Spotlight on once-monthly long-acting injectable aripiprazole and its potential as maintenance treatment for bipolar I disorder in adult patients.

The lack of long-term medication adherence is a challenge in the treatment of bipolar disorder, particularly during the maintenance phase when symptoms are less prominent. The rate of nonadherence is ~20%-60% depending on how strict a definition is used. Nonadherence worsens the course of bipolar disorder and can add hundreds of thousands of dollars to the lifetime cost of treating the illness. Long-acting injectable (LAI) medication is an attractive alternative to daily dosing of oral medication, especially among patients who are ambivalent about treatment. The purpose of this paper is to review the evidence for the safety and efficacy of LAI aripiprazole, which was recently approved for the treatment of bipolar disorder. The approval was based on a single double-blind, placebo-controlled, multisite trial that recruited participants from 103 sites in 7 countries. A total of 731 participants with bipolar disorder were enrolled in the study. Out of that total, 266 were successfully stabilized on LAI aripiprazole and entered the randomization phase. Treatment-emergent adverse events were, for the most part, mild to moderate. Akathisia was the most common adverse event, which, combined with restlessness, was experienced by 23% of the sample. At the end of the 52-week study period, nearly twice as many LAI-treated participants remained stable compared to those treated with placebo. Stability during the maintenance phase is arguably the most important goal of treatment. It is during this period of relative freedom from symptoms that patients are able to build a meaningful and satisfying life. The availability of a new treatment agent, particularly one that has the potential to enhance long-term adherence, is a welcome development.

The Utility of Low-Dose Aripiprazole for the Treatment of Bipolar II and Bipolar NOS Depression.

BACKGROUND: Despite initial reports of efficacy in bipolar depression, multicenter trials did not show aripiprazole to be better than placebo, possibly because the doses used were too high, leading to lower efficacy and high dropout rates. This study evaluated the effects of low-dose aripiprazole. Extensive clinical experience has suggested that doses beyond 5 mg are rarely efficacious. METHODS: Data were gathered from patients with bipolar II or bipolar not otherwise specified depression using a retrospective chart review. Efficacy was assessed with the Clinical Global Impression-Improvement score. Patients who had at least 2 trials of aripiprazole were included in a retrospective off-on-off-on experimental design. All patients were on other medications when aripiprazole was started. Patients were treated with doses of 1 to 5 mg. FINDINGS: On average, patients were rated improved or very much improved compared with baseline. Sixteen of 211 patients worsened or experienced no change. Forty-four patients (21%) discontinued due to adverse effects. The group of patients who underwent off-on-off-on trials experienced statistically significant improvement when they started and restarted aripiprazole, and statistically significant worsening when they discontinued it. CONCLUSIONS: When treating bipolar II or bipolar not otherwise specified depression, low doses of aripiprazole, 5 mg or less, may be more effective and better tolerated than higher ones. Clinicians should start treatment with a very low dose and give patients time to respond.

Elevated levels of circulating thyroid hormone do not cause the medical sequelae of hyperthyroidism.

BACKGROUND: Clinicians have been reluctant to use high dose thyroid (HDT) to treat affective disorders because high circulating levels of thyroid hormone have traditionally been equated with hyperthyroidism, and understood as the cause of the medical sequelae of hyperthyroidism, such as osteoporosis and cardiac abnormalities. This conclusion is not supported by (HDT) research. METHODS: A literature review of research related to the morbidity and mortality of HDT treatment was performed. RESULTS: There exists a large body of research involving the use of HDT treatment to prevent the recurrence of differentiated thyroid cancer and to treat affective disorders. A review of this literature finds a lack of support for HDT as a cause of osteoporosis, nor is there support for an increase in morbidity or mortality associated with HDT. This finding contrasts with the well-established morbidity and mortality associated with Graves' disease, thyroiditis, and other endogenous forms of hyperthyroidism. DISCUSSION: The lack of evidence that exogenous HDT causes osteoporosis, cardiac abnormalities or increases mortality compared with the significant morbidity and mortality of hyperthyroidism requires an alternative cause for the medical sequelae of hyperthyroidism. One possibility is an autoimmune mechanism. CONCLUSION: High circulating levels of thyroid hormone is not the cause of the sequela of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted.

Treatment preferences among problem drinkers in primary care.

