What are the different types of antipsychotics, including typical (United States Medical Licensing Examination (USMLE) Step 2) and atypical antipsychotics, that I need to know for the exam?

Antipsychotics for USMLE Step 2: Typical vs. Atypical Classifications

For USMLE Step 2 preparation, you need to understand that antipsychotics are divided into two main classes: typical (first-generation) and atypical (second-generation) antipsychotics, with distinct mechanisms, efficacy profiles, and side effect patterns.

Typical (First-Generation) Antipsychotics

• Typical antipsychotics primarily block dopamine D2 receptors and are characterized by their high risk of extrapyramidal side effects (EPS) and tardive dyskinesia 1
• These medications are effective for positive symptoms of schizophrenia but have limited efficacy for negative symptoms 2

Key Side Effects of Typical Antipsychotics:

• Extrapyramidal symptoms (EPS): acute dystonia, akathisia, parkinsonism 2
• Tardive dyskinesia: characterized by involuntary movements, particularly affecting the face and mouth 2
• Neuroleptic malignant syndrome: a potentially fatal complication with hyperthermia, muscle rigidity, autonomic instability 2
• Cognitive effects: sedation, cognitive blunting, memory deficits (especially with low-potency agents) 2
• Other effects: hyperprolactinemia, orthostatic hypotension, weight gain, sexual dysfunction, QT prolongation 2

Examples of Typical Antipsychotics:

• High-potency agents: haloperidol, droperidol (less sedating but more EPS) 2
• Low-potency agents: chlorpromazine, thioridazine (more sedating but fewer EPS) 2

Atypical (Second-Generation) Antipsychotics

• Atypical antipsychotics have a different receptor binding profile, with significant serotonin 5-HT2A antagonism in addition to dopamine D2 receptor blockade 1, 3
• They are generally better tolerated than typical antipsychotics with lower risk of EPS and tardive dyskinesia 2
• Atypical antipsychotics are considered first-line treatment for schizophrenia due to their improved side effect profile and efficacy for both positive and negative symptoms 2

Key Side Effects of Atypical Antipsychotics:

• Metabolic effects: weight gain, hyperglycemia, diabetes mellitus, dyslipidemia 4
• Cardiovascular effects: orthostatic hypotension, QT prolongation 2
• Sedation: varies among agents 2
• Lower risk of EPS and tardive dyskinesia compared to typical antipsychotics 1

Examples of Atypical Antipsychotics:

Clozapine:

• Most effective antipsychotic for treatment-resistant schizophrenia 1
• Requires special monitoring due to risk of agranulocytosis (1% of patients) 5
• Weekly blood monitoring required for first 6 months, then biweekly 2
• Other side effects: seizures (3%), sedation, weight gain, hypersalivation, orthostatic hypotension 2
• Only used after failure of at least two other antipsychotics due to side effect profile 2

Risperidone:

• Higher risk of EPS among atypicals, especially at higher doses 2
• Significant weight gain and metabolic effects 4
• Prolactin elevation more common than with other atypicals 4

Other Atypicals (Olanzapine, Quetiapine, Ziprasidone, Aripiprazole):

• Varying degrees of weight gain (olanzapine > quetiapine > risperidone > ziprasidone/aripiprazole) 2
• Different sedation profiles (quetiapine and olanzapine more sedating) 2
• Quetiapine: requires baseline and 6-month eye exams due to theoretical risk of cataracts 2
• Aripiprazole: partial dopamine agonist ("third-generation" antipsychotic) with lower metabolic risk 2

Mechanism of Action Differences

• Typical antipsychotics: primarily D2 receptor antagonists 3
• Atypical antipsychotics: 5-HT2A/D2 antagonism (except amisulpride which is selective D2/D3 antagonist) 6
• The "fast dissociation" theory suggests atypicals bind to D2 receptors with lower affinity and dissociate more rapidly 6
• Atypicals may enhance neurogenesis and increase BDNF levels, while typicals like haloperidol may reduce BDNF and potentially cause neuron apoptosis 7

Clinical Applications for USMLE Step 2

• For acute agitation in emergency settings: benzodiazepines (lorazepam, midazolam) or conventional antipsychotics (haloperidol, droperidol) are effective as monotherapy 2
• For patients with known psychiatric illness: atypical antipsychotics are preferred for both acute management and maintenance 2
• For cooperative but agitated patients: combination of oral benzodiazepine (lorazepam) and oral antipsychotic (risperidone) 2
• Monitoring requirements: baseline and regular assessment of metabolic parameters, EPS, and specific monitoring for certain medications (e.g., clozapine requires WBC monitoring) 4, 5

Common Pitfalls to Avoid

• Don't confuse the side effect profiles: typical antipsychotics primarily cause EPS and tardive dyskinesia, while atypicals primarily cause metabolic effects 1
• Remember clozapine's unique monitoring requirements for agranulocytosis (weekly blood counts for 6 months, then biweekly) 2
• Be aware that risperidone, despite being an atypical, has a higher risk of EPS than other atypicals 2
• Don't forget that atypical antipsychotics require monitoring for metabolic syndrome (weight, glucose, lipids) 4
• Remember that QT prolongation can occur with both typical and atypical antipsychotics 2