Treatment-Resistant Depression

Being told your depression is resistant to treatment can be incredibly disheartening. You may worry that nothing will work, which is a heavy load on top of the depression symptoms you’re already experiencing.

Treatment-resistant depression is typically defined as depression that has not responded adequately to at least two antidepressant trials. Though it’s normal to expect some symptom relief after two kinds of medication, it’s also normal to take several tries until you find something that works for you.^[1]

Understanding what to do when antidepressants fail is the first step toward finding alternative treatment-resistant depression options. This article will cover:

• What treatment-resistant depression is, its causes, and its risk factors.
• Why depression relapse and resistance occur.
• Advanced depression treatment options.
• Therapy for options for treatment-resistant depression in adults.

What Is Treatment-Resistant Depression (TRD)?

Treatment-resistant depression (TRD) doesn’t currently have an official definition, which makes it difficult to discuss its prevalence, risk factors, and effective treatments with certainty.^[2]

However, the most commonly used definition of TRD is an “inadequate response to a minimum of two antidepressants”.^[2] About 30% of people with depression may potentially have TRD. However, many more will have poor treatment outcomes due to not adhering to medication plans or being prescribed inadequate treatments.^[2][3]

Major depressive disorder resistant cases are concerning, as the rate of suicidality, including death by suicide, is disproportionately higher in people with treatment-resistant depression.^[2]

It’s crucial that you get relief for your symptoms so that your life can return to some normality and that you can have a better sense of well-being. This is possible, but it is first necessary to understand why you may have developed TRD and the many options available to you.

Causes of Treatment-Resistant Depression

People with treatment-resistant depression have very similar experiences to those with depression. The causes of these conditions are most likely the same, which include:^[4]

• Adverse experiences in childhood, such as abuse or neglect.
• Stressful life events, such as bereavement or financial difficulties.
• Certain thinking styles, such as blaming yourself or ruminating frequently.
• Co-occurring mental health problems, such as anxiety or post-traumatic stress disorder (PTSD).
• Long-term physical health problems that cause pain or impact lifestyle.
• Conditions that affect the brain and nervous system.
• Sleep problems.
• Hormonal changes, such as thyroid problems or those relating to the menstrual cycle.
• A family history of depression.
• Using alcohol and substances.
• Inadequate sleep, exercise, or diet.

Despite depression and treatment-resistant depression having the same root causes, experts have identified several risk factors that typically reduce the effectiveness of depression treatments.^[2]

Risk Factors for Developing Treatment-Resistant Depression

The factors that can hinder depression treatments can be clinical or related to life experiences. These include:^[2][3]

• Being an older adult.
• Being a woman (although this could be because women are more likely to experience depression generally).
• Lower income, education, or unemployment.
• Maltreatment in childhood.
• Childhood emotional abuse.
• Stressful life events.
• Experiencing longer depressive episodes.
• Co-occurring mental health conditions, such as personality disorders or substance use.
• Experiencing psychotic or anxiety symptoms alongside depressive ones.
• Physical health conditions like type 2 diabetes, osteoporosis, metabolic syndrome, and cardiovascular disease.

While these factors put you at greater risk of TRD, they don’t mean that there are no feasible alternatives to antidepressants. There are several other treatment options that could work effectively. Understanding complex treatment cases, depression relapse, and resistance patterns can help you and your provider choose the most appropriate ones.

Treatment-Resistant Depression Options

When depression is diagnosed as being resistant to treatment, your doctor may first suggest switching or combining antidepressants.^[2] If you don’t want to try another antidepressant, you can ask them about alternative chronic depression treatment strategies.

Below are several of the other treatments available, which you can ask your doctor about. These new treatments for depression in adults provide opportunities for those who have not responded to traditional approaches.

Ketamine Therapy for Depression in Adults

Ketamine therapy for depression in adults is one of several advanced depression treatment options now available for those with TRD. Ketamine is a psychedelic and dissociative drug that’s used both medically and recreationally. It can produce:^[5]

• Dissociation.
• Sedation.
• Pain relief.
• Feelings of euphoria.

Ketamine has been used as an anesthetic for decades, but has more recently been discovered as a potentially effective treatment for depression.^[5]

Ketamine (administered by injection) and esketamine (administered by nasal spray) are effective treatments for treatment-resistant depression. Research finds that it can rapidly improve suicidal ideation and other depression symptoms, typically within 40 minutes.^[2][5]

Usually, ketamine is prescribed alongside an antidepressant and administered under medical supervision. You should receive guidance for avoiding misusing ketamine, as its euphoric high can be addictive for some people.^[2][5]

Furthermore, it should be avoided or used with caution for the following groups of people:^[5]

• Those with a history of schizophrenia or psychosis
• Those with a history of substance use disorder
• Teenagers
• Pregnant women and those who are breastfeeding
• Older people with dementia symptoms

Ketamine is not a cure for TRD; it only alleviates symptoms for a certain amount of time. It is possible that ketamine therapy will become less effective over time, which means the dosage may need to be continually increased.^[5]

This is something that will need to be discussed with your provider, with the benefits and potential downsides weighed up.

