Gender and Body Mass Index-Related Serum Level of Adipokines and Metabolic Syndrome Components in Bipolar Patients Who Received Lithium and Valproic Acid

Introduction

The prevalence of metabolic syndrome in bipolar disorder (BD) patients is of important interest, because there is rare information about this. ¹ Study by Fagiolini et al. ² indicated a prevalence of metabolic syndrome BDs, 30% when compared with the general population. McEvoy et al. reported that metabolic syndrome may occur in patients with Severe Mental Illnesses and in 30%–60% for BD. ³ Diagnosis and treatment of mental disorders has an important challenge for clinicians and the patients. Some studies have shown that the prevalence of obesity in mental disorder patients is up to 55%. ^4,5 It is reported that there is an association between obesity and overweight BD patients and increased rates of metabolic syndrome. ^{5 –8}

A study has indicated that BD is associated with medical mortality. ⁹ The risk of mortality because of vascular disease among BD patients is correlated with elevated weight, insulin resistance, and increased glucose and lipid levels. It is revealed that the increasing prevalence of obesity has risen the prevalence of metabolic syndrome. ¹⁰ Clinical Studies on BD patients have revealed that there are alterations in adipokines levels. ^{11 –13} Adipokines may promote inflammation and obesity-linked metabolic disorders. ¹⁴ Among adipokines, leptin and adiponectin are of interest because of their contrast biologic functions ¹⁴ and their association with body weight. Leptin is an adipocyte-derived hormone, which shows an important role in regulating appetite, reproductive capacity, and energy consumption.

Some clinical studies have indicated that there is an association between serum leptin level and total body weight and fat mass. It is reported that serum leptin levels increased and decreased in obesity and low body weight, respectively. ¹⁵ Adiponectin is produced by adipocytes and improves insulin sensitivity and fat oxidation. ^16,17 Adiponectin is an adipose-specific plasma protein that is produced by adipocytes. ^18,19 In vitro studies have shown that adiponectin may have anti-inflammatory and antiatherogenic activities. ^{20 –22} Some studies have indicated that Injections of recombinant adiponectin protein in mice decreased plasma fatty acids, glucose, insulin sensitivity, and body weight. ^{23 –25} Many studies have shown that decreased levels of adiponectin were seen in subjects with obesity, type 2 diabetes mellitus, and coronary heart disease. ^20,26,27

These studies show that adiponectin may be clinically practical biomarkers to show the development of subjects with MS. ^20,26,27 Lithium (Li) and valproic acid (VPA) used as drugs in the BD patients' treatment. ²⁸ Studies have shown that treatment of the BD patients with VPA may cause side effects such as weight gain, gastrointestinal symptoms, sedation, tremor, and mild elevation of hepatic enzymes. ²⁹

A study indicated that obese subjects treated with VPA have been shown higher levels of serum insulin and leptin when compared with subjects who do not gain weight. ³⁰ Other findings showed that subjects treated with VPA had higher serum insulin levels, but not leptin levels, when compared with control groups with the same body mass index (BMI). ³¹ Treatment of the BD patients with Li indicated weight gain as its side effect in 25%–62% of BD patients. ^{2,32 –36} The exact mechanisms of these side effects are not exactly clear. It is unclear that development of metabolic syndrome occurs in some patients and in some other patients, it does not. ³⁷ It is reported that there is an association between antipsychotics and metabolic syndrome, and some other studies have shown no association between mood stabilizers and metabolic syndrome. ¹

Studies have indicated that there is a converse correlation between serum levels of adiponectin with BMI and fat mass in adults. ³⁸ Some other studies have revealed that there is an association between hyperleptinemia and hypoadiponectinemia with increased insulin resistance, diabetes, and metabolic syndrome. ^{39 –41} The aim of our study was to assess fasting serum adiponectin and leptin, triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), blood sugar, blood pressure, and waist circumference (WC) differences after treatment with Li and VPA monotherapy in the BD patients for 12 weeks, according to gender and BMI (normal weight and obesity) and compare them with healthy controls. We also determined the association between leptin and adiponectin levels and metabolic syndrome components, in women, men, normal weight, and obese BD patients who received Li and VPA.

