A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder.

NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference -1.8, p = 0.22, 80 mg pooled mean difference -1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference -8.2; Cohen's d for Stages 1 and 2 = -0.11 and -0.64, p = 0.04), and CPFQ scores (pooled mean difference -1.9; Cohen's d for Stages 1 and 2 = -0.28 and -0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (-2.5; Cohen's d Stages 1 and 2 = -0.03 and -0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.

Experimental medication treatment approaches for depression.

Depression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression-including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors-about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression. After a brief review of the efficacy of approved antidepressant therapies, we will discuss experimental medication treatments for depression. Specifically, we examine novel medications that are thought to primarily modulate the glutamatergic, cholinergic and opioid systems to achieve antidepressant efficacy. We also give examples of anti-inflammatories, neurokinin-1 modulators, vasopressin antagonists and neurogenesis enhancers that may have a therapeutic role in treatment-resistant depression. The current pipeline of antidepressant treatments is shifting towards medications with novel mechanisms, which may lead to important, life-changing discoveries for patients with severe disease.

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.

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder.

Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments--especially for treatment-resistant depression (TRD)--are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

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.

Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study.

Despite decades of intensive research, the development of a diagnostic test for major depressive disorder (MDD) had proven to be a formidable and elusive task, with all individual marker-based approaches yielding insufficient sensitivity and specificity for clinical use. In the present work, we examined the diagnostic performance of a multi-assay, serum-based test in two independent samples of patients with MDD. Serum levels of nine biomarkers (alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, cortisol, epidermal growth factor, myeloperoxidase, prolactin, resistin and soluble tumor necrosis factor alpha receptor type II) in peripheral blood were measured in two samples of MDD patients, and one of the non-depressed control subjects. Biomarkers measured were agreed upon a priori, and were selected on the basis of previous exploratory analyses in separate patient/control samples. Individual assay values were combined mathematically to yield an MDDScore. A 'positive' test, (consistent with the presence of MDD) was defined as an MDDScore of 50 or greater. For the Pilot Study, 36 MDD patients were recruited along with 43 non-depressed subjects. In this sample, the test demonstrated a sensitivity and specificity of 91.7% and 81.3%, respectively, in differentiating between the two groups. The Replication Study involved 34 MDD subjects, and yielded nearly identical sensitivity and specificity (91.1% and 81%, respectively). The results of the present study suggest that this test can differentiate MDD subjects from non-depressed controls with adequate sensitivity and specificity. Further research is needed to confirm the performance of the test across various age and ethnic groups, and in different clinical settings.

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.

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.

Efficacy of the sequential integration of psychotherapy and pharmacotherapy in major depressive disorder: a preliminary meta-analysis.

BACKGROUND: Prevention of relapse and recurrence represents an important task in the successful treatment of major depressive disorder (MDD). The aim of this meta-analysis was to examine the efficacy of the sequential integration of psychotherapy and pharmacotherapy in reducing the risk of relapse and recurrence in MDD. METHOD: Keyword searches were conducted in Medline, EMBASE, PsycINFO and the Cochrane Library from inception of each database to December 2008. Randomized controlled trials examining the efficacy of the administration of psychotherapy after successful response to acute-phase pharmacotherapy in the treatment of adults with MDD were considered for inclusion in the meta-analysis. RESULTS: Eight high-quality studies with 442 patients in a sequential treatment arm and 433 in a control treatment arm were included. The pooled risk ratio (RR) for relapse/recurrence was 0.797 [95% confidence interval (CI) 0.659-0.964] according to the random-effects model, suggesting a relative advantage in preventing relapse/recurrence for the sequential administration of treatments compared with control conditions. Performing subgroup analyses, we found a trend favoring psychotherapy during continuation of antidepressant drugs compared to antidepressants or treatment as usual (RR 0.842, 95% CI 0.674-1.051). Patients randomized to psychotherapy while antidepressants were discontinued were significantly less likely to experience relapse/recurrence compared to controls (RR 0.650, 95% CI 0.463-0.912). CONCLUSIONS: We found evidence that the sequential integration of psychotherapy and pharmacotherapy is a viable strategy for preventing relapse and recurrence in MDD. In addition, our findings suggest that discontinuation of antidepressant drugs may be feasible when psychotherapy is provided.

A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder.

