A considerable minority of patients who suffer from major depression may not respond to typical treatment strategies, and if they do, it could take weeks and several medication switches to find the right match. Clearly, there is a need to develop agents with novel antidepressant mechanisms that provide effective treatment more rapidly.

Data from testing four novel approaches in individuals with major depressive disorder (MDD) that are proving to be rapidly effective were presented in a symposium at the American Psychiatric Association Annual Meeting, held online May 1-3, 2021. These new strategies rely on alternative mechanisms of action to previously approved agents and include ketamine and other glutamatergic agents, the hallucinogen psilocybin, the neurosteroids, and accelerated theta-burst r-TMS. Below are the highlights.

Ketamine for Major Depression

Charles DeBattista, MD, director of the Depression Research Clinic at Stanford University,  reviewed studies on ketamine’s various putative mechanisms of action (NMDA antagonism, mu opioid agonism) that could explain its clinical efficacy. Originally developed and approved as an anesthetic agent, ketamine has long been used as an analgesic for chronic pain syndromes – but because of its ability to produce psychotic symptoms, is commonly misused.

Dr. DeBattista provided evidence supporting the conclusion that ketamine provides rapid antidepressant effects, but they are short-lived. In a pivotal study of adults with treatment-resistant depression (TRD), ketamine showed improvement in depression within 2 hours, which remained throughout the following week.1 A later study comparing ketamine with midazolam showed that patients treated with ketamine had greater improvements in the Montgomery-Asberg Depression Rating Scale (MADRS) 24 hours after treatment, giving support to NMDA receptor modulation as the mechanism for providing accelerated improvement in severe and chronic forms of depression.2

Esketamine, a ketamine enantiomer, is approved by the FDA as an adjunctive agent for the treatment of severe depression and is being studied for its effects on suicidality. According to Dr. DeBattista, tolerance to both drugs has been reported, but their “baggage” is related to their potential for abuse, which is a problem in many parts of the world, particularly Asia, and side effects including hypertension, tachycardia, and dissociation, along with the requirements required for their use in the clinic.

Psilocybin  for Refractory Depression

Psilocybin, being actively studied for the treatment of refractory and non-refractory depression, is a potent serotonin 2a/c receptor agonist (5HT2a) that has been used for centuries by indigenous people as a mushroom-based psychedelic agent. Studied again as an adjunct to psychotherapy in the 1950s and 1960s, its use was outlawed by the Controlled Substances Act (CSA) of 1970. However, it has regained attention in recent years.

Psilocybin acts differently than standard antidepressants. Dr. DeBattista explained that by depressing the Default Node Network – the network of connections in the brain that allow us to function in the world – the psychedelic induces a dissociative state in which areas of the brain can communicate that do not normally communicate. In TRD, psilocybin’s effects were shown to have a rapid (30 to 60 min) onset and sustained (up to 3 months) effect.3

Studies in patients living with cancer and comorbid depression and anxiety showed rapid and sustained benefits for more than 6 months after a single dose of psilocybin combined with psychotherapy.4  Currently, a Phase 2b dose-ranging study of psilocybin therapy with psychotherapy in TRD is underway in 216 participants in 25 study centers worldwide. (NCT03775200).

See also, when your client asks to try psychedelics.

Neurosteroids and Postpartum Depression

Samantha Meltzer-Brody, MD, MPH, founder and director of the University of North Carolina Perinatal Psychiatry Program of the UNC Center for Women’s Mood Disorders, provided an update on the development of neurosteroids, which are allopregnanolone derivatives developed to treat postpartum depression (PPD) as well as refractory MDD.

“Mental health issues not only weigh down new mothers but often go untreated, leading to $14.2 billion in economic costs,” she told the APA audience. Maternal mental health markedly worsened during the COVID-19 pandemic.

The postpartum period is considered crucial for maternal-infant bonding and attachment. Untreated or poorly treated PPD can leave lasting negative effects for the mother, infant, and partner. PPD is a unique subtype of MDD, impacting an estimated 11.5% of new mothers in the United States each year, and it is a substantial contributor to maternal morbidity and mortality.

