Mixed mania: apparent induction by a tricyclic antidepressant in five consecutively treated patients with bipolar depression.
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Adult↗
Biomedical subjects
A C Swann
Publications and source records attributed to A C Swann.
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↗
Mixed or dysphoric manic states: psychopathology and treatment.
Although the diagnostic criteria for the phenomenon of mixed states are not well defined, it is clear that this variant of bipolar disorder is prevalent, severe, and difficult to treat. The presence of complicating factors, such as substance abuse, neurologic insults or disorders, or developmental disorders, appears to increase the risk for developing mixed states. Several investigators have reported that patients with mixed episodes are less responsive to lithium therapy than are patients with pure mania. This review, however, reports that only limited data are available to support the efficacy of other antimanic agents. Divalproex appears to be more efficacious than lithium for patients in mixed states, but studies with larger patient populations are needed for confirmation. More than one agent may be required to bring about effective treatment, a factor that complicates simple comparator studies. When conventional pharmacotherapy fails, electroshock therapy often proves useful.
Bipolar Disorder↗
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↗
Depressive mania: response of residual depression to bupropion.
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Adult↗
Cation transport mediated by Na+,K(+)-adenosine triphosphatase in lymphoblastoma cells from patients with bipolar I disorder, their relatives, and unrelated control subjects.
In an investigation of cation transport in bipolar affective disorder, we have measured parameters related to Na+,K(+)-adenosine triphosphatase, the enzyme that carries out active transport of sodium and potassium, in lymphoblastoid cells cultured from patients with bipolar affective disorder, age-matched nonaffected family relatives, and unrelated control subjects. Patients had lower ion transport per cell and per transport enzyme site than did related or unrelated control subjects. The rate of transport per cell appeared higher in nonaffected relatives of patients than in unrelated control subjects, though this difference did not reach significance. These data suggest that abnormally regulated ion transport may be associated with bipolar affective disorder independently of clinical state.
Biological Transport, Active↗
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↗
Noradrenergic receptor mechanisms in neophobia.
We have previously demonstrated that depletion of forebrain norepinephrine (NE) led to an attenuation of neophobia in a novel environment, as defined by a greater preference for novel food over familiar food. To study further the role of forebrain NE in neophobia we chronically infused noradrenergic receptor ligands or forskolin into the lateral ventricles of sham and 6-hydroxydopamine dorsal bundle lesioned rats. Chronic NE infusions into lesioned animals reversed the lesion-induced shift in relative food preference. The beta receptor agonist isoproterenol had moderate effects similar to those of NE in lesioned and sham animals. Phenylephrine, an alpha-1 agonist, was without effect. Forskolin, an adenylate cyclase activator, mimicked the effects of NE infusions. These data suggest a role for noradrenergic stimulation of adenylate cyclase in neophobia.
Adenylyl Cyclases↗
A comparison of clinical features in trichotillomania and obsessive-compulsive disorder.
Trichotillomania (TM) recently has been conceptualized as a variant of obsessive-compulsive disorder (OCD). However, no systematic data have compared the clinical features of these two disorders. Here we report data from 8 TM and 13 OCD patients which suggest important clinical differences between groups. First, TM patients reported a significantly greater degree of pleasure during hair-pulling than OCD patients reported during performance of ritualistic behaviors. Second, TM was accompanied by significantly fewer associated obsessive-compulsive symptoms. Third, the groups differed with regard to other clinical features including anxiety, depression, and personality characteristics. We conclude that TM is not conceptualized best as a variant of OCD.
Adult↗
Dysphoric mania.
Lithium remains the mainstay of therapy for most patients with bipolar disorder. Patients with syndromal variations of bipolar disorder, such as those experiencing mixed states or dysphoria have generally had a rather poor therapeutic response to lithium. Our group conducted a double-blind, parallel-group comparison of lithium and valproate for the control of mania in 27 patients with bipolar disorder. The study addressed the question of whether certain illness characteristics might be predictive of a positive response to a particular pharmacologic agent. There were significant differences in the cohort of patients who responded favorably to valproate compared with those who did not. Pretreatment depression scores were higher in the patients responding to valproate than in nonresponders. Patients with depressed mood or anxiety associated with mixed states responded equally to lithium and valproate. Studies are needed to clarify the clinical and pathophysiologic status of mixed or dysphoric manic states and to validate predictors of response to therapeutic agents.
Bipolar Disorder↗
Hypothalamic-pituitary-adrenocortical function in mixed and pure mania.
There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.
Adult↗
A double-blind comparison of valproate and lithium in the treatment of acute mania.
OBJECTIVE: This study was carried out to compare the efficacy of lithium carbonate with that of valproate in acute mania and to determine whether pretreatment clinical characteristics, such as the presence of a mixed affective state, might predict a differential response to the two drugs. METHOD: Twenty-seven patients meeting DSM-III-R criteria for acute manic episodes underwent a 3-week, randomized, double-blind, parallel-groups trial of treatment with lithium carbonate or valproate. Symptom severity was measured by using the Schedule for Affective Disorders and Schizophrenia, change version (SADS-C), the Global Assessment Scale (GAS), and the Brief Psychiatric Rating Scale (BPRS). Drug effects were compared by using repeated measures analysis of variance (ANOVA). RESULTS: At the end of the study, nine of 14 patients treated with valproate and 12 of 13 patients treated with lithium had responded favorably, as measured by changes in the SADS-C mania, BPRS, and GAS scores. Elevated pretreatment SADS-C depression scores were associated with good response to valproate. ANOVA revealed a significant interaction between drug and mixed affective state with respect to treatment response. CONCLUSIONS: Lithium and valproate were both effective in improving manic symptoms, and lithium was slightly more efficacious overall. Unlike the case with lithium, favorable response to valproate was associated with high pretreatment depression scores. Therefore, treatment with valproate alone may be particularly effective in manic patients with mixed affective states.
