Major depressive disorder (MDD) affects a large proportion of the world's population, but much still needs to be done to categorically improve the lives of people with this condition. Major depression is a syndrome defined by the presence of subjective symptoms and consequent suffering or dysfunction. This nonetiological categorization renders major depression a highly heterogeneous condition,1 which is reflected in the high variability of associated features, such as age of onset, symptom clustering, longitudinal course, comorbidities, relationship to life events, and psychological experiences. Most relevantly, the patterns of pharmacological treatment response are also inconsistent, and it is unclear whether differences in pathophysiology of the depressive condition or in the individual's interaction with antidepressant agents explain such variability in treatment response.
Depression and antidepressant effect: underlying mechanism
The role of neurotransmitters and neuromodulators in the pathophysiology of depression and the mechanism of action of antidepressant agents has been the subject of intensive study for many decades. Early neurobiology hypotheses, informed primarily by the pharmacological understanding of antidepressant mechanisms, postulated that depression was the result of a deficiency of monoamine neurotransmitters.2,3
However, the evolved understanding of the dynamic functional balance of neuronal plasticity and apoptosis in response to stress,4 and the molecular events that follow agonist-receptor interactions5 led to more complicated models that explain both the pathophysiology of depression and the mechanisms underlying the effects of antidepressants.6-10
Integration of information from imaging studies, health psychology, genetic epidemiology, and molecular psychiatry has made it clear that a full understanding of the biology of depressive disorders must incorporate knowledge of a broad range of neurochemicals, and take into account the possible toxic effects of drugs, medical illness, stressful life events, and psychological risk features. We must also consider the role of multiple genetic influences that confer vulnerability and be able to explain how these effects converge to alter the structure and function of the brain's emotion and cognition circuits, culminating in the symptoms that define depressive disorders.11 Consequently, the treatment and recovery processes for MDD may be anticipated to be similarly variable and complicated.
Although organized psychiatry uniformly recognizes the need for treatment of major depression to remission in order to favor functional recovery and minimize risk of comorbidities, complications, and recurrence,12 the standard categorical outcome for clinical trials of antidepressants in most cases continues to be treatment response. Antidepressant response is often defined as a 50% decrease in the global score on depression rating scales.
Of course, many of the so-called responders truly fail to become categorically "undepressed." Meta-analytical studies of antidepressant clinical trials and recent large-scale collaborative studies for MDD suggest a response rate of 40% to 60% and a remission rate of 25% to 35%.13,14 An important question arises: when is an individual who remains depressed, in spite of adequate treatment, considered treatment-resistant?
Conceptualization of treatment-resistant depression as a phenotype
Many definitions of treatment-resistant depression (TRD) have been proposed. Some of them are simply categorical; others are based on numbers or types of treatments received and failed, offering a continuum of resistance.15 It is clear, however, that many people with depression are unlikely to respond to most conventional treatments when used at sufficiently high doses to anticipate therapeutic benefit. A number of questions remain:
- Why does resistance happen?
- Is it because certain patients have a pathophysiological mechanism different from those with "treatment- responding" depressions?
- Do they have a more severe form of the same unique depressive condition for which the usual pharmacological "correction" is insufficient?
- Do their pharmacokinetic profiles allow them to metabolize treatment agents at an exaggerated rate that renders the agent ineffective?
- And, is it possible that some of these questions may be addressed with the use of genetic techniques?
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