OBJECTIVE: Alcohol misuse is common among primary care patients, yet many do not receive treatment because doctors believe problem drinkers are "in denial," or are unwilling to change their drinking habits. The real problem, however, may be that patients are being offered treatment modalities that do not meet their needs. This study was designed to measure the acceptability of various treatment options among drinkers who were currently not receiving treatment. METHOD: Patients in a primary care clinic were given a self-report questionnaire that included: (1) the Alcohol Use Disorders Questionnaire, (2) a measure of readiness to change drinking behavior, and (3) a list of treatment modalities to be rated based on level of interest. RESULTS: Within a random sample of 402 patients, 40.2% reported high risk drinking and 16.3% reported problem drinking. Among the latter group, 89.3% were either considering change, or had begun to take steps to make changes in their drinking behaviors. When asked about treatment preferences, the modalities most frequently recommended by physicians-group therapy and Alcoholics Anonymous-were among the least acceptable. The most popular options were getting help from a primary care doctor and taking a medication that would make it easier to avoid drinking without making them sick if they drank. CONCLUSIONS: The belief that problem drinkers are unwilling to change was not supported by this study. Treatment for problem drinking should involve a collaborative evaluation of options with an emphasis on patient preference and treatment within the primary care setting.

The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS.

BACKGROUND: Dextromethorphan is an over-the-counter antitussive agent that may be a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA receptor antagonist. METHODS: We conducted a retrospective chart review of depressed patients with treatment resistant bipolar II or bipolar NOS disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ taken once or twice a day was added to participants׳ drug regimen. No changes were made to the pre-existing drug regimen during the course of treatment with DMQ. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment. RESULTS: Seventy-seven participants met the inclusion criteria. All had been experiencing depressive symptoms for at least two years, and the mean number of failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1-2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse effects, chiefly nausea. LIMITATIONS: Because this was a retrospective chart review with no control group, conclusions about causation cannot be made. Nevertheless, the duration of depressive symptoms prior to starting DMQ makes spontaneous recovery less likely. CONCLUSIONS: DMQ, an NMDA antagonist, may be effective in the treatment of bipolar depression. Because its putative mechanism does not depend on the monoaminergic system, it may be appropriate for patients who have not responded to other medications. Unlike ketamine, DMQ does not require i.v. administration.

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.

Identifying harmful drinking using a single screening question in a psychiatric consultation-liaison population.

BACKGROUND: Harmful drinking is common in medical inpatients, yet commonly missed due in part to time pressures. A screening question about past year heavy drinking recommended by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has been validated in primary care and emergency room settings. We tested the psychometric properties of a modified single screening question (SSQ) in hospitalized patients referred to a consultation-liaison service. METHODS: A psychiatry attending (n = 40), a psychiatry resident (n = 30) and a medical student (n = 30) administered the SSQ, followed by a self-report 10-item Alcohol Use Disorders Identification Test (AUDIT) to a sample of 100 consultation-liaison patients who were able to give informed consent for participation. RESULTS: Using the AUDIT as a reference, the sensitivity and specificity of the SSQ to detect harmful drinking in this sample were .96 and .82, respectively. Gender differences in specificity were not found. The single question also had a strong correlation with dependence (r(b) = .457, p < .001), and harmful use (r(b) = .620, p < .001) subscales of the AUDIT. CONCLUSION: The SSQ about past year heavy drinking can rapidly identify harmful drinking in alert nonpsychotic consultation-liaison patients.

Association of clinical characteristics and cessation of tobacco, alcohol, and illicit drug use during pregnancy.

Pregnancy is a time of relative urgency and opportunity for the treatment of substance use disorders in women, yet little is known about modifiable factors that contribute to successful abstinence. We examined self-worth, depression, anxiety, and novelty seeking in the context of substance use cessation during pregnancy in a sample of women with a high prevalence of substance abuse. Subjects were 448 birth mothers who participated in a prospective adoption study. Discontinuation rates were: tobacco 22.2%, alcohol 64.7%, marijuana 77.2%, and other drugs, 73.7-100%. Depression, anxiety, and novelty seeking were lower among women who discontinued substance use, compared to those who did not. Self-worth was higher in women who discontinued substance use. Among 110 polysubstance users, the number of substances discontinued during pregnancy was correlated with depression, anxiety, and self-worth in the hypothesized direction. Possible clinical implications are discussed.

An automated Internet application to help patients with bipolar disorder track social rhythm stabilization.

