The side effect profile of antipsychotic medications, an unsuitable option for those at risk for frank psychosis

Understanding Antipsychotic Medications: Uses, Side Effects and Management

Introduction

Antipsychotic medications are the first-line, evidence-based treatment for schizophrenia and other primary psychotic disorders. These medications are also approved for use in conditions such as bipolar disorder, treatment-resistant depression, autism, and Tourette's disorder. Additionally, antipsychotics are often prescribed off-label for a range of other conditions, including borderline personality disorder, obsessive-compulsive disorder, anorexia nervosa, insomnia, delirium, and various forms of dementia, including Alzheimer's disease. While these medications can be effective in managing symptoms, their utility is often hampered by a range of adverse effects, necessitating a careful balance between benefits and risks.

?Types of Antipsychotic Medications

Antipsychotic medications are broadly classified into two main categories: first-generation (typical) antipsychotics (FGAs) and second-generation (atypical) antipsychotics (SGAs). Each class has distinct mechanisms of action and side effect profiles.

First-Generation Antipsychotics or Typical Antipsychotics: FGAs primarily function as dopamine receptor antagonists (DRAs). They are effective in treating the positive symptoms of schizophrenia, such as hallucinations and delusions. However, they are associated with several adverse effects, including:

-????? Extrapyramidal Symptoms (EPS): These include tremors, rigidity, bradykinesia and tardive dyskinesia—a potentially irreversible condition characterised by repetitive, involuntary movements.

-????? Sedation: Due to their histamine receptor blocking action, FGAs like chlorpromazine can cause significant sedation, impairing daily functioning and cognitive abilities.

-????? Anticholinergic Side Effects: These include dry mouth, constipation, urinary retention, and blurred vision, particularly with low-potency FGAs.

-????? Cardiovascular Risks: FGAs can lead to orthostatic hypotension, QTc prolongation, and, in severe cases, ventricular arrhythmias and sudden cardiac death.

-????? Neuroleptic Malignant Syndrome (NMS): A rare but life-threatening reaction characterised by muscle rigidity, fever, and autonomic instability.

Second-Generation Antipsychotics or Atypical Antipsychotics: SGAs target both dopamine and serotonin receptors, broadening their therapeutic effects to include both positive and negative symptoms of schizophrenia. However, they also present their own set of side effects:

-????? Metabolic Syndrome: SGAs are associated with significant weight gain, dyslipidemia, and increased risk of diabetes. Medications like olanzapine and clozapine are particularly known for causing these metabolic disturbances.

-????? Sedation and Cognitive Impairment: Similar to FGAs, SGAs such as quetiapine can cause sedation, which may impair cognitive function and reduce quality of life.

-????? Extrapyramidal Symptoms: Although less common than with FGAs, SGAs like risperidone can still cause EPS, especially at higher doses.

-????? Cardiovascular Risks: Some SGAs, such as ziprasidone, are known to prolong the QTc interval, increasing the risk of cardiac arrhythmias.

-????? Hematologic Effects: Clozapine, in particular, requires regular monitoring due to the risk of agranulocytosis (a severe drop in white blood cells).

Why Antipsychotics May Be Unsuitable for At-Risk Individuals

Clinical high risk for psychosis (CHR-P) refers to a stage in which an individual displays symptoms suggestive of heightened risk for developing a psychotic disorder such as schizophrenia, is well-recognised worldwide and diagnosed reliably using established diagnostic criteria and instruments. For individuals at risk of developing psychosis but who have not yet experienced a full-blown psychotic episode, the side effects of antipsychotic medications might outweigh their potential benefits. Administering antipsychotics to these individuals may expose them to severe side effects like EPS, metabolic syndrome or sedation, which could significantly impact their quality of life without necessarily providing substantial benefit. Furthermore, antipsychotics can cause sedation and cognitive impairment, potentially worsening an individual's ability to function daily and maintain social relationships. Long-term use may also lead to tolerance or dependency, with discontinuation potentially resulting in withdrawal symptoms or rebound psychosis. Despite guidelines advising against the prescription of antipsychotics, these medications are frequently administered, with exposure rates ranging from 25% to 75%. Multiple meta-analyses have revealed that CHR-P individuals on antipsychotics have a higher risk of transitioning to frank psychosis compared to those not on these medications, suggesting a negative prognostic impact.

