Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis

The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral ‘limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal ‘associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness

Temporal disintegration: a phenomenological and neurophysiological investigation

© 2017 Dr. Francesco GiorlandoThe primary aim of this PhD research programme was to explore the neurophysiological correlates of temporal disintegration. This phenomenon is typified by disturbing anomalies in the normal flow and experience of time, and is a significant co-morbidity in a variety psychiatric illnesses. The research focused on the application of sub-second and supra-second psychophysical methods as well as neuroimaging to explore neural correlates of temporal disintegration. Experiments were conducted with two cohorts: patients with bipolar disorder, and healthy participants who were administered the dissociative agent ketamine. The bipolar disorder study utilised a longitudinal, repeated measures design. The ketamine experiments were randomised, double blind studies with placebo controls. Three main types of measurements were used in the studies. Firstly, questionnaires were administered which measured mood states, dissociative states and temporal disintegration. Secondly, behavioural responses to visual stimuli were measured in two temporal domains: sub-second perceptual ordering, and supra-second perceived duration judgement. Thirdly, during performance of the sub-second task, neuroimaging was conducted: fMRI for participants given ketamine and EEG for patients with bipolar disorder. The sub-second method was adapted from the temporal order judgement task of Morrone et al. [2005]. Participants reported the order of two briefly flashed stimuli presented close to the time that they made an eye movement. In this task, the stimuli may appear to be inverted in temporal order, especially when eye movements coincide with the flashed stimuli. The supra-second method was adapted from the colour-time task of Coull et al. [2004]. It involved judging the relative duration of two successive stimuli that cycled through a range of colours over time. In the bipolar disorder patients, a strong association was found between measures of mood, dissociative symptoms and the phenomenon of temporal dissociation. For the supra-second task, we found lower mood scores (measured by the Bipolar Depression Rating Scale) were associated with a greater number of errors in the time condition than the colour condition. For the sub-second psychophysical tests, the proportion of inverted temporal judgements increased in association with manic symptoms (11% increase for each point increase in Young Mania Rating Scale, p<0.05). Manual reaction times in 2AFC responses to temporal judgements were lengthened by ketamine and in inverted judgements. The fMRI results showed increased BOLD signal for inverted trials bilaterally in the insular/claustral regions and in the anterior cingulate cortex (p<0.001). In inverted trials, temporal disintegration as measured by the Temporal Integration Inventory was correlated with the activity of the left temporoparietal junction (Kendall’s τ = 0.48, p < 0.01). Together, these findings indicate that there is a significant linkage between mood and dissociative states and the phenomenon of temporal disintegration. They also reveal that both sub-second and supra- second timing performance are altered by ketamine induced dissociation and with mood changes in bipolar disorder. The findings provide support for an integrated functional network involved in sub-second temporal processing which includes the claustrum and temporoparietal junctions. These insights are important in that they can inform our understanding of the determinants of temporal disintegration and may also provide insights into the underlying pathology of bipolar disorder

Hyponatraemia: an audit of aged psychiatry patients taking SSRIs and SNRIs

Objective:&nbsp;Hyponatraemia is a serious adverse event commonly reported in elderly people treated with serotonergic antidepressants. The mechanism, incidence and risk factors for antidepressant induced hyponatraemia are not&nbsp;fully understood. Method: In a retrospective chart analysis, depressed patients aged &gt;63 years were investigated for change in serum sodium levels between two time points, separated by a median period of 45.5 days, with the first specimen taken prior to&nbsp;treatment. Patients were grouped into three cohorts; treated with an SSRI or SNRI (n=77), treated with an antidepressant other than an SSRI or SNRI (n=54) and not treated with an antidepressant (n=128). Results: For change in sodium level between measurements and total number of patients with hyponatraemia, there was no significant difference between cohorts. However, the rate of reduction of serum sodium levels between time points was&nbsp;significantly greater for SSRI and SNRI treated patients (p&lt;0.001) and patients treated with other antidepressants (p=0.03)&nbsp;compared to patients not treated with antidepressants. Moreover, the distribution of values of change in serum sodium was&nbsp;skewed towards reduced serum sodium in patients treated with SSRI or SNRIs (skew -0.43) and patients treated with&nbsp;other antidepressants (skew -0.09) but not for patients without antidepressants (skew 0.25).Conclusions: These data suggest that antidepressant treatment is associated with hyponatraemia affecting a subgroup of individuals only. Generalised linear modelling showed that the risk of hyponatraemia increases with increased age, female&nbsp;gender, and particularly the antidepressant agents sertraline and escitalopram. The findings are of clinical significance as they demonstrate that hyponatraemia can occur rapidly with antidepressants, and SSRI/SNRI medications induce more&nbsp;rapid changes. They support the use of electrolyte monitoring early in antidepressant treatment in patients receiving antidepressants.</div

