Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a complex and difficult-to-treat disorder, affecting 10-20% of military veterans. Previous research has raised the question of whether a non-trauma-focused treatment can be as effective as trauma exposure therapy in reducing PTSD symptoms. This study aimed to compare the non-trauma-focused practice of Transcendental Meditation (TM) with prolonged exposure therapy (PE) in a non-inferiority clinical trial, and to compare both therapies with a control of PTSD health education (HE). METHODS: We did a randomised controlled trial at the Department of Veterans Affairs San Diego Healthcare System in CA, USA. We included 203 veterans with a current diagnosis of PTSD resulting from active military service randomly assigned to a TM or PE group, or an active control group of HE, using stratified block randomisation. Each treatment provided 12 sessions over 12 weeks, with daily home practice. TM and HE were mainly given in a group setting and PE was given individually. The primary outcome was change in PTSD symptom severity over 3 months, assessed by the Clinician-Administered PTSD Scale (CAPS). Analysis was by intention to treat. We hypothesised that TM would show non-inferiority to PE in improvement of CAPS score (Δ=10), with TM and PE superior to PTSD HE. This study is registered with ClinicalTrials.gov, number NCT01865123. FINDINGS: Between June 10, 2013, and Oct 7, 2016, 203 veterans were randomly assigned to an intervention group (68 to the TM group, 68 to the PE group, and 67 to the PTSD HE group). TM was significantly non-inferior to PE on change in CAPS score from baseline to 3-month post-test (difference between groups in mean change -5·9, 95% CI -14·3 to 2·4, p=0·0002). In standard superiority comparisons, significant reductions in CAPS scores were found for TM versus PTSD HE (-14·6 95% CI, -23·3 to -5·9, p=0·0009), and PE versus PTSD HE (-8·7 95% CI, -17·0 to -0·32, p=0·041). 61% of those receiving TM, 42% of those receiving PE, and 32% of those receiving HE showed clinically significant improvements on the CAPS score. INTERPRETATION: A non-trauma-focused-therapy, TM, might be a viable option for decreasing the severity of PTSD symptoms in veterans and represents an efficacious alternative for veterans who prefer not to receive or who do not respond to traditional exposure-based treatments of PTSD. FUNDING: Department of Defense, US Army Medical Research.

Emotional proprioception: Treatment of depression with afferent facial feedback.

We develop the concept of emotional proprioception, whereby the muscles of facial expression play a central role in encoding and transmitting information to the brain's emotional circuitry, and describe its underlying neuroanatomy. We explore the role of facial expression in both reflecting and influencing depressed mood. The circuitry involved in this latter effect is a logical target for treatment with botulinum toxin, and we review the evidence in support of this strategy. Clinical trial data suggest that botulinum toxin is effective in treating depression. We discuss the clinical and theoretical implications of these data. This novel treatment approach is just one example of the potential importance of the cranial nerves in the treatment of depression.

Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial.

UNLABELLED: Converging lines of evidence suggest a role for facial expressions in the pathophysiology and treatment of mood disorders. To determine the antidepressant effect of onabotulinumtoxinA (OBA) treatment of corrugator and procerus muscles in people with major depressive disorder, we conducted a double blind, randomized, placebo-controlled trial. In an outpatient clinical research center, eighty-five subjects with DSM-IV major depression were randomized to receive either OBA (29 units for females and 40 units for males) or saline injections into corrugator and procerus frown muscles (74 subjects were entered into the analysis). Subjects were rated at screening, and 3 and 6 weeks after OBA treatment. The primary outcome measure was the response rate, as defined by ≥ 50% decrease in score on the Montgomery-Asberg Depression Rating Scale (MADRS). Response rates at 6 weeks from the date of injection were 52% and 15% in the OBA and placebo groups, respectively (Chi-Square (1) = 11.2, p < 0.001, Fisher p < 0.001). The secondary outcome measure of remission rate (MADRS score of 10 or less) was 27% with OBA and 7% with placebo (Chi-square (1) = 5.1, p < 0.02, Fisher p < 0.03). Six weeks after a single treatment, MADRS scores of subjects were reduced on average by 47% in those given OBA, and by 21% in those given placebo (Mann-Whitney U, p < 0.0005). In conclusion, a single treatment with OBA to the corrugator and procerus muscles appears to induce a significant and sustained antidepressant effect in patients with major depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01556971.

