Joanna Fitzsimons

A review of clozapine safety

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.

Monitoring the Safe Use of Clozapine A Consensus View from Victoria, Australia

Clozapine is an important antipsychotic agent that has a unique profile of clinical benefits, but that has also been associated with several serious and potentially life-threatening safety concerns. In order to minimise the impact of haematological adverse events, health professionals treating patients with clozapine are currently required to register their patients on a centrally administered data network and to conform to strict protocols. The consensus statement documented in this article extends existing protocols by recommending monitoring of patients treated with clozapine for additional adverse effects during treatment. This consensus statement reflects the current practice at five major public psychiatric hospitals in Victoria, Australia, for the monitoring and management of clozapine-related adverse events, and has been implemented at these sites because of emerging safety concerns associating clozapine with cardiovascular and metabolic adverse effects.

Clozapine and cardiotoxicity: echocardiography findings from Barwon Health.

249 little is known about patterns of anxiety across this period. This study aimed to 1) assess patterns of anxiety and depression across pregnancy and the postpartum, 2) investigate associations between antenatal mood and HPA axis hormones and 3) determine the extent to which antenatal anxiety, depression and HPA axis activity predict postnatal mood disorders. Methods: Participants were recruited antenatally as part of a prospective study undertaken at the Royal Hospital for Women, Sydney. Ninety-four women completed self-report measures of anxiety and depression at 30–32 and 36-38 weeks gestation, and at 6 months postpartum. They were also administered a structured diagnostic interview (MINI-Plus) at 36–38 weeks gestation and at 6 months postpartum to determine the presence of DSM-IV anxiety and depression. Blood samples were collected at 30–32 weeks gestation for bioassays of HPA axis hormones (CRH, ACTH and cortisol). Results: The data indicate signifi cant stability in maternal mood across pregnancy and the postpartum and associations between anxiety and depression were moderate-high at each assessment. Despite the stability of depression, an anxiety disorder in pregnancy appears to be a greater risk factor for a postnatal anxiety [odds ratio (OR) = 10.20, P < 0.005] or depressive disorder (OR = 7.90, P < 0.005) than antenatal depression. Antenatal neuroendocrine parameters were unrelated to either antenatal or postnatal anxiety or depression. Conclusion: These results clearly highlight the importance of anxiety in both the preand postnatal periods.

Clozapine : an investigation of cardiac related adverse effects

Advances in understanding recovery and effective communitybased and balanced care leave a dilemma. A significant subgroup of people treated for psychosis in affluent countries remain severely disabled, take little part in community life and are socially isolated, as illustrated by recent work in Australia and the UK. Most of those with psychosis in poorly resourced countries receive no formal care despite successful demonstration of community rehabilitation approaches. What can be done to make better use of community resources and the hospital and other components of balanced care, and to avoid reinstitutionalisation in any form?Aims: Although the age-dependent neurobiological processes leading to cognitive decline in the elderly remains to be fully understood, there is now growing evidence to suggest that age-dependent increases in pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF), might play a role in such age-associated cognitive decline. The aim of this work was to examine, using a mouse model, the effect of a deficiency of TNF (TNF−/−) on cognitive function throughout aging. Methods: A standardized survey on cognition-like behaviour assessing learning and retention, spatial learning/memory, and cognitive flexibility was used to measure the cognitive-behavioural profile of TNF knockout and wildtype mice, across three age periods; 3, 6 and 12 months of age, respectively. Results: All studied mice strains demonstrated successful exploration and learning processes during the training phases of the tests, which made the specific cognition like tests valid in these mice strains. In the specific cognition-like tests, the B6.TNF−/− mice demonstrated, at 3 months of age, significantly poorer learning and retention in the novel object test as compared to B6.WT mice. In addition, spatial learning and learning effectiveness were significantly poorer in B6.TNF−/− mice, at 3 months of age, as compared to B6.WT mice. While the absence of TNF was correlated with poor cognitive functioning in early adulthood, over time the deletion of TNF resulted in better cognitive performance compared to B6.WT mice. Conclusion: Low-levels of TNF under non-inflammatory immune conditions appear essential for normal cognitive function. Moreover, the absence of TNF with age appears to protect against age-associated cognitive decline. Collectively, these findings suggest a possible role for TNF in the molecular and cellular mechanisms subserving age-related changes in learning, memory and cognition.

Clozapine and cardiotoxicity : echocardiographic findings from Barwon Health

Although schizophrenia is considered one of the most serious psychiatric illnesses, at many times during the last century it has been relegated to the background. Focus on schizophrenia research, patient care, and connections with the family members of a person who suffers from schizophrenia began to change during the 1980s. Looking back, several events propelled this change, including the initiation of the Winter Workshop on Schizophrenia Research, the emergence of NAMI as an advocacy and support group for families with a schizophrenic member, the National Plan for Schizophrenia Research initiated by the National Institute of Mental Health (NIMH), and the International Congress on Schizophrenia Research (ICOSR). The ICOSR held its first meeting in 1987 in order to provide a venue for active investigators in schizophrenia research. Nearly every attendee provided a poster, paper, or plenary presentation with the result that the meeting was characterized by the establishment of new collaborations and a wish for the Congress to continue. Since that time, the goal of the first meeting has remained the focus of the ICOSR—a venue for the active investigator. An extension of this goal has been to attract a broad range of investigators from the fields of neuroscience, cognitive neuroscience, basic and clinical psychopharmacology, psychosocial interventions, and genetics. Thus, participation is broad ranging and stimulating. Past meetings have been characterized by the extension of results from basic science to the clinical testing arena as well as the investigation of basic underpininnings of reports from the fields of psychopharmacology and neuropsychology. At the time of the initiation of the ICOSR, there was consensus that too few young faculties had taken an interest in the field of schizophrenia research. Thus, the Young Investigator Program has been a part of all the ICOSR meetings. During the last 3 meetings, the Young Investigator Program has been supported by the NIMH, to whom the organizers express their gratitude. A recent assessment of the recipients of the Young Investigator Awards has revealed that numerous of todays leaders in the field, presenters at the ICOSR, and the mentors of recent Young Investigator Award winners have been initially supported by the Congress. Because schizophrenia is a worldwide illness, the original meeting attracted investigators from outside the United States. The organizers have been pleased to welcome an ever-increasing number of schizophrenia scientists from around the world. For example, at the meeting held in Savannah, Georgia, in 2005, the majority of attendees were from outside the United States and represented more than 45 different countries. The establishment of collaborations has, therefore, extended beyond the boundaries of contingent universities to international programs aimed at solving the problems facing people with schizophrenia. With the growth of interest in schizophrenia research and the ICOSR, has come the challenge of dissemination of the results presented at the meeting. The ICOSR has been pleased to collaborate with Schizophrenia Bulletin and Schizophrenia Research in the publication of abstracts from the meeting. These collaborations allowed for a useful compendium for attendees and distribution to subscribers and libraries around the world. As the International Congress on Schizophrenia Research has expanded from a group of 175 initial delegates to larger than 1500 active investigators, support for the meeting has needed to expand as well. The organizers wish to acknowledge several very instrumental supporters of the Congress, including the NIMH, the William K. Warren Foundation, several very faithful pharmaceutical companies for unrestricted grants to the Congress, the University of Marylands MPRC, the University of Texas at Southwestern, and the University of Minnesota. The organizers recognize that the financial and administrative support of the groups mentioned above are only a part of the picture of the sustenance of the ICOSR. The most valuable resource for the Congress over the years has been the enthusiasm and careful preparation made by the active investigators attending the meeting. Their excitement for their work, their wish to share and stimulate their colleagues, and their participation with the Young Investigators makes the ICOSR a meeting that is always highly anticipated.

Clozapine associated cardiotoxicity : findings from Barwon Health

Background: Seclusion is of limited therapeutic value and can be a harmful and traumatic experience for psychiatric consumers. Many psychiatric facilities have made substantial efforts to eliminate seclusion or reduce this practice to negligible levels. Aims: To review the research on seclusion-reduction initiatives in psychiatric facilities. Methods: We reviewed the peer-reviewed, English-language literature on seclusion reduction initiatives. We sourced 16 papers that focused on seclusion reduction initiatives and in which pre- and post-seclusion data were reported. Opinion-based papers and research that focused solely on pharmaceutical methods to reduce seclusion were excluded from our review. Results: Successful seclusion reduction initiatives typically involved senior management implementing multiple changes within the facilities. Although commonalities exist with regard to the interventions used in these facilities to reduce seclusion (e.g., treatment plan improvement, monitoring seclusion episodes, changing the therapeutic environment), the ways in which these initiatives were combined tended to be unique to each organisation. State-level organisations sometimes provided the impetus for such changes to be made. There is strong evidence that changes made to psychiatric facilities were effective in reducing or eliminating seclusion. Conclusion: Seclusion reduction in psychiatric facilities requires strong leadership from senior management. Sometimes leadership from state-level organisations accelerates a seclusion reduction agenda.Context: Although it may seem preposterous to consider the need to reduce the use of summary executions in acute psychiatric inpatient settings because practitioners simply would not consider using such inhumane treatment, it is sobering that many mental health professionals do not hesitate to use seclusion. Objectives: We draw attention to the assumption that underlies the thinking of many mental health professionals that seclusion is acceptable simply because it is available. Key messages: The letter of the law (seclusion is legal) is frequently given precedence over the spirit of the law (seclusion should used as a method of last resort, if at all). The availability of seclusion as an intervention makes its use inevitable. Although sufficient checks and balances exist in society to prevent psychiatric staff from adding summary executions to their ‘‘treatment’’ paradigms, legislators need to set the bar much higher. Outside intervention, in the form of legislation, is needed because the mental health professions seem incapable of discontinuing the use seclusion despite evidence of the trauma it causes to both patients and staff and despite the lack of evidence that it achieves any desirable outcomes. Conclusion: The use of seclusion is unacceptable and should be as impossible and unthinkable as summarily executing our patients. By the use of what would seem, at first glance, an absurd analogy between seclusion and summary execution we highlight the need for a shift in policy and legislation regarding the use of traumatising interventions.

Medical and psychiatric outcomes in a large cohort of patients treated with clozapine

A pilot study was conducted to evaluate the usefulness of granisetron for the treatment of antidepressant induced sexual dysfunction in women. Twelve women with antidepressant induced sexual dysfunction (AISD) were assigned granisetron (n=5) or placebo (n=7) in a 14-day randomized, double-blind, placebo-controlled study. One participant in the granisetron group did not complete the study. Participants were assessed at baseline, day 7 and day 14 using the Feiger Sexual Function and Satisfaction Questionnaire and the Arizona Sexual Experience Scale. No statistical differences were measured at baseline or at endpoint between the granisetron or placebo group. This study did not produce evidence supporting the usefulness of granisetron in AISD.