To compare the effects of maintenance treatment with aripiprazole or placebo on the incidence of metabolic syndrome in bipolar disorder.
Patients with bipolar I disorder were stabilized on aripiprazole for 6–18 weeks prior to double-blind randomization to aripiprazole or placebo for 26 weeks. The rate of metabolic syndrome in each group was calculated at maintenance phase baseline (randomization) and endpoint for evaluable patients using an LOCF approach. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria.
At entry into the maintenance phase, overall 45/125 patients (36.0%) met criteria for metabolic syndrome. Mean changes in the five components of metabolic syndrome (waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure and glucose) from baseline to Week 26 were small except for a meaningful reduction in triglycerides (placebo −18.9 mg/dL; aripiprazole −11.5 mg/dL). By the end of the maintenance phase (endpoint, LOCF), 5/18 placebo-treated patients (27.8%) and 4/14 aripiprazole-treated patients (28.6%) no longer met metabolic syndrome criteria. The proportion of patients with metabolic syndrome was similar in the placebo and aripiprazole groups both at baseline and Week 26. There were no significant changes in any of the individual components of metabolic syndrome between aripiprazole- and placebo-treated patients during maintenance phase treatment.
The prevalence of metabolic syndrome in patients with bipolar disorder is higher than commonly reported in the general population. The effect of 26 weeks of treatment with aripiprazole on the incidence of metabolic syndrome and its components was similar to placebo.
bipolar disorder; metabolic syndrome; cholesterol; obesity; triglycerides; blood pressure; maintenance trial
To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder (RCBD) and comorbid substance abuse and/or dependence.
A 6-month, double-blind, parallel group comparison was carried out in recently manic/hypomanic/mixed patients who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy.
Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%; nonresponse: 25%; intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% relapsed (24% into depression and 76% into a manic/hypomanic/mixed episode), 26% completed the study, and 19% were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (p=NS). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% and 53%, respectively. The rate of depressive relapse in both arms was 13%, while the rate of relapse into a manic, hypomanic, or mixed episode was 44% for lithium monotherapy and 40% for the combination of lithium and divalproex.
A small subgroup of patients in this study stabilized after six months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of RCBD in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.
Bipolar disorder; Rapid cycling; Dual-diagnosis; Substance use disorder; Maintenance trial; Placebo-controlled trial; Lithium; Divalproex; Combination pharmacotherapy
Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode.
Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eighty-four patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation–Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period.
Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period.
Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.
Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
To examine the benefits of 4 disorder-specific psychotherapies in conjunction with pharmacotherapy on time to recovery and the likelihood of remaining well after an episode of bipolar depression.
Randomized controlled trial.
Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder.
A total of 293 referred outpatients with bipolar I or II disorder and depression treated with protocol pharmacotherapy were randomly assigned to intensive psychotherapy (n=163) or collaborative care (n=130), a brief psychoeducational intervention.
Intensive psychotherapy was given weekly and biweekly for up to 30 sessions in 9 months according to protocols for family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy. Collaborative care consisted of 3 sessions in 6 weeks.
Main Outcome Measures
Outcome assessments were performed by psychiatrists at each pharmacotherapy visit. Primary outcomes included time to recovery and the proportion of patients classified as well during each of 12 study months.
All analyses were by intention to treat. Rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions. Patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care (hazard ratio, 1.47; 95% confidence interval, 1.08–2.00; P=.01). Patients in intensive psychotherapy were 1.58 times (95% confidence interval, 1.17–2.13) more likely to be clinically well during any study month than those in collaborative care (P=.003). No statistically significant differences were observed in the outcomes of the 3 intensive psychotherapies.
Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression. Future studies should compare the cost-effectiveness of models of psychotherapy for bipolar disorder.
clinicaltrials.gov Identifier: NCT00012558
Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated.
We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression.
A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes.
While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.
bipolar disorder; factor analysis; major depression; mixed state; psychosis; subtype; suicide; symptom stability
This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (N=127) vs. placebo+MS (N=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.
Metabolic syndrome; medical comorbidity; treatment remission; ziprasidone
This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.
In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference >35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months.
