Anticonvulsant Shows Promise in Major Depression

Megan Brooks

November 06, 2018

The anticonvulsant ezogabine (also known as retigabine) significantly reduced depressive symptoms, anhedonia, and increased resilience to stress in a small open-label study of patients with major depressive disorder (MDD).

"The results of this study are exciting because we haven't had a new medicine to treat depression in decades," senior author James Murrough, MD, PhD, director of the mood and anxiety disorders program at the Icahn School of Medicine at Mount Sinai in New York City, said in a news release.

"Most antidepressants are in the same class of drugs and work by increasing serotonin. Our research suggests a different molecular target that works through other brain mechanisms and could be helpful for patents," added Murrough.

The study was published online on November 1 in Molecular Psychiatry.

New Target for Drug Development?

Ezogabine is a first-in-class KCNQ-selective potassium channel opener approved by the US Food and Drug Administration as adjunctive treatment for partial-onset seizures. By activating (or opening) KCNQ transmembrane potassium ion channels, ezogabine is thought to reduce brain excitability likely leading to its anticonvulsant effect.

"This KCNQ channel is not that well known to psychiatry and drugs that affect this channel could be the next way in drug discovery in psychiatry," Murrough noted in an interview with Medscape Medical News. "This is a target known in neurology because its known to reduce cell firing, and therefore be antiepileptic, but there hasn't really been any study to see if it can affect a mood disorder."

In earlier studies in mice, the Mount Sinai team found that ezogabine has significant antidepressant effects, expressed in the animals as increased social interactions and preferences for natural rewards.

In the open-label study, they tested the effects of ezogabine on reward circuity using functional magnetic resonance imaging (fMRI) and clinical symptoms of depression in 18 medication-free patients with MDD experiencing a major depressive episode. Patients received up to 900 mg/day ezogabine orally for 10 weeks.

Treatment with ezogabine was associated with a significant reduction of depressive symptoms from pretreatment week 0 to post-treatment week 10 (mean Montgomery–Asberg Depression Rating Scale [MADRS] score change, −13.7; P < .001; Cohen's d = 2.08) and throughout the study as a function of time. Pairwise comparisons showed a significant improvement from week 3 onwards. Overall, after 10 weeks of treatment, patients showed a 45% reduction in MADRS score from baseline.

The Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score was significantly reduced at the end of the study compared with baseline (mean change, −5.72; P < .001; Cohen's d = 1.64).

Eight (44%) patients met criteria for response and five (28%) met remission criteria. Eleven (61%) patients were judged as "much improved" or "very much improved" on the Clinical Global Impression-Improvement (CGI-I) scale.

Treatment with ezogabine also led to significant improvement in anhedonia (mean Snaith–Hamilton Pleasure Scale [SHAPS] score change, −6.1; P < .001; Cohen's d = 1.00) and resilience on the Connor–Davidson Resilience Scale (mean change, 8.2; P < .01).

Beyond Paper and Pencil

Improvement in depression and anhedonia were significantly associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex. A subgroup of patients tested with a computerized probabilistic reward task showed increased reward learning following treatment.

The most common adverse event was dizziness, which occurred in eight patients. Less frequent adverse events were confusion and headache that were reported in three and two patients, respectively. No one discontinued ezogabine because of side effects and no serious adverse events occurred during the course of the study.

"This type of study is important in psychiatry, where we are trying to get beyond the simple paper and pencil questionnaire that determines the effect of a drug on mood and actually determine what is going on in the brain," Murrough told Medscape Medical News.

"The study was positive in the sense that patients, on average, showed a relatively substantial reduction in their depression. And we further showed that the drug affects the ventral striatum, which is important for human emotion, reward, and depression," he noted.

Based on the promising results of this small pilot study, the Mount Sinai team is currently conducting a larger multicenter, double-blind, placebo-controlled trial of ezogabine in patients with depression to further determine its efficacy in treating depression. The trial, which is funded by the National Institute of Mental Health (NIMH), is expected to be completed in the next year.

"Understanding ezogabine's mechanism of action in the human brain could lead to additional novel treatments of depression focused on promoting active biological mechanisms of resilience, rather than reversing the pathological changes associated with the syndrome, which has dominated antidepressant drug discovery efforts to date. These resilience-enhancing or 'active antidepressant' strategies may open up new avenues of drug discovery for mood disorders," they write.

A Godsend?

Commenting on the findings for Medscape Medical News, Michael Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, said he's not surprised by these findings "because several other medications originally developed for treatment of epilepsy are known to have antidepressant effects; three of these medications (carbamazepine, divalproex, and lamotrigine) are approved for treatment of bipolar disorder."

"That said, these interesting findings must now be followed by larger and better controlled studies, which can help to take into account the added benefit that seems to come when newly introduced medications are first given to long-suffering patients, as well as the need to take into account the treatment histories and likely magnitude of the placebo effect in study populations," said Thase. 

"It often takes three to five larger studies, including hundreds of patient volunteers, to sort out whether an exciting preliminary finding is actually the real thing," he added.

Thase said he agrees fully with Murrough that "we need new treatments that work differently for our many patients who do not respond to conventional therapies. I hope this one turns out to be a godsend."

Funding for this study was provided by the Friedman Brain Institute and Ehrenkranz Laboratory for Human Resilience, both part of the Icahn School of Medicine at Mount Sinai. Additional research support was provided by the Doris Duke Charitable Foundation and NIMH. Thase has reported no relevant financial relationships. Murrough has provided consultation services to Sage Therapeutics, Boehringer Ingelheim, Novartis, Allergan, Fortress Biotech, Janssen Research and Development, Genentech, MedAvante-ProPhase, and Global Medical Education, has received research support from Avanir Pharmaceuticals, and is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders. Disclosures for the other authors are listed in the article.

Mol Psychiatry. Published online November 1, 2018. Abstract

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