1. First-generation antipsychotics (FGAs) are a class of drugs used to treat psychosis, such as the symptoms of schizophrenia. They share a single primary mechanism that accounts for their antipsychotic effect. What is that shared primary mechanism of action?
A) They stimulate dopamine D2 receptors, increasing dopamine signaling in the brain
B) They competitively block dopamine D2 receptors, preventing the brain's own dopamine from activating them
C) They increase the amount of dopamine released from nerve terminals
D) They block the reuptake of serotonin from the synapse, raising serotonin levels
E) They permanently destroy the dopamine-producing neurons of the brain
ANSWER: B
Rationale:
All first-generation antipsychotics work as competitive antagonists at dopamine D2 receptors, meaning they occupy the receptor and block the access of the body's own dopamine without activating the receptor themselves. This dopamine blockade in the mesolimbic pathway is what produces the antipsychotic effect, and it is the unifying feature of the entire class regardless of which specific agent is used.
Option A: Option A is incorrect because FGAs block rather than stimulate D2 receptors; an agonist that stimulated dopamine receptors would be expected to worsen psychosis, not treat it.
Option C: Option C is incorrect because FGAs act at the receptor itself and do not work by increasing dopamine release.
Option D: Option D is incorrect because blocking serotonin reuptake describes a mechanism of certain antidepressants, not the dopamine-blocking action that defines FGAs.
Option E: Option E is incorrect because the D2 blockade is competitive and reversible; the drug does not destroy neurons, and the receptors become available again as the drug dissociates and is cleared.
2. A student notices that haloperidol is effective at 2 to 5 mg per day while chlorpromazine requires 400 to 800 mg per day, and concludes that haloperidol must be a much stronger antipsychotic. In pharmacology, the term "potency" for these drugs refers specifically to which of the following?
A) The dose in milligrams needed to reach a given level of D2 receptor blockade, not the maximum antipsychotic effect the drug can produce
B) The maximum antipsychotic effect the drug is capable of producing at any dose
C) How quickly the drug begins to work after it is taken
D) How long the drug remains active in the body before it is eliminated
E) How likely the drug is to cause dependence with long-term use
ANSWER: A
Rationale:
Potency refers only to the milligram dose required to achieve a given level of D2 receptor occupancy; it does not describe the ceiling effect the drug can reach. Haloperidol is high-potency because its high D2 affinity lets a small dose reach the therapeutic occupancy range, while chlorpromazine is low-potency because its lower affinity requires a much larger dose for the same occupancy. When each is titrated to equivalent D2 occupancy, the two produce comparable antipsychotic effect, so the student's conclusion that haloperidol is a "stronger" antipsychotic confuses potency with efficacy.
Option B: Option B is incorrect because that describes efficacy (the maximum achievable effect), which is comparable across FGAs at equivalent occupancy, not potency.
Option C: Option C is incorrect because speed of onset describes a pharmacokinetic property, not potency.
Option D: Option D is incorrect because duration in the body reflects half-life and elimination, not potency.
Option E: Option E is incorrect because dependence liability is unrelated to the definition of potency.
3. Among the first-generation antipsychotics, one agent is considered the prototypical high-potency drug: it belongs to the butyrophenone chemical group, has very high affinity for the D2 receptor, and produces relatively little sedation or dry-mouth-type effects at standard doses. Which agent is this?
A) Chlorpromazine
B) Thioridazine
C) Clozapine
D) Haloperidol
E) Promethazine
ANSWER: D
Rationale:
Haloperidol is the prototypical high-potency FGA. As a butyrophenone with very high D2 affinity and little meaningful activity at histamine H1, muscarinic M1, or alpha-1 adrenergic receptors at standard doses, it produces relatively low sedation and anticholinergic (dry-mouth-type) burden, and it is available in oral, intramuscular, and long-acting injectable forms.
Option A: Option A is incorrect because chlorpromazine is a low-potency aliphatic phenothiazine with heavy H1, M1, and alpha-1 blockade.
Option B: Option B is incorrect because thioridazine is a low-potency phenothiazine notable for cardiac risk, not a high-potency prototype.
