Brian P. Brennan

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100–200 mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm3 voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d=3.4; p<0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohens d=1.2; p=0.023). NAA levels increased significantly from baseline to week 6 (d=1.2; p=0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d=1.4; p=0.053), but was negatively associated in the POC (d=9.6; p<0.001). Riluzole seems to rapidly increase Gln/Glu ratios—suggesting increased glutamate–glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted.

A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder.

Functional neuroimaging studies have converged to suggest that cortico-striatal-thalamo-cortical (CSTC) circuit dysfunction is a core pathophysiologic feature of obsessive-compulsive disorder (OCD). Now, complementary approaches examining regional neurochemistry are beginning to yield additional insights with regard to the neurobiology of aberrant CSTC circuitry in OCD. In particular, proton magnetic resonance spectroscopy, which allows for the in vivo quantification of various neurochemicals in the CSTC circuit and other brain regions, has recently been used extensively in studies of OCD patients. In this review, we summarize the diverse and often seemingly inconsistent findings of these studies, consider methodological factors that might help to explain these inconsistencies, and discuss several convergent findings that tentatively seem to be emerging. We conclude with suggestions for possible future proton magnetic resonance spectroscopy studies in OCD.

Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment.

Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant augmentation strategy for depressed men. We sought to assess the antidepressant effects of testosterone augmentation of a serotonergic antidepressant in depressed, hypogonadal men. For this study, we recruited 100 medically healthy adult men with major depressive disorder showing partial response or no response to an adequate serotonergic antidepressant trial during the current episode and a screening total testosterone level of 350 ng/dL or lower. We randomized these men to receive testosterone gel or placebo gel in addition to their existing antidepressant regimen. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression Scale, and the Quality of Life Scale. Our primary analysis, using a mixed effects linear regression model to compare rate of change of scores between groups on the outcome measures, failed to show a significant difference between groups (mean [95% confidence interval] 6-week change in HDRS for testosterone vs placebo, −0.4 [−2.6 to 1.8]). However, in one exploratory analysis of treatment responders, we found a possible trend in favor of testosterone on the HDRS. Our findings, combined with the conflicting data from earlier smaller studies, suggest that testosterone is not generally effective for depressed men. The possibility remains that testosterone might benefit a particular subgroup of depressed men, but if so, the characteristics of this subgroup would still need to be established.

Human Growth Hormone Abuse in Male Weightlifters

In a study of performance-enhancing substance use among 231 experienced young male weightlifters, we found that 27 (12%) reported illicit use of human growth hormone (HGH) or its bioactive derivative, insulin-like growth factor-1. All of these 27 men also reported use of anabolic-androgenic steroids (AAS) and 22 (81%) met criteria for current or past AAS dependence. Fifteen (56%) also reported current or past dependence on opioids, cocaine, and/or ecstasy. These findings suggest that among young male weightlifters, illicit HGH use has become a common form of substance abuse, frequently associated with both AAS dependence and classical substance dependence. 

Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study†

To assess the efficacy of duloxetine for irritable bowel syndrome (IBS).

Testosterone Gel Replacement Improves Sexual Function in Depressed Men Taking Serotonergic Antidepressants: A Randomized, Placebo-Controlled Clinical Trial

Testosterone replacement is the most effective treatment for sexual dysfunction in hypogonadal men. Comorbid depression and antidepressant side effects may reduce its influence. The authors conducted a 6-week, double-blind, placebo-controlled clinical trial of testosterone gel versus placebo gel in men with major depressive disorder who were currently taking a serotonergic antidepressant and exhibited low or low-normal testosterone level. A total of 100 men were enrolled at 2 study sites (Boston, Massachusetts, USA, and Tel Aviv, Israel). The effects of testosterone augmentation on sexual functioning were determined using domain scores on the International Index of Erectile Function (IIEF). Complete pre- and posttrial IIEF data were available for 63 subjects. Men randomized to testosterone (n = 31) and placebo (n = 32) were similar in age, baseline testosterone levels, and baseline IIEF scores. At study termination, men randomized to placebo showed virtually no change from baseline in mean (95% CI) IIEF score (−0.7 [−6.5, 5.2]), whereas those receiving testosterone exhibited a substantial increase (15.8 [8.5, 23.1]). The estimated mean difference between groups was 16.8 [7.5, 26.1]; p = .001 by linear regression with adjustment for age and study site. There were also significant between-group differences in each of the 5 IIEF subscales, as well as on the single question involving ejaculatory ability (p ≤ .03 in all cases). Effect sizes in these comparisons remained little changed, and generally remained statistically significant, when we further adjusted for change in depression scores on the Montgomery Asberg Depression Rating Scale. It is notable that the subgroup of men with the highest baseline testosterone levels showed virtually the same improvement as those with lower levels, suggesting that the observed improvement was unlikely to be due simply to correction of hypogonadism alone. In depressed men with low or low-normal testosterone levels who continued to take serotonergic antidepressants, treatment with exogenous testosterone was associated with a significant improvement in sexual function, particularly including ejaculatory ability.

Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development.