This column describes a pilot study of a fully automated, Internet-based program that provides a key element of interpersonal and social rhythm therapy, a form of psychotherapy shown to be effective in the treatment of bipolar disorder when combined with mood-stabilizing medication. Participants (N=64) recorded the time they completed activities of daily living and their mood at the time of each entry. After 90 days they demonstrated a 31% increase in social rhythm stability and a small, though statistically significant, decrease in symptoms of abnormal mood. Internet-based programs can enhance access to a best practice in the management of bipolar disorder.

Desvenlafaxine in major depressive disorder: an evidence-based review of its place in therapy.

INTRODUCTION: Desvenlafaxine, the active metabolite of venlafaxine, is a serotonin norepinephrine reuptake inhibitor (SNRI) recently approved for the treatment of major depressive disorder. It is one of only three medications in this class available in the United States. AIMS: The objective of this article is to review the published evidence for the safety and efficacy of desvenlafaxine, and to compare it to other antidepressants to delineate its role in the treatment of depression. EVIDENCE REVIEW: At the recommended dose of 50 mg per day the rate of response and remission was similar to other SNRIs, as was the adverse effect profile. The rate of discontinuation was no greater than placebo, and a discontinuation syndrome was not observed at this dose. Higher doses were not associated with greater efficacy, but they did lead to more side effects, and the use of a taper prior to discontinuation. The most common side effects reported were insomnia, somnolence, dizziness, and nausea. Some subjects experienced clinically significant blood pressure elevation. PLACE IN THERAPY: Like duloxetine, desvenlafaxine inhibits the reuptake of both norepinephrine and serotonin at the starting dose. Dual reuptake inhibitors have been shown to have small but statistically significantly greater rates of response and remission compared to selective serotonin reuptake inhibitors, and they have also shown early promise in the treatment of neuropathic pain. Desvenlafaxine may prove to be a valuable treatment option by expanding the limited number of available dual reuptake inhibitors.

The role of gender in single vs married individuals with bipolar disorder.

BACKGROUND: Despite the importance of marriage as a source of social support, it has been largely neglected in studies of bipolar disorder; and differential effects on men and women have not been explored. METHODS: Data on episodes of depression, mania, and mixed states were collected for the previous 2 years from a sample of 282 bipolar individuals using the National Institute of Mental Health Life Chart Methodology. RESULTS: Effects unique to women included the following: Bipolar women were significantly more likely to be married. Married women had fewer episodes of depression during the past 2 years than never-married women, and the cumulative severity of depression was lower. There were no differences in diagnostic subtype or age of onset between married and never-married women. Among men, never-married men were more likely to have bipolar I disorder and had an earlier age of onset compared with married men. There were no differences between married and never-married men in frequency, duration, or severity of mood episodes. CONCLUSIONS: Partner selection processes as they relate to bipolar disorder may be different for men and women. The bipolar I diagnostic subtype and early age of onset were associated with a lower likelihood of being married for men, but not for women. Marriage was associated with less depression in women during a 2-year period; but marital status was not associated with disease course differences in men, suggesting that women may be more sensitive to the positive effects of social support available within a stable marital relationship.

A randomized comparison of online and paper mood charts for people with bipolar disorder.

BACKGROUND: Longitudinal mood instability is the essential feature of bipolar disorder, however most rating scales are cross sectional in nature, and focus on acute symptoms. By contrast, the NIMH Life Chart Methodology (LCM) characterizes in detail the severity, duration, and frequency of mood episodes. Adherence to daily rating, however, tends to be low. In this study an online version of the LCM, designed to enhance adherence, was compared to the standard paper version. METHODS: Patients from a mood disorders specialty clinic were randomized to the standard LCM or an online, open-source adaptation. The online version used hypertext links embedded in a daily email as the primary rating interface. Participants rated for 90 days. The total number of days rated and the number of days with complete data were compared for the two groups. RESULTS: Forty-eight patients participated in the study. The online group rated approximately twice as many days compared to the standard group (44.3 versus 20.4, p=.029). The online group also entered complete data for a larger portion of days (55.2% versus 27.7%, p=.039). LIMITATIONS: This was a small, short-term study. The implications for longer-term rating are unclear. CONCLUSIONS: Despite the advantages of documenting mood fluctuation on a daily basis, the LCM is not commonly used, in part because ensuring adequate adherence can be resource intensive. An easily accessible online adaptation that utilizes email checking behavior can make this tool available to a wider range of patients.

