Adam I. Kaplin, MD, PhD* and Ryan E. Stagg, MD
Johns Hopkins University
School of Medicine, Meyer 121
600 N Wolfe St.
Baltimore, MD 2128-7121

INTRODUCTION

Current estimates suggest the prevalence of multiple sclerosis (MS) may be approximately 600,000 people in the United States [1].  Although attention is typically focused on the physical disability associated with MS, the profound impact of mood disorders on the presentation and prognosis has recently begun to be appreciated [2-6].  Depression as an early and important clinical manifestation of MS is not a new observation, although it has taken over a century for systematic investigations to be undertaken.

Recently, more efforts have been made by providers to treat depression as part of the comprehensive and holistic approach provided to patients with various general medical conditions.  The prevalence and impact of comorbid depression in patients with MS cannot be ignored; notably, of all the mental state changes that could potentially occur with MS, depression is the most common by far.  Independent of the premorbid prevalence of depression in patients diagnosed with MS, numerous reports have found that the incidence of depression after the onset of MS remarkably elevated four-fold [7].  The profound impact that depression can have on a patient with MS necessitates its ascertainment and intervention.

EPIDEMIOLOGY AND IMPACT OF DEPRESSION ON MS

From its earliest characterization, depression was among the first symptoms recognized as being associated with MS.  Jean-Martin Charcot (1825–1893) was the first individual to provide an accurate and comprehensive clinicopathological description of MS that he termed disseminated sclerosis [8].  Charcot noted early on that grief, vexation, and adverse changes in social circumstance were related to the onset of MS.  Even from its initial description, depression has been recognizable as a serious and potentially life-threatening component of MS.

Depression is extremely common in MS, with a point prevalence of major depression in MS clinic patients of 15-30%, and a lifetime prevalence of 40-60% [9].  This rate of depression is 3 to 10 times that of the general population, and depression is more common in MS than in other chronic illnesses, including other neurologic disorders [10].  Depression in MS patients not only causes great personal suffering, but it can dramatically affect a patient’s function, quality of life and longevity.  Multiple studies have demonstrated that depression is the primary determining factor in a patient’s self-reported quality of life, with a greater impact than other variables investigated including physical disability, fatigue, and cognitive impairment [11-13].  MS patients with depression and/or anxiety disorders have been shown to be almost 5 times more likely to have difficulty with adherence to MS treatment [14].

Function

Compared to other major causes of chronic disability in the general medical outpatient population, depression is second only to coronary artery disease in the degree of functional impairment it causes [15].  The level of depression in patients with MS is the primary determining factor in the quality of their primary relationships when rated both by the patients and significant others [16], which has important long-term implications for the ability of MS patients to maintain their stable social support systems.  In MS patients, depression is associated with increased time lost from work, disruption of social support, and decreased adherence to neuromedical treatment regimens for MS [4].

Cognition

Some degree of impaired cognitive functioning occurs in 50% of MS patients in epidemiologic studies of community samples, even when patients with depression are excluded [17].  Although quite varied, the most common cognitive impairments in MS involve memory recall, information processing speed, executive functioning, and working memory.  These cognitive deficits are also common in depressed individuals.  Although the association between depression and cognitive dysfunction in MS is complex, generating mixed findings in the literature, recent work suggests that performance in depressed MS patients may be less impaired on routine tasks than on tasks that demand effortful attention [18].  Treating depression has been found to improve cognitive functioning in many affected MS patients.

Fatigue

Depression is strongly associated with the impact of fatigue on the lives of MS patients.  Fatigue is a common symptom of both MS and depression.  MS patients with depression are six-times more likely to report disabling fatigue [19].  When mental fatigue and physical fatigue are separately measured, depression is more strongly correlated with mental fatigue (r=0.54, p<0.0001) than with physical fatigue (r=0.31,  p<0.01) [19].  Recently, a study of a large community sample of MS patients investigated disabling fatigue, defined as fatigue that often or almost always interferes with activities [20].  Subjects with clinically significant depressive symptoms were six times more likely to report disabling fatigue, and the presence of disabling fatigue had a sensitivity and specificity of 70% for predicting clinically significant levels of depression.  Moreover, it has been shown that treatment of depression leads to reduction of fatigue in MS patients in proportion to the improvement in their mood, with an efficacy comparable to the effectiveness of treatments that directly target the symptoms of fatigue [21].

