Schizophrenia

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Schizophrenia - Comprehensive Medical Student Review

1. Definition & Epidemiology

Schizophrenia is the prototypical psychotic disorder, defined by positive symptoms (psychosis), negative symptoms, and significant functional impairment lasting at least 6 months.

Parameter	Value
Lifetime prevalence	~1% (some sources cite 1-2%)
Annual incidence	~15 per 100,000
Peak onset	Late adolescence to young adulthood
Sex	Slightly more common in males; males have earlier onset
Life expectancy	Shortened by 10-15 years
Suicide risk	Lifetime ~5-6%

Goldman-Cecil Medicine, p. 3764
Ganong's Review of Medical Physiology, p. 160

2. DSM-5-TR Diagnostic Criteria

At least 2 of the following (at least one must be from items 1-3), each present for a significant time during a 1-month period:

Delusions
Hallucinations (most commonly auditory)
Disorganized speech (derailment, incoherence)
Grossly disorganized or catatonic behavior
Negative symptoms - affective flattening, alogia, avolition

Plus:

Major impairment in social/occupational functioning
Duration of at least 6 months (including prodromal and residual phases)
Rule out schizoaffective disorder, mood disorder with psychosis, substance use, and general medical conditions
Goldman-Cecil Medicine, Table 362-11, p. 3765

Spectrum Disorders (Duration-based):

Diagnosis	Duration
Brief Psychotic Disorder	< 1 month
Schizophreniform Disorder	1-6 months
Schizophrenia	> 6 months
Schizoaffective Disorder	Schizophrenia + mood episodes

3. Symptoms in Detail

Positive Symptoms (excess/distortion of normal function)

Delusions - fixed false beliefs (persecutory most common; bizarre delusions are more specific)
Hallucinations - auditory most common (hearing voices commenting on behavior; command hallucinations)
Disorganized thought - loose associations, word salad, tangentiality, circumstantiality, clang associations
Disorganized behavior - agitation, catatonia, waxy flexibility, echopraxia

Negative Symptoms ("5 A's") - more treatment-refractory

Symptom	Description
Affective flattening	Reduced emotional expression
Alogia	Poverty of speech
Avolition	Lack of goal-directed behavior
Anhedonia	Inability to experience pleasure
Asociality	Social withdrawal

Cognitive Symptoms

Impaired working memory, attention, executive function
Often the most disabling and most resistant to treatment
Kaplan and Sadock's Synopsis of Psychiatry, p. 1112

4. Pathophysiology & Neurobiology

A. Dopamine Hypothesis (most tested concept)

The core hypothesis: too much dopaminergic activity in subcortical regions + too little in the prefrontal cortex.

Evidence for dopamine involvement:

All antipsychotic drugs have high affinity for D2 receptors; antipsychotic potency correlates with D2 binding affinity
Dopamine-increasing drugs (amphetamine, cocaine) cause psychotomimetic effects and worsen symptoms
D2 receptors elevated in postmortem schizophrenia brains
Functional neuroimaging shows altered dopamine function mainly in the dorsal striatum

The Dual Imbalance Model:

Region	Dopamine	Resulting Symptoms
Mesolimbic / Striatum	Hyperactivity	Positive symptoms (hallucinations, delusions)
Mesocortical / Prefrontal Cortex	Hypoactivity	Negative/cognitive symptoms

This explains why typical antipsychotics (pure D2 blockers) treat positive symptoms well but worsen negative symptoms.

Kaplan and Sadock's Synopsis, p. 1112
Goodman & Gilman's Pharmacological Basis, p. 320

B. Glutamate Hypothesis

Phencyclidine (PCP) - a glutamate (NMDA) receptor antagonist - produces a schizophrenia-like syndrome including both positive AND negative symptoms
Ketamine (another NMDA antagonist) similarly induces psychosis
This led to the hypothesis of NMDA receptor hypofunction, particularly on GABAergic interneurons, disinhibiting glutamate release elsewhere
More complete than the dopamine hypothesis in explaining negative and cognitive symptoms

