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Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

Objective The objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment. Background Chronic CH is a highly debilitating disease with a substantial and unmet medical need. Methods Patients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52-week open-label extension and 16-week posttreatment follow-up (washout). This is a secondary analysis and long-term follow-up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings. Results A total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab-treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment-emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open-label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo-controlled treatment period in laboratory values, vital signs, or ECGs. Conclusions Galcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment.

Background CGAR, a Phase 3b open-label study, evaluated the long-term safety of galcanezumab in patients with cluster headache who completed one of two Phase 3 double-blind studies in chronic or episodic cluster headache. Methods Patients (N = 164) received galcanezumab 300 mg subcutaneously up to once a month. Primary endpoint was safety, as assessed by treatment-emergent adverse events, serious adverse events, and suicidality. Other endpoints included discontinuation rates, immunogenicity, efficacy as assessed by the Patient Global Impression of Improvement, and health values. Results At baseline, mean (standard deviation) age was 48.3 (9.8) years, 75.0% were men, and 85.4% were white. Treatment-emergent adverse events (n = 119 [72.6%]) were mostly mild-to-moderate, with nasopharyngitis the most commonly reported (22.0%). One of 18 serious adverse events was judged as treatment related (constipation). Two patients (1.2%) reported suicidal ideation. Five patients (3.1%) discontinued due to an adverse event. Eight patients were treatment-emergent anti-drug antibody positive, two of whom were not treatment-emergent anti-drug antibody positive in the parent studies. On the Patient Global Impression of Improvement, ≥81% reported their cluster headache status as very much, much, or a little better at Months 1, 6, and 12. Health value scores generally improved from baseline. Conclusions In this open-label study, galcanezumab was generally well tolerated and improved patient-reported cluster headache status. Trial registration number: NCT02797951; https://clinicaltrials.gov/ct2/show/NCT02797951

Background Cluster headache (CH) is a highly disabling primary headache disorder. To date, characterization of outcomes in the preventive treatment of episodic CH, including precise definitions of clinically meaningful attack frequency reduction and impact on acute treatment management, is lacking. Methods This was a Phase 3, randomized, double-blind, placebo-controlled study in patients (men or women aged 18-65 years) diagnosed with episodic CH as defined by the International Classification of Headache Disorders-3 beta criteria. In this post hoc analysis, we evaluated the median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attack frequency, and impact on acute medication use. An anchor-based assessment of clinically relevant attack frequency reduction using the Patient Global Impression of Improvement (PGI-I) scores at Week 4 was also assessed. Results The median time-to-first occurrence of ≥50, ≥75, or 100% reduction from baseline in CH attacks was consistently shorter (9-10 days sooner) with galcanezumab vs placebo (median [95% confidence interval, 95% CI]: ≥50%, 5 days [4.0 to 7.0] vs 14 days [6.0 to 19.0]; ≥75%, 11 days [7.0 to 16.0] vs 21 days [13.0 to 26.0]; 100%, 22 days [16.0 to 37.0] vs 32 days [23.0 to 34.0]). Mean reduction from baseline in the overall frequency of weekly pooled acute medication use across Weeks 1-3 was significantly greater with galcanezumab vs placebo (11.0 vs 5.5; odds ratio, OR [95% CI]: 5.52 [1.02, 10.01]; P value = .017). Patients reporting "much better" on the PGI-I experienced a median weekly CH attack reduction of approximately 43% from baseline across Weeks 1-3. The overall odds of achieving an attack reduction threshold of 43% across Weeks 1-3 was significantly higher with galcanezumab vs placebo (Weeks 1-3: OR [95% CI], 2.60 [1.3 to 5.3]). Conclusions Faster median time-to-first occurrence of response rates, lower frequency of pooled acute medications use, and a greater proportion of patients achieving a response anchored by patient-reported improvement were observed for galcanezumab vs placebo.

Background This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. Methods Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. Findings Across studies, 5.9–11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6–12.4% in the galcanezumab group and 0.5–1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3–6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. Interpretation These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

