Antipsychotic Drugs

Correct Answer

B — Thioridazine

Rationale

Thioridazine is classified as a low-potency first-generation antipsychotic, requiring doses of 200 to 1000 milligrams per day to achieve therapeutic dopamine D2 receptor occupancy. Haloperidol, fluphenazine, and perphenazine are all classified as high-potency first-generation antipsychotics, achieving equivalent D2 blockade at doses of 2 to 20 milligrams per day. Potency refers exclusively to the milligram dose required for therapeutic effect — it does not predict clinical efficacy.

Correct Answer

D — Haloperidol decanoate

Rationale

Haloperidol decanoate is a long-acting injectable (depot) formulation of haloperidol, administered once monthly as an oil-based intramuscular injection that is slowly absorbed from the injection site. Haloperidol lactate is the short-acting intramuscular formulation of haloperidol used for acute agitation — it reaches peak plasma levels within 20 to 40 minutes but does not provide sustained delivery. Thioridazine and chlorpromazine are oral low-potency first-generation antipsychotics with no depot formulations in clinical use.

Correct Answer

A — Valbenazine

Rationale

Valbenazine is classified as a vesicular monoamine transporter 2 inhibitor and is one of two drugs with regulatory approval specifically for tardive dyskinesia (the other being deutetrabenazine). Benztropine is an anticholinergic agent used to treat acute dystonia and drug-induced parkinsonism. Propranolol is a non-selective beta-adrenergic blocker used as first-line treatment for akathisia. Dantrolene is a muscle relaxant used in the treatment of neuroleptic malignant syndrome.

Correct Answer

C — Prochlorperazine

Rationale

Prochlorperazine is a phenothiazine derivative developed primarily as an antiemetic and is routinely used in emergency medicine for nausea, vestibular disorders, and migraine-associated nausea. Like other phenothiazines, it blocks dopamine D2 receptors and can produce extrapyramidal symptoms. Valbenazine is a vesicular monoamine transporter 2 inhibitor used specifically for tardive dyskinesia. Haloperidol is a butyrophenone — a chemically distinct subclass from the phenothiazines. Aripiprazole is a partial D2 agonist in the third mechanistic category of antipsychotics.

Correct Answer

B — Benztropine

Rationale

Benztropine is classified as an anticholinergic agent and is a first-line treatment for antipsychotic-induced acute dystonia and drug-induced parkinsonism. It is administered intramuscularly or intravenously for acute dystonia and produces resolution within 15 to 30 minutes. Propranolol is a non-selective beta-adrenergic blocker — the first-line treatment for akathisia. Dantrolene is a muscle relaxant used in neuroleptic malignant syndrome. Valbenazine is a vesicular monoamine transporter 2 inhibitor used specifically for tardive dyskinesia.

Correct Answer

A — Dantrolene

Rationale

Dantrolene is classified as a muscle relaxant and is a key pharmacological treatment for neuroleptic malignant syndrome. It reduces the severe generalized muscle rigidity of neuroleptic malignant syndrome by inhibiting calcium release from the sarcoplasmic reticulum in skeletal muscle, thereby reducing hyperthermia and rigidity. Benztropine is an anticholinergic agent used for acute dystonia and drug-induced parkinsonism. Propranolol is a beta-adrenergic blocker used for akathisia. Valbenazine is a vesicular monoamine transporter 2 inhibitor used for tardive dyskinesia.

Correct Answer

C — Blockade of the hERG potassium channel impairs cardiac repolarization, prolonging the QTc interval and predisposing to torsades de pointes

Rationale

Thioridazine is a potent blocker of the hERG potassium channel, which is responsible for the rapid component of cardiac repolarization. By impairing this channel, thioridazine prolongs the QTc interval in a dose-dependent manner. At doses above 300 milligrams per day, the prolonged repolarization can trigger torsades de pointes — a potentially fatal polymorphic ventricular tachycardia. This cardiac risk distinguishes thioridazine from other first-generation antipsychotics and is the primary reason it requires a baseline electrocardiogram before initiation and is restricted to patients who have failed safer alternatives. Alpha-1 adrenergic blockade produces orthostatic hypotension rather than QTc effects. Muscarinic M1 blockade produces anticholinergic effects. Dopamine D2 receptors are not expressed in the cardiac conduction system in a clinically relevant way.

