We combined data from two studies that examined physical comorbidity in bipolar patients. We have provided individual descriptions of the methods of each study below. Specific inclusion or exclusion criteria of the studies have been previously reported(19, 20).
Study 1 assessed atorvastatin (20mg/day) versus placebo in the treatment of lithium users with nephrogenic diabetes insipidus (DI). It was a double blind, placebo-controlled RCT at three tertiary mental health sites in Montreal, Québec: Douglas Mental Health University Institute (DMHUI), Jewish General Hospital (JGH), and McGill University Health Centre (MUHC). Patients were lithium users aged 18-85, with any psychiatric disorder. At baseline, patients self reported demographic information, past medical and psychiatric history, and somatic complaints. Current medication was obtained from medical charts and confirmed by the patient. At each visit (baseline, 4-weeks, 12-weeks), psychiatric symptoms were measured using the Montgomery-Asberg Depression Scale (MADRS)(21) and Young Mania Rating Scale (YMRS)(22). Finally, physical measures (BMI and waist circumference), serum cholesterol levels, serum glucose levels, and thyroid function were also measured at each visit. For this analysis, baseline data from Study 1 was used from patients with BD (n=43).
Study 2 examined the relationship between mood, sleep, and food intake in bipolar patients. Patients were recruited from those presenting at the Bipolar Disorders clinic at the DMHUI. This is a specialized clinic where the diagnosis of patients has been systematically evaluated and scrutinized before acceptance. Patients were 18 years or older and were receiving care exclusively as outpatients. Medication, demographic, clinical, and laboratory information were retrieved for the initial visit. Two in-person visits, two weeks apart, were used to evaluate physical measures and mood. For this analysis, baseline data from Study 2 was used (n=86).
Exposures – Lithium Users and Non-Users:
Primarily, we classified patients with BD into current lithium users or non-users. This was achieved by a chart review of any prescriptions within a 2-week period before or after the initial baseline visit. Psychotropic exposure categories were dichotomous, without consideration of treatment dose or duration.
Our primary outcome was obesity, measured via body mass index (BMI). Obesity was chosen as lithium and other mood stabilizers have frequently been associated with weight gain, which may lead to treatment non-adherence and metabolic complications. It is also a value that can be easily measured and trended, no matter the healthcare setting. BMI was calculated using a standard formula: BMI= weight (kg) / height2 (meters). A BMI ≥ 30 was taken to indicate obesity, according to the National Institute of Health (NIH).
Our secondary outcomes were average BMI, BMI classes, MetS, and hemoglobin A1c (HbA1c). The BMI classes are designated by the NIH: BMI < 19.0 (underweight), BMI 19-24.9 (normal), BMI 25.0 – 29.9 (overweight), BMI 30.0-34.9 (class I obesity), BMI 35.0+ (class II & III obesity).
MetS was diagnosed in patients who fulfilled three or more of the five criteria based on the National Cholesterol Education Program Treatment Panel III (NCEP III): 1) Abdominal obesity: waist circumference ≥ 102cm for men and ≥ 88cm for women. Waist circumference was measured in two ways: at the top of the iliac crest as per the NIH, and midway between the last palpable rib and the top of the iliac crest according to World Health Organization (WHO) standards; 2) Glucose dysmetabolism: impaired fasting plasma glucose (5.5-6.9mmol/L) or diabetes (fasting plasma glucose ≥ 7mmol/L 3) Dyslipidemia: elevated plasma triglyceride (≥1.7mmol/L) 4) Dyslipidemia (second, separate criteria): decreased high-density lipoprotein (HDL) (<1.03mmol/L for men and <1.30mmol/L for women); and 5) Hypertension. Hypertension was defined as a high blood pressure reported on history or necessitating pharmacologic intervention according to a medication report.
Hemoglobin A1c was measured to assess glucose dysmetabolism and examine the prevalence of type II diabetes. Hemoglobin A1c is the most widely used clinical test to diagnose diabetes, indicating the mean glucose concentration over 120 days, though it is not traditionally used in the diagnosis of MetS.
Finally, our exploratory outcomes were the constituents of MetS: abdominal obesity, glucose dysmetabolism, dyslipidemia, and hypertension. Additionally, we supplemented these with thyroid function, as it is a frequent adverse event during lithium use. Hypothyroidism was characterized as a thyroid stimulating hormone (TSH) value > 5.0mIU/L or necessitating thyroid hormone replacement.
Data was initially assessed for normality using the Shapiro-Wilk test. We compared the exposure groups for demographic values, as well as for primary, secondary, and exploratory outcomes. We used Mann-Whitney U tests to examine continuous variables (eg. HbA1C) for non-normal distributions. Chi-squared tests were employed for dichotomous variables (eg. Diabetes Yes/No). A two-tailed alpha of 0.05 was used to determine statistical significance and all analyses were performed using IBM SPSS 26.0 (IBM SPSS Inc, Chicago, IL, USA).