In the Journals

Ezogabine may decrease symptoms in major depression

Patients with major depressive disorder experienced reduced depressive symptoms after receiving treatment with the FDA-approved anticonvulsant ezogabine, according to study data.

“Recent preclinical evidence has highlighted the KCNQ-type voltage-gated potassium channel as a promising novel molecular target for the treatment of depression,” Aaron Tan, PhD candidate, from the departments of psychiatry and neuroscience, Icahn School of Medicine at Mount Sinai, and colleagues wrote in Molecular Psychiatry. “Systemic injection of ezogabine, a KCNQ-selective potassium channel opener, also led to the amelioration of depressive behaviors in susceptible mice.”

In this open-label pilot study, researchers examined whether ezogabine significantly engaged the brain reward system and affected clinical symptoms in 18 medication-free patients with major depression. Patients currently in a major depressive episode received ezogabine up to 900 mg per day orally over 10 weeks, and the investigators collected resting state functional MRI data at baseline and post-treatment.

Tan and colleagues measured participants’ reward learning while they completed a computer-based probabilistic reward task, where they were asked to distinguish between two stimuli — a short vs. long mouth displayed rapidly in a schematic face — to receive a monetary reward.

After receiving ezogabine, patients with MDD experienced a 45% drop in depressive symptoms as measured by change in Montgomery-Asberg Depression Rating Scale score (P < .001). Anhedonic symptoms, measured by change in Snaith-Hamilton Pleasure Scale score, also decreased from baseline to week 10 (P < .001). These results remained significant after controlling for overall depression severity, according to the researchers. Patients also showed an improvement in resilience.

In total, 44% (n = 8) and 28% (n = 5) of patients met response and remission criteria, and 61% (n = 11) saw notable improvements in illness severity.

The results also revealed that improvement in depression was linked to reduced functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex in 14 patients (P < .005). Further, after testing a subgroup of nine patients with the probabilistic reward task, the researchers observed increased reward learning after treatment with ezogabine.

“Based on the findings of this preliminary study, future randomized controlled trials of ezogabine in depressive disorders are warranted,” Tan and colleagues wrote.

“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,” they continued. “These resilience-enhancing or, ‘active antidepressant’ strategies may open up new avenues of drug discovery for mood disorders.” – by Savannah Demko

Disclosure: Tan reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Patients with major depressive disorder experienced reduced depressive symptoms after receiving treatment with the FDA-approved anticonvulsant ezogabine, according to study data.

“Recent preclinical evidence has highlighted the KCNQ-type voltage-gated potassium channel as a promising novel molecular target for the treatment of depression,” Aaron Tan, PhD candidate, from the departments of psychiatry and neuroscience, Icahn School of Medicine at Mount Sinai, and colleagues wrote in Molecular Psychiatry. “Systemic injection of ezogabine, a KCNQ-selective potassium channel opener, also led to the amelioration of depressive behaviors in susceptible mice.”

In this open-label pilot study, researchers examined whether ezogabine significantly engaged the brain reward system and affected clinical symptoms in 18 medication-free patients with major depression. Patients currently in a major depressive episode received ezogabine up to 900 mg per day orally over 10 weeks, and the investigators collected resting state functional MRI data at baseline and post-treatment.

Tan and colleagues measured participants’ reward learning while they completed a computer-based probabilistic reward task, where they were asked to distinguish between two stimuli — a short vs. long mouth displayed rapidly in a schematic face — to receive a monetary reward.

After receiving ezogabine, patients with MDD experienced a 45% drop in depressive symptoms as measured by change in Montgomery-Asberg Depression Rating Scale score (P < .001). Anhedonic symptoms, measured by change in Snaith-Hamilton Pleasure Scale score, also decreased from baseline to week 10 (P < .001). These results remained significant after controlling for overall depression severity, according to the researchers. Patients also showed an improvement in resilience.

In total, 44% (n = 8) and 28% (n = 5) of patients met response and remission criteria, and 61% (n = 11) saw notable improvements in illness severity.

The results also revealed that improvement in depression was linked to reduced functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex in 14 patients (P < .005). Further, after testing a subgroup of nine patients with the probabilistic reward task, the researchers observed increased reward learning after treatment with ezogabine.

“Based on the findings of this preliminary study, future randomized controlled trials of ezogabine in depressive disorders are warranted,” Tan and colleagues wrote.

“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,” they continued. “These resilience-enhancing or, ‘active antidepressant’ strategies may open up new avenues of drug discovery for mood disorders.” – by Savannah Demko

Disclosure: Tan reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.