Application and efficacy of quetiapine in patients with high-risk factors for bipolar disorder: A randomized controlled trial

Abstract

BACKGROUND

Bipolar disorder (BD), marked by recurring manic and depressive episodes, often coexists with anxiety disorder (AD), which increases treatment complexity and morbidity. Although quetiapine, an atypical antipsychotic, has demonstrated efficacy in treating BD and AD, further investigation is needed regarding its effectiveness and safety in patients with AD at high-risk factors for BD.

AIM

To explore the application and efficacy of quetiapine in combination therapy for patients with AD at high-risk factors for BD.

METHODS

This study included 67 patients, with two excluded, leaving 65 divided into Group A (sertraline treatment) and Group B (combination treatment). All patients received sertraline, with Group B additionally receiving quetiapine. Efficacy was assessed using the Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), and Bech-Rafaelsen Mania sale (BRMS) throughout the treatment period. Side effects and physiological indicators were also monitored.

RESULTS

No significant baseline differences existed between the two groups at treatment onset. Over the treatment course, Group B exhibited significantly lower HAMA scores than Group A at the end of weeks 1 and 24. HAMD scores gradually decreased over time, with Group B consistently showing lower scores than Group A. BRMS scores decreased significantly from baseline by week 8. In Group A, 27.27% of patients received zolpidem treatment compared to 10.53% in Group B, which was a significant difference. Incidence of adverse reactions did not differ significantly between groups at treatment onset, but most patients experienced relief from adverse reactions within 4 weeks.

CONCLUSION

Combination of quetiapine and sertraline can more rapidly alleviate anxiety and depressive symptoms in patients with AD at high-risk factors for BD, improving treatment outcomes.

Key Words: Bipolar disorder; Anxiety disorders; Quetiapine; Comorbidity; Risk factor

Core Tip: This study evaluated the efficacy and safety of quetiapine combined with sertraline in patients with anxiety disorder (AD) and high-risk factors for bipolar disorder (BD). In a 24-week randomized trial involving 65 patients, those receiving combination therapy (Group B) showed significantly lower Hamilton anxiety scale scores than those on sertraline monotherapy (Group A) at weeks 1 and 24. Group B also demonstrated faster and sustained reductions in Hamilton depression scale and Bech-Rafaelsen Mania sale scores. Group B required less adjunctive zolpidem for insomnia, with no significant difference in adverse reactions between the groups. These findings support the use of quetiapine as an adjunctive treatment for managing complex AD at high-risk factors for BD, offering a safer and more effective strategy for high-risk patients.

INTRODUCTION

Bipolar disorder (BD) affects approximately 2.8% of adults globally, and is characterized by complex etiology involving biochemical imbalances, seasonal changes, and stressful life events. Patients with BD frequently experience rapid mood swings and emotional dysregulation, complicating the treatment and management of the illness, while greatly increasing its social and economic burden. BD not only affects mood regulation but is often accompanied by other mental disorders, with anxiety disorder (AD) being one of the most common comorbidities[1]. AD is a mental disorder characterized by persistent and excessive anxiety and fear. Research indicates that up to 50% of BD patients also have comorbid AD, and often display more complex clinical symptoms[2]. Importantly, compared to patients who have BD alone, those with comorbid AD are more likely to experience fast cycling, greater emotional instability, and a heightened risk of suicide[3]. Therefore, how to effectively treat BD patients with comorbid AD has become an important area of research in psychiatry[4].

Current BD treatment focuses on mood stabilization and symptom control, with physicians actively exploring patient psychological states to implement effective interventions[5]. The main medications used for treating BD are mood stabilizers, such as lithium and valproate. However, monotherapies of this kind often take effect slowly, are less effective at stabilizing the condition, and have numerous side effects with long-term use, limiting their clinical application[6]. Common anxiety medications like sertraline carry the risk of triggering mood swings and increasing mania risk when used alone in BD patients[7]. Therefore, finding a drug combination or single medication that can effectively address both BD and AD has become a key therapeutic challenge.