Pioglitazone decreased depression symptom severity from a total IDS score of 40.3 ± 1.8 to 19.2 ± 1.8 at week 12 (p<.001). Among partial responders (≥ 25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration = 24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (−0.8 ± 0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (−0.87 ± 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects.
These data are limited by a small sample size and an open-label study design with no placebo control.
Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia.
English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated.
Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.
Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.
To estimate the number needed to treat to harm (NNTH) for discontinuation due to adverse events with atypical antipsychotics relative to placebo during the treatment of bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD).
English-language literature published and cited in MEDLINE from January 1966 to May 2009 was searched with the terms antipsychotic, atypical antipsychotic, generic and brand names of atypical antipsychotics, safety, tolerability, discontinuation due to adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal side effect; and bipolar depression, major depressive disorder, or generalized anxiety disorder, and randomized, placebo-controlled clinical trial. This search was augmented with a manual search.
Studies with a cumulative sample of ≥ 100 patients were included.
The NNTHs for discontinuation due to adverse events, somnolence, sedation, ≥ 7% weight gain, and akathisia relative to placebo were estimated with 95% confidence intervals to reflect the magnitude of variance.
Five studies in bipolar depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole and olanzapine have been studied in bipolar depression and refractory MDD. Only quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH for discontinuation due to adverse events was 14 in bipolar depression, but was not significantly different from placebo in MDD. For olanzapine, the mean NNTHs were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to adverse events during quetiapine-XR treatment appeared to be associated with dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for GAD.
At the same dose of quetiapine-XR, patients with GAD appeared to have a lower tolerability than those with bipolar depression or MDD, Due to flexible dosing, the risk for discontinuation due to adverse events in the treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics could not be compared.
A rapid-cycling course in bipolar disorder has previously been identified as a risk factor for attempted suicide. This study investigated factors associated with suicide attempts in patients with rapid-cycling bipolar I or II disorder.
Cross-sectional data at the initial assessment of patients who were enrolled into 4 clinical trials were used to study the factors associated with suicide attempt. An extensive clinical interview and the Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid-cycling bipolar disorder, substance use disorders, anxiety disorders, psychosis, and other clinical variables. Chi-square, t test, and logistic regression or Poisson regression were used to analyze the data where appropriate, with odds ratios (ORs) for relative risk estimate. The data were collected from September 1995 to June 2005.
In a univariate analysis, 41% of 561 patients had at least 1 lifetime suicide attempt. Earlier age of depression onset, bipolar I subtype, female sex, unmarried status, and a history of drug use disorder, panic disorder, sexual abuse, and psychosis were associated with significantly higher rates of attempted suicide (all p<.05). After considering 31 potential confounding factors in the stepwise logistic regression model (n = 387), any Axis I comorbidity (OR=2.68, p = .0219), female sex (OR= 2.11, p = .0005), psychosis during depression (OR = 1.84, p = .0167), bipolar I subtype (OR= 1.83, p = .0074), and history of drug abuse (OR = 1.62, p = .0317) were independent predictors for increased risk of attempted suicide. However, white race was associated with a lower risk for suicide attempt (OR = 0.47, p = .0160). Psychosis during depression (p = .0003), bipolar I subtype (p = .0302), and physical abuse (p = .0195) were associated with increased numbers of suicide attempts by 248%, 166%, and 162%, respectively; white race was associated with a 60% decrease in the number of suicide attempts (p=.0320).
In this highly comorbid group of patients with rapid-cycling bipolar disorder, 41% had at least 1 suicide attempt. Among the demographics, female sex was positively associated, but white race was negatively associated, with the risk for suicide attempt. Independent clinical variables for increased risk and/or number of attempted suicides were any Axis I comorbidity, psychosis during depression, bipolar I subtype, a history of drug abuse, and physical abuse.
To pilot the efficacy and safety data of lamotrigine adjunctive therapy to lithium and divalproex in patients with rapid-cycling bipolar disorder (RCBD) and a recent substance use disorder (SUD).
