Disturbance In Bipolar Disorder Research Articles

Sleep Disturbance in Bipolar Disorder. Treatment Implications

IntroductionRelationship between sleep and bipolar disorder involves the following aspects: decreased need for sleep is a fundamental marker of the manic state, sleep deprivation is one cause of mania and may in fact be a fundamental etiological agent in mania, total sleep time is a predictor of future manic episodes, and total sleep time may be a marker of response as well as a target of treatment in mania.ObjectivesThis e-poster aimed to summarize evidence regarding the sleep disturbance in Bipolar Disorder.MethodsBibliopgraphical review was performed using PubMed platform. All relevant articles were found using the keywords: sleep disturbance, bipolar disorder, mania.ResultsSleep disturbances are frequent in BD patients in different phases of illness, including the euthymic state and remission. These sleep aberrations are represented not only by insomnia but also by sleep–wake rhythm disorders, especially delayed sleep–wake phase disorders. During the manic state, most patients experience a reduced need for sleep and longer sleep onset latency. Likewise, in the depressive state, insomnia and hypersomnia are commonly observed. Meta-analyses of trials conducted on remitted BD patients demonstrated prolonged total sleep time, increased awakenings after sleep onset, greater variability of sleep–wake variables, and reduced sleep efficiency.ConclusionsOverall, all kinds of sleep disorders and parasomnias are very common especially in youth patients with BD. Thus, compared to the general population, youth with BD exhibit lower sleep efficiency, longer slow wave sleep, and reduced REM sleep, features that could affect the genesis and prognosis of the disorder. Sleep disturbances may also be used as predictors of the onset of BD in a subset of high-risk young subjects.Disclosure of InterestNone Declared

A comparative study of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in bipolar mania and schizophrenia

Objectives The role of immunological disturbance in bipolar disorder (BD) and schizophrenia has been highlighted by some studies. There are few studies available that compared the inflammatory markers between schizophrenia and BD, but only one study demonstrated the difference in terms of neutrophil/lymphocyte ratio (NLR) and Platelet/lymphocyte ratio (PLR) between them. So this study was conducted to compare the NLR and PLR values among schizophrenia, bipolar mania, and healthy controls in order to find out a potential biomarker for these disorders. Material and Methods Eighty consecutive patients suffering from bipolar mania, 80 suffering from schizophrenia, and 80 healthy controls were recruited in the psychiatric center situated at a tertiary care hospital. Blood samples of all groups were transferred to the laboratory for complete blood count analysis. Thereafter, all the groups were compared by applying proper statistics. Results Significant higher level of neutrophil count and NLR value was seen in both bipolar mania and schizophrenia groups compared to healthy controls. There was no difference observed between schizophrenia and the bipolar mania group regarding NLR, PLR, neutrophils, lymphocytes, and platelets values. Conclusion NLR has appeared as a potential marker in our study, and it reflects a state of low-grade inflammation in both schizophrenia and bipolar mania. BD and schizophrenia have been considered as part of one continuum, which is also supported by the findings of our study. These markers can help in the prognosis and treatment of at least a subsection of patients and also are inexpensive and easy to assess.

Hypnotic and Melatonin/Melatonin-Receptor Agonist Treatment in Bipolar Disorder: A Systematic Review and Meta-Analysis.

