A 43-year-old male chef was referred for a consultation by another psychiatrist. The chief complaint was, “I have been depressed for 13 years.” He was living with a male friend and spent most of his time in bed, rarely going out of the house. He was found to be disabled by depression and AIDS in 1983.
Describing an onset of symptoms in high school, the patient also gave a history of 2- to 3-week episodes of “hypomania” and mixed states over his past history. He gave a history of five previous hospitalizations, the most recent being 5 years ago. He had no history of suicide attempts despite repeated episodes of suicidal ideation. He had abused alcohol, cannabis, and methamphetamine up until 14 years ago. He gave a family history of a mother and maternal aunt with bipolar disorder and an alcoholic father.
His medication included tranylcypromine (Parnate) 60 mg/day; lithium carbonate 1,200 mg; lamotrigine 175 mg; carbamazepine 1,000 mg; and chlorpromazine 100 mg and mirtazapine 30 mg at night.
In the past, the patient reported a failure to respond to one course of 10 sessions of electroconvulsive therapy (ECT), three SSRIs, two SRNIs, a course of amitriptyline at 250 mg, a course of phenelzine (dose unknown) and a course of tranylcypromine over the past 9 years, with doses ranging from 60 mg daily to as high as 180 mg.
The tranylcypromine was increased gradually to 120 mg and ziprasidone up to 80 mg was added, resulting in significant akathisia. Ziprasidone was discontinued, and quetiapine was given from 400 to 600 mg, resulting in improved sleep at night but no change in depression. Nortriptyline, 25 to 100 mg was added and dextroamphetamine augmentation of 5 to 10 mg twice a day tried with no help noted.
The dextroamphetamine was poorly tolerated and discontinued. Based on the patient’s lack of response, it was decided to taper the patient off of tranylcypromine.
Four weeks later, clomipramine was given from 75 mg to 225 mg at night. Significant mood improvement was noted, but the patient still had some psycho-motor retardation, difficulty initiating behaviors, and poor concentration. The depression gradually recurred and quetiapine was re-added with little antidepressant effect. Clomipramine was discontinued; after 4 weeks, a daily Selegiline patch of 12 mg was given, along with nortriptyline 100 mg, without any response. A second course of 12 bilateral ECT was then given, without response.
Because of these treatment failures and the fact that the patient had shown some antidepressant response to clomipramine, it was given again, this time at an increased dose of 300 mg daily. This time, the patient responded more fully. The patient had applied for vagal nerve stimulation (VNS) implantation and was approved by his insurance carrier, so the procedure was completed despite his improvement on clomipramine, since his sustained response was not predictable.
Shortly after, the patient had a 1-week hypomanic episode characterized by increased spending followed by recurrence of moderate depression. He then eventually remitted on continued clomipramine 300 mg at night and VNS. After 2 months, he again felt withdrawn, and aripiprazole (Abilify) 5 mg increased to 15 mg was added with improvement. The patient’s improvement continued, he became more functional and more social, becoming a deacon at his church. The settings of his VNS device were monitored and increased to the point of him experiencing the side effect of pain in his throat, requiring a decrease in dosage.
Two years after these treatments, the patient had a depressive recurrence with anhedonia, low energy, and insomnia. Pramipexole 0.5 mg (increased to 3.0 mg at night) was added to his regimen. He initially responded, but 2 months later complained of worsening fatigue.
Dextroamphetamine 10 mg twice a day was added to his regimen, with a rapid full response and no hypomania. The response continued and, as of a follow-up visit in June, the patient has remained in remission. He expressed the wish to be able to contribute something with his life and is taking college nursing courses with an aim of returning to part-time work as a patient care assistant nurse. He is very social, entertaining and cooking for his friends again.
The patient is currently maintained on clomipramine 225 mg, pramipexole 3.0 mg, and dextroamphetamine 10 mg three times a day, lithium carbonate 900 mg and quetiapine 200 mg at bedtime, and monitored VNS maintenance. At his last appointment, the patient stated, “I’m better now than at any time in the past 14 years.”
Treatment-Resistant Bipolar Depression
This patient illustrates many of the difficulties in treating bipolar depression. While it is difficult to disentangle the effects of VNS vis-a-vis various medications, his course showed that he suffered depressive relapses, requiring changes in medication management, although his recurrences did not seem as severe as the episode that had resolved on clomipramine just as his scheduled VNS implantation was performed. Certainly, clomipramine showed a positive response after many previous failures with both ECT and monoamine oxidase inhibitor (MAOI) treatment. The addition of pramipexole seemed to produce further positive results that were augmented by dextroamphetamine, resulting in the combination of a direct-acting dopamine agonist1 with an indirect-acting stimulant.
It seems notable that this patient failed to respond, even acutely, to two courses of bilateral ECT, and two courses of different MAO inhibitors, one known to have been given in high doses, only to show an initial response to clomipramine when given at initially high doses (300 mg once a day). Pramipexole augmentation reversed a partial recurrence, and then dextroamphetamine augmentation reversed a second partial recurrence, when it had failed to help before the use of pramipexole. This has been observed by the author in several other patients but could be a random effect.
Aiken reviewed three studies (one with 174 major depression patients, and two small studies of 17 subjects each, all placebo controlled with bipolar-depressed patients) and found an average response dose of 1.7 mg across these studies, but it was not clear whether the patients were treatment-resistant.1 The use of higher doses of pramipexole, gradually increased by 0.5 mg or less, while watching for emerging side effects (nausea, daytime drowsiness, psychotic hallucinations, sex or gambling addiction, or orthostatic hypotension causing dizziness) to 4 mg have seemed to be useful in a small series of treatment-resistant patients. There is one small, naturalistic follow-up to 9 months published, showing encouraging long-term effects, but more long-term effect data is obviously needed.2
This author is currently pondering the question: What is plan B, in the event the patient recurs on his present regimen, other than increasing pramipexole by a click or two? The battle goes on.
- Aiken C. Pramipexole in psychiatry. J Clin Psychiatry. 2007 68:8:1230–1236. doi:10.4088/JCP.v68n0810 [CrossRef]
- El-Mallakh RS, Penagaluri P, Kantamneni A, et al. Psych Q, 2010:81(3):207–213. doi:10.1007/s11126-010-9130-6 [CrossRef]