Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants.

BACKGROUND: We investigated the structure of manic episodes by determining whether there was evidence for distinct groups of patients differing in clinical characteristics and course of illness. METHODS: The subjects were 162 patients hospitalized for manic episodes who underwent comprehensive evaluations of behavior, symptoms, and history before a treatment study. Pretreatment behavior ratings (Schedule for Affective Disorders and Schizophrenia, rated by clinicians, and Affective Disorder Rating Scale, rated by nurses) entered a principal components factor analysis, followed by a cluster analysis of the subjects based on their factor scores. Members of the resulting clusters were compared with respect to clinical characteristics and history of illness. RESULTS: The six factors were impulsivity, hyperactivity, anxious pessimism, distressed appearance, hostility, and psychosis. The four clusters were characterized as depressive, with high anxious pessimism (n=22), delusional, with high psychosis (n=39), classic (n=72), and irritable, with high distressed appearance and hostility (n=29). Depressive manics had the earliest onset of illness and the highest density of episodes/year, while irritable manics had later onset and the fewest previous episodes. LIMITATIONS: The number of subjects was smaller than ideal for multivariate analysis, subjects were limited to those able to consent and meet criteria for a randomized clinical trial, and course of illness was determined retrospectively. CONCLUSIONS: Manic episodes have a dimensional structure but appear to fall naturalistically into types that differ with respect to previous history, symptoms, and clinical characteristics. Whether these are distinct clinical subtypes will require further research.

Unsuspected depressive mania in pre-pubertal Hispanic children referred for the treatment of 'depression' with history of social 'deviance'.

BACKGROUND: Despite an emerging Literature on the mixed nature of pediatric mania, initial presentation with conduct problems continues to mislead mental health clinicians. The present report focuses on Hispanic pre-pubertal children referred for the treatment of depression in the context of conduct problems. METHODS: Eleven boys and two girls received a structured psychiatric assessment in a practice setting to make sense of the presenting clinical complexity. Diagnoses were assigned using the DSM-IV criteria. RESULTS: Ten of the boys and both girls met criteria for depressive mania. Their family histories were replete with affective disorder. Five (50%) of the boys and both of the girls (100%) with depressive mania had family histories of bipolar disorder. Six (60%) of the boys and neither of the girls with depressive mania had psychotic features. Those with depressive mania exhibited clear-cut circadian changes in symptomatology. Euphoria, oscillating with affective states indicative of psychic pain, was characteristically restricted to the evenings or nighttime. However, the drive to seek treatment had stemmed from social 'deviance'. CONCLUSION: Children with depressive mania are often unrecognized in clinical settings. Boys with conduct problems may be disproportionately represented among such children. These data support Akiskal's hypothesis that externalizing (conduct) problems in clinically referred children with depression are indicative of bipolar disorder.

ECT in mixed affective states: a case series.

There is limited information regarding the effectiveness of electroconvulsive therapy (ECT) as a treatment for patients in a mixed affective state. The authors report their experience using this treatment in medication-resistant patients meeting Research Diagnostic Criteria (RDC) for both mania and major depression. Clinical and response characteristics of these patients are described. Forty-one consecutively admitted patients meeting the RDC for mania received pharmacotherapy. Eight patients failing to respond to pharmacotherapy were referred for ECT, and seven consented. All met RDC for both mania and major depressive disorder. All patients receiving ECT remitted. The patient who did not accept ECT did not improve and ultimately needed transfer to a state hospital for longer term care. Mixed manic-depressive states are responsive to ECT, even in medication-refractory patients.

Mania: differential effects of previous depressive and manic episodes on response to treatment.

OBJECTIVE: We compared effects of previous depressive or manic episodes on antimanic response. METHOD: In-patients in a parallel-groups, double-blind comparison of lithium, divalproex or placebo for manic episodes had comprehensive evaluations of illness history. We used non-linear curve fitting of change in Manic Syndrome Score (MSS) of the Schedule for Affective Disorders and Schizophrenia (SADS) versus previous depressive or manic episodes to investigate their relationships to MSS improvement. RESULTS: Response to lithium, but not to divalproex or placebo, worsened with increased depressive or manic episodes. More than 11 manic, or four depressive, episodes was associated with response to lithium that did not differ from placebo. Effects of previous depressive and manic episodes appeared independent, and could not be accounted for by increased rapid cycling or mixed states. CONCLUSION: At least four previous depressive or 12 previous manic episodes are associated with reduced antimanic response to lithium.

Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania.

OBJECTIVE: The authors investigated the relationship between number of lifetime episodes of affective disorder and the antimanic response to lithium, divalproex, or placebo. METHOD: The subjects were 154 of the 179 inpatients with acute mania who entered a 3-week parallel group, double-blind study. The primary efficacy measure was the manic syndrome score from the Schedule for Affective Disorders and Schizophrenia. The relationship between improvement and number of previous episodes was investigated by using nonlinear regression analysis. RESULTS: An apparent transition in the relationship between number of previous episodes and response to antimanic medication occurred at about 10 previous episodes. For patients who had experienced more episodes, response to lithium resembled the response to placebo but was worse than response to divalproex. For patients who had experienced fewer episodes, however, the responses to lithium and divalproex did not differ and were better than the response to placebo. This differential response pattern was not related to rapid cycling or mixed states. CONCLUSIONS: A history of many previous episodes was associated with poor response to lithium or placebo but not to divalproex.

Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations.

OBJECTIVE: A substantial number of manic episodes include conspicuous depressive symptoms. Manic episodes have been clinically classified a posteriori using preset criteria. The aim of this study was to investigate the possibility that there might be a natural division of manic episodes into clinical types. METHOD: One hundred and five inpatients met Research Diagnostic Criteria and DSM-III-R criteria for manic episodes and were rated before institution of pharmacological treatment. The authors conducted a factor analysis of 37 behavior rating items from the Schedule for Affective Disorders and Schizophrenia. The resulting factors were used as independent variables in a cluster analysis of the patients. RESULTS: This analysis revealed four factors corresponding to manic activation, depressed state, sleep disturbance, and irritability/paranoia. Cluster analysis separated the patients into two groups. One included patients with major depressive disorder and mania. Blind, a priori clinical classification into classic and mixed mania (mania plus depression) showed that all of the patients in the depressed cluster, and about 40% of those in the nondepressed cluster, were in a mixed state according to clinical criteria. Comparison of the clinically mixed and nonmixed patients in the nondepressed cluster revealed that the mixed patients in that cluster had higher scores for items related to anger, worry, dysphoria, and irritability. CONCLUSIONS: These data suggest that manic episodes can be naturalistically classified as classic (predominately euphoric), dysphoric, or depressed.

Mania: gender, transmitter function, and response to treatment.

Noradrenergic and GABA systems may be involved in mania, but there is little information about relationships between the function of these systems and response to specific antimanic treatments. We investigated relationships between indices of catecholamine or GABA system function, pretreatment mania severity and antimanic response to divalproex, lithium, or placebo. Plasma GABA and urinary excretion of catecholamine metabolites were measured before randomization to lithium, divalproex or placebo in patients hospitalized for manic episodes. Severity of mania was evaluated using the Manic Syndrome, Behavior and Ideation and Mania Rating Scale scores from the SADS-C. Multiple regression analysis showed that pretreatment plasma GABA was related to severity of manic symptoms. This relationship seemed stronger in women. Multiple regression analysis showed that pretreatment levels of urinary MHPG correlated with improvement in manic syndrome scores. These data suggest that GABA and norepinephrine may be related to different aspects of the manic state and to its pharmacologic sensitivity.

Droperidol in the interim management of severe mania: case reports and literature review.

There is little information in the literature concerning the use of droperidol in psychiatry. This article presents three cases in which extremely agitated and treatment-refractory persons with mixed mania derived benefit from droperidol administered orally. Symptomatic improvement, including decreased agitation and intrusiveness, improved sleep, and decreased rates of sleep, was observed with the use of oral droperidol at doses ranging from 10-80 mg daily. The only adverse reaction was a dystonia in one patient. This article also reviews the limited available literature on the use of droperidol in psychiatry. Only eight English language articles describing the use of droperidol for psychosis or agitation were found. Future controlled studies to examine the usefulness of oral dosing of droperidol in mania are suggested.

