Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive

The data reported herein show clearly that major depression is a commonly occurring and burdensome disorder. The high prevalence, early age of onset, and high persistence of MDD in the many different countries where epidemiologic surveys have been administered confirm the high worldwide importance of depression. Although evidence is not definitive that MDD plays a causal role in its associations with the many adverse outcomes reviewed here, there is clear evidence that depression has causal effects on a number of important mediators, making it difficult to assume anything other than that depression has strong causal effects on many dimensions of burden. These results have been used to argue for the likely cost -effectiveness of expanded depression treatment from a societal perspective. Two separate, large-scale, randomized, workplace depression treatment effectiveness trials have been carried out in the United States to evaluate the cost effectiveness of expanded treatment from an employer perspective. Both trials had positive returns on investment to employers. A substantial expansion of worksite depression care management programs has occurred in the United States subsequent to the publication of these trials. However, the proportion of people with depression who receive treatment remains low in the United States and even lower in other parts of the world. A recent US study found that only about half of workers with MDD received treatment in the year of interview and that fewer than half of treated workers received treatment consistent with published treatment guidelines. Although the treatment rate was higher for more severe cases, even some with severe MDD often failed to receive treatment. The WMH surveys show that treatment rates are even lower in many other developed countries and consistently much lower in developing countries. Less information is available on rates of depression treatment among patients with chronic physical disorders, but available evidence suggests that expanded treatment could be of considerable value. Randomized, controlled trials are needed to expand our understanding of the effects of detection and treatment of depression among people in treatment for chronic physical disorders. In addition, controlled effectiveness trials with long-term follow-ups are needed to increase our understanding of the effects of early MDD treatment interventions on changes in life course role trajectories, role performance, and onset of secondary physical disorders.

Research on major depression has confirmed that it is caused by an array of biopsychosocial and lifestyle factors. Diet, exercise and sleep are three such influences that play a significant mediating role in the development, progression and treatment of this condition. This review summarises animal- and human-based studies on the relationship between these three lifestyle factors and major depressive disorder, and their influence on dysregulated pathways associated with depression: namely neurotransmitter processes, immuno-inflammatory pathways, hypothalamic-pituitary-adrenal (HPA) axis disturbances, oxidative stress and antioxidant defence systems, neuroprogression, and mitochondrial disturbances. Increased attention in future clinical studies on the influence of diet, sleep and exercise on major depressive disorder and investigations of their effect on physiological processes will help to expand our understanding and treatment of major depressive disorder. Mental health interventions, taking into account the bidirectional relationship between these lifestyle factors and major depression are also likely to enhance the efficacy of interventions associated with this disorder. Copyright © 2013 Elsevier B.V. All rights reserved.

Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured with a high-sensitivity method in serum samples from 241 adult men and women with major depressive disorder randomly allocated to 12-week treatment with escitalopram (N=115) or nortriptyline (N=126). The primary outcome measure was the score on the Montgomery-Åsberg Depression Rating Scale (MADRS), administered weekly. CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome. An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.