Alisabet Clain

l-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder.

OBJECTIVE To examine the comparative antidepressant efficacy of S-adenosyl-L-methionine (SAMe) and escitalopram in a placebo-controlled, randomized, double-blind clinical trial. METHOD One hundred eighty-nine outpatients (49.7% female, mean [SD] age = 45 [15] years) with DSM-IV-diagnosed major depressive disorder (MDD) were recruited from April 13, 2005, to December 22, 2009, at the Massachusetts General Hospital and at Butler Hospital. Patients were randomized for 12 weeks to SAMe 1,600-3,200 mg/d, escitalopram 10-20 mg/d, or placebo. Doses were escalated at 6 weeks in the event of nonresponse. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17). Tolerability was assessed by the Systematic Assessment for Treatment of Emergent Events-Specific Inquiry (SAFTEE-SI). RESULTS All 3 treatment arms demonstrated a significant improvement of about 5-6 points in HDRS-17 scores (P < .001 for all), and no significant differences were observed between the treatment arms (P > .05 for all). Response rates in the intent-to-treat sample were 36% for SAMe, 34% for escitalopram, and 30% for placebo. Remission rates were 28% for SAMe, 28% for escitalopram, and 17% for placebo. No comparisons between treatment groups attained significance (P > .05 for all). Tolerability was good, with gastrointestinal side effects (19% for stomach discomfort and 20% for diarrhea) as the most common in the SAMe arm. Significant differences were observed between treatment groups for dizziness, anorgasmia, diminished mental acuity, and hot flashes (P < .05 for all). CONCLUSIONS The results fail to support an advantage over placebo for either the investigational treatment SAMe or the standard treatment escitalopram for MDD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00101452.

Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group.

OBJECTIVE To reanalyze data from a 2002 study by the Hypericum Depression Trial Study Group to determine whether patients who believed they were receiving active therapy rather than placebo obtained greater improvement, independent of treatment. METHOD Three hundred forty adults with major depressive disorder (according to the Structured Clinical Interview for DSM-IV) and baseline scores of ≥ 20 on the 17-item Hamilton Depression Rating Scale (HDRS-17) were randomized to Hypericum perforatum 900-1,500 mg/d, sertraline 50-100 mg/d, or placebo and were asked to guess their assigned treatment after 8 weeks. This reanalysis of data was performed from October 1, 2009, to April 15, 2011. The intent-to-treat sample included 207 subjects (mean age = 44 years) who had (1) at least 1 postbaseline visit; (2) adherence data based on serum levels of hyperforin, sertraline, and desmethylsertraline; and (3) guess data. Univariate factorial analysis of variance was used to determine whether treatment assignment affected clinical improvement according to HDRS-17 score and whether this effect was moderated by patient guess of sertraline, Hypericum, or placebo. Analysis of covariance was used to determine whether side effects mediated improvement in the context of patient guess and assigned treatment. χ₂ analyses compared response rates (≥ 50% decrease in HDRS-17 score) between the guess groups and between the treatment groups within each guess group. RESULTS Assigned treatment had no significant effect on clinical improvement (P = .65), but patient guess was significantly associated with improvement (P < .001), and treatment and guess interacted significantly (P = .005). Among subjects who guessed placebo, clinical improvement was small and did not differ significantly across treatments. Among subjects who guessed Hypericum, improvement was large and did not differ significantly across treatments. Among subjects who guessed sertraline, those who received placebo or sertraline had large improvements, but those who received Hypericum had significantly less improvement (P < .001). Similar findings were obtained for response rates. CONCLUSIONS Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received, and the strength of this association may depend upon the particular combination of treatment guessed and treatment received.

Differences in depressive symptoms between Korean and American outpatients with major depressive disorder.

Previous epidemiologic studies have revealed that East-Asian populations experience fewer depressive symptoms than American populations do. However, it is unclear whether this difference applies to clinical patients with major depressive disorder (MDD). This present study included 1592 Korean and 3744 American outpatients who were 18 years of age or older and met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for single or recurrent episodes of nonpsychotic MDD, and evaluated their symptoms of depression using the Hamilton Depression Rating Scale and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form. Korean patients scored significantly lower for guilt and depressed mood items, and higher for hypochondriasis and suicidality items than American patients did, after adjusting for total Hamilton Depression Rating Scale scores. Conversely, no significant differences were found in quality and function of daily life between groups. Multivariate logistic regression analyses revealed that Korean patients experienced less frequent depressed mood and guilt, including verbal and nonverbal expression of depressed mood [adjusted odds ratio (AOR)=0.14, 95% confidence interval (CI) 0.08–0.23] and feelings of punishment (AOR=0.036, 95% CI 0.025–0.054) when compared with Americans after adjusting for age and sex. Conversely, Korean patients experienced more frequent suicidality and hypochondriasis, including suicidal ideas or gestures (AOR=2.10, 95% CI 1.60–2.76) and self-absorption of hypochondriasis (AOR=1.94, 95% CI 1.70–2.20). In conclusion, decreased expression of depressed mood and guilt may cause underdiagnosis of MDD in Korean patients. Early diagnosis of and intervention for depression and suicide may be delayed because of this specific cross-cultural difference in depression symptoms.

