Human Psychopharmacology Clinical and Experimental

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Online ISSN: 1099-1077
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Article
Early pharmacological studies in animals demonstrated that ABIO-08/01, a new isoxazoline, exerted anxiolytic and anticonvulsant, but also cognition-enhancing properties. Thus, the aim of the present double-blind, placebo-controlled multiple-ascending-dose study was to investigate the effect of the new compound on event-related potentials (ERPs). In a randomized ascending-dose design for phase-1 studies, 16 young healthy male subjects aged 30.2 +/- 5.7 years received three ascending drug doses (10, 20, and 40 mg) and placebo for 7 days, with a washout period of 8 days in between. Auditory ERPs were recorded pre-dose and 2 h post-dose on days 1 (acute effect) and 5 (subacute and absolute superimposed effect). Descriptive statistics with one confirmatory statement on P300 latency demonstrated a significant shortening after acute, subacute, and superimposed administration of 40 mg ABIO-08/01. While ERP amplitudes showed only minor effects, low-resolution brain electromagnetic tomography (LORETA) demonstrated that ABIO-08/01 promotes more efficient information processing by reallocating perceptual and cognitive ERP resources. Thus, our ERP studies confirm early pharmacological findings in animals of a cognition-enhancing effect of ABIO-08/01, which is interesting in the context of the anxiolytic mode of action of the compound as its CNS effects are quite different from those of anxiolytic sedatives, such as benzodiazepines.
 
Article
MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') is a psychoactive substance, sold primarily over the Internet and in 'head' shops as a 'legal high'. Synthesised and used as a research chemical in the 1990s, MDAI has structural similarities to MDMA (3,4-methylenedioxy-N-methylamphetamine) and shares its behavioural properties. Recreational use of MDAI appears to have started in Europe around 2007, with a noticeable increase after 2009 in the UK and other countries. Calls to National Poisons Information Services started in 2010, although there were few presentations to emergency departments by patients complaining of undesirable physical and psychiatric effects after taking MDAI. Recreational use of this drug has been reported only occasionally by online user fora. There is little scientifically based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of this drug. Recent literature (including 'grey') was searched to update what is known about MDAI, especially on its toxicity. The resultant information is presented, including on the first three UK deaths involving MDAI use in 2011 and 2012. 'Serotonin syndrome' appears to be a possible factor in these fatalities. It is vital that any other cases, including non-fatal overdoses, are documented so that a scientific evidence base can be established for them. Copyright © 2013 John Wiley & Sons, Ltd.
 
Article
We examined the relationships of plasma levels of carbamazepine (CBZ) and its two major metabolites, carbamazepine-10,11-epoxide (CBZ-E) and carbamazepine-10,11-diol (CBZ-D), with antimanic efficacy and side effects in patients with schizoaffective disorder. Positive relationships were found among plasma concentrations of CBZ-E and the degree of clinical improvement and side effects, whereas neither plasma CBZ nor CBZ-D levels were correlated with the degree of clinical improvement or side effects. Copyright 2000 John Wiley & Sons, Ltd.
 
Article
The strength of sedation due to antihistamines can be evaluated using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy following oral administration of cetirizine (10 and 20 mg) in order to examine dose dependency. Fifteen healthy male volunteers (age range, 20-35 years) were divided into 3 subgroups and were studied following single oral administration of cetirizine at 10 mg (n = 5) and 20 mg (n = 5) or hydroxyzine at 30 mg (n = 5) using PET with 11C-doxepin. Each subject was scanned also following the administration of placebo. Binding potential and H(1)RO values were calculated in the prefrontal and anterior cingulate cortices. Subjective sleepiness was also measured, and the correlation to H(1)RO was examined for each antihistamine. The averaged H(1)ROs of cetirizine 10 mg, 20 mg, and hydroxyzine 30 mg in the prefrontal and cingulate cortices was 12.6%, 25.2%, and 67.6%, respectively. The H(1)RO of hydroxyzine 30 mg correlated well with subjective sleepiness (p < 0.001); however, those of cetirizine 10 and 20 mg showed no correlation with subjective sleepiness. It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H(1)RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders.
 
