Abstract
Purpose of Review
This narrative review summarizes the current evidence regarding functional impairment in MDD and the factors contributing to it.
Recent Findings
Major depressive disorder (MDD) is a leading cause of disability and is associated with substantial economic burden, largely due to the functional impairment common among MDD patients. Despite the prevalence of functional impairment in MDD, it has not typically been investigated as a primary treatment outcome in MDD until recently, as treatment studies have largely focused on symptoms. Notably, studies consistently demonstrate the divergent trajectories of improvement of depression symptoms and functional impairment. Furthermore, the most consistent findings point to MDD symptom severity, cognitive deficits, sleep, fatigue, low energy, and social isolation as key contributors to functional outcomes in MDD. There is currently a paucity of data regarding neurobiological mechanisms of functional impairment. The findings from published literature are organized into a proposed working biopsychosocial model of functional impairment in MDD that highlights the strengths and existing research gaps in the field. The implications of these findings on depression treatment strategies are also discussed.
Summary
Our proposed biopsychosocial model of functioning in depression may serve to define an individual’s “functional impairment profile,” which can be used to identify targeted and personalized treatments for depression, and lead to improved outcomes.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
With over 350 million individuals affected globally, major depressive disorder (MDD) is a leading cause of disability and a significant contributor to the burden of disease worldwide [1]. A great proportion of MDD-related economic burden is an indirect result of productivity losses often related to reduced functioning. Depression symptoms such as fatigue and concentration difficulties, cut across multiple areas of functioning, including work, social relationships, physical ability, and other daily activities. As a result, the majority of patients experience functional impairments in at least one domain [2]. Yet functioning is not typically explored as a primary outcome or rigorously measured in MDD treatment studies. However, as our understanding of functioning improves, there has been a shift towards focusing on its direct assessment in recent years. This narrative review aims to summarize current findings on functional impairment in MDD and identify the potential contributors within the framework of a biopsychosocial model to inform treatment and research. The biopsychosocial model of functioning presented here may serve as a clinically relevant tool to guide personalized assessment of depression features that may be important to prioritize in order to more effectively treat functional impairment and improve MDD patient outcomes.
Importance of Studying Functioning in Depression
Estimates of moderate and severe impairments in functioning range between 41.9 and 60% of MDD patients [3•, 4]. Importantly, while MDD symptoms contribute to impaired functioning, they do not account for most of the variance; thus, functioning has been proposed as a distinct construct [5•, 6]. Furthermore, several treatment studies reported that improvements in functioning lag behind symptom improvement [7•, 8, 9]. For example, Lam et al. [10•] reported improvements in functioning after 4 weeks of antidepressant treatment, while improvement in depressive symptoms was observed at 2 weeks. Functional remission may also occur less frequently than depressive symptom remission [10•, 11•, 12•, 13]. Notably, while patients who achieve symptomatic remission may have better functioning compared to responders, their functioning continues to be worse than the general population [14]. Indeed, the presence of residual impairments in functioning may be associated with greater relapse risk [8]. The severity of functional impairment may also be a useful predictor of treatment outcomes. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, remission rates were significantly lower in patients with moderate-to-severe impairment than those with no to minimal impairment after treatment (15.5% vs. 66.7%, respectively) [3•]. These findings suggest that improvement in functioning has a different, and likely delayed, trajectory to symptom improvement.
MDD remission is defined based on resolution of depressive symptoms, which tends to be the chief priority for clinicians; however, patients commonly rank functional restoration higher [15•]. Zimmerman and colleagues redefined MDD remission from the patient perspective by having patients rank outcomes that they identified with remission [6]. Out of the 16 outcomes, the ability to “Return to usual level of functioning at work, home, or school” was rated as “very important” by 70.3% of patients [6]. McKnight and Kashdan [8] suggest that while symptoms may be an early indicator of treatment response, improvements in functioning represent meaningful change.
Conceptualization of Functioning
Functional impairment can span several domains that may include, but are not limited to, occupation, interpersonal relationships, physical activity, planning, finances, and daily chores. Certain domains may be more impaired than others. For example, approximately 50% of the MDD-related financial burden is due to presenteeism and absenteeism in the workplace [16]. Presenteeism refers to being present at work but not functioning to one’s full capacity. Absenteeism refers to the habitual, and often unscheduled, absence from work [16]. In one study, 8% of hours were missed and 35.2% of hours had reduced productivity as a result of depression [17]. Due to the arguably more tangible effects of occupational and social impairments on global burden, these domains are the most commonly studied in MDD. Importantly, domains of functioning can be impacted by a variety of factors and the manifestation of functional impairment can vary significantly across patients. Thus, it is imperative that functional impairment be conceptualized as a multidimensional construct to better understand and treat depression.
Functional Competence vs Functional Performance
Even in cases where functional impairment manifests similarly across MDD patients, the underlying mechanisms may be multifaceted [11•, 18•]. Functional competence (or functional capacity) describes the objective capability of an individual to perform behaviors critical for daily functioning (i.e., what one can do), whereas functional performance describes the individual’s actual real-world functioning within the constraints of daily life (i.e., what one actually does) [18•]. While an individual may possess the competence to complete certain activities, these skills may not translate to real-world performance if they have perceived incapability. In this way, we can also distinguish an individual’s subjective belief about their competence and/or performance.
The distinction between functional competence and real-world performance in MDD requires significantly more research. However, there is early evidence that both competence and performance are impaired in MDD patients relative to healthy individuals. In a study by Milanovic et al. [11•], MDD patients had significantly worse functional competence than controls, specifically in the finances and communication subdomains of the UCSD Performance-based Skills Assessment (UPSA). Patients also underestimated their functional abilities, believing that they had performed significantly worse than they did. Furthermore, there was a significant correlation between low self-perception and actual task performance in MDD patients. In contrast, controls were able to accurately gauge their actual task performance and how they function in the real-world.
Certain depressive symptoms may be more closely related to functional competence than performance. The most prominent appear to be related to impaired cognition, self-efficacy, and maladaptive social behaviors [19,20,21,22,23]. However, the relationships among objectively measured functional competence, actual real-world functional performance, and one’s self-perception of these constructs are unclear and more studies are needed to understand how these influence functional impairment in MDD.
Contributors to Impaired Functioning
Following a broad literature search of functioning in MDD, several areas stood out as key contributors including symptom severity, residual symptoms, comorbidities, neurocognition, reward processing, socioeconomic status (SES), sociodemographic variables, and stigma. The factors identified in this narrative review as potential contributors to functional impairment in MDD are organized across three categories: biological, psychological, and social. While there are several ways to categorize these factors, we believe a biopsychosocial approach captures the multidimensionality of functional impairment and provides insight on potential interactions across factors.
Biological Factors
Brain Structure, Activity, and Neurotransmitters
Studies exploring the associations between functioning and brain structure, activity, and neurotransmitters are in their infancy. Structural brain imaging data suggest increased white matter hyperintensities (WMH) are associated with accelerated functional decline in elderly MDD populations [24]. Functional brain imaging data reveal that networks involved in motivation, interest, and emotional regulation may have importance in functioning [25, 26]. Studies found impaired putamen and medial orbitofrontal-striatal connectivity related to effort and work-related activities in MDD [27, 28]. In addition, associations between social functioning impairment and activity in the prefrontal cortex during a verbal fluency task have been reported in bipolar depressed patients [25]. Indirect evidence supports the role of activity in the amygdala, insula, and ventrolateral prefrontal cortex in response to social exclusion and association with anhedonia and self-esteem, which the authors proposed are risk factors for impaired social functioning [29].