Suicide

There is a 30% lifetime incidence of suicidal intent in patients with MS, defined as a desire to kill oneself, and, overall, an astounding 6-12% of MS patients make a suicide attempt [6, 20].  It is, therefore, not surprising that studies have suggested that suicide, the most acutely grave consequence of severe depression, occurs in MS at a rate 7.5 times that of the age-matched general population [22].  In a Maryland based forensics study, suicide (8%) was second only to cardiovascular disease (18%) among the leading causes of unexpected death of 50 autopsies [23].  In a large Canadian study, suicide was found to be the third leading cause of death, accounting for 15% of all deaths during this 16-year period [22].  Patients dying from suicide were considerably younger and less disabled compared to the other two leading causes in this cohort.  A Danish MS study found an elevated rate of suicide compared to the general population, with overall 2.12-fold more suicides in MS patients [24].  The elevated rate of suicide continued to be twice the anticipated rate even 20-45 years after the MS diagnosis.  In a separate study of MS outpatients, suicidal intent was not related to gender, employment status, disease duration, physical disability or cognitive status [25].  The three most important variables for predicting suicidal intent were severity of major depression, living alone, and alcohol abuse, which in combination had an 85% predictive accuracy for suicidal intent.  The lack of association between suicidal intent and physical disability strongly argues against this being merely a reaction to the stress of adverse circumstances associated with MS, but rather a lethal outcome of the co-morbid depression associated with this disease.

Based on its profound impact on patients’ quality of life, function and longevity, depression represents what is perhaps the most treatable cause of morbidity and mortality in patients with MS.  Despite this important impact, depression in MS is frequently under-diagnosed and under-treated.  In 2005, the Goldman Consensus stated that despite the severe negative impact depression can have on the course of MS, many cases remain undiagnosed and untreated, leading the group to encourage better screening and treatment by neurologists of depression in their MS patients [4].

Demoralization

Sometimes an individual’s capacity to adapt is overwhelmed by the stresses with which he is confronted, and he becomes discouraged, bewildered, and overwhelmed.  This is state is called demoralization.  Demoralization has been defined [26] as a state of helplessness, hopelessness, confusion, subjective incompetence, isolation, and diminished self-esteem.  The subjective experience of demoralization involves feeling incapable of meeting both internal and external expectations, feelings of being trapped and powerless to change or escape, and feelings of being unique and, therefore, not understood.  The combined effect usually leads to frustration, bewilderment, and isolation.

A study of MS patients whose average time since diagnosis was nine years, examined their subjective experiences and the psychosocial consequences of their disease [27].  The results of this study are very instructive, in that they demonstrate that even though autoimmune neurologic diseases can be difficult to adapt to acutely, most patients appreciate, over time, that there are beneficial as well as detrimental effects of their illness on their lives [27].

WHAT IS DEPRESSION?

Criteria For Major Depression:

The Diagnostic and Statistical Manual (DSM)-IV criteria for Major Depression requires the presence of five or more of the following symptoms during the same two-week period accompanied by functional impairment:

  1. insomnia or hypersomnia
  2. loss of interest or pleasure (anhedonia)
  3. feelings of worthlessness or inappropriate/excessive guilt
  4. fatigue or loss of energy
  5. depressed mood
  6. diminished ability to think or concentrate, or indecisiveness
  7. significant weight loss when not dieting or weight gain, or decrease or increase in appetite
  8. psychomotor agitation or retardation
  9. recurrent thoughts of death or suicide

In order to meet criteria for Major Depression, at least one of the five or more symptoms that are present must either be depressed mood or loss of interest/pleasure [28].

