Dear Colleagues,

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As general psychiatrists, you are often the first point of contact for patients grappling with major depressive disorder (MDD). Your role is not just to treat but to guide your patients through the myriad of treatment options available beyond traditional oral antidepressants.

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Beyond Monoamines: A Call to Action for You

The traditional reliance on monoaminergic antidepressants has been a cornerstone of MDD treatment. However, recent findings, including those from the comprehensive STAR*D study—with over 4,000 patients—suggest that only about one-third of individuals achieve remission after multiple rounds of monoamine-based therapies.

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A recent study by L. Alison McInnes MD, MS, and Tobias F Marton MD, PhD, sheds light on the limitations of traditional monoaminergic antidepressants and introduces a fresh perspective on alternative treatment modalities.

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Key Takeaways from the Review:

• Traditional monoaminergic antidepressants may not be effective for the majority of MDD patients.

• Alternative treatments like brain stimulation, glutamate receptor modulators, and psychedelic medicines show promise.

• Precision psychiatry could guide the selection of these alternative treatments, enhancing patient outcomes.

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The Etymology and Label of “Treatment-Resistant Depression” (TRD) is Limiting

The term TRD may contribute to misconceptions about the nature of depression and inadvertently stigmatize patients. It suggests a one-dimensional view of depression, centered on monoaminergic circuitry, which is increasingly seen as inadequate.

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Understanding Depression Beyond Monoamines

The label “TRD” implies that the patient has not responded adequately to at least two different antidepressant treatments, namely monaminergic antidepressants—which may represent just one subtype of depression, and may not even be the most common subtype. Regardless of the controversies surrounding the re-analyses for the Sequenced Treatment Alternatives for Depression data set, we know that the side-effect profile of serotonin-based drugs, including emotional numbing and weight gain, are intolerable for many patients.

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The current review advocates for a shift in perspective away from a one-size-fits-all approach toward a moer personalized one. Consider depression as a spectrum of biotypes with distinct biological underpinnings, which could respond differently to various treatments like ketamine or esketamine, targeting the glutamatergic system.

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The Emerging Alternatives: Ketamine, Esketamine, and TMS

Since the turn of this century, researchers and clinicians have been gathering experience with mechanistically distinct pharmacological and non-pharmacological treatment options for patients including brain stimulation, glutamate receptor modulators and psychedelic medicines.

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1. Brain Stimulation: Techniques like transcranial magnetic stimulation (TMS) offer new hope, with studies showing a 50% response rate after 4-6 weeks of treatment.
2. Glutamate Receptor Modulators: Drugs like esketamine represent a new class of treatment. For example, esketamine has shown a 50% response rate at 4 weeks, with a significant delay in time to relapse when used as a maintenance therapy.
3. Psychedelic Medicines: Emerging research suggests that substances like ketamine can offer rapid and effective relief for some patients with TRD, with about a 50% response rate at 2 weeks post-treatment.

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Your patients are increasingly informed and may seek out these alternatives independently. It's imperative that you, as their trusted advisor, are well-versed in these options to guide them effectively.

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Current Clinical Decision-Making

While these new treatment modalities have the potential to enhance patient outcomes, clinicians and patients currently lack a framework to guide their choices other than cost, feasibility, personal preference, and certain medical contraindications.The review highlights the need for a more nuanced approach, considering the individual's unique clinical profile and the comparative strengths and weaknesses of available treatments, including ECT, TMS, SGAs, esketamine, and ketamine infusion therapy (KIT).

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Here’s a framework for General Psychiatrists to weigh benefits and harms of 5 current treatment alternatives for depression that is not responssive to monoaminergic agents:

Understanding which treatments align with specific patient profiles can significantly enhance treatment outcomes and patient satisfaction. Here's a detailed guide to help you make informed decisions based on individual patient characteristics:

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Transcranial Magnetic Stimulation (TMS)

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Indications:

• Suitable for patients without significant cardiovascular (CV) risks.
• Can be considered for individuals seeking non-pharmacological interventions.

Contraindications:

• Not recommended for patients with comorbid post-traumatic stress disorder (PTSD).
• Avoid in individuals with implanted metallic devices or deep brain stimulators.

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Electroconvulsive Therapy (ECT)

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Indications:

• Effective for older patients, particularly those with depression and psychotic features.
• Beneficial for individuals with severe depression who have not responded to other treatments.

Contraindications:

• Consider risks in patients with certain cardiovascular conditions, although ECT can be safely administered with appropriate monitoring.

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Second-Generation Antipsychotics (SGAs)

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Indications:

• An option for patients requiring augmentation of antidepressants.

Contraindications:

• Avoid in patients with a high risk of metabolic syndrome or those with cardiovascular risk factors.
• Not recommended for pregnant or breastfeeding women due to potential risks.

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Esketamine

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Indications:

• Useful for patients with TRD, including those with comorbid PTSD.
• Consider for older adults, although response rates may vary.

Contraindications:

• Avoid in patients with uncontrolled hypertension or those with elevated liver enzymes (above three times the normal limit).
• Not recommended for pregnant or breastfeeding women.

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Ketamine Infusion Therapy (KIT)

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Indications:

• Effective for rapid reduction of depressive symptoms, including in patients with suicidal ideation.
• Can be considered for patients with comorbid alcohol use disorder when combined with harm reduction therapy.

Contraindications:

• Not advised for patients with uncontrolled hypertension or elevated liver enzymes.
• Use with caution in patients with a history of substance use disorder.

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The Role of Precision Psychiatry in Your Practice

Precision psychiatry will reshape your approach to treatment. You can advocate for tailored interventions based on individual patient profiles. Subscribe to the Psychiatry Tomorrow newsletter to stay informed about the latest research and developments. Understanding the the unique biological underpinnings of your patients' depression helps you guide them toward the most effective treatment.

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Conclusion:

The study by McInnes and Marton encourages clinicians to look beyond traditional monoaminergic antidepressants and consider a broader array of treatment options for MDD. As precision psychiatry evolves, the future of depression treatment is poised to become more personalized, effective, and hopeful for patients struggling to find lasting relief. These innovations in treatment and treatment selection could relegate “treatment-resistant depression” to the history books.

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Read the full review here.