Objective To report efficacy and safety of galcanezumab in adults with chronic cluster headache. Background Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptide and inhibits its biological activity. Methods This study comprised a prospective baseline period, a 12-week double-blind, placebo-controlled treatment period, and a 52-week open-label period. Up to six protocol-specified concomitant preventive medications were allowed if patients were on a stable dose for 2 months prior to the prospective baseline period. Patients were randomized 1:1 to monthly subcutaneous galcanezumab (300 mg) or placebo. The primary endpoint was overall mean change from baseline in weekly attack frequency with galcanezumab compared to placebo. Key secondary endpoints were ≥50% response rate and percentage of patients meeting sustained response. Results from the double-blind treatment period are reported. Results A total of 237 patients were randomized and treated (120 placebo; 117 galcanezumab). At baseline, the mean age was 45 years and 63% were using ≥1 preventive drug. The primary endpoint was not met; mean change in weekly attack frequency was −4.6 placebo versus −5.4 galcanezumab ( p = 0.334). Key secondary endpoints also were not met. Injection site-related treatment-emergent adverse events were more common in the galcanezumab than the placebo group, with significantly more injection site erythema. Conclusion Treatment with galcanezumab 300 mg did not achieve its primary and key secondary endpoints. This study underscores the potential distinct biology of cCH as well as the significant unmet need for safe, effective, and well-tolerated preventive treatment. The safety profile of galcanezumab in cCH is consistent with that observed in trials of episodic CH and migraine. Trial registration NCT02438826; https://www.clinicaltrials.gov/ct2/show/NCT02438826 .

J Scott Andrews,1 David Kudrow,2 Mallikarjuna Rettiganti,1 Tina Oakes,1 Jennifer N Bardos,1 Richard Wenzel,1 Dulanji K Kuruppu,1 Charly Gaul,3 James M Martinez1 1Eli Lilly and Company, Indianapolis, IN, USA; 2California Medical Clinic for Headache, Santa Monica, CA, USA; 3Headache Center, Frankfurt, GermanyCorrespondence: Mallikarjuna RettigantiEli Lilly and Company, Lilly Corporate Center, 893 Delaware St., Indianapolis, IN, 46285, USATel +1 3176519378Email rettiganti_mallikarjuna@lilly.comPurpose: In a phase 3 study, galcanezumab significantly reduced the frequency of episodic cluster headache attacks across weeks 1– 3 (primary endpoint) compared with placebo. However, multiple pain dimensions may contribute to the total burden of episodic cluster headache pain. This post hoc analysis assessed the impact of galcanezumab on the total pain burden of episodic cluster headache using a composite measure.Patients and Methods: Patients with episodic cluster headache were randomized 1:1 to galcanezumab 300 mg or placebo once monthly for 8 weeks. Mean weekly total pain burden was calculated (daily cluster headache attack frequency × average duration × average pain severity summed over 7 days) using data collected in an electronic patient-reported outcomes diary. Change from baseline in weekly total pain burden across weeks 1– 3 was compared between galcanezumab and placebo. To explore construct validity, mean weekly total pain burden scores were stratified by Patient Global Impression of Improvement (PGI-I) responses at the week 4 clinic visit.Results: The reduction from baseline in mean weekly total pain burden was significantly greater with galcanezumab (N=49) than with placebo (N=57): the least squares mean difference was − 11.18 severity-weighted hours (p=0.035). Median weekly total pain burden decreased as PGI-I ratings improved, from 33.6 to 5.0 severity-weighted hours for patients who felt “very much worse” and “very much better,” respectively.Conclusion: Galcanezumab significantly reduced mean weekly total pain burden compared with placebo in patients with episodic cluster headache. The composite pain measure demonstrated construct validity. Total pain burden may provide a holistic measure of the pain of episodic cluster headache.Clinical Trials: ClinicalTrials.gov, NCT02397473.Keywords: composite pain, frequency, severity, duration, CGRP

Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache.We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed.Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain.Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).

Background and objectiveAs new migraine prevention treatments are developed, the onset of a preventive effect, how long it is maintained and whether patients initially non-responsive develop clinically meaningful responses with continued treatment can be assessed.MethodsAnalyses were conducted post-hoc of a double-blind, placebo-controlled, phase II-a study in patients with episodic migraine receiving galcanezumab 150 mg or placebo biweekly for 12 weeks (Lancet Neurol13:885, 2014). The number of migraine headache days per week, and onset of efficacy measured as the first week galacanezumab separated from placebo were determined. Patients with ≥50%, ≥75% and 100% reduction in migraine headache days from baseline at months 1, 2 and 3 were calculated and defined as sustained responses. Non-responders (ResultsPatients were randomised to galcanezumab (n=107) or placebo (n=110). A significant (p=0.018) change of −0.89±0.11 (galcanezumab) vs −0.53±0.11 (placebo) migraine headache days indicated onset at week 1. Forty-seven per cent of galcanezumab and 25% of placebo patients responding at month 1 maintained response through months 2 and 3. Of non-responders at month 1, 27% on galcanezumab and 20% on placebo responded on months 2 and 3, and 50% of galcanezumab non-responders in months 1 and 2 responded on month 3, vs 24% on placebo.ConclusionsThe onset of efficacy of galcanezumab is within 1 week in a majority of patients, and patients receiving galcanezumab are twice more likely to maintain responses than placebo patients. Early non-responders may respond by month 2 or month 3.Trial registration numberNCT01625988.