There is only one study to our knowledge that directly assesses neurotransmitters and functioning. Among treatment-resistant depression patients who received deep brain stimulation (DBS), higher dopamine D2/D3 receptor binding (reflective of less dopaminergic tone in the brain) in the areas of the prefrontal cortex, thalamus, insula, and hippocampus correlated with poorer life functioning, driven by changes in work and social functioning [30]. Notably, reduced levels of dopamine commonly found in MDD affect pleasure and goal-driven behavior, which may negatively impact functioning [31]. Other neurotransmitters, while not directly studied, likely have an impact on functioning based on their role in depressive symptoms (e.g., energy, motivation, anxiety) [32] and indirect inference from treatment studies (see “Effects of Treatment on Functioning” below).
Fatigue and Low Energy
Fatigue is one of the most common symptoms of MDD, occurring in more than 90% of MDD patients [33]. Fatigue has been associated with impairment in specific functional domains as well as in overall functioning [12•, 34]. Low energy and feeling physically slowed down were the most common symptoms reported by MDD patients that were also associated with workplace functioning [35•].
Data from several studies suggest that high baseline and residual levels of fatigue may predict whether a patient will experience persistent functional impairment [13, 36, 37]. Thase et al. [36] reported that patients with lower baseline energy and motivation were more likely to improve following treatment with levomilnacipran extended-release (ER). However, higher baseline fatigue was associated with decreased mental and physical functioning, as well as more overall severe functional impairment in MDD patients receiving citalopram [37]. Similarly, Lam et al. [13] found that patients with high fatigue were more likely to experience functional impairment after treatment and early improvements in energy were associated with functional remission at study endpoint. These findings suggest that fatigue may be an important target when treating functional impairment.
Sleep
While sleep disturbances may contribute to fatigue in MDD, it is a separate symptom which may impact functioning via unique mechanisms. Sleep disturbances may include insomnia, subjective sleep quality, and sleep latency, which may be affected by factors such as anxiety, pain, substance abuse, and family history [12•, 38]. Like fatigue, sleep disturbance is highly prevalent in MDD irrespective of severity [38]. Insomnia often persists even after symptomatic remission, with one study reporting that 66.6% of remitters experienced sleep disturbances [12•].
It is well established that individuals with sleep disturbances are more likely to experience poor quality of life and functioning [35•, 39, 40]. The mechanism by which sleep impacts functioning is not entirely clear, but may be related to the role of sleep in brain development, cognitive performance, and protection against somatic and psychiatric comorbidities [40]. In MDD, the impact of sleep on cognition, such as memory consolidation, and emotion regulation may be of particular importance.
The phase of insomnia may also differentially impact functioning. Buckner et al. [41] observed that social anxiety was correlated with late insomnia rather than early or middle insomnia, and this was significantly related to functional impairment [41]. However, the directionality of this relationship is unclear. Some studies reported a higher prevalence of middle insomnia in remitted depression compared to early and late insomnia, which may have some implications in function due to its impact on subjective sleep quality [38].
Sleep disturbances during adolescence can also have a significant impact on current and future functional impairment due to the importance of sleep on brain development [40]. Adolescents with sleep disturbances often demonstrate early signs of functional impairment, such as reduced cognitive and academic ability and poor ability to interact with their peers due to emotional dysregulation [40]. With the high prevalence of insomnia among MDD patients, identifying and targeting sleep disturbances should be a priority to alleviate functional impairment.
Psychological Factors
MDD Symptoms and Illness Severity
There is substantial evidence that functioning deteriorates with MDD severity; however, the literature is unclear on the nature of this relationship. For example, as severity of depression increases, productivity may decrease linearly [17]. However, other studies report depression and functional impairment do not improve at the same rate [3•, 35•], and moreover, that functional improvement itself does not improve in a linear fashion [8]. Notably, while symptom severity accounts for a low to moderate portion of the variance contributing to impaired functioning, the substantial unexplained variance suggests other factors are involved [42]. This inconsistency may be explained by differential effects of MDD severity across domains of functioning and overall functioning. One study demonstrated that while both work and social functioning improved simultaneously with mood, social functioning may have a stronger relationship with mood symptoms [43, 44].
Furthermore, McIntyre et al. [45] reported that while MDD symptom severity accounted for greater variability in global functioning over cognitive impairment, the opposite was true for occupational functioning. Another explanation may be due to the heterogeneity of depressive symptoms, and therefore, individual symptoms may have a disparate impact on functioning. For example, low mood, anhedonia, and impaired cognition have the most robust effects on impaired functioning and its persistence during remission [44]. It is also important to note that early changes in functioning may predict symptomatic remission months later [46, 47], even when functioning improves independently of depression severity [47].
MDD Residual Symptoms
Despite the efforts to treat MDD, several studies report that approximately half of patients experience residual symptoms after remission [12•, 48]. While it is well-known that residual symptoms are associated with relapse, they may also continue to impact functioning [49]. For example, the prevalence of general functional impairment and impairment in occupation, family, and social domains was reported to be higher in MDD patients with residual symptoms [12•]. Nil et al. [48] determined that after 1 year of escitalopram treatment, 41% of MDD patients experienced residual symptoms and 50% still had some level of functional impairment. Furthermore, while patients in remission may demonstrate significant improvements in their work functioning, they often continue to function worse than the general population [14, 50]. Thus, despite being in remission symptomatically, residual symptoms may still negatively impact functioning [34].
Reward Processing
Reward processing includes facets such as lack of interest, motivation, effort, and pleasure. MDD patients commonly rate low energy, interest, motivation, and pleasure as symptoms which interfere with their work and have been shown to be significant predictors of presenteeism [35•]. Notably, motivation and effort are among the “energy-consuming” facets, which may be linked to their impact on functioning. For example, 70% of MDD patients in the STAR*D treatment study continued to experience motivational deficits which accounted for 53% of the variance in functional impairment, independent of MDD severity and duration [44]. Similarly, other studies have noted that improvements in motivation and interest had more robust impacts on improvements in functioning after treatment over other symptoms [47].
Effort is often deficient in MDD due to altered cost–benefit analyses which impacts goal-driven behaviors, subsequently impairing functioning [28]. MDD patients show a tendency to overestimate the effort required to obtain rewards, have altered reward valuation, and have disproportionate responses to positive and negative feedback. In one study, MDD patients were more likely to anticipate and respond to negative reinforcement with high-effort and were unmotivated by low-effort positive reinforcement, whereas the opposite trend was found in patients with schizophrenia [28]. This suggests the reward processing deficits that impact functioning may be disorder specific, warranting additional studies.
Cognitive Ability
Cognitive impairment is a prevalent in MDD, with up to 90% of patients reporting difficulties in concentration, memory, and/or decision making [51, 52]. An individual’s cognitive status is an important predictor of their functional capabilities, even after controlling for other depressive symptoms [53, 54•, 55]. Certain cognitive deficits in attention, executive function, and verbal memory are consistently associated with functional impairment, even after remission [56, 57]. In one MDD study, reduced concentration was a significant predictor of occupational, social, and overall functioning, but not family functioning [58]. Work functioning was the only domain also associated with delayed recognition, working memory, and attention. These findings suggest that occupational functioning may be sensitive to changes in objective cognition.
Cognitive deficits may also impact functioning via objective or perceived impairments. Among patients with treatment-resistant depression, neurocognition was associated with functional competence, whereas depressive symptoms were associated with functional performance [59]. Perceived cognitive impairments may also have an independent effect on functioning, demonstrated by findings that perceived inattention had a greater impact on occupational functioning than depression severity [45]. Interestingly, some studies have demonstrated that while subjective cognitive ability had a strong impact on overall functioning across multiple domains, objective cognitive ability was not a significant predictor [60,61,62]. Nevertheless, evidence consistently demonstrates a strong relationship between functional impairment in MDD and cognitive impairment, whether perceived or objective.
