International Review of Psychiatry

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Depression in multiple sclerosis

Scott B. Patten, Ruth Ann Marrie & Mauro G. Carta

To cite this article: Scott B. Patten, Ruth Ann Marrie & Mauro G. Carta (2017): Depression in
multiple sclerosis, International Review of Psychiatry, DOI: 10.1080/09540261.2017.1322555

To link to this article: http://dx.doi.org/10.1080/09540261.2017.1322555

Published online: 06 Jul 2017.

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INTERNATIONAL REVIEW OF PSYCHIATRY, 2017
https://doi.org/10.1080/09540261.2017.1322555

REVIEW

Depression in multiple sclerosis

Scott B. Pattena, Ruth Ann Marrieb,c and Mauro G. Cartad
a
Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; bDepartment of Internal Medicine
(Neurology), University of Manitoba, Manitoba, Canada; cDepartment of Community Health Sciences, University of Manitoba,
Manitoba, Canada; dDepartment of Medical Sciences and Public Health, Quality of Care, University of Cagliari, Cagliari, Italy

ABSTRACT ARTICLE HISTORY

Depressive disorders occur in up to 50% of people living with multiple sclerosis (MS). Prevalence Received 6 January 2017
estimates are generally 2–3-times higher than those of the general population. Myriad aetiologic Revised 21 February 2017
factors may contribute to the aetiology of depression in MS including biological mechanisms Accepted 20 April 2017
(e.g. hippocampal microglial activation, lesion burden, regional atrophy), as well as the stressors,
threats, and losses that accompany living with an unpredictable and often disabling disease. KEYWORDS
Some prominent risk factors for depression such as (younger) age, (female) sex, and family his- Depression; depressive
tory of depression are less consistently associated with depression in MS than they are in the disorders; major depressive
general population. Management of depression in MS has not been well studied, but available disorder; multiple sclerosis
data on detection and treatment align with general principles of depression management. While
the validity of standard measurement scales has often been questioned, available evidence sug-
gests that standard scales provide valid ratings. Evidence for the effectiveness of depression
treatments in MS is limited, but available evidence supports the effectiveness of standard
treatment approaches, including both cognitive behavioural therapies and antidepressant
medications.

Introduction (Koch, Glazenborg, Uyttenboogaart, Mostert, &

The goal of this narrative review is to provide a synthe-
sis of current evidence related to the identification and
management of depression in MS. The review draws
upon past publications, including previous review
articles and related literature, in addition to primary
studies. As the topical content of the review was not
restricted to a specific research question, systematic
approaches (e.g. defined literature search strategies,
formal quality assessment protocols and instruments)
were not employed. Recently, the American Academy
of Neurology published a clinical practice guideline
that was based on detailed systematic literature review
strategies combined with formal grading of the quality
of available evidence (Minden et al., 2014). This guide-
line supplemented earlier consensus-based guidance
(Goldman Consensus Group, 2005). Both initiatives
highlighted a lack of high quality studies, especially
the lack of high quality randomized controlled trials
of depression treatments. The latter point, as it
pertains specifically to pharmacological treatment, was
also corroborated by a Cochrane Library review
De Keyser, 2011). Despite the lack of high quality evi-
dence, clinicians are nevertheless tasked with providing
mental healthcare for people with MS. Therefore, the
aim of the current review is to synthesize available data
in a clinically salient fashion.
What is multiple sclerosis (MS)?
Multiple sclerosis (MS) is a chronic immune-medi-
ated, inflammatory disease of the central nervous sys-
tem (Goldenberg, 2012). MS is a demyelinating
disease, but is also associated with degenerative
changes affecting normal-appearing white matter and
grey matter (Murray, 2006). While
15% of cases
begin with a progressive course, generally MS begins
with a relapsing-remitting pattern that may later
evolve into a secondary progressive phase. MS is said
to be the most common disabling neurological disease
in young adults (Murray, 2006). About 50% of people
with MS need assistance walking within 15 years of
symptom onset (Weinshenker et al., 1989).

