Hippocampal glutamatergic/NMDA receptor functioning in bipolar disorder: a combined MMN and 1H-MRS study

Disturbances in the hippocampal glutamate (Glu)/N-methyl-d-aspartate (NMDA) system have been implicated in the pathophysiology of bipolar disorder (BD). Here we aim to provide a targeted integration of two measures of glutamatergic functioning in BD; the association between mismatch negativity (MMN) and in vivo hippocampal-Glu measured via proton magnetic resonance spectroscopy ((1)H MRS). Participants comprised of 33 patients with BD and 23 matched controls who underwent a two-tone passive, duration deviant MMN paradigm and (1)H MRS. Levels of Glu/creatine (Cr) in the hippocampus were determined. Pearson's correlations were used to determine associations between MMN and Glu/Cr. In controls, MMN amplitude was positively associated with Glu/Cr at the left temporal site. We did not find any significant associations with Glu/Cr and frontocentral MMN nor did we find any significant associations in BD patients. The results provide further insight into the neurophysiology of MMN, with evidence supporting the role of hippocampal-Glu signalling through the NMDA receptor in temporal MMN. Our data also demonstrate that Glu/Cr regulation of MMN is dampened in BD, which may indicate a lack of tightly regulated hippocampal NMDA functioning. These findings provide insight into the underlying basis of glutamatergic transmission disturbances implicated in the disorder.NHMRC Australia Fellowship 46491

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult.

In a series of neurophysiological and neuroimaging studies we investigated the neurobiology related to alcohol use in young people with bipolar disorder. Impairments were identified across frontal and temporal representations of event-related potential and proton magnetic resonance spectroscopy markers; mismatch negativity and in vivo glutathione, respectively. We propose these findings reflect impairments in the N-methyl-D-aspartate receptor and antioxidant capacity. This review seeks to place these findings within the broader literature in the context of two propositions: 1. Pathophysiological impairments in N-methyl-D-aspartate receptor functioning in bipolar disorder contribute to susceptibility toward developing alcohol problems. 2. Alcohol aggravates bipolar disorder neuroprogression via oxidative stress. A neurobiological model that incorporates these propositions is presented, with a focus on the potential for N-methyl-D-aspartate receptor antagonism and glutathione augmentation as potential adjunctive pharmacotherapies to treat the comorbidity. While this review highlights the importance of alcohol monitoring and reduction strategies in the treatment of bipolar disorder, the clinical impact of the proposed model remains limited by the lack of controlled trials of novel pharmacological interventions.NHMRC Australia Fellowship 46491

A longitudinal proton magnetic resonance spectroscopy study investigating oxidative stress as a result of alcohol and tobacco use in youth with bipolar disorder

Alcohol and tobacco have been suggested to be "aggravating factors" for neuroprogression in bipolar disorder (BD), however the impact of these substances on the underlying neurobiology is limited. Oxidative stress is a key target for research into neuroprogression in BD and in accordance with this model, our previous cross-sectional studies have found that risky alcohol and tobacco use in BD is associated with increased oxidative stress, investigated via in vivo glutathione (GSH) measured by proton magnetic resonance spectroscopy ((1)H-MRS) in the anterior cingulate cortex (ACC). What remains unknown is whether the negative impact on GSH levels can be modified as a result of limiting alcohol and tobacco use. Thirty BD patients were included in the study. (1)H-MRS and tobacco and alcohol measures were conducted at baseline and follow-up assessments (15.5±4.6 months apart). Pearson׳s correlations were performed between percentage change in GSH concentration and changes in alcohol/tobacco use. Regression analyses were then conducted to further explore the significant correlations. An increase in GSH was associated with a decrease in alcohol consumption (r=-0.381, p<0.05) and frequency of tobacco use (-0.367, p=0.05). Change in alcohol consumption, tobacco use and age were significant predictors of change in GSH concentration (F (3, 26)=3.69, p<0.05). Due to the high comorbidity of alcohol and tobacco use in the sample, the individual effects of these substances on GSH levels could not be determined. This study offers longitudinal evidence that changing risky drinking patterns and tobacco use early in the course of BD is associated with improvements in antioxidant capacity, and therefore may be specific targets for early intervention and prevention of neuroprogression in BD.NHMRC Australia Fellowship 46491

What is the prevalence, and what are the clinical correlates, of insulin resistance in young people presenting for mental health care? A cross-sectional study

Objectives: To report the distribution and predictors of insulin resistance (IR) in young people presenting to primary care-based mental health services. Design: Cross-sectional. Setting: Headspace-linked clinics operated by the Brain and Mind Centre of the University of Sydney. Participants: 768 young people (66% female, mean age 19.7±3.5, range 12–30 years). Main outcome measures: IR was estimated using the updated homeostatic model assessment (HOMA2-IR). Height and weight were collected from direct measurement or self-report for body mass index (BMI). Results: For BMI, 20.6% of the cohort were overweight and 10.2% were obese. However,6.9 mmol/L). By contrast, 9.9% had a HOMA2-IR score \u3e2.0 (suggesting development of IR) and 11.7% (n=90) had a score between 1.5 and 2. Further, there was a positive correlation between BMI and HOMA2-IR (r=0.44, p Conclusions: Emerging IR is evident in a significant subgroup of young people presenting to primary care based mental health services. While the major modifiable risk factor is BMI, a large proportion of the variance is not accounted for by other demographic, clinical or treatment factors. Given the early emergence of IR, secondary prevention interventions may need to commence prior to the development of full-threshold or major mood or psychotic disorders

