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.

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.

Functional connectivity and brain networks in schizophrenia.

Schizophrenia has often been conceived as a disorder of connectivity between components of large-scale brain networks. We tested this hypothesis by measuring aspects of both functional connectivity and functional network topology derived from resting-state fMRI time series acquired at 72 cerebral regions over 17 min from 15 healthy volunteers (14 male, 1 female) and 12 people diagnosed with schizophrenia (10 male, 2 female). We investigated between-group differences in strength and diversity of functional connectivity in the 0.06-0.125 Hz frequency interval, and some topological properties of undirected graphs constructed from thresholded interregional correlation matrices. In people with schizophrenia, strength of functional connectivity was significantly decreased, whereas diversity of functional connections was increased. Topologically, functional brain networks had reduced clustering and small-worldness, reduced probability of high-degree hubs, and increased robustness in the schizophrenic group. Reduced degree and clustering were locally significant in medial parietal, premotor and cingulate, and right orbitofrontal cortical nodes of functional networks in schizophrenia. Functional connectivity and topological metrics were correlated with each other and with behavioral performance on a verbal fluency task. We conclude that people with schizophrenia tend to have a less strongly integrated, more diverse profile of brain functional connectivity, associated with a less hub-dominated configuration of complex brain functional networks. Alongside these behaviorally disadvantageous differences, however, brain networks in the schizophrenic group also showed a greater robustness to random attack, pointing to a possible benefit of the schizophrenia connectome, if less extremely expressed.

Stargazin involvement with bipolar disorder and response to lithium treatment.

OBJECTIVES: Multiple reports have implicated chromosomal region 22q13.1 in both schizophrenia and bipolar disorder. The calcium channel gamma-2 subunit gene (cacng2, Stargazin) located on 22q13.1 was recently reported to be associated with schizophrenia. We aimed to examine the expression levels of Stargazin in post-mortem brain samples of patients with schizophrenia, patients with bipolar disorder (BPD) and healthy controls, test for genetic association between Stargazin and these disorders and test for genetic association between Stargazin and response to lithium treatment. METHODS: Expression analysis was carried out by quantitative reverse transcription-PCR in RNA samples from dorsolateral prefrontal cortices of patients with schizophrenia, patients with BPD and controls (n=35 each). Twelve single nucleotide polymorphisms encompassing Stargazin were genotyped in DNA samples from two cohorts, 'Aberdeen' and 'Cagliari' (n=410, 170, respectively). Patients were treated with lithium and divided into groups according to their response. RESULTS: A 1.6-fold overexpression of Stargazin was observed in patients with BPD (P=0.000036). No difference in expression was observed in patients with schizophrenia. None of the 12 genotyped single nucleotide polymorphisms were associated with BPD, but three of them were significantly associated with lithium response: one in both cohorts (rs2284017) and two (rs2284018, rs5750285) each in a different cohort. Haplotype analysis revealed significant 'response-protective' and 'response-inhibitive' haplotypes in both cohorts. CONCLUSION: Our findings suggest that Stargazin dysregulation may be involved with the pathophysiology of BPD, but not with that of schizophrenia, and that Stargazin polymorphisms may play a role in the response to lithium treatment.

An investigation of the alpha1A-adrenergic receptor gene and antipsychotic-induced side-effects.

Antipsychotic treatment is hampered by the induction of side-effects such as tardive dyskinesia (TD), weight gain, sedation and extrapyramidal side-effects (EPS). Identification of the factors related to their development would facilitate their avoidance and the improvement of antipsychotic treatment. It has been hypothesised that genetic variants in drug targeted receptors may contribute to the development of side-effects. In this study, we have investigated the possible influence of genetic variants (-563-C/T, -4155-G/C and -4884-A/G) of the alpha(1A)-adrenergic receptor, an important target of atypical antipsychotic drugs, and development of side-effects after antipsychotic medication in a sample of N = 427 US Caucasian patients. We found several marginal associations (p < 0.05) between alpha(1A)-adrenergic genetic variants and antipsychotic-induced side-effects which did not reach statistical significance after corrections for multiple analyses. These results do not support a major role of alpha(1A)-adrenergic genetic variants in obesity and other side-effects observed after prolonged treatment with antipsychotic medications.

A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients Schizophrenia Trial of Aripiprazole: (STAR) study.

BACKGROUND: Naturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting. METHOD: In this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the Investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression - Global Improvement (CGI-I) and Clinical Global Impression - Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC. RESULTS: Aripiprazole treatment (n=268) resulted in significantly better effectiveness than SOC treatment (n=254; P<0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P=0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P<0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as "much better" on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P<0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole. CONCLUSIONS: Aripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.