Objective To characterize demographics, clinical characteristics, and treatment patterns of patients with cluster headache (CH). Background CH is an uncommon trigeminal autonomic cephalalgia with limited evidence‐based treatment options. Patients suffer from extremely painful unilateral headache attacks and autonomic symptoms with episodic and chronic cycles. Design/Methods This retrospective analysis used insurance claims from Truven Health Analytics MarketScan® research databases from 2009 to 2014. Two cohorts were compared: CH patients (with ≥2 CH claims) were propensity score matched with 4 non‐headache controls, all with continuous enrollment for 12 months before and after the date of first CH claim or matched period among controls. Results CH patients (N = 7589) were mainly male (57.4%) and 35‐64 years old (73.2%), with significantly more claims for comorbid conditions vs controls (N = 30,341), including depressive disorders (19.8% vs 10.0%), sleep disturbances (19.7% vs 9.1%), anxiety disorders (19.2% vs 8.7%), and tobacco use disorders (12.8% vs 5.3%), with 2.5 times greater odds of suicidal ideation (all P 12 unique prescription drug claims. Most commonly prescribed drug classes for CH patients included: opiate agonists (41%), corticosteroids (34%), 5HT‐1 agonists (32%), antidepressants (31%), NSAIDs (29%), anticonvulsants (28%), calcium antagonists (27%), and benzodiazepines (22%). Only 30.4% of CH patients received recognized CH treatments without opioids during the 12‐month post‐index period. These patients were less likely to visit emergency departments or need hospitalizations (26.8%) as compared to CH patients with no pharmacy claims for recognized CH treatments or opioids (33.6%; P

Background: Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and subsequent outcomes of partial responder patients. Methods: Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score 410 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort (n¼1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months. Results: At 3 months, 29.4% of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI (s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission (po0.05). Limitations: FINDER was an observational study; the current analysis was conducted post-hoc. Multivariable methods were not applied and findings are primarily descriptive and exploratory. Conclusions: Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission.

To estimate direct and indirect costs in patients with a diagnosis of cluster headache in the US.Adult patients (18-64 years of age) enrolled in the Marketscan Commercial and Medicare Databases with ≥2 non-diagnostic outpatient (≥30 days apart between the two outpatient claims) or ≥1 inpatient diagnoses of cluster headache (ICD-9-CM code 339.00, 339.01, or 339.02) between January 1, 2009 and June 30, 2014, were included in the analyses. Patients had ≥6 months of continuous enrollment with medical and pharmacy coverage before and after the index date (first cluster headache diagnosis). Three outcomes were evaluated: (1) healthcare resource utilization, (2) direct healthcare costs, and (3) indirect costs associated with work days lost due to absenteeism and short-term disability. Direct costs included costs of all-cause and cluster headache-related outpatient, inpatient hospitalization, surgery, and pharmacy claims. Indirect costs were based on an average daily wage, which was estimated from the 2014 US Bureau of Labor Statistics and inflated to 2015 dollars.There were 9,328 patients with cluster headache claims included in the analysis. Cluster headache-related total direct costs (mean [standard deviation]) were $3,132 [$13,396] per patient per year (PPPY), accounting for 17.8% of the all-cause total direct cost. Cluster headache-related inpatient hospitalizations ($1,604) and pharmacy ($809) together ($2,413) contributed over 75% of the cluster headache-related direct healthcare cost. There were three sub-groups of patients with claims associated with indirect costs that included absenteeism, short-term disability, and absenteeism + short-term disability. Indirect costs PPPY were $4,928 [$4,860] for absenteeism, $803 [$2,621] for short-term disability, and $3,374 [$3,198] for absenteeism + disability.Patients with cluster headache have high healthcare costs that are associated with inpatient admissions and pharmacy fulfillments, and high indirect costs associated with absenteeism and short-term disability.

To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy.Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (≤14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16; scored 0-3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue).Http://clinicaltrials.gov, NCT00021528.Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression ≤7 or QIDS-SR16 ≤5); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS).At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment-emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P 0.0001), and reduced mental and physical function at outcome (P ≤ 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P 0.0001), indicative of more severe functional impairment.Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post-hoc analysis design.

