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Med/Psych Update

Is multiple sclerosis patient depressed, stressed, or both?

How to sort through overlapping symptoms and provide appropriate treatment.

Vol. 7, No. 4 / April 2008

Mrs. S, age 50, has had relapsing-remitting multiple sclerosis (MS) for approximately 10 years. She describes her mood as “up and down” and is referred by her neurologist for psychiatric assessment of mood swings and possible depression. Fatigue limits her ability to work full-time, perform household duties, socialize with friends and family, and enjoy mental or physical exercise. In addition, her 18-year-old daughter—an important source of psychological support—is planning to leave home.

Mrs. S experienced depression 5 years ago during her divorce. She was prescribed paroxetine, 20 mg/d, and had a positive response. She took the medication for 6 months, then discontinued.

One-half of MS patients experience major depression in their lifetimes,1 and the suicide rate is approximately doubled in MS patients compared with the general population.2 Depression in MS patients often has an atypical presentation, with irritability and anger being as prominent as sadness.3 Not all emotional changes experienced by MS patients represent depressive disorders, however.

When evaluating MS patients who are struggling with depression, you can help them by diagnosing comorbid mood disorders, determining suicide risk, and providing psychological support as they cope with the impact of their illness.

MS disease course

MS is a disease of the brain and spinal cord, characterized by:

  • inflammatory demyelination and gliosis
  • neuronal and axonal loss
  • a variety of presenting symptoms as different CNS regions are affected.

Focal areas of demyelination followed by a reactive gliosis cause white matter lesions in the brain, spinal cord, and optic nerve. Neurologic dysfunction can manifest as visual changes, spastic paresis, hypoesthesia and paresthesia, ataxia, and bowel and bladder dysfunction. MS presentation also can include optic neuritis and transverse myelitis. MS symptoms often are intensified by heat exposure.

After the initial episode, months or years may pass before additional neurologic symptoms appear. Based on its course, MS can be classified as:

  • relapsing-remitting, when the disease does not progress between attacks
  • secondary progressive, characterized by a gradually progressive course after an initial relapsing-remitting pattern
  • primary progressive, when patients experience gradual progressive disability from symptom onset (Table 1).

Table 1

Clinical classification of multiple sclerosis (MS)




Symptoms appear during relapses, resolve during remissions, and do not progress between relapses

Secondary progressive

MS symptoms that previously followed a relapsing-remitting pattern steadily become more severe and progress without relapse

Primary progressive

Gradual progression from symptom onset, without relapses or remission

Clinically isolated syndrome

A single attack that may indicate MS has occurred—such as optic neuritis or transverse myelitis—but clinical requirements for the diagnosis have not been met

* Patients often progress from relapsing-remitting to secondary progressive MS

CASE CONTINUED: Progressing symptoms

Mrs. S has had multiple MS presentations, including optic neuritis, lower extremity weakness, balance problems, and urinary incontinence. Recently, her MS symptoms have gradually progressed even in the absence of attacks, and her diagnosis has been revised to secondary progressive MS.

During psychiatric evaluation, Mrs. S denies persistent changes in sleep or appetite. She describes fatigue that starts after physical exertion and increases as the day progresses. She denies feelings of worthlessness, helplessness, excessive guilt, and suicidal ideation and does not have a history of inappropriate anger or irritability.

Diagnosing depression in MS

Normal emotional adjustment to MS can include reactions to loss of function or changes in social or occupational roles. Further, MS patients—similar to non-MS patients—experience life changes and transitions not related to the illness, such as divorce or a grown child moving away. Emotional responses to life stressors often are self-limited but may warrant an adjustment disorder diagnosis if they are associated with excessive distress or substantial impairment in social, occupational, or academic functioning (Table 2).4

Table 2

Questions to consider when assessing MS patients for depression

Ask yourself


Are symptoms part of normal emotional changes?

Not all mood changes are pathologic or meet criteria for major depression

Is this an adjustment disorder?