Option C: Option C is incorrect because clozapine is a second-generation (atypical) antipsychotic, not an FGA, and is covered in a later module.
Option E: Option E is incorrect because promethazine is a phenothiazine derivative used mainly as an antihistamine and antiemetic, not as a high-potency antipsychotic.
4. Which first-generation antipsychotic was the first such drug introduced into clinical practice (in 1952), is a low-potency aliphatic phenothiazine, and is historically credited with launching the modern pharmacological treatment of psychosis?
A) Haloperidol
B) Fluphenazine
C) Chlorpromazine
D) Trifluoperazine
E) Loxapine
ANSWER: C
Rationale:
Chlorpromazine, introduced in 1952, was the first antipsychotic drug and the agent whose clinical activity launched the modern pharmacological treatment of psychosis. It is a low-potency aliphatic phenothiazine that requires relatively large doses to reach therapeutic D2 occupancy and, at those doses, produces substantial sedation, anticholinergic effects, and orthostatic hypotension.
Option A: Option A is incorrect because haloperidol is a later high-potency butyrophenone, not the first agent introduced.
Option B: Option B is incorrect because fluphenazine is a high-potency piperazine phenothiazine introduced after chlorpromazine.
Option D: Option D is incorrect because trifluoperazine is also a later high-potency piperazine phenothiazine.
Option E: Option E is incorrect because loxapine is a structurally distinct intermediate-potency agent introduced well after chlorpromazine.
5. Imaging studies that measure how much of the D2 receptor population a drug occupies have defined a therapeutic "window" for first-generation antipsychotics. Within roughly which range of striatal D2 receptor occupancy is antipsychotic response reliable while side effects from excessive blockade are still largely avoided?
A) 5 to 15 percent
B) 20 to 30 percent
C) 40 to 50 percent
D) 90 to 100 percent
E) 65 to 80 percent
ANSWER: E
Rationale:
Positron emission tomography (PET, a brain-imaging method that measures receptor occupancy) studies show that reliable antipsychotic response occurs when about 65 to 80 percent of D2 receptors are occupied. Below roughly 65 percent the response is inconsistent, and above roughly 80 percent extrapyramidal side effects (movement side effects from dopamine blockade) emerge without any additional therapeutic benefit, which is why this band represents the target occupancy.
Option A: Option A is incorrect because 5 to 15 percent occupancy is far below the threshold for a reliable antipsychotic effect.
Option B: Option B is incorrect because 20 to 30 percent is still below the therapeutic window and would give inconsistent response.
Option C: Option C is incorrect because 40 to 50 percent occupancy still falls short of the reliable-response threshold.
Option D: Option D is incorrect because occupancy of 90 to 100 percent lies above the window and predicts extrapyramidal side effects without added benefit.
6. Extrapyramidal side effects (EPS) are movement disturbances caused by dopamine blockade in the brain's motor pathways. One EPS syndrome appears earliest — within hours to a few days of the first dose — and consists of sudden, sustained, often painful muscle contractions, such as forced upward eye deviation (oculogyric crisis) or twisting of the neck (torticollis). Which syndrome is this?
A) Acute dystonia
B) Tardive dyskinesia
C) Drug-induced parkinsonism
D) Neuroleptic malignant syndrome
E) Akathisia
ANSWER: A
Rationale:
Acute dystonia is the earliest extrapyramidal syndrome, typically emerging within hours to about five days of starting or increasing a first-generation antipsychotic. It consists of sudden, sustained muscle contractions producing abnormal postures, with classic presentations including oculogyric crisis (forced upward deviation of the eyes) and torticollis (neck spasm with head rotation).
Option B: Option B is incorrect because tardive dyskinesia develops late, after months to years of exposure, not in the first hours to days.
Option C: Option C is incorrect because drug-induced parkinsonism emerges over days to weeks and presents with rigidity, bradykinesia, and tremor rather than sudden sustained spasms.
Option D: Option D is incorrect because neuroleptic malignant syndrome is a systemic emergency with fever and rigidity, not an isolated dystonic posture.
