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.

Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS).

This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1 month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.

General medical burden in bipolar disorder: findings from the LiTMUS comparative effectiveness trial.

OBJECTIVE: This study examined general medical illnesses and their association with clinical features of bipolar disorder. METHOD: Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively. RESULTS: The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14). CONCLUSION: The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials.

BACKGROUND: Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. METHOD: To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥ 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. RESULTS: As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. CONCLUSIONS: LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. LIMITATIONS: Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

Urinary free cortisol levels among depressed men and women: differential relationships to age and symptom severity?

BACKGROUND: Preclinical and clinical models of depression suggest sex differences may be mediated at least in part, by differences in hormonal modulation of hypothalamic-pituitary-adrenal (HPA) axis activity. Unraveling the consequences of moderating influences from the effect of sexual dimorphism will be vital to elaborating models of pathophysiology. METHODS: The current study investigated urinary free cortisol (UFC) among younger adults with mild to moderate major depressive disorder to clarify the relationship with potential demographic and clinical moderators. RESULTS: Male patients had higher mean UFC levels than female patients. Moreover, significant interactions between age and severity were found among men, but not women. In contrast to prior findings, neither age nor severity effects on UFC levels were found among female patients. LIMITATIONS: Conclusions from the current study are limited by the absence of cortisol data from matched controls. Thus it was not possible to disentangle sex differences in baseline physiology from that of pathophysiological differences tied specifically to depression. CONCLUSIONS: Despite several methodological limitations, the interactions between sex and both age and severity in this large sample of depressed patients are suggestive of differential pathophysiology for regulation of UFC excretion, and could reflect a neuroprotective effect for estrogen among younger depressed women.

Management of treatment-resistant depression: psychotherapeutic perspectives.

Treatment-resistant depression is a heterogeneous condition that occurs within a psychosocial milieu. The impact of prior pharmacologic interventions may have been adversely affected by a poor therapeutic alliance, low social support, life stress, or chronic adversity and cognitive or personality factors such as neuroticism or pessimism. This article considers the psychosocial factors that predispose to treatment-resistant depression and the psychotherapeutic principles thought to be helpful in both shorter- and longer-term treatment plans. We focus on the interpersonal, cognitive, and behavioral forms of treatment that constitute the depression-focused psychotherapies, which have been studied in major depressive disorder. Also discussed are modifications in treatment planning necessary to take into account the complexity of treatment-resistant depression.

Effect of concurrent anxiety on response to sertraline and imipramine in patients with chronic depression.

Anxiety commonly complicates the clinical presentation of depression and has been associated with poorer long-term outcome, but little information is available on the clinical correlates, and comparative effect on treatment response, of subsyndromic or secondary anxiety. Patients diagnosed with chronic major or double depression were randomized to 12 weeks of double-blind treatment with either sertraline or imipramine in a 2:1 ratio. A high anxiety subgroup was operationally defined by a HAM-D anxiety/somatization factor score > or = 7. The effect of study treatment was measured utilizing the HAM-D, CGI, HAM-D anxiety/somatization factor, as well as a quality of life measure (Q-LES-Q) and a measure of psychosocial functioning (the MOS-SF-36). Two hundred nine patients were treated with imipramine and 426 patients were treated with sertraline. Thirty-six percent of the total met criteria for the high anxiety subgroup. According to Kaplan-Meier probability estimates, patients with significant concurrent anxiety symptoms were more likely to respond by 12 weeks (66.4%) than those without significant anxiety symptoms (54.2%). There was no significant difference in response rates for sertraline vs. imipramine. Both drugs were effective at treating high baseline levels of anxiety, with 60% of sertraline patients and 58% of imipramine patients having 50% or greater reduction from baseline in HAM-D anxiety/somatization factor scores, and only 4.6% and 9.9%, respectively, reporting treatment-emergent worsening in anxiety at study endpoint. Despite the chronicity of depressive illness, acute treatment with both sertraline and imipramine significantly improved psychosocial and quality of life measures. High baseline levels of anxiety did not reduce overall antidepressant response but did somewhat delay the onset of response to sertraline or imipramine in patients with chronic depression.

Topical anesthetics update: EMLA and beyond.