Structured Clinical interviews were used to ascertain DSM-IV diagnosis of RCBD, SUDs, and other Axis I disorders. Patients who did not meet the criteria for a bimodal response after up to 16-weeks of open-label treatment with lithium plus divalproex, as measured by MADRS (Montgomery-Asberg Depression Rating Scale) ≤ 19, YMRS (Young Mania Rating Scale) ≤ 12 and GAF (Global Assessment of Functioning) ≥ 51 for 4 weeks, were rendomized to a 12-week, double-blind addition of lamotrigine or placebo to lithium plus divalproex. Primary and secondary outcomes were analyzed with ANCOVA, t-test, of chi-square/Fisher's exact.
Of 98 patients enrolled into the study, 36 were randomized to receive lamotrigine (n = 18) or placebo (n = 18), and 8 patients per arm completed the study. No patient discontinued due to adverse events. The change in MADRS total score from baseline to endpoint was –9.1 ± 11.2 in lamotrigine-treated patients versus –4.5 ± 13.1 in placebo-treated patients (p = 0.27). Therre were no significant differences in changes in YMRS total scores and rates of response or remission.
Lamotrigine adjunctive therapy was well toletated in patients previously non-responsive to initial treatment of lithium plus divalproex. A larger study is warranted to determine the efficacy and safety of adjunctive lamotrigine versus placebo in RCBD with a recent SUD.
Bipolar disorder; substance use disorder; mood stabilizer; lamotrigine; placebo-controlled trial; treament-refractory
Quetiapine extended-release (quetiapine-XR) has been studied in patients with schizophrenia, bipolar mania, bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). The purpose of this study was to compare the tolerability and sensitivity of quetiapine-XR among these psychiatric conditions. The discontinuation due to adverse events (DAEs) and reported somnolence in randomized, double-blind, placebo-controlled studies of quetiapine-XR in these psychiatric conditions were examined. The absolute risk reduction or increase and the number needed to treat to benefit (NNTB) or harm (NNTH) for DAEs and reported somnolence of quetiapine-XR ≥300 mg/d relative to placebo were estimated. Data from one study in schizophrenia (n=465), one in mania (n=316), one in bipolar depression (n=280), two in refractory MDD (n=624), two in MDD (n=669) and three in GAD (n=1109) were available. The risk for DAEs of quetiapine-XR relative to placebo was significantly increased in bipolar depression (NNTH=9), refractory MDD (NNTH=8), MDD (NNTH=9), and GAD (NNTH=5), but not in schizophrenia and mania. The risk for reported somnolence of quetiapine-XR relative to placebo was significantly increased in schizophrenia (600 mg/d NNTH=15 and 800 mg/d NNTH=11), mania (NNTH=8), bipolar depression (NNTH=4), refractory MDD (NNTH=5), MDD (NNTH=5) and GAD (NNTH=5). These results suggest that patients with GAD had the poorest tolerability during treatment with quetiapine-XR, but they had a similar sensitivity as those with bipolar depression and MDD. Patients with schizophrenia or mania had a higher tolerability and a lower sensitivity than those with bipolar depression, MDD, or GAD.
Atypical antipsychotic; bipolar disorder; generalized anxiety disorder; major depressive disorder; schizophrenia
This randomized controlled study of 164 outpatients with bipolar disorder in a community mental health center who received standardized psychoeducation (Life Goals Program [LGP]) or treatment as usual sought to determine whether there were differences between the groups in medication adherence attitudes and behaviors.
Patients were randomly assigned to treatment as usual (N=80) or treatment as usual plus LGP (N=84) and were assessed at baseline and at the three-, six-, and 12-month follow-up. Primary outcomes were change in score from baseline on the Drug Attitude Inventory (DAI) and on self-reported treatment adherence behaviors (SRTAB).
At baseline, there were no significant differences between the two groups. Slightly less than half (N=41, 49%) of the LGP group participated in most or all (four to six) LGP sessions, 14% (N=12) participated in one to three sessions, and 37% (N=31) did not participate in any sessions. At the 12-month follow-up there was improvement among all patients, with no significant differences between the two groups, in DAI scores, SRTAB, symptoms, psychopathology, and functional status. Greater depressive severity at baseline was associated with more negative attitudes toward treatment over time, although this finding was not significant (p=.056). Secondary analysis of persons in the LGP group found that compared with those who did not go to any LGP sessions, those with partial or full participation in LGP sessions had improved attitudes toward medication at the three- and six-month follow-up, but no difference was found between the three LGP subgroups by the 12-month follow-up.
