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C H A P T E R 1 9
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
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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)
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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 - 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 MSrelated 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
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hippocampal atrophy, temporal lobe atrophy, and decreased
right hemisphere brain volume. 10 -
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 -
19
Consisting of two questions pertaining to the primary
symptoms of MDD, depressed mood and anhedonia, the PHQ2 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
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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), serotoninnorepinephrine 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
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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
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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
FIGURE 19.1 Comparison of depressive symptoms and
fatigue in individuals with multiple sclerosis (MS).
Fatigue can be assessed using the Fatigue Severity Scale
(FSS), the Modified Fatigue Index Scale (MFIS), and the
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Neurological Fatigue Index for MS (NFI-MS), all of which
have been validated for use in individuals with MS. 31 - 33 The
FSS is a 9-item self-report measure of fatigue severity in
individuals with chronic medical conditions like MS and lupus
(see Table 19.2). The MFIS is a self-report measure of fatigue
interference (i.e., how much fatigue interferes with daily
activities) that consists of 21 items divided into physical,
cognitive, and psychosocial subscales. The NFI-MS is a 10item outcome measure that assesses the presence of physical
and cognitive fatigue. 31 , 34 -
36
TABLE 19.2
Fatigue Severity Scale (FSS)
Please circle the number between 1 and 7 which you
feel best fits the following statements. This refers to
your usual way of life within the last week. 1
Indicates “strongly disagree” and 7 indicates
“strongly agree.”
Read and Circle a Number Strongly Disagree →
Strongly Agree
1. My motivation is lower when I am fatigued
1 2 3 4 5 6 7
2. Exercise brings on my fatigue
1 2 3 4 5 6 7
3. I am easily fatigued
1 2 3 4 5 6 7
4. Fatigue interferes with my physical
functioning
1 2 3 4 5 6 7
5. Fatigue causes frequent problems for me
1 2 3 4 5 6 7
6. My fatigue prevents sustained physical
functioning
1 2 3 4 5 6 7
7. Fatigue is among my most disabling
symptoms
1 2 3 4 5 6 7
8. Fatigue interferes with my work, family, or
social life
1 2 3 4 5 6 7
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