Assessing cost-effectiveness in mental health: family interventions for schizophrenia and related conditions

Objective: Existing evidence suggests that family interventions can be effective in reducing relapse rates in schizophrenia and related conditions. Despite this, such interventions are not routinely delivered in Australian mental health services. The objective of the current study is to investigate the incremental cost-effectiveness ratios (ICERs) of introducing three types of family interventions, namely: behavioural family management (BFM); behavioural intervention for families (BIF); and multiple family groups (MFG) into current mental health services in Australia. Method: The ICER of each of the family interventions is assessed from a health sector perspective, including the government, persons with schizophrenia and their families/carers using a standardized methodology. A two-stage approach is taken to the assessment of benefit. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted. The second stage involves application of 'second filter' criteria (including equity, strength of evidence, feasibility and acceptability to stakeholders) to results. The robustness of results is tested using multivariate probabilistic sensitivity analysis. Results: The most cost-effective intervention, in order of magnitude, is BIF (A$8000 per DALY averted), followed by MFG (A$21 000 per DALY averted) and lastly BFM (A$28 000 per DALY averted). The inclusion of time costs makes BFM more cost-effective than MFG. Variation of discount rate has no effect on conclusions. Conclusions: All three interventions are considered 'value-for-money' within an Australian context. This conclusion needs to be tempered against the methodological challenge of converting clinical outcomes into a generic economic outcome measure (DALY). Issues surrounding the feasibility of routinely implementing such interventions need to be addressed.

Low prenatal vitamin D alters morphology, cell density and gene expression in adult rat brain: Correlations with schizophrenia

Statement of the study: Based on data from ecological and analytic epidemiological studies, we have proposed that low prenatal vitamin D is a candidate risk-modifying factor for schizophrenia. Previously, we demonstrated that low prenatal vitamin D adversely affected brain development in neonatal rats (Eyles et al, 2003). Here we examine the impact of both prenatal and early life hypovitaminosis D on various outcomes in the adult rat brain. Methods: Female Sprague-Dawley rats were made vitamin D deficient via the use of a special diet (Dyets CA) and lighting conditions that excluded UVB radiation. Animals were kept under these conditions for 6 weeks then mated with males kept under normal conditions. Vitamin deplete dams were kept under these conditions during pregnancy. Offspring from two test groups were examined. Offspring were either reared with dams repleted with vitamin D at birth or remained under deplete conditions till weaning. Both test groups were weaned under normal vitamin D conditions and remained so till testing at adulthood. We compared the brains of adult offspring kept under both test conditions with animals from control environments. Summary of results: We found a significant persistent dose-related increase in lateral ventricle volume and alterations in anterior cingulate and prefrontal cortical cell densities (consistent with the known prodifferentiation properties of this steroid). In both test groups we observed a reduced expression of NGF as well as a down-regulation of transcripts coding for GABAA alpha 4 receptor and two neuronal structural elements; MAP2 and Neurofilament L. Conclusion: These findings provide further evidence that vitamin D is involved in brain development. An increase in prefrontal cortical cell density, a reduction neuronal structural elements and persistent ventriculomegaly are all common anatomical findings in the brains of patients with schizophrenia. The specific reduction in transcripts for neuronal structural proteins but not GFAP is also in accordance with the proposal that frontal cortical architecture in schizophrenia reflects a reduction in connectivity rather than a reduction in glial processes(Goldman-Rakic and Selemon, 1997). These findings confirm the biological plausibility of early life hypovitaminosis D as a risk factor for schizophrenia.

Age-at-first-registration for affective psychosis and schizophrenia

We compared the age-at-first-registration for patients with schizophrenia and affective psychosis in a statewide mental health register. After excluding those receiving (1) a diagnosis of both schizophrenia (ICD-9 295.x) and affective psychosis (ICD-9 296.x), or (2) a diagnosis of ICD-9 296.1 (which can cover major depressive episode), we adjusted the distributions for the age structure of the background general population. We found that all distributions showed a wide age range of onset, with a similar male modal age group of 20-24 for schizophrenia and 25-29 for affective psychosis. The female modal age group was 50-54 for both diagnoses. Although more individuals were diagnosed with schizophrenia (males = 2,434, females = 1,609) than with affective psychosis (males = 670, females = 913), the shape of the two distributions was similar. This finding suggests that factors influencing age-at-first-registration for schizophrenia and affective psychosis may be similar, especially for females.

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging ( FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Developmental vitamin D deficiency alters adult behaviour: An informative animal model of schizophrenia