CONTACT Scott B. Patten patten@ucalgary.ca Department of Community Health Sciences, University of Calgary, 3rd Floor TRW Building, 3280
Hospital Drive NW, Calgary, Alberta, Canada
ß 2017 Institute of Psychiatry and Johns Hopkins University
2 S. B. PATTEN ET AL.
How common is depression in MS?
Depression can be defined and assessed as a symptom
(depressed mood), a severity-rated dimensional syn-
drome, or as one of several depressive disorders.
Depressed mood, when conceived as a symptom, lacks
clinical specificity, since sadness is a universal emotion
and a component of normal emotional experience.
Depression is more often regarded as a syndrome that
manifests across a dimension of symptom severity.
Dimensional ratings are obtained using depression rat-
ing scales, which produce ordinal scores that represent
the current (usually past week or past 2-week) severity
of depressive symptoms. Such scales often apply cut
points that indicate, if not a diagnosis, a level of symp-
toms that are likely to be clinically significant. Assessed
this way, clinically significant depressive symptoms
occur in
20–40% of people with MS in clinical set-
tings (Amtmann et al., 2014; Patten, Fridhandler, Beck,
and Metz, 2003; Patten, Lavorato, & Metz, 2005; Sacco
et al., 2016; Schippling et al., 2016). Some community
studies have produced even higher prevalence esti-
mates (Bamer, Cetin, Johnson, Gibbons, & Ehde,
2008). Whereas most studies have used either samples
from clinical settings or volunteer community samples,
a recent national survey conducted in Canada used the
Brief Patient Health Questionnaire (Kroenke & Spitzer,
2002; Spitzer, Kroenke, Williams, & Group, 1999), or
PHQ-9, in a probability sample representative of the
household population. The sample included 630 indi-
vidual respondents with MS (Viner, Fiest, 2014). With
application of the traditional PHQ-9 cut-point of 10þ,
a point prevalence of 26% was reported (Viner, Fiest,
2014). In comparison, the general population preva-
lence according to the 10 þ PHQ-9 cut-point is 8.4% in
Canada (Patten & Schopflocher, 2009).
The largest prevalence study of depression in MS
was conducted at multiple sites in Italy (Solaro et al.,
2016). This study used the Beck Depression
Inventory-II to assess depressive symptoms in 1011
patients with MS or clinically isolated syndromes
likely to evolve into MS. In this sample, 33.9% of
patients had BDI-II scores 14, indicating at least
minimal levels of depressive symptoms.
Other studies have examined the prevalence of
major depressive episodes using semi-structured diag-
nostic instruments such as the Structured Clinical
Interview for DSM-IV (SCID) (First, Spitzer, Gibbon,
& Williams, 1997), the Schedule for Affective
Disorders and Schizophrenia (SADS) (Endicott &
Spitzer, 1978), or the Schedules for Assessment
in Neuropsychiatry (SCAN) (Bebbington, 1992).
Using the SCID, Feinstein and Feinstein (2001)
reported a lifetime prevalence of 17% in a consecutive
series of 100 patients with MS, whereas Sadovnick
et al. (1996) reported 34.4% lifetime prevalence in a
British Columbia study employing the same measure.
Two studies using the SADS have reported lifetime
prevalence in the range of 40–50% (Joffe, Lippert,
Gray, Sawa, & Horvath, 1987a; Minden, Orav, & Reich,
1987).
Semi-structured interviews are difficult to employ
in population surveys since they must be administered
by a trained clinician. Community studies have more
often used fully structured interviews such as the
Composite International Diagnostic Interview (CIDI)
(Kessler & Ustun, 2004) or its Short Form, the CIDI-
SF (Kessler, Andrews, Mroczek, Ustun, & Wittchen,
1998). In one study the CIDI produced a lifetime
prevalence estimate of 22.8% (Patten, Metz, & Reimer,
2000), whereas past-year prevalence according to the
CIDI-SF was found to be 15.7% (Patten, Beck,
Williams, Barbui, & Metz, 2003).
More recently, studies have begun to assess preva-
lence by applying validated case definitions in admin-
istrative data sources such as hospitalization and
physician billing data. Using population-based admin-
istrative health data from four Canadian provinces,
Marrie, Fisk, (2015) found a crude prevalence of
depression of 20.1% in a sample of 44 452 people
with MS, compared to 11.9% in a matched general
population sample. Most epidemiological studies have
assessed major depressive episodes, but such episodes
can occur both in Major Depressive Disorder and in
Bipolar Disorder. An epidemiological association of
MS with bipolar disorder has long been suspected
(Joffe et al., 1987a; Minden & Schiffer, 1990), but not
until recently has this been confirmed and quantified.
With access to larger sample sizes, Marrie, Fisk, et al.
(2015) was able to estimate bipolar disorder preva-
lence: 4.7% in people with MS, compared to 2.3% in
a matched general population sample. A case-control
study by Carta, Moro, Lorefice, Trincas et al. (2014)
has confirmed that this association is evident across
the bipolar spectrum, including Bipolar I and II dis-
order, as well as cyclothymia, and that, in the case of
Bipolar II, there may be an impact on quality-of-life
exceeding even that of major depression (Carta,
Moro, Lorefice, Picardi, et al., 2014).
While the studies cited above used a variety of dif-
ferent instruments, there is a common theme. The
reported prevalence of major depression is always
2–4-times the reported prevalence, using a similar
measurement strategy, in the general population. For
example, whereas CES-D studies have reported a

