Efficacy of Lithium Carbonate Combined with Olanzapine, Risperidone, or Quetiapine in Bipolar Disorder Treatment and Effects on Glycolipid Metabolism

Summary

The aim of this study is to observe the therapeutic effect of lithium carbonate combined with three drugs and its impact on glucose and lipid metabolism. It was found that combining lithium carbonate with risperidone has a better effect and less metabolic impact.

Abstract

Bipolar disorder (BD) patients are often accompanied by glycolipid metabolism abnormalities, which reduce disease treatment adherence and increase the risk of cardiovascular disease, bringing certain challenges to current clinical treatment. This retrospective study aims to observe the efficacy of lithium carbonate combined with olanzapine, risperidone, and quetiapine, respectively, in the treatment of BD and its effect on glycolipid metabolism. The 210 patients with BD from Chengdu Jinxin Mental Diseases Hospital were selected between February 2023 and August 2024 and were categorized into LO (Lithium carbonate combined with olanzapine), LR (Lithium carbonate combined with risperidone), and LQ (Lithium carbonate combined with quetiapine) groups according to treatment. The primary outcomes were assessed as changes in the Bech-Rafaelsen mania scale (BRMS) scores, clinical outcomes, and glycolipid metabolism indicators, including triglyceride (TG), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and fasting blood glucose (FBG) in each group. Secondary outcomes included BD severity, measured with the Clinical Global Impression-Bipolar Disorder (CGI-BP) scale, and quality of life, evaluated with the Generic Quality of Life Inventory-74 (GQOLI-74). The indicators of the three groups post-treatment were statistically significant (P < 0.05) compared with the pre-treatment. The LR group had the lowest BRMS scores and CGI-BP-s scores, the highest clinical efficacy, and GQOLI-74 scores. The LO group had markedly increased TC, TG, and LDL levels, while the LR group had markedly increased TG levels, and the LQ group had markedly increased TC and TG levels (P < 0.05). No marked difference in adverse reactions was observed among the three groups (P > 0.05). All three treatment modalities have therapeutic effects on BD, among which LR has remarkable efficacy, significantly improving the patient’s condition and having a relatively small impact on glycolipid metabolism, thus warranting clinical popularization and application.

Introduction

Bipolar disorder (BD) is a common chronic mental disorder characterized by recurrent mood (affective) changes, with manic episodes and depressive episodes as the main clinical manifestations, and belongs to the category of severe mental illnesses¹. The course of BD is polymorphic, with episodic, cyclic, and mixed prolonged episodes, with intermittent periods of relatively normalized social functioning of varying durations. BD characterized by marked manic episodes or mixed episodes with severe depressive episodes is called bipolar type I (BD-I), and BD characterized by severe depressive episodes and mild manic episodes is described as bipolar type II (BD-II)². BD belongs to the category of severe psychosis, which is a serious and highly relapsing disorder that imposes a relatively high burden on individuals, families, and society³. At present, in the research on BD, many scholars have studied the pathogenesis, neurotransmitters, neuroendocrine, neurophysiology, neuroplasticity, and neurotrophic aspects of BD⁴. BD is a multifactorial disorder with a complex clinical presentation characterized by early onset, recurrent episodes, and chronic outcomes associated with severe functional impairment, mortality, and suicide risk, including abnormalities of the emotional core, cognitive deficits, sleep/wakefulness disorders, and a high proportion of co-morbidities⁵.

In treating patients with BD, lithium salts are widely used clinically as an effective antimanic and prophylactic treatment for mood disorders. Current international treatment guidelines have recommended lithium salts as first-line treatment for BD to prevent depressive or manic episodes^6,7. In addition, antipsychotic drugs are also commonly used treatment methods, and their mechanism of action is to promote or inhibit the release of neurotransmitters, thereby affecting specific neural pathways, such as the expression and release of inflammatory factors, and the imbalance of neurotransmitters⁸. Lithium salts, some second-generation antipsychotics (olanzapine, etc.) have shown good clinical efficacy in preventing nerve damage or apoptosis and slowing down cognitive decline⁹. Thus, it seems that the combination of multiple drugs in the clinic seems to be a viable option to slow down cortical atrophy and protect nerves¹⁰. Lithium has limited effectiveness in the therapy of bipolar depression, whereas the short-term efficacy of second-generation antipsychotics for BD is coming to the force, such as olanzapine, risperidone, and quetiapine, which are more common in clinical practice¹¹. Leif Lindström et al.'s meta-analysis found that second-generation antipsychotics as adjunctive treatments to mood stabilizers, quetiapine, ziprasidone, and aripiprazole, overall reduced the risk of relapse in patients, and quetiapine reduced the adjunctive medication for manic and depressive episodes¹². Risperidone is commonly used in the treatment of schizophrenia, and is particularly effective for affective symptoms (anxiety, depression, etc.)¹³.

