Pipeline Robust for Treatment of Depression, but Studies in Children Still Rare

May 25, 2010 (New Orleans, Louisiana) — The drug development pipeline for the future treatment of major depressive disorder (MDD) is robust, based on the number and types of clinical trials in progress, according to investigators who described the clinical trial landscape here at the American Psychiatric Association (APA) 2010 Annual Meeting.

Aarti Gupta, MBBS, the principal investigator, who is a psychiatry resident at the University of Texas Health Sciences Center, Houston, noted that many trials are evaluating agents with novel mechanisms of action and a few are augmentation studies.

"Unfortunately, only 5% of the studies were in children and adolescents," she reported, citing this as a high research need. "The number of clinical trials in adults was about 10 times more than in children and adolescents in most categories, and no augmentation studies were conducted in children," she told Medscape Psychiatry.

Dr. Aarti Gupta

The investigators searched the national registry for all clinical trials (clinicaltrials.gov) to identify the ongoing treatment trials in MDD. They identified 411 relevant studies, with sample sizes varying from just 2 to 2000 subjects. Of these, 25% were uncontrolled, 45% had an active comparator, and 30% were placebo-controlled.

Most, 57%, were evaluating drug treatments, whereas 29% were evaluating psychosocial treatment, 8% transcranial magnetic stimulation, and 6% combined modalities. Virtually all studies were for primary treatment, although 3% were augmentation studies.

Drug studies constituted 60% of the trials in adults compared with 37% of those in children, whereas the reverse was true for psychosocial studies, which constituted 25% of adult studies and 58% of studies in children and adolescents.

Many Novel Mechanisms Being Evaluated

Importantly, many studies were of drugs with novel mechanisms of action, including, for example, triple reuptake inhibitors, selective norepinephrine reuptake inhibitors, nicotinic receptor antagonists, CRF-1 antagonists, 5HT-7 antagonists, and so forth.

Dr. Gupta's poster displayed some of the physiologic effects of these novel agents. For example, TC-5214 antagonizes neuronal nicotinic receptors, riluzole modulates the glutaminergic system and is potentially neuroprotective and plasticity enhancing, AZD2327 is a high-affinity enkephalinergic agonist, and BCI-540 directly affects neurogenesis without affecting serotonin levels.

Six compounds were being evaluated for augmentation of an antidepressant, most commonly omega-3 fatty acids, which act as a source of second messengers within or between neurons and inhibit proinflammatory cytokines, she said. Other drugs for augmentation included cimicoxib, saredutant, cysteamine bitartrate, D-cycloserine, and creatine monohydrate.

Of the listed drugs, 11 were already approved by the US Food and Drug Administration for conditions other than MDD. Comorbid anxiety disorders were also targeted along with MDD in some trials.

Industry-Funded Trials Much Larger

Industry-funded trials were generally larger, with a median planned sample size of 376 subjects compared with 90 for non–industry-sponsored studies (P < .0001).

"Smaller sample sizes may reduce the study's impact, and we wonder if these very small studies are clinically meaningful," Dr. Gupta said.

Although the pipeline is strong and drugs with novel mechanisms should be coming to market, she concluded, trials evaluating psychotherapy continue to be few and children and adolescents continue to be neglected.

Julie Hatterer, MD, who serves on the APA Council on Communications, commented on the findings for Medscape Psychiatry. "The good news is there are a number studies looking at treatment of depression using novel approaches; however, the bad news is that 25% are uncontrolled, and only 5% are studying depression in children, which, in addition to studies in the elderly, are sorely needed."

"Furthermore, the findings demonstrate that we have yet to find sources other than the pharmaceutical industry to support these studies," she continued. She said that scrutiny about funding sources is particularly important "given the media's attack on the efficacy of antidepressants."

Dr. Gupta and Dr. Hatterer have disclosed no relevant financial relationships.

American Psychiatric Association (APA) 2010 Annual Meeting: Abstract NR1-33.