First- and Second-Generation Antipsychotics

• How are first- and second-generation antipsychotics alike and different? What is the mechanism of action for each?
• What are extrapyramidal symptoms, and why do they happen? How do you treat them?
• What are the key considerations in monitoring patients on these medications?

Antipsychotic medications are integral to managing various psychiatric disorders, including schizophrenia and bipolar disorder. These drugs are categorized into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), which differ in their mechanisms of action, efficacy, and side effect profiles. Understanding these differences, the reasons for extrapyramidal symptoms (EPS), and key monitoring considerations is crucial for optimizing treatment outcomes.

Alike and Different: First- and Second-Generation Antipsychotics

Similarities
Both FGAs and SGAs are primarily used to manage symptoms of psychosis, such as hallucinations and delusions. They work by modulating dopamine activity in the brain, which is central to the pathophysiology of schizophrenia and other psychotic disorders. Both classes are effective in reducing positive symptoms of schizophrenia, such as hallucinations and delusions.

Differences
FGAs, also known as typical antipsychotics, primarily act as dopamine D2 receptor antagonists. Examples include haloperidol and chlorpromazine. By blocking dopamine in the mesolimbic pathway, FGAs effectively reduce positive symptoms but often fail to alleviate negative symptoms, such as social withdrawal and lack of motivation. Their strong dopamine blockade is associated with a higher risk of EPS and tardive dyskinesia (TD).

SGAs, or atypical antipsychotics, include medications like risperidone, olanzapine, and clozapine. They act on both dopamine and serotonin (5-HT2A) receptors, providing a broader mechanism of action. This dual receptor antagonism not only reduces positive symptoms but also shows some efficacy in improving negative and cognitive symptoms. SGAs generally have a lower risk of EPS but are more likely to cause metabolic side effects, such as weight gain, hyperlipidemia, and diabetes mellitus.

Mechanisms of Action

First-Generation Antipsychotics (FGAs)
FGAs primarily block dopamine D2 receptors in the brain. By reducing dopamine activity in the mesolimbic pathway, they effectively control positive psychotic symptoms. However, the blockade of dopamine in other pathways, such as the nigrostriatal and tuberoinfundibular pathways, contributes to adverse effects like EPS and hyperprolactinemia.

Second-Generation Antipsychotics (SGAs)
SGAs also antagonize dopamine D2 receptors but to a lesser extent than FGAs. Their additional action on serotonin 5-HT2A receptors enhances dopamine release in certain brain areas, which helps mitigate negative symptoms and reduces the risk of EPS. This broader receptor activity makes SGAs more versatile but increases the risk of metabolic complications.

Extrapyramidal Symptoms (EPS): Causes and Management

Causes
EPS are a group of movement disorders caused by the antagonism of dopamine D2 receptors in the nigrostriatal pathway. FGAs are more likely to cause EPS due to their strong dopamine blockade. These symptoms include:

• Parkinsonism: Tremors, rigidity, and bradykinesia.
• Akathisia: Inner restlessness and an urge to move.
• Acute dystonia: Involuntary muscle contractions causing abnormal postures.
• Tardive dyskinesia (TD): Late-onset, repetitive, involuntary movements, often irreversible.

Management

• For acute symptoms: Anticholinergic agents like benztropine or diphenhydramine are effective in treating dystonia and parkinsonism. Beta-blockers or benzodiazepines may be used for akathisia.
• For tardive dyskinesia: Medications like valbenazine and deutetrabenazine, both vesicular monoamine transporter 2 (VMAT2) inhibitors, are approved treatments. Early detection and reducing or discontinuing the offending antipsychotic are crucial.
• Preventive strategies: Using SGAs instead of FGAs and employing the lowest effective dose of antipsychotics can reduce the risk of EPS.

Key Considerations in Monitoring Patients on Antipsychotics

Monitoring patients on antipsychotic medications is essential for ensuring efficacy and minimizing adverse effects. Key considerations include:

1. Symptom Response
   • Regularly assess for reduction in psychotic symptoms.
   • Evaluate improvement in functional status and quality of life.
2. Adverse Effects
   • EPS and TD: Use tools like the Abnormal Involuntary Movement Scale (AIMS) to detect early signs.
   • Metabolic Side Effects: Monitor weight, body mass index (BMI), fasting glucose, lipid profile, and blood pressure, particularly for SGAs.
   • Prolactin Levels: Check for signs of hyperprolactinemia, such as galactorrhea and amenorrhea.
3. Routine Laboratory and Clinical Assessments
   • Conduct baseline and periodic monitoring of liver and kidney function, as antipsychotics may affect these organs.
   • Monitor complete blood counts, especially for clozapine, which carries a risk of agranulocytosis.
4. Patient Education
   • Educate patients about the importance of adherence, recognizing early signs of side effects, and lifestyle modifications to mitigate metabolic risks.
5. Individualized Care
   • Tailor medication choice and dosage to the patient’s specific needs, considering their medical history, co-existing conditions, and risk factors for adverse effects.

Conclusion

FGAs and SGAs are cornerstone treatments in managing psychosis, with distinct differences in mechanisms of action and side effect profiles. While FGAs are effective for positive symptoms, SGAs offer broader benefits with a lower risk of EPS but higher metabolic risks. EPS, resulting from dopamine blockade, can significantly impact quality of life but are manageable with proper treatment and prevention strategies. Comprehensive monitoring and individualized care are paramount to ensuring safe and effective use of antipsychotic medications.