What Are Dopamine Depleting Drugs?
Movement disorders are neurological conditions manifested either by slowness of movement, seen in Parkinson's disease or abnormal involuntary movements, the so-called hyperkinesias (hyper: too much, kinesis: movement). The hyperkinesias are characterized by excessive, involuntary, repetitive, twisting or random jerk-like movements which may involve the face, limbs, or the entire body.
The neurochemical alterations underlying involuntary movement disorders are not well understood, but excess dopamine or increased sensitivity of dopamine receptors have been postulated to play a dominant role in many hyperkinetic movement disorders, particularly tardive dyskinesia, Huntington's disease and Tourette syndrome. The traditional antipsychotic or antiemetic drugs, also called neuroleptics, block dopamine receptors and are sometimes used to treat the various hyperkinetic movement disorders. However, these drugs carry the risk of tardive dyskinesia and, therefore, are not appropriate for the chronic therapy of movement disorders. Other drugs that act by reducing the dopaminergic transmission and thus ameliorate hyperkinesias include reserpine, tetrabenazine (TBZ; Xenazine), deutetrabenazine (DBZ; Austedo) and valbenazine (VBZ; Ingrezza).
These drugs cause depletion of dopamine in the brain, but reserpine also causes dopamine depletion in the peripheral nervous system and therefore may cause low blood pressure, diarrhea and other adverse effects. The primary pharmacologic action of TBZ, DBZ and VBZ is depletion of dopamine in the central nervous system by inhibiting the human vesicular monoamine transporter isoform 2 (hVMAT2).
TBZ is effective and safe and unanimously recommended to the FDA approval of TBZ (Xenazine) for the treatment of chorea associated with Huntington's disease. Although not approved by the FDA yet, TBZ is also used to treat patients with Tourette's syndrome and tardive dyskinesia.
Although considered safe when appropriately administered and monitored, TBZ does have potential side effects, such as drowsiness, changes on electrocardiogram (prolonged QT interval), slowness of movement (parkinsonism), mood changes (depression), nervousness/anxiety and restlessness (akathisia). The labeling for TBZ draws special attention to potential depression and suicidality and recommended genotyping patients (for CYP2D6) to determine if they are slow metabolizers when dosage above 50 mg per day is prescribed (see package insert for additional precautions, contraindications and other prescribing information). The side effects of TBZ are reversible, meaning that they resolve with either dose reduction or drug cessation. Most importantly, there has been no documented cases of TBZ-induced tardive dyskinesia, and, therefore, this dopamine depleting agent has a distinct advantage over the dopamine-blocking agents (neuroleptics) in the treatment of a variety of hyperkinetic movement disorders. Combination of tetrabenazine with some other medications might cause potentially dangerous side effects so make sure your neurologist and other prescribing physicians are aware of all medications you are taking including over-the-counter drugs.
DBZ is chemically similar to TBZ, except for the incorporation of deuterium (“heavy hydrogen”), which makes the drug more resistant to metabolism by the human body. This creates several advantages compared to TBZ: steadier drug levels in the blood, lower peak concentration, lower doses and less frequent (twice daily vs three times daily) drug administration while maintaining the same relative effect. For these reasons, DBZ is felt to be better tolerated compared to TBZ. The mechanism of action and side effects of DBZ are the same as TBZ.
Similar to TBZ, DBZ is also used off-label for Tourette’s syndrome and tardive dyskinesia. The side-effects of DBZ are similar to those of TBZ and similarly resolve upon dose reduction or drug withdrawal. DBZ has not been associated with tardive dyskinesia. DBZ is typically dosed as 6-24mg twice daily.
VBZ is a purified prodrug of TBZ, meaning that it is metabolized (converted) into some of the same active substances as TBZ. Due to its pharmacological profile, VBZ is administered once daily compared to three times daily for TBZ, and is felt to be better tolerated than TBZ. The mechanism of action and side effect profile of VBZ are the same as TBZ and DBZ.
The FDA’s approved VBZ for the treatment of tardive dyskinesia. It is currently being marketed for this indication by Neurocrine Biosciences Inc. under the trade name Ingrezza. VBZ is also used off-label for chorea in Huntington’s disease and Tourette’s syndrome. The side-effects of VBZ are similar to those of TBZ and DBZ and similarly resolve upon dose reduction or drug withdrawal. VBZ has not been associated with tardive dyskinesia. VBZ is typically dosed as 80mg once daily.