Option E: Option E is incorrect because akathisia is a syndrome of restlessness and an urge to move, not sustained muscle contraction.
7. After months to years of treatment with a first-generation antipsychotic, a patient develops involuntary, repetitive movements of the mouth and tongue — lip smacking, tongue protrusion, and chewing motions. This late-appearing movement disorder is known as which of the following?
A) Acute dystonia
B) Tardive dyskinesia
C) Akathisia
D) Drug-induced parkinsonism
E) Neuroleptic malignant syndrome
ANSWER: B
Rationale:
Tardive dyskinesia is a movement disorder that develops after prolonged exposure to dopamine-receptor-blocking drugs, classically appearing only after months to years of therapy. Its most common form involves involuntary, repetitive, purposeless movements of the orolingual region — lip smacking, tongue protrusion, chewing, and facial grimacing.
Option A: Option A is incorrect because acute dystonia appears within the first hours to days, not after months to years.
Option C: Option C is incorrect because akathisia is motor restlessness with an urge to move, not repetitive orofacial movements.
Option D: Option D is incorrect because drug-induced parkinsonism presents with rigidity, bradykinesia, and tremor over days to weeks rather than late orofacial dyskinesia.
Option E: Option E is incorrect because neuroleptic malignant syndrome is an acute febrile emergency, not a chronic involuntary-movement disorder.
8. A long-acting injectable (LAI, or "depot") antipsychotic is one given as an injection every few weeks instead of a daily pill. Among the first-generation antipsychotics, two agents are the established long-acting injectable formulations. Which pair is correct?
A) Chlorpromazine and thioridazine
B) Trifluoperazine and perphenazine
C) Haloperidol decanoate and fluphenazine decanoate
D) Loxapine and molindone
E) Promethazine and prochlorperazine
ANSWER: C
Rationale:
The two established first-generation long-acting injectable formulations are haloperidol decanoate and fluphenazine decanoate. Both are esterified with a fatty acid to create an oil-based depot that is slowly absorbed from the intramuscular injection site, allowing dosing every two to four weeks and converting daily adherence into a periodic clinical contact.
Option A: Option A is incorrect because chlorpromazine and thioridazine are low-potency oral agents without established depot forms.
Option B: Option B is incorrect because, although fluphenazine has a depot form, trifluoperazine and perphenazine do not, so this pair is wrong.
Option D: Option D is incorrect because loxapine and molindone are not available as long-acting injectables.
Option E: Option E is incorrect because promethazine and prochlorperazine are used mainly as antiemetics and are not FGA depot antipsychotics.
9. Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal reaction to antipsychotic drugs. It is recognized clinically by a characteristic tetrad (group of four) of features. Which of the following best lists that tetrad?
A) Low body temperature, muscle flaccidity, stable vital signs, and full alertness
B) Skin rash, joint pain, eosinophilia, and fever resolving spontaneously
C) Hypertension, headache, blurred vision, and chest pain alone
D) High fever, severe muscle rigidity, autonomic instability, and altered consciousness
E) Diarrhea, weight loss, tremor, and heat intolerance from thyroid excess
ANSWER: D
Rationale:
NMS is defined by a tetrad of hyperthermia (high fever), severe "lead-pipe" muscle rigidity, autonomic instability (fluctuating blood pressure, tachycardia, and diaphoresis), and altered consciousness. It is thought to result from rapid, extensive D2 blockade in the nigrostriatal pathway and hypothalamus, and creatine kinase (a muscle enzyme released by muscle injury) is typically markedly elevated.
Option A: Option A is incorrect because it inverts the syndrome; NMS produces high fever and rigidity, not low temperature and flaccidity.
Option B: Option B is incorrect because rash, joint pain, and eosinophilia describe a drug hypersensitivity reaction rather than NMS.
Option C: Option C is incorrect because hypertension with headache and chest pain alone does not capture the fever, rigidity, and altered consciousness that define NMS.
Option E: Option E is incorrect because diarrhea, weight loss, tremor, and heat intolerance describe thyroid hormone excess (thyrotoxicosis), not NMS.
