Treatment-Resistant Depression: Management Challenges

Treatment-resistant depression (TRD) poses a significant challenge within major depressive disorders due to its resistance to traditional treatments. This review, published in the journal Neuropsychiatric Disease and Treatment, compiled existing literature to analyze the complexities and management strategies of TRD. Despite varying definitions and staging models, the common criterion is the inadequate response to multiple antidepressant trials. Challenges in assessing TRD are highlighted, prompting a review of pharmacological augmentation strategies such as lithium and second-generation antipsychotics, along with switching antidepressant classes. Somatic therapies, including brain stimulation modalities like electroconvulsive therapy and repetitive transcranial magnetic stimulation, are explored. Psychotherapeutic strategies and emerging treatments like ketamine and psilocybin are also discussed. The review underscores the need for further large-scale research to establish effective treatment pathways for TRD, emphasizing personalized approaches tailored to individual patient needs. Overall, it offers insights into managing TRD and informs future research and clinical practice in addressing this complex mental health condition.

Key Findings

1. Prevalence and Definition:

• Around 30% of people with MDD suffer from TRD, which doesn't respond to standard treatments like antidepressants.

• Lack of consensus on TRD definition and staging hinders effective management.

2. Challenges in Treatment:

• The heterogeneity of MDD (varying biological vulnerability, age of onset, symptoms, and comorbidities) complicates treatment.

• Late-life TRD presents unique challenges due to age-related factors and intensifies symptom persistence.

3. Treatment Options:

• Multimodal approaches combining pharmacological, psychological, and brain stimulation therapies show promise.

• Augmentation strategies involve adding non-antidepressant medications like lithium, thyroid hormones, or second-generation antipsychotics.

• Optimizing, combining, and switching antidepressant pharmacotherapy can be effective.

• Psychotherapy, particularly cognitive-behavioural therapy, offers benefits when combined with other treatments.

4. Brain stimulation therapies:

• ECT (electroconvulsive therapy) remains highly effective for severe cases, despite the stigma.

• rTMS (repetitive transcranial magnetic stimulation) is a non-invasive option with proven efficacy.

• Magnetic seizure therapy (MST) and deep brain stimulation (DBS) are emerging alternatives with promising results.

• Vagus nerve stimulation (VNS) offers a unique approach with bimodal response timing.

5. Novel Treatments:

• Ketamine, a rapid-acting antidepressant, has revolutionized TRD treatment, especially for those with comorbid anxiety.

• Psilocybin, a psychedelic compound, shows potential in early research for TRD patients who haven't responded to conventional options.

• Targeting inflammation through medications like infliximab and brexanolone is a promising new avenue.

6. Future Directions:

• Further research is crucial to understanding and effectively treating TRD.

• Developing and evaluating novel therapeutic compounds targeting various neurotransmitter systems holds significant promise.

• Exploring and optimizing combined treatment approaches tailored to individual needs is essential for improving TRD outcomes.

The Challenge of Treatment-Resistant Depression

Several large-scale clinical trials have examined response rates to traditional therapeutic approaches for depression. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the cumulative remission rate after 4 trials of antidepressant treatment (within 14 months) was 67%. Even after sequential treatments, 10% to 20% of the MDD patients remained significantly symptomatic for 2 years or longer. In general, it is accepted that although antidepressant medications can be effective in treating MDD, they fail to achieve remission in approximately 1 out of 3 patients.

Once two adequate antidepressant trials have been unsuccessful, the illness is termed treatment-resistant depression (TRD). TRD can also be associated with prolonged, costly periods of inpatient treatment. Several definitions and criteria have been proposed to identify true TRD, but a consensus has not yet been reached.

