Could pharmacogenetics play a role as predictor in treatment of depressive disorders?

Whilst the pharmacological treatment of major depressive disorder with antidepressants continues to improve, the responses remain poor in 30–50% of patients, with many patients discontinuing the medication due to distressing side effects and lag periods of more than 4 weeks before efficacy been proven. Highly complex mechanisms underlie this variability in drug responses, which can be attributed to genetic factors and several physiological and environmental factors, including age, renal and liver function, nutritional status, smoking, and alcohol consumption.

The study of genetically determined interindividual variations in the responses to drugs is called pharmacogenetics. Although it has been established for almost half a century that genetic factors also influence both the efficacy of a drug and the likelihood of adverse reactions, efficient clinical predictors remain to be established.

The genetic differences in responses to antidepressants may be due to variants that affect the function of genes involved in both pharmacokinetics and pharmacodynamics. Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs. Drug metabolism is a critical determinant of the therapeutic and adverse effects of many antidepressants. CYP2D6 is the best-characterized P450 enzyme that exhibits polymorphism in humans, and many antidepressants are metabolized primarily by CYP2D6. Three phenotypes have been identified to date: slow/poor metabolizers, rapid/extensive metabolizers, and ultrarapid metabolizers. Individuals with a homozygous poor-metabolizer genotype who receive sertraline experience adverse effects (dizziness and nausea) (Wang et al. 2001), which may be due to toxic accumulation of the drug due to the elimination rate being too slow. Thus, individual dose adjustment may be necessary for poor metabolizers to achieve the optimal therapeutic effect and avoid adverse effects.

The term pharmacodynamics encompasses all the processes that influence the relationship between drug concentration and drug effects. Antidepressants have a wide variety of targets within neurotransmitter systems, including neurotransmitter synthesis, degradation of enzymes, storage, receptors, and specific transporter proteins. There is considerable evidence that imbalances in the neurotransmitter systems contribute to the various symptoms that are associated with depression, and that alterations to neurotransmitter systems are important for optimal antidepressant effects (Delgado et al. 1993). Therefore, neurotransmitter-related genes are important targets of antidepressant medication, with serotonin-related genes being the most widely investigated.

The brain 5-HT transporter (5-HTT) is the principal site of action of many antidepressants. This transporter takes up 5-HT into the presynaptic neuron, thus terminating synaptic actions, and recycles it into the neurotransmitter pool. A functional polymorphism (5-HTTLPR) within the promoter of the 5-HTT gene has been identified.

Several studies have examined the relevance of 5-HTT polymorphisms to therapeutic efficacies in depressive patients. In Caucasian populations, the s allele of 5-HTTLPR is reportedly associated with a poor response to selective serotonin reuptake inhibitors (SSRIs) (Lee 2005). In contrast, Asian depressive patients (e.g., Koreans and Japanese) with the 5-HTTLPR s/s genotype exhibit better responses to acute antidepressant treatments than those with other genotypes (Lee 2005). Therefore, the relationships between 5-HTTLPR genotypes and responses to antidepressant treatments remain controversial.

The frequencies of the s and l alleles among Asians are approximately 86 and 14%, respectively, while the corresponding figures for Caucasians are 43 and 57% (Lee 2005). The discrepancies between the responses to antidepressant treatments in different ethnic groups may therefore be partially due to differences in allele frequencies. However, antidepressants do appear to be effective across ethnicities.

Pharmacogenetic studies exhibit certain limitations. Though a single gene may affect the responses to antidepressants, it would play only a relatively minor role where a complex mechanism is involved. For example, it has been determined that the 5-HTTLPR polymorphism accounts for 5–7% of the variance in SSRI responses (Lee 2005), and that the tryptophan hydroxylase A218C genetic polymorphism accounts for approximately 5% of the variance in SSRI efficacy, with the effect being independent of that of the 5-HTTLPR polymorphism (Lee 2005). Mossner et al. (2000) have demonstrated that brain-derived neurotrophic factor (BDNF) acts as a neurotransmitter modulator that may influence serotonin uptake in lymphocytes, and preferential regulation of the serotonin transporter has been observed in cells of the l/l genotype of the polymorphism in the serotonin transporter gene promoter. Therefore, it may be of interest to explore the interaction of BDNF and serotonin transporter genetic polymorphisms in responses to SSRI antidepressants. Therefore, pharmacogenetics investigations should consider interactions between many genes. In addition, understanding the frequencies and genetic relationships of haplotypes will improve the selection of suitable intragenic markers for genetic association studies.

Previous studies have had diverse designs, in terms of factors such as antidepressant types, sample size, presence and absence of placebo controls, rating scales, outcome measures, and treatment length, all of which may greatly influence the results. In contrast, successful pharmacogenetic studies may required well-characterized phenotypes, methodologies, and criteria for the selection of candidate genes.

Pharmacogenetic research has revealed that the metabolism, clinical effectiveness, and side-effect profiles differ significantly between patients. The utility and possible applications of these research methodologies in clinical settings remain to be determined. Information concerning the relative efficiencies of drug-metabolizing enzymes obtained through genotyping and phenotyping methodologies could be useful to clinicians who provide pharmacotherapeutic services to patients.

The different genetic make-ups are considered to substantially contribute to the differing responses to antidepressants, for which efficient clinical predictors are not yet available. However, pharmacogenetic studies have the potential to improve our understanding of how antidepressants operate, and thereby also improve both their safety and efficacy in clinical applications.