A staggering 300 million people suffer from some degree of depression, with one third not responding to current treatments. A recent paper published in The New England Journal of Medicine suggests a novel oral antidepressant for adults suffering from moderate to major depressive disorder, which targets the gamma- aminobutyric type A (GABAA) receptors in the brain. “This hypothesis is supported by evidence that reduced GABA levels have been observed in plasma, cerebrospinal fluid, and cortical brain tissues of patients with depression”, writes Dr. Gunduz-Bruce and coauthors. 

This phase 2, double blind experiment included 89 participants suffering from major depression disorder who were randomized to receive either a daily dose of SAGE-217, a synthetic steroid that acts as a positive allosteric modulator of GABAA receptors, or placebo for 14 days. At day 15, researchers measured the mean change from baseline in the Hamilton Depression Rating Scale (HAM-D), with higher scores indicating more severe depression. Results showed a significantly greater mean change from baseline in the treatment versus placebo group, with about 79% of those treated with SAGE-217 experiencing a greater than 50% reduction in HAM-D depression scores, compared with the mere 41% in the placebo group. 

SAGE-217 treated individuals did not experience any serious side effects, with the most common being headache in 18% of participants, nausea in 11%, and dizziness in 11%.  The rapid therapeutic effects and noteworthy effect size seen with this trial are not typical of most antidepressants currently on the market. Current treatments can take as long as 4-8 weeks to have a positive effect, while negative side effects are often extremely variable and experienced immediately after drug administration. Most antidepressants are monoaminergic and involve two neurotransmitters, serotonin and noradrenaline/norepinephrine, blocking their uptake, and ultimately alleviating common symptoms of depression.  Despite the therapeutic benefits of these selective serotonin reuptake inhibitors (SSRIs), the late onset effects, compared to SAGE-217, pose a great disadvantage.  

Although these findings are promising, one must consider the study’s limitations. The study’s small sample size and limited racial diversity amongst both the treatment and placebo groups present a barrier to the generalizability of these results.  Additionally, the trial was not designed to detect changes in levels of depression after the 15 day period. Further research is necessary to determine the long-term efficacy of SAGE-217 in order to make a valid comparison with drugs on the market. Although follow up studies can correct these limitations, they are unable to erase the red flag raised by the conflict of interest inherit in this research. 

“Sage Therapeutics designed the trial, provided the SAGE-217 and placebo, collected and analyzed the data, and paid for professional writing assistance,” states the paper. Ties with the pharmaceutical industry are commonly seen in medicine and have been shown to be extremely beneficial through research collaborations that improve both individual and public health. At the same time, financial ties with industry are raising concerns regarding the influence personal monetary gain may have on professional judgement of researchers. Often, one can determine the stakeholders and how the research is being funded through the acknowledgement section at the end of any published paper. This section can provide readers with information as to where the money is coming from or going. In today’s age, such conflicts of interest lead to a loss of trust by the public towards medicine, as financial ties are seen as threatening to the integrity and objectivity of the research being done. 

Despite these barriers, this research introduces a novel mechanism and should be further investigated with the hope of providing an alternative treatment for a disorder that can have such debilitating effects on the lives of those affected.

Still, I am left wondering, should these conflicts of interest be eliminated or managed moving forward? And if so, how? 

References:

Depression. (n.d.). Retrieved from https://www.who.int/news-room/fact-sheets/detail/depression.

Gardier A. Mechanism of action of antidepressant drugs: importance of genetically modified mice in the pharmacological in vivo approach. Therapie. 2005;60:469–476

Gunduz-Bruce, H., Silber, C., Kaul, I., Rothschild, A. J., Riesenberg, R., Sankoh, A. J., … Kanes, S. J. (2019). Trial of SAGE-217 in Patients with Major Depressive Disorder. New England Journal of Medicine, 381(10), 903–911. doi: 10.1056/nejmoa1815981

About the author:

My name is Noa Mecica and I am an MS1 at Sackler School of Medicine. I’m from Toronto where I majored in Biomedical Science at Ryerson University with specific interest in cancer cell biology and public health. Looking forward to the coming years here at Sackler!