Reduced frontal-subcortical white matter connectivity in association with suicidal ideation in major depressive disorder.

Major depressive disorder (MDD) and suicidal behavior have been associated with structural and functional changes in the brain. However, little is known regarding alterations of brain networks in MDD patients with suicidal ideation. We investigated whether or not MDD patients with suicidal ideation have different topological organizations of white matter networks compared with MDD patients without suicidal ideation. Participants consisted of 24 patients with MDD and suicidal ideation, 25 age- and gender-matched MDD patients without suicidal ideation and 31 healthy subjects. A network-based statistics (NBS) and a graph theoretical analysis were performed to assess differences in the inter-regional connectivity. Diffusion tensor imaging (DTI) was performed to assess topological changes according to suicidal ideation in MDD patients. The Scale for Suicide Ideation (SSI) and the Korean version of the Barrett Impulsiveness Scale (BIS) were used to assess the severity of suicidal ideation and impulsivity, respectively. Reduced structural connectivity in a characterized subnetwork was found in patients with MDD and suicidal ideation by utilizing NBS analysis. The subnetwork included the regions of the frontosubcortical circuits and the regions involved in executive function in the left hemisphere (rostral middle frontal, pallidum, superior parietal, frontal pole, caudate, putamen and thalamus). The graph theoretical analysis demonstrated that network measures of the left rostral middle frontal had a significant positive correlation with severity of SSI (r=0.59, P=0.02) and BIS (r=0.59, P=0.01). The total edge strength that was significantly associated with suicidal ideation did not differ between MDD patients without suicidal ideation and healthy subjects. Our findings suggest that the reduced frontosubcortical circuit of structural connectivity, which includes regions associated with executive function and impulsivity, appears to have a role in the emergence of suicidal ideation in MDD patients.

A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine (SAMe) in a recent failed randomized clinical trial (RCT) for adults with major depressive disorder. METHODS: Data from a 2-site, 12-week, double-blind RCT (n=189) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor (escitalopram) were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response. RESULTS: When assessing the efficacy outcomes within each gender separately, SAMe was superior to placebo among males (n=51), but not among females (n=62). Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale (4.3 point difference; p=0.034; d=0.95), while females did not show significant change. This finding emerged despite equivalence on baseline measures of depression severity between the gender groups. CONCLUSION: RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe, with greater therapeutic effect found in males. The underlying mechanism is still relatively unknown. Further work is needed to replicate this observation in independent samples.Clinicaltrials.gov identifier: NCT00101452.

Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties.

BACKGROUND: Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. METHOD: In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). RESULTS: Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. CONCLUSIONS: These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.

Complementary medicine, exercise, meditation, diet, and lifestyle modification for anxiety disorders: a review of current evidence.

Use of complementary medicines and therapies (CAM) and modification of lifestyle factors such as physical activity, exercise, and diet are being increasingly considered as potential therapeutic options for anxiety disorders. The objective of this metareview was to examine evidence across a broad range of CAM and lifestyle interventions in the treatment of anxiety disorders. In early 2012 we conducted a literature search of PubMed, Scopus, CINAHL, Web of Science, PsycInfo, and the Cochrane Library, for key studies, systematic reviews, and metaanalyses in the area. Our paper found that in respect to treatment of generalized anxiety or specific disorders, CAM evidence revealed current support for the herbal medicine Kava. One isolated study shows benefit for naturopathic medicine, whereas acupuncture, yoga, and Tai chi have tentative supportive evidence, which is hampered by overall poor methodology. The breadth of evidence does not support homeopathy for treating anxiety. Strong support exists for lifestyle modifications including adoption of moderate exercise and mindfulness meditation, whereas dietary improvement, avoidance of caffeine, alcohol, and nicotine offer encouraging preliminary data. In conclusion, certain lifestyle modifications and some CAMs may provide a beneficial role in the treatment of anxiety disorders.

St John's wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: continuation data from a 26-week RCT.