Fostering early and mid-career research in affective disorders

In the area of affective disorders, the life of an early/mid-career researcher (EMCR; i.e. the first 5&#8211;10 years post-PhD) has become increasingly difficult. Statistics on the 2014 grant outcomes from Australia&#8217;s peak medical funding body, the National Health and Medical Research Council (NHMRC), indicate that in comparison to the 30.1% success rate for senior fellowships, just 22.4% of early career and 13.5% of mid-career fellowship applications were successful. Statistics regarding NHMRC Project Grant outcomes are similarly disheartening, with less than 30% of all successful project grants going to Chief Investigators (CIAs) without a full or Associate Professorship and only 6.5% of successful applications awarded to new investigators (National Health and Medical Research Council, 2014). Moreover, despite wide recognition that depressive disorders are among the leading causes of disease burden worldwide (Ferrari et al., 2013; World Health Organization, 2004), less than five of the 183 early/mid-career fellowships offered went to individuals with projects specifically targeting bipolar or depressive disorders (based on project titles and keywords listed in the summary details of the 17 Oct 2014 Announcement (National Health and Medical Research Council, 2014)). When seated in the context of mental health research in general, compared to other National Health Priority Areas, mental health received only a very small proportion of available grant funding (7.1% compared to 18.3% and 15.3% for cancer and cardiovascular disease, respectively), which suggests that research targeting mental health is underfunded in Australia at this time. This is particularly clear in relation to the support of early/mid scholars working in these areas (National Health and Medical Research Council, 2014). Successful funding for EMCRs is largely determined by academic track record and translation of outcomes. To develop a competitive track record, EMCRs are acutely aware that they need to &#8216;publish or perish&#8217;, &#8216;make broad collaborations&#8217;, &#8216;cement relationships with industry partners&#8217; &#8211; and the list goes on. However, without the proper supportive infrastructure, at best this kind of progression is significantly hampered and, at worst, the impending exodus of imminent research leaders leaves the future of mental health in a state of uncertainty. This is a sentiment echoed elsewhere in the world (Clark, 2014; National Institute of Health, 2014). High-impact research requires good mentorship and funding. Successful funding requires a good track record and collaborations; but, as young researchers, particularly those of us in the first 2&#8211;3 years post-PhD, we ask &#8216;Is this really obtainable? Where do we begin? Where do we find genuine support to help us to become legitimately competitive?&#8217;. These questions led us to form the Early/Mid-Career Researcher Sub-Committee of the Australasian Society for Bipolar and Depressive Disorders (ASBDD). This committee is dedicated to activities aimed at retaining and promoting early-career scholars working in affective disorder research. In a voluntary capacity, the committee, with the support of the ASBDD, will provide a much needed support network for such researchers through ASBDD membership. We believe that for research output in mood disorders to match the needs in the community, a significant increase in career opportunities for EMCRs will be required. Therefore, we aim to foster improved EMCR outcomes by lobbying for affective disorder-specific EMCR fellowship and project grant funding. We also aim to initiate activities that will facilitate EMCR careers, including collaborative publications, relevant seminars and workshops to discuss and promote EMCRs. These activities would act as a significant impetus for new researchers to enter the field and to actively promote further research in mood disorders. In this way, we aim to build a collaborative cohort of future leaders in bipolar and depressive disorders that will contribute to the promotion of a better research landscape for the future. We invite interested EMCRs to become a part of the ASBDD EMCR membership to promote affective disorders research in Australia

Ketamine perturbs perception of the flow of time in healthy volunteers

Ketamine induced selective impairments in timing, which could not be explained by more fundamental effects on the ability to hold information in WM. Rather our collected findings suggest that ketamine may disturb timing by selectively impairing the way in which information is temporally manipulated within WM

An update on adjunctive treatment options for bipolar disorder

Objectives: Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. Methods: Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. Results: A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. Conclusions: Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder

Youth depression alleviation-augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD