Metabolic Comorbidity and Physical Health Implications for Bipolar Disorder: An Update
This article has been corrected.
VIEW CORRECTIONAbstract
Medical comorbidities are overrepresented in individuals with bipolar disorder, including, but not limited to, cardiovascular conditions, autoimmune diseases, cancer, and metabolic disorders. Overweight/obesity, metabolic syndrome, and type 2 diabetes mellitus are highly prevalent in individuals with bipolar disorder. Evidence from epidemiological studies indicates that the aforementioned medical comorbidities are responsible for significant morbidity and early mortality. Results from disparate studies indicate that metabolic comorbidities modify and complicate the clinical presentation of bipolar disorder; metabolic comorbidities are associated with a more chronic and severe course of illness, as well as resistance to pharmacological treatment. Furthermore, co-occurrence of obesity or type 2 diabetes mellitus and bipolar disorder has been suggested to contribute to cognitive dysfunction, a core feature of bipolar disorder and a principal mediator of functional disability, highlighting the clinical relevance of this association. Multiple factors contribute to high frequency of metabolic comorbidities in individuals with bipolar disorder. An overlap of risk factors, including psychosocial stress, adverse socioeconomic conditions, and childhood trauma, between the two conditions has been documented. Inadequate diet and sedentary lifestyle, as well as treatment-emergent adverse effects have also been shown to play a role. Nonetheless, accumulating evidence indicates that the relationship between bipolar disorder and metabolic illnesses is bidirectional. Results from mechanistic studies indicate that interacting physiological systems that mediate metabolism are also involved in pathophysiological processes of bipolar disorder. The high prevalence and substantial impact of metabolic comorbidities on the clinical outcome in bipolar disorder underscore the need for prioritizing the management of metabolic health in this clinical population.
Introduction
Bipolar disorder (BD) is a highly prevalent syndrome, with an estimated global prevalence of approximately 1.5% when narrowly defined (1, 2). Bipolar disorder often pursues a chronic, unremitting course and is associated with substantial morbidity. Bipolar disorder is a leading cause of years lived with disability (YLDs) and disability-adjusted life years (DALY), highlighting BD as a public health priority (3–5). Moreover, it has been amply documented that the mortality rate of individuals with BD is greater than that of the general population. Mortality studies indicate that the excess and premature deaths in BD are largely a consequence of natural causes (e.g., cardiovascular disease, diabetes mellitus) rather than unnatural causes (e.g., suicide) (6–9). For example, a cohort study estimated that individuals with BD lost approximately 9 years of potential year of life compared with the general population (8).
The alarming rate of medical comorbidity in BD has provided the impetus to prioritize research in psychiatry toward the investigation of traditional and emerging risk factors that predispose and portend medical comorbidity. Individuals with BD are differentially affected by a wide range of communicable and noncommunicable medical illnesses (10), which are characterized by higher prevalence and earlier age of onset of medical conditions, including, but not limited to, cardiovascular conditions, hypertension, metabolic imbalances, autoimmunity, and cancer (8, 11–17). Conversely, overweight/obesity has been reported to increase the risk of onset of significant depressive symptoms and manic episodes (18–21). Considering the high impact of obesity and BD on disability and morbidity, the co-occurrence of these conditions is pertinent not only in the clinical ecosystem but also from a public health perspective, given the additive illness-associated burden imparted by concurrent medical disorders (22–24).
Epidemiology and Clinical Impact
Epidemiological studies have reported that the prevalence of obesity and metabolic syndrome is substantially increased in individuals with BD when compared with the general population, by a factor of twofold (24–26). The occurrence of comorbid obesity is increased in later stages of the illness (26–28); nonetheless, individuals in early stages are also significantly affected (29–31). Evidence indicates that one-third of youth (age 6–18) with BD exhibited 2 or more chronic health conditions (29). Women with BD, when compared with men with BD, have higher rates of abdominal obesity; however, overall obesity is more frequent in both sexes when compared with the general population (32).
The presence of comorbid obesity has been linked to a distinct and more complicated clinical presentation of BD. Evidence from clinical studies indicates that obesity predisposes BD patients to a predominantly depressive illness, insofar as the duration of depressive episodes tends to be longer and hospitalizations for depression are more frequent (33). Furthermore, a more severe and chronic course of illness, with higher functional disability, as well as an increased risk of suicide, were reported in adults with BD with comorbid obesity (34, 35). Comorbid anxiety disorders are also reported to be more common in overweight/obese individuals with BD (35). Moreover, obesity has been suggested to negatively impact treatment outcomes in BD. For example, results from a clinical trial indicated that higher BMI is associated with poor response to pharmacological treatment, including lithium and valproate (36).
More recently, the role of metabolic comorbidities as moderators of cognitive function has been increasingly recognized (37–45). Cognition has been considered a core dimension of psychopathology in BD (46–50). Cognitive dysfunction has been consistently demonstrated as a core dimension of psychopathology in BD across a number of studies that reported small to moderate overall effect sizes; nonetheless, approximately 25%–50% of the patients exhibited pronounced deficits (48–50). Cognitive deficit in mood disorders is noted to be a principal mediator of psychosocial impairment and disability, independent of concurrent mood symptoms (51–53), and disproportionately accounts for the overall illness-associated costs (54).
