Management of treatment-resistant depression: Challenges and strategies

This review (2020) details the background and therapeutic challenges associated with treatment-resistant depression. A wide range of treatments are evaluated, including novel therapeutics such as ketamine and psilocybin.

Abstract

“Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder which does not respond to traditional and first-line therapeutic options. There are several definitions and staging models of TRD and a consensus for each has not yet been established. However, in common for each model is the inadequate response to at least 2 trials of antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing literature regarding the challenges and management of TRD has been compiled. A PubMed search was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we address the confounds in the definitions and staging models of TRD, and subsequently the difficulties inherent in assessing the illness. Pharmacological augmentation strategies including lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is switching of antidepressant class. Somatic therapies, including several modalities of brain stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new directions are reviewed in this manuscript. Our review of the evidence suggests that further large-scale work is necessary to understand the appropriate treatment pathways for TRD and to prescribe effective therapeutic options for patients suffering from TRD.”

Authors: Daphne Voineskos, Zafiris J. Daskalakis & Daniel M. Blumberger

Summary

Introduction

Major Depressive Disorder (MDD) and associated mood syndromes can present at any age across the life span, and 30% of people with MDD are resistant to conventional treatments.

Several large-scale clinical trials have examined response rates to traditional therapeutic approaches for depression. However, 1 out of 3 patients remain significantly symptomatic after 2 adequate antidepressant trials have been unsuccessful, and treatment-resistant depression presents its own challenges for therapeutic approaches and effective treatments.

Defining Treatment-Resistant Depression

Although many definitions for treatment resistance have been proposed, the general consensus appears to be 2 unsuccessful trials of antidepressant pharmacotherapy. Several staging models have been proposed to assess levels of treatment resistance in depression. TRD is defined as at least 2 suitable trials of AD without adequate response, although there is not consensus on what constitutes an “adequate response”. The term “difficult-to-treat depression” has been suggested as an alternative term.

Challenges in Assessing TRD

TRD may be difficult to diagnose in patients who were prescribed suboptimal doses of AD or who had early discontinuation of a medication for any number of reasons. When interviewing patients in assessment of TRD, it is important to consider recall bias and to use objective clinical scales and treatment history forms. The ATHF-SF is a standardized approach to assessing the level of treatment resistance in the current episode of depression.

Therapeutic Options for TRD

Lithium

Lithium is a naturally occurring salt that was first used in psychiatric treatment in the 1960s. It is just as effective as second-generation antipsychotics for augmentation of antidepressant pharmacotherapy, but it continues to be under-utilized and under-prescribed.

Thyroid hormone levels have a significant effect on mood, and T3 is usually prescribed in augmentation of AD pharmacotherapy. However, open-label studies have shown some promise, but no statistically significant superiority over augmentation with lithium was discovered.

Second-Generation Antipsychotics

Second-generation antipsychotics (SGAs) have been investigated as adjunctive therapies in combination specifically with current first-line treatment strategies (i.e. SSRIs and SNRIs) for treating TRD. Several large-scale placebo-controlled RCTs have shown that SGAs can be helpful in treating affective illnesses.

Optimizing, Combining and Switching Classes of Antidepressant Pharmacotherapy

Patients with MDD are initially started on selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors as first-line treatments for MDD. Switching to an MAOI after non-response to SSRI/SNRI medications increases response rates, but is associated with poorer tolerance of the MAOI.

Psychotherapy

Psychotherapy may be undertaken in combination with somatic or pharmacological treatments, or on their own once several other interventions have been attempted. Cognitive behavioural therapy appears to have the best effects in the medium and long term.

Brain Stimulation

Electroconvulsive Therapy

ECT is the established best therapeutic option for TRD, but its neurophysiological mechanism of action is yet to be elucidated.

ECT is used to treat TRD, and can be applied 2 – 3 times per week. Over half of the subjects showed an improvement within the first week.

ECT has suffered from extensive stigma in the public eye, likely due to the invasive nature of the treatment and negative portrayals in the media. As a result, only 0.25% of patients with a mood disorder receive ECT, despite significant progress in reducing cognitive side effects.

ECT remains the most effective option to treat TRD, especially in situations where a patient’s life may be at risk.

ECT has a high efficacy rate in treating TRD, with a response rate of up to 75% for Bitemporal Standard pulse ECT and 75% for Right Unilateral Ultrabrief ECT.

Repetitive Transcranial Magnetic Stimulation

rTMS is a form of brain stimulation that targets TRD, among other psychiatric diagnoses. It is applied non-invasively, on the scalp, and usually targeted over the DLPFC using a handheld magnetic coil.

rTMS was initially tested in healthy volunteers, but did not show significant effects in patients with MDD. However, using focal, high-frequency TMS, George and colleagues found strikingly beneficial effects in four of six patients with TRD.

