Mood Disorders in Multiple Sclerosis

Jagriti “Jackie” Bhattarai

Jeffrey G. Portnoy

Frederick W. Foley

Meghan Beier

Introduction

Mood disorders, such as depression, anxiety, and bipolar disorder are substantially more common among individuals with multiple sclerosis (MS) compared with the general population.¹ Mood symptoms can impact quality of life, reduce adherence to disease-modifying medications, and increase risk of suicide, pain, fatigue, cognitive impairment, and poor health behaviors, such as excessive alcohol use and smoking.²,³ The prevalence of mood disorders, as well as their impact on functional activity, necessitates the medical provider to assess, monitor, and adequately treat these symptoms in their patients with MS. The following chapter introduces the prevalence and typical presentation of common mood disorders found in multiple sclerosis. Options for assessment, treatment, and exemplifying case examples are also described.

Depression

Depression is a disorder characterized by low mood and anhedonia (the loss of interest or pleasure in ones normal activities).⁴ The presentation of depression symptoms may vary from individual to individual and can include any of the following (as presented in Table 19.1): observed and/or
reported depressed mood, anhedonia, feelings of excessive guilt or worthlessness, loss of interest in usual activities, sleep or diet changes, fatigue or an increase in existing fatigue, and difficulty with cognitive functioning, particularly in terms of attention/concentration and decision-making.

TABLE 19.1 FEATURES OF DEPRESSION BASED ON THE DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS, FIFTH EDITION (DSM-5) OF THE AMERICAN PSYCHIATRIC ASSOCIATION (APA; 2013)⁴

298.0 (F32.3) Major Depressive Disorder (MDD)
Five or more symptoms (with at least one of the symptoms being number 1 or 2) must be present in the same 2-wk period Single or recurrent episodes (2 consecutive months between single episodes)	Depressed mood most of the day (subjective or observed) Loss of interest or pleasure in usual activities Significant change in weight or appetite Insomnia or hypersomnia Psychomotor agitation (observed) Loss of energy or fatigue Worthlessness or excessive guilt Diminished concentration or indecisiveness Thoughts of death, suicidal ideation, or suicidal attempt
300.4 (F34.1) Persistent Depressive Disorder (Dysthymia)
Depressed mood on most days for at least 2 y Two or more (of six) symptoms present for at least 2 y Criteria for MDD may be met for 2 y	Poor appetite or overeating Insomnia or hypersomnia Low energy or fatigue Low self-esteem Poor concentration or difficulty making decisions Feelings of hopelessness
V62.82 (Z63.4) Uncomplicated Bereavement is a normal reaction to a significant loss during which some individuals present with symptoms of depression. This should be differentiated from depressive disorders during assessment.

22% to 54% of individuals with MS will experience depression during their lifetime.¹,⁵,⁶,⁷ One might presume that depressive symptoms arise as an emotional reaction to the negative impact MS symptoms have on a person’s life. However, research suggests that biological and neuroimmunological factors may also be at play. In other words, depression may be a psychosocial response to difficult life circumstances, including living with
a chronic progressive medical condition; a direct consequence of physiological changes caused by MS; or both.⁸,⁹ The stability of depressive symptoms over time lends support to the notion that MS-related depression is not always reactionary. One longitudinal study found that depressive symptoms remained relatively stable over 4 years, suggesting that depression in MS may resemble persistent depressive disorder, a chronic low-grade level of depressed mood, unlike the waxing and waning episodes seen in major depressive disorder (MDD; see Table 19.1).⁵ Additionally, structural brain changes have been observed in depressed persons with MS, including hippocampal atrophy, temporal lobe atrophy, and decreased right hemisphere brain volume.¹⁰,¹¹,¹²

In the event that patients or their families report symptoms of depression, it is advisable to administer brief screener to assess for the presence and severity of symptoms as well as the potential need for intervention. Repeat use of the following screening tools is advisable, as higher rates of depressive symptomatology have been observed during relapses/exacerbations.¹³ There are several validated self-report questionnaires for assessing depressive symptoms in persons with MS: the 9-item and 2-item forms of Patient Health Questionnaire (PHQ-9 and PHQ-2, respectively); Beck Depression Inventory Fast Screen (BDI-FS); Hospital Anxiety and Depression Scale (HADS); and the Center for Epidemiological Studies Depression Scale (CES-D).³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹ Consisting of two questions pertaining to the primary symptoms of MDD, depressed mood and anhedonia, the PHQ-2 is the most practical to administer. Tools such as these are especially critical for detecting depression symptoms in individuals with MS.