Article
Previous research from our laboratory demonstrated that administration of single doses (120, 240, 360 mg) of standardised Ginkgo biloba extract (GBE) had linear, dose-dependent, positive effects on the speed of performing attention tasks in comparison to placebo. However, whilst the lowest dose, which is typical of a recommended daily dose, had no effect on the speed of attention task performance it did engender mild improvements in secondary memory performance. The current study presents a reanalysis of data from three methodologically identical studies that each included a treatment of 120 mg GBE and matched placebo. All three studies were of a multiple dose, placebo-controlled, double-blind, balanced-crossover design, employing four or five treatment arms in total. Across the studies 78 healthy young participants received 120 mg GBE and placebo in randomly counterbalanced order, separated by a wash-out period of at least 7 days. On each study day participants' performance on the Cognitive Drug Research (CDR) computerised cognitive assessment battery was measured immediately prior to dosing and at 1, 2.5, 4 and 6 hr following treatment, with scores collapsed into the six measures (speed of attention, accuracy of attention, secondary memory, working memory, speed of memory, quality of memory) which have previously been derived by factor analysis of the data from CDR subtests. The results showed that 120 mg of Ginkgo engendered a significant improvement on the ‘quality of memory’ factor that was most evident at 1 and 4 hr post-dose, but had a negative effect on performance on the ‘speed of attention’ factor that was most evident at 1 and 6 hr post-dose. The current study confirmed the previous observation of modestly improved memory performance following 120 mg of GBE, but suggests that acute administration of this typical daily dose may have a detrimental effect on the speed of attention task performance which is opposite to that seen previously following higher doses. Copyright
 
Article
We aimed to probe for regional cerebral effects of S-ketamine on in vivo GABA-A-receptor binding in healthy human subjects. We investigated I-123-iomazenil SPECT before, during and after administration of S-ketamine in a blinded placebo-controlled study design (n = 12 in both groups). Analyses of SPECT were performed with voxel-based statistical parametric mapping (SPM), and statistical comparisons were made between the groups. We also assessed biochemical and behavioural changes during S-ketamine infusion. S-ketamine induced positive and negative symptoms measured by the Brief Psychiatric Rating scale (BPRS). It increased the cortisol and prolactin levels. Image analysis revealed significantly decreased I-123-iomazenil binding in bilateral dorsomedial prefrontal cortex during S-ketamine administration when compared to placebo. Our study delivers preliminary evidence for an in vivo interaction of S-ketamine with GABA-A-receptors in human dorsomedial prefrontal cortex.
 
Article
This survey assessed the impact of four months supplementation with 120 mg/day of the standardized Ginkgo biloba special extract (LI 1370) on activities of daily living and various aspects of mood and sleep in a population of free living older volunteers using both observer- and self-rated scales. 5028 Participants (mean age 68.9 years) were recruited through a magazine editorial. One thousand received Ginkgo biloba extract (GBE) and the remainder were allocated to the Control group. The B-ADL (activities of daily living) Scale was completed at baseline and at the end of month 4 by an informant familiar with the participant, a Self-rating ADL scale and Line Analogue Ratings Scales of mood and sleep were completed by the participants at the end of months 1, 2, 3, and 4. There were significant differences between the GBE and Control groups on all scales at each time point. The GBE group felt better able to cope with their daily activities and showed positive changes in mood and sleep compared to the Control group. These results suggest that GBE supplementation has beneficial effects on areas of functioning that have implications for quality of life in an older population. Copyright 2000 John Wiley & Sons, Ltd.
 
Article
Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia.
 
Article
The original article to which this Erratum refers was published in Human Psychopharmacology: Clinical and Experimental 16 (3) 2001, 247-255.
 
Article
Given the legal status of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, face-to-face access to participants is sometimes difficult. The number of participants in studies of cognitive performance amongst Ecstasy users is variable, with the average being around 30. Access to a larger number of participants is clearly desirable. The present investigation accessed a larger sample size using a web-based design. A website was developed and used for data collection. Prospective memory ability was assessed using the Prospective Memory Questionnaire. Self-report of day-to-day memory performance was investigated using the Everyday Memory Questionnaire. The Drug Questionnaire assessed the use of other substances as well as Ecstasy, allowing a regression design to isolate the contribution of each substance to any variance on the cognitive measures. Preliminary findings (N = 488) indicate that there is a clear double dissociation between the impact of Ecstasy and cannabis. We found that cannabis was associated with reports of 'here-and-now' cognitive problems in short-term and internally cued prospective memory. In contrast, Ecstasy was associated with reports of long-term memory problems, which were more related to storage and retrieval difficulties. Copyright 2001 John Wiley & Sons, Ltd.
 
