CNS Drugs (2018) 32:65–74

https://doi.org/10.1007/s40263-018-0490-z

REVIEW ARTICLE

Fatigue in Patients with Major Depressive Disorder: Prevalence,

Burden and Pharmacological Approaches to Management
Helia Ghanean1 • Amanda K. Ceniti2,3 • Sidney H. Kennedy1,2,3,4,5,6

Published online: 30 January 2018

Ó Springer International Publishing AG, part of Springer Nature 2018

Abstract Fatigue is a frequently reported symptom in findings. The efficacy of non-pharmacological interven-
major depressive disorder, occurring in over 90% of tions is also discussed, including light therapy and exercise.
patients. Clinical presentations of fatigue within major
depressive disorder encompass overlapping physical, cog-
nitive and emotional aspects. While this review addresses
Key Points
the epidemiology, burden, functional impact and manage-
ment of fatigue in major depressive disorder, the main
Fatigue is a common symptom in major depressive
focus is on available pharmacotherapy options and their
disorder, both during a major depressive episode and
comparative efficacies. Our review of the effects of phar-
as a residual symptom, which has significant effects
macological treatments on fatigue in major depressive
on cognitive and functional outcomes.
disorder found that medications with dopaminergic and/or
noradrenergic action such as modafinil, flupenthixol and A review of pharmacological interventions for
atomoxetine were most effective in improving symptoms fatigue within major depressive disorder indicates
of fatigue and low energy. However, significant variation that medications with primarily dopaminergic and/or
across studies in assessment tools and study inclusion/ex- noradrenergic action are most effective in reducing
clusion criteria may have contributed to inconsistent fatigue, though variation in assessment tools and
sample characteristics may have led to inconsistent
findings.
Future clinical trials should focus on norepinephrine
Helia Ghanean and Amanda K. Ceniti are joint first authors. and dopamine as targets for treatment of residual
& Sidney H. Kennedy
fatigue within depression, and should emphasise
Sidney.Kennedy@uhn.ca standardised assessments in data collection.
1
Centre for Mental Health, University Health Network,
Toronto, ON, Canada
2
Institute of Medical Science, University of Toronto, Toronto,
ON, Canada
3
ASR Suicide and Depression Studies Program, St. Michael’s 1 Distinguishing Fatigue from Related Constructs
Hospital, 193 Yonge Street, Suite 6-001A, Toronto, ON
M5B 1M8, Canada Fatigue is a complex phenomenon with high morbidity and
4
Department of Psychiatry, University of Toronto, Toronto, prevalence. It remains a relatively understudied symptom
ON, Canada from both clinical and physiological perspectives in major
5
Krembil Research Institute, Toronto Western Hospital, depressive disorder (MDD) [1]. Fatigue refers to a loss of
Toronto, ON, Canada energy, tiredness or exhaustion, occurring even without
6
Li Ka Shing Knowledge Institute, Toronto, ON, Canada physical exertion. It can be distinguished from separate but
66
overlapping constructs such as anhedonia and loss of
motivation; an individual may remain interested in activi-
ties and derive pleasure from them, but not have adequate
energy to seek out or complete them. Fatigue within the
context of MDD is a separate construct from chronic fati-
gue syndrome (CFS), a profound fatigue lasting at least
6 months with an unclear aetiological basis: CFS is not the
focus of this review. Though MDD and CFS display con-
siderable overlap, studies suggest that symptoms such as
anhedonia, guilt and lack of motivation, favour MDD over
CFS [2]. Without treatment, fatigue is a major contributor
to functional impairment in MDD and contributes to both
treatment resistance and chronicity [3].
2 Prevalence and Centrality of Fatigue
within Major Depressive Disorder: Implications
for Function
Fatigue is particularly prominent within MDD, where it has
been reported in 95% of patients [4], and is associated with
a negative impact on functioning and quality of life [5, 6].
Within the general population, women experience fatigue
more often than men; life events such as childbirth,
menopause and socially imposed roles may confer unique
