Modafinil's Effects on Cognition in Remitted MDD
Modafinil's Effects on Cognition in Remitted MDD
Cognitive difficulties such as indecisiveness or inability to concentrate are core symptoms
 of depression with up to 90% of untreated depressed individuals experiencing these symptoms.
 As many as half of those who remit from a major depressive episode continue to experience
 residual cognitive deficits, but these symptoms are frequently overlooked in clinical
 practice. This leads to persistent cognitive deficits which can cause reduced level of
 functioning and loss of productivity. As standard antidepressants have an inadequate impact
 on these residual cognitive symptoms, further treatment options are required. Modafinil is a
 wakefulness agent with evidence that it improves some domains in cognition such as memory in
 those whose non-cognitive depressive symptoms have been treated over a short term period.
 This medication may have favourable lasting effects on cognition, such as the ability to plan
 and execute tasks in those who receive modafinil for a longer time period. The aim of this
 study is to investigate whether modafinil can enhance cognition and have additional effects
 on functioning and work productivity in a sample of participants who were treated for
 depression but who continue to experience cognitive deficits.
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.
Inclusion Criteria:

 1. Diagnostic and Statistical Manual (DSM)-5 criteria for past Major Depressive Episode
 within MDD, confirmed through Mini-International Neuropsychiatric Interview (MINI)
 diagnosis

 2. Age between 18 and 55 years

 3. Montgomery-Åsberg Depression Rating Scale < 7 (in remission)

 4. Ability to read and understand English

 5. Participant has been treated with an antidepressant for ≥ 6 months prior to enrolment

 6. Participant agrees to remain on a stable antidepressant regimen for the duration of
 the trial (8 weeks)

 7. Participant is currently experiencing cognitive deficits, as confirmed by an NCI >1
 standard deviation below the mean on CNS Vital Signs cognitive battery

 8. Women of child bearing potential must agree to use birth control for the duration of
 the study and 1 month following discontinuation of the study drug

 Exclusion Criteria:

 1. Pregnancy/lactation

 2. Lifetime history of Bipolar I, II or psychosis; other comorbidities (e.g. Generalized
 Anxiety, Panic Disorder) may be allowed by clinician judgement

 3. Subject has current clinical diagnosis of autism, dementia, intellectual disability,
 or mild cognitive impairment

 4. Meets DSM-5 criteria for active Post-Traumatic Stress Disorder, confirmed through MINI
 diagnosis

 5. Subject meets criteria for current personality disorder

 6. Concomitant use of monoamine oxidase inhibitors and/or other psychotropic drugs
 including lithium, clomipramine, and triazolam

 7. Recent (< 6 months) stimulant use, such as medications used for attention deficit
 hyperactivity disorder

 8. Subject is taking antipsychotics

 9. Subject is taking herbaceuticals (i.e. natural products that have psychoactive
 properties, such as St. John's wort)

 10. Concomitant use of medications that may interact with modafinil, including warfarin
 and cyclosporine

 11. Medical condition requiring immediate investigation or treatment

 12. Recent (< 6 months)/current history of drug abuse/dependence (other than caffeine or
 nicotine)

 13. Previous intolerance or failure to respond to an adequate trial of modafinil

 14. Any past history of head injury or concussion, as confirmed by the Ohio State
 University Traumatic brain injury (TBI) Identification Short Form

 15. Current suicidal ideation (MADRS Item 10 ≤2 or by clinician judgement)

 16. History of coronary artery disease, recent (<1 year) myocardial infarction, or
 unstable angina

 17. History of left ventricular hypertrophy, ischemic ECG changes, chest pain, arrhythmia,
 or clinically significant manifestations of mitral valve prolapse in association with
 use of CNS stimulants

 18. Involvement in another treatment study during the time of the study