Therapeutic Options for Depression in MS

Several behavioral and pharmacological treatments for depression have been recommended for individuals with MS. There are a limited number of randomized controlled trials of antidepressant medications in this population, but open-label trials of duloxetine, fluoxetine, sertraline, moclobemide, imipramine, and tranylcypromine concluded efficacy for patients with MS. Both a Cochrane review and an American Academy of Neurology 2014 consensus paper described insufficient evidence to advocate use of one pharmacologic agent over another without head-to-head trials.⁶,⁹,¹⁴

Use of psychotropic pharmacotherapy in MS is widespread, and while further study is needed to improve the efficacy of first-line therapies and better tailor treatments to patients’ needs, best practices do currently support the use of antidepressant medications for the treatment of depression in MS.⁵ The choice of which medication to prescribe for depressive symptoms often involves some degree of trial and error, and ideally the initiation and management of a psychotropic medication regimen would be aided by the expertise of a psychiatrist or other prescribing mental health practitioner. In MS, prescriptive decisions are further complicated by the
variety of additional symptoms that patients experience and the potential for interaction with other prescribed medications, including disease-modifying agents. The risk of noncompliance due to adverse events should be monitored closely by the prescriber. However, patients should also be counseled that side effects may lessen or abate entirely once they have adjusted to the antidepressant medication and that they should persist with medication trials past the initiation phase if possible to determine long-term efficacy and tolerability.

Sexual dysfunction is widespread in MS, and antidepressants acting broadly on serotonergic systems, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) can exacerbate sexual symptoms. Atypical antidepressants, such as mirtazapine and bupropion, are options for these patients, although the latter is contraindicated in MS patients who experience seizures. Mirtazapine may also be considered in patients who regularly experience nausea or suffer from poor appetite; SSRIs and SNRIs can increase these symptoms, and mirtazapine not only carries a lower risk of nausea but may reduce such symptoms and promote weight gain in patients with these difficulties. Mirtazapine’s sedative effect can also be beneficial in patients with sleep disorders. It should be noted that while these efficacy profiles have been described generally, there have been few studies evaluating mirtazapine specifically in MS.

Fatigue is a highly prevalent MS symptom, and there is limited evidence that bupropion can reduce fatigue symptoms while treating depression. Further studies are needed to explore the best treatments for patients with comorbid fatigue and mood disturbance, particularly those taking other stimulant medications for fatigue, which can exacerbate mood dysfunction.

TCAs are generally not tolerated as well as newer antidepressants but should be considered in patients with neuropathic pain, insomnia, or urinary incontinence. The risk of anticholinergic side effects should be monitored, and patients may experience cognitive disturbance, dizziness, dry mouth, visual changes, and constipation. Orthostatic hypotension and weight gain are also possible side effects and are an important consideration in prescribing TCAs to patients who are overweight or possess other cardiovascular risk factors. SNRIs, including duloxetine and venlafaxine, should be considered in patients with nerve pain, migraine, or other headache disorder.³,¹⁴

Individuals on antidepressants that can prolong the QT interval may be at risk for torsades de pointes when starting fingolimod, a disease-modifying medication that can result in decreased heart rate upon initiation. If unable to switch antidepressants or take a break from the medication during initiation of fingolimod, these individuals should be monitored overnight.

For patients with preexisting medication adherence difficulties, antidepressants with longer half-lives should be considered, as they carry a lower risk of adverse events if doses are missed. Fluoxetine is dosed such that patients need only take a single pill, and missed doses are less harmful than in paroxetine, a comparable SSRI.³

In addition, there is considerable evidence supporting the use of behavioral interventions for depressive symptoms in MS. Both in-person and telephone-based randomized controlled trials of cognitive behavioral therapy (CBT) have shown decreased depressive symptomatology, with the benefits of psychotherapy persisting over time.⁹,²⁰,²¹

The Overlap of Depression and Fatigue

Fatigue is commonly found alongside, or in the midst of, depressive symptoms in individuals with MS. Fatigue alone affects up to 90% of this population.²²,²³ Etiology thought to be multifactorial (physiological, cognitive, and behavioral), and the underlying mechanisms are not yet fully understood.²³,²⁴ Fatigue is considered either primary (caused by the MS disease process, including immunological factors, demyelination, and axonal loss in the central nervous system [CNS]) or secondary, resulting from conditions comorbid with MS such as sleep disturbance and depression.²²,²³,²⁵,²⁶

The association between MS-related depression and fatigue is complex.²⁷,²⁸ While some individuals will experience fatigue independent of depression, in many cases there is a mutual relationship (see Figure 19.1).¹⁸,¹⁹,²⁹ Shared symptoms between the two conditions include anergia,
diminished attention/concentration, slowed processing speed, sleep disturbance, and decreased social participation. When patients present with these shared symptoms, validated fatigue measures should be administered alongside validated depression measures (see recommendations described above). Providers are advised to be vigilant regarding the presence of both conditions in younger patients with higher levels of disability, as these groups are the most vulnerable to concurrent depression and fatigue.³⁰