Alternative Approaches for At-Risk Populations

Considering the significant side effects associated with antipsychotics, alternative treatment approaches should be considered for individuals at risk of psychosis:

-????? Psychotherapy: Cognitive-behavioural therapy and other forms of psychotherapy can help manage prodromal symptoms and reduce the risk of developing full-blown psychosis without the side effects associated with medications.

-????? Lifestyle Modifications: Encouraging healthy lifestyle changes, such as regular exercise, a balanced diet, and stress management, can help reduce the risk of psychosis and improve overall well-being.

-????? Monitoring and Early Intervention: Close monitoring for signs of psychosis and early intervention with lower doses of antipsychotics or alternative medications may reduce the risk of severe side effects.

-????? Use of Medications with a Favourable Side Effect Profile: If medication is necessary, selecting antipsychotics with a lower risk of side effects (e.g., aripiprazole) may be a better option.

Managing Adverse Effects of Antipsychotics

When adverse effects occur, several strategies can be employed to manage them effectively:

-????? Lower the Dose: Reducing the dosage of an antipsychotic can be an effective strategy if the medication has provided benefits but also caused dose-related side effects. This approach is widely recommended and can help reduce effects such as parkinsonism, sedation, and orthostatic hypotension.

-????? Switch to an Antipsychotic with a Different Adverse Effect Profile: Switching to a medication that is not likely to cause the problematic effect is a common strategy that has been proven effective for at least some adverse effects. Switching should ideally be done gradually to avoid symptom exacerbation and other rebound phenomena.

-????? Use Non-Pharmacologic Interventions: Non-pharmacologic interventions to reduce adverse effects are appealing but generally unavailable. Diet and exercise programs are modestly effective in addressing weight gain and related lipid abnormalities.

-????? Treat with a Concomitant Medication: Using medications to manage antipsychotic side effects is common but often suboptimal because they may have adverse effects and drug interactions may occur. For example, anticholinergic medications used to treat parkinsonism are associated with cognitive impairment and constipation.

Specific Adverse Effects and Their Management

-????? Neurologic Side Effects: Extrapyramidal symptoms such as dystonia, akathisia, and parkinsonism are prominent with antipsychotic medications. Management strategies include dose reduction, switching medications, and using anticholinergic or other drugs to manage symptoms.

-????? Tardive Dyskinesia: A potentially irreversible condition that can occur with long-term use of antipsychotics. Management includes dose reduction, switching medications, or using medications such as valbenazine.

-????? Metabolic Effects: Antipsychotic medications are commonly associated with weight gain, hypertension, and adverse effects on lipid and glucose metabolism. Management strategies include lifestyle modifications, switching medications, and treating metabolic symptoms.

-????? Other Side Effects: Other side effects, such as sedation, sialorrhea, and prolactin elevation, are managed with dose adjustments, switching medications, and, in some cases, adjunctive treatments.

Conclusion

Antipsychotic medications are vital tools in the management of schizophrenia and other psychiatric disorders. However, their use must be carefully balanced against the risk of adverse effects, particularly for individuals who are at risk of psychosis but have not yet developed full-blown symptoms. A personalised approach to prescribing, informed by each patient's specific needs and circumstances, is essential to maximising the benefits of these medications while minimising potential harm. Regular monitoring and a willingness to adjust treatment plans are crucial for optimising patient outcomes and enhancing quality of life. As our understanding of these medications continues to evolve, it is imperative to remain vigilant in applying the best evidence-based practices to ensure the safest and most effective use of antipsychotics.

Disclaimer

This article provides general information and discussions about health and related subjects, as well as discussions on the scientific/pharmaceutical landscape in selected areas of interest to us. The information and other content provided here or in any linked materials are not intended and should not be considered or used as a substitute for medical advice, diagnosis or treatment. If you or any other person has a medical concern, you should consult with your healthcare provider or seek other professional medical treatment immediately. Never disregard professional medical advice or delay in seeking it because of something that you have read here or in any linked materials.