High-dose tricyclics potentiation with mirtazapine,lithium and partial sleep-deprivation: why not tricyclics in combination strategies for resistant melancholia?

Introduction

In recent years, combination strategies (which involve adding additional antidepressants with a different neurochemical profile) and augmentation (with nonantidepressant drugs such as lithium, T3 and atypical antipsychotics) are being used more frequently to treat resistant unipolar melancholic depression [Yazici, 2009; Blier et al. 2010; Ruiz-Doblado et al. 2010]. The use of different combination and augmentation strategies in severe, resistant depression is based clinically and physiopathologically on the neurochemical complementarity of drugs, their synergies, on the improved tolerability and reduced undesirable effects when a second drug is associated, and also on the growing body of experience with combinations of antidepressants in naturalistic conditions of ‘real’ clinical practice [Rush et al. 2009].

However, the use of the strategy of combining several drugs in resistant diseases also presents a serious predicament in other areas of medicine (e.g. high-activity antiretroviral therapy [HAART], resistant hypertension, etc.). Given that the final objective of antidepressant treatment should be complete remission of the resistant melancholia and not just a simple response, different observations have endorsed that simultaneous administration of two antidepressants may produce neurochemical changes more quickly.

Case report

A 49-year-old woman who had been admitted to hospital with severe melancholia, hypertension on treatment and with a history of six serious melancholic episodes since she was 24 years old (first puerperium), was treated by our group. She had no previous history of mania or hypomania. The current episode, which was very severe (Beck Depression Inventory [BDI] score: 58) and had a seasonal pattern, was treated first line with a combination of venlafaxine extended release 450 mg + mirtazapine 45 mg + lamotrigine 200 mg daily, resulting in only a poor response in the fourth week (BDI score: 40). This response was manifested essentially at the BDI ITEMS which evaluates symptoms of anxiety, with a scant improvement in qualitatively specific symptoms of mood, thought, speech and psychomotor inhibition. Given the insufficient clinical response and persistence of suicidal ideas, it was decided to change the treatment to clomipramine 375 mg + mirtazapine 45 mg + lithium 800 mg daily + partial sleep deprivation. After 6 weeks, the patient achieved complete remission (BDI score: 3), with a euthymic mood, recovery of her premorbid level of functioning and complete disappearance of suicidal thoughts. It should be pointed out that in spite of being a hypertensive patient, her blood pressure, monitored daily, stayed within the normal range of 130 mmHg/70 mmHg. Biochemical parameters, creatinine, liver function laboratory tests, TSH and EKG showed no changes with the combined treatment. Lithaemia was 0.66 mEq/L at the sixth week. No adverse effects were reported with the exception of dry mouth and moderate constipation, both well tolerated by the patient.

Discussion

The combination of high doses of both clomipramine [Gervasoni et al. 2009] and mirtazapine achieved a high level of synergy, acting at pharmacodynamic level through triple serotoninergic enhancement (reuptake inhibition by clomipramine, alpha-2 and 5-HT2 antagonistic effects of mirtazapine) and dual noradrenergic enhancement (reuptake inhibition by clomipramine and its active metabolite desmethylclomipramine, antagonistic alpha-2 effect of mirtazapine). In addition, blockage of the 5-HT2 and 5-HT3 receptors achieved with mirtazapine can help to reduce the serotoninergic sexual (5-HT2) and digestive (5-HT3) adverse effects of clomipramine. It is also known that sustained 5-HT2 blockage improves sleep and increases the gene expression of the 5-HT1A receptor (synergy between 5-HT2 antagonism and 5-HT1A stimulation) [Ruiz-Doblado et al. 2010]. In addition, both clomipramine and mirtazapine were considered two of the most effective antidepressant drugs in a recent review of the evidence [Montgomery et al. 2007]. Furthermore, lithium enhancement has a stabilizing effect on membranes and also on sodium cellular transportation, as well as the upregulation of gene expression associated with neurotransmission via second messengers (phosphatidylinositol). Finally, partial rapid eye movement sleep deprivation, during the second half of the night, can enhance pharmacological effect. Although its efficacy is known at the empirical level, the mechanism of action of its antidepressant effect remains unclear. Nowadays there are ‘cleaner’ combinations in treatment algorithms for resistant melancholia, such as those associating venlafaxine or duloxetine (both dual 5-HT-NA antidepressants) with a second antidepressant or mood regulator [Hannan et al. 2007; De la Gándara et al. 2008; Yazici, 2009], but some works have shown that the noradrenergic effect of these new drugs may be inferior to that of clomipramine, which achieves a powerful noradrenaline reuptake inhibition due to both the drug itself and its metabolite (clomipramine + desmethylclomipramine) [Gillman, 2007].

According to our current state of knowledge, this is the first documented case of response to this combination of drugs in resistant melancholia at these doses. The conclusions to be drawn, without losing sight of the limitations intrinsic to a case report, suggest the use of combination and energetic enhancement in the management of resistant melancholic depression, given that, although they are not supported by the results of clinical trials, they are supported by their pharmacological rationality, their molecular synergy and their tolerability and efficacy in naturalistic, ‘real clinical practice’ conditions. Therefore, the use of the old tricyclics, which are powerful, widely documented and have proven efficacy in melancholia, should not be ruled out when designing combination strategies. This case does emphasize the need for additional studies with larger samples for documenting the efficiency of this and other combinations in resistant melancholic depression. This would give psychiatrists more aggressive, fast-acting combination strategies with a reasonable safety margin.