Defining Treatment-Resistant Depression

Although many definitions for TRD have been proposed, the general consensus appears to be two unsuccessful trials of antidepressant pharmacotherapy (AD). Several "staging" models to classify levels of treatment resistance have been proposed. The initial model proposed by Thase and Rush included treatment resistance levels ranging from one failed AD trial to a lack of response to electroconvulsive therapy (ECT). Further staging models have included the Massachusetts General Hospital Staging method, which carefully documents the optimization of medication doses and the number of failed medications. The Souery Operational Criteria for TRD provides a slightly different approach to staging TRD as an illness by defining TRD as any single failure of an adequate (6–8 week) trial of an AD. The Maudsley Staging Method (MSM) assesses treatment resistance in depression in a "multi-dimensional" manner. The majority of investigations into TRD utilize the definition of at least two suitable trials of AD without an adequate response. Even the term TRD may not be the ideal term to define a depressive illness that is not responding to therapeutic interventions. The term "difficult-to-treat depression" has been suggested, with the benefit of not introducing any "therapeutic nihilism" to the psychiatrist-patient relationship.

Treatment of TRD

1.Augmentation:

Augmentation, or adjunctive therapy, represents a novel approach to managing TRD. It involves the addition of a second medication, one not typically classified as an antidepressant, to an initial pharmacotherapeutic option. In this section, we delve into three primary augmentation strategies that have demonstrated robust evidence for their efficacy in comparison to placebo.

Lithium

Lithium, a naturally occurring salt, was first employed in psychiatric treatment during the 1960s. Its augmentative benefits are most evident when combined with tricyclic antidepressants (TCAs). Studies have showcased its ability to enhance response rates significantly, even when added to selective serotonin reuptake inhibitors (SSRIs). The STAR*D trial reported a 16% remission rate in patients taking citalopram augmented by lithium. Despite these successes, lithium remains underutilized and under-prescribed, despite its well-documented anti-suicidal properties.

T3: Harnessing the Power of Thyroid Hormones

Thyroid hormones play a pivotal role in mood regulation, with triiodothyronine (T3) being the preferred form for augmenting antidepressant therapy. Studies demonstrate its effectiveness, particularly when used with TCAs. While the augmentation of SSRIs with T3 shows promise, it did not exhibit significant superiority over lithium in the STAR*D trial. Importantly, T3 is better tolerated than lithium and requires less clinical monitoring.

Second-Generation Antipsychotics: A Modern Approach

Second-generation antipsychotics (SGAs) have emerged as promising adjunctive therapies in combination with SSRIs and SNRIs, providing an alternative to traditional augmentative options. Medications such as quetiapine, aripiprazole, olanzapine, and risperidone have shown strong evidence in augmenting antidepressants for TRD. For instance, quetiapine, when combined with SSRIs, yielded up to 48% response and 24.5% remission rates, leading to FDA approval for adjunctive treatment of MDD. Olanzapine has also demonstrated promise in combination with fluoxetine, with a 60% response rate.

Optimizing, Combining, and Switching Antidepressant Pharmacotherapy

When patients do not respond adequately to initial antidepressant treatment, optimizing, combining, or switching classes of medication becomes essential. Both the CANMAT and NICE guidelines provide recommendations on optimizing pharmacotherapy for MDD when patients exhibit a partial or no symptom response to their initial antidepressant trial. While SSRIs and SNRIs serve as first-line treatments, older classes of antidepressants are reserved for later stages. Notably, changing classes of medication after non-response to the initial class of antidepressant pharmacotherapy has been shown to significantly increase response rates. For instance, switching to tricyclic antidepressants (TCAs) after SSRI/SNRI treatment failure has led to response rates of 44–73%. Monoamine Oxidase Inhibitors (MAOIs), including tranylcypromine, phenelzine, and moclobemide, have also proven effective when switching from a TCA. Studies have reported response rates of up to 60%. However, it's important to note that MAOIs come with specific considerations, including dietary restrictions and potential side effects.