We analyzed the public STAR*D database to better characterize the baseline clinical characteristics and functional outcomes of patients with major depressive disorder (MDD) who experienced partial response in order to better understand the burden associated with this outcome.Patients (n=2,876) received treatment with citalopram. The last available Quick Inventory of Depressive Symptoms (QIDS-SR) from the 12-week treatment period was used to assign subjects to one of three groups: remitters QIDS-SR≤5; non-responders QIDS-SR5 and25% reduction from baseline; and partial responders QIDS-SR5 and ≥25% reduction from baseline. Baseline sociodemographic and clinical characteristics were compared across groups, as well as functional outcomes at Level 1 exit. RESULTS. Of the 2,876 patients, 943 patients (33%) were classified as remitters, 1069 (37%) as partial responders, and 854 (30%) as non-responders. The groups differed on a number of pre-treatment course of illness variables and comorbidities. In addition, remitters, partial responders, and non-responders all separated on posttreatment quality of life and functional outcomes at Level 1 exit.Partial responders demonstrated significant functional impairment at Level 1 exit, differing significantly from the patients who remitted on quality of life, mental and physical functioning, and social and work-related impairment. Adjusted outcomes showed similar differences. Differences in baseline rates of suicidality, comorbidity, and atypical presentations of depression were also observed between outcome groups. Given the substantial clinical and economic burden associated with functional impairment in depression, the need to fully treat partially responding patients to achieve depression remission and restoration of functioning is highlighted by this work.

This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major depressive disorder, who completed the 10-week randomized, double-blind, placebo-controlled acute phase of the study.All patients were treated with edivoxetine during the extension phase. The mean age of the patients was 45 years, and most were white females. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), laboratory and vital sign measures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whether changes from baseline were statistically significant from zero. The overall completion rate was 54%. Adverse event was the most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 TEAE was reported by 72.3% of patients, of which headache (10.8%) and hyperhidrosis (10.1%) were the most common; 2.8% of patients had ≥1 serious adverse events, and there were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALT values occurred in 1.8% of patients, and either normalized or had decreased by the last assessment. Mean increases in blood pressure and pulse were consistent with those observed in the acute phase and appeared to reach a plateau within 3 to 5 months of treatment. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile.

BACKGROUND: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania. METHODS: In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined. RESULTS: Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups. CONCLUSIONS: The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

Painful physical symptoms are common in patients with major depressive disorder (MDD) and can negatively affect patient outcomes. Duloxetine has demonstrated efficacy in treating MDD and other certain painful conditions; this study specifically evaluated patients with both MDD and MDD-associated pain.This randomized, double-blind clinical trial enrolled adult outpatients with MDD (DSM-IV-TR criteria; Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory, Short Form [BPI] average pain rating ≥3). Patients received placebo (N = 266) or duloxetine (N = 261) 60 mg once daily (QD) (after starting dose of 30 mg QD for 1 week). This study replicated another study evaluating MDD and MDD-associated pain.Clinicaltrials.gov (NCT01070329).Co-primary outcomes were the MADRS total score (change from baseline at 8 week endpoint) and BPI average pain rating (overall main effect over 8 weeks of treatment). The Sheehan Disability Scale (SDS) global functional impairment score at week 8 assessed functioning as a secondary outcome. Changes were analyzed using mixed-effects model repeated measures (MMRM), and the MADRS remission rate (total score ≤12 at 8-week endpoint) was analyzed using the Cochran-Mantel-Haenszel test.Both co-primary objectives and the first two gated secondary objectives were achieved: compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, SDS global functional impairment score, and remission of depression at 8-week endpoint (all p 0.01). The third gated secondary objective, evaluating remission of depression at the last two non-missing visits, was not achieved. The within-group MADRS remission rate was greater for duloxetine-treated patients with ≥50% (versus50%) improvement in BPI average pain (p 0.001). Safety outcomes were similar to previous reports. This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin.These results replicated findings supporting the efficacy and tolerability of duloxetine compared to placebo as treatment for depression and pain in patients with MDD and at least moderate pain associated with MDD.

Importance Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. Objective To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. Design, Setting, and Participants A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. Interventions Short-term migraine treatments were allowed as needed except for opioids or barbiturates. Main Outcomes and Measures To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. Results Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days; 90% BCI, −5.4 to −4.2 days vs 95% superiority threshold [Bayesian analysis] −3.7 days; 90% BCI, −4.1 to −3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. Conclusions and Relevance Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. Trial Registration clinicaltrials.gov Identifier:NCT02163993

Bipolar disorders are prevalent and severe illnesses that are associated with a high risk of suicide. Patients with bipolar disorder who have had prior suicide attempts are at a substantially higher risk for future suicidality, even after controlling for other risk factors. Despite the magnitude of this problem, there is a paucity of controlled prospective data to guide clinical care, most likely due to the difficulties inherent in such studies. The most robust literature supports the use of lithium as a suicide-protective agent in bipolar disorder, but a definitive controlled study in a generalizable population is warranted. As in other areas of psychiatry, a careful assessment of the individual patient risk is of paramount importance.

Objectives: Bipolar disorders are associated with high rates of suicide attempts (SAs) and completions. Several factors have been reported to be associated with suicide in persons with bipolar disorder, but most studies to date have been retrospective and have not utilized multivariate statistics to account for the redundant prediction among variables submitted for analysis. Methods: This study examined the association between baseline clinical and demographic variables and subsequent SAs and completions through 2 years of follow-up of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder using a pattern-mixture model. Results: Of the sample with complete data (n = 1,556), 57 patients (3.66%) experienced an SA or completion (CS). Several variables predicted suicidality (SA + CS) in this data set when considered alone, but after controlling for redundant prediction from other baseline characteristics, only history of suicide [odds ratio (OR) = 4.52, p

This is the first case report of a patient who received long-term (69-month) adjunctive vagus nerve stimulation (VNS) therapy for treatment-resistant depression (TRD) and reached VNS battery end-of-service (EOS).The patient is a 41-year-old female with depression who entered a study of adjunctive VNS therapy for TRD. Her Hamilton Rating Scale for Depression (HAM-D) scores dropped from a mean of 33.5 (pre-implantation baseline period) to 16 at the end of the 12-week acute-phase treatment period, and then fluctuated from

Little is known about serious adverse events that occur in the context of clinical care for bipolar disorder. This study examined predictors of serious adverse events in a large cohort of patients with bipolar disorder.Types and frequency of serious adverse events were tabulated on the basis of data from the first 1,000 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). STEP-BD follows a large cohort of patients longitudinally. Treatments are provided as deemed most appropriate by the treating psychiatrist. Logistic regression was used to identify variables present at study entry that were associated with the occurrence of a serious adverse event within one year.A total of 161 serious adverse events were reported among 118 participants. The most frequent serious adverse event was hospitalization for suicidal ideation (44 participants, or 27 percent). A greater number of previous psychiatric medications was predictive of the occurrence of a psychiatric serious adverse event among participants who had less than one year of study follow-up data. A history of psychosis, current substance abuse, lower household income, and a fully syndromic baseline mood state were associated with the occurrence of a psychiatric serious adverse event among participants who had one full year of follow-up data.These data identify clinical and demographic factors that warrant closer clinical follow-up, because these factors may be predictive of poor outcomes in the following year, even in the context of expert care.

This study compared the stabilized duloxetine dose through approximately 12 weeks of treatment in patients initiating duloxetine therapy with that in patients switching to duloxetine from selective serotonin reuptake inhibitors or venlafaxine. All patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder. Patients (n = 112) exhibiting suboptimal response or poor tolerability to their current antidepressant medication (citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or venlafaxine) were switched to duloxetine 60 mg once daily (QD) without intermediate tapering or titration ("switching" group). A comparator group (n = 137), comprising patients not currently receiving antidepressant medication, was randomized to receive duloxetine 30 or 60 mg QD ("initiating" group). At the end of week 1, patients receiving 30 mg QD had their dose increased to 60 mg QD. During the remainder of the study, each patient's duloxetine dose could be titrated on the basis of degree of response within a range from 60 to 120 mg QD, with 90 mg QD as an intermediate dose. At the study end point, approximately one third of the patients in each treatment group were stabilized at each of the 3 studied duloxetine doses (60, 90, and 120 mg QD), and the distribution of stabilized doses among patients initiating duloxetine therapy did not differ significantly from that observed in patients switching to duloxetine. The efficacy of duloxetine in patients switching from selective serotonin reuptake inhibitor/venlafaxine did not differ significantly from that observed in untreated patients initiating duloxetine therapy (baseline-to-end point mean changes: 17-Item Hamilton Rating Scale for Depression total score, -13.1 vs. -13.5; Hamilton Rating Scale for Anxiety, -10.6 vs. -10.3; and Clinical Global Impression of Severity, -2.22 vs. -2.38, respectively). The rate of discontinuation caused by adverse events among patients switched to duloxetine was significantly lower than that in patients initiating duloxetine therapy (6.3% vs. 16.1%, P = 0.018). Treatment-emergent adverse events occurring in more than 10% of patients in both treatment groups were nausea, headache, dry mouth, insomnia, diarrhea, and constipation. In the first week of therapy, patients switched to duloxetine reported significantly lower rates of headache and fatigue compared with patients initiating duloxetine. Thus, the efficacy of duloxetine in switched patients was comparable to that observed in patients initiating duloxetine therapy. Immediate switching from a selective serotonin reuptake inhibitor or venlafaxine to duloxetine (60 mg QD) was well tolerated.