Multiple metabolic abnormalities are independently associated with poor cognitive function. Studies in both nonclinical and clinical populations have shown that impaired glucose metabolism and insulin resistance (38, 39, 41–43, 45), visceral adiposity (37, 43), dyslipidemia (40, 45), and high blood pressure (40, 44) are related to impaired executive function. Overweight/obesity, metabolic syndrome, and type 2 diabetes mellitus have all been consistently shown to negatively impact several cognitive domains (55–58). The relevance of the effects of metabolic diseases in neurocognitive function is further underscored by evidence indicating that weight loss in overweight/obese individuals significantly improves cognitive performance (59, 60).
Neurocognitive dysfunction is more severe in overweight/obese individuals when compared with normal weight patients with a mood disorder as evidenced by poor performance in tests measuring attention and psychomotor processing speed, independent of mood symptom severity (61, 62). The role of cognition as moderator of mood disorders can be conceptualized in two nonmutually exclusive ways. Metabolic and mood disorders are independently associated with poor cognitive performance; therefore, the co-occurrence of these conditions may have a synergistic detrimental effect (61–63), consequently leading to greater cognitive impairment. Cognitive dysfunction has been contemplated as a vulnerability factor for mood disorders (64, 65). Cognitive factors, particularly those related to cognitive control, regulation of motivation and reward, as well as the cognitive response to stress, have also been reported to be prominently involved in the development of obesity (66–68). Taken together, neurocognition could be conceptualized as a factor with broader modulatory effect, concurrently regulating the risk for both conditions and moderating the relationship between the conditions.
A meta-analysis of cross-sectional and cohort studies documented a bidirectional association between mood disorders and metabolic syndrome (69). Individuals with BD have been shown to have increased waist circumference, higher proportion of visceral adiposity, raised levels of serum lipids, and higher incidence of hypertension, and consequently, to meet criteria for metabolic syndrome more frequently (16, 70–74). Similar to comorbid obesity, metabolic syndrome has been associated with a more severe disease course and higher risk of suicide in BD patients (15, 70).
A bidirectional relationship between mood disorders and diabetes mellitus has also been proposed. The rate of mood disorders is increased in type 2 diabetes mellitus and vice versa independent of the presence of overweight or obesity (75, 76). The risk of developing type 2 diabetes mellitus is 3 times higher in individuals with BD (13). Furthermore, studies have shown increased morbidity in BD patients with comorbid type 2 diabetes mellitus (77, 78), insofar as individuals with BD and type 2 diabetes mellitus were more likely to have a chronic course of illness, rapid mood cycling, and worse functional impairment, when compared with nondiabetic subjects (77). Insulin resistance (IR), a precursor of type 2 diabetes mellitus and a key marker of metabolic dysfunction and IR prevalence, is also significantly elevated in individuals with BD (79).
Risk Factors
Metabolic disorders and BD share several environmental risk factors. Traditionally, chronic psychosocial stress is accepted as one of the most significant triggers of mood episodes and has been consistently associated with weight gain and subsequent development of obesity (80–82). Evidence from epidemiological studies demonstrates a high prevalence of adverse socioeconomic situations, including poverty, social isolation, lack of support, and low education, in both obese and BD patients (22, 83, 84). Nonetheless, one of the more compelling convergent causative factors is childhood trauma. A history of physical, emotional, or sexual abuse is well established as one of the most impactful environmental risk factors for BD (85–87). More recently, accumulating evidence indicates that early adversity in the form of traumatic experiences has a significant impact on metabolic health; early adversity has been shown to increase the risk of obesity, type 2 diabetes mellitus, and metabolic syndrome in adulthood (88–91).
Emerging evidence highlights the possible roles of inadequate diet and lack of physical exercise, the two mainstays of weight gain, in the onset of BD illness (92–95). Epidemiological data indicates that individuals with BD, on average, have an excessive caloric intake and high glycemic load (94, 95). Moreover, reduced intake of polyunsaturated fatty acids, including, but not limited to, eicosapentaenoic acid and docosahexaenoic acid, has been reported among BD patients (96, 97). Nonetheless, there are contradictory reports to suggest that BD patients consume fewer total calories from carbohydrates and fats when compared with healthy controls (98). Evidence from studies using subjective and objective measurements suggests that individuals with BD were significantly less active and more sedentary than the general population (95, 99).
Treatment-emergent adverse events are also known to contribute to the ever-increasing rates of obesity and the metabolic syndrome. Notwithstanding the well-documented detrimental metabolic effects of atypical antipsychotics (e.g., risperidone, olanzapine, quetiapine), these therapeutic drugs have been increasingly used in the treatment of BD (100). Lithium and valproic acid have also been associated with clinically significant weight gain, as have several of the second-generation antipsychotics (101, 102). Among the most commonly prescribed medications for the treatment of BD, only lamotrigine, aripiprazole, ziprasidone, asenapine, and lurasidone are considered to be “metabolically neutral”; therefore, it is highly likely that most individuals with BD were exposed, at one point or another, to a pharmacological therapy that could potentially promote weight gain and/or metabolic abnormalities.