Schild regression analysis of antidepressant and bicuculline antagonist effects at the GABAA receptor.

We showed previously that antidepressants inhibit GABA-stimulated 36Cl- uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABAA receptors. GABA concentration-response curves for 36Cl- uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABAA receptor antagonist, bicuculline. The pA2 values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 +/- 0.2, 5.5 +/- 0.3, 4.4 +/- 0.1 and 6.2 +/- 0.6, respectively. The respective Schild slope values were 0.7 +/- 0.1, 0.6 +/- 0.03, 0.7 +/- 0.2 and 1.0 +/- 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABAA receptor-chloride-ionophore complex in the rat cerebral cortex.

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.

Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania.

This study was undertaken to assess links between suicidality, panic disorder, psychosis, bipolar depression, depressive-mania and pure-mania. The subjects are a consecutive series of 129 persons with bipolar disorder who were admitted to a university teaching hospital; 53 had bipolar depression, 32 had depressive-mania and 44 had pure-mania. They met the Research Diagnostic Criteria (RDC) for major depressive disorder (bipolar depression), primary mania (pure-mania) or both disorders (depressive-mania) at entry into the study. Suicidality, intra-episode panic disorder (IEPD) and psychotic features were ascertained using structured interviews. Sources of data included a routine clinical interview, serial clinical assessments, the Schedule for Affective Disorders and Schizophrenia (SADS), the Structured Clinical Interview for DSM-III-R and reviews of charts. Multivariate logistic regression analysis was used to determine the strength of the relationships between suicidality, IEPD, psychotic features and the phase of illness. The rates of suicidality (79.3%, 56.3% and 2.3%), IEPD (62.3%, 62.5% and 2.3%) and psychotic features (52.8%, 96.9% and 88.6%) differed significantly between the groups with bipolar depression, depressive-mania and pure-mania. Subjects with bipolar depression and depressive-mania resembled one another with respect to the severity, but not rate of suicidality. They had identical rates of IEPD. Subjects with bipolar depression had a higher probability of being suicidal and a lower probability of being psychotic than persons with either subtype of mania. Pure-mania was distinguished by low rates of suicidality and IEPD. The authors describe directions for prospective studies of the relationships between phase of illness and phenomena in groups of bipolar persons.

Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other Axis I disorders.

The lifetime rate of suicide attempts among subjects in the Epidemiologic Catchment Area database with bipolar disorder, unipolar disorder, and any other DSM-III-defined Axis I disorder were determined. The latter constituted a control or reference group. The lifetime rates of suicide attempts of persons in these diagnostic groups were 29.2%, 15.9%, and 4.2%, respectively. Multivariate logistic regression analysis was used to calculate the odds ratio of subjects within a diagnostic group having a history of a suicide attempt relative to subjects in a second group. The odds ratio of subjects with bipolar disorder having a history of a suicide attempt relative to subjects in the control group was 6.2 (df 1, x(2) = 5347.2, p < .0001). The odds ratio of subjects with unipolar disorder having a history of a suicide attempt relative to subjects in the control group was 3.1 (df = 1, x(2) = 4785.2, p < .0001). The odds ratio of subjects with bipolar disorder having a history of a suicide attempt relative to unipolar subjects was 2.0 (df = 1, x(2) = 697.9, p < .0001). Bipolar disorder has a strong relationship to a history of suicide attempts relative to unipolar disorder and other Axis I disorders.

Bulimia and anorexia nervosa in winter depression: lifetime rates in a clinical sample.

Symptoms of an eating disorder (hyperphagia, carbohydrate craving, and weight gain) are characteristic of wintertime depression. Recent findings suggest that the severity of bulimia nervosa peaks during fall and winter months, and that persons with this disorder respond to treatment with bright artificial light. However, the rates of eating disorders among patients presenting for the treatment of winter depression are unknown. This study was undertaken to determine these rates among 47 patients meeting the DSM-III-R criteria for major depression with a seasonal pattern. All were evaluated using standard clinical interviews and the Structured Clinical Interview for DSM-III-R. Twelve (25.5%) patients met the DSM-III-R criteria for an eating disorder. Eleven patients had onset of mood disorder during childhood or adolescence. The eating disorder followed the onset of the mood disorder. Clinicians should inquire about current and past symptoms of eating disorders when evaluating patients with winter depression.

Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders.

The lifetime rates of obsessive-compulsive disorder (OCD) among subjects with histories of (1) bipolar disorder, (2) major depressive disorder but not of hypomania or mania (unipolar disorder), and (3) any Axis I disorder defined in DSM-III other than bipolar or unipolar disorders (i.e., 'other' disorder) was determined using the Epidemiologic Catchment Area (ECA) data base. The strengths of the relationships between OCD and diagnostic group, as well as between OCD and suicidality, were assessed in a multivariate logistic regression analysis. The lifetime rates of OCD among subjects with bipolar, unipolar and other Axis I disorder are 21.0, 12.2, and 5.9%, respectively. The odds ratios of subjects with bipolar and unipolar disorders meeting the criteria for OCD relative to subjects with any other Axis I disorder are 3.2 and 1.6, respectively. The odds ratio of subjects with bipolar disorder meeting the criteria for OCD relative to subjects with unipolar disorder is 2.0. The rates of panic disorder among subjects with bipolar disorder who do and do not meet the criteria for OCD are 37.1 and 16.7%, respectively. The ECA data base supports the conclusion that the lifetime rate of comorbidity for OCD is particularly high among bipolar subjects. OCD may be associated with panic disorder. These data highlight the potential value of clinical study of comorbidity for OCD in bipolar illness.

Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey.

OBJECTIVE: The authors' goal was to determine the rate of comorbid panic disorder in individuals with bipolar disorder. METHOD: They used the Epidemiologic Catchment Area survey database to determine the prevalence of comorbid panic disorder in individuals with unipolar depression, those with bipolar disorder, and comparison subjects without bipolar or unipolar disorder. RESULTS: The lifetime prevalence of panic disorder among subjects with bipolar disorder was 20.8%; among subjects with unipolar depression it was 10.0%, and among comparison subjects it was 0.8%. CONCLUSIONS: Individuals with bipolar disorder have a particularly high risk of comorbid panic disorder. The evaluation of patients with bipolar disorder should include screening for panic disorder.

Suicidality in patients with pure and depressive mania.

OBJECTIVE: A previous comprehensive literature review indicated that suicide accounted for 18.9% of the deaths of 9,389 individuals with manic-depressive illness. The literature associates these deaths with the depressed phase of the disease. This study was designed to determine the rate and severity of suicidality among patients with pure and depressive mania. METHOD: The patients were 93 persons who met the Research Diagnostic Criteria (RDC) for bipolar I disorder (N = 75) or schizoaffective disorder (N = 18). All met the RDC for primary mania and the DSM-III-R criteria for bipolar disorder, manic or mixed. Patients with depressive mania met the RDC for mania and major depressive disorder concurrently. Severity of current suicidality was measured by using the Schedule for Affective Disorders and Schizophrenia suicide subscale. Differences in the mean suicidality scores between any two groups were assessed with the Kruskal-Wallis test. Relationships of age, gender, type of affective illness (bipolar I versus schizoaffective disorder), psychosis, race, and mania subtype to suicidality were assessed by using multivariate logistic regression analysis. RESULTS: One (2.0%) of the 49 patients with pure mania was suicidal. In contrast, 24 (54.5%) of the 44 patients with depressive mania were suicidal. This difference was highly significant. Gender and psychosis were not related to suicidality. African-Americans were less likely to be suicidal than Caucasians. Subtype of mania had the strongest relationship to suicidality. CONCLUSIONS: A subgroup of manic patients are severely suicidal. Presentation in the manic state is an indication for careful assessment of depressive symptoms and suicidality.

Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group.

OBJECTIVE: To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. DESIGN: Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. PATIENTS: A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. INTERVENTIONS: After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 mumol/L (150 micrograms/mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. MAIN OUTCOME MEASURES: Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P = .017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P = .004) and 49% for lithium (P = .025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. CONCLUSIONS: Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium.