Change in metabolic parameters in bipolar disorder: A retrospective-to-current evaluation design.

Persons with bipolar disorder (BD) are at an increased risk of early all-cause mortality than the general population with cardiovascular causes being one of the important causes of premature mortality.[ 1 2 ] Metabolic syndrome (MetS) is an important risk factor associated with premature mortality.[ 3 4 ] The MetS includes a group of cardiovascular risk factors that increase the risk of cardiovascular morbidity and mortality in the future.[ 5 ] The presence of MetS in BD has been shown to lead to poorer physical health, poor psychological health, poorer quality of life, poorer disease outcomes, and a higher socio-economic burden on the patient and family members.[ 6 7 8 9 10 ] It is also seen that obesity leads to personal distress, body image issues, and a decrease in self-confidence and self-esteem in patients. Obesity also leads to poor medication adherence, even when obesity may be due to other confounding factors.[ 11 ] Most of the available studies on the prevalence of MetS are cross-sectional, with only a few longitudinal studies.[ 12 13 14 15 16 17 18 19 20 21 22 ] The prevalence of MetS in BD ranges from 36% to 49% in cross-sectional studies from the United States of America,[ 13 14 15 ] and 18% to 26% in cross-sectional studies from European countries.[ 15 16 17 18 ] A meta-analysis of 37 studies involving around 7,000 patients with BD estimated the pooled prevalence of MetS to be 37.3%.[ 4 ] The limited number of longitudinal studies show that the prevalence of MetS at baseline ranged from 7% to 54.2% and on follow-up increased from 11% to 66.1%, with an increment ranging from 4% to 11.9%, after 3 months to 5 years of follow-up.[ 18 19 20 21 22 ] Various factors associated with MetS among patients with BD include the type of psychotropics, and lifestyle factors like lack of physical activity, unhealthy diet, poor self-awareness, and low self-care quality.[ 23 24 ] The illness-related variables that are associated with abnormal metabolic parameters include higher severity of the episode, difficult to treat the index episode, a higher mean number of manic and depressive episodes, onset of the illness with a depressive episode, late onset of mania, during the acute episodes, later age at first treatment, unhealthy diet, lack of physical activity and family history of diabetes mellitus.[ 25 ] A few cross-sectional studies from India have assessed MetS in BD patients and have reported the prevalence to range from 40% to 55.5%.[ 18 ] A few longitudinal studies from India have evaluated the change in the prevalence of the MetS among SMI patients. One study estimated the prevalence of MetS in BD reported that it rose from 40% at baseline to 44% at 3 months and 48% at six months.[ 6 ] Another study reported an increase in the prevalence of MetS by 11.9% in BD patients over a follow-up period of 5 years with raised waist circumference (WC) being the most common abnormality.[ 26 ] Another study evaluated the effect of antipsychotics in 40 patients suffering from schizophrenia and 20 patients suffering from mood disorders and after 3 months of treatment, the incidence of MetS was 11.6%.[ 27 ] In view of the limited number of studies from India, especially longitudinal studies, this study aimed to compare the prevalence of metabolic markers in patients with BD at two different times.

Seventy-four patients with a mean age of 44.08 years (SD: 13.21; range: 24 to 71; median: 42.5) at the follow-up assessment formed the study sample. Most of the participants were male (69.3%), married (74.7%), unemployed (54.7%), and from urban background (76%). The mean age of onset was 28.24 (SD: 10.17; Median: 26) years at the follow-up assessment [ Table 1 ]. The mean gap between the two assessments was 44.01 (SD: 35.25) months, with a median of 32.5. Clinical profile at the baseline ECT: Electroconvulsive therapy; BD=Bipolar disorder The severity of illness was evaluated by using HDRS and YMRS. The mean HDRS score was 1.8 (SD: 2.72), with 95.9% scoring HDRS <7 at the follow-up assessment. The mean YMRS score was 1.41 (SD: 2.53), with 98.6% of the participants scoring ≤7 at the follow-up assessment [ Table 1 ]. At the follow-up assessment, lithium (70.3%) was the most prescribed mood stabilizer, followed by valproate (24.3%). Most of the patients were receiving concomitant antipsychotics (81.1%), with olanzapine (40.5%) being the most prescribed antipsychotic, followed by quetiapine (24.3%). About one-fifth (21.6%) of the participants were also receiving antidepressants, with fluoxetine (6.8%) being the most common agent. About two-fifths (41.9%) of the participants had a physical comorbidity at the follow-up assessment, with 14.9% being diagnosed with hypertension, 25.7% diagnosed with diabetes mellitus and 12.2% had hypothyroidism [ Table 2 ]. About one-sixth of the patients were on antidiabetic medications, about one-fifth were on antihypertensive, and one-sixth were on medications for dyslipidemia [ Table 2 ]. Physical Comorbidity and their treatment in patients with bipolar disorder at the time of follow-up assessment Approximately one-third (37.8%) of individuals at the baseline evaluation met the MetS criteria, with most of the participants having abnormal WC, followed by abnormal triglyceride, abnormal FBS levels, abnormal HDL and abnormal BP was the least common abnormality [ Table 3 ]. Change in metabolic parameters from baseline to the assessment for the study in bipolar disorder BMI: Body Mass Index, FBS: Fasting Blood Sugar, LDL: Low-Density Lipoprotein, VLDL: Very Low-Density Lipoprotein, HDL: High-Density Lipoprotein, BP: Blood Pressure, MetS: Metabolic Syndrome Compared to the baseline assessment, a significant increase was seen in diastolic blood pressure, weight, BMI, WC, Hba1c, triglyceride levels, and very-low-density lipoprotein (VLDL) levels at the time of follow-up assessment. There was also a significant increase in the prevalence of BMI ≥25 kg/m 2 , abnormal WC, abnormal HDL levels, diabetes mellitus, and MetS [ Table 3 ]. In terms of changes in metabolic parameters from baseline to the assessment for the study, the highest proportion of the subjects were noted to have a rise in WC, followed by increases in body weight and triglyceride levels, and a reduction in HDL values [ Table 4 ]. The incidence (i.e., detected for the first time at the time of follow-up assessment) of diabetes mellitus was 16.7%, hypertension was 4.5%, dyslipidemia was 14.9%, and that of MetS was 41.3% [ Table 5 ]. Change in metabolic parameters in bipolar disorder FBS: Fasting Blood Sugar, HDL: High-Density Lipoprotein, BP: Blood Pressure Incidence of metabolic abnormalities in patients with bipolar disorder @ For computing the incidence, the denominator for each variable was the number of participants without the abnormality. ## For estimating the incidence/year, the incidence for each abnormality was divided by the duration between both assessments Female gender [Odds Ratio (OR): 3.3], being married (OR: 1.49), being unemployed (OR: 2.35), longer duration of illness (OR: 1.08), and age of onset (OR: 1.05) were associated with the development of MetS at baseline.

Although many studies across the globe have estimated the MetS prevalence in BD patients, there are limited numbers of longitudinal studies. Further, most of the studies which have evaluated the metabolic parameters longitudinally are limited by the sample sizes and short duration of follow-up. These limitations suggest the need to expand the literature in this area, by following up the cohorts longitudinally, to have a better understanding of the progression of existing metabolic parameters and the development of new metabolic abnormalities. Accordingly, the purpose of this study was to assess the prevalence of MetS at two different time periods, the variation in the prevalence of metabolic parameters, and the incidence of diabetes mellitus, hypertension, and dyslipidemia in BD patients. The prevalence of MetS at the baseline assessment was 37.8%. However, after a follow-up duration of 44.01 (SD: 35.25) months, with a median of 32.5 months, the MetS prevalence increased from 37.8% at the baseline assessment to 63.5% at the follow-up assessment, with an absolute increase of 25.7% over about 4 years and this increase was statistically significant. These prevalence figures at both assessments are in accordance with the reported range in various cross-sectional studies.[ 4 18 19 20 21 22 23 ] Previous longitudinal studies, which have followed up the patients for a duration of 3 months to 6 years,[ 25 26 27 28 ] have reported an increase in the prevalence range of 4% to 15.5%. Based on the findings of the present study, it is possible to say that individuals with BD who are of Indian descent are more susceptible to MetS and other metabolic disorders when the results of this study are contrasted with those of previous studies. When the findings present study are compared with these studies, it can be said that patients of BD, of Indian origin, are more vulnerable to developing MetS and other metabolic abnormalities. There is lack of data on an annual incidence of various metabolic abnormalities in patients with BD. The annual incidence of diabetes mellitus was 2.42%, hypertension was 5.05%, dyslipidemia was 8.54%, and that of MetS was 8.33%. All these factors need careful observation and taking these things into account at the time of selecting drugs. In the present study, the most common metabolic abnormality at both assessments was raised WC, followed by abnormal triglyceride levels, low HDL levels, followed by abnormal blood pressure, and abnormal fasting blood glucose levels. Further, when the prevalence of different abnormalities was contrasted, compared to the baseline assessment there was a significant increase in the prevalence of abnormal WC and abnormal HDL levels. When findings of the present study are compared with the existing literature, previous studies have also reported abnormal WC to be the most common abnormality.