Background: Vagus nerve stimulation (VNS) had antidepressant effects in an initial open, acute phase pilot study of 59 participants in a treatment-resistant major depressive episode (MDE). We examined the effects of adjunctive VNS over 24 months in this cohort. Method: Adult outpatients (N = 59) with chronic or recurrent major depressive disorder or bipolar (I or II) disorder and experiencing a treatment-resistant, nonpsychotic MDE (DSM-IV criteria) received 2 years of VNS. Changes in psychotropic medications and VNS stimulus parameters were allowed only after the first 3 months. Response was defined as > or = 50% reduction from the baseline 28-item Hamilton Rating Scale for Depression (HAM-D-28) total score, and remission was defined as a HAM-D-28 score < or = 10. Results: Based on last observation carried forward analyses, HAM-D-28 response rates were 31% (18/59) after 3 months, 44% (26/59) after 1 year, and 42% (25/59) after 2 years of adjunctive VNS. Remission rates were 15% (9/59) at 3 months, 27% (16/59) at 1 year, and 22% (13/59) at 2 years. By 2 years, 2 deaths (unrelated to VNS) had occurred, 4 participants had withdrawn from the study, and 81% (48/59) were still receiving VNS. Longer-term VNS was generally well tolerated. Conclusion: These results suggest that patients with chronic or recurrent, treatment-resistant depression may show long-term benefit when treated with VNS.

Despite the availability of numerous treatment options, many patients continue to suffer with chronic or recurrent major depression due to treatment non-response or intolerance. Several novel interventions for the treatment of mood disorders are under study, including vagus nerve stimulation (VNS). VNS involves intermittent electrical stimulation of the vagus nerve via the NeuroCybernetic Prosthesis system. This intervention has demonstrated acute and long-term safety and efficacy in the treatment of refractory epilepsy, and several lines of evidence suggest a role for VNS in the treatment of depression. Studies investigating the safety and efficacy of VNS in patients with treatment-resistant chronic or recurrent depression are currently underway, and results thus far are promising. This article provides an overview of VNS, including its current clinical uses, the rationale for studying VNS as a treatment for depression, current data regarding VNS in treatment-resistant depression, and suggestions for future directions of VNS in mood disorders.

Marangell LB, Martinez JM, Ketter TA, Bowden CL, Goldberg JF,Calabrese JR, Miyahara S, Miklowitz DJ, Sachs GS, Thase ME.Lamotrigine treatment of bipolar disorder: data from the first 500patients in STEP-BD.Bipolar Disord 2004: 6: 139–143. a Blackwell Munksgaard, 2004Objective: To describe the frequency and correlates of lamotriginetherapy among the first 500 patients enrolled into the SystematicTreatment Enhancement Program for Bipolar Disorder (STEP-BD)study.Method: Systematic recording of psychiatric history and medicationdata at intake into the STEP-BD project.Results: Of the participants with bipolar disorder type I or II(n ¼ 483), 77 (15.4%) were currently taking lamotrigine (mean dose:258.12 mg/day) and 52 (10.4%) reported prior lamotrigine use. Thegroups were comparable with regard to duration of illness and moodstate at study entry. Compared with participants who had never takenlamotrigine, those currently treated with lamotrigine were significantlymore likely to have a prior history of rapid cycling (62.5% vs. 43.1%;p < 0.01)andanantidepressant-inducedswitchto(hypo)mania(49.3%vs. 33.3%; p < 0.01). In contrast, only 16.9% of lamotrigine-treatedparticipantsweretakinganantidepressantatstudyintake,ascomparedwith 29.1% of participants with no history of lamotrigine therapy(p < 0.03).Conclusions: While noting the limitations of a cross-sectionalassessment, these data suggest that lamotrigine therapy was commonlyusedintheseacademiccentersforpatientswithbipolardisorderseveralyears before it was recommended in the American PsychiatricAssociationpracticeguidelines,particularlyinpatientswithahistoryofrapid cycling or antidepressant-induced mania.

Background: We report a clinical trial of olanzapine in the treatment of prominent apathy in the absence of depression in patients on long-term treatment with selective serotonin reuptake inhibitors (SSRIs) for nonpsychotic major depression. Method: Participants were 21 men and women who met DSM-IV criteria for major depressive disorder in full remission (Montgomery-Asberg Depression Rating Scale [MADRS] score ≤ 12) who had been taking an SSRI for at least 3 months. Data are presented (last observation carried forward) based on 20 enrolled participants who completed at least 1 follow-up visit. Participants had significant symptoms of apathy, defined as a Clinical Global Impressions-Severity of Illness scale (CGI-S) score ≥ 3, an Apathy Evaluation Scale (AES) score > 30, and a MADRS item 8 (inability to feel) score ≥ 2. Participants with a personal or family history of psychosis were excluded. Olanzapine was titrated in 2.5-mg increments at weekly intervals, until CGI-S score improved ≥ 2 points from baseline or ≥ 1 point with dose-limiting side effects, and participants continued in the protocol for 8 weeks at a stable dose following this improvement. Results: Improvement was clinically evident and demonstrable on all symptom assessments: AES (mean ± SD change in score = -21.3 ± 8.7; p

OBJECTIVE Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. METHOD Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. RESULTS Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). CONCLUSIONS Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. TRIALS REGISTRATIONS ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340.

