Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy

Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research.

Conformational changes in redox pairs of protein structures

Disulfides are conventionally viewed as structurally stabilizing elements in proteins but emerging evidence suggests two disulfide subproteomes exist. One group mediates the well known role of structural stabilization. A second redox-active group are best known for their catalytic functions but are increasingly being recognized for their roles in regulation of protein function. Redox-active disulfides are, by their very nature, more susceptible to reduction than structural disulfides; and conversely, the Cys pairs that form them are more susceptible to oxidation. In this study, we searched for potentially redox-active Cys Pairs by scanning the Protein Data Bank for structures of proteins in alternate redox states. The PDB contains over 1134 unique redox pairs of proteins, many of which exhibit conformational differences between alternate redox states. Several classes of structural changes were observed, proteins that exhibit: disulfide oxidation following expulsion of metals such as zinc; major reorganisation of the polypeptide backbone in association with disulfide redox-activity; order/disorder transitions; and changes in quaternary structure. Based on evidence gathered supporting disulfide redox activity, we propose disulfides present in alternate redox states are likely to have physiologically relevant redox activity.

Atom probe tomography investigation of heterogeneous short-range ordering in the 'komplex' phase state (K-state) of Fe-18Al (at.%)

We study an Fe-18Al (at.%) alloy after various thermal treatments at different times (24-336 h) and temperatures (250-1100 °C) to determine the nature of the so-called 'komplex' phase state (or "K-state"), which is common to other alloy systems having compositions at the boundaries of known order-disorder transitions and is characterised by heterogeneous short-range-ordering (SRO). This has been done by direct observation using atom probe tomography (APT), which reveals that nano-sized, ordered regions/particles do not exist. Also, by employing shell-based analysis of the three-dimensional atomic positions, we have determined chemically sensitive, generalised multicomponent short-range order (GM-SRO) parameters, which are compared with published pairwise SRO parameters derived from bulk, volume-averaged measurement techniques (e.g. X-ray and neutron scattering, Mössbauer spectroscopy) and combined ab-initio and Monte Carlo simulations. This analysis procedure has general relevance for other alloy systems where quantitative chemical-structure evaluation of local atomic environments is required to understand ordering and partial ordering phenomena that affect physical and mechanical properties.

Origins of inflated responsibility in obsessive compulsive disorder

The pivotal role of inflated responsibility beliefs in the maintenance and treatment of obsessive-compulsive disorder (OCD) has been clearly demonstrated (Rachman, 1993; Salkovskis, 1998; Shafran, 1997; van Oppen & Arntz, 1994). Yet little is known about the origins of these beliefs, their contribution to a sense of inflated responsibility or the symptoms of OCD, or the contribution of personality to inflated responsibility and to OCD, The aims of this thesis were to investigate a model of the inter-relationships among the personality dimensions of neuroticism and psychoticism, inflated responsibility and OCD, and the origins of inflated responsibility to inflated responsibility and to OCD. In order to achieve these aims, a scale was developed to assess the origins of inflated responsibility based upon the five pathways proposed by Salkovskis, Shafran, Rachman, and Freeston (1999) and the additional domains of guilt, vigilance and thought-action fusion (Shafran, Thordarson, & Rachman, 1996; Shafran, Watkins & Charman, 1996; Tallis, 1994). Eighty-four participants with OCD (age M = 43.36) and 74 control participants (age M =37.14) volunteered to participate in the two studies of this thesis. The aim of Study 1 was to develop and validate a measure of the Origins of Inflated Responsibility (OIR). The results of the first study yielded a 25-ttem scale, the Origins of Inflated Responsibility Questionnaire (OIRQ) with five independent factors: responsibility, strictness, protection from responsibility, critical incidents, and peer blame which demonstrated both internal reliability and temporal stability over a 2-week period. In Study 2, participants also completed the Responsibility Attitudes Scale (Salkovskis, Wroe, Gledhill, Morrison, Forrester, Richards, ct al. (2000) (a measure of inflated responsibility), the Padua Inventory (Sanavio, 1988) (to measure of the symptoms of OCD)y and the Eysenck Personality Inventory-Revised (Eysenck & Eysenck, 1991). Multivariatc Analysis of Variance revealed that the OCD group scored higher on all variables than the control group except for strictness where the groups were not different, and psychoticism where the OCD group scored lower. A series of Multiple Regression analyses revealed that both group and the OIR contributed to inflated responsibility (R2 = .56). When all variables, OIR, inflated responsibility and neuroticism were entered as predictors of OCD, 60% of the variance in OCD was explained however, 49% of the variance was shared by the independent variables suggesting the presence of some underlying construct. Structural Equation Modelling, where all the constructs in the model were examined simultaneously, revealed that neuroticism contributed to the OIR, inflated responsibility and OCD. The OIR were also significant predictors of inflated responsibility and indirectly through inflated responsibility predictive of OCD. The OIR also directly predicted OCD and when the total effects are considered, their contribution was greater than the total effect for inflated responsibility alone. The results of these studies provide good support for the origins of inflated responsibility proposed by Salkovskis et al. (1999), as measured by the OIRQ developed for use in the current thesis. The results also support the contribution of inflated responsibility and neuroticism, as well as the OIR, to OCD, The large amount of variance shared by the OIR, inflated responsibility and neuroticism suggest that there might be some underlying construct, perhaps of a biopsychosocial nature, that requires further investigation for its role in the onset and maintenance of OCD. The clinical relevance of these findings is discussed in terms of early prevention strategies and interventions.