The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS.

BACKGROUND: Thyroid hormone plays a role in both serotonin and catecholamine functions in the brain, and has been linked to abnormal mood states in bipolar disorder. Unlike most studies which have included only patients with bipolar I, this study evaluated triiodothyronine (T3) as an augmentation agent for treatment-resistant depression in patients with bipolar II and bipolar disorder NOS. METHODS: This study was a retrospective chart review of patients treated in a private clinic between 2002 and 2006. The charts of 125 patients with bipolar II disorder and 34 patients with bipolar disorder NOS were reviewed. RESULTS: Patients had been unsuccessfully treated with an average of 14 other medications before starting T3. At an average dose of 90.4 mcg (range 13 mcg-188 mcg) the medication was well tolerated. None of the patients experienced a switch into hypomania, and only 16 discontinued due to side effects. Improvement was experienced by 84%, and 33% experienced full remission. LIMITATIONS: The limitations are those associated with the retrospective chart review design. CONCLUSIONS: A high percentage of bipolar II and bipolar NOS patients with treatment resistant depression improved on T3. Despite the use of higher than usual doses in many of the patients, the medication was well tolerated. Augmentation with supraphysiologic doses of T3 should be considered in cases of treatment resistant bipolar depression.

Antidepressant-induced mania with concomitant mood stabilizer in patients with comorbid substance abuse and bipolar disorder.

Antidepressant use in the treatment of bipolar disorder is controversial due the risks of affective switching and cycle acceleration. Studies of non-comorbid samples suggest that the risk can be mitigated with the use of a concomitant mood stabilizer. However, the majority of patients with bipolar disorder will experience a comorbid substance use disorder and little is known about these individuals because they are typically excluded from clinical trials. Patients entering a substance abuse treatment program who had a history of bipolar disorder were interviewed to evaluate antidepressant-induced affective switching with and without concomitant mood stabilizer. Among 41 comorbid participants, the total lifetime antidepressant-induced switch rate was 76%. The switch rate was 56% for patients taking a mood stabilizer and an antidepressant concomitantly. There was no difference between patients with bipolar I and bipolar II disorders.

Long term augmentation with T3 in refractory major depression.

BACKGROUND: The addition of triiodothyronine (T(3)) is one of the most widely studied augmentation strategies for refractory depression. Despite this there are no long term studies or studies of doses above 100 mcg. METHOD: Long term and high dose augmentation with T(3) for refractory unipolar major depression was studied. Seventeen patients were assessed for symptom improvement with the Clinical Global Impression of Improvement Scale. RESULTS: Fourteen of 17 patients showed improvement. One patient saw no improvement and 2 dropped out due to side effects. The patients who benefited showed an average CGI improvement of 2.5 (SD: 0.52). The average dose used was 80 mcg (SD: 30.2, range: 25 mcg-150 mcg). The average length of time on T(3) was 24.2 months (SD: 19.4, range: 11.8-86.7). This case series shows that T(3) may be successfully employed as a long term treatment augmentation of major depression if over time dosage levels are increased beyond the traditional 50 mcg.

Evaluation of the stability and validity of participant samples recruited over the Internet.

Research conducted via the Internet has the potential to reach important clinical populations of participants who would not participate in traditional studies. Concerns exist, however, about the validity of samples recruited in this manner, especially when participants are anonymous and never have contact with study staff. This study evaluated two anonymous samples that were recruited over the Internet to test an online program designed to help problem drinkers. The two studies were conducted 3 years apart, and different recruitment strategies were utilized. Despite these differences, the two samples were highly similar in demographic and clinical features. Correlations that have been found between variables in traditional non-anonymous studies were also found in both online samples, supporting the validity of the data that was collected. Appropriate skepticism is required when critically evaluating Internet studies. Nevertheless, the results of this study indicate that it is possible to obtain stable, valid data from anonymous participants over the Internet, even when there are significant differences in the way the participants are obtained.

Pathways to change: the effect of a Web application on treatment interest.

Most individuals with drinking problems do not receive treatment, generally because they do not perceive the need for it. It is difficult to access this population of problem drinkers in order to encourage treatment-seeking. A Web-based program was written, designed to increase motivation for change. The program guided non-treatment-seekers through a multi-stage assessment and provided them with feedback. The level of interest in treatment was measured pre-and post-intervention. Compared to baseline, after the intervention, significantly more individuals rated themselves "very interested" in participating in some form of traditional treatment (19% vs. 28%), and their focus on a specific modality increased.

