Aripiprazole monotherapy in the treatment of bipolar disorder: a meta-analysis

Introduction

Aripiprazole is approved for the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder. The aim of the present work was to review and meta-analyze the findings of all the available randomized double-blind controlled trials (RCTs) on the efficacy of aripiprazole in the treatment of bipolar disorder.

Material and methods

Aripiprazole RCTs were identified with a systematic search of MEDLINE and repositories. Standard meta-analytic techniques were applied.

Results

Two thousand three hundred and three patients took part in the aripiprazole acute mania RCTs. At week 3 the pooled aripiprazole vs. placebo effect size was 0.34 and the NNT was 6 for response and 14 for remission. On average, response started at day 3. Suicide rates were negligible for all groups in mania but they were not reported in the acute depression trials. The meta-analysis of acute bipolar depression RCTs revealed a significant difference at week 8 with a weak effect size equal to 0.17. The analysis of maintenance data suggest that the median survival time for the aripiprazole group was not evaluable (very long), while the median survival time for placebo was 118-203 days depending on the clinical subpopulation.

Discussion

The current meta-analysis supports the usefulness of aripiprazole during all phases of bipolar illness. Its effect against acute bipolar depression is weak and the efficacy during the maintenance phase is proven only against new manic episodes in patients with an index manic episode who had previously responded to aripiprazole during the acute phase.     

The clinical utility of different quantitative methods for measuring treatment resistance in major depression

Background

Despite the acknowledged healthcare and economic burdens of chronic major depression, there is no agreed method to rate the degree to which patients are conceptualised as being refractory to treatment. There are a variety of tools which can be used to describe treatment resistance but their utility in clinical practice is uncertain.

Methods

We used a range of contemporary tools to rate the treatment histories of patients in a variety of care settings which included: primary care; affective disorders specialist clinics; patients receiving ECT; referrals to a tertiary affective disorders service; and patients undergoing neurosurgical treatment (vagus nerve stimulation or anterior cingulotomy) for chronic, refractory major depression.

Results

All tools demonstrated statistically significant differences in scores between care settings, as well as between tiers of service, although differences between some groups were small and confidence intervals were wide. The Massachusetts General Hospital staging method appeared to perform as well as more complex scoring methods and represents a reasonable compromise between time to complete and its ability to inform management decisions.

Limitations

Numbers in some groups were low, but are likely to be representative. The ability of such tools to predict outcome was not examined and the proposed cut-offs require validation.

Conclusions

Currently available staging methods appear to have the ability to differentiate between clinically-relevant sub-groups of patients with major depression. Further development of such tools is warranted due to their ability to not only describe characteristics of patients in different care settings, but also meet the need to have meaningful cut-offs which might guide referral to specialist treatment.     

Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: A medium-term evaluation of cost benefits

Background

We earlier reported an open study of 50 unipolar and bipolar treatment resistant depressed patients indicating that psychostimulants may have differential superiority for the melancholic depressive sub-type. We designed an extension study to examine cost benefits of psychostimulants more closely for those only with melancholic depression.

Method

The sample comprised patients clinically diagnosed with melancholic depression who had failed to respond to and/or experienced significant side-effects with at least two antidepressants. Data were collected for 61 unipolar and 51 bipolar II patients receiving a psyschostimulant for a mean interval of 69 weeks. Benefits and side-effects were assessed.

Results

Effectiveness ratings were similar across unipolar and bipolar sub-sets. Psychostimulants were judged as ‘very’ effective for 20% of patients and ‘somewhat’ effective for 50%. Forty percent judged the psychostimulant as being ‘as effective’ or as ‘superior’ to previously prescribed antidepressants, and worthy of being maintained. Significant side-effects were experienced by 40% of patients, requiring medication to be ceased in 12%. Twenty percent of the bipolar patients experienced a worsening of highs.

Limitations

The study was uncontrolled and retrospective, no formal rater-completed or patient-completed interval measures of severity were completed, while diagnostic judgments about melancholic depression and bipolar disorder were clinically judged.

Conclusions

This open study suggests that psychostimulants may be efficacious antidepressant options for managing unipolar and bipolar melancholia, often seemingly having very rapid onset and generally requiring only low doses, and arguing the need for controlled studies in melancholic patients.     

The high prevalence of obstructive sleep apnea among patients with bipolar disorders

Introduction: Sleep plays an important role in maintaining stability in bipolar disorders, and sleep disturbances can trigger mood episodes. Obstructive sleep apnea (OSA) is a common sleep disorder, yet the co-occurrence with bipolar disorder has not been methodically studied. Methods: This is a chart review of 482 consecutively seen patients with a bipolar disorder who underwent routine screening for OSA using a self-report sleep apnea questionnaire. Positive screens were referred for a sleep study. Results: A positive screen was found in 214 (44.4%) patients. Sleep studies were obtained on 114 patients, and 101, were diagnosed with OSA: point prevalence 21%. Discussion: The 21% prevalence fails to consider the false negative rate of the questionnaire, or the exclusion of patients who screened positive but failed to get a sleep study. Taking these into consideration it is estimated that the true prevalence of OSA in this study may be as high as 47.5%. The co-occurrence of OSA and bipolar disorders is markedly higher than previously thought. Of note, OSA may play a role in refractory bipolar, disorders, and carries significant mortality and morbidity that overlap, with the mortality and morbidity found with bipolar disorders. Limitations: This was a retrospective study based on a self-report questionnaire. Polysomnographic confirmation was performed in only a subgroup of subjects. Conclusions: The data suggest that unrecognized OSA may play a major role in the mortality and morbidity of bipolar disorders. All patients diagnosed with a bipolar disorder should be screened with an OSA questionnaire.     

Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder

Imaging studies indicate smaller orbitofrontal cortex (OFC) volume in mood disorder patients compared with healthy subjects. We sought to determine whether child and adolescent patients with bipolar disorder have smaller OFC volumes than healthy controls. Fourteen children and adolescents meeting DSM-IV criteria for bipolar disorder (six males and eight females with a mean age+/-S.D.=15.5+/-3.2 years) and 20 healthy controls (11 males and nine females with mean age+/-S.D.=16.9+/-3.8 years) were studied. Orbitofrontal cortex volume was measured using magnetic resonance imaging. Male bipolar patients had smaller gray matter volumes in medial (p=0.044), right medial (0.037) and right (p=0.032) lateral OFC subdivisions compared to male controls. In contrast, female patients had larger gray matter volumes in left (p=0.03), lateral (p=0.012), left lateral (p=0.007), and trends for larger volumes in right lateral and left medial OFC subdivisions compared with female controls. Male patients exhibit smaller gray matter volumes, while female patients exhibit larger volumes in some OFC sub-regions. Gender differences in OFC abnormalities may be involved in illness pathophysiology among young bipolar patients.     

The development of a motivational interviewing intervention to promote medication adherence among inner-city, African-American adolescents with asthma

Objective

To develop and assess the feasibility of a motivational interviewing (MI) based asthma self-management program for inner-city, African-American, adolescents with asthma.

Methods

37 African-American adolescents (age 10-15 years) recently seen in an inner-city emergency department for asthma and prescribed an asthma controller medication participated in the newly developed program consisting of 5 home visits. Adolescents and their caregivers completed phone-based surveys before and after the intervention.

Results

95% of the adolescents completed all 5 sessions; 89% of caregivers and 76% of adolescents believed other families would benefit from the intervention. Caregivers were more likely to report 100% adherence post-intervention compared to pre-intervention and reported a trend for adolescents taking greater responsibility for their asthma. There were no pre-post-differences in adolescent-reported medication adherence, but adolescents did reported increased motivation and readiness to adhere to treatment. Caregivers and adolescents each reported statistically significant increases in their asthma quality of life.

Conclusions

The findings from this pilot study suggest that MI is a feasible and promising approach for increasing medication adherence among inner-city adolescents with asthma and is worthy of further evaluation in a randomized trial.

Practice Implications

Incorporating MI into disease management programs may enhance their effectiveness.     

Association of exercise with quality of life and mood symptoms in a comparative effectiveness study of bipolar disorder

Background

Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health.

Methods

The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed.

Results

Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms.

Limitations

Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited.

Conclusion

There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively.     

The effects of respiratory sinus arrhythmia on anger reactivity and persistence in major depression

The experience of anger during a depressive episode has recently been identified as a poor prognostic indicator of illness course. Given the clinical implications of anger in major depressive disorder (MDD), understanding the mechanisms involved in anger reactivity and persistence is critical for improved intervention. Biological processes involved in emotion regulation during stress, such as respiratory sinus arrhythmia (RSA), may play a role in maintaining negative moods. Clinically depressed (MDD; n = 49) and nondepressed (non‐MDD; n = 50) individuals were challenged with a stressful computer task shown to increase anger, while RSA (high frequency range 0.15–0.4 Hz) was collected. RSA predicted future anger, but was unrelated to current anger. That is, across participants, low baseline RSA predicted anger reactivity during the task, and in depressed individuals, those with low RSA during the task had a greater likelihood of anger persistence during a recovery period. These results suggest that low RSA may be a psychophysiological process involved in anger regulation in depression. Low RSA may contribute to sustained illness course by diminishing the repair of angry moods.     

Autonomic correlates of lifetime suicidal thoughts and behaviors among adolescents with a history of depression

Suicidal thoughts and behaviors (STBs) have been associated with emotion dysregulation and atypical responses to affective and stressful stimuli. To investigate the psychophysiology involved, we measured changes in respiratory sinus arrhythmia (RSA) and cardiac pre‐ejection period (PEP; indexing parasympathetic and sympathetic functioning, respectively) in response to stressful‐ and sadness‐eliciting laboratory probes. Our sample included adolescents with a history of depression and STBs (n = 177), adolescents with a history of depression but no history of STBs (n = 47), and healthy controls (n = 175). The outcome of interest was the most severe form of clinician‐rated STBs across the subject’s lifetime. In partial support of our hypotheses, during the stressful task, adolescents with a history of depression and STBs did not evidence the RSA decrease that was exhibited by controls and displayed greater PEP shortening compared to ever‐depressed adolescents with no lifetime STBs. No group differences were found in either RSA or PEP reactivity to the sadness‐eliciting stimulus. As expected, severity of STBs was positively correlated with the extent of PEP shortening during the stressful task. The results suggest that adolescents with a history of depression and STBs experience blunted parasympathetic responses to stress along with compensatory efforts. Our findings contribute to a better understanding of STBs among youths and underscore that future studies should examine physiological risk factors for these psychopathological outcomes.     