The high morbidity and mortality in the chronic persistent course of the disease with BD make it one of the key causes of disability in the young adult population¹⁴. Analysis of its high mortality rate revealed that the main causes of premature death in BD patients are cardiovascular disease¹⁵. An in-depth exploration of the causes may be due to the fact that patients with bipolar disorder are usually accompanied by the risk of dyslipidemia, and glucose-lipid metabolism disorders, while obesity, dyslipidemia, and diabetes happen to be important risk factors for cardiovascular disease as well¹⁶. A study found that serum lipocalin levels were markedly lower in female patients with a biphasic depressive phase than in healthy controls, a finding that provides a rationale for the promotion of metabolic disorders by BD¹⁷.

In clinical work, the combination of mood stabilizers with antipsychotic medication is a more common treatment, considering the variability of manic and depressive symptoms in patients with BD. However, the effects of mood stabilizers, such as lithium salts, on lipid metabolism are unknown. Therefore, this study used lithium carbonate combined with olanzapine, risperidone, and quetiapine to treat BD and analyzed their efficacy and effects on glucose and lipid metabolism to improve the effectiveness of patients' treatments and provide more therapeutic options for the clinic.

Protocol

The research was conducted in compliance with the Declaration of Helsinki and Chengdu Jinxin Mental Diseases Hospital's ethical guidelines and approved by the hospital's ethical committees (Approval No. 2024017).

Study design and participants

This study is a systematic evaluation and integration aimed at comparing the efficacy and effects on glycolipid metabolism of treating BD with lithium carbonate in combination with olanzapine, risperidone, or quetiapine. 210 BD patients admitted to Chengdu Jinxin Mental Diseases Hospital between February 2023 and August 2024 were selected and categorized into three groups by different interventions: the LO group, the LR group, and the LQ group. The flowchart is illustrated in Figure 1.

Inclusion and exclusion criteria

Inclusion criteria: (1) Meets the international classification of diseases (ICD-10) diagnostic criteria for BD¹⁸; (2) The treatment regimen was lithium carbonate combined with a single antipsychotic drug (olanzapine, risperidone, quetiapine); (3) After 4 weeks of treatment, patients were confirmed to have achieved marked symptomatic improvement by two or more attending physicians, as defined by a ≥50% reduction in the total score of the Bech-Rafaelsen mania rating scale (BRMS); (4) Age 15–55 years old; (5) Patients with good compliance and willingness to cooperate with the treatment plan developed by the study; (6) Patients in basic health, without major physical diseases. They can truthfully express their complaints about the symptoms and answer the relevant questions from the medical staff; (7) They can tolerate the drugs involved in the study; (8) The patients and their family members are informed and agreeable and sign the informed consent form.

Exclusion criteria: (1) Comorbid serious somatic (cardiac, renal, hepatic, etc.) diseases; (2) Comorbid chronic infectious diseases; (3) Dependence or abuse of psychoactive substances; (4) Patients who have been involved in a clinical drug trial or a clinical research study; (5) Taking psychiatric medication 2 weeks prior to the admission, or using long-acting injections; (6) Comorbid metabolic diseases such as hyperlipidemia and diabetes; (7) Pregnant and breastfeeding women; (8) Requesting discontinuation of treatment or automatic discharge for personal reasons; (9) Allergic to the medication used in this study; (10) Other conditions that the study physician believes should not be included; (11) Other conditions that affect the indicators of subsequent observation.

Interventions

Patients in all three groups were treated with lithium carbonate, oral lithium carbonate tablets, with a starting dose of 0.25 g/times, 2 times/day, and then gradually increasing the dose to 1.0–1.5 g/day according to the patient’s condition for 8 consecutive weeks. Regularly monitor serum lithium concentration (at 1, 2, and 4 weeks of treatment, and then every 4 weeks during follow-up), with the target treatment serum lithium level maintained at 0.6–1.0 mmol/L. The LO group added olanzapine treatment. Olanzapine tablets were taken orally at a starting dose of 10 mg/day once, and then the dose was adjusted to 10–20 mg/day depending on the patient's condition, and the drug was used for 8 consecutive weeks. The LR group added risperidone treatment. Risperidone tablets were administered orally at an initial dose of 1 mg once/day, and then the dose was increased by 1–2 mg per week according to the actual condition of the patients, and the maximum dose should not be more than 6 mg, and the drug was administered for 8 weeks consecutively. The LQ group added quetiapine treatment. Quetiapine fumarate tablets were taken orally, the dose on the 1st day was 0.1 g/times, 1 time/day, the dose on the 2nd day was 0.2 g/day, the dose on the 3rd day was 0.3 g/day, the dose on the 4th day was 0.4 g/day, and the dose was maintained at 0.4~0.7 g/day in one week depending on the condition, and was given continuously for 8 weeks.