Diagnosing Depression In MS Patients

Recognizing depression in MS patients can be challenging because of the overlap of symptoms between these psychiatric and neurologic illnesses.  For example, fatigue, cognitive impairment, poor appetite and insomnia occur in many non-depressed MS patients, making reliance on these symptoms difficult in making a diagnosis of depression.  Nonetheless, certain symptoms, such as feelings of self-blame, guilt, and self-recrimination are not common reactions to a medical illness, but are almost always found to some degree in depression [29].  The pervasiveness of symptoms can also suggest depression.  Low mood most of the time or loss of pleasure in activities that require skills that are made more difficult because of neurologic deficits can occur commonly in MS.  This is particularly true during the first few weeks of adjustment to this disease, as this is a period wrought with uncertainty and the conception of loss of health.  However, persistent low mood and lack of pleasure in all activities should raise suspicion for depression.  Similarly, failure to progress beyond the acute shock of being diagnosed with MS after many months or years should raise questions about a supervening depression.  If an individual was progressing well initially in terms of recovery from his neurologic deficits, but suddenly stopped improving and, in fact, began to lose ground, the possibility of depression as a cause should be entertained [30].  Finally, suicidal thoughts should prompt an urgent assessment by a trained physician or mental health professional, because the rate of suicide in MS depression appears at least as great, if not greater, compared other medical conditions [22].  Suicide is universally considered the most extreme consequence of depressive illness; concern for suicide in a patient with a medical condition presents a major healthcare priority to identify and treat an underlying affective illness.

Several points need to be considered when making the diagnosis of depression in MS patients.  First, there are common presentations of these symptoms that may suggest one condition over the other.  Early morning awakening, for example, is commonly seen in patients with depression whereas difficulty initiating or maintaining sleep is more prevalent in MS related insomnia [31].  Diurnal variation in patient’s mood and energy level is common in depression, with patients progressively improving during the course of the day [32].  MS patients more commonly report worsening fatigue in the latter half of the day.  Debilitating fatigue that almost always interferes with a patient’s activities should be considered a symptom likely made worse by an underlying depression until proven otherwise [20].  Cognitive impairment in depression is often characterized by a fluctuating course and a tendency on the part of patients to highlight their difficulties and put forth poor effort on testing because of limited motivation [33].  Effort and attention are commonly affected by depression.  MS cognitive impairment, by contrast, typically is stable when present, and patients tend to conceal their difficulties and provide good effort on testing.  With experience, the different qualities of these overlapping symptoms in depression and MS can become apparent to the clinician practiced in mental status examination.

The second consideration in diagnosing depression in MS patients is that frequently these symptoms can be multi-factorial.  Clinically, it is common for patients who become depressed to have a dramatic worsening in their pre-existing fatigue and concentration problems, which may improve substantially with effective treatment of their depression [17, 21, 34].  Because depression is currently often far more responsive to treatment than are the other comorbid symptoms of MS such as fatigue and cognitive impairment, clinicians should not miss the opportunity to alleviate these symptoms by treating a suspected underlying depression.

The third consideration is the observation that symptom-guided pharmacologic treatments can occasionally worsen the patient’s other conditions.  For instance, a patient with a missed underlying depression who is presumed to be suffering solely from MS-related fatigue might be given modafanil, that can exacerbate insomnia, prompting the addition of a benzodiazepine, that worsens cognition, leading to donapezil, that worsens appetite and in turn lowers energy and increases fatigue.  If an underlying depression was responsible for a significant portion of the patient’s fatigue and concentration difficulties, then the use of an antidepressant would likely prove much more efficacious.

Fourth and perhaps most important in correctly diagnosing depression is to resist the temptation to attribute a patient’s distress as solely a reaction to environmental stressors, and miss a possible endogenous contribution.  As mentioned earlier, although demoralization is common in many medical conditions, depression is a separate entity, the devastating manifestations of which should not be underappreciated.  The presence or severity of depression in MS does not correlate well with the degree of physical disability, suggesting that involvement of the brain and not the degree of stress is paramount in precipitating depression [25, 35, 36].  Stress alone is not sufficient to precipitate depression, although it may play a role in its genesis in vulnerable individuals.  A patient’s mood state should not be dismissed as solely a reaction to stressful circumstances.

CAUSES OF DEPRESSION IN MS

Mounting evidence suggests that depression in MS is immune-mediated and the result of brain inflammation rather than the patient’s environmental situation (Table 1).  The existing evidence is consistent with a cytokine-mediated pathogenesis of depression in MS, with these same mediators of inflammatory damage to the CNS causing perturbations in mood regulation [37-40].  Taken from this vantage point, depression can be viewed as both a pathophysiological complication as well as a clinical symptom of MS.  This would suggest that the management of depression is an integral part of the general management of MS, entirely analogous to the treatment of other disease-related disabilities involving motor, sensory, and autonomic dysfunction, with potential prognostic implications for the overall course of the disease progression.