Attachment and temperament profiles among the offspring of a parent with bipolar disorder

Introduction

Attachment is associated both with the risk of developing a mood disorder and temperamental profile. Relatively little is known about these associations in children of a parent with bipolar disorder (BD). The present study is a preliminary analysis of the association between attachment, temperament and psychopathology among high-risk offspring.

Methods

As part of an ongoing prospective cohort study, offspring from families with one parent with BD (HR) and offspring from families with unaffected parents (C) were clinically assessed using KSADS-PL format interviews annually. Validated self-report measures of perceived attachment and temperament were completed.

Results

Perceived attachment did not differentiate HR from C offspring and did not predict psychopathology or mood disorder in particular. However, high emotionality significantly predicted the risk of psychopathology in HR offspring, where 1 standard deviation increase in emotionality significantly increased the hazard of psychopathology by a factor of 1.36 (p=0.0009) and mood disorder by a factor of 1.24 (p=0.02).

Limitations

Use of retrospective measures and low sample size for some models.

Conclusions

There may be no gross abnormalities in attachment among HR compared to C offspring. It remains unclear if emotionality is a barometer of illness or a true risk factor in this population. More longitudinal research is needed to advance understanding of the influential pathways by which psychosocial risk factors impact the development of BD. This research has implications for targeted early interventions in HR youth.     

Gender differences in the longitudinal structure of cognitive diatheses for depression in children and adolescents

In a school-based, four-wave, longitudinal study, children (grades 4–7) and young adolescents (grades 6–9) completed questionnaires measuring depressive symptoms and depressive cognitions, including positive and negative cognitions on the Cognitive Triad Inventory for Children (CTI-C; Kaslow, Stark, Printz, Livingston, & Tsai, 1992) and self-perceived competence on the Self-Perception Profile for Children (SPPC; Harter, 1985). Application of the Trait-State-Occasion model (Cole, Martin, & Steiger, 2005) revealed the existence of a time-invariant trait factor and a set of time-varying occasion factors. Gender differences emerged, indicating that some cognitive diatheses were more trait-like for girls than for boys (i.e., positive and negative cognitions on the CTI-C; self-perceived physical appearance and global self-worth on the SPPC). Implications focus on the emergent gender difference in depression, the design of longitudinal studies, and clinical decisions about the implementation of prevention versus intervention programs. © 2009 Wiley Periodicals, Inc. J Clin Psychol 65:1–15, 2009.     

An assessment of patient preference and adherence to treatment with Wellbutrin SR: a web-based survey

BACKGROUND: Research has shown that lack of treatment adherence is a serious problem, especially among patients with psychiatric disorders. The current study was conducted to assess adherence and patient preference among individuals taking Wellbutrin SR (bupropion) for depression, as well as their interest in a once-daily formulation of bupropion. METHODS: A 20-item web-based survey was administered to 527 individuals (276 men and 251 women) recruited through an online panel. All participants were at least 18 years of age, diagnosed with major depressive disorder, and had been taking Wellbutrin SR for at least 6 weeks. Survey items addressed treatment regimen, adherence, satisfaction with Wellbutrin SR, and interest in a once-daily formulation of bupropion. RESULTS: The majority of respondents reported taking Wellbutrin SR twice a day (67%). Only 15% of once-daily users were nonadherent compared to 37% of twice-daily users and 65% of thrice-daily users. The most common reason reported for missing a dose of Wellbutrin SR was simply forgetting to take it (49% of twice-daily users and 65% of thrice-daily users). Results indicated that 77% of twice-daily users and 94% of thrice-daily users were interested in a once-daily formula. CONCLUSIONS: A reduction in dosing frequency is favored by Wellbutrin SR users and likely to improve their adherence to treatment. Because greater adherence has been shown to facilitate symptom relief, improvements in quality of life, and reductions in healthcare expenses, the results of this study support the value of the recently released once-daily formulation, Wellbutrin XL.     

Complex depression: The treatment of major depression and severe personality pathology

The intensive treatment of a patient presenting with major depression, chronic suicidal ideation, and a borderline personality disorder with narcissistic features is described as it developed over an 18-month treatment. The treatment approach is a transdiagnostic one with an emphasis on change in the patient's representation of self and others, identity and interpersonal functioning. The intended change is not only in the reduction of depression and suicidal ideation but also an improvement in interactions with others at work and intimate relations. The combination of rich clinical information from the therapist and independent research ratings of patient progress provide a complex picture of the treatment.