10. Low-potency first-generation antipsychotics such as chlorpromazine tend to cause much more sedation, dry mouth and constipation, and dizziness on standing than high-potency agents such as haloperidol. What is the best explanation for why low-potency agents produce this heavier burden of these particular side effects?
A) Low-potency agents bind the D2 receptor far more tightly, and that tight binding directly causes sedation and dry mouth
B) Low-potency agents are always given by injection, and the injection route itself causes these effects
C) Because low-potency agents need large doses to block enough D2 receptors, those large doses also block histamine H1, muscarinic M1, and alpha-1 receptors, producing sedation, dry mouth, and orthostatic dizziness
D) Low-potency agents are eliminated so rapidly that the body produces these effects as a withdrawal reaction
E) These side effects come entirely from blockade of the D2 receptor and have nothing to do with other receptors
ANSWER: C
Rationale:
Low-potency agents have relatively low D2 affinity, so they must be given at large doses to reach the therapeutic occupancy range. At those large doses they also produce meaningful blockade at histamine H1 receptors (causing sedation and weight gain), muscarinic M1 receptors (causing dry mouth, constipation, and urinary retention), and alpha-1 adrenergic receptors (causing orthostatic hypotension with dizziness on standing). High-potency agents reach therapeutic D2 occupancy at small doses that leave these other receptors largely untouched.
Option A: Option A is incorrect because low-potency agents bind D2 less tightly, not more, and these side effects come from other receptors rather than from D2 binding.
Option B: Option B is incorrect because these agents are commonly oral and the route is not the cause.
Option D: Option D is incorrect because the effects are direct receptor-blocking effects, not a withdrawal reaction.
Option E: Option E is incorrect because these specific side effects arise from H1, M1, and alpha-1 blockade, not from D2 blockade.
11. A patient develops acute dystonia — sudden sustained muscle spasm — shortly after receiving a high-potency first-generation antipsychotic. Which treatment produces rapid relief, typically within 15 to 30 minutes, by countering the relative cholinergic excess in the basal ganglia?
A) An additional dose of the same antipsychotic to deepen the blockade
B) A beta-blocker such as propranolol given by mouth
C) Intravenous fluids and external cooling alone
D) A selective serotonin reuptake inhibitor antidepressant
E) An anticholinergic or antihistamine agent such as benztropine or diphenhydramine given by injection
ANSWER: E
Rationale:
Acute dystonia arises when dopamine blockade unmasks a relative excess of cholinergic (acetylcholine) activity in the basal ganglia. Giving an agent that blocks acetylcholine — an anticholinergic such as benztropine or the antihistamine diphenhydramine, which also has anticholinergic action — by intramuscular or intravenous injection restores the balance and relieves the spasm rapidly, usually within 15 to 30 minutes.
Option A: Option A is incorrect because adding more antipsychotic would deepen the dopamine blockade and worsen the dystonia.
Option B: Option B is incorrect because propranolol is the treatment of choice for akathisia, not acute dystonia.
Option C: Option C is incorrect because fluids and cooling are supportive measures for neuroleptic malignant syndrome, not the specific treatment for dystonia.
Option D: Option D is incorrect because a serotonin reuptake inhibitor has no role in reversing acute dystonia.
12. Akathisia is a syndrome of motor restlessness and an intense inner urge to move, and it is one of the most common reasons patients stop their antipsychotic. After considering a dose reduction, which medication has the strongest evidence as a pharmacological treatment for akathisia, particularly for the subjective restlessness?
A) Propranolol, a non-selective beta-adrenergic blocker
B) Benztropine, an anticholinergic agent
C) Dantrolene, a muscle relaxant acting on the ryanodine receptor
D) Bromocriptine, a dopamine agonist
E) Valbenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor
ANSWER: A
Rationale:
Propranolol, a non-selective beta-adrenergic blocker, has the strongest evidence base for treating akathisia and is particularly effective against the subjective restlessness component, reflecting the noradrenergic contribution to the syndrome. Management begins with dose reduction when feasible, and propranolol is the preferred pharmacological agent.