C. Other Neurotransmitters

System	Role
Serotonin (5-HT2A)	Excess may cause positive and negative symptoms; 5-HT2A blockade by atypical antipsychotics reduces EPS and treats negative symptoms
GABA	Loss of GABAergic hippocampal neurons → disinhibition of dopamine → psychosis
Acetylcholine	Muscarinic/nicotinic receptor deficits impair cognition; explains high smoking rates in schizophrenia

D. Neurodevelopmental Hypothesis

Schizophrenia is increasingly understood as a neurodevelopmental disorder - abnormal brain development long before symptom onset
GWAS studies implicate genes regulating synaptic pruning (especially complement pathway genes like C4) and immune response (MHC region)
Winter/spring birth excess suggests prenatal viral exposure (especially influenza in 2nd trimester)
Urban birth, migration, childhood adversity, and cannabis use are environmental risk factors

E. Neural Circuit / Disconnect Hypothesis

Not a focal lesion but disrupted connectivity: prefrontal cortex - limbic system - basal ganglia - thalamus circuit dysfunction
Anterior cingulate-basal ganglia circuit → positive symptoms
Dorsolateral prefrontal circuit → negative/cognitive symptoms
Kaplan and Sadock's Synopsis, pp. 1113-1114

5. Genetics & Risk Factors

Risk Factor	Approximate Risk
General population	~1%
One affected parent	~13%
Dizygotic (fraternal) twin	~17%
Monozygotic (identical) twin	~50%
Both parents affected	~46%

Heritability up to 50%; multifactorial with many gene loci
Large number of ultrarare mutations related to synaptic plasticity
No single causative gene identified

Environmental risk factors: Winter/spring birth, urban upbringing, migration, cannabis use, prenatal maternal infection, childhood trauma, obstetric complications

Goldman-Cecil Medicine, p. 3765

6. Pharmacological Treatment

Classification of Antipsychotics

First-Generation (Typical) Antipsychotics - FGAs

Mechanism: D2 receptor antagonism
Treat positive symptoms well; little effect on negative/cognitive symptoms
Key drugs and chlorpromazine equivalents:

Drug	Initial Dose	Target Dose	CPZ Equivalent
Chlorpromazine	100 mg qd	300-1000 mg/day	100 mg
Thioridazine	50-100 mg qd	300-800 mg/day	100 mg
Haloperidol	2-5 mg qd	5-20 mg/day	High potency
Fluphenazine	—	—	High potency

Side effect profile:

High-potency FGAs (haloperidol, fluphenazine): Extrapyramidal symptoms (EPS) - dystonia, akathisia, parkinsonism, tardive dyskinesia; hyperprolactinemia
Low-potency FGAs (chlorpromazine, thioridazine): Anticholinergic effects, orthostatic hypotension, QT prolongation, cholestatic jaundice
Thioridazine: pigmentary retinopathy at high doses

Second-Generation (Atypical) Antipsychotics - SGAs

Mechanism: D2 + 5-HT2A antagonism (mainly); lower D2 occupancy, faster dissociation
Lower EPS, less hyperprolactinemia
Treat positive symptoms; some benefit for negative symptoms
Side effects: metabolic syndrome (weight gain, type 2 diabetes, hyperlipidemia), QT prolongation

Drug	Key Feature
Clozapine	Most efficacious (including treatment-resistant); risk of agranulocytosis (1-2%), requires CBC monitoring; also reduces suicide risk
Olanzapine	High metabolic side effects
Risperidone	Dose-dependent EPS; hyperprolactinemia
Quetiapine	Sedation; low EPS
Ziprasidone	QT prolongation; low metabolic risk
Aripiprazole	Partial D2 agonist; weight-neutral; functional selectivity

Third-Generation / Partial D2 Agonists

Aripiprazole: Partial D2 agonist - acts as antagonist in hyperdopaminergic striatum, agonist in hypodopaminergic PFC; may address both positive and negative symptoms; also D3 agonist and 5-HT1A partial agonist
Brexpiprazole: Aripiprazole derivative; lower D2 agonism, strong 5-HT1A partial agonism; approved for schizophrenia and adjunctive depression
Cariprazine: Partial D2/D3 agonist (higher D3 affinity); may be superior for negative symptoms vs. risperidone; approved for schizophrenia and bipolar disorder
Goodman & Gilman's, pp. 320-321
Goldman-Cecil Medicine, Table 362-12

