Treatment-Resistant Depression: The Role of Gene Factors

Assessing for genetic association, we studied 3 subject groups. One included patients with a history of MDD who were capable of achieving remission. Another consisted of patients with current MDD who had not achieved or maintained appropriate antidepressant response after at least 2 trials of standard FDA-approved antidepressant drugs. These patients had well-documented TRD based on a clinical assessment, verification of past medical rec-ords, determination of adequacy of treatments with the standardized antidepressant history form, and had met criteria to be enrolled in a treatment study with vagus nerve stimulation. A third group of healthy volunteers who denied a personal or family history of major depression were used as genetic controls. False discovery rate methods were used to control for multiple comparisons given the large number of genes and genotypes tested.

In this largely European sample, the STin2 promoter was found to be significantly different between the patients who were depressed and controls, with the (ll) genotype being overrepresented in the healthy control group. Important as well, the intron 3 polymorphism of the dopamine(Drug information on dopamine) receptor-4 gene was significantly different between patients with TRD and treatment responders, with those homozygous for the 7 repeat allele being twice as likely to respond to an antidepressant. Interestingly, the gene explaining genetic vulnerability to depression did not explain treatment response. Furthermore, patients with TRD had a larger number of risk genotypes than treatment responders, who in turn had a greater number of risk genotypes than the healthy controls. This finding supports a model in which the additive small effects of multiple risk genes explain depression and treatment resistance (Figure 2).

When confronted with TRD a number of approaches have been suggested, and although there is limited evidence to support a specific algorithm for treatment, the following 4 principles (4 Ds of depression) are often proposed: diagnosis, dosage, duration, and drug.

Establishing an accurate diagnosis and identifying comorbidities and certain specific features that may predict a specific response currently facilitate treatment. It is possible that in the future, genetic approaches may help establish alternative phenotypes or genetically informed diagnosis with preferential response to certain treatments. For example, the s-allele of the 5-HTTLPR has been associated with increased neuroticism, increased amygdala response to threats, and more depression and suicide outcome in the context of increased environmental stress. The same polymorphism is associated with decreased antidepressant response and greater intolerance to treatment in some populations of European origin. Although the clinical applicability of this knowledge remains limited because of the small effect conferred by a single gene, it is easy to anticipate that in the future we will be able to redefine conditions and select treatment approaches based not only on genetically informed phenotypes but also on genetic predictors of tolerability, safety, and efficacy.

What dosage will ensure the greatest likelihood of an optimal response in efficacy, tolerability, and safety? Genetic polymorphisms of drug-metabolizing enzymes are now receiving clinical attention given the commercial availability of microarrays for cytochrome P-450 genotyping. Availability, cost of genotyping, and interpretation of the findings are becoming more accessible to clinicians, although currently, establishing a patient's genetic metabolic profile is often reserved for cases of multiple drug intolerance or resistance. Understanding the role of genetics in drug metabolism, clinicians should remember that manufacturer-recommended dosages are seldom "one size fits all."

The traditional concept of optimization suggests that maximizing the dosage and duration of each trial may improve outcome, especially for patients who experience partial response. There have been a few reports of certain genetic polymorphisms associated with variable speed of onset of antidepressant response with certain drugs.²⁹ Since we are not currently testing for all these potential factors, it may still be useful to remember that there may be a perfectly logical pharmacogenetic rationale to extend the initial trial period of an antidepressant in patients whose depression has not responded or remitted.

Selection of a drug must be based on aspects of tolerability, safety, and efficacy. As the body of literature on antidepressant pharmacogenetics increases and more consistency is found, genetic information may also aid in the selection of drugs based on benefit and tolerability. For example, Murphy and colleagues³² reported a clinically and statistically significantly greater rate of paroxetine(Drug information on paroxetine) versus mirtazapine(Drug information on mirtazapine) discontinuation in patients who were homozygous for the c-allele of the serotonin receptor 2A.

In some areas of medicine, genetics approaches already help improve prediction of individual treatment response, adverse effects, and optimization; facilitate identification of homogeneous populations; and improve understanding of mechanisms of illness and the nature of treatment response, all of which may lead to specifically designed therapies for some patients. In psychiatry, although many pertinent findings exist, the clinical application of this knowledge is still limited. TRD and the contributions from pharmacology or neurobiology that make an individual vulnerable to this phenomenon remain an enigma in spite of exciting recent developments. Large collaborative approaches such as STAR*D may help address the many questions that remain.