Bipolar disorder (BD) is a chronic relapsing-remitting psychiatric disorder. Sleep and circadian rhythm disturbances persist during acute mood episodes of the disorder and during euthymia. However, the treatment potential of hypnotic agents that might be used to manage sleep disturbance in BD is not well understood. Similarly, melatonin and medications with a melatonin-receptor agonist mechanism of action may have chronotherapeutic potential for treating people with the disorder, but the impact of these substances on sleep and circadian rhythms and core symptoms in BD is unclear. Our aim was to conduct a systematic review and meta-analysis evaluating the current evidence for hypnotic and melatonin/melatonin-receptor agonist pharmacotherapy for symptoms of sleep disturbance, mania, and depression in patients with BD. AMED, Embase, MEDLINE and PsychINFO databases were searched for studies published in English from the date of inception to 31 October 2021. Studies included in this review were randomised controlled trials (RCTs) and non-controlled/non-randomised studies for BD that examined hypnotic medications selected based on a common pattern of usage for treating insomnia (i.e. chloral, clomethiazole, diphenhydramine, doxepin, doxylamine, promethazine, suvorexant, zaleplon, zolpidem, zopiclone, and eszopiclone) and melatonin and the melatonin-receptor agonist drugs ramelteon and agomelatine. Risk of bias was assessed using the RoB2 and AXIS tools. Pooled effect sizes for RCT outcomes were estimated using random-effects models. A total of eleven studies (six RCTs and five experimental feasibility studies) involving 1279 participants were included. Each study examined melatonin or melatonin-receptor agonists. No studies of hypnotics were found that fulfilled the review inclusion criteria. Pilot feasibility studies suggested beneficial treatment effects for symptoms of sleep disturbance, depression, and mania. However, the pooled effect of the two available RCT studies assessing sleep quality via Pittsburgh Sleep Quality Index scores was not statistically significant (g=-0.04 [95% CI -0.81 to 0.73]) and neither was the pooled effect for depressive symptoms (four studies; g=-0.10 [95% CI -0.27 to 0.08]). Some RCT evidence suggests ramelteon might prevent relapse into depression in BD. The largest efficacy signal detected was for manic symptoms (four studies; g=-0.44 [95% CI -1.03 to 0.14]) but there was substantial heterogeneity between studies and patient characteristics. In the two RCTs assessing manic symptoms during acute mania, adjunctive melatonin demonstrated superior treatment effects versus placebo. There is a paucity of studies examining pharmacological interventions for sleep and circadian rhythm disturbance in BD. Few studies assessed sleep-related symptoms, and none quantitatively examined endogenous melatonin patterns or other circadian rhythms. Melatonin may be a promising candidate for the adjunctive treatment of bipolar mania. However, dose-finding studies and studies with larger sample sizes are needed to confirm its efficacy. We recommend parallel monitoring of sleep and circadian rhythms in future trials. Chronobiology-informed trial designs are needed to improve the quality of future studies. PROSPERO (CRD42020167528).

Commentary: Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms.

Commentary: Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms.

Thought and language disturbance in bipolar disorder quantified via process-oriented verbal fluency measures

Bipolar disorder (BD) is characterized by speech abnormalities, reflected by symptoms such as pressure of speech in mania and poverty of speech in depression. Here we aimed at investigating speech abnormalities in different episodes of BD, including mixed episodes, via process-oriented measures of verbal fluency performance – i.e., word and error count, semantic and phonological clustering measures, and number of switches–, and their relation to neurocognitive mechanisms and clinical symptoms. 93 patients with BD – i.e., 25 manic, 12 mixed manic, 19 mixed depression, 17 depressed, and 20 euthymic–and 31 healthy controls were administered three verbal fluency tasks – free, letter, semantic–and a clinical and neuropsychological assessment. Compared to depression and euthymia, switching and clustering abnormalities were found in manic and mixed states, mimicking symptoms like flight of ideas. Moreover, the neuropsychological results, as well as the fact that error count did not increase whereas phonological associations did, showed that impaired inhibition abilities and distractibility could not account for the results in patients with manic symptoms. Rather, semantic overactivation in patients with manic symptoms, including mixed depression, may compensate for trait-like deficient semantic retrieval/access found in euthymia.“For those who are manic, or those who have a history of mania, words move about in all directions possible, in a three-dimensional ‘soup’, making retrieval more fluid, less predictable.” Kay Redfield Jamison (2017, p. 279).

Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms.

