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Diagnosing depression in MS in the face of overlapping symptoms.

Depression is an important problem in multiple sclerosis (MS), but the diagnosis is challenging since symptoms of depression overlap with those of MS. In the past, the main strategy has been to remove physical symptoms from scales assessing depressive symptoms in MS, but these attempts have not been successful. Depression and overlapping MS symptoms may actually share pathophysiological mechanisms, so the strategy of attempting to exclude such symptoms may be fundamentally flawed. Current diagnostic criteria provide a pragmatic solution, but it may be possible to develop improved definitions.

Depressive disorders occur frequently (1) and are among the most important determinants of quality of life in MS. (2) Three randomized, controlled trials have reported modest beneficial effects from short-term treatment with desipramine, (3) sertraline or cognitive behavioural therapy (4) and paroxetine. (5) These studies used diagnostic definitions from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), the latter two used criteria from the latest (fourth) edition (DSM-IV). (6) The DSM-IV definition of a Major Depressive Episode requires that one of two key symptoms be present: depressed mood or loss of interest or pleasure, or both. Further, the diagnostic criteria stipulate that at least five symptoms from a list of nine must be present. These symptoms may include: disturbances of sleep; changes in appetite; fatigue; cognitive problems; excessive guilt or worthlessness; motor changes (agitation or retardation); and persistent thoughts of death or suicide. Three of these symptoms, cognitive deficits, (7) fatigue (8) and sleep disturbance, (9) occur in a large proportion of people with MS. This combination of factors creates a dilemma for clinicians: clinical trials emphasize the need to diagnose and treat depressive disorders, but diagnostic definitions for these disorders include symptoms that overlap with MS itself and do not necessarily indicate that a depressive disorder is present.

The problem of overlapping symptoms has been targeted by several studies conducted during the past two decades. The main strategy proposed has been to remove offending items from conventional assessment instruments. For example, Mohr et al (10) proposed removal of three items (fatigue, work difficulty and concerns about health) from the Beck Depression Inventory. This recommendation was based on the observation that these items made a greater percentage contribution to total depression scores in MS patients than in major depression patients and controls. Nyenhuis et al proposed the use of a multidimensional scale, the Chicago Multiscale Depression Inventory (CMDI), to disassociate changes in mood from other symptom categories. (11,12) Neither approach has been very successful in practice. Later studies did not confirm that removal of Beck rating scale items improved validity (13,14) and the CMDI has not been used in any trials of depression treatment. The root of these problems lies in the nature of depression itself. Depressed mood is not in itself a medical problem; it occurs in many contexts (most notably bereavement, but also during adaptation to other losses, stressors and life events) in which a diagnosis of a depressive disorder is not warranted. Antidepressant medications are not used for treatment of depressed mood when this symptom occurs in isolation. In view of these considerations, the lack of success resulting from various proposals to de-emphasize physical symptoms in the assessment of depression in MS becomes more understandable. By de-emphasizing symptoms that are key to the diagnosis of depressive disorders, these approaches distance themselves from one of the problems that they seek to resolve: that of identifying those patients who can benefit from treatment.

An interesting development in the field of psychiatric assessment is the emergence of assessment scales as an alternative to traditional symptom rating scales. These scales are increasingly used when brief instruments for case-finding or clinical monitoring are needed. The most prominent example is the brief version of the Patient Health Questionnaire (PHQ-9). (15-17) This scale's items closely resemble the DSM-IV criteria and can be scored using an algorithm rather than a cut-point. The scoring algorithm requires that the symptom profile resemble that of the DSM-IV criteria rather than simply summing scores for a set of depressive symptoms. This alternative approach to scoring moves the scale's ratings closer to the clinical concept of a depressive disorder.

When a person with MS develops a classic depressive syndrome, existing clinical trial evidence can be applied in a straightforward way. The DSM diagnostic criteria provide an empirical bridge between clinical trial results and clinical practice when diagnostic definitions are met. Furthermore, the problems presented by overlapping symptoms in clinical practice are often not as difficult to overcome as they may seem to be in theory. Clinical assessment provides an opportunity to explore symptoms that may or may not be manifestations of a depressive disorder. Changes in the pattern and severity of cognitive deficits, fatigue and sleep problems, particularly if these changes occur along with other signs and symptoms of depression, provide evidence in support of a diagnosis. It may also be noted that although some symptoms of depression overlap with those of MS, others do not. The emergence of a negative cognitive style (pessimism, inappropriate guilt, low self-esteem) provides strong clinical evidence of a depressive disorder, and are referenced by the 'worthlessness' or 'guilt' item in DSM-IV.

