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Efficacy of Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression

Mauricio Tohen et al.Nov 1, 2003

Background: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression.Objective: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.Design: Double-blind, 8-week, randomized controlled trial.Setting: Eighty-four sites (inpatient and outpatient) in 13 countries.Patients: A total of 833 randomized adults with bipolar I depression with a Montgomery-A ˚sberg Depression Rating Scale (MADRS) score of at least 20.Intervention: Patients were randomly assigned to receive placebo (n=377); olanzapine, 5 to 20 mg/d (n=370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86).Main Outcome Measure: Changes in MADRS total scores using mixed-effects model repeated-measures analyses.Results: During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (PϽ.001 for all).The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8.At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapinefluoxetine groups, respectively.Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/ 351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group.Treatment-emergent mania (Young Mania Rating Scale score Ͻ15 at baseline and Ն15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]).Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea.Conclusions: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

Pharmacology

Internal Medicine

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Oxytocin Increases Gaze to the Eye Region of Human Faces

Adam Guastella et al.Oct 2, 2007

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In nonhuman mammals, oxytocin has a critical role in peer recognition and social approach behavior. In humans, oxytocin has been found to enhance trust and the ability to interpret the emotions of others. It has been suggested that oxytocin may enhance facial processing by increasing focus on the eye region of human faces.In a double-blind, randomized, placebo-controlled, between-subject design, we tracked the eye movements of 52 healthy male volunteers who were presented with 24 neutral human faces after intranasal administration of 24 IU oxytocin or placebo.Participants given oxytocin showed an increased number of fixations and total gaze time toward the eye region compared with placebo participants.Oxytocin increases gaze specifically toward the eye region of human faces. This may be one mechanism by which oxytocin enhances emotion recognition, interpersonal communication, and social approach behavior in humans. Findings suggest a possible role for oxytocin in the treatment of disorders characterized by eye-gaze avoidance and facial processing deficits.

Genetics

Social Psychology

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The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

Isabella Pacchiarotti et al.Sep 13, 2013

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Prevalence and Associations of Epiretinal Membranes

Philip Mitchell et al.Jun 1, 1997

Abstract

Purpose: The purpose of the study is to determine the prevalence and associations of epiretinal membranes in a defined older Australian population and to assess their influence on visual acuity. Methods: Three thousand six hundred fifty-four persons 49 years of age or older, representing 88% of permanent residents from an area west of Sydney, underwent a detailed eye examination, including stereo retinal photography. Epiretinal membranes were diagnosed clinically and from photographic grading. Results: Signs of epiretinal membranes were found in 243 participants (7%; 95% confidence interval [CI], 6.1, 7.6), bilateral in 31 %. The prevalence was 1.9% in persons younger than 60 years of age, 7.2% in persons 60 to 69 years of age, 11.6% in persons 70 to 79 years of age, and 9.3% in persons 80 years of age and older, with slightly higher rates in women. Two stages were identified: an early form without retinal folds, termed "cellophane macular reflex" present in 4.8%, and a later stage with retinal folds, termed "preretinal macular fibrosis" (PMF), found in 2.2% of the population. Preretinal macular fibrosis, but not cellophane macular reflex, had a small, significant effect on visual acuity. Preretinal macular fibrosis was significantly associated with diabetes, after age-gender adjustment, in subjects without signs of diabetic retinopathy (odds ratio, 3.2; 95% CI, 1.4, 7.2). Preretinal macular fibrosis also was associated with increased fasting plasma glucose (odds ratio, 1.2; 95% CI, 1.1, 1.3). Epiretinal membranes were found in 16.8% of persons who had undergone cataract surgery in one or both eyes (including PMF in 3.7%), in 16.1% of retinal vein occlusion cases (PMF in 12.5%), both significantly higher rates than in subjects without these conditions (P < 0.0001), and in 11% of persons with diabetic retinopathy (PMF in 3.6%), not significantly higher (P = 0.17). Conclusions: This study has documented the frequency and mild effect on vision of epiretinal membranes in an older population. Diabetes was associated significantly with idiopathic cases, whereas well-known associations with past cataract surgery and retinal disease were confirmed.

