What is the difference between first generation (typical) and second generation (atypical) antipsychotics in terms of mechanism of action and side effect profile?

Differences Between First-Generation and Second-Generation Antipsychotics

The traditional classification of antipsychotics into first and second generations is clinically misleading and should not guide treatment selection—instead, choose medications based on their specific receptor profiles, side effect profiles, and patient-specific factors. 1, 2

Mechanism of Action

First-Generation Antipsychotics (Typical)

• First-generation antipsychotics function primarily as CNS dopamine D2 receptor antagonists, with their clinical effects determined mainly by the degree of D2 blockade 1
• These agents are subdivided by potency rather than mechanism:
  • High-potency agents (haloperidol, droperidol): Less sedating but significantly more likely to cause extrapyramidal symptoms 1
  • Low-potency agents (chlorpromazine, thioridazine): More sedating with fewer extrapyramidal symptoms but greater anticholinergic, antihistaminic, and alpha-adrenergic receptor activity 1, 2

Second-Generation Antipsychotics (Atypical)

• Second-generation antipsychotics act as serotonin-dopamine receptor antagonists with varying receptor affinities—the fundamental mechanism involves serotonin 5-HT2A receptor antagonism combined with dopamine D2 receptor antagonism or partial agonism 1, 3
• Each agent has a unique receptor binding profile that determines its clinical effects and side effect profile 3
• Examples include risperidone, olanzapine, quetiapine, clozapine, and aripiprazole (though aripiprazole is mechanistically distinct as a dopamine D2 partial agonist) 1, 3

Side Effect Profile Differences

Extrapyramidal Symptoms (EPS)

• First-generation antipsychotics, particularly high-potency agents, cause significantly more extrapyramidal symptoms than second-generation agents 1, 4
• Second-generation antipsychotics induce fewer extrapyramidal side-effects than haloperidol, even at low doses 4
• However, extrapyramidal syndrome does occur with second-generation agents, though at lower rates—risk varies by specific agent, with clozapine carrying the lowest risk and risperidone the highest 5
• Low-potency first-generation antipsychotics show comparable extrapyramidal side effects to second-generation agents 6

Metabolic Effects

• Second-generation antipsychotics generally cause more metabolic problems, especially clozapine and olanzapine 1
• Highest metabolic risk is associated with clozapine and olanzapine, while aripiprazole, ziprasidone, lurasidone, asenapine, and iloperidone have the lowest metabolic risk 3
• With the exception of aripiprazole and ziprasidone, second-generation antipsychotics induced more weight gain than haloperidol but not more than low-potency first-generation drugs 4
• All atypical antipsychotics have been associated with hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain 7, 8

Tardive Dyskinesia

• Both first- and second-generation antipsychotics carry risk for tardive dyskinesia—a syndrome of potentially irreversible, involuntary, dyskinetic movements 7, 8
• The risk increases with duration of treatment and cumulative dose for both classes 8

Cardiac Effects

• Both typical and atypical antipsychotics carry similarly increased risks of sudden cardiac death, with dose-dependent effects 2
• Second-generation antipsychotics as a class carry increased atrial fibrillation risk, with clozapine, olanzapine, and quetiapine showing highest risk 3
• Never combine multiple QT-prolonging antipsychotics due to fatal arrhythmia risk 3

Clinical Efficacy

• Four second-generation drugs demonstrated superior overall efficacy compared to first-generation antipsychotics: amisulpride, clozapine, olanzapine, and risperidone, with small to medium effect sizes 4
• The other second-generation drugs were not more efficacious than first-generation drugs, even for negative symptoms 4
• Efficacy on negative symptoms cannot be a core component of atypicality 4
• Aside from clozapine, first-generation and second-generation antipsychotics represent a diverse group with heterogeneous receptor profiles and side effects but comparable clinical efficacy 6

Clinical Approach to Selection

Start with aripiprazole as first-line monotherapy due to its superior metabolic profile 1, 3

Key Selection Principles:

• Base treatment decisions on individual drug pharmacodynamic profiles, specific side effect profiles, and patient-specific factors rather than generational labels 1, 2
• Avoid agents with high anticholinergic properties in elderly or cognitively impaired patients 3
• When switching antipsychotics, choose compounds with different pharmacodynamic profiles rather than relying on generational categories 2
• Reserve clozapine for treatment-resistant cases after failure of at least two other antipsychotics 3

Monitoring Requirements:

• Before initiating any antipsychotic, measure BMI, waist circumference, blood pressure, HbA1c, glucose, lipids, prolactin, liver function, urea, electrolytes, complete blood count, and EKG 1, 3
• Follow-up monitoring should include glucose at 4 weeks, BMI/waist/blood pressure weekly for 6 weeks, then all parameters at 3 months and annually 1, 3

Common Pitfalls

• Do not assume atypical antipsychotics are universally safer—both classes carry cardiac risks and require monitoring 2
• The distinction between first-generation and second-generation antipsychotics is not a distinct category from either a pharmacological or clinical perspective and should not guide psychotropic choice 2
• Second-generation antipsychotics are very heterogeneous with respect to their effectiveness and side effects—they should not be treated as a homogeneous class 9, 4
• In developing countries where second-generation agents are unavailable, first-generation antipsychotics should be used judiciously at very low doses 1