Psychiatric Comorbidities
MDD is often accompanied by psychiatric comorbidity, which predicts more severe impairment. Since the most predominant comorbidities with MDD are anxiety disorders, they are the most studied in the context of functioning [20, 34]. The presence of at least one anxiety disorder and more severe anxiety predicted poor remission and functioning, independent of MDD severity [63]. Studies including patients with various psychiatric diagnoses (e.g., post-traumatic stress disorder, phobias, generalized anxiety disorder, and substance-use disorder) suggest functional impairment may be more associated with the number of comorbid anxiety diagnoses and severity [26, 64, 65]. Importantly, comorbidities may worsen functioning by exacerbating symptoms. For example, patients with anxious depression often experience greater amotivation, threat, worrying, and rumination [31]. Furthermore, some studies have indicated that treatment of these symptoms may have a greater impact on functioning [47]. Further research on comorbidities and functioning in MDD is needed.
Self-efficacy/Self-esteem
Low self-esteem and low self-efficacy are common among individuals with MDD. Low self-esteem or lack of self-efficacy may influence a patient’s ability to function adequately or impair their drive to do so. A study by Cardenas et al. [66•] suggests that self-efficacy may act as the link between an individual’s functional competence and functional performance. They reported that only when self-efficacy was low was the correlation between functional competence and performance low. Although this study was not conducted in MDD, these results may explain the discrepancy between functional competence and real-life functioning [66•]. Yeh et al. [67] reported significant differences in the level of self-efficacy between patients in remission and those with recurrent episodes, with the latter having lower self-efficacy. They suggest that patients with higher self-efficacy may have more positive beliefs in their ability to manage their depression and associated functional impairment.
Childhood Trauma
Trauma has a significant association with MDD and elevated functional impairment [68,69,70]. Several studies propose that insecure attachment may influence this association [42, 71, 72] due to the development of anxiety which often precedes depression onset and impaired functioning [70, 73]. Studies have primarily focused on trauma induced by and in mothers [71, 74, 75]. Ruiz et al. [76•] reported that functional impairment in mothers may perpetuate functional impairment in their children. However, this relationship with functioning was only present in children with anxious attachment. Mothers experiencing ongoing effects from childhood trauma are more likely to perpetuate insecure attachment styles and functional impairment in their children [77, 78]. Dennis and colleagues found that mothers who experienced greater amounts of adverse childhood experiences were more likely to have physical and social functioning impairment, which perpetuated intergenerational dysfunction [75]. There is some indication that impersonal trauma (e.g., serious injury, natural disaster, war) may also increase functional impairment [65, 74, 78, 79]. Further research is required to disentangle the specific effects of trauma on functioning.
Social Factors
Social Isolation and Loneliness
Individuals with MDD who experience social isolation, loneliness, and poor social support often show functional impairment at higher rates and severity. Substantial evidence suggests that poor support networks, exclusion at work, divorce, and perceived lack of support are associated with greater overall impairment in the occupational and social domains [80,81,82,83]. Indeed, several treatment strategies are centered on strengthening support networks, especially in older demographics [81, 83, 84]. Ciechanowski et al. [85] found that elderly MDD patients undergoing 12 months of community-based treatments experienced greater improvements in functioning relative to antidepressant only groups. Several studies have also demonstrated the effectiveness of providing greater social support in children to reduce early-onset depression and functional impairment [80, 86]. In a systematic review assessing the effects of psychosocial support interventions on the mental health and function of children, the authors concluded that interventions resulted in improved functional impairment through increased hope, coping abilities, and social support [87].
Socioeconomic Status
Individuals with low SES face limitations such as reduced access to healthcare, reduced time with family, increased stress, and poor work conditions. Low SES often perpetuates intergenerationally, resulting in the persistence of impaired function [88]. It is important to note that SES and an individual’s impairments have a bidirectional relationship [89•]. Education is often used as a proxy of SES due to its association with prestigious occupations and higher income [57, 90, 91]. In a longitudinal study, education, employment status, age of onset, and previous hospitalizations predicted changes in occupational and social functioning in MDD patients after treatment [4]. Furthermore, other studies suggest that higher education is related to reduced work or social functioning [12•, 42].
Substantial evidence has linked work difficulties, unemployment, and low income with MDD severity and impaired function [88, 92, 93]. The WHO also determined that high work stress and low household income were strong predictors of MDD-related disability and impairment, independent of illness characteristics [42]. Furthermore, Domènech-Abella et al. [91] found that several SES indicators may influence depression either directly or indirectly. These indicators included education, occupation, income, marital status, illness status, substance abuse, financial strains, and social isolation. This highlights the complexity of SES and the need to explore other variables that may impact functioning.
Stigma
Mental illness–related stigma, both public and internalized, can have an important impact on functioning. One study estimated that 43.6% of MDD patients experienced moderate to high stigma, independent of sociodemographic and other clinical variables [94]. Patients with higher internalized stigma are also more likely to have poorer functioning globally and within social, occupational, physical, and school domains [95, 96]. Other studies have noted that stigma was negatively correlated with age, while being positively correlated with employment status and interpersonal sensitivity, which may have a role in functioning [92]. Stigma may also impact functioning via reduced self-efficacy. By employing several cognitive schemas and models, Shimotsu and Horikawa [97] concluded that self-stigma may mediate the relationship between perceived cognitive deficits and dysfunction in MDD through reduced self-efficacy.
Effects of Treatment on Functioning
Pharmacotherapy
Current evidence strongly suggests that many patients considered to be in symptomatic remission from commonly used antidepressants continue to experience suboptimal outcomes in functioning across a range of domains [6, 45, 98•]. While selective serotonin reuptake inhibitors (SSRIs) may improve functional outcomes [99, 100], they often do not alleviate symptoms such as fatigue, reduced interest, and decreased pleasure, which are each associated with functional impairment [31]. It is possible that other antidepressant classes like serotonin-norepinephrine reuptake inhibitors (SNRIs) may be better in targeting these and other residual symptoms due to their additional action on norepinephrine. The SNRI levomilnacipran ER had a significantly greater effect on global functioning than placebo [47]. However, escitalopram monotherapy, escitalopram plus bupropion, and venlafaxine plus mirtazapine all showed similar results in improving functioning [101]. Additionally, treatment with agomelatine, melatonin agonist and serotonin 5HT2C antagonist, demonstrated positive impacts on functioning relative to placebo; however, it may be less effective relative to SNRIs or bupropion [74, 102, 103]. Importantly, antidepressants may impact functioning via alleviation of symptoms associated with it. For example, improvements in cognition observed with vortioxetine, a serotonin modulator, have been shown to translate into improvements in functional outcomes in MDD [55, 58, 104]. While further study is needed across and between antidepressants, the present literature suggests that current pharmacotherapies have beneficial effects on functioning [103].
Psychotherapy
Psychotherapies that target cognitive symptoms may offer benefits in treating functional impairment [103, 105]. Cognitive behavioral therapy (CBT), which focuses on distorted thinking and behavioral patterns, may improve psychosocial and work functioning [106,107,108,109]. Cognitive remediation, which directly targets neurocognitive symptoms like memory, attention, and executive function, has demonstrated some success improving functioning relative to relaxation training [110]. Other psychotherapies including memory support, especially in elderly populations, have also resulted in higher success in functional improvement [111,112,113]. Attention-based therapies, such as mindfulness, have shown benefits in daily functioning through early improvements in executive function and selective attention [114]. A recent meta-analysis examining the efficacy of psychotherapy and pharmacotherapy on functioning found that each intervention yielded independent small to moderate effect sizes for improved functioning and quality of life, with no significant differences between interventions [115•]. Furthermore, medication and psychotherapy combined resulted in significantly better functional outcomes. While psychotherapy has some positive impact on functioning, further studies are required to understand its effects more thoroughly and identify which modalities may be most beneficial.
