What are the differences in efficacy and side effect risks between first generation (FGA) and second generation antipsychotics (SGA)?

Comparison of First-Generation and Second-Generation Antipsychotics: Efficacy and Side Effects

Second-generation antipsychotics (SGAs) offer modest efficacy advantages over first-generation antipsychotics (FGAs) for overall symptom control with significantly lower risk of extrapyramidal side effects, though they generally cause more metabolic complications. This difference in side effect profile rather than superior efficacy is the primary clinical distinction between these medication classes.

Efficacy Comparison

Overall Efficacy

• Only four SGAs demonstrate superior overall efficacy compared to FGAs: clozapine (strongest effect size -0.52), amisulpride (-0.31), olanzapine (-0.28), and risperidone (-0.13) 1
• Most other SGAs show similar efficacy to FGAs for positive symptoms
• The notion that SGAs as a class are superior for negative symptoms is not supported by evidence; only amisulpride and cariprazine show meaningful advantages for negative symptoms 2

Treatment-Resistant Schizophrenia

• Clozapine remains the gold standard for treatment-resistant schizophrenia
• Treatment resistance is defined as failure of at least two adequate antipsychotic trials (6+ weeks at therapeutic doses) 3
• Long-acting injectable (LAI) formulations should be considered in cases of suspected non-adherence before labeling a case as treatment-resistant 3

Side Effect Comparison

Extrapyramidal Side Effects (EPS)

• FGAs: High risk of EPS including:
  • Acute dystonia (muscle contractions, often early in treatment)
  • Akathisia (restlessness)
  • Parkinsonism (rigidity, tremor)
  • Tardive dyskinesia (long-term risk)
• SGAs: Significantly lower risk of EPS, particularly at therapeutic doses 1, 4
• High-potency FGAs (e.g., haloperidol) have higher EPS risk than low-potency FGAs
• Even at low doses, haloperidol causes more EPS than most SGAs 1

Metabolic Side Effects

• Weight gain:

  • Most SGAs (except aripiprazole and ziprasidone) cause more weight gain than haloperidol
  • Clozapine and olanzapine have the highest risk of weight gain 1, 5
  • FGAs with low potency have similar weight gain risk to many SGAs

• Metabolic syndrome:

  • SGAs have varying risks of metabolic complications (diabetes, dyslipidemia)
  • Clozapine and olanzapine pose the highest metabolic risks
  • Aripiprazole and ziprasidone have the lowest metabolic risks among SGAs 5

Cardiovascular Effects

• QT prolongation:
  • Sertindole and amisulpride have higher risk of QT prolongation 2
  • Some FGAs (particularly thioridazine) also carry significant QT prolongation risk

Endocrine Effects

• Prolactin elevation:
  • FGAs typically cause significant prolactin elevation
  • Among SGAs, risperidone, paliperidone, and amisulpride cause the highest prolactin elevation 2
  • Consequences include sexual dysfunction, amenorrhea, galactorrhea, and bone mineral density loss

Sedation

• Both classes can cause sedation but with different patterns:
  • Low-potency FGAs (e.g., chlorpromazine) are highly sedating
  • Among SGAs, clozapine, olanzapine, and quetiapine are more sedating
  • Aripiprazole and ziprasidone are less sedating 1, 6

Clinical Decision Algorithm

1. For first-episode psychosis:

   • Start with an SGA due to lower EPS risk
   • Consider metabolic risk factors in medication selection
   • Monitor closely for both efficacy and side effects

2. For patients with high metabolic risk:

   • Consider aripiprazole, ziprasidone, or high-potency FGA with careful EPS monitoring
   • Avoid clozapine and olanzapine as first-line options

3. For treatment-resistant cases:

   • Clozapine is the treatment of choice after failure of at least two adequate antipsychotic trials
   • Consider LAI formulation to rule out non-adherence before labeling as treatment-resistant 3

4. For patients with high EPS risk:

   • Avoid high-potency FGAs
   • Consider SGAs with lowest EPS risk
   • Monitor closely if FGAs must be used

Common Pitfalls and Caveats

1. Assuming all SGAs are equally effective: There is significant heterogeneity within the SGA class for both efficacy and side effects 1, 2

2. Overlooking metabolic monitoring: Regular monitoring of weight, glucose, and lipids is essential with SGAs, particularly clozapine and olanzapine

3. Inadequate trial duration: Antipsychotic trials should last at least 6 weeks at therapeutic doses before determining efficacy 3

4. Ignoring non-adherence: Consider LAI formulations when adherence is a concern before switching medications 3

5. Focusing only on positive symptoms: Assessment should include positive, negative, cognitive symptoms, and quality of life measures

In conclusion, the choice between FGAs and SGAs should be guided primarily by side effect profiles and individual patient risk factors rather than by substantial efficacy differences. The heterogeneity within both classes means that medication selection should be tailored to the patient's specific symptom profile and medical comorbidities.