The worldwide prevalence of sleep disorders is approximately 50%, with an even higher occurrence in a psychiatric population. Bipolar disorder (BD) is a severe mental illness characterized by shifts in mood and activity. The BD syndrome also involves heterogeneous symptomatology, including cognitive dysfunctions and impairments of the autonomic nervous system. Sleep abnormalities are frequently associated with BD and are often a good predictor of a mood swing. Preservation of stable sleep–wake cycles is therefore a key to the maintenance of stability in BD, indicating the crucial role of circadian rhythms in this syndrome. The symptom most widespread in BD is insomnia, followed by excessive daytime sleepiness, nightmares, difficulty falling asleep or maintaining sleep, poor sleep quality, sleep talking, sleep walking, and obstructive sleep apnea. Alterations in the structure or duration of sleep are reported in all phases of BD. Understanding the role of neuroglia in BD and in various aspects of sleep is in nascent state. Contributions of the different types of glial cells to BD and sleep abnormalities are discussed in this paper.

Light exposure at night and sleep quality in bipolar disorder: The APPLE cohort study

BackgroundSleep disturbance in bipolar disorder (BD) is common and is associated with a risk for mood episode recurrence. Thus, it is important to identify factors that are related to sleep disturbance in BD. This cross-sectional study investigated the association between exposure to light at night (LAN) and sleep parameters in patients with BD. MethodsThe sleep parameters of 175 outpatients with BD were recorded using actigraphy at their homes for seven consecutive nights and were evaluated using the Insomnia Severity Index (ISI). The average LAN intensity in the bedroom during bedtime and rising time was measured using a portable photometer, and the participants were divided into two groups: “Light” (≥5 lx) and “Dark” (<5 lx). The association between LAN and sleep parameters was tested with multivariable analysis by adjusting for potential confounder such as age, gender, current smoker, mood state, day length, daytime light exposure, and sedative medications. ResultsAfter adjusting for potential confounder, the actigraphy sleep parameters showed significantly lower sleep efficiency (mean, 80.1%vs. 83.4%; p = 0.01), longer log-transformed sleep onset latency (2.9 vs. 2.6 min; p = 0.01), and greater wake after sleep onset (51.4 vs. 41.6 min; p = 0.02) in the Light group than in the Dark group. Whereas, there were no significant differences in the ISI scores between the groups. LimitationsThis was a cross-sectional study; therefore, the results do not necessarily imply that LAN causes sleep disturbance. ConclusionsReducing LAN exposure may contribute to improved sleep quality in patients with BD.

Disruptions in resting state functional connectivity in euthymic bipolar patients with insomnia symptoms

Insomnia is prevalent in bipolar disorder (BD) even during periods of euthymic mood. We compared resting state brain activity and cognitive function between euthymic BD with and without insomnia, and secondarily to healthy individuals. BD patients with insomnia symptoms showed a significantly lower functional connectivity within the task-positive network, compared to those without insomnia. They also showed significantly slower cognitive processing speed. These two features of BD with insomnia appeared relatively independent of each other. Preliminary findings suggest that exploration of the mechanisms of sleep disturbance in BD could lead to improved understanding and treatment of inattention in BD.

Hypersomnia: an overlooked, but not overestimated, sleep disturbance in bipolar disorder

ABSTRACT FROM: Steinan MK, Scott J, Lagerberg TV, et al . Sleep problems in bipolar disorders: more than just insomnia. Acta Psychiatr Scand 2016;133:368–77. Sleep disturbances are common across bipolar...

Sleep and circadian rhythm disturbance in bipolar disorder.

Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls. Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires. Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL. BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.