Article
The popular recreational drug Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and related congeners) is neurotoxic upon central serotonergic systems in animal studies. So far, the most convincing evidence for neurotoxicity-related functional deficits in humans derives from neurocognitive studies demonstrating dose-related memory problems in Ecstasy users. The aim of the current investigation was to study the relationship between the psychological profile of recreational Ecstasy users and the patterns of their drug use. Twenty-eight abstinent recreational Ecstasy users with concomitant use of cannabis only and two equally sized, matched groups of cannabis users and non-users were administered standardized self-rating scales for the assessment of psychological problems which are thought to be related to central serotonergic function. Ecstasy users had elevated scores on subscales measuring impulsiveness, anxiety, sensation seeking, somatic complaints, obsessive-compulsive behavior and psychoticism. Higher scores were associated with both heavier Ecstasy and heavier cannabis use. After controlling for cannabis use, most group differences in psychometric scores no longer achieved statistical significance. The present data are in line with other reports demonstrating a broad range of psychological problems in Ecstasy users. However, the concomitant use of other drugs, specifically cannabis, seems to be crucial in this respect. Therefore, compared with cognitive deficits, psychological problems appear to be less suitable functional indices of Ecstasy-related neurotoxic damage of central serotonergic systems in humans. Copyright 2001 John Wiley & Sons, Ltd.
 
Article
The prevalence of tobacco smoking is known to be higher in patients with schizophrenia than other psychiatric disorders and general population. These patients also show reduced prepulse inhibition (PPI) of the startle response. PPI refers to a reduction in response to a strong startling stimulus if preceded shortly by a stimulus of sub-threshold intensity. PPI is thought of as an objective index of sensorimotor gating. Nicotine administered subcutaneously or via cigarette smoking enhances PPI in healthy human beings. It also enhances PPI at low, but not high, doses in the rat. We examined the influence of smoking on PPI of the acoustic startle response in 46 male patients with chronic schizophrenia. In a naturalistic design, patients (n = 9) who smoked a cigarette less than 10 min prior to being tested on PPI were compared with other smoking (n = 23) and non-smoking patients (n = 14). We found that the group of patients who smoked a cigarette prior to being tested had significantly greater PPI than other two groups. These observations suggest a PPI-enhancing effect of cigarette smoking on PPI in patents with schizophrenia. Higher prevalence of cigarette smoking in schizophrenic patients may reflect an attempt to improve sensorimotor gating deficits. Copyright 2001 John Wiley & Sons, Ltd.
 
Article
It has been reported that nizatidine may reduce the weight gain in schizophrenic patients receiving olanzapine treatment. Previous studies have demonstrated a relation between olanzapine-induced weight gain and serum leptin levels. Therefore, in the present study, it was planned to investigate the efficacy of nizatidine on the treatment of olanzapine-induced weight gain, and if available, whether leptin levels were associated with reductions in weight gain. Of the patients with schizophrenia on olanzapine treatment, 59 who gave informed consent entered a 3 month open-label screening period. Of them, 35 patients (59%) showed weight gain in excess of 2.5 kg. These patients were randomly divided into two groups; olanzapine plus nizatidine (group I) and olanzapine plus placebo (group II) for an 8-week double-blind phase. The patients were evaluated at the baseline and at week 8 with respect to the positive and negative syndrome scale, body mass index, weight and serum leptin levels. In the open-label period, olanzapine led to a considerable marked increase in weight and in serum leptin levels. There was no statistically significant difference between the groups with respect to weight at the beginning of the 8-week double-blind treatment period. Throughout the 8 week double-blind period, in group I, the weight decreased by 4.5 +/- 2.2 kg ( p<0.05). In contrast, weight increased in group II by a mean of 2.3 +/- 0.9 kg ( p>0.05). The leptin levels decreased by 4.4 +/- 2.3 ng/ml in group I ( p<0.01), and increased by 1.8 +/- 0.6 ng/ml in group II ( p>0.05). These changes were accompanied by changes in the leptin levels in both groups I and II. It is concluded that leptin seems to be strongly associated with olanzapine-induced weight gain and that nizatidine treatment may reduce the weight gain and the correlated leptin levels in patients with schizophrenia on olanzapine treatment.
 