Background: There is growing evidence that vitamin D is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, we have explored the role of vitamin D in the developing brain and behaviour using whole animal models. Methods: Sprague-Dawley rats were fed a vitamin D deficient diet (DVD) or control diet 6 weeks prior to mating and housed under UVB-free lighting conditions. On the day of birth all rats were fed a control diet for the remainder of the study. We observed behaviour at two timepoints; on the day of birth to study maternal behaviour, and at 10 weeks of age to study offspring behaviour in adulthood, under baseline and drug induced conditions (MK-801, haloperidol, amphetamine). Results: Prenatal vitamin D deficiency results in subtle alterations in maternal behaviour as well as long lasting effects on the adult offspring, despite a return to normal vitamin D levels during postnatal life. These affects were specific to transient prenatal vitamin D depletion as adult vitamin D depletion, combined prenatal and chronic postnatal vitamin D depletion, or ablation of the vitamin D receptor in mice led to markedly different outcomes. Conclusions: The developmental vitamin D (DVD) model now draws strength from epidemiological evidence of schizophrenia and animal experiments. Although the DVD model does not replicate every aspect of schizophrenia, it has several attractive features: (1) the exposure is based on clues from epidemiology; (2) it reproduces the increase in lateral ventricles; (3) it reproduces well-regarded behavioural phenotypes associated with schizophrenia (e.g. MK- 801 induced hyperlocomotion); and (4) it implicates a disturbance in dopamine signaling. In summary, low prenatal levels of vitamin D can influence critical components of orderly brain development and that this has a long lasting effect on behaviour.

Lateralized deficit of response inhibition in early-onset schizophrenia

Background. The ability to inhibit inappropriate or unwanted actions is a key element of executive control. The existence OF executive function deficits in schizophrenia is consistent with frontal lobe theories of the disorder. Relatively few Studies have examined response inhibition in schizophrenia, and none in adolescent patients with early-onset schizophrenia (EOS). Methods. Twenty-one adolescents with (lie onset of clinically impairing psychosis before 19 years of age and 16 matched controls performed a stop-signal task to assess response inhibition. The patients with EOS were categorized Lis paranoid (n= 10) and Undifferentiated subtypes (n= 11). The undifferentiated group had higher levels of negative symptomatology. Stop-signal reaction time (SSRT) and go-signal reaction time (Go-RT) were analysed with respect to hand of response. Results. The Undifferentiated early-onset patients had significantly longer SSRTs, indicative of poor response inhibition, for the left hand compared to the paranoid early-onset patients and control participants. No differences existed for inhibitory control with the right hand. The three groups did not differ in Go-RT. Conclusions. Our results indicate a specific lateralized impairment of response inhibition in patients With Undifferentiated, but not paranoid, EOS. These findings are consistent with reports of immature frontostriatal networks in EOS and implicate areas such as the pre-motor cortex and Supplementary motor area (SMA) that are thought to play a role in both voluntary initiation and inhibition of movement.

Cognitive deficits, length of illness and symptom severity in schizophrenia

Background Research using neuropsychological testing has demonstrated that patients with schizophrenia show deficits in multiple neurocognitive domains. The aim of this study is to identify cognitive deficits that correlate with length of illness and symptom severity. Method Twenty clinically stable outpatients with chronic schizophrenia (18M : 2F) and 14 healthy controls (13M : 1F), matched on age, gender and parental education, were administered a neuropsychological battery consisting of the Hayling Sentence Completion Test (HSCT), WMS-III Verbal Paired Associates & Letter Number Sequencing, Modified Card Sort Test (MCST), Pyramids & Palm Trees Test, National Adult Reading Test (NART), Controlled Oral Word Association Test (COWAT), and WAIS-III. Severity of symptoms was rated with the Structured Clinical Interview – Positive and Negative Syndromes Scale (SCI-PANSS). Results In comparison to controls, patients showed significant deficits on all of the neuropsychological tasks except for the COWAT. MCST total categories, NART, Verbal IQ and arithmetic, similarities & digit symbol of the WAIS-III had the largest effect size between the groups. The longer the illness duration, the poorer the performance on WAISIII block design and the lower the performance IQ score. The poorer the performance on WMS-III letter number sequencing, the greater the positive symptoms, negative symptoms and general psychopathology. Conclusion Compared to controls, patients showed large effect sizes on measures of executive functioning, intelligence, working memory, verbal comprehension and speed of processing. The findings suggest that impairment in executive functioning and performance IQ is associated with length of illness, while impairment in working memory is associated with heightened symptom severity.

Normal and anomalous classification of category exemplars in schizophrenia

Background Schizophrenia has been associated with semantic memory impairment and previous studies report a difficulty in accessing semantic category exemplars (Moelter et al. 2005 Schizophr Res 78:209–217). The anterior temporal cortex (ATC) has been implicated in the representation of semantic knowledge (Rogers et al. 2004 Psychol Rev 111(1):205–235). We conducted a high-field (4T) fMRI study with the Category Judgment and Substitution Task (CJAST), an analogue of the Hayling test. We hypothesised that differential activation of the temporal lobe would be observed in schizophrenia patients versus controls. Methods Eight schizophrenia patients (7M : 1F) and eight matched controls performed the CJAST, involving a randomised series of 55 common nouns (from five semantic categories) across three conditions: semantic categorisation, anomalous categorisation and word reading. High-resolution 3D T1-weighted images and GE EPI with BOLD contrast and sparse temporal sampling were acquired on a 4T Bruker MedSpec system. Image processing and analyses were performed with SPM2. Results Differential activation in the left ATC was found for anomalous categorisation relative to category judgment, in patients versus controls. Conclusions We examined semantic memory deficits in schizophrenia using a novel fMRI task. Since the ATC corresponds to an area involved in accessing abstract semantic representations (Moelter et al. 2005), these results suggest schizophrenia patients utilise the same neural network as healthy controls, however it is compromised in the patients and the different ATC activity might be attributable to weakening of category-to-category associations.