Analysis of Variance↗
Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania.
OBJECTIVE: The authors reviewed available evidence regarding the status of dysphoric or mixed mania as a distinct clinical state and formulated operational criteria for its diagnosis. METHOD: Studies of dysphoric mania or hypomania in patients with bipolar disorder were analyzed with regard to clinical characteristics, prevalence, demographic features, course of illness, outcome, family history, associated conditions, biological tests, and response to biological treatment. RESULTS: Although some studies suggest that dysphoric and nondysphoric mania are similar conditions, others suggest that, compared with nondysphoric mania, dysphoric mania may be more severe; more likely to occur in women; more likely to be associated with suicidality, a younger age at onset, a longer duration of illness, higher rates of personal and familial depression, concomitant alcohol or sedative-hypnotic abuse, neuropsychiatric abnormalities, and poorer outcome; more frequently associated with cortisol nonsuppression; and less likely to respond adequately to lithium but perhaps more likely to respond to ECT or anticonvulsants. CONCLUSIONS: Substantial evidence suggests that dysphoric mania may be a distinct affective state. Contrary evidence, however, suggests that dysphoric mania may be a form of typical mania, a stage-related or severe form of mania, or a transitional state between mania and depression. Because the evidence may be inconsistent because of varying definitions of dysphoric mania among studies, the authors propose preliminary operational diagnostic criteria for the future study of dysphoric mania.
Adolescent↗
Brain Na+,K(+)-ATPase regulation in vivo: reduction in activity and response to sodium by intracerebroventricular tetrodotoxin.
We investigated the effects of intracerebroventricular infusion of tetrodotoxin on activity and function of brain Na+,K(+)-ATPase. Infusion of 1 or 3 micrograms/h for 2, 4 or 7 days by osmotic minipump reduced the number of Na+,K(+)-ATPase sites as measured by ouabain binding in cerebral cortex. Tetrodotoxin infusions substantially reduced the functional transport capacity of Na+,K(+)-ATPase, measured by the maximal increase in synaptoneurosomal 86Rb+ uptake in the presence of monensin. The effects were maximal at 4 days, with a possible partial recovery of activity at 7 days. Results of ouabain inhibition curves suggested that the effect of tetrodotoxin was not specific for enzyme with high or low affinity for ouabain.
Animals↗
Mania: sympathoadrenal function and clinical state.
We investigated sympathoadrenal and sympathetic nervous system activity, catecholamine disposition, and clinical state in 19 hospitalized manic patients. Severity of the core manic syndrome, anxiety, and hostility correlated with 24-hour urinary excretion of epinephrine relative to its metabolites, but only weakly with norepinephrine. Agitation, however, correlated most strongly and significantly with norepinephrine. Eight of the patients had mixed states: concurrent manic and depressive syndromes. There were no differences between mixed and pure manic patients with respect to catecholamine or metabolite excretion or precursor/product ratios, but mixed manic patients tended to have higher excretion of norepinephrine and had increased variance with respect to catecholamine measures. These data suggest that the function of the adrenal medulla, whether directly or indirectly, is important in the symptoms of both mixed and pure mania.
Adrenal Medulla↗
Treatment of trichotillomania with fluoxetine.
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Adult↗
Lithium distribution in mania: single-dose pharmacokinetics and sympathoadrenal function.
We examined lithium distribution after a single dose of 25 mEq in 14 drug-free manic patients. Lithium concentrations were measured in plasma, red blood cells, and urine. Maximum concentrations of lithium, times at which they were attained, and influx and efflux rate constants for extracellular fluid, red blood cell, and muscle-like compartments were estimated using a three-compartment pharmacokinetic model. Tissue lithium concentrations may continue to increase for hours after plasma lithium concentrations have peaked. Rate constants for absorption, excretion, and influx and efflux for the tissue compartments were similar to those previously reported for normal subjects. Rate constants for transport into and out of the tissue compartments correlated negatively with norepinephrine or epinephrine excretion and positively with the plasma/red cell Na+ gradient. Rate constants for efflux from red blood cell and muscle compartments correlated with measures of adrenocortical function and were higher in dexamethasone nonsuppressors than in suppressors. These data show that distribution of lithium may be related to sympathodrenal activity and Na+ distribution in manic patients.
Adrenal Cortex↗
Ethanol and (Na+,K+)-ATPase: alteration of Na(+)-K+ selectivity.
Relative internal concentrations of Na+ and K+ are important in regulating (Na+,K+)-ATPase in situ. Ethanol is known to inhibit (Na+,K+)-ATPase and to reduce K+ affinity, but the concentrations required for these effects in vitro are large compared with those probably attainable in vivo. Yet, there is evidence suggesting that ethanol has physiologically relevant effects on (Na+,K+)-ATPase. We have investigated the effects of ethanol on selectivity for Na+ versus K+. At 150 mM, ethanol had little effect on (Na+,K+)-ATPase activity under the usual assay conditions, slightly (but nonsignificantly) reduced K+ affinity, and had no effect on extrapolated Na+ affinity in the absence of K+. However, ethanol had marked effects on cation selectivity, doubling the Ki for K+ on Na+ affinity and halving the Ki for Na+ on K+ affinity. These data show that ethanol, at concentrations too small for effects on (Na+,K+)-ATPase activity under optimal assay conditions, can alter its responses to changes in Na+ or K+.
Adenosine Triphosphate↗