A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder.

BACKGROUND: Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low winter light levels in Seasonal Affective Disorder (SAD). We hypothesize that functional sequence variation in the melanopsin gene could contribute to increasing the light needed for normal functioning during winter in SAD. METHODS: Associations between alleles, genotypes, and haplotypes of melanopsin in SAD participants (n=130) were performed relative to controls with no history of psychopathology (n=90). RESULTS: SAD participants had a higher frequency of the homozygous minor genotype (T/T) for the missense variant rs2675703 (P10L) than controls, compared to the combined frequencies of C/C and C/T. Individuals with the T/T genotype were 5.6 times more likely to be in the SAD group than the control group, and all 7 (5%) of individuals with the T/T genotype at P10L were in the SAD group. LIMITATIONS: The study examined only one molecular component of the non-visual light input pathway, and recruitment methods for the comparison groups differed. CONCLUSION: These findings support the hypothesis that melanopsin variants may predispose some individuals to SAD. Characterizing the genetic basis for deficits in the non-visual light input pathway has the potential to define mechanisms underlying the pathological response to light in SAD, which may improve treatment.

Short exposure to light treatment improves depression scores in patients with seasonal affective disorder: A brief report.

Light therapy is an effective treatment of seasonal affective disorder (SAD), when administered daily for at least several weeks. We have previously reported a small improvement in mood in SAD patients following exposure to the first hour of treatment. We now reevaluate retrospectively mood changes during shorter exposures comparing depression ratings at baseline, 20, 40, and 60 minutes of light. Participants were 15 depressed patients with SAD, untreated, who were tested during the winter season. The treatment consisted of 10,000 lux of white cool fluorescent light. Depression was measured using the 24-item NIMH scale (24-NIMH). The data were analyzed using ANOVA on ranks and Wilcoxon signed rank tests. Light resulted in significant improvement in mood at every interval when compared with baseline (p< .001). The 40 minute exposure resulted in a greater improvement than the 20 minute exposure (p < .001) but was not different from the 60 minute exposure (p < = .068). We conclude that immediate improvement in mood can be detected after the first session of light with exposures as short as 20 minutes, and that 40 minutes of exposure is not less effective than 60 minutes.

Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL.

BACKGROUND: Seasonal affective disorder (SAD) can cause significant distress and impairment. No antidepressant studies have previously attempted to prevent the onset of autumn-winter depression. METHODS: Three prospective, randomized, placebo-controlled prevention trials were conducted on 1042 SAD patients, enrolled in autumn and treated while still well, across the northern US and Canada. Patients received either bupropion XL 150-300 mg or placebo daily by mouth from enrollment until spring and were then followed off medications for 8 additional weeks. Primary efficacy variables were end-of-treatment depression-free rates and survival distributions of depressive recurrence. RESULTS: Despite a reported average of 13 previous seasonal depressive episodes, almost 60% of patients had never previously been treated for depression. Major depression recurrence rates during the three studies for bupropion XL and placebo groups were 19% versus 30% (p = 0.026), 13% versus 21% (p = 0.049), and 16% versus 31%; yielding a relative risk reduction across the three studies of 44% for patients taking bupropion XL. Survival analyses for depression onset also favored bupropion XL over placebo (p = .081, .057, and <.001). CONCLUSIONS: It is possible to prevent recurrence of seasonal major depressive episodes by beginning bupropion treatment early in the season while patients are still well.

Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study.

BACKGROUND: Data remain limited on treatment strategies for adults with attention-deficit/hyperactivity disorder (ADHD). This study evaluated the efficacy and safety of an extended-release, once-daily formulation of bupropion (XL) in the treatment of adults with ADHD. METHODS: This multisite, placebo-controlled, 8-week prospective trial evaluated 162 adult patients diagnosed with ADHD (combined and inattentive types). Subjects were treated with up to 450 mg/day of bupropion XL. The primary efficacy endpoint was the proportion of ADHD responders (defined as at least a 30% reduction in the investigator-rated ADHD Rating Scale score) at week 8 (last observation carried forward [LOCF]). RESULTS: Bupropion XL responders (53%) exceeded placebo responders (31%) (p =.004 at week 8) with a significantly greater proportion of bupropion XL responders as early as week 2 (p = .01). Treatment effect size calculated for the ADHD Rating Scale total score was .6. Bupropion XL appeared to provide sustained benefit throughout the day compared with placebo (morning p =.033, afternoon p =.004, evening p = .024). Bupropion XL was safe and well tolerated, with no serious or unexpected adverse events and a low rate of drug-related study discontinuation (5%). CONCLUSIONS: The results from this multisite study indicate that bupropion XL is an effective and well-tolerated nonstimulant treatment for adult ADHD.