Neurostimulation
There are limited published data regarding the benefits of neurostimulation therapies such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), repetitive transcranial direction current stimulation (rTDCS), and deep brain stimulation (DBS) on functional impairment. Several studies reported improvements in functioning after completion of ECT [116,117,118,119]. McCall et al. [9] found that 87% of MDD patients had improvements in health-related quality of life immediately after ECT, and 78% of patients maintained these improvements after 6 months. Patients undergoing ECT may also experience greater improvements in functioning and relapse protection compared to patients treated with pharmacotherapy after 12 months [118]. Available evidence also suggests that rTMS is effective at improving global functional impairment in MDD [120,121,122,123,124]. In their study on mothers facing postpartum depression, Myczkowski et al. [122] found that rTMS treatment produced small gains in social functioning. Increased social functioning was also found by Pirmoradi et al. [123] in recurrent MDD patients after 20 sessions of rTMS. DBS has also shown efficacy in improving quality of life and functioning in MDD [125,126,127,128,129,130]. These improvements are reported to persist 4 years [125] and 8 years [130] post-surgery. Kennedy et al. [126] found improvements in social functioning post-surgery, persisting for 3 to 6 years.
Model of Functional Impairment in MDD
In this narrative review, the heterogeneous and multidimensional nature of functional impairment in MDD was explored and the current literature on potential contributors was summarized in the context of a biopsychosocial model (Fig. 1). Overall, taking a biopsychosocial approach provides insight on the relative impact of each factor on functioning, how they may interact, and identifies relationships and gaps in the literature. According to this model, there is evidence to support direct impacts of biological, psychological, and social factors on functioning in MDD. Importantly, mediation effects across the categories were not typically explored and so how, for example, social factors impact functioning through interactions with cognitive or biological factors remains a significant research gap.
Biopsychosocial model of contributors of functional impairment in MDD. Solid arrows represent evidence supporting direct impacts of biological, psychological, and social factors on functioning. Dashed arrows reflect a lack of evidence to determine the interaction of the categories in causing functional impairment. * indicates consistent findings across studies, ◊ indicates inconsistent findings across studies, and ∆ indicates a lack of sufficient evidence or too few studies conducted
The direct impact of psychological factors on functioning was the most extensively studied, with most studies focusing on the relationship of depression symptoms to functioning. Some symptoms of depression, such as amotivation, cognitive impairments, and poor self-esteem, may have more significant impacts on functioning than others. Notably, the literature on the direct neurobiological contributors to impaired functioning in MDD is limited. Other biological factors, however, such as sleep, low energy, and fatigue, have been more widely studied and are consistently associated with poor functional outcomes. Furthermore, brain activity related to depressive symptoms that have a strong relationship with functional impairment, like cognitive impairment, may mediate the effect of brain impairments on functioning, and these potential interactions should be further explored. With respect to social factors, social isolation and loneliness have consistently been associated with worse functional outcomes, while more research is needed to better understand the important role of stigma and SES variables in this context. While we may be able to identify social risk factors for functional impairment, solutions to these issues are not straightforward and require changes on larger scales. To this point, approaches that increase accessibility of mental health resources, stigma reduction in adolescents, and increased community-based activity within elderly populations may be effective starting points towards change.
The model highlights key contributors to functional impairment that could be utilized as a tool to optimize treatment strategies or as a basis to explore novel treatment development. Specifically, this model could be used to ascertain a particular patient’s “profile” of functional impairment, which would bring clarity to the treatment strategies that could be used. For example, one patient may need to optimize psychological factors, while another may need to optimize social factors. Assessment of a patient according to the biopsychosocial model would allow for a more comprehensive conceptualization that takes into account the various factors that may be contributing to their functioning and can then be used to determine which factors to target using more tailored treatment approaches. Current treatment methods primarily focus on alleviating depressive symptoms with function as a secondary outcome. Given the range of factors associated with functional impairment identified in Fig. 1, it is not surprising that current treatments are not able to target all of them. For treatment development, the model suggests that therapies that optimize sleep as well as reward processing and cognitive function could have a very strong impact on functioning and should be further explored. Importantly, this model provides a foundation to expand on and modify as new findings are discovered.
There are certain limitations to the data presented in this review. Due to the complexity of MDD symptoms, contributors, and treatment responses, it is difficult to disentangle the independent effects of these factors. Despite the numerous variables that may impact functioning, we only included factors with data directly linked to functioning. However, this does not mean other factors are not significant. A key limitation is the dearth of MDD studies investigating functioning as a primary outcome, though a recent trend in the literature suggests a shift in the direction of prioritizing functional outcomes. Another important limitation is the relatively small number of studies examining the longer-term impacts on functioning past the duration of treatment, which is typically 6–12 weeks in the most studies. This is of particular importance when studying functioning as improvements may not be realized until months following treatment [46, 47]. There may also be other ways to structure a model of functional impairment in MDD, however, the comprehensive summary of factors presented from the perspective of a biopsychosocial model provides insight into our current understanding of the internal (biological and psychological) and external (social, environmental) contributors and allows us to explore their direct and indirect impacts, as well as identify promising treatment avenues.
Conclusion
Functional impairment is one of the leading debilitating outcomes associated with MDD, cutting across domains of social, occupational, and general life functioning. This narrative review investigated the multidimensional nature of functional impairment in MDD, synthesizing the literature to propose a working biopsychosocial model. This model suggests that based on available evidence, biological factors (e.g., brain structure/function, sleep, fatigue), psychological factors (e.g., MDD symptoms, cognitive ability, reward processing), and social factors (e.g., social isolation, socioeconomic status, stigma) are direct contributors to overall functional impairment, though more research is needed to clarify how these factors may interact to mediate functional outcomes in MDD. In particular, our narrative review points to research gaps where neurobiological factors and certain social factors (e.g., stigma and SES) are concerned, as these may represent promising treatment targets, especially in the context of persistent functional impairment in symptomatic remission of MDD. The proposed biopsychosocial model can be a useful clinical tool in conceptualizing the factors contributing to an individual’s functioning, helping to define a personalized “functional impairment profile” that can then be used to tailor treatment and improve functional outcomes for patients with depression.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
World Health Organization. WHO | Depression. World Health Organization: WHO; 2017.
Kessler RC, Barber C, Beck A, Berglund P, Cleary PD, McKenas D, et al. The World Health Organization Health and Work Performance Questionnaire (HPQ). J Occup Env Med. 2003;45:156–74.
Jha MK, South C, Trivedi J, Minhajuddin A, Rush AJ, Trivedi MH. Prediction of acute-phase treatment outcomes by adding a single-item measure of activity impairment to symptom measurement: development and validation of an interactive calculator from the STAR*D and CO-MED trials. Int J Neuropsychopharmacol. 2019;22:339–48. Consistent with findings that functional impairment improves with antidepressant treatment independent of depression severity, and further finds that functional impairment (as assessed by a single-item self-report measure of activity impairment) can be a useful clinical predictor of treatment outcome.
Iorfino F, Hermens DF, Cross SP, Zmicerevska N, Nichles A, Badcock C-A, et al. Delineating the trajectories of social and occupational functioning of young people attending early intervention mental health services in Australia: a longitudinal study. BMJ Open. 2018;8: e020678.
Greer TL, Kurian B, Trivedi MH. Defining and measuring functional recovery from depression. CNS Drugs. 2010;24:267–84. Provides a review of different types of functional impairments in depression along with an overview of the key tools to evaluate, assess, and treat them.
Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boerescu D. How should remission from depression be defined? The depressed patient’s perspective. Am J Psychiatry. 2006;163:148–50.
Lin C, Chou L, Chen M, Chen C. The relationship between symptom relief and functional improvement during acute fluoxetine treatment for patients with major depressive disorder. J Affect Disord. Elsevier; 2015;182:115–20. Finds that depression symptom relief occurs earlier than improvement in functioning during treatment with fluoxetine, lending evidence that these may be distinct domains that would benefit from being addressed separately.
McKnight PE, Kashdan TB. The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research. Clin Psychol Rev Elsevier Ltd. 2009;29:243–59.
McCall WV, Reboussin BA, Cohen W, Lawton P. Electroconvulsive therapy is associated with superior symptomatic and functional change in depressed patients after psychiatric hospitalization. J Affect Disord. 2001;63:17–25.
Lam RW, Endicott J, Hsu M-A, Fayyad R, Guico-Pabia C, Boucher M. Predictors of functional improvement in employed adults with major depressive disorder treated with desvenlafaxine. Int Clin Psychopharmacol. 2014;29:239–51. Post hoc analysis of a randomized controlled trial of desvenlafaxine whose findings suggest that early improvement in depression symptoms may predict likelihood of improved workplace functioning later in the course of treatment.
Milanovic M, Holshausen K, Milev R, Bowie CR. Functional competence in major depressive disorder: objective performance and subjective perceptions. J Affect Disord. Elsevier B.V.; 2018;234:1–7. Evaluates and defines objective and subjective aspects of functioning in depression, and suggests objective performance-based measures are valuable indicators of real-world functional outcomes in depression.
Xiao L, Feng L, Zhu X quan, Feng Y, Wu W yuan, Ungvari GS, et al. Comparison of residual depressive symptoms and functional impairment between fully and partially remitted patients with major depressive disorder: a multicenter study. Psychiatry Res. Elsevier Ireland Ltd; 2018;261:547–53. Highlights the importance of treating residual symptoms of depression, as these persistent symptoms are associated with functional impairment.
Lam RW, Wajsbrot DB, Meier E, Pappadopulos E, MacKell JA, Boucher M. Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: a pooled analysis. J Psychopharmacol. 2017;31:1204–14.
Sacchetti E, Frank E, Siracusano A, Racagni G, Vita A, Turrina C. Functional impairment in patients with major depression in clinical remission. Int Clin Psychopharmacol. 2015;30:129–41.
Demyttenaere K, Donneau AF, Albert A, Ansseau M, Constant E, Van Heeringen K. What is important in being cured from depression? Discordance between physicians and patients (1). J Affect Disord. Elsevier; 2015;174:390–6. Study showing a difference between physicians and patients with respect to desired treatment outcomes, with physicians aiming for symptom reduction and patients desiring improved affect.
Greenberg T, Chase H, Almeida J, Stiffler R, Zevallos C, Aslam H, et al. Moderation of the relationship between reward expectancy and prediction error-related ventral striatal reactivity by anhedonia in unmedicated major depressive disorder: findings from the EMBARC study. Am J Psychiatry. 2015;172:881–91.
Beck A, Lauren Crain A, Solberg LI, Unutzer J, Glasgow RE, Maciosek MV, et al. Severity of depression and magnitude of productivity loss. Ann Fam Med. 2011;9:305–11.
Gupta M, Bassett E, Iftene F, Bowie CR. Functional outcomes in schizophrenia: understanding the competence-performance discrepancy. J Psychiatr Res. Elsevier Ltd; 2012;46:205–11. Describes functioning according to two key constructs (competence and performance) in the context of schizophrenia, and investigates the gap between the two. Illustrates the importance of considering these constructs separately in order to better identify factors that contribute to real-word functional outcomes.
Karpov B, Joffe G, Aaltonen K, Suvisaari J, Baryshnikov I, Näätänen P, et al. Level of functioning, perceived work ability, and work status among psychiatric patients with major mental disorders. Eur Psychiatry. 2017;44:83–9.
Adams GC, Balbuena L, Meng XF, Asmundson GJG. When social anxiety and depression go together: a population study of comorbidity and associated consequences. J Affect Disord Elsevier. 2016;206:48–54.
Jerez-Roig J, de Oliveira NPD, de Lima Filho BF, de Farias Bezerra MA, Matias MGL, Ferreira LM, et al. Depressive symptoms and associated factors in institutionalized elderly. Exp Aging Res. 2016;42:479–91.
Zajecka J, Kornstein SG, Blier P. Residual symptoms in major depressive disorder: prevalence, effects, and management. J Clin Psychiatry. 2013;74:407–14.
Cha DS, Carmona NE, Subramaniapillai M, Mansur RB, Lee Y, Hon Lee J, et al. Cognitive impairment as measured by the THINC-integrated tool (THINC-it): association with psychosocial function in major depressive disorder. J Affect Disord Elsevier BV. 2017;222:14–20.
Hybels CF, Pieper CF, Payne ME, Steffens DC. Late-life depression modifies the association between cerebral white matter hyperintensities and functional decline among older adults. Am J Geriatr Psychiatry. 2016;24:42–9.
Nishimura Y, Takahashi K, Ohtani T, Ikeda-Sugita R, Okada N, Kasai K, et al. Social function and frontopolar activation during a cognitive task in patients with bipolar disorder. Neuropsychobiology. 2015;72:81–90.
Fresco DM, Roy AK, Adelsberg S, Seeley S, García-Lesy E, Liston C, et al. Distinct functional connectivities predict clinical response with emotion regulation therapy. Front Hum Neurosci. 2017;11:86.
Rothkirch M, Tonn J, Köhler S, Sterzer P. Neural mechanisms of reinforcement learning in unmedicated patients with major depressive disorder. Brain. 2017;140:1147–57.
Park IH, Lee BC, Kim J-J, Kim JII, Koo M-S. Effort-based reinforcement processing and functional connectivity underlying amotivation in medicated patients with depression and schizophrenia. J Neurosci. 2017;37:4370–80.
Kumar P, Waiter GD, Dubois M, Milders M, Reid I, Steele J. Increased neural response to social rejection in major depression. Depress Anxiety. 2017;34:1049–56.
Rizvi SJ, Rusjan P, Strafella A, Giacobbe P, Lozano AM, Kennedy SH. Effect of baseline D2/D3 binding potential on functional outcomes with DBS. Neuropsychopharmacology. 2014;39:S565–6.
Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21:461–71.
Shelton RC, Tomarken AJ. Can recovery from depression be achieved? Psychiatr Serv. 2001;52:1469–78.
Ghanean H, Ceniti AK, Kennedy SH. Fatigue in patients with major depressive disorder: prevalence, burden and pharmacological approaches to management. CNS Drugs. 2018;32:65–74.
Kennedy N, Foy K, Sherazi R, McDonough M, McKeon P. Long-term social functioning after depression treated by psychiatrists: a review. Bipolar Disord. 2007;9:25–37.
Lam RW, Michalak EE, Bond DJ, Tam EM, Axler A, Yatham LN. Which depressive symptoms and medication side effects are perceived by patients as interfering most with occupational functioning ? 2012;2012. Identifies certain depression symptoms and medication side effects related to sleep, energy, cognition, and irritability that are perceived by patients as interfering most with their functioning. Suggests that it may be clinically useful to target these factors when selecting an antidepressant in order to improve functional outcomes.
Thase ME, Gommoll C, Chen C, Kramer K, Sambunaris A. Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder. Int Clin Psychopharmacol. 2016;31:332–40.
Ferguson M, Dennehy EB, Marangell LB, Martinez J, Wisniewski SR. Impact of fatigue on outcome of selective serotonin reuptake inhibitor treatment: secondary analysis of STAR*D. Curr Med Res Opin. 2014;30:2109–18.
Lai YC, Huang MC, Chen HC, Lu MK, Chiu YH, Shen WW, et al. Familiality and clinical outcomes of sleep disturbances in major depressive and bipolar disorders. J Psychosom Res Elsevier Inc. 2014;76:61–7.
