Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression.

The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.

Relationship of lithium chloride dose to treatment response in acute mania.

Three separate lithium chloride doses, calculated according to body weight, and a placebo were administered under double-blind conditions to 68 manic inpatients. The relationship of lithium chloride treatment dose to steady-state serum lithium levels (day 7 to 10 of treatment) and clinical response were examined. High (0.72 mEq/kg/day) and medium (0.5 mEq/kg/day) lithium chloride doses were more efficacious than placebo (P<.001 and P<.05, respectively), as determined by decrements in global mania ratings (day 7 to 10 of treatment). A low dose (0.24 mEq/kg/day) was not found to be more efficacious than placebo. The proportion of patients with improved manic ratings increased markedly as a function of increased steady-state serum lithium level(chi-squared for trend in proportions, 17.91; P<.001).

The effect of psychobiological research on treatment outcome. A controlled study.

Recent advances in psychiatric research methodology promise major progress. Simultaneously, however, mounting concerns about ethnics of human experimentation have resulted in increased scrutiny and regulation that threaten scientific productivity. Virtually no systematic data have been gathered about the effects of research participation on treatment outcome or patient satisfaction. In this study 56 hospitalized depressed patients, who had agreed to participate in psychobiological research protocols, were then randomly assigned to treatment on a research unit or on standard adult inpatient (nonresearch) units. Research participants received more diagnosis-related somatic treatments, had a longer mean length of stay, and experienced trends toward greater symptom reduction and better consumer satisfaction. We conclude that research participation may be helpful to patients but that more systematic study is needed to help to resolve ethical questions and to assist risk-benefit evaluations.

Blunted beta-adrenergic responsivity of peripheral blood mononuclear cells in endogenous depression. Isoproterenol dose-response studies.

Previous studies of peripheral blood mononuclear cells isolated from drug-free, hospitalized patients with endogenous major depression have demonstrated a diminished adenosine 3',5'-monophosphate (cyclic AMP) response to single concentrations of isoproterenol as compared with that obtained from normal control subjects. We now report results of isoproterenol dose-response studies that indicate lower basal levels of cyclic AMP as well as diminished cyclic AMP levels in response to isoproterenol stimulation at concentrations ranging from 10(-10) to 10(-5) mol/L in drug-free, hospitalized patients with endogenous depression. The major factor responsible for the diminished cyclic AMP production in the depressed patients was a loss of receptor sites capable of cyclic AMP production. Taken together with our previously reported finding that beta-adrenergic antagonist binding was normal in peripheral blood mononuclear cells obtained from depressed patients, the results of the dose-response studies suggest a loss of receptor function (desensitization) rather than a diminished number of receptor binding sites (down-regulation) as the underlying mechanism. Potential explanations for beta-adrenergic desensitization and its implications for the catecholamine hypothesis of depressive disorders are discussed.

Imipramine treatment for chronic depression.

Antidepressant drugs in the treatment of chronic depressions have received little systematic study. We used a two-week, single-blind placebo washout followed by a six-week, double-blind comparison of imipramine hydrochloride and placebo in a sample of 76 outpatients with DSM-III dysthymic disorder entered into a trial at two centers. Subjects were preponderantly female, had insidious onset at an early age, and had depressions of moderate severity; 96% also met the DSM-III criteria for major depressive disorder at the time of presentation. Sixty percent had a history of persistent depressive symptoms sufficient to meet criteria for major depression for longer than two years. Markedly favorable responses occurred in 45% of imipramine-treated (n = 29) and 12% of placebo-treated (n = 25) patients and, respectively, 59% and 13% of those who completed the study. Imipramine produced significant advantage in measures of depressive symptoms, global severity of illness, and self-rated social and vocational function. Recovered patients experienced remission from both long-standing symptoms and deficits as well as more recently exacerbated aspects of their syndrome. Patients with pure dysthymic disorder of a mild, subsyndromal type were uncommon in these clinical settings. However, anti-depressant medication was effective for many moderately severe chronic depressions, which had previously been untreated or undertreated, presumably related to misdiagnosis.