prevalence of 20–40% with application of the trad-
itional cut-point of 16 þ (see above), a systematic
review of CES-D validation studies conducted in the
general population or primary care reported a median
prevalence of 8.8% (Vilagut, Forero, Barbaglia, &
Alonso, 2016), similar to the value obtained with the
PHQ-9, when scored with its traditional cut-point, as
noted previously. The lifetime prevalence of major
depression in the general population, according to the
CIDI is in the range of 10–15%, and annual preva-
lence is
5% (Alonso et al., 2004; Kessler et al., 2003;
Patten, et al. 2014). In each case, the estimate among
people living with MS is roughly 3-times higher.
However, while many studies have found a 2–4-fold
increase in depressive disorder prevalence, the surveys
conducted with screening tools (which generally assess
very recent symptoms, such as past-week symptoms)
have produced relative estimates that appear to be at
the higher end of this range (e.g. see the PHQ-9 data,
26% vs 8%, a 3-fold increase), whereas population-
based lifetime prevalence estimates have in some cases
been at the lower end of this range, e.g. 22.8% with
the CIDI (Patten et al., 2000) vs general population
estimates are about half this value (Patten et al., 2006,
Patten et al., 2014), possibly reflecting a greater ten-
dency towards chronicity of depressive disorders in
MS. This hypothesis is further substantiated by
reports of long-term correlations between symptom
ratings in individual patients (Koch et al., 2015).
However, it has long been suspected that screening
scales in samples of people with MS would show a
higher percentage of false positive ratings, because of
the aforementioned overlap of symptoms.
A synthesis of these estimates is difficult to achieve
due to the heterogeneity of measures employed in this
literature, resulting in a large range of prevalence esti-
mates. However, random-effects meta-analysis can
support estimation of pooled estimates in circumstan-
ces of such heterogeneity by allowing methodological
differences between studies to manifest as between-
study variability. A recent systematic review reported
an overall pooled estimate of depression prevalence of
23.7% and that for bipolar disorder of 5.8% (Marrie,
Reingold, et al., 2015).
What is the differential diagnosis of depression
in MS?
As noted above, the term depression can refer either
to a symptom (low mood), a syndromal dimension
(as would be assessed by a rating scale), or as a nom-
inal category such as a depressive disorder. Within
the latter domain, there are several sub-types.
INTERNATIONAL REVIEW OF PSYCHIATRY 3
Anecdotally, adjustment disorders are believed to be
very common in MS, especially at times of role transi-
tions. By definition, an adjustment disorder follows
the occurrence of a stressor and does not meet diag-
nostic criteria for a mood disorder (American
Psychiatric Association, 2013). However, emotional
reactions to stressful events can resemble mild major
depressive episodes or intensify existing disorders.
Adjustment disorders resolve spontaneously, with sup-
portive interventions or psychotherapy (Carta,
Balestrieri, Murru, & Hardoy, 2009). The strategy of
‘watchful waiting’ may also be useful in such instances
(National Collaborating Centre for Mental Health,
2011). Watchful waiting means arranging for near-
future reassessment, usually of a mild episode, rather
than immediately initiating treatment.
As noted above, bipolar disorder is associated with
MS (Marrie, Fisk, et al., 2015, Marrie, Reingold,
2015), having a prevalence of
5%. The distinction
between major depressive disorder and bipolar dis-
order is important, even though major depressive epi-
sodes that occur during the course of bipolar disorder
can be identical to those seen in major depression
(American Psychiatric Association, 2013). Although
there are no trials of treatment for bipolar disorders
in MS, it is known that antidepressant medications
are capable of triggering hypomanic or manic epi-
sodes in people with these disorders (Patel et al.,
2015). Indeed, since the diagnosis of bipolar disorder
is based on the first occurrence of manic or hypo-
manic episodes, it is inevitable that a proportion of
patients with MDD will subsequently transition to the
bipolar disorder category over time. One long-term
study of non-MS hospitalized patients with a diagno-
sis of MDD reported this transition to occur at a rate
of
1% per year (Angst, Sellaro, Stassen, & Gamma,
2005). Due to the elevated risk of bipolar disorder,
this transition rate may be even higher in people with
MS. A high index of suspicion is appropriate for
patients with a possible bipolar diathesis, including
young people (especially males), those with a family
history of bipolar disorder, or those whose depression
that is poorly responsive to antidepressant treatments.
Recent editions of DSM, including DSM-5, contain
categories for mood disorders that are due to identifi-
able physical causes or drugs: Depressive Disorder
Due to a Another Medical Condition and Substance/
Medication-Induced Depressive Disorder (American
Psychiatric Association, 2013). The question may arise
as to whether a depressive syndrome occurring in MS
