Depression in multiple sclerosis: a review
R J Siegert, D A Abernethy
J Neurol Neurosurg Psychiatry 2005;76:469–475. doi: 10.1136/jnnp.2004.054635
Several studies have reported high rates of depression in
multiple sclerosis (MS) with a lifetime prevalence of ,50%
and an annual prevalence of 20% not uncommon. Concern
about the potential of new drug treatments to exacerbate or
precipitate depression in MS has led to increased interest in
the relation between MS and depression. This review on
MS and depression identifies the following key issues: How
common is depression in people with MS? Is depression in
MS associated with lesions in specific regions of the central
nervous system? Is there an increased risk of suicide in MS?
Is there a higher than expected incidence of anxiety
disorders in MS? Are fatigue and depressed mood related
in MS? Is there a relation between depression and
cognitive impairment in MS? Which psychosocial variables
affect the development of depression in MS? Does
treatment with interferon increase the risk of depression?
How effective are treatments for MS patients with
depression? Each of these issues is briefly reviewed with
critical commentary, and some priorities for future research
See end of article for
R J Siegert, Rehabilitation
Teaching and Research
Unit, Department of
School of Medicine,
University of Otago, PO
Box 7343, Wellington
South, New Zealand;
22 September 2004
In revised form
2 December 2004
13 December 2004
he presence of psychiatric symptoms in
multiple sclerosis (MS) has been known
since Charcot gave the first detailed clinico-
pathological description of ‘‘disseminated sclero-
sis’’ in his lectures at the Salpeˆtrie`re hospital in
the nineteenth century.
Among the psychiatric
symptoms noted by Charcot were pathological
laughing and weeping, euphoria, mania, hallu-
cinations, and depression. Indeed, Charcot’s
patient Mademoiselle V was described as experi-
encing a fit of lypemania (or severe depression),
along with hallucinations and paranoia.
However, it was not until the 1950s that
empirical research on the frequency of depres-
sion among people with MS really began.
addition to the neurological symptoms that
characterise MS, major depression is common,
with estimates of lifetime prevalence of major
depression in MS as high as 50%.
historically it has been difficult to disentangle
the direct effects of the disorder upon mood from
the non-specific effects of chronic illness, a
recent study suggests that the annual prevalence
of major depression in MS is elevated compared
with that in both healthy people and other
In that study, Patten et al
reported a 12 month prevalence rate of 25.7% for
major depression in people with MS in the 18–45
years age range. Of further concern is the finding
that suicidal ideation is relatively common
among people with MS, and that depression in
people with MS is often not detected and
Moreover, depression is an important
determinant of quality of life (QoL) in MS and
may well be the most important determining
Recently considerable interest has been
generated about the possible role of interferon
beta in precipitating depression in MS, and
although these concerns may not be warranted,
the issue of major depression in MS remains a
significant issue notwithstanding.
of the present review are to:
provide a brief overview of research on
depression in multiple sclerosis
highlight some of the issues emerging from
suggest priorities for future research on this
PREVALENCE OF DEPRESSION IN MS
Unipolar or major depression is a mental
disorder characterised by the presence of five of
the following symptoms for at least two weeks:
a sad mood for most of the day/most days
a loss of pleasure or interest in one’s usual
psychomotor retardation or agitation
reduced appetite with weight loss (or the
a negative self-image
feelings of guilt and self-blame
reduced concentration and suicidal thinking.
The five symptoms must include sad, depressed
mood and/or loss of interest and pleasure in
A recent Australian study
reported a 12 month prevalence rate for major
depression in the community of 6.3%.
In a 1990
of affective disturbances in MS, Schiffer
noted that most studies had reported a higher
incidence and prevalence for depressive symp-
toms in MS compared with controls with a
different neurological illness. However, he also
commented that all these studies had design
weaknesses of varying degrees. In particular,
Schiffer noted that in most of these studies the
clinicians diagnosing depression were not blind
to the patient’s condition or to the hypotheses
at issue. He also noted problems relating to
Abbreviations: BDI, Beck Depression Inventory; CBT,
cognitive behavioural therapy; CES-D, Centre for
Epidemiological Studies’ Depression Scale; MS, multiple
sclerosis; SSRI, selective serotonin reuptake inhibitor
selection, diagnostic criteria and the vexed issue of the most
appropriate control group to compare MS patients with.