Article
This study examined the reported psychological effects of different patterns of MDMA use in men and women, and how they are modified by use of other psychoactive substances. A semi-structured interview was conducted with 466 regular MDMA users, exploring the perceived acute, sub-acute and long-term subjective effects of this drug. Factor analysis established three main categories of acute effects of MDMA: (i) positive and (ii) negative effects on mental health, and (iii) physical effects. In terms of subacute effects, 83% of participants reported experiencing low mood and 80% reported impaired concentration between ecstasy-taking sessions. Factors affecting these effects included age, gender, extent of MDMA use and concomitant use of cocaine or amphetamine. The long-term effects most frequently reported included the development of tolerance to MDMA (59%), impaired ability to concentrate (38%), depression (37%) and 'feeling more open towards people' (31%). In terms of what might persuade users to stop using MDMA, their most prominent concern was the drug's long-term effects on mental health.
 
Article
Objective: Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Dopamine beta-hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine, and plasma DBH activity is altered in TD patients. This study examined whether the functional DBH 5'-Ins/Del polymorphism was associated with TD severity in Chinese patients with schizophrenia. Methods: We compared the rate of this polymorphism in patients with (n = 312) and without TD (n = 435), and healthy controls (n = 625). The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). Results: There were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls, or between the patients with and without TD. Also, there was no significant difference in the AIMS total score between the three genotype groups. However, the PANSS positive symptom subscore was significantly higher in patients with Del/Del genotype (13.2 ± 5.2) than those with Ins/Del (11.2 ± 4.9) and Ins/Ins (11.1 ± 3.1) genotypes (both p < 0.05). Conclusion: These results suggest that although the DBH 5'-Ins/Del polymorphism was not associated with susceptibility to TD in patients with schizophrenia, it might be related to positive symptoms of schizophrenia.
 
Article
The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.
 
Article
In addition to psychoses, antipsychotic drugs are nowadays also prescribed for other psychiatric disturbances, such as mood disorders. We wanted to find out whether there is any association between the use of antipsychotic drugs and suicidality in cases of psychotic and non-psychotic disorders. Our sample was the population-based Northern Finland 1966 Birth Cohort. Information on the use of prescribed drugs was collected in 1997 from the nationwide medication register and with a postal questionnaire (N = 8218). The presence of suicidal ideation was assessed cross-sectionally using the Symptom Check List-25 questionnaire. We studied associations between suicidal ideation, adjusted for symptoms of depression and anxiety, and antipsychotic medication in different diagnostic groups (schizophrenia, other psychosis and no psychosis). Individuals receiving antipsychotic medication (n = 70, 0.9%) had in general more suicidal ideation regardless of diagnostic group, although the associations diminished when taking other symptoms into account. There were no statistically significant differences between those taking typical and atypical antipsychotics. In the non-psychotic group, higher antipsychotic doses were associated with more suicidal ideation even when adjusted for symptoms of depression and anxiety (p < 0.05). In the cases of schizophrenia or other forms of psychosis, no such associations were observed. Our results suggest that one should take suicidal ideation into account when prescribing antipsychotic medication, especially for off-label use. Copyright
 
Article
Buprenorphine safety in overdose has been debated recently, but no mortality data related to this compound from the UK have been published. To gather together all of the buprenorphine mortality figures, a number of different sources have been checked. To inform on buprenorphine safety issues, accessible information related to its availability indicators (i.e. prescriptions; seizures) data for the 1980-2002 time frame have been sought. In the UK, during this period, buprenorphine was mentioned in 43 fatalities. Typically, victims were males in the 25-44 age group. In 12 cases (28% of total), a verdict of suicide was given. Buprenorphine was detected on its own in seven cases; more frequently, it was found together with benzodiazepines and other opiates. Large quantities of buprenorphine were prescribed both in England in 1985-1989 and in 1991-1992 in Scotland, where seizures reached their highest levels. Buprenorphine prescriptions seemed to peak again after 1999, when high dose buprenorphine formulations entered the UK market. No positive correlation was found between the number of buprenorphine deaths over the years and either buprenorphine dispensings/prescriptions or seizures. However, an increase in buprenorphine-related deaths since 1999 was identified and this may be an issue which should be carefully monitored over the next few years.
 
