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.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Maintenance desipramine for dysthymia: a placebo-controlled study.

BACKGROUND: This study examines the efficacy of maintenance pharmacotherapy in dysthymia without concurrent major depression, i.e. 'pure dysthymia'. No published data exist on this topic. METHODS: Responders to a 10-week open trial of desipramine (DMI) whose therapeutic response persisted during a 4-month continuation phase were eligible to begin a 2-year placebo-controlled maintenance phase. We analyzed the subgroup with DSM-III-R pure dysthymia (n=27) that entered maintenance. Time to recurrence during maintenance therapy was compared between the two treatment groups. RESULTS: Six of 13 patients receiving placebo and none of 14 patients receiving ongoing DMI experienced a recurrence. Risk of recurrence was significantly greater for placebo patients. Five of six placebo recurrences occurred within the first 6 months of maintenance. LIMITATIONS: Larger replication studies are needed. CONCLUSION: Desipramine was efficacious as a maintenance treatment in patients with pure dysthymia who responded to 7 months of acute and continuation DMI.

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.

Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: effects on personality.

OBJECTIVE: Although previous studies have shown that dysthymia, or chronic depression, commonly responds to antidepressant medications (with improvements in depressive symptoms and psychosocial functioning), there have been no systematic studies of the impact of antidepressant treatment on personality variables in patients with this disorder. METHOD: In a multicenter study, 410 patients with early-onset primary dysthymia were treated in a randomized prospective fashion with sertraline, imipramine, or placebo. The data were analyzed in terms of the subjects' scores on the Tridimensional Personality Questionnaire, a 100-item self-report instrument that measures four temperamental dimensions: harm avoidance, reward dependence, novelty seeking, and persistence. RESULTS: At baseline, the harm avoidance scores of the dysthymic subjects were approximately 1.5 standard deviations higher than those of a previously reported community sample. After treatment, there was a significant decrease in harm avoidance scores, with no significant between-group differences. Remission of dysthymia was associated with significantly greater improvement in harm avoidance, with the greatest numerical change found in the patients treated with sertraline. Subjects' Tridimensional Personality Questionnaire scores were correlated at a 0.50 level with the Social Adjustment Scale both pre- and posttreatment, suggesting that a high degree of harm avoidance may be associated with poor social functioning. CONCLUSIONS: Before treatment, chronically depressed patients demonstrate an abnormality in temperament, as measured by elevated degrees of harm avoidance. Remission of dysthymia is associated with improvement in this aspect of temperament.

Qualitative differences in manic symptoms during mixed versus pure mania.

Previous studies have compared demographic and clinical-outcome features of bipolar patients with mixed or pure mania. However, little is known about the potential differences in the nature and extent of manic symptoms in mania either with or without an accompanying depression. This study examined DSM-III-R manic symptoms in a cohort of 183 bipolar I inpatients hospitalized for mixed mania (diagnosed by broad or narrow criteria) or pure manic episodes. Inpatient charts were reviewed to determine the presence of individual affective symptoms. The results indicate that clinicians were more likely to diagnose a pure mania from the beginning to end of an episode than to diagnose a mixed mania from its beginning to end. Mixed-manic patients had significantly fewer manic symptoms than pure manic patients. Grandiosity, euphoria, pressured speech, and a decreased need for sleep were more prevalent during pure versus mixed mania. Grandiosity and a diminished need for sleep were especially notable during pure mania compared with mixed mania as defined by narrow criteria for mixed states. The observed differences in manic symptom profiles between mixed and pure mania may aid in the clinical assessment of dysphoric states among bipolar patients. The data also lend support to the use of broad diagnostic criteria for defining mixed mania as an entity phenomenologically distinct from pure mania.

New strategies for treating chronic depression.

This article provides an update on the diagnosis of chronic depression subtypes, the clinical and public health significance of chronic depression, and a review of what is known about its treatment. The efficacy of antidepressant medications for pure dysthymia and double depression has been established, yet fewer than 50% of patients have achieved full remission with a single agent. Traditional antidepressant psychotherapies appear to have limited effectiveness for chronic depression. In one recent study, a combination of cognitive behavioral analysis system of psychotherapy and a newer antidepressant, nefazodone, yielded the highest response and remission rates ever reported in this population (73% response rate, 48% remission rate in an intent-to-treat sample). This combination merits further study for treatment of chronic depression.

A history of substance abuse complicates remission from acute mania in bipolar disorder.