Materials and Methods

Eighty seven subjects from 200 patients (36 women and 51 men) were directed to 5th Azar Education Hospital Neuropsychiatry department, Golestan University of Medical Sciences, in Gorgan, Iran. The mean ages of women and men were 41.22 ± 12.18 and 40.19 ± 26.12 years, respectively. The causal method was used to choose the patients. The patients were chosen according to our study conditions. Our study conditions were different when compared to other studies. From the beginning of our study, the patients used Li and VPA. These drugs were utilized by new case BD patients for 12 weeks. All tests were carried out in the Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University of Medical Sciences.

The study was conducted according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Golestan University of Medical Sciences Ethics Committee (Ethic number: IR.GOUMS.REC.1397.261). Written informed consent was provided by all subjects before they entered the study. Thirty one patients received 975 mg/day VPA and 25 patients received 600 mg/day Li monotherapy for 12 weeks. There were 31 healthy subjects. Patients' relatives or health care workers were chosen as the healthy subjects. Healthy subjects were selected if they had no metabolic syndrome, drug consumption, history of any psychiatric disorder, and some different diseases, etc. The healthy subjects had also a similar BMI, sex, and age to the patient group.

Biochemical parameters were determined in healthy subjects by biochemical tests (the results are not shown in the article) and some others were determined by questionnaire form with the help of a physician. Psychiatry expert diagnosed BD patients with the method Diagnostic and Statistical Manual of Mental Disorders (DSM-5). ⁴² The patient relatives and general practitioners assisted to collect patient medical information. The exclusion criteria for patients included the previous use of Li and VPA, physical illness, dependence to alcohol and substance, and immunologic abnormalities.

Patients with different diseases such as immunodeficiency, neurological, kidney and liver diseases, hypertension, malignancies, any additional psychiatric disorder or mental retardation, and also abnormal laboratory tests or any chronic medical condition and psychotropic medications other than Li or VPA were also excluded. Blood samples were collected from subjects fasted for 12 hr and centrifuged at 2000 r.p.m. Serum was collected and stored in −20°C until we utilized it for the experimental parameters.

Metabolic syndrome components according to the NCEP ATP III criteria ⁴³ include: (1) WC: ≥102 cm (male), ≥88 cm (female); (2) TG levels: ≥150 mg/dL; (3) HDL-C levels: <40 mg/dL (male), <50 mg/dL (female); (4) Blood pressure: ≥110/≥85 mmHg; and (5) fasting blood glucose levels: ≥110 mg/dL. Commercial kits were used to determine fasting blood sugar, HDL-C, and TGs by using a spectrophotometer. BMI was calculated using the metric scale and formula body weight (kg)/height (meters) ² . Normal weight was defined if the subjects have a BMI 18.5–22.9 kg/m² and obesity was defined as 25–29.9 kg/m² according to the World Health Organization. ⁴⁴ WC measurement was carried out with a tape in centimeters. A digital blood pressure monitor was used to measure systolic and diastolic blood pressure in all subjects (Omron 70JCP; Omron Matsusaka, Mie-Ken, Japan).

Commercial kits were used to measure fasting blood sugar, total cholesterol, low-density lipoprotein-cholesterol, HDL-C, and TGs using a spectrophotometric technique (JENWAY6305). Adiponectin and leptin levels were measured by Micro enzyme-linked immunosorbent assay (ELISA). Serum adiponectin (μg/mL) was measured by a commercial ELISA kit (ZellBio GmbH, Germany) and serum leptin (ng/mL) was determined by an LDN Diagnostics kit (Germany) in BD patients and healthy subjects according to the manufacturer's instructions.

Results

Clinical data are summarized in Tables 1 –9. The results in Table 1 show that no significant differences were observed between BD patients who received Li and VPA in both genders. The comparison of study parameters of BD patients who received Li and VPA with healthy controls according to gender is shown in Tables 2 and 3. Comparison of WC and TG levels in BD patients who received Li and VPA with healthy controls did significantly differ in women and men (P < 0.05).

