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Biomedical subjects

Paul E Keck

Publications and source records attributed to Paul E Keck.

At least 19 recordsLinked to original sources
PubMed2007

Open-label aripiprazole in the treatment of acute bipolar depression: a prospective pilot trial.

BACKGROUND: Increasing evidence indicates that some second-generation antipsychotics are efficacious in bipolar depression, but there are few data on this illness for the novel agent aripiprazole. METHODS: Aripiprazole response was prospectively assessed for 8 weeks with the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale Modified for Bipolar Illness (CGI-BP), and the Young Mania Rating Scale (YMRS) in 31 bipolar patients with acute depression inadequately responsive to 1 mood stabilizer. Side effects and body weight were also evaluated. Outcome measures were analyzed with repeated measures ANOVAs. RESULTS: Patients showed a significant decrease in mean MADRS total and CGI-BP-Depression Severity scores, but only 14 (45%) completed the 8-week trial. Thirteen (42%) patients met criteria for response (> or =50% reduction in MADRS total score), 11 (35%) patients met criteria for remission (final MADRS total score < or =12), and 9 (29%) patients discontinued aripiprazole for side effects, most commonly akathisia (N=4). As a group, patients showed statistically insignificant weight gain (0.8+/-2.5 kg) over the 8-week trial. CONCLUSION: Aripiprazole was associated with beneficial effects on mood in some patients with bipolar depression, but also had a high discontinuation rate, primarily due to side effects. Double-blind, placebo-controlled studies are necessary to determine aripiprazole's efficacy, tolerability, and safety in bipolar depression.

Acute Disease↗
PubMed2007

Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania.

CONTEXT: Cannabis use disorders commonly co-occur in bipolar disorder; however, the effects of cannabis abuse on outcome have been minimally studied. OBJECTIVE: To identify how the sequence of the onsets of a cannabis use disorder and bipolar disorder is associated with the subsequent course of each condition. DESIGN: Inception cohort. SETTING: Academic medical center. PATIENTS: Patients (N = 144) were studied who met criteria for bipolar I disorder (manic or mixed), were 12 to 45 years old, and had no previous hospitalizations and minimal previous treatment. Patients were followed up for up to 5 years and included 33 in whom the onset of a cannabis use disorder preceded the onset of bipolar disorder (cannabis first), 36 in whom bipolar disorder onset preceded the onset of cannabis abuse (bipolar first), and 75 with bipolar disorder only. MAIN OUTCOME MEASURES: Symptomatic recovery and recurrence of both conditions and percentage of follow-up time with affective and cannabis use disorder symptoms. RESULTS: The cannabis first group exhibited better recovery than the other groups, although when adjusted for potential mediator variables these results did not persist. Cannabis use was associated with more time in affective episodes and with rapid cycling. Most cannabis use disorders remitted immediately after hospitalization, followed by rapid rates of recurrence. CONCLUSIONS: The effects of the sequence of onsets of bipolar and cannabis use disorders were less pronounced than observed in co-occurring alcohol and bipolar disorders. Aggressive drug abuse treatment immediately after a first psychiatric hospitalization might decrease rates of recurrence and new cases of cannabis use disorder in the course of bipolar disorder.

Adolescent↗
PubMed2007

Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study.

STUDY OBJECTIVE: To quantify the risk of diabetes mellitus associated with atypical antipsychotics compared with conventional antipsychotics in managed care Medicaid patients with bipolar disorder. DESIGN: Retrospective nested case-control study. DATA SOURCE: Integrated seven-state Medicaid managed care claims database from January 1, 1998-December 31, 2002. PATIENTS: Two hundred eighty-three patients with diabetes (cases) and 1134 controls matched by age, sex, and the index date on which bipolar disorder was diagnosed. MEASUREMENTS AND MAIN RESULTS: Cases were defined as those having an International Classification of Diseases, Ninth Revision diagnosis of diabetes or those receiving treatment with antidiabetic drugs. Both case and control patients had at least a 3-month exposure to either conventional or atypical antipsychotic agents or three filled prescriptions related to treatment for bipolar disorder. Of the 283 cases, 139 (49%) received atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and clozapine) and 133 (47%) were prescribed conventional antipsychotics. To compare the risk for new-onset diabetes associated with atypical versus conventional antipsychotics, we conducted a Cox proportional hazard regression, in which we controlled for age; sex; duration of bipolar disorder follow-up; use of lithium, anticonvulsants, antidepressants, and other drugs; and psychiatric and medical comorbidities. Compared with patients receiving conventional antipsychotics, the risk of diabetes was greatest among patients taking risperidone (hazard ratio [HR] 3.8, 95% confidence interval [CI] 2.7-5.3), olanzapine (3.7, 95% CI 2.5-5.3), and quetiapine (2.5, 95% CI 1.4-4.3). The risk for developing diabetes was also associated with weight gain (HR 2.5, 95% CI 1.9-3.4), hypertension (HR 1.6, 95% CI 1.2-2.2), and substance abuse (HR 1.5, 95% CI 1.0-2.2). CONCLUSION: Olanzapine, risperidone, and quetiapine are all associated with development or exacerbation of diabetes mellitus in patients with bipolar disorder. When prescribing therapy for this patient population, metabolic complications such as diabetes, weight gain, and hypertension need to be considered.