Quetiapine, an atypical antipsychotic, has demonstrated efficacy in treating both BD and AD in recent years[8]. Originally developed for schizophrenia treatment, quetiapine functions through dual antagonism of serotonin (5-HT2A) and dopamine (D2) receptors, contributing to its anxiolytic and mood-stabilizing properties[9]. Studies have shown that quetiapine effectively improves depressive symptoms in BD patients, and reduces the occurrence of anxiety during treatment. Quetiapine also has better tolerability, with fewer extrapyramidal side effects than other antipsychotics and is thus more suitable for long-term treatment. Due to its anxiolytic properties, quetiapine is an important therapeutic option for BD patients with comorbid AD[10]. Currently, although quetiapine does show individual efficacy in treating both BD and AD, research on its efficacy in patients with AD at high-risk factors for BD is still scarce[11]. To understand what kind of therapeutic effect quetiapine can have in this patient group, researchers have begun to explore its use combined with other drugs. The current study evaluated the effects, efficacy and safety of quetiapine combined with commonly used anxiolytic sertraline in patients with AD at high-risk factors for BD, to provide new clinical treatment for these patients[11].

MATERIALS AND METHODS

General information

Inclusion criteria: (1) Patients diagnosed with social AD, panic disorder, or generalized AD (GAD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; (2) Patients with BD with at least one of the following high-risk factors: Age < 18 years, family history of BD, significant negative thoughts or behaviors, or subthreshold manic symptoms [score between 1 and 5 on the Bech-Rafaelsen Mania scale (BRMS)]; (3) Individuals of Han ethnicity aged 18-60 years; (4) Total score of ≥ 14 on the Hamilton anxiety scale (HAMA) and < 17 on the Hamilton depression scale (HAMD); (5) No medication use for > 2 weeks prior to registration; and (6) Approval from the hospital ethics committee, voluntary participation in the study, and signed written informed consent.

Exclusion criteria: (1) Patients with a history of substance, alcohol, or other psychoactive substance abuse; (2) Patients with significant abnormalities found in laboratory and auxiliary examinations; (3) Patients unable to cooperate or complete examinations due to consciousness, vision, hearing, language expression, or comprehension disorders; (4) Patients with severe physical illnesses such as heart, lung, liver, kidney dysfunction, shock, malignant tumors, and autoimmune diseases; (5) Patients taking glucocorticoids, immunomodulators, antipyretics, and analgesics; and (6) Women who were pregnant or breastfeeding.

Withdrawal criteria: (1) Patients who voluntarily requested to withdraw their consent; (2) Nonadherence to research protocols during the study; (3) Presence of psychiatric symptoms such as agitation or delusions; (4) Disturbances of consciousness; or (6) Pregnancy.

Between January 2021 and December 2022, 67 patients were admitted to our hospital, with two withdrawing from treatment for various reasons. The remaining 65 patients were divided into Group A (sertraline treatment group) with 32 cases and Group B (combination treatment group) with 33 cases. In Group A, there were 13 males and 19 females with an average age of 44.31 ± 11.7 years. Among the 32 patients, two were unmarried and two were divorced. The average disease course was 64.03 ± 62.92 months, and the average duration of education was 10.03 ± 3.54 years. All patients in Group A were diagnosed with GAD. In Group B, there were 11 males and 22 females with an average age of 43.00 ± 13.76 years; seven were unmarried and two were divorced. The average disease course was 65.24 ± 66.613 months, and the duration of education was 9.48 ± 3.801 years. In Group B, 32 patients were diagnosed with GAD and panic disorder. The general data of the two groups were not significantly different (P > 0.05).

Treatment methods

At the commencement of the study, participants in both groups were administered sertraline, with the dose incrementally adjusted according to individual response. In addition to sertraline, Group B also received quetiapine as part of the treatment regimen. For patients experiencing severe insomnia at night, a bedtime dose of 10 mg zolpidem tartrate was recommended. To evaluate the therapeutic effects, participants were assessed using HAMA, HAMD and BRMS at the beginning of the experiment (baseline) and at the end of weeks 1, 2, 4, 8, 16 and 24. The treatment emergent symptom scale was utilized to evaluate potential side effects of the medication. Complete blood count, hepatic and renal functions, thyroid function, and electrocardiograms were monitored at baseline and at the end of weeks 2, 4, 8, 16 and 24 (Figure 1).