A controlled, mirror-image study of second-generation antipsychotics in the treatment of schizophrenia.

Second-generation antipsychotics are now treatments of choice in many countries. In this study, we aimed to compare hospital stay and admissions to hospital in patients switching from first-generation (conventional) to second-generation (atypical) antipsychotics with patients switching from one first-generation drug to another. This was a retrospective, 6-year, controlled mirror-image study conducted in an acute general psychiatry services in an inner-city area. Subjects were consisted of patients diagnosed with schizophrenia or schizoaffective disorder receiving continuous prescription of antipsychotics over at least a 6-year period between 1994 and 2002. The main outcome measures were number of days spent in hospital and number of admissions to hospital. In 36 patients switched from first to second-generation antipsychotics, total number of days spent in hospital increased, from a mean of 90 days in the 3 years before switching, to a mean of 200 days in the 3 years after (P<0.001). Mean number of admissions did not change significantly (1.61 before vs. 1.44 after, P=0.360). In 36 matched control patients, switching between first-generation antipsychotic drugs, mean number of days in hospital fell from 64 to 50 (P=0.189) and number of admissions was virtually unchanged (1.42 before vs. 1.03 after, P=0.202). Mean days in hospital were significantly increased in the second-generation antipsychotic group compared with the first-generation antipsychotic (control) group (P<0.001). Switching from first to second-generation antipsychotics resulted in an important increase in number of days spent in hospital. Switching from one first-generation antipsychotic drug to another did not significantly affect number of days in hospital.

A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate.

Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia.

When should clozapine be initiated in schizophrenia?: Some arguments for and against earlier use of clozapine.

Clozapine is one of the original atypical antipsychotics. It was withdrawn from the market in 1974 because of haematological safety concerns, but since 1989 has enjoyed a renaissance for the management of treatment-resistant schizophrenia under systems where case registration allows regular haematological monitoring. Clozapine continues to show enduring superiority across many aspects of the clinical pharmacology of the treatment of schizophrenia, e.g. it has specific anti-suicidal properties and recent broader trials have shown continuing superiority in wide groups of patients. This article considers some of the arguments for unshackling clozapine from its current license for schizophrenia (its superiority overall in treatment-resistant schizophrenia, its potential for use in first-episode patients, and its anti-suicidal potential), and tries to synthesise these into some of the national guidelines available for the treatment of schizophrenia.

The antidepressant desipramine requires the ABCB1 (Mdr1)-type p-glycoprotein to upregulate the glucocorticoid receptor in mice.

The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoids-but this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region (+31%; p=0.045); in contrast, in abcb1ab (-/-) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (-45%; p=0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (-/-) mice, but in abcb1ab (-/-) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (-/-) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (-39%; p=0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (-9 to -23%), but had no effect on 11beta-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes.

Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population.

Discontinued drugs in 2005: schizophrenia drugs.

This paper is the third in a series discussing drugs dropped from development in 2005. Schizophrenia is particularly interesting with regard to pipeline discontinuation, and appears to be unique in this data set because the number of discontinuations far exceeds that for other neuropsychiatric conditions. If this is taken as a proxy for overall drug discovery activity, it represents a very large amount of activity across a wide range of big pharmaceutical corporations. It is also clear that many of the discontinued drugs have mechanisms of action that would make them theoretically suitable as treatments for schizophrenia. Why should so much activity be directed towards what many may consider an undeserving, relatively untreatable and relatively non-rehabilitatable group of patients? This is debated in this opinion piece.

Association of the dysbindin gene with bipolar affective disorder.

OBJECTIVE: In the study of bipolar affective disorder and schizophrenia, there is some evidence suggesting a phenotypic and genetic overlap between the two disorders. A possible link between bipolar affective disorder and schizophrenia remains arguable, however. The authors hypothesized that dysbindin, which is a probable susceptibility gene for schizophrenia, was associated with bipolar affective disorder and tested this hypothesis using a case-control design study. METHOD: Participants included 213 patients with bipolar I disorder and 197 comparison subjects. In each subject, 10 polymorphisms in the dysbindin gene were genotyped and assessed. RESULTS: Two polymorphisms showed individual genotypic association with bipolar I disorder. Multiple marker haplotypes were more strongly associated, with the rarer of the two common haplotypes being overrepresented in the patients with bipolar affective disorder. A similar finding was reported in patients with schizophrenia in a previous study. CONCLUSIONS: Findings suggest that the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder, which underscores a potentially important area of etiological overlap with schizophrenia. The existence of shared genetic risk factors will, in time, lead to changes in the current nosology of major psychoses.

