Depression isn’t always easy to treat, even with the right therapies. In fact, approximately 1 in 3 patients with medication-treated major depressive disorder will go on to develop treatment-resistant depression (TRD). 

TRD is defined as a lack of response to at least two different antidepressant treatments at an adequate dose and duration during the current depressive episode. TRD is associated with increased healthcare burden and costs, which can be up to tenfold higher compared to patients without TRD. It also significantly impacts patients' quality of life, functioning, and work impairment. 

Thankfully, even if conventional treatment has failed you or your patients, integrative medicine offers a multitude of therapies to focus on the root cause and get you feeling better. In this article, we will cover what TRD is, what testing can help identify contributing factors, and what therapies are most effective when traditional treatment has failed.

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What is Treatment-Resistant Depression (TRD)? 

Major depressive disorder (MDD) can sometimes evolve into a more stubborn form known as treatment-resistant depression (TRD). Essentially, TRD is characterized by persistent depressive symptoms despite undergoing at least two separate treatments of ample dose and duration, usually involving selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors. If typical treatments prove ineffective, a specialist, such as a psychiatrist, may be needed to explore alternative approaches.

What Are The Diagnostic Criteria For Treatment-Resistant Depression (TRD)?  

The diagnosis of TRD can be somewhat ambiguous, but generally, it is established if depressive symptoms persist despite the use of at least two first-line antidepressant medications, such as SSRIs, SNRIs, bupropion, or mirtazapine, over a duration of six to eight weeks each. Importantly, it's essential to confirm that the patient has adhered to their medication regimen since nonadherence is a common challenge in the treatment of depression. If there's no noticeable improvement, the next step involves a comprehensive assessment by a psychiatrist who reviews your medical and mental health history. This assessment includes a review of all medications, over-the-counter drugs, and herbal supplements you're taking, as some may interfere with the efficacy of antidepressants. 

A psychiatrist would also evaluate your experience with psychotherapy, the presence of any physical health conditions like thyroid disease or chronic pain, and potential substance use issues that could be contributing to or exacerbating depression. Furthermore, the psychiatrist may consider whether a different mental health condition could be more fitting to your symptoms, such as bipolar disorder or a personality disorder. After this thorough evaluation, if your symptoms remain consistent with depression unresponsive to treatment, a TRD diagnosis may be given, and alternative treatment options explored (3,5). 

What Are The Causes of Treatment-Resistant Depression (TRD)?

The causes of TRD are not precisely understood, but a blend of factors, including genetics, brain chemistry, and potentially even chronic stress affecting the hypothalamic-pituitary-adrenal (HPA) axis – a key player in stress adaptation – could be at play (3).  

TRD is also often associated with a range of physical health conditions, such as autoimmune and thyroid diseases, heart disease, and cerebrovascular disease. Other contributory elements could include inconsistent adherence to medication regimens, premature discontinuation of drugs due to side effects, and potential interactions between different medications. Additionally, some medical conditions like heart disease, cancer, thyroid problems, and substance abuse issues can exacerbate depression, making it harder to treat. Finally, a misdiagnosis could contribute to treatment resistance, emphasizing the importance of a precise diagnosis by a mental health expert (3). 

Common Symptoms of Treatment-Resistant Depression

Individuals diagnosed with TRD typically exhibit the common symptoms associated with major depressive disorder, such as persistent low mood, disturbed sleep patterns, and alterations in appetite. However, TRD can often present with certain distinct characteristics, which might include (3):

• An escalation in the intensity of depressive symptoms
• Longer duration of depressive episodes
• A pronounced lack of pleasure or interest in activities (also known as anhedonia)
• An increased number of depressive episodes over one's lifetime.
• Accompanying anxiety
• Frequent thoughts about suicide and potentially suicidal behavior

Functional Medicine Labs That Can Help Individualize Treatment for Patients With Treatment-Resistant Depression

Functional medicine labs offer a variety of tests that can help tailor treatment to patients, allowing providers to optimize management strategies.

Stool Testing

This test provides a comprehensive evaluation of the gut microbiome, which plays an important role in overall health, including mental health. Imbalances in gut bacteria can influence mood and cognition, potentially contributing to conditions such as depression or anxiety.

Neurotransmitters Test 

Neurotransmitters play an indispensable role in maintaining mood balance. This test measures levels of various neurotransmitters and their derivatives, helping to identify imbalances that could be contributing to mood disorders such as depression.

DUTCH Complete Test 

This test offers a comprehensive analysis of hormone production and metabolism, including hormones related to stress, sleep, and thyroid function. Identifying imbalances in these areas can provide insights into the hormonal contributions of TRD (10). 

Autoimmune Profile 

As autoimmune diseases have been associated with TRD, a comprehensive autoimmune profile can help identify any underlying autoimmune conditions that might be contributing to the disorder (3). 

Cardiometabolic Profile 

Cardiometabolic conditions such as heart disease and cerebrovascular disease have been linked to TRD. Therefore, evaluating a patient's cardiometabolic profile can help pinpoint physical health issues that need to be addressed as part of the overall treatment plan (3). 