Normalization of blunted lymphocyte beta-adrenergic responsivity in melancholic inpatients by a course of electroconvulsive therapy.

Electroconvulsive therapy has been reported to desensitize brain beta-adrenergic receptors in rodents, but this effect has not been studied in man. We examined the effect of a course of electroconvulsive therapy on lymphocyte beta-adrenergic responsivity in 19 inpatients with melancholia. Before treatment, beta-adrenergic cyclic adenosine monophosphate response to isoproterenol was significantly blunted in the patients compared with controls. Following a course of electroconvulsive therapy, beta-adrenergic responsivity increased such that patients no longer differed from controls. Thus, blunted lymphocyte beta-adrenergic responsivity is a state-dependent effect of melancholia that can be corrected by a therapeutic course of electroconvulsive therapy. The effect of electroconvulsive therapy on this beta-adrenergic system is in the opposite direction to that reported for rodent forebrain, where electroconvulsive therapy causes desensitization, and may reflect differences between peripheral and central effects, species differences, or disease effects.

A controlled study of the antidepressant efficacy and side effects of (-)-deprenyl. A selective monoamine oxidase inhibitor.

Monoamine oxidase (MAO) inhibitors are effective antidepressants whose use is limited because of unwanted side effects and the possibility of a tyramine-induced hypertensive crisis (cheese reaction). (-)-Deprenyl (the official nonproprietary name for this substance is selegiline), a selective MAO type B inhibitor, may be safer and have fewer side effects, but its antidepressant efficacy is uncertain. A double-blind placebo-controlled study was carried out in depressed outpatients who were treated with (-)-deprenyl in an MAO type B selective dose range and at a higher nonselective dose range. (-)-Deprenyl did not have a statistically significant antidepressant effect after three weeks of treatment at doses of 10 mg/d. However, after six weeks and at higher doses (averaging about 30 mg/d for the second three weeks), (-)-deprenyl was superior to placebo in antidepressant effect with a positive response rate of 50% vs 13.6% and with a 41% reduction in the Hamilton Depression Rating Scale mean score vs 10% in the placebo-treated group. No hypertensive crises were seen. The rate of occurrence of side effects with (-)-deprenyl was no greater than with placebo. It was concluded that (-)-deprenyl is an effective antidepressant in a dose range where it is distinguished by the absence of many of the side effects typical of nonselective MAO inhibitors.

Treatment of depressive symptoms in human immunodeficiency virus-positive patients.

BACKGROUND: This randomized clinical trial compared 16-week interventions with interpersonal psychotherapy, cognitive behavioral therapy, supportive psychotherapy, and supportive psychotherapy with imipramine for human immunodeficiency virus (HIV)-positive patients with depressive symptoms. METHODS: Subjects (N = 101; 85 male, 16 female) with known HIV seropositivity for at least 6 months were randomized to 16 weeks of treatment. Inclusion criteria were 24-item Hamilton Depression Rating Scale score of 15 or higher, clinical judgment of depression, and physical health sufficient to attend outpatient sessions. Therapists were trained in manualized therapies specific for HIV-positive patients. Treatment adherence was monitored. RESULTS: Subjects randomized to interpersonal psychotherapy (n = 24) and supportive psychotherapy with imipramine (n = 26) had significantly greater improvement on depressive measures than those receiving supportive psychotherapy (n = 24) or cognitive behavioral therapy (n = 27). Similar results appeared in the completer subsample. CONCLUSIONS: Depressive symptoms appear treatable in HIV-positive patients. Interpersonal psychotherapy may have particular advantages as a psychotherapy for patients who have experienced the significant life events of HIV infection.

Maintenance therapy for chronic depression. A controlled clinical trial of desipramine.