Lithium and clozapine rechallenge: a retrospective case analysis.

BACKGROUND: Clozapine is a uniquely effective antipsychotic, although its use is limited by the risk of neutropenia. Lithium is occasionally prescribed during a clozapine rechallenge, with the hope that it will prevent a second neutropenia or agranulocytosis. There are concerns, however, that lithium use will mask the onset of a neutropenia, leading to a more severe dyscrasia. The objective of this analysis was to determine the utility and safety of lithium coprescription in clozapine rechallenge. METHOD: A retrospective case analysis was performed of all patients who had experienced a previous clozapine-induced blood dyscrasia and had a clozapine rechallenge with lithium coprescribed in a tertiary referral center between September 1998 and September 2003. RESULTS: Twenty-five patients met the study criteria; 1 patient (4%) had a second episode of neutropenia or agranulocytosis while undergoing the rechallenge. This rate was significantly lower (p = .021) than the national (U.K.) rate (21.2%). Although recurrent dyscrasias were not more common, or more severe, than those seen with rechallenge in general, our single case did show some evidence that the patient's neutropenia was masked by lithium use. CONCLUSION: This study provides support for the utility of lithium in preventing neutropenias in rechallenge; extra vigilance may be required, however, to detect masked blood dyscrasias.

Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.

OBJECTIVE: The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge. METHOD: The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150). RESULTS: People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. CONCLUSIONS: The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.

Expression of the alpha1A-adrenergic receptor in schizophrenia.

The alpha1-adrenergic receptors may contribute to cognitive functions relevant to schizophrenia. Following the discovery of an association between polymorphisms in the regulatory region of the alpha1A-adrenergic receptor and schizophrenia we investigated the expression of mRNA for this receptor between schizophrenics (n=19) and controls (n=19) using a TaqMan approach in post-mortem brains. No differences were found suggesting that mRNA levels are not altered in schizophrenia. Genotypic data for the subjects found that possession of the previously associated genotypes did not convey a difference in mRNA expression suggesting that these polymorphisms do not affect the level of transcription.

Is there cognitive impairment in clinically 'healthy' abstinent alcohol dependence?

AIMS: The aim of this study was to determine neuropsychological performance in apparently cognitively, mentally, and physically healthy abstinent alcohol-dependent subjects compared with control subjects who were recruited for a number of different neuroimaging studies. METHODS: All subjects completed a battery of neuropsychological tests as part of the neuroimaging protocol. RESULTS: The group dependent on alcohol performed as well as controls on a non-verbal memory test and verbal fluency but performed worse in the verbal memory task, Trail A + B, and total IQ derived from Silverstein's short-form of the WAIS-R. However, the IQ performance of both groups was above average. In both groups, age was associated with slower performance on the Trail A + B task. In the alcohol-dependent group, severity of dependence and length of abstinence was not associated with performance of any task. CONCLUSIONS: In this apparently clinically healthy population of abstinent alcohol-dependent subjects, frontal lobe dysfunction was detectable using the Trail A + B and digit symbol tasks. This was despite above-average WAIS-R IQ scores. Consideration needs to be given to routine incorporation of cognitive testing in alcohol dependence since subtle deficits may not be easily apparent and may impact on treatment outcome.

Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 1: eradication of Helicobacter in the cachexia of idiopathic parkinsonism.

BACKGROUND: Neuronal damage in idiopathic parkinsonism may be in response to ubiquitous occult infection. Since peptic ulceration is prodromal, Helicobacter is a prime candidate. AIM: To consider the candidature of Helicobacter in parkinsonism with cachexia. METHODS: We explore the relationship between being underweight and inflammatory products in 124 subjects with idiopathic parkinsonism and 195 controls, and present the first case-series evidence of efficacy of Helicobacter eradication, in parkinsonism advanced to the stage of cachexia. RESULTS: Association of a low body mass index with circulating interleukin-6 was specific to parkinsonism (p = .002), unlike that with antibodies against Helicobacter vacuolating-toxin and cytotoxicity-associated gene product (p < .04). Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years. The latter presented with postprandial bloating, and persistent nausea: following eradication, radioisotope gastric-emptying returned towards normal, and upper abdominal symptoms regressed. Reversibility of their cachexia/disability contrasts with the outcome of anti-Helicobacter therapy where eradication repeatedly failed (one case), and in non-Helicobacter gastritis (three cases). Anti-parkinsonian medication remained constant. Intestinal absorption and barrier function were normal in all. CONCLUSION: Categorization, according to presence or absence of Helicobacter infection, was a useful therapeutic tool in late idiopathic parkinsonism.