Francesco Giorlando

Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors

There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways.

Minocycline: therapeutic potential in psychiatry.

Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.

A consensus statement for safety monitoring guidelines of treatments for major depressive disorder

Objective: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. Method: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. Results: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. Conclusion: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.

Time, action and psychosis: using subjective time to investigate the effects of ketamine on sense of agency.

Sense of agency refers to the experience of initiating and controlling actions in order to influence events in the outside world. A disturbed sense of agency is found in certain psychiatric and neurological disorders, most notably schizophrenia. Sense of agency is associated with a subjective compression of time: actions and their outcomes are perceived as bound together in time. This is known as ‘intentional binding’ and, in healthy adults, depends partly on advance prediction of action outcomes. Notably, this predictive contribution is disrupted in patients with schizophrenia. In the present study we aimed to characterise the psychotomimetic effect of ketamine, a drug model for psychosis, on the predictive contribution to intentional binding. It was shown that ketamine produced a disruption that closely resembled previous data from patients in the early, prodromal, stage of schizophrenic illness. These results are discussed in terms of established models of delusion formation in schizophrenia. The link between time and agency, more generally, is also considered.

The role of alprazolam for the treatment of panic disorder in Australia

Objective: To investigate the potential impact of increasing prescription rates of alprazolam for the treatment of panic disorder (PD) in Australia through a review of efficacy, tolerability and adverse outcome literature. Methods: Data were sourced by a literature search using MEDLINE, Embase, PsycINFO and a manual search of scientific journals to identify relevant articles. Clinical practice guidelines from the American Psychiatric Association, National Institute of Clinical Excellence, Royal Australian and New Zealand College of Psychiatrists and World Federation of Societies of Biological Psychiatry were sourced. Prescription data were sourced from Australian governmental sources. Results: Alprazolam has shown efficacy for control of PD symptoms, particularly in short-term controlled clinical trials, but is no longer recommended as a first-line pharmacological treatment due to concerns about the risks of developing tolerance, dependence and abuse potential. Almost no evidence is available comparing alprazolam to current first-line pharmacological treatment. Despite this, prescription rates are increasing. A number of potential issues including use in overdose and impact on car accidents are noted. Conclusion: Although effective for PD symptoms in clinical trials, a number of potential issues may exist with use. Consideration of its future place in PD treatment in Australia may be warranted.

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.

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

OBJECTIVE 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 fully understood. METHOD In a retrospective chart analysis, depressed patients aged >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 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 significantly greater for SSRI and SNRI treated patients (p<0.001) and patients treated with other antidepressants (p=0.03) compared to patients not treated with antidepressants. Moreover, the distribution of values of change in serum sodium was skewed towards reduced serum sodium in patients treated with SSRI or SNRIs (skew -0.43) and patients treated with 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 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 rapid changes. They support the use of electrolyte monitoring early in antidepressant treatment in patients receiving antidepressants.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin.

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.

An update on adjunctive treatment options for bipolar disorder

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.

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 5–10 years postPhD) has become increasingly difficult. Statistics on the 2014 grant outcomes from Australia’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 ‘publish or perish’, ‘make broad collaborations’, ‘cement relationships with industry partners’ – 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 2–3 years postPhD, we ask ‘Is this really obtainable? Where do we begin? Where do we find genuine support to help us to become legitimately competitive?’. These questions led us to form the Early/Mid-Career Researcher SubCommittee 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 Commentaries