Clinical practice guidelines on the assessment and management of cognitive impairment in major depressive disorder

INTRODUCTION Epidemiology Cognitive deficit is a trivialized symptom of a most prevalent psychiatric condition called major depressive disorder (MDD).[1] With a staggering global prevalence of approximately 350 million, MDD contributes to a significant loss in quality of life and increased economic burden.[2] One or more cognitive faculties in MDD patients are adversely affected and tend to persist despite the remission of the episode [Figure 1].[3]Figure 1: Concise framework of assessment and management of Cognition in Subjects with Major Depressive DisorderUpon resolution of a major depressive episode, the affected individual may show or experience considerable improvement in cognitive measures. but there are still residual cognitive symptoms that continue to exist. [Table 1].[4] The deficit in one or more cognitive faculties has been reported to be one or more standard deviations below normative value, in 25–50% of subjects with MDD.[4]Table 1: Cognitive domains affected in Major depressive disorderCognitive deficit in major depressive disorder: an epiphenomenon or an endophenotype Recent research suggests that cognitive impairment in depression may be more accurately conceptualized as an endophenotype rather than merely an epiphenomenon. As an endophenotype, cognitive impairment may represent a heritable trait that increases vulnerability to depression and persists even during periods of remission.[5] The presence of this cognitive endophenotype in depression may create a “double hit” effect, where the underlying cognitive vulnerability interacts with the neurotoxic effects of depressive episodes, potentially accelerating neurodegeneration and increasing the risk of developing conditions such as mild cognitive impairment (MCI) or even dementia. This interplay between cognitive deficits and depressive symptoms may create a vicious cycle, with each exacerbating the other over time, ultimately leading to more profound and persistent neurocognitive impairments.[6] Aside from this continuum, lies pseudodementia. This reversible dementia-like phenomenon appears to be a mood-cognition medius. Table 2 gives a concise comparison of cognitive phenotypes associated with different conditions. This mood and cognition interplay further gets complicated when the iatrogenic factor takes the wheel. The mechanisms as to how psychotropics may lead to cognitive deterioration have been presented in Table 3.[7]Table 2: Comparison of disorders lying on the mood-cognition spectrumTable 3: Mechanisms underlying psychotropic induced cognitive impairmentDissecting mdd phenotypic definition The DSM5 (Diagnostic and Statistical Manual 5) typology for depression includes discrete clinical phenotypes such as: melancholia, anxious distress, atypicality, presence of psychotic features or mixed features, and those with peripartum onset. Williams et al. 2013, took a neural circuitry-based approach to define biotypes of depression [Table 4].[13]Table 4: Different Biotypes of Depression biotypes based on neural circuitryAgainst the prevailing belief, that cognitive problems in depression would automatically improve when depressive symptoms got better, mediation models show that improvements in cognitive control directly influence the reduction of depressive symptoms and enhancement of quality of life after treatment.[4] Course of cognitive deficits across various domains Previously we have discussed the involvement of several cognitive faculties [Table 1] in MDD. However, there is heterogeneity in cognitive functioning across different domains and across different points in the course of major depressive disorder independent of treatment[14]Table 5 below summarizes the longitudinal change in cognition across various domains.Table 5: The temporal evolution of impairment in different domains of cognitive functioning in MDDNeurobiological underpinnings Depression is a multisystem disorder with aberrancy starting at the level of genetic architecture and evolving into a myriad of cascades. Various chronic proinflammatory mechanisms and neuroimmune axis alterations, in the advent of any stressor, translate to changes at the level of neurochemistry and brain connectivity. This leads to a shift of control mechanisms from the “rational brain” towards the “emotional/sensory brain.” This leads to increased processing of the negative stimuli.[17] Predictors of outcome The line of evidence regarding cognitive outcomes in MDD is limited and often mixed. While the plethora of studies is incredible, the duration of research investigating various demographic and age-related variables was short. However, Table 6 below summarizes findings in respective reviews regarding outcome predictors.