BACKGROUND: Topical anesthetics remain a powerful, new advance for pain relief prior to cutaneous procedures. They are frequently used by dermatologists to decrease the pain associated with laser pulses, surgical procedures, or soft tissue augmentation. EMLA is the most commonly used agent, however, several new topical anesthetic agents have been released recently that claim increased efficacy and a faster onset of action. OBJECTIVE: We review and compare the efficacy of several commonly used topical anesthetics and provide a look into the future. CONCLUSION: EMLA remains the most widely used topical anesthetic given its proven efficacy and safety by several clinical trials. There has been a recent release of several new topical anesthetic agents with some demonstrating efficacy after a 30-minute application time. A reservoir of anesthetic is located and stored in the upper skin layers during application, providing additional anesthetic benefit 30 minutes after removal. As the options for the practitioner continue to grow, the demand for faster onset, comparative efficacy, and safety trials will continue to be of paramount importance.

Venlafaxine and treatment-resistant depression.

Treatment-resistant depression (TRD) is an important clinical problem. This paper briefly reviews the definition of TRD and summarizes methodological issues that pertain to treatment research. Recent studies of venlafaxine treatment for TRD also are reviewed. It is concluded that venlafaxine at higher doses is a reasonably well-tolerated and an effective alternative for patients with TRD and typically should be used before tricyclic antidepressants or monoamine oxidase inhibitors. Further research is needed to confirm the prediction that switching a SSRI nonresponder to venlafaxine is a more effective strategy than switching to a second SSRI. The relative merits of switching from a SSRI to venlafaxine versus adding a norepinephrine reuptake inhibitor also warrant careful study.

Treatment of men with major depression: a comparison of sequential cohorts treated with either cognitive-behavioral therapy or newer generation antidepressants.

OBJECTIVE: This report compares response to cognitive-behavioral therapy (CBT) and pharmacotherapy in sequential cohorts of men with DSM-III-R major depression. METHOD: Patients were enrolled in consecutive standardized 16-week treatment protocols conducted in the same research clinic. The first group (N = 52) was treated with Beck's model of CBT, whereas the second group (N = 23) received randomized but open-label treatment with either fluoxetine (N = 10) or bupropion (N = 13). Crossover to the alternate medication was permitted after 8 weeks of treatment for antidepressant nonresponders. The patient groups were well matched prior to treatment. Outcomes included remission and nonresponse rates, as well as both independent clinical evaluations and self-reported measures of depressive symptoms. RESULTS: Despite limited statistical power to detect differences between treatments, depressed men treated with pharmacotherapy had significantly greater improvements on 4 of 6 continuous dependent measures and a significantly lower rate of nonresponse (i.e., 13% vs. 46%). The difference favoring pharmacotherapy was late-emerging and partially explained by crossing over nonresponders to the alternate medication. The advantage of pharmacotherapy over CBT also tended to be larger among the subgroup of patients with chronic depression. CONCLUSION: Results of prior research comparing pharmacotherapy and CBT may have been influenced by the composition of study groups, particularly the gender composition, the choice of antidepressant comparators, or an interaction of these factors. Prospective studies utilizing flexible dosing of modern antidepressants and, if necessary, sequential trials of dissimilar medications are needed to confirm these findings.

Is cognitive behavior therapy just a 'nonspecific' intervention for depression? A retrospective comparison of consecutive cohorts treated with cognitive behavior therapy or supportive counseling and pill placebo.

BACKGROUND: There is a dearth of placebo-controlled studies of cognitive behavior therapy (CBT) of depression and the largest such study, by Elkin et al. (Arch. Gen. Psychiatry 46 (1989) 971-982), failed to find a significant difference between CBT and a clinical management plus placebo condition. METHODS: The outcomes of two consecutive cohorts of out-patients with major depressive disorder, treated with either CBT (n=90) or a nonspecific control condition (support-counseling-placebo; SCP: n=100), were compared. Although the principal comparisons between the CBT and SCP conditions were delimited to the first 4 weeks of treatment, a secondary set of analyses addressed the subset of 16 patients who received 12 additional weeks of supportive therapy. RESULTS: A consistent pattern of statistically and clinically significant differences favoring CBT over SCP was found in both weeks 4 and 16. LIMITATIONS: Interpretation of these findings are subject to several potential confounds, including the non-randomized nature of the groups and the greater amount of therapeutic contact during the first 4 weeks of CBT. CONCLUSIONS: While these results do not lessen the need for additional prospective studies, our findings do suggest that CBT has therapeutic effects beyond those attributable to placebo-expectancy and other nonspecific factors.

Is psychotherapy an effective treatment for melancholia and other severe depressive states?

