Vicent-Gil et al. BMC Psychiatry (2019) 19:135 https://doi.org/10.1186/s12888-019-2117-4 STUDY PROTOCOL Open Access Testing the efficacy of INtegral Cognitive REMediation (INCREM) in major depressive disorder: study protocol for a randomized clinical trial Muriel Vicent-Gil1,3, Beatriz Raventós1, Eduardo D. Marín-Martínez1, Sara González-Simarro1, Anabel Martínez-Arán2, Caterina del Mar Bonnin2, Joan Trujols1, Josefina Pérez-Blanco1, Javier de Diego-Adeliño1, Dolors Puigdemont1, Maria Serra-Blasco3, Narcís Cardoner3 and Maria J. Portella1* Abstract Background: Given the limitation of pharmacological treatments to treat cognitive symptoms in patients with Major Depressive Disorder (MDD), cognitive remediation programs has been proposed as a possible procognitive intervention but findings are not conclusive. This study investigates the efficacy of an INtegral Cognitive REMediation (INCREM) that includes a combination of a Functional Remediation (FR) strategy plus a Computerized Cognitive Training (CCT) in order to improve not only cognitive performance but also the psychosocial functioning and the quality of life. Methods: A single blind randomized controlled clinical trial in 81 patients with a diagnosis of MDD in clinical remission or in partial remission. Participants will be randomized to one of three conditions: INCREM (FR + CCT), Psychoeducation plus online games and Treatment As Usual (TAU). Intervention will consist in 12 group sessions, of approximately 110 min once a week. The primary outcome measure will be % of change in psychosocial functioning after treatment measured by the Functional Assessment Short Test (FAST); additionally, number of sick leaves and daily activities will also be recorded as pragmatic outcomes. Discussion: To our knowledge, this is the first randomized controlled clinical trial using a combination of two different approaches (FR + CCT) to treat the present cognitive deficits and to promote their improvements into a better psychosocial functioning. Trial registration: Clinical Trials NCT03624621. Date registered 10th of August 2018 and last updated 24th August 2018. Keywords: Cognitive remediation, Depression, Functional remediation, Computerized cognitive training, Clinical trial Background recovery and functional disability [3–5]. In fact, current Cognitive dysfunction is considered a new treatment pharmacological treatments for MDD have not been target to improve psychosocial functioning and enhance considered useful for the improvement of cognitive the quality of life in patients with Major Depressive dysfunction probably because they are focused on im- Disorder (MDD) [1, 2]. Previous research suggests that proving mood [6]. The only antidepressants that seem to cognitive symptoms explain the low rates of global have a potential procognitive impact are duloxetine and vortioxetine [7–9], but further studies are needed to * Correspondence: mportella@santpau.cat clarify these findings. 1 Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut Regarding non-pharmacological treatments, Cognitive d’Investigació Biomèdica Sant Pau (IBB-Sant Pau), Universitat Autònoma de Remediation (CR) is a psychotherapeutic approach that Barcelona (UAB), Sant Antoni Ma Claret 167, 08025 Barcelona, Catalonia, has shown improvement in cognition in other neuro- Spain Full list of author information is available at the end of the article psychiatric disorders [10, 11] However, only few studies © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 2 of 8 have been conducted in MDD patients [12–15]. The cognitive symptoms in MDD would be a combination of design features of the interventions differ from one a group FR plus a personalized CCT. The inclusion of another, making it difficult to demonstrate their efficacy. both aspects will allow the intervention to focus on the Moreover, samples included in CR studies were very present deficits through the formation of new strategies heterogeneous with different disease burden, which with compensatory techniques and promoting their use would have impeded conclusions about the specific into everyday life. effect of CR for MDD. Analyses were also limited by the fact that not all patients show the same profile of cogni- Aims of the study tive impairment. It is estimated that 50% of depressed This study aims to show the efficacy of an INtegral patients [16, 17] present enduring cognitive deficits, Cognitive REMediation (INCREM) program specifically- which would significantly interfere in workplace and in designed for MDD patients so as to improve psycho- psychosocial functioning, while another large percentage social functioning through the treatment of cognitive of patients do not suffer from cognitive dysfunction. symptoms. Apart from that, most of CR programs have been Primary research aims: based on neurological models designed to reverse cognitive deficits acquired after or associated