[ 26 ] These findings suggest that all clinicians should regularly monitor the WC of their patients and take appropriate measures in the form of dietary and lifestyle measures to reduce the risk of development of the MetS and subsequent cardiovascular morbidity and mortality. In terms of absolute values, over the period of about 4 years, there was a significant increase in the diastolic blood pressure, weight, BMI, prevalence of obesity as defined as BMI of ≥25 kg/m 2 , Hba1c levels, triglyceride levels, and VLDL levels. These findings suggest that, in some patients, although the levels may not exceed the threshold to be considered as abnormal, over time there is a significant increase in the absolute values for these parameters. Accordingly, while monitoring these parameters, clinicians should not only focus on the absolute values being in the abnormal range or not, but should compare the findings with the previous assessment and take necessary steps to prevent the progression of these abnormalities. The present study has certain limitations. The study was a part of academic research to ensure good level of transparency. The study sample was small and the study followed a retrospective-to-current evaluation design. We did not assess the association of metabolic abnormalities with the type of medications taken over the intervening period and medication adherence. We also did not evaluate the dietary patterns and lifestyle factors of these patients. The baseline assessment did not involve the inclusion of drug-naïve patients. This was an exploratory and we did not control for multiple comparisons. In the future, there is a need for a longitudinal study that will involve the assessment of participants at various time points and evaluate the treatment-related factors to understand the factors associated with the development of MetS and various metabolic abnormalities. To conclude, the present study suggests that 37.8% of patients with BD have MetS, and this prevalence increases significantly over 4 years to 63.5%. Abnormal WC is the most prevalent metabolic anomaly in BD patients, followed by abnormal triglyceride levels, low HDL levels, followed by abnormal blood pressure, and abnormal FBS levels. The present study also suggests that over 4 years weight, BMI, waist size, FBS, HbA1c, triglycerides, VLDL, and the prevalence of type-II diabetes mellitus increased significantly. There are no conflicts of interest. The authors attest that there was no use of generative artificial intelligence (AI) technology in the generation of text, figures, or other informational content of this manuscript.

The study cohort was assessed at two time points (i.e., patients’ data at one point was extracted from the files and they were assessed again at the time of intake) and we used retrospective-to-current evaluation design. The study participants were enrolled from the patient population attending the outpatient psychiatry services of a tertiary care hospital in North India during the period of July 2019 to June 2020. The institutional ethics committee granted ethical clearance. A purposive sampling method was adopted. The study sample comprised 74 patients suffering from BD. The study was limited to participants aged ≥18 years at the time of follow-up assessment, of either gender and diagnosed with BD, as per the DSM-5 criteria and having a recent MetS data (evaluated <1 week prior to being enrolled) or were willing to undergo evaluation for metabolic parameters. A written informed consent was obtained from all the study participants. Patients who did not give consent, had comorbid intellectual disability or a diagnosis of organic brain syndrome were excluded from the study. The treatment records of the consenting patients were reviewed for the availability of information on a previous assessment of metabolic profile and anthropometry. If such information was available that was at least 1 year prior to the current evaluation, the patients were evaluated on other study’s selection criteria, and those who fulfilled the same were recruited into the study. Patients having a metabolic profile and anthropometry data recorded at least 1 year back were evaluated for metabolic parameters and their anthropometry was assessed. The patients were screened for MetS using the definition proposed by the Consensus group of the International Diabetic Federation (IDF), that is, the presence of 3 out of the 5 following criteria.[ 28 ] The five components include a high WC (≥90 cm in males and ≥80 cm in females), high blood pressure (systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg) or a diagnosis of hypertension, low high density lipoprotein cholesterol (HDL-C) (<40 mg/dL in males, <50 mg/dL in females) or a diagnosis of dyslipidemia, elevated triglycerides (≥150 mg/dL) or a diagnosis of dyslipidemia, and increase fasting blood sugar (FBS) (≥100 mg/dL) or a diagnosis of diabetes mellitus. All the patients were then evaluated on Hamilton depression rating scale (HDRS)[ 29 ] and the Young Mania rating scale (YMRS)[ 30 ] to assess the level of psychopathology. Additionally demographic data and clinical profile was recorded based on the information provided by the patients, their caregivers and review of treatment records. The data obtained from the treatment records were considered as the baseline assessment and the data collected at the time of evaluation of the study was the follow-up assessment. The data was analyzed using Statistical Package for Social Sciences, 24 th Version (SPSS-24) (IBM, Chicago, IL, USA). Continuous variables were described by mean, and standard deviation with range. Categorical variables have been described using frequency and percentage. Comparison of baseline and follow-up data on MetS parameters was done using the McNemar test and paired t -test.