Tables 4 and 5 show the comparison of study parameters of BD patients received Li and VPA with healthy controls according to normal weight and obesity. In normal weight BD patients who received Li and VPA, significant differences were considered in HDL-C, WC, and TG levels when compared to healthy controls (P < 0.05), whereas no significant differences were observed in obese BD patients who received Li, but there were significant differences in TG, leptin, and adiponectin levels in obese BD patients who received VPA when compared to healthy controls (P < 0.05).

In normal weight BD patients who received Li and VPA, significant difference was seen in adiponectin level when compared to healthy controls (P < 0.05).Tables 6 and 7 show correlations between leptin and adiponectin levels and metabolic syndrome components in women and men BD patients who received Li and VPA. There were significant negative correlations between leptin and adiponectin, and WC and TG in women who received Li (P < 0.05) (Table 6) while there were significant positive correlations between leptin and adiponectin, and WC and TG in men BD patients who received VPA (P < 0.05) (Table 7).Tables 8 and 9 show correlations between leptin and adiponectin levels and metabolic syndrome components in normal weight and obese BD patients who received Li and VPA.

There were significant positive correlation between leptin and adiponectin, and WC and TG and significant negative correlation with HDL-C in normal weight BD patients who received VPA and Li, respectively (P < 0.05), while there was only a significant positive correlation between leptin and adiponectin, and TG in obese BD patients who received VPA (P < 0.05). The correlation between leptin and adiponectin and TG is different in patients who received VPA and Li in obese BD patients. There was not any correlation between leptin and adiponectin and metabolic syndrome components in obese BD patients who received Li (P > 0.05).

Discussion

This study revealed that the monitoring of Li and VPA drugs' effects on studying factors is important in BD patients. This is the study to assess possible alterations on adiponectin, leptin, and metabolic syndrome components in women and men BD patients with normal weight and obesity who received VPA and Li for 12 weeks. These conditions may affect directly or indirectly the clinical effects of the BD patients. According to our finding, after the beginning of Li and VPA monotherapy by 3 months showed almost the same effect on women and men (increased in TG and WC in both gender) when compared to healthy controls. However, no difference on adiponectin and leptin in women and men was observed in BD patients in comparison to healthy controls. It has been reported an effect of gender on adipokines levels in BD patients. ⁴⁵

There are conflicting results on adipokines levels in BD patients compared to healthy controls. Some of these studies have been shown to increase ^12,46,47 and decreased levels of adiponectin ^11,13 and leptin. ^48,49 Studies have also indicated that obesity may cause the differences between BD patients and healthy controls in adipokines levels. ^12,49 Studies have shown that adipokines, especially leptin and adiponectin, have an important role in many metabolic processes. ⁵⁰ Study of Ebert indicated higher and lower serum levels of adiponectin and leptin in healthy adults compared with overweight/obese subjects, respectively. ⁵¹

Some other studies have revealed that the increase in plasma adiponectin was only significantly associated with BMI and WCs, but not with fasting plasma glucose, insulin, TGs, and HDL-C. ⁵² Our results showed adiponectin levels increasing after Li treatment in only normal weight BD patients. Some studies have revealed that there are a lower adiponectin levels in metabolic syndrome, characterized by obesity, insulin resistance, impaired glucose tolerance, and hyperlipidemia. ⁵³

There were significant positive correlation between leptin and adiponectin and WC and TG and negative correlation with HDL-C in normal weight BD patients who received VPA and Li, respectively. Significant positive correlation was between leptin and adiponectin, and TG in obese BD patients received VPA after 12 weeks. The correlation between leptin and adiponectin and TG is different in obese BD patients who received VPA and Li. Leptin and adiponectin showed no correlation with any metabolic syndrome components in obese BD patients who received Li. In normal weight BD patients, correlation between leptin and adiponectin, and WC, TG, and HDL-C may be depending on the effect of these drugs on the leptin and adiponectin levels.

These correlations may cause to change metabolic syndrome components in normal weight BD patients who received VPA and Li. The association of Li and metabolic syndrome components are not exactly understood. Some researchers have reported that there is an association between Li and metabolic dysregulation. ⁵⁴ It was reported that the BD patients indicated weight gain throughout the 6 weeks of Li treatment, according to using the side effects scale (Udvalg for Kliniske Undersøgelser, Scandinavian Society for Psychopharmacology). According to their findings, there were no differences in weight gain of Li-treated BD patients during the follow-up and after treatment with Li levels of adiponectin and leptin.

