A 19-year-old woman, accompanied by her parents, presents after a one-week history of abnormal behavior, delusions, and unusual aggression. She denies fever, seizures or illicit drug use. Family history is negative for psychiatric illnesses. She was started on risperidone and sent home with her parents. Three days later, she is brought to the emergency department with fever and confusion. She is not verbally responsive. At the hospital, her temperature is 39.8°C (103.6°F), the blood pressure is 100/60 mm Hg, the pulse rate is 102/min, and the respiratory rate is 16/min. She is extremely diaphoretic and appears stiff. She has spontaneous eye-opening but she is not verbally responsive and she is not following commands. Laboratory studies show: Sodium 142 mmol/L Potassium 5.0 mmol/L Creatinine 1.8 mg/dl Calcium 10.4 mg/dl Creatine kinase 9800 U/L White blood cells 14,500/mm3 Hemoglobin 12.9 g/dl Platelets 175,000/mm3 Urinalysis shows protein 1+, hemoglobin 3+ with occasional leukocytes and no red blood casts. What is the best first step in the management of this condition?

Switch risperidone to clozapine

A 24-year-old man with a history of schizophrenia presents for follow-up. The patient says that he is still having paranoia and visual hallucinations on his latest atypical antipsychotic medication. Past medical history is significant for schizophrenia diagnosed 1 year ago that failed to be adequately controlled on 2 separate atypical antipsychotic medications. The patient is switched to a typical antipsychotic medication. Which of the following is the mechanism of action of the medication that was most likely prescribed for this patient?

Dopaminergic receptor antagonist

Serotonergic receptor antagonist

A 33-year-old woman comes to the emergency department for the evaluation of a headache and increased sweating for the last two hours. The patient also reports palpitations and nausea. Yesterday, she was started on venlafaxine for treatment-resistant depression. She took citalopram for four weeks, but stopped three days ago because her symptoms of depression did not improve. She does not smoke or drink alcohol. Her temperature is 39°C (102.2°F), pulse is 120/min, and blood pressure is 150/90 mm Hg. On mental status examination, the patient is only oriented to person, but not to place or time. Examination shows tremors in all extremities. She has impaired gait. Deep tendon reflexes are 3+ bilaterally. Which of the following is the most likely cause of this patient's symptoms?

Increased CNS serotonergic activity

A 26-year-old man is brought to the hospital by his wife who complains that her husband has been behaving oddly for the past few hours. The patient’s wife says that she has known him for only 4 months. The wife is unable to give any past medical history. The patient’s speech is difficult to follow, and he seems very distracted. After 15 minutes, he becomes agitated and starts to bang his head on a nearby pillar. He is admitted to the psychiatric ward and is given an emergency medication, after which he calms down. In the next 2 days, he continues to become agitated at times and required 2 more doses of the same drug. On the 4th day of admission, he appears very weak, confused, and does not respond to questions appropriately. His vital signs include: temperature 40.0°C (104.0°F), blood pressure 160/95 mm Hg, and pulse 114/min. On physical examination, he is profusely diaphoretic. He is unable to stand upright or even get up from his bed. Which of the following is the mechanism of action of the drug which most likely caused this patient’s current condition?

Agonistic effect on dopamine receptors

First-generation antipsychotics for USMLE Step 3: High-Yield Psychiatry Lessons

Mechanism of Action - Dopamine's Dominators

Primary action: Potent blockade of dopamine D₂ receptors across all major CNS pathways. This non-selective action leads to both therapeutic and adverse effects.

Dopaminergic pathways and associated symptoms

⭐ High-potency FGAs (e.g., Haloperidol) bind D₂ receptors more tightly, correlating with a higher risk of EPS. Low-potency agents (e.g., Chlorpromazine) have weaker D₂ blockade but more antihistaminic and anticholinergic effects.

Potency & Classification - The High and Low Show

High-Potency FGAs
- Strong D₂ receptor blockade → ↑ risk of Extrapyramidal Symptoms (EPS).
- Less sedating, anticholinergic, and hypotensive effects.
- Examples: Haloperidol, Fluphenazine, Trifluoperazine.
- 📌 Mnemonic: "Tri to Fluy High" (Trifluoperazine, Fluphenazine, Haloperidol).
Low-Potency FGAs
- Weaker D₂ blockade → ↓ risk of EPS.
- Significant antihistaminic (sedation), anticholinergic, and α₁-adrenergic blocking (orthostatic hypotension) effects.
- Examples: Chlorpromazine, Thioridazine.

⭐ Exam Favorite: Chlorpromazine is associated with corneal deposits, while Thioridazine carries a risk of irreversible retinal pigmentation at high doses.

Adverse Effects - The EPS Freak Show

Caused by Dopamine (D₂) receptor blockade in the nigrostriatal pathway. Effects are often dose and potency-dependent (High-potency > Low-potency).

📌 ADAPuT Mnemonic for EPS Timeline:

Extrapyramidal Symptoms from First-Generation Antipsychotics

⭐ Tardive Dyskinesia (TD) involves chronic, often irreversible, choreoathetoid movements (especially orofacial). Risk increases with prolonged use. Discontinue the FGA and switch to a second-generation agent like clozapine.

Other Major Adverse Effects:
- Neuroleptic Malignant Syndrome (NMS): ⚠️ Medical emergency! Fever, "lead pipe" rigidity, autonomic instability, ↑CK.
- Endocrine: Hyperprolactinemia → amenorrhea, galactorrhea, gynecomastia.
- Anticholinergic/Antihistaminic/α₁-blockade: More common with low-potency agents (e.g., Chlorpromazine). Includes dry mouth, sedation, and orthostatic hypotension.

Neuroleptic Malignant Syndrome - The FEVER Pitch

A life-threatening idiosyncratic reaction to antipsychotics, particularly high-potency first-generation drugs (e.g., Haloperidol).
Characterized by central dopamine (D2) receptor blockade.
📌 FEVER Mnemonic:
- Fever: High fever, often >40°C.
- Encephalopathy: Altered mental status, confusion, delirium.
- Vitals Unstable: Tachycardia, labile blood pressure.
- Elevated Enzymes: ↑ Creatine Kinase (CK), often >1000 U/L; myoglobinuria.
- Rigidity: Diffuse, severe "lead-pipe" muscle rigidity.
Management:
- Immediate cessation of the antipsychotic.
- Supportive care (hydration, cooling).
- Pharmacotherapy: Dantrolene, Bromocriptine.

⭐ NMS is distinguished from serotonin syndrome by the presence of severe muscular rigidity and hyporeflexia, whereas serotonin syndrome typically presents with hyperreflexia and myoclonus.

High‑Yield Points - ⚡ Biggest Takeaways

First-generation antipsychotics primarily block D2 dopamine receptors, most effective for positive symptoms.

High-potency agents (Haloperidol, Fluphenazine) carry a higher risk of extrapyramidal symptoms (EPS).

Low-potency agents (Chlorpromazine) have more anticholinergic, antihistaminic (sedation), and anti-alpha-1 (orthostatic hypotension) side effects.

Be vigilant for Neuroleptic Malignant Syndrome (NMS): characterized by fever, muscle rigidity, and autonomic dysfunction.

Chronic use can lead to tardive dyskinesia, an often irreversible movement disorder.

Dopamine blockade in the tuberoinfundibular pathway causes hyperprolactinemia.

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First-generation antipsychotics