Women's cognitive and emotional processing during sexual arousal : the effects of erotic film and absorption

Sexual arousal is a complex and dynamic element of women’s sexuality. Accounts vary, however most multidimensional models highlight the cognitive, affective and physiological components of the female sexual arousal response. While literature examining the peripheral physiological changes that occur during female sexual arousal abounds, there has been a dearth of literature pertaining to the cognitive and affective components. Thus, while many authors have included cognitive and emotions as independent components of the female sexual arousal response, there has been little empirical research to validate this approach. The aim of the current thesis was to examine the cognitive and affective components of female sexual arousal in more depth, investigating the nature of the relationship between these components under various experimental conditions. In order to do so, two integrated studies were conducted, each highlighting the effects of either external or internal variables on women’s subjective sexual arousal, absorption, positive affect and negative affect. Study One was designed to evaluate women’s emotional and cognitive processing of two elements of erotic film – foreplay and erotic context. 60 women were asked to report their subjective sexual arousal, absorption, positive affect and negative affect in response to one of four erotic film excerpts. The erotic excerpts varied in accordance with the degree of foreplay (low vs. high) depicted and the context in which the sexual activities took place (novel vs. habitual context). Women in the study responded more favourably to the high foreplay erotic film excerpt, subsequently reporting higher degrees of subjective sexual arousal, absorption and positive affect. Women also responded favourably to the erotic excerpt filmed in a novel context, reporting greater subjective sexual arousal as a result. The environment in which the sexual encounters were filmed failed to have an effect however, on women’s absorption or their positive or negative affect. The results of Study One suggest that stimulus specific variables, such as the degree of foreplay depicted, have a significant influence on female cognitive and emotional processing of erotic film. The results also suggest that a relationship exists between absorption, subjective sexual arousal and positive affect, albeit a correlational one. Specifically, there was evidence of parallel processing during sexual arousal, as participant reported sexual arousal, absorption and positive affect all increased and decreased in unison. Based on the results it was suggested that future research attempt to experimentally manipulate one of these variables, to examine its direct effect on the remaining variable. Thus, Study Two aimed to examine the effects of absorption on women’s cognitive and emotional processing of erotica. Study Two manipulated absorption at two levels (high vs. low), examining the impact of these states on participants’ subsequent absorption, subjective sexual arousal and positive and negative affect. 62 women were asked to read one of two sets of test session instructions. The first, participant-oriented instruction set, instructed participants to immerse themselves in the erotic film excerpt, as if they were active participants in the sexual exchange. The second, spectator-oriented instruction set, directed participants to observe and evaluate the erotic film. These instructions were designed to elicit high and low degrees of absorption, respectively. The utility of this approach when manipulating female absorption, was demonstrated by self reported ratings of absorption, given at the conclusion of the film presentation. Participants were also asked to report their subjective sexual arousal and positive and negative affect at the conclusion of the erotic film presentation. The findings of this study suggest that the adoption of a participant-oriented (high absorption) perspective elicits more favourable responses from participants than a spectator-oriented (low absorption) perspective, with participants in the former experimental group reporting greater degrees of subjective sexual arousal and positive affect. Negative affect was equivalent across experimental conditions, with the participants reporting that they experienced little to no aversive feelings during either of the experimental conditions. The results suggest that the degree to which a women immerses and absorbs herself in a sexual stimulus has a significant impact in her subsequent cognitive and affective processing of that stimulus. More specifically, it appears that women respond more favourably when they are highly absorbed and immersed in a stimulus, reporting greater subjective sexual arousal and positive affect. Overall, the results of Studies One and Two highlight the dynamic and complex nature of female sexual arousal. It appears that women have definite cognitive and affective responses to sexual stimuli. The magnitude of these responses may be mediated by a number of factors however, including the intrinsic qualities of the stimulus and the degree to which the woman attends to the stimulus. Both these variables act to either enhance or inhibit the sexual arousal response. There results have important implications for current sexuality literature. While women’s cognitions and emotions in response to erotic film were generally highly correlated, in some instances they differed, warranting their inclusion as separate elements in models of female sexual arousal. Furthermore, it might be suggested that the inclusion of an additional variable – absorption – into current models of female sexual arousal would prove beneficial, aiding researchers to better understand and predict the arousal process. As such, recommendations are made for a revised model of female sexual arousal. In terms of future directions, the results of the present thesis have implications for the treatment of sexual dysfunctions, suggesting that clinicians need to understand the internal and external variables that might contribute to the aetiology and maintenance of their presenting problems.

