Defining remission in depression: the challenge of complete recovery

b y J . M e n d l e w i c z , B e l g i u m

Faculty of Medicine
Free University of Brussels
Brusssels, BELGIUM

DEPRESSIVE DISORDERS CONSTITUTE A MAJOR PUBLIC HEALTH issue, and it is estimated by the World Health Organization that they will rank in second position among all diseases in terms of prevalence by the year 2010, thus contributing heavily to the global burden of disease in humans. Advances in the treatment of depressive disorders will therefore constitute a major challenge for the medical community and for society in the years to come. The concept of clinical remission in the treatment of major depressive disorders has gained growing attention in the last few years. The reasons for this relatively recent interest are severalfold: depressed patients as well as patient organizations are not totally satisfied with the current effectiveness and tolerability of available antidepressant medications. Despite the obvious benefits of antidepressants, many depressed patients still suffer from incapacitating residual symptoms, and these patients are at a higher risk of relapse or recurrence than patients who achieve full remission after antidepressant therapy. Patients who reach full remission after treatment have a better level of functioning and an improved prognosis compared with patients who are nonremitters.
Adequate clinical remission is therefore of great functional importance to the patient, because it seems to be a predictor of long-term stability and a rather good indicator of better psychological functioning, the latter being of utmost importance when assessing the quality of life of our depressed patients. For the above reasons, it is becoming of great interest to the scientific community and our patients to consider not only rates of response, but also remission rates, in order to assess the real clinical efficiency of antidepressants in everyday practice and to evaluate new treatments in outcome studies. This issue of Medicographia brings together experts in the field of affective disorders to discuss from different perspectives the critical issues related to the concept of true remission in depression.
◆ H. J. Möller et al review current knowledge on the natural course of a depressive episode, symptoms that may be predictive of response and remission, and the time course of their alleviation during antidepressant therapy.
◆ D. Baldwin and A. Lopes focus on the differential effects of antidepressants on endogenous depression and depression associated with anxiety disorders, in relation to the time course of depression and the quality of remission in depression.
◆ P. Monteleone and M. Maj look at the relevance of circadian rhythm disturbances in depression and the impact that the resynchronization of circadian rhythms has on the quality of remission.
◆ C. Soldatos and C. Theleritis reflect on the quality of the sleep-wake cycle as a potential marker of remission in depression. They also deal with such issues as the persistence of sleep disruption after antidepressant treatment, and the promises of sleep-restorative antidepressants.
◆ S. Kennedy and S. Rizvi emphasize the importance of the maintenance of proper sexual functioning and quality of life in patients in remission from depression, which is also a key factor for drug compliance.
◆ J. Price and G. Goodwin analyze the impact of antidepressant therapy on cognitive and emotional reactivity after remission and the implications this has for relapse.
◆ E. Paykel draws a list of the residual symptoms whose presence signals incomplete remission from depression and stresses the need for longer than usual continuation antidepressant treatment, which may be aided by cognitive therapy, to avoid the risk of relapse.
◆ C. Muñoz reviews the pharmacological mode of action and clinical benefits of agomelatine, a new melatonergic antidepressant.
◆ W. Choucha and J. F. Allilaire discuss the various clinical management approaches to treating remitted patients over the long term.
◆ G. Fava and D. Visani advocate the sequential use of pharmacotherapy and psychotherapy to address residual symptoms in patients having recovered from depression as the best model for avoiding relapse or recurrence, and stress the implications of this method in terms of treatment planning.
◆ J. D. Guelfi discusses the merits and pitfalls of various methods to assess remission, relapse, and residual symptoms in depression.

Definitions of remission can vary across the literature, and questions arise as to the boundary between full remission and partial remission, the presence after treatment of residual symptoms, and the return (or not) to premorbid psychosocial functioning. According to a consensus conference of the MacArthur Foundation, clinical response is defined as a period of time during which there is some improvement in symptoms, but not of enough magnitude as to represent achievement of full remission, with the persistence of some residual symptoms. On depression rating scales, this state usually corresponds to at least a 50% improvement in scores. By contrast, full remission is obtained when clinical improvement is such that the patient becomes almost asymptomatic. Clinical remission is usually defined by a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HAM-D17) or a score of 10 to 12 or less on the MontgomeryÅsberg Depression Rating Scale (MADRS). The persistence of remission over time while on maintenance antidepressant therapy is of obvious clinical relevance, as considered in the concept of recovery.
Clinical recovery can only be defined in an individual after the persistence of remission for at least 3 to 4 months. A task force of the American College of Neuropsychopharmacology carried out a review of the literature regarding potential associated factors that may influence remission in terms of timing and stability. Among others, these factors include the type of treatment, the dose, the treatment duration, the baseline severity of depressive symptoms, the stage of treatment resistance (Treatment Resistant Depression [TRD] stage), compliance, the presence of Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM-IV) Axis I, II, or III conditions, environmental stressors, the degree of social support, the retrospective morbidity of the illness, as well as neurobiological and genetic vulnerability.
There is no general consensus about the length of time the depressed patient in remission should remain in remission for it to qualify as genuine, but according to most experts, this period of remission needs to last for between 4 and 6 months to be of clinical relevance to the patient. The length of the remission period is obviously of great clinical importance to the patient, and it is also dependent on the continuation of antidepressant treatment.
Unfortunately, a significant number of patients do not achieve a fully symptom-free state, and display residual subsyndromal depression or subthreshold depression. These patients have been shown to have a higher risk of early relapse into depression, lower levels of social and psychological functioning, and greater rates of physical morbidity for conditions such as cardiovascular disease and stroke, as well as higher rates of mortality. Several therapeutic strategies have been proposed to achieve remission or treat residual symptoms in patients suffering from major depressive disorder. The most frequent residual symptoms targeted include anxiety, sleep disturbances, depressed mood, work difficulties, fatigue, and lack of interest. Among such residual depressive symptoms, severe chronic current insomnia—one of the most frequently observed manifestations of sleep disturbance in depression—appears to be an important residual core symptom of depression, which may be related to the persistence of cognitive problems such as asthenia, anhedonia, trouble in concentrating, and short-term memory difficulties. The rather high manifestation of residual symptoms observed in non fully remitted depressed patients justifies the need for research into various therapeutic strategies such as switching, augmentation, and combination therapies, including with cognitive behavioral therapy, and the search for new targets to develop novel and more efficacious antidepressant treatments. There is a general consensus among experts that full clinical remission after acute antidepressant treatment should be the gold standard and one of the priority objectives to be achieved in modern antidepressant therapy. ◆