Effects of tryptophan depletion and catecholamine depletion on immune parameters in patients with seasonal affective disorder in remission with light therapy.

BACKGROUND: Altered immunologic parameters are found in symptomatic depressed patients relative to remitted depressed patients and healthy controls. We investigated whether tryptophan depletion and catecholamine depletion induce alterations in immunologic parameters in patients with seasonal affective disorder remitted on light therapy, and whether these changes are associated with changes in mood. METHODS: Remitted patients with seasonal affective disorder underwent tryptophan depletion, catecholamine depletion, and sham depletion in a prospective randomized, double-blind crossover design. Measures of depression, plasma levels of tryptophan and catecholamine metabolites, and plasma levels of cytokines (sIL-4, IL-6, neopterin, sTNF-R1 and sTNF-R2) were obtained at baseline, and 7, 24, and 30 hours after monoamine depletion. RESULTS: Tryptophan depletion decreased plasma total and free tryptophan levels; catecholamine depletion decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Tryptophan depletion and catecholamine depletion, but not sham depletion, induced a transient exacerbation of depressive symptoms (p <.001); plasma neopterin levels increased during tryptophan depletion and catecholamine depletion (p <.05). Tryptophan depletion and catecholamine depletion induced a transient reduction of plasma sIL-4 levels (p <.05). A significant correlation was found between sIL-4R levels and depression ratings after tryptophan depletion (r = -.61, p <.05). CONCLUSIONS: The monoamine depletion-induced alterations of humoral and cellular immunity suggest a potential role of immunologic parameters in the pathophysiology of seasonal affective disorder; however, the results must be considered preliminary and require further study.

Patients with seasonal affective disorder have lower odor detection thresholds than control subjects.

BACKGROUND: Behavioral changes in patients with seasonal affective disorder resemble seasonal changes in photoperiodic animals. Because the olfactory system has a modulatory role in seasonal photoperiodic responses in certain species, we hypothesized that olfactory function may differ between patients with seasonal affective disorder and healthy control subjects. METHODS: Fourteen patients who had winter seasonal affective disorder and 16 healthy volunteers were studied once in winter and once in the subsequent summer. We administered a phenyl ethyl alcohol detection threshold test to each side of the nose in a counterbalanced order, with the nostril contralateral to the tested site occluded. Patient and control data were compared using a 4-way repeated measure analysis of covariance (with group and gender as between-subjects factors, season and side-of-the-nose as within-subjects factors, and age as a covariate). RESULTS: The patients exhibited lower thresholds than did the controls (F(1,25) = 9.2; P =.006). There was no main effect of season. CONCLUSION: In humans, marked seasonal behavioral rhythms with recurrent winter depression may be associated with a more acute sense of smell.

Double-blind, placebo-controlled study of single-dose metergoline in depressed patients with seasonal affective disorder.

A role for serotonin in season affective disorder (SAD) has been explored with a variety of serotonergic pharmacologic agents. The authors initially hypothesized that metergoline, a nonspecific serotonin antagonist, would exacerbate depressive symptoms. In a small, open-label pilot study, the authors observed the opposite effect. They decided to follow up on this finding with this formal study. The study followed a double-blind, randomized cross-over design. Sixteen untreated, depressed patients with SAD received single oral doses of metergoline 8 mg and of placebo, spaced 1 week apart. Fourteen patients were restudied after 2 weeks of light treatment. Depression ratings using the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version were performed at baseline and at 3 and 6 days after each intervention. These data were analyzed by baseline-corrected repeated measures with analysis of variance. In the off-lights condition, severity of depression was diminished after metergoline compared with placebo administration (p = 0.001). Patient daily self-ratings suggested that the peak effect occurred 2 to 4 days after study drug administration. In contrast, after 2 weeks of treatment with bright artificial light, metergoline did not demonstrate a significant effect on mood. These data suggest that single doses of metergoline may have antidepressant effects that last several days. Possible mechanisms include 5-hydroxytryptamine(2) receptor downregulation and dopamine agonism.