Hypericum perforatum (St John's wort: SJW) has been extensively studied as an antidepressant in short-term trials, however little research has been conducted on longer-term efficacy.Our objective was to analyze the continuation data from a 26-week randomized, double-blind, controlled study of SJW (LI-160) vs. sertraline and placebo in major depressive disorder. 124 participant "responders" continued treatment after week 8, until week 26. They continued randomly assigned SJW (900-1 500 mg), sertraline (50-100 mg) or matching placebo.At week 26, on the primary outcome, Hamilton depression rating scale (HAM-D) completer scores were: SJW (6.6±4.5), sertraline (7.1±5.4) and placebo (5.7±5.4) with a significant effect for time (p=0.036). Comparisons between all treatments were however non-significant (p=0.61). This effect was mirrored on the other outcomes: the BDI, CGI-severity, CGI-improvement, and on intention-to-treat analyses.While the continuation data revealed an equivocal outcome between treatments at week 26, both SJW and sertraline were still therapeutically effective, with a pronounced "placebo-effect" impeding a significant result at week 26.

Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder.

UNLABELLED: Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosylmethionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD. OBJECTIVES: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. METHODS: Forty-six serotonin-reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment. RESULTS: There was a greater improvement in the ability to recall information (P=0.04) and a trend towards statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance. CONCLUSIONS: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication.

SAMe and sexual functioning.

BACKGROUND: Sexual dysfunction is a known side effect of antidepressant treatment (ADT), affecting up to 58-73% of those who receive ADT, potentially affecting antidepressant adherence. Consequently, it is vital to develop novel treatments that target antidepressant-induced sexual dysfunction. METHODS: We examined whether adjunctive S-adenosyl-l-methionine (SAMe) is associated with greater improvement in sexual functioning than adjunctive placebo by measuring changes in sexual functioning using the Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH-SFQ) during a 6-week, single-center, randomized, double-blind trial of SAMe augmentation for SSRI/SNRI- nonresponders. RESULTS: Controlling for the degree of arousal dysfunction at baseline as well as the degree of change in HDRS-17 scale scores during the course of the study, men treated with adjunctive SAMe demonstrated significantly lower arousal dysfunction at endpoint than those treated with adjunctive placebo. In addition, controlling for the degree of erectile dysfunction at baseline as well as the degree of change in HDRS-17 scale scores, men treated with adjunctive SAMe demonstrated significantly lower erectile dysfunction at endpoint than those treated with adjunctive placebo. CONCLUSIONS: In the present study, we have observed that adjunctive SAMe can have positive benefit on male arousal and erectile dysfunction, independent of improvement in depressive symptoms. These findings are preliminary, and warrant replication. CLINICAL TRIALS.GOV IDENTIFIER: NCT00093847; titled 'Optimizing the Effectiveness of Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment-Resistant Depression', accessible at: http://clinicaltrials.gov/ct2/show/NCT00093847.

The potential relationship between levels of perceived stress and subtypes of major depressive disorder (MDD).

OBJECTIVE: We wanted to explore whether major depressive disorder (MDD) subtypes (melancholic depression, atypical depression, double depression, and MDD with anger attacks) were related to levels of perceived stress, as measured by the Perceived Stress Scale (PSS). METHOD: Our sample [n = 298; female = 163 (55%); mean age 40.1 +/- 10.5 years] consisted of out-patients with MDD. The Structured Clinical Interview for DSM-III-R, the 17-item Hamilton Rating Scale for Depression, the Anger Attack Questionnaire, and the PSS were administered prior to initiating treatment. RESULTS: Depressed women had significantly higher levels of perceived stress (P = 0.02) than depressed men. Greater severity of depression at baseline was significantly related to higher levels of perceived stress (P < 0.0001). After adjusting for age, gender, and severity of depression at baseline, higher levels of perceived stress were significantly related to the presence of anger attacks (P < 0.0001; t = -4.103) as well as to atypical depression (P = 0.0013; t = 3.26). CONCLUSION: Out-patients with MDD who are more irritable and/or present with atypical features have higher levels of perceived stress, indicating a potential reactive component to their depression.

Clinical and sociodemographic predictors of response to augmentation, or dose increase among depressed outpatients resistant to fluoxetine 20 mg/day.

