Interleukin-6 and total antioxidant capacity levels following N-acetylcysteine and a combination nutraceutical intervention in a randomised controlled trial for bipolar disorder.

OBJECTIVE: The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N-acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS). METHODS: This study involved secondary analysis of a placebo-controlled randomised trial (n = 163). Serum samples were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers. RESULTS: In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS χ2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, χ2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that individuals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment (p = 0.023). CONCLUSION: Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.

Cognitive and emotional impairments underpinning suicidal activity in patients with mood disorders: an fMRI study.

OBJECTIVE: Mood disorders are strongly associated with suicide, the prevention of which is predicated on timely detection of suicidal activity (ideation, behaviour). Building on our previous work, we sought to determine the nature of neural responses to an emotional-cognitive task in patients with varying degrees of suicidal activity. METHOD: Seventy-nine patients with mood disorders were assessed clinically and scanned using fMRI. Neural responses to an Emotional Face-Word Stroop task were compared with 66 healthy controls. We identified regions of interest from seven key networks and examined responses to incongruent stimuli (Happy face-'Sad' word; Sad face-'Happy' word). RESULTS: In comparison with healthy controls, patients had differential activity during both incongruent conditions. When examining for associations with suicidal activity within the patient group, those with higher scores had decreased default mode network activity for Happy face-'Sad' word manipulation, and increased basal ganglia network activity for Sad face-'Happy' word manipulation, after controlling for patient characteristics. CONCLUSION: The fMRI findings suggest that suicidal activity in patients with mood disorders may be underpinned by cognitive-emotional deficits. These findings have implications for future suicide research and for achieving a deeper understanding of suicidal activity that may ultimately inform clinical detection and management.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Cognitive effects of adjunctive N-acetyl cysteine in psychosis.

BACKGROUND: Cognitive deficits are predictors of functional outcome in patients with psychosis. While conventional antipsychotics are relatively effective on positive symptoms, their impact on negative and cognitive symptoms is limited. Recent studies have established a link between oxidative stress and neurocognitive deficits in psychosis. N-acetylcysteine (NAC), a glutathione precursor with glutamatergic properties, has shown efficacy on negative symptoms and functioning in patients with schizophrenia and bipolar disorder, respectively. However, there are few evidence-based approaches for managing cognitive impairment in psychosis. The present study aims to examine the cognitive effects of adjunctive NAC treatment in a pooled subgroup of participants with psychosis who completed neuropsychological assessment in two trials of both schizophrenia and bipolar disorder. METHOD: A sample of 58 participants were randomized in a double fashion to receive 2 g/day of NAC (n = 27) or placebo (n = 31) for 24 weeks. Attention, working memory and executive function domains were assessed. Differences between cognitive performance at baseline and end point were examined using Wilcoxon's test. The Mann-Whitney test was used to examine the differences between the NAC and placebo groups at the end point. RESULTS: Participants treated with NAC had significantly higher working memory performance at week 24 compared with placebo (U = 98.5, p = 0.027). CONCLUSIONS: NAC may have an impact on cognitive performance in psychosis, as a significant improvement in working memory was observed in the NAC-treated group compared with placebo; however, these preliminary data require replication. Glutamatergic compounds such as NAC may constitute a step towards the development of useful therapies for cognitive impairment in psychosis.

Chronobiology of mood disorders.

OBJECTIVE: As part of a series of papers examining chronobiology ['Getting depression clinical guidelines right: time for change?' Kuiper et al. Acta Psychiatr Scand 2013;128(Suppl. 444):24-30; and 'Manipulating melatonin in managing mood' Boyce & Hopwood. ActaPsychiatrScand 2013;128(Suppl. 444):16-23], in this article, we review and synthesise the extant literature pertaining to the chronobiology of depression and provide a preliminary model for understanding the neural systems involved. METHOD: A selective literature search was conducted using search engines such as MEDLINE/PubMed, combining terms associated with chronobiology and mood disorders. RESULTS: We propose that understanding of sleep-wake function and mood can be enhanced by simultaneously considering the circadian system, the sleep homoeostat and the core stress system, all of which are likely to be simultaneously disrupted in major mood disorders. This integrative approach is likely to allow flexible modelling of a much broader range of mood disorder presentations and phenomenology. CONCLUSION: A preliminary multifaceted model is presented, which will require further development and testing. Future depression research should aim to examine multiple systems concurrently in order to derive a more sophisticated understanding of the underlying neurobiology.

Getting depression clinical practice guidelines right: time for change?