Correct Answer

A — The symptoms represent akathisia, not worsening psychosis — increasing the dose worsens akathisia; propranolol is the first-line pharmacological treatment

Rationale

Akathisia is a syndrome of motor restlessness with a compelling subjective sense of inner tension and an irresistible urge to move — it typically emerges within days to weeks of starting an antipsychotic. The most dangerous clinical error is misidentifying akathisia as worsening psychosis or agitation and responding by increasing the antipsychotic dose, which worsens the syndrome further. Any patient who becomes more agitated or restless after starting or increasing an antipsychotic should be evaluated specifically for akathisia before the dose is adjusted. Propranolol, a non-selective beta-adrenergic blocker, is the most evidence-supported pharmacological treatment and is particularly effective for the subjective restlessness component. Anticholinergic agents such as benztropine are generally less effective for akathisia than for acute dystonia or drug-induced parkinsonism. Acute dystonia presents with sustained involuntary muscle contractions, not restlessness. Drug-induced parkinsonism presents with bradykinesia, rigidity, and tremor. Tardive dyskinesia presents with involuntary orofacial or choreiform movements after months to years of exposure.

Correct Answer

D — Anticholinergic drugs reduce the relative excess of cholinergic tone in the striatum that results from dopamine D2 blockade, restoring the dopamine-acetylcholine balance

Rationale

Normal striatal function depends on a balance between dopaminergic and cholinergic neurotransmission. Antipsychotic D2 blockade in the nigrostriatal pathway reduces dopaminergic inhibition of striatal interneurons, leaving a relative excess of cholinergic tone. This cholinergic excess drives the abnormal sustained muscle contractions of acute dystonia. Anticholinergic drugs such as benztropine and diphenhydramine restore the dopamine-acetylcholine balance by reducing cholinergic activity — without removing the antipsychotic from the D2 receptor. This mechanism also explains why anticholinergic agents are effective for drug-induced parkinsonism but less so for akathisia, which has a different pathophysiological basis. Resolution of acute dystonia with intramuscular benztropine or diphenhydramine typically occurs within 15 to 30 minutes.

Correct Answer

B — Once injected, the depot formulation cannot be rapidly removed — if intolerable adverse effects occur, they will persist for weeks with no way to rapidly reduce drug exposure

Rationale

Haloperidol decanoate is an oil-based depot preparation that is slowly absorbed from the intramuscular injection site over approximately one month. Unlike an oral tablet, which can be stopped and cleared within days if a patient develops intolerable adverse effects, a depot formulation cannot be removed once injected. If a patient experiences severe akathisia, acute dystonia, or other intolerable effects after receiving haloperidol decanoate, those effects will persist at therapeutic drug levels for weeks. For this reason, oral tolerability testing with the same drug is a mandatory clinical step before any patient is converted to a long-acting injectable. The depot formulation does not change the receptor-binding profile or adverse effect type of haloperidol — it changes only the delivery kinetics, not the pharmacodynamics.

