Pharmacology of Antipsychotic Drugs

1. Introduction/Overview

Antipsychotic drugs, also termed neuroleptics, constitute a cornerstone class of psychotropic medications primarily employed in the management of psychotic disorders. Their introduction in the mid-20th century with chlorpromazine revolutionized psychiatric care, enabling deinstitutionalization and providing a biological foundation for understanding severe mental illness. The clinical relevance of these agents extends beyond their primary indication for schizophrenia spectrum disorders to encompass bipolar disorder, treatment-resistant depression, and various neuropsychiatric conditions characterized by agitation, delusions, or hallucinations. Mastery of their pharmacology is essential for clinicians to optimize therapeutic outcomes while minimizing the significant adverse effect burden associated with many agents in this class.

The following learning objectives are intended to guide the study of this chapter:

• Differentiate between first-generation (typical) and second-generation (atypical) antipsychotics based on receptor affinity profiles and clinical implications.
• Explain the dopamine hypothesis of schizophrenia and the receptor mechanisms underlying both therapeutic efficacy and major adverse effects of antipsychotic drugs.
• Compare and contrast the pharmacokinetic properties, therapeutic applications, and characteristic adverse effect profiles of major antipsychotic agents.
• Identify serious adverse drug reactions, including metabolic syndrome, extrapyramidal symptoms, and neuroleptic malignant syndrome, and outline appropriate monitoring and management strategies.
• Apply knowledge of drug interactions and special population considerations to develop safe and effective treatment plans.

2. Classification

Antipsychotics are systematically classified according to their historical development, chemical structure, and receptor binding profiles. The primary clinical classification distinguishes between first-generation and second-generation agents.

2.1. Generational Classification

First-Generation Antipsychotics (FGAs; Typical Antipsychotics): These drugs, discovered from the 1950s onward, are characterized by high affinity for dopamine D₂ receptors. Their antipsychotic efficacy correlates strongly with D₂ receptor blockade in the mesolimbic pathway. This class is further subdivided based on potency, which often correlates with the propensity to cause certain adverse effects.

• Low Potency: e.g., Chlorpromazine, Thioridazine. Generally have higher anticholinergic and antihistaminergic effects but lower risk of extrapyramidal symptoms (EPS) at therapeutic doses.
• High Potency: e.g., Haloperidol, Fluphenazine. Exhibit more potent D₂ blockade with lower anticholinergic activity, leading to a higher relative risk of EPS.

Second-Generation Antipsychotics (SGAs; Atypical Antipsychotics): Introduced from the 1990s, these agents are defined by a lower incidence of acute extrapyramidal symptoms and tardive dyskinesia at clinically effective doses, though this distinction is not absolute. Their mechanism involves a broader receptor profile, typically combining serotonin 5-HT_2A receptor antagonism with D₂ receptor blockade.

2.2. Chemical Classification

The chemical structure influences receptor affinity, pharmacokinetics, and adverse effect profiles. Major chemical classes include:

• Phenothiazines: e.g., Chlorpromazine, Fluphenazine, Perphenazine. Contain a tricyclic phenothiazine nucleus. Subclasses (aliphatic, piperidine, piperazine) differ in potency and side effects.
• Butyrophenones: e.g., Haloperidol, Droperidol. High-potency D₂ antagonists.
• Thioxanthenes: e.g., Thiothixene, Flupentixol. Structurally similar to phenothiazines but with a carbon atom replacing nitrogen in the central ring.
• Dibenzodiazepines and Related Heterocyclics: e.g., Clozapine, Olanzapine, Quetiapine. Characteristic of many SGAs, often with high 5-HT_2A affinity.
• Benzisoxazoles/Benzisothiazoles: e.g., Risperidone, Paliperidone, Ziprasidone.
• Quinolinones: e.g., Aripiprazole, Brexpiprazole, Cariprazine. Function as partial agonists at the D₂ receptor.
• Others: Includes indoles (e.g., Sertindole), benzamides (e.g., Amisulpride, not available in all countries), and the recently approved muscarinic receptor agonist/antagonist (e.g., Xanomeline-Trospium combination).

3. Mechanism of Action

The primary mechanism of action for antipsychotic drugs involves modulation of dopaminergic neurotransmission, though other neurotransmitter systems are critically involved, particularly for second-generation agents.