Observational indicators

Primary indicators

Assessment of illness

The BRMS was utilized to assess the patient's condition¹⁹, which included 13 items such as hallucinations, sexual interest, and contact, with a 5-point scale of 0 to 4 corresponding to asymptomatic, mild, moderate, pronounced, and severe symptoms, respectively, for a total of 52 scores. The higher the rating, the more severe the condition.

Clinical efficacy

Post-treatment, patients with a BRMS score <10 showed a clear effect; those with ≥50% decrease in BRMS score were considered effective, and those with <50% decrease in BRMS score were considered ineffective.

Total efficacy rate = obvious effect + effective.

Glycolipid metabolism analysis

Subjects were fasted for at least 8 h. Venous blood was collected early the next morning, and the fully automated biochemical analysis system was applied to measure lipid triglyceride (TG), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and fasting blood glucose (FBG).

Secondary indicators

BD severity

The clinical general impression-BD disease seriousness (CGI-BP-s) scale was used²⁰. The scores assessed the seriousness of BD before and after treatment of three groups of patients, which consisted of a total of three dimensions, with each dimension scoring 7 points, and the higher the score, the more severe the patient's bipolar disorder was.

Quality of life score

The quality of life of the three groups was assessed using the life qualities integrated assessment questionnaire-74 (GQOLI-74) score²¹, which includes 4 aspects of somatic functioning, psychological functioning, social functioning, and material life. Each aspect has a score of 1 to 100, and the worse the score, the worse the life quality.

Adverse reaction

Observe adverse reaction occurrences during the treatment process and follow-up period across the three groups, and calculate the total incidence rate of adverse reactions.

Follow-up visits

Follow-up visits at 6 months after treatment were primarily scheduled in this study to assess the durability of the effects and to address any potential adverse reactions or problems.

Sample size calculation

Given the retrospective, observational nature of this study, the sample size was determined by the number of eligible BD patients identified in hospital medical records between February 2023 and August 2024. A total of 210 eligible patients were identified, and based on clinical treatment decisions, they were evenly assigned to the LO, LR, and LQ groups (70 patients per group). This sample size is sufficient to ensure the reliability and generalizability of the research conclusions, as it includes all consecutive eligible cases during the study period and provides sufficient statistical power to compare clinical efficacy and metabolic index differences between the three groups.

Statistical methods

Use SPSS 27.0 software to analyze the data. Continuous data that conforms to a normal distribution is represented as mean ± standard deviation (SD), while categorical data is represented as counts (percentages). For the comparison between three treatment groups, one-way analysis of variance (ANOVA) was used for normally distributed continuous data, and chi-square test (chi-square test) was used for categorical data. When significant main effects were observed (P < 0.05), Bonferroni correction was used for post hoc pairwise comparisons to control for type I error rates associated with multiple comparisons. The superscripts (a, b, c) in Table 2-6 correspond to the post hoc test results after Bonferroni correction, where different superscripts indicate statistically significant differences between groups (P < 0.05 after correction). The paired t-test is used to compare continuous variables within each group before and after treatment. A bilateral P value < 0.05 is considered statistically significant.

Results

Basic information

In this study, 210 patients with BD from Chengdu Jinxin Mental Diseases Hospital between February 2023 and August 2024 were allocated to LO, LR, and LQ groups with 70 patients in each group based on different interventions. No marked discrepancy in baseline demographics and characteristics among the three groups was observed (Table 1; P > 0.05). For continuous variables such as age, disease duration, and baseline BRMS score, all pairwise compariso...

Discussion

Bipolar disorders are a group of common chronic mental disorders with complex clinical manifestations, typically characterized by both manic or hypomanic and depressive episodes, often co-morbid with substance abuse or anxiety symptoms in complex cases, and hallucinations, delusions, or catatonic psychotic symptoms in severe cases²². The course of BD is polymorphic, with episodic, cyclic, and mixed prolonged episodes, with intervals of relatively normalized social functioning of varying durations....

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Lithium carbonate tablets	Hunan Qianjin Xiangjiang Pharmaceutical Co., Ltd.	H43020372	NA
Olanzapine tablets	Jiangsu Haosen Pharmaceutical Co., Ltd.	H20052688	NA
Risperidone tablets	Qilu Pharmaceutical Co., Ltd.	H20041808	NA
Quetiapine fumarate tablets	Hunan Dongting Pharmaceutical Co., Ltd.	H20061218	NA