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Depression Therapy

What Is Treatment-Resistant Depression?

7 min read

While depression is usually highly responsive to treatment, with between 70% and 90% of individuals experiencing positive outcomes, there are some cases where conventional interventions prove ineffective. Despite the effectiveness of medications and psychotherapy for most, there are some individuals that struggle with treatment-resistant depression.

For individuals who are facing severe depression, hospitalization or participation in an outpatient treatment program may be necessary until symptoms alleviate. However, when even with treatment, improvement seems unattainable, this could indicate treatment-resistant depression.

What is treatment-resistant depression?

When treatment proves to be ineffective for you, you might have TRD.

Treatment-resistant depression (TRD) is a major depressive disorder (MDD) that is characterized by persistent depressive symptoms despite the use of multiple antidepressants. Although there’s no universally accepted definition for this mental health condition, TRD is usually identified when at least two different first-line antidepressants fail to alleviate symptoms, even when taken at adequate dosages and for a sufficient duration (usually six to eight weeks). TRD happens to individuals when the traditional treatments for depression or first-line antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), do not work. These medications are commonly prescribed due to their relatively mild side effects compared to the other antidepressants. However, TRD can develop even in individuals who initially responded well to these medications.

How common is treatment-resistant depression?

Contrary to popular belief, treatment-resistant depression is actually common among individuals who are diagnosed with major depressive disorder. Approximately 30% of the people diagnosed with major depressive disorder who have tried medications for their condition experience TRD, meaning their depressive symptoms still persist even if they already had multiple treatment attempts.

What are the symptoms of treatment-resistant depression?

The symptoms of treatment-resistant depression are similar to the symptoms of major depressive disorder.

  • More Severe Symptoms
    Symptoms of depression in TRD are often more intense and debilitating compared to MDD.
  • Prolonged Depressive Episodes
    Depressive episodes in TRD tend to last longer, with symptoms persisting despite treatment interventions.
  • Anhedonia
    Individuals who are diagnosed with TRD frequently experience anhedonia, characterized by a reduced ability to experience pleasure from activities once enjoyed.
  • Increased Lifetime Depressive Episodes
    People that have TRD typically have a history of more depressive episodes over their lifetime compared to those with non-resistant depression.
  • Anxiety
    Anxiety symptoms are commonly comorbid with TRD, contributing to increased distress and functional impairment.
  • Suicidal Ideation and Behavior
    Individuals who are diagnosed TRD are at a higher risk of experiencing suicidal thoughts and engaging in suicidal behavior compared to those with non-resistant depression. 

What causes treatment-resistant depression?

Treatment-resistant depression is a complex depressive condition with causes that may differ from person to person. Here are some several factors that may contribute to the development of TRD:

  • Biological Factors
    There are some differences in the brain chemistry or neurobiology of an individual that can impact how they respond to antidepressant medications. Variations in neurotransmitter systems, such as serotonin, norepinephrine, and dopamine, may play a role in treatment resistance.
  • Genetic Predisposition
    An individual’s genetic factors can influence their susceptibility to depression and their response to antidepressant treatments. Family history of depression or TRD may increase the likelihood of developing treatment resistance.
  • Underlying Medical Conditions
    There are some certain medical conditions, such as thyroid disorders, chronic pain conditions, or neurological disorders, can exacerbate or contribute to depression and may make treatment more challenging.
  • Psychological Factors
    Some coexisting mental health disorders like anxiety disorders or substance use disorders, can complicate the treatment of depression and contribute to treatment resistance.
  • Environmental Stressors
    Chronic stress, trauma, adverse childhood experiences, or ongoing life challenges can impact mood regulation and increase the risk of treatment resistance.
  • Medication Factors
    Non-adherence to prescribed medication regimens, inadequate dosages, or inappropriate medication selection can possibly undermine treatment effectiveness and contribute to treatment resistance.
  • Lifestyle Factors
    The lifestyle of an individual such as their sleep hygiene, lack of physical activity, unhealthy diet, and substance abuse can worsen depressive symptoms and interfere with treatment outcomes.
  • Neurobiological Changes
    Long-term exposure to stress or depression can lead to structural and functional changes in the brain of an individual, which makes it more resistant to treatment interventions over time. 

What are the risk factors for treatment-resistant depression?