with – To develop and to prove the efficacy of INCREM; neurological conditions [18, 19], while the focus of CR this includes a FR program and a CCT. programs in psychiatric diseases should be more directed – To improve psychosocial functioning in MDD patients. in improving everyday functioning rather than merely – To decrease the rate of patients with enduring recovering cognitive losses. Computerized Cognitive cognitive symptoms, and to reduce the risk of Training (CCT), which is based on cognitive exercises and further relapses. games, appears to be, by contrast, an optimal method to improve cognitive functioning in affective disorders due to Secondary research aims: the flexibility given to adjust the tasks to the needs of each patient. In addition, and according to a recent meta-ana- – To establish cognitive profiles in MDD patients, to lysis [20], CCT improved depressive symptomatology and tailor the Integral Cognitive Remediation therapy so everyday functioning in patients with MDD, though pro- as to achieve full remission. ducing inconsistent effects on cognition. – To increase the effect size of the intervention by The scarce evidence on the efficacy of cognitive combining traditional group sessions plus interventions may have prevented a broad implementa- computerized individual sessions. tion of such programs in the clinical setting. Moreover, – To study the specific elements (cognitive and research should define how cognitive remediation pro- psychosocial aspects) that mediate clinical and grams are to be administered (e.g., number of sessions), functional improvement, which can be ascertain what cognitive domains are to be trained, and how this through well-being and decrements in cognitive intervention can impact on psychosocial functioning. complaints. Therefore, there is a strong need of randomized clinical trials so as to demonstrate the efficacy of such interven- Methods and Design tions [14, 15]. This is a single blind, randomized controlled clinical trial Recently, one new ‘ecological’ intervention named approved by the Research Ethics Board of the Hospital Functional Remediation (FR) has been designed with the de la Santa Creu i Sant Pau. All participants will receive aim of transferring cognitive improvements to the daily extended information about the study and must give functioning, by using neurocognitive techniques and their written informed consent prior to the inclusion. training but also through psychoeducation on cognition The study will be carried out in accordance with the and problem-solving. The FR program includes ethical principles of the declaration of Helsinki and modeling techniques, role-playing, verbal instructions, Good Clinical Practices, complying with data protection self-instructions, positive reinforcement and meta-cogni- laws with the anonymization of all the information tive cues using real-life problems [21]. FR in bipolar dis- collected (Data Protection Act 2018). order has shown significant enhancement of functional outcomes as well as subsyndromal symptomatology [22– Participants 24]. This is a group intervention and, thus, it is difficult Patients aged between 18 to 60 years with a diagnosis of to tailor the tasks to the specific needs of each MDD (DSM-5 criteria) will be recruited from the individual. psychiatry department of the Hospital de la Santa Creu i Considering the above, the evidence accumulated Sant Pau in Barcelona (Catalonia, Spain) to participate indicates that the most adequate intervention to treat in the present study. This center covers a population of Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 3 of 8 400.000 inhabitants, and therefore, the recruitment will After 3 months of treatment (12 sessions) efficacy be achieved. All patients will have to be in clinical remis- measures will be collected: Functioning Assessment sion or in partial remission, defined by scores below 14 Short Test (FAST) [28], Perceived Deficit Questionnaire in the HDRS-17. To be allocated in one of the treatment (PDQ-20) [29, 30], Hamilton Depression Rating Scale arms, patients will have to display objective cognitive (HDRS-17) [31, 32], Remission from Depression deficits (measured with the Screening for Cognitive Questionnaire (RDQ) [33] and 36-Item Short Form Impairment in Psychiatry – SCIP, defined by a score Health Survey, Version 2 (SF-36-V2) [34]. Then, 6 below 80) [25, 26] together with psychosocial dysfunc- months after the intervention, a complete demographic, tion, defined by a score from 12 to 20 (mildly impaired) clinical, neuropsychological and functional assessment in the FAST [27]. All patients will continue with their will be performed in order to evaluate the eventual long usual pharmacological treatment. Exclusion criteria are: term effects. To promote retention and interest in the i) an intelligence quotient (IQ) below 85, ii) any medical study by the participants, a detailed