3.1. The Dopamine Hypothesis and D₂ Receptor Blockade

The classical dopamine hypothesis of schizophrenia posits that hyperactivity of dopaminergic transmission in the mesolimbic pathway contributes to positive symptoms (hallucinations, delusions). All effective antipsychotics share the property of antagonizing dopamine D₂ receptors in this pathway. The degree of D₂ receptor occupancy is a key determinant of antipsychotic response; occupancy of 60-80% is typically required for therapeutic effect, while occupancy exceeding 80% is associated with a higher risk of extrapyramidal side effects. Positron emission tomography (PET) studies have consistently demonstrated this relationship.

Conversely, blockade of D₂ receptors in the nigrostriatal pathway is responsible for drug-induced parkinsonism and other EPS. Blockade in the tuberoinfundibular pathway leads to hyperprolactinemia by removing tonic inhibition of prolactin secretion. The cognitive and negative symptoms (avolition, anhedonia, blunted affect) of schizophrenia may be related to hypodopaminergic function in the mesocortical pathway, complicating the simple hyperactivity model.

3.2. Serotonin-Dopamine Antagonism

Many second-generation antipsychotics, such as risperidone, olanzapine, and clozapine, exhibit high affinity for serotonin 5-HT_2A receptors, often exceeding their affinity for D₂ receptors. 5-HT_2A antagonism is believed to modulate dopaminergic activity. Serotonergic neurons project to dopaminergic cell bodies and exert an inhibitory influence. By blocking 5-HT_2A receptors, these drugs may increase dopamine release in the nigrostriatal and mesocortical pathways, which could theoretically mitigate EPS and improve negative/cognitive symptoms, respectively. This mechanism forms the basis of the serotonin-dopamine antagonist hypothesis of atypicality.

3.3. Receptor Affinity Profiles and Clinical Correlates

Beyond D₂ and 5-HT_2A receptors, antipsychotics interact with a wide array of receptors, which shapes their efficacy and adverse effect profiles.

• Muscarinic M₁ Receptor Antagonism: Associated with anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive impairment. It may also reduce the risk of EPS. High in clozapine and olanzapine.
• Histamine H₁ Receptor Antagonism: Causes sedation and weight gain. Prominent in clozapine, olanzapine, and low-potency FGAs like chlorpromazine.
• Adrenergic α₁ Receptor Antagonism: Contributes to orthostatic hypotension, dizziness, and reflex tachycardia. Notable with clozapine, quetiapine, and low-potency FGAs.
• Adrenergic α₂ Receptor Antagonism: May increase noradrenergic and dopaminergic transmission, potentially influencing mood and cognition.
• Partial D₂ Agonism: A unique mechanism of agents like aripiprazole, brexpiprazole, and cariprazine. These drugs stabilize dopamine signaling, acting as functional antagonists in hyperdopaminergic states and functional agonists in hypodopaminergic states, which may offer a favorable balance between efficacy and tolerability.
• Other Receptors: Some agents have affinity for 5-HT_1A (partial agonism may have anxiolytic/pro-cognitive effects), 5-HT_2C, 5-HT₇, and D₃ and D₄ receptors, though the clinical significance of these interactions is an area of ongoing research.

3.4. Cellular and Molecular Effects

Chronic antipsychotic administration induces adaptive changes in the brain. Long-term D₂ blockade leads to depolarization blockade of dopaminergic neurons in the midbrain, reducing their firing rate. Furthermore, antipsychotics can alter gene expression and induce neuroplastic changes. For instance, they may increase the expression of brain-derived neurotrophic factor (BDNF) and promote synaptic remodeling. These downstream effects may underlie the delayed onset of full therapeutic action, which often takes several weeks, despite immediate receptor occupancy.

4. Pharmacokinetics

The pharmacokinetic properties of antipsychotics vary widely between agents, influencing dosing schedules, titration requirements, and the potential for drug interactions.