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Conventional Treatment for Treatment-Resistant Depression

Conventional treatments for TRD encompass a wide range of strategies. Psychotherapy is employed, utilizing different techniques such as cognitive-behavioral therapy (CBT), although evidence for its effectiveness in treatment-resistant cases is limited. Pharmacotherapy is another major approach where a variety of antidepressant medications, including tricyclic antidepressants, monoamine oxidase inhibitors, and second-generation antidepressants, are used, with the choice often based on side effects, patient's history of response, and cost. Electroconvulsive therapy is primarily used for treatment-resistant cases, showing effectiveness, though its long-term effectiveness remains uncertain (5). 

Integrative Treatment Options for Treatment-Resistant Depression

Integrative treatment options for TRD aim to blend conventional and complementary methods. These approaches look beyond standard pharmaceutical and psychotherapeutic interventions to include modalities like lifestyle modifications, nutritional support, and mind-body therapies. An integrative strategy seeks to address the whole individual, considering biological, psychological, and social factors that may be contributing to the disorder. The key goal is to optimize the treatment plan by personalizing it to the individual's unique needs, experiences, and circumstances while improving all factors of health. 

Nutritional Interventions for TRD Treatment

Emerging research underscores the influential role that diet plays in depression, suggesting that a healthy, nutrient-rich diet could potentially prevent and even treat depressive symptoms. Consuming nutrient-dense whole foods, known for their anti-inflammatory properties and support for gut health, is highly recommended for improving mental well-being.

Key nutrients such as folate, B vitamins, omega-3 fatty acids, and zinc, which are vital cofactors to neurotransmitters affecting mood and brain function, should be emphasized in one's diet. For instance, omega-3 fatty acids, available in foods like seaweed, wild fish, and avocados, are crucial for optimal brain function and cognition. B vitamins, abundant in leafy greens, are crucial for neurotransmitter function and nervous system health (15). 

Probiotic-rich foods such as yogurt and kimchi, as well as natural sources of digestive enzymes like pineapple, can counteract dysbiosis, promoting better mental health. Diet can influence mental health via multiple pathways, including inflammation modulation, oxidative stress management, and gut microbiota alteration. Evidence highlights that dietary interventions, particularly calorie-restricted diets, could lead to lower depression scores and improved mental well-being, particularly for individuals struggling with obesity and depression (15). 

Key Nutrients and Supplements that Support TRD Treatment

Herbal medicine is an important complementary therapy with several medicinal herbs demonstrating the potential to improve depressive symptoms. Some notable examples include Camellia sinensis (green tea), which has been linked to mood enhancement through the regulation of the HPA axis; Crocus sativus (saffron), reported to improve symptoms in mild to moderate depression; and Hypericum perforatum (St. John's Wort), a widely known herb with proven clinical efficacy for depression.

Other herbs, such as Echium amoenum (Borage) and Piper methysticum (Kava), have also been tested in clinical trials and found to potentially alleviate depression. Rhodiola rosea (Rose Root) has traditionally been used as a mental booster, and studies show it may repair damaged neuronal cells in the hippocampus, supporting its role in depression treatment. Lastly, Lavandula angustifolia (lavender) has shown antidepressant properties and potential benefits in alleviating depressive symptoms, particularly when used in aromatherapy (23). 

Beyond these herbs, certain nutrients and supplements also play a role in managing depressive symptoms. These include omega-3 fatty acids, known for their mood-regulating properties; vitamin D, deficiency of which has been linked to depression; B vitamins, including niacin, folate, and B12, which support mental health; and specific amino acids like tryptophan, tyrosine, phenylalanine, and methionine, which have been reported to help treat mood disorders, including depression.

Components of an Integrative Medicine Approach for TRD

Integrative medicine approaches for TRD focus on various modalities such as lifestyle changes, well-known therapies such as cognitive-behavioral therapy and electroconvulsive therapy, as well as new alternative pharmacotherapies such as the prescription drug ketamine.

Activities like exercise, yoga, meditation, tai chi, and qi gong have shown potential in alleviating symptoms and improving mental health. In particular, exercise seems highly effective for TRD and PTSD, while yoga and mindfulness-based cognitive therapy have also shown positive results. Add-on psychotherapy, combined with existing treatments, has also shown moderate effectiveness, especially for individuals suffering from severe depression. 

Non-conventional options like deep brain stimulation, exercise, and yoga, already used for other psychiatric disorders, are being studied for their potential in TRD management as well, although the current research is in its infancy. 

In regards to therapies, electroconvulsive therapy (ECT) has been traditionally seen as reliable for treating TRD. Despite this, it has frequently encountered reluctance due to its public image and feasibility concerns. A significant breakthrough was the FDA's approval of intranasal esketamine in 2019, offering a potential alternative to ECT. Furthermore, cognitive-behavioral therapy, esketamine, and risperidone have exhibited substantial effectiveness for TRD.

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Summary

In summary, treatment-resistant depression calls for a comprehensive approach that goes beyond conventional methods. The integration of personalized nutrition, appropriate supplementation, and mindful practices alongside traditional therapies can potentially enhance the effectiveness of TRD management. Continued research is pivotal in refining these strategies and broadening our understanding of TRD. Ultimately, our goal is to ensure more effective and holistic treatment for those enduring this persistent condition.