Machine Learning Prediction of Quality of Life Improvement During Antidepressant Treatment of Patients With Major Depressive Disorder: A STAR*D and CAN-BIND-1 Report.

Background: Quality of life (QoL) is an important patient-centric outcome to evaluate in treatment of major depressive disorder (MDD). This work sought to investigate the performance of several machine learning methods to predict a return to normative QoL in patients with MDD after antidepressant treatment.Methods: Several binary classification algorithms were trained on data from the first 2 weeks of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (n = 651, conducted from 2001 to 2006) to predict week 9 normative QoL (score ≥ 67, based on a community normative sample, on the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form [Q-LES-Q-SF]) after treatment with citalopram. Internal validation was performed using a STAR*D holdout dataset, and external validation was performed using the Canadian Biomarker Integration Network in Depression-1 (CAN-BIND-1) dataset (n = 175, study conducted from 2012 to 2017) after treatment with escitalopram. Feature importance was calculated using SHapley Additive exPlanations (SHAP).Results: Random Forest performed most consistently on internal and external validation, with balanced accuracy (area under the receiver operator curve) of 71% (0.81) on the STAR*D dataset and 69% (0.75) on the CAN-BIND-1 dataset. Random Forest Classifiers trained on Q-LES-Q-SF and Quick Inventory of Depressive Symptomatology-Self-Rated variables had similar performance on both internal and external validation. Important predictive variables came from psychological, physical, and socioeconomic domains.Conclusions: Machine learning can predict normative QoL after antidepressant treatment with similar performance to that of prior work predicting depressive symptom response and remission. These results suggest that QoL outcomes in MDD patients can be predicted with simple patient-rated measures and provide a foundation to further improve performance and demonstrate clinical utility.Trial Registration: ClinicalTrials.gov identifiers NCT00021528 and NCT01655706.

Blue-Light Therapy for Seasonal and Non-Seasonal Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To determine the efficacy and safety of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control conditions. METHODS: We searched Web of Science, EMBASE, Medline, PsycInfo, and Clinicaltrials.gov through January 17, 2022, for randomized controlled trials (RCTs) using search terms for blue/blue-enhanced, light therapy, and depression/seasonal affective disorder. Two independent reviewers extracted data. The primary outcome was the difference in endpoint scores on the Structured Interview Guide for the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD) or the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) between blue light and comparison conditions. Secondary outcomes were response (≥ 50% improvement from baseline to endpoint on a depression scale) and remission rates (endpoint score in the remission range). RESULTS: Of 582 articles retrieved, we included nine RCTs (n = 347 participants) assessing blue-light therapy. Seven studies had participants with seasonal MDD and two studies included participants with non-seasonal MDD. Four studies compared blue light to an inactive light condition (efficacy studies), and five studies compared it to an active condition (comparison studies). For the primary outcome, a meta-analysis with random-effects models found no evidence for the efficacy of blue-light conditions compared to inactive conditions (mean difference [MD] = 2.43; 95% confidence interval [CI], -1.28 to 6.14, P = 0.20); however, blue-light also showed no differences compared to active conditions (MD = -0.11; 95% CI, -2.38 to 2.16, P = 0.93). There were no significant differences in response and remission rates between blue-light conditions and inactive or active light conditions. Blue-light therapy was overall well-tolerated. CONCLUSIONS: The efficacy of blue-light therapy in the treatment of seasonal and non-seasonal MDD remains unproven. Future trials should be of longer duration, include larger sample sizes, and attempt to better standardize the parameters of light therapy.

Functional outcomes with bright light in monotherapy and combined with fluoxetine in patients with major depressive disorder: Results from the LIFE-D trial.

