Mania from dexfenfluramine.
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Anti-Obesity Agents↗
Biomedical subjects
C L Bowden
Publications and source records attributed to C L Bowden.
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↗
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↗
Role of newer medications for bipolar disorder.
The quest for additional effective therapies for bipolar study commenced in the 1960s, even before regulatory approval of lithium. This was driven by the recognition that patient response to lithium varied from excellent to poor; thus, significant numbers of patients faced its frequent adverse effects and risks without sustaining any benefit. These needed advances have been slowed by the unusual difficulties of studying bipolar disorder in controlled, rigorously designed protocols. These difficulties are reviewed both from the perspective of their effects on research and on clinical practice. In addition, the results of two blinded, placebo-controlled studies of divalproex in the treatment of acute mania are compared with results from earlier open and comparator studies. The comparisons indicate that open-study results with divalproex and other forms of valproic acid have yielded results quite similar to those observed under rigorous study conditions. Whereas substantial evidence exists regarding the efficacy of divalproex and carbamazepine and their roles in treating patients with bipolar disorder, studies evaluating other putative mood-stabilizing agents and antidepressants in bipolar disorder are few in number and inconsistent in results. With few exceptions, studies of these latter drugs do not provide clear guidelines for treatment.
Antidepressive Agents↗
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↗
Thioridazine-induced retinopathy.
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Dose-Response Relationship, Drug↗
Dosing strategies and time course of response to antimanic drugs.
Mania is one of the few emergent conditions in psychiatry. Vigorous treatment, aimed at achieving symptom control as promptly as possible while avoiding adverse effects, is therefore important. Strategies to accomplish this aim are possible, but differ for each of the three antimanic drugs principally employed. For lithium, uncomplicated manic patients can be started at 15 mg/kg of body weight, with dosage increase every 3 to 4 days until response, complicating adverse effects, or a serum level of 1.2 to 1.4 mEq/L occurs. Valproate, if administered as divalproex, can usually be initiated at a dosage of 20 mg/kg of body weight, which is associated with earlier improvement than that observed with lithium. Carbamazepine requires a relatively slow dosage escalation from an initial 200 mg once or twice daily, due to the possibility of neuromuscular and cognitive adverse effects. Adjunctive medications are frequently necessary and add to the importance of a thorough knowledge of the dosing strategies needed at different points in early therapy of bipolar disorder.
Bipolar Disorder↗
Clonidine plus haloperidol in the treatment of schizophrenia/psychosis.
Because of the evidence for increased norepinephrine (NE) production in psychotic patients, we studied the effects of combining the alpha 2-adrenergic agonist clonidine with haloperidol for the treatment of schizophrenic psychosis. Twelve hospitalized schizophrenic patients were taken off their antipsychotic medication for 2 to 4 weeks before double-blind treatment with haloperidol (20 mg/day) combined with either clonidine or placebo. The group receiving clonidine was significantly more improved on the thought disorder subscale of the Brief Psychiatric Rating Scale (p = 0.02). The groups differed initially in the level of negative symptoms, but not controlling for this difference statistically by analysis of covariance did not change the finding with regard to the superiority of combining clonidine with haloperidol. We conclude that larger treatment trials of combining haloperidol with clonidine are warranted.
Adrenergic alpha-Agonists↗
Homovanillic acid and monoamine oxidase in sons of substance-abusing fathers: relationship to conduct disorder.
OBJECTIVE: Children of substance-abusing (SA) fathers have been found to have increased rates of conduct disorder (CD). Substance abuse and antisocial behavior have been linked to alterations in dopaminergic regulation and to monoamine oxidase (MAO) in adults. This study assessed the relationship between homovanillic acid (HVA), the metabolite of dopamine (DA), and MAO, the enzyme facilitating the conversion of DA to HVA, with CD in boys of SA and non-SA fathers. METHOD: Male youths (N = 65), between the ages of 6 and 15 years, admitted to a residential setting because of behavior problems, were studied through peripheral blood samples and structured interviews. RESULTS: The findings indicated that MAO activity was significantly higher in boys of SA fathers with CD than (1) in boys of non-SA fathers with CD and (2) in boys of SA fathers without CD. HVA levels did not differ significantly among the groups. CONCLUSIONS: In the context of previous studies, the findings support the concept of dopaminergic dysregulation in sons of SA fathers, manifested by alterations in MAO activity levels in those youths with CD.
Adolescent↗
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↗
Delusional misidentification of the self associated with nondominant cerebral pathology.
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Brain↗
Predictors of response to divalproex and lithium.
Predictors of response to mood stabilizers are of interest to psychiatrists because patients want and deserve prompt improvement, need to preserve limited hospital benefits, and desire agents that are both efficacious and free of adverse effects. Clinically practical guidelines for the likelihood of lithium responsiveness include mild and uncomplicated illness, pure manic symptomatology, prior response to lithium, and infrequent episodes. Divalproex has a broader spectrum of responders and has approximately equal benefit for patients with pure mania as for those with several forms of bipolar disorder that respond poorly to lithium (e.g., mixed mania, rapid cycling, comorbid substance abuse, and secondary bipolar disorder). Carbamazepine may be effective in patients who failed to respond to lithium and is more likely to be effective as part of combined drug therapy than as monotherapy. This review points out that, although the number of firm findings regarding predictors of response and the features associated with response are few, many of these can be combined with other general clinical information about the status of the patient to provide a guide to treatment selection and implementation of a therapeutic regimen.
