Rachel Morehouse

Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial

IMPORTANCE Bright light therapy is an evidence-based treatment for seasonal depression, but there is limited evidence for its efficacy in nonseasonal major depressive disorder (MDD). OBJECTIVE To determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo- and sham-controlled, 8-week trial in adults (aged 19-60 years) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers. Data were collected from October 7, 2009, to March 11, 2014. Analysis was based on modified intent to treat (randomized patients with ≥1 follow-up rating). INTERVENTIONS Patients were randomly assigned to (1) light monotherapy (active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride, 20 mg/d); (3) combination light and antidepressant; or (4) placebo (inactive negative ion generator plus placebo pill). MAIN OUTCOMES AND MEASURES Change score on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to the 8-week end point. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS score ≤10 at end point). RESULTS A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination (effect size [d] = 1.11; 95% CI, 0.54 to 1.64) and light monotherapy (d = 0.80; 95% CI, 0.28 to 1.31) were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy (d = 0.24; 95% CI, -0.27 to 0.74) was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%). Combination therapy was superior to placebo in MADRS response (β = 1.70; df = 1; P = .005) and remission (β = 1.33; df = 1; P = .02), with numbers needed to treat of 2.4 (95% CI, 1.6 to 5.8) and 3.5 (95% CI, 2.0 to 29.9), respectively. All treatments were generally well tolerated, with few significant differences in treatment-emergent adverse events. CONCLUSIONS AND RELEVANCE Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD. The combination treatment had the most consistent effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00958204.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder Section 5. Complementary and Alternative Medicine Treatments

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Complementary and Alternative Medicine Treatments” is the fifth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John’s wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. Conclusions: For MDD of mild to moderate severity, exercise, light therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions.

Development of an adjective checklist to measure five FACES of fatigue and sleepiness Data from a national survey of insomniacs

Development and initial validation of the FACES of fatigue and sleepiness adjective checklist. An initial item pool of 65 adjectives, descriptive of fatigue, sleepiness and related deprivation states, was developed and administered to 372 individuals referred by their family physicians for psychiatric investigation and treatment of severe insomnia. Participants attended one of six Canadian university-affiliated sleep clinics where they completed a psychiatric assessment and a 766-item questionnaire, including a number of standard indices of sleep-related behavior and symptoms, medical history, sleep hygiene, psychosocial well-being and psychopathology. Principal-components and item analyses were undertaken to refine the initial 65-item pool to a smaller 50-item set, consisting of five subscales: Fatigue, Anergy, Consciousness, Energized and Sleepiness. Coefficient alpha was calculated and indicated high internal consistency reliability for all subscales. Convergent and discriminant validity were also evaluated by calculating correlations between FACES subscales and a number of independent indices. The resulting five-scale FACES questionnaire appears to offer a promising self-report instrument for the measurement of fatigue and related subjective experiences.

Therapeutic mechanism in seasonal affective disorder: do fluoxetine and light operate through advancing circadian phase?

In the context of Lewys phase delay hypothesis, the present study tested whether effective treatment of winter Seasonal Affective Disorder (SAD) is mediated by advancing of circadian phase. Following a baseline week, 78 outpatients with SAD were randomized into 8 weeks of treatment with either fluoxetine and placebo light treatment or light treatment and placebo pill. Depression levels were measured on the Ham17+7 and the BDI‐II, and circadian phase was estimated on the basis of daily sleep logs and self‐reported morningness‐eveningness. Among the 61 outpatients with complete data, both treatments were associated with significant antidepressant effect and phase advance. However, pre‐ and post‐treatment comparisons found that the degree of symptom change did not correlate with the degree of phase change associated with treatment. The study therefore provides no evidence that circadian phase advance mediates the therapeutic mechanism in patients with SAD. Findings are discussed in terms of the limitations of the circadian measures employed.

Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents.

BACKGROUND Previous work has indicated that low temporal coherence of ultradian sleep electroencephalographic rhythms is characteristic of depressed patients and of depressed women, in particular. It may also be evident in one quarter of those at high risk, based on a family history of depression. METHODS The present study evaluated temporal coherence of sleep electroencephalographic rhythms in 41 adolescent girls with a maternal history of depression (high risk) and 40 healthy controls (low risk). The entire sample was followed clinically every 6 months for 2 years. RESULTS Temporal coherence was significantly lower among the high-risk girls than in controls. Regression analyses predicted group from coherence values and correctly classified 70% of the high-risk group with a false-positive rate of 5% among controls. Moreover, 54% of the high-risk girls were identified with extreme low coherence. On clinical follow up, 14 girls showed depressive symptoms, 9 in the high-risk group (22.5%) and 5 controls (12.2%). Six met DSM-IV criteria for first-episode major depressive disorder, five high-risk and one control. Most importantly, 41% of those identified as having the most abnormal coherence values either showed symptoms of depression or met diagnostic criteria upon follow up. CONCLUSIONS Low temporal coherence is evident in adolescent girls at high risk for depression. The more abnormal the coherence, the greater the risk of a first episode of major depressive disorder within 2 years of sleep study, approximately 10 times greater than in controls.

Quality of life as an outcome indicator in patients with seasonal affective disorder : results from the Can-SAD study

BACKGROUND Although a host of studies have now examined the relationship between quality of life (QoL) and non-seasonal depression, few have measured QoL in seasonal affective disorder (SAD). We report here on results from the Can-SAD trial, which assessed the impact of treatment with either antidepressant medication or light therapy upon QoL in patients diagnosed with SAD. METHOD This Canadian double-blind, multicentre, randomized controlled trial included 96 patients who met strict diagnostic criteria for SAD. Eligible patients were randomized to 8 weeks of treatment with either: (1) 10000 lux light treatment and a placebo capsule or (2) 100 lux light treatment (placebo light) and 20 mg fluoxetine. QoL was measured with the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Medical Outcomes Study (MOS) Short-Form General Health Survey (SF-20) at baseline and 8 weeks. RESULTS Both intervention groups showed significant improvement in QoL over time with no significant differences being detected by treatment condition. Q-LES-Q scores increased significantly in seven of eight domains, with the average scores rising from 48 x 0 (S.D.=10 x 7) at baseline to 69 x 1 (S.D.=15 x 6) at week 8. Treatment-related improvement in QoL was strongly associated with improvement in depression symptoms. DISCUSSION Patients with SAD report markedly impaired QoL during the winter months. Treatment with light therapy or antidepressant medication is associated with equivalent marked improvement in perceived QoL. Studies of treatment interventions for SAD should routinely include broader indices of patient outcome, such as the assessment of psychosocial functioning or life quality.

Barriers to achieving treatment goals: a focus on sleep disturbance and sexual dysfunction.

BACKGROUND Patients who meet the criteria for a major depressive episode experience a constellation of symptoms, and different symptom configurations may reflect distinct underlying neurological disturbances. Similarly, the differing receptor profiles of the various antidepressants may explain relatively low remission rates and persistent symptoms even after remission. In particular, depressed patients frequently display altered circadian rhythms, sleep disturbances, and diurnal mood variation. Exploring treatments that can restore mood while having a positive impact on circadian rhythms and sleep would greatly improve the ability to treat this core features of depression. METHODS The mechanisms of action of the various classes of antidepressants, their effects on sleep and issues beyond sleep, including sexual dysfunction, are explored, along with questions relating to adherence. RESULTS Unfortunately, persistent sleep problems are among the most difficult-to-treat residual symptoms of depression. Many of the currently available antidepressants have adverse effects on circadian processes, including sleep, and may actually worsen sleep problems. Tolerability is also an enduring issue; SSRI and SNRI antidepressants are associated with central nervous sysytem and gastrointestinal effects, sexual side effects and suicidality. Improved drug tolerability would not only minimize distressing adverse effects, but would also improve adherence, thus maximizing the chances of successful treatment. CONCLUSIONS The complexity of managing a major depressive episode is well illustrated by sleep disturbance and sexual dysfunction, two core symptoms of MDD that may also be caused or exacerbated by antidepressant therapy. Future antidepressants should alleviate symptoms without adversely affecting sleep or sexual function.

Neuropsychological functioning following craniopharyngioma removal

The neuropsychological functioning of patients who had undergone surgical removal of craniopharyngiomas was compared to that of an endocrine control group composed of patients with nontumor hypopituitarism, an obese control group, and a normal control group. Neuropsychological assessments consisting of measures of intelligence, memory, attention, and executive functioning were carried out. The craniopharyngioma group had lower Performance IQ than did the normal control group, but their Performance IQ was comparable to that of the hypopituitarism and obese control groups. The craniopharyngioma patients did not differ in Verbal or Full Scale IQs from the remaining groups. There were no group differences on measures of verbal or nonverbal memory, ability to sustain attention, or executive functioning including measures of verbal or figural fluency, nonverbal problem solving, ability to copy a complex geometric figure, and visual motor and visual sequencing skills. The group mean scores on the measures of intelligence and neuropsychological abilities for the craniopharyngioma patients were in the low-average to average range. While craniopharyngioma patients can have significant morbidity including endocrine and visual deficits as well as obesity resulting from hyperphagia, neuropsychological deficits are not always present. Their neuropsychological outcome is more benign than some previous studies have suggested.

Depression and short REM latency in subjects with chronic fatigue syndrome.

Objective The hypothesized polysomnographic marker for depression, Rapid Eye Movement Latency (REML), was used to investigate two groups of subjects; Chronic Fatigue Syndrome (CFS)-not depressed and CFS-depressed. Method CFS subjects were classified into depressed and not depressed groups, using the Diagnostic Interview Schedule (DIS), and subsequently were studied in a sleep laboratory to ascertain REML. Results Short REML showed a statistically significant correlation with the depressed state in CFS subjects. Conclusion Short REM latency is associated with depression in the CFS population.

The characteristics of asymptomatic female adolescents at high risk for depression: the baseline assessment from a prospective 8-year study

OBJECTIVES This longitudinal 8-year study assesses potential predictors of major depressive disorder (MDD) in a cohort of healthy adolescent females at high familial risk for MDD. The objective of this study was to ascertain whether risk factors for female onset MDD would differentiate youth at high or usual risk for MDD, prior to the onset of depressive symptomology. METHODS Subjects (ages 12-15 years) were assigned to a high (n=43) or usual (n=40) risk group according to maternal history of MDD. Depressive symptomatology (Beck Depression Inventory, Hamilton Rating Scale for Depression), pubertal development (Pubertal Developmental Staging Questionnaire), social support (Social Support Scale), and cognitive vulnerability (Depressive Experiences Questionnaire) were assessed. RESULTS High risk and usual risk group demonstrated no significant differences in demographic variables such as age, body mass index, and grade. Significantly more youth in the high risk group (n=40, 93%) had started menstruation, compared to youth in the usual risk group (n=31, 77.5%). There were no significant differences between the groups on measures of dysphoric cognitive style, perceived overall number of social supports, or satisfaction with social support. CONCLUSIONS Females at high familial risk for the onset of depression have significant differences in pubertal development, but not in demographics, depressive symptoms, social supports, or dysphoric cognitive style, when compared to females at usual risk for depression. These findings suggest that in prevention trials for depression in asymptomatic young women no non-biological risk factors for MDD aid in identifying females at higher risk for MDD.