Mood symptoms can be caused by a major stressor such as a recent diagnosis or personal loss

Is fatigue secondary to MS or depression?

MS typically causes fatigue after physical activity and heat exposure; fatigue early in the day points to depression

Are cognitive deficits related to MS or depression?

Negative thoughts point to depression whereas cognitive deficits may be caused by depression, MS, or both

Is this an atypical presentation?

MS patients may present with anger or irritability

Is this a pseudobulbar problem?

Patients with IEED might describe more concern about affect dysregulation than mood swings

MS: multiple sclerosis; IEED: involuntary emotional expression disorder

Female MS patients and those who report high stress or a family history of affective disorder may be more likely to develop clinical depression.5 Several studies have reported correlations between structural brain abnormalities and depression in MS. Feinstein et al6 reported that extensive hyper intense lesion volume in the left medial inferior prefrontal region with atrophy affecting the dominant anterior temporal lobe was associated with major depression. However, a depression diagnosis in MS patients remains a clinical one that does not require brain imaging studies.

Lack of interest or enjoyment as a symptom of depression can be difficult to identify because MS can diminish enjoyment of some activities. Although patients with MS may need to change their activity patterns to accommodate their illness, the lack of enjoyment in all—or almost all—activities remains a valid indicator of depressive disorder.

MS treatment includes the use of disease-modifying medications such as interferon beta-1b and interferon beta-1a. Several years ago researchers were concerned that interferon beta might cause depression in MS patients based on reports of a suicide and attempted suicide during an early trial of interferon beta-1b in relapsing-remitting MS.7 Subsequent studies did not substantiate this concern, however (Box 1).8,9

Overlapping symptoms such as fatigue and cognitive deterioration could complicate the diagnosis. Look for changing patterns of these symptoms and other signs of depression. Rating scales that do not emphasize fatigue and cognitive impairment—such as the Beck Depression Inventory10 and the Center for Epidemiologic Studies Depression Rating Scale11—can help identify depression in MS patients.

Fatigue is one of MS’ most common and troublesome symptoms.12,13 It typically mounts gradually during the day and after activity or heat exposure. Thus, fatigue early in the morning or manifesting as diminished motivation may point to a depressive disorder.

Cognitive deterioration. Clinically significant cognitive dysfunction occurs in 45% to 65% of MS patients.14 The disease can cause losses in short-term memory, attention, information processing, problem solving, multitasking, and language function.

Bedside cognitive function tests such as the Mini-Mental State Examination15 often are not sensitive enough to detect MS-related cognitive dysfunction. Be alert for changes in cognitive style when assessing for depressive disorders in these patients. Feelings of worthlessness and guilt or suicidal ideation are not normal MS symptoms and point to depression.

MS patients may experience pathological laughing and crying—also known as involuntary emotional expression disorder (IEED)—a neurologic phenomenon that causes uncontrollable laughing, crying, or anger in the absence of subjective emotional distress. IEED has been reported in approximately 10% of patients with MS (Box 2).16-22

CASE CONTINUED: Learning to adjust

Since discontinuing paroxetine 5 years ago, Mrs. S has not experienced another depressive episode. However, she describes a history of mood changes associated with pressured speech, increased activity, irritability, and insomnia during cortisone treatment for idiopathic thrombocytopenic purpura 4 years earlier. These episodes were mild, and she did not seek psychiatric treatment.

Mrs. S’ mood episode does not seem to be a recurrence of major depressive disorder because she lacks persistent depressed mood and major depressive symptoms. Her diagnosis is best understood as an adjustment disorder to the progression of her illness and her daughter leaving home. Fatigue is her most debilitating MS symptom.

Medication options

Use a cautious approach to pharmacotherapy. MS patients may have diminished cognitive reserves and might be at increased risk of medication-related delirium.