Option B: Option B is incorrect because anticholinergics such as benztropine are less consistently effective for akathisia than for dystonia or parkinsonism and are not first-line here.
Option C: Option C is incorrect because dantrolene is used to reduce rigidity and hyperthermia in neuroleptic malignant syndrome, not for akathisia.
Option D: Option D is incorrect because bromocriptine is used to restore dopaminergic tone in neuroleptic malignant syndrome, not to treat akathisia.
Option E: Option E is incorrect because valbenazine, a VMAT2 inhibitor, is a treatment for tardive dyskinesia, not akathisia.
13. Thioridazine, a low-potency phenothiazine, has been largely restricted to last-resort use because of one particularly dangerous adverse effect. It potently blocks a cardiac potassium channel (the hERG channel) that controls the heart's electrical recovery. What is the resulting danger that limits its use?
A) Irreversible kidney failure from direct toxicity to the renal tubules
B) Dose-dependent QTc prolongation that can progress to a dangerous ventricular arrhythmia (torsades de pointes)
C) Sudden severe liver necrosis within hours of the first dose
D) Permanent loss of hearing from damage to the inner ear
E) Aplastic anemia from suppression of all blood cell lines
ANSWER: B
Rationale:
Thioridazine is a potent blocker of the cardiac hERG potassium channel, which is responsible for repolarization (the heart's electrical recovery). Blocking it produces dose-dependent prolongation of the QTc interval that can progress to polymorphic ventricular tachycardia, including torsades de pointes, especially at higher doses. This cardiac risk is the reason regulators restricted thioridazine to patients who have failed other antipsychotics.
Option A: Option A is incorrect because the dose-limiting toxicity is cardiac, not renal tubular injury.
Option C: Option C is incorrect because chlorpromazine, not thioridazine, is the phenothiazine classically linked to cholestatic liver injury, and that is not the reason thioridazine is restricted.
Option D: Option D is incorrect because thioridazine's signature ocular toxicity is pigmentary retinopathy affecting vision, not hearing loss, and it is not the channel-blocking effect described.
Option E: Option E is incorrect because aplastic anemia is not the characteristic dose-limiting toxicity of thioridazine.
14. Cigarette smoking strongly increases the activity of a liver enzyme (CYP1A2) that breaks down chlorpromazine and several other antipsychotics. For a patient stabilized on a CYP1A2-metabolized antipsychotic while smoking, what is the expected effect of this interaction on their drug levels?
A) Smoking has no measurable effect on the levels of these antipsychotics
B) Smoking raises the drug level by blocking the enzyme that breaks the drug down
C) Smoking raises the drug level by slowing its elimination through the kidneys
D) Smoking lowers the drug level because increased enzyme activity breaks the drug down faster
E) Smoking converts the drug into a more potent active form, increasing its effect
ANSWER: D
Rationale:
Cigarette smoking induces (increases the amount and activity of) CYP1A2, the enzyme that metabolizes chlorpromazine and similar agents. More enzyme activity means the drug is broken down faster, so plasma levels fall — by roughly 30 to 50 percent in heavy smokers compared with non-smokers. This is clinically important in both directions: a patient who stops smoking, such as on admission to a smoke-free unit, can have rising levels and toxicity unless the dose is adjusted.
Option A: Option A is incorrect because the interaction is substantial, not negligible.
Option B: Option B is incorrect because smoking induces rather than blocks the enzyme, so levels fall rather than rise.
Option C: Option C is incorrect because the effect is through hepatic enzyme induction, not changes in renal elimination.
Option E: Option E is incorrect because smoking accelerates breakdown of the drug rather than converting it to a more potent form.
15. Two agents are specifically approved for the treatment of tardive dyskinesia. Both work by inhibiting the vesicular monoamine transporter 2 (VMAT2), the carrier that loads dopamine into storage vesicles for release, thereby reducing dopamine release at supersensitive receptors. Which option names this drug class and a correct example?
