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1.  Stage managing bipolar disorder 
Bipolar disorders  2013;16(5):471-477.
Clinical staging is widespread in medicine—it informs prognosis, clinical course and treatment, and assists individualized care. Staging places an individual on a probabilistic continuum of increasing potential disease severity, ranging from clinically at-risk or latency stage through first threshold episode of illness or recurrence and finally to late or end-stage disease. The aim of this paper was to examine and update the evidence regarding staging in bipolar disorder, and how this might inform targeted and individualized intervention approaches.
We provide a narrative review of the relevant information.
In bipolar disorder, the validity of staging is informed by a range of findings that accompany illness progression, including neuroimaging data suggesting incremental volume loss, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Staging informs the adoption of a number of approaches, including the active promotion of both indicated prevention for at-risk individuals and early intervention strategies for newly diagnosed individuals, and the tailored implementation of treatments according to the stage of illness.
The nature of bipolar disorder implies the presence of an active process of neuroprogression that is considered at least partly mediated by inflammation, oxidative stress, apoptosis and changes in neurogenesis. It further supports the concept of neuroprotection, in that a diversity of agents have putative effects against these molecular targets. Clinically, staging suggests that the at-risk state or first episode is a period that requires particularly active and broad-based treatment, consistent with the hope that the temporal trajectory of the illness can be altered. Prompt treatment may be potentially neuroprotective and attenuate the neurostructural and neurocognitve changes that emerge with chronicity. Staging highlights the need for interventions at a service delivery level and implementing treatments at the earliest stage of illness possible.
PMCID: PMC3864129  PMID: 23782499
bipolar disorder; clinical staging; depression; early intervention; mania; neuroprogression; treatment
2.  Neural Antecedents of Emotional Disorders 
Biological psychiatry  2013;74(4):265-272.
Emotional symptoms (ES) emerge forme fruste in adolescence, prior to manifesting as fully-fledged emotional disorders (ED). Studies indicate that subsyndromal ES precede the onset of ED. We hypothesised that adolescents showing subsyndromal ES will show perturbations in the emotion regulatory fronto-limbic network (FLN) during emotion-processing.
Fifty-eight female adolescents underwent functional magnetic resonance imaging (fMRI) whilst viewing an image-based emotion-processing task. Within this sample 33 (56.9%) displayed emotional symptoms and 25 (43.1%) did not. Clinical measures including assessments of mood and anxiety were administered and participants were allocated to one of two groups based on the presence (ES+) or absence (ES−) of subsyndromal ES. Group comparisons were used to identify differential patterns of neural engagement and their relationship to clinical variables.
Groups displayed emotion-specific differences in FLN activity with increased frontal activity in ES+ girls during positive emotion-processing and decreased frontal and limbic activity during negative emotion-processing. Trait anxiety was the strongest clinical predictor of group membership (ES+ versus ES−) and displayed a significant negative correlation with hippocampal neural activity during negative emotion-processing. In addition, between the groups the hippocampus displayed a pattern of reverse coupling with the amygdala and insula that was also significantly correlated with trait anxiety.
There is divergence in the pattern of FLN neural processing in adolescent females determined by emotional symptoms. Future research is needed to corroborate these findings and to underline their implications longitudinally.
PMCID: PMC4435696  PMID: 23477296
fMRI; depression; anxiety; adolescents; emotional network; emotional disorders
3.  Mentalizing in male schizophrenia patients is compromised by virtue of dysfunctional connectivity between task-positive and task-negative networks 
Schizophrenia research  2012;140(0):51-58.
Schizophrenia can be conceptualized as a disorder of functional connectivity within the fronto-temporal (FT) and/or default-mode (DM) networks. Recent evidence suggests that dysfunctional integration between these large neural networks may also contribute to the illness, and that the ability to mentalize or have a ‘theory of mind’ (ToM) is discernibly impaired in patients with schizophrenia. Hence in this study, we examined whether impaired functional network connectivity (FNC) contributes to a compromise in the ability to mentalize in patients with schizophrenia. Functional magnetic resonance imaging data were acquired from 20 male schizophrenia patients and 19 matched healthy controls whilst performing a well-known ToM task. The study revealed that relative to non-ToM the engagement of ToM produced reduced neural activity in the lateral FT and insula networks in patients, as compared to healthy subjects. The findings also indicated that in comparison to healthy subjects the DM and medial FT networks are less suppressed in patients irrespective of the task (ToM/non-ToM). Further, FNC analyses showed that the degree of functional connectivity between task-positive (lateral FT and insula) and task-negative (medial FT, posterior DM) networks was significantly reduced in patients as compared to controls. Of note, a significant correlation between the functional connectivity strength of the lateral FT network with the medial FT and the degree to which this is modulated by the ToM task, suggest that mentalizing deficits in male schizophrenia patients may stem from impaired communication between neural networks that comprehend the mental states of self (medial FT) and others (lateral FT).