should be categorized as ‘Secondary to MS’. However,
the strategy of building aetiological judgements into
4 S. B. PATTEN ET AL.
the diagnostic categorization of mood disorders is
highly questionable (Yates, Wesner, & Thompson,
1991). There is no evidential basis for making this dis-
tinction for an individual patient, and no trials of treat-
ment of Mood Disorder Due to a General Medical
Condition in MS have been conducted. However,
depressive and hypomanic symptoms have been shown
to occur with an increased frequency during cortico-
steroid treatment of MS relapses (Minden, Orav, &
Schildkraut, 1988; Morrow, Barr, Rosehart, & Ulch,
2015), so drug-induced aetiologies should not be
ignored.
What demographic groups are at highest risk of
depression in MS?
In the general population the prevalence of major
depression is higher in women and tends to decline
with increasing age. In MS, the sex difference has
been much less consistently reported. In a population-
representative study of past-year MDE prevalence, the
estimate for women was 16.7%, whereas that for men
was not very different, at 13.1% (Patten, Beck, et al.,
2003). A cross-sectional study that used the CIDI and
was based on a random sample drawn from an MS
population registry found that lifetime prevalence of
major depression was not significantly elevated in
women following adjustment for other risk factors
(Patten et al., 2000). A longitudinal study using an
abbreviated version of the CES-D (Andresen,
Malmgren, Carter, & Patrick, 1994) similarly found
that sex did not affect depressive symptom levels, nor
predict changes in depressive symptom levels (Beal,
Stuifbergen, & Brown, 2007). All of these studies,
however, found more depression in younger age
groups. The association of disease course with mood
disorder prevalence has been inconsistently reported
across studies (Lorefice et al., 2015; Zabad, Patten, &
Metz, 2005).
The study by Solaro et al. (2016) found no associ-
ation for sex, age, age at diagnosis, or time since diag-
nosis, but found that higher Extended Disability
Status Scale (EDSS) scores and relapsing-remitting or
secondary progressive disease course was associated
with higher depression prevalence.
What causes depression in MS?
As in other contexts, the aetiology of depression in
MS is likely to be multifactorial, and to include bio-
logical, psychological, and social determinants. Family
history of depression has not generally been found to
be associated with depression in MS (Joffe et al.,
1987b; Minden et al., 1987), with a single exception
(Patten et al., 2000). A population study of a nation-
ally representative cohort in Sweden found no associ-
ation between having a sibling with a psychiatric
disorder (including depression) and the risk of devel-
oping MS (Johansson et al., 2014).
A review of evidence from brain imaging studies
identified a growing and increasingly consistent litera-
ture implicating lesion volume and cerebral atrophy
in frontal and temporal regions as being associated
with depression in MS (Feinstein, Magalhaes, Richard,
Audet, & Moore, 2014). Lower fractional anisotropy
in normal appearing white matter as well as higher
mean diffusivity in normal appearing grey matter may
also contribute (Feinstein et al. 2010).
Inflammatory changes are implicated in the aeti-
ology of depression generally (Miller & Raison, 2016),
providing another set of candidate mechanisms that
may link depression to MS (Feinstein et al., 2014).
Using a brain imaging marker (18-kD translocator pro-
tein assessed using positron emission tomography) of
microglial activation in an MS sample, a correlation of
microglial activation with depressive symptom ratings
has recently been reported (Colasanti et al., 2016). This
provides preliminary evidence of a direct link between
immune activation and depression in MS (Manning,
2016). However, this preliminary study did not specif-
ically differentiate people with clinically significant
depression, so its implications for the aetiology of
depressive disorders remains unclear. Ultimately, med-
ications that modify inflammatory responses may
emerge as therapeutic options. Indeed, modulation of
inflammation may be a beneficial effect of antidepres-
sant medications in this context (Manning, 2016).
Another issue is the possible role of beta interferons
in the aetiology of depression in MS. There are reports
of suicidality in early trials of interferon-beta 1b (IFNB
Multiple Sclerosis Study Group, 1995; Klapper, 1994),
along with reports of mood disturbances that were
associated with interferon alpha treatment of liver dis-
ease, a context in which mood disturbances may occur
in as many as one in four patients undergoing treat-
ment (Udina et al., 2012). However, subsequent studies
have failed to confirm an association in MS (Feinstein,
O’Connor, & Feinstein, 2002; Patten & Metz, 2001,
2002; Schippling et al., 2016; Zephir et al., 2003).
Notably, comparison of physician-ascribed reports of
depression during these trials did uncover an associ-
ation, suggesting that a syndrome resembling depres-
sion may sometimes occur in interferon-treated
patients (Patten, Francis, et al. 2005). Notably, inter-
feron-induced depression or depression-like syndromes

