Thyroid Augmentation of Mirtazapine: A Case Report

Sir: Depression is a common but debilitating illness in the United States with a prevalence rate ranging from 4.8% to 9.2% in primary care practice.¹ Fortunately, there are many antidepressant medications to treat patients with depression. However, up to 46% of patients treated with antidepressants do not adequately respond to treatment.² A smaller number—5% to 10%—will continue to experience depression despite numerous therapeutic interventions.³ Clinicians are then left to treat these patients who do not experience a full response using a number of treatment options.

We describe the case of a patient diagnosed with depression who, having not previously responded to 2 classes of antidepressants, partially responded to a third class and achieved remission with thyroid hormone augmentation. To our knowledge, augmentation of mirtazapine with thyroid hormone has not previously been reported.

Case report. Ms. A, a 33-year-old woman, was diagnosed with a major depressive episode, severe without psychotic features (DSM-IV criteria). Her symptoms included a loss of energy, decreased concentration, insomnia, anxiety, guilt, and a feeling of hopelessness. She was experiencing an inability to take care of her family, had quit her job as an aerobics instructor, and had stopped her college studies. She had no previous psychiatric history and enjoyed good physical health. Ms. A denied the use of alcohol, tobacco, or illicit substances. She was taking hydrochlorothiazide, 25 mg/day, for essential hypertension and denied the concurrent use of over-the-counter medications. Her family physician had prescribed her nortriptyline, 100 mg/day, which she took for 6 weeks prior to stopping it due to bothersome side effects and not feeling better. Her physician then started her on fluoxetine, 20 mg/day, shortly after stopping nortriptyline treatment. Early on, she felt that the fluoxetine made her anxiety worse; fluoxetine caused her headaches, nausea, loose stools, and an overall feeling of restlessness. This trial was cut short after a week. Ms. A then was referred to the psychiatry service, but in the lapse overdosed with a combination of trazodone given to her for insomnia and the remaining supply of fluoxetine. She was initially admitted to the medical intensive care unit, where her condition was stabilized prior to her transfer to the psychiatry service.

Once Ms. A was at the psychiatry ward, it was decided after initial workup to initiate a trial of mirtazapine, 15 mg, to target her constellation of depressive and anxious symptoms. Because mirtazapine potentially induces orthostatic hypotension, the medication was given at bedtime to diminish the possibility that such an effect would be problematic. The treatment team also felt that mirtazapine would be a good choice given Ms. A's previous problems with continued loose stools following treatment with fluoxetine. Buspirone, 5 mg t.i.d., was also started to help treat her anxiety. Over the next 10 days, mirtazapine was titrated up to 30 mg/day, and her mood improved slightly. Ms. A's suicidal ideation had dissipated, and she readily contracted for safety and was discharged home.

At the first outpatient follow-up appointment, Ms. A voiced wanting to discontinue buspirone, which she did not feel was helping her. She also was impatient with regard to not feeling better despite reassurance about the time necessary for antidepressants to begin to work. She did not feel she could wait a full 8 weeks for a fair therapeutic trial. A decision was made to augment her mirtazapine with levothyroxine (T₄) at 50 µg/day titrated up to 200 µg/day over the following 2 weeks. Prior to initiation of treatment with T₄, her thyroid-stimulating hormone level was checked and found to be within normal limits (0.71 µIU/mL). Over the next 2 to 3 weeks, Ms. A noted a significant improvement. She started back to school, began to exercise again, and took the reins in the daily running of the household. Her mirtazapine dosage was increased to 45 mg/day, and the daily T₄ dosage was tapered by 25 µg/week. Ms. A continues to participate in bimonthly supportive therapy and is maintained on mirtazapine, 45 mg daily, with no noted adverse side effects.

A number of options exist for clinicians to treat patients who do not adequately respond to antidepressants. Those options include switching to a different class of antidepressant, augmenting with lithium or thyroid hormone, combining classes of antidepressants, electroconvulsive therapy, steroid suppression therapy, and/or augmenting with atypical antipsychotics.⁴ Other options include addition of psychostimulants, buspirone, pindolol, yohimbine, and tryptophan.⁵ Transcranial magnetic stimulation is a recent arrival to the list of treatment options.³ Joffe² points out that substitution or switching classes is the most widely used treatment for patients who fail to respond to an antidepressant and the most widely used by both psychiatrists and family physicians. He states that there is no evidence in the literature suggesting that substitution is more efficacious than augmentation or combination strategies.²

In the above case, I describe a patient who had partially responded to mirtazapine, had not tolerated buspirone, and was impatient to wait for completion of a full therapeutic trial. Reportedly, 80% of psychiatrists would also not wait a full 8 weeks in making a therapeutic change in a patient not responding.⁶ Nelson⁵ also points out that augmentation may be a more attractive strategy in severely depressed patients, since it avoids the time lost in tapering one agent while adding a second and can be helpful in an impatient patient. I decided to augment with T₄, although triiodothyronine (T₃) is more widely used and studied.² Joffe is reluctant to interpret the findings over the last 25 to 30 years as indicating that T₃ is more effective than T₄.² I also felt that I was at a point in treatment where an augmenting agent would possibly show efficacy; Nelson⁵ writes that agents are rarely added after an extended period (> 1 month). To my pleasure, Ms. A had a favorable response after adding T₄, and I continued T₄ treatment for another 3 weeks prior to tapering it.

To my knowledge, this is the first reported case of successful augmentation of mirtazapine with thyroid hormone. Single case reports should be interpreted with caution, but this finding suggests that further studies are needed looking at the benefits of augmentation strategies in combination with mirtazapine. As the number of Americans diagnosed with depression increases, the number of patients prescribed antidepressants will increase as well. In 1998, approximately $5.52 billion were spent on antidepressants.⁷ Family physicians will no doubt see the majority of those patients and will be faced with treatment dilemmas in the partial, slow, or nonresponders. These very patients may well benefit from augmentation strategies like the one described here.

Conclusions and opinions expressed are those of the authors and do not necessarily reflect the opinion or policy of the U.S. Government, Department of Defense, Department of the Army, or the U.S. Army Medical Command.