New and Emerging Treatments for Major Depressive Disorder

In my clinical work, patients with “treatment-resistant depression” are among the most difficult to treat. Unfortunately, up to 30% of people diagnosed with major depressive disorder (MDD) are resistant to traditional drug treatments (Jaffe et al 2019).

In December 2323, Amelia Talbot blogged about the experience of treatment-resistant depression and the need to rethink treatment, including more innovative approaches. It was therefore heartening to read Njenga and all‘s state of the art overview published in the BMJ in July of this year (Njenga et al., (2024).

Their goal was to create a ‘narrative review focusing on new and emerging treatments for MDD (at each stage of the treatment cycle, from first episode to treatment failure) and their effectiveness, safety, and real-world applicability.’ Today I will summarize this review.

Sprouts of hope for treatment-resistant depression?

Methods

The team searched PsycINFO, Medline, EMBASE, and Web of Science using the search terms: “depression*” AND “novel treatment*” OR “emerging treatment*” OR “innovative treatment*” OR “psychedelics” OR “neuromodulation”. They completed the search twice, with both searches covering the period from January 2017 through June 2023.

There were clear inclusion and exclusion criteria for the search to ensure that it was limited to recent new or emerging treatments. They also included only interventional data, not theoretical or observational evidence, so that applicability to clinical practice was maximised. This resulted in 42 articles that were included in the study.

Results

The topics of the selected articles are grouped into two broad categories: pharmacotherapy and neuromodulation, with two articles focusing on psychological interventions in addition to new and emerging interventions.

1. Pharmacological

Psychedelics

• Esketamine and Ketamine
  • Rapid, short-term improvement in suicidality and mood.
  • Limited evidence of sustained improvement, e.g. after 28 days.
  • A Cochrane review of glutamate receptor modulators found that ketamine was more effective than placebo.
  • ECT (electroconvulsive therapy) may be better.
  • Clinical application – 40 minute infusions once a week for several weeks are already being used in healthcare systems including the NHS as a mainstream alternative to ECT.
• Psilocybin
  • Drug psychotherapy (2 therapists who support each other for a maximum of 10 hours during use).
  • Rapid improvement in mood with a lasting effect after 28 days.
  • Compared to escitalopram, there is no statistical difference after 6 weeks.
  • There is new evidence that it increases suicidal behavior.
  • Clinical application – Scalability can be an issue as each treatment requires two therapists, taking up to 10 hours.
• Ayahuasca and dimethyltryptamine – traditional herbal medicine from the Amazon region.
  • An open-label study and one RCT have shown some short-term improvement in MDD.
  • There are serious gastrointestinal side effects with vomiting, which may limit wider use.
  • Clinical application – single dose with support if necessary.
  • Current data do not support broader use.

New treatments

• Neuropeptide Y – intranasal adjuvant to antidepressants; beneficial effects after 24 hours, but not longer than 48 hours.
• Minocycline – positive effect as an addition to antidepressants, but monotherapy is unclear.
• Nonsteroidal anti-inflammatory drugs – Celecoxib tested as an adjunctive treatment, with positive results so far.
• Statins – Adjunctive treatment versus antidepressants alone has shown positive effects.
• Omega-3 fatty acid – Tested as monotherapy or as an adjunct, where a significant reduction in symptoms was found.
• Buprenorphine samidorphaan – daily supplementation has shown greater reduction in depressive symptoms than placebo.
• Onabotulinumtoxin A – Single injection in the glabellar region; monotherapy or adjunctive. Significant antidepressant effect compared to placebo.

There is much interest in psychedelics as a possible adjunctive treatment, for example psychedelic-assisted psychotherapy.

2. Neuromodulation

Transcranial Magnetic Stimulation (TMS)

Repetitive transcranial magnetic stimulation (rTMS) is a form of neuromodulation that involves the targeted use of magnetic fields to primarily stimulate the dorsolateral prefrontal cortex (DLPFC) and is recommended by NICE for moderate to severe MDD. Newer regimens and modalities include:

• Accelerated TMS (aTMS): more effective than sham therapy, but not significantly more effective than rTMS after 4 weeks.
• Theta burst stimulation (continuous cTBS or intermittent iTBS): more effective than sham therapy. Effect lasted 2 weeks or 4-6 weeks. iTBS greater response and remission after 3 months than rTMS.
• Stanford neuromodulation therapy (SNT): iTBS accelerated mean reduction in depression scores at 1 week and remained significant at 4 weeks.
• Low Field Magnetic Stimulation (LFMS); no more effective than sham therapy.

Bilateral TBS has the potential to be the most effective of the 16 neuromodulation procedures evaluated for treatment-resistant depression. Although TBS or aTMS may not be more effective than rTMS, both can be administered in a significantly shorter time frame than rTMS and are well tolerated, so they may have greater clinical utility.

New treatments

• Transcranial direct current stimulation (tDCS) – more effective than sham therapy in vascular depression. ‘Non-inferior’ to sham therapy in other forms of depression. tDCS and CBT have no significant antidepressant effect compared to CBT or CBT and sham therapy.
• Clear light therapy – as part of triple chronotherapy produced a rapid and sustained antidepressant effect. With rTMS greater reduction of depressive symptoms than rTMS alone.
• Photobiomodulation – significant reduction in symptoms compared to sham therapy.
• Deep Brain Stimulation (DBS) – DBS appears less effective than rTMS; higher discontinuation rates than sham therapy.
• Magnetic seizure therapy – ‘non-inferior’ to ECT, but with a higher discontinuation rate.

Newer forms of transcranial magnetic stimulation (TMS) can be administered more quickly and are well tolerated.

Conclusions

Psychedelics and newer forms of repetitive transcranial magnetic stimulation have emerged as the main new treatments being tried for MDD. Research on psychedelics to date has shown rapid onset of short-term improvements in mood and suicidality, although with limited sustained benefit.

Of the emerging pharmacotherapeutic agents, minocycline currently appears to be the most promising. Bright light therapies offer an intriguing mechanism for enhancing the effects of other forms of neuromodulation.

However, the authors emphasize that

The treatment of MDD requires a holistic, bio-psychosocial approach and so the psychological and social aspects must be considered alongside the treatment of the neurobiological aspects. Some of the most robust evidence has been for treatments that combine psychedelic interventions with psychological support.

Strengths and weaknesses

There is no specific critical appraisal process for state-of-the-art reviews, but some principles of systematic review can be applied to assess this research.

There was a clear focused question/interest area and they were specifically looking for intervention papers that could then be applied in practice. Many papers were removed from the search, although with clearly documented rationale. The results were grouped into pharmacological interventions and neuromodulation and this may have been contributed to by some of the search criteria specifically mentioning psychedelics and neuromodulation, which could be seen as selection bias. I wonder if they had included specific psychological terms in their search (e.g. third wave interventions, mindfulness etc) whether this would have resulted in additional papers? In short, this review is a decent summary of psychedelics and neuromodulation for depression, but it is not a comprehensive summary of all the new and emerging treatments for major depressive disorder, so the title is a little misleading.

The results and quality of studies are commented on without combination, allowing the reader to merge the results. As this was a narrative review, there was no summative assessment of the papers, potentially leaving the reader with more questions than answers.

This state-of-the-art overview shows the interest in future care options.

Implications for practice

As a clinician, it is incredibly helpful for me to have the evidence in one place about potential treatment options for patients with severe ‘treatment-resistant depression’. It also helps me to understand the evidence so that I can support patients in participating in future research protocols.

For these new and emerging treatments to gain wider acceptance, their effectiveness will need to be compared to that of established treatments. The authors have suggested possible future research questions (below) that I fully agree with, and we should see these types of results before we can move forward with robust treatment regimens.

Possible research questions:

• Which psychotherapeutic approaches are most effective in enhancing and maintaining the antidepressant effect of psychedelic drugs in people with major depressive disorder?
• What measures should be taken to monitor the misuse, effectiveness, and adverse outcomes of new and emerging treatments for people with depressive disorders?
• What is the clinical and cost-effectiveness of new and emerging treatments for people with MDD compared to existing treatments?
• Are there specific patient groups for whom new and emerging treatments for MDD are better indicated?

I also wonder how they will overcome the problem of how to blind the intervention with such different treatment modalities and effects? Here’s a cover of a psychedelic rock classic to listen to while we all ponder the possibilities…

Declaration of interests

I have no conflict of interest with respect to this article

Links

Primary paper

Njenga C, Ramanuj PP, the Magellan FJC, Pins HA. (2024) New and Emerging Treatments for Major Depressive Disorder BMJ 2024; 386 :e073823 https://doi.org/10.1136/bmj-2022-073823

Other references

Jaffe DH, Rive B, Denee TR (2019). The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry 2019;19:247. doi:10.1186/s12888-019-2222-4

Photo credits