A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder.

The efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) were evaluated in two similarly designed, phase 3, randomized, double-blind, placebo-controlled, venlafaxine-extended-release-referenced, flexible-dose studies of outpatients with a primary diagnosis of major depressive disorder. Owing to a high placebo response, the individual studies were underpowered. Therefore, a post-hoc pooled analysis was performed (desvenlafaxine and placebo data were pooled; venlafaxine extended release data were not, owing to different flexible-dose regimens in the two studies). The primary outcome measure was the change from baseline on the 17-item Hamilton Rating Scale for Depression; the Clinical Global Impressions-Improvement item score was a secondary outcome. Analysis of the pooled data (using a mixed-effect model for repeated measures) revealed that after 8 weeks of treatment, desvenlafaxine was significantly better than placebo on 17-item Hamilton Rating Scale for Depression [-14.21 vs. -11.87 for desvenlafaxine and placebo, respectively; magnitude of effect=-2.34 (P<0.001)] and Clinical Global Impressions-Improvement item scores [1.95 vs. 2.32 for desvenlafaxine and placebo, respectively; magnitude of effect=-0.37 (P<0.001)]. Adverse events were comparable to those found with other drugs sharing a similar mechanism of action. These data support the efficacy, safety, and tolerability of desvenlafaxine in the treatment of major depressive disorder.

A technological approach to reaching a hidden population of problem drinkers.

OBJECTIVE: The most common obstacle to the treatment of individuals with drinking problems is that most do not seek treatment. This study compared a group of treatment-seeking patients with users of an alcohol-evaluation Web site to determine whether an Internet application could reach a population of problem drinkers who are distinct from those served by currently available forms of care. METHODS: An open-source application was developed that was modeled on the Drinker's Check-Up, which has been shown to increase motivation for behavior change while presenting itself as a nonthreatening evaluation. To recruit non-treatment seekers, the program was offered as a way to increase understanding of the effects of alcohol, rather than as a way to initiate change. RESULTS: Most of the 1,060 Internet study participants had serious alcohol-related pathology, although the pathology was less than that found in the treatment-seeking comparison group of 952 patients. Members of the online group were younger, and a larger proportion was female and employed. Online users had lower levels of problem recognition than did persons in the comparison group, according to the recognition subscale of the Stages of Change Readiness and Treatment Eagerness Scale. The ranked scores of the comparison group were divided into ten equal parts, and the online group's average was in the lowest decile. Online users were also less likely to take steps to change their drinking behavior and were in the lowest decile on the taking steps subscale in relation to the comparison group. The level of concern about the possibility of harm from alcohol use was comparable in both groups. CONCLUSIONS: Problem drinkers who do not use available forms of treatment will engage with an interactive Web site. Despite low levels of illness recognition, significant concern among the online group about their alcohol use indicates a potential role for an Internet application designed to increase motivation for change.

Combinations of DSM-IV-TR criteria sets for bipolar disorders.

BACKGROUND: DSM-IV-TR is the standard for making psychiatric diagnoses in many countries. The diagnostic categorization of DSM-IV-TR is valued for its reliability, however it is well accepted that patients with the same diagnosis demonstrate substantial heterogeneity. In order to quantitatively characterize the degree of possible heterogeneity that can exist, combinatorial mathematics was used to calculate the number of possible ways to satisfy symptom criteria for the diagnosis of bipolar disorder as an example of this problem. SAMPLING AND METHODS: The formula n!/(r!(n - r)!), which calculates the number of different ways of choosing an unordered number of items without repetition from a larger set, was used to calculate the number of combinations which meet the criteria for the core episodes of bipolar disorder and the specifiers. RESULTS: The number of possible combinations for the core episodes ranged from 163 for a manic episode to 37,001 for a mixed episode. When the full collection of specifiers that DSM-IV-TR applies to bipolar disorder was used, the number of combinations was over 5 billion. CONCLUSIONS: The precision of medical communication about bipolar disorder is called into question by the billions of different ways that the criteria for this diagnosis can be met. As DSM-V is developed, the possible combinations for each diagnostic criterion should be calculated, and the effect this number has on clinical communication should be considered.