Objective To conduct a pilot study on the safety and tolerability of a dosage strategy for divalproex sodium beginning with 30 mg/kg/day. It is hypothesized that loading at this level will reach therapeutic levels of valproate more quickly, which in turn will decrease the latency of the therapeutic effect. Method We conducted a retrospective chart review of all acutely manic patients admitted to our facility over a 12-month period. Those inpatients treated with initial divalproex sodium dosages of 30 mg/kg/day for 2 days, followed by 20 mg/kg/day thereafter, were then included in the study. The serum valproate levels and daily Brief Psychiatric Rating Scale (BPRS) scores were documented for each subject. Any adverse changes in daily vital signs, serum liver enzymes, and blood cell counts were noted as well. Nursing and physician notes were then reviewed for any observed or reported adverse effects. Results Twelve acutely manic inpatients were enrolled in the study. Three subjects did not complete the treatment and are not included in this analysis. The remaining nine subjects completed the treatment, had a mean decrease in BPRS scores of 33.3%, and were discharged at least in partial remission. Six subjects had serum valproate levels drawn within 48–72 h of the initial dose, with a mean valproate level of 93.5 mcg/ml. All nine subjects tolerated the treatment reasonably well, with one subject reporting sedation, one reporting sedation and constipation, and one reporting nausea, emesis, and urinary frequency. A transient, asymptomatic decrease in white blood cell count and a low granulocyte count were also noted in one subject. Conclusion A divalproex dosage strategy beginning with 30 mg/kg/day for 2 days, followed by 20 mg/kg/day thereafter, was reasonably well tolerated in this group of acutely manic patients, even with the concurrent use of other psychotropic medications. Blood levels of 56 to 124 mcg/ml were observed within 3 days after initating treatment. Depression and Anxiety 7:83–86, 1998. © 1998 Wiley-Liss, Inc.

In self-identified white patients with major depressive disorder (N=126) treated with open-label duloxetine (60-120 mg/d), a significant association of (P=0.020) of a composite risk score (based on SLC6A2 rs5569 [G1287A] AA, HTR1A rs6295 [C(-1019)G] GG, and COMT rs174697 AA/AG) with 17-item Hamilton Depression Rating Scale total score change from baseline to 12 weeks was observed.

Painful physical symptoms are common in patients with major depressive disorder (MDD) and may predict poorer treatment outcomes. Duloxetine has demonstrated efficacy in treating both MDD and certain other painful conditions. This randomized, double-blind clinical trial assessed the effects of duloxetine in patients with both MDD and MDD-associated physical pain.Participants were outpatient adults with current MDD (DSM-IV-TR criteria; Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory Short Form [BPI] average pain rating ≥3) and with at least one prior episode of MDD. Patients received placebo (N = 266) or duloxetine (N = 262) 60 mg once daily. This trial is registered at clinicaltrials.gov (NCT01000805).Coprimary outcomes were MADRS total score (change from baseline at 8 weeks) and BPI average pain rating (overall main effect over 8 weeks). The Sheehan Disability Scale (SDS) global functional impairment score (change from baseline at 8 weeks) was used to assess functioning. Remission was defined as MADRS total score ≤12 at the 8-week endpoint. Changes were analyzed using mixed-effects model repeated measures (MMRM).Compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, and SDS global functional impairment score (all p ≤ 0.05 for analyses described above). The remission rate was significantly greater with duloxetine compared with placebo (p = 0.001) and was greater for duloxetine-treated patients with ≥50% versus50% improvement in BPI average pain score (p ≤ 0.001). Treatment emergent adverse events that occurred in at least 5% of duloxetine-treated patients and at twice the rate of placebo included nausea, somnolence, constipation, decreased appetite, and hyperhidrosis. Rates of discontinuation due to adverse events were greater for duloxetine than placebo (8.0% vs 3.4%, respectively; p = 0.024). This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin.These results support the efficacy and tolerability of duloxetine in the treatment of depression and associated painful physical symptoms in patients with MDD and at least moderate MDD-associated pain.