Article
To investigate the effect of dose and other factors on plasma clozapine concentrations in patients aged 65 years and over. Audit of clozapine therapeutic drug monitoring data, 1996-2010. There were 1930 samples [778 patients, 363 men aged (median, range) 67 (65-100) years and 415 women aged 68 (65-90) years]. There was no significant difference in the mean plasma clozapine concentration between men (0.56 mg/l) and women (0.58 mg/l), although the mean dose was higher in men (323 mg/d) than women (264 mg/d). The higher proportion of men (46%) compared with women (37%) smokers could explain this finding. Overall, 32% of samples had plasma clozapine below, and 37% above, a target range of 0.35-0.60 mg/l. Overall, the median dose decreased from 300 (65-70 years) to 200 mg/d (age 85 years and over). However, prescription of >350 mg/d was associated with a 50% likelihood that the plasma clozapine would exceed 0.60 mg/l. For a subgroup of 196 patients (114 men, 82 women), mean plasma clozapine was significantly higher after age 65 despite significantly lower dosage. Clozapine dosage in elderly patients should be reviewed regularly to minimise the risk of adverse effects.
 
Article
The present study reports on all deaths related to taking ecstasy (alone, or in a polydrug combination) occurring in England and Wales in the time frame August 1996-April 2002. Data presented here are based on all information recorded in the National Programme on Substance Abuse Deaths (np-SAD) database. The np-SAD regularly receives all information on drug related deaths in addicts and non addicts from coroners. A total of 202 ecstasy-related fatalities occurred in the chosen time-frame, showing a steady increase in the number of deaths each year. The ratio male:female was 4:1 and 3 of 4 victims were younger than 29. In 17% of cases ecstasy was the sole drug implicated in death and in the remaining cases a number of other drugs (mostly alcohol, cocaine, amphetamines and opiates) have been found. According to toxicology results, MDMA accounted for 86% of cases and MDA for 13% of cases; single deaths were associated with MDEA and PMA. This is the largest sample of ecstasy related deaths so far; possible explanations are given for the observed steady increase in ecstasy-related deaths and a tentative 'rationale' for this polypharmacy combination is then proposed.
 
Article
Since its discovery 50 years ago, the role of the indoleamine 5-HT (5-hydroxytryptamine; serotonin) in the pathogenesis of depression and in the mechanism of action of antidepressant drugs has been the subject of considerable research. Advances in molecular biology and radioligand techniques have led to the functional characterisation of at least 14 serotonin receptor subtypes. This classification has led to the development of selective compounds that have aided in the efforts of dissecting the complex role of 5-HT in depression and in mediating the antidepressant response. This review focuses largely on novel strategies of targeting specific 5-HT receptors subtypes, especially the presynaptic 5-HT(1A) and 5-HT(1B/1D) receptors. These subtypes are of primary importance in that they control the firing of the 5-HT neuron and the release of 5-HT. In addition, a number of postsynaptic 5-HT receptors have been shown to be dysfunctional in depression and are also potential targets for a number of antidepressants. We conclude that selective targeting of 5-HT receptors may lead to a faster acting and more efficient antidepressant response. Copyright 2000 John Wiley & Sons, Ltd.
 
Article
To assess effects of a semi-acute administration of buspirone in comparison to a placebo on cognitive function and negative symptoms in patients with schizophrenia and schizoaffective disorder. In a 6-week, double-blind, placebo-controlled, independent groups study 18 subjects (14 males, four females) received in random order either placebo or buspirone (15-30 mg/day). A neuropsychological assessment using the Hopkins verbal learning test (HVLT) simple reaction time (SRT), choice reaction time (CRT), n-back spatial working memory task and the stroop colour and word test was performed at baseline and final visit. Symptom rating scales were administered at testing weeks 0, 2, 4 and 6. Repeated measures ANOVA was used to examine changes in performance on tests over time. There were no statistically significant differences between placebo and buspirone treatments on either cognitive function measures or symptom ratings. Semi-acute adjunct treatment with buspirone may be too short to be clinically efficacious in patients with schizophrenia. Intrinsic activation of 5-HT(1A) receptors by atypical antipsychotics may hinder the ability of buspirone to further improve cognitive functions. Buspirone did not affect clinical outcomes for this chronically ill group of patients being treated with atypical antipsychotic drugs.
 