Figure 1 Study flow chart. HAMA: Hamilton anxiety scale; HAMD: Hamilton depression scale; BRMS: Bech-Rafaelsen Mania sale.

Random number generation

The random number generation for allocating participants to Groups A and B was conducted using a computer-generated random number sequence. This method ensured that each participant had an equal chance of being assigned to either group, thereby maintaining the integrity of the randomization process.

Statistical analysis

Statistical analysis was performed using SPSS 23.0. Measurement data were analyzed using independent samples t tests, with a significance level of P < 0.05. All comparisons were conducted between the two groups.

RESULTS

Comparison of HAMA scores

At the onset of treatment, there were no significant differences in baseline scores between the two groups (P > 0.05). However, as the treatment progressed, HAMA scores gradually decreased. At the end of weeks 1 and 24, scores in Group B were significantly lower than those in Group A (P < 0.05). However, the score differences between the two groups at weeks 2, 4, 8 and 16 did not reach significance (P > 0.05) (Table 1). Line graphs have been added to illustrate the trajectories of HAMA scores for both groups over the 24-week study period (Supplementary Figure 1).

Table 1 Comparison of the Hamilton anxiety scale score (mean ± SD).

	Baseline	1 week	2 weeks	4 weeks	8 weeks	16 weeks	24 weeks
A group	22.31 ± 2.49	16.31 ± 3.34	11.47 ± 3.44	7.84 ± 3.85	6.00 ± 3.47	4.94 ± 2.66	5.44 ± 3.13
B group	22.18 ± 2.87	13.09 ± 3.15	9.79 ± 4.34	6.15 ± 4.24	4.76 ± 3.90	3.97 ± 3.10	3.79 ± 3.36
t value	0.196	4.007	1.729	1.683	1.355	1.349	2.046
P value	0.845	< 0.001	0.089	0.097	0.180	0.182	0.045

Comparison of HAMD scores

At the beginning of treatment, there were no significant differences in HAMD scores between the two groups (P > 0.05). As the treatment progressed, the HAMD scores showed a gradual decline. Group B consistently had lower scores than Group A throughout the treatment period, and this difference was significant (P < 0.05). However, at weeks 4, 8, 16 and 24 of the treatment, the score differences between the two groups were not significant (P > 0.05) (Table 2).

Table 2 Comparison of the Hamilton depression scale score (mean ± SD).

	Baseline	1 week	2 weeks	4 weeks	8 weeks	16 weeks	24 weeks
A group	12.97 ± 2.50	8.44 ± 2.79	5.44 ± 3.48	4.28 ± 2.67	3.41 ± 2.09	2.91 ± 1.61	2.81 ± 1.66
B group	13.33 ± 2.29	6.64 ± 2.00	3.42 ± 2.68	3.45 ± 2.86	2.79 ± 2.22	2.48 ± 1.79	2.45 ± 1.89
t value	-0.614	2.998	2.617	1.204	1.155	0.997	0.812
P value	0.541	0.004	0.011	0.233	0.252	0.323	0.420

Comparison of BRMS scores

From baseline to the end of week 24 follow-up, the changes in scores between the two groups did not show significant differences (P > 0.05). However, both groups exhibited a significant reduction in scores compared to baseline levels by the end of the treatment (week 8) (P < 0.05), indicating a positive impact of the treatment on symptom improvement in patients (Table 3).

Table 3 Comparison of the Bech-Rafaelsen Mania scale score (mean ± SD).