There were no differences between two groups in treatment attitudes at the 12-month follow-up. Low attendance rates mitigated effects on primary outcomes. Effects of LGP may become lost over time without ongoing intervention, and individuals with depression may have reduced response to LGP.
Bipolar disorder is a chronic mental illness associated with substantial impairment in quality of life and function. Although there has been tremendous growth in understanding bipolar disorder with respect to treatments, very little study has focused on the viewpoint of affected individuals. The purpose of this study was to examine the subjective experience of illness among 19 men and women with rapid cycling bipolar disorder receiving treatment at an academic psychiatry clinic.
Personal constructs of illness with respect to life-trajectory and societal reaction to the individual, specifically the issue of stigma, were evaluated using a semistructured, open-ended anthropological interview.
Participants perceived bipolar disorder as a disease with biologic underpinnings. Stigma was a major issue for all individuals. In common with individuals without serious mental illness, individuals with bipolar disorder work at mastering developmental tasks appropriate for their life stage. At times, younger individuals appeared to have difficulty separating their own identity from the effects of illness. For older individuals with bipolar disorder, life was perceived to be disrupted by bipolar disorder, with early plans and dreams often “derailed.”
Although bipolar disorder may severely alter an individual’s planned life trajectory, accomplishment of life goals can at least partially offset the sense of loss that is often seen in bipolar illness.
Bipolar disorder; stigma; rapid cycling; life course; aging; subjective experience
The present study examined the relationship between medical burden in bipolar disorder and several indicators of illness severity and outcome. It was hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would impact the response to treatment with lithium and valproate.
Data were analyzed from two studies evaluating lithium and valproate for rapid-cycling presentations of bipolar I and II disorder. General medical comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). Descriptive statistics and logistic regression analyses were conducted to explore the relationships between medical burden, body mass index (BMI), substance use disorder status, and depressive symptom severity.
Of 225 patients enrolled, 41.8% had a recent substance use disorder, 50.7% were male, and 69.8% had bipolar I disorder. The mean age of the sample was 36.8 (SD = 10.8) years old. The mean number of comorbid medical disorders per patient was 2.5 (SD = 2.5), and the mean CIRS total score was 4.3 (SD = 3.1). A significant positive correlation was observed between baseline depression severity and the number of organ systems affected by medical illness (p = 0.04). Illnesses of the endocrine/metabolic system were inversely correlated with remission from depressive symptoms (p = 0.02), and obesity was specifically associated with poorer treatment outcome. For every 1-unit increase in BMI, the likelihood of response decreased by 7.5% [odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.87–0.99; p = 0.02] and the likelihood of remission decreased by 7.3% (OR = 0.93, 95% CI: 0.87–0.99; p = 0.03). The effect of comorbid substance use on the likelihood of response differed significantly according to baseline BMI. The presence of a comorbid substance use disorder resulted in a lower odds of response, but only among patients with a BMI ≥ 23 (p = 0.02).
Among patients with rapid-cycling bipolar disorder receiving lithium and valproate, endocrine/metabolic illnesses, including overweight and obesity, appear to be associated with greater depressive symptom severity and poorer treatment outcomes.
endocrine; inflammation; insulin resistance; lithium; medical comorbidity; obesity; substance use disorders; treatment response; valproate
The primary purpose of this study was to examine the extent to which the initiation of stimulant and antidepressant medication was associated with the subsequent onset of juvenile bipolar I disorder (BP I). Another aim was to investigate differences in clinical presentation between youths prescribed stimulant or antidepressant medication before and after the onset of juvenile BP I disorder.
Youths between the ages of 5 and 17 years meeting full, unmodified DSM-IV diagnostic symptom criteria for BP were included in this study. Data regarding the age of onset of BP I, psychiatric comorbidities, and current symptoms of mania and depression were obtained. Medication history was recorded as part of the assessment interview with parents and youths.