Objectives: Bipolar patients frequently relapse within 12 months of their previous mood episode, even in the context of adequate treatment, suggesting that better continuation and maintenance treatments are needed. Based on recent research of the pathophysiology of bipolar disorder, we review the evidence for mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential treatments. Methods: We reviewed the literature about mitochondrial dysfunction and potential MMs worthy of study that could improve the course of bipolar disorder, reduce subsyndromal symptoms, and prevent subsequent mood episodes. Results: MM treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy metabolism and the dysregulation of multiple mitochondrial genes in patients with bipolar disorder. Several tolerable and readily available candidates include N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin. The specific metabolic pathways by which these MMs may improve the symptoms of bipolar disorder are discussed and combinations of selected MMs could be of interest as well. Conclusions: Convergent data implicate mitochondrial dysfunction as an important component of the pathophysiology of bipolar disorder. Clinical trials of individual MMs as well as combinations are warranted.

Memantine in the treatment of binge eating disorder: An open-label, prospective trial†

OBJECTIVE To assess preliminarily the efficacy of memantine in binge eating disorder. METHOD This was an open-label, 12-week, flexible-dose (5-20 mg/day) trial of memantine in binge eating disorder. The primary outcome was frequency of binge days. Secondary outcomes included frequency of binge episodes, body-mass index (BMI), weight, Clinical Global Impressions Severity (CGI-S), Three Factor Eating Questionnaire (TFEQ), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and Sheehan Disability Scale (SDS). Longitudinal random regression analysis was performed for frequency of binge days and episodes, BMI, weight, and CGI-S; analysis of baseline to endpoint change was performed for all outcomes. RESULTS Sixteen individuals received memantine; 15 completed at least one postbaseline evaluation, 9 completed the study. Mean dose at endpoint was 18.3 mg/day. Memantine was associated with significant reductions in frequency of binge days and episodes, severity of illness (p < .001 for both analyses), disinhibition on the TFEQ (p = .015), and disability on the SDS (p < .05 for three subscales). There was no significant change in BMI, weight, MADRS, HAM-A, and TFEQ cognitive restraint and hunger. CONCLUSION In this open-label trial, memantine was well tolerated and effective in reducing binge eating, severity of illness, and disability, but had little effect on BMI and weight.

An Examination of Rostral Anterior Cingulate Cortex Function and Neurochemistry in Obsessive–Compulsive Disorder

The anterior cingulate cortex is implicated in the neurobiology of obsessive–compulsive disorder (OCD). However, few studies have examined functional and neurochemical abnormalities specifically in the rostral subdivision of the ACC (rACC) in OCD patients. We used functional magnetic resonance imaging (fMRI) during an emotional counting Stroop task and single-voxel J-resolved proton magnetic resonance spectroscopy (1H-MRS) in the rACC to examine the function and neurochemistry of the rACC in individuals with OCD and comparison individuals without OCD. Between-group differences in rACC activation and glutamine/glutamate ratio (Gln/Glu), Glu, and Gln levels, as well as associations between rACC activation, Gln/Glu, Glu, Gln, behavioral, and clinical measures were examined using linear regression. In a sample of 30 participants with OCD and 29 age- and sex-matched participants without OCD, participants with OCD displayed significantly reduced rACC deactivation compared with those without OCD in response to OCD-specific words versus neutral words on the emotional counting Stroop task. However, Gln/Glu, Glu, and Gln in the rACC did not differ between groups nor was there an association between reduced rACC deactivation and Gln/Glu, Glu, or Gln in the OCD group. Taken together, these findings strengthen the evidence for rACC dysfunction in OCD, but weigh against an underlying association with abnormal rACC glutamatergic neurotransmission.

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

BACKGROUND Anabolic-androgenic steroid (AAS) use is associated with psychiatric symptoms including increased aggression as well as with cognitive dysfunction. The brain effects of long-term AAS use have not been assessed in humans. METHODS This multimodal magnetic resonance imaging study of the brain compared 10 male weightlifters reporting long-term AAS use with 10 age-matched weightlifters reporting no AAS exposure. Participants were administered visuospatial memory tests and underwent neuroimaging. Brain volumetric analyses were performed; resting-state fMRI functional connectivity (rsFC) was evaluated using a region-of-interest analysis focused on the amygdala; and dorsal anterior cingulate cortex (dACC) metabolites were quantified by proton magnetic resonance spectroscopy (MRS). RESULTS AAS users had larger right amygdala volumes than nonusers (P=0.002) and reduced rsFC between right amygdala and frontal, striatal, limbic, hippocampal, and visual cortical areas. Left amygdala volumes were slightly larger in AAS users (P=0.061) but few group differences were detected in left amygdala rsFC. AAS users also had lower dACC scyllo-inositol levels (P=0.004) and higher glutamine/glutamate ratios (P=0.028), possibly reflecting increased glutamate turnover. On a visuospatial cognitive task, AAS users performed more poorly than nonusers, with the difference approaching significance (P=0.053). CONCLUSIONS Long-term AAS use is associated with right amygdala enlargement and reduced right amygdala rsFC with brain areas involved in cognitive control and spatial memory, which could contribute to the psychiatric effects and cognitive dysfunction associated with AAS use. The MRS abnormalities we detected could reflect enhanced glutamate turnover and increased vulnerability to neurotoxic or neurodegenerative processes, which could contribute to AAS-associated cognitive dysfunction.