	Baseline	1 week	2 weeks	4 weeks	8 weeks	16 weeks	24 weeks
A group	3.59 ± 2.86	1.09 ± 1.69	0.28 ± 0.58	0.16 ± 0.45	0.16 ± 0.57	0.16 ± 0.44	0.31 ± 0.93
B group	3.15 ± 2.86	1.18 ± 1.55	0.33 ± 0.85	0.15 ± 0.44	0.06 ± 0.24	0.03 ± 0.17	0.15 ± 0.57
t value	0.623	-0.219	-0.287	0.043	0.880	1.503	0.845
P value	0.536	0.827	0.775	0.966	0.382	0.138	0.401

Comparison of zolpidem usage between the two groups

In this study, 27.27% of the patients in Group A received zolpidem treatment, compared to 10.53% in Group B. This difference between the two groups was significant (P < 0.05), indicating a marked disparity in the utilization of zolpidem between the groups.

Adverse reactions

During the first week of treatment, four adverse reactions were recorded in Group B, primarily manifesting as gastrointestinal symptoms and headaches. Upon entering the second week of treatment, three patients in Group A reported adverse reactions, with symptoms including gastrointestinal discomfort and fatigue. Although adverse reactions were reported in both groups, there was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). However, it is noteworthy that within 4 weeks after treatment, 85.71% of the patients experienced alleviation of adverse reactions. These data suggest that despite the occurrence of some adverse reactions during the treatment process, the majority of patients were able to recover in the short term.

We monitored complete blood counts, hepatic and renal functions, thyroid function, and electrocardiograms at baseline and at the end of weeks 2, 4, 8, 16 and 24 (Supplementary Table 1). All parameters remained within normal clinical ranges throughout the study, and no significant differences were observed between the two groups at any time point (P > 0.05).

DISCUSSION

ADs are typically marked by excessive tension, worry, or fear. Research indicates that individuals with ADs are nine times more likely to develop BD than the general population[12]. BD, also known as manic-depressive illness, is a prevalent and disabling mental health condition marked by emotional instability and alternating episodes of mania and depression, sometimes exhibiting mixed features[13]. It is widely acknowledged that diagnosis of BD is often delayed, with some patients waiting as long as a decade for a correct diagnosis. BD frequently co-occurs with other conditions, including ADs, eating disorders, personality disorders, and substance use disorders[14]. In adolescent patients, anxiety symptoms are considered a risk factor for the development of BD, with some individuals diagnosed with ADs during their teenage years. Anxiety symptoms are also common in patients with BD, with research by Inoue et al[15] indicating that > 50% of patients with BD will experience anxiety symptoms at some point in their lives.

The significantly lower HAMA and HAMD scores in Group B (combination therapy) suggest a synergistic effect of quetiapine and sertraline. The anxiolytic and mood-stabilizing properties of quetiapine, attributed to its dual antagonism of 5-HT2A and D2 receptors, likely contributed to the observed benefits. This aligns with previous research indicating the efficacy of quetiapine in managing anxiety and depressive symptoms in BD patients[16]. Our findings are consistent with studies that reported improved mood disorders in adolescents using a similar combination therapy. However, our study extends these results by focusing on a specific high-risk population, providing further evidence for the utility of quetiapine in preventing treatment destabilization in patients prone to BD.

Although the comorbidity of BD and AD is common, the underlying causes are not fully understood, and research in this area is limited[17]. Current evidence suggests that this comorbidity may be associated with neurobiological, genetic, traumatic, and other sociopsychological factors[16]. Some researchers propose that AD may be a component of BD, a significant risk factor for its onset, or even a prodromal symptom[18]. The occurrence of ADs in young people may predict a genetic predisposition to BD[19]. However, further research is needed to establish these specific associations.

Although studies[20] have shown that patients with comorbid BD and AD do not exhibit a more severe course or frequency of episodes, some research indicates that patients with comorbidity may have an earlier age of onset, increased cognitive impairments, prolonged disease duration, higher chances of disease relapse, increased suicide risk, and even shorter lifespans[21]. In a 2-year follow-up, patients with comorbidity had higher depression scores at various time points and lower remission rates[22]. These risks and characteristics pose challenges for treatment, making the exploration of appropriate therapeutic strategies at the level of comorbidity of significant clinical value[23].