Conventional High Frequency Left DLPFC rTMS

rTMS was found to have a remission rate of 14.1% in the blinded study and approximately 30% in the follow-up open-label trial. It also had an adverse effect discontinuation rate of 4.5%, in stark contrast to the 25.1% discontinuation rate for antidepressant medication.

Deep rTMS

rTMS can be applied with coils of different designs to target areas deeper into the cortex. These coils have been shown to be well tolerated, especially in late-life populations, and may be a further therapeutic option in TRD.

Theta-Burst Stimulation

Theta-burst stimulation (TBS) is a newly developed form of rTMS that delivers bursts of 3 stimuli at a frequency of 50Hz, 5 times per second. It is delivered in either an intermittent (2 s of stimuli then 8 s off for a 10-s train manner) or continuous pattern.

Accelerated rTMS Protocols

Newer protocols of multiple treatment sessions per day have been proposed for patients with TRD who require urgent response.

Neurophysiological evidence supports the use of multiple rTMS sessions in one day, and a dose – response relationship has been posed. A randomized control trial has found no difference in response or remission rates between accelerated and standard rTMS, however there were higher rates of treatment discomfort. Williams et al143 treated 6 patients with iTBS for 5 days, and found that 4 out of 6 achieved remission.

There are several forms of rTMS and numerous approaches attempting to maximize response, so it can be challenging to keep track of the best rTMS approach for patients with TRD. A novel analysis of 81 rTMS studies found that rTMS is an effective and well-tolerated therapeutic option.

Magnetic Seizure Therapy

Magnetic seizure therapy (MST) uses a powerful repetitively discharged magnet to induce focal synchronous activity in the targeted cortical region, which then spreads, resulting in a generalized seizure in a similar procedure to ECT. Few clinical trials have yet to be reported regarding the efficacy of MST in treating TRD, but early studies have shown that MST has a clear antidepressant effect with fewer cognitive or memory side effects. A recent paper reported that high-frequency MST resulted in the highest remission rates in patients with moderately resistant TRD, and that cognitive scores remained unaffected, aside from autobiographical memory scores, which would be expected to decrease over time.

Deep Brain Stimulation

DBS is a permanent neurosurgical implant that stimulates a specific area of the brain. The subgenual cingulate cortex has shown the most promise and has a 92% response rate at 2 years post-implantation.

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is proposed to modulate brain activity via stimulation of the tenth cranial nerve, the vagus nerve. VNS systems require surgical implantation, but transcutaneal systems are not yet FDA approved for TRD.

A large meta-analysis of non-surgical brain stimulation in TRD found that ECT, high frequency left and low-frequency right rTMS and transcranial direct current stimulation (tDCS) were effective. ECT has the best evidence in the literature to enter a maintenance or continuation phase of therapy.

Novel Therapeutics

Ketamine

Ketamine is a widely investigated N-methyl-D-aspartate (NDMA) antagonist that has been shown to have antidepressant effects in patients with TRD. It is considered a rapid acting antidepressant (RAAD) and has a preferential treatment effect in individuals with comorbid anxiety or an “anxious depression”.

Psilocybin

Psilocybin is the psychedelic compound isolated from hallucinogenic mushrooms. It is metabolized by the body into psilocin, a partial serotonin receptor agonist, and has shown promising results in small studies of patients with TRD.

Anti-Inflammatories

Inflammation is increasingly thought to play a role in TRD, and anti-inflammatory therapy may be useful in treating patients who demonstrate markers of inflammation. Infliximab, a tumour necrosis factor antagonist, was investigated in TRD patients with elevated plasma CRP levels.

Novel Therapeutic Compounds and Rapid Acting Antidepressants

Research into MDD and TRD has led to the development of novel therapeutic compounds, including RAADs, cholinergic modulators and GABA modulators. The endogenous opioid system is also of interest in TRD, and novel compounds targeting the delta opioid receptor have shown promise.

A positive allosteric GABAA receptor modulator, SAGE-217, was investigated in a multi-site trial of 89 patients with MDD for its potentially acute antidepressant effects. The drug showed promise in effectively treating TRD.

Conclusions

There are several challenges in treating TRD, not the least of which is the relatively large proportion of patients with MDD who may be classified as having TRD. However, several guidelines have been developed to help treat TRD, but specific guidelines for TRD have not been widely accepted. Despite several guidelines, there is little known about maintaining remission from TRD, aside from ECT. Individualizing maintenance interventions may help save patients the time, frustration and hopelessness that accompanies numerous failed treatment trials.