Psychotherapy: A Complementary Approach

In cases where traditional pharmaceutical treatments fall short, psychotherapeutic approaches come into play, either in conjunction with other treatments or as standalone interventions. Notably, patients with comorbid personality disorders may experience diminishing returns with first-line pharmacological treatments, making psychotherapy a valuable alternative. A Cochrane review examined various psychological interventions for TRD, including dialectical behavioral therapy, cognitive behavioral therapy, interpersonal therapy, and intensive short-term dynamic psychotherapy. The results indicate that psychotherapy, when combined with standard care, leads to improvements in depressive symptoms, especially when cognitive-behavioral therapy is employed. Cognitive behavioral therapy, in particular, has demonstrated long-term efficacy in reducing depression scores, making it a noteworthy option for managing TRD.

4.Brain Stimulation Therapies

When traditional therapies such as pharmacotherapy and psychosocial interventions fail to provide relief, alternative treatment options become crucial. Brain stimulation therapies have emerged as a ray of hope for individuals struggling with TRD. In this comprehensive guide, we delve into various modalities of brain stimulation, exploring their mechanisms, effectiveness, and the future of TRD treatment.

Electroconvulsive Therapy (ECT) is a well-established, yet often misunderstood, therapeutic option for TRD. ECT involves the application of high-frequency electrical pulses to the brain, inducing a generalized, tonic-clonic seizure. This unique approach remains highly effective, with over 50% of patients unresponsive to traditional antidepressant medication trials experiencing positive outcomes with ECT. Despite its efficacy, ECT has long suffered from a stigma associated with its portrayal in the media, limiting its utilization. However, ECT continues to be the most effective option for TRD, especially in severe cases. Recent research indicates that ECT is particularly beneficial for patients with catatonic or psychotic symptoms, showcasing its versatility in addressing different forms of depression.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain stimulation method that has gained recognition for its efficacy in TRD treatment. This technique involves the repetitive discharge of electromagnetic pulses over the scalp to stimulate cortical neurons, altering neural excitability without inducing seizures. rTMS, approved by various regulatory agencies worldwide, has been the subject of numerous studies and meta-analyses. Accelerated rTMS Protocols: Multiple rTMS sessions in one day have been proposed for TRD patients requiring urgent response. Studies have shown improved remission and response rates, making it a valuable option for those in critical need of rapid treatment.

Magnetic seizure therapy (MST) represents a groundbreaking alternative to ECT. MST uses a powerful magnet to induce focal synchronous activity in the brain, ultimately resulting in a seizure. Unlike ECT, MST offers significantly fewer cognitive side effects, making it a promising option for TRD treatment. Several studies have reported response rates ranging from 38% to 69%, comparable to ECT's efficacy.

Deep Brain Stimulation (DBS) involves the surgical implantation of a device in the brain, targeting specific regions to modulate brain activity. Studies have explored the nucleus accumbens, ventral capsule, striatum, and subgenual cingulate cortex as potential DBS targets. The efficacy of DBS in TRD treatment is evident, with a 92% response rate reported in one study. DBS has shown variable response rates over several months, ranging from 29% to 75%, and appears to improve over time.

Vagus Nerve Stimulation (VNS) offers a unique approach to TRD treatment by modulating brain activity through stimulation of the vagus nerve. While most VNS systems require surgical implantation, recent developments in transcranial systems are promising. The FDA has approved VNS as an adjunctive long-term therapy for TRD in patients who have not responded to multiple medications. Notably, VNS therapy exhibits a bimodal distribution in terms of response timing, with some patients responding acutely while others experience improvements after approximately three months of treatment.