BACKGROUND: Bright light therapy has been shown to improve depressive symptoms in patients with nonseasonal major depressive disorder (MDD) but there are few studies examining functional outcomes. METHODS: We examined secondary functional outcomes in the 8-week randomized, placebo-sham-controlled LIFE-D trial comparing light therapy, fluoxetine, and the combination in patients with nonseasonal MDD. Functional assessments included the Sheehan Disability Scale (SDS) and, for employed participants, the Lam Employment Absence and Productivity Scale (LEAPS). Analysis of covariance (ANCOVA) was conducted with SDS and LEAPS change scores from baseline to week 8 as dependent variables, treatment modality (light, fluoxetine) as an independent variable, and baseline SDS and LEAPS scores as covariates. RESULTS: Of 122 randomized participants, SDS data were available for 105 and LEAPS data for 70. For the SDS, there were no interaction effects, but there was a significant small- to medium-sized main effect of light treatment on total SDS scores with corresponding significant effects in the Social Life and Family Life domains, but not in the Work/Study domain. There were no significant interaction or main effects with LEAPS scores. CONCLUSION: Light therapy significantly improved social and family life functioning in patients with MDD. However, work functioning was not significantly improved despite large effect sizes; these results were limited by low statistical power because of small sample sizes. Future studies should use longer treatment durations and be powered to detect clinically relevant differences in functional outcomes.

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

Potential therapeutic benefits of cannabinoid products in adult psychiatric disorders: A systematic review and meta-analysis of randomised controlled trials.

The utility of cannabinoids and cannabinoid-based products (CBPs) as a pharmacological aid to treat psychiatric disorders in adulthood is still poorly understood despite a number of comprehensive general reviews discussing the topic. With a focus on randomized controlled trial (RCT) data, this review and meta-analysis aimed to aggregate and evaluate all current high-quality (Level-1) research that specifically assessed the effectiveness of a CBP on a diagnosed adult psychiatric disorder. The following databases, from their inception to September 2020, were included in the search: Academic Search Premier, PubMed, Ovid MEDLINE®, Web of Science™, PsycARTICLES, PsycINFO, CINAHL (Nursing and Allied Health), and Scopus. Risk of bias for each study was individually assessed using the revised Cochrane tool. Of the 2397 papers identified, thirty-one RCTs met criteria for inclusion: ten trials focused on treating cannabis use disorder, six on schizophrenia, five on opioid/tobacco use disorder, three on anxiety disorders, two on Tourette's disorder, two on anorexia nervosa, and one trial each for attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and obsessive compulsive disorder. This review finds limited evidence for the effectiveness of CBPs to acutely treat a narrow range of psychiatric symptoms. We report no evidence supporting the mid- to long-range effectiveness of any currently available CBP. In general, quality of the evidence was assessed as low- to moderate. Importantly, none of the studies discussed in this review presently endorse the use of cannabis flower as a method of treatment for any recognized psychiatric disorder. Larger, hypothesis driven RCTs are required prior to making further therapeutic recommendations.

Quality of Life Impacts of Bright Light Treatment, Fluoxetine, and the Combination in Patients with Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial.

OBJECTIVE: Bright light therapy is increasingly recommended (alone or in combination with antidepressant medication) to treat symptoms of nonseasonal major depressive disorder (MDD). However, little is known about its impacts on quality of life (QoL), a holistic, patient-valued outcome. METHODS: This study utilizes secondary outcome data from an 8-week randomized, controlled, double blind trial comparing light monotherapy (n = 32), fluoxetine monotherapy (n = 30), and the combination of these (n = 27) to placebo (n = 30). QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Treatment-related differences in QoL improvements were assessed using a repeated measures analysis of variance. The influence of potential predictors of QoL (demographic variables and change in depressive symptoms) were investigated via hierarchical linear regression. RESULTS: Q-LES-Q-SF scores significantly improved across all treatment conditions; however, no significant differences were observed between treatment arms. QoL remained poor relative to community norms by the end of the trial period: Across conditions, 70.6% of participants had significantly impaired QoL at the 8-week assessment. Reduction in depressive scores was a significant predictor of improved QoL, with the final model accounting for 54% of variance in QoL change scores. CONCLUSION: The findings of this study emphasize that improvement in QoL and reduction in depressive symptoms in MDD, while related, cannot be taken to be synonymous. Adjunctive therapies may be required to address unmet QoL needs in patients with MDD receiving antidepressant or light therapies. Further research is required to explore additional predictors of QoL in order to better refine treatments for MDD.