Internal Medicine

Endocrinology

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Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial

Colleen Loo et al.Jan 1, 2012

Background Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. Aims To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov : NCT00763230). Method Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. Results There was significantly greater improvement in mood after active than after sham treatment ( P <0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS ( P <0.05). There was no decline in neuropsychological functioning after 3–6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. Conclusions Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Internal Medicine

Cognitive Neuroscience

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Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression

Ian Hickie et al.Mar 1, 2005

Background Hippocampal volume reduction has been reported inconsistently in people with major depression. Aims To evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors. Method Totals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected. Results Reduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance. Conclusions Although reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.

Internal Medicine

Clinical Psychology

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Refractive errors in an older population

Karin Attebo et al.Jun 1, 1999

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To determine prevalence and associations with refractive errors in a defined older population.Cross-sectional study.A total of 3654 residents, aged 49-97, of the Blue Mountains, west of Sydney, Australia.Comprehensive questionnaire and detailed eye examination, including refraction.Refractive error of phakic eyes, age, gender, and education.Prevalence rates were determined for myopia (15%), hyperopia (57%), and emmetropia (28%). Hyperopia prevalence was age-related, increasing from 36% in persons aged <60 years to 71 % of persons aged > or = 80 (P < 0.0001), whereas myopia prevalence decreased with age, from 21 % in persons aged <60 years to 10% of persons aged > or = 80 years (P < 0.0001). Younger myopic subjects in this population reported first wearing distance correction at a significantly younger age than older subjects, P < 0.0001. After adjustment for age, women were slightly more hyperopic (mean +0.75 diopters [D]) than men (mean +0.59 D, P = 0.0012. The gender-adjusted mean spherical error increased with age from +0.03 D in persons aged <60 years to +1.2 D in persons aged > or = 80 years (P < 0.0001). The gender-adjusted mean cylinder power also increased with age, from -0.6 D in persons aged <60 years to -1.2 D in persons aged > or = 80 years (P < 0.0001). The mean axis of astigmatism was "against the rule" in all age groups. Anisometropia increased with age, from a mean of 0.4 D in persons aged <60 to 0.9 D in persons aged > or = 80 years (P < 0.0001). Higher education was associated with myopia in men (P = 0.009) but not in women (P = 0.21) after adjustment for age.This report has documented the detailed refractive status of an older population, confirming previously described trends but also finding an apparent higher prevalence of myopia among younger members of this community.

Epidemiology

Ophthalmology

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Subcortical hyperintensities on magnetic resonance imaging: Clinical correlates and prognostic significance in patients with severe depression

Ian Hickie et al.Feb 1, 1995

In 39 hospital inpatients with severe primary depressive disorders, we evaluated the relationships between subcortical hyperintensities on magnetic resonance imaging (MRI) and clinical features, neuropsychological impairment and response to standard therapies. Both white matter and gray nuclei lesions were associated with older age and the absence of a family history of affective disorder. White matter hyperintensities were also associated with onset of first affective episode after the age of 50 years and impaired psychomotor speed. Most importantly, the severity of white matter hyperintensities predicted a poorer response to treatment (r = −0.44, p < .01). Negative correlations of the same order were detected in those (n = 20) who received electroconvulsive therapy (r = −0.42, p = .06) and those (n = 19) who received pharmacotherapy alone (r = −.49, p < .05). This study provides preliminary evidence supporting the clinical and prognostic significance of extensive white matter hyperintensities in patients with severe depression.

Pharmacology

Internal Medicine

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Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Mirko Manchia et al.Jun 19, 2013

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Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Genetics

Philosophy

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Exploring the genetics of lithium response in bipolar disorders

Marisol Herrera-Rivero et al.Jun 12, 2024

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Genetics

Internal Medicine

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Genetics

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