Some of the most difficult patients to manage in my clinical work are 'treatment resistant depression' and unfortunately, up to 30% of people diagnosed with major depressive disorder (MDD) are resistant to conventional 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 to include more innovative approaches. So reading Njenga was heartwarming and b's most up-to-date review published in the BMJ this July (.
Their goal is toA narrative review focusing on new and emerging treatments for MDD (at any stage of the treatment cycle, from initial episode to non-response) and their efficacy, safety, and real-world application.' Today I will summarize this review.
Germs of hope for treatment-resistant depression?
Methods
The team searched PsycINFO, Medline, EMBASE, and Web of Science using the search terms: “depression*” AND “new treatment*” OR “emerging treatment*” OR “innovative treatment*” OR “psychedelics” OR “neuromodulation”. They completed the search twice, with both searches between January 2017 and June 2023.
There were clear inclusion and exclusion criteria to ensure that the search was limited to recent new or emerging therapies. They also included only interventional data and not theoretical or observational evidence, which maximized applicability to clinical practice. This produced 42 articles included in the study.
Results
From the selected articles, topics were grouped into 2 broad categories: pharmacotherapy and neuromodulation, with 2 articles focusing on psychological interventions as well as new and emerging interventions.
1. Pharmacological
Psychedelics
- Esketamine and ketamine
- Rapid, short-term improvement in suicidality and mood.
- Limited evidence of sustained improvement, eg at 28 days.
- A Cochrane review of glutamate receptor modulators found ketamine to be more effective than placebo.
- ECT (electroconvulsive therapy) may be superior.
- Clinical application – infusions of 40 minutes per week for several weeks are already used in health systems, including the NHS, as an off-licence alternative to ECT.
- Psilocybin
- Medication-facilitated psychotherapy (2 therapists providing support for up to 10 hours during use).
- Rapid mood improvement with definite lasting effect in 28 days.
- Compared to escitalopram, there is no statistical difference at 6 weeks.
- Emerging evidence that it increases suicide.
- Clinical application – Scalability can be an issue as 2 therapists are required for up to 10 hours per treatment.
- Ayahuasca and dimethyltryptamine – traditional Amazonian herbal medicine.
- An open-label study and 1 RCT showed some short-term improvement in MDD.
- Significant gastrointestinal side effects with vomiting that may limit wider use.
- Clinical application – single dose with support as needed.
- Current data do not support wider use.
Emerging treatment methods
- Neuropeptide Y – intranasal supplement for antidepressant; It has a beneficial effect in 24 hours, but does not last after 48 hours.
- Minocycline – positive effect in addition to antidepressants, but monotherapy is not clear.
- Non-steroidal anti-inflammatory drugs – Celecoxib has been tested as an adjunctive treatment with positive results to date.
- Statins – Only additional treatment against antidepressants has a positive effect.
- Omega-3 fatty acid – Tried as monotherapy or as an adjunct and found significant reduction in symptoms.
- Buprenorphine-samidorphan – daily supplementation showed a greater reduction in depressive symptoms compared to placebo.
- Onabotulinumtoxin A – Single injection in the glabellar area; monotherapy or addn. Significant antidepressant effect compared to placebo.
There is great interest in psychiatry as potential adjunctive therapies, such as 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 modes and forms include:
- Rapid 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. The effect lasts for 2 weeks or 4-6 weeks. iTBS has greater response and remission at 3 months than rTMS.
- Stanford Neuromodulation Therapy (SNT): accelerated iTBS resulted in mean reductions 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 16 neuromodulation procedures evaluated for treatment-resistant depression. Although neither TBS nor aTMS is more effective than rTMS, both can be administered for a significantly shorter time than rTMS and are well tolerated, so they may have greater clinical utility.
Emerging treatment methods
- 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 did not have a significant antidepressant effect over CBT or CBT and sham therapy.
- Bright light therapy – showed rapid and sustained antidepressant effect as part of triple chronotherapy. Greater reduction in depressive symptoms with rTMS than with rTMS alone.
- Photobiomodulation – significant reduction of symptoms compared to sham therapy.
- Deep Brain Stimulation (DBS) – DBS was found to be less effective than rTMS; 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 delivered more quickly and are well tolerated.
Results
Psychedelic and newer forms of repetitive transcranial magnetic stimulation have emerged as major new treatments being tested for MDD. Psychiatric research to date has shown rapid onset of short-term improvement in mood and suicidality, albeit with limited sustained benefit.
Among the pharmacotherapy agents in development, minocycline offers the most promise. Bright light therapies offer an interesting mechanism for enhancing the effects of other forms of neuromodulation.
But the authors emphasize that
Treatment of MDD requires a holistic, bio-psychosocial approach, and therefore psychological and social should be considered in addition to neurobiological treatment. Indeed, some of the strongest evidence has been for treatments that combine psychological support with psychological interventions.
Strengths and limitations
There is no specific critical appraisal process for state-of-the-art reviews, but some principles of systematic review can be adopted to help evaluate this research.
There was a clearly focused area of question/interest and they looked specifically at documenting interventions that could then be applied in practice. Despite clearly documented justifications, many documents were excluded from the search. Results were grouped into pharmacological interventions and neuromodulation, and this may have been aided by some search criteria specifically naming psychiatry and neuromodulation, which could be viewed as a selection bias. I wonder if they included specific psychological terms in their search (eg, third wave interventions, mindfulness, etc.) In short, this review is a decent summary of psychedelics and neuromodulation for depression, but it is a comprehensive summary of all new and emerging treatments for major depressive disorder it's not, so the title is a bit misleading.
Results and quality of studies were interpreted without pooling; leave it to the reader to combine the results. As this was a narrative review, no final evaluation was performed on articles that left the reader with more questions than answers.
This modern vision is fueling the appetite for future care options.
Implications for practice
As a clinician, I found it incredibly helpful to gather the evidence in one place; both regarding possible treatment options for patients suffering from significant “treatment-resistant depression” and understanding the evidence to support patient enrollment in future research protocols.
For these new and emerging treatments to be more widely accepted, their effectiveness needs to be compared with established treatments. The authors suggested potential future research questions (below), with which I fully agree, and we need to see these kinds of results before we can move forward with strong treatment regimens.
Potential research questions:
- What psychotherapeutic approaches are most effective in enhancing and maintaining the antidepressant effects of psychedelic agents in people with MDD?
- What measures should be taken to monitor the abuse, misuse, efficacy, and adverse outcomes of new and emerging treatments for people with MDD?
- What is the clinical and cost-effectiveness of new and emerging treatments for people with MDD compared with established treatments?
- Are there specific patient subpopulations for whom new and emerging treatments for MDD are better indicated?
I wonder how they will overcome the problem of how to spoil the intervention with such different treatments and effects? Here's a cover of a psychedelic rock classic to listen to while we all ponder the possibilities…
Statement of interest
I have no conflicting interests related to this paper
Connections
Primary paper
MagellanNew and emerging treatments for major depressive disorder
Other references
Jaffe DH, Rive B, Denee TR (2019). Human 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