Light Therapy for Patients With Bipolar Depression: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Bipolar disorder (BD) is challenging to treat, and fewer treatments are available for depressive episodes compared to mania. Light therapy is an evidence-based nonpharmacological treatment for seasonal and nonseasonal major depression, but fewer studies have examined its efficacy for patients with BD. Hence, we reviewed the evidence for adjunctive light therapy as a treatment for bipolar depression. METHODS: We conducted a systematic review of databases from inception to June 30, 2019, for randomized, double-blind, placebo-controlled trials of light therapy in patients with BD (CRD42019128996). The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes included clinical response, remission, acceptability, and treatment-emergent mood switches. We quantitatively pooled outcomes using meta-analysis with random-effects models. RESULTS: We identified seven trials representing 259 patients with BD. Light therapy was associated with a significant improvement in Hamilton Depression Rating Scale score (standardized mean difference = 0.43, 95% confidence interval [CI], 0.04 to 0.82, P = 0.03). There was also a significant difference in favor of light therapy for clinical response (odds ratio [OR] = 2.32; 95% CI, 1.12 to 4.81; P = 0.024) but not for remission. There was no difference in affective switches between active light and control conditions (OR = 1.30; 95% CI, 0.38 to 4.44; P = 0.67). Study limitations included different light treatment parameters, small sample sizes, short treatment durations, and variable quality across trials. CONCLUSION: There is positive but nonconclusive evidence that adjunctive light therapy reduces symptoms of bipolar depression and increases clinical response. Light therapy is well tolerated with no increased risk of affective switch.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

AIMS: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS: PRISMA-based systematic review of the literature. RESULTS: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

Appetitive Symptoms Differentially Predict Treatment Response to Fluoxetine, Light, and Placebo in Nonseasonal Major Depression.

OBJECTIVE: We previously reported that morning bright light therapy is efficacious in adults with nonseasonal major depressive disorder (MDD), both on its own and in combination with fluoxetine. Given that appetitive symptoms predict response to bright light therapy in seasonal depression, we examined, in this secondary analysis, whether the same held true in these nonseasonal MDD patients. METHODS: Data were collected from October 7, 2009, to March 11, 2014. One hundred twenty-two patients who met DSM-IV-TR criteria for MDD without a seasonal pattern were randomly assigned to light monotherapy, fluoxetine, combination light and fluoxetine, or double-placebo (inactivated negative ion generator plus placebo pill). Multiple regression assessed the percentage change in Montgomery-Asberg Depression Rating Scale (MADRS) scores based on treatment condition, appetitive symptom score at baseline (sum of 4 items on the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version), and the condition-by-appetitive score interaction. Sex was considered as a possible moderator of these effects. RESULTS: The overall regression model predicting treatment response was highly significant (P < .001), and the treatment condition-by-appetitive score interaction was a strong predictor of MADRS change scores (t = 2.65, P = .009). For individuals in the placebo group, more appetitive symptoms at baseline predicted less decrease in MADRS scores at 8 weeks (r = -0.37; large effect size). In contrast, for individuals in the active treatment groups, more appetitive symptoms at baseline predicted more of a decrease in depression scores at 8 weeks (fluoxetine group r = +0.23, medium effect size; light therapy group r = +0.11, small effect size; combination group r = +0.32, medium to large effect size). No moderation effect of sex was found. CONCLUSIONS: More severe appetitive symptoms at baseline predicted treatment response differentially across the 4 treatment groups. Contrary to prior findings in seasonal depression, this association was not robust for MDD patients receiving light therapy alone, although it was stronger in patients receiving fluoxetine with or without light. As the group sample sizes were modest, the current findings should be considered as preliminary only. 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.

(Reprinted by permission of SAGE Publications, Inc., from The Canadian Journal of Psychiatry 2016; 61:576-587. Copyright © 2016 by the Authors [https://doi.org/10.1177/0706743716660290]).

A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

Subcortical structural volumes in recently remitted first episode mania.