Chronic and recurrent major depressive episodes are associated with significant morbidity and mortality, and available treatments often are ineffective or only partially effective. This issue is of particular concern in children and adolescents, because major affective disorders often begin early in life and follow a chronic, progressive course. Because the current treatment armamentarium for depressive episodes in this age group is limited, the investigation for safe and effective treatment interventions is warranted. Vagus nerve stimulation therapy has proven safety, tolerability, and efficacy in the treatment of epilepsy, and early findings suggest safety and efficacy in the treatments of adults with chronic and recurrent treatment-resistant mood disorders. This intervention also holds promise as a potential treatment in children and adolescents, although research is currently lacking.

Based on the putative relationship between depleted omega-3 fatty acids and postpartum depression, we initiated an open-label pilot study of omega-3 fatty acid supplementation with the aim of preventing postpartum depression. Euthymic pregnant females with a past history of depression in the postpartum period were started on 2960 mg of fish oil (1.4:1 eicosapentaenoic acid:docosahexaenoic acid) per day between the 34th to 36th week of pregnancy and assessed through 12 weeks postpartum. Four of seven participants had a depressive episode during the study period. No participants withdrew from the study due to adverse events. This preliminary, small, open-label pilot study failed to show promising results for the use of omega-3 fatty acid monotherapy beginning at 34 to 36 weeks gestation for the prevention of postpartum depression in patients with a prior postpartum depression history. Controlled studies are lacking.

OBJECTIVE: This study was an evaluation of the omega-3 fatty acid docosahexaenoic acid (DHA) for the treatment of major depression. METHOD: Thirty-six depressed patients were randomly assigned to receive DHA, 2 g/day, or placebo for 6 weeks. Response was defined a priori as a ≥50% reduction in the score on the Montgomery-Asberg Depression Rating Scale. Thirty-five participants were evaluable; 18 received DHA, and 17 received placebo. RESULTS: Response rates were 27.8% in the DHA group and 23.5% in the placebo group. The difference in response rates between groups did not reach statistical significance. CONCLUSIONS: This trial failed to show a significant effect of DHA monotherapy in subjects with major depression.

David G Perahia,1 Mark E Bangs,2 Qi Zhang,2 Yingkai Cheng,2 Jonna Ahl,2 Elijah P Frakes,2 Michael J Adams,2 James M Martinez2 1Neurosciences, Lilly Research Centre, Windlesham, Surrey, UK; 2Neurosciences, Eli Lilly and Company, Indianapolis, IN, USA Purpose: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Methods: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies. Differences between NSAID user and non-user subgroups from clinical trial data were analyzed by a logistic regression model that included therapy, NSAID use, and therapy-by-NSAID subgroup interaction. In addition, to determine if higher duloxetine doses are associated with an increased incidence of bleeding-related TEAEs, and whether the use of concomitant NSAIDs might influence the dose effect if one exists, placebo-controlled clinical trials with duloxetine fixed doses of 60 mg, 120 mg, and placebo were analyzed. Also, the incidence of bleeding-related TEAEs reported for duloxetine alone was compared with the incidence in patients treated with duloxetine and concomitant NSAIDs. Finally, the number of bleeding-related cases reported for duloxetine in the FAERS database was compared with the numbers reported for all other drugs. Results: Across duloxetine clinical trials, there was a significantly greater incidence of bleeding-related TEAEs in duloxetine- versus placebo-treated patients overall and also in those patients who did not take concomitant NSAIDS, but no significant difference was seen among those patients who did take concomitant NSAIDS. There was no significant difference in the incidence of bleeding-related TEAEs in the subset of patients treated with duloxetine 120 mg once daily versus those treated with 60 mg once daily regardless of concomitant NSAID use. The combination of duloxetine and NSAIDs was associated with a statistically significantly higher incidence of bleeding-related TEAEs compared with duloxetine alone. A similarly higher incidence of bleeding-related TEAEs was seen in patients treated with placebo and concomitant NSAIDs compared with placebo alone. Bleeding-related TEAEs reported in the FAERS database were disproportionally more frequent for duloxetine taken with NSAIDs compared with the full FAERS background, but there was no difference in the reporting of bleeding-related TEAEs when the cases reported for duloxetine taken with NSAIDs were compared against the cases reported for NSAIDs alone. Conclusion: Concomitant use of NSAIDs was associated with a higher incidence of bleeding-related TEAEs in clinical trials regardless of whether patients were taking duloxetine or placebo; bleeding-related TEAEs did not appear to increase along with duloxetine dose regardless of NSAID use. In spontaneously reported post-marketing data, the combination of duloxetine and NSAID use was not associated with an increased reporting of bleeding-related events when compared to NSAID use alone. Keywords: antidepressant, gastrointestinal bleeding, NSAID, aspirin