O’Brien EM, Chelminski I, Young D, Dalrymple K, Hrabosky J, Zimmerman M. Severe insomnia is associated with more severe presentation and greater functional deficits in depression. J Psychiatr Res Elsevier Ltd. 2011;45:1101–5.
Brand S, Kirov R. Sleep and its importance in adolescence and in common adolescent somatic and psychiatric conditions. Int J Gen Med. 2011;4:425–42.
Buckner JD, Bernert RA, Cromer KR, Joiner TE, Schmidt NB. Social anxiety and insomnia: the mediating role of depressive symptoms. Depress Anxiety. 2008;25:124–30.
Verboom CE, Sentse M, Sijtsema JJ, Nolen WA, Ormel J, Penninx BWJH. Explaining heterogeneity in disability with major depressive disorder: effects of personal and environmental characteristics. J Affect Disord Elsevier BV. 2011;132:71–81.
Aikens JE, Kroenke K, Nease DE, Klinkman MS, Sen A. Trajectories of improvement for six depression-related outcomes. Gen Hosp Psychiatry. 2008;30:26–31.
Fervaha G, Foussias G, Takeuchi H, Agid O, Remington G. Motivational deficits in major depressive disorder: cross-sectional and longitudinal relationships with functional impairment and subjective well-being. Compr Psychiatry. 2016;66:31–8 (Elsevier Inc.).
McIntyre RS, Soczynska JZ, Woldeyohannes HO, Alsuwaidan MT, Cha DS, Carvalho AF, et al. The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. Compr Psychiatry. 2015;56:279–82. https://doi.org/10.1016/j.comppsych.2014.08.051 (Elsevier Inc.).
Andrea H, Bültmann U, Van Amelsvoort LGPM, Kant Y. The incidence of anxiety and depression among employees - the role of psychosocial work characteristics. Depress Anxiety. 2009;26:1040–8.
Blier P, Gommoll C, Chen C, Kramer K. Effects of levomilnacipran ER on noradrenergic symptoms, anxiety symptoms, and functional impairment in adults with major depressive disorder: post hoc analysis of 5 clinical trials. J Affect Disord Elsevier. 2017;210:273–9.
Nil R, Lütolf S, Seifritz E. Residual symptoms and functionality in depressed outpatients : a one-year observational study in Switzerland with escitalopram. J Affect Disord Elsevier. 2016;197:245–50.
Bortolato B, Miskowiak KW, Köhler CA, Maes M, Fernandes BS, Berk M, et al. Cognitive remission: a novel objective for the treatment of major depression? BMC Med. 2016;14:9.
Dennehy EB, Marangell LB, Martinez J, Balasubramani GK, Wisniewski SR. Clinical and functional outcomes of patients who experience partial response to citalopram. J Psychiatr Pract. 2014;20:178–87.
Wesnes KA, Gommoll C, Chen C, Sambunaris A, McIntyre RS, Harvey PD. Effects of levomilnacipran extended-release on major depressive disorder patients with cognitive impairments. Int Clin Psychopharmacol. 2017;32:72–9.
Hollon SD, Shelton RC, Wisniewski SR, Warden D. Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res. 2006;40:59–69.
Bowie CR, Gupta M, Holshausen K. Cognitive remediation therapy for mood disorders: rationale, early evidence, and future directions. Can J Psychiatry-Revue Can Psychiatr. 2013;58:319–25.
Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006;145:39–48. Provides data showing that deficits in neurocognition assessed at baseline were predictive of poor functioning at 6 months, independent of mood symptoms. This underscores the importance of assessing and treating neurocognitive deficits in depression.
McIntyre RS, Lee Y. Cognition in major depressive disorder: a ‘Systemically Important Functional Index’ (SIFI). Curr Opin Psychiatry. 2016;29:48–55.
Kim JM, Chalem Y, di Nicola S, Hong JP, Won SH, Milea D. A cross-sectional study of functional disabilities and perceived cognitive dysfunction in patients with major depressive disorder in South Korea: the PERFORM-K study. Psychiatry Res. 2016;239:353–61.
Woo YS, Rosenblat JD, Kakar R, Bahk W, Mcintyre RS. Cognitive deficits as a mediator of poor occupational function in remitted major depressive disorder patients. 2016;14:1–16.
Levada OA, Troyan AS. Cognitive-functional relationships in major depressive disorder: crucial data from a Ukrainian open-label study of vortioxetine versus escitalopram. J Affect Disord. 2019;250:114–22. https://doi.org/10.1016/j.jad.2019.03.040 (Elsevier B.V.).
Gupta M, Holshausen K, Best MW, Jokic R, Milev R, Bernard T, et al. Relationships among neurocognition, symptoms, and functioning in treatment-resistant depression. Arch Clin Neuropsychol. 2013;28:272–81.
Lam RW, Kennedy SH, McIntyre RS, Khullar A. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry. 2014;59:649–54.
Srisurapanont M, Suttajit S, Eurviriyanukul K, Varnado P. Discrepancy between objective and subjective cognition in adults with major depressive disorder. Sci Rep. Springer US; 2017;7:1–7.
Serra-Blasco M, Torres IJ, Vicent-Gil M, Goldberg X, Navarra-Ventura G, Aguilar E, et al. Discrepancy between objective and subjective cognition in major depressive disorder. Eur Neuropsychopharmacol. 2019;29:46–56. https://doi.org/10.1016/j.euroneuro.2018.11.1104 (Elsevier B.V.).
Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C, et al. The International Study to Predict Optimized Treatment in Depression (iSPOT-D): outcomes from the acute phase of antidepressant treatment. J Psychiatr Res. 2015;61:1–12. https://doi.org/10.1016/j.jpsychires.2014.12.018 (Elsevier Ltd).
Cavicchioli FL, Maes M, Roomruangwong C, Bonifacio KL, Barbosa DS, Anderson G, et al. Associations between severity of anxiety and clinical and biological features of major affective disorders. Psychiatry Res Elsevier Ireland Ltd. 2018;260:17–23.
Neria Y, Olfson M, Gameroff MJ, Wickramaratne P, Gross R, Pilowsky DJ, et al. The mental health consequences of disaster-related loss: findings from primary care one year after the 9/11 terrorist attacks. Psychiatry Interpers Biol Process. 2010;71:339–48.
Cardenas V, Abel S, Bowie CR, Tiznado D, Depp CA, Patterson TL, et al. When functional capacity and real-world functioning converge: the role of self-efficacy. Schizophr Bull. 2013;39:908–16. Tests the hypothesis that motivational factors (e.g., self-efficacy) play a key role in translating functional capacity to functional outcomes in patients with schizophrenia. The study findings support this hypothesis, suggesting that improvement in functional capacity may be necessary but insufficient to bring about real-world functional improvement, and that targeting motivation (self-efficacy) may be important in the treatment process.
Yeh MY, Lee Y, Sung SC, Tung TH. Clinical predictors associated with full remission versus episode of major depressive disorder outpatients: the experience at a teaching hospital in Taiwan. BMC Psychiatry. 2014;14:1–9.
Ohayon MM, Schatzberg AF. Social phobia and depression: prevalence and comorbidity. J Psychosom Res. 2010;68:235–43 (Elsevier Inc.).
Stein MB, Fuetsch M, Müller N, Höfler M, Lieb R, Wittchen H-U. Social anxiety disorder and the risk of depression. Arch Gen Psychiatry. 2003;58:251.
Conradi HJ, de Jonge P. Recurrent depression and the role of adult attachment: a prospective and a retrospective study. J Affect Disord. 2009;116:93–9 (Elsevier B.V.).
Cummings EM, Keller PS, Davies PT. Towards a family process model of maternal and paternal depressive symptoms: exploring multiple relations with child and family functioning. J Child Psychol Psychiatry Allied Discip. 2005;46:479–89.