Bipolar Disorder↗
History of the development of valproate for treatment of bipolar disorder.
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Animals↗
Visual-perceptual disturbances in delusional misidentification.
The delusional misidentification syndromes can involve physical misidentification. Delusional misidentification of the physical make-up of the self shares delusional dysmorphic symptoms with delusional disorder of the somatic type. In this article, we discuss how the study of delusional and perceptual symptoms in delusional misidentification syndromes may lead to a better understanding of the delusional dysmorphic process.
Adult↗
Depressive mania versus agitated depression: biogenic amine and hypothalamic-pituitary-adrenocortical function.
The existence of mixed affective states challenges the idea of specific biological abnormalities in depression and mania. We compared biogenic amines and hypothalamic-pituitary-adrenocortical (HPA) function in mixed manic (n = 8), pure manic (n = 11), agitated bipolar depressed (n = 20), and nonagitated bipolar depressed (n = 27) inpatients (Research Diagnostic Criteria). Mixed manics met Research Diagnostic Criteria for primary manic episodes and also met criteria for major depressive episodes except for duration. The norepinephrine metabolite methoxyhydroxy phenthylene glycol (MHPG) was higher in cerebrospinal fluid from mixed manic than from agitated depressed patients, consistent with differences previously reported between the overall samples of depressed and manic patients. Similarly, patients in a mixed state had higher urinary excretion of norepinephrine (NE) and elevated output of NE relative to its metabolites. HPA activity was similar in mixed manic and agitated depressed patients. These data suggest that mixed manics combine certain biological abnormalities considered to be characteristic of mania and of depression.
Adult↗
The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine.
The study describes a sequential analysis of depression-related physical symptoms and their relationship to imipramine and amitriptyline plasma levels over 4 weeks of treatment in 79 unipolar and bipolar patients hospitalized for major depressive disorder. Insomnia diminished in all patients after 2 weeks of drug administration. After 4 weeks, the sleep of patients whose depressive disorder has significantly improved was nearly normal, whereas patients who remained depressed showed continued sleep impairment. Reductions in loss of appetite, weight and sexual interest paralleled mood improvement. Tricyclic plasma levels significantly correlated with improved sleep. The findings suggest a close link between depressed mood and physical symptoms during recovery from major depressive disorder.
Adult↗
Drug-induced actions on brain neurotransmitter systems and changes in the behaviors and emotions of depressed patients.
Despite cumulative evidence that the tricyclic drugs result in significant changes in the functioning of brain serotonergic (5-HT) and nordrenergic (NE) systems, such changes have not been found to be associated with recovery from depression. Based upon evidence that the 5-HT and NE systems were associated with different emotions, it was hypothesized that changes in these systems were associated with different components of behavior in drug-responsive patients and not with changes in the "whole" disorder. Findings from this multihospital study of 104 unipolar and bipolar depressed patients showed early drug-associated reductions in anxiety and hostility in treatment responders to precede changes in motor retardation and depressed mood. Adopting this approach of looking for relationships between changes in components of major depression and changes in neurotransmitter system function, decreases in 5-HT and NE metabolite concentrations in cerebrospinal fluid (CSF) in patients treated with tricyclics, were found to be correlated with changes in specific behaviors. Results indicated the following: (1) drug-induced changes in the 5-HT system to be associated with mood aspects, notably anxiety, and depressed mood; changes in NE primarily with the psychomotor, secondarily with the mood components of the depressed state; (2) the pattern of relationships between changes in 5-HT and in mood in the unipolar was different than that in the bipolar subtype. The results indicate that in determining the relationships of biochemical changes to behavioral ones, that it is important to take into account the type of depression (bipolar or unipolar), as well as examining individually and over time those components that make up the disorder of depression. These results support evidence that tricyclics have multiple behavioral actions, that response is mediated through changes in specific behaviors and that this approach warrants further application in prospective studies of antidepressant drug mechanisms and their therapeutic actions.
Amitriptyline↗
Sensation seeking in psychiatrically disturbed youth: relationship to biochemical parameters and behavior problems.
OBJECTIVE: Relatively little research has been conducted on the relationship of personality traits or behavioral tendencies with biological parameters in youth. This study was intended to determine whether relationships exist between self-reported sensation-seeking tendencies and biochemical parameters in boys. METHOD: Twenty-five male youth aged 8 to 15 years admitted to a residential diagnostic center because of noncompliant, disruptive, and/or antisocial behavior were studied. Biochemical parameters associated with sensation seeking in adults or antisocial behavior were measured along with diagnoses, behavior ratings, and self-reported sensation seeking. RESULTS: High sensation seeking, as assessed on a newly developed sensation-seeking scale for children, was inversely correlated with 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in the older youth (> or = 12.0 years) but not in the younger boys (< 12.0 years) in the group. Elevations on the sensation seeking scale also correlated marginally in these older youth with parent-reported problems on a behavior rating scale, reflecting "delinquent" behavioral tendencies. CONCLUSIONS: The findings support hypothesized noradrenergic dysregulation in some sensation-seeking persons (including youth > or = 12.0 years) and the relationship between high sensation-seeking tendencies and antisocial or disruptive behavioral disorder.
Adolescent↗