When depression treatments fail, it can leave people feeling hopeless, isolated, and at fault for their own suffering. Medication-resistant depression is a serious condition that affects many people with major depressive disorder (MDD). It can negatively impact family relationships, work productivity, and other responsibilities, as well as increase the risk of suicide.
Keep reading for a deep dive on medication-resistant depression, how to recognize it, and treatment options that are available to help patients take back control over their lives.
Medication-resistant depression, or treatment-resistant depression (TRD), is when a major depressive episode doesn’t go away after trying two or more different antidepressants. It often comes with more serious symptoms, a higher risk for suicidal ideation, and a longer course of illness. Research estimates that up to 31% of people with depression may meet the criteria for medication-resistant depression.
In some cases, antidepressants may only partially relieve symptoms. In others, there may be little to no noticeable improvement at all. When this happens, it may indicate that traditional treatments aren’t enough, and a different approach is needed.
While some improvements in mood can take several weeks, there are certain warning signs that suggest that a medication may not be the right fit. These include:
There are several factors that can contribute to or cause medication-resistant depression. By getting to the root of your diagnosis, your provider will be better equipped to create a treatment plan that’s more effective.
A recent study found that people with high genetic scores for neuroticism, depressive affect, and insomnia were more likely to develop treatment-resistant depression. These traits are linked to emotional instability, negative thinking, and disrupted sleep, all of which can contribute to poor treatment outcomes.
Research shows that those with medication-resistant depression often have elevated levels of inflammatory markers like cortisol. Cortisol is the body’s main stress hormone, or our fight-or-flight response. When cortisol levels stay high for too long, they can destabilize moods, affect sleep, impair memory, and shrink parts of the brain related to emotional control. As antidepressants do not typically address inflammation, medications designed to regulate mood may be less effective or fail to work at all.
In some cases, TRD may not be depression, but undiagnosed bipolar disorder. Many people who experience agitation, racing thoughts, irritability, or impulsive behavior during depressive episodes may not meet the full criteria for bipolar disorder, but they still fall somewhere on the spectrum. When this occurs, antidepressants can worsen symptoms or trigger emotional instability. This is why a correct diagnosis is important because treating bipolar disorder requires a different approach than treating depression.
Treating medication-resistant depression depends on the person, their treatment history, medical conditions, and symptom severity. Once TRD is diagnosed, healthcare providers will work with you to determine your next steps.
Many people with major depressive disorder begin their treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). These are first-line treatments due to their safety and tolerability.
However, when these don’t improve symptoms, older classes of antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), may be considered. While these medications are reserved for later treatment stages due to adverse side effects and dietary restrictions (MAOIs), they can be effective for some individuals who haven’t responded to newer drugs.
In cases where an antidepressant alone isn’t effective, doctors may recommend adjunctive treatment, which is when they add a second medication to boost the first medication. One example is lithium, a mood stabilizer used to treat bipolar disorder. Research shows that lithium is just as effective as second-generation antipsychotics when used to augment antidepressants in TRD.
Second-generation antipsychotics like quetiapine, aripiprazole, olanzapine, and risperidone are also used in combination with antidepressants. These medications can help stabilize mood, reduce agitation, and improve sleep.
While medication can help with depression symptoms, psychotherapy has been found to be just as effective, especially when combined with antidepressants. For many, therapy helps reshape how people view themselves and their illness. Instead of internalizing depression as a personal failure, patients learn to see it as a treatable condition that’s separate from their identity. Common therapies include:
Not every type of therapy will work for every person, and it may even be beneficial to combine strategies from different ones for the most impact. If you feel therapy isn’t working for you, your therapist will be able to find alternative approaches or recommend other treatment options.
Administered in low doses through intravenous (IV) infusions, ketamine can reduce depressive symptoms and suicidal ideation. In clinical studies, more than 50% of patients with medication-resistant depression showed a significant reduction in symptoms after completing a short course of ketamine therapy.
Ketamine is generally well tolerated; however, common side effects may include:
Unlike most antidepressants that can take weeks to work, ketamine’s effects can be felt within 40 minutes of treatment. This is useful in acute cases and for those who need fast relief when other options have failed.
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation that delivers short magnetic pulses through a coil that’s placed against the scalp. The pulses activate mood-regulating areas of the brain without the need for anesthesia or surgery. In a recent study of adults with treatment-resistant depression, 63% responded to TMS treatment, 15% partially responded, and 42% achieved full remission.
Sessions are scheduled five days a week for four to six weeks. Side effects, including scalp discomfort and headaches, are usually mild and temporary. In rare cases, TMS can cause seizures (especially in those with a history of seizures) or trigger a manic episode in someone with bipolar disorder.
Electroconvulsive therapy (ECT) is the oldest brain stimulation procedure and is delivered under general anesthesia. During treatment, a brief electrical current induces a controlled seizure that can change brain chemistry, which may be off balance due to depression.
ECT has shown rapid response and remission in a majority of patients with life-threatening medication-resistant depression. Effects can be seen within a few weeks of treatment.
Vagus nerve stimulation (VNS) is the only FDA-approved implanted neurostimulation therapy for serious, chronic medication-resistant depression. A small pulse generator placed in the chest sends regular electrical impulses to the left cervical vagus nerve and modulates brain circuits responsible for mood regulation.
Typical side effects, including temporary hoarseness, cough, or shortness of breath, happen only during the 30-second stimulation cycles.
If you’re struggling with depression that hasn’t improved despite multiple treatments, you still have options. From psychotherapy and TMS to medication management, Cura Behavioral Health offers comprehensive, evidence-based treatments for medication-resistant depression.
Take the next step today. Contact our office to begin a treatment plan that’s built just for you.
Depression: Managing Resistance and Partial Response to Treatment – American Family Physician
Bipolar spectrum disorder masquerading as treatment resistant unipolar depression – CNS Spectrums
Ketamine for treatment-resistant depression: When and where is it safe? – Harvard Health Publishing
Electroconvulsive therapy for treatment-resistant depression – Progress in Brain Research
Determining if TMS therapy suits your mental health journey should involve consultation with a qualified professional. At Cura Behavioral Health, we provide comprehensive assessments to help you make informed treatment decisions.
Don’t let a mental health condition hold you back any longer. Schedule a consultation with Cura Behavioral Health today. Our experienced team is ready to answer your questions and create a personalized treatment plan tailored to your unique needs.
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Dr. Kevin Simonson, an esteemed Medical Director at Cura Behavioral Health, brings over 15 years of experience in psychiatry. A graduate from a top medical school, he specializes in the treatment of mood disorders and anxiety, employing a patient-centered approach. His dedication to evidence-based care and his commitment to advancing mental health practices have made him a respected figure in the field. Dr. Simonson’s leadership ensures the highest standard of care for the community at Cura Behavioral Health.
