During Psych Congress 2023 (September 6-10, 2023; Nashville, TN), Charles DeBattista, DMH, MD, walked attendees through the current state of depression treatment. He highlighted the primary shortcomings of current therapies and identified several upcoming agents progressing through phase II and phase III clinical trials. He also described some interesting device-based interventions used to treat severe depression.

While current antidepressant treatments provide great options to improve the lives of patients struggling with depression. However, there are notable shortcomings in available therapies, as outlined by Dr DeBattista. Most of today’s antidepressant medications have a slow onset of action. Additionally, monoamine agents fail to offer adequate response in a significant percentage of patients, and newer drugs can be very cost prohibitive. Toxicity data for existing antidepressants leaves room for improvement. Finally, the field has yet to identify reliable biomarkers to accurately predict response or tolerability. Fortunately, these are active areas of research today.

Dr DeBattista discussed key findings for novel antidepressant agents, including psychedelics, opiate-like agents, gamma-aminobutyric acid (GABA)-A modulators, N-methyl-D-aspartate (NMDA) antagonists, and combination medications. In recent studies, psychedelics—most notably psilocybin—have statistically significant effects on depression symptoms. Published findings also show rapid onset of action,  durable effects, and tolerable side effect profiles.

Additionally, the use of ketamine and esketamine has recently been evaluated. The effects of ketamine appear to be rapid but repeated doses are required for sustained results.  Furthermore, studies on ketamine tend to be limited due to a lack of sufficient placebo. Esketamine provides increased potency compared to ketamine with promising efficacy. Challenges remain for this category of drugs, such as the risk of abuse and the requirement for observation in acute administration. GABA-A modulators show rapid and sustained improvement in postpartum depression (PPD), with tolerable side effects. However, infusion drugs in this category require lengthy and supervised administration, and they have not been approved for the treatment of major depressive disorder (MDD).

Opiate-like agents are demonstrating rapid, robust, and sustained differences in depression symptoms, as well as encouraging rates of remission. These agents also have favorable adverse event profiles. Interesting combination drugs such as bupropion and dextromethorphan have widespread mechanisms of action and show exciting, sustained improvements in depression scores. Patient-reported depression outcomes are also impressive.

Device-based treatments for depression, such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS), provide exciting options as well. Nonsurgical ECT boasts incredible efficacy rates in treatment-resistant depression (TRD). However, mild-to-severe cognitive side effects have been reported. VNS offers effective relief from TRD but does require an invasive and cosmetically noticeable surgical procedure. TMS offers favorable response and remission rates. The Stanford Accelerated Intelligent Neuromodulation Treatment (SAINT) protocol shows remarkable effects on depression symptom scores within just 5 days of treatment. However, this protocol involves a lengthy administration over the course of 5 days.

Overall, several rapidly acting agents are emerging for depression and TRD, with various administration options. Device-based therapies are also exhibiting exceptionally rapid responses. This exciting time in the field will ideally yield an increase in options for depressed patients, particularly those who are not currently responsive to treatment or have adherence issues with long-term medications.

Reference:
DeBattista C. State of the science: focus on major depressive disorder. Presented at: Psych Congress; September 6-10, 2023; Nashville, TN.