CNS Pharmacology: Antipsychotics

Introduction/Overview

Antipsychotic agents constitute a cornerstone of treatment for a spectrum of psychotic disorders, including schizophrenia, schizoaffective disorder, and certain mood disorders with psychotic features. Their utilization remains pivotal in reducing symptom burden, preventing relapse, and improving functional outcomes. As both first‑generation (typical) and second‑generation (atypical) agents are employed across diverse patient populations, a nuanced understanding of their pharmacologic properties is essential for clinical decision‑making. This chapter aims to equip medical and pharmacy students with a comprehensive foundation in antipsychotic pharmacology, facilitating evidence‑based practice.

• Identify the major classes of antipsychotic agents and their chemical scaffolds.
• Explain the receptor‑level interactions that underpin therapeutic and adverse effects.
• Summarize pharmacokinetic parameters influencing dosing strategies.
• Recognize the spectrum of approved indications, off‑label uses, and patient‑specific considerations.
• Appreciate the profile of adverse reactions, warnings, and interaction potentials.

Classification

First‑Generation (Typical) Antipsychotics

Typical agents, such as haloperidol, chlorpromazine, and fluphenazine, are primarily characterized by potent dopamine D₂ receptor antagonism. Their chemical structures are diverse, encompassing benzamides, phenothiazines, butyrophenones, and thioxanthene derivatives. The classification is largely based on their affinity for D₂ receptors relative to other targets.

Second‑Generation (Atypical) Antipsychotics

Atypical agents, including clozapine, olanzapine, risperidone, quetiapine, and ziprasidone, exhibit a broader receptor profile, with significant serotonin 5‑HT₂A antagonism in addition to D₂ blockade. Within this class, further sub‑grouping is possible based on pharmacodynamic and pharmacokinetic characteristics, such as the presence of active metabolites (e.g., risperidone’s 9‑OH metabolite) or distinct half‑life profiles.

Other Notable Agents

Several agents, such as aripiprazole, brexpiprazole, and cariprazine, function as partial agonists at D₂ receptors or act as functional antagonists via modulation of intracellular signaling pathways. Their classification is more nuanced and may be considered under the broader atypical umbrella due to shared receptor targets.

Mechanism of Action

Receptor Pharmacology

All antipsychotics share antagonistic effects at dopamine D₂ receptors, which are implicated in the positive symptom domain of schizophrenia. The degree of antagonism, receptor occupancy thresholds, and intrinsic activity differ among agents, influencing both efficacy and tolerability. Additionally, many atypical drugs possess high affinity for serotonin 5‑HT₂A receptors; antagonism at this site is associated with attenuation of negative and cognitive symptoms and a reduced propensity for extrapyramidal side effects.

Additional Targets

Agents such as clozapine exhibit significant activity at histamine H1, norepinephrine α₁, and muscarinic M₁ receptors, contributing to sedation, weight gain, and anticholinergic effects. Quetiapine demonstrates affinity for H1 and α₁ receptors, while ziprasidone blocks 5‑HT₂A and D₂ receptors with minimal anticholinergic activity. Partial agonism at D₂ receptors, as seen with aripiprazole, provides functional antagonism in hyperdopaminergic states while preserving dopaminergic transmission in hypodopaminergic regions.

Molecular and Cellular Effects

D₂ antagonism reduces cyclic AMP (cAMP) levels in dopaminergic neurons, thereby decreasing neuronal excitability. Concurrent 5‑HT₂A blockade mitigates downstream glutamatergic and cholinergic dysregulation, potentially improving negative symptoms. Partial agonists modulate intracellular signaling cascades, such as the MAPK pathway, to stabilize dopamine neurotransmission. These molecular interactions underscore the therapeutic benefits and side‑effect profiles observed clinically.

Pharmacokinetics

Absorption

Oral bioavailability varies widely among agents. Typical drugs often exhibit high absorption (e.g., haloperidol ~70–80%). Atypical agents may have lower bioavailability due to first‑pass metabolism (e.g., olanzapine ~60%). Intravenous formulations provide immediate systemic exposure, but are seldom used outside acute settings.

Distribution

High lipophilicity facilitates penetration of the blood–brain barrier. Plasma protein binding ranges from moderate (e.g., risperidone ~92%) to extensive (e.g., clozapine ~95%). Volume of distribution approximates 1–4 L/kg, reflecting significant tissue distribution. Some agents, such as quetiapine, exhibit a large apparent volume due to extensive peripheral binding.

Metabolism

Cytochrome P450 (CYP) enzymes mediate hepatic metabolism. Typical agents are primarily metabolized by CYP3A4 (e.g., haloperidol, fluphenazine). Atypical drugs involve multiple CYP isoforms: clozapine by CYP1A2 and CYP3A4; olanzapine by CYP1A2 and CYP2D6; risperidone by CYP2D6; quetiapine by CYP3A4; ziprasidone by minimal CYP involvement. The presence of active metabolites (e.g., risperidone’s 9‑OH metabolite) can contribute to pharmacodynamic effects.

Excretion

Renal excretion accounts for a significant fraction of drug elimination, particularly for drugs with low hepatic metabolism. For instance, haloperidol is excreted unchanged in the urine (~20–30%). In contrast, clozapine undergoes extensive hepatic metabolism, with a minor urinary component (<10%).

Half‑Life and Dosing Considerations

Elimination half‑lives range from several hours (e.g., ziprasidone ~6 h) to multiple days (e.g., clozapine ~24 h). Dosing schedules are adjusted accordingly; agents with longer half‑lives permit once‑daily or even twice‑weekly dosing (e.g., paliperidone palmitate). Therapeutic drug monitoring may be considered for agents with narrow therapeutic windows or significant inter‑individual variability, such as clozapine and olanzapine. Dose titration should account for age, hepatic function, and potential drug interactions.

Therapeutic Uses/Clinical Applications

Approved Indications

Typical antipsychotics are approved primarily for schizophrenia and acute agitation. Atypical agents receive approvals for schizophrenia, schizoaffective disorder, bipolar disorder (manic or mixed episodes), and adjunctive treatment for major depressive disorder. Clozapine is specifically indicated for treatment‑resistant schizophrenia, defined by inadequate response to at least two antipsychotics.

Off‑Label Uses

Common off‑label applications include the management of nausea and vomiting (e.g., ondansetron‑like profiles), prophylaxis of chemotherapy‑induced nausea, and treatment of chronic pain in selected cases. Off‑label use is also frequent in the management of behavioral disturbances in dementia and autism spectrum disorder, albeit with caution regarding safety profiles.

Adverse Effects

Common Side Effects

• Extrapyramidal symptoms (EPS) – dystonia, akathisia, parkinsonism, tardive dyskinesia (predominantly with typical agents).
• Metabolic disturbances – weight gain, dyslipidemia, hyperglycemia (notably with olanzapine, clozapine).
• Sedation – mediated by H1 antagonism.
• Anticholinergic effects – dry mouth, blurred vision, constipation.
• Cardiovascular effects – orthostatic hypotension, QT prolongation (especially with ziprasidone and thioridazine).

Serious or Rare Adverse Reactions

• Severe agranulocytosis (clozapine); requires regular white blood cell monitoring.
• Neuroleptic malignant syndrome (NMS); characterized by hyperthermia, rigidity, autonomic instability.
• Serotonin syndrome (rare with atypicals, particularly clozapine and combinations with serotonergic agents).
• Severe metabolic syndrome leading to cardiovascular events.
• Severe cutaneous adverse reactions (e.g., Stevens–Johnson syndrome).

Black Box Warnings

• Clozapine: agranulocytosis, myocarditis, cardiomyopathy, seizures, and increased mortality in schizophrenia. Monitoring protocols are mandated.
• All antipsychotics: risk of suicide in patients with bipolar disorder or major depressive disorder. Risk of increased mortality in elderly patients with dementia‑related psychosis.

Drug Interactions

Major Drug‑Drug Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can elevate plasma concentrations of agents metabolized by this pathway, increasing risk of toxicity.
• CYP1A2 inhibitors (e.g., fluvoxamine) may raise clozapine levels; dose adjustment is advised.
• Anticholinergic agents (e.g., atropine) can potentiate sedation and cognitive impairment.
• Serotonergic agents (e.g., SSRIs) may increase risk of serotonin syndrome when combined with clozapine.
• Cardiac conduction modifiers (e.g., amiodarone, macrolide antibiotics) can prolong QT interval when combined with agents such as ziprasidone.

Contraindications

• Severe hepatic impairment (for drugs with extensive hepatic metabolism).
• Known hypersensitivity to the drug or any excipient.
• Concurrent use of other agents that cause severe orthostatic hypotension (e.g., clonidine) without dose adjustment.

Special Considerations

Pregnancy and Lactation

Data suggest that antipsychotics cross the placenta and are excreted in breast milk. The potential for neonatal adverse effects (e.g., withdrawal, hypotonia) exists, particularly with agents possessing high lipophilicity. Risk–benefit assessment is essential, and alternative therapy should be considered when feasible.

Pediatric Considerations

Use in children and adolescents is generally limited to specific indications such as schizophrenia or severe behavioral disorders. Dosing requires careful titration due to increased sensitivity to extrapyramidal side effects and variable pharmacokinetics. Monitoring for growth parameters and metabolic changes is advised.

Geriatric Considerations

Older adults exhibit increased susceptibility to anticholinergic burden, orthostatic hypotension, and metabolic disturbances. Dose initiation at the lowest effective level is recommended. The risk of falls and cognitive decline necessitates vigilant assessment.

Renal and Hepatic Impairment

Renal impairment primarily affects agents with significant renal excretion. Dose adjustment or avoidance of agents with predominant renal clearance is advisable. Hepatic impairment impacts drugs with extensive CYP metabolism; hepatic function should be assessed prior to initiation and periodically thereafter.

Summary/Key Points

• Antipsychotics are categorized into typical and atypical based on receptor profiles and chemical scaffolds.
• D₂ antagonism underlies the antipsychotic effect; 5‑HT₂A antagonism mitigates extrapyramidal symptoms and may improve negative symptoms.
• The pharmacokinetic profile, including metabolism via CYP enzymes, dictates dosing frequency and monitoring needs.
• First‑generation agents carry a higher risk of EPS, whereas atypicals are associated with metabolic adverse effects.
• Clozapine requires rigorous monitoring due to agranulocytosis and cardiotoxicity; black‑box warnings apply to all antipsychotics for suicide risk and mortality in dementia.
• Drug interactions involving CYP enzymes, anticholinergic load, and QT prolongation must be considered when prescribing.
• Special populations—including pregnant patients, children, elderly, and those with organ dysfunction—necessitate individualized dose adjustments and close surveillance.
• Clinical decision‑making should balance symptom control against the spectrum of potential adverse effects, guided by evidence‑based guidelines and patient preference.

References

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