Adolescent↗
PubMed2006

Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder.

BACKGROUND: The results of pilot trials suggest that omega-3 fatty acids may have efficacy in the treatment of mood symptoms in bipolar disorder. METHODS: We conducted a 4-month, randomized, placebo-controlled, adjunctive trial of ethyl-eicosapentanoate (EPA) 6 g/day in the treatment of bipolar depression and rapid cycling bipolar disorder. Subjects were receiving mood-stabilizing medications at therapeutic doses or plasma concentrations. The measures of efficacy were early study discontinuation, changes from baseline in depressive symptoms (Inventory for Depressive Symptomology total score) and in manic symptoms (Young Mania Rating Scale total score), and manic exacerbations ("switches"). We also measured side effects and bleeding time, a biomarker of drug action. RESULTS: Overall, there were no significant differences on any outcome measure between the EPA and placebo groups. CONCLUSIONS: This study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.

Adult↗
PubMed2006

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

ARNTL Transcription Factors↗
PubMed2006

Lithium augmentation of topiramate for bipolar disorder with comorbid binge eating disorder and obesity.

OBJECTIVE: To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management. METHOD: We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment. RESULTS: A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition. CONCLUSION: Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.

Adult↗
PubMed2006

New findings from the Bipolar Collaborative Network: clinical implications for therapeutics.

In this article, we highlight recent Bipolar Collaborative Network data. We found that childhood-onset bipolar illness is common, often goes untreated for more than a decade, and carries a poor prognosis. During randomized studies of adjunctive medications in depression: 1) Venlafaxine showed higher switch rates than bupropion or sertraline; 2) Tranylcypromine was as well tolerated as lamotrigine; and 3) Modafinil was more effective than placebo. Finally, in treatment of overweight and obesity, topiramate and sibutramine showed equal efficacy but poor tolerability, and zonisamide data showed that it may be useful for mood and weight loss.

Adult↗
PubMed2006

Phenomenology associated with age at onset in patients with bipolar disorder at their first psychiatric hospitalization.

OBJECTIVE: To compare the clinical presentation of patients with early-onset (age <18 years) and typical-onset (age 20-30 years) bipolar disorder at the time of first hospitalization. METHODS: Patients, aged 12-45 years at their first psychiatric hospitalization, with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were evaluated on measures of manic, depressive, and positive psychotic symptoms. Differences in symptom profiles between early- and typical-onset groups were examined. RESULTS: One hundred three early-onset and 58 typical-onset patients were compared. Mixed episodes were more common in the early-onset group, while psychotic features and current substance use were more common in the typical-onset group. There was no significant difference in manic symptom severity ratings between early- and typical-onset groups (F = 1.8, df = 11, 144, p = 0.06). However, these groups differed in depressive (F = 4.2, df = 16, 139, p < 0.001) and positive psychotic (F = 2.8, df = 16, 139, p = 0.001) symptom profiles. Typical-onset bipolar patients reported more severe weight loss and formal thought disorder compared with early-onset patients. CONCLUSIONS: Depressive and positive psychotic symptoms may differ in association with age at onset among patients with bipolar disorder. Additional studies are necessary to determine whether homogeneous phenotypes of bipolar disorder can be delineated based upon age at onset.

Adolescent↗
PubMed2006

Antidepressants and suicidal behavior in bipolar disorder.

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167-181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.

Antidepressive Agents↗
PubMed2006

Comorbidity of eating disorders with bipolar disorder and treatment implications.

OBJECTIVES: To review the scientific evidence examining the comorbidity among eating disorders and bipolar disorder (BD). METHODS: We reviewed all published English-language studies addressing the comorbidity of anorexia nervosa, bulimia, bulimia nervosa, and binge eating disorder in patients with BD and studies of comorbidity of BD in patients with eating disorders. In addition, we discuss the pharmacologic treatment implications from reviewed studies of agents used in BD and eating disorders. RESULTS: Community and clinical population studies of the lifetime prevalence rates of eating disorders in patients with BD, and of BD in patients with eating disorders, particularly when subthreshold and spectrum manifestations of these disorders are included, indicate high rates of comorbidity among these illnesses. CONCLUSIONS: Pharmacologic treatment approaches to patients with BD and a co-occurring eating disorder require examination of the possible adverse effects of the treatment of each syndrome on the other and attempts to manage both syndromes with agents that might be beneficial to both.

Antidepressive Agents↗
PubMed2006

Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers.

OBJECTIVE: The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression. METHOD: One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method. RESULTS: Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch. CONCLUSIONS: Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

Adult↗
PubMed2006

Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants.

