Depression Therapy Ketamine Therapy Spravato Treatment

How To Treat Treatment-Resistant Depression 

7 min read

Symptoms of treatment-resistant depression (TRD) vary in severity and may require searching for multiple approaches to find effective relief. If you’ve previously attempted antidepressant treatments without success, there’s no need to worry. It could simply mean that the right dose, medication, or combination of treatments tailored to your needs is yet to be determined by your current healthcare provider.

What Is Treatment-Resistant Depression?

Treatment-resistant depression (TRD) refers to a condition where standard treatments for depression, such as antidepressant medications and psychotherapy, fail to alleviate symptoms effectively. While feeling sad or hopeless occasionally is a normal part of life, individuals with depression may experience these feelings intensely and persistently, impacting their daily functioning at work, home, or school. Usually, depression is managed through a combination of antidepressant medication and psychotherapy, which proves effective for many individuals. However, around 10–15% of people with depression do not experience significant improvement with antidepressants. An additional 30–40% may notice only partial relief of their symptoms despite treatment efforts.

When depression does not respond adequately to two different trials of antidepressant medications from distinct classes, it is classified as treatment-resistant depression. This condition is also known as treatment-refractory depression, signifying its resistance to conventional therapeutic approaches.

For individuals experiencing treatment-resistant depression, standard treatments prescribed by primary care doctors may not be sufficient. In such cases, seeking specialized care from mental health professionals who specialize in treating resistant forms of depression is recommended. These experts can provide tailored approaches and therapies that may offer better outcomes for managing this challenging condition. 

If you suspect you or someone you know may have treatment-resistant depression, seeking professional guidance can lead to more effective treatment strategies and improved quality of life.

How Is Treatment-Resistant Depression Diagnosed?

Unlike many medical conditions, there’s no single test to definitively diagnose treatment-resistant depression. It’s a diagnosis reached through a process of elimination and careful evaluation by a mental health professional. The threshold for diagnosing treatment-resistant depression (TRD) hinges primarily on the lack of response to antidepressant medications despite adequate trials. 

Doctors typically consider treatment-resistant depression (TRD) if a patient hasn’t gotten better after trying at least two different types of antidepressants from different classes, at the right doses, and for long enough (usually 6-8 weeks). But before confirming TRD, further evaluation is important for a few reasons. First, it’s crucial to make sure the initial diagnosis of depression is correct, since other conditions can look like depression. Also, things like anxiety disorders or medical problems that haven’t been diagnosed could be making the depression harder to treat and need attention. Checking how well someone is taking their medication, including the right amount and sticking to the schedule, is also key. Sometimes adjusting these factors can help improve symptoms. 

While antidepressants usually take time to start working fully, if they haven’t helped after a reasonable period, it may be time to try different treatments tailored to handle TRD. Even though it can be tough, getting a diagnosis of TRD is an important step towards creating a personalized plan with healthcare providers to better manage depression.

What Causes Treatment-Resistant Depression?

Several theories attempt to explain treatment-resistant depression (TRD), shedding light on potential underlying reasons: 

Missed Diagnosis
One theory suggests that some cases of TRD may stem from misdiagnosis. Individuals experiencing symptoms resembling depression may actually have conditions like bipolar disorder or other mental health disorders that require different treatment approaches. Correctly identifying the underlying condition is crucial for effective treatment.

Genetic Influence
Genetics likely play a significant role in TRD. Variations in certain genes may affect how antidepressants are metabolized in the body, potentially reducing their effectiveness. Moreover, genetic factors can influence how individuals respond to antidepressant medications overall. While more research is needed, genetic testing is increasingly being explored to tailor treatment plans and identify antidepressants that may work best for each patient.

Metabolic and Nutrient Factors
Another theory focuses on metabolic factors and nutrient processing. Research suggests that individuals with TRD may have differences in how they process certain nutrients. For example, low levels of folate in the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) have been linked to poor response to antidepressant treatment in some studies. However, understanding the reasons behind these metabolic differences and their exact connection to TRD requires further investigation.

