Are Antidepressants as Effective as Claimed? Yes, but …

(Can J Psychiatry 2007;52:98-99) Major depressive disorder (MDD) is a serious mental illness with a 1-year prevalence rate of 4.1% to 4.8% in Canada and a lifetime prevalence of 8%.' The human cost of the illness in terms of impaired social and emotional functioning cannot be emphasized enough, and the societal burden from an economic standpoint alone is substantial. According to the WHO, the disability levels caused by depression are even higher than those caused by other common medical conditions, including arthritis, hypertension, and diabetes.2 Emerging evidence also suggests an overlapping pathoetiology between mood disorders and other chronic medical conditions such as diabetes mellitus and cardiovascular disease. As such, few would argue with the need for treatments for depression. Although comparable outcomes have been reported for pharmacotherapy and evidence-based psychotherapies, antidepressant medications are the most available first-line treatments for moderate-to-severe major depressive episodes. Effectiveness and the Scope of the Debate For the purpose of this debate, current first-line selective serotonin reuptake inhibitors and dual-action agents will be considered to represent antidepressants and the term effective will reflect real-world outcome when these medications are prescribed under some form of measurement-based conditions. This is explicitly not a debate about efficacy and the difference between active treatment and placebo outcomes. It is implicitly about the evidence to support a disease-centred model of depression and the capacity to demonstrate that antidepressants alter the depressive substrate. According to Moncrieff and Cohen,3 the challenge in supporting a disease-centred model for MDD is to present evidence that drugs correct an abnormal brain state, that therapeutic results are related to a favourable impact on disease pathology, and that effects differ between patients and volunteers. These criteria are borrowed from other systemic disorders such as diabetes mellitus, where this model of disease and the therapeutic effects of treatments can be readily evaluated. Until recently, limited technology and understanding of brain complexity have delayed the application of these criteria to depression. Evidence to Support the Disease-Centred Model of Depression There is ample evidence at varying levels of analysis to make this case. At the neuropsychological level, altered cognition, executive function, and reward behaviour, as well as neurobiological findings including alterations to circadian rhythm, the hypothalamo-pituitary-adrenal axis, or the immune system, are frequently demonstrated in states of clinical depression. Studies of stress and depression have more recently focused on the effects of stress on neurotrophic factors implicated in mood disorders. Brain-derived neurotrophic factor (BDNF) is one protein, important in neuronal development and survival, that has been of particular interest insofar as both acute and chronic stress tend to decrease its expression. However, increasing data suggest that antidepressants upregulate the production of BDNF, enhancing hippocampal neurogenesis and promoting neuroplasticity.4 Still, the most germane evidence in support of the disease-centred model of depression and antidepressant effectiveness is derived from structural and functional neuroimaging studies. Structural imaging studies have demonstrated that recurrent episodes of depression and a longer duration of untreated illness correlate with decreased hippocampal volume and with neurocognitive impairment5; in contrast, the same relation did not appear in patients treated with antidepressants. Further, depression patients treated with antidepressants have shown improved performance on various neurocognitive measures, compared with untreated depression patients.6 At the level of functional neuroimaging, glucose metabolism studies are instructive in regard to all 3 requirements for the disease-centred model. …

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