New systematic study for managing treatment-resistant bipolar depression

Depression in bipolar illness is often difficult to treat and life-threating. Frequently it fails to respond to standard treatments. In the current issue of Psychotherapy and Psychosomatics a new drug combination is suggested. A case of treatment-resistant bipolar depression with a robust remission after treatment with the combination of buspirone 5 mg and melatonin 3 mg plus bupropion 75 mg added to lithium and lamotrigine (with prior failure of high-dose lithium and lamotrigine alone) is reported.

A 35-year-old single white unemployed female with onset of bipolar I disorder (that met full DSM-IV criteria, first for a major depressive episode then followed by a full manic episode) at the age of 23 has had recurrent episodes of severe treatment-resistant bipolar I depression and experienced yet another episode that had persisted for 24 months [the mean Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) score was 14 - moderate severity (SD = 4.1; maximum = 23, minimum = 6) with the minimal score of 6 sustained for no more than 2 weeks]. She would typically meet full DSM-IV criteria for a bipolar major depressive episode along with irritability and anxiety and intense hopelessness with frequent suicidal ideation. Her current episode of chronic depression did not respond to multiple treatments (given at maximally tolerated doses for at least 6-8 weeks usually in combination) including lithium carbonate 900 mg (level 0.9 mEq/l) plus lamotrigine 400 mg, carbamazepine 800 mg, aripiprazole 30 mg, olanzapine 5 mg (intolerant), ziprasidone 160 mg (intolerant), fluoxetine 80 mg, duloxetine 90 mg, selegiline patch 6 mg, modafinal 400 mg, acamprosate 666 mg, N-acetyl-cysteine 2 mg and 11 unilateral electroconvulsive therapy treatments plus 3 hospitalizations for suicidal ideation.Previous treatments for past episodes that had been tried included lamotrigine plus lithium, mood stabilizers plus multiple antidepressants, plus trials with olanzapine and quetiapine, and a trial of pramipexole. She had a prior treatment with electroconvulsive therapy that had not helped. She had trials of formal cognitive behavioral therapy and dialectical behavioral therapy that also did not help during the current chronic depressive episode. After 7 weeks of treatment with the selegiline patch 6 mg, her QIDS-SR score was 20 (severe range). Selegiline was discontinued. She was then restarted on lamotrigine (with appropriate taper-up), controlled-release lithium carbonate 900 mg plus buspirone 5 mg and melatonin 3 mg. Bupropion 75 mg was added 10 days later. After 3 weeks, the QIDS-SR score was 13 (moderate) without mania or hypomania. After 15 weeks, the QIDS-SR was 14 (moderate) and after 19 weeks, it was 2 (normal range) without any symptoms of depression, mania, hypomania, anxiety or irritability. Her remission has been sustained for 3 months, the longest period thus far that she has felt well in the past 15 years. She resumed school, earning top grades and was able to move in with her boyfriend. On further follow-up, she discontinued the melatonin after 3 months because of daytime sedation, continued on the buspirone, bupropion, lithium and lamotrigine and has sustained a full remission for another 7 months, for a total of 10 months.

In this complex case, a sustained response occurred after buspirone, bupropion and melatonin had been added to lithium and lamotrigine. While it is possible that this patient responded to lithium and lamotrigine alone, it is unlikely given that she had not responded to this combination earlier during this episode of depression. Buspirone and melatonin were combined to help with anxiety and insomnia in the context of discontinuing monoamine oxidase B inhibitor selegiline and to set up the combination of buspirone and bupropion. It is also possible that this patient could have responded to the buspirone and melatonin alone, to buspirone and bupropion alone or to any combination of the 5 medications. Stopping the melatonin after 3 months and continuing on the other 4 medications further complicates interpreting cause and effect. Of course, it is possible that she simply cycled out of her depression, but this is unlikely given that this resistant episode had lasted for 2 years and after treatment she felt the best she had in 15 years.

In summary, this case brings up the intriguing possibility that low-dose buspirone plus melatonin and low-dose bupropion added to a mood stabilizer may be worthy of further systematic study for the management of treatment-resistant bipolar depression.