How Is Treatment-Resistant Depression Treated?

While the term “treatment-resistant” might sound discouraging, there are effective strategies to manage TRD. It may simply involve finding the right approach that works best for you. Here’s a breakdown of some common treatment options:


When initial antidepressants fail to produce results, your doctor may suggest trying a medication from a different class. These classes target various brain chemicals involved in regulating mood. Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly tried first, but other options include Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs), and more. Combination therapy, using two antidepressants from different classes, can sometimes yield better results than monotherapy.


While medications are crucial, managing treatment-resistant depression (TRD) often requires a multifaceted approach: 

Techniques such as Cognitive Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT) provide tools to manage negative thinking patterns and enhance interpersonal skills, which can significantly affect mood. 

Brain Stimulation Techniques
Evidence-based treatments like Repetitive Transcranial Magnetic Stimulation (rTMS) and Electroconvulsive Therapy (ECT) are effective for severe depression. These methods use magnetic pulses or electrical currents to stimulate nerve cells in the brain.

Spravato Nasal Spray Treatment

Spravato (esketamine) nasal spray is a prescription medication used in combination with an oral antidepressant to treat adults with treatment-resistant depression (TRD) and adults with major depressive disorder (MDD) who have suicidal thoughts or actions. In clinical trials lasting 4 weeks, Spravato effectively reduced depression symptoms compared to a placebo when used alongside an oral antidepressant. The most significant improvement typically occurred within the first 24 hours after administration. Following this initial trial, participants who showed significant improvement continued into a year-long study, where Spravato continued to demonstrate effectiveness in maintaining reduced depression symptoms and preventing relapse compared to the placebo.

Other Strategies

Beyond the medications, therapy, and treatments, there are also some strategies you can try to manage your TRD effectively, such as:

Lifestyle Changes

Incorporating regular exercise, such as aerobic activities or strength training, not only improves physical health but also enhances mood by promoting the release of endorphins and reducing stress hormones. Healthy sleep patterns, including maintaining consistent sleep schedules and practicing good sleep hygiene, are crucial for regulating mood and cognitive function. A balanced diet rich in fruits, vegetables, whole grains, and lean proteins provides essential nutrients that support overall well-being and can positively impact mental health. 

Light Therapy

Light therapy, also known as phototherapy, involves exposure to artificial light sources that mimic natural sunlight. It is particularly effective for individuals with seasonal affective disorder (SAD), a type of depression that typically occurs during certain seasons, usually winter. Light therapy helps regulate the body’s internal clock and improves mood by enhancing serotonin production, thereby alleviating symptoms related to disrupted sleep-wake cycles and seasonal mood changes. 

Investigating Underlying Conditions

Addressing undiagnosed medical issues, such as thyroid disorders or chronic pain conditions, is crucial as these conditions can contribute to depressive symptoms and treatment resistance. Additionally, identifying and treating co-existing mental health conditions like anxiety disorders or substance abuse disorders can significantly improve outcomes in managing treatment-resistant depression. Comprehensive evaluation by healthcare professionals ensures that all contributing factors are adequately addressed to optimize treatment efficacy and patient well-being.

Manage Your Treatment-Resistant Depression with Spravato

If you’re seeking effective treatment for treatment-resistant depression (TRD), consider Spravato (esketamine) Nasal Spray Treatment. It’s an FDA-approved prescription nasal spray used alongside an oral antidepressant to help adults with TRD. Unlike traditional oral antidepressants that primarily increase neurotransmitter levels like serotonin, norepinephrine, and dopamine, Spravato targets the N-methyl-D-aspartate (NMDA) receptor in the brain, though its exact mechanism isn’t fully understood. Clinical trials have demonstrated positive outcomes, making Spravato a potential option for those who haven’t responded well to other treatments. 

To determine if Spravato nasal spray treatment is suitable for your needs, contact Marpa Minds, a Westchester County-based Spravato treatment clinic dedicated to providing you with the relief you have been seeking. Contact us today or call us 1877-88-MARPA.