OBJECTIVE: Patients with major depressive disorder often show only partial or no response to antidepressants, necessitating next-step interventions such as dose increase or augmentation. Factors moderating response to these next-step interventions are not well-studied. METHOD: In this randomized, double-blind investigation of next-step treatments in 101 outpatients who failed to respond to fluoxetine 20 mg for 8 weeks, the impact of depressive course and sociodemographic factors on likelihood of treatment response following dose increase or lithium or desipramine augmentation was examined. RESULTS: After controlling for depression severity at baseline, current marriage and earlier onset of depression were associated with greater likelihood of response in a logistic regression. Intervention strategy was not predictive of response. CONCLUSION: Marital status and earlier onset of depression may be clinically useful in predicting outcome following any next-step intervention for treatment resistance, rather than with particular strategies.

Management of major depression in the primary care setting.

BACKGROUND: Patients treated in community clinics, particularly those of minority status, may rely more heavily on primary care physicians (PCPs) for the diagnosis and management of depression. We wished to determine how PCPs in a community clinic setting initially manage patients newly diagnosed with major depression. METHODS: 698 patients were screened for major depression by the Structural Clinical Interview for DSM-III-R in a community-based primary care health center. Forty outpatients (29 Hispanic) were found to suffer from major depression. A letter explaining positive findings was sent to the patients' PCPs. Medical record charts were reviewed 3 months later to determine the PCP's management following the diagnosis. RESULTS: Of the 38 patients who remained in the study at 3 months, 20 (53%) received no intervention from the PCP by the end of 3 months after diagnosis, and of these, 14 were Hispanic. Five (13%) were prescribed an antidepressant by the PCP. Nine (24%) were referred to mental health services for medication, psychotherapy or combination treatment. Four (11%) were prescribed an antidepressant and then referred to mental health services. Differences between management of Hispanic and non-Hispanic patients were not statistically significant. CONCLUSIONS: Independent screening by psychiatrists in primary care settings may not be adequate enough to ensure appropriate management of depression by PCPs. Possible explanations may include time constraints during primary care visits, patient and/or physician reticence, and insufficient education of PCPs about depression.

Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression.

BACKGROUND: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness.

Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: a survey of clinicians.

OBJECTIVE: To examine treatment practices in cases where selective serotonin reuptake inhibitors (SSRIs) are ineffective. METHODS: We surveyed 801 clinicians (including 630 psychiatrists) attending the Massachusetts General Hospital's annual psychopharmacology review course. Clinicians were presented with a vignette about a patient with depression who had responded partially to an SSRI and were asked to choose among various strategies available to manage this patient. RESULTS: Of those surveyed, 466 clinicians had been in practice a mean of 16.6 years (SD 10.7). Not all clinicians chose to answer every question. Among 455 respondents, 84% (n = 382) chose to increase the dose of the SSRI, 10% (n = 47) chose augmentation or combination, and 7% (n = 31) opted for switching agents. When asked to switch to another agent, 448 responded, of whom 52% (n = 235) chose a newer antidepressant, 34% (n = 152) chose another SSRI, 10% (n = 44) chose a tricyclic antidepressant (TCA), 2% (n = 8) chose a serotonin norepinephrine reuptake inhibitor (SNRI), 1% (n = 5) chose a monoamine oxidase inhibitor (MAOI), and 1% (n = 4) chose an undefined "other" agent. Among 445 respondents, bupropion was the most widely chosen augmenting agent (30%, n = 134), followed by lithium (22%, n = 98). West coast and Canadian clinicians preferred to switch to another SSRI rather than to a newer antidepressant. Canadian clinicians preferred lithium to bupropion as their first-choice augmenting agent, as did clinicians from academic settings. Clinicians from community, individual practice, or group settings favoured bupropion. More experienced clinicians preferred bupropion as a first-choice augmenter, whereas less experienced ones showed a slight preference for lithium. Canadian clinicians were more likely to use MAOIs as second-line agents. CONCLUSIONS: Clinicians in this sample often followed strategies different from those recommended in the literature. Bupropion may have an important role in augmentating treatment with SSRIs.