Case series of aripiprazole monotherapy in bipolar disorder with delayed sleep-wake phase syndrome

Abstract

Introduction

Patients with bipolar disorder (BD) who also experience delayed sleep-wake phase (DSWP) disorder/syndrome may tend to be younger, have a higher risk of relapse, and exhibit more severe impairments in social functioning. However, few studies have explored this area, and there are currently no established treatment guidelines, prompting us to investigate this further through a case series.

Methods

We report on a chart review of 15 patients diagnosed with bipolar disorder (BD) and delayed sleep-wake phase (DSWP) syndrome, who received Aripiprazole (APZ) monotherapy for 12 to 135 weeks.

Results

Efficacy was observed within the first two weeks, indicated by reductions in Clinical Global Impressions-Severity (CGI-S) scores and an advancement of the sleep-wake cycle. By the final visit, 93.3% (14/15) of participants had achieved clinical remission (defined as CGI-S < 3), with their social functioning returning to normal. The most common adverse events were extrapyramidal side effects and weight gain, but both were reversible.

Conclusion

In summary, APZ monotherapy may be an effective and safe treatment option for BD patients with DSWP syndrome. Our chart review highlights the potential value of further systematic investigation through a clinical trial.

Introduction

Sleep disturbances are common symptoms of bipolar disorder (BD), affecting 30–60% of patients and increasingly recognized as a prognostic indicator [1–3]. In the past, most studies on sleep disturbances in BD have focused on insomnia, with fewer examining delayed sleep-wake phase (DSWP) disorder/syndrome in BD cases. DSWP disorder is one of the most prevalent circadian rhythm sleep-wake phase disorders (CRSWPD), characterized by a bedtime and wake time delayed by two or more hours beyond what is considered typical [4]. DSWP disorder is most common observed in adolescents and young adults, affecting approximately 1.1%−4.6% of this population [5–8]. Among adults, its prevalence is reported to be about 0.2–1.7% [7, 9].

DSWP disorder/syndrome is more frequent in BD patients than in the general population. A cross-sectional study from Norway found that approximately 10% (42/404) of adult BD patients have DSWP disorder [10]. Another small sample-controlled study targeting young patients (average age 23.2 ± 4.7) with BD or depression found that the incidence of DSWP disorder was as high as 62% (18/29) among BD patients [11]. Even in euthymic BD patients, the incidence of DSWP disorder reached 26% [12].

Compared to BD patients without DSWP disorder, those with DSWP disorder tend to be younger, have a higher mean Body Mass Index (BMI), and are more likely to be prescribed mood stabilizers and antidepressants [10]. They also exhibit more impaired energy and activity levels [10]. In euthymic BD patients, those with DSWP disorder tend to be younger, have an earlier onset of BD, and a higher family history of suicide, along with more residual symptoms of depression and behavioral inhibition (such as motivation, receptivity, interpersonal interaction, and cognition) [12, 13]. Regarding circadian preference, as measured by the Morningness-Eveningness Questionnaire, BD patients with an evening chronotype tend to be younger [14]have higher rates of eating disorders (e.g., binge-eating, bulimia nervosa, nocturnal eating binges) and unhealthy eating behaviors [14] as well as higher BMI [14, 15]comorbid anxiety [15] and a greater risk of intentional self-harm [16]. Additionally, a prospective study found that evening chronotype predicts more depressive episodes over the next five years in BD patients [17].

Based on these findings, it is reasonable to speculate that BD with DSWP disorder/syndrome may represent a distinct subtype of BD. Studies have demonstrated that aripiprazole is an efficacious medication for the treatment of DSWP syndrome [18, 19]. Unfortunately, no established treatments currently exist for the complex comorbidity of BD and DSWP disorder/syndrome. Therefore, we present a chart review of 15 patients with BD and DSWP syndrome who were treated with aripiprazole monotherapy.

