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Biomedical subjects

Charles L Bowden

Publications and source records attributed to Charles L Bowden.

16 recordsLinked to original sources
PubMed2003

Maintenance efficacy of divalproex in the prevention of bipolar depression.

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

Adolescent↗
PubMed2003

Oral topiramate for treatment of alcohol dependence: a randomised controlled trial.

BACKGROUND: Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence. METHODS: We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving. FINDINGS: At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them. INTERPRETATION: Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.

Administration, Oral↗
PubMed2003

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.

BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P =.02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.

Adult↗
PubMed2003

Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling.

BACKGROUND: A substantial proportion of patients with bipolar disorder are characterized by a rapidly cycling course and are particularly resistant to conventional treatment. METHODS: This secondary analysis, defined a priori, was conducted on a larger data set from patients with bipolar I disorder to determine the efficacy of a 3-week treatment with the atypical antipsychotic olanzapine (5-20 mg/day, n=19) versus placebo (n=26) in patients with >or=4 episodes in the preceding year. RESULTS: Significantly fewer placebo patients completed treatment (34.6 vs. 73.7%, P=0.016), and more than half discontinued due to lack of efficacy (53.8 vs. 21.1%, P=0.035). Olanzapine reduced Young Mania Rating Scale (YMRS) total scores significantly more than placebo (-13.9 vs. -4.1, P=0.011). Clinical responses, defined as >or=50% improvement in YMRS, were achieved in 58% of olanzapine patients, compared with 28% of placebo patients (P=0.066). Extrapyramidal symptoms were not significantly changed in either group. Somnolence was the most common adverse event in both groups (olanzapine: 52.6%, placebo: 23.1%; P=0.060). No event occurred significantly more frequently with olanzapine than with placebo. No patients discontinued due to an adverse event. LIMITATIONS: The duration of this study was limited to 3 weeks, precluding conclusions about long-term efficacy of olanzapine. Moreover, a sizeable placebo effect was obtained, possibly masking optimal therapeutic effect. Despite these limitations, treatment differences in efficacy were highly significant. CONCLUSIONS: These results indicate that olanzapine was effective in reducing symptoms of mania and well tolerated in patients with bipolar I disorder with a rapid-cycling course.

Adult↗
PubMed2003

Acute and maintenance treatment with mood stabilizers.

Treatment of bipolar disorder is complicated by the multiple phases of the illness, dimensional symptomatology that varies considerably across individuals, and a limited spectrum of activity for all mood stabilizers. Randomized, blinded, placebo-controlled studies provide clear guidelines to the overall efficacy of treatments for mania. However, for secondary questions, such as the treatment to employ when lithium or valproate is inadequate as monotherapy, evidence is incomplete, and usually derived from both smaller and less well-designed studies. For mania, the spectrum of efficacy of valproate is broader than for other mood stabilizers. However, many patients obtain inadequate benefit from monotherapy regimens of all mood stabilizers. Recent studies indicate that for patients who develop mania while taking a mood stabilizer, combinations of an antipsychotic and a mood stabilizer yield greater improvement than does continuation of the mood stabilizer alone. Maintenance-treatment studies support the efficacy of lithium, valproate and lamotrigine, although with a different spectrum of benefits and limitations for each. Valproate and lithium provide greater benefits for prevention of manic relapses and control of manic symptomatology than for depression. Several studies indicate actual worsening in depressive aspects of bipolar disorder with lithium treatment. Lamotrigine appears effective in delaying relapse into a new episode, with most benefits limited to delaying time to depression. Lamotrigine has not shown anti-manic activity in placebo-controlled studies. In contrast to traditional antidepressant medications, lamotrigine has not been associated with induction of mania, or of rapid-cycling illness symptomatology. Recent studies reported that carbamazepine was inferior to valproate in acute mania, and inferior to lithium in maintenance treatment. Other putative mood stabilizers have to date yielded negative or inconclusive results in studies in mania. Systematic studies are needed to clarify treatment guidelines for youth with bipolar disorder, and for other special populations, e.g. pregnant women and the elderly.

Antimanic Agents↗
PubMed2003

Valproate.

OBJECTIVES: This article summarizes the role of valproate as a treatment for bipolar disorder and related conditions. METHODS: Published studies and reviews were systematically reviewed. Results from randomized, parallel group, double-blind, placebo-controlled studies that included an active comparator are emphasized. RESULTS: Valproate is an effective treatment for manic patients. Valproate was superior to placebo in one 1-year randomized, parallel group study in rate of recurrence requiring discontinuation, rate of depression requiring discontinuation, total early termination and time to 25% of patients relapsing with mania, and in controlling mild depressive symptoms. On some measures, including time to development of a manic episode, valproate did not differ from placebo. Assessments of maintenance efficacy of valproate and other putative prophylactic treatments for bipolar disorder are problematic, because of the need to analyze multiple indices of efficacy, and practical and ethical issues that limit generalizability of results of placebo-controlled studies. Valproate has some advantages over lithium in treatment of mania for persons with more severe illnesses. Valproate benefits a broader spectrum of bipolar conditions than lithium. Valproate appears at best modestly effective for bipolar depression. Used in combination with several other treatments, additive benefits result, that are greater than with any of the treatments as monotherapy. Side effects are generally mild and manageable, particularly with divalproex. Weight gain and pharmacokinetic interaction with lamotrigine are perhaps the most consistent problems in use. Valproate contributes to neural tube defects if taken during the first trimester of pregnancy, and this risk must be conveyed to women. CONCLUSIONS: Valproate is an effective and useful treatment for bipolar disorder. Studies clarifying its spectrum of efficacy, its safety and efficacy in combination regimens, and its mechanisms of action are warranted.