Anxious depression and early changes in the HAMD-17 anxiety-somatization factor items and antidepressant treatment outcome

The objective of this study was to assess the relationship between early changes in anxiety/somatization symptoms and treatment outcome among major depressive disorder patients during a 12-week trial of fluoxetine. We also examined the relationship between anxious depression and treatment response. Five hundred and ten major depressive disorder patients received 12 weeks of fluoxetine with flexible dosing [target dosages: 10 mg/day (week 1), 20 mg/day (weeks 2–4), 40 mg/day (weeks 4–8), and 60 mg/day (weeks 5–12)]. We assessed the relationship between early changes in 17-item Hamilton Rating Scale for Depression (HAMD-17)-anxiety/somatization factor items and depressive remission, as well as whether anxious depression at baseline predicted remission at study endpoint. Baseline HAMD-17 scores were considered as covariates and the Bonferroni correction (P≤0.008) was used for multiple comparisons. Adjusting for baseline HAMD-17 scores, patients who experienced greater early improvement in somatic symptoms (gastrointestinal) were significantly more likely to attain remission (HAMD-17 <8) at endpoint than those without early improvement (P=0.006). Early changes in the remaining items did not predict remission, nor did anxious depression at baseline. In conclusion, among the anxiety/somatization factor items, only early changes in somatic symptoms (gastrointestinal) predicted remission. Future studies are warranted to further investigate this relationship as well as that between anxious depression and treatment outcome.

Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

OBJECTIVE To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. METHODS We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20-60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined. RESULTS Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response. CONCLUSION The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.

Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine.

BackgroundRelapse of major depressive disorder (MDD) is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia) predict risk of relapse during the continuation and maintenance treatment of MDD.MethodsA total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1) for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia) and 22, 23, 24 (hypersomnia) of the Hamilton Depression Rating Scale (HDRS). Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse.ResultsThe severities of early (P > 0.05), middle (P > 0.05), late (P > 0.05), or total (P > 0.05) residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05), oversleeping (P > 0.05), napping (P > 0.05), or total (P > 0.05) residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment.ConclusionThe present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD.Trial RegistrationClinicalTrials.gov Identifier: NCT00427128

A Randomized, Controlled, Pilot Study of Acamprosate Added to Escitalopram in Adults With Major Depressive Disorder and Alcohol Use Disorder

We sought to examine the efficacy and safety of acamprosate augmentation of escitalopram in patients with concurrent major depressive disorder (MDD) and alcohol use disorders. Twenty-three adults (43% female; mean ± SD age, 46 ± 14 years) were enrolled and received 12 weeks of treatment with psychosocial support; escitalopram, 10 to 30 mg/d; and either acamprosate, 2000 mg/d (n = 12), or identical placebo (n = 11). Outcomes included change in clinician ratings of depressive symptoms, MDD response and remission rates, changes in frequency and intensity of alcohol use, retention rates, and adverse events. Twelve subjects (acamprosate, n = 7; placebo, n = 5) completed the study. There was significant mean reduction in ratings of depressive symptoms from baseline in both treatment arms (P < 0.05), with no significant difference between the groups. Those in the acamprosate group had a 50% MDD response rate and a 42% remission rate, whereas those in the placebo arm had a 36% response and remission rate (not significant). Those assigned to acamprosate had significant reduction in number of drinks per week and drinks per month during the trial, whereas those assigned to placebo demonstrated no significant change in any alcohol use parameter, but the between-group difference was not significant. There were no significant associations between change in depressive symptoms and change in alcohol use. Attrition rates did not differ significantly between the 2 arms. Acamprosate added to escitalopram in adults with MDD and alcohol use disorders was associated with reduction in the frequency of alcohol use. The present study was not powered to detect superiority versus placebo. Further study in a larger sample is warranted.

Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study.

Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.

Race/Ethnicity and Other Social Determinants of Psychological Well-being and Functioning in Mental Health Clinics

Significant racial and ethnic differences exist in the receipt of psychiatric care and help-seeking. We examined the relationship between race/ethnicity and psychological well-being and functioning in psychiatric outpatients. We analyzed intake data for 8,697 adult patients in psychiatry clinics in New England between 2008 and 2010. Patients rated psychological wellbeing using the Schwartz Outcome Scale (SOS-10); clinicians rated the Global Assessment of Functioning (GAF). In an analysis of variance with covariates, race/ethnicity exhibited a small but statistically significant association with GAF (F(4,8481)=17.902, p<.001) and SOS-10 scores (F(4,8165)=7.271, p<.001). However, after adjustment for physical health and socioeconomic variables, these differences became insignificant or were reversed. Our findings suggest that the relationship between race/ethnicity and mental health may be confounded by other socioeconomic or health differences and may be small compared with the effect of those variables. Future studies on race and psychological well-being should take social determinants of health into consideration.