Notwithstanding these methodological issues, the finding of
a high rate of depression in MS seemed quite consistent.
Minden and colleagues examined 50 patients with MS
selected quasi-randomly from a patient register using a
structured psychiatric interview and standardised rating
scales for depression.
They reported that 54% of their
sample met the research diagnostic criteria (RDC) for major
depression at least once since their diagnosis whereas only
14% had met these criteria prior to it. Joffe et al assessed 100
consecutive patients attending an MS clinic in Canada using
the RDC for major depression and reported a lifetime
prevalence of 42%.
This figure did not include a proportion
of their sample that met the criteria for bipolar affective
disorder. In a study of 221 consecutive patients attending an
MS clinic in Vancouver, Sadovnick et al reported a lifetime
prevalence of 50% using a structured psychiatric interview.
They noted that this figure was considerably higher than the
rates of depression typically reported for samples with
chronic illness. Chwastiak et al undertook a mail survey of
1374 members of the Multiple Sclerosis Association in King
County, WA with 739 responses (a 54% response rate).
found that 42% of that sample had ‘‘clinically significant
depressive symptoms’’ according to the Centre for
Epidemiological Studies’ Depression Scale (CES-D) and 29%
scored in the moderate or severe range.
In a recent study, Patten et al used data from the Canadian
Community Health Survey (CCHS) to provide a population
based perspective on major depression and MS.
here is that previous studies mostly relied upon patients
attending MS clinics, or on current health centre registers,
and consequently could have overestimated the prevalence of
depression. Patten and colleagues examined a sample of
115 071 participants, aged 18 or older, from the CCHS and
found 322 with MS. The 12 month prevalence of depression
was 25.7% compared with 8.9% for people without MS.
In summary, studies have repeatedly reported that the
prevalence of depression in MS is high even when compared
with other groups with a chronic illness. For example,
lifetime prevalence rates of 40–50% and 12 month prevalence
rates around 20% have been typically reported for samples
taken from patients attending MS clinics. However, a number
of methodological issues suggest caution in interpreting these
figures. Most of the prevalence studies have taken samples
from patients attending an MS clinic, and those patients
coping well in the community might be underrepresented.
Another issue concerns the wide variety of measures used to
diagnose and quantify the severity of depression. There seems
little or no consensus among researchers as to the clinical
‘‘gold standard’’ for diagnosing depression in patients with
MS. Added to this is the risk with MS that the somatic
symptoms, such as fatigue, may lead to inflated estimates of
depression. This is perhaps most likely when behavioural
rating scales that were designed for use in a general
psychiatric setting are relied upon. Consequently, it might
be prudent to use those screening measures validated in
populations of patients with chronic illness.
behoves us to remember that many of the issues involved
in screening for depression among patients with MS, such as
missing the diagnosis or failing to treat the depression, are
also important issues in primary health care and not unique
to the neuropsychiatry of MS.
LOCATION OF BRAIN LESIONS
The question as to whether or not depression in MS is
associated with lesions in specific areas of the central nervous
system has generated considerable interest recently. This
question has particular relevance for understanding and
treating depression in patients with MS. It may also be
important for developing a clearer understanding of the
complex relation that exists between biological and psycho-
social factors in the genesis of depression.
In one of the
earlier studies of this nature Rabins et al examined the
computed tomography (CT) scans of 37 patients who were
part of a larger sample of 102 patients with MS in whom
psychiatric symptoms were studied longitudinally.
observed that MS patients with brain lesions were more
depressed than those patients with lesions only in the spinal
cord and also that depression was positively correlated with
the extent of neurological impairment. However, the 37
patients whose scans were compared, were those for whom a
CT scan had already been completed prior to the study or
where one was requested during the study as part of their
ongoing medical care. Hence they may not be fully
representative of the larger group of 102 patients in that
study or of patients with MS in general.
Honer et al used magnetic resonance imaging (MRI) to
compare eight MS patients with psychiatric disorders with
eight matched control MS patients and concluded that these
disorders were associated with temporal lobe lesions.