The association between insomnia-related sleep disruptions and cognitive dysfunction during the inter-episode phase of bipolar disorder

Sleep disturbance and cognitive dysfunction are two domains of impairment during inter-episode bipolar disorder. Despite evidence demonstrating the importance of sleep for cognition in healthy and sleep-disordered samples, this link has been minimally examined in bipolar disorder. The present study tested the association between insomnia-related sleep disruptions and cognitive dysfunction during inter-episode bipolar disorder. Forty-seven participants with bipolar disorder and a comorbid insomnia diagnosis (BD-Insomnia) and 19 participants with bipolar disorder without sleep disturbance in the last six months (BD-Control) participated in the study. Two domains of cognition were assessed: working memory and verbal learning. Insomnia-related sleep disruptions were assessed both categorically (i.e., insomnia diagnosis) and dimensionally (i.e., total wake time, total sleep time, total wake time variability, and total sleep time variability). Hierarchical linear regressions, adjusting for participant age, demonstrated that insomnia diagnosis did not have an independent or interactive effect on cognition. However, regardless of insomnia diagnosis, greater total sleep time variability predicted poorer working memory and verbal learning performance. Further, following sleep treatment, a reduction in total wake time predicted improved working memory performance and a reduction in total sleep time variability predicted improved verbal learning performance. These findings raise the possibility that sleep disturbance may contribute to cognitive dysfunction in bipolar disorder and highlight the importance of treating sleep disturbance in bipolar disorder.

The role of sleep in bipolar disorder.

Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep–wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder.

Emotion in bipolar I disorder: Implications for functional and symptom outcomes.

Despite the centrality of emotion disturbance in neurobiological models of bipolar disorder, the behavioral literature has not yet clearly identified the most central aspects of emotion disturbance in bipolar disorder. Toward this aim, we gathered a battery of emotion-related measures in 67 persons diagnosed with bipolar I disorder as assessed with the SCID and a well-matched control group of 58 persons without a history of mood disorders. Those with bipolar disorder were interviewed monthly until they achieved remission, and then tested on emotion measures. A subset of 36 participants with bipolar disorder completed symptom severity interviews at 12-month follow-up. Factor analyses indicated 4 emotion factor scores: Negative Emotion, Positive Emotion, Reappraisal, and Suppression. Bivariate analyses suggested that bipolar disorder was tied to a host of emotion disturbances, but multivariate analyses suggested that bipolar disorder was particularly tied to elevations of Negative Emotion. High Negative Emotion, low Positive Emotion, and high Suppression were conjointly related to lower functioning. Reappraisal predicted declines in depression over time for those with bipolar disorder. Findings highlight the importance of considering the overall profile of emotion disturbance in bipolar disorder. Emotion and emotion regulation appear central to a broad range of outcomes in bipolar disorder.

Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder

BackgroundSleep disturbance in bipolar disorder (BD) is common during and between mood episodes. In recovered (euthymic at least two months) BD patients, we assessed sleep compared to controls and its relationships with residual mood symptoms and mood episode recurrence. MethodRecovered Stanford University BD Clinic patients diagnosed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation and monitored with the STEP-BD Clinical Monitoring Form (CMF) for >1 year and healthy controls completed the Pittsburgh Sleep Quality Index (PSQI). PSQI parameters were compared in BD patients versus controls, and the most robustly differentiating PSQI parameter was assessed in relationship to residual mood symptoms, and time to mood episode recurrence in BD patients. ResultsEighty nine recovered BD patients compared to 56 healthy controls had significantly worse PSQI global score, more sleep medication use, longer sleep latency, and worse daytime dysfunction. PSQI global score had the greatest BD patient versus control effect size, and among BD patients, correlated significantly with residual mood symptoms and predicted earlier mood episode recurrence, even after covarying for residual mood symptoms. LimitationsUse of subjective (PSQI) rather objective (polysomnography) sleep metric. Statistical power limited by small sample size. Potential psychotropic medication confound. Northern California tertiary BD clinic referral sample. ConclusionFurther research is needed to confirm that in recovered BD patients, poor sleep quality correlates with residual mood symptoms, and independently predicts mood episode recurrence. If confirmed, these observations suggest potential mood benefit for focusing on sleep quality in interventions for recovered BD patients.

