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Biomedical subjects

J R Calabrese

Publications and source records attributed to J R Calabrese.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1994

Clozapine in treatment-refractory mood disorders.

Lithium remains the mainstay of treatment for patients with bipolar affective disorder; however, nearly half of patients with bipolar disorder fail to respond to lithium. Recently, there have been an increasing number of preliminary clinical reports that clozapine, an atypical antipsychotic agent, has potential efficacy in patients with mood disorders. We review the available clinical data supporting the potential use of clozapine in these psychiatric disorders and report our preliminary data from a study that used clozapine in the acute treatment of mania in treatment-refractory patients. Twenty-five patients meeting the DSM-III-R criteria for the manic phase of either bipolar or schizoaffective disorder entered a 13-week open prospective trial of clozapine. These patients either had failed to respond to or had been intolerant to treatment with lithium, an anticonvulsant, and at least two typical neuroleptics. Eighteen of 25 patients demonstrated a greater than 50% decrease in the Young Mania Rating Scale score. These preliminary data as well as the clinical reports reviewed indicate that the efficacy of clozapine in treatment-resistant patients is not limited to patients with schizophrenia.

Affective Disorders, Psychotic↗
PubMed1993

Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion.

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing's disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing's disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing's disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-Releasing Hormone↗
PubMed1993

Predictors of valproate response in bipolar rapid cycling.

Multiple regression/discriminant analyses were separately conducted to generate predictors of acute and prophylactic antimanic and depressive outcome in 101 valproate-treated bipolar rapid cyclers. Predictors of good antimanic response included decreasing or stable episode frequencies and nonpsychotic mania. Predictors of good antidepressant response included nonpsychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. This report confirms prior findings that indicate that valproate possesses marked acute and prophylactic antimanic and antimixed effects with only poor to moderate antidepressant properties.

Adult↗
PubMed1993

Rapid cycling bipolar disorder and its treatment with valproate.

A large subgroup of lithium-resistant manic patients are rapid cyclers and as many as 82% of them exhibit poor responses to lithium. Thus, a substantial percentage of poor responses to lithium is accounted for on the basis of rapid cycling. Although controlled trials have demonstrated the efficacy of carbamazepine for the treatment of rapid cycling bipolar disorder, the response to carbamazepine frequently deteriorates. Furthermore, its ability to auto-induce and hetero-induce drug metabolism complicates its routine use. These findings suggest that substantial numbers of rapid cyclers do not respond to either carbamazepine or lithium and that additional mood stabilizers are needed. Our recent findings on 101 rapid cycling bipolar patients continue to support the impression that valproate has marked antimanic efficacy and poor to moderate antidepressant properties. Most patients with mixed states exhibited good antimixed state responses but then became depressed. Predictors of a good antimanic response included decreasing or stable episode frequencies and non psychotic mania. Predictors of a good antidepressant response were non psychotic mania worsening over the years of the illness and absence of borderline personality disorder comorbidity. These open prospective trials, as well as other positive reports of valproate's efficacy in bipolar rapid cycling, await replication with ongoing, controlled maintenance trials.

Adult↗
PubMed1992

Spectrum of efficacy of valproate in 78 rapid-cycling bipolar patients.

The rapid-cycling variant of bipolar disorder constitutes about 15%-20% of all bipolar patients, and 72%-82% of these patients exhibit less than adequate response to lithium therapy. Valproate's spectrum of efficacy was examined in 78 patients with rapid-cycling bipolar disorder in a prospective, open, 15.8-month trial. Thirty patients received valproate monotherapy and 48 received combination therapy. Treatment assignment was nonrandomized and based on prior treatment history. A marked acute response was seen in 54% of the patients with mania, 87% of those with mixed states, and 19% of those with depression. Marked prophylactic responses were seen in 72% of manic patients, 94% of mixed states patients, and 33% of depressed patients. In addition, moderate acute antimanic responses were observed in another 31% of the patients, prophylactic antimanic responses in 17%, acute antimixed state responses in 0%, prophylactic antimixed state responses in 0%, acute antidepressant responses in 25%, and prophylactic antidepressant responses in mixed states in 34%. Pattern analysis was conducted to examine the spectrum of efficacy of valproate in various cells (e.g., the cohort of patients who had an acute antimanic response to the drug). Pattern analysis showed that 40% of the patients with a marked prophylactic antimanic response had a marked antidepressant response to valproate. However, among the patients with a marked antidepressant response to valproate, 91% had a marked antimanic response. The most common side effects of valproate in our study, as in earlier studies, were gastrointestinal problems (nausea, stomach cramps, diarrhea), tremors, lethargy, and hair thinning.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Fluoxetine in the treatment of borderline and schizotypal personality disorders.

Twenty-two patients meeting the criteria for borderline or schizotypal personality disorder or both participated in a prospective, nonblind 12-week trial of fluoxetine. There were significant reductions in self-injury and in scores on the Hopkins Symptom Checklist regardless of diagnosis. The results suggest that controlled trials of fluoxetine and investigations of the serotonergic system in these disorders would be useful.

Adult↗
PubMed1991

Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications.

To explore whether possible differences in central nervous system neuromodulators contribute to the differential presentation of affective symptomatology in Cushing's disease and major depression, we examined the levels of immunoreactive CRH and ACTH in the cerebrospinal fluid (CSF) of 11 patients with Cushing's disease, a patient with ectopic ACTH secretion, 34 patients with major depression, and 60 healthy subjects. We elected to measure these peptides not only because both are classically involved in pituitary-adrenal regulation, but also because their primarily arousal-producing and anorexigenic behavioral effects in experimental animals suggest that they may play a role in the symptom complex of depressive syndromes. We also explored whether the CSF levels of these peptides were more helpful in determining the often difficult differential diagnosis between major depression and Cushing's disease than the plasma ACTH response to ovine CRH, a currently used but somewhat insensitive laboratory means of distinguishing these disorders. CSF levels of immunoreactive CRH and ACTH were significantly lower in Cushing's disease patients [21.9 +/- 2.7 and 15.4 +/- 1.8 pg/mL, (mean +/- SEM), respectively] compared to patients with major depression [38.4 +/- 2.3 pg/mL (P less than 0.01) and 24.5 +/- 1.6 pg/mL (P less than 0.01), respectively] and controls [38.4 +/- 1.6 pg/mL (P less than 0.001) and 26.3 +/- 1.1 pg/mL (P less than 0.001), respectively]. The coexistence of high plasma ACTH and low CSF ACTH in Cushing's disease yielded a CSF/plasma ACTH ratio consistently less than that in depressed patients, with only 2 of 31 subjects comprising both groups showing values that overlapped. In contrast, 9 of the combined patients showed ACTH responses to ovine CRH that overlapped. These data suggest that differences in centrally directed CRH secretion may account for the differential presentation of the dysphoric syndromes seen in major depression and Cushing's disease. Hence, the classic form of major depression (melancholia), is often associated with evidence of pathological hyperarousal, such as intense anxiety, sleeplessness, and anorexia, while that of Cushing's disease is associated with evidence of pathological hyperarousal, including hyperphagia, fatigue, and inertia. Moreover, measurement of the CSF/plasma ACTH ratio may serve as a clinically useful adjunct to the ovine CRH stimulation test and other laboratory measures in determining the differential diagnosis between major depression and Cushing's disease.

Adolescent↗