Background:
Major Depressive Disorder (MDD) is a chronic mental disorder with a lifetime prevalence of
5-20% (Kessler et al., 2003; Woo et al., 2016). While depressed mood and loss of interest in
activities are core features of MDD, cognitive deficits such as indecisiveness and
inattention are present and interfere with work and social functioning (McIntyre et al.,
2013). These cognitive deficits frequently persist beyond remission from a Major Depressive
Episode (MDE), with up to 94% of those impaired during an episode continuing to experience
deficits after the episode (Bhalla et al., 2006), including deficits in attention, executive
functioning, and psychomotor speed (Salagre et al., 2017). These residual cognitive symptoms
often persist and are associated with poor functioning and loss of productivity (Lam et al.,
2014).
In a systematic review examining MDD patients in remission, multiple regression analyses
found that MDD predicted lower performance on measures of attention, processing speed, and
cognitive flexibility relative to healthy controls (HCs; Hasselbalch et al., 2011). Further
evidence for the presence of neuropsychological deficits in remitted MDD patients comes from
a systematic review and meta-analysis that found the remitted MDD patient group had executive
function and attentional deficits, while symptomatic patients exhibited executive function,
attentional, and memory deficits (Roc et al., 2013).
Importantly, there are no medications with evidence to modify cognition in remitted
depression. This suggests that in order to assist in the recovery of cognitive and functional
abilities, additional novel treatment options are required.
There is considerable evidence that subjective and objective measures of cognition are not
well correlated in MDD. This has informed the investigators' choice of separate subjective
and objective measures for this study. In addition, cognitive disturbances affect
psychosocial function and quality of life across several areas, and this necessitated
measurement of quality of life. In this study, the investigators will use a computerized
version of the Central Nervous System (CNS) Vital Signs Cognitive Battery, which will provide
a Neurocognitive Index score (NCI). The NCI is a global measure of cognitive functioning,
averaging the scores from 7 tests over 5 domains: composite memory, psychomotor speed,
reaction time, complex attention, and cognitive flexibility.
Pilot results from the The Canadian Biomarker Integration Network in Depression (CAN-BIND)-1
study, involving treatment with escitalopram, have clearly documented the nature of deficits,
and are in line with expectations in remitted depression. In this pilot sample of 208
participants, 15% of participants had global cognitive impairment despite 8 weeks of
antidepressant treatment and achievement of clinical remission (McInerney, personal
communication).
In an 8-week antidepressant study, those who significantly improved in global cognitive
functioning (assessed using NCI) had superior functioning and work productivity relative to
those who did not significantly improve (Hasselbalch et al., 2011). Vortioxetine is the only
antidepressant with modest evidence for improving cognitive parameters during a depressive
episode (Rock et al., 2013). Research into the use of psychostimulants as a treatment for
cognitive deficits in depressed patients has led to the consideration of modafinil and
methylphenidate as potential novel pharmacological treatments (Minzenberg et al., 2008).
Modafinil is a well-tolerated wakefulness agent where only two clinical studies have
previously examined its role on cognition in depression; one where currently depressed
patients had improvements in one measure of executive function after 4 weeks of treatment as
an adjuvant (DeBattista et al., 2004), and the other where there were improvements in memory
after a single dose in depressed participants who achieved remission (Kaser et al., 2016).
Unlike methylphenidate, modafinil appears to impact both "hot" (emotion-laden) and "cold"
(independent of emotion) cognitive deficits, which are commonly seen in remitted depression.
Immediate effects of modafinil on cognition have been shown (Kaser et al., 2016) and the
investigators will be the first to examine the pro-cognitive effects in a remitted depressed
sample over 8 weeks. The dose of modafinil (200mg) used in the study, sample size, and
randomized control trial (RCT) study design parallels those described in the immediate effect
study, and this maintains continuity. However, the study does not examine whether the
immediate effects are maintained. More importantly, it is unclear whether the cognitive
improvements translate into improvement in functioning.
The added focus on functional outcomes fits with patient-centered models of healthcare, as
functional outcomes are of greatest importance to most patients. Thus, the RCT study and
choice of outcome variables have been carefully designed with specific endpoints to delineate
these aspects. Cognitive flexibility, memory, and attention will be domains of importance in
this study, since these domains have been shown in previous literature to be improved by
modafinil (Minzenberg et al., 2008; DeBattista et al., 2004; Kaser et al., 2016).
Objectives, Hypotheses, and Impact:
The primary objective of this study is to delineate the cognitive effects of modafinil in
patients with remitted depression at baseline and 4 weeks, and monitor whether these effects
are maintained with continual dosage over an 8-week period. The secondary objective of this
study is to understand the effect of modafinil in patients with remitted depression on
measures of functioning at baseline, 4 weeks, and 8 weeks, and whether these effects parallel
the cognitive changes.
The investigators' overarching hypothesis is that specific aspects of cognitive functioning,
including the domains of memory, attention, and cognitive flexibility, will improve through
treatment with modafinil. The investigators hypothesize that participants with remitted
depression who continue to experience cognitive deficits and are taking modafinil will have
improvements in aspects of cognitive domains at 4 weeks, and these improvements will be
sustained at 8 weeks. It is also hypothesized that functional improvements will parallel the
improvements in cognitive domains.
The study ensures a closer examination of modafinil's effect on individual facets of
cognition in patients with remitted MDD. This enhanced understanding will enable the
development of new treatment plans for residual cognitive symptoms, where none currently
exist. Moreover, it could spur interest in new drug development programs to address an unmet
need of targeting cognition across disorders where depression is a central feature (e.g.
Bipolar Disorder, Generalized Anxiety Disorder). Finally, the study would delineate the
specific endophenotypes within cognition (e.g. working memory) and functional improvement
(e.g. social functioning), which would lead to personalized treatment options based on the
endophenotype profile.
Methods In this randomized control trial, remitted MDD patients with residual cognitive
deficits (n=50) will have cognitive symptoms and functioning evaluated before and after an
8-week trial of modafinil 200mg or placebo. Participants will be recruited through the
ongoing CAN-BIND 1 Wellness Study; the Depression Program at St. Michael's Hospital; the
shared care network at St. Michael's Hospital; and referrals from residents, family doctors,
and other St. Michael's psychiatrists. All participants who meet inclusion criteria will be
asked to enrol in this study and provide written informed consent.
Participants will be on a stable dose of an antidepressant for at least 6 months prior to
enrolment. They will be required to remain on this stable dose for the duration (8 weeks) of
the trial. They will be prescribed modafinil or placebo at a dose of 100 mg for the first
week then 200mg for 7 weeks. After week 8, participants will be informed of which group they
were in and if they were taking modafinil, they can choose to continue on modafinil or to
discontinue.
Participants will undergo an 8-week randomized, placebo controlled treatment trial of
modafinil 200mg with a total of 3 study visits. Participants may require more clinical visits
as needed. Screening will be done to confirm study eligibility. At the screening visit all
participants will provide demographic data (age, gender, education, ethnicity, occupation,
family history of mental illness), undergo a structured diagnostic assessment
(Mini-International Neuropsychiatric Interview), complete the CNS Vital Signs cognitive
battery, and have the Montgomery-Asberg Depression Rating Scale administered. At the baseline
visit, participants will initiate the study drug trial, complete clinician rated and
self-report scales, and complete the cognitive battery in CNS Vital Signs. Participants will
start with a 100 mg dose at baseline, and increase to the 200 mg dose at week 1 if the drug
is well tolerated. Participants will repeat all measures at week 4 and 8. Adverse events will
be recorded at each study visit. For participants who wish to discontinue the study drug at
week 8, they will first have their dose decreased to 100 mg for one week and attend an
additional week 9 safety visit to evaluate adverse events before full discontinuation of the
study drug.