LAS VEGAS – There remains a great unmet need for more effective and rapidly acting treatments for major depressive disorder, and research is revealing that both new and existing drugs may help, according to one expert.

One argument for additional treatment options is the current rate of suicide in the United States, which ranks as the 10th leading cause of death among persons aged 10 years and older, Gerard Sanacora, MD, PhD , said at an annual psychopharmacology update held by the Nevada Psychiatric Association. Another argument for new antidepressants stems from the results of the STAR*D trial, which found that 37% of patients with major depressive disorder who were treated with citalopram monotherapy had remission with the first treatment.

“Even if you do get the patient into remission, the chance of relapse is high,” said Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn. “While our current treatments are good and effective and help many people, there is a substantial proportion of the population that are either not completely benefiting from these drugs or not able to sustain them.”

Dr. Sanacora, who is also director of the Yale Depression Research Program, said that there is a reconceptualization of how clinicians think about the pathophysiology of depression and the path to novel treatment development. A variety of novel pharmacologic and somatic treatments, with new mechanisms of action, are currently undergoing validation for treatment-resistant depression. These include glutamatergic, GABAergic, opioid, and anti‐inflammatory drugs.

Drugs that modulate GABAergic and glutamatergic neurotransmission have anxiolytic and antidepressant activities in rodent models of depression. In addition, the robust, rapid, and relatively sustained antidepressant effects of low-dose ketamine have been observed in double-blind placebo crossover trials in patients with treatment-resistant major depression ( Biol Psych. 2000 Feb 15;47[4]:351-4 and Arch Gen Psych. 2006 Aug;63[8]:856-64) . Currently, Dr. Sanacora said, more than 80 clinics in the United States provide ketamine therapy, yet clinicians face balancing the potential benefits of the drug with inherent limitations of the ketamine studies to date. These include the fact that the study drug blinding is ineffective; the optimal dose, route, or frequency has not been determined; the duration of effect is unknown; the long-term effectiveness and safety are unclear; and the moderators and mediators of response are unknown.

Results from a National Institutes of Mental Health–funded double-blind, placebo-controlled study examining various doses of ketamine in treatment-resistant depression are anticipated sometime this year. In 2013, a trial sponsored by Janssen Research & Development titled a Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-Resistant Depression ( SYNAPSE ) set out to assess the efficacy and dose response of intranasal esketamine (panel A: 28 mg, 56 mg, and 84 mg; panel B: 14 mg and 56 mg), compared with placebo, in improving depressive symptoms in participants with treatment-resistant depression. The researchers found a positive effect of esketamine vs. saline placebo with some evidence of a dose-response curve, suggesting higher doses to be more effective. Some published studies suggest that chronic ketamine use causes impairments in working memory and other cognitive effects ( Addiction. 2009 Jan;104[1]:77-87 and Front Psych. 2014 Dec 4;5:149 ), while others have found that ketamine does not cause memory deficits when given on up to six occasions ( Int J Neuropsychopharmacol. 2014 Jun 25;17[11]:1805-13 and J Psychopharmacol. 2014 Apr 3;28[6]:536-44 ).

Another drug being studied for major depressive disorder is the investigational agent SAGE-547, an allosteric neurosteroid modulator of both synaptic and extrasynaptic GABA receptors. Preliminary results from a double-blind, placebo-controlled phase II trial in 21 patients with postpartum depression showed that the Hamilton Rating Scale for Depression (HAM-D) total score was reduced by SAGE-547, compared with placebo, at 60 hours (P = .008).

Buprenorphine, a partial mu opioid agonist commonly used in addiction treatment, may also play a future role in helping patients with treatment-resistant depression. One randomized study of 88 patients found that those who took very low doses of buprenorphine for 2 or 4 weeks had significantly lower scores on the Beck Suicide Ideation Scale, compared with their counterparts on placebo ( Am J Psychiatry. 2016 May 1;173[5]491-8 ).

Drugs with anti-inflammatory properties may also have a role. One study of 60 patients found that the tumor necrosis factor–alpha antagonist infliximab may benefit patients with treatment-resistant depression who have high inflammatory biomarkers at baseline ( JAMA Psychiatry. 2013 Jan;70[1]:31-41 ).

“Active participation in clinical research efforts is critical to the advancement of future treatment approaches,” he wrote.

Dr. Sanacora disclosed having received consulting fees and/or research agreements from numerous industry sources. In addition, free medication was provided to Dr. Sanacora by sanofi‐aventis for a study sponsored by the National Institutes of Health.


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