Correct Answer

C — Plasma chlorpromazine levels will rise because smoking-induced cytochrome P450 1A2 induction is removed, slowing drug metabolism

Rationale

Cigarette smoking strongly induces the cytochrome P450 1A2 enzyme — a major metabolic pathway for chlorpromazine and several other phenothiazines. In heavy smokers, this induction increases drug metabolism and reduces plasma concentrations by 30 to 50 percent compared with non-smokers at the same oral dose. When a patient stops smoking, the CYP1A2 induction is gradually removed over days to weeks, and metabolism of chlorpromazine slows toward non-smoker pharmacokinetics. Plasma levels rise on the same dose, potentially producing adverse effects or toxicity. This is a clinically important interaction in any inpatient setting where smoking is prohibited: a patient stabilized on chlorpromazine as an outpatient smoker may develop toxicity during a smoke-free admission. The same interaction — with even greater magnitude — applies to olanzapine and clozapine. Chlorpromazine is not primarily renally eliminated; it undergoes extensive hepatic metabolism.

Correct Answer

A — Chronic D2 blockade causes striatal dopamine D2 receptors to upregulate in number and sensitivity; dose reduction unmasks this supersensitivity, allowing endogenous dopamine to produce hyperkinetic movements

Rationale

Tardive dyskinesia develops after months to years of antipsychotic exposure through a mechanism of dopamine receptor supersensitivity. Chronic D2 blockade in the striatum causes postsynaptic D2 receptors to compensatorily upregulate — increasing in both number and sensitivity. As long as the antipsychotic maintains high D2 occupancy, this supersensitivity is masked. When the antipsychotic dose is reduced or stopped, the now-supersensitive receptors are activated by normal levels of endogenous dopamine, producing the involuntary hyperkinetic movements characteristic of tardive dyskinesia. This withdrawal-emergent worsening is a clinically deceptive feature — it can lead to the mistaken conclusion that dose reduction caused the dyskinesia, when the underlying supersensitivity developed throughout the entire course of treatment.

Correct Answer

D — The severe sustained muscle rigidity causes rhabdomyolysis, releasing creatine kinase from damaged skeletal muscle into the circulation

Rationale

Neuroleptic malignant syndrome is characterized by a tetrad of hyperthermia, severe generalized lead-pipe muscle rigidity, autonomic instability, and altered consciousness. The intense and sustained muscle rigidity produces rhabdomyolysis — breakdown of skeletal muscle fibers — releasing large amounts of creatine kinase into the circulation. Creatine kinase levels are often markedly elevated, frequently above 10,000 units per liter, and serve as an important diagnostic clue as well as a marker of severity. The rhabdomyolysis also releases myoglobin into the circulation, creating risk of myoglobinuria and acute kidney injury. Elevated creatine kinase in this context reflects the severity of the muscle injury from rigidity — it is not a direct effect of dopamine blockade, hyperthermia on enzyme synthesis, or cardiac ischemia from autonomic dysfunction.

Correct Answer

B — Low-potency agents produce significant histamine H1 and muscarinic M1 blockade at therapeutic doses, which partially offsets the motor consequences of nigrostriatal D2 blockade

Rationale

When a low-potency first-generation antipsychotic such as chlorpromazine is given at the large doses required to achieve therapeutic D2 occupancy, it simultaneously produces substantial blockade of histamine H1 and muscarinic M1 receptors. The anticholinergic activity from M1 blockade partially restores the dopamine-acetylcholine balance in the striatum — the same balance that is targeted therapeutically when benztropine is given to treat acute dystonia. This intrinsic anticholinergic offset reduces extrapyramidal symptom risk, at the cost of significant sedation, anticholinergic adverse effects, and orthostatic hypotension. High-potency agents such as haloperidol achieve D2 occupancy at low doses with minimal off-target receptor activity, so there is no anticholinergic offset — the full motor consequence of nigrostriatal D2 blockade is expressed. Both drug classes achieve equivalent D2 occupancy at their respective therapeutic doses; the difference is not in the degree of D2 blockade but in the presence or absence of receptor interactions that buffer its motor effects.

