Which antipsychotics (Anti-Psychotic medications) exacerbate Parkinsonism the most?

From the Guidelines

Typical antipsychotics, particularly high-potency ones, worsen Parkinsonism the most due to their strong dopamine D2 receptor blockade in the nigrostriatal pathway. Among atypical antipsychotics, risperidone appears to be the most likely to produce extrapyramidal side effects, including parkinsonism, due to its relatively higher affinity for dopamine D2 receptors 1. The risk of exacerbating parkinsonism is dose-dependent, with higher doses causing more severe symptoms. Elderly patients are particularly vulnerable to these effects.

Key Points to Consider

• Typical antipsychotics have a higher risk of worsening parkinsonism compared to atypical antipsychotics.
• Among atypical antipsychotics, risperidone has a higher risk of causing extrapyramidal side effects, including parkinsonism, compared to other atypical antipsychotics like quetiapine or clozapine.
• The mechanism involves blocking dopamine receptors in the basal ganglia, further reducing dopaminergic transmission and worsening motor symptoms.
• When antipsychotics are necessary for patients with Parkinson's disease or parkinsonism, atypical antipsychotics with lower D2 affinity such as quetiapine or clozapine are preferred options.

Clinical Implications

• Clinicians should exercise caution when prescribing antipsychotics to patients with Parkinson's disease or parkinsonism.
• Atypical antipsychotics like quetiapine or clozapine may be preferred over typical antipsychotics or risperidone due to their lower risk of exacerbating parkinsonism.
• Close monitoring of motor symptoms is necessary when initiating or adjusting antipsychotic medications in patients with Parkinson's disease or parkinsonism.

From the FDA Drug Label

Table 12: Adverse reactions associated with EPS in a short-term, placebo-controlled multiple fixed-dose Phase III schizophrenia trial (6 weeks duration)

Preferred Term	Quetiapine 75 mg/day (N=53)	Quetiapine 150 mg/day (N=48)	Quetiapine 300 mg/day (N=52)	Quetiapine 600 mg/day (N=51)	Quetiapine 750 mg/day (N=54)	Placebo (N=51)
Dystonic event	2 3.8	2 4.2	0 0.0	2 3.9	3 5.6	4 7.8
Parkinsonism	2 3.8	0 0.0	1 1.9	1 2.0	1 1.9	4 7.8
Akathisia	1 1.9	1 2.1	0 0.0	0 0.0	1 1.9	4 7.8
Dyskinetic event	2 3.8	0 0.0	0 0.0	1 2.0	0 0.0	0 0.0
Other extraphyrmidal	2 3.8	0 0.0	3 5.8	3 5.9	1 1.9	4 7.8

Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75,150,300,600,750 mg/day) were: -0.6; -1.0, -1.2; -1.6; -1.8 and -1.8.

The antipsychotic quetiapine has a relatively low incidence of Parkinsonism compared to placebo.

• The incidence of Parkinsonism was 3.8% for quetiapine 75 mg/day and 1.9% for quetiapine 300 mg/day, 2.0% for quetiapine 600 mg/day, and 1.9% for quetiapine 750 mg/day.
• In contrast, the incidence of Parkinsonism was 7.8% for placebo. However, the question of which antipsychotics exacerbate Parkinsonism the most cannot be answered based on this information alone, as it only provides data on quetiapine and placebo, and not on other antipsychotics 2.

From the Research

Antipsychotics and Parkinsonism

The relationship between antipsychotic medications and Parkinsonism is complex, with some antipsychotics exacerbating Parkinsonism more than others.

• The study 3 found that risperidone is associated with the most extrapyramidal side effects (EPS), while clozapine and quetiapine have the fewest EPS.
• Another study 4 noted that typical antipsychotic agents, such as haloperidol, can induce extrapyramidal syndromes like tardive parkinsonism, whereas atypical antipsychotics like clozapine, quetiapine, and olanzapine have a lower risk of EPS.
• The research 5 showed that patients with Parkinson's disease are almost four times more likely to start taking antipsychotic drugs than controls, with haloperidol being the most frequently prescribed antipsychotic.

Comparison of Antipsychotics

A comparison of antipsychotics reveals that:

• Antipsychotic drugs that elicit little or no Parkinsonism, such as clozapine, melperone, and seroquel, bind more loosely to dopamine D2 receptors than those that cause Parkinsonism, like haloperidol and risperidone 6.
• A systematic review and Bayesian network meta-analysis 7 found that clozapine has an effective and relatively safe profile for treating psychosis in Parkinson's disease, while other atypical antipsychotics like olanzapine, quetiapine, and risperidone may worsen motor function compared to placebo.

EPS Liability

The EPS liability of antipsychotics differs among various medications, with:

• Risperidone having a higher EPS liability compared to other atypical antipsychotics 3.
• Clozapine and quetiapine having a lower EPS liability, making them suitable options for patients with Parkinson's disease 3, 4.