Novel Treatment

Ketamine, originally known for its psychomimetic properties, has emerged as a game-changer in the realm of TRD. This N-methyl-D-aspartate (NMDA) antagonist has swiftly garnered attention as a rapid-acting antidepressant. The intriguing aspect of ketamine's impact is its effect on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors downstream from the initial NMDAR effects. What's truly remarkable is the speed of response. After a low-dose intravenous infusion, the antidepressant effects of ketamine manifest within hours of discontinuation, persisting over several days. Clinical studies have reaffirmed these findings, highlighting a substantial reduction in suicidal ideation among TRD patients. The efficacy of ketamine is particularly pronounced in individuals with comorbid anxiety or "anxious depression." Recent developments have seen the emergence of an intranasal form of esketamine, a ketamine enantiomer, which, when combined with an oral antidepressant, has gained FDA approval for restricted use in TRD. This advancement opens new doors for individuals seeking respite from the clutches of treatment-resistant depression.

The Magic of Psilocybin Psilocybin, the psychedelic compound found in hallucinogenic mushrooms, offers another intriguing avenue in the quest to conquer TRD. Research has primarily focused on small-scale, open-label, or pilot trials examining the potential of psilocybin in patients with TRD. In a study involving 12 TRD patients, high-dose psilocybin displayed impressive response rates of 58% up to three months after administration. These patients received an initial low dose for safety assessment, followed by a subsequent high dose (25mg) one week later. Despite the psychedelic effects lasting approximately six hours, psilocybin's impact endured. It's important to note that transient anxiety and mild tachycardia were observed, but the overall safety and efficacy of psilocybin in TRD are undeniably promising. This psychedelic compound could be a beacon of hope for those who have exhausted conventional treatment options.

Taming Inflammation Inflammation has recently taken center stage in the understanding of TRD. Elevated C-reactive protein and cytokine levels are often observed in patients with Major Depressive Disorder (MDD) and, more specifically, TRD. To counter this inflammation, various strategies have been explored. Initially, cyclooxygenase-2 inhibitors (COX-2 inhibitors) were investigated as augmentation options for traditional antidepressant pharmacotherapy. These inhibitors block prostaglandin production, which tends to be elevated in some TRD patients. More recently, attention has shifted to a tumor necrosis factor (TNF) antagonist, infliximab. This substance has shown promise, particularly in TRD patients with elevated plasma CRP levels. In another breakthrough, the neurosteroid brexanolone, an intravenous form of allopregnanolone, was FDA-approved for the treatment of postpartum depression. By enhancing GABAergic inhibition through allosteric modulation of GABAA receptors, it offers a unique approach to TRD treatment.

Exploring Novel Therapeutic Compounds

As we delve deeper into the pathophysiology of TRD, novel therapeutic compounds are coming to light. These compounds encompass various central neurotransmitter modulators, including opioid, cholinergic, and γ-aminobutyric acid (GABA) modulators. Among these, rapid-acting antidepressants (RAADs) have gained considerable attention, with ketamine leading the way. Novel compounds targeting the delta opioid receptor have shown promise, as have combinations of existing medications like buprenorphine, designed to better target mu and kappa opioid receptors. These combinations are well-tolerated and can induce a moderate antidepressant effect, making them a valuable adjunctive therapy. Furthermore, anticholinergic compounds like scopolamine have been repurposed with favorable results. In patients with MDD, intravenous scopolamine significantly reduced depression and anxiety symptoms within days. The GABA system, too, is under scrutiny due to its downstream effects on the serotonergic and noradrenergic systems, along with evidence of reduced GABA levels in MDD patients. SAGE-217, a positive allosteric GABAA receptor modulator, has shown promise in multi-site trials, offering acute antidepressant effects.

Conclusions

The treatment of TRD presents numerous challenges, chiefly due to the high proportion of individuals with MDD who may transition to TRD. While several traditional and novel approaches have been developed, further research is essential to fully understand and treat TRD effectively.In the absence of widely accepted TRD-specific guidelines, a logical approach involves beginning with the least invasive and most evidence-based interventions. Promising options like iTBS and intranasal esketamine, which have received FDA approval for TRD, show potential.

Reference Articles

Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020). Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatric disease and treatment, 16, 221–234. https://doi.org/10.2147/NDT.S198774

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