BACKGROUND: Substance abuse frequently complicates the course of bipolar illness, promotes mixed states, and contributes to poor outcome in mania. Preliminary open trials suggest that anticonvulsant mood stabilizers may enhance remission rates and outcome for bipolar patients with substance abuse. This study compared remission patterns for mixed or pure manic episodes among bipolar inpatients with or without substance abuse histories. METHOD: Hospital records were retrospectively reviewed for 204 DSM-III-R bipolar I inpatients. Clinical features were compared for those with or without substance abuse/dependence histories predating the index manic episode. Time until remission was analyzed by Kaplan-Meier survival analysis. Naturalistic treatment outcome with lithium or anticonvulsant mood stabilizers was compared for those with or without past substance abuse. RESULTS: Past substance abuse was evident in 34% of the bipolar sample and comprised most often alcoholism (82%), followed by cocaine (30%), marijuana (29%), sedative-hypnotic or amphetamine (21%), and opiate (13%) abuse. Substance abuse was more common among men (p < .05) and those with mixed rather than pure mania (p < .05). Remission during hospitalization was less likely among patients with prior substance abuse (p < .05), especially alcohol or marijuana abuse, and among mixed manic patients with past substance abuse (p < .05). Bipolar patients with substance abuse histories who received divalproex or carbamazepine remitted during hospitalization more often than did those who received lithium as the sole mood stabilizer (p < .05). CONCLUSION: These findings support previous reports suggesting that bipolar patients with past substance abuse have poorer naturalistic treatment outcomes, but may show a better response to anticonvulsant mood stabilizers than lithium.

Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder.

OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state.

Six months of desipramine for dysthymia: can dysthymic patients achieve normal social functioning?

BACKGROUND: There is evidence that antidepressant medication improves social dysfunction during acute treatment in dysthymic patients but it is unknown if the gain in social functioning persists or progresses with longer-term antidepressant treatment. We examine the effect of 6 months of desipramine treatment on social functioning in dysthymic patients. METHODS: Forty-six subjects with DSM-III-R dysthymia (70% with superimposed major depression) who had responded to 10 weeks of open-label desipramine (DMI) treatment received 16 additional weeks of continuation DMI. Social functioning was measured at weeks 0, 10 and 26 with the Social Adjustment Scale-Self Report. RESULTS: Euthymia was maintained and a marginally significant trend for further improvement in overall social functioning appeared during continuation treatment. Only 24% of subjects achieved normative level of social adjustment after 6 months of DMI treatment. LIMITATIONS: The main limitation was the lack of a placebo control group. CONCLUSION: Acute improvement in social functioning persists during continuation treatment. However, most dysthymic patients did not achieve a community level of social adjustment. Significant social dysfunction persists in dysthymic patients with low levels of depressive symptomatology after 6 months of intense DMI treatment.

A beneficial effect on mood in partial epilepsy patients treated with gabapentin.

PURPOSE: Antiepileptic drugs (AEDs) are frequently used for their beneficial psychoactive effects on affective disorders. We sought to demonstrate a psychoactive effect of gabapentin (GBP) when used as add-on AED therapy. METHODS: Forty adult patients with partial epilepsy were studied in a prospective, non-randomized fashion with interviewer-rated and self-rated scales of mood and anxiety: the Cornell Dysthymia Rating Scale (CDRS), Beck Depression Inventory (BDI), and Hamilton Depression (Ham-D) and Anxiety (Ham-A) Scales. After completion of baseline mood and anxiety scales (time 1), 20 of the 40 patients were prescribed add-on GBP (treated group). The remaining 20 patients served as a control group. Both groups were similar in age and sex distribution. Follow-up mood and anxiety scales were performed in all patients approximately 3 months later (time 2). The average GBP dose at time 2 was 1,615 mg/day. All patients were taking stable doses of one to four AEDs at baseline and throughout the study. Seizure frequency was monitored throughout. Statistical significance was assessed by analysis of variance (ANOVA) by using a two-factor repeated-measures model. RESULTS: The GBP-treated group had a significant decrease in CDRS score over time compared with the control group (p = 0.04). No significant differences between the control and the treated groups were found for any of the remaining mood scales (BDI, p = 0.58; Ham-D, p = 0.59; Ham-A, p = 0.93). There was no significant difference or change in seizure frequency between groups. CONCLUSIONS: GBP treatment is associated with mood improvement as measured by the CDRS. This improvement was not accounted for by seizure improvement.

Cost effectiveness of screening for clinical trials by research assistants versus senior investigators.

