Neurobiology of schizophrenia spectrum disorders: The role of oxidative stress

Mitochondrial dysfunction and oxidative stress are increasingly implicated in the pathophysiology of schizophrenia. The brain is the body's highest energy consumer, and the glutathione system is the brain's dominant free radical scavenger. In the current paper, we review the evidence of central and peripheral nervous system anomalies in the oxidative defences of individuals with schizophrenia, principally involving the glutathione system. This is reflected by evidence of the manifold consequences of oxidative stress that include lipid peroxidation, protein carboxylation, DNA damage and apoptosis - all potentially part of the process of neuroprogression in the disorder. Importantly, oxidative stress is amenable to intervention. We consider the clinical potential of some possible interventions that help reduce oxidative stress, via augmentation of the glutathione system, particularly N-acetyl cysteine. We argue that a better understanding of the mechanisms and pathways underlying oxidative stress will assist in developing the therapeutic potential of this area.

Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial.

While statins target many of the pathways to neuroprogression in schizophrenia, the safety and efficacy of statins for treating schizophrenia has never been examined. This is an 8-week randomized double blind controlled clinical trial examining the efficacy and safety of adjunctive lovastatin (20 mg/day) treatment or placebo for people with schizophrenia. The baseline characteristics of the two groups were not different. Endpoint changes in Positive and Negative Syndrome Scale (PANSS) total and subscale scores did not differ between the two groups. However there was a significant difference between the doses of risperidone used in the two groups. The mean dose in the lovastatin and placebo groups were 4.8(1.8) and 3.4(1.4) mg/day, respectively (P<.03). No serious adverse events were reported. Slowness of movements, muscle rigidity, increased appetite, and decreased energy were the most common adverse effects, and these rates did not differ between the two groups. This study failed to demonstrate a benefit of lovastatin on symptoms of schizophrenia. This combination was well tolerated. However, a higher dosage of risperidone was used for treating the disorder in those taking concomitant lovastatin compared to placebo.

Towards stage specific treatments: Effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia.

Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomized in a double fashion to 24weeks (placebo=62; NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into <10years, 10-<20years and >20years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effects related outcomes. The pattern of changes suggests this mediator effect of duration of illness in response to treatment is more evident in those participants with 20years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments.

Psychotropic medication use and autism spectrum disorders: caregiver and invidividual perspectives

 This thesis examined psychotropic medication use in Autism Spectrum Disorders in an Australian sample from caregiver and individual perspectives. This thesis found there is a clear need for collaboration between individuals with an ASD, their caregivers and professionals to ensure that psychotropic medication is used in an appropriate and transparent manner.

A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: results from the second Australian national psychosis survey

Introduction It remains uncertain whether schizoaffective disorder (SAD) is a discrete diagnostic entity, is a variant of either a psychotic mood disorder such as bipolar disorder (BDP) or schizophrenia (SCZ), or exists on a spectral continuum between these disorders. The present study examined whether SCZ, SAD, and BDP differed qualitatively on demographic and clinical variables based on a large Australian dataset.

Fetal programming of schizophrenia: select mechanisms

Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia.

Mitochondrial dysfunction in schizophrenia : Pathways, mechanisms and implications.

Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities. Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.

Interventions to improve medication adherence in adult kidney transplant recipients: a systematic review.

In kidney transplantation, adherence to immunosuppressive therapy is paramount for long-term graft survival. This systematic review aimed to assess the effectiveness of interventions to improve medication adherence in adult kidney transplantation.

Impact of medication reconciliation and review on clinical outcomes

To examine the evidence regarding the effectiveness of medication reconciliation and review and to improve clinical outcomes in hospitals, the community, and aged care facilities.

Interventions to reduce medication errors in pediatric intensive care

To systematically examine the research literature to identify which interventions reduce medication errors in pediatric intensive care units.

Medication errors in ED: do patient characteristics and the environment influence the nature and frequency of medication errors?

Background: Medication safety is of increasing importance and understanding the nature and frequency of medication errors in the Emergency Department (ED) will assist in tailoring interventions which will make patient care safer. The challenge with the literature to date is the wide variability in the frequency of errors reported and the reliance on incident reporting practices of busy ED staff. Methods: A prospective, exploratory descriptive design using point prevalence surveys was used to establish the frequency of observed medication errors in the ED. In addition, data related to contextual factors such as ED patients, staffing and workload were also collected during the point prevalence surveys to enable the analysis of relationships between the frequency and nature of specific error types and patient and ED characteristics at the time of data collection. Results: A total of 172 patients were included in the study: 125 of whom patients had a medication chart. The prevalence of medication errors in the ED studied was 41.2% for failure to apply patient ID bands, 12.2% for failure to document allergy status and 38.4% for errors of omission. The proportion of older patients in the ED did not affect the frequency of medication errors. There was a relationship between high numbers of ATS 1, 2 and 3 patients (indicating high levels of clinical urgency) and increased rates of failure to document allergy status. Medication errors were affected by ED occupancy, when cubicles in the ED were over 50% occupied, medication errors occurred more frequently. ED staffing affects the frequency of medication errors, there was an increase in failure to apply ID bands and errors of omission when there were unfilled nursing deficits and lower levels of senior medical staff were associated with increased errors of omission. Conclusions: Medication errors related to patient identification, allergy status and medication omissions occur more frequently in the ED when the ED is busy, has sicker patients and when the staffing is not at the minimum required staffing levels.