Long-Acting Injectable (LAI) Antipsychotics

Fluphenazine decanoate, haloperidol decanoate (FGAs)
Risperidone, paliperidone, aripiprazole (SGAs) in LAI form
Associated with greatest reduction in relapse rates (along with clozapine) in large trials

7. Extrapyramidal Side Effects (EPS) - High Yield

EPS Type	Timing	Features	Treatment
Acute dystonia	Hours to days	Muscle spasm, torticollis, oculogyric crisis	Benztropine, diphenhydramine (IM)
Akathisia	Days to weeks	Motor restlessness, inability to sit still	Reduce dose; propranolol, benzodiazepines
Drug-induced parkinsonism	Weeks	Tremor, rigidity, bradykinesia	Benztropine, amantadine
Tardive dyskinesia	Months to years	Involuntary repetitive orofacial movements	Reduce/stop antipsychotic; VMAT2 inhibitors (valbenazine, deutetrabenazine)
NMS	Any time	Fever, rigidity, autonomic instability, elevated CK	Stop antipsychotic; dantrolene, bromocriptine

8. Non-Pharmacological Treatment

Psychosocial rehabilitation - assertive community treatment (ACT), especially important at first episode
Cognitive behavioral therapy (CBT) for psychosis
Family therapy and psychoeducation
Social skills training
Supported employment (Individual Placement and Support)
Comprehensive early psychosis intervention programs improve long-term outcomes

9. Prognosis

Poor prognostic factors:

Male sex
Younger age at first onset
Prominent negative symptoms
Poor premorbid functioning
Long duration of untreated psychosis (DUP)
Enduring psychosocial stressors and family discord
Substance use comorbidity

Good prognostic factors:

Female sex
Later onset
Acute onset with identifiable precipitant
Good premorbid functioning
Married
Predominant positive symptoms
No family history

Course: Typically recurrent psychotic exacerbations with progressive baseline deterioration. Some patients have a favorable course; a small proportion recover completely.

Goldman-Cecil Medicine, p. 3765

10. Differential Diagnosis (High-Yield for Exams)

Condition	Key Distinguishing Feature
Brief Psychotic Disorder	< 1 month duration
Schizophreniform Disorder	1-6 months, may return to baseline
Schizoaffective Disorder	Psychosis + concurrent mood episodes; psychosis also occurs without mood episodes
Bipolar Disorder with psychosis	Psychosis only during mood episodes
Major Depression with psychotic features	Psychosis only during depressive episodes
Delusional Disorder	Nonbizarre delusions only, no other positive symptoms, functioning preserved
Substance-induced psychosis	Temporal relation to substance use
Autoimmune encephalitis (e.g., Anti-NMDA receptor)	Rule out in first-episode psychosis - fever, seizures, CSF abnormalities
Medical causes	CNS tumors, temporal lobe epilepsy, SLE, Wilson's disease

Quick Memory Aids

Positive symptoms = Things that shouldn't be there (hallucinations, delusions, disorganized speech/behavior) Negative symptoms = Things that should be there but aren't (5 A's: Affect flat, Alogia, Avolition, Anhedonia, Asociality)

Dopamine tract mnemonic for antipsychotic side effects:

Mesolimbic blocked → treats positive symptoms
Mesocortical blocked → worsens negative symptoms
Nigrostriatal blocked → EPS
Tuberoinfundibular blocked → hyperprolactinemia → galactorrhea, amenorrhea, gynecomastia

Treatment-resistant schizophrenia? → Think Clozapine (after failure of 2 antipsychotics)

Sources: Goldman-Cecil Medicine (pp. 3764-3766); Kaplan and Sadock's Synopsis of Psychiatry (pp. 1110-1115); Goodman & Gilman's Pharmacological Basis of Therapeutics (pp. 319-321); Ganong's Review of Medical Physiology (p. 160)

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