The presence of comorbidity complicates the diagnosis of the disease and increases the difficulty of confirmation. In patients with comorbid conditions, ADs often appear earlier than BD, which may lead to the misdiagnosis of BD as AD and inappropriate treatment, such as the prescription of antidepressants. Previous research has shown that antidepressants, commonly used as a first-line treatment for anxiety, can trigger manic episodes and are associated with irritability, rapid cycling, treatment resistance, and suicidal behavior[24]. This delay in appropriate treatment may result in inadequate initial management and lead to future relapses and functional impairment[25].

The efficacy of antidepressants has been well established, and they are recommended for the treatment of various ADs[26]. In some cases, acute depressive and anxiety episodes can be controlled through combined treatment with lithium, valproic acid, or atypical antipsychotic drugs. This study primarily focused on patients with AD at high risk for BD and observed the effects of sertraline alone and in combination with quetiapine. Sertraline, a selective serotonin reuptake inhibitor, is the first-choice drug in the clinical treatment of ADs due to its single pharmacological mechanism of action and lack of addictive potential[27]. Lithium is a classic mood stabilizer that can reduce the sensitivity of serotonin receptors and increase the release of serotonin, thereby improving physiological functions and exerting both antidepressant and anxiolytic effects. However, some studies have shown that individuals with BD and anxiety symptoms may not respond well to lithium. Atypical antipsychotic drugs mainly work by blocking dopamine receptors and also affect α1-adrenergic receptors, histamine receptors, and γ-aminobutyric acid receptors, serving as adjunctive treatments for GAD, panic disorder, and post-traumatic stress disorder. Quetiapine, an atypical antipsychotic drug, was used in the study group and compared with the sertraline-only group.

The results of this study indicate that the combined use of sertraline and quetiapine significantly reduced HAMA and HAMD scores compared to the use of sertraline alone, suggesting a potential synergistic effect in reducing symptoms of anxiety and depression[28]. The anxiolytic effects of quetiapine seemed to be sustained over time, with Group A having higher HAMA scores than Group B at the end of week 24. These findings are consistent with a study by Blasco-Fontecilla et al[29], who also reported that combined treatment with sertraline and quetiapine significantly improved mood disorders, depression, and anxiety symptoms in patients after stroke.

The Systematic Treatment Enhancement Program for BD (STEP-BD) study found that over half of the patients had comorbid anxiety, beginning at an early stage[29]. In this study, patients had at least one high-risk factor for BD. However, the overall older age of the patients, longer disease history, and absence of manic or hypomanic symptoms lasting > 4 days in the longer disease history suggest that the risk of developing BD in patients with a longer history of AD may be lower[30]. The study followed these patients for 24 weeks, and neither group exhibited significant manic symptoms.

The findings of this study have significant clinical implications, particularly in alignment with the STEP-BD recommendations for adjunctive antipsychotics in high-risk cases. The combination of sertraline and quetiapine not only demonstrated faster and more sustained improvements in anxiety and depressive symptoms but also required less adjunctive zolpidem for insomnia. This supports the use of adjunctive antipsychotics in managing complex comorbid conditions, especially in patients with high-risk factors for BD. Our results provide further evidence for the efficacy and safety of this approach, offering clinicians a valuable treatment option for patients who may not respond adequately to traditional monotherapies.

Despite the promising results, our study had some limitations. The sample size was small, and the follow-up period was short, which may affect the generalization of the findings. Additionally, the lack of a placebo control limits our ability to fully attribute observed effects to the combination therapy. Future studies should consider larger sample sizes, longer follow-up periods, and the inclusion of a placebo group to validate these findings. Additionally, exploring the long-term effects of quetiapine in this population could provide valuable insights into its role in preventing the onset of BD.

CONCLUSION

In summary, combination therapy with quetiapine for patients with AD and high-risk factors for BD can more rapidly alleviate symptoms of anxiety and depression, thereby improving treatment outcomes. However, this study did not find any evidence to suggest that the combined use of quetiapine has an impact on the risk of developing BD in patients with a long history of AD. It is important to note that this study had some limitations, including a small sample size, longer patient disease history, use of different medications, and a short follow-up period. These limitations may affect the conclusions of the study, and future research should address these limitations with further investigation.