metabolic risk. Atypical: D2 + 5‑HT2A antagonism → lower EPS, higher weight/diabetes risk. Clozapine vs. Other Atypicals Clozapine: Superior efficacy in TRS, reduces suicide; requires blood monitoring. Other Atypicals: Safer monitoring profile, less potent for TRS. Positive vs. Negative Symptoms Positive: Respond well to dopamine blockade. Negative: Poorly responsive to antipsychotics; need psychosocial/rehab interventions. Prodrome vs. First‑Episode Psychosis Prodrome: Subthreshold symptoms, functional decline, high risk but not yet full psychosis. FEP: Full psychotic symptoms; DUP begins. ⚠️ Common Misunderstandings “Schizophrenia = multiple personalities.” – It is a single disorder with fragmented reality testing, not dissociative identity disorder. “Antipsychotics cure schizophrenia.” – They control symptoms; the illness is chronic and often requires lifelong management. “Only positive symptoms matter.” – Negative and cognitive deficits drive functional disability and predict long‑term outcome. “All atypicals have the same side‑effect profile.” – Metabolic risk varies (e.g., clozapine > olanzapine > aripiprazole). 🧠 Mental Models / Intuition “Dopamine overdrive → false salience” – Excess dopamine tags irrelevant stimuli as important → hallucinations & delusions. “Prediction‑error mismatch” – NMDA hypofunction reduces the brain’s ability to update priors; leads to rigid, bizarre beliefs. “Clockwork analogy for DUP” – The longer the clock runs untreated, the harder it is to reset functional “gears.” 🚩 Exceptions & Edge Cases Late‑onset schizophrenia (≥40 yr) – Often milder positive symptoms, more prominent mood features. Substance‑induced psychosis – Cannabis/amphetamines can mimic schizophrenia; must ensure persistence >1 mo after abstinence before diagnosis. Clozapine agranulocytosis – Rare (<4 %); risk highest in first 18 weeks, but can occur later. 📍 When to Use Which First‑line: Any second‑generation antipsychotic (e.g., risperidone, olanzapine) unless contraindicated. If EPS prominent: Switch to an atypical or add anticholinergic. If metabolic risk high (obesity, diabetes): Prefer agents with lower weight gain (e.g., aripiprazole, ziprasidone). Treatment‑resistant: Initiate clozapine after ≥2 failed trials. Adherence concerns: Offer LAI depot formulation. Prominent negative/cognitive deficits: Add cognitive remediation, CBT‑p, and social skills training. 👀 Patterns to Recognize Auditory hallucination → “voices commenting” suggests primary schizophrenia vs. substance‑induced. Early‑onset (<17 yr) + family history → high genetic load, consider intensive early‑intervention services. Rapid weight gain within 1 mo of starting olanzapine → anticipate metabolic monitoring and diet/exercise counseling. Persistent anhedonia with intact pleasure response → reward‑prediction deficit rather than true hedonic loss. 🗂️ Exam Traps Distractor: “Clozapine is first‑line for all patients.” – Clozapine is reserved for TRS due to safety concerns. Distractor: “Negative symptoms improve with higher doses of antipsychotics.” – Negative symptoms are largely medication‑resistant. Distractor: “A single episode of psychosis guarantees remission without medication.” – Relapse risk rises after a second episode; maintenance therapy is usually indicated. Distractor: “All patients with schizophrenia have a prodromal phase.” – Up to 75 % do, but not universal; absence does not rule out schizophrenia. Distractor: “First‑rank symptoms are required for diagnosis.” – They are helpful but not mandatory under DSM‑5/ICD‑11.