The precise etiology of PPD is unknown but it may be the result of hormonal changes during pregnancy, altered regulation of stress response pathways, hypothalamic-pituitary axis (HPA) axis activation, dysfunctional gamma-aminobutyric acid (GABA) signaling, and inflammation, among other causes. Acute stress can result in imbalances between GABAergic and glutamatergic signaling, and adaptation to chronic stress may reset the signaling balance at a lower level, contributing to depression.5

Dr. Meltzer-Brody discussed how data implicating the potential role of GABAergic signaling and the GABAA receptor-positive allosteric modulator allopregnanolone in PPD were used to develop brexanolone, the first drug specifically approved by the FDA for the treatment of postpartum depression. Brexanolone is a novel, soluble synthetic formulation of the natural hormone allopregnanolone and acts as a positive allosteric modulator of the GABAA receptor, thereby increasing the activity of the GABAA receptor protein in the CNS.

Prior to the approval of brexanolone in March 2019, the standard of care for PPD primarily has been to prescribe a drug from the selective serotonin reuptake inhibitor (SSRI) class, but these antidepressants may take weeks to months to take effect and they do not directly target any of the proposed mechanisms of PPD.5 Results of three double-blind, randomized, placebo-controlled trials in women with PPD showed that brexanolone, which is given as a 3-day intravenous infusion, reduced PPD symptoms within 24 hours of administration with sustained effects for at least 30 days after infusion. Because of its sedative side effects, brexanolone must be administered in full compliance with a Risk Evaluation and Mitigation Strategy (REMS) program.

Depression and Brain Stimulation: SAINT Advances

Nolan Williams, MD, director of the Stanford Brain Stimulation Lab at Stanford Medicine, California,  presented recent data on accelerated theta-burst stimulation, which targets theta wave activity and appears to induce positive change for patients with TRD in less than 3 days. The treatment appears to be faster in onset than traditional repetitive transcranial magnetic stimulation (rTMS) and to be safe.

rTMS delivers bursts of highly concentrated magnetic field to the left prefrontal cortex without requiring anesthesia or sedation. The approved method for treatment is 10Hz stimulation for 40 minutes over the left dorsolateral prefrontal cortex (L-DLPFC) for a 6-week treatment course. Intermittent theta-burst stimulation (iTBS) is a newer form of noninvasive brain stimulation with faster and stronger effects that has been approved by the FDA for TRD.

A newer form of iTBS, Stanford Accelerated Intelligent Neuromodulation Therapy, or SAINT, improves on FDA-approved protocols by treating patients with multiple sessions per day at optimally spaced intervals, increasing the number of magnetic pulses, and precision targeting the pulses according to each individual’s neurocircuitry.

Dr. Wiliams reported the results of an open-label trial, in which 19 of 21 participants who were severely depressed at baseline scored within the non-depressed range on diagnostic tests following treatment. In addition, although all participants reported suicidal thoughts before treatment, none reported having such thoughts after treatment.6

During the trial, The SAINT researchers increased the number of pulses from 600 to 1800 per session. Study participants underwent 10 sessions per day of 10-minute treatments, with 50-minute breaks in between. Most participants experienced relief from depression after 3 days of therapy. In TMR, the treatment is aimed at the dorsolateral prefrontal cortex, but in SAINT, researchers used magnetic-resonance imaging to locate a subregion within the dorsolateral prefrontal cortex that has a relationship with the subgenual cingulate, an area that is overactive in those experiencing depression. Stimulating this region reduces its activity, allowing the dorsolateral prefrontal cortex to resume its role in regulating executive functions. In fact, cognitive testing before and after treatment showed that participants’ ability to switch between mental tasks and to solve problems had improved, indicating they were no longer depressed. One month after treatment, 60% of participants were still in remission.6

Citing the statistic that one-third of those with MDD will develop TRD, Dr. Williams noted that such patients are stuck in “ER purgatory,” as psychiatry beds are overloaded three-fold, and electroconvulsive therapy  (ECT), while effective, has only a 48% remission rate in TRD. “Ironically,” he said, “as you increase acuity in major depression, you lose the number of treatments that work, unlike disorders such as cardiovascular disease, where as you increase acuity, the number of treatments increases.” As treatments that rely on alternative mechanisms of action continue to evolve, it is hoped that more patients with TRD will achieve rapid and long-lasting benefits.


Last Updated: May 25, 2021