Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit

Phospholipase C-β1 (PLC-β1) is a critical component of multiple signalling pathways downstream of neurotransmitter receptors. Mice lacking this enzyme display a striking behavioural phenotype with relevance to human psychiatric disease. Glutamatergic dysfunction is strongly associated with several abnormal behavioural states and may underlie part of the phenotype of the phospholipase C-β1 knockout (KO) mouse. A heightened response to glutamatergic psychotomimetic drugs is a critical psychosis-related endophenotype, and in this study it was employed as a correlate of glutamatergic dysfunction. Control (n=8) and PLC-β1 KO mice (n=6) were treated with MK-801, a NMDA receptor (NMDAR) antagonist, following either standard housing or environmental enrichment, and the motor function and locomotor activity thus evoked was assessed. In addition, MK-801 binding to the NMDAR was evaluated through radioligand autoradiography in post-mortem tissue (on a drug-naive cohort). We have demonstrated a significantly increased sensitivity to the effects of the NMDA antagonist MK-801 in the PLC-β1 KO mouse. In addition, we found that this mouse line displays reduced hippocampal NMDAR expression, as measured by radioligand binding. We previously documented a reversal of specific phenotypes in this mouse line following housing in an enriched environment. Enrichment did not alter this heightened MK-801 response, nor NMDAR expression, indicating that this therapeutic intervention works on specific pathways only. These findings demonstrate the critical role of the glutamatergic system in the phenotype of the PLC-β1 KO mouse and highlight the role of these interconnected signalling pathways in schizophrenia-like behavioural disruption. These results also shed further light on the capacity of environmental factors to modulate subsets of these phenotypes.

Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.

Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different.

Psychotic-like experiences in a community sample of adolescents: implications for the continuum model of psychosis and prediction of schizophrenia

Studies conducted in community samples suggest that psychotic-like experiences are common in the general population, leading to suggestions that they are either variations of normal personality or are different expressions of underlying vulnerability to psychotic disorder. Different types of psychotic symptoms may exist, some being normal variants and some having implications for mental health and functioning. The aim of the present study was to determine if different subtypes of psychotic-like experiences could be identified in a community sample of adolescents and to investigate if particular subtypes were more likely to be associated with psychosocial difficulties, that is, distress, depression and poor functioning, than other subtypes. Eight hundred and seventy-five Year 10 students from 34 schools participated in a cross-sectional survey that measured psychotic-like experiences using the Community Assessment of Psychic Experiences; depression using the Centre for Epidemiologic Studies Depression Scale; and psychosocial functioning using the Revised Multidimensional Assessment of Functioning Scale. Factor analysis was conducted to identify any subtypes of psychotic experiences. Four subtypes of psychotic-like experiences were identified: Bizarre Experiences, Perceptual Abnormalities, Persecutory Ideas, and Magical Thinking. Intermittent, infrequent psychotic experiences were common, but frequent experiences were not. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas were strongly associated with distress, depression and poor functioning. Magical Thinking was only weakly associated with these variables. Overall these findings may suggest that infrequent psychotic-like experiences are unlikely to be a specific risk factor for onset of a psychotic disorder in community samples. Given that the different subtypes had varying associations with current difficulties it is suggested that not all subtypes confer the same risk for onset of psychotic disorder and poor outcome. Bizarre Experiences, Perceptual Abnormalities and Persecutory Ideas may represent expressions of underlying vulnerability to psychotic disorder, but Magical Thinking may be a normal personality variant.

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.

The relationship between personality traits and psychotic like experiences in a large non-clinical adolescent sample

Objective: The relationship between personality and psychosis is well established. It has been suggested that this relationship may be partly accounted for by higher levels of depression in individuals with certain personality traits. We explored whether the link between personality and psychotic symptoms is already apparent in adolescence, and if this association would still hold when depression was controlled for. Method: 654 secondary school students were surveyed via self-report questionnaires measuring the Five-Factor model of personality (NEO-FFI), depression (CES-D) and psychotic-like experiences (CAPE). Results: Positive associations were found between Neuroticism and all CAPE-subscales except Magical Thinking, which was in turn associated with all other personality traits when at high levels. Agreeableness was negatively associated with all CAPE-subscales, while Openness to Experience was only positively associated with Persecutory Ideas and Magical Thinking. After controlling for depression, many of the significant associations remained. Conclusion: Our findings suggest that the chance of having psychotic like experiences is more likely for adolescents with certain personality traits. These associations are not fully explained by depression, especially when psychotic experiences are at higher levels. Future research is needed to investigate if these personality traits might put a person at risk for the development of full-blown psychosis.

Cost implications of specific and non-specific treatment for young persons at ultra high risk of developing a first episode of psychosis

Aim: Costs associated with mental health treatment for young persons at 'ultra' high risk (UHR) of developing a psychotic disorder have not previously been reported. This paper reports cost implications of providing psychological and pharmacological intervention for individuals at UHR for psychosis compared with minimal psychological treatment.