BACKGROUND: Previous studies have shown the efficacy of antidepressants in the treatment of chronic depression. We report the results of a long-term study comparing desipramine hydrochloride and placebo for maintenance therapy of remitted patients with chronic depression. METHODS: Outpatients who met DSM-III-R diagnostic criteria for "pure" dysthymia (n = 51), dysthymia with current major depression ("double depression") (n = 64), or chronic major depression (n = 14) were treated on an open basis with desipramine. Full and partial remitters after 10 weeks entered a continuation phase of open treatment with desipramine for 16 weeks. Remitted patients then were randomized to continue desipramine treatment or tapered to placebo treatment for a maintenance phase of up to 2 years. Relapse rates and time to relapse during maintenance therapy were compared between the two treatment groups. RESULTS: Acute-phase treatment results did not differ significantly according to chronic depression subtype. Remission persisted with a high degree of stability during the continuation phase. Relapse rates during the maintenance phase were 52% for the placebo group and 11% for the active desipramine group (chi 2 = 8.1, P = .004). Most placebo relapses occurred during the first 6 months of maintenance therapy. Active medication was significantly more effective than placebo in that subgroup entering the maintenance phase in full remission and in those patients who fulfilled criteria for a diagnosis of pure dysthymia or double depression on entry to the study. CONCLUSION: Long-term maintenance treatment with desipramine appeared to be effective in the prevention or postponement of relapse of depression in patients who responded to desipramine during the acute and continuation phases.

A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia.

BACKGROUND: Despite the high prevalence of dysthymia and its associated morbidity, few controlled trials have evaluated the efficacy of antidepressant medication for this disorder. A 12-week, double-blind, placebo-controlled, randomized, multicenter trial was performed to evaluate the safety and efficacy of sertraline hydrochloride and imipramine hydrochloride in treating dysthymia. METHODS: A total of 416 outpatients (271 women and 145 men) aged 25 to 65 years with DSM-III-R-defined, early-onset, primary dysthymia without concurrent major depression were randomized to 12 weeks of treatment with sertraline, imipramine, or placebo. RESULTS: Both active treatments resulted in significantly reduced scores on the 17-item Hamilton Rating Scale for Depression (P = .04 and P = .01 for sertraline and imipramine vs placebo, respectively), the Montgomery-Asberg Depression Rating Scale (P = .01 and P = .003 vs placebo, respectively), Hopkins Symptom Checklist (P < .05), and the self-rated version of the Inventory of Depressive Symptoms (P < .05). With the use of a Clinical Global impressions improvement score of 1 or 2 (very much or much improved) to define response, response rates were 59% for sertraline, 64% for imipramine, and 44% for placebo (P = .02 for sertraline vs placebo and P < .001 for imipramine vs placebo). A significantly greater proportion of patients receiving imipramine than those receiving sertraline or placebo discontinued treatment because of adverse events (P = .001 and P < .001, respectively). CONCLUSIONS: Pharmacotherapy provides considerable relief from the symptoms of dysthymia in patients suffering from this chronic affective disorder, with both sertraline and imipramine being more effective than placebo. The greater tolerability of sertraline is an important consideration because of the chronicity of dysthymia, which may require prolonged treatment with antidepressant medication.

Delusional depression and inappropriate antidiuretic hormone secretion.

Two cases of delusional major depression associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are described. Delusional depression and SIADH may both result from alterations of brain catecholamine neurotransmitters, and may coexist more commonly than previously thought. Implications for clinical practice and future research are discussed.

Dexamethasone suppression in major depression.

Overnight 1 mg dexamethasone suppression tests were performed on 37 hospitalized patients with unipolar major depression and 13 psychiatric controls: 62% of the depressives and 38% of controls failed to suppress below 6 micrograms/dl of plasma cortisol at least once on the day after dexamethasone. Specificity for depressive diagnosis was only 62% but rose to 100% when a plasma cortisol value of 10 micrograms/dl was used as the criterion for normal suppression. Depressed patients were significantly more likely to show normal suppression if they were under age 65 (56% vs. 24% in the geriatric sample). Other demographic and clinical variables examined in the depressed sample did not assort by suppressor status.