Correct Answer

D — Blockade of the hERG potassium channel impairs cardiac repolarization, prolonging the QTc interval

Rationale

Thioridazine is a potent blocker of the hERG potassium channel, which mediates the rapid component of ventricular repolarization. By impairing this channel, thioridazine prolongs the action potential duration and, consequently, the QTc interval on the electrocardiogram. This dose-dependent effect is the primary reason thioridazine is restricted to patients who have failed other antipsychotics and requires a baseline electrocardiogram before initiation. A QTc above 500 milliseconds, as in this patient, substantially increases the risk of torsades de pointes — a potentially fatal polymorphic ventricular tachycardia. This cardiac risk is unique to thioridazine and pimozide among first-generation antipsychotics and is mechanistically distinct from the cardiovascular effects of alpha-1 blockade or muscarinic receptor interactions seen with other agents in the class.

Correct Answer

C — Removal of smoking-induced cytochrome P450 1A2 induction slows chlorpromazine metabolism, raising plasma levels on the same dose

Rationale

Cigarette smoking strongly induces cytochrome P450 1A2, a major metabolic enzyme for chlorpromazine. In this heavy smoker, CYP1A2 induction accelerated chlorpromazine metabolism, maintaining plasma levels low enough to be tolerated on 600 milligrams daily. When he stops smoking in the smoke-free unit, CYP1A2 induction is gradually removed over days to weeks. Chlorpromazine metabolism slows toward non-smoker pharmacokinetics, and plasma levels rise substantially on the same dose — producing the adverse effects of chlorpromazine excess: sedation from histamine H1 blockade, orthostatic hypotension from alpha-1 adrenergic blockade, and confusion from muscarinic M1 and central nervous system effects. This interaction is clinically important for any patient on a cytochrome P450 1A2-substrate antipsychotic admitted to a smoke-free environment. The same interaction applies to olanzapine and clozapine with even greater clinical magnitude. Chlorpromazine is primarily hepatically metabolized, making renal clearance of metabolites a minor pathway.

Correct Answer

A — Benztropine reduces the relative excess of cholinergic tone in the striatum that results from dopamine D2 blockade, restoring the dopamine-acetylcholine balance

Rationale

Acute dystonia results from an imbalance in the striatum between dopaminergic and cholinergic neurotransmission. Haloperidol blocks dopamine D2 receptors in the nigrostriatal pathway, reducing dopaminergic inhibition of striatal interneurons and leaving a relative excess of cholinergic tone. This cholinergic excess drives the sustained abnormal muscle contractions of acute dystonia. Benztropine, an anticholinergic drug, blocks muscarinic receptors in the striatum and reduces the cholinergic excess — restoring the dopamine-acetylcholine balance without removing haloperidol from the D2 receptor. This mechanism explains both the effectiveness of anticholinergic drugs for acute dystonia and their relative ineffectiveness for akathisia, which has a different and less well-defined pathophysiological basis. The rapid response — typically 15 to 30 minutes — reflects the speed of muscarinic receptor blockade once benztropine reaches therapeutic concentrations.

Correct Answer

B — Years of D2 blockade caused striatal D2 receptors to become supersensitive; reducing the blockade allows endogenous dopamine to activate these supersensitive receptors, producing more pronounced hyperkinetic movements

Rationale

This patient has tardive dyskinesia — a hyperkinetic movement disorder caused by dopamine receptor supersensitivity that develops after prolonged antipsychotic exposure. Chronic D2 blockade in the striatum triggers a compensatory upregulation of D2 receptors, increasing their number and sensitivity. While the antipsychotic maintains high receptor occupancy, this supersensitivity is masked. When the dose is reduced, the degree of D2 blockade falls, and endogenous dopamine gains access to the now-supersensitive receptors — producing a worsening of the hyperkinetic movements. This withdrawal-emergent phenomenon is a defining and clinically important feature of tardive dyskinesia: it can appear to implicate the dose reduction as the cause of the movements, when in reality the supersensitivity developed throughout the years of treatment. Haloperidol has minimal anticholinergic activity, making acetylcholine excess an implausible explanation. Haloperidol is a first-generation antipsychotic with no meaningful serotonin 5-HT2A blockade.