Methods

A sample of 15 BD patients with DSWP syndrome who had undergone aripiprazole (APZ) monotherapy was included in this study. Of these, nine were outpatients (60%) and six were inpatients (40%). Bipolar disorder was diagnosed by the attending physician based on the diagnostic criteria of the International Classification of Diseases, 10th Revision (ICD-10) [20]. The diagnosis of Delayed Sleep-Wake Phase syndrome (DSWPS) was primarily based on the criteria for Delayed Sleep-Wake Phase Disorder (DSWPD) from the International Classification of Sleep Disorders, 3rd edition (ICSD-3) [21] with the exception that the duration of DSWPS was less than three months.

Since some patients were already hospitalized or receiving medication at the time of recruitment, it would have been unethical to discharge them solely for study inclusion or to delay treatment in order to monitor them for at least 7 days (ideally 14 days) using a sleep diary or actigraphy. Therefore, in this study, the diagnosis of DSWPS was based on subjective reports from patients and their family members regarding their medical history, indicating that the patient had experienced a delayed sleep phase for at least 7 days (preferably 14 days, including both work and non-work days).

Given that aripiprazole is an off-label treatment for bipolar disorder, particularly in adolescents in China, written informed consent was obtained from all participants, as well as from guardians for those under 18 years of age. Data on participants’ baseline clinical and demographic characteristics, medication use, efficacy, and safety information were extracted from the electronic medical record, medical laboratory examination, and electrocardiogram examination systems at the Third Affiliated Hospital of Sun Yat-sen University. The use of this information in the study was also approved by all participants and their guardians, with written informed consent provided.

This study was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University, with ethics approval number: II2023-188-02.

Results

Subject demographics and clinical features

As shown in Table 1, of the 15 participants, 11 (73.3%) were female, 13 (86.7%) were students, and 14 (93.3%) were unmarried. At the time of initiating aripiprazole (APZ) monotherapy, 14 participants (93.3%) were experiencing a mixed episode, while 1 (6.7%) was in a manic episode. Three participants (20%) had a positive family history of mental disorders, 4 (26.7%) had a history of non-suicidal self-injury (NSSI), and 3 (20%) were comorbid with generalized anxiety disorder (GAD). The average age of the participants was 20.7 ± 6.4 years, with an average educational level of 12.9 ± 3.2 years. The average age of bipolar disorder onset was 17.2 ± 6.0 years (Median = 16, Min = 10, Max = 32). The median duration of bipolar disorder was 2.5 years, with a range of 0.3 to 9.0 years.

Table 1.

Demographic and clinical characteristic of the cases

No.	Age before APZ-monotherapy	Gender	Job	Education (year)	Marital status	Family history	NSSI history	Onset age of mental illness	Diagnosis history before APZ-monotherapy	Diagnosis when using APZ-monotherapy	Comorbidity	Medication history	Mood episode before APZ-monotherapy	Course of BD until APZ-monotherapy (year)
1	15	M	student	9	unmarried	0	0	13	GAD	BD	GAD	Topiramate 50 mg/d, Oxazepam 30 mg/d	Mania	2.5
2	15	F	student	8	unmarried	0	0	14	None	BD	None	None	Mixed	1.5
3	18	F	student	12	unmarried	0	1	10	MDD	BD	GAD	Sertraline, Bupropion (dose unknown)	Mixed	7.0
4	14	F	student	8	unmarried	1	1	11	MDD	BD	None	Sertraline 50 mg/d, Quetiapine 25 mg/d	Mixed	3.0
5	21	F	student	15	unmarried	0	0	16	MDD	BD	None	Escitalopram oxalate 10 mg/d, Valproate 200 mg/d, Lithium carbonate 900 mg/d, Olanzapine 2.5 mg/d	Mixed	2.5
6	21	M	student	16	unmarried	0	0	17	BD	BD	None	Sertraline, Olanzapine (dose unknown)	Mixed	4.0
7	28	F	student	18	unmarried	0	0	27	None	BD	None	None	Mixed	1.5
8	16	M	student	10	unmarried	0	0	16	None	BD	None	None	Mixed	0.4
9	18	F	student	12	unmarried	0	1	16	BD	BD	GAD	Sulpiride 800 mg/d, Quetiapine 12.5 mg/d, Artane 4 mg/d	Mixed	2.5
10	16	M	student	12	unmarried	0	1	15	MDD	BD	None	Sertraline100mg/d, Sulpiride100mg/d	Mixed	1.2
11	24	F	unemployed	12	unmarried	0	0	15	BD	BD	None	None	Mixed	9.0
12	39	F	housewife	15	married	0	0	32	None	BD	None	None	Mixed	7.0
13	23	F	student	16	unmarried	1	0	21	None	BD	None	None	Mixed	2.0
14	22	F	student	16	unmarried	0	0	22	None	BD	None	None	Mixed	0.3
15	21	F	student	15	unmarried	1	0	13	BD	BD	None	None	Mixed	8.0

Among the 15 participants, five had previously been misdiagnosed with Major Depressive Disorder (MDD) and treated with antidepressants such as sertraline, escitalopram, bupropion, or fluoxetine. One participant had been diagnosed with GAD and treated with topiramate and oxazepam. Two participants received the correct diagnosis of BD at their first psychiatric visit and had been treated with other medications, including quetiapine, lithium carbonate, valproate, and olanzapine. However, all these participants failed to respond to previous treatments and were switched to APZ monotherapy. The remaining seven participants had never received any psychopharmaceutical treatment prior to the study and began their treatment with APZ monotherapy from the outset.

Treatment

As shown in Table 2, the average initial dose of APZ monotherapy was 3.5 ± 1.3 mg (Median = 2.5, Min = 2.5, Max = 5 mg), the average maximal dose was 11.2 ± 6.7 mg (Median = 10, Min = 5, Max = 25 mg), and the average final dose was 8.8 ± 5.8 mg (Median = 7.5, Min = 2.5, Max = 25 mg). The average time from the initial dose to reaching the maximal dose was 10.0 ± 11.4 weeks (Median = 4, Min = 1, Max = 36 weeks). The average time from the initial dose to the maintenance dose was 22.7 ± 24.5 weeks (Median = 16, Min = 1, Max = 76 weeks), and the average total duration of APZ monotherapy was 53.7 ± 37.8 weeks (Median = 49, Min = 12, Max = 135 weeks).

Table 2.

APZ-monotherapy records and sleep records of the cases

No.	APZ(mg)			The time from the initial dose to reaching the maximal dose(week)	The time from the initial dose to the maintenance dose(week)	Total duration of APZ-monotherapy(week)	Other medications
	Initial dose	Maximal dose	Final dose
1	2.5	20	15	36	76	135	Benzhexol 4 mg
2	2.5	10	5	24	60	110	None
3	2.5	10	5	28	49	86	None
4	2.5	12.5	10	4	50	84	None
5	2.5	10	10	4	4	79	Benzhexol 4 mg
6	5	10	10	20	20	59	None
7	5	7.5	5	5	17	31	None
8	2.5	7.5	7.5	2	2	12	Benzhexol 4 mg
9	2.5	25	15	3	11	30	Benzhexol 4 mg, Oxazepam 7.5-15 mg; obvious anxiety was reported at the final visit, combined use of Tandospirone
10	2.5	25	25	3	3	52	Benzhexol 4 mg
11	5	5	5	1	1	21	None
12	5	5	5	2	2	18	None
13	5	7.5	5	4	30	49	Benzhexol 2 mg
14	2.5	5	2.5	2	4	12	Obvious depression was reported at the final visit, combined use of Lamotrigine
15	5	7.5	7.5	12	12	27	None

Efficacy and safety

Efficacy

Based on the available data from electronic medical records, Clinical Global Impressions-Severity (CGI-S) scores and sleep timing at four timepoints (baseline, 2 weeks, 12 weeks, and the final visit) were used to assess the efficacy of APZ monotherapy. As shown in Fig. 1, the average CGI-S score of BD patients was 4.9 ± 0.7 at baseline, 3.0 ± 0.0 at 2 weeks, 2.2 ± 0.6 at 12 weeks, and 1.7 ± 0.9 at the final visit. A significant reduction in CGI-S scores was observed in all participants within two weeks of starting APZ monotherapy. By the final visit, 14 participants (93.3%) had attained clinical remission of emotional symptoms (CGI-S ≤ 2), confirming robust treatment efficacy.

Fig. 1.

a Efficacy of APZ-monotherapy. b Efficacy of APZ-monotherapy

At the four timepoints (baseline, 2 weeks, 12 weeks, and the final visit), the median bedtime (min-max) of participants was 03:00 (00:00–07:00), 00:00 (22:00–02:00), 23:00 (22:00–01:00), and 23:00 (22:00–02:00), respectively. The median wake time was 11:00 (07:00–17:00), 08:00 (06:00–11:00), 07:00 (05:00–11:00), and 08:00 (05:00–08:00), respectively. The median sleep duration was 8 h at baseline, 7 h at 2 weeks, and 8 h at both 12 weeks and the final visit. As shown in Fig. 2, by 2 weeks, 66.7% (10/15) of participants were able to fall asleep before 01:00 am, and 100% (15/15) could fall asleep before 03:00 am. By 12 weeks and the final visit, the proportion of participants who could fall asleep before 01:00 am increased to 93.3% (14/15). Similarly, wake times advanced for all participants, with 86.6% (13/15) waking before 09:00 am at 2 weeks, and by the final visit, 100% were waking before 09:00 am.

Fig. 2.

a Bedtime records. b Wake time records. c Change of the bedtime median and wake time median

In addition, all participants showed significant improvement in social functioning after APZ treatment. Prior to treatment, social functioning was severely impaired: the 13 students had suspended their studies, the housewife was unable to manage her household duties, and the unemployed participant was unable to care for herself. Following APZ treatment, all 13 students returned to school, with four successfully graduating from university. The housewife regained her ability to manage daily housework independently, and the unemployed participant was able to care for herself and began preparing for the next college entrance examination by joining a study program. In summary, the social functioning of most participants (14/15) returned to normal.

Safety

During the period of APZ monotherapy, 40% (6/15) of participants reported experiencing extrapyramidal symptoms. Specifically, 4 participants had akathisia, 1 had acute dystonia, and 1 had facial expression stiffness. These symptoms were alleviated by reducing the APZ dose and/or adding Benzhexol or benzodiazepines. Weight gain (approximately 10 kg within six months) was observed in 13.3% (2/15) of participants but was managed with health education on weight control. No other adverse events were noted in the medical records. Routine safety monitoring, including blood tests (routine, liver function, renal function), blood lipids, blood glucose, uric acid, thyroid function, serum prolactin, and electrocardiogram, showed no clinically significant abnormalities.

Discussion and conclusions

Our study found that APZ monotherapy was both effective and safe for treating adolescent and adult BD patients with DSWP syndrome/disorder. APZ not only alleviated mood symptoms but also normalized the delayed sleep rhythm. Additionally, there was significant improvement in social functioning among all participants. Efficacy was evident within the first two weeks of treatment and was sustained for up to two years or more. While extrapyramidal side effects and weight gain were the most common adverse events, they were all reversible. These findings align with recent meta-analyses showing that aripiprazole is effective and safe for BD treatment [22]. They also partially confirm conclusions from two case reports indicating that low-dose aripiprazole as an adjunctive therapy can restore delayed sleep rhythms in patients with depression [18, 23]. Although previous reports have noted improvements in circadian sleep disorders and bipolar stability with APZ as an adjunctive therapy, this is the first report of successful treatment of BD with DSWP symptoms/disorder using APZ monotherapy, particularly in the adolescent BD population.

The success of APZ in treating BD with DSWP syndrome/disorder may be attributed to its unique pharmacological mechanisms. As a partial agonist at dopamine D2 and 5-hydroxytryptamine (5-HT)1 A receptors [24]APZ has dual effects: it inhibits dopamine activity in the mesolimbic pathways, which helps manage manic and psychotic symptoms, while activating the mesocortical dopamine pathways to improve depressive and cognitive symptoms. Additionally, APZ stabilizes the 5-HT system, contributing to its efficacy in mood regulation. APZ also has the potential to regulate the circadian central clock, specifically the hypothalamic suprachiasmatic nucleus (SCN), by modulating intracellular signaling pathways such as 5-HT1AR-mediated cAMP signaling. This action helps desynchronize SCN neurons and enhances entrainment to phase-advanced light-dark cycles [25]. Given that several studies have implicated the dopamine system in regulating the sleep-wake cycle [26–29] APZ’s stabilization of the dopamine system likely plays a significant role in treating DSWP syndrome/disorder.

However, caution is needed when interpreting the conclusions of this study. First, all participants were in manic or mixed episodes at the time of the study, so the effectiveness of APZ for bipolar depression with DSWP syndrome/disorder remains uncertain. Second, the diagnosis of DSWP syndrome was not based on objective measures such as sleep diaries, actigraphy, or biological indices Like body temperature or serum melatonin levels, which could impact the validity of the diagnosis. Third, the APZ doses in this study ranged from 2.5 mg/day to 30 mg/day. While this range is higher than typically used for DSWP symptoms in depression as an adjunctive treatment, it is lower than doses commonly used for BD [30]. This variability makes it difficult to determine the optimal dose for treating BD with DSWP syndrome/disorder. A previous clinical trial [30] has shown that fixed high doses of APZ are associated with higher dropout rates. Given APZ’s non-linear pharmacokinetic profile, an individualized and dynamic dosing strategy may be essential for effective treatment. Finally, this study has inherent limitations typical of case reports, including a small sample size, retrospective data collection, lack of control groups, open-label design, and limited ability to establish causality.

Limitations

Due to the lack of a control group or randomization in this small case series, further research is needed to generalize this result to a larger population. As a small sample study, the results may not be generalizable to a wider population. Due to the reliance on retrospective data, some clinical information may not be fully recorded, resulting in recall bias or selection bias in the analysis. The limited long-term follow-up data of patients may affect the comprehensive evaluation of disease prognosis or treatment effectiveness.

Abbreviations

APZ

Aripiprazole

BD

Bipolar disorder

BMI

Body mass index

CGI-S

Clinical Global Impressions-Severity

CRSWPD

Circadian rhythm sleep-wake phase disorders

DSWP

Delayed sleep-wake phase

DSWPD

Delayed sleep-wake phase disorder

DSWPS

Delayed sleep-wake phase syndrome

5-HT

5-hydroxytryptamine

GAD

Generalized anxiety disorder

MDD

Major depressive disorder

ICSD-3

The International Classification of Sleep Disorders, 3rd edition

ICD-10

The diagnostic criteria of the International Classification of Diseases, 10th Revision

SCN

Suprachiasmatic nucleus

Authors’ contributions

Li Tong and Yang Ting extracted and interpreted patient information from the medical records under the guidance and supervision of Gan Zhaoyu. Li Tong wrote the first draft of the manuscript, while Yang Ting and Lin Yuchen made substantial contributions to the editing and final draft. All authors read and approved the final manuscript.

Funding

None.

Data availability

Data is provided within the manuscript.

Declarations

Ethics approval and consent to participate

The study was approved by the Clinical Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University (II2023-188-02). The use of this information in the study was also approved by all participants and their guardians, with written informed consent provided. Our study adhered to the Declaration of Helsinki.

Consent for publication

All authors agree to publish. All participants and their guardians gave written informed consent for their personal or clinical details along with any identifying images to be published in this study.

Competing interests

The authors declare no competing interests.