Understanding Drug-Induced Parkinsonism (DIP)
Drug-induced parkinsonism (DIP) is a reversible neurological syndrome that mimics the symptoms of idiopathic Parkinson's disease (PD) [1.2.2]. It is the most common form of secondary parkinsonism and is caused by exposure to medications that interfere with dopamine transmission in the brain [1.3.3, 1.4.2]. The core symptoms include bradykinesia (slowness of movement), rigidity, resting tremor, and problems with walking and balance [1.7.2]. Unlike PD, which is a progressive neurodegenerative disorder, DIP symptoms typically develop acutely or subacutely after starting or increasing the dose of an offending drug and often resolve within weeks to months after the medication is discontinued [1.6.4, 1.7.3]. However, in some cases, symptoms can persist for longer, and differentiating DIP from unmasked PD can be challenging [1.6.6, 1.7.1].
The Primary Culprits: Dopamine Receptor Antagonists
The fundamental cause of DIP is the blockade of dopamine receptors, particularly the D2 receptors, in the brain's nigrostriatal pathway [1.2.2, 1.4.1]. This pharmacologic state closely resembles the dopamine depletion seen in Parkinson's disease [1.2.2]. The medications most frequently implicated are those with potent D2 receptor-blocking properties [1.2.6].
First-Generation Antipsychotics (FGAs): The Most Common Cause
Typical antipsychotics, also known as first-generation antipsychotics (FGAs) or neuroleptics, are the most common and well-documented cause of DIP [1.2.3, 1.2.4]. These drugs were first developed in the 1950s and have a high affinity for blocking D2 receptors [1.2.2]. This potent blockade is effective for treating psychosis but carries a significant risk of causing extrapyramidal symptoms (EPS), including parkinsonism [1.8.2].
High-potency FGAs are particularly associated with a higher risk of DIP [1.2.2]. Examples of FGAs include:
- Haloperidol [1.2.2]
- Chlorpromazine [1.2.2]
- Fluphenazine [1.4.3]
- Perphenazine [1.2.6]
- Trifluoperazine [1.2.2]
Second-Generation Antipsychotics (SGAs): A Lower but Variable Risk
Second-generation antipsychotics (SGAs), or atypical antipsychotics, were developed to have a better side-effect profile than FGAs [1.8.1]. They generally have a lower affinity for D2 receptors and a higher ratio of serotonin 5-HT2a to dopamine D2 receptor blockade, which is thought to reduce the risk of EPS [1.2.2, 1.8.2]. However, the risk is not eliminated and varies significantly among different SGAs, especially at higher doses [1.8.4, 1.8.6].
- Higher Risk SGAs: Risperidone and paliperidone are associated with a moderate risk of DIP [1.2.2, 1.4.3].
- Lower Risk SGAs: Quetiapine and clozapine have the lowest risk of inducing parkinsonism and are often preferred for patients with pre-existing PD who require antipsychotic treatment [1.2.2, 1.8.1].
Other Significant Drug Groups Causing Parkinsonism
While antipsychotics are the primary cause, several other classes of drugs that block dopamine receptors or deplete dopamine can also induce parkinsonism [1.5.2].
Antiemetics and Gastrointestinal Prokinetics
Certain drugs used to treat nausea, vomiting, and gastric motility disorders are structurally similar to antipsychotics and act by blocking D2 receptors [1.2.6].
- Metoclopramide: A widely used prokinetic that is a well-known cause of drug-induced movement disorders, including parkinsonism [1.2.6, 1.5.1].
- Prochlorperazine: An antiemetic with the potential to cause DIP [1.2.6, 1.5.4].
- Levosulpiride: Used in some European and Asian countries, this drug frequently causes parkinsonism [1.5.1].
Other Implicated Medications
- Calcium Channel Blockers (CCBs): Certain CCBs, particularly flunarizine and cinnarizine (primarily available outside the US), can cause parkinsonism by blocking dopamine receptors [1.5.1, 1.5.3].
- Antidepressants: While less common, some antidepressants like SSRIs and amoxapine (which has dopamine-blocking properties) have been reported to cause or worsen parkinsonism [1.5.3, 1.5.4].
- Antiepileptic Drugs: Valproic acid is the anticonvulsant most associated with inducing parkinsonism, although the mechanism is not fully understood and may relate to mitochondrial dysfunction [1.5.1, 1.5.3].
- Lithium: Rarely, lithium can induce parkinsonism, though its mechanism is not thought to involve direct dopamine receptor blockade [1.5.1, 1.5.3].
Comparison of Causative Drug Classes
| Drug Class | Mechanism of Action | Risk Level | Example Drugs |
|---|---|---|---|
| First-Gen Antipsychotics | High-affinity D2 receptor blockade [1.2.2] | High | Haloperidol, Chlorpromazine, Fluphenazine |
| Second-Gen Antipsychotics | Variable D2 / 5-HT2a receptor blockade [1.2.2] | Low to High | Risperidone (higher), Quetiapine (lower) |
| Antiemetics / Prokinetics | D2 receptor blockade [1.2.6, 1.5.1] | Moderate | Metoclopramide, Prochlorperazine |
| Calcium Channel Blockers | D2 receptor blockade (some agents) [1.5.1] | Low-Mod | Flunarizine, Cinnarizine |
| Antiepileptics | Unclear; may involve mitochondrial dysfunction [1.5.1] | Low | Valproic Acid |
Diagnosis and Management
Diagnosing DIP involves a thorough review of the patient's medication history in the context of a new onset of parkinsonian symptoms [1.6.3, 1.7.3]. Clinical features that can sometimes help distinguish DIP from PD include more symmetric symptoms and the absence of non-motor symptoms like loss of smell, though the presentation can be indistinguishable [1.2.2, 1.7.2].
The cornerstone of management is prevention by using the lowest effective dose of a causative agent for the shortest duration possible [1.6.6]. If DIP develops, the primary treatment is to discontinue the offending medication under medical supervision [1.6.2, 1.6.3]. Symptoms usually improve or resolve completely within weeks to months after withdrawal [1.6.4]. If the medication cannot be stopped, options include reducing the dose or switching to an agent with a lower risk profile, such as quetiapine or clozapine [1.6.5].
Conclusion
The group of drugs most frequently implicated in causing drug-induced parkinsonism is, unequivocally, the antipsychotics, with first-generation agents like haloperidol posing the highest risk due to their potent D2 receptor antagonism [1.2.4]. While newer second-generation antipsychotics generally have a lower risk, this benefit is not absolute and varies between agents [1.8.4]. Other common medications, such as the antiemetic metoclopramide, also contribute significantly to the prevalence of DIP [1.5.1]. Awareness and recognition of these causative agents are critical for clinicians to prevent, diagnose, and manage this reversible condition, primarily by stopping or adjusting the offending medication.
Authoritative Link: For more information, you can visit the American Parkinson Disease Association.
