LAS VEGAS – The risk-benefit ratio of new and emerging drugs for depression is going to be under the spotlight more than ever before, according to an expert in mood disorders.
Doug Brunk/MDedge News
Dr. Alan F. Schatzberg
“We’ve seen a shift in the landscape,” Alan F. Schatzberg, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association. The risk-benefit ratio is going to become increasingly more of a focus in drug development, in terms of increasing risk.”
The development of the SSRIs, he continued, led to the introduction of agents that were generally effective and well tolerated.
“Particularly, they were well tolerated in terms of their wide safety margin,” said Dr. Schatzberg, who directs the Mood Disorders Center at Stanford (Calif.) University. “It’s difficult to [die by suicide] on an SSRI. Because of that, we had greater numbers of individuals treated than we did with the tricyclics.” The introduction of SSRIs led to “widening of the net in terms of the numbers of depressed patients,” he said. “Combine that with DSM-III, and DSM-IV having relatively easy criteria to obtain a diagnosis [of depression, and] you see a large group of subjects who are exposed to treatment. But a lot of those people may not respond to a particular agent. As new treatments are promulgated and tried, what you find is [that] a reasonable number of subjects are, in fact, truly resistant. That becomes a tough nut to crack for all of us who treat depression.”
Drugs for depression that clinicians commonly have in their armamentarium commonly revolve around monoaminergic function. New and emerging agents include hallucinatory serotonin 2a agonists, glutamatergic drugs such as ketamine, GABAergic neurosteroids, opioid modulators, and onabotulinumtoxinA.
In 2013, the Food and Drug Administration approved the multimodal agent vortioxetine for the treatment of major depressive disorder. The recommended dosing is 20 mg/day, and the drug appears to have a positive effect on cognition. A meta-analysis of vortioxetine, duloxetine, and placebo comparison trials evaluated the effect of each treatment on the Digit Symbol Substitution Test (Int J Neuropsychopharmacol. 2016 Jun 15;19[10]). Vortioxetine was superior to placebo in all three trials and was superior to duloxetine in two trials. Duloxetine was not superior to placebo in two trials.
In two double-blind studies, researchers evaluated the effects of psilocybin in cancer patients with comorbid depression and anxiety. Full doses of psilocybin were 0.3 mg/kg or 22-30 mg per 70 kg. Both studies demonstrated sustained responses at full doses (J Psychopharmacol. 2016 Nov 30;30[12]:1181-97 and J Psychopharmacol. 2016 Nov 30;30[12]:1165-80).
In an open label study of psilocybin in refractory major depression, 12 patients received 10 mg on day 1 and 25 mg on day 8. Eight of 12 patients responded at 1 week, and 7 of the 12 maintained response at 3 months (Lancet Psychiatry. 2016 Jul;3[7]:619-27). According to Dr. Schatzberg, this trial became the basis for a blinded study that Compass is conducting in the United States and in the United Kingdom in which refractory patients are going to be randomized to 1 mg, 10 mg, or 25 mg psilocybin using an independent rater. “These patients are accompanied during this experience by two therapists for up to 8 hours. It’s not quite a guided therapy; it’s kind of a safety net therapy if the patient needs [help]. We’ll see what happens.”
Another agent being studied is ketamine, which works on the glutamate system, an excitatory neurotransmitter. “Glutamate is the juice that keeps us going,” said Dr. Schatzberg, who is also the Kenneth T. Norris Jr. professor of psychiatry and behavioral sciences at the university. “We can’t live without glutamate.” An anesthetic agent that has been used for 50 years, ketamine is a N-methyl-d-aspartate antagonist that has mu opioid agonist effects and stimulant properties. “It causes a psychotomimetic dissociative kind of reaction,” he said. “The doses used in depression are subanesthetic. They may put the patient asleep, but they usually don’t. The problem with the antidepressant effect is that 70% of people who initially respond don’t continue to respond beyond 1 week.”
In a randomized, placebo-controlled, double-blind crossover study of patients with treatment-resistant depression, subjects who received ketamine showed significant improvement in depression, compared with subjects who received placebo within 110 minutes after injection, which remained significant throughout the following week (Arch Gen Psychiatry. 2006;63:856-64). Specifically, of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.
In an effort to further evaluate the antidepressive effects of ketamine, researchers conducted a two-site, parallel-arm, randomized, controlled trial of a single infusion of ketamine, compared with an active placebo control condition, the anesthetic midazolam (Am J Psychiatry. 2013 Oct;170[10]:1134-42). After adjustment for baseline scores and site, the Montgomery-Åsberg Depression Rating Scale score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18), with response rates of 64% and 28%, respectively.
In 2019, the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression. In three phase 3 double-blind studies of esketamine in treatment-refractory depression, one was positive, two were nearly positive, and the effect sizes were mild. One maintenance discontinuation trial was positive. Based on this data, Dr. Schatzberg said, there “is not much evidence” that patients get further gain beyond an antidepressant alone in the first 24-48 hours following ketamine administration. “It makes me wonder: Should we be continuing to give this drug intranasally beyond 48 hours?” he asked. “The reason I have concern is that in certain cultures, ketamine is a highly abusable drug.”
He and Gerard Sanacora, PhD, MD, addressed the topic in a 2015 opinion piece entitled, “Ketamine: Promising path or false prophecy in the development of novel therapeutics for mood disorders?”
“If we step back for a moment and look at where we are – an intravenously administered agent that is a street drug of abuse, works rapidly, and whose enantiomers are being studied by industry for intranasal use – we should be anxious, “ they wrote (Neuropsychopharmacology. 2015 Jan;40[2]:259-67). “We need to be as careful and conservative as possible and understand how it is acting and rule out the possibility of whether it acts as an opioid.”
Dr. Schatzberg disclosed that he has served a consultant to Alkermes, Avanir, Bracket, Compass, Delpor, Epiodyne, Janssen, Jazz, Lundbeck, McKinsey, Merck, Myriad Genetics, Owl, Neuronetics, Pfizer, Sage, and Sunovion. He has received research funding from Janssen and also holds an ownership interest in Corcept, Dermira, Delpor, Epiodyne, Incyte Genetics, Madrigal, Maerck, Owl Analytics, Seattle Genetics, Titan, and Xhale.