Antimanic Agents↗
PubMed2002

Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II.

Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered.

Bipolar Disorder↗
PubMed2002

Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.

BACKGROUND: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. METHODS: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). RESULTS: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. CONCLUSION: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.

Acute Disease↗
PubMed2002

National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders.

A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Bipolar Disorder↗
PubMed2002

Pattern of response to divalproex, lithium, or placebo in four naturalistic subtypes of mania.

We investigated effects of antimanic treatments on specific aspects of mania, prediction of response, and the existence of naturalistic subgroups of patients with different treatment response in 179 inpatients randomized to antimanic treatment with lithium, divalproex, or placebo. Psychiatric symptom ratings were conducted by clinicians and nurses before and during treatment. Factor analysis using physician and nurse rating scales, followed by a cluster analysis, yielded anxious-depressive, psychotic, classic, and irritable subtypes. We compared: (1) treatment effects on factor scores; (2) responses to treatment across subtypes; and (3) pattern of symptom change with each treatment. The anxious-depressed subtype did not respond to any treatment; the psychotic and classic subtypes responded similarly to lithium and to divalproex; and the irritable-dysphoric subtype responded better to divalproex than to lithium. Overall, divalproex improved impulsivity and hostility significantly more than placebo, and lithium or divalproex improved hyperactivity more than placebo. These data suggest that there are naturalistic subtypes of manic episodes with different responses to treatment.

Adult↗
PubMed2002

Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) , Unites States and Food and Drug Administration (FDA), Unites States participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.

Antidepressive Agents↗
PubMed2002

Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety.

OBJECTIVE: The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania. METHOD: This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures. RESULTS: The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively. CONCLUSIONS: Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated.

Acute Disease↗
PubMed2002

Lamotrigine in the treatment of bipolar disorder.

Lamotrigine has undergone a remarkable series of systematic studies since 1994 that now establish it as an efficacious, well-tolerated treatment in bipolar disorder. Its efficacy principally addresses both acute and maintenance phase benefits on depressive symptomatology. These benefits have been demonstrated in placebo-controlled studies, rapid cycling patients, bipolar I and II patients and monotherapy as well as in combination therapy, although this has been less well studied. The drug is exceptionally well-tolerated in long-term treatment, although initial dosing requires gradual dosage escalation to avoid the risk of inducing serious rashes with features within the spectrum of Stevens-Johnson syndrome. Administration with valproate requires a slower dosage titration, whereas, as with many drugs, administration with carbamazepine requires a more rapid dosage increase. In contrast to marketed antidepressants, lamotrigine appears not to induce manic or hypo-manic episodes, nor to increase cycling frequency. This combination of properties makes it a first-choice treatment for acute bipolar depression and continuation treatment, especially, but not limited to, prophylaxis against recurrent depression and depressive symptoms. Lamotrigine appears not to have acute antimanic properties. A small number of studies suggest a broader spectrum of efficacy, including in some axis I disorders that are comorbidly associated with bipolar disorder.

Antidepressive Agents↗
PubMed2002

Report of the Texas Consensus Conference Panel on medication treatment of bipolar disorder 2000.

BACKGROUND: The process and outcome of a consensus conference to develop revised algorithms for treatment of bipolar disorder to be implemented in the public mental health system of Texas are described. These medication algorithms for bipolar disorder are an update of those developed for the Texas Medication Algorithm Project, a research study that tested the clinical and economic impact of treatment guidelines for major psychiatric illnesses treated in the Texas public mental health system (Texas Department of Mental Health and Mental Retardation [TDMHMR]). METHOD: Academic clinicians and researchers, practicing clinicians in the TDMHMR system, administrators, advocates, and consumers participated in a consensus conference in August 2000. Participants attended presentations reviewing new evidence in the pharmacologic treatment of bipolar disorder and discussed the needs of consumers in the TDMHMR system. Principles were enumerated, including balancing of evidence for efficacy, tolerability, and safety in medication choices. A set of 7 distinct algorithms was drafted. In the following months, a subcommittee condensed this product into 2 primary algorithms. RESULTS: The panel agreed to 2 primary algorithms: treatment of mania/hypomania, including 3 pathways for treatment of euphoric symptoms, mixed or dysphoric symptoms, and psychotic symptoms; and treatment of depressive symptoms. General principles to guide algorithm implementation were discussed and drafted. CONCLUSION: The revised algorithms are currently being disseminated and implemented within the Texas public mental health system. The goals of the Texas initiative include increasing the consistency of appropriate treatment of bipolar disorder, encouraging systematic and optimal use of available pharmacotherapies, and improving the outcomes of patients with bipolar disorder.

Algorithms↗
PubMed2002

Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management.

BACKGROUND: The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder. METHOD: A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. RESULTS: A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. CONCLUSION: Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

Anticonvulsants↗