Antipsychotic cariprazine may ease Huntington’s motor symptoms

Medication may balance dopamine levels when they're too high, low

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Cariprazine, an oral medication approved for schizophrenia, may ease some motor symptoms people with Huntington’s disease experience across different stages of the condition, a small study suggests.

How cariprazine works in Huntington’s still isn’t clear, but researchers think it may balance out dopamine levels when they’re too high, as in the early stages of the disease, or too low, like in the later stages. Dopamine is a major brain signaling molecule involved in motor control. The study, “The improvement of motor symptoms in Huntington’s disease during cariprazine treatment,” was published in the Orphanet Journal of Rare Diseases.

In Huntington’s, a genetic disease, progressive neurodegeneration typically leads to symptoms in the fourth or fifth decades of life. Its early stages feature involuntary jerking or writhing movements, called chorea, whereas later stages affect balance and walking, in part due to the effect on voluntary movement. The nature of Huntington’s motor symptoms may depend on dopamine’s levels, which are unusually high in the early stages, but tend to drop as the disease progresses.

Certain medications that reduce dopamine are approved for easing chorea associated with Huntington’s. Over time, however, they may worsen nonmotor symptoms, such as slowed thinking or loss of motivation.

“Dopamine D2-D3 partial agonists could be a promising treatment option in [Huntington’s], as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course,” the researchers wrote.

D2 and D3 are two of the five subtypes of dopamine receptors. D2 activation is involved in chorea, whereas “growing evidence suggests that D3 stimulation has … neuroprotective and neurorestorative effects on dopamine neurons,” wrote the researchers, who say it may help prevent “alterations underlying neurodegeneration.” A partial agonist binds to a receptor, activating it, but triggers a response that’s lower than that of the substance that normally binds to it.

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Cariprazine’s effect on dopamine

Cariprazine, an oral antipsychotic sold as Vraylar in the U.S. and Reagila in Europe for treating schizophrenia is among this class of dopamine D2-D3 partial agonists. In the U.S., it’s also approved for symptoms of bipolar disorder or as an add-on to antidepressants for major depressive disorder.

Other antipsychotics have been used off-label to manage some Huntington’s motor and psychotic symptoms, but cariprazine binds to D3 more strongly than dopamine itself, making it “the only drug that can occupy the D3 receptors in the presence of dopamine,” the researchers wrote.

This and other molecular properties may make cariprazine effective for treating Huntington’s motor symptoms throughout the disease course.

To test this, researchers in Hungary reviewed the medical records of 15 adults (11 women, four men) with Huntington’s who took cariprazine off-label for up to 12 weeks, or three months. Their mean age was 48.1 and they’d been living with the disease for a mean of 3.8 years.

Thirteen patients received 1.5 mg of cariprazine each day, one received 3 mg/day, and another 4.5 mg/day. Ten patients continued taking tetrabenazine, an oral medication sold as Xenazine and available as generics that’s approved for Huntington’s-related chorea.

Cariprazine treatment resulted in significant improvements in the Total Motor Score (TMS), which measures the severity of motor symptoms on a scale from 0 (none) to 60 (severe).

Mean TMS fell from 36.8 points at the start to 27.4 points after eight weeks, or two months, of treatment, a 26% improvement. After 12 weeks, mean TMS fell to 24 points, an additional 12% improvement.

Reductions were observed across most motor symptoms, suggesting cariprazine may be “effective in the treatment of a wide range of motor symptoms.” Further analyses showed “patients with more severe symptoms at [study’s start] experienced greater improvements during the treatment period.”

Cariprazine was generally safe and well tolerated. Side effects were reported in three patients — restlessness in three and weight loss in one.

Besides its potential with motor symptoms, research by some of the scientists in this study showed cariprazine may help manage some nonmotor symptoms such as mood changes, cognitive impairment, and loss of motivation.

“Our findings indicate that cariprazine is a promising medication that has the potential to alleviate both motor and nonmotor symptoms of HD while being well-tolerated by patients,” wrote the researchers, who recommended larger studies to confirm its effects in motor and nonmotor symptoms.