OBJECTIVE: As part of a series of papers ['Chronobiology of mood disorders' Malhi & Kuiper. Acta Psychiatr Scand 2013;128(Suppl. 444):2-15; and 'It's time we managed depression: The emerging role of chronobiology' Malhi et al. Acta Psychiatr Scand 2013;128(Suppl. 444):1] examining chronobiology in the context of depression, this article examines recent western clinical practice guidelines (CPGs) for the treatment of depression with respect to the recommendations they make, in particular as regards chronobiological treatments, and briefly considers the implications of their methodology and approach. METHOD: Five international treatment guidelines, which had been published in the past 5 years, were identified, representing North American and European views. Chosen guidelines were reviewed by the authors, and the relevant recommendations were distributed for discussion and subsequent synthesis. RESULTS: Most current guidelines do not address chronobiology in detail. Chronotherapeutic recommendations are tentative, although agomelatine is considered as an option for major depression and bright light therapy for seasonal affective disorder. Sleep deprivation is not routinely recommended. CONCLUSION: Recommendations are limited by the lack of reliable therapeutic markers for chronotherapeutics. Current evidence supports use of light therapy in seasonal depression, but in non-seasonal depression there is insufficient evidence to support reliance on chronotherapeutics over existing treatment modalities.

Pharmacological management of unipolar depression.

OBJECTIVE: To be used in conjunction with 'Psychological management of unipolar depression' [Lampe et al. Acta Psychiatr Scand 2013;127(Suppl. 443):24-37] and 'Lifestyle management of unipolar depression' [Berk et al. Acta Psychiatr Scand 2013;127(Suppl. 443):38-54]. To provide clinically relevant recommendations for the use of pharmacological treatments in depression derived from a literature review. METHOD: Using our previous Clinical Practice Guidelines [Malhi et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 2009;119(Suppl. 439):27-46] as a foundation, these clinician guidelines target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated alongside clinical experience. RESULTS: The pharmacotherapy of depression is an iterative process that often results in partial and non-response. Beyond the initiation of antidepressants, the options within widely used strategies, such as combining agents and switching between agents, are difficult to prescribe because of the paucity of pertinent research. However, there is some evidence for second-line strategies, and a non-prescriptive algorithm can be derived that is based broadly on principles rather than specific steps. CONCLUSION: Depression is by its very nature a heterogeneous illness that is consequently difficult to treat. Invariably, situation-specific factors often play a significant role and must be considered, especially in the case of partial and non-response. Consulting with colleagues and trialling alternate treatment paradigms are essential strategies in the management of depression.

The identification, assessment and management of difficult-to-treat depression: An international consensus statement.

BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.

Clinical practice recommendations for depression.

OBJECTIVE: To provide clinically relevant evidence-based recommendations for the management of depression in adults that are informative, easy to assimilate and facilitate clinical decision making. METHOD: A comprehensive literature review of over 500 articles was undertaken using electronic database search engines (e.g. MEDLINE, PsychINFO and Cochrane reviews). In addition articles, book chapters and other literature known to the authors were reviewed. The findings were then formulated into a set of recommendations that were developed by a multidisciplinary team of clinicians who routinely deal with mood disorders. The recommendations then underwent consultative review by a broader advisory panel that included experts in the field, clinical staff and patient representatives. RESULTS: The clinical practice recommendations for depression (Depression CPR) summarize evidence-based treatments and provide a synopsis of recommendations relating to each phase of the illness. They are designed for clinical use and have therefore been presented succinctly in an innovative and engaging manner that is clear and informative. CONCLUSION: These up-to-date recommendations provide an evidence-based framework that incorporates clinical wisdom and consideration of individual factors in the management of depression. Further, the novel style and practical approach should promote uptake and implementation.

Clinical practice recommendations for bipolar disorder.

OBJECTIVE: To provide clinically relevant evidence-based recommendations for the management of bipolar disorder in adults that are informative, easy to assimilate and facilitate clinical decision-making. METHOD: A comprehensive literature review of over 500 articles was undertaken using electronic database search engines (e.g. MEDLINE, PsychINFO and Cochrane reviews). In addition articles, book chapters and other literature known to the authors were reviewed. The findings were then formulated into a set of recommendations that were developed by a multidisciplinary team of clinicians who routinely deal with mood disorders. These preliminary recommendations underwent extensive consultative review by a broader advisory panel that included experts in the field, clinical staff and patient representatives. RESULTS: The clinical practice recommendations for bipolar disorder (bipolar CPR) summarise evidence-based treatments and provide a synopsis of recommendations relating to each phase of the illness. They are designed for clinical use and have therefore been presented succinctly in an innovative and engaging manner that is clear and informative. CONCLUSION: These up-to-date recommendations provide an evidence-based framework that incorporates clinical wisdom and consideration of individual factors in the management of bipolar disorder. Further, the novel style and practical approach should promote their uptake and implementation.

Pain during depression and relationship to rejection sensitivity.

OBJECTIVE: Approximately 50% of patients with depression report symptoms of pain, yet the clinical and biological mechanisms underlying this association remain unclear. Recent neuroimaging studies, however, support the contention that depression, as well as pain distress and rejection distress, share the same neurobiological circuits. In this study, we aimed to examine the hypothesis that perception of increased pain during depression is related to increased rejection sensitivity. METHOD: The present study analysed data from a study of 186 treatment-resistant depressed patients who met DSM-IV criteria for depression and had completed a self-report questionnaire regarding currently perceived pain and rejection sensitivity. RESULTS: A major increase in the experience of pain during depression was predicted by a major increase in rejection sensitivity during depression. CONCLUSION: The experience of increased pain during depression is related to increased rejection sensitivity. Research to further elucidate this relationship is required.