Interventions for Sleep Disturbance in Bipolar Disorder.

Bipolar disorder is a severe and chronic disorder, ranked in the top 10 leading causes of disability worldwide. Sleep disturbances are strongly coupled with interepisode dysfunction and symptom worsening in bipolar disorder. Experimental studies suggest that sleep deprivation can trigger manic relapse. There is evidence that sleep deprivation can have an adverse impact on emotion regulation the following day. The clinical management of the sleep disturbances experienced by bipolar patients, including insomnia, hypersomnia delayed sleep phase, and irregular sleep-wake schedule, may include medication approaches, psychological interventions, light therapies and sleep deprivation.

Effect of quetiapine XR on depressive symptoms and sleep quality compared with lithium in patients with bipolar depression

BackgroundBipolar depression is one of the most serious psychiatric conditions. In addition, sleep disturbance in bipolar disorder is common, and therapeutic agents restoring sleep disturbances in bipolar disorder patients will be clinically beneficial. In the current study, we compared the effect of quetiapine XR with lithium on depressive symptoms and sleep in bipolar depression patients during 8 weeks of trial. MethodsAn open-label, randomized comparison of sleep-activity and depressive symptoms between 8-week quetiapine XR monotherapy and lithium monotherapy for bipolar depression was conducted. Each assessment consisted of HDRS-17, Clinical Global Impression-severity (CGI-S), and self-reported Pittsburgh Sleep Quality Index (PSQI). Actigraphy-measured sleep parameters were assessed. ResultsA total of 42 patients (35.7±10.9 years; gender: male 15, female 27) with bipolar depression were screened out. Out of 42 patients, six patients were excluded before randomization. After randomization, seven patients were withdrawn. Twenty-nine patients with more than two visits after randomization (lithium group: 17, quetiapine XR group: 12, mean age: 36.1±10.4, gender: male 13, female 16) were included in the final analysis. In both groups, Hamilton Depression Rating Scale (HDRS) scores were significantly decreased at weeks 1, 2, 4, 6, and 8 compared with baseline. Remission rate (HDRS≤7) in the quetiapine XR was significantly higher than that of the lithium group. In the quetiapine XR group, PSQI scores at weeks 1, 2, 4, 6, and 8 was significantly decreased compared with baseline. Sleep efficiency at weeks 6 and 8 was significantly increased. WASO at week 8 was significantly decreased. LimitationsFirst, the present study was conducted with the relatively small number of study subjects. Second, bias could have affected the study results due to its open-label design. Third, study subjects were made up of high proportion of bipolar II disorder patients. ConclusionsQuetiapine XR monotherapy was more effective in treating bipolar depression than lithium. In particular, quetiapine XR treatment improved both subjective and objective sleep quality in patients with bipolar depression. However, relationship between favorable sleep quality and depressive symptom improvement were limited.

A Novel Home Sleep Monitoring Device and Brief Sleep Intervention for Bipolar Disorder: Feasibility, Tolerability, and Preliminary Effectiveness

Sleep disturbance is common in bipolar disorder and negatively impacts its course of illness. The purpose of this study is to assess the feasibility and tolerability of a novel EKG-based home sleep monitoring device (M1) as well as a brief (two session) psychosocial sleep intervention for individuals with bipolar disorder. The sleep intervention is individually tailored for patients with insomnia or hypersomnia and is designed to extend skills designed for non-psychiatric populations as well as include specific considerations for sleep disturbance in bipolar disorder. We found that both the M1 monitor and the sleep intervention were feasible and well tolerated. Participants' sleep duration improved after the brief sleep intervention, but the sleep was more unstable as measured by the M1. Self-reported sleepiness, sleep quality, and mood symptoms improved; however, only some measures reached statistical significance (i.e., duration of sleep, dysfunction due to sleepiness). These data suggest that the M1 device is a feasible means to obtain objective sleep quality and quantity data in individuals with bipolar disorder. A brief sleep intervention may be helpful in improving sleep in a bipolar population at risk for substantial sleep disturbance, but larger, longitudinal studies are warranted.