BACKGROUND: Magnetic resonance imaging (MRI) studies have yielded inconsistent findings with regard to subcortical volumetric abnormalities in patients with bipolar I disorder. Duration of illness and long term medication intake could have confounded the findings. METHOD: Volumes of nine subcortical structures were compared between 63 patients who recently remitted from their first manic episode and 77 healthy volunteers. The volumetric segmentation was performed with the automated segmentation algorithm Freesurfer version 5.1. RESULTS: There were no significant volumetric differences between the two groups in any of the structures examined including caudate, putamen, globus pallidum, nucleus accumbens, amygdala, thalamus, cerebellum, hippocampus and lateral ventricles (q > 0.05-false discovery rate corrected). LIMITATIONS: All patients were on psychotropic medications at the time of scanning, which might have confounded the results. Sample size may not be large enough to detect small volumetric changes. CONCLUSIONS: Patients with bipolar I disorder do not appear to have any significant subcortical volumetric abnormalities during the early stage of the disease. Thus, early stage bipolar disorder may present an opportunity for intervention to arrest neuroprogression of the disease.

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.

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 (ß = 1.70; df = 1; P = .005) and remission (ß = 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.

Enhanced inflammatory and T-helper-1 type responses but suppressed lymphocyte proliferation in patients with seasonal affective disorder and treated by light therapy.

BACKGROUND: Animals show seasonal changes in the endocrine and immune system in response to winter stressors. Even though increased inflammation has been implicated in the pathophysiology of depression, whether immune disorder is a key mediator in seasonal affective depression (SAD) is unknown. Here, we hypothesized that short photoperiods in winter may induce inflammatory response, which contributes to SAD, and that light treatments should normalize immune function and improve depressive symptoms. METHODS: Twenty patients with a diagnosis of SAD, and a score on the HAM-29 of 20 or higher were recruited for this study. Twenty-one healthy subjects with no personal and family history of psychiatric disorder were matched to patients according to age and sex. Patients and controls were sampled during winter between November and January, inclusive. A subset of SAD patients (N=13) was re-sampled after 4 weeks of light therapy. Blood samples were assayed for macrophage activity, lymphocyte proliferation and cytokine release. RESULTS: SAD patients showed significantly higher macrophage activity and lower lymphocyte proliferation in winter compared to healthy subjects. The concentrations of macrophage-produced proinflammatory cytokines interleukin-1ß and tumour necrosis factor-α, and T-helper (Th)-1 produced cytokine, interferon-γ were all significantly increased. In contrast, no significant changes in Th2-produced cytokines were observed. Light therapy significantly improved depressive scores, which was associated with attenuation of decreased lymphocyte functions, increased macrophage activity and level of proinflammatory cytokines. CONCLUSION: SAD patients have increased macrophage and Th1 type responses in winter, and light therapy normalized immune functions and depressive symptoms. These results support an inflammatory hypothesis for SAD and an immunomodulatory role of light therapy.

Direct health care costs of treating seasonal affective disorder: a comparison of light therapy and fluoxetine.

Objective. To compare the direct mental health care costs between individuals with Seasonal Affective Disorder randomized to either fluoxetine or light therapy. Methods. Data from the CANSAD study was used. CANSAD was an 8-week multicentre double-blind study that randomized participants to receive either light therapy plus placebo capsules or placebo light therapy plus fluoxetine. Participants were aged 18-65 who met criteria for major depressive episodes with a seasonal (winter) pattern. Mental health care service use was collected for each subject for 4 weeks prior to the start of treatment and for 4 weeks prior to the end of treatment. All direct mental health care services costs were analysed, including inpatient and outpatient services, investigations, and medications. Results. The difference in mental health costs was significantly higher after treatment for the light therapy group compared to the medication group-a difference of $111.25 (z = -3.77, P = 0.000). However, when the amortized cost of the light box was taken into the account, the groups were switched with the fluoxetine group incurring greater direct care costs-a difference of $75.41 (z = -2.635, P = 0.008). Conclusion. The results suggest that individuals treated with medication had significantly less mental health care cost after-treatment compared to those treated with light therapy.

Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication.