They also conclude that Li decreases adiponectin and change weight and metabolic alterations in 6 weeks. McIntyre reported increased leptin levels by the sixth month of treatment with Li. ⁵⁵ Some studies have revealed that leptin levels were significantly found lower in with BD patients compared to the control group. ¹¹

Some other studies have indicated that the leptin levels and BMI increased significantly in patients with BD after a 8-week Li. ⁴⁸ These are not in accordance with our results. This may be because of a longer treatment of BD patients with Li in our study (12 weeks). Our study suggests that Li does not change our study parameters in obese BD patients, but normal weight BD patients may cause the increased risk for metabolic complications. Study of Elmslie of metabolic syndrome-related factors in overweight patients with BD treated with VPA in comparison with healthy controls showed that WC, hypertension, and fasting hyperglycemia were similar in both groups. ¹²

These findings were not in accordance with our findings in women and men BD patients. They found also lower HDL-C than the healthy controls for the patients with BD treated with VPA. ¹² These findings show that VPA indicates different effects on women and men, which are not in accordance with our study.

A study has shown that BD patients are associated with decreased serum leptin levels. ⁴⁸ Correlation between leptin level in patients with depression and BMI was not revealed in some other studies. ⁵⁶ It has also shown that in depression, leptin levels were not alternated and an association between the role of leptin and the loss of body weight in depressed patients were not shown. ⁵⁷ In our study, serum leptin levels were not significantly higher and lower in women and men BD patients who received VPA and Li compared to healthy controls.

There were significant negative and positive correlation between leptin and adiponectin and WC and TG in women and men BD patients who received VPA and Li monotherapy after 12 weeks, respectively. This result may depend on using new case patients, used dose differences, and differences in genetic. Some studies have indicated that the most obese patients have higher leptin levels, ⁵⁷ which is not in accordance with our results.

Our findings indicated that high level of adiponectin in BD patient who received VPA and Li may increase WC and TG and decrease HDL-C (Metabolic factors) in normal weight (high level of adiponectin in Li and VPA received patients) and obese BD patients (high level of adiponectin in VPA received patients) when compared to healthy controls. These results are not in accordance with the study, which showed that plasma adiponectin levels were higher in nonobese than in the obese subjects. ²⁶ A study has indicated that there is an association between adiponectin and obesity, diabetes mellitus, and dyslipidemia. ⁵⁸

The increase of serum adiponectin in normal weight and obese BD patients may depend on time of Li and VPA therapy. It is reported that Li therapy in BD patients for 6 weeks ⁵⁹ reduces adiponectin levels, which is not in agreement with our study (Li therapy in BD patients were for 12 weeks).

Study of Pylvanen on VPA-received obese patients and obese healthy controls revealed no differences in leptin levels. ³¹ Another study indicates that serum leptin decreased in BD patients. ⁵⁶ Some studies of obese patients have indicated higher leptin levels. ⁵⁷ According to our findings, only obese BD patients showed high levels of leptin and TG in VPA-received patients that our study results are not in agreement with other findings. ^31,56 In our study, serum leptin levels were significantly higher in obese BD patients who received VPA compared to healthy controls. The effect of VPA on leptin levels in BD patients may increase the TG level in these patients. This may depend on longer time of VPA therapy in obese BD patients who received VPA that it may increase leptin level.

Thus, this may change TG level. There were no significant changes in obese BD patients who received Li in levels of leptin, adiponectin, and metabolic syndrome components.

There was a limitation in our study. The only limitation of the present study was the restricted sample size (small sample size), especially after separating the BD patients to subgroups according to gender, normal weight, and obese BD patients.

Confirmation Statement

The authors submitted the present article in their own personal professional capacity and are not employees of any US-sanctioned government.

Authors' Contributions

A.M.: conceived and designed the experiments; contributed reagents, materials, analysis tools, or data; and wrote the article. J.Y.: conceived and designed the experiments. M.Z.K. and T.A.: analyzed and interpreted the data. N.D.: analyzed and performed the experiments. M.M.: contributed reagents, materials, analysis tools, or data and wrote the article.