However, this rather small sample comprised a mixed group
of psychiatric diagnoses and it is not clear how specific that
conclusion might be with regard to depression. A study by
Ron and Logsdail compared rate of psychiatric morbidity in a
sample of 116 MS patients with a control group with physical
They reported a significantly higher frequency
of psychiatric ‘caseness’ in the MS group. The focus of this
study was not on depression per se but rather on psychiatric
illness in general. However, the authors did note that
flattened affect (and also delusions and thought disorder)
was associated with greater pathology in the temporal-
parietal region. Pujol et al examined 45 consecutive out-
patients at an MS clinic in Barcelona and looked for a relation
between scores on the Beck Depression Inventory (BDI) and
lesion location and volume.
Although no relation was found
between total lesion volume and depression, they did find
that BDI scores were significantly associated with lesions in
the arcuate fasciculus of the left hemisphere. This relation
accounted for 17% of the total variance in BDI scores.
However, it should be noted that only seven of the patients
had scores in the moderate to severe range according to the
BDI (that is, .17). Thus it is uncertain quite what the
implications of their results might be for patients with MS
diagnosed as having major depression.
Zorzon and colleagues reported an MRI study of 95
consecutive patients with definite MS at a clinic in Trieste.
They used the Hamilton Rating Scales for Depression and
Anxiety and a psychiatric interview by a clinician who was
blind to the hypotheses. Of their 95 patients 18 (19%) met the
criteria for major depression. The regional brain volumes and
lesion loads of the depressed and non-depressed patients
were compared. The authors reported that severity of
depression and a diagnosis of major depression were
correlated with right frontal lesion load and with right
temporal brain volume. They also noted that severity of
depressive symptoms correlated significantly with total
temporal volume as well as right hemisphere volume.
However, although statistically significant, these correlations
were all modest and in the range 0.20–0.30.
The most recent imaging study of MS and depression, and
arguably the strongest in methodological terms, was reported
by Feinstein and colleagues, who used brain MRI to compare
21 MS patients with major depression with 19 carefully
matched non-depressed MS patients.
A feature of this study
was that the depressed patients all met the DSM-IV criteria
for major depression as assessed by a structured psychiatric
interview. In addition, the authors screened over a thousand
470 Siegert, Abernethy
consecutive patients at an MS clinic according to rigorous
exclusion criteria. For example, any patient with a premorbid
history of psychiatric disorder, including depression, was
excluded. The major finding from this study was that the
depressed MS patients had ‘‘more hyperintense lesions in the
left inferior medial frontal regions and greater atrophy of left
anterior temporal regions’’.
Together, these two brain
regions accounted for ,42% of the variance in a logistic
regression model for predicting depression.
In summary, imaging studies to date vary widely in both
their design and rigour and there are few if any unequivocal
conclusions that can be made. However, on balance the
evidence seems to favour an association between depression
in MS with greater neuropathology in the left anterior
temporal/parietal regions. There is a need for further research
on this question. Perhaps what is most lacking thus far is any
clear theoretical model of the neuropathology of depression
and how precisely this relates to MS. Given recent advances
in our understanding of the neuropathology, neuropsychol-
ogy and neuroimaging of depression, this may soon occur.
SUICIDE AND MS
The high prevalence rates for depression in MS raise the
question as to whether or not patients with MS might then be
at elevated risk of suicide. Sadovnick and colleagues analysed
the causes of death in a large sample of patients at two
Canadian MS clinics, one in Ontario and one in British
The combined sample from both clinics com-
prised ,3126 patients and a total of 145 deaths occurred in
the time period 1972–88. The cause of death was able to be
clearly established from records for 119 patients of whom 56
died as a direct result of complications of MS. Out of the
remaining 63 patients whose deaths were not as a result of
MS complications, 18 (28.6%) died by suicide. A further two
patients whose deaths came under the category of ‘‘mis-
cellaneous causes’’ were suspected suicides. The authors
concluded that the proportion of suicides as a cause of death
was 7.5 times that for the age-matched general population.
The authors noted that earlier studies had not reported such
high rates of suicide in MS samples. In addition, one might
expect higher rates of distress in a sample of clinic attendees.
A Danish study employed the Danish Multiple Sclerosis
Registry and the Danish National Register of Cause of Death
to examine the prevalence of suicide among people with
The authors were able to examine data covering ,5525
cases for whom the onset of MS occurred between 1953
and1985. They reported a total of 53 suicides over this period
and noted that the expected number of suicides in a group of
this size (adjusting for age and so forth) would be 28. They
noted that the risk was highest among the younger, male
patients. In a recent study, Feinstein examined a sample of
140 consecutive patients attending an MS clinic in Canada
using standardised measures to detect suicidal ideation and
He reported a lifetime prevalence for suicidal intent
of 28.6% (40 participants) and nine (6.4%) had actually
attempted suicide. Feinstein examined those variables that
predicted suicidal intent using logistic regression and found
that living alone, severe depression and alcohol problems
together accounted for ‘‘an 85% predictive accuracy for
suicidal intent’’. Of particular concern in that study were
that two thirds of those patients with ‘‘current major
depression’’ were not receiving antidepressants and a third
of suicidal patients had not received any psychological
ANXIETY AND DEPRESSION IN MS
The high rate of comorbidity among anxiety and mood
disorders might suggest that anxiety disorders will also be
common in people with MS. Whereas the existing literature
tends to support this notion the amount of rigorous
epidemiological evidence seems limited compared with that
for depression. For example, in a recent review of research on
the assessment of emotional problems in people with MS,
only five of the 15 cited studies had included a standardised
measure of anxiety.
However, those studies that have
specifically assessed anxiety have typically reported quite
high rates. For example, Smith and Young assessed the
prevalence of both anxiety and depression in a sample of 88
consecutive patients attending an MS clinic, using the BDI
and the Hospital Anxiety and Depression Scale (HADS).
They reported that 34% scored as ‘‘cases’’ for anxiety on the
HADS with 22 patients (25%) needing treatment for it. In a
study where the focus was on the neural correlates of
depression and anxiety in MS, Zorzon et al assessed ‘‘95
consecutive unselected patients with clinically definite MS’’
They reported a median anxiety score on the
HADS of 18 (the usual cut-off for highly probable cases is 10/
11). Janssens and colleagues surveyed 101 newly diagnosed
patients and their partners and found high rates of anxiety in
both the patients (34%) and their partners (40%).
Thus several recent studies have reported high levels of
anxiety in people with MS. However, these studies have all
employed samples taken from patients attending clinics who
might well have higher levels of symptoms than a commu-
nity based sample of people with MS. Moreover, even among
the patients attending clinics there is no detailed information
regarding the specific subtypes of anxiety disorder present.
FATIGUE AND DEPRESSION IN MS
One puzzling aspect of MS for clinicians and researchers alike
is the nature of the relation between depression and fatigue
in MS. Fatigue is a common symptom in both depression and
MS. Mohr et al note that ‘‘A relationship between fatigue and
depression has long been suspected in MS’’, but ‘‘While
depression and fatigue are often assumed to be related in MS,
why or how this relationship might exist has remained
They also note two studies in
which medication that has been effective for fatigue in MS
has not shown any concomitant impact upon depression. It
appears that earlier studies examining fatigue and depression
in MS actually found little evidence for a close link between
the two. For example, Krupp et al compared 32 consecutive
patients attending an MS clinic in New York with healthy
controls matched by age and sex.
Although 47% of the MS
patients had scores suggesting clinical depression on the
CES-D, they found no significant correlation with fatigue as
measured by a visual analogue scale. Nor was fatigue
correlated with neurological disability as measured by the
Expanded Disability Status Scale (EDSS). However, fatigue
was a common and distressing symptom among the MS
group and the authors’ conclusion emphasised the impor-
tance of viewing fatigue as a discrete symptom of MS that is
not accounted for by depression. A subsequent study by this
group also reported no correlation between depression and
fatigue in patients with either MS or systemic lupus
Similarly, a study in the Netherlands by
Vercoulen et al observed that fatigue was a common and
troubling symptom in patients with MS but found no
correlation with depression (BDI) or disability (EDSS).
contrast with these earlier studies more recent research has
tended to report a relationship between depression and
One of the first studies to report a statistically significant
correlation between depression and fatigue in people with
MS was an investigation of psychosocial correlates of fatigue
in 139 American patients with MS. However, the correlations
were low, with fatigue severity and depression correlating at
A stronger association was noted by Ford et al
MS and depression 471
who examined fatigue and depression in 78 consecutive
patients attending an MS clinic and claimed to be the ‘‘first
reported study to … demonstrate a significant correlation
between fatigue and mood level’’.