A) VMAT2 inhibitors, such as valbenazine and deutetrabenazine
B) Anticholinergics, such as benztropine and trihexyphenidyl
C) Beta-blockers, such as propranolol and metoprolol
D) Dopamine agonists, such as bromocriptine and amantadine
E) Benzodiazepines, such as lorazepam and diazepam
ANSWER: A
Rationale:
Valbenazine and deutetrabenazine are selective VMAT2 inhibitors and are the agents specifically approved for tardive dyskinesia. By inhibiting VMAT2, they reduce the loading of dopamine into presynaptic storage vesicles and thus lower dopamine release, decreasing the excessive stimulation at the supersensitive receptors that drive the involuntary movements.
Option B: Option B is incorrect because anticholinergics treat dystonia and parkinsonism and can actually worsen tardive dyskinesia.
Option C: Option C is incorrect because beta-blockers such as propranolol treat akathisia, not tardive dyskinesia.
Option D: Option D is incorrect because dopamine agonists such as bromocriptine are used in neuroleptic malignant syndrome and would tend to aggravate dyskinetic movements.
Option E: Option E is incorrect because benzodiazepines provide only nonspecific symptomatic relief and are not the approved VMAT2-inhibitor treatment described.
16. Long-acting injectable (depot) antipsychotics are given as an injection every few weeks rather than as a daily pill. What is the principal clinical problem these formulations are designed to address?
A) The high cost of brand-name oral tablets compared with generic injections
B) The tendency of oral antipsychotics to cause severe stomach ulcers
C) Non-adherence to daily oral medication, which is among the strongest predictors of relapse in schizophrenia
D) The inability of antipsychotics to cross the blood-brain barrier when taken by mouth
E) The need to deliver a much larger total dose than any oral form can provide
ANSWER: C
Rationale:
The central rationale for long-acting injectable antipsychotics is to address non-adherence to daily oral medication, which is one of the strongest predictors of relapse in schizophrenia; studies show 40 to 60 percent of outpatients are non-adherent within the first year. A depot injection replaces the daily-pill requirement with a fixed pharmacokinetic profile established at each injection, converting adherence from a daily behavior into a periodic clinical contact.
Option A: Option A is incorrect because cost is not the problem these formulations are designed to solve, and depot products are not chosen primarily to save money.
Option B: Option B is incorrect because oral antipsychotics are not characteristically ulcerogenic, so this is not the rationale.
Option D: Option D is incorrect because oral antipsychotics do cross the blood-brain barrier and reach the brain; absorption, not brain penetration, is the issue.
Option E: Option E is incorrect because the depot delivers a controlled maintenance exposure, not a larger total dose than oral therapy could achieve.
17. A clinician titrates haloperidol and chlorpromazine each to the same level of D2 receptor occupancy in two comparable patients with schizophrenia. Based on the relationship between potency and efficacy established earlier, what should the clinician expect?
A) Haloperidol will produce a substantially greater maximum antipsychotic effect because it is high-potency
B) Chlorpromazine will produce a substantially greater maximum antipsychotic effect because it is given at a higher dose
C) Neither drug will produce any antipsychotic effect unless combined with the other
D) Haloperidol will fail to treat the psychosis because small doses cannot be effective
E) The two will produce comparable antipsychotic effect, but their side-effect profiles will differ because of the different doses required
ANSWER: E
Rationale:
Potency and efficacy are distinct: when haloperidol and chlorpromazine are each titrated to the same D2 occupancy, they produce comparable antipsychotic effect. What differs is the side-effect profile, because chlorpromazine must be given at large doses that also block H1, M1, and alpha-1 receptors, whereas haloperidol reaches the same occupancy at small doses with little off-target blockade.
Option A: Option A is incorrect because high potency means a smaller effective dose, not a greater maximum effect.
Option B: Option B is incorrect because the larger dose of chlorpromazine reflects its lower potency, not greater efficacy.
Option C: Option C is incorrect because each drug is independently effective and combining them is unnecessary and inappropriate.
Option D: Option D is incorrect because a small dose of a high-potency agent is fully effective once it reaches therapeutic occupancy.