TREATING MS DEPRESSION

Unlike depression in the general population that resolves spontaneously in roughly 75% of patients over an average of 6-12 months, MS depression generally is unremitting and tends to worsen without therapeutic intervention [41].  The literature on the treatment outcomes in depressed MS patients is limited and largely anecdotal (Table 2).  The first randomized double-blind placebo-controlled trial of an antidepressant to treat MS depression involved five weeks of desipramine compared to placebo [42].  Patients treated with desipramine improved significantly more than the placebo group, but side effects limited desipramine dosage in half of the treated patients.  A three-month open label study of fluvoxamine 200 mg to treat MS depression found 79% of patients achieved response, and the drug was well tolerated [43].  Two separate open label design three-month trials of either sertraline or meclobemide demonstrated positive responses in 90% of subjects [44, 45].  A more recent double blinded placebo trial of paroxetine showed a trend towards improvement  in symptoms compared to placebo.  However, most of the endpoints were not statistically significant [46].

Empirical studies have examined several types of psychotherapy to treat MS depression, including cognitive behavioral, relaxation, and supportive group therapies.  Psychotherapy with an emphasis on coping skills have been found more likely to be effective than insight oriented therapy in treating depression in MS patients [41].  Cognitive Behavioral Psychotherapy (CBT) has been found to be particularly effective in treating MS depression, and there are a number of small studies—some of them randomized—demonstrating the short and long-term efficacy of this form of treatment.  Because many MS patients with mobility impairments have difficulty attending a clinic on a regular basis, researchers conducted a 16-week randomized, controlled study of telephone administered CBT compared to supportive emotion-focused therapy [47].  Improvements in MS patients’ depression using telephone administered CBT was significantly greater in the active treatment group.  Adherence to disease modifying treatments was improved in subjects who received telephone CBT compared to subjects in the usual care conditions.  A new study looking at the use of cognitive rehabilitation showed improvements in attention, executive functioning, and information processing in MS patients [48].

Currently, there are studies underway looking at the benefits of physical activity on mood in MS patients.  Ehde and Bombardier reviewed the potential benefits of exercise as an adjunct treatment for MS depression [3].  Exercise has been shown to have many functional benefits in patients with MS, including improving mood, sexual function, pain and fatigue.  In the general population, even moderate exercise (e.g. 20 minutes per day at 60% maximum heart rate) has shown benefit in decreasing anxiety and stress components of depression.  The two limitations of this intervention are motivating depressed patients to begin a new schedule of exercise, and the rapid loss of efficacy for depression if regular exercise is terminated.

Antidepressant Selection In Treating MS Depression:

There are three general strategies that can be applied to selecting an antidepressant to treat an MS patient suffering from depression.  First, try to minimize the patient’s side effect and potential drug-drug interactions, as these patients are often taking multiple medications.  Escitalopram and sertraline are distinguished by their relatively low side-effect burden and little to no clinically significant risk of drug-drug interactions [49, 50].  These medications are serotonin selective reuptake inhibitors (SSRIs) that have no significant anticholinergic (e.g., sedation, dry mouth, constipation, urinary hesitancy), antihistaminergic (sedation, weight gain), or antiadrenergic (orthostatic hypotension) side-effects.  Their primary drawback for patients with MS is that, like the other SSRIs, they cause sexual side-effects in up to 30-60% of patients [51].  Bupropion by contrast is devoid of any sexual side-effects but does lower seizure threshold [52].  Although there is a theoretical concern that patients with MS are at an increased risk of seizures, there are no reports of bupropion-related seizures in patients with MS, and we have found it quite effective in many MS patients.

The second approach is to tailor the side-effects of medication to alleviate the patient’s depressive symptoms.  For example, bupropion, fluoxetine, and venlafaxine tend to be activating and can partially ameliorate MS fatigue in some patients.  Desipramine, mirtazepine, and paroxetine by contrast are sedating and stimulate appetite, which is useful for patients with insomnia and loss of appetite.  Although there is the theoretical potential for tricyclics to interfere with cognition [53], it has been our experience that they are well tolerated when dosed correctly in MS patients (i.e. start low, and go slow during the initial dose escalation).

