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Biomedical subjects

J R Calabrese

Publications and source records attributed to J R Calabrese.

At least 19 recordsLinked to original sources
PubMed1999

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.

BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.

Adult↗
PubMed1999

Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder.

The designs employed in bipolar maintenance studies have evolved greatly over the last 28 years. Consequently, there has been minimal consensus set for methods used to demonstrate the ability of any new putative mood stabilizers to prevent relapse and recurrence in bipolar disorder. The methods that have evolved the most include enrollment procedures, randomization schemes, use of outcome measures, statistical analyses, and country-specific commercial and regulatory issues. This article contrasts the various methods employed in first- and second-generation placebo-controlled bipolar I maintenance studies. This article also explores the advantages and disadvantages associated with various designs.

Anticonvulsants↗
PubMed1998

Clinical studies on the use of lamotrigine in bipolar disorder.

New mood stabilizers that possess efficacy in the depressed phase of bipolar disorder are needed. The use of marketed antidepressants puts bipolar patients at some increased risk for drug-induced hypomania/mania and rapid cycling. During the development of the antiepileptic, lamotrigine, the drug was observed to improve mood, alertness, and social interactions in some patients with epilepsy. These early observations provided the rationale for investigations into lamotrigine's potential efficacy in bipolar disorder. There are now 14 open clinical reports involving a total of 207 lamotrigine-treated patients with bipolar disorder that suggest this drug possesses a broad spectrum of efficacy in the management of the depressed, hypomanic, manic, and mixed phases of bipolar disorder. In an attempt to replicate and extend these preliminary open-label prospective findings, a series of multicenter, double-blind, placebo-controlled studies evaluating the efficacy and dose-response relationships of lamotrigine in the various phases of the illness, including both acute and maintenance designs in both bipolar I and II disorder, is ongoing.

Anticonvulsants↗
PubMed1997

Depression during mania. Treatment response to lithium or divalproex.

BACKGROUND: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes. METHODS AND DESIGN: In a parallel-group, double-blind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in patients with and without depressive symptoms at baseline according to nurse- or physician-rated scales. RESULTS: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history. CONCLUSIONS: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients.

Adult↗
PubMed1997

Lamotrigine in rapid-cycling bipolar disorder.

BACKGROUND: We evaluated the antidepressant and mood-stabilizing effects of lamotrigine, a novel anticonvulsant, in a group of rapid-cycling bipolar patients. Most were already nonresponders or poor partial responders to other conventional mood-stabilizing agents. METHODS: This open, naturalistic, and prospective study was conducted with five rapid-cycling bipolar patients (DSM-IV). Each received lamotrigine titrated to a minimum dose of 150 mg/day as monotherapy or in combination with other psychotropic agents. Patients were assessed with the Global Assessment Scale (GAS), Beck Depression Inventory (BDI), and Young Mania Rating Scale (YMRS) for evidence of cycling mood. RESULTS: Lamotrigine was used at a mean +/- SD dose of 185.0 +/- 33.5 mg/day for 225.8 +/- 28.0 days. Random regression modeling of data showed significant dose- and time-dependent improvements in depressive symptoms and social function of patients taking lamotrigine (Dose: z = 2.17, p < .03 for BDI, z = 4.44, p < .001 for GAS; Time: z = -3.79, p < .001 for BDI, z = 2.16, p < .03 for GAS). Further random regression modeling analysis of change over time in symptoms prior to lamotrigine compared with symptoms during lamotrigine treatment showed a significant treatment by time effect for GAS (z = 2.40, p < .016) and a trend for BDI scores (z = -1.79, p < .073). No significant time or dosage effect or time by treatment effect was observed for YMRS. Finally, t statistics showed a significant reduction in mean BDI scores following treatment with lamotrigine (t = -5.26, p < .006). Lamotrigine was well tolerated by all patients; only one patient experienced several side effects, which were probably due to interaction between several psychotropic medications. CONCLUSION: Lamotrigine augmentation therapy and monotherapy appeared to have mood-stabilizing and antidepressant efficacy in the treatment of five rapid-cycling bipolar patients. The effect persisted for an average of 7.5 months.

