Antipsychotic Pharmacology

1. Background & Indications

• Katzung's Basic and Clinical Pharmacology, 16th Ed., p.801

2. Neurotransmitter Hypotheses

Dopamine Hypothesis

• All antipsychotics strongly block postsynaptic D2 receptors, especially in mesolimbic and striatal-frontal systems
• Dopaminergic drugs (levodopa, amphetamine, bromocriptine) aggravate or induce psychosis
• Postmortem studies show increased D2-receptor density in untreated schizophrenics
• Imaging shows increased amphetamine-induced striatal dopamine release

Serotonin Hypothesis

• Hallucinogens (LSD, mescaline) are 5-HT agonists, prompting study of serotonergic mechanisms
• 5-HT2A blockade is a key mechanism of second-generation antipsychotics (SGAs): these drugs are inverse agonists at 5-HT2A receptors, modulating dopamine, norepinephrine, glutamate, GABA and acetylcholine in cortex and limbic regions
• 5-HT2C inverse agonism (clozapine, asenapine, olanzapine) disinhibits cortical and limbic dopamine release

Glutamate/NMDA Hypothesis

• PCP and ketamine (NMDA receptor blockers) worsen both positive and negative symptoms in schizophrenia
• Proposed mechanism: NMDA hypofunction on GABAergic interneurons → reduced inhibitory tone → disinhibited downstream glutamate activity → cortical hyperstimulation via non-NMDA receptors
• Supports development of mGluR2/3 agonists and glycine transport inhibitors as novel targets
• Katzung's Basic and Clinical Pharmacology, 16th Ed., pp.801-803

3. Classification & Chemical Types

First-Generation (Typical) Antipsychotics (FGAs)

Second-Generation (Atypical) Antipsychotics (SGAs)

• Katzung's Basic and Clinical Pharmacology, 16th Ed., p.805

4. Mechanisms of Action

D2 Receptor Blockade (All Antipsychotics)

• Primary antipsychotic mechanism
• Effective in mesolimbic pathway - reduces positive symptoms
• Blockade in nigrostriatal pathway - causes EPS (the unwanted effect)
• Blockade in tuberoinfundibular pathway - causes hyperprolactinaemia (galactorrhea, amenorrhea)
• Blockade in mesocortical pathway - may worsen negative symptoms and cognition

D2 Partial Agonism

• Aripiprazole, brexpiprazole, cariprazine act as partial D2 agonists - "dopamine system stabilizers"
• Act as functional antagonists where dopamine is high (mesolimbic) and as functional agonists where dopamine is low (mesocortical)
• Result: antipsychotic effect without worsening cognition, lower EPS, minimal prolactin elevation

Additional Receptor Effects

5. Dopamine Pathways - Clinical Relevance

6. Major Adverse Effects

Extrapyramidal Symptoms (EPS)

• TD prevalence: ~20-30% with long-term FGA use; ~7.2% with SGAs
• Kaplan and Sadock's Synopsis of Psychiatry; Katzung 16th Ed.

Neuroleptic Malignant Syndrome (NMS)

• Medical emergency
• Features: hyperthermia, lead-pipe muscle rigidity, altered mental status, autonomic instability (BP fluctuations, diaphoresis, tachycardia)
• Associated with all typical antipsychotics and most atypicals (aripiprazole, clozapine, olanzapine, risperidone, ziprasidone)
• Lab: markedly elevated CK, leukocytosis, elevated LFTs
• Management: discontinue antipsychotic, supportive care, dantrolene sodium, bromocriptine/amantadine (dopamine agonists)

Metabolic Effects (SGAs >> FGAs)

• Highest risk: clozapine, olanzapine, high-dose quetiapine
• Weight gain, dyslipidemia (hypertriglyceridemia), impaired glucose tolerance/diabetes
• A 2025 meta-analysis in JAMA Psychiatry [PMID: 40864439] confirmed antipsychotics dysregulate glucose homeostasis significantly
• Monitoring: fasting glucose, lipids, weight, waist circumference at baseline and periodically

Endocrine Effects

• Hyperprolactinaemia: FGAs (especially haloperidol, fluphenazine), risperidone, amisulpride
• Leads to: galactorrhea, gynecomastia, amenorrhea, sexual dysfunction, osteoporosis
• SGAs like olanzapine, quetiapine, aripiprazole cause minimal or no prolactin elevation

Clozapine-Specific Risks

• Agranulocytosis (~1%): requires mandatory weekly/biweekly CBC monitoring
• Seizures (dose-dependent, up to 5% at high doses)
• Myocarditis/cardiomyopathy (rare but serious)
• Hypersalivation, obesity, sedation
• Despite this, clozapine remains the gold standard for treatment-resistant schizophrenia (response rate 40-60%)

Cardiovascular

• QTc prolongation: thioridazine, ziprasidone, haloperidol (IV high-dose), iloperidone - risk of torsades de pointes
• Orthostatic hypotension: chlorpromazine, clozapine, quetiapine (α1 blockade)

Other

• Anticholinergic effects (low-potency FGAs, clozapine): dry mouth, constipation, urinary retention, blurred vision
• Photosensitivity, corneal deposits (chlorpromazine - long term)
• Thioridazine: irreversible pigmentary retinopathy at high doses

7. Drug-Specific Pharmacokinetics

• Most antipsychotics are highly lipophilic, with large volumes of distribution and long half-lives
• Extensively metabolized by CYP enzymes (especially CYP1A2, CYP3A4, CYP2D6)
• Long-acting injectable (LAI) formulations (haloperidol decanoate, fluphenazine decanoate, risperidone microspheres, paliperidone palmitate, aripiprazole lauroxil) are available to improve adherence
• Plasma level monitoring is clinically meaningful for several agents (clozapine, olanzapine, haloperidol)

8. Clinical Use Summary

9. Newer Agents

• Cariprazine: Preferential D3 partial agonist/D2 partial agonist; also approved for bipolar depression and schizophrenia; useful for negative symptoms
• Brexpiprazole: D2/D3 partial agonist + 5-HT1A partial agonist + 5-HT2A antagonist; "next-gen aripiprazole" with less akathisia
• Lumateperone: Novel multitarget agent; D2 postsynaptic antagonist + presynaptic D2 partial agonist + 5-HT2A antagonist + serotonin reuptake inhibitor; approved for schizophrenia and bipolar depression
• Amisulpride: Selective D2/D3 antagonist; low doses act preferentially at presynaptic D2 receptors (increasing dopamine release) - useful for negative symptoms

10. Key Pharmacology Table

• Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 801-830
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 19
• Kaplan and Sadock's Synopsis of Psychiatry
• The Maudsley Prescribing Guidelines in Psychiatry, 15th Edition
• Recent evidence: Antipsychotics and cognitive function - JAMA Psychiatry 2025 (PMID 39412783); Antipsychotics and glucose dysregulation - JAMA Psychiatry 2025 (PMID 40864439)

Dopamine Pathways and Receptor Types

The Five Dopamine Pathways in the Brain

1. Nigrostriatal Dopamine Pathway

Direct vs. Indirect Motor Pathways

• Direct ("Go") pathway: D1 receptors on GABA neurons projecting to globus pallidus interna (GPi) - dopamine stimulates this pathway, promoting movement
• Indirect ("Stop") pathway: D2 receptors on GABA neurons projecting to globus pallidus externa (GPe) - dopamine inhibits this pathway (removes the brake), also promoting movement
• Net result: dopamine facilitates smooth motor movement through both pathways

Disease relevance:

• Too little DA (e.g., Parkinson's disease): bradykinesia, rigidity, tremor
• Too much DA (or D2 blockade by antipsychotics): drug-induced parkinsonism, dystonia, tardive dyskinesia
• Antipsychotic D2 blockade in this pathway = EPS (extrapyramidal side effects)

2. Mesolimbic Dopamine Pathway

Clinical relevance:

• This is considered the final common pathway of all reward and reinforcement - food pleasure, orgasm, music appreciation, drug "highs"
• Hyperdopaminergia (too much DA): positive psychotic symptoms (hallucinations, delusions), drug-induced euphoria, agitation, impulsivity
• Hypodopaminergia (too little DA): anhedonia, apathy, lack of motivation - seen in depression and negative symptoms of schizophrenia
• Antipsychotic D2 blockade here = therapeutic effect (reduces hallucinations and delusions)

3. Mesocortical Dopamine Pathway

Key difference from mesolimic pathway (shown in diagram below):

Clinical relevance:

• Hypodopaminergia here causes: cognitive symptoms (poor working memory, executive dysfunction) and negative symptoms (blunted affect, social withdrawal)
• Antipsychotic D2 blockade here may worsen negative symptoms and cognition - a major limitation of FGAs
• SGAs (especially partial D2 agonists like aripiprazole) are designed to spare or enhance this pathway

4. Tuberoinfundibular Dopamine Pathway

Clinical relevance:

• Normal: dopamine tonically inhibits prolactin release
• Postpartum: tuberoinfundibular DA activity decreases → prolactin rises → lactation occurs
• Drug-induced D2 blockade (antipsychotics, metoclopramide, domperidone) → hyperprolactinaemia
• Consequences: galactorrhea, gynecomastia, amenorrhea, sexual dysfunction, infertility, decreased bone mineral density
• Drugs with high D2 affinity (haloperidol, risperidone, amisulpride) cause most hyperprolactinaemia; aripiprazole, quetiapine cause minimal effect

5. Thalamic Dopamine Pathway (5th Pathway)

• Stahl's Essential Psychopharmacology, p.101

Dopamine Receptor Types

Two Families Based on G-Protein Coupling

Dopamine Receptors
├── D1-FAMILY (D1, D5)
│   ├── G-protein: Gs (stimulatory)
│   ├── Effect: ↑ Adenylyl cyclase → ↑ cAMP
│   ├── Location: postsynaptic only
│   └── Distribution: striatum, nucleus accumbens, frontal cortex
│
└── D2-FAMILY (D2, D3, D4)
    ├── G-protein: Gi (inhibitory)
    ├── Effect: ↓ Adenylyl cyclase → ↓ cAMP
    ├── Location: postsynaptic AND presynaptic (autoreceptors)
    └── Distribution: striatum, nucleus accumbens, limbic areas, pituitary

Individual Receptor Subtypes in Detail

Autoreceptor Regulation

1. Shuts off neuronal impulse flow (somatodendritic autoreceptors in VTA/SN)
2. Inhibits further dopamine release from nerve terminals (presynaptic autoreceptors)
3. Reduces dopamine synthesis

• Stahl's Essential Psychopharmacology, p.100; Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p.428-429

Summary: Pathways, Function, and Antipsychotic Impact

• Stahl's Essential Psychopharmacology: Neuroscientific Basis, pp. 100-106
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, pp. 428-429
• Katzung's Basic and Clinical Pharmacology, 16th Edition