18. A 19-year-old man with no prior antipsychotic exposure receives his first dose of intramuscular haloperidol in the emergency department. About three hours later his eyes deviate forcibly upward and his neck twists to one side. Based on the syndrome this represents and its established treatment, what is the most appropriate next step?
A) Increase the haloperidol dose to overcome the abnormal movements
B) Recognize acute dystonia and give intramuscular benztropine or diphenhydramine for rapid relief
C) Recognize tardive dyskinesia and start valbenazine
D) Recognize akathisia and start oral propranolol
E) Begin dantrolene and external cooling for neuroleptic malignant syndrome
ANSWER: B
Rationale:
A young, antipsychotic-naive man developing forced upward eye deviation (oculogyric crisis) and neck twisting (torticollis) within hours of a first high-potency dose has acute dystonia, the earliest extrapyramidal syndrome and one most common in exactly this demographic. The established treatment is an injectable anticholinergic or antihistamine such as benztropine or diphenhydramine, which relieves the spasm within 15 to 30 minutes.
Option A: Option A is incorrect because increasing the dose deepens the dopamine blockade and worsens the dystonia.
Option C: Option C is incorrect because tardive dyskinesia develops after months to years, not within hours, so valbenazine does not apply.
Option D: Option D is incorrect because akathisia is restlessness with an urge to move, not sustained dystonic spasm, so propranolol is not the indicated treatment here.
Option E: Option E is incorrect because there is no fever, rigidity, or autonomic instability to indicate neuroleptic malignant syndrome.
19. A patient started on haloperidol several days earlier cannot sit still, paces constantly, and describes an unbearable inner urge to move. A covering clinician interprets this as worsening agitation and raises the haloperidol dose, after which the restlessness becomes worse. What does this sequence most likely represent?
A) Worsening psychosis that correctly warranted the dose increase
B) Acute dystonia that should be treated with the dose increase
C) Tardive dyskinesia unmasked by the dose increase
D) Akathisia, which can be mistaken for agitation and is worsened when the antipsychotic dose is raised
E) Neuroleptic malignant syndrome developing from the higher dose
ANSWER: D
Rationale:
Motor restlessness with a compelling inner urge to move, appearing within days of starting an antipsychotic, is akathisia. It is commonly mistaken for psychomotor agitation or worsening psychosis, which leads to the clinical error of increasing the antipsychotic dose; because akathisia is itself driven by the dopamine blockade, raising the dose worsens it — exactly the pattern described.
Option A: Option A is incorrect because the worsening with a higher dose points away from simple worsening psychosis and toward a dose-related adverse effect.
Option B: Option B is incorrect because acute dystonia is sustained muscle spasm, not restless pacing, and would not be helped by a dose increase.
Option C: Option C is incorrect because tardive dyskinesia appears after months to years and consists of involuntary orofacial movements, not an urge to move.
Option E: Option E is incorrect because there is no fever, rigidity, or autonomic instability to suggest neuroleptic malignant syndrome.
20. A patient maintained on a first-generation antipsychotic for several years develops lip-smacking and tongue movements that become more noticeable when the dose is lowered. Applying the concepts established earlier in this set, how should this be interpreted and approached?
A) This is tardive dyskinesia; the movements were partly masked by ongoing blockade and became visible on dose reduction, and a VMAT2 inhibitor such as valbenazine is an approved treatment
B) This is acute dystonia caused by the dose reduction and should be treated by returning to the higher dose permanently
C) This is akathisia and should be treated with propranolol
D) This is neuroleptic malignant syndrome and requires dantrolene
E) This is simple drug withdrawal that will resolve within a few hours and needs no specific evaluation
ANSWER: A
Rationale:
Involuntary orofacial movements appearing after years of antipsychotic exposure are tardive dyskinesia. Lowering the dose can make the movements more apparent because ongoing blockade had been partly concealing dyskinesia at supersensitive receptors — the withdrawal-emergent or unmasking pattern — so the dyskinesia was present but suppressed rather than newly caused. A VMAT2 inhibitor such as valbenazine is an approved treatment, consistent with the mechanism established earlier in this set.