OBJECTIVES: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. METHOD: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score > or =3 (mildly ill). RESULTS: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. CONCLUSIONS: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

Adult↗
PubMed2006

Ziprasidone: efficacy and safety in patients with bipolar disorder.

Atypical antipsychotics have been increasingly shown to have efficacy in the treatment of various phases of bipolar disorder. Ziprasidone acts primarily through serotonergic and dopaminergic receptor antagonism, and exerts effects as an inhibitor of serotonin and norepinephrine reuptake. Ziprasidone exhibits dose proportional, linear changes in exposure and is hepatically metabolized primarily by aldehyde oxidase. In studies of patients with acute manic or mixed episodes, treatment with ziprasidone monotherapy or in combination with lithium, resulted in rapid symptom improvement and was generally well tolerated. Results from open-label extension studies of ziprasidone indicate continued improvement in manic symptoms. Preliminary data in pediatric patients with bipolar disorder also suggest it may be efficacious in this population. Ziprasidone is considered as a first-line treatment option in patients with bipolar manic or mixed episodes, with or without psychosis and displays a favorable side-effect profile.

Bipolar Disorder↗
PubMed2006

Extended-release carbamazepine capsules as monotherapy in bipolar disorder : pooled results from two randomised, double-blind, placebo-controlled trials.

OBJECTIVES: Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted. METHODS: Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity. RESULTS: Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo. CONCLUSIONS: These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder.

Adolescent↗
PubMed2006

Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials.

BACKGROUND: Randomized, controlled trials have demonstrated efficacy for atypical antipsychotics in the treatment of mania in bipolar disorder, either as monotherapy or adjunctive treatment. However, there are no published comparisons of individual atypical antipsychotics for mania. DATA SOURCES AND STUDY SELECTION: We conducted a systematic review and meta-analysis of randomized, placebo-controlled monotherapy and adjunctive therapy trials of atypical antipsychotics for acute bipolar mania. Studies published through 2004 were identified using searches of PubMed/MEDLINE with the search terms mania, placebo, and each of the atypical antipsychotics, limited to randomized, controlled clinical trials; review of abstracts from the 2003 meetings of the American College of Neuropsychiatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and consultations with study investigators and representatives of pharmaceutical companies that market atypical antipsychotics. DATA EXTRACTION: Analyses were performed on the changes in Young Mania Rating Scale or Mania Rating Scale total scores from baseline to endpoint, using last observation carried forward and computing the difference in change scores between each drug and its corresponding placebo arm. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of the antipsychotics to each other and to placebo. DATA SYNTHESIS: Data from 12 placebo-controlled monotherapy and 6 placebo-controlled adjunctive therapy trials involving a total of 4304 subjects (including 1750 placebo-treated subjects) with bipolar mania were obtained. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone all demonstrated significant efficacy in monotherapy (i.e., all confidence intervals exclude zero). However, after adjusting for multiple comparisons, pairwise comparisons of individual effects identified no significant differences in efficacy among antipsychotics. Magnitude of improvement was similar whether the antipsychotic was utilized as monotherapy or adjunctive therapy. CONCLUSIONS: The 5 newer atypical antipsychotics were all superior to placebo in the treatment of bipolar mania. For monotherapy and add-on therapy, cross-trial comparisons suggest that differences in acute efficacy between the drugs, if any, are likely to be small.

Antipsychotic Agents↗
PubMed2006

A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder.

OBJECTIVE: To investigate the safety and efficacy of aripiprazole in preventing relapse of a mood episode in recently manic- or mixed-episode patients with bipolar I disorder stabilized on aripiprazole. METHOD: This randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolled patients from 76 centers in 3 countries (Argentina, Mexico, United States) from March 2000 to June 2003. Bipolar I disorder (DSM-IV) patients who had recently been hospitalized and treated for a manic or mixed episode entered an open-label stabilization phase (aripiprazole monotherapy: 15 or 30 mg/day, 6-18 weeks). After meeting stabilization criteria (Young Mania Rating Scale score of < or = 10 and Montgomery-Asberg Depression Rating Scale score of < or = 13 for 6 consecutive weeks), 161 patients were randomly assigned to aripiprazole or placebo for the 26-week, double-blind phase. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy). RESULTS: Aripiprazole was superior to placebo in delaying the time to relapse (p = .020). Aripiprazole-treated patients had significantly fewer relapses (25%) than placebo patients (43%; p = .013). Aripiprazole was superior to placebo in delaying the time to manic relapse (p = .01); however, no significant differences were observed in time to depressive relapse (p = .68). Weight gain (> or = 7% increase) occurred in 7 (13%) aripiprazole-treated and 0 placebo-treated patients. Adverse events (> or = 5% incidence and twice that of placebo) reported by aripiprazole-treated patients were akathisia, pain in the extremities, tremor, and vaginitis. CONCLUSIONS: Aripiprazole, 15 or 30 mg/day, was superior to placebo in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who were stabilized and maintained on aripiprazole treatment for 6 weeks, as shown by a longer time to relapse.

Adult↗