Article
The treatment of depression in senile patients with dementia is difficult with the drugs used formerly. The effects of a new anxiolytic drug, tandospirone, were investigated on depression symptoms in nine senile patients with dementia using Hamilton Depression Rating Scale (HAM-D) items. Tandospirone improved the symptoms, especially the depressive mood, agitation and anxiety, although a slight gastrointestinal symptom was found in one patient. The findings in the present study may suggest that tandospirone is a useful and comparatively safe drug for depression symptoms in senile patients with dementia.
 
Article
The anterior cingulate region has been implicated in the pathophysiology of mood disorders. Studies have reported anatomical and functional abnormalities in this region in bipolar disorder patients. Few neurochemical studies have evaluated this region, especially on medicated bipolar patients. Lithium has been reported to increase NAA levels but not by all studies. We used proton magnetic spectroscopy ((1)HMRS) to measure the levels of N-acetyl-L-aspartate (NAA) and choline (Cho) relative to creatine (Cr) in the anterior cingulate of euthymic medicated bipolar subjects. (1)HMRS was performed using a GE Signa 1.5 Tesla scanner in 13 euthymic bipolar patients who were taking lithium for at least four weeks before the scan and in 15 normal controls. The (1)HMRS signal was collected from an 8 cm(3) voxel placed in the anterior cingulate. Data analysis was performed with the automated PROBE/SV quantification tool. NAA/Cr and Cho/Cr ratios were not significantly different between patients and controls (NAA/Cr: 1.60 +/- 0.34 in patients, 1.68 +/- 0.34 in controls; Cho/Cr: 1.13 +/- 0.13 in patients, 1.11 +/- 0.20 in controls). We did not find a significant difference in the NAA/Cr and Cho/Cr ratio between bipolar patients and healthy controls. Chronic administration of psychotropic drugs could have had an effect on NAA/Cr levels of bipolar patients.
 
Article
Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies. This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder. Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily. The primary efficacy endpoint was reduction in Hamilton Anxiety Scale (HAM-A) total scores from baseline after 8 weeks of treatment. Key secondary outcomes were changes from baseline in HAM-A total scores for the 2.5 and 10 mg dose, Hospital Anxiety and Depression anxiety subscore, 36-Item Short-Form Health Survey, Sheehan Disability Scale, and Clinical Global Impression-Improvement Scale score, as well as HAM-A response rate at week 8. Neither vortioxetine dose achieved a statistically significant improvement over placebo on the primary endpoint (least-squares mean difference ± standard error from placebo: -0.87 ± 0.803 [p = 0.279] for 2.5 mg and -0.81 ± 0.791 [p = 0.306] for 10 mg vortioxetine) or on any secondary efficacy endpoints. Common adverse events (≥5% in either vortioxetine group) were nausea, dry mouth, headache, diarrhea, constipation, and vomiting. Vortioxetine 2.5 and 10 mg treatment did not significantly improve generalized anxiety disorder symptoms versus placebo. Vortioxetine was safe and well tolerated in this patient population. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
'Depression 2000' is a major epidemiological study conducted in a representative sample of 412 primary care settings (which examined a total of 15,081 unselected patients) in Germany in order to address the current lack of information on the prevalence, recognition and treatment of depression in primary care. The study revealed that depression is a key challenge in primary care because of its prevalence (point prevalence according to ICD-10: 10.9%), type of presenting complaints and the time constraints of the doctors. Participating doctors had a very high workload (average of 62 patients per day) and perceived the management of depressed patients as a major burden. The majority of cases of depression identified met criteria for moderate or severe depression, and 51% had a chronic and/or recurrent course. A total of 55% of patients were correctly diagnosed as having a clinically significant depressive disorder, although only 21% received a diagnosis of 'definite' depression. In conclusion, these findings confirm the high prevalence of depressive disorders in primary care settings and underline the particular challenges posed by these patients. Although recognition rates among more severe major depressive patients, as well as treatments prescribed, appear to be more favourable than in previous studies, the high proportion of unrecognised patients with definite depression still raises significant concerns. It remains of continued prime importance to educate primary care doctors to better recognise depression in order to increase the patients' chances of receiving appropriate treatment.
 