Method: Mental health service costs associated with a randomized controlled trial of two treatments (Specific Preventive Intervention: SPI and Needs-Based Intervention: NBI) for UHR young persons were estimated and compared at three time points: treatment phase, short-term follow up and medium-term follow up.

Results: Although the SPI group incurred significantly higher treatment costs than the NBI group over the treatment phase, they incurred significantly lower outpatient treatment costs over the longer term.

Conclusion: This study indicates that specific interventions designed to treat young persons who are identified as being at UHR of psychosis might be associated with some cost savings compared with non-specific interventions.

A naturalistic study of treatment outcomes with aripiprazole in young people with first episode psychosis

Objective: Adequate treatment of a first psychotic episode in young people is a difficult challenge but may be of critical importance for changing the course of psychotic illness. Pharmacotherapy is the standard treatment of psychosis, however there is a paucity of data specific to first-episode psychosis.
Methods: In this study 12 young people who presented with a psychotic episode at a specialised early intervention service were commenced on treatment with aripiprazole. They were assessed at baseline and weeks 4, 6, 24 and 48 using a broad battery of outcome measures. Case notes were also examined.
Results: Data was available for 6 participants at week 48, and of those, one remained on treatment with Aripiprazole at endpoint. Case histories were typified by presentations that included illicit substance use and treatments characterised by several changes in medications. No single treatment choice predominated. Most participants tolerated treatment and showed symptomatic improvement with individualised therapy.
Conclusion: Most participants showed improvement during the treatment period. Aripiprazole was one of many medications used in this study and may have been useful for the treatment of some individuals with first episode psychosis.

Melatonin : an overlooked factor in schizophrenia and in the inhibition of anti-psychotic side effects

This paper reviews melatonin as an overlooked factor in the developmental etiology and maintenance of schizophrenia; the neuroimmune and oxidative pathophysiology of schizophrenia; specific symptoms in schizophrenia, including sleep disturbance; circadian rhythms; and side effects of antipsychotics, including tardive dyskinesia and metabolic syndrome. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this review using keywords: schizophrenia, psychosis, tardive dyskinesia, antipsychotics, metabolic syndrome, drug side effects and melatonin. Articles were selected on the basis of relevance to the etiology, course and treatment of schizophrenia. Melatonin levels and melatonin circadian rhythm are significantly decreased in schizophrenic patients. The adjunctive use of melatonin in schizophrenia may augment the efficacy of antipsychotics through its anti-inflammatory and antioxidative effects. Further, melatonin would be expected to improve sleep disorders in schizophrenia and side effects of anti-psychotics, such as tardive dyskinesia, metaboilic syndrome and hypertension. It is proposed that melatonin also impacts on the tryptophan catabolic pathway via its effect on stress response and cortisol secretion, thereby impacting on cortex associated cognition, amygdala associated affect and striatal motivational processing. The secretion of melatonin is decreased in schizophrenia, contributing to its etiology, pathophysiology and management. Melatonin is likely to have impacts on the metabolic side effects of anti-psychotics that contribute to subsequent decreases in life-expectancy.

Elementary phenomena, body disturbances and symptom formation in ordinary psychosis

In my research, I examined body phenomena in psychosis by exploring onset, triggering events and stabilisation in psychosis. I concluded that body disturbances can be important indicators for the onset of psychosis and, that these disturbances provide a framework for better understanding the recovery from psychosis, particularly in schizophrenia.

Costs of psychosis in 2010: findings from the second Australian national survey of psychosis

Objectives
To estimate the annual costs of psychosis in Australia from societal and government perspectives and assess whether average costs per person differ by principal service provider at time of census.

Methods
Costs of psychosis encompassing health sector costs, other sector costs, and productivity losses were assessed for 2010 using a prevalence-based, bottom-up approach. Resource use data were obtained from the second Australian National Survey of Psychosis and unit costs were from government and non-government organization (NGO) sources. Costs to society were assessed by principal service provider at census: public specialized mental health services (PSMHS) and NGOs during the census month (current clients), and PSMHS in the 11 months preceding census (recent clients), and any differences were ascertained.

Results
The average annual costs of psychosis to society are estimated at $77,297 per affected individual, comprising $40,941 in lost productivity, $21,714 in health sector costs, and $14,642 in other sector costs. Health sector costs are 3.9-times higher than those for the average Australian. Psychosis costs Australian society $4.91 billion per annum, and the Australian government almost $3.52 billion per annum. There are significant differences between principal service providers for each cost category. Current PSMHS clients had the highest health sector costs overall, and the highest mental health ambulatory, inpatient, and antipsychotic medication costs specifically. NGO clients had the highest other sector costs overall and the highest NGO assistance, supported employment, and supported accommodation costs. Recent PSMHS clients had the lowest productivity losses for reduced participation and the highest costs for absenteeism and presenteeism.

Conclusions
The costs of psychosis are broad ranging and very high. Development and implementation of cost-effective prevention, treatment, and support strategies is critical to maximizing the efficiency of service delivery. A needs-based framework based on principal service provider and recency of contact may facilitate this process.