occurring in the context of hepatitis C can be pre-
vented by antidepressant treatment (Udina et al.,
2014). In distinction to the concerns about interferon
beta, several recent reports have suggested that fingoli-
mod may improve depressive symptoms (Hunter et al.,
2016; Montalban et al., 2011).
MS tends to have an onset in young people who
are often struggling to establish important interper-
sonal relationships and careers. This can lead to
losses, threats, and stressors, all of which contribute to
the aetiology of depression—an idea supported by epi-
demiological data from those few studies that have
measured psychosocial variables (Beal et al., 2007;
Patten et al., 2000, Patten, Beck, 2003). A related issue
is coping. Employment of problem-focused rather
than emotion-focused coping strategies is associated
with better adjustment to the challenges of living with
MS (Pakenham, 1999).
Why is depression important in MS?
Depression, along with the associated symptoms of
fatigue and anxiety, are strong determinants of quality-
of-life in MS (Salehpoor, Rezaei, & Hosseininezhad,
2014). Carta, Moro, Lorefice, Picardi, et al. (2014)
reported that a co-morbid lifetime diagnosis of a mood
disorder substantially lowered perceptions of quality-
of-life (as measured by the SF-12) relative to people
with MS having no history of mood disturbance.
Depressive symptoms are almost as strongly assoicated
with health-related quality-of-life in MS as disability,
and exerts both direct and indirect effects (Berrigan,
et al. 2016). As such, depression potentially aggrevates
clinically burdensome issues such as pain, fatigue, anx-
iety, and cognitive impairment in MS (Feinstein et al.,
2014). Also, Mohr, et al. (1997) have suggested that
treating depression may improve adherence to treat-
ment in MS.
Adverse health behaviours such as excessive drink-
ing and smoking (which can be considered emotion-
focused coping strategies) are also associated with
depression and/or anxiety in MS (Bombardier, et al.
2004; McKay et al., 2016; Quesnel & Feinstein, 2004).
However, this does not necessarily mean that alcohol
consumption is higher in people with MS. In one
study (Fragoso et al., 2015), this comorbidity had a
lower prevalence than the general population.
Irrespective of the relative prevalence, people with MS
who drink excessively tend to have a more negative
mental health status (Bombardier et al., 2004; Quesnel
& Feinstein, 2004).
Another issue is that of suicide risk. A series of
studies conducted in Denmark indicate that, after
INTERNATIONAL REVIEW OF PSYCHIATRY 5
adjustment for age and sex, the risk of suicide is
approximately doubled in people with MS—with the
standardized mortality ratio being especially elevated
in the year following diagnosis (Brønnum-Hansen,
Stenager, Stenager, & Koch-Henriksen, 2005). Rates of
completed suicide are higher in men than in women
(Brenner, et al. 2016). In one study, one in five people
with MS reported suicidal ideation at least once dur-
ing 6 months of follow-up (Viner, Patten, Berzins,
Bulloch, & Fiest, 2014). In this study, low levels of
self-efficacy and low levels of task-oriented coping
were predictive of suicidal ideation.
What is the best way to identify depression in
clinical practice?
In theory, there are many reasons to believe that
depression symptom ratings in people with MS would
be invalid. Cognitive deficits and fatigue are both
‘overlapping’ symptoms of MS and the syndrome of
depression. Generally, scales that minimally reflect
physical symptoms, such as the Hospital Anxiety and
Depression Scale (HADS) (Snaith & Zigmond, 1986)
and the Beck Depression Fast Screen (Benedict,