vulnerability [7]. Fatigue is also a common presenting
complaint in individuals who have anaemia, various neu-
roendocrine and neurological disorders, autoimmune dis-
orders, infections or neoplastic disease [1]. Chronic
insomnia and social stresses, including bereavement, may
also perpetuate the subjective experience of fatigue [8].
Fatigue has been identified over the full course of MDD:
as a prodrome, within a major depressive episode (MDE),
and as a residual symptom following successful treatment.
Based on a large US Epidemiological Catchment Area
study carried out at two time points, individuals reporting
fatigue both at baseline and at a 13-year follow-up (de-
termined by the question, ‘‘Has there ever been a period
lasting two weeks or more when you felt tired out all the
time?’’) were found to be at a significantly higher risk of
developing depression than those who did not have these
persistent symptoms (relative risk = 28.4) [9]. Given the
potential impairments associated with fatigue and lack of
sleep, early diagnosis and intervention in primary care may
play a significant role in preventing subsequent MDD [8].
Within an MDE, fatigue is highly connected to other
symptoms of the disorder. A network analysis of baseline
data from the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) trial found that loss of energy
exhibited the greatest node strength centrality, or con-
nectedness, across symptoms extracted from the Inventory
of Depressive Symptomatology [10]. The same authors
also identified fatigue as one of the three symptoms
H. Ghanean et al.
associated with the greatest functional impairment in
STAR*D patients prior to treatment with citalopram [11].
Fatigue may also be experienced as a side effect of
antidepressant medications, occurring in approximately
20% of patients who receive a selective serotonin reuptake
inhibitor (SSRI) [12] and is also common in those treated
with a tricyclic antidepressant [13].
Finally, following remission of an MDE, fatigue com-
monly persists as a residual symptom. In one report, lack of
energy was endorsed by 90% of individuals during an
MDE, and persisted in 35% as a residual symptom fol-
lowing remission [14]. These residual symptoms may have
a significant impact on functional outcomes. A naturalistic
study of 573 patients with depression found that low
energy was a stronger predictor of poor social and work
functioning than other depressive symptoms. Furthermore,
it was reported that enhanced work productivity was more
strongly related to an improvement in energy than an
overall decrease in the number of depressive symptoms
[15]. These findings emphasise the importance of
addressing fatigue and energy in MDD, particularly when
improving functional outcomes is a focal point in patient
management.
3 Deconstructing Fatigue Presentations
within Major Depressive Disorder
Fatigue and loss of energy are multifactorial symptoms that
may present differently in MDD. When considering sub-
types, fatigue or loss of energy occurs more frequently in
MDD with atypical features [16], which includes ‘leaden
paralysis’, a feeling of heaviness in the arms or legs.
Across all subtypes within MDD, fatigue may be pre-
dominantly expressed through physical, emotional or
cognitive symptoms. Physical aspects of fatigue incorpo-
rate complaints of tiredness, low energy, reduced physical
endurance, and limb weakness or heaviness, and are often
associated with non-restorative sleep and daytime sleepi-
ness [17], while emotional fatigue may manifest as
decreased motivation and interest accompanied by reduced
energy [18]. Symptoms of cognitive fatigue may include
decreased concentration and attention, as well as dimin-
ished focus, word finding difficulties and impaired recall
[19]; however, it is important to consider the overlap
between the cognitive aspects of fatigue and cognitive
dysfunction as its own symptom within MDD. These
domains of fatigue may cluster with other symptoms of the
disorder; for instance, physical fatigue may be more closely
associated with psychomotor retardation and pain, whereas
mental fatigue may be more associated with cognitive
dysfunction, apathy and lack of motivation [20].
Fatigue in Major Depressive Disorder 67

4 Measurement of Fatigue antidepressant medications play a role in relieving fatigue;

Despite the clinical importance of fatigue associated with
MDD, few patient-reported outcome instruments are
designed specifically to assess fatigue and its impact on
patients with depression [21]. Table 1 summarises the
psychometric properties of commonly used scales for
assessing fatigue in MDD.
5 Potential Mechanisms of Fatigue
5.1 Neurotransmitter Dysregulation
Of the classical monoamine neurotransmitters involved in
MDD, norepinephrine and dopamine are the most relevant
to fatigue, with the cerebellum and striatum acting as
mediating areas of physical fatigue [29]. In addition,
acetylcholine and histamine may influence mental fatigue
at the cortical level. At the brain circuit level, there is
evidence of reduced prefrontal cortical activity in patients
with depression with fatigue [20]. Given the overlap in the
disturbance of neurotransmitters and neural circuitry
associated with MDD and fatigue, it is not surprising that
this will be examined in a later section of this review
(Table 2).
5.2 Neuroimmune Dysfunction
Links between the immune system and fatigue have been
studied extensively in other diseases such as cancer and
chronic inflammatory diseases, but have not been specifi-
cally investigated within MDD to our knowledge. Broadly,
peripheral inflammation has been shown to influence the
activity and metabolism of monoaminergic neurotransmit-
ters, potentially contributing to symptoms of fatigue through
disruption of frontostriatal and insular networks [30].
5.3 Hypothalamic-Pituitary-Adrenal Axis
Involvement
The impact of hypothalamic-pituitary-adrenal axis dys-
function on fatigue has been studied primarily within the
pathophysiology of CFS, where heightened negative feed-
back and dampened responsiveness of the hypothalamic-
pituitary-adrenal axis have been reported [31]. Broadly
speaking, hypothalamic-pituitary-adrenal axis dysfunction

Table 1 Psychometric properties of fatigue scales for use in major depressive disorder (MDD)
Scale Measure Number Validation sample Internal Test-retest
of items consistency reliabilityb,c
reliabilitya

Fatigue Associated with Subjective experience and 13 MDD (n = 317) C 0.88 C 0.78b
Depression (FAsD) impact of fatigue
Questionnaire [22]
Motivation and Energy Inventory Fatigue and lassitude across 27 MDD (n = 809 across two 0.75–0.89 Not
(MEI) [23] domains of mental energy, studies) reported
physical energy and social
motivation
Fatigue Severity Scale (FSS) [24] Unidimensional measure of 9 MDD (n = 72) 0.95 0.99b
fatigue
National Institutes of Health-Brief Fatigue, using questions from 7 MDD (n = 89) 0.81–0.88 0.49b
Fatigue Inventory (NIH-BFI) existing depression and (single
[25] mania scales item)
Piper Fatigue Scale (PFS) [26] Sensory, affective meaning, 22 Breast cancer (n = 382) 0.97 Not
behavioural/severity and reported
cognitive/mood subscales
Multidimensional Fatigue General fatigue, mental 20 MDD (n = 137) 0.89 0.73c
Inventory (MFI) [27] fatigue, physical fatigue,
reduced motivation and
reduced activity
Patient-reported outcomes Experience of fatigue and its 7 Fibromyalgia (n = 72), 0.72–0.86 Not
measurement information impact on daily activities cardiometabolic risk (n = 63), reported
system (PROMIS) Fatigue Item sickle cell disease (n = 60) and
Bank-Short Form [28] pregnancy (n = 72)
a
Cronbach’s a (values of C 0.70 are considered acceptable for reliability)
b
Intraclass correlation coefficient
c
Pearson correlation
 68

Table 2 Summary of studies included in review, sorted by fatigue change scores

Authors, year Sample, na Study design Drug, dose Drug class Duration Instrument used to Symptom Pre- Post- Change in Reported
measure fatigue reported treatment treatment fatigue p value
score score (%)

Vallé-Jones and MDD aged C 60 years, Open-label Flupenthixol Antipsychotic 2 wk Single item (rated 0–4) Fatigue 2.1 0.8 - 61.9 \0.001
Swarbrick, n = 95 dihydrochloride, agent
1981 [47] 0.5–1 mg/day
Konuk et al. 2006 MDD with residual fatigue, Open-label Modafinil augmentation, Wakefulness- 6 wk FSS Fatigue 5.4 ± 0.8 2.8 ± 1.3 - 48.3 \0.001
[46] n = 25 100–200 mg/day promoting
agent
Papakostas et al. MDD responders or Retrospective Atomoxetine NRI 4–10 wk BFI Fatigue 41.9 ± 14.9 24.3 ± 13.4 - 42.0 0.0015
2006 [49] remitters with residual chart review augmentation,
fatigue, n = 14 40–80 mg
Søgaard et al. MDD (atypical subtype), Randomised, Sertraline, SSRI 12 wk BQOLB, energy/ Energy 74.6 ± 11.8 45.1 ± 19.8 - 39.5 NR
1999 (1)d [50] n = 100 double-blind 50–100 mg/day vitality dimension
Dunlop et al. MDD, n = 34 Double-blind, Modafinil augmentation, Wakefulness- 6 wk Visual analogue scale Fatigue 6.5 ± 2.1 4.1 ± 2.6 - 36.9 NR
2007 [44] placebo- 100–300 mg/day promoting
controlled RCT agent
Bould et al. 2012 MDD, n = 233 Open-label RCT Reboxetine, 8 mg/day NRI 12 wk BDI and QIDS items, Fatigue 8.57 5.56 - 35.1 NR
(1)d [51] measuring (SD 1.87) (SD 2.54)
energy/fatigue
Bould et al. 2012 MDD, n = 253 Open-label RCT Citalopram, 20 mg/day SSRI 12 wk BDI and QIDS Fatigue 8.48 5.75 - 32.2 NR
(2)d [51] energy/fatigue items (SD 1.99) (SD 2.59)
Søgaard et al. MDD (atypical subtype), Randomised, Moclobemide, RIMA 12 wk BQOLB, energy/ Energy 76.2 ± 12.4 52.9 ± 23.6 - 30.6 NR
1999 (2)d [50] n = 97 double-blind 300–450 mg/day vitality dimension
Shen et al. 2011 MDD, n = 16 Open-label Mirtazapine, 30 mg/day TCA 58 days FIS Fatigue impact 82.2 ± 64.4 - 28.6 NR
[43] 11.9 SE (SD 49.4)
Lundt, 2004 [48] SAD with fatigue, n = 13 Open-label pilot Modafinil, Wakefulness- 8 wk FSS Fatigue 5.3 3.9 (SD - 26.4 \0.01
study 100–200 mg/day promoting (SD 0.8) 1.3)
agent
Cheon et al. 2017 MDD unresponsive to C 1 Open-label RCT Aripiprazole Atypical 6 wk IFS Fatigue 42.18 (SD 32.2 - 23.7 0.047b
(1)d [52] SSRI, n = 56 augmentation, antipsychotic 4.31)
2.5–20 mg/day agent
Fava et al. 2005 MDD with partial response Double-blind, Modafinil augmentation, Wakefulness- 8 wk FSS Fatigue 5.6 (SD 4.6 (SD - 17.9 NR
[41] to SSRI, n = 156 placebo- 100–200 mg/day promoting 0.8) 1.6)
controlled RCT agent BFI Fatigue 6.0 (SD 4.8 (SD - 20 NR
1.8) 2.5)
Han et al. 2015 MDD with inadequate ADT Randomised, Aripiprazole Atypical 6 wk IFS Fatigue 43.0 35.5 - 17.4 NR
[45] response, n = 50 rater-blinded augmentation, antipsychotic (SD 5.8)
2–15 mg/day agent
Cheon et al. 2017 MDD unresponsive to C 1 Open-label RCT Bupropion augmentation, NDRI 6 wk IFS Fatigue 40.98 (SD 34.72 - 15.3 0.047b
(2)d [52] SSRI, n = 47 150–300 mg/day 5.14)
H. Ghanean et al.
Fatigue in Major Depressive Disorder 69

ADT antidepressant treatment, BDI Beck Depression Inventory, BFI Brief Fatigue Inventory, BQOLB Battelle Quality of Life Battery, FIS Fatigue Impact Scale, FSS Fatigue Severity Scale, HRSD Hamilton Rating Scale for
Depression, IFS Iowa Fatigue Scale, MDD major depressive disorder, NDRI norepinephrine-dopamine reuptake inhibitor, NR not reported, NRI norepinephrine reuptake inhibitor, QIDS Quick Inventory of Depressive Symp-
tomatology, RIMA reversible monoamine oxidase inhibitor, RCT randomised controlled trial, SAD seasonal affective disorder, SD standard deviation, SE standard error, SNRI serotonin-norepinephrine reuptake inhibitor, SSRI selective
is known to be implicated in MDD [32]; however, it is
Reported
p value

0.02
currently unclear whether this dysfunction may specifically
contribute to the development of fatigue within MDD.
Change in
fatigue

- 10.8
(%)

6 Reconceptualising Fatigue: From DSM-5

and ICD-10 to an RDoC Approach
treatment

7.05
score
Post-

While fatigue is not currently one of the two core symp-

toms of MDD identified in the Diagnostic and Statistical
7.9 ± 1.5
treatment

Manual of Mental Disorders, Fifth Edition [33], it does

score

appear as a core symptom within the International Statis-

Pre-

tical Classification of Diseases and Related Health Prob-

lems, 10th Revision framework [34]. As an alternative to
Symptom

using either diagnostic system, the multifactorial and

reported

Energy

heterogeneous nature of fatigue may lend itself well to a

dimensional approach to classification. In 2013, Cuthbert
and Insel proposed the Research Domain Criteria (RDoC)
HRSD, psychomotor
retardation factorc
Instrument used to

as an alternative method of classifying mental disorders,

measure fatigue

based on behavioural dimensions and neurobiological

measures, with the explicit goal of linking psychopathol-
ogy to abnormalities in genetics and brain circuitry [35].
Five systems are proposed encompassing: positive valence,
Duration

negative valence, cognitive function, social processing and

12 wk

arousal/regulatory systems, all of which could contribute to

the presence of fatigue [36]. To our knowledge, this
research domain criteria approach has not been specifically
Drug class

applied to the study of fatigue, but it may represent a

SNRI

promising avenue for future exploration of this symptom,

given its transdiagnostic and multidimensional nature.
Three studies are active comparisons between drugs, and each appears twice in the table

7 Non-Pharmacological Treatments for Fatigue

Desvenlafaxine,
50 mg/day

Reported n is the number of individuals enrolled in the given treatment group only
Drug, dose

Several non-pharmacological treatments have shown effi-

cacy in relieving symptoms of fatigue within MDD. Light
therapy as an adjunct to pharmacotherapy has been shown
HRSD psychomotor retardation factor comprises items 1, 7, 8 and 14

to be effective, hastening and amplifying a therapeutic

Study design

Randomised

benefit as compared with pharmacotherapy alone [37].

Significance between aripiprazole and bupropion SR scores

Regular anaerobic exercise consisting of 30 min walking

serotonin reuptake inhibitor, TCA tricyclic antidepressant

on most days of the week, maintaining interpersonal rela-

tionships and consistent work can have a positive effect on
MDD, employed, n = 285

any type of fatigue [38].

8 Pharmacological Management of Fatigue

Sample, na

in Major Depressive Disorder

Table 2 continued

Not surprisingly, the wide range of expressions of fatigue

Lam et al. 2014

as well as its prominence as a symptom of MDD contribute

Authors, year

to the difficulty in identifying specific ‘anti-fatigue’ treat-

ments [39]. In view of the limited number of studies
[42]

specifically evaluating antidepressant medication effects on

b

d
a

c
70
fatigue in patients with MDD and the heterogeneity of
fatigue presentations, a systematic search was conducted
with the goal of examining the comparative efficacy of
various pharmacological interventions in reducing symp-
toms of fatigue within MDD.
The databases MEDLINE and Web of Science were
systematically searched independently by two of the
authors (HG and AKC) in October 2017 to identify rele-
vant articles, generating 1769 records. Terms such as ‘fa-
tigue’, ‘energy’, ‘depress*’ and ‘antidepress*’ were used in
the searches. Names of commonly used fatigue scales as
well as drug classes and individual drug names derived
from the Antidepressant Treatment History Form were also
included as search terms to increase the breadth of the
review in identifying papers with specific foci. No
restrictions were placed on publication year, but only
English language results were considered. The full search
strategy can be found in the ‘‘Appendix’’.
Studies were included in the review if they fulfilled the
following criteria: (1) primary research article, (2) peer
reviewed, (3) English language, (4) included a group with
MDD, (5) studied an adult population (aged C 18 years),
(6) evaluated the efficacy of a pharmacological interven-
tion and (7) included fatigue or energy as an outcome
measure, with pre- and post-treatment values reported.
Exclusion criteria included: (1) review articles, (2) case
reports, (3) animal studies, (4) non-pharmacological
Records idenfied through
database searching
(n = 1769)
Duplicate records removed
Records screened
(n = 1408)
Full-text arcles assessed
for eligibility
(n = 139)
Studies included in review
(n = 12)
Fig. 1 Preferred reporting items for systematic reviews and meta-analyses flow diagram outlining the process for selecting studies included in
the review [40]. MDD major depressive disorder
H. Ghanean et al.
interventions and (5) records in which no full-text article
was available (e.g. published conference abstracts). Data
pertaining to study design, sample size, treatment type and
duration, instrument used to measure fatigue and effect on
fatigue were extracted from the included articles. Records
were first screened by title, then by abstract, and finally by
full text to determine eligibility.
The literature search of all included databases generated
1769 records, 361 of which were removed as duplicate
records. The remaining 1408 records were manually
screened to determine relevance, and 1269 were excluded
at this stage. Upon reviewing the remaining 139 full-text
articles, studies were excluded if they did not specifically
include a measure of fatigue or energy (n = 45), were not
primary research articles (n = 24), were animal studies
(n = 4), included other psychiatric diagnoses or MDD as a
secondary diagnosis (n = 10), were case studies or case
series (n = 6), were not peer reviewed (n = 2) or did not
include a specific pharmacological intervention (n = 15).
Studies that did not report pre- and post-treatment values
for their included fatigue measure were also excluded
owing to their limited comparability. The systematic
evaluation of these studies according to the inclusion/ex-
clusion criteria is represented below (Fig. 1). After apply-
ing inclusion/exclusion criteria to all articles, 12 articles
were eligible for inclusion in the review.
(n = 361)
Records excluded
(n = 1269)
Full-text arcles excluded
(n = 127)
• No outcome measure of fague n = 45
• Animal study n=4
• Not primary arcle n=24
• MDD as secondary diagnosis or non-unipolar n=10
• Case study/series n=6
• Non-pharmacological intervenon n=3
• No specific intervenon n=12
• Not peer-reviewed n=2
• No pre- and post-treatment fague values n=21
Fatigue in Major Depressive Disorder
The review included four studies comparing the effec-
tiveness of a drug with placebo [41–44], one study com-
paring antidepressant medication augmentation and
switching strategies [45], three open-label studies with no
placebo group [46–48], one retrospective chart review [49]
and three drug–drug comparisons [50–52]. Five of the
articles contained an MDD sample with a history of
antidepressant medication non-response or partial response
with residual symptoms [45, 46, 49, 52, 53]. In terms of
special populations, one study was conducted in late-life
depression (C 60 years of age) [47], another was conducted
in patients with seasonal affective disorder [48], while a
third was restricted to individuals with atypical depression
[50]. The studies included in the review have been grouped
by drug class, and the results are summarised below.
8.1 Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors are common first-
line recommendations for the treatment of MDD and act by
increasing the synaptic availability of serotonin [54].
Within the current review, two studies evaluated the effi-
cacy of SSRIs in reducing fatigue [50, 51]. Sogaard et al.
reported a 39.5% decrease in Brief Fatigue Inventory
scores after 12 weeks of double-blind treatment with ser-
traline in patients with atypical MDD [50]. Similar
reductions were reported by Bould et al., who conducted a
12-week, open-label randomised controlled trial investi-
gating changes in energy and fatigue in patients receiving
either the SSRI citalopram or the norepinephrine reuptake
inhibitor reboxetine. The authors found no significant dif-
ference between citalopram and reboxetine in reducing
levels of fatigue (32.2 and 35.1%, respectively) [51].
8.2 Norepinephrine Reuptake Inhibitors
Norepinephrine reuptake inhibitors inhibit the reuptake of
norepinephrine, which is thought to be particularly
important in the pathophysiology of anergia and fatigue.
Bould et al.’s comparative study of citalopram and
reboxetine found no statistically significant difference
between the two antidepressant medications in reducing
fatigue (32.2 vs. 35.1%) [51]. However, high levels of
baseline fatigue were associated with a more favourable
response to reboxetine as compared with citalopram, sug-
gesting that norepinephrine concentrations may indeed
play a role in influencing treatment outcome.
8.3 Serotonin-Norepinephrine Reuptake Inhibitors
Serotonin-norepinephrine reuptake inhibitors act to
increase synaptic concentrations of both serotonin and
norepinephrine, and may be effective in treating a wider
71
range of symptoms of MDD including fatigue owing to
their more distributed effects on the monoamine trans-
porters [55]. However, in this review, the study of
desvenlafaxine showed a low effect in improving fatigue
symptoms, with only a 10.8% decrease in fatigue scores
(Hamilton Rating Scale for Depression psychomotor
retardation factor) over 12 weeks of randomised treatment
in an employed MDD sample [42].
8.4 Antipsychotic Agents
Antipsychotic agents act on the dopamine D2 receptor [56],
improving dopamine transmission by transiently occupying
and then dissociating from the receptors. A significant
improvement in fatigue was seen after 2 weeks of treat-
ment with flupenthixol dihydrochloride in patients with
MDD aged C 60 years; this study reported a 61.9%
decrease in fatigue rating over the course of treatment as
measured by a single Likert-scale item [47]. Newer atyp-
ical antipsychotic agents were also shown to exert modest
effects on fatigue symptoms. Two studies investigated
aripiprazole over a 6-week treatment course in patients
with MDD with an inadequate antidepressant medication
response or non-response to an SSRI, and reported similar
reductions on the Iowa Fatigue Scale (23.7 and 17.4%)
[45, 52].
8.5 Reversible Inhibitors of Monoamine Oxidase A
The effects of moclobemide were studied by Sogaard
et al., who randomised patients to receive treatment
with either moclobemide or sertraline. Moclobemide led
to a 30.6% decrease in fatigue as measured by the
energy/vitality dimensions of the Battelle Quality of
Life Battery, but did not surpass sertraline in efficacy
(- 39.5%).
8.6 Norepinephrine-Dopamine Reuptake Inhibitors
Given the association of noradrenergic and dopaminergic
systems with fatigue, norepinephrine-dopamine reuptake
inhibitors would be expected to have more robust effects
on reducing levels of fatigue and increasing energy than
other medication classes not involving these neurotrans-
mitters. One included study examined the impact of the
norepinephrine-dopamine reuptake inhibitor bupropion in
patients with MDD with a history of non-response to one or
more SSRIs [52]. Surprisingly, only modest reductions in
fatigue were found with bupropion (15.3%), as measured
by the Iowa Fatigue Scale. Bupropion was also found to be
less effective in reducing fatigue than aripiprazole (23.7%
reduction).
72
8.7 Wakefulness-Promoting Agents
Novel wakefulness-promoting agents such as modafinil
that act on the dopaminergic system have received sub-
stantial interest in recent years, and have gained traction in
the treatment of sleep disorders [57]. In the current review,
four identified studies investigated modafinil as an
adjunctive treatment for fatigue within MDD
[41, 44, 46, 48]. Outcome measures included the Fatigue
Severity Scale and Brief Fatigue Inventory, and reductions
in fatigue post-intervention ranged from 17.9 to 48.3%
across all studies.
9 Discussion and Limitations
Despite the emergence of a considerable number of new
antidepressant medications over the past two decades, a
substantial proportion of patients do not respond fully to
SSRIs, resulting in chronic functional impairment. Among
the symptoms that are inadequately addressed by seroton-
ergic antidepressant medications are fatigue and loss of
energy [58]. Between 10 and 35% of patients with
depression who achieve remission after treatment continue
to experience fatigue [59]. This provides a rationale for the
co-prescribing of adjunctive therapies such as modafinil or
atomoxetine that have predominantly dopaminergic and
noradrenergic actions to improve residual fatigue [60].
Indeed, the results from this review support the use of
drugs with primarily dopaminergic and noradrenergic
action, though results are somewhat inconsistent across
studies in part owing to methodological differences.
It is important to recognise several limitations of this
review. First, differing definitions of fatigue in the litera-
ture may lead to conflicting results across studies. Second,
the wide range of methodologies and scales used to mea-
sure fatigue may limit comparability across studies. Third,
the sample size ranges from 13 to 285 subjects across
included trials, which can give inappropriate emphasis on
outcomes in small studies. In addition, the varied sample
characteristics across studies may influence results,
regardless of the drug being studied; for instance, those
with previous treatment failures are less likely to derive
benefit from a given drug because it is known that remis-
sion rates decrease with an increasing number of historical
failed treatment trials [61]. Indeed, this pattern was seen in
the current review; the studies that consisted of MDD
samples with previous treatment failures comprised three
of the four studies reporting the poorest outcomes on
fatigue measures.
Because of strict exclusion criteria, pooled analyses,
meta-analyses and papers in which pre- and post-treatment
absolute values of fatigue measures were not stated were
H. Ghanean et al.
excluded. While this had the advantage of permitting direct
quantitative comparisons across studies, it also limited the
scope of the review by excluding additional studies on
fatigue that did not meet these criteria, including studies of
bupropion [62, 63], venlafaxine [64], levomilnacipran
[65, 66] and osmotic release oral system methylphenidate
[67], which also showed reductions in fatigue following
treatment.
10 Conclusion
Fatigue is a multifaceted symptom that is prevalent
throughout the course of MDD and confers a significant
burden. The current review suggests that treatments tar-
geting dopamine and norepinephrine may be most effective
in targeting fatigue within MDD; however, methodological
variability in assessment tools and sample selection across
studies resulted in inconclusive findings. Additional studies
are needed to provide a better understanding of how
patients with various types of fatigue (physical, emotional,
mental) respond to different treatments and the effects of
these agents on the functional and social impairments
associated with fatigue.
Compliance with Ethical Standards
Funding No funding was received for the preparation of this article.
Conflict of interest Sidney H. Kennedy has received research
funding or honoraria from the following sources: Abbott, Allergan,
AstraZeneca, BMS, Brain Cells Inc., Brain Canada, Canadian Insti-
tutes for Health Research, Clera, Janssen, Lundbeck, Lundbeck
Institute, Ontario Mental Health Foundation, Ontario Brain Institute,
Ontario Research Fund, Otsuka, Pfizer, Servier, St. Jude Medical,
Sunovion and Xian-Janssen. Helia Ghanean and Amanda K. Ceniti
have no conflicts of interest directly relevant to the content of this
article.
Appendix: Search Strategy for Review
of Pharmacological Interventions for Fatigue
in Major Depressive Disorder
((fatigu*) OR (energy) OR (anerg*) OR (FSS) OR (Fatigue
Severity Scale) OR (FAD) OR (Fatigue Associated with
Depression) OR (MAF) OR (Multidimensional Assessment
of Fatigue) OR (PFS) OR (Piper Fatigue Scale) OR (BFI)
OR (Brief Fatigue Inventory) OR (MFS) OR (Mental
Fatigue Scale) OR (MEI) OR (Motivation and Energy
Inventory))
AND
((MDD) OR (depression) OR (major depressive disorder))
AND
Fatigue in Major Depressive Disorder
((antidepress*) OR (SSRI) OR (selective serotonin
reuptake inhibit*) OR (TCA) OR (tricyclic) OR (MAOI)
OR (monoamine oxidase inhibitor) OR (SNRI) OR (sero-
tonin norepinephrine reuptake inhibit*) OR (fluoxetine)
OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR
(*citalopram) OR (duloxetine) OR (*venlafaxine) OR
(amitriptyline) OR (nortriptyline) OR (*pramine) OR
(maprotiline) OR (doxepin) OR (nomifensine) OR (pro-
triptyline) OR (phenelzine) OR (moclobemide) OR (se-
legiline) OR (tranylcypromine) OR (isocarboxazid) OR
(bupropion) OR (mirtazapine) OR (*zodone) OR
(amoxapine) OR (reboxetine) OR (lithium) OR (carba-
mazepine) OR (lamotrigine) OR (benzodiazepine) OR
(alprazolam) OR (*ketamine) OR (*milnacipran))
NOT (Review[ptyp])
Search filters: limit to human studies, limit to English
results.
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