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 44-year-old man presents to his psychiatrist for a follow-up appointment. He is currently being treated for schizophrenia. He states that he is doing well but has experienced some odd movement of his face recently. The patient's sister is with him and states that he has been more reclusive lately and holding what seems to be conversations despite nobody being in his room with him. She has not noticed improvement in his symptoms despite changes in his medications that the psychiatrist has made at the last 3 appointments. His temperature is 99.3°F (37.4°C), blood pressure is 157/88 mmHg, pulse is 90/min, respirations are 14/min, and oxygen saturation is 98% on room air. Physical exam is notable for rhythmic movements of the patient's mouth and tongue. Which of the following is a side effect of the next best step in management?

Worsening of psychotic symptoms

A 23-year old man is brought to the emergency department by his brother after trying to jump out of a moving car. He says that the Federal Bureau of Investigation has been following him for the last 7 months. He recently quit his job at a local consulting firm to work on his mission to rid the world from evil. He does not smoke, drink alcoholic beverages, or use illicit drugs. He takes no medications. His temperature is 36.7°C (98.1°F), pulse is 90/min, respirations are 20/min, and blood pressure is 120/86 mm Hg. On mental status examination, his response to the first question lasted 5 minutes without interruption. He switched topics a number of times and his speech was pressured. He spoke excessively about his plan to “bring absolute justice to the world”. He has a labile affect. There is no evidence of suicidal ideation. A toxicology screen is negative. He is admitted to the hospital for his symptoms and starts therapy. One week later, he develops difficulty walking and a tremor that improves with activity. Which of the following is the most likely cause of this patient's latest symptoms?

Selective serotonin reuptake inhibitor

Serotonin–norepinephrine reuptake inhibitor

A 28-year-old female patient with a history of schizophrenia, type 2 diabetes mellitus, and hypothyroidism comes to clinic stating she would like to be put back on a medication. She recently stopped taking her haloperidol as it made it hard for her to "sit still." She requests to be put on olanzapine as a friend from a support group said it was helpful. Why should this medication be avoided in this patient?

The patient has type 2 diabetes

The patient may develop galactorrhea

Tardive dyskinesia will likely result from the prolonged use of olanzapine

There is a high risk for retinopathy

The patient is at a high risk for torsades de pointes

Antipsychotic side effect management for USMLE Step 3: High-Yield Psychiatry Lessons

Extrapyramidal Symptoms - The Unwanted Moves

Timeline: 📌 ADAP-Tive response: Acute Dystonia → Akathisia → Parkinsonism → Tardive Dyskinesia.
Pathophysiology: Dopamine ($D_2$) blockade in the nigrostriatal pathway.

Acute Dystonia (hours-days): Sudden, sustained muscle contractions. Torticollis, oculogyric crisis.
Akathisia (days-weeks): Subjective restlessness; inability to stay still.
Parkinsonism (weeks-months): Bradykinesia, cogwheel rigidity, resting tremor.
Tardive Dyskinesia (months-years): Involuntary choreoathetoid movements, esp. orofacial.

⭐ Exam Favourite: While anticholinergics (e.g., benztropine) treat most EPS, they can worsen or unmask Tardive Dyskinesia. Always assess for TD before prescribing.

Tardive Dyskinesia - The Late Grimace

Pathophysiology: Prolonged D2 blockade leads to dopamine receptor upregulation and supersensitivity.
Clinical: Involuntary choreoathetoid movements, classically orofacial (lip-smacking, grimacing).
Onset: Late-onset, typically after >6 months of exposure.
Monitoring: Use the Abnormal Involuntary Movement Scale (AIMS) at baseline and regular intervals.

Symptoms of Tardive Dyskinesia

⭐ Key Fact: While stopping the drug is first-line, symptoms can be irreversible or may even worsen initially upon antipsychotic withdrawal.

Metabolic Syndrome - The Weighty Sidekicks

Associated with Second-Generation Antipsychotics (SGAs), causing significant weight gain, dyslipidemia, and hyperglycemia.

Highest Risk: Olanzapine, Clozapine (📌 Mnemonic: Old Clothes are weighty).
Lower Risk: Aripiprazole, Ziprasidone.
Monitoring Protocol:
- Baseline & regular checks of: BMI, fasting glucose, lipid panel, blood pressure.
- Weight check at every visit.
Management:
- Switch to a lower-risk agent.
- Prioritize lifestyle modifications (diet/exercise).
- Consider adding metformin to mitigate weight gain & insulin resistance.

⭐ The risk is not uniform across all SGAs; olanzapine and clozapine carry the highest risk for metabolic disturbances.

Metabolic Syndrome Components and Associated Conditions

Other Major Side Effects - The Rogue's Gallery

Neuroleptic Malignant Syndrome (NMS): Life-threatening reaction to dopamine antagonists.
- 📌 FEVER: Fever, Encephalopathy, Vitals unstable, Elevated enzymes (CK), Rigidity ("lead pipe").
- Management:

Metabolic Syndrome: Common with atypicals (esp. olanzapine, clozapine).
- Monitor: Weight, BMI, fasting glucose, lipids.
Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision.
Orthostatic Hypotension: Due to α1-blockade. Advise slow position changes.
Sedation: Due to histamine (H1) blockade.

⭐ NMS is an idiosyncratic reaction, not dose-dependent, and can occur any time during treatment. Mortality is 5-20%.

Acute dystonia (torticollis, oculogyric crisis) is an emergency managed with benztropine or diphenhydramine.

For akathisia (restlessness), beta-blockers (propranolol) are first-line, followed by benzodiazepines.

Treat drug-induced parkinsonism (bradykinesia, tremor) with anticholinergics like benztropine or amantadine.

For Tardive Dyskinesia (TD), the key is to switch to clozapine or use a VMAT2 inhibitor.

NMS is a medical emergency: stop the antipsychotic, provide supportive care, and administer dantrolene or bromocriptine.

Manage metabolic syndrome by monitoring lipids/glucose and switching to weight-neutral agents like aripiprazole.

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