This study evaluates the relationship between interviewer level of experience and the positive predictive value and cost of telephone screening of subjects for randomized clinical trials. This is a previously uninvestigated area. Respondents to advertisements for chronic depression treatment research received brief, semi-structured telephone interviews (N = 347) either by research assistants (RAs) or by a senior investigator (SI). Those who met criteria based on the phone interview were then interviewed in person using the SCID-P. The RAs did not significantly differ from the SI in the proportion of phone screen positives who were also SCID positive or the proportion of phone screen positives who were randomized. While the SI performed phone interviews significantly faster than the RAs, the SI's higher salary generated a phone screening cost per randomized subject 56% more than that of RAs. The results suggest that trained research assistants are more cost effective than senior investigators for initial screening of depressed patients for research protocols. Further studies are needed to determine whether the findings reported would generalize to other research settings or patient populations.

Sexual dysfunction secondary to depressive disorders.

Human sexuality has received less systematic study and is less well understood than other aspects of mental and physical health. Although depression itself, apart from medication, is generally believed to be associated with sexual dysfunction, the few existing studies report wide discrepancies with regard to frequency, gender, and quality of sexual dysfunction. Loss of libido is frequently and consistently associated with major depression. Moreover, sexual dysfunction secondary to depression or other factors is often mistaken for that caused by antidepressant medication. Although antidepressants have long been associated with sexual dysfunction, the precise nature and magnitude of sexual side effects have not been fully appreciated. This article will review the literature on sexual dysfunction associated with unmedicated depression and offer a guide for the clinician evaluating and treating depressed patients with sexual problems.

Correlates of suicidal ideation in dysphoric mania.

BACKGROUND: Previous investigations have reported that suicidal ideation and behavior are more prevalent during mixed than pure mania. Uncertainties exist about whether suicidality in mania arises from multiple concurrent depressive symptoms, or rather, as a categorical phenomenon, reflecting dysphoria without necessarily a full major depression. To elucidate the relationship between suicidal ideation and dysphoric mania, we analyzed clinical and demographic features associated with suicidal versus nonsuicidal dysphoric manic inpatients. METHODS: Records were reviewed for 100 DSM-III-R bipolar I manic inpatients at the Payne Whitney Clinic of New York Hospital from 1991-1995. All had > or = 2 concomitant depressive symptoms (other than suicidality). Affective and psychotic symptoms, past suicide attempts, prior illness, and related clinical/demographic variables were assessed by a standardized protocol. RESULTS: Suicidal ideation was significantly more common among dysphoric manics who were caucasian, took antidepressant medications in the week prior to admission, had histories of alcohol abuse/dependence, and made past suicide attempts. Suicidal ideation was evident for nearly half of dysphoric manic patients with < or = 3 depressive symptoms who did not meet DSM criteria for a mixed state. No individual manic or depressive symptoms other than dysphoric mood were more common among suicidal than nonsuicidal patients. LIMITATIONS: Findings from this retrospective study require confirmation using a prospective assessment. Treatments were naturalistic and may have differentially influenced hospital course and illness characteristics. Factors related to suicide attempts (rare in this cohort) or completions (not a focus of this study) may differ from those related only to suicidal ideation. CONCLUSIONS: Caucasian dysphoric manic patients with past suicide attempts and substance abuse may have a significantly elevated risk for suicidality, even when full major depression does not accompany mania. Suicidality is a clinically important consideration in a majority of dysphoric manic patients.

Maintenance phase efficacy of sertraline for chronic depression: a randomized controlled trial.

CONTEXT: The chronic form of major depression is associated with a high rate of prevalence and disability, but no controlled research has examined the impact of long-term treatment on the course and burden of illness. OBJECTIVE: To determine if maintenance therapy with sertraline hydrochloride can effectively prevent recurrence of depression in the high-risk group of patients experiencing chronic major depression or major depression with antecedent dysthymic disorder ("double depression"). DESIGN: A 76-week randomized, double-blind, parallel-group study, conducted from September 1993 to November 1996. SETTING: Outpatient psychiatric clinics at 10 academic medical centers and 2 clinical research centers. INTERVENTION: Maintenance treatment with either sertraline hydrochloride (n = 77) in flexible doses up to 200 mg or placebo (n = 84). PATIENTS: A total of 161 outpatients with chronic major or double depression who responded to sertraline in a 12-week, double-blind, acute-phase treatment trial and continued to have a satisfactory therapeutic response during a subsequent 4-month continuation phase. MAIN OUTCOME MEASURE: Time to recurrence of major depression. RESULTS: Sertraline afforded significantly greater prophylaxis against recurrence than did placebo (5 [6%] of 77 in the sertraline group vs 19 [23%] of 84 in the placebo group; P = .002 for the log-rank test of time-to-recurrence distributions). Clinically significant depressive symptoms reemerged in 20 (26%) of 77 patients treated with sertraline vs 42 (50%) of 84 patients who received placebo (P = .001). With use of a Cox proportional hazards model, patients receiving placebo were 4.07 times more likely (95% CI, 1.51-10.95; P = .005) to experience a depression recurrence, after adjustment for study site, type of depression, and randomization strata. CONCLUSIONS: Maintenance therapy with sertraline is well tolerated and has significant efficacy in preventing recurrence or reemergence of depression in chronically depressed patients.