However, the situation becomes less straightforward when a patient's clinical presentation deviates markedly from the classic pattern; here, some more fundamental issues arise. The DSM diagnostic criteria for major depression are empirical in their orientation and are intended to provide a clinically meaningful definition of the disorder. The criteria have shown some utility in clinical trials where they have been used, but it is not necessarily true that these criteria provide the best possible definition for people with MS. A case in point emerges from the possible role of inflammation in the pathophysiology of depression. Interactions between inflammatory cytokines and the pathophysiological domains potentially related to depression (neurotransmitter metabolism, neuroendocrine function and neural plasticity) have been extensively documented in the literature (see review by Miller et al (11)). It is possible that the role of inflammation in MS-related depression is especially important, as highlighted by the observation that major depression may occur more commonly in relapsing-remitting MS than in progressive forms. (12) Aspects of cytokine-induced sickness behaviour (including fatigue, cognitive problems and sleep disturbances) may therefore be related to depression at a pathophysiological level. In a placebo-controlled clinical trial of paroxetine pre-treatment before exposure to high-dose interferon alpha (IFN?) treatment in malignant melanoma, depressive and neurotoxic symptoms were lower in the paroxetine-treated group. (20) Antidepressant treatment has been associated with decreases in inflammatory markers in some studies, reviewed by Miller et al. (11) One recent MS study reported a trend towards reduction of new enhancing lesions in association with fluoxetine treatment. (13)

Physical pain is often a manifestation of depression (14) and may share neural substrates with social pain. (15) The anterior cingulate cortex mediates emotional aspects of physical pain, but anterior cingulate activation has also been reported in response to unfair treatment, (16) following the death of a loved one (17) and during treatment of hepatitis C with IFN?. (18)

The most consistently observed neuroendocrine change in major depression is diminished feedback control of the hypothalamic-pituitary-adrenal (HPA) system, (19) resulting in cortisol non-suppression on the dexamethasone suppression test and corticotrophinreleasing hormone stimulation test after dexamethasone administration. Similar changes have been reported in MS (28) and may result from diminished binding affinity and reduced sensitivity of glucocorticoid receptors. (29) One study found that HPA dysregulation in MS normalized with combined corticosteroid and antidepressant (moclobemide) treatment even in the absence of any psychiatric disorder. (30)

In contrast to the viewpoint that physical symptoms in MS merely contaminate or cloud the assessment of depression, accumulating evidence suggests that depression may be closely intertwined at a pathophysiological level with symptoms related to inflammation, pain and neuroendocrine dysfunction. Conceivably, these physical symptoms and abnormalities are especially important to the syndrome of depression as it occurs in people with MS.

In dealing with the problem of overlapping symptoms of depression and MS, the main emphasis in the past has been on disentangling physical symptoms from psychological ones by developing more highly focused measurement strategies. The conceptual purity gained by this approach may be valuable in some theoretical and research applications, but may come at the cost of greater distance from underlying clinical and pathophysiological realities. Alternative viewpoints need to be considered. Conceivably, the most useful diagnostic definition for depression in MS may place greater, rather than less, emphasis on physical 'overlapping' symptoms than the current DSM criteria do. More evidence, however, is needed in order to determine whether this is true.

Key Points

* Depressive disorders in MS are important and generally responsive to treatment, but difficult to diagnose.

* The difficulties with diagnosis relate to overlapping symptoms, including cognitive problems, fatigue and sleep abnormalities.

* Overlapping symptoms may reflect related underlying pathophysiologic processes and their significance for therapeutic outcome is unknown.

* The diagnosis of depression is best based on a global judgment incorporating all available evidence.


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SB Patten

Departments of Community Health Sciences and Psychiatry, University of Calg ary, Calgary, Canada
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Title Annotation:Commentary
Author:Patten, S.B.
Publication:The International MS Journal
Article Type:Report
Geographic Code:1CANA
Date:Mar 1, 2010
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