Option B: Option B is incorrect because acute dystonia is sudden sustained spasm seen early in treatment, not late orofacial movements, and permanently raising the dose to mask tardive dyskinesia is the wrong strategy.
Option C: Option C is incorrect because akathisia is restlessness with an urge to move, not orofacial dyskinesia.
Option D: Option D is incorrect because there is no fever, rigidity, or autonomic instability to suggest neuroleptic malignant syndrome.
Option E: Option E is incorrect because tardive dyskinesia is often persistent and warrants assessment, not a self-limited withdrawal effect.
21. A patient stabilized on thioridazine needs an antibiotic that is itself known to prolong the QTc interval. Drawing on the cardiac property of thioridazine established earlier, what is the most appropriate concern and the safest general approach?
A) There is no interaction to consider because thioridazine affects only the brain, not the heart
B) The combination lowers the QTc and reduces arrhythmia risk, so no monitoring is needed
C) The two QTc-prolonging effects are additive and raise the risk of torsades de pointes, so switching to a different antipsychotic for the course of the QTc-prolonging drug is the safest approach
D) Smoking should be encouraged during the antibiotic course to raise thioridazine levels and offset the antibiotic
E) The antibiotic will inactivate thioridazine, so the antipsychotic dose should be doubled
ANSWER: C
Rationale:
Thioridazine prolongs the QTc by blocking the cardiac hERG potassium channel, and its effect is additive with other QTc-prolonging drugs such as certain antibiotics, increasing the risk of torsades de pointes. The safest general approach in most cases is to switch to a different antipsychotic for the duration of the QTc-prolonging co-medication rather than attempting combination management.
Option A: Option A is incorrect because thioridazine has a well-established cardiac effect, so there is a real interaction.
Option B: Option B is incorrect because the effects add together and raise, rather than lower, arrhythmia risk.
Option D: Option D is incorrect because encouraging smoking to manipulate drug levels is inappropriate and does not address the additive cardiac risk; smoking affects CYP1A2-metabolized agents and is not a strategy here.
Option E: Option E is incorrect because the antibiotic does not inactivate thioridazine, and doubling the antipsychotic would worsen the cardiac risk.
22. Several days after a haloperidol dose increase, a patient develops a high fever, stiff "lead-pipe" muscle rigidity, fluctuating blood pressure and heart rate, and a clouded level of consciousness; the creatine kinase (a muscle enzyme released by muscle injury) is markedly elevated, above 10,000 units per liter. A reflex examination shows reduced rather than brisk reflexes. Applying the syndrome defined earlier, which interpretation is correct?
A) This is akathisia, and the haloperidol dose should simply be raised further
B) This is acute dystonia, treatable with a single dose of intramuscular diphenhydramine
C) This is tardive dyskinesia unmasked by the dose increase
D) This is uncomplicated drug-induced parkinsonism requiring only an anticholinergic
E) This is neuroleptic malignant syndrome; the lead-pipe rigidity, slow onset, and reduced reflexes distinguish it from serotonin syndrome, which instead shows brisk reflexes and clonus
ANSWER: E
Rationale:
The combination of high fever, lead-pipe rigidity, autonomic instability, altered consciousness, and a markedly elevated creatine kinase after a dose increase is the defined tetrad of neuroleptic malignant syndrome. The reduced reflexes, the lead-pipe character of the rigidity, and the relatively slow onset distinguish it from serotonin syndrome, which instead features hyperreflexia (brisk reflexes) and clonus with a more rapid onset.
Option A: Option A is incorrect because this is not akathisia, and raising the dose would be dangerous in a patient with this presentation.
Option B: Option B is incorrect because acute dystonia is an isolated sustained spasm without fever, autonomic instability, or markedly elevated creatine kinase.
Option C: Option C is incorrect because tardive dyskinesia consists of involuntary orofacial movements without fever or rigidity.
Option D: Option D is incorrect because drug-induced parkinsonism produces rigidity and bradykinesia but not the high fever, autonomic instability, and very high creatine kinase that define this emergency.
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