Fishman, McClellan, Bakshi, & Weinstock-Guttman,
2003), the Beck Depression Inventory and a 2-question
screen (Minden et al., 2014), have been favoured in the
MS literature. However, it should be emphasized that
the literature examining the validity of depression
scales in MS is poorly developed (Hind et al., 2016).
In spite of these concerns, any actual (as opposed
to theoretical) problems with the performance of these
scales in MS has been difficult to confirm. One study
looked at the performance of the Beck Depression
Inventory II in patients with and without severe
fatigue and daytime sleepiness, but failed to find evi-
dence that the depression ratings were confounded by
these symptoms (Crawford & Webster, 2009). Two
other studies have validated traditional scales and the
HADS against structured interviews, and failed to find
evidence that the latter is superior (Patten et al., 2015;
Watson, Ford, Worthington, & Lincoln, 2014).
What treatments for depression are effective
in MS?
The literature about pharmacological depression treat-
ment in MS has been subject to an interpretive ambi-
guity. On the one hand, available literature of clinical
trials of depression treatment in MS is quite limited.
On the other hand, extensive literature documents the
effectiveness of the same depression treatments in
other populations.
6 S. B. PATTEN ET AL.
The first randomized controlled trial of depression
in MS evaluated desipramine, a tricyclic antidepres-
sant (Schiffer & Wineman, 1990), and subsequent
studies examined sertraline (Mohr, Boudewyn,
Goodkin, Bostrom, & Epstein, 2001) and paroxetine
(Ehde et al., 2008), two serotonin-specific antidepres-
sants. Uncontrolled studies have reported positive out-
comes from various other types of antidepressants,
including moclobemide (Barak, Ur, & Achiron, 1999)
and duloxetine (Solaro et al., 2013).
The American Academy of Neurology Guideline
(Minden et al., 2014) found inadequate evidence to
recommend the use of antidepressants. A Cochrane
review was also unable to confirm the efficacy of anti-
depressants (Koch et al., 2011). A 2016 systematic
review, with the addition of one more study, reported
a standardized mean difference of –0.45 (Fiest, et al.,
2016), consistent with the broader literature’s esti-
mates of antidepressant effect sizes. There is a poten-
tial safety issue involving some antidepressants and
fingolimod, a second line disease modifying treatment.
This medication is associated with bradycardia and
transient AV conduction delays following administra-
tion of the first dose. Antidepressant medications that
prolong the QTc interval may need to be discontinued
during the initiation of this treatment as a result.
However, no clinically significant changes in the QTc
were observed in a study examining the combination
in patients following 2 weeks on fingolimod (Bayas,
Schuh, Baier, Vormfelde, & Group, 2016).
Both the American Academy of Neurology guide-
line (Minden et al., 2014) and an additional review
(Fiest et al., 2016) found evidence of the efficacy of
telephone-administered cognitive behavioural therapy
for depression in MS. A meta-analytic estimate by
Fiest et al. (2016) of the effect size for cognitive
behavioural therapy was –0.45 across nine studies,
identical to that for pharmacological treatment.
Comparable results were reported in a 2014 systematic
review of cognitive behavioural therapy (Hind et al.,
2014). With removal of an outlying study, the stand-
ardized mean difference was –0.46. Online (Fischer
et al., 2015) and telephone administered (Mohr et al.,
2000) cognitive behavioural therapy, both potentially
