Treatment-Resistant Depression: The Role of Gene Factors

The field of genetics represents one of the most promising approaches to understanding the mechanisms underlying disease and behavior. Well-evidenced examples of this include genetic associations with personality traits, cognitive style, temperament, intellect, psychiatric diagnoses, and treatment outcomes. Major depression has been established as a heritable phenotype based in genetic epidemiology studies. However, similar to the examples listed above, its non-mendelian pattern of inheritance, also called "complex," exhibits effects that are difficult to predict and limits what inferences can be made about their function (ie, multiple susceptibility genes are involved, most of which have small effects and inconsistent clinical influence; these genes may also cause other disorders, and nongenetic depressions may also occur).¹⁶ The high complexity of depression genetics undoubtedly affects the patterns of illness course, severity, and drug response.

Although traditional genetic epidemiology studies use an approach that supports the role of genetic factors over environment in the determination of heritability, the interaction of gene and environment has long been observed. Recent evidence comes from genetic-association studies using candidate gene approaches. Caspi and colleagues¹⁷ reported an association between the presence of the short (s) allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) and an increased risk for depressive episodes, depressive symptoms, and suicidal ideation in early adulthood but only in those with a history of severe life stressors—a finding that has been replicated and extended.^18-20 Possession of the s-allele also magnifies the depressogenic effects of neuroticism²¹ and harsh early environments²² on risk for depressive symptoms. Similarly, it has long been postulated that early life events, developmental issues, and ongoing environmental stress are important factors that affect outcome of treatment. For example, in a large collaborative study of treatment of chronic depression, Nemeroff and colleagues²³ reported that patients with a history of childhood trauma experienced a decreased rate of antidepressant response to nefazodone(Drug information on nefazodone) but a greater response to treatment with cognitive-behavioral analysis system psychotherapy.

The reciprocal interplay of genetic and environmental factors takes place in the human mind and brain. Factors such as biological kindling and learned behaviors and reactions may significantly alter an individual's vulnerability to depressive recurrences, making it less closely related to genetic or external environmental events.²⁴

Individual variability in the effectiveness and tolerability of drugs is a well-known medical fact. For over half a century, specific enzymatic deficiencies that explain these differences have been identified. Advances in genomic medicine have provided evidence that the genes encoding for virtually all metabolizing enzymes have polymorphic variants that significantly affect clinical function. Figure 1 [Figure restricted. Please see print edition for content] provides a comprehensive summary of drug-metabolizing enzymes that exhibit gene polymorphisms with well-supported clinical consequences.²⁵ Drug transporters such as G-glycoprotein also possess clinically relevant genetic variability that affects CNS passage through the blood- brain barrier.²⁶ Testing for a number of pharmacokinetically relevant genes may soon become clinically meaningful.

Since all available antidepressants exert their effects through functional modification of monoamine neurotransmitters, common drug targets include synthetic or metabolic enzymes, neurotransmitter transporters, receptors, coupling proteins, and postsynaptic cellular factors. Genes encoding for these targets have, in many cases, clinically relevant polymorphisms. The first example of this was the association of the long (l) allele of the 5-HTTLPR with a better antidepressant response to the SSRI fluvoxamine(Drug information on fluvoxamine).²⁷ Since the appearance of this report, multiple studies using different antidepressants in various population samples have been conducted. This finding has been mostly replicated in studies in which SSRI drugs are used in patients of European descent.²⁸

Multiple studies in Asian populations have yielded largely inconsistent and contradictory results. In a recent study from Korea, depressed patients were randomly assigned to receive treatment with an SSRI (fluoxetine or sertraline(Drug information on sertraline)) or nortriptyline(Drug information on nortriptyline), which is primarily a norepinephrine(Drug information on norepinephrine) reuptake inhibitor (NRI). Genetic polymorphisms in the 2 common serotonin transporter gene polymorphisms (5-HTTLPR and intron 2 [STin2]) as well as the norepinephrine transporter gene (NET) were analyzed. Response to the SSRI was significantly associated with the s-allele of 5-HTTLPR, in stark contrast to findings in European populations, again underscoring the ethnic/racial variability of findings not only in allele frequency distribution but also in association with clinical phenotypes.

The most striking finding of that study was that patients homozygous for the long (l) genotypeof STin2 had a 69% rate of response to SSRIscompared with only 9% for the other genotypes. Another very interesting finding was that patients carrying the GGpolymorphism of NET G1287A had a higher response rate to NRI than SSRI treatment(83% vs 59%), making this one of the first comparative reports that suggest the benefit of genotyping for treatment selection.²⁹

These findings are exciting and consistent with current antidepressant hypotheses; however, the large variability and conflicting results for the various racial groups impedes generalization of this knowledge and limits clinical application. Similar to the example described above, dozens of reports involving many pharmacodynamically related genes involving serotonin, norepinephrine, dopamine(Drug information on dopamine), G-proteins, neurotrophic factors, and hypothalamic-pituitary-adrenal systems, as well as circadian, immunological, and vascular systems, among others, have been analyzed. Mostly those yielding statistically significant associations have been reported, and many have subsequent inconsistent replications. (See Serretti and Olgiati³⁰ for a comprehensive review.)

The genetic discrepancy between 2 diagnostically similar groups (although phenotypically different in antidepressant response profiles) may be detectable and provide insight into the biology of TRD. A recent pilot study from our group assessed 20 candidate genes selected for their relationship to synthesis, transport, recognition, or degradation of neurotransmitters, or their putative intracellular responses to receptor activation such as G-protein coupling, transcription, and neurotrophic factors (Table).³¹