Adult↗
PubMed1997

Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study.

Maintenance studies in bipolar disorder have received increased attention in recent years. The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies, as well as interest in a new group of drugs with mood-stabilizing properties. The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder. We present the methodology of a recently completed randomized, double-blind, placebo-controlled, parallel-group comparison of divalproex and lithium. We examine the consequences of salient design features, along with their implications for future studies. A fundamental conclusion is that such maintenance studies should be designed and executed to emphasize enrollment of patients with relatively active, severe forms of the illness. This goal is not achieved simply, as inherent features of long-term, placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder. Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies designed to achieve adequate statistical power.

Adult↗
PubMed1996

Plasma GABA predicts acute response to divalproex in mania.

Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium, or placebo in a previously reported parallel group multicenter, double-blind, randomized, controlled acute phase treatment trial. Plasma concentrations of gamma aminobutyric acid (GABA) were measured before and after treatment. Higher pretreatment plasma GABA levels were significantly (p = .04) related to a better clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not correlate with response to either lithium (n = 13) or placebo (n = 31). Following treatment with divalproex sodium, plasma GABA levels decreased significantly (p < .05), compared to placebo. Pretreatment plasma GABA levels were not related to overall severity of manic symptoms. Plasma GABA may predict response to pharmacologic agents acting on the GABA system.

Adult↗
PubMed1996

Predictors of response to mood stabilizers.

Although lithium remains the preferred treatment of bipolar disorder, only 60 to 80% of patients with the classic presentation have an adequate response to this drug. When the response rate to lithium is considered across the entire spectrum of bipolar disorders, this rate probably decreases to 50%. Natural history, illness subtype, and comorbidity are all important general predictors of response to treatment. At present, the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling. An overview of clinical presentations that predict general and differential response to mood stabilizers is provided.

Antimanic Agents↗
PubMed1996

Clozapine for treatment-refractory mania.

OBJECTIVE: The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. METHOD: The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). RESULTS: Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. CONCLUSIONS: These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

Adult↗
PubMed1996

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Acute Disease↗
PubMed1995

Lithium therapy: limitations and alternatives in the treatment of bipolar disorders.

As clinical experience with lithium treatment of bipolar disorders accumulates, factors predictive of nonresponse are emerging. Prominent among these are conditions such as comorbid substance abuse and the presence of the malignant variants rapid cycling and mixed states. Lithium therapy is further complicated by noncompliance, attributable in large measure to burdensome side effects such as memory impairment and cognitive slowing. The issues of lithium nonresponse and noncompliance have driven the search for alternative agents, such as the anticonvulsants carbamazepine and valproic acid. While preliminary evidence suggests that these agents may provide improvements over lithium in terms of tolerability and response (especially in rapid cycling and mixed states), methodologic limitations temper the conclusiveness of these findings. The natural history of bipolar disorders is defined by characteristic symptom clusters which evolve in intensity and duration over long time scales, resulting in a high morbidity and mortality. These features raise critical concerns for research design, especially concerning the ethics of placebo controls and the need to generate long-term observational data upon which to predicate meaningful treatment recommendations. With the apparent increase in lithium nonresponse in recent years, the need to identify and definitively evaluate alternative agents is becoming imperative.

Anticonvulsants↗
PubMed1995

Illness characteristics of patients in clinical drug studies of mania.

