Neurotransmitters, Pharmacologic Synergy, and Clinical Strategies

Before discussing specific combination and augmentation strategies for treatment resistance, it is important to highlight 2 basic principles of psychopharmacology: the first is to combine mechanisms, not drugs. Combining drugs with different mechanisms promotes "pharmacologic synergy,"⁵ whereas combining drugs with similar mechanisms may simply promote unnecessary redundancy. The second principle is understanding the mechanisms underlying the drugs' side effects. Successfully combining drugs with opposing side-effect profiles will promote tolerability. In fact, the best drug combinations obey both rules, namely, they offer a synergistic boost to efficacy because of the different mechanisms of action of each agent and in- creased tolerability because of side ef- fects that cancel one another out.

Many strategies are used to address treatment resistance in psychiatric patients, including adjunctive treatment with thyroid hormone, lithium(Drug information on lithium) or anticonvulsant mood stabilizers, omega-3 essential fatty acids, bupropion, psychostimulants, atypical antipsychotics, buspirone(Drug information on buspirone), adrenal hormones, sex hormones, aerobic exercise, B-complex vitamins, folate, and other nutrient supplementation. Unfortunately, there are few randomized controlled studies in the literature to guide us in our treatment choices. Some of the most common augmentation strategies for de- pression (such as supplementing a first-line drug with the noradrenergic/ dopaminergic agent bupropion, psychostimulants like methylphenidate(Drug information on methylphenidate), and atypical antipsychotics like risperidone(Drug information on risperidone), olanzapine, quetiapine, ziprasidone, and aripiprazole(Drug information on aripiprazole)) are those with the least evidence from controlled studies.¹ On the other hand, augmentation with thyroid hormones and lithium, 2 strategies for which there is substantial evidence from controlled studies, is much less common.¹

Despite the relative lack of controlled studies for the atypical antipsychotics, there are now a few good studies that speak to their efficacy in treatment resistance. The findings of a recent randomized, double-blind, placebo- controlled trial of 542 patients with either bipolar I or II depression taking up to 600 mg of quetiapine(Drug information on quetiapine) daily for 8 weeks showed that this atypical antipsychotic was efficacious for the treatment of acute bipolar depression and, because of its lower incidence of extrapyramidal side effects and reduced risk of tardive dyskinesia, was well tolerated.⁶ Based on this and several other studies, it has been suggested that some of the atypical antipsychotics may be more aptly termed "broad-spectrum psychotropics," because they are able to address affective states, such as mania and depression, along with psychotic symptoms.⁷ In any event, much more research needs to be done to document the effectiveness of the atypical antipsychotics as adjunctive treatments for refractory depression.

Thyroid hormone, particularly triiodothyronine, has been used to augment and to accelerate the effectiveness of traditional antidepressants, particularly those that mediate serotonergic neurotransmission.^8,9 Thyroid hormones are particularly useful because of their favorable safety and side-effect profiles. Interestingly, there is even evidence to suggest that supplemental thyroid hormone administered to patients with depression unresponsive to first-line antidepressants can boost the effectiveness of the antidepressant even when the patient is not overtly hypothyroid.⁵ Thyroid hormone, particularly thyroxine, has sometimes been used successfully for rapid-cycling bipolar disorder that was otherwise resistant to mood stabilizers.¹⁰ The mechanism of action is presumed to involve either potentiation of neurotransmission at the level of the cell membrane or stimulation of gene transcription at the nuclear level.⁸

Administration of dehydroepiandrosterone (DHEA), an adrenocortical hormone secreted by the hypothalamic-pituitary-adrenal stress axis, appears to offer some promise for protection from depression, even in patients without documented adrenal insufficiency.¹¹ In a double-blind trial, after 6 months of using 50 mg of DHEA per day, a "remarkable increase in perceived physical and psychological well-being" was reported in both men and women.¹² In another double-blind, randomized, placebo-controlled study involving men and women with midlife-onset depression, after only 6 weeks of taking up to 90 mg of DHEA per day, subjects showed a statistically significant improvement in depression (both major and minor).¹³ The efficacy of long-term DHEA treatment is not known, nor do we know how realistic it is to be concerned that the exogenous administration of DHEA will, over time, suppress the body's endogenous produc- tion of it. Nonetheless, adjunctive treatment with DHEA does appear to offer some promise, so further studies are warranted.

Epidemiologic and treatment studies^14-21 support the following hypotheses regarding the association between omega-3 polyunsaturated fatty acids (PUFAs) and depression: (1) deficits in dietary-based PUFAs may be a contributing factor in mood disorders; (2) low plasma concentrations of PUFAs are linked to depression; and (3) supplementation with at least 1 g daily of eicosapentaenoic acid (EPA), an omega-3 PUFA, provides some therapeutic benefit. It remains unclear whether omega-3 supplementation is effective for patients with depression in general or only for those with abnormally low concentrations of PUFAs.^14-21 More evidence is also needed to determine which omega-3 fatty acid, EPA or docosahexaenoic acid(Drug information on docosahexaenoic acid), will provide greater benefit.