Depression. Two randomized, controlled trials have confirmed antidepressants’ efficacy for treating depression in MS patients. The studies investigated the tricyclic antidepressant desipramine23 and the selective serotonin reuptake inhibitor (SSRI) sertraline.24

In a double-blind clinical trial, 28 patients were randomly assigned to a 5-week trial of desipramine and individual psychotherapy or placebo and psychotherapy. Patients receiving desipramine showed significantly greater improvement than the placebo group, as measured by clinical judgment.

A 16-week study compared the efficacy of cognitive-behavioral therapy (CBT), supportive-expressive group therapy (SEG), and sertraline in 63 MS patients with major depressive disorder. Results showed that CBT and sertraline were more effective in reducing depression than SEG.24

SSRIs are a common first choice because of their ease of use and general tolerability among MS patients.25 Recommended dosages include:

  • citalopram, 20 to 40 mg/d
  • fluoxetine, 20 to 40 mg/d
  • fluvoxamine, 50 to 300 mg/d
  • paroxetine, 20 to 50 mg/d
  • sertraline, 50 to 200 mg/d.

There is no consensus that any one antidepressant is best for all MS patients, however. When selecting an antidepressant, consider side-effect profiles, potential for drug-drug interactions, and a history of response to a particular antidepressant. Highly sedating antidepressants such as mirtazapine could aggravate fatigue. Highly anticholinergic agents such as amitriptyline may impair cognitive function.

Fatigue. Amantadine is the mainstay pharmacologic treatment for fatigue in MS, but evidence for its efficacy is weak.26 Clinical trials of psychostimulants generally have reported disappointing results. One randomized, double-blind trial found no significant differences in fatigue levels between patients receiving pemoline or placebo.27

Some studies have reported reduced MS-related fatigue with modafinil,28-30 but the only double-blind, placebo-controlled trial showed no significant difference between modafinil and placebo in patient fatigue levels.31 In this study, modafinil reduced physical fatigue only in patients with daytime somnolence.

Box 1

Neuropsychiatric effects of multiple sclerosis medications

Do interferon beta-1a and 1b—agents used to treat relapsing-remitting MS—cause or aggravate depression?

Two large-scale clinical trials of interferon beta-1a included a validated measure of depressive symptoms—the Center for Epidemiologic Studies Depression Rating Scale.8,9 This scale allowed researchers to conduct a detailed analysis that compared changes in depression symptoms over time in study participants treated with interferon or placebo. Evidence did not indicate increased depressive symptoms in association with interferon treatment.

Conclusion. Depression symptoms that emerge during treatment with one of these agents are not likely caused by the treatment and usually can be managed without discontinuing the drug.

Other psychiatric disorders

Bipolar disorder occurs more frequently in MS patients than in the general population.32 Additionally, some patients with advanced MS might experience benign feelings of euphoria.33 Euphoria can be differentiated from mania by assessing for mania’s other symptoms, such as erratic and disinhibited behavior, rapid speech, increased libido, decreased need for sleep, and excessive energy.

Antidepressants and corticosteroids could aggravate the course of bipolar disorder, and drug-illness interactions with lithium could make side effects such as tremor, diarrhea, and polyuria more difficult to tolerate. Mood stabilizing anticonvulsants such as valproate and carbamazepine are a useful alternative for treating the bipolar patient with comorbid MS. To avoid sedation, start with a low dose and increase gradually.

Box 2

Uncontrollable crying may be pseudobulbar affect, not depression

Approximately 10% of multiple sclerosis (MS) patients develop inappropriate affective expression—anger, laughing, or crying—in the absence of prominent mood changes.16 Involuntary emotional expression disorder (IEED)—or pathologic laughing or crying—is a form of pseudobulbar affect. IEED occurs when affective motor control becomes disinhibited as a result of brain damage from neurologic disease or injury. Conditions associated with IEED include amyotrophic lateral sclerosis, MS, traumatic brain injury, stroke, and dementia.17

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