advantageous for patients with mobility impairments,
have been evaluated in MS, with positive results.
However, a word of caution about online therapy is
necessary. One qualitative study has reported that
computerized therapy may increase feelings of isola-
tion in people with MS, and in some cases included
content and style that people with MS viewed as being
inappropriate (Hind et al., 2010).
Physical exercise is useful in the management of
depression, particularly as an add-on strategy with
conventional treatments (Mura, Moro, Patten, &
Carta, 2014). Two systematic reviews have found pre-
liminary evidence that exercise may assist with the
management of depression in MS, but the overall
quality of studies was low and the observed effect
sizes were small (Dalgas, Stenager, Sloth, & Stenager,
2015; Ensari, Motl, & Pilutti, 2014). In MS, where
fatigue is a burdensome issue and excessive physical
activity (particularly in a hot environment) can lead
to intensified symptoms, personalization of exercise
participation is an important clinical issue.
Summary
Depression is a very common, and very important
comorbidity in multiple sclerosis. As the literature
concerned with this issue has advanced it has become
increasingly evident that depression in MS can be
identified and managed in ways similar to the man-
agement of depressive disorders in other clinical con-
texts. Health policy and health administrative
advances are now needed to ensure appropriate access
to evidence-based care.
Longstanding concerns about the validity of meas-
urement instruments for depression in MS appear to
have been overstated. This suggests that conventional
scales could be used for screening, but it should be
emphasized that the success of screening depends pri-
marily on other factors than accurate measurement
(Patten, Berzins, & Metz, 2010). In neurological set-
tings, validated scales are likely to be helpful for
assessment and monitoring of depression in people
with MS.
While there is limited evidence for the effectiveness
of treatment, the best available data indicates that
depression treatments have comparable efficacy in
people with MS as in other populations. The ‘art’ of
delivering these treatments, however, involves numer-
ous considerations that are not addressed in the litera-
ture. A good example is the role of fatigue in the
assessment of MS. The simplistic idea that fatigue
would substantially contaminate, or perhaps invali-
date, symptom ratings is not supported by evidence.
However, clinical experience suggests that the fatigue
associated with depression is often most severe in the
morning, whereas in MS it often worsens with activity
as the day progresses. Furthermore, MS fatigue is
often described in physical terms (‘my hands feel as if
I have lead gloves on them’), whereas in depression
descriptions of fatigue are often connected to a lack
of motivation or interest. MS fatigue is often heat

sensitive, which does not occur in depression.
Anecdotally, irritability may be as important as sad-
ness or anhedonia in the assessment of depression in
MS (Feinstein & Feinstein, 2001). Delivery of cogni-
tive behavioural treatment needs to address visual
problems, cognitive deficits, and dysgraphia in its use
of homework assignments. Much more remains to be
learned about depression in MS. Despite the gaps in
current knowledge, there is little doubt that depres-
sion is a major burden for people living with MS, and
an opportunity for healthcare professionals to facili-
tate positive changes.
Disclosure statement
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
paper.
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