Although that claim
might be debatable in the light of the aforementioned study,
a notable feature of Ford’s study was that it conceptualised
fatigue as multidimensional with separate scores for mental,
physical, and total fatigue. Depression was more strongly
related to mental fatigue (r = 0.54, p,0.0001) than physical
(r = 0.31, p,0.01). Subsequent research has mostly tended to
confirm the relation between fatigue and depression but has
also highlighted its complexity—emphasising the multi-
dimensional nature of fatigue and the influence of moderat-
ing variables such as helplessness and recreational activity.
One longitudinal study found that the relation was dynamic
as ‘‘relationships of fatigue with physical and mental health
change during the course of a year’’.
Another found that
depression and fatigue were independent predictors of QoL
Although fatigue is well recognised as a somatic symptom
accompanying depression and anxiety, prolonged fatigue is
also common in community based studies of psychological
Moreover it appears that some people who
appear to have no other explanation experience fatigue as the
main feature of a psychological illness.
For this reason
some psychiatrists interested in the epidemiology and
classification of psychological illness have recommended
the recognition of neurasthenia to account for this group of
patients and to analyse the value of treatments.
not fatigue results directly from brain lesions in MS or as a
psychological reaction to the illness in a predisposed person
remains uncertain. However, there is increasing acknowl-
edgement that fatigue in MS is multidimensional and that
both mental and physical fatigue need to be assessed.
41 42 48
Treating depression in MS patients does seem to produce
improvements in self-reports of fatigue. However, the
evidence to date is based upon one uncontrolled study of
patients who received either cognitive behaviour therapy
(CBT) or supportive group therapy or sertraline.
approach would not be expected to be as effective in those
patients without any symptoms of depression. The serotonin
selective reuptake inhibitors (SSRIs) have been shown not to
be useful in the treatment of chronic fatigue syndrome,
reversible inhibitors of monoamine oxidase inhibitor-A
(RIMAs) are helpful in treating some aspects of fatigue
syndromes, and CBT is beneficial.
Whether a CBT
approach is also as useful in MS is unknown at present.
COGNITIVE IMPAIRMENT AND DEPRESSION IN MS
There is a substantial body of evidence that impaired
cognitive functioning is common in MS with prevalence
rates in community samples typically around 40% or
For example, a British study of 200 people selected
quasi-randomly from an MS register, reported cognitive
impairment in 46% with memory problems in 34% and
executive problems in 33%.
In contrast with the confusing
picture about depression and lesion location noted above Rao
has observed that ‘‘The degree and pattern of cognitive
dysfunction is highly correlated with the amount and
location of white-matter disease within the cerebral hemi-
Cognitive impairment is also now well documen-
ted in depression, although this may only be the case for
depression in older and middle aged patients with a history of
Consequently, it is important to under-
stand the nature of the relation, if any, between cognitive
impairment and depression in MS.
As with fatigue, most of the earlier studies reported no
clear relation between cognitive dysfunction and depression
in MS whereas more recent research has tended to report a
positive correlation. For example, in his 1986 review of the
neuropsychology of MS, Rao noted that: ‘‘Euphoria, apathy,
lack of interest, and irritability are frequently noted to occur
in patients with widespread cerebral involvement, while
depression, postulated to be of a reactive type, is more
commonly seen in patients without cognitive dysfunction or
with only mild involvement’’.
Similarly, in 1995 he observed
that ‘‘Recent studies have suggested that measures of
cognitive dysfunction and depression are not correlated
suggesting that depression is not a causative factor in the
development of cognitive dysfunction’’.
The same conclu-
sion was reached by Brassington and Marsh in a more recent
review of the neuropsychology of MS.
In that paper they
summarised 10 studies that addressed this issue and
concluded thus: ‘‘Numerous studies have reported no
association between cognitive impairment and depression
in patients with MS’’.
This lack of any association between depression and
cognitive impairment in MS seems rather surprising given
the mounting evidence for the neuropsychological deficits
that can accompany depression.