The treatment of chronic depression, part 1: study design and rationale for evaluating the comparative efficacy of sertraline and imipramine as acute, crossover, continuation, and maintenance phase therapies.

BACKGROUND: Chronic depressions are common, disabling, and undertreated, and prior chronicity predicts future chronicity. However, few studies directly inform the acute or maintenance phase treatments of chronic depressions and even less is known about the effects of treatment on psychosocial functioning. METHOD: We describe the design and rationale for 2 parallel double-blind, randomized, multicenter acute and maintenance phase treatment trials. One focused on DSM-III-R major depression currently in a chronic (> or = 2 years) major depressive episode, the other on DSM-III-R major depression with concurrent DSM-III-R dysthymia ("double depression"). RESULTS: Considering the critical knowledge deficits, we designed a 12-week acute phase safety and efficacy trial of sertraline versus imipramine, followed by a 16-week continuation treatment phase for subjects with a satisfactory therapeutic response. Patients receiving sertraline who successfully completed the continuation phase entered a 76-week maintenance trial to compare sertraline with placebo; those taking imipramine continued without a placebo substitution. As part of the acute trial, subjects completing but failing to respond to the initial 12-week acute phase medication were crossed over (double-blind) to the alternative medication for a 12-week acute phase trial. We obtained naturalistic follow-up data (up to 18 months) for subjects exiting the protocol at any time. CONCLUSION: Multiphase protocols for chronic depression can test efficacy by randomized contrasts as well as shed light on key clinical issues such as the degree of response or attrition expected at particular times in a trial or the preferred medication sequence in a potential multistep treatment program.

The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine.

BACKGROUND: Chronic depression appears to be a common, frequently disabling illness that is often inadequately treated. Unlike episodic depressions with shorter illness duration, neither acute nor long-term treatment approaches for chronic depression have been well studied. METHOD: 635 outpatients at 12 sites who met DSM-III-R criteria for chronic major depression or double depression were randomly assigned to 12 weeks of double-blind treatment with either sertraline (in daily doses of 50-200 mg) or imipramine (in daily doses of 50-300 mg). Efficacy and safety were assessed either weekly or every 2 weeks during the 12 weeks of acute treatment. RESULTS: Despite high rates of chronicity (mean duration of major depression = 8.9+/-9.1 years; mean duration of dysthymia = 23+/-13 years) and high rates of comorbidity, 52% of patients achieved a satisfactory therapeutic response to sertraline or imipramine (by a conservative, intent-to-treat analysis). Approximately 21% of the patients who had achieved a therapeutic response at week 12 had not done so at week 8, confirming the longer time to response in depressions with high chronicity. Patients treated with sertraline reported significantly fewer adverse events and were significantly less likely to discontinue treatment due to side effects than imipramine-treated patients (6.3% vs. 12.0%). CONCLUSION: These results indicate that patients suffering from depression with high chronicity can achieve a good therapeutic response to acute treatment with either sertraline or imipramine, although sertraline is better tolerated.

Association of recurrent suicidal ideation with nonremission from acute mixed mania.

OBJECTIVE: The authors' goal was to examine suicidality in relation to acute symptom remission in inpatients with mixed and pure bipolar disorder. METHOD: Using chart review of 184 adult inpatients with bipolar I disorder, the authors assessed patients' past and current suicidality, other psychopathology, treatment, and remission. RESULTS: Past, current, and recurrent suicidality were significantly more common among patients with mixed mania than among those with pure mania. The probability of remission declined by 49% for every suicide attempt made before the index manic episode. Mixed mania, multiple previous hospitalizations, and previous suicide attempts were significantly associated with current suicidality. CONCLUSIONS: Suicidality is linked with mixed manic states and may be a clinical marker for recurrent dysphoric mania. Multiple suicide attempts are associated with nonremission from mixed manic episodes.