4.1. Absorption and Bioavailability

Most antipsychotics are administered orally and are generally well absorbed from the gastrointestinal tract. However, extensive first-pass metabolism in the liver significantly reduces the systemic bioavailability of many agents. For example, the bioavailability of haloperidol is approximately 60%, while that of olanzapine is about 40-50%. Food can significantly affect absorption; the bioavailability of ziprasidone, for instance, nearly doubles when taken with a high-fat meal. Several antipsychotics are available in alternative formulations to bypass first-pass metabolism or improve adherence, including orally disintegrating tablets, oral solutions, short-acting intramuscular injections, and long-acting injectable (LAI) depot preparations.

4.2. Distribution

Antipsychotics are highly lipophilic, leading to extensive distribution into body tissues, including the brain. They have large volumes of distribution (often >10 L/kg) and are highly protein-bound, primarily to albumin and α₁-acid glycoprotein. The high lipid solubility contributes to their accumulation in fatty tissues and a prolonged elimination phase. The concentration in the central nervous system typically exceeds that in plasma.

4.3. Metabolism

Hepatic metabolism is the principal route of elimination for nearly all antipsychotics. The major pathways involve the cytochrome P450 (CYP) enzyme system. Key isoenzymes include:

• CYP2D6: Metabolizes risperidone (to paliperidone), haloperidol, thioridazine, and perphenazine. Genetic polymorphisms can create poor or ultrarapid metabolizers, leading to significant interindividual variability in plasma levels and clinical response.
• CYP3A4: Involved in the metabolism of quetiapine, clozapine, haloperidol, ziprasidone, and lurasidone. This enzyme is highly inducible by other drugs (e.g., carbamazepine, rifampin) and inhibited by others (e.g., ketoconazole, fluvoxamine).
• CYP1A2: Primarily metabolizes clozapine and olanzapine. Activity is induced by smoking and inhibited by fluvoxamine.

Many antipsychotics undergo phase II glucuronidation, which is less susceptible to drug interactions. Paliperidone, the active metabolite of risperidone, is primarily renally excreted with minimal hepatic metabolism.

4.4. Excretion and Half-Life

Elimination occurs mainly via the kidneys as metabolites, with minimal unchanged drug excreted in urine. The elimination half-life (t_1/2) determines dosing frequency. Most oral antipsychotics have half-lives ranging from approximately 20 hours (e.g., risperidone) to over 30 hours (e.g., olanzapine, aripiprazole), allowing for once-daily dosing. Quetiapine has a shorter half-life (≈6-7 hours), often requiring twice-daily administration. The half-life of long-acting injectable formulations is determined by the rate of release from the intramuscular depot and ranges from 2-4 weeks (e.g., paliperidone palmitate, aripiprazole lauroxil) to up to 3 months (e.g., paliperidone palmitate every-3-months formulation). The principle of accumulation is critical; steady-state plasma concentrations are typically reached after 4-5 half-lives of consistent dosing.

5. Therapeutic Uses/Clinical Applications

While primarily indicated for psychotic disorders, the utility of antipsychotic drugs spans multiple psychiatric and medical conditions.

5.1. Approved Indications

• Schizophrenia: Treatment of acute psychotic episodes and long-term maintenance to prevent relapse. Clozapine is reserved for treatment-resistant schizophrenia, defined as inadequate response to at least two different antipsychotics.
• Bipolar Disorder: Used for the treatment of acute manic and mixed episodes (e.g., olanzapine, risperidone, quetiapine, aripiprazole, asenapine, cariprazine) and for maintenance treatment to prevent recurrence of mood episodes. Some agents (e.g., quetiapine, lurasidone) are also approved for bipolar depression.
• Major Depressive Disorder (Adjunctive Therapy): Several SGAs (e.g., aripiprazole, brexpiprazole, quetiapine extended-release) are approved as augmentation agents for patients with inadequate response to antidepressant monotherapy.
• Irritability Associated with Autistic Disorder: Risperidone and aripiprazole are approved for this indication in pediatric patients.
• Tourette’s Syndrome: Haloperidol, pimozide, and aripiprazole are used to suppress motor and vocal tics.

5.2. Common Off-Label Uses

• Behavioral and Psychological Symptoms of Dementia (BPSD): Used cautiously for severe agitation, aggression, or psychosis, though with a black box warning for increased mortality in elderly patients with dementia-related psychosis.
• Treatment-Resistant Obsessive-Compulsive Disorder: Low-dose antipsychotics (e.g., risperidone, haloperidol) may be added to serotonin reuptake inhibitors.
• Post-Traumatic Stress Disorder: For nightmares, hypervigilance, and intrusive thoughts.
• Borderline Personality Disorder: For transient psychotic symptoms, impulsivity, and affective dysregulation.
• Delirium: For severe agitation or psychosis in hospitalized patients, particularly when haloperidol is used intravenously or intramuscularly.
• Severe Nausea and Vomiting: Prochlorperazine and other phenothiazines with potent anti-dopaminergic activity in the chemoreceptor trigger zone.
• Intractable Hiccups: Chlorpromazine may be effective.

6. Adverse Effects

The adverse effect profile is a major determinant in antipsychotic selection and requires vigilant monitoring.

6.1. Neurological Adverse Effects

• Extrapyramidal Symptoms (EPS): More common with high-potency FGAs.
  • Acute Dystonia: Sudden, sustained muscle contractions (e.g., oculogyric crisis, torticollis, laryngospasm). Typically occurs within hours to days of initiation. Treated with anticholinergic agents (e.g., benztropine).
  • Parkinsonism: Bradykinesia, rigidity, tremor, and postural instability. Usually develops within weeks. Management may involve dose reduction, switching to an SGA, or adding an anticholinergic or amantadine.
  • Akathisia: A subjective feeling of inner restlessness and an objective inability to remain still. Can be severely distressing and is associated with poor adherence and increased suicide risk. Treatment options include beta-blockers (e.g., propranolol), benzodiazepines, or dose reduction.
• Tardive Dyskinesia (TD): A potentially irreversible syndrome of involuntary, choreoathetoid movements (e.g., tongue protrusion, lip smacking, grimacing) that develops after months to years of treatment. Risk is higher with FGAs, high doses, and increasing age. Prevention is paramount. Treatment involves switching to a lower-risk SGA or clozapine. The vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine are approved for the treatment of TD.
• Neuroleptic Malignant Syndrome (NMS): A rare but life-threatening idiosyncratic reaction characterized by hyperthermia, severe muscle rigidity, altered mental status, autonomic instability (labile blood pressure, tachycardia), and elevated creatine kinase. Requires immediate discontinuation of the antipsychotic, intensive supportive care, and specific pharmacotherapy (e.g., dantrolene, bromocriptine).
• Sedation: Common with agents possessing high H₁ antagonism (e.g., clozapine, quetiapine, olanzapine).
• Seizures: Dose-dependent risk, particularly with clozapine, requiring caution and possibly prophylactic anticonvulsants at higher doses.

6.2. Metabolic and Endocrine Adverse Effects

• Weight Gain and Metabolic Syndrome: A major concern with many SGAs, especially clozapine and olanzapine. Mechanisms include H₁ and 5-HT_2C receptor blockade. Metabolic syndrome encompasses central obesity, dyslipidemia (elevated triglycerides, lowered HDL), hypertension, and insulin resistance leading to type 2 diabetes mellitus. Baseline and regular monitoring of weight, waist circumference, fasting glucose, and lipid profile is mandatory.
• Hyperprolactinemia: Caused by D₂ blockade in the tuberoinfundibular pathway, disinhibiting prolactin secretion. Common with risperidone, paliperidone, and FGAs. Can lead to galactorrhea, gynecomastia, menstrual irregularities, sexual dysfunction, and long-term risks like osteoporosis.
• Diabetes Mellitus: May occur independent of weight gain through mechanisms involving insulin resistance and possibly impaired β-cell function.

6.3. Cardiovascular Adverse Effects

• Orthostatic Hypotension: Due to α₁-adrenergic blockade, especially during initial titration of clozapine, quetiapine, and low-potency FGAs.
• QTc Interval Prolongation: A serious effect that increases the risk of torsades de pointes, a potentially fatal ventricular arrhythmia. Risk is higher with thioridazine, ziprasidone, iloperidone, and intravenous haloperidol. Concomitant use with other QT-prolonging drugs or conditions causing electrolyte disturbances (hypokalemia, hypomagnesemia) should be avoided.
• Myocarditis and Cardiomyopathy: A rare but serious risk associated with clozapine, most frequently in the first two months of treatment. Symptoms may include fever, flu-like symptoms, chest pain, tachycardia, and dyspnea.