The third approach is to select an antidepressant that is useful in simultaneously treating depression and also the comorbid symptoms related to the MS separate from the depression.  Tricyclic antidepressants can help with detrussor hyperactivity urinary urgency (because they are anticholinergic) as well as treat neuropathic pain, both of which are common in MS patients [54].  Duloxetine also is effective in treating neuropathic pain, in addition to treating depression [55].  The possibility of preventing polypharmacy through the use of a single medication for multiple symptoms (such as nortiptyline for depression, neuropathic pain, urinary urgency, and insomnia) is often ideal for the appropriate MS patients.

Potential Impact Of Treating Depression On MS Disease Course

Depression can have a profound impact on varied aspects of MS.  Depression is associated with immune dysregulation, including elevated proinflammatory cytokines [56].  Depression is also associated with adverse CNS changes, as evidenced by reports from several studies that have shown a reduction in hippocampal volume that is more severe in patients with multiple previous depressive episodes and longer durations of depression without any antidepressant treatment [57].  The posterior segment of the hippocampus appears primarily reduced in volume in depressed patients, which is consistent with cognitive studies that showed that learning and memory are altered in patients with a major depressive disorder [58].  Recent MRI studies have shown that MS patients have smaller hippocampi when compared to controls, and increased cortisol levels were found in MS patients with depressive symptoms [59].  Because of immune activation and brain dysfunction, it would be plausible that depression could lead to worse neurologic outcomes in MS patients.

The idea that psychological states could trigger disease activity was originally described by Charcot, who speculated that grief, vexation, and adverse changes in social circumstances were related to the onset of MS [8].  Depression is a state of extreme, prolonged psychological stress, and there has been a growing consensus in the literature that specific types of chronic stress are linked to increased risk for clinical relapse as well as accrual of disability [60].  A recent prospective study tracked number of stressful life events per week and found up to a five-fold increased risk of MS relapse in patients with three or more stressful life events during a four week period [61].  A meta-analysis found a significantly elevated risk of relapse associated with stressful life events in 13 of 14 investigations [62].  The degree that stress increased the risk of MS relapse in this meta-analysis was on average 60% greater than the magnitude of beneficial treatment effect of interferon-beta (IFNb) treatment, suggesting that a therapy that completely prevented relapses in response to stress would be more effective than IFNb in MS.

The effects of treating depression on MS disease course was more directly investigated in a longitudinal study demonstrating that treatment-related reductions in depression in MS patients are associated with reductions in T-cell production of interferon-gamma (IFNg) [63].  IFNg is an important proinflammatory cytokine produced by activated T-cells and is thought to be a key player in MS pathogenesis, particularly in lesion formation and clinical relapse.  T-cells isolated from depressed MS patients were found to be primed to produce twice the levels of IFNg than T-cells from non-depressed controls.  Reductions in depression with sertraline or psychotherapy were paralleled by declines in T-cell IFNg production, which returned to control levels in the MS patients who showed a mood response to either treatment.  This study suggested that treatment for depression can have a highly specific effect on immune mechanisms involved in MS pathogenesis.

Barriers To Seeking And Accepting Treatment For MS Depression

Rehabilitation and recovery from the disability associated with MS relapses or progression can constitute a painstaking and laborious journey.  Depression can derail this process of adjustment.  Unfortunately, classic symptoms of depression, such as hopelessness and loss of interest or motivation, are commonly interpreted as “giving up” and equated with being “weak” or “lazy” rather than interpreted as symptoms of an illness that needs to be treated.  Moreover, laypeople sometimes equate being depressed and seeking treatment for depression with being “crazy” and so avoid seeking evaluation and treatment for fear of being stigmatized.

Preconceptions and myths about antidepressants also represent common barriers to accepting treatment for depression.  Antidepressants specifically target and treat changes in the brains of patients who are suffering from depression, but they have no mood elevating effects on individuals who are not depressed.  As a result, antidepressants are not addicting, unlike drugs of abuse that induce euphoria, and they have no street value.  Antidepressants do not give people “fake” feelings or make them feel things they would not normally feel.  Instead, antidepressants restore the normal cycle of ups and downs, in response to life’s rewards and stresses that is lost in individuals suffering from depression.  Finally, individuals occasionally refrain from using antidepressants based on a perception that they do not want to “end up like a zombie” based on knowing or having heard of someone who was not the same once they started taking medication.  The fallacy in this argument is that depression is far more likely to make someone appear impaired than is the medication that treats their mood disorder.  While it is true that many medications including those used to treat mental illness can produce noticeable side effects, such as over-sedation, the judicious use of antidepressants by trained professionals results in a return to previous functioning in patients in whom depression is responsible for changed behavior.  The goal with antidepressant therapy is to return affected individuals to the helm of their own ships, and allow them to better chart the course of their thoughts, emotions, and behaviors as they regain control of the direction their life is taking.  Rather than develop noticeable side effects that suggest a person is being treated for depression with medication, the only thing that other people notice is that the person being treated seems “more like their old self.”  However, the biggest barrier to seeking and accepting treatment for depression, bar none, is the effects of depression itself, which makes people hopeless, unmotivated, and unable to imagine that things could get better.