Of the 245 youths with BP I, 65% (n = 160) were treated with stimulant medication; 32% (56/173) were treated after the onset of BP I, and 19% (32/173) were treated before the onset of BP I. Forty-six percent (113/245) were treated with antidepressant medication; 33% (67/206) were treated after the onset of BP I, and 3% (7/206) were treated before the onset of BP I. Patients who were treated with stimulants after the onset or BP I were significantly more likely to be younger (p < 0.0001). Patients who were treated with antidepressants before the onset of BP I were significantly more likely to be older and to have lower levels of mania on the Young Mania Rating Scale at assessment (p < 0.01)
Data from this retrospective case series do not support the association between initial stimulant or antidepressant use and the onset of BP I or presenting symptoms of depression or manic symptoms.
adolescents; antidepressants; bipolar disorder; children; stimulants
National Comorbidity Survey data indicate that bipolar disorder is characterized by high lifetime rates of co-occurring anxiety and substance use disorders (SUDs). Although compelling evidence suggests SUD comorbidity predicts non-response to treatment, the relationship between medical comorbidity and treatment response has not been studied adequately. In an attempt to understand the impact of medical comorbidity on treatment outcome, an analysis was conducted to inform the relationship between co-occurring medical illness, the phenomenology of bipolar disorder, and response to treatment with mood stabilizers.
A total of 98 adult outpatients with rapid-cycling bipolar I or II disorder and co-occurring SUDs were prospectively treated with the combination of lithium and valproate for up to 24 weeks. A logistic regression analysis was conducted to explore the relationship between phenomenology, response to mood stabilizers, and medical comorbidity as assessed by the Cumulative Illness Rating Scale (CIRS). High and low medical comorbidity burden were defined as a CIRS total score ≥ 4 and ≤ 3, respectively.
Every patient enrolled into this study had at least 1 medical illness (most commonly respiratory, 72%) and on average had 4.9 different medical conditions. Over half of patients (52%) exhibited illnesses across four or more different organ systems, 24% had uncontrollable medical illnesses, and the mean overall total CIRS score was 5.56. The average body mass index (BMI) was 28.1 with 38% being overweight and 29% being obese. High medical burden was observed in 64% and was most strongly predicted by a diagnosis of bipolar I disorder (OR=34.9, p=0.002, 95%CI=3.9–316.1). A history of attempted suicide (OR=10.3, p=0.01, 95%CI=1.7–62.0), a history of physical abuse (OR=7.6, p=0.03, 95%CI=1.3–45.7) and advancing age (OR=1.2, p<0.001, 95%CI=1.1–1.3) also independently predicted a high burden of general medical problems. Only 21% (N=21) of subjects enrolled into this study showed a bimodal response to treatment with lithium plus valproate, and neither BMI nor any summary CIRS measure predicted response.
Rapid cycling with co-occurring substance use is not only associated with poor response to mood stabilizers, but is also a harbinger of serious medical problems. A high burden of medical comorbidity was associated with the bipolar I subtype, a history of attempted suicide, a history of physical abuse, and advancing age.
Bipolar disorder is being diagnosed and treated in children and adolescents at a rapidly increasing rate, despite the lack of validated instruments to help screen for the condition or differentiate it from more common disorders. The goal of the present study was to develop and validate a brief (10 item) instrument in a large sample of outpatients presenting with a variety of different DSM-IV diagnoses, including frequent comorbid conditions.
Parents completed the Parent General Behavior Inventory (P-GBI), a 73 item mood inventory, as part of a screening assessment that included a semi-structured psychiatric interview of both the parent and the child to determine the child’s diagnoses.
637 youths completed the diagnostic assessment and the mood inventory. A 10 item form derived from this 73 item inventory had good reliability (.92), correlated .95 with the original scale, and showed significantly better discrimination of bipolar disorders (Area Under ROC Curve [AUROC] of .856 versus .832 for full scale, p < .005), with good precision for estimation of individual scores for cases up to two standard deviations elevated on the latent trait. The 10-item scale also did well discriminating bipolar from unipolar (AUROC = .86) and bipolar from ADHD cases (AUROC = .82).
Findings suggest that parents most notice elated mood, high energy, irritability, and rapid changes in mood and energy as the prominent features of juvenile bipolar disorder.
