Bright light in elderly subjects with nonseasonal major depressive disorder: a double blind randomised clinical trial using early morning bright blue light comparing dim red light treatment

<p>Abstract</p> <p>Background</p> <p>Depression frequently occurs in the elderly. Its cause is largely unknown, but several studies point to disturbances of biological rhythmicity. In both normal aging, and depression, the functioning of the suprachiasmatic nucleus (SCN) is impaired, as evidenced by an increased prevalence of day-night rhythm perturbations, such as sleeping disorders. Moreover, the inhibitory SCN neurons on the hypothalamus-pituitary adrenocortical axis (HPA-axis) have decreased activity and HPA-activity is enhanced, when compared to non-depressed elderly. Using bright light therapy (BLT) the SCN can be stimulated. In addition, the beneficial effects of BLT on seasonal depression are well accepted. BLT is a potentially safe, nonexpensive and well accepted treatment option. But the current literature on BLT for depression is inconclusive.</p> <p>Methods/Design</p> <p>This study aims to show whether BLT can reduce non-seasonal major depression in elderly patients. Randomized double blind placebo controlled trial in 126 subjects of 60 years and older with a diagnosis of major depressive disorder (MDD, DSM-IV/SCID-I). Subjects are recruited through referrals of psychiatric outpatient clinics and from case finding from databases of general practitioners and old-people homes in the Amsterdam region. After inclusion subjects are randomly allocated to the active (bright blue light) vs. placebo (dim red light) condition using two Philips Bright Light Energy boxes type HF 3304 per subject, from which the light bulbs have been covered with bright blue- or dim red light- permitting filters. Patients will be stratified by use of antidepressants. Prior to treatment a one-week period without light treatment will be used. At three time points several endocrinological, psychophysiological, psychometrically, neuropsychological measures are performed: just before the start of light therapy, after completion of three weeks therapy period, and three weeks thereafter.</p> <p>Discussion</p> <p>If BLT reduces nonseasonal depression in elderly patients, then additional lightning may easily be implemented in the homes of patients to serve as add-on treatment to antidepressants or as a stand-alone treatment in elderly depressed patients. In addition, if our data support the role of a dysfunctional biological clock in depressed elderly subjects, such a finding may guide further development of novel chronobiological oriented treatment strategies.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier: NCT00332670</p

Bright Light Treatment in Elderly Patients With Nonseasonal Major Depressive Disorder A Randomized Placebo-Controlled Trial

Context: Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD. Objective: To determine the efficacy of BLT in elderly patients with MDD. Design: Double-blind, placebo-controlled randomized clinical trial. Setting: Home-based treatment in patients recruited from outpatient clinics and from case-finding using general practitioners' offices in the Amsterdam region. Participants: Eighty-nine outpatients 60 years or older who had MDD underwent assessment at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2). Intervention: Three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux). Main Outcome Measures: Mean improvement in Hamilton Scale for Depression scores at T1 and T2 using parameters of sleep and cortisol and melatonin levels. Results: Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%; 95% confidence interval, 4%- 23%; P=.03) and from T0 to T2 (21%; 7%-31%; P=.001). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7% (P<.001), sleep efficiency increased by 2% (P=.01), and the steepness of the rise in eveningmelatonin levels increased by 81% (P=.03) compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% (P=.001) and the 24- hour urinary free cortisol level was 37% lower (P=.003) compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group (P=.02). Conclusions: In elderly patients with MDD,BLTimproved mood,enhancedsleep efficiency,andincreased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment. © 2011 American Medical Association. All rights reserved

Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder

CONTEXT: The orbitofrontal cortex (OFC)-striatal circuit, which is important for motivational behavior, is assumed to be involved in the pathophysiology of obsessive-compulsive disorder (OCD) according to current neurobiological models of this disorder. However, the engagement of this neural loop in OCD has not been tested directly in a cognitive activation imaging paradigm so far. OBJECTIVE: To determine whether the OFC and the ventral striatum show abnormal neural activity in OCD during cognitive challenge. DESIGN: A reversal learning task was employed in 20 patients with OCD who were not receiving medication and 27 healthy controls during an event-related functional magnetic resonance imaging experiment using a scanning sequence sensitive to OFC signal. This design allowed investigation of the neural correlates of reward and punishment receipt as well as of "affective switching," ie, altering behavior on reversing reinforcement contingencies. RESULTS: Patients with OCD exhibited an impaired task end result reflected by a reduced number of correct responses relative to control subjects but showed adequate behavior on receipt of punishment and with regard to affective switching. On reward outcome, patients showed decreased responsiveness in right medial and lateral OFC as well as in the right caudate nucleus (border zone ventral striatum) when compared with controls. During affective switching, patients recruited the left posterior OFC, bilateral insular cortex, bilateral dorsolateral, and bilateral anterior prefrontal cortex to a lesser extent than control subjects. No areas were found for which patients exhibited increased activity relative to controls, and no differential activations were observed for punishment in a direct group comparison. CONCLUSIONS: These data show behavioral impairments accompanied by aberrant OFC-striatal and dorsal prefrontal activity in OCD on a reversal learning task that addresses this circuit's function. These findings not only confirm previous reports of dorsal prefrontal dysfunction in OCD but also provide evidence for the involvement of the OFC-striatal loop in the pathophysiology of OC

Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder

CONTEXT: The orbitofrontal cortex (OFC)-striatal circuit, which is important for motivational behavior, is assumed to be involved in the pathophysiology of obsessive-compulsive disorder (OCD) according to current neurobiological models of this disorder. However, the engagement of this neural loop in OCD has not been tested directly in a cognitive activation imaging paradigm so far. OBJECTIVE: To determine whether the OFC and the ventral striatum show abnormal neural activity in OCD during cognitive challenge. DESIGN: A reversal learning task was employed in 20 patients with OCD who were not receiving medication and 27 healthy controls during an event-related functional magnetic resonance imaging experiment using a scanning sequence sensitive to OFC signal. This design allowed investigation of the neural correlates of reward and punishment receipt as well as of "affective switching," ie, altering behavior on reversing reinforcement contingencies. RESULTS: Patients with OCD exhibited an impaired task end result reflected by a reduced number of correct responses relative to control subjects but showed adequate behavior on receipt of punishment and with regard to affective switching. On reward outcome, patients showed decreased responsiveness in right medial and lateral OFC as well as in the right caudate nucleus (border zone ventral striatum) when compared with controls. During affective switching, patients recruited the left posterior OFC, bilateral insular cortex, bilateral dorsolateral, and bilateral anterior prefrontal cortex to a lesser extent than control subjects. No areas were found for which patients exhibited increased activity relative to controls, and no differential activations were observed for punishment in a direct group comparison. CONCLUSIONS: These data show behavioral impairments accompanied by aberrant OFC-striatal and dorsal prefrontal activity in OCD on a reversal learning task that addresses this circuit's function. These findings not only confirm previous reports of dorsal prefrontal dysfunction in OCD but also provide evidence for the involvement of the OFC-striatal loop in the pathophysiology of OC

Regional Brain Volume in Depression and Anxiety Disorders

Context: Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. Objective: To identify the unique and shared neuro-anatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. Design: Cross-sectional study. Setting: Netherlands Study of Depression and Anxiety. Participants: Outpatients with MDD (n=68), comorbid MDD and anxiety (n=88), panic disorder, and/or social anxiety disorder without comorbid MDD (n=68) and healthy controls (n=65). Main Outcome Measures: Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. Results: We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. Conclusions: Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder. Arch Gen Psychiatry. 2010;67(10):1002-101

Regional Brain Volume in Depression and Anxiety Disorders

CONTEXT: Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE: To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN: Cross-sectional study. SETTING: Netherlands Study of Depression and Anxiety. PARTICIPANTS: Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS: We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS: Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorde

Demographic and clinical data for patients with obsessive-compulsive disorder (OCD), patients with major depressive disorder (MDD), and healthy controls.

<p># chi-square ‡ One-way ANOVA * Tukey and Scheffe post-hoc tests.</p

Behavioral data on the task switching paradigm for patients with obsessive-compulsive disorder (OCD), patients with major depressive disorder (MDD), and healthy controls.

<p>Behavioral data on the task switching paradigm for patients with obsessive-compulsive disorder (OCD), patients with major depressive disorder (MDD), and healthy controls.</p

The letter/digit task switching paradigm.

<p>In this example (consecutive trials are running from top-left to bottom-right) the events-of-interest are displayed. Subjects are presented two stimuli on each trial, i.e. a letter and a digit, for 4000 ms maximally. Subjects select either stimulus by pressing the left or right button on a button box, after which a fixation cross is presented for 500 ms. Each letter/digit pair is presented in either blue or red color. The trial color cues the task to be performed. In the letter task, subjects indicate whether the letter presented is a vowel or a consonant. In the digit task, subjects indicate whether the digit presented is odd or even. Two consecutive trials never contain the same letter or digit. Trial color changes, and therefore task switching, occurs randomly after 4–6 trials to avoid predictability. The first trials immediately after task switching are defined ‘switch events’ (SEs), all other trials as ‘repeat events’ (REs). Color-task and stimulus-response associations were counterbalanced across participants.</p

Group x task interaction effects on the task switching paradigm for the group of patients with obsessive-compulsive disorder (OCD), patients with major depressive disorder (MDD), and healthy controls. All activations at p<.001 uncorrected.

<p>Group x task interaction effects on the task switching paradigm for the group of patients with obsessive-compulsive disorder (OCD), patients with major depressive disorder (MDD), and healthy controls. All activations at p<.001 uncorrected.</p