What is the purpose and effect of antipsychotics?

Purpose and Effects of Antipsychotic Medications

Antipsychotic medications are the cornerstone of schizophrenia treatment, primarily working by antagonizing dopamine receptors to reduce positive symptoms such as hallucinations and delusions, though they may not markedly improve negative symptoms or cognitive defects. 1, 2

Primary Mechanisms and Effects

Antipsychotics work through several mechanisms:

• Dopamine antagonism: Most antipsychotics block dopamine D2 receptors, addressing the regional imbalance in dopamine function that contributes to schizophrenia symptoms 2
• Receptor profile: Many antipsychotics, especially atypical ones, also affect other neurotransmitter systems (serotonin, histamine, acetylcholine) 1
• Symptom domains affected:
  • Highly effective for positive symptoms (hallucinations, delusions, disorganized behavior)
  • Limited efficacy for negative symptoms (apathy, avolition, anhedonia)
  • Variable impact on cognitive symptoms 1, 2

Types of Antipsychotics

Antipsychotics are generally classified into two categories:

1. Typical (First-generation) Antipsychotics:

   • Primary action through strong D2 receptor blockade
   • Higher risk of extrapyramidal side effects
   • Examples: haloperidol, chlorpromazine

2. Atypical (Second-generation) Antipsychotics:

   • More complex mechanism involving multiple receptor systems
   • Lower risk of extrapyramidal side effects
   • May have advantages in treating negative symptoms and cognitive impairment in some patients
   • Examples: clozapine, olanzapine, risperidone, quetiapine, aripiprazole 3

Clinical Applications

Antipsychotics are used in several conditions:

• Schizophrenia: Primary indication, with approximately 70% of patients requiring long-term or lifetime medication 1
• Bipolar disorder: Effective for acute mania and maintenance treatment 4
• Dementia-related psychosis/agitation: Used with caution due to modest benefits and significant risks 1
• Treatment-resistant cases: Clozapine is specifically indicated after failure of two adequate trials of different non-clozapine antipsychotics 2

Side Effects and Monitoring

Antipsychotics are associated with significant side effects that require careful monitoring:

• Extrapyramidal symptoms: Acute dystonia, parkinsonism, akathisia 5
• Tardive dyskinesia: Potentially irreversible dyskinetic movements that may develop with prolonged use 6, 5
• Metabolic effects: Weight gain, diabetes, dyslipidemia (particularly with some atypical antipsychotics) 1
• Cardiovascular effects: Orthostatic hypotension, QT prolongation 5
• Other effects: Sedation, hyperprolactinemia, sexual dysfunction 1

Treatment Approach

The evidence supports a structured approach to antipsychotic use:

1. Start with monotherapy: Antipsychotic monotherapy is strongly recommended as first-line treatment 2
2. Adequate trial: Sufficient dosage for 4-6 weeks before considering changes 2
3. Clozapine for resistance: After failure of two adequate trials of different non-clozapine antipsychotics 2
4. Consider polypharmacy only after monotherapy failure: Antipsychotic polypharmacy may be considered when monotherapy with non-clozapine antipsychotics and clozapine have failed 1

Common Pitfalls in Antipsychotic Use

• Premature switching before adequate trial (4-6 weeks)
• Delaying clozapine in treatment-resistant cases
• Excessive polypharmacy before optimizing monotherapy
• Inadequate monitoring of metabolic and other side effects
• Neglecting psychosocial interventions 2

Long-term Considerations

Recent research raises concerns about long-term metabolic effects of antipsychotics on brain tissue. Some patients may experience reduced oxidative metabolic capacity with prolonged use, potentially resulting in tissue remodeling 7. This highlights the importance of using the lowest effective dose and regularly reassessing the need for continued treatment.

While antipsychotics remain essential in treating psychotic disorders, their use requires careful balancing of benefits against potential harms, with ongoing monitoring and adjustment to optimize outcomes.