[18,19]Table 6: The good and poor cognitive outcomes in Subjects with MDDThe existing qualitative research suggests that the improvement in patient-related quality of life measures is held as a priority by a large number of mental healthcare professionals.[20] This guideline aims to provide evidence-based recommendations for the assessment and management of cognitive impairment in individuals with depressive disorders. OBJECTIVES To standardize the assessment of cognitive impairment in depressive disorder. To standardize the assessment of cognitive impairment in depressive disorder patients once they achieve remission. To outline evidence-based management strategies for cognitive impairment during and persisting after the remission is achieved To enhance awareness and understanding of cognitive impairment in depressive disorders among end users i.e., Psychiatrists and other mental health professionals. SCOPE This guideline is intended for use by psychiatrists, clinical psychologists, and other mental health professionals involved in the care of individuals with depressive disorders. ASSESSMENT OF COGNITIVE IMPAIRMENT General evaluation of Depressive features [Figure 1]:Any individual in a clinical setting undergoes preliminary assessment which screens them for any psychopathology, and its severity. The clinical presentation should fulfill the ICD 10 and DSM 5 criteria, required to reach a diagnosis of MDD. Neither of these classifications mentions cognitive dysfunction as an MDD phenotype. These guidelines are to be used in conjunction with the Clinical Practice Guidelines issued by the Indian Psychiatry Society for the general and elderly population.[21,22]Evaluation of Cognitive features: A baseline cognitive assessment entails ruling out other cognitive illnesses. The cognition itself is not the primary pathology. Hence while it is not relevant to have an exclusive assessment of the same, it is empirical to be cognizant that cognitive deficits might be a predictive and prognostic marker of treatment outcome and functioning. The widely used scales such as HAM-D 21 and MADRS have 2 items each assessing cognitive symptomatology. These scales provide insufficient information. Several cognitive screening tools that have been validated for indian population have been listed in [Table 7]. For comprehensive evaluation, prominent institutional bodies have constructed tools for application in indian population [Table 8].Table 7: Screening tools for cognitionTable 8: Various comprehensive cognitive tests standardized for Indian populationCommon neuropsychological tests: Trail-making test Digit span test Controlled oral word association test Token Test Stroop test Rey Complex figure test Wisconsin Card test Symbol digit modalities test and digit symbol substitution test: California Verbal Learning Test/Ray auditory Verbal Learning Test Clock drawing test Weschler Adult Intelligence Scale 4th edition (WAIS-IV) Indian adaptation Other tests: Not validated in India yet Perceived Deficits Questionnaire-Depression (PDQ-D) 20: measures subjective cognitive deficits in 4 domains of cognition, namely: attention/concentration, retrospective memory, prospective memory, and planning/organization.[3] Online computerized tests[3]: THINC-it® is a computerized cognition screening resource for patients with MDD. CANTAB: Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer-based cognitive assessment system. MANAGEMENT There is no one way of addressing the challenges associated with cognitive impairments associated with MDD. In cognizance of same, several modalities of treatment have been studied. [Figure 2].Figure 2: Modalities and crucial elements influencing cognitive outcomesA. Stand-alone or adjunctive pharmacotherapy AntidepressantsThere are several randomized controlled trials (RCTs) and NMAs comparing the effect of a wide range of antidepressants on cognition across various domains as in Table 9. Only Shilyansky et al. 2016[24] and Prado et al. 2018[23], meta-analyses study focused on conventional antidepressants. The rest of the meta-analyses included a multimodal agent Vortioxetine. In three other studies, Vortioxetine consistently outperformed other common antidepressants in terms of its cognitive benefits.[26–29]Table 9: NMA (Network Meta Analyses) and meta-analyses describing cognitive outcomes.Adjunctive atypical antipsychoticsThere is only one study that showed beneficial results in executive and continuous attention domains of cognition. favoring the addition of aripiprazole to antidepressants.[30] The cognitive improvement is likely to be an indirect effect of remission of psychotic symptoms and stabilizing mood.[31]Non-conventional Drug therapies Ketamine/Eketamine modulates glutamate neurotransmission, which can have rapid antidepressant and procognitive effects.