6.4. Other Adverse Effects

• Anticholinergic Effects: Dry mouth, constipation, urinary retention, blurred vision, cognitive clouding.
• Hematological: Clozapine carries a risk of agranulocytosis (≈1%), necessitating mandatory registration with a patient monitoring service and weekly, then later monthly, absolute neutrophil count checks.
• Hepatic: Transient elevation of liver enzymes is common; rare cases of cholestatic jaundice have been reported with phenothiazines.
• Ocular: Thioridazine at high doses can cause irreversible pigmentary retinopathy.
• Cutaneous: Photosensitivity reactions, especially with low-potency phenothiazines.

6.5. Black Box Warnings

Several class-wide or drug-specific black box warnings exist:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis: All antipsychotics carry this warning due to a 1.6 to 1.7-fold increased risk of death, primarily from cardiovascular events or infections.
• Suicidality in Children, Adolescents, and Young Adults: Antidepressants and antipsychotics used for depression or other indications may increase suicidal thoughts and behaviors in patients under 24.
• Clozapine: Specific warnings for agranulocytosis, seizures, myocarditis, and orthostatic hypotension.

7. Drug Interactions

Antipsychotics are involved in numerous pharmacokinetic and pharmacodynamic interactions.

7.1. Pharmacokinetic Interactions

• CYP Enzyme Inducers: Drugs like carbamazepine, phenytoin, rifampin, and St. John’s wort can significantly reduce plasma concentrations of antipsychotics metabolized by CYP3A4 or CYP1A2, potentially leading to treatment failure.
• CYP Enzyme Inhibitors: Fluoxetine, paroxetine (CYP2D6 inhibitors), and fluvoxamine (CYP1A2 and CYP3A4 inhibitor) can increase levels of relevant antipsychotics, raising the risk of toxicity. For example, fluvoxamine can dramatically increase clozapine levels.
• Smoking: Tobacco smoke induces CYP1A2, leading to lower plasma levels of clozapine and olanzapine. Smoking cessation can cause a clinically significant rise in drug levels.

7.2. Pharmacodynamic Interactions

• CNS Depressants: Additive sedation and respiratory depression can occur with concomitant use of alcohol, benzodiazepines, opioids, or sedating antidepressants.
• Anticholinergic Agents: Concurrent use with other drugs having anticholinergic properties (e.g., tricyclic antidepressants, antiparkinsonian agents) can lead to an additive anticholinergic burden, increasing the risk of confusion, constipation, urinary retention, and hyperthermia.
• Antihypertensives: The α₁-blocking effects of some antipsychotics can potentiate the effects of other antihypertensive drugs, leading to excessive hypotension.
• QTc-Prolonging Drugs: Concomitant use with other drugs that prolong the QT interval (e.g., class IA and III antiarrhythmics, certain antibiotics, methadone) is contraindicated or requires extreme caution with close ECG monitoring.
• Levodopa and Direct Dopamine Agonists: These antiparkinsonian drugs may be rendered less effective by the dopamine receptor blockade of antipsychotics.

7.3. Contraindications

Absolute contraindications are relatively few but important:

• Known hypersensitivity to the drug or its components.
• Comatose states or significant CNS depression from other agents (e.g., alcohol, opioids).
• Concurrent use of drugs with high risk of QTc prolongation for agents like thioridazine and ziprasidone.
• Severe hematological disorders (for clozapine).
• Uncontrolled epilepsy (relative contraindication for many, especially clozapine).

8. Special Considerations

8.1. Pregnancy and Lactation

The use of antipsychotics during pregnancy requires a careful risk-benefit analysis. Untreated maternal psychosis poses significant risks to both mother and fetus, including poor prenatal care, nutritional deficiency, and potential harm. Most antipsychotics are classified as Pregnancy Category C (risk cannot be ruled out). Epidemiological data have suggested a possible small increased risk of gestational diabetes, large-for-gestational-age infants (with SGAs), and neonatal EPS or withdrawal symptoms (e.g., agitation, hypertonia) if exposed in the third trimester. Clozapine use may be associated with gestational diabetes and a theoretical risk of neonatal agranulocytosis. Regarding lactation, antipsychotics are excreted in breast milk in varying amounts. Agents with lower milk-to-plasma ratios, minimal sedation, and established safety data in infants (e.g., olanzapine, quetiapine) may be preferred, but infant monitoring for sedation and developmental milestones is advised.