Standard of Care for Neurologists Diagnosing and Treating MS Depression:

The Goldman Algorithm, as presented by Schiffer et al. based upon evidence presented at the Goldman Consensus Conference [4, 64], aims to establish a standard of care for neurologists to identify and treat major depression in MS patients (Table 3).  Key steps in the algorithm include regularly screening for the presence of depressive symptoms in all MS patients, diagnosing major depression when present, establishing the functional impact of the depression, and screening for the presence of suicidality.  If a severe depression is diagnosed and causes severe impairment, referral to a psychiatrist is in order.  If the patient does not have significant depression, or the patient does not wish to receive psychiatric treatment in the setting of minimal to moderate impairment, treatment by the neurologist is recommended with future regular reassessments.

Shoring up Support: Who Cares for the Caregivers?

There are both positive and negative aspects of being a caregiver; being able to care for the people whom we love in their time of need is both a privilege and a burden.  Caregivers are dramatically impacted by both MS and depression in the people for whom they care.  The majority of caregivers report that the demands of caregiving disrupt their other obligations to friends, family and career [65].  Caregivers often feel unable to leave the care-recipient alone, which leads to a perception of confinement [41].  Frequently MS patient’s perception about the degree of their caregiver’s burden is less than that reported by the caregiver [66].  Caregivers, patients, and health care providers usually focus virtually all of their attention on the well being of the MS patient, often to the neglect of concerns for the caregiver who usually functions as the patient’s primary source of support.  This occurs despite the fact that the wellbeing of the patient is often vitally dependent on the continued efforts and support from the caregiver, which can best be furnished by a healthy individual.

Poor social support and living alone are both associated with significantly higher rates of suicide in MS patients [66].  Poor social support also has been implicated as a factor in increasing the rate of MS relapses [67].  Conversely, social support acts as a buffer in the relationship between depression and immune activation [68].  As noted previously, depression is associated with worsening MS disease course possibly related to increased IFNg production from T-cells.  The effect of depression on T-cell production of IFNg was significantly moderated by social support.  Specifically, the relationship between depression and IFNg production was particularly strong among patients with low levels of support, but was virtually non-existent among patients with high social support.  This suggests that maximizing social support might buffer the effects of stress and depression on MS pathogenesis and be a crucial part of the treatment of MS patients.

Four considerations can be recommended for caregivers to keep in mind while caring for their loved ones without neglecting themselves.  First, caregivers should enhance their problem-focused coping skills.  This usually involves recognizing what can and cannot be changed, and trying different solutions to the problems that arise until the right one is found.  Second, education is crucial because what caregivers don’t know about MS and depression will increase their anxiety and prevent them from being able to efficiently problem solve.  Peer education opportunities are often invaluable for both information and support.  Third, caregivers must remember to take care of their own needs, which should not be viewed as being in conflict with the care recipient’s needs.  Knowing how to get additional help is often critical to the wellbeing of both parties.  And fourth, caregivers and care recipients must not lose sight of the fact that they share common struggles and rewards together.  Coping strategies must, therefore, be complimentary.  There are often multiple solutions to the same problems, so a premium should be placed on maintaining enough flexibility to maximize the benefits for both care recipients and caregivers.

