Carissa Coulston

Potential Mechanisms of Action of Lithium in Bipolar Disorder

Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

A functional MRI study of Theory of Mind in euthymic bipolar disorder patients

OBJECTIVES To determine the neural responses invoked in Theory of Mind (ToM) in euthymic bipolar patients as compared with healthy subjects. METHODS This study examined 20 euthymic bipolar patients (11 males and 9 females) and 20 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in a ToM task. Within-scanner eye movements were monitored to ensure task engagement. The activation paradigm involved observing ToM and random-motion animated sequences in a block design. Both within group (ToM versus random motion) and random effects between group analyses were performed on fMRI data using the BrainVoyager software package. Demographic and clinical data, along with subject ratings of fMRI stimuli, were collated and analysed. RESULTS Patients were compromised in their ability to appropriately rate the ToM stimuli and assess them for intention as compared to healthy subjects. This was reflected in the fact that patients had few within-group significant activations in response to ToM animated sequences, namely, the left anterior cingulate, and precuneus and cuneus bilaterally. In contrast, robust activations in response to ToM animated sequences in healthy subjects were widespread and involved regions recognized for mental state reasoning, in particular the insula, inferior frontal, supramarginal and angular gyri, and temporal cortex. The between-group random effects analysis exclusively favoured the healthy subjects, with many activations occurring in regions overlapping with those found in the within-group analyses. CONCLUSIONS The findings of this novel neuroimaging study suggest that in a social context, euthymic bipolar patients, though seemingly well and capable of engaging aspects of ToM, are perhaps constrained in their ability to mentalize fully, and furthermore cannot reliably adopt an alternate cognitive perspective when appropriate. Impairment of this capacity, though subtle, may in effect compromise their ability to understand the emotions and intentions of others, and also may limit appreciation of their own illness and symptoms. Such a deficit in bipolar disorder perhaps impacts upon interpersonal relationships and adversely affects social cognition and clinical functioning. The potential implications of this putative mentalizing compromise in euthymic patients with bipolar disorder are substantial, both for the individual and for understanding the neural substrate of the illness, and therefore warrant further investigation.

Bordering on bipolar: The overlap between borderline personality and bipolarity

Objective: There is much debate over whether borderline personality disorder (BPD) belongs to the bipolar spectrum. The diagnosis of bipolar disorder (BD) in BPD patients, and conversely, BPD in BD patients is common, indicating prevalent co-morbidity, as well as potential misdiagnosis in either group. BD and BPD are often indistinguishable given the core characteristics of emotional dysregulation and impulsivity that feature in both. However, it may be argued that the manifestation of these characteristics in the two groups is different, and that the symptoms are driven by distinct aetiological factors. The primary objective of this paper was to examine where potential areas of discrimination lie between BD and BPD. Methods: A literature search was conducted using MEDLINE and PubMed databases to identify studies that have researched BD and BPD across the recognised domains of emotional dysregulation, impulsivity, childhood trauma, and their putative neurobiological substrates. Results: Research comparing BD and BPD patients on self-report measures is limited, and no studies have examined their neurobiological underpinnings in the same design. One possible differentiating variable is childhood trauma which shapes the circumstances in which emotional dysregulation and impulsivity are triggered, the types of behaviours exhibited, and the frequency and duration of mood states. There is growing evidence that childhood trauma not only predisposes individuals to both disorders, but also modulates the clinical expression and course of bipolar illness, particularly rapid cycling BD, a form of bipolarity that resembles the clinical profile of BPD, yet presents quite distinctly from other BD subtypes. Conclusions: This paper provides an overview of BD and BPD with respect to emotional dysregulation, impulsivity, childhood factors, and neurobiological substrates. Based on findings predominantly within the independent areas of BD and BPD, it tentatively provides an integrated behavioural, aetiological and neurobiological approach for investigating the question of whether BPD belongs to the bipolar spectrum.

The neuropsychology of cannabis and other substance use in schizophrenia: review of the literature and critical evaluation of methodological issues

Research on the neuropsychology of substance use in schizophrenia has been steadily growing over the past decade. However, significant gaps remain in the knowledge of individual substances and their relationship to cognition in the schizophrenia spectrum disorders. Approximately 65 studies to date have directly examined this relationship. Of these, approximately 20 have focused on nicotine, 15 on alcohol, 10 on cocaine, three on stimulants/hallucinogens, one on benzodiazepines, 10 on polydrug abuse, and seven on cannabis. Research on cannabis is especially lacking, given that worldwide it is the most commonly used illicit drug in schizophrenia, is used at higher rates in schizophrenia than in the general population, and makes its own unique contribution to the onset and prognosis of schizophrenia. In the present paper an overview of the neuropsychology literature on substance use in schizophrenia is presented, with special emphasis on cannabis. This incorporates a discussion of the methodological limitations inherent in these studies, and range of potential confounding variables that were not considered or controlled, providing directions for future research into the cognitive correlates of cannabis and other substance use in schizophrenia.

Who picks psychiatry? Perceptions, preferences and personality of medical students

Objectives: This study aimed to characterise the personality profiles of junior medical students most likely to choose psychiatry as a career, determine aspects of psychiatry that most attract potential recruits, and identify misperceptions about psychiatry that may dissuade students from pursuing this specialism. Method: A total of 580 second-year medical students from the University of New South Wales, Australia completed a set of questionnaires that measured the likelihood with which various medical specialties were being considered as careers, personality traits using the NEO Five-Factor Inventory (NEO-FFI), and the degree to which students perceived each specialty as attractive across a number of parameters. Results: Only 86 students (15%) indicated a strong likelihood of choosing psychiatry, compared to other specialties which attracted higher proportions of students (range 19–49%). These 86 students had significantly higher openness scores than those who indicated a lesser likelihood of pursuing psychiatry. Students who were highly interested in psychiatry ranked it as very attractive in respect to providing interesting and challenging subject matter, and relatively attractive in respect to financial reward, work enjoyment, good lifestyle, having a bright and interesting future, and association with colleagues. However, psychiatry remained less attractive with respect to prestige, perceived low effectiveness of treatments, degree to which it draws upon aspects of medical training, and lack of reliable scientific foundation. Within the entire sample, psychiatry was ranked most unattractive compared to the other specialties across eight of the 13 parameters assessed. Conclusions: Students interested in psychiatry are more likely to be ‘open’ and view the specialty as interesting and challenging. Such characteristics should be promoted more widely along with countering myths that as a specialty, psychiatry lacks a scientific foundation or is somehow different from mainstream medicine in terms of training and outcomes. Championing psychiatry in this manner may attract more recruits and enhance its prestige.

Modeling bipolar disorder suicidality

To review the psychosocial, neuropsychological, and neurobiological evidence regarding suicide and bipolar disorder (BD), to enable the development of an integrated model that facilitates understanding, and to provide a useful framework for future research.

Predicting bipolar disorder on the basis of phenomenology: implications for prevention and early intervention

Bipolar disorder is a multifaceted illness and there is often a substantial delay between the first onset of symptoms and diagnosis. Early detection has the potential to curtail illness progression and disorder‐associated burden but it requires a clear understanding of the initial bipolar prodrome. This article summarizes the phenomenology of bipolar disorder with an emphasis on the initial prodrome, the evolution of the illness, and the implications for prevention and early intervention.

Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder.

Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder

Familiarity breeds respect: attitudes of medical students towards psychiatry following a clinical attachment

Objective: The aim of this paper was to examine the influence of a clinical attachment in psychiatry on medical students’ attitudes to psychiatry as a specialty and potential career. Method: Medical students at Sydney Medical School were surveyed following an 8-week clinical attachment in psychiatry. Secondary analyses sought to identify associations with variables such as age, gender and level of clinical experience as a medical student. Results: Following a clinical attachment in psychiatry, 80% of students rated their attitude to psychiatry as more positive. Approximately 32% rated themselves as likely or very likely to choose a career in psychiatry. No differences were seen with respect to gender, age or stage of training. The quality of the teaching, enthusiasm of the clinical teachers, the holistic approach and scientific basis of psychiatry were cited by students as factors influencing attitudes. Conclusions: The clinical rotation in psychiatry is a significant factor influencing medical student attitudes towards psychiatry.

Reliability of the care and needs scale for assessing support needs after traumatic brain injury.

ObjectiveTo investigate the reliability of the Care and Needs Scale (CANS) for measuring the level and types of support needs of people with traumatic brain injury (TBI). MethodInterrater reliability was examined in a cohort of 30 community clients with TBI by comparing CANS ratings completed by 2 occupational therapists (OTs) and a case manager. CANS ratings on the same clients were also completed 1 week later to examine test-retest reliability. Reliability of proxy ratings was investigated in a cohort of 40 community clients with TBI by comparing CANS ratings completed by a clinical researcher, multidisciplinary team, relative, and client. ResultsLevel of support need as measured by the CANS showed excellent interrater reliability both within and across disciplines: ICC = 0.95 between 2 OTs and ICC = 0.93 and 0.96 between OTs and case manager. Test-retest reliability of the CANS over a 1-week period was also excellent (ICC = 0.98). Although the agreement between the clinical researcher and multidisciplinary team was excellent (ICC = 0.92), ICCs with relative and client ratings were variable, ranging from 0.37 to 0.72. ConclusionsThe excellent inter-rater and test-retest reliability findings from this present study, together with the evidence for validity reported previously, indicate that the CANS is a reliable and valid instrument for application in clinical practice.