Two recent large-scale studies of the effectiveness and safety of divalproex versus lithium and placebo in the manic phase of bipolar disorder have provided an opportunity to investigate the characteristics of patients enrolled in clinical drug trials of mood stabilizers. Both studies are randomized, double-blind, parallel-group, multicenter trials; the first addresses effectiveness in acute mania, and the second addresses effectiveness in prevention of manic episodes. Data on demographic, illness severity, and treatment response characteristics were compared between Study 1 and six other clinical drug trials in acute mania from the past decade that had data in comparable domains. Although patients experienced onset of bipolar disorder in their early twenties, the average age of enrollment in the studies was about 40. Approximately equal numbers of men and women were enrolled. The patients were severely ill at the time of enrollment, with mean scores on the Global Assessment Scale ranging from 20 to 37. Overall, characteristics were remarkably similar across studies and representative of those reported in epidemiological studies. From Study 2, which is currently in progress, characteristics of patients recruited into the trial were determined. At least 10 subjects were initially assessed for each subject actually enrolled in the trial. The two factors most associated with failure to move from the open phase of the study to the randomized phase were administrative problems (principally failure of subjects to adhere to the medication regimen and protocol requirements) and inability, even with an open treatment protocol, to achieve adequate recovery from the index manic episode within 3 months.

Adolescent↗
PubMed1995

A medication algorithm for treatment of bipolar rapid cycling?

Individuals with the rapid cycling form of bipolar disorder represent 13% to 20% of the bipolar population. Although lithium remains the treatment of choice for classic bipolar disorder, failure rates as high as 72% to 82% have been reported for lithium among those who have the rapid cycling variant. Treatment alternatives, including the use of divalproex sodium and carbamazepine, have shown promise for this often treatment-refractory group of patients. Predictors of positive outcome for the acute and prophylactic management of mania with divalproex sodium have emerged; they include nonpsychotic mania, the occurrence of decreasing or stable episode frequencies, mild mania, and mixed states. Predictors for positive acute and prophylactic antidepressant responses to divalproex sodium include nonpsychotic mania, increasingly severe mania, and the absence of borderline personality. Mixed results have been reported for studies using carbamazepine therapy for the treatment of rapid cycling bipolar disorder. Some investigators have reported success with carbamazepine in conjunction with other medications, while others have not. A psychopharmacologic algorithm for the treatment of rapid cycling bipolar disorder is proposed. There is a growing opinion among psychiatrists that patients who rapidly cycle should be treated with an anticonvulsant prior to lithium. However, until homogeneous cohorts of rapid cyclers undergo at least random assignment to different open treatments, these recommendations remain controversial.

Algorithms↗
PubMed1994

Quantification of occipital EEG changes in Alzheimer's disease utilizing a new metric: the fractal dimension.

In a retrospective preliminary investigation, the occipital electroencephalogram (EEG) changes associated with Alzheimer's disease (AD) were examined using a novel quantification metric: the fractal dimension. The mean occipital EEG fractal dimension was determined for each of three patient groups representing a spectrum of clinical and EEG pathology: controls, probable AD, and autopsy-confirmed AD. The fractal dimension was significantly reduced in each of the AD groups with respect to controls (p < 0.001); and within the AD groups, it was significantly reduced in autopsy-confirmed AD relative to probable AD (p < 0.01). The fractal dimension findings paralleled the manifest EEG abnormalities in a way that suggests it has potential clinical utility in metric studies on the EEG, especially when applied to the dementias. Additionally, the EEG pathology studied here was particularly well-described by the fractal dimension, providing further support for a nonlinear approach to the background activity of the EEG.

Alzheimer Disease↗
PubMed1994

Effects of chronic treatment with valproate on serotonin-1A receptor binding and function.

Valproate is effective in treating bipolar disorder characterized by rapid cycling or acute mania, although the mechanism of action is unclear. In contrast to other treatments for depression, 21 days of treatment in rats with valproate (1,, 200 or 400 mg/kg) did not significantly alter the hypothermia induced by 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors. Treatment with valproate also had no effect on radioligand binding to serotonin-1A, serotonin-2 or beta-adrenergic receptors. Based on these animal studies in frontal cortex and hippocampus, the therapeutic benefit of valproate in mood disorders does not appear to involve adaptive changes in serotonin-1A, serotonin-2 or beta-adrenergic receptor number.

8-Hydroxy-2-(di-n-propylamino)tetralin↗