CONCLUSION

The importance of making the appropriate and timely diagnosis of depression in MS patients cannot be overestimated.  Often what is most debilitating is not the requirement for assistance with walking or adaptations to disability that must be endured, but the depression that leads to difficulty getting out of bed, social isolation, and lowered pain tolerance.  Routinely for MS patients with depression, the majority of the functional impact of their disability is due to the depression, and treatment usually leads to a dramatic increase in their function.  Fortunately, depression is one of the most treatable comorbidities of MS, with the usual expectation that individuals who receive adequate treatment will make a complete recovery.  What is required to achieve this result is often the same level of aggressive management that MS patients routinely invest in managing other aspects of the effects of their disease, such as injecting immunomodulatory treatments to curb inflammation, physical therapy and rehabilitation to enhance ambulation, or urologic management for urinary incontinence.

Before depression can be adequately treated, however, it must be properly recognized, diagnosed, and comprehensively managed.  It is imperative to consider the impact that MS and depression have on both patients and their loved ones, because successful management will ultimately be measured by how well individuals are functioning in the context of their families and their collective lives together.

More work is needed to thoroughly explore the bidirectional influence that MS and depression exert on one another, and the impact of inflammation in mediating this influence (Figure 1).  We have reviewed here evidence that MS causes depression and that depression worsens MS.  Elucidation of the degree to which treatment of MS protects affected patients from co-morbid depression, and treatment of depression helps to ameliorate the inflammation and progression of MS, awaits further study.

Table 1.  Evidence for immune-mediated depression in multiple sclerosis (MS).

Observations in the Literature

  • No correlation between severity of depression and physical disability [25, 35, 36].
  • Risk studies suggest that genetic contribution to the development of depression in MS is small compared to the effects of MS itself [69].
  • Potentially mood destabilizing effects of steroid treatment of MS patients requires careful monitoring during management of neurologic exacerbations [70].
  • Increased rate of suicide at times of relapse [71-73].
  • Neuroimaging shows differences in hippocampal size in depressed MS patients vs. controls [59].
  • Differences in presence/location of lesions and brain atrophy identified with MRI in patients with depression [74].

Models for Immune Mediation

  • Cytokine model: Well documented role in autoimmune diseases; cytokines have been shown to be elevated in depressed patients and correlate with treatment outcome [38-40, 56, 75].
  • Role of Interferons: Identified as contributing to development of depression in patients with hepatitis C infection and possibly MS [76].
  • Role of Glucocorticoids: Shown to have a plethora of neuropsychiatric effects including producing symptoms of depression, mania, psychosis, and delirium [4, 70].

Table 2.  Current Evidence for Treatment Efficacy in MS Depression.

Antidepressant Class Conclusions Reference
Desipramine (Norpramin) TCA Double-blind, placebo controlled. Improved significantly over placebo. [42]
Paroxetine (Paxil) SSRI Double-blind, placebo controlled. Improved but not statistically significant. [46]
Fluvoxamine (Luvox) SSRI 79% of participants improved and tolerated dosage [43]
Sertraline (Zoloft) SSRI 90% improvement rate [44]
Cognitive Behaviorial Therapy Therapy Adherence to disease modifying treatments was improved in subjects who received telephone CBT compared to subjects given usual care.

Cognitive rehabilitation showed improvements in attention, executive functioning, and information processing in MS patients

[47]

 

[48]

Alternative Medicines CAM Studies are needed to evaluate the potential benefits of CAM in the treatment of depression in MS patients N/A

CAM=complementary and alternative medicines, CBT=cognitive behavioral therapy, SSRI=selective serotonin reuptake inhibitor, TCA=tricyclic antidepressants

Table 3.  Diagnosing and Treating MS Depression

 