Research shows that individuals who are diagnosed with treatment-resistant depression are more prone to various physical health conditions compared to those who have non-treatment-resistant major depressive disorder. These conditions include autoimmune diseases, thyroid disorders, heart disease, and cerebrovascular disease.

How is treatment-resistant depression diagnosed?

Healthcare providers usually diagnose treatment-resistant depression by identifying the depressive symptoms after multiple attempts of medicinal treatment. If the individual’s symptoms still persist after trying two or more antidepressant medications such as SSRIs, SNRIs, Bupropion, and Mirtazapine, then the healthcare provider may refer them to a psychiatrist for further evaluation. The diagnosis is then based on multiple steps that will be undertaken for evaluation, such as:

  • Reviewing all medications, including prescriptions, over-the-counter drugs, herbal supplements, and non-prescribed substances, as some may impede antidepressant efficacy or exacerbate depression.
  • Evaluating medication adherence.
  • Assessing the impact of psychotherapy on managing depression symptoms.
  • Examining physical health conditions that may contribute to or worsen depression, such as thyroid disorders or chronic pain.
  • Investigating substance use concerns.
  • Considering whether other mental health conditions, such as bipolar disorder or personality disorders, better explain your symptoms.

Treatment Options For Treatment-Resistant Depression

How is treatment-resistant depression treated?

Addressing treatment-resistant depression is not easy, as it often involves a series of strategies that require a lot of patience, hope, and perseverance. Initially, during evaluation, your psychiatrist might:

  • Allow more time for your current antidepressant to take effect.
  • Adjust the dosage of your existing first-line antidepressant.
  • Introduce a different class of antidepressant alongside your current medication regimen.
  • Encourage engagement in psychotherapy with a psychologist. Finding the right therapist and modality may require some exploration, as various types of psychotherapy exist.

If these initial approaches prove ineffective, your psychiatrist may suggest alternative medications or therapies. Currently, the U.S. Food and Drug Administration (FDA) has approved five medications for treating TRD:

  • Aripiprazole (Abilify®) and brexpiprazole (Rexulti®)
    Third-generation antipsychotic medications that may modulate serotonin and norepinephrine levels to alleviate depression symptoms.
  • Quetiapine (Seroquel®) and olanzapine (Zyprexa®)
    Second-generation antipsychotics. Quetiapine is endorsed as an adjunct to antidepressants for TRD, while olanzapine is approved when combined with fluoxetine (Prozac®). These medications may influence dopamine levels and have sedative properties.
  • Esketamine nasal spray (Spravato®)
    An esketamine derivative, FDA-approved in 2019 as an adjunctive treatment for adults with TRD alongside oral antidepressants. Esketamine can rapidly alleviate depressive symptoms within hours but necessitates administration in a clinical setting due to risks of sedation, dissociation, and potential misuse, with post-administration monitoring mandated for at least two hours.

When To Seek Help For Treatment-Resistant Depression 

When should I see my healthcare provider about treatment-resistant depression?

Regular communication with your healthcare provider is crucial when navigating treatment-resistant depression (TRD) to evaluate the effectiveness of your treatment plan. However, specific circumstances warrant immediate attention from your provider:

  • Bothersome Side Effects
    If you experience any bothersome side effects from your medication regimen, it’s important to notify your healthcare provider promptly. They can assess the situation and adjust your treatment as necessary.
  • Lack of Improvement or Worsening Symptoms
    If you notice that your depressive symptoms are not improving or even worsening despite adhering to your treatment plan, it’s essential to inform your healthcare provider. They can reassess your condition and explore alternative treatment options.
  • Consideration of Medication Changes
    If you’re contemplating discontinuing your medication due to concerns or discomfort, it’s crucial to discuss this with your healthcare provider before making any decisions. They can provide guidance and support to address your concerns and explore alternative options if needed.

Always remember that there is hope, and that you are not alone. Around 30% of individuals with major depressive disorder experience treatment-resistant depression, and there are numerous treatment options available. Your healthcare provider and psychiatrist are dedicated to supporting you throughout your journey to find the most effective treatment for your condition. If you’re considering Spravato® ketamine therapy, you can reach out to discuss available options and determine the best course of action for your needs. Whether through direct contact or by calling 1-877-88-MARPA, our team is here to assist you.

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