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What Do I Do When My Antidepressant Stops Working?

Approximately 25 percent of patients with major depressive disorder (MDD) experience a recurrent depressive episode while on an adequate maintenance dose of antidepressant medications, according to a 2014 metanalysis published in Innovations in Clinical Neuroscience. The clinical term for this medication poop-out or antidepressant tolerance is antidepressant treatment (ADT) tachyphylaxis. While psychiatrists and neuroscientists don’t know exactly why this happens, it could be due to a tolerance effect from chronic exposure to a medication.

I address this topic because I have experienced antidepressant poop-outs myself, but also because I often hear this concern from persons in my depression communities: What do I do when my antidepressant stops working? 

The following strategies are a blend of clinical suggestions from the metanalysis mentioned above and other medical reports I’ve read, as well as my own insights on recovering from a relapse.

1. Consider all reasons for your relapse.

It’s logical to blame the return of your depressive symptoms on the ineffectiveness of a drug; however, I would also consider all other potential reasons for a relapse. Are you in the midst of any life changes? Are your hormones in flux (perimenopause or menopause)? Are you experiencing loss of any kind? Are you under increased stress?Did you just start therapy or any kind of introspective exercise? I say this because I experienced a relapse recently when I starting intensive psychotherapy. While I am confident it will lead to long-term emotional resiliency, our initial sessions triggered all kinds of anxiety and sadness. I was tempted initially to blame the crying and emotional outbursts on ineffective medication, but soon realized that my pills had nothing to do with the pain.

Watch out especially for increased levels of stress, which will commonly drive symptoms.

2. Rule out other medical conditions.

Another medical condition can complicate your response to medications or contribute to a worsening mood. Some conditions that are associated with depression include: vitamin D deficiency, hypothyroidism, low blood sugar, dehydration, diabetes, dementia, hypertension, low testosterone, sleep apnea, asthma, arthritis, Parkinson’s disease, heart disease, stroke, and multiple sclerosis. Get a thorough check up with a primary care physician to rule out any underlying condition.

Make sure to test for a MTHFR gene mutation, how you process folate, which can definitely affect antidepressant results. If you experience any elevation of mood with your symptoms of depression, be sure to discuss those with your doctor. More than half of people with bipolar disorder are misdiagnosed as clinically depressed and don’t receive the proper treatment they need, including a mood stabilizer.

3. Take your medication as prescribed.

Before I list some of the clinical suggestions, it’s worth mentioning that many people don’t take their medication as prescribed. According to a 2016 review in the World Journal of Psychiatry, about half of the patients diagnosed with bipolar disorder become non-adherent during long-term treatment, a rate similar to other chronic illnesses. Some psychiatrists assert that the real problem isn’t so much the effectiveness of medications as much as it is getting patients to take medications as prescribed. Before switching up your medication, ask yourself: Am I really taking my meds as prescribed?

4. Increase the current antidepressant dose.

Increasing the dose of an antidepressant is a logical next course of action if you and your doctor determine that your relapse has more to do with a medication poop-out than anything else. Many patients take too little medication for too short period of time to achieve a response that can last. In a 2002 review in Psychotherapy and Psychosomatic, doubling the dose of Prozac (fluoxetine) from 20 to 40mg daily was effective in 57 percent of patients, and doubling the 90mg from once weekly to twice weekly was effective in 72 percent of patients.

5. Experiment with a drug holiday or lowering the antidepressant dose.

Since some medication poop outs are a result of a tolerance built up from chronic exposure, the metanalysis recommends a drug holiday among its strategies for tachyphylaxis, however this needs to be done very carefully and under close observation. In some patients where the symptoms are severe, this is not a feasible option. The length is of a drug holiday varies, however the minimum interval required to restore receptor sensitivity is typically three to four weeks. This all seems counterintuitive, however, in some studies, like the one by Byrne and Rothschild published in Clinical Journal of Psychology, decreasing the dosage of an antidepressant led to positive results.

6. Change your drug.

Your doctor might want to switch medications, either to another drug in the same class or to another class. You may need to try several medications to find one that works for you, according to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, the largest and longest study ever conducted to evaluate depression funded by the National Institute of Mental Health (NIMH).

If the first choice of medication does not provide adequate symptom relief, switching to a new drug is effective about 25 percent of the time. It might make sense to introduce a drug that has an entirely different mechanism of action in order to regain the response blunted by the drug tolerance of the one you’re on.

The transition between meds needs to be handled carefully. Typically it’s better to introduce the new drug while tapering off the old, not to quit it abruptly.

7. Add an augmentation drug.

According to the STAR*D study, only one in three patients in the first sequence of monotherapy (that is, taking one drug) achieved remission. Meta-analyses of antidepressant trials of nonchronic patients with major depressive disorder report remission rates of 30 to 45 percent on monotherapy alone. Augmentation drugs considered include dopaminergic agonists (i.e. bupropion), tricyclic antidepressants, buspirone, mood stabilizers (lithium and lamotrigine), antipsychotic medications, SAMe or methylfolate, and thyroid supplementation. According to STAR*D, adding a new drug while continuing to take the first medication is effective in about one-third of people.

8. Try psychotherapy.

According to a 2013 Canadian Psychology Association report, mild to moderate depression can respond to psychotherapy alone, without medication. They found that psychotherapy is as effective as medication in treating some kinds of depression and is more effective than medication in preventing relapse in some cases.

Also, for some patients, the combination of psychotherapy and medication was more beneficial than either treatment on its own. According to a study published in the Archives of General Psychiatry, adding cognitive therapy to medication for bipolar disorder reduced relapse rates. This study examined 103 patients with bipolar 1 disorder who, despite taking a mood stabilizer, experienced frequent relapses. During a 12-month period, the group receiving cognitive therapy had significantly fewer bipolar episodes and reported less mood symptoms on the monthly mood questionnaires. They also had less fluctuation in manic symptoms.

It’s normal to panic in the days and weeks your symptoms return; however, as you can see, there are many options to pursue. If the first approach doesn’t work, try another. Persevere until you achieve full remission and feel like yourself again. It will happen. Trust me on that.

What Do I Do When My Antidepressant Stops Working?

Therese J. Borchard

Therese J. Borchard is a mental health writer and advocate. She is the founder of the online depression communities Project Hope & Beyond and Group Beyond Blue, and is the author of Beyond Blue: Surviving Depression & Anxiety and Making the Most of Bad Genes and The Pocket Therapist. You can reach her at thereseborchard.com or on Facebook, Twitter, Instagram, or LinkedIn.


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APA Reference
Borchard, T. (2019). What Do I Do When My Antidepressant Stops Working?. Psych Central. Retrieved on April 25, 2019, from https://psychcentral.com/blog/what-do-i-do-when-my-antidepressant-stops-working/
Scientifically Reviewed
Last updated: 11 Mar 2019
Last reviewed: By a member of our scientific advisory board on 11 Mar 2019
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