30 56 59
If physically healthy
people with depression are prone to cognitive dysfunction it
seems paradoxical that this is not the case for people with MS
who are depressed. However, a recent programme of research
by Peter Arnett and colleagues may shed some light on this
Arnett has suggested that it is effortful
rather than automatic information processing that is most
likely to be compromised in depressed MS patients. Hence
performance may be quite normal on routine tasks but
impaired on those tasks that place demand upon attentional
resources—such as speeded tests of information processing,
working memory and complex tests of executive function-
Additional support for a link comes from the work of
Demaree and DeLuca.
These authors have criticised some
of the earlier studies for relying upon correlation analyses
and using neuropsychological measures that are not sensitive
to the cognitive effects of depression. They note that the
relation between depression and cognitive impairment is best
established for severe depression and primarily in relation to
information processing speed and working memory. Arnett
and colleagues have also reported that cognitive impairments
in patients with MS seem to be closely correlated with mood
and negative self-evaluations but less so with the vegetative
symptoms of depression.
In summary, earlier research studies consistently failed to
find any clear relation between depression and cognitive
impairment in MS. However, some recent work suggests that
information processing speed, working memory and execu-
tive functioning may indeed be affected in cases where the
depression is in the moderate to severe range. Whether or not
these impairments are reversible upon treating the depres-
sion remains unknown.
A growing body of research attests to the importance of
psychosocial factors in determining whether or not a person
with MS develops depression.
The variables that have
attracted the most attention are coping style and social
support. The research findings on coping with MS closely
resemble those in the broader literature on coping with
stress—that is, positive adjustment is typically associated
with problem focused coping and higher symptom levels are
associated with emotion focused coping or escape avoid-
However, it is our impression that some methodolo-
gical and theoretical advances in research on coping have yet
to be fully used in the research on coping in MS. For example,
Folkman has suggested that narrative research methods can
supplement standardised checklists to determine ways of
coping that are not tapped by such measures.
This might be
472 Siegert, Abernethy
important when considering coping in people dealing with
one specific illness such as MS.
Social support is also associated with better adjustment
although the relation is clearly not a simple linear one. For
example, Pakenham examined the stress and coping model
of illness in people with MS and found that social support
had a beneficial effect on adjustment but only under
circumstances of high perceived threat.
Uccelli and collea-
gues found that participating in a peer support group for MS
patients had little consistent positive effect upon mood and
may have actually been a negative influence on those
participants who were coping well at the outset of the
A recent study by Mohr and colleagues has suggested
that treating depression actually results in improvements on
a number of aspects of social support. Such findings are not
as perplexing as might first seem and there is evidence that
depression may actually cause reduced social support.
again, we suspect that clarification of the complex relation
between depression and social support in people with MS,
will be achieved by closer integration with the broader
literature on stress, coping, and social support. Other
psychosocial variables that might affect mood in MS include
illness intrusiveness, uncertainty, hope, and spirituality.
INTERFERON AND DEPRESSION IN MS
With the advent of interferon beta as a treatment for
relapsing remitting MS in the early 1990s concern arose
regarding the potential for this drug to cause or exacerbate
The initial concern apparently sprang from
reports of a suicide and four attempted suicides that occurred
among the treated group in the first clinical trial.
recent case report may have added to this concern with the
authors claiming that the case ‘‘suggests a causal link
between interferon beta-1a treatment of MS and major
However, with the high prevalence
rates for depression in MS noted above, it is difficult to draw
any meaningful conclusions from anecdotal accounts or
individual case reports. As this issue was comprehensively
reviewed by Feinstein in 2000, we will limit our discussion to
studies published since that review. In that review Feinstein
concluded that ‘‘Given the many methodological pitfalls
inherent in all studies to date, it is premature to conclude
that disease modifying drugs are associated with depres-
However, data from the Controlled High-Risk
Subjects Avonex Multiple Sclerosis Prevention Study
(CHAMPS) study was published soon after, in which a
significantly higher rate of depression (20%) was reported
among the 193 patients treated with interferon than among
the 190 controls who received only a placebo (13%).
Notwithstanding that finding most recent studies have
found little in the way of firm evidence that interferon
treatment is likely to result in depression among people with
For example, the Prevention of Relapses and
Disability by Interferon beta-1a Subcutaneously in Multiple
Sclerosis (PRISMS) clinical trial included ,560 participants
with relapsing remitting MS from 22 centres across nine
countries randomly allocated to two treatment arms or a
placebo control group and used three standardised measures
of depressive symptoms. The authors concluded that pre-
treatment depressed mood was the best predictor of
subsequent depressive symptoms but found no differences
in reported levels of depression across the three groups.