Increased anterior cingulate and caudate activity in bipolar mania.

BACKGROUND: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS: We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate.

Lithium maintenance: factors affecting outcome.

The authors reviewed the charts of 61 manic-depressive outpatients maintained on lithium for 6--75 months for relationships between clinical outcome and various demographic, clinical, and pharmacological variables. Good outcome (50% reduction in episode frequency) did not correlate with any demographic or most natural history variables. A history of frequent episodes was correlated with decreased episode frequency but not with a lower percentage of prophylaxis failure during follow-up. A nonsignificant trend toward decreasing episode occurrence with increasing duration of lithium maintenance was present. Depression occurred considerably more frequently than manic episodes at adequate maintenance plasma lithium levels. More medication noncompliance was found among patients who experienced both manic and depressive relapses.

A critical discussion of DSM-III dysthymic disorder.

The authors review the history of the concept of dysthymia and the literature on the epidemiology, course, and treatment of chronic depression. They present a critical discussion of DSM-III and DSM-III-R criteria for dysthymic disorder. On the basis of this review, they suggest that future revisions of the nomenclature include further subcategorization of chronic depressive disorders and that the term "dysthymic disorder" be reserved for chronic depressive disorders with an insidious onset at an early age. The relationships between dysthymic disorders and personality disorders and the response of subcategories of chronic depression to different treatment modalities need to be researched.

Retreatment for relapse following desipramine discontinuation in dysthymia.

OBJECTIVE: It is an accepted yet unproven belief that prior favorable response to an antidepressant medication predicts good response to the same antidepressant during a subsequent depressive episode. The authors studied desipramine retreatment for dysthymic patients who had responded to desipramine during acute and continuation treatment and then subsequently relapsed after discontinuation of desipramine. METHOD: The subjects were 12 patients who had pure dysthymia or dysthymia with major depression who relapsed while taking placebo during maintenance treatment. Each patient received open desipramine treatment at a dose equal to or greater than that received during the continuation phase. RESULTS: Eleven (91.7%) of the 12 relapsed patients achieved full remission after an average of 4.7 weeks (range = 2-8 weeks, median = 4 weeks) of desipramine retreatment, a significant response rate. CONCLUSIONS: Positive response to desipramine strongly predicts favorable response to retreatment for depressive relapse following desipramine discontinuation.

Desipramine for the treatment of "pure" dysthymia versus "double" depression.

The authors report results of an 8-week, open trial of desipramine in 42 patients with DSM-III-R dysthymia with a concurrent diagnosis of major depression ("double" depression) and 33 patients with dysthymia who had no other depressive diagnosis ("pure" dysthymia). Either complete or partial remission was achieved by 70% of the patients with "pure" dysthymia. This compared favorably with but was not significantly different from results in the "double" depression group.

A controlled study of satisfaction among psychobiology research patients.

Because of the controversy regarding research involving human subjects, the authors designed an 18-item questionnaire to measure research patients' satisfaction with hospital treatment. They compared the questionnaire scores of 25 hospitalized depressed patients treated on a psychobiology study unit with those of 18 comparable patients treated on standard inpatient psychiatric units. Satisfaction was equally high in both groups. Satisfaction and improvement in depression scores were significantly correlated in study unit patients but not among patients on standard units. The authors believe that these data provide valuable information for institutional review boards, potential research subjects and referral sources, researchers, and the public at large.

Imipramine and social-vocational adjustment in chronic depression.

The authors compared the effects of 6 weeks of imipramine treatment with 6 weeks of placebo treatment on social and vocational impairment in chronic depression. Imipramine was associated with significantly greater pre- to posttreatment improvement of social-vocational impairments in chronic depression, suggesting that these impairments may have represented affective symptoms rather than characterologic deficits.