Karsten J, Penninx BWJH, Verboom CE, Nolen WA, Hartman CA. Course and risk factors of functional impairment in subthreshold depression and anxiety. Depress Anxiety. 2013;30:386–94.
Bifulco A, Kwon J, Jacobs C, Moran PM, Bunn A, Beer N. Adult attachment style as mediator between childhood neglect/abuse and adult depression and anxiety. Soc Psychiatry Psychiatr Epidemiol. 2006;41:796–805.
Targum SD, Wedel PC, Fava M. Changes in cognitive symptoms after a buspirone e melatonin combination treatment for major depressive disorder. J Psychiatr Res Elsevier Ltd. 2015;68:392–6.
Dennis CH, Clohessy DS, Stone AL, Darnall BD, Wilson AC. Adverse childhood experiences in mothers with chronic pain and intergenerational impact on children. J Pain. 2019;20:1209–17.
Ruiz SK, Harris SJ, Martinez P, Gold PM, Klimes-Dougan B. Young adult’s attachment style as a partial mediator between maternal functioning and young adult offsprings’ functioning. J Affect Disord [Internet]. Elsevier B.V.; 2018;232:393–9. Available from: https://doi.org/10.1016/j.jad.2017.12.034Offers evidence that maternal depression may influence functional outcomes in offspring later in life via developmental attachment as a mediator. This study highlights the importance of considering multiple contributors to functioning in the context of depression, such as trauma and developmental factors.
Miller S, McTeague LM, Gyurak A, Patenaude B, Williams LM, Grieve SM, et al. Disorder patients : results from the iSPOT-D trial. Depress Anxiety. 2015;32:594–604.
Klein DN, Arnow BA, Barkin JL, Dowling F, Kocsis JH, Leon AC, et al. Early adversity in chronic depression: clinical correlates and response to pharmacotherapy. Depress Anxiety. 2009;26(8):701–10.
Mugisha J, Muyinda H, Malamba S, Kinyanda E. Major depressive disorder seven years after the conflict in northern Uganda: burden, risk factors and impact on outcomes (The Wayo-Nero Study). BMC Psychiatry. 2015;15:1–12.
Rice F, Sellers R, Hammerton G, Eyre O, Bevan-Jones R, Thapar AK, et al. Antecedents of new-onset major depressive disorder in children and adolescents at high familial risk. JAMA Psychiat. 2017;74:153–60.
Theeke LA, Goins RT, Moore J, Campbell H. Loneliness, depression, social support, and quality of life in older chronically ill Appalachians. J Psychol Interdiscip Appl. 2012;146:155–71.
Korczak DJ, Ofner M, LeBlanc J, Wong S, Feldman M, Parkin PC. Major depressive disorder among preadolescent Canadian children: rare disorder or rarely detected? Acad Pediatr. 2017;17:191–7 (Elsevier Inc).
Alpass FM, Neville S. Loneliness, health and depression in older males. Aging Ment Heal. 2003;7:212–6.
Kim BR, Park S, Bishop-Saucier J, Amorim C. Community-based services and depression from person-environment fit perspective: focusing on functional impairments and living alone. J Gerontol Soc Work Routledge. 2017;60:270–85.
Ciechanowski P, Wagner E, Schmaling K, Schwartz S, Williams B, Diehr P, et al. Community-integrated home-based depression treatment in older adults: a randomized controlled trial. J Am Med Assoc. 2004;291:1569–77.
Eisses AMH, Kluiter H, Jongenelis K, Pot AM, Beekman ATF, Ormel J. Risk indicators of depression in residential homes. Int J Geriatr Psychiatry. 2004;19:634–40.
Purgato M, Gross AL, Betancourt T, Bolton P, Bonetto C, Gastaldon C, et al. Focused psychosocial interventions for children in low-resource humanitarian settings: a systematic review and individual participant data meta-analysis. Lancet Glob Heal [Internet]. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license; 2018;6:e390–400. Available from: https://doi.org/10.1016/S2214-109X(18)30046-9
Topuzoʇlu A, Binbay T, Ulaş H, Elbi H, Aksu Tanik F, Zaʇli N, et al. The epidemiology of major depressive disorder and subthreshold depression in Izmir, Turkey: prevalence, socioeconomic differences, impairment and help-seeking. J Affect Disord. 2015;181:78–86.
Culpepper L, Lam RW, McIntyre RS. Cognitive impairment in patients with depression: awareness, assessment, and management. J Clin Psychiatry. 2017;78:1383–94. Clinically relevant review paper that describes the role of cognitive impairment in functional recovery from depression, reviews assessment tools, and presents treatment strategies.
Carmassi C, Dell’oste V, Ceresoli D, Moscardini S, Bianchi E, Landi R, et al. Frequent attenders in general medical practice in Italy: a preliminary report on clinical variables related to low functioning. Neuropsychiatr Dis Treat. 2019;15:115–25.
Domènech-Abella J, Mundó J, Leonardi M, Chatterji S, Tobiasz-Adamczyk B, Koskinen S, et al. The association between socioeconomic status and depression among older adults in Finland, Poland and Spain: a comparative cross-sectional study of distinct measures and pathways. J Affect Disord. 2018;241:311–8 (Elsevier B.V.).
Shi-Jie F, Hong-Mei G, Li W, Bin-Hong W, Yi-Ru F, Gang W, et al. Perceptions of stigma and its correlates among patients with major depressive disorder: a multicenter survey from China. Asia Pac Psychiatry. 2017;9:9–14.
Gade K, Malzahn D, Anderson-Schmidt H, Strohmaier J, Meier S, Frank J, et al. Functional outcome in major psychiatric disorders and associated clinical and psychosocial variables: a potential cross-diagnostic phenotype for further genetic investigations? World J Biol Psychiatry. 2015;16:237–48.
Picco L, Pang S, Lau YW, Jeyagurunathan A, Satghare P, Abdin E, et al. Internalized stigma among psychiatric outpatients: associations with quality of life, functioning, hope and self-esteem. Psychiatry Res. 2016;246:500–6. https://doi.org/10.1016/j.psychres.2016.10.041 (Elsevier).
Picco L, Lau YW, Pang S, Abdin E, Vaingankar JA, Chong SA, et al. Mediating effects of self-stigma on the relationship between perceived stigma and psychosocial outcomes among psychiatric outpatients: findings from a cross-sectional survey in Singapore. BMJ Open. 2017;7: e018228.
Yen CF, Chen GC, Lee Y, Tang TC, Ko CH, Yen JY. Association between quality of life and self-stigma, insight, and adverse effects of medication in patients with depressive disorders. Depress Anxiety. 2009;26:1033–9.
Shimotsu S, Horikawa N. Self-stigma in depressive patients: Association of cognitive schemata, depression, and self-esteem. Asian J Psychiatr. 2016;24:125–9 (Elsevier B.V.).
Conradi HJ, Ormel J, De Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74. Shows that residual symptoms (particularly problems with cognition, energy and sleep) persist and are highly prevalent during remission in patients with depression, occurring nearly half the time in remission. This suggests that remission may not be a sufficient target for improvement, and functional outcomes are relevant in this regard.
Sheehan DV, Mancini M, Wang J, Berggren L, Cao H, Dueñas HJ, et al. Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors. Hum Psychopharmacol. 2016;31:53–63.
Gyurak A, Patenaude B, Korgaonkar MS, Grieve SM, Williams LM, Etkin A. Archival report frontoparietal activation during response inhibition predicts remission to antidepressants in patients with major depression. Biol Psychiatry Elsevier. 2016;79:274–81.
Jha MK, Teer RB, Minhajuddin A, Greer TL, Rush AJ, Trivedi MH. Daily activity level improvement with antidepressant medications predicts long-term clinical outcomes in outpatients with major depressive disorder. Neuropsychiatr Dis Treat. 2017;13:803–13.
Kennedy SH, Avedisova A, Belaïdi C, Picarel-blanchot F. Debodinat C Sustained efficacy of agomelatine 10 mg, 25 mg, and 25–50 mg on depressive symptoms and functional outcomes in patients with major depressive disorder. a placebo-controlled study over 6 months. Eur Neuropsychopharmacol. 2016;26:378–89 (Elsevier).
Lee Y, Rosenblat JD, Lee JG, Carmona NE, Subramaniapillai M, Shekotikhina M, et al. Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: a systematic review. J Affect Disord. 2018;227:406–15.
Chokka P, Bougie J, Rampakakis E, Proulx J. Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC): primary analysis from a Canadian open-label study of vortioxetine in patients with major depressive disorder (MDD). CNS Spectr. 2019;24:338–47.
Knight MJ, Air T, Baune BT. The role of cognitive impairment in psychosocial functioning in remitted depression. J Affect Disord. 2018;235:129–34 (Elsevier B.V.).
Dunn TW, Vittengl JR, Clark LA, Carmody T, Thase ME, Jarret RB. Change in psychosocial functioning and depressive symptoms during acute-phase cognitive therapy for depression. Psychol Med. 2012;42:317–26.
Matsunaga M, Okamoto Y, Suzuki S, Kinoshita A, Yoshimura S, Yoshino A, et al. Psychosocial functioning in patients with Treatment-Resistant Depression after group cognitive behavioral therapy. BMC Psychiatry. 2010;10:22.
Lam RW, Parikh SV, Ramasubbu R, Michalak EE, Tam EM, Axler A, et al. Effects of combined pharmacotherapy and psychotherapy for improving work functioning in major depressive disorder. Br J Psychiatry J Ment Sci. 2013;203:358–65.
Ezawa ID, Bartels GC, Strunk DR. Getting down to business: an examination of occupational outcomes in cognitive behavioral therapy for depression. Cogn Behav Ther. 2021;50:479–91.
Norell-Clarke A, Jansson-Fröjmark M, Tillfors M, Holländare F, Engström I. Group cognitive behavioural therapy for insomnia: effects on sleep and depressive symptomatology in a sample with comorbidity. Behav Res Ther. 2015;74:80–93.
Huang AX, Delucchi K, Dunn LB, Nelson JC. A systematic review and meta-analysis of psychotherapy for late-life depression. Am J Geriatr Psychiatry. 2015;23:261–73. https://doi.org/10.1016/j.jagp.2014.04.003 (Elsevier Inc).
Renn BN, Areán PA. Psychosocial treatment options for major depressive disorder in older adults. Curr Treat Options Psychiatry. 2017;4:1–12.
Fiske A, Wetherell JL, Gatz M. Depression in older adults. Annu Rev Clin Psychol. 2009;5:363–89.
Listunova L, Roth C, Bartolovic M, Kienzle J, Bach C, Weisbrod M, et al. Cognitive impairment along the course of depression: Non-pharmacological treatment options. Psychopathology. 2018;51:295–305.
Kamenov K, Twomey C, Cabello M, Prina AM, Ayuso-Mateos JL. The efficacy of psychotherapy, pharmacotherapy and their combination on functioning and quality of life in depression: a meta-analysis. Psychol Med. 2017;47:414–25. Meta-analysis of 153 randomized controlled trials reports that both psychotherapy and pharmacotherapy are efficacious at improving functioning and quality of life, and that their combination is superior to either alone, with overall small to moderate effects. Also reports that both treatments are better at improving depression symptoms than functioning, suggesting treatment gaps exist.
Antunes PB, Fleck MP. Clinical outcomes and quality of life in patients submitted to electroconvulsive therapy. J ECT. 2009;25:182–5.
McCall WV, Dunn AG, Rosenquist P, Hughes D. Proxy validation of patient self-reports of ADL and IADL function before and after electroconvulsive therapy. J ECT. 2002;18:74–9.
McCall WV, Dunn A, Rosenquist PB. Quality of life and function after electroconvulsive therapy. Br J Psychiatry. 2004;185:405–9.
McCall WV, Lisanby SH, Rosenquist PB, Dooley M, Husain MM, Knapp RG, et al. Effects of a right unilateral ultrabrief pulse electroconvulsive therapy course on health related quality of life in elderly depressed patients. J Affect Disord Elsevier. 2017;209:39–45.
Dumas R, Richieri R, Guedj E, Auquier P, Lancon C, Boyer L. Improvement of health-related quality of life in depression after transcranial magnetic stimulation in a naturalistic trial is associated with decreased perfusion in precuneus. Health Qual Life Outcomes. 2012;10:1–7.
Giacobbe P, Mithani K, Meng Y, Vila-Rodriguez F, Daskalakis ZJ, Downar J, et al. Evaluation of the effects of rTMS on self-reported quality of life and disability in treatment-resistant depression: a THREE-D study. J Affect Disord. 2020;268:127–33. https://doi.org/10.1016/j.jad.2020.03.002 (Elsevier B.V.).
Myczkowski ML, Dias ÁM, Luvisotto T, Arnaut D, Bellini BB, Mansur CG, et al. Effects of repetitive transcranial magnetic stimulation on clinical, social, and cognitive performance in postpartum depression. Neuropsychiatr Dis Treat. 2012;8:491–500.
Pirmoradi M, Rostami R, Ghayyomi R, Khomami S. Social functioning increase after repetitive transcranial magnetic stimulation (rTMS) in patients with recurrent major depression. Int J Med Res Heal Sci. 2016;5:282–6.
Solvason HB, Husain M, Fitzgerald PB, Rosenquist P, McCall WV, Kimball J, et al. Improvement in quality of life with left prefrontal transcranial magnetic stimulation in patients with pharmacoresistant major depression: acute and six month outcomes. Brain Stimul. 2014;7:219–25. https://doi.org/10.1016/j.brs.2013.10.008 (Elsevier Ltd).
Bewernick BH, Kayser S, Sturm V, Schlaepfer TE. Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology Nature Publishing Group. 2012;37:1975–85.
Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Yasunori N, Mayberg HS, et al. Deep brain stimulation for treatment-resistant depression: Follow-up after 3 to 6 years. Am J Psychiatry. 2011;168:502–10.
Saleh C, Hasler G. Deep brain stimulation for psychiatric disorders: is there an impact on social functioning? Surg Neurol Int. 2017;8:134.
Schlaepfer TE, Bewernick BH, Kayser S, Mädler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73:1204–12.
Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461–7.
Crowell AL, Riva-Posse P, Holtzheimer PE, Garlow SJ, Kelley ME, Gross RE, et al. Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression. Am J Psychiatry. 2019;176:949–56.
Author information
Authors and Affiliations
Contributions
Troy K. Chow and Sakina J. Rizvi contributed to the conception and design of the review. Troy K. Chow completed the narrative review and model construction, and drafted the manuscript. All other authors provided critical review and contributed to revising the manuscript.
Corresponding author
Ethics declarations
Competing Interests
Sakina J. Rizvi has received research funding or consultancy fees from Pfizer Canada, Quintiles, Janssen, Allergan, and Takeda. Troy K. Chow, Christopher R. Bowie, Michael Morton, Aleksandra Lalovic, and Shane J. McInerney do not have anything to disclose.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Mood and Anxiety Disorders
Rights and permissions
About this article
Cite this article
Chow, T.K., Bowie, C.R., Morton, M. et al. Contributors of Functional Impairment in Major Depressive Disorder: a Biopsychosocial Approach. Curr Behav Neurosci Rep 9, 59–72 (2022). https://doi.org/10.1007/s40473-022-00247-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40473-022-00247-y