Moreover, the finding that the best predictor of depression in
MS patients treated with interferon is a previous history of
depressed mood has been consistently reported elsewhere.
A subsequent study by this group also concluded that
‘‘depression is not a side effect of interferon B1a’’ when used
to treat patients with secondary progressive MS.
colleagues have also reported that rates of depression are the
same for patients treated with interferon as for patients
treated with glatiramer acetate in clinical settings.
is also accumulating from other research groups that the
concerns about interferon treatment and depression may
have been undue.
Perhaps the important message here for
clinicians is that screening for depression and monitoring of
mood should be a feature of the medical management of all
patients with MS—regardless of whether or not they are
TREATMENT OF DEPRESSION IN MS
There is a small but growing literature on the treatment of
depression in patients with MS. Schiffer and colleagues
reported the first and only double blind, controlled trial of
antidepressants in the treatment of depression in people with
In that study they found that tricyclics (desipramine)
were more effective than a placebo while noting that some
patients had problems with anticholinergic side effects which
limited their dosage. Interestingly, significant improvements
were observed according to clinical judgement and the
Hamilton Rating Scale for Depression but not on the BDI.
There is also some evidence from open label trials that SSRIs
and the monoamine oxidase inhibitor moclobemide can be
effective treatments. Feinstein cautions that SSRIs may have
impaired sexual functioning as a side effect and this is a
particular concern given that it is also a common symptom of
Mohr and Goodkin found five studies that they considered
rigorous enough for inclusion in a meta-analysis.
concluded that depressed MS patients responded well to
treatment with either psychotherapy or antidepressants
(desipramine) but noted that psychotherapy with an
emphasis on coping skills was more likely to be effective
than insight oriented therapy. The results of their meta-
analysis also suggested that if left untreated depression in
people with MS was likely to worsen. Interestingly, these
authors also speculate that depression in MS might be
particularly responsive to treatment, arguing that most MS
patients lack any extensive history of depression and rarely
have comorbid psychiatric diagnoses. The same laboratory
has since reported that both CBT and sertraline (an SSRI)
were effective in the treatment of depression in MS patients
compared to supportive-expressive group therapy.
In summary, there is a small body of controlled studies
indicating that depression in people with MS responds well
to two treatments—psychotherapy that emphasises the
development of active coping skills (such as CBT) and
antidepressant medication. In cases where a patient with MS
fails to respond to SSRIs, Feinstein advises clinicians to
consult the general psychiatric literature.
Depression is common in MS with annual prevalence rates as
high as 20% reported and lifetime prevalence rates of 50% not
uncommon. There is some evidence that depression in MS is
associated with greater neuropathology in the left anterior
temporal/parietal region although the evidence for a close
association between depression and lesion locality is not
strong. There is some evidence that MS patients may have an
increased risk of suicide and this is probably most true for
younger male patients and those patients who are socially
isolated, severely depressed and have alcohol problems.
Anxiety disorders also seem more prevalent in MS although
the research here is both less extensive and less rigorous than
for depression and it is largely reliant upon data from
samples attending MS clinics. Earlier research on fatigue and
depression in MS consistently found no obvious relation
although recent studies have tended to report a correlation.
At the same time, these recent studies have also suggested
MS and depression 473
that the relation is a complex, dynamic one and that fatigue
is best conceptualised as multidimensional. Early studies also
found little evidence for a relation between depression and
cognitive impairment. However, recent studies suggest that
cognitive impairment is likely to be exacerbated when
depression is in the moderate to severe range. The initial
concern about interferon treatment causing depression in
patients with MS seems unwarranted in the light of several
recent studies addressing this issue. While all of these issues
merit further research the outstanding question continues to
be why depression among people with MS is not routinely
screened. Moreover, given the evidence for its responsiveness
to treatment why is it that depression in people with MS is so
R J Siegert, D A Abernethy, Department of Medicine, Wellington School
of Medicine and Health Sciences, University of Otago, Wellington, New
Competing interests: D Abernethy has acted as an unpaid consultant to
Schering NZ the manufacturers of Interferon B-1b (Betaferon)
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