Effects of N-acetylcysteine on substance use in bipolar disorder : a randomized placebo controlled clinical trial

Objective: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).

Methods: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.

Results: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.

Conclusion: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

Effects of N-acetyl cysteine on cognitive function in bipolar disorder

Aims

Bipolar disorder is characterized by progressive changes in cognition with declines in executive functioning, memory and sustained attention. Current pharmacotherapies for bipolar disorder target mood symptoms but have not addressed these cognitive changes resulting in euthymic individuals who still experience cognitive deficits. N-acetyl cysteine (NAC) has been shown to have effects on antioxidant status, glutamate transmission, inflammation and neurogenesis. Adjunctive treatment with NAC improves the symptoms experienced by those with bipolar disorder, particularly depression, and it was hypothesized that cognition may also be improved following NAC treatment.
Methods

As part of a larger randomized, double-blind, placebo-controlled trial, participants in the current report were tested at baseline and 6 months to assess changes in cognitive function following either 2000 mg of NAC daily or placebo.
Results

This study failed to find changes in cognitive function following treatment with NAC compared to placebo.
Conclusions

While an important pilot study, this study had a small sample size and included a limited battery of cognitive tests. Further investigations on the effects of NAC on cognitive performance in bipolar disorder are required.

The adjustment of children of Australian Vietnam veterans: is there evidence for the transgenerational transmission of the effects of war-related trauma?

Objective: The presence of posttraumatic stress disorder (PTSD) in trauma survivors has been linked with family dysfunction and symptoms in their children, including lower self-esteem, higher disorder rates and symptoms resembling those of the traumatized parent. This study aims to examine the phenomenon of intergenerational transfer of PTSD in an Australian context.

Method: 50 children (aged 16–30) of 50 male Vietnam veterans, subgrouped according to their fathers' PTSD status, were compared with an age-matched group of 33 civilian peers. Participants completed questionnaires with measures of self-esteem, PTSD symptomatology and family functioning.

Results: Contrary to expectations, no significant differences were found between the self-esteem and PTSD symptomatology scores for any offspring groups. Unhealthy family functioning is the area in which the effect of the veteran's PTSD appears to manifest itself, particularly the inability of the family both to experience appropriate emotional responses and to solve problems effectively within and outside the family unit.

Conclusion: Methodological refinements and further focus on the role of wives/mothers in buffering the impact of veterans' PTSD symptomatology on their children are indicated. Further effort to support families of Veterans with PTSD is also indicated.

Factors associated with functioning style and coping strategies of familes with a child with an autism spectrum disorder

A survey of parents/caregivers of a child with an autism spectrum disorder (ASD) was conducted to examine the relationship between ASD characteristics, family functioning and coping strategies. Having a child with ASD places considerable stress on the family. Primary caregivers of a child with ASD from a regional and rural area in Victoria, Australia (N = 53) were surveyed concerning their child with ASD, family functioning (adaptability and cohesion), marital satisfaction, self-esteem and coping strategies. Results suggest that these caregivers had healthy self-esteem, although they reported somewhat lower marital happiness, family cohesion and family adaptability than did norm groups. Coping strategies were not significant predictors of these outcome variables. Results highlight the need for support programmes to target family and relationship variables as well as ASD children and their behaviours, in order to sustain the family unit and improve quality of life for parents and caregivers as well as those children.

Addressing the potential adverse effects of school-based BMI assessments on children

Introduction. Do child obesity prevention research and intervention measures have the potential to generate adverse concerns about body image by focussing on food, physical activity and body weight? Research findings now demonstrate the emergence of body image concerns in children as young as 5 years. In the context of a large school-community-based child health promotion and obesity prevention study, we aimed to address the potential negative effects of height and weight measures on child wellbeing by developing and implementing an evidence-informed protocol to protect and prevent body image concerns. fun 'n healthy in Moreland! is a cluster randomised controlled trial of a child health promotion and obesity prevention intervention in 23 primary schools in an inner urban area of Melbourne, Australia. Body image considerations were incorporated into the study philosophies, aims, methods, staff training, language, data collection and reporting procedures of this study. This was informed by the published literature, professional body image expertise, pilot testing and implementation in the conduct of baseline data collection and the intervention. This study is the first record of a body image protection protocol being an integral part of the research processes of a child obesity prevention study. Whilst we are yet to measure its impact and outcome, we have developed and tested a protocol based on the evidence and with support from stakeholders in order to minimise the adverse impact of study processes on child body image concerns.