Over the past few years, a number of studies have suggested that the treatment of major depressive disorder (MDD) with anti-depressants enhancing both noradrenergic as well as serotonergic neurotransmission may result in higher response or remission rates than treatment with anti-depressants selectively enhancing serotonergic neurotransmission. The objective of this paper was to compare response rates among patients with MDD treated with either mirtazapine, an anti-depressant thought to simultaneously enhance both noradrenergic and serotonergic neurotransmission, or selective serotonin reuptake inhibitors (SSRIs). Medline/Pubmed were searched. No year of publication limits were used. Double-blind, randomized clinical trials comparing mirtazapine with an SSRI for the treatment of MDD. Data were extracted with the use of a pre-coded form. Analyses were performed comparing response rates between the two anti-depressant agents. Data from 10 reports involving a total of 1904 outpatients with MDD were identified and combined using a random-effects model. Patients randomized to treatment with mirtazapine were as likely to experience clinical response as patients randomized to treatment with an SSRI (RR = 1.07; 95% CI: 0.96-1.2, P = 0.181). Simply pooling response rates between the two agents revealed a 67.1% response rate for mirtazapine and a 62.1% response rate for the SSRIs. There was no difference in overall discontinuation rates (RR = 1.1; 95% CI: 0.7-1.5; P = 0.550), discontinuation rates due to adverse events (RR = 0.9; 95% CI: 0.6-1.2; P = 0.497), or discontinuation rates due to lack of efficacy (RR = 0.9; 95% CI: 0.4-2.0; P = 0.871) between the two groups. Fewer mirtazapine-treated patients complained of insomnia (RR = 0.5; 95% CI: 0.3-0.9; P = 0.017), nausea (RR = 0.3; 95% CI: 0.3-0.5; P < 0.0001), whereas fewer SSRI-treated patients complained of fatigue (RR = 1.5; 95% CI: 1.1-2.4; P = 0.028), excessive sleepiness (RR = 1.3; 95% CI: 1.1-1.7; P = 0.020), weight-gain (RR = 3.8; 95% CI: 2.3-6.4; P < 0.0001) or dry mouth (RR = 1.8; 95% CI: 1.3-2.4; P < 0.0001) during the course of treatment. These results suggest that mirtazapine and the SSRIs differ with respect to their side-effect profile but not their overall efficacy in the treatment of MDD.

A detailed examination of cytokine abnormalities in Major Depressive Disorder.

Recent technological advances offer an opportunity to further elucidate the complex cytokine network in Major Depressive Disorder (MDD). Twenty cytokines were simultaneously assessed in 49 individuals with MDD and 49 age and gender matched controls. Multiple pro-inflammatory and two anti-inflammatory cytokines were significantly elevated in the MDD sample, including an antidepressant naïve subset. These data support a generalized chronic inflammatory state in MDD, and implicate additional cytokines and chemokines previously linked to cardiovascular disease.

Continuation cognitive-behavioural therapy maintains attributional style improvement in depressed patients responding acutely to fluoxetine.

BACKGROUND: Little is known about how continuation and maintenance cognitive-behavioural therapy (CBT) influences important psychological constructs that may be associated with long-term outcome of major depressive disorder. The goal of this study was to examine whether CBT would help maintain attributional style changes experienced by patients during acute phase fluoxetine treatment. METHOD: Three hundred and ninety-one patients with major depressive disorder were enrolled in an open, fixed-dose 8 week fluoxetine trial. Remitters to this acute phase treatment (N= 132) were randomized to receive either fixed-dose fluoxetine (meds only) or fixed-dose fluoxetine plus cognitive-behavioural therapy (CBT+meds) during a 6-month continuation treatment phase. The Attributional Style Questionnaire (ASQ) was completed by patients at three time points - acute phase baseline, continuation phase baseline and continuation phase endpoint. Analysis of covariance was used to compare continuation phase ASQ composite score changes between groups. RESULTS: Patients in both treatment groups experienced significant gains in positive attributional style during the acute phase of treatment. Continuation phase ASQ composite change scores differed significantly between treatment groups, with the CBT + meds group maintaining acute phase positive attributional style changes, and the meds only group exhibiting a worsening of attributional style. The two treatment groups did not significantly differ in rates of relapse and final continuation phase visit HAMD-17 scores. CONCLUSIONS: In this sample, the addition of CBT to continuation psychopharmacological treatment was associated with maintenance of acute treatment phase attributional style gains. Further research is needed to evaluate the role of such gains in the long-term course of depressive illness.

A survey of prescribing preferences in the treatment of refractory depression: recent trends.

The objective of this study was to gather data from a large group of clinicians on antidepressant prescribing practices in the treatment of refractory depression. Eight hundred and thirty-five clinicians about to attend the annual Massachusetts General Hospital psychopharmacology review course were asked to respond to a brief questionnaire regarding a hypothetical clinical case vignette. The case was of a patient who suffered from a new onset, unipolar, nonpsychotic, severe major depressive episode. Three hundred and four (36%) clinicians agreed to participate and filled out our questionnaire. Of the respondents, 260 (85.5%) indicated their preference for an initial treatment that combined medication and psychotherapy, as opposed to either modality alone. Furthermore, given this patient's nonresponse to two adequate selective serotonin reuptake inhibitor (SSRI) trials and one atypical antidepressant trial over an 8-month period, 39.8% of respondents indicated venlafaxine monotherapy as their next choice, whereas combining antidepressants (20.1%) and augmentation (18.4%) were the second and third most preferred treatment choices at this time point. Further on in the course of treatment, with the patient not having responded to any interventions during a 16-month period, 80.9% of survey respondents indicated electroconvulsant therapy (ECT) as their next preference. Among 304 clinicians surveyed, a combination of therapy and medication is the most preferred choice for treating severely depressed outpatients with new onset depression. Switching to venlafaxine, using two antidepressants together, and augmentation of an antidepressant regimen with a second agent accounted for 78.3% of respondents' preferences when faced with treating a depressed patient who had not responded to two adequate SSRI trials and one adequate atypical antidepressant trial. Of the respondents, 80.9% indicated ECT as a treatment preference after 16 months of multiple failed medication trials and nonresponse to psychotherapy. Further research is necessary to elucidate the factors that influence clinicians' reasoning for selecting one strategy over another.