Anxiety disorders (AD) and substance use disorders (SUD) commonly co-occur with bipolar disorder. This study was undertaken to assess AD-SUD-bipolar subtype interactions.
Extensive clinical interview and MINI were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBPDI) or II (RCBPDII) disorder, SUDs, and ADs including generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). Data at the initial assessment of four studies was used to compare the prevalence differences in ADs between RCBPDI and RCBPDII by using protocol-defined SUD categories, “Never,” “Lifetime, but not recent,” or “Recent.”
Five-hundred sixty-six of 568 patients (RCBPDI n=320, RCBPDII n=246) were eligible for analyses. In the “Never” group (n=191), patients with RCBPDI and RCBPDII had similar risk for ADs. In the “Lifetime, but not recent” group (n=195), RCBPDI patients had significantly higher risks for GAD (OR=3.29), PD (OR=2.95), but not OCD, compared with their RCBPDII counterparts. Similarly, in the “Recent” group (n=180), RCBPDI patients also had significantly higher risks for GAD (OR=3.6), PD (OR=3.8), but not OCD, compared with their RCBPDII counterparts.
Data were cross-sectional and not all ADs were included.
In this large cohort of patients with rapid cycling bipolar disorder, risk for having GAD, PD, but not OCD increased significantly in patients with bipolar I disorder compared to their bipolar II counterparts when a history of SUD was present. However, there were no significant differences in the risk for GAD, PD, or OCD between the subtypes among patients without a history of SUD.
Rapid cycling bipolar disorder; anxiety disorder; substance use disorder; comorbidity; interaction
This study assessed the operating characteristics of the Mood Disorder Questionnaire (MDQ) among offenders arrested and detained at a county jail.
The MDQ, a brief self-report instrument designed to screen for all subtypes of bipolar disorder (BP I, II and NOS) was voluntarily administered to adult detainees at the Ottawa County Jail in Port Clinton, Ohio. A confirmatory diagnostic evaluation was also performed using the Mini-International Neuropsychiatric Interview (MINI). The MDQ was scored using a standard algorithm requiring endorsement of 7/13 mood items as well as two items that assess whether manic or hypomanic symptoms co-occur and cause moderate to severe functional impairment. In addition to the standard algorithm for scoring the MDQ, modifications were also tested in an attempt to improve overall sensitivity.
Among 526 jail detainees who completed the MDQ, 37 (7%) screened positive for bipolar disorder. Of 164 detainees who agreed to a research diagnostic evaluation, 32 (19.5%) screened positive on the MDQ, while 55 (33.5%) met criteria for bipolar disorder according to the MINI. When administered to the sample of 164 adult jail detainees, the sensitivity of the MDQ was 0.47 and the specificity was 0.94. The MDQ was significantly better at detecting BP I (0.59) than BP II/NOS (0.19; p = 0.008). Modification of scoring the MDQ improved the sensitivity for detection of BP II from 0.23 to 0.54 with minimal decrease in specificity (0.84). The optimum sensitivity and specificity of the MDQ was achieved by decreasing the item threshold to 3/13 and eliminating the symptom co-occurrence and functional impairment items.
The MDQ was found to have limited utility as a screening tool for bipolar disorder in a correctional setting, particularly for the BP II subtype.
Bipolar Disorder; Mood Disorder Questionnaire; Jail; Screening; Bipolar II; Psychometrics
For the majority of patients with bipolar disorder, major depressive episodes represent the most debilitating and difficult-to-treat illness dimension. Patients spend significantly more time depressed than manic or hypomanic, and attempt suicide more frequently during this illness phase, yet the availability of treatments remains limited. The discovery of more effective therapeutics for managing depressive episodes is arguably the greatest unmet need in bipolar disorder. This article provides an evidence-based summary of pharmacological treatments for the acute and longitudinal management of bipolar depression. Clinical trial results are reviewed for a diverse array of compounds, inclusive of traditional mood stabilizers (eg, lithium and divalproex), atypical antipsychotics, unimodal antidepressants, and modafinil. Where applicable, differences in efficacy across compounds are examined through discussion of number needed to treat and effect size determinations. A pragmatic clinical approach is presented for management of the depressed phase of bipolar disorder.
