6.4 Antipsychotics
Antipsychotics (neuroleptics) treat psychosis in schizophrenia, bipolar disorder, and other conditions. All share D2 dopamine receptor antagonism as a common mechanism.
Dopamine Hypothesis of Schizophrenia
Mesolimbic Pathway
Hyperactivity → positive symptoms (hallucinations, delusions)
D2 blockade here → therapeutic effect
Mesocortical Pathway
Hypoactivity → negative symptoms (flat affect, anhedonia), cognitive deficits
D2 blockade here → may worsen negative symptoms
Nigrostriatal Pathway
D2 blockade → extrapyramidal symptoms (EPS)
Tuberoinfundibular Pathway
D2 blockade → ↑ prolactin (hyperprolactinemia)
Typical (First-Generation) Antipsychotics
Mechanism
High-affinity D2 receptor antagonists (requires ~70% occupancy for efficacy)
Non-selective—block D2 in all pathways
High-Potency Typical
Haloperidol, fluphenazine - strong D2 blockade
High EPS risk, low sedation/anticholinergic effects
Low-Potency Typical
Chlorpromazine, thioridazine - weaker D2 blockade
Lower EPS, but more sedation, anticholinergic, α₁-blockade effects
Clinical Use
Effective for positive symptoms of schizophrenia
Less effective for negative/cognitive symptoms
Largely replaced by atypicals due to side effects
Extrapyramidal Symptoms (EPS)
Acute Dystonia
Hours to days: muscle spasms, torticollis, oculogyric crisis
Treatment: anticholinergics (benztropine, diphenhydramine)
Parkinsonism
Days to weeks: bradykinesia, rigidity, tremor, shuffling gait
Treatment: anticholinergics or reduce dose
Akathisia
Days to weeks: inner restlessness, inability to sit still
Treatment: β-blockers (propranolol), benzodiazepines
Tardive Dyskinesia
Months to years: involuntary choreiform movements (tongue, face, limbs)
Often irreversible—prevention crucial (use lowest effective dose)
VMAT2 inhibitors (valbenazine, deutetrabenazine) can help
Atypical (Second-Generation) Antipsychotics
Mechanism
D2 antagonism + 5-HT2A antagonism
5-HT2A blockade → ↓ EPS risk, may improve negative symptoms
Variable effects on other receptors (H₁, muscarinic, α₁)
Common Atypicals
Risperidone: potent D2/5-HT2A antagonist, EPS at high doses
Olanzapine: broad receptor profile, weight gain/metabolic effects
Quetiapine: sedating, low EPS, useful for bipolar depression
Aripiprazole: D2 partial agonist, lower weight gain
Ziprasidone: 5-HT/NE reuptake inhibition, QT prolongation
Clozapine - "Gold Standard"
Most effective for treatment-resistant schizophrenia
Low D2 affinity, high 5-HT2A, multiple other receptors
Risk: Agranulocytosis (1-2%) → requires weekly CBC monitoring
Also: seizures, myocarditis, metabolic syndrome
Metabolic Side Effects of Atypicals
Weight Gain
Most common with olanzapine, clozapine
H₁ antagonism → ↑ appetite
Can be >10 kg within months
Metabolic Syndrome
Hyperglycemia, dyslipidemia, insulin resistance
↑ Risk of diabetes, cardiovascular disease
Monitor fasting glucose, lipids
Lower Risk Atypicals
Aripiprazole, ziprasidone, lurasidone
Preferred when metabolic concerns present
Hyperprolactinemia
Risperidone>typical>other atypicals
Galactorrhea, amenorrhea, sexual dysfunction, osteoporosis
Neuroleptic Malignant Syndrome (NMS)
Life-Threatening Emergency
Rare but serious reaction to any antipsychotic (especially high-potency typical)
Symptoms: Hyperthermia, severe muscle rigidity, altered mental status, autonomic instability
Labs: ↑↑ CK (rhabdomyolysis), leukocytosis
Treatment: Stop antipsychotic immediately, supportive care, dantrolene (muscle relaxant), bromocriptine (DA agonist)
Similar to serotonin syndrome but distinct pathophysiology