PMCID: PMC4429863  PMID: 22795367
functional network connectivity; FNC; independent component analysis; ICA; fMRI; schizophrenia; theory of mind
4.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
PMCID: PMC4091043  PMID: 24030475
5.  Impact of acute administration of escitalopram on the processing of emotional and neutral images: a randomized crossover fMRI study of healthy women 
Acute neural effects of antidepressant medication on emotion processing biases may provide the foundation on which clinical outcomes are based. Along with effects on positive and negative stimuli, acute effects on neutral stimuli may also relate to anti-depressant efficacy, yet these effects are still to be investigated. The present study therefore examined the impact of a single dose of the selective serotonin reuptake inhibitor escitalopram (20 mg) on positive, negative and neutral stimuli using pharmaco-fMRI.
Within a double-blind, randomized, placebo-controlled crossover design, healthy women completed 2 sessions of treatment administration and fMRI scanning separated by a 1-week washout period.
We enrolled 36 women in our study. When participants were administered escitalopram relative to placebo, left amygdala activity was increased and right inferior frontal gyrus (IFG) activity was decreased during presentation of positive pictures (potentiation of positive emotion processing). In contrast, escitalopram was associated with decreased left amygdala and increased right IFG activity during presentation of negative pictures (attenuation of negative emotion processing). In addition, escitalopram decreased right IFG activity during the processing of neutral stimuli, akin to the effects on positive stimuli (decrease in negative appraisal).
Although we used a women-only sample to reduce heterogeneity, our results may not generalize to men. Potential unblinding, which was related to the subjective occurrence of side effects, occurred in the study; however, manipulation check analyses demonstrated that results were not impacted.
These novel findings demonstrate that a single dose of the commonly prescribed escitalopram facilitates a positive information processing bias. These findings provide an important lead for better understanding effects of antidepressant medication.
PMCID: PMC4074238  PMID: 24690370
6.  The impact of escitalopram on vagally mediated cardiovascular function to stress and the moderating effects of vigorous physical activity: a randomized controlled treatment study in healthy participants 
Recent concerns over the impact of antidepressant medications, including the selective serotonin reuptake inhibitors (SSRIs), on cardiovascular function highlight the importance of research on the moderating effects of specific lifestyle factors such as physical activity. Studies in affective neuroscience have demonstrated robust acute effects of SSRIs, yet the impact of SSRIs on cardiovascular stress responses and the moderating effects of physical activity remain to be determined. This was the goal of the present study, which involved a double-blind, randomized, placebo-controlled, cross-over trial of a single-dose of escitalopram (20 mg) in 44 healthy females; outcomes were heart rate (HR) and its variability. Participants engaging in at least 30 min of vigorous physical activity at least 3 times per week (regular exercisers) showed a more resilient cardiovascular stress response than irregular vigorous exercisers, a finding associated with a moderate effect size (Cohen's d = 0.48). Escitalopram attenuated the cardiovascular stress response in irregular exercisers only (HR decreased: Cohen's d = 0.80; HR variability increased: Cohen's d = 0.33). HR during stress under escitalopram in the irregular exercisers was similar to that during stress under placebo in regular exercisers. These findings highlight that the effects of regular vigorous exercise during stress are comparable to the effects of an acute dose of escitalopram, highlighting the beneficial effects of this particular antidepressant in irregular exercisers. Given that antidepressant drugs alone do not seem to protect patients from cardiovascular disease (CVD), longitudinal studies are needed to evaluate the impact of exercise on cardiovascular stress responses in patients receiving long-term antidepressant treatment.
PMCID: PMC3781330  PMID: 24069000
selective serotonin reuptake inhibitors (SSRIs); escitalopram; exercise; physical activity; cardiovascular stress response; heart rate; heart rate variability; HRV
7.  DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions 
BMC Medicine  2013;11:202.
The recent release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association has led to much debate. For this forum article, we asked BMC Medicine Editorial Board members who are experts in the field of psychiatry to discuss their personal views on how the changes in DSM-5 might affect clinical practice in their specific areas of psychiatric medicine. This article discusses the influence the DSM-5 may have on the diagnosis and treatment of autism, trauma-related and stressor-related disorders, obsessive-compulsive and related disorders, mood disorders (including major depression and bipolar disorders), and schizophrenia spectrum disorders.
PMCID: PMC3846446  PMID: 24229007
DSM-5; Psychiatry; Autism; PTSD; Mood disorders; Bipolar; Obsessive-compulsive disorders; Depression; Schizophrenia
8.  Size and shape of the caudate nucleus in individuals with bipolar affective disorder 
The caudate nucleus (CN) is a crucial component of the ventral striatum, which is part of a prefrontal-striatal-thalamic circuit that is modulated by limbic structures to subserve emotional processing. Bipolar disorder is thought to be underpinned by dysfunctional anterior limbic networks, although MRI studies examining the CN have shown equivocal results. As gross volumetric analyses may not detect subtle regional change, we aimed to clarify the role of the CN in bipolar disorder by undertaking shape analysis to detect regional reductions.
The CN was manually traced on MRI scans from 27 patients with bipolar-I disorder and 24 matched controls. A non-parametric spherical harmonic shape analysis was undertaken using the SPHARM toolkit.
Whilst the left CN volume was consistently larger in the sample, there was no effect of group or gender or significant interactions between these variables. Volume did not correlate with illness duration or lithium dosage, but was larger in those with a history of psychosis at trend level. However, left caudate shape differed significantly between groups, with deflation in an area along the ventromedial surface (connecting to dorsolateral prefrontal regions) in bipolar patients. Psychotic patients showed increases in the dorsal head and body at trend level overall, in regions connecting to medial and orbitofrontal regions.
These findings suggest that subtle rather than gross structural changes occur in the CN, which may not be detectable by volumetric analysis alone, and reflect alterations in specific frontostriatal circuitry in the disorder.
PMCID: PMC3328643  PMID: 22368240
Bipolar affective disorder; frontostriatal; ventral striatum; caudate nucleus; limbic system
9.  The functional epistasis of 5-HTTLPR and BDNF Val66Met on emotion processing: a preliminary study 
Brain and Behavior  2012;2(6):778-788.
An epistatic interaction of 5-HTTLPR and BDNF Val66Met polymorphisms has been implicated in the structure of rostral anterior cingulate cortex (rACC) and amygdala (AMY): key regions associated with emotion processing. However, a functional epistasis of 5-HTTLPR and BDNF Val66Met on overt emotion processing has yet to be determined. Twenty-eight healthy, Caucasian female participants provided saliva samples for genotyping and underwent functional magnetic resonance imaging (fMRI) during which an emotion processing protocol were presented. Confirming the validity of this protocol, we observed blood oxygen level–dependent (BOLD) activity consistent with fMRI meta-analyses on emotion processing. Region-of-interest analysis of the rACC and AMY revealed main effects of 5-HTTLPR and BDNF Val66Met, and an interaction of 5-HTTLPR and BDNF Val66Met. The effect of the BDNF Met66 allele was dependent on 5-HTTLPR alleles, such that participants with S and Met alleles had the greatest rACC and AMY activation during the presentation of emotional images relative to other genetic groupings. Increased activity in these regions was interpreted as increased reactivity to emotional stimuli, suggesting that those with S and Met alleles are more reactive to emotional stimuli relative to other groups. Although limited by a small sample, this study contributes novel and preliminary findings relating to a functional epistasis of the 5-HTTLPR and BDNF Val66Met genes in emotion processing and provides guidance on appropriate methods to determine genetic epistasis in fMRI.
PMCID: PMC3500464  PMID: 23170240
5-HTTLPR; BDNF Val66Met; emotion processing; epistasis; fMRI; healthy subjects
10.  Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial 
BMC Medicine  2012;10:91.
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.
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.
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.
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).
PMCID: PMC3482580  PMID: 22891797
N-acetyl cysteine; depression; bipolar disorder; maintenance; mania; oxidative
11.  A consensus statement for safety monitoring guidelines of treatments for major depressive disorder 
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.
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.
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.
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.
PMCID: PMC3190838  PMID: 21888608
12.  Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use 
Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal) and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.
PMCID: PMC3428612  PMID: 22937266
13.  Neurocognition in Bipolar Disorder and Juvenile Bipolar Disorder 
In the ongoing quest for improved diagnostic markers of bipolar illness, the focus of research has gradually shifted to examining the onset of mood difficulties early in life and investigating the potential corollaries of such early onset such as cognitive impairment, disruption of social and emotional functioning, and constriction of quality of life. This article considers the disruptions to cognitive functioning that accompany bipolar disorder and compares adult and child profiles to ascertain the likelihood of identifying a neurocognitive biomarker of the illness.
A succinct review of the literature pertaining to cognition in both adult and childhood populations is synthesised following Medline and PsychINFO searches using key-terms including ‘cognition’, ‘bipolar disorder’, ‘neurocognitive’ ‘child’, ‘adolescent’ and a range of neuropsychological domain names. In addition, literature known to the authors was scrutinised and relevant references further pursued.
Findings from the literature are contextualised and key findings are summarised and provide a basis for future recommendations.
A number of deficits have been consistently identified in both adolescent and adult populations that perhaps reflect disease traits. Future research needs to focus on these and employ multimodal tests in pristine patient groups, with a view to identifying reliable biomarkers.
PMCID: PMC2732728  PMID: 19718423
bipolar disorder; neurocognition; juveniles
14.  An event-related functional MRI study of working memory in euthymic bipolar disorder 
Bipolar disorder (BD) is emerging as an illness marred by neurocognitive deficits, many of which do not resolve on recovery. Deficits affecting working memory (WM) in particular appear to be significant. WM comprises temporally separated biological processes that involve the on-line retention and manipulation of information. Previous neuroimaging studies have not sought to dissect the individual contributions of WM and examined WM subprocesses in euthymic BD. In this study, we investigated the encode, delay and response components of WM to identify the neural substrates and respective contributions to the WM deficits found in BD.
We used event-related functional magnetic resonance imaging and a parametric WM task, incorporating 3 load conditions, to delineate individual WM subprocesses in 10 euthymic BD patients and 10 control subjects.
Patients exhibited attenuated patterns of activity, predominantly in frontal brain regions, across all WM components.
Based on the attenuated activity observed in the patients, the clinical deficits in WM found in BD may reflect broad fronto-cortico-limbic dysfunction that is not confined to any single WM component. This is important in understanding the pathophysiology of BD and for future studies on executive functions in patients with this illness.
PMCID: PMC1863556  PMID: 17476364
bipolar disorder, fMRI, gyrus, memory, mood disorders.
15.  “Getting physical”: the management of neuropsychiatric disorders using novel physical treatments 
To summarize and review the utility of physical interventions in the treatment of psychiatric disorders.
A systematic review of the literature pertaining to novel physical interventions, namely, transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, and neurosurgery, was conducted using MEDLINE, EMBASE, and PSYCHLIT. Bibliographies of papers were scrutinized for further relevant references along with literature known to the authors.
Currently available physical interventions worldwide are reviewed with respect to efficacy, applications, and putative indications. Physical interventions have experienced a resurgence of interest for both the investigation of brain function and the treatment of neuropsychiatric disorders. The widespread availability of neuroimaging technology has advanced our understanding of brain function and allowed closer examination of the effects of physical treatments. Clinically, transcranial magnetic stimulation seems likely to have a role in the management of depression, and its use in other neuropsychiatric disorders appears promising. Following on from its success in the management of intractable epilepsy, vagus nerve stimulation is undergoing evaluation in the treatment of depression with some success in refractory cases. Deep brain stimulation has improved mood in patients with Parkinson’s disease and may also relieve symptoms of obsessive-compulsive disorder. Neurosurgery has re-invented itself by way of increased technical sophistication, and although further assessment of its efficacy and clinical utility is still needed, its widespread practice reflects its increasing acceptance as a viable treatment of last resort.
It is clear that physical treatments are here to stay and “getting physical” offers a useful addition to the neuropsychiatrist’s therapeutic armamentarium. However, like all new treatments these interventions need to remain under rigorous scientific scrutiny to determine accurately their immediate and long-term effects.
PMCID: PMC2671781  PMID: 19412461
physical treatments; psychosurgery; transcranial magnetic stimulation; vagus nerve stimulation; deep brain stimulation; neuropsychiatry

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