[14–16] Concerns have been raised regarding the long-term effects of this modulator on cognition in MDD.[32] Cholinesterase inhibitors, such as donepezil and galantamine, have shown limited for their effects on cognitive symptoms in MDD. These inhibitors have been found to ameliorate subsyndromal depression in patients with dementia and improve cognition and behavioral symptoms. However, the effects of these inhibitors on cognitive function and mood in older adults with MDD are inconsistent[33,34] Eugeroics: These agents promote wakefulness and enhance cognitive function by modulating dopamine and other neurotransmitters. Few studies show that modafinil and armodafinil improve symptoms of depression, reduce fatigue, and improve cognition.[34,35] Memantine, an NMDAR antagonist, effects on cognitive outcomes in MDD patients are not well established. One RCT assessed the efficacy of adjunct memantine in old MDD patients and showed beneficial results in delayed recall and executive functioning in this group.[23] Psychological treatments Cognitive Remediation Therapy (CRT) is an evidence-based intervention designed to improve cognitive functioning. Components: Computerized Exercises: Patients engage in structured computer-based tasks that challenge cognitive processes. Strategy Training: Participants learn compensatory strategies to manage cognitive difficulties. Group Sessions: CRT often involves group-based training to foster social interaction and support. CRT is tailored to each person’s specific cognitive deficits and needs. It can be combined with other therapies (e.g., psychotherapy, pharmacotherapy) for comprehensive treatment.[36] Cognitive behavior Therapy (CBT):In a meta-analysis by Cristea et al. (2015), CBT showed a significant robust medium effect on improving dysfunctional thinking in adults with depression. Its ability to improve cognitive restructuring and behavioral activation is based on the available evidence. There were no differences between CBT and pharmacotherapy on dysfunctional thoughts. More research is needed to fully understand the differential cognitive effects of various psychotherapies for depression.[37,38]Other Psychotherapies: There is less extensive data on the effect of other psychological therapies on cognitive outcomes. Neurostimulation Transcranial Magnetic Stimulation (TMS): Individual studies report improvement in cognitive functioning however there is heterogeneity in the montage used, stimulation intensity, and pulse pattern.[39,40] Clinical practice guidelines for the therapeutic response of rTMS in neuropsychiatric disorders mention evidence supporting the role of rTMS in the relative improvement of executive functioning with improvement in depression outcome.[41] A systematic review of 58 studies reported improvement in mental faculties.[42] Transcranial direct current stimulation (tDCS): Anodal tDCS is usually applied over the left dorsolateral prefrontal cortex (DLPFC). Transcranial Direct Current Stimulation (tDCS) has shown promising results in improving cognitive outcomes in depression based on case-control studies conducted on depressed patients. However, three prominent randomized controlled trials ELECT-TDCS, SELECT-TDCS, and DepressionDC trial findings did not corroborate with those findings.[43] Electroconvulsive Therapy (ECT): Electroconvulsive therapy (ECT) for major depressive disorder can have acute, short-term, and long-term effects on cognitive functions such as processing speed, executive function, memory, and attention.[44] Studies suggest that ECT may not have persistent negative effects on cognition, and achieving remission can improve subjective memory and verbal memory recall.[45] It is important to note that cognitive outcomes can vary based on factors such as age, premorbid intellectual function, gender, and anesthetic agent and ECT technique used.[46] Therefore, ECT is an alternate neurostimulation method recommended for better cognitive outcomes[47] Vagus Nerve Stimulation (VNS) Figure 3 below illustrates the bottom-up mechanism of vagus-mediated cognitive enhancement. Through a preclinical study, vagus nerve stimulation was found efficacious when it was paired with the learning or consolidation phase of a memory task.Figure 3: Mechanism of vagus-mediated cognitive enhancementThere was also superior cognitive efficacy of transcutaneous Cervical VNS over transcutaneous auricular VNS. Two open trial data demonstrated significant improvement in cognitive and clinical outcomes in patients diagnosed with treatment-resistant depression.[48,49] While learning and memory showed improvement within a month, other cognitive functions showed gradual improvement. The effects were sustained even at 12 months[48] Complementary and Alternative medical treatments (CAMTs): It is defined as “a group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine.” Mind–Body MedicineMindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) have a body of evidence supporting good cognitive outcomes in at-least one domain in patients with at least mild depressive symptomatology.[50] However, the methodology of the studies inspecting these mindfulness-based studies is not uniform. Additionally, it requires properly trained instructors to administer the treatment.Aerobic ExerciseA systematic review and meta-analyses of 12 randomized trials reported overall improvement in global cognitive function, with significant improvement in memory and executive functioning in patients with major depressive disorder. There was a significant improvement in those on antidepressant use. This study concluded that an optimal exercise with parameters of moderate-to-vigorous intensity, 3 times per week, with session times less than 60 minutes, and a duration of 12 weeks or less, as a complementary treatment is an effective intervention for cognitive symptoms in individuals with MDD. The intervention works especially well when combined with antidepressant medication and in inpatient settings.[51]Natural products ProbioticsA 2019 RCT reported improvement in cognitive performance in depressed patients on adjunctive psychobiotic Lactobacillus Plantarum 299v (LP299v) which also aligned with a decrease in serum kynurenine levels.[52] A systematic review and meta-analyses reported improved episodic verbal memory in depressed patients on adjunctive short-term, high doses of probiotics.[53]Nootropics: Recombinant erythropoietin (EPO): In a double-blind, randomized, placebo-controlled, recombinant erythropoietin showed significant improvement in verbal learning and memory in a mood-independent manner.[27] Other potential and novel nootropics: The evidence for the cognitive efficacy of various other nootropics is still limited. Well-designed, large-scale RCTs are needed to further investigate their efficacy and safety. However, we describe below the nootropics with potential cognitive benefits.[54] Minocycline Insulin and Antidiabetic Agents (e.g., Thiazolidinediones). S-Adenosyl Methionine (SAMe) Omega-3 Polyunsaturated Fatty Acids N-acetylcysteine (NAC) Curcumin Statins Coenzyme Q10 Gingko biloba extract EGb761.[55] Cognitive rehabilitation: In MDD, there is impairment in cognitive flexibility results in impairment in performing goal-directed activity. Cognitive rehabilitation employs repetitive use of faculties like working memory, processing speed, or continuous attention causing activation of respective disrupted neural circuitry.[56] A 2016 meta-analysis reported an improvement of moderate to large effect size for overall cognition, attention, and working Memory. It is of two types: Strategy-based training: Personalising the training strategies to target the deficit in a specific cognitive faculty, for example, training in inductive reasoning.[57] Process-based training: The training is programmed to entrain the participant in a hierarchy of tasks that cumulatively engage a specific cognitive process. For example, training on speed of processing and attentional breadth or Task-switching training.[57] Computerized working memory tasks: The most commonly used Paced Auditory Serial Addition Test (PASAT), has shown potential in improving the cognitive skills of MDD patients. A study measuring the effect of PASAT on mental abilities, conducted by Sommer et al., reported enhancement in metacognitive skills, a decrease in maladaptive thought patterns (i.e., rumination), and improvement in depressive symptom severity. Moreover, Computer-based, mental arithmetic exercises, that focus on sequencing, have been shown to improve intelligence quotient (IQ), increase psychosocial functioning, as well as hippocampal and frontotemporal activation in MDD.[56] CONCLUSION Cognitive impairment in MDD is much more prevalent than previously thought. This is observed during both the symptomatic as well as remission and recovery phases of the MDD. There is multidomain involvement of cognition with some patients of MDD being more vulnerable than others. Early detection and watchful prompt assessment of cognitive impairment are needed in all patients with MDD. Based on the available resources and needs of the patient assessment should be tailor-made and should include repeated screening and detailed assessment. The management of cognitive impairment should include pharmacotherapy, alternative medical and lifestyle management, psychotherapy, and neuromodulation and or its combination based on the available resources. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.