8.2. Pediatric and Geriatric Populations

Pediatrics: Antipsychotic use in children and adolescents is increasing, primarily for autism-associated irritability, early-onset schizophrenia, and bipolar disorder. Dosing is typically weight-based (mg/kg). This population may be more sensitive to certain adverse effects, particularly weight gain, metabolic changes, sedation, and hyperprolactinemia. Long-term effects on the developing brain are not fully understood.

Geriatrics: Age-related pharmacokinetic changes (reduced hepatic metabolism, decreased renal clearance, altered body composition) and pharmacodynamic sensitivity necessitate the principle of “start low and go slow.” Elderly patients are exquisitely sensitive to adverse effects such as orthostatic hypotension, sedation, anticholinergic effects (leading to confusion and falls), and EPS. The black box warning for increased mortality in dementia-related psychosis mandates extreme caution and a thorough discussion of risks with caregivers.

8.3. Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is generally not required for most antipsychotics that are extensively metabolized. However, for drugs with significant renal excretion of active metabolites (e.g., paliperidone) or the parent drug (e.g., sulpiride), dose reduction is necessary in moderate to severe renal impairment. In end-stage renal disease, accumulation of metabolites may occur.

Hepatic Impairment: For antipsychotics that undergo extensive hepatic metabolism (the majority), clearance may be reduced in patients with liver cirrhosis or severe impairment, leading to increased drug exposure and a higher risk of adverse effects. Dose reduction and careful titration are recommended. Baseline and periodic liver function tests are prudent.

9. Summary/Key Points

• Antipsychotics are classified as first-generation (typical) or second-generation (atypical), with the latter generally having a lower risk of extrapyramidal symptoms but a higher risk of metabolic adverse effects.
• The primary mechanism involves antagonism of dopamine D₂ receptors in the mesolimbic pathway. Atypical agents often combine this with serotonin 5-HT_2A receptor blockade, which may modulate dopaminergic tone in other pathways.
• Pharmacokinetics are characterized by high lipophilicity, extensive hepatic metabolism via CYP enzymes, and long half-lives enabling once-daily dosing for most oral agents. Long-acting injectable formulations provide sustained delivery over weeks to months.
• Therapeutic applications extend beyond schizophrenia to include bipolar disorder, adjunctive treatment of major depression, and management of agitation in various neuropsychiatric conditions.
• Adverse effect profiles are diverse and often dictate drug choice. Key concerns include extrapyramidal symptoms (FGAs), metabolic syndrome (many SGAs), hyperprolactinemia, QTc prolongation, and rare but serious events like neuroleptic malignant syndrome and clozapine-induced agranulocytosis.
• Significant drug interactions occur via CYP enzyme inhibition/induction and additive pharmacodynamic effects (e.g., sedation, QTc prolongation).
• Special caution is required in vulnerable populations: the elderly (increased mortality in dementia, fall risk), pregnant women (risk-benefit analysis), and patients with hepatic or renal impairment (altered clearance).

Clinical Pearls:

1. The choice of antipsychotic should be individualized, balancing efficacy for target symptoms against the patient’s susceptibility to specific adverse effects (e.g., avoid olanzapine in a patient with obesity/prediabetes; avoid risperidone in a patient concerned about sexual function).
2. Clozapine remains the gold standard for treatment-resistant schizophrenia but requires rigorous hematological monitoring due to the risk of agranulocytosis.
3. Long-acting injectable antipsychotics should be strongly considered for any patient with a history of poor adherence, as non-adherence is the leading cause of relapse.
4. Proactive monitoring for metabolic adverse effects (weight, waist circumference, blood glucose, lipids) is a standard of care, not an option, especially with second-generation agents.
5. When discontinuing an antipsychotic, a gradual taper is generally recommended to minimize the risk of withdrawal symptoms or early relapse, unless discontinuation is due to a severe adverse reaction like NMS.

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