BACKGROUND: In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT in 2008-2009 to reflect advances in the field. This article, one of five in the series, reviews new studies of psychotherapy in the acute and maintenance phase of MDD, including computer-based and telephone-delivered psychotherapy. METHODS: The CANMAT guidelines are based on a question-answer format to enhance accessibility to clinicians. Evidence-based responses are based on updated systematic reviews of the literature and recommendations are graded according to the Level of Evidence, using pre-defined criteria. Lines of Treatment are identified based on criteria that included evidence and expert clinical support. RESULTS: Cognitive-Behavioural Therapy (CBT) and Interpersonal Therapy (IPT) continue to have the most evidence for efficacy, both in acute and maintenance phases of MDD, and have been studied in combination with antidepressants. CBT is well studied in conjunction with computer-delivered methods and bibliotherapy. Behavioural Activation and Cognitive-Behavioural Analysis System of Psychotherapy have significant evidence, but need replication. Newer psychotherapies including Acceptance and Commitment Therapy, Motivational Interviewing, and Mindfulness-Based Cognitive Therapy do not yet have significant evidence as acute treatments; nor does psychodynamic therapy. LIMITATIONS: Although many forms of psychotherapy have been studied, relatively few types have been evaluated for MDD in randomized controlled trials. Evidence about the combination of different types of psychotherapy and antidepressant medication is also limited despite widespread use of these therapies concomitantly. CONCLUSIONS: CBT and IPT are the only first-line treatment recommendations for acute MDD and remain highly recommended for maintenance. Both computer-based and telephone-delivered psychotherapy--primarily studied with CBT and IPT--are useful second-line recommendations. Where feasible, combined antidepressant and CBT or IPT are recommended as first-line treatments for acute MDD.

Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. V. Complementary and alternative medicine treatments.

BACKGROUND: In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT in 2008-2009 to reflect advances in the field. There is widespread interest in complementary and alternative medicine (CAM) therapies in the treatment of major depressive disorder (MDD). METHODS: The CANMAT guidelines are based on a question-answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included evidence and expert clinical support. This section on "Complementary and Alternative Medicine Treatments" is one of 5 guideline articles. RESULTS: There is Level 1 evidence to support light therapy in seasonal MDD and St. John's wort in mild to moderate MDD. There is also some evidence for the use of exercise, yoga and sleep deprivation, as well as for omega-3 fatty acids and SAM-e . Support for other natural health products and therapies is still limited. LIMITATIONS: The evidence base remains limited and studies often have methodological problems, including small samples, variability in dose, short duration of treatment, unknown quality of the agent and limited long-term data. Safety data are also sparse with little information about drug interactions. CONCLUSIONS: Some CAM treatments have evidence of benefit in MDD. However, problems with standardization and safety concerns may limit their applicability in clinical practice.

Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder.

BACKGROUND: Retinal sensitivity anomalies have been reported in patients affected by seasonal affective disorder (SAD). We used the electroretinogram (ERG) to assess seasonal change in retinal function in patients with SAD and healthy participants, as well as in patients following 4 weeks of light therapy. METHODS: ERG assessments were obtained in 22 SAD patients (2 men, 20 women, mean age 31 +/- 9 years) in the fall/winter season before and after 2 and 4 weeks of light therapy and in summertime. Matched healthy participants (2 men, 14 women; mean age 29 +/- 8 years) were evaluated once in the fall/winter and once in summer. The 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version was administered. Standard ERG parameters were derived from the photopic and scotopic luminance response functions. Salivary melatonin concentration during ERG was assessed in both groups but during fall/winter assessments only. RESULTS: A significantly lower cone ERG maximal amplitude and lower rod sensitivity was found in SAD patients before light therapy compared with healthy participants. Following 4 weeks of light therapy, a normalization of cone and rod ERG function occurred. ERG parameters in the summer and melatonin concentrations in fall/winter were not significantly different between groups. CONCLUSIONS: Depressed patients with SAD demonstrate ERG changes in the winter compared with healthy comparison subjects with lower rod retinal sensitivity and lower cone maximal amplitude. These changes normalized following 4 weeks of light therapy and during the summer, suggesting that ERG changes are state markers for SAD.