Mismatch negativity/P3a complex in young people with psychiatric disorders : a cluster analysis

Background: We have recently shown that the event-related potential biomarkers, mismatch negativity (MMN) and P3a, are similarly impaired in young patients with schizophrenia- and affective-spectrum psychoses as well as those with bipolar disorder. A data driven approach may help to further elucidate novel patterns of MMN/P3a amplitudes that characterise distinct subgroups in patients with emerging psychiatric disorders. Methods: Eighty seven outpatients (16 to 30 years) were assessed: 19 diagnosed with a depressive disorder; 26 with a bipolar disorder; and 42 with a psychotic disorder. The MMN/P3a complex was elicited using a two-tone passive auditory oddball paradigm with duration deviant tones. Hierarchical cluster analysis utilising frontal, central and temporal neurophysiological variables was conducted. Results: Three clusters were determined: the 'globally impaired' cluster (n = 53) displayed reduced frontal and temporal MMN as well as reduced central P3a amplitudes; the 'largest frontal MMN' cluster (n = 17) were distinguished by increased frontal MMN amplitudes and the 'largest temporal MMN' cluster (n = 17) was characterised by increases in temporal MMN only. Notably, 55% of those in the globally impaired cluster were diagnosed with schizophrenia-spectrum disorder, whereas the three patient subgroups were equally represented in the remaining two clusters. The three cluster-groups did not differ in their current symptomatology; however, the globally impaired cluster was the most neuropsychologically impaired, compared with controls. Conclusions: These findings suggest that in emerging psychiatric disorders there are distinct MMN/P3a profiles of patient subgroups independent of current symptomatology. Schizophrenia-spectrum patients tended to show the most global impairments in this neurophysiological complex. Two other subgroups of patients were found to have neurophysiological profiles suggestive of quite different neurobiological (and hence, treatment) implications

clusterBMA: Bayesian model averaging for clustering

Various methods have been developed to combine inference across multiple sets of results for unsupervised clustering, within the ensemble clustering literature. The approach of reporting results from one `best' model out of several candidate clustering models generally ignores the uncertainty that arises from model selection, and results in inferences that are sensitive to the particular model and parameters chosen. Bayesian model averaging (BMA) is a popular approach for combining results across multiple models that offers some attractive benefits in this setting, including probabilistic interpretation of the combined cluster structure and quantification of model-based uncertainty. In this work we introduce clusterBMA, a method that enables weighted model averaging across results from multiple unsupervised clustering algorithms. We use clustering internal validation criteria to develop an approximation of the posterior model probability, used for weighting the results from each model. From a consensus matrix representing a weighted average of the clustering solutions across models, we apply symmetric simplex matrix factorisation to calculate final probabilistic cluster allocations. In addition to outperforming other ensemble clustering methods on simulated data, clusterBMA offers unique features including probabilistic allocation to averaged clusters, combining allocation probabilities from 'hard' and 'soft' clustering algorithms, and measuring model-based uncertainty in averaged cluster allocation. This method is implemented in an accompanying R package of the same name

Frontal lobe changes occur early in the course of affective disorders in young people

<p>Abstract</p> <p>Background</p> <p>More severe and persistent forms of affective disorders are accompanied by grey matter loss in key frontal and temporal structures. It is unclear whether such changes precede the onset of illness, occur early in the course or develop gradually with persistence or recurrence of illness. A total of 47 young people presenting with admixtures of depressive and psychotic symptoms were recruited from specialist early intervention services along with 33 age matched healthy control subjects. All participants underwent magnetic resonance imaging and patients were rated clinically as to current stage of illness. Twenty-three patients were identified as being at an early 'attenuated syndrome' stage, while the remaining were rated as having already reached the 'discrete disorder' or 'persistent or recurrent illness' stage. Contrasts were carried out between controls subjects and patients cohorts with attenuated syndromes and discrete disorders, separately.</p> <p>Results</p> <p>The patients that were identified as having a discrete or persisting disorder demonstrated decreased grey matter volumes within distributed frontal brain regions when contrasted to both the control subjects as well as those patients in the attenuated syndrome stage. Overall, patients who were diagnosed as more advanced in terms of the clinical stage of their illness, exhibited the greatest grey matter volume loss of all groups.</p> <p>Conclusions</p> <p>This study suggests that, in terms of frontal grey matter changes, a major transition point may occur in the course of affective illness between early attenuated syndromes and later discrete illness stages.</p

White matter integrity in individuals at ultra-high risk for psychosis: a systematic review and discussion of the role of polyunsaturated fatty acids

&copy; 2016 The Author(s). Background: Schizophrenia is thought to be a neurodevelopmental disorder with pathophysiological processes beginning in the brain prior to the emergence of clinical symptoms. Recent evidence from neuroimaging studies using techniques such as diffusion tensor imaging has identified white matter abnormalities that are suggestive of disrupted brain myelination and neuronal connectivity. Identifying whether such effects exist in individuals at high risk for developing psychosis may help with prevention and early intervention strategies. In addition, there is preliminary evidence for a role of lipid biology in the onset of psychosis, along with well-established evidence of its role in myelination of white matter tracts. As such, this article synthesises the literature on polyunsaturated fatty acids (PUFAs) in myelination and schizophrenia, hypothesizing that white matter abnormalities may potentially mediate the relationship between PUFAs and schizophrenia. Methods: Diffusion tensor imaging studies were identified through a systematic search of existing literature. Studies examined white matter integrity in ultra-high risk (UHR) samples, as assessed using structured diagnostic interviews. Data was extracted and summarised as a narrative review. Results: Twelve studies met inclusion criteria, and findings identified reduced fractional anisotropy and higher diffusivity. Although the exact location of abnormalities remains uncertain, fronto-temporal and fronto-limbic connections, including the superior longitudinal and uncinate fasiculus, cingulum, and corpus callosum appear to be implicated. Because of preliminary evidence suggesting lipid biology may be relevant for the onset of psychosis, a discussion is provided of the role of polyunsaturated fatty acids (PUFAs) in myelination and risk for psychosis. Conclusions: While the function of PUFAs in myelination is well-established, there is growing evidence of reduced PUFA concentration in UHR samples, highlighting the need for research to examine the relationship between PUFA and white matter integrity in high-risk samples and age-matched healthy controls. Such investigations will help to better understand the pathophysiology of the disorder, and potentially assist in the development of novel treatment and early intervention strategies

Pathways to depression by age 16 years: Examining trajectories for self-reported psychological and somatic phenotypes across adolescence

Sex differences in rates of depression emerge during adolescence. However, it is unclear whether symptom patterns and trajectories differ significantly according to gender in youth. Barriers to research include the fact that most self-report tools are weighted towards psychological rather than somatic symptoms.Data were collected on symptoms of depression in about 1800 individuals at ages 12, 14 and 16 years. Odds ratios and 95% confidence intervals were used to examine the trajectory of psychological and somatic phenotypes and self-reported depression caseness over time.At age 12, 24% of participants met criteria for self-reported depression caseness. Although there was only a small incremental increase in the prevalence over time (about 5%), 57% of participants met criteria for self-reported depression caseness at least once. Generic symptoms at age 12 were associated with depression longitudinally, although early transition to caseness was reported in females only. Categorization as a psychological phenotype at age 12 predicted depression at age 14 and/or 16 years, especially in females. The somatic phenotype was more common in males, but showed a weaker association with self-reported depression caseness over time.Depression was assessed by self-report; only 30% of participants had ratings for age 12, 14 and 16.Although sub-threshold psychological and somatic syndromes often co-occur in cases of self-reported depression in adolescence, longitudinally they may represent independent symptom trajectories. However, it is important to remember that self-reported depression is indicative of, but not confirmation of a depressive episode that meets diagnostic criteria

Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention With Agomelatine in People With Depression: A Proof of Concept Open Label Study

Background: Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which also has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms.Objective: This proof of concept open-label study sought to determine if improvements in depressive symptoms following an adjunctive multimodal intervention including agomelatine intake are associated with the magnitude of circadian realignment. This was investigated in young people with depression, a subgroup known to have high rates of delayed circadian rhythms.Methods: Young people with depression received a psychoeducation session about sleep and circadian rhythms, were asked to progressively phase advance their wake up time, and completed an 8 weeks course of agomelatine (25–50 mg). Participants underwent semi-structured psychological assessments, ambulatory sleep-wake monitoring and measurement of melatonin circadian phase before and after the intervention.Results: Twenty-four young adults with depression (17–28 years old; 58% females) completed the study. After the intervention, depressive symptoms were significantly reduced [t(23) = 6.9, p &lt; 0.001] and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 h earlier [t(18) = 4.4, p &lt; 0.001]. On average, sleep onset was phase shifted 28 min earlier [t(19) = 2.1, p = 0.047] and total sleep time increased by 24 min [t(19) = –2.6, p = 0.018]. There was no significant change in wake-up times. A strong correlation (r = 0.69, p = 0.001) was found between the relative improvements in depression severity and the degree of phase shift in DLMO.Conclusion: Although this needs to be replicated in larger randomized controlled trials, these findings suggest that the degree of antidepressant response to a multimodal intervention including psychoeducation and agomelatine intake may be associated with the degree of change in evening melatonin release in young people with depression. This offers promising avenues for targeted treatment based on the prior identification of objective individual characteristics