Pilot Studies Reveal Promising Therapies Outside of Psychiatric Arena

Given the large amount of resources and time needed to shepherd a promising therapeutic agent through the R&D pipeline—not to mention the high risk of failure along the way—a growing number of groups have started to test existing medications for other uses. The psychiatry arena, wherein many prescribed medications are decades old, is no exception. At the end of 2015 there were some exciting though preliminary findings that revealed potential new agents for treating mental disorders.

Leukemia Medication May Slow Cognitive Decline in Patients With PD

While a medication for cancer may seem an unlikely candidate to treat a neurodegenerative disorder like Parkinson’s disease (PD)—as one disease involves uncontrolled cell growth while the other is associated with cell death—a pilot study by researchers at Georgetown University Medical Center suggests that the FDA-approved leukemia medication nilotinib may reduce some symptoms of the disease.

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Charbel Moussa, M.D., Ph.D., director of Georgetown’s Laboratory of Dementia and Parkinsonism, and colleagues gave patients with Parkinson’s disease or Lewy body dementia 150 mg to 300 mg of nilotinib daily for six months. Eleven of the 12 patients who completed the trial showed meaningful improvements in both cognitive and motor assessments. Analysis of the patients’ cerebrospinal fluid also showed stable or reduced levels of toxic PD-associated proteins, as well as increased levels of dopamine, which is progressively destroyed during PD progression.

According to Moussa, the latter finding suggests that patients taking nilotinib might be able to reduce their use of other dopamine-stimulating medications, which are effective in improving symptoms of PD but can cause psychiatric side effects including psychosis.

When used for leukemia, nilotinib forces cancer cells into autophagy—a process wherein cells consume themselves and die. “But, in the smaller doses we used, nilotinib turns on autophagy for only a few hours—long enough to clean out the cells without causing cell death,” Moussa said in a press release.

Moussa cautioned that this pilot study was primarily meant to assess how well the patients could tolerate nilotinib and did not include any controls or comparison groups taking other medications for PD. The group is now planning larger clinical trials specifically aimed at addressing the efficacy of the medication in PD patients, as well as launching a small study testing nilotinib in patients with Alzheimer’s disease.

Moussa’s work is funded by the National Institute on Aging and Georgetown University.

Targeting Insulin Resistance May Reduce Depressive Symptoms

Previous studies have identified strong associations between metabolic and mental health problems. Researchers believe this may be due to the prodigious amount of sugar that the brain needs to function.

Now a team of researchers from Stanford University and the University of California, San Francisco, has found that the insulin-sensitizing drug pioglitazone may help to alleviate depression in patients who are insulin resistant.

In the December 30, 2015, issue of Psychiatry Research, Natalie Rasgon, M.D., Ph.D., a professor of psychiatry and behavioral sciences at Stanford, and colleagues described the results of a 12-week, double-blind, randomized, controlled trial of pioglitazone in 37 patients with depression who failed to remit under standard treatment.

The researchers found that while there was no difference between insulin-sensitive participants given pioglitazone or placebo in addition to their normal medication, those who were insulin resistant reported fewer depressive symptoms when given this agent.

Rasgon suggested that high blood insulin or some other aspect of insulin resistance may interfere with antidepressant drugs, leading some patients to be resistant to treatment. “The pioglitazone does not improve symptoms by itself, but rather removes the barrier preventing antidepressant action,” she said. More work is needed to elucidate this mechanism, as not every insulin-resistant patient in the trial responded when given pioglitazone, she added.

This study was supported by a grant from the National Institute of Mental Health.

Anti-Inflammatory Medication May Offer an Alternative to Lithium

Even failed drugs can offer new options for patients with psychiatric disorders, as may be the case with ebselen, an anti-inflammatory medication that was found to be safe but ineffective at treating strokes.

Research has shown that ebselen can pass the blood-brain barrier and inhibits an enzyme called inositol monophosphatase, which is also a target of lithium. Subsequent work in mice suggested that ebselen has lithium-like properties (for example, reducing the activity of the 5-HT2 serotonin receptor and lowering hyperactive and impulsive behaviors in the animals).

To evaluate the safety of ebselen in people, Grant Churchill, Ph.D., an associate professor of pharmacology at the University of Oxford, and colleagues compared healthy study participants given oral ebselen with those who took placebo (eight people in each group).

They found that ebselen was associated with reduced levels of inositol in the brain and changes in sleep behavior and emotional processing. Ebselen also produced limited side effects, such as headache and nausea, at the same rate as placebo.

“Lithium has been used for over 60 years and remains the most effective treatment for bipolar disorder, but it has many side effects,” Churchill said in a statement. “These side effects also encourage people to stop taking it, which can lead to relapse.”

These results were published November 23 in Neuropsychpharmacology.

The research was supported by a grant from the Biotechnology and Biological Sciences Research Council and the John Fell Oxford University Press Research Fund. ■