bipolar disorder; bipolar depression; anticonvulsant; unimodal antidepressant; atypical antipsychotic; number needed to treat; maintenance trial
The essential features of bipolar affective disorder involve the cyclical occurrence of high (manic or hypomanic episodes) and low mood states. Depressive episodes in both bipolar I and II disorder are more numerous and last for longer duration than either manic or hypomanic episodes. In addition depressive episodes are associated with higher morbidity and mortality. While multiple agents, including all 5 atypical antipsychotics, have demonstrated efficacy and earned US FDA indication for manic phase of bipolar illness, the acute treatment of bipolar depression is less well-studied. The first treatment approved by the US FDA for acute bipolar depression was the combination of the atypical antipsychotic olanzapine and the antidepressant fluoxetine. Recently, quetiapine monotherapy has demonstrated efficacy in the treatment of depressive episodes associated with both bipolar I and II disorder and has earned US FDA indication for the same.
bipolar disorder; quetiapine; BOLDER studies
The study measured the accuracy of the Italian version of the Mood Disorder Questionnaire (MDQ) as a screening instrument for bipolar disorders in a psychiatric setting.
154 consecutive subjects attending the Division of Psychiatry of the University of Cagliari (Italy), were screened for bipolar disorders using the Italian translation of the MDQ, and diagnostically interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) by physicians.
On the basis of the SCID: 51 (33.1%) received a diagnosis of bipolar or schizoaffective bipolar type disorders, 63 (40.9%) were diagnosed as having at least one psychiatric disorder in Axis I (other than bipolar or schizoaffective bipolar type disorders), whilst 40 (25.9%) were unaffected by any type of psychiatric disorder. MDQ showed a good accuracy for bipolar or schizoaffective bipolar type disorders: the cut-off 4 had sensitivity 0.90 and specificity 0.58; the cut-off 5 had sensitivity 0.84 and specificity 0.70; and the cut-off 6 had sensitivity 0.76 and specificity 0.86. The accuracy for bipolar II disorders was sufficient but not excellent: the cut-off 4 had sensitivity 0.80 and specificity 0.45; the cut-off 5 had sensitivity 0.70 and specificity 0.55; and the cut-off 6 had sensitivity 0.55 and specificity 0.65.
Our results seem to indicate a good accuracy of MDQ, and confirm the results of recent surveys conducted in the USA. Moreover the instrument needs to be validated in other settings (e.g. in general practice).
bipolar disorder; mood disorders; screening; mood disorder questionnaire
To study predictors of non–stabilization (i.e., not bimodally stabilized for randomization or not randomized due to premature discontinuation) during open-label treatment with lithium and divalproex in patients with rapid-cycling bipolar disorder (RCBD) with or without comorbid recent substance use disorders (SUDs).
Data from the open-label phase of two maintenance studies were used. The reasons for non-stabilization were compared between patients with a recent SUD and those without. Predictors for non-stabilization were explored with logistic regression analyses.
Of 149 patients with recent SUD and 254 without recent SUD enrolled into the open-label acute stabilization phase, 21% and 24% were stabilized and randomized, respectively. Compared to those without recent SUD, patients with recent SUD were more likely to discontinue the study due to non-adherence to the protocol, 53% versus 37% (OR = 1.92) or refractory mania/hypomania, 15% versus 9% (OR = 1.87), but less likely due to refractory depression 16% versus 25% (OR = 0.58) or adverse events, 10% versus 19% (OR = 0.44). A history of recent SUDs, early life verbal abuse, female gender, and late onset of first depressive episode were associated with increased risk for non-stabilization with ORs of 1.85, 1.74, 1.10, and 1.04, respectively.
During open treatment with lithium and divalproex in patients with RCBD, a recent SUD, a lifetime history of verbal abuse, female gender, and late onset of first depression independently predicted non-stabilization. The non-stabilization for patients with SUD was related to non-adherence and refractory mania/hypomania.
Bipolar disorder; anxiety disorder; substance use disorder; mood stabilizer; non-stabilization