Article
The purpose of the study was to evaluate the frequency of reported sexual dysfunction (SD) in schizophrenia and its associations with sociodemographic and clinical variables in selected Asian countries. A total of 5877 schizophrenia patients in nine Asian countries and territories were examined between 2001 and 2009. The patients' sociodemographic and clinical characteristics, prescription of psychotropic drugs, and drug-induced side effects were recorded using a standardized protocol and data collection. SD was evaluated as "present" or "absent" according to the clinical judgment of experienced psychiatrists. The frequency of reported SD in the whole sample in women and men was 3.0%, 0.8%, and 4.6%, respectively, with variations across study sites. In the multivariate analyses, male sex, more second-generation antipsychotics, benzodiazepines, and antidepressants were independently associated with higher likelihood of reported SD, whereas negative symptoms had an inverse association with reported SD. The results of this study indicate that SD was seldom recorded as a side effect by Asian psychiatrists while treating patients with schizophrenia. It is unclear whether the low prevalence of reported SD compared with Western data is real or whether the results are being insufficiently recognized. Copyright © 2011 John Wiley & Sons, Ltd.
 
Article
The empirical use of combinations of antipsychotic agents appears to be increasing with little research support for the relative efficacy, safety or cost-effectiveness of this practice. Such treatment was evaluated in hospitalized psychiatric patients. Samples of consecutive inpatients treated with > or = 2 ('polytherapy') vs 1 antipsychotic ('monotherapy') were matched on age, sex, diagnosis and admission clinical ratings, and these groups were compared on total daily chlorpromazine-equivalent doses, days in hospital, and changes in clinical ratings between admission and discharge. The study sample included 69 polytherapy and 115 well-matched monotherapy subjects. Despite matching for initial CGI and GAF ratings, polytherapy was associated with high PANSS subscale scores of positive symptoms among affective psychosis, and relatively greater PANSS subscale ratings of excitement-agitation among patients diagnosed with schizophrenia. Estimated clinical improvement during hospitalization was similar among poly- and monotherapy patients, but total daily CPZ-eq doses at discharge averaged twice-greater with polytherapy, and hospitalization lasted 1.5 times longer. Antipsychotic polytherapy as well as the types of agents combined may reflect clinician responses to particular symptom patterns. The value of specific combinations of antipsychotic agents and their comparison with monotherapies requires specific, prospective, randomized and well-controlled trials that consider matching on clinical characteristics and truly comparable doses across regimens.
 
Article
Major changes in antipsychotic treatment in recent years encouraged a survey of inpatient practice in 2002, compared with earlier samples. Based on records of a random sample of McLean Hospital inpatients prescribed antipsychotics in 2002, the study recorded DSM-IV discharge diagnosis, all psychotropic treatments and doses, initial, peak and final doses of all antipsychotics, clinical status at admission and discharge, and adverse effects reported. Results were compared with similar data from our earlier surveys. Subjects were 344 inpatients (n = 202 women, 59%), diagnosed with psychotic (n = 102, 30%), bipolar (n = 93, 27%), major depressive (n = 67, 19.5%), dementia (n = 19, 5.5%), substance-use (n = 28, 8%) or other psychiatric disorders (n = 35, 10%). Second-generation antipsychotics accounted for 88% of antipsychotic prescriptions; 17% of patients received > or = 2 antipsychotics and total CPZ-eq discharge does in 2002 averaged 291 +/- 305 mg/day (22% less than a 1998 peak). Doses were unrelated to age, but higher in men, among psychotic vs major affective disorder patients, and with greater illness-severity and longer hospitalization. There was a 3.3-fold increase in the simultaneous use of > or = 3 psychotropic agents since 1998. The use of second-generