10 Possible Solutions for Treatment-Resistant Depression

Hoping for some relief, people with treatment-resistant depression (i.e., difficult-to-treat depression) have often tried a variety of interventions. For instance, some have tried contemplative practices such as mindfulness meditation; some, deep brain stimulation and similar neurostimulation treatments; others, psychedelics like psilocybin (magic mushrooms).

But do these interventions work? And what does the latest research say about safe and effective ways of managing the symptoms of severe depression?

Published in the October 2023 issue of World Psychiatry, a recent paper by R. S. McIntyre and collaborators discusses the diagnosis and evidence-based management of treatment-resistant depression. Here's what it found.

What is Treatment-Resistant Depression?

According to the Food and Drug Administration (FDA), treatment-resistant depression requires failure to respond to two or more antidepressants. But many other definitions have also been proposed. Most of these differ in the following ways:

• Number of interventions (e.g., unresponsive to one versus two, three, or more treatments).
• Importance of baseline symptom severity.
• Significance of comorbidity (e.g., personality disorders).
• Intervention type (e.g., pharmacological augmentation, psychotherapy, electroconvulsive therapy).

Over 100 million people around the world meet the criteria for treatment-resistant depression, according to at least one of the definitions.

Treatment-resistant depression is costly, not only for individuals but also for society. It is associated with greater impairment in functioning, physical illnesses (e.g., heart disease, diabetes, obesity), work absenteeism, need for disability benefits, health care utilization, carer burden, and the frequency and intensity of interventions required to manage it.

Risk Factors

Risk factors for treatment-resistant depression include the following.

• Lower socioeconomic position: Lower income and education.
• Adverse experiences: Life stress and history of childhood trauma and emotional abuse.
• Certain clinical factors: Higher baseline severity and duration of depression, anhedonia (i.e. inability to experience pleasure), anxiety, psychotic symptoms, comorbid diseases (metabolic syndrome, heart disease, diabetes, osteoporosis), and cognitive deficits—especially deficits in attention, working memory, processing speed, and executive function.

Effective Management of Treatment-Resistant Depression

So, what works in managing difficult-to-treat depression? According to the available evidence, the following 10 strategies may be worth pursuing.

1. Extending the antidepressant trial: Research shows that a proportion of patients who have not responded to antidepressants in the first four to six weeks may respond during the five to eight or even nine to 12 weeks.
2. Switching antidepressants: If the current medication is not tolerated well, it may be helpful to switch antidepressants, especially to one with a different mechanism of action (e.g., from SSRIs to SNRIs or tricyclics).
3. Combining antidepressants: Using multiple medications can relieve residual symptoms, as in the case of mirtazapine for insomnia; and help manage side effects, as in the case of bupropion for SSRI-induced sexual dysfunction.
4. IV Ketamine: Intravenous ketamine has been shown to not only reduce suicidal ideation but also improve certain depressive symptoms more quickly than SSRIs.
5. Intranasal esketamine spray: Esketamine is typically used in combination with (but not a replacement for) an antidepressant. Akin to IV ketamine, esketamine is associated with rapid improvement of symptoms, especially suicidality. Preliminary evidence suggests it is also superior to the second-generation antipsychotic quetiapine.
6. Second-generation antipsychotics: Some evidence suggests the antipsychotic olanzapine, when combined with the SSRI fluoxetine, might be another effective therapy for difficult-to-treat depression.
7. Electroconvulsive therapy (ECT): ECT is one of the most effective interventions for managing treatment-resistant depression. Yet it is underused, partly due to tolerability concerns and other barriers such as stigma and lack of skilled ECT practitioners.
8. Repetitive transcranial magnetic stimulation (rTMS): Like ECT, rTMS is a neurostimulation therapy. Furthermore, in its newer forms (e.g., the Stanford Neuromodulation Therapy), it is generally more acceptable to patients and associated with fewer side effects. According to a 2022 investigation, “16 out of the 17 studies” reviewed found rTMS to be “effective, safe and tolerated.”
9. Vagus nerve stimulation: Vagus nerve stimulation is another effective neurostimulation therapy. It has been approved by the FDA for the management of depression in patients who have not responded to at least four antidepressant trials.
10. Psychotherapy: Evidence supports the use of psychotherapy as an adjunct—that is, in combination with antidepressants. The modalities most often studied are interpersonal psychotherapy, cognitive behavioral therapy (CBT), and mindfulness-based cognitive therapy.

Concerns and Risks

Potential problems associated with interventions for difficult-to-treat depression include the following.

• High cost and lack of availability: This is true of many newer interventions, like vagus nerve stimulation.
• Drug-drug interactions: Combining antidepressants (SSRIs, tricyclics, MAOIs) increases the likelihood of adverse drug reactions such as serotonin syndrome.
• Insufficient data on long-term use: For instance, we need long-term data on the efficacy of rTMS and the safety and tolerability of IV ketamine (particularly, withdrawal effects and abuse potential).
• Side effects: Antipsychotics, for instance, are associated with significant side effects, including metabolic syndrome (abdominal weight gain, high blood sugar, abnormal cholesterol) and extrapyramidal symptoms (muscle spasms, tremors, rigidity, restlessness).

Takeaway

To manage depression that has not responded to only one previous antidepressant, useful strategies include a trial of second-generation antipsychotics, rTMS, and adjunctive psychotherapy.

To manage depression that has not responded to multiple antidepressants, the authors recommend esketamine nasal spray, IV ketamine, adjunctive psychological therapies, ECT, and rTMS.

Meanwhile, many other therapies are under investigation. Some examples are S-adenosylmethionine, anti-inflammatory agents (e.g., COX-2 inhibitors, statins), buspirone, dextromethorphan-bupropion combination, lithium, L-methylfolate, thyroid hormone, and zuranolone.

Significant research has focused on psychedelics such as psilocybin—and for good reason, given the promising preliminary findings.

Depression Essential Reads

Tackling Treatment Resistant Depression with Multiple Tools

What Fitness Exercises Treat Depression the Best?

In short, numerous effective treatment options are available and many new ones are being studied.

If You Have Difficult-to-Treat Depression

If you have treatment-resistant depression, talk to your doctor about the advantages and disadvantages of different interventions, including the best antidepressant for you.

In the meantime, you can make healthy lifestyle changes that may improve both your physical and mental well-being. So, try to get sufficient sleep, exercise regularly, eat healthy, and use stress-reduction techniques (e.g., deep breathing, yoga, meditation, relaxation training).

To find a therapist, please visit the Psychology Today Therapy Directory.

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