Despite the importance of the foregoing contributing factors to metabolic abnormalities associated with BD, preliminary evidence demonstrates that these factors alone may not explain the obesity-BD association in its entirety. For example, a study reported an overweight/obesity prevalence of 40.8% among drug-naive BD patients, significantly higher than the comparison group (30). Another study evaluating subjects in the acute phase of treatment found no significant differences in metabolic abnormalities between subjects with and without a history of psychotropic medication (31). A recent study using a large and heterogeneous sample found that although antidepressants, mood stabilizers, and antipsychotics were associated with low HDL and high triglyceride levels, they were not associated with hypertension, hyperlipidemia, or diabetes (103).
Obesity and metabolic abnormalities have been documented as risk factors for the development of mood changes and depression. Diabetes and markers of glucose metabolism, such as fasting glucose and glycated hemoglobin, were associated with a higher risk for the development of depressive symptoms in follow-up studies (104, 105). Similar results were found with obesity, particularly when accompanied by other cardiovascular risk factors (e.g., blood pressure, lipids levels) (106). A recent study linked obesity in childhood and adolescence to a higher risk of depression in adulthood (107), while a separate cohort study reported that a pre-existing diagnosis of obesity is associated with an adolescent onset diagnosis of BD (108). Moreover, obesity and BD share several genetic risk factors, as well as abnormalities in biological systems (e.g., hypothalamic-pituitary-adrenal axis, inflammation). These results indicate that interacting physiological systems that mediate metabolism and manifest phenotypically as metabolic disturbance (e.g., obesity) may underlie etiopathological and psychopathological characteristics of BD.
Management
The high prevalence and impact of metabolic comorbidities in BD provide the impetus to prioritize the management of metabolic health in clinical practice. Clinicians are encouraged to screen and systematically monitor for comorbid conditions in all individuals with BD. Accurate diagnosis and appropriate treatment of metabolic comorbidities are imperative to ensure optimal health outcome in BD patients (109, 110). Dietary intake and physical exercise, as described previously, are relevant factors that should be routine targets of inquiry and recommendations in the clinical practice. Despite the well-known difficulties of adherence to diet and exercise recommendations experienced by most clinicians, recent clinical trials have reported successful results. A behavioral weight-loss intervention for individuals with serious mental illness, including BD, characterized by tailored weight-management sessions and exercise sessions, was shown to significantly reduce weight in overweight and obese patients (111). Moreover, evidence from pharmacological and nonpharmacological weight-loss interventions in major depressive disorder have reported positive effects of weight reduction in mood symptoms (112–115). Nonetheless, there is an unmet need for the development of empirically based therapeutic strategies specifically focused on the management of weight and lifestyle.
Metabolic dysfunction in BD may also be relevant in the context of prevention. A population-based study comprising 800,000 subjects reported that individuals with untreated type 2 diabetes mellitus had a 2.6-fold increase in the risk of developing BD. However, individuals receiving a combination of sulfonylurea and metformin had a significantly reduced incidence of BD, suggesting that treating diabetes may prevent the onset of BD (116). As the field of psychiatry moves toward a model centered on preemptive and preventive strategies, metabolic-based approaches have been considered to be particularly promising, insofar as they involve nonpharmacological interventions (e.g., diet and physical exercise), which may be safely and ethically applied to a wide array of at-risk individuals.
Limitations
Notwithstanding the accumulating body of evidence linking obesity, metabolic abnormalities, and BD, there are important methodological limitations that should be considered. A significant number of studies failed to find an association between these conditions or could not support the idea that this association incurred in differences in phenomenology, trajectory, or treatment response (117–119). This variability in results is meaningful and could be explained by some factors. First, most of the aforementioned studies did not consider age and gender in the analyses. As it is known that weight and mood disorders, as well as other important clinical characteristics, are distributed differently between age groups or gender (32), this omission could have biased some of the results. Second, BD is known to be phenotypically and pathogenically heterogeneous. Genetic and psychometric studies have reported that the symptomatic criteria for BD do not reflect a single underlying factor (120), and, as a result, there is a noteworthy interindividual variability in risk/resilience factors, phenomenology, trajectory, and treatment response. Overall, evidence indicates that the same is true for the incidence and impact of medical comorbidities, and, therefore, it is likely that only a subset of individuals with BD are more vulnerable to the effects of medical comorbidities described in this review.
Footnote
Rodrigo B. Mansur, M.D., Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada., Interdisciplinary Laboratory of Clinical Neuroscience (LINC), Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil
Roger S. McIntyre, M.D., Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto, Toronto, Canada
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Published in print: Winter 2015
Published online: 23 February 2015
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