Antipsychotic Medications for Depression

Your doctor may suggest a prescription for antipsychotic medication alongside an antidepressant. This has been found to be effective; in particular, second-generation antipsychotic medications such as aripiprazole, brexpiprazole, and quetiapine XR.^[2]

Only the combination of olanzapine (antipsychotic) and fluoxetine (antidepressant) has been FDA-approved for treating TRD. However, your primary care doctor may explore other combinations with you.^[2]

You may not wish to take this route, however, as antipsychotic medications come with a different range of side effects, and there are other options available.

Transcranial Magnetic Stimulation (TMS) Therapy

Another FDA-approved option for treating TRD is transcranial magnetic stimulation therapy (TMS).^[2] In TMS sessions, brief magnetic pulses are applied to your brain, which stimulates it non-invasively. Typically, you’ll have five daily treatment sessions for 3-6 weeks.^[6]

Higher frequency TMS sessions have been found to alleviate symptoms of depression, while lower frequencies can alleviate both anxiety and depression. Research finds that:^[6]

• People have lower cortisol (a stress hormone) the morning after sessions.
• TMS has remission rates of between 30-40%.

These TMS therapy depression results make it a viable option for people who want to try something other than medication.^[6]

Electroconvulsive Therapy (ECT)

Though its name can evoke frightening images of mid-twentieth-century psychiatry, modern electroconvulsive therapy (ECT) is an effective intervention for treatment-resistant depression. It’s also used for people with bipolar disorder and schizophrenia.^[2]

ECT is administered under anesthesia, so that you don’t feel any pain. It uses an electric current to stimulate small seizures in the brain, which are thought to alter brain chemistry to alleviate symptoms of depression.^[7]

The effectiveness of ECT for depression is well-established. Trials found that suicidal ideation is relieved in:^[7]

• 38% of people after 1 week.
• 61% of people after 2 weeks.
• 81% of people after a complete course of ECT.

Despite its effectiveness, doctors will be cautious to recommend ECT if your cardiovascular system is already compromised, if you’re pregnant, or if you’re elderly.^[7]

Psychedelic Treatments

Though not yet approved by the FDA, clinical trials are finding psychedelic substances to be effective at treating TRD, as well as PTSD and other conditions.^[1]

Psilocybin is the psychoactive compound found in hallucinogenic mushrooms, which gives users a psychedelic experience similar to LSD. If it is approved by the FDA, psychedelic treatments will likely be administered in controlled environments with psychotherapists on hand to give support.^[1][3]

Early clinical trials suggest psilocybin is well-tolerated in clinical settings, although people may experience transient moments of anxiety and body shakes. One study of people with treatment-resistant depression found that almost 60% were still responding to the treatment up to three months after.^[3]

While clinical trials are the only way you could legally try this treatment at the moment, psilocybin-assisted therapy may receive FDA approval in the coming years.

Psychoeducation

Psychoeducation is essentially learning about your brain, body, and mental health. For example, it’s very common in cognitive behavioral therapy (CBT) to be taught about the body’s stress response and how it can contribute to anxiety disorders.

If you have treatment-resistant depression, psychoeducation could be a helpful option alongside other treatments. Whether it’s delivered by your primary care doctor or a therapist, psychoeducation can teach you:^[1]

• How long it takes for mental health medication to build up in your system.
• How to weigh the benefits and side effects of medications.
• Lifestyle factors that contribute to depressive symptoms, such as sleep, exercise, and substance use.
• Thoughts and behaviors that maintain a cycle of depression.

Often, psychoeducation is provided in directive forms of counseling and psychotherapy, such as CBT. However, it’s worth asking therapists for other approaches if you’re interested.

Counseling and Psychotherapy

Though counseling and psychotherapy are not proven to be effective treatments for TRD on their own, they’re found to offer significant relief of depression symptoms for TRD when combined with antidepressants.^[2]

In particular, people with TRD and a history of trauma respond well to psychological interventions like therapy.^[2] Therapy for resistant depression can address underlying patterns and provide coping strategies that medication alone may not offer.

Find Evidence-Based Support for Treatment-Resistant Depression With Mission Connection

At Mission Connection, we understand how difficult it is to try multiple treatments and see no significant change.

We treat a range of mental health conditions, prioritizing outpatient treatment approaches that are both evidence-based and personalized. That means that your treatment will be effective and cater to your unique needs and circumstances.

If you’re looking for treatment for depression in adults, we offer the following proven methods:^[2][3]

• Cognitive behavioral therapy (CBT)
• Mindfulness-based cognitive-behavioral therapy (mCBT)
• Transcranial magnetic stimulation
• Dialectical behavioral therapy (DBT)
• Short-term dynamic psychotherapy

We know how busy life can be, which is why we offer flexible outpatient treatment program options, including in-person treatment at our locations, virtual telehealth, and hybrid programs that combine in-person and virtual care.

If you’d like to hear more about how we can help you find depression treatment that addresses your needs, call us at 866-833-1822 or reach out to us online. We’re here to help support you in any way we can.