The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression. METHOD: Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011. RESULTS: The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F1,520.9 = 1.98, P = .067), and the groups did not separate at week 12 (t360.3 = -1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score ≥ 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t221.03 = -2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events. CONCLUSIONS: Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by NAC in depression pathogenesis, principally oxidative and inflammatory stress and glutamate, although definitive confirmation remains necessary. TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN12607000134426.

Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial.

BACKGROUND: N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder. METHOD: The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes. RESULTS: There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures. CONCLUSIONS: There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. TRIAL REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting.

N-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.

A functional MRI study of Theory of Mind in euthymic bipolar disorder patients.

OBJECTIVES: To determine the neural responses invoked in Theory of Mind (ToM) in euthymic bipolar patients as compared with healthy subjects. METHODS: This study examined 20 euthymic bipolar patients (11 males and 9 females) and 20 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in a ToM task. Within-scanner eye movements were monitored to ensure task engagement. The activation paradigm involved observing ToM and random-motion animated sequences in a block design. Both within group (ToM versus random motion) and random effects between group analyses were performed on fMRI data using the BrainVoyager software package. Demographic and clinical data, along with subject ratings of fMRI stimuli, were collated and analysed. RESULTS: Patients were compromised in their ability to appropriately rate the ToM stimuli and assess them for intention as compared to healthy subjects. This was reflected in the fact that patients had few within-group significant activations in response to ToM animated sequences, namely, the left anterior cingulate, and precuneus and cuneus bilaterally. In contrast, robust activations in response to ToM animated sequences in healthy subjects were widespread and involved regions recognized for mental state reasoning, in particular the insula, inferior frontal, supramarginal and angular gyri, and temporal cortex. The between-group random effects analysis exclusively favoured the healthy subjects, with many activations occurring in regions overlapping with those found in the within-group analyses. CONCLUSIONS: The findings of this novel neuroimaging study suggest that in a social context, euthymic bipolar patients, though seemingly well and capable of engaging aspects of ToM, are perhaps constrained in their ability to mentalize fully, and furthermore cannot reliably adopt an alternate cognitive perspective when appropriate. Impairment of this capacity, though subtle, may in effect compromise their ability to understand the emotions and intentions of others, and also may limit appreciation of their own illness and symptoms. Such a deficit in bipolar disorder perhaps impacts upon interpersonal relationships and adversely affects social cognition and clinical functioning. The potential implications of this putative mentalizing compromise in euthymic patients with bipolar disorder are substantial, both for the individual and for understanding the neural substrate of the illness, and therefore warrant further investigation.

Diagnosing bipolar disorder: how can we do it better?

Accurate diagnosis of bipolar disorder is essential for effective treatment. The diagnosis of bipolar disorder is particularly complex, resulting in lengthy delays between first presentation and initiation of appropriate therapy. Inappropriate therapy destabilises the course and outcome of the disease. Although the defining features of bipolar disorder are manic or hypomanic episodes, patients typically present for treatment of depression and commonly deny symptoms of mood elevation. A correct diagnosis can easily be masked by comorbidities, personality issues and complex phenomenology. A diagnosis of bipolar disorder can be assisted by: asking about symptoms of mania or hypomania in every patient presenting with symptoms of depression. recognising mixed states in which manic and depressive symptoms occur simultaneously. identifying the features of bipolar depression that distinguish it from unipolar depression. There is a risk of over-diagnosis of bipolar disorder among patients who are histrionic, show abnormal illness behaviour and/or have issues of secondary gain.