The treatment of severe depression with psychotherapy, alone, is controversial. In this paper, we review the historical, conceptual, and empirical contexts of this controversy. In addition to work by others, we review recent work from our institute which has examined the psychobiological substrates of response to treatment in depressive subtypes. We examine the traditional categories that describe severe depressions. The features and psychobiological correlates of melancholia are discussed, as is the relationship between melancholia and aging. Research on treatment of melancholia and other severe depressive states with psychotherapies such as cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT) is reviewed in detail. We conclude that although some melancholic patients are responsive to IPT or CBT, there is not yet compelling evidence that melancholic patients respond to psychotherapy as well as they do to medications. The potentially mediating effects of hypercortisolism, alterations of sleep neurophysiology, and disturbances of information processing and regional cerebral metabolism represent fertile grounds for future investigation. We discuss the practical implications of the literature reviewed.

Treating antidepressant nonresponders with augmentation strategies: an overview.

This paper provides an overview of antidepressant nonresponse and the role of augmentation strategies in the management of treatment-resistant depression. When effective, the more widely used augmentation strategies, including lithium salts, thyroid hormones, pindolol, buspirone, and psychostimulants, share two important advantages when compared with "switching" strategies: avoidance of ill effects associated with discontinuing the initial antidepressant and rapidity of onset of action. Ideally, advances in the understanding of the neurobiology of mood disorders and mechanisms of antidepressant response will permit a more efficient and specific matching between patient, initial antidepressant, and subsequent strategy for enhancing response to treatment.

A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy.

The definitions that are commonly employed to describe the outcome of the depressive disorders are often used in inconsistent ways and remain largely untested. The lack of a standard and valid set of outcome definitions hinders the study of the naturalistic course and treatment of depressive disorders. In the present study, we operationalized definitions for response, remission, relapse, recovery, and recurrence and examined their validity in a sample of depressed patients treated with cognitive behavior therapy. Validity was evaluated by the ability of the definitions to predict subsequent outcome in acute treatment and during a 3 year follow-up period. All five definitions demonstrated moderate to excellent validity. Moreover, we were able to empirically distinguish response from remission, and relapse from recurrence, despite the frequent confusion of these terms in the literature. Several of the findings suggest that continued refinement of the outcome definitions may enhance validity even further.

Ocular blood flow velocity in age-related macular degeneration.

BACKGROUND: Changes in the structure of the ocular blood vessels associated with age-related macular degeneration (AMD) have been described in some detail, but comparatively little is known of the concomitant circulatory changes. The goal of this study is to evaluate changes in the ocular circulation that may be associated with AMD. METHODS: Ocular blood flow velocities and vessel pulsatilities were measured in volunteers with and without AMD using a color Doppler imaging unit. Spectral analyses were recorded from the ophthalmic artery, central retinal artery and vein, the temporal and nasal short posterior ciliary arteries, and the four vortex veins. RESULTS: Adjusting for age, pulsatility indices of all arteries were higher in subjects with AMD (central retinal artery [P = 0.02]; temporal and nasal short posterior ciliary arteries [P = 0.06 and 0.002, respectively]; and ophthalmic artery [P = 0.24]). End-diastolic blood flow velocity of the short posterior ciliary arteries tended to decrease in the presence of AMD. CONCLUSIONS: The combination of increased pulsatility and decreased velocity of the short posterior ciliary arteries, observed in the presence of AMD, are interpreted as evidence of increased vascular resistance. The clinical signs of AMD may be related to degradation of the metabolic transport function of the retinal pigment epithelium, resulting from impaired choroidal perfusion.

Vitrectomy alone for the management of uncomplicated recurrent retinal detachments.

BACKGROUND: The role of vitrectomy for the treatment of uncomplicated recurrent retinal detachments has not been defined clearly. The authors report their experience with vitrectomy alone for the management of such cases. METHODS: Pars plana vitrectomy with internal subretinal fluid drainage and long-term tamponade was performed on nine patients with uncomplicated recurrent retinal detachments after primary scleral buckling surgery. The duration of follow-up was a minimum of 6 months (mean, 39 months). RESULTS: Anatomic success was achieved after the initial reoperation in seven eyes (78%). The overall success rate was 89%. The visual acuity was 20/30 or better in three patients, 20/ 40 to 20/80 in three patients, and 20/200 in two patients. Complications included progressive nuclear sclerosis and macular pucker. CONCLUSION: Vitrectomy is effective and may have advantages over other methods for the management of uncomplicated recurrent retinal detachments.

Thoracic intraspinal lipoma.

Intraspinal lipomas are rare congenital tumours that most commonly occur at the conus. We describe a thoracic intraspinal lipoma presenting with a myelopathy and imaged by MRI. Surgical decompression and dural enlargement appears to be the treatment of choice in those patients who develop spinal cord dysfunction associated with an intraspinal lipoma.