STEP DETAILS AND CLINICAL RECOMMENDATIONS
Screen for presence of Depression Problem Our present care in the US fails to identify over half of the MS patients with depressive disorders [4, 64].
Diagnostic and Statistical Manual IV Screening for the presence of depression in MS with DSM-IV is complicated by the fact that four of the nine symptoms of depression laid out by DSM-IV are also symptoms of MS—fatigue, psychomotor retardation, decreased concentration, and sleep disturbance. Experienced physicians agree that depression can still be distinguished from MS associated symptoms with the DSM-IV criteria during a clinical interview.
Beck Depression Inventory [78] The BDI is the most commonly used depression scale in MS-associated depression. It is a self-report scale with 21 items. Using the BDI with a 13-point cut-off score screens for about 70% of MS patients with significant depression [79, 80]. The BDI-Fast Screen has also been developed to select for the most sensitive items in relation to MS patients [81].
Center for Epidemiologic Studies – Depression Scale [82] CES-D is a scale that has gained visibility in several large World Health Organization epidemiologic studies. It has been shown to be a fairly consistent scale that screens positive for about 30% of MS patients at any visit. On a year to year basis, only about 5% of the patients increase scores dramatically (by more than 10 points) [83].
Multi-Scale Depression Inventory [84] MDI is a screening device that has subscales to help separate depressive symptoms that are vegetative and physical from those that are affective and cognitive.
Inventory of Depressive Symptomatology [85] IDS is a scale that has the advantage of having both clinician-rated and self-report versions.
Patient Health Questionnaire-9 [86] PHQ-9 consists of the nine DSM-IV items and rates them on a four-point scale on the extent to which patients have been bothered by the symptom over the past two weeks.
Hospital Anxiety and Depression Scale [87] A recent study of HADS showed that a threshold score of 8 on the depression subscale resulted in 90% sensitivity in screening MS patients for depression [88].
Suicidality Most important acute consideration. Obtaining this history should not wait for referral to psychiatrist, but rather should be elicited immediately by the treating neurologist. If present, emergent psychiatric evaluation in an emergency room is advised..
Consider level of impairment presented by depression Patients who meet screening thresholds for depression or endorse suicidal ideations should be actively assessed for severity and quality of depression. They should be considered for follow-up treatment recommendations and referred to a psychiatrist for moderate to severe depression.
Consider and discuss treatment options with patient Problem When depressed MS patients are identified, many are not properly treated [4, 64].
Psychotherapy A variety of psychotherapeutic treatments used in group settings have been shown to be effective in reducing depression severity in MS groups [89]. Individual psychotherapy using a cognitive-behavioral approach has also been shown to lower self-report measures of depression compared to other neuromedical treatments [90].
Pharmacotherapy Multiple studies have shown the effectiveness of antidepressants in treating depression in MS patients [42, 44, 91]. In one study, setraline and CBT were both shown to be roughly equal in their effectiveness of treating depression in MS patients [92].
Integrated Biopsychosocial Treatment The treatment of depression in a complex matter and should be individualized for each person. According to the Goldman Consensus Group, an integrated approach involving both psychotherapy and medication should be the gold standard to be used, at least for the more severe depression [4, 64, 77].
Maintenance or Surveillance Psychotherapy Psychotherapy should continue as long as the patient benefits.
Pharmacotherapy With little to no history of depressive episodes, medication can be tapered and discontinued after about a year of use. If the patient relapses, medication should be restarted.

For patients with history of chronic depression, or more than three depressive episodes, indefinite continuation of medications is recommended, although the dose may be reduced [93].

BDI=Beck Depression Inventory, CBT=cognitive behavioral therapy, CES-D= Center for Epidemiologic Studies – Depression Scale, DSM=Diagnostic and Statistical Manual, HADS=Hospital Anxiety and Depression Scale, IDS= Inventory of Depressive Symptomatology, MDI= Multi-Scale Depression Inventory, MS=multiple sclerosis, PHQ-9= Patient Health Questionnaire-9.

Figure 1

FIGURE LEGEND

Figure 1.  The association of multiple sclerosis (MS), depression, and inflammation.

A.    Lithium has been shown to be protective and beneficial in studies of experimental autoimmune encephalomyelitis [94].  It has been postulated to affect inflammatory signaling, including decreasing activity of COX-1 and COX-2 as well as decreasing one of their prostaglandin products in rats [95].

B.     Antidepressants (selective serotonin reuptake inhibitors and tricyclics) have been shown to improve symptoms of MS including fatigue, cognition, and overall morbidity.  Current evidence suggests an anti-inflammatory effect of these medications, including decreased production of interferon-gamma [96] and effects on the arachidonic pathway [95].

C.     Studies demonstrate superior efficacy in treatment of depressive disorders with concominant use of antidepressants and COX-2 inhibitors suggesting a role for anti-inflammatory agents in treating mood disorders [97].

D.    Studies suggest that Omega 3 fatty acids (N-3 polyunsaturated fatty acids) improve mood as well as have significant effects in the prostaglandin production pathways, again implying a role for anti-inflammatory agents in treating mood disorders [98].

E.     As more agents become available which target inflammation in MS specifically, it may be possible to further evaluate the effects of decreased inflammation on the symptoms of depression.

 

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