report about their condition that may affect neuropsychological perform- evolution will be provided to them. ance, iii) presence of any comorbid psychiatric condition Estimation of sample size was set at 27 participants in including non-nicotine substance use disorders on the each treatment arm, assuming a minimum difference on previous three months, iv) having received electrocon- 6 points on the FAST (primary outcome), and consider- vulsive therapy on the previous year or psychological ing a bilateral significance level of 5% and a statistical intervention in the previous 6 months. power of 80%, adjusted by a 20% rate of dropouts. Study design Figure 1 provides a schedule of the study. Detailed oral Demographic and clinical assessment and written information about the study will be provided A semi-structured interview will be used to assess to all potential candidates to participate in the study. If demographic and clinical variables at baseline. Demo- they are interested in participate, informed consent will graphic assessment will include gender, age, years of be signed and demographic, clinical, neuropsychological education, age at which schooling was completed, and functional assessments will be performed by an work situation, work adjustment, marital status, experienced clinical neuropsychologist. After the fulfill- cohabiting characteristics, and the number of children ment of the inclusion criteria, patients will be random- if any. ized to one of the three possible treatment options: The Cognitive Reserve Assessment Scale in Health INCREM program which includes both a FR program (CRASH; in press) will be included so as to estimate adapted to depression, and a CCT; Psychoeducation plus the cognitive reserve. It is a semi-structured online mental skill games; and Treatment as Usual interview-based scale that evaluates three domains (TAU). A more detailed explanation of the two active considered fundamental in the construct of cognitive treatment arms is provided below. An independent reserve: education, occupation and intellectual and statistician from the Department of Epidemiology leisure activities. (Hospital de la Santa Creu i Sant Pau) will carry out the The clinical evaluation will cover age at illness onset, randomization by means of computer-generated random number of previous episodes, age of first psychiatric numbers. In order to ensure balanced sample sizes hospitalization, number of hospitalizations, period of across groups over time, a block randomization method clinical stability, seasonal pattern, presence of rapid cyc- will be used. The block size will be set to 27, so as to ling depression, presence of melancholy, atypical depres- have 9 patients per treatment arm, in 3 consecutive sion and psychotic symptomatology during depression, blocks. Blocks will then be randomly chosen to deter- comorbidities in axis I, II and III, life history of suicidal mine patients’ final assignment. Another experienced ideation, life history of suicide attempts, number of clinical researcher will assign participants to the corre- attempts, method and medical severity used, and family sponding intervention. The psychologists conducting history of psychiatric disorders and suicide. The treatment interventions will be different from the clin- HDRS-17 will be used to evaluate current depressive ical neuropsychologist who will carry out the assess- symptoms and assess clinical changes. In addition, the ments and who will be blind to the treatment RDQ will be used to evaluate the patient-perceived assignment. The intervention will be discontinued in remission that includes subscales for symptoms of de- case of request by the participant. Any other concomi- pression, other symptoms such as anxiety and irritability, tant psychological treatment will not be permitted coping ability, positive mental health, functioning, life during the trial. Finally, to ensure adherence to interven- satisfaction and a general sense of well-being. These two tion, after one unjustified absence rated by the psycholo- scales will be analyzed as secondary clinical outcomes to gist, a phone call will be done prior to the next session. evaluate the possible lasting effects. Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 4 of 8 Fig. 1 Schedule of enrolment, interventions, and assessments Neuropsychological assessment and visual memory. Processing speed will be measured Following the clinical assessment, a neuropsychological by the Digit Symbol Substitution Test (DSST; battery of tests will be administered by experienced WAIS-IV) and the Trail Making Test Part A neuropsychologists at the beginning of the study and at (TMT-A) [39]. Finally, executive functioning will be 12 months after intervention. It comprises standardized measured with the Trail Making Test Part B (TMT-B) tests to assess attention, working memory, verbal and [39], the Stroop Color and Word Test (STROOP) visual memory, processing speed and executive function. [40], the Wisconsin Card Sorting Test (WCST) [41], Premorbid Intelligence will be estimated with Vocabu- the Tower of London (TOL) [42] and the Category lary and Block Design subtests of the Wechsler Adult Fluency and PMR (adapted for Spanish speaking Intelligence Scale version-IV (WAIS-IV) [35]. Attention population) [43, 44]. TMT-B is used to evaluate and verbal working memory performance will be evalu- set-shifting abilities, STROOP interference is used to ated with Digit forward and backward (WAIS-IV). The evaluate difficulties with response inhibition, WCST Conners Continuous Performance Test 3rd Edition assess abstract reasoning ability and the ability to (CPT-III) [36] will be used to assess sustained attention. shift cognitive strategies in response to changing Verbal learning memory will be measured by the environmental contingencies, TOL is used to detect California Verbal Learning Test (CVLT) [37]. Copy and deficits in planning and problem-solving and Category recall of the Rey-Osterrieth Complex Figure (ROCF) Fluency and PMR are used to measure semantic and [38] will be used to evaluate visuoconstructive abilities phonemic verbal fluency, respectively. Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 5 of 8 Intervention information about the disease and its treatment, and the Selected patients are going to be randomized to three second one (sessions 5 to 12) will consist of introducing possible intervention arms: INCREM; PSYCHOEDUCA- different cognitive-behavioral techniques that have proven TION + online games; and Treatment as Usual (TAU). to be effective for depression. The specific explanation of INCREM will consist of 12 sessions, of approximately the sessions is developed in Table 2. The online game will 110 min once a week, involving a FR and a CCT. FR pro- be applied right after the psychoeducation sessions during gram was originally developed for bipolar patients [45] and 20 min. The games will be facilitated by a free mini-game it will be adapted for depressed patients creating a more in- online website (www.frivplus.com). No records will be tensive program focused on executive functions, memory gathered on this last part, as it is only used to make com- and attention. The sessions aim at improving daily func- parable the two active treatment arms. tioning based on ecological tasks where they need to use TAU will consist in giving the usual treatment to compensatory techniques. The specific explanation of the patients according to accepted standards for depres- sessions is developed in Table 1. CCT will be applied right sion (except psychotherapy which will not be allowed after FR group sessions in individual computer sessions 6 months before the study nor during it). during 20 min. The modules of training will be facilitated by the licensed game-like software CogniFit (https://www. cognifit.com). This neurocognitive stimulation program Outcome measures consists of a battery of tasks that allows depressed patients The primary outcome measure of the study will be the to improve their cognitive skills depending on their individ- change in psychosocial functioning after treatment, which ual performance throughout different activities. will be measured by means of the FAST. The FAST is a PSYCHOEDUCATION will consist of 12 sessions, 90 scale created to assess disability in functioning in mental min once a week involving psychoeducation sessions health which contains 24 items evaluating autonomy, plus 20 min online non-directed game playing. This occupational functioning, cognitive functioning, financial treatment arm has been designed as the control inter- issues, interpersonal relationships and leisure time. The vention arm due to its beneficial effects for depression. scores range from 0 to 72, with higher scores indicating a The material for the psychoeducation intervention has greater disability. A sum of ≥12 represents a mildly to been specifically designed for the study and is based on severe functional impairment in patients with bipolar validated treatment protocols [46–48]. Information disorder [27]. Given the complexity of the possible effects about the disease is provided during the sessions so as of the intervention, changes in pragmatic variables of to gain knowledge and strategies to cope with their own psychosocial functioning will also be evaluated: number of difficulties and to improve their quality of life. Therefore, sick leaves and number of daily activities. the intervention will be divided in two modules: the first Table 2 Content of the 12-week Psychoeducational Program module (sessions 1 to 4) will consist in providing Session Topics Covered 1. What is depression? (I) Concept of depression Table 1 Content of the 12-week Functional Rehabilitation 2. What is depression? (II) Definition, symptoms, prevalence Program and course Session Topics Covered 3. Etiology of depression Biopsychosocial model, psychobiology 1. What is attention? (I) Strategies of concentration and psychological theories 2. What is attention? (II) Strategies to improve attention 4. Treatment of depression Pharmacological, psychological and 3. Reading Recovering the habit of reading other treatment options 4. What is memory? (I) Mnemonic strategies 5. Behavioral Activation (I) Introduction to Behavioral Activation 5. What is memory? (II) The use of diaries and external 6. Behavioral Activation (II) Exposition to positive activities aids 7. Cognitive Distortions Cognitive distortions, automatic negative thoughts and cognitive 6. What are executive functions? (I) Self-instructions restructuring technique 7. What are executive functions? (II) Programing activities, prioritization 8. Anxiety Anxiety management strategies and time management 9. Social Skills (I) Social skills deficits and 8. What are executive functions? (III) Problem solving strategies communicational styles 9. What are executive functions? (IV) Working memory strategies 10. Social Skills (II) Social skills training 10. Stress Stress and neurocognition 11. Problem-Solving Problem-Solving training 11. Communication Communication skills and Technique assertiveness 12. Relapse Prevention Summary of the sessions and relapse 12. Autonomy Independence and autonomy prevention Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 6 of 8 Different secondary outcome measures will be psychosocial functioning. This study aims to improve analyzed: i) the change in cognitive performance across psychosocial functioning through the improvement in cognitive domains (through composite scores of the cognitive performance. To our knowledge, this is the first different cognitive domains and a global composite randomized clinical trial using an INtegral Cognitive cognitive score); ii) change in subjective appraisal of cog- REMediation (INCREM) composed by 12 sessions of a FR nitive functioning evaluated with the PDQ-20 which is a program and a CCT. self-reported questionnaire that measures the patients’ The major strength of this study is the combination of perception of their cognitive functioning. It consists of two different approaches at the same time: a group 20 items assessing attention, retrospective memory, format therapy together with a computerized program prospective memory, and planning and organization; iii) that allows a personalized delivery of the intervention. change in depressive symptoms with the HDRS-17); iv) This synergistic approach may represent the path to change in patients’ perspective of clinical remission with optimize treatment response and ensure better func- the RDQ; and v) change in quality of life assessed with tional outcomes in patients with MDD. The presence of the SF-36-V2. It evaluates the patients’ health-related an active control group beyond treatment as usual quality of life gauging eight sections: vitality, psychical (TAU) is another relevant strength of the study. A large functioning, bodily pain, general health perceptions, battery of primary and secondary outcome measures will physical role functioning, emotional role functioning, be used to evaluate the efficacy of the intervention. Pa- social role functioning and mental health. tients will be approached six months after finishing the intervention to assess the maintenance of possible Statistical analysis plan changes. Furthermore, this study will take into account Data will be collected in three different moments: baseline, the specific cognitive deficits of each patient by adapting post-intervention and follow-up through a logbook data CCT to individual performance. collection. Then, an online application called Clinapsis will A potential limitation of the present study is inherent be used for data collection, which ensures anonymisation to any clinical trial, given that participation and of data (through encoding system). This system will grant follow-up of the interventions could be more compli- public access to the full protocol and dataset at cated. A 20% of dropouts are calculated throughout the participant-level for further analysis beyond this proposal. intervention and/or follow-up has been estimated, but The data will be analyzed using the Statistical Package this percentage could be higher, which would limit the of Social Sciences (SPSS, IL, Chicago, version 20) and R power of the analysis. Patients should be in remission or Package (version 3.1.2). First, baseline differences be- in partial remission with cognitive deficits and difficul- tween groups will be investigated using chi-square tests ties in daily life, so that recruitment and inclusion might and ANOVAs depending on the nature of the variables. be more complicated. Concomitant medication might Secondly, mixed-models will be carried out to assess the also represent a possible limitation because of side ef- impact of the three different treatment options on the fects or even procognitive effects of newer drugs. Medi- psychosocial functioning scores assessed with the FAST cation regimes will be recorded during the different scale (primary outcome measure). Effect sizes of inter- phases of the study and then will be taken into account ventions will be calculated. Secondary variables will also in the analyses. In any case, in the clinical practice, poly- be analyzed with the same statistical approach. Mixed medicated patients are the rule rather than the excep- repeated measures ANOVAs will be carried out to inves- tion. Hence, it might limit internal validity but it is tigate the long-term effects of interventions on second- strength for the generalization of the results. ary outcomes. Finally, in order to investigate predictors of treatment response, a study of mediators and modera- tors will be conducted. For the main statistical analysis, Conclusion the Last Observation Carried Forward method will be The presence of residual cognitive symptoms, observed used to minimize the effect of dropout rates at 6 months in the clinical settings, may impede the achievement of of follow-up after intervention. full remission in patients with depression. Therefore, ef- fective cognitive treatments are an unmet need. If the re- Discussion sults of this study are conclusive, the INCREM could be Cognitive impairment is nowadays considered a core added to the therapeutic arsenal for depression. This symptom of MDD and a critical determinant of psycho- non-pharmacological treatment may seem expensive as social and workplace outcomes, as well as health outcomes it consists in 12 sessions, but if one considers the direct such as the health-related quality of life. CR has been used and indirect social and healthcare costs of depression to treat these cognitive deficits suggesting significant [49], then targeting cognitive symptoms with a cognitive improvements in cognition but with small effect sizes for program will likely be cost-effective. Vicent-Gil et al. BMC Psychiatry (2019) 19:135 Page 7 of 8 Abbreviations Publisher’s Note CCT: Computerized Cognitive Training; CPT-III: Conners Continuous Springer Nature remains neutral with regard to jurisdictional claims in Performance Test 3rd Edition; CR: Cognitive Remediation; CRASH: Cognitive published maps and institutional affiliations. Reserve Assessment Scale in Health; CVLT: California Verbal Learning Test; DSST: Digit Symbol Substitution Test; FAST: Functioning Assessment Short Author details 1 Test; FR: Functional Remediation; HDRS-17: Hamilton Depression Rating Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Scale; INCREM: INtegral Cognitive REMediation; IQ: Intelligence Quotient; Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut MDD: Major Depressive Disorder; PDQ: Perceived Deficit Questionnaire; d’Investigació Biomèdica Sant Pau (IBB-Sant Pau), Universitat Autònoma de RDQ: Remission from Depression Questionnaire; ROCF: Rey-Osterrieth Barcelona (UAB), Sant Antoni Ma Claret 167, 08025 Barcelona, Catalonia, Complex Figure; SCIP: Screening for Cognitive Impairment in Psychiatry; SF- Spain. 2Bipolar and Depressive Disorders Unit, Institute of Neurosciences, 36-V2: 36-Item Short Form Health Survey, Version 2; STROOP: Stroop Color Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de and Word Test; TAU: Treatment As Usual; TMT-A: Trail Making Test Part A; Salud Mental (CIBERSAM), IDIBAPS, University of Barcelona (UB), Barcelona, TMT-B: Trail Making Test Part B; TOL: Tower of London; WAIS-IV: Wechsler Catalonia, Spain. 3Mental Health Unit, Hospital Universitari Parc Taulí, Centro Adult Intelligence Scale version-IV; WCST: Wisconsin Card Sorting Test de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònoma de Acknowledgements Barcelona (UAB), Sabadell, Barcelona, Catalonia, Spain. We thank Dr. Ignasi Gich, from the Department of Epidemiology (Hospital de la Santa Creu i Sant Pau, Barcelona), for his help in the randomization Received: 7 February 2019 Accepted: 12 April 2019 process. Funding References This study is financed by a governmental grant from the Spanish Ministry of 1. McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Science, Innovation and Universities, Instituto Carlos III. Project number: Kudlow P, et al. Cognitive deficits and functional outcomes in major PI17/00056. Duration: from 1th January 2018 to 31th December 2020. This depressive disorder: determinants, substrates, and treatment interventions. funding source had no role in the design of this study and will not have any Depress Anxiety. 2013;30:515–27. role during its execution, analyses, interpretation of the data, or decision to 2. Chakrabarty T, Hadjipavlou G, Lam RW. Cognitive dysfunction in major submit results. depressive disorder: assessment, impact, and management. 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