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Quantitative real-time polymerase chain reaction (PCR) is an effective approach in investigating the effects of exogenous compounds on gene expression. This is often achieved by exploiting so-called 'housekeeping' genes as baseline controls to normalise expression levels, which have historically been assumed to have a relatively stable expression pattern. Recent non-in-vitro studies have questioned the validity of this, but previous in-vitro data were lacking following antidepressant treatment. We here investigated the stability of 12 housekeeping genes during treatment of the mouse L929 fibroblast cell line with escitalopram and nortriptyline. Cells were cultured in the presence of antidepressant at 1 µM or 10 µM for 30 min, 24 h or 48 h, and RNA subjected to quantitative PCR (qPCR). Stability of relative transcript expression values was assessed via gene-gene expression ratios and intra- and inter-group variation (using geNorm and NormFinder programs). The three most stable transcripts were adenosine triphosphate (ATP) synthase, H+ transporting mitochondrial F1 complex, β subunit, β-2 microglobulin and cytochrome c-1. The least stable were Gapdh, eukaryotic translation initiation factor 4A2 and Calnexin (Canx). In conclusion, care must be taken when choosing reference transcripts for analysis in qPCR. For in-vitro pharmacological studies, it should not be assumed that 'housekeeping' genes are stable. [ABSTRACT FROM AUTHOR]

Aripiprazole has recently received approval for the treatment of moderate to severe manic episodes in bipolar I disorder and prevention of new manic episodes in aripiprazole-responsive patients. Aripiprazole differs from other antipsychotics in its pharmacology, and the need for prescribing guidance in the UK was recently identified. A UK multidisciplinary panel was convened in November 2007. This report describes the consensus agreed during the meeting on the optimal approach to prescribing aripiprazole: how best to approach initiation of, and switching to, treatment with aripiprazole and management strategies for side effects. A literature review of the randomised controlled clinical trials of aripiprazole in mania supports these recommendations. Aripiprazole should be initiated at 15 mg/day (range 5-20 mg/day). If necessary, adjunctive medication should be used in early treatment to manage side effects or assist in management of symptoms such as agitation. When switching to aripiprazole, the therapeutic dose of current treatment should be maintained while adding aripiprazole 15 (5-20) mg/day. Only once an effective dose of aripiprazole is reached should previous medication be reduced. Nausea, insomnia and agitation typically resolve within days. Some principles for dosing and switching are provided to assist with a successful treatment outcome with aripiprazole in mania. [ABSTRACT FROM AUTHOR]

The Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) was developed to provide a comprehensive measure for rating non-neurological adverse drug reactions (ADRs) to antipsychotics. Although there were already available measures that adequately rated specific non-neurological ADRs, such as sexual side effects, a need was identified for a scale that comprehensively rated the full range of non-neurological ADRs commonly seen across the spectrum of first and second generation antipsychotic drugs, including metabolic and autonomic ADRs. This article reports on work to establish the interrater reliability of an early version and a later, more comprehensive version of the ANNSERS (versions 1 and 2, v1 and v2, respectively). The measures were administered in London centres to patients treated with clozapine. Trained clinicians rated the patients simultaneously and independently. Interrater reliability on the scores was calculated using the kappa coefficient method. The results (mean kappa coefficients of 0.77 and 0.72, respectively) indicate that substantial interrater reliability was achieved for both versions. Items for which the main basis for rating was laboratory investigations rather than patient interview were largely excluded from this study, and kappas were also not calculated for items with a low frequency (less than 10%) of endorsement. Samples of patients on other antipsychotics would be required to reliably calculate kappa coefficients for these items. In conclusion, the ANNSERS represents a clinically applicable research innovation, with good interrater reliability on clinician judged items, which is now available for the comprehensive assessment of non-neurological ADRs to antipsychotics, to aid the processes of clinical audit, research and drug discovery. [ABSTRACT FROM AUTHOR]

Despite the common use of MDMA (ecstasy) in the UK, the mechanism underlying associated potentially fatal cerebral oedema is unclear. We used a new experimental approach working directly with dubbers to perform a study on 30 (17 male) experienced dubbers (mean 6.6 years of dubbing). Pre- and post clubbing measurements were performed to compare plasma levels of pituitary hormones (vasopressin, oxytocin), plasma and urine osmolality, urinary pH, and plasma sodium and urea. Ecstasy consumption was confirmed by using urinary drug screening pre- and post-clubbing. MDMA was detected in the urine samples of 17 subjects, three of which tested positive during pre-clubbing tests. Mean plasma vasopressin concentration increased in the MDMA group (1.28 ± 0.29 to 143 ± 0.41 pmol/l), but fell in other participants (1.23 ± 0.42 to 1.16 ± 0.0.34 pmol/l). Similarly, mean plasma oxytocin concentrations increased after ingestion of MDMA (2.02 ± 0.29 to 243 ± 0.24 pmol/l), but fell in the group that did not use MDMA (2.17 ± 0.36 pmol/l to 1.89 ± 0.37pmol/l). There was a significant group by time interaction for plasma osmolality and plasma sodium (p = 0.001 and p = 0.003, respectively) and between change in urinary osmolality (p<0.001) and MDMA use, with the pattern of change being consistent with the induction of inappropriate vasopressin secretion (also known as SIADH) by MDMA. This report demonstrates SIADH in ecstasy-using 'clubbers', which has important clinical implications. [ABSTRACT FROM AUTHOR]

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is highly expensive in calculable and incalculable costs. Measures which impact the cost in the most severely affected are likely to produce the greatest cost reductions. Studies regarding clozapine in the USA have demonstrated clear cost-effectiveness, despite the high prescription costs. There are no prior UK studies.Method: We performed a cost-effectiveness analysis comparing the three years prior to commencing clozapine to the period following establishment of clozapine treatment (mean 36.4 months) for 26 patients with chronic schizophrenia or schizoaffective disorder.Results: There was a significant improvement in all clinical ratings applied (and a mean net saving of ponds 3768 per annum). The cost-effectiveness of clozapine was double that of conventional neuroleptics (15.2 pre-, 33.0 post-clozapine, P < 0.005).Conclusions: As a naturalistic study our data provide valuable information on the cost-effectiveness of clozapine in the UK. Our methodology could be applied in a community setting or in the study of another atypical neuroleptic. [ABSTRACT FROM AUTHOR]