Evangelia M. Tsapakis

Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population

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 clubbers to perform a study on 30 (17 male) experienced clubbers (mean 6.6 years of clubbing). 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 con.rmed by using urinary drug screening preand 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 1.43 ± 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 2.43 ± 0.24 pmol/l), but fell in the group that did not use MDMA (2.17 ± 0.36 pmol/l to 1.89 ± 0.37 pmol/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.

Regulation of working memory by dopamine D4 receptor in rats.

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D1 and D2 receptors, with most evidence suggesting a dominant role for the D1 receptor. Since the dopamine D4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D4 receptor in working memory, and suggest innovative, D4-based, treatment of cognitive deficits associated with neuropsychiatric disorders.

Risk of osteoporosis and fracture incidence in patients on antipsychotic medication

Introduction: In patients suffering from schizophrenia and bipolar disorder, antipsychotics are the mainstay of treatment worldwide. By blocking D2 brain mesolimbic receptors, antipsychotics are believed to reduce and control psychotic experiences, but recent evidence has suggested that they may also have adverse effects on bone mineral architecture and fracture incidence. Areas covered: This study reviews current literature surrounding the use of antipsychotics and their effects on bone homeostasis. The primary medical search engines used for the study are Ovid MEDLINE (1950 – April 2010), EMBASE (1988 – April 2010) and PsychINFO (1987 – April 2010) databases. Expert opinion: Typical antipsychotics, in addition to the atypical antipsychotics risperidone and amisulpride, have been shown to increase serum prolactin levels in in vivo human studies. Results from animal and human in vitro and in vivo studies have demonstrated that high concentrations of prolactin have been shown to adversely affect bone cell metabolism and accelerate the rate bone mineral density loss, thereby increasing fracture risk. Increasing awareness of the side effect profile of antipsychotic medications on bone metabolism may prompt clinicians to screen patients at high risk of antipsychotic-induced osteoporosis and provide treatment, which may reduce the incidence of potentially avoidable fractures.

Clinical management of negative symptoms of schizophrenia: An update.

Overwhelming research evidence suggests that the negative symptoms of schizophrenia (NSS) contribute more to impaired quality of life and poor functioning than positive symptoms, and that NSS, including affective flattening, alogia and avolition are present in at least one-fifth of patients diagnosed with schizophrenia. Despite this, management of NSS continues to be a major clinical unmet need as treatment with current antipsychotic medication seems to reach at best modest efficacy. A critical review of the current pharmacological, non-pharmacological and psychosocial treatments available for NSS is presented here, using data retrieved from the MEDLINE/PUBMED, the Cochrane Database of Systematic Reviews and the ClinicalTrials.gov databases. An early and accurate diagnosis using selective scales is essential for documentation and monitoring of change in NSS according to treatment response. Typical and atypical antipsychotic drugs, showed modest efficacy in managing NSS. Conflicting results were obtained with the use of glycinergic neuromodulators, anticholinergics, antidepressants, anticonvulsants, psychostimulants, modafinil and 5-HT3 receptor antagonists. Moreover, non-pharmacological therapies including psychological therapies have failed to address NSS effectively. At present, it appears that the best effective approach for clinical management of NSS is achieved by complementing drug therapy with psychosocial therapies. Continuing basic and clinical research for the understanding of the genetic, behavioral and neural basis of NSS should yield novel pharmacotherapies with superior efficacy, tolerability and long-term maintenance for improved treatment of NSS.

Pharmacogenetic studies of change in cortisol on ecstasy (MDMA) consumption.

In this study we investigate the association of cytochrome P450 enzyme CYP2D6, catechol-O-methyl transferase (COMT, Val158Met) and serotonin transporter promoter (5-HTTLPR) genotypes on change in cortisol concentration following 3, 4-methylenedioxy-methamphetamine (MDMA, ‘ecstasy’) consumption. Forty-eight subjects (30 males, mean age 23 years), self-nominating regular clubbers provided ‘in the field’ pre- and post-clubbing biological samples and associated information. Of the 39 subjects who provided a post-clubbing urine sample, 21 were positive for MDMA. Plasma cortisol concentrations increased in subjects (n = 48) tested for cortisol, with changes being significantly greater in the MDMA-positive group (736.9 ± 83.2 vs. 350.9 ± 34.5 mmol/l, p = 0.001). We found a positive association between the low activity COMT genotype (Met/Met) and MDMA-induced change in cortisol and also between this and change in cortisol in the whole sample (p = 0.039, Bonferroni corrected). For CYP2D6, there was an association between genotype and change in cortisol, confined to subjects with MDMA-positive urine post-clubbing (p = 0.003, Bonferroni corrected). There was no association with 5-HTTLPR genotype. These associations suggest that chronic use of MDMA may lead to HPA axis dysregulation and that the magnitude of this may be moderated by genetic polymorphism, and warrant further investigation in a larger sample of those who consume the drug on a regular basis.

Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in CYP2D6 and COMT:

We hypothesised that genetically determined poor metabolism of 3,4-methylene dioxymetamphetamine (MDMA) due either to the presence of CYP2D6 genotypes giving absent or low CYP2D6 enzyme activity, or a COMT genotype predicting low COMT enzyme activity would be associated with a greater degree of MDMA-induced reduction in plasma sodium and osmolality than other genotypes at these genes following consumption of ‘ecstasy’ tablets by clubbers. Of the 48 subjects who returned to the test site post-clubbing, 30 provided samples for measurement of vasopressin (AVP), plasma sodium, urea and plasma and urine osmolality. Genotyping was performed for functional variants in CYP2D6 (n = 29) and COMT (Val158Met, n = 30). In subjects with urinary MDMA detected post-clubbing, there was a significant association between change in plasma osmolality (p = 0.009) and in plasma sodium (p = 0.012) and CYP2D6 genotypic category. Individuals with the low-activity but readily inhibitable CYP2D6 extensive metaboliser/intermediate metaboliser (EM/IM) genotype showed greater reductions in these measures than all other CYP2D6 genotypic categories. COMT low-activity genotypes (Met/Met and Val/Met) were also significantly associated with reductions in plasma osmolality (p = 0.028) and in plasma sodium (p = 0.003). On conservative Bonferroni correction for two independent genes, the CYP2D6 and COMT plasma sodium findings remain significant. The relatively high frequency of the low-activity CYP2D6 and COMT genotypes in the population warrants further attention, since consumption of free water following ingestion of MDMA in these individuals may trigger dilutational hyponatraemia and increased risk of syndrome of inappropriate antidiuretic hormone secretion.

Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?:

Background: The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes. Methods: A Caucasian sample of 70 patients was recruited in 1996–1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months prior to assessment. All patients were genotyped for CYP2D6 alleles*3–5, *41, and for amplifications of the gene. Results: There were 13 patients with TD. The mean (standard deviation (SD)) years of duration of antipsychotic treatment in TD-positive was 15.8 (7.9) vs TD-negative 11.1 (7.4) (p=0.04). Increased odds of experiencing TD were associated with increased ability to metabolize CYP2D6, as measured by genotypic category (odds ratio (OR)=4.2), increasing duration in treatment (OR=1.0), and having drug-induced Parkinsonism (OR=9.7). Discussion: We found a significant association between CYP2D6 genotypic category and TD with the direction of effect being an increase in the number of functional CYP2D6 genes being associated with an increased risk of TD. This is the first study to examine the association between TD and CYP2D6 in Caucasians with this number of genotypic categories. In the future, metabolomics may be utilized in the discovery of biomarkers and novel drug targets.

Effects of Antidepressant Drug Exposure on Gene Expression in the Developing Cerebral Cortex

To clarify the basis of limited responses in children and adolescents to antidepressant treatments considered standard in the treatment of adult major depressive disorder, juvenile Sprague–Dawley rats were subjected to 21‐day treatment with dissimilar antidepressant drugs fluoxetine, imipramine, or vehicle control. Total RNA was extracted from brain frontal cortices and hybridized to the Affymetrix 230.2 chip. A total of 18 microarrays were analyzed (i.e., six biological replicates in three treatment groups). Transcripts identified were validated using Taqman real‐time quantitative PCR methodology, and the relative expression of each gene was also determined. In both the imipramine‐ and fluoxetine‐treated animals, expression of six genes was down‐regulated (ANOVA‐filtered gene expression data using dChip [version 2005]): Gpd1; Lrrn3; Sult1A1; Angptl4; Mt1a; Unknown. Furthermore, four genes were over‐expressed: P4Ha1; RDG1311476; Rgc32; and SLC25A18‐like by both imipramine and fluoxetine. These data demonstrate that antidepressant drugs interfere with the expression of genes involved in cell signaling, survival, and protein metabolism. Our results show that antidepressants regulate the induction of highly specific transcriptional programs in the developing frontal cortex. These findings provide novel insights into the long‐term molecular actions of antidepressant drugs in the developing brain. Synapse 68:209–220, 2014.

Clinical and therapeutic role of mentalization in schizophrenia—a review

Recent empirical findings from clinical and genetic studies suggest that mentalization, a key area of social cognition, is a distinct construct, although it is closely related to the neurocognitive deficits and symptoms of schizophrenia. Mentalization contributes a great deal to impaired social functioning. Current measures often display methodological problems, and many aspects should be taken into account when assessing mentalization. Moreover, advances in cognitive and affective neurosciences have led to the development of more advanced behavioral methods to assess the relationship between cognitive functions, symptoms, and social cognition based on their underlying neural mechanisms. The development of assessment tools that better examine the neural circuitry of such relationships may lead to the development of new psychosocial and pharmacological treatments.

Using a preclinical approach to reveal potential mechanisms of ADRs to antidepressants in adolescents

A recent meta-analysis of the efficacy of all types of antidepressants in juvenile major depressive disorder patients [1] urged that additional research be undertaken to clarify the basis of limited responses in adolescents and children to antidepressant treatments considered standard in the treatment of adult major depressive disorder (MDD). Sprague-Dawley rats were treated chronically with fluoxetine, imipramine, tranylcypromine or vehicle control. Total RNA was extracted from brain cortices, cRNA was fragmented and hybridised to Affymetrix Rat Genome 230 2.0 microarrays. A total of 24 microarrays were analysed (ie, 6 biological replicates in 4 treatment groups) and information on the probesets of interest was obtained using different websites. Taqman real-time qPCR methodology was used to validate the transcripts identified from the microarray data-analysis as the most significantly differentially expressed in response to treatment with imipramine or fluoxetine compared to vehicle. The relative expression of each gene was also determined. In both the imipramine- and fluoxetine-treated animals, expression of several genes was altered. These function in signal transduction (e.g., angiopoietin-like 4 protein), protein metabolism (e.g., sulfotransferase family 1A, phenol-preferring, member 1), cell survival (e.g., response gene to complement 32, metallothionein 1a), and nuclear functions (e.g., similar to Cat eye syndrome critical region protein 2). Therefore, in the developing rodent cortex, antidepressants alter the expression of genes involved in signalling, cellular survival and protein metabolism, involved in critical functions including neuronal plasticity. These findings have implications for the mechanisms of ADRs to antidepressants in children and adolescents.