The prevalence of metabolic syndrome in drug-naïve bipolar II disorder patients before and after twelve week pharmacological intervention

BackgroundAccumulating evidence indicates a high prevalence rate of metabolic disturbance in bipolar disorder (BP) patients. However, the prevalence across BP subtypes has been investigated to a lesser degree. In the current study, we surveyed the prevalence of metabolic syndrome among drug-naïve bipolar II patients. Moreover, the effects of pharmacological treatment on metabolic indexes were also evaluated. MethodsThis study recruited fifty-six drug-naïve BP II patients diagnosed according to the DSM-IV criteria. Among them, forty-four patients completed a 12-week pharmacological intervention with valproic acid, fluoxetine and lorazepam. Metabolic profiles and body mass index (BMI) were measured at baseline and 2 weeks, 8 weeks, and 12 weeks after receiving medication. ResultsThe mean age of the 56 patients was 30.3±11.1. Before receiving medication, 6.5% of the patients met the ATP III criterion for metabolic syndrome. Among the 44 patients who completed the 12-week pharmacological intervention, the prevalence of metabolic syndrome increased from 7% to 10%. Repeated measurements showed that the changes in metabolic indexes were not significant, with the exceptions of BMI, waist circumference, and buttock circumference. In addition, the interaction between the improvement of hypomanic symptoms and BMI change was significant. LimitationsThe study was limited by the follow-up duration and sample size. ConclusionsIn drug-naïve BP II patients, the prevalence of metabolic syndrome was significantly lower than that observed before in BP I patients. However, medications use was also associated with an increased risk of metabolic disturbance, although the impact was lesser. Clinical evidence suggests that metabolism and emotion homeostasis might share common mechanisms.

A Review and Synthesis of Positive Emotion and Reward Disturbance in Bipolar Disorder

Although positive emotion research has begun to flourish, the extremes and potential costs of positive emotion remain understudied. This is an ideal clinical model for studying the ways in which positive emotions are disrupted in bipolar disorder. Bipolar disorder is characterized by extreme bouts of expansive and persistent positive feelings. This paper reviews recent experimental studies, selectively examining positive emotion, in individuals at risk for, and diagnosed with, bipolar disorder. As an extension of this body of work, I present an account of positive emotion disturbance in bipolar disorder, referred to as positive emotion persistence. Implications are discussed for the study of bipolar disorder and positive emotion that follow.

Functional impact of biological rhythm disturbance in bipolar disorder

Bipolar disorder (BD) is characterized by frequent recurrence, incomplete recovery, cognitive dysfunction and poor functioning. Impairment lingers in the interepisodic period and mechanisms leading to this dysfunctional state are not fully comprehended. To our knowledge the association of biological rhythm dysfunction with functioning in BD has not been assessed directly. The objective of this study was to measure and quantify the impact of rhythm dysfunction on interepisodic functioning in BD. We also tested the association between executive functioning and sleep and rhythm problems. Eighty-one outpatients with BD and 79 matched control subjects were consecutively recruited. Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and biological rhythms with the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). A subsample had their executive functioning assessed with the Wisconsin Card Sorting Test (WCST). Patients and control subjects were well matched. Functioning and rhythm scores were correlated in patients and control subjects. The BRIAN score was the strongest predictor of functioning in the regression model. Biological rhythms partially mediated the impairment associated with bipolar disorder. The rhythm score was also associated with executive functioning. Biological rhythm dysfunction was a potent predictor of functioning in interepisodic patients with bipolar disorder; it may also mediate much of the disorder-induced disability. These results further the notion that biological rhythms may be interesting targets for diverse interventions aiming to improve functioning and prevent relapse in interepisodic bipolar disorder.