What is pimozide?
Pimozide is a potent, conventional antipsychotic medication belonging to the diphenylbutylpiperidine class, first discovered in the 1960s. While it was initially investigated for its use in schizophrenia, its primary approved use in the United States today is for managing severe motor and phonic tics associated with Tourette's Disorder. This medication is not a first-line treatment and is reserved for patients whose symptoms are severe and debilitating, and who have not responded adequately to other, more standard therapies. Pimozide is available in tablet form and is known for its selective blocking of dopamine receptors. The brand name for pimozide, Orap, has been discontinued, but the generic version remains available.
How pimozide works: Mechanism of action
Pimozide's therapeutic effect is primarily a result of its potent antagonism of dopamine type 2 (D2) receptors in the brain. By blocking these receptors, pimozide decreases excessive dopamine neurotransmission, which is believed to play a role in the neurological dysfunction that causes tics. The drug's mechanism is highly selective for dopamine receptors compared to some other antipsychotics, which may contribute to a different side effect profile, though not necessarily fewer side effects.
It is worth noting that pimozide also has some affinity for other receptors, including certain serotonin and alpha-adrenergic receptors, which could contribute to its overall pharmacological effects. The blockage of dopamine receptors not only helps control tics but is also responsible for many of the associated adverse effects, particularly the movement-related ones.
Approved uses and indications
The main indication for pimozide is for the treatment of severe motor and phonic tics in patients with Tourette's Disorder. This prescription is generally for patients who have already tried and failed to respond to other treatments, such as haloperidol or other medications. The goal of treatment is not a complete cure but a reduction in the number and severity of tics that significantly interfere with daily life, learning, or work.
Other potential and investigational uses
While pimozide's approved indication is limited, some other uses have been explored, though they are often considered off-label or secondary to other therapies.
- Schizophrenia: In some regions and historically, pimozide has been used as a maintenance antipsychotic for chronic psychosis, though it has largely been replaced by newer drugs with fewer extrapyramidal side effects.
- Delusional Infestation: It has been used off-label to treat delusional infestation, a rare psychiatric condition where a person holds a persistent false belief of being infested with parasites or insects.
- Investigational Uses: Researchers have explored potential anti-cancer effects of pimozide in various types of cancer, including melanoma and glioblastoma, by targeting specific cellular pathways. These uses are currently investigational and not part of standard clinical practice.
Serious warnings and side effects
Pimozide carries several serious risks that necessitate careful patient selection and monitoring. These are often highlighted by black box warnings, which are the most stringent warnings from the FDA.
- Cardiac Effects: Pimozide can prolong the QT interval of the electrocardiogram, which can lead to a dangerous, and potentially fatal, form of irregular heartbeat called Torsades de Pointes. Regular ECG monitoring is required during treatment.
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Older patients with dementia who are treated with antipsychotic drugs like pimozide have an increased risk of death compared to those taking a placebo. Pimozide is not approved for the treatment of such conditions.
- Tardive Dyskinesia (TD): This syndrome of involuntary, dyskinetic movements can become permanent, especially with long-term or high-dose use. Symptoms include uncontrollable movements of the face, tongue, mouth, or jaw. There is no known treatment for established TD.
- Neuroleptic Malignant Syndrome (NMS): A rare but potentially fatal reaction characterized by high fever, muscle rigidity, altered mental status, and irregular heartbeat. Immediate medical attention is required if NMS is suspected.
Common adverse effects
In addition to the more severe risks, patients taking pimozide may experience a range of other side effects.
- Central Nervous System (CNS) Effects: Drowsiness, sedation, dizziness, restlessness (akathisia), insomnia, headache, and mood or behavior changes are frequently reported.
- Extrapyramidal Symptoms (EPS): These include slowed movement (akinesia), muscle stiffness, tremor, loss of balance, and a shuffling walk, similar to the symptoms of Parkinson's disease.
- Gastrointestinal Distress: Common issues include dry mouth, constipation, nausea, and vomiting.
- Endocrine and Other Effects: These can include decreased sexual ability in men, menstrual changes, and weight gain or loss.
Drug interactions
Pimozide is metabolized by the liver, primarily by the CYP2D6 and CYP3A4 enzyme systems. Interactions with other drugs that inhibit these enzymes can significantly increase pimozide levels in the body, increasing the risk of adverse effects like QT prolongation.
Interactions to be aware of include:
- CYP3A4 Inhibitors: Medications such as some macrolide antibiotics (e.g., clarithromycin, erythromycin) and HIV protease inhibitors (e.g., ritonavir) can dramatically increase pimozide levels. Grapefruit and grapefruit juice can also inhibit this enzyme and should be avoided.
- CYP2D6 Inhibitors: Strong inhibitors like paroxetine can increase pimozide exposure. Dosage adjustments are necessary for individuals who are poor metabolizers of CYP2D6 due to genetic variations.
- QT Prolonging Drugs: Combining pimozide with other medications known to prolong the QT interval, such as certain antiarrhythmics and other antipsychotics, should be avoided due to the additive risk.
- CNS Depressants: The sedative effects of pimozide can be potentiated by alcohol, sedatives, and pain medications.
Comparison with atypical antipsychotics
Pimozide, as a conventional or typical antipsychotic, differs from newer, atypical antipsychotics in several ways, primarily regarding receptor selectivity and side effect profiles.
| Feature | Pimozide (Typical Antipsychotic) | Atypical Antipsychotics |
|---|---|---|
| Dopamine Receptor Specificity | Highly potent and selective D2 receptor antagonist. | Bind to D2 receptors with less affinity and also block serotonin (5-HT2A) and other receptors. |
| Risk of Tardive Dyskinesia (TD) | Higher risk due to strong D2 blockade, especially with long-term use. | Generally lower risk of TD compared to typicals. |
| Risk of Extrapyramidal Symptoms (EPS) | Higher risk of EPS, such as muscle stiffness and tremors. | Lower risk of EPS at therapeutic doses. |
| Cardiac Risk (QT Prolongation) | Notable risk of QT prolongation and fatal cardiac arrhythmia, especially at higher doses. | Risk is present but varies among different drugs; generally considered to have less cardiac risk overall compared to pimozide. |
| Primary Use in Tourette's | Reserved for severe cases unresponsive to other treatments. | Some atypical antipsychotics, such as risperidone or aripiprazole, are more commonly used as initial treatment options for tics due to a more favorable side effect profile. |
Conclusion
Pimozide is a powerful, conventional antipsychotic with a specific and limited role in modern medicine: managing the most severe and treatment-resistant cases of Tourette's Disorder. Its efficacy stems from its potent blockade of dopamine D2 receptors, which helps control debilitating tics. However, this mechanism also gives rise to a significant risk profile, including serious cardiac complications and movement disorders like tardive dyskinesia. The existence of safer alternative treatments, especially for milder cases and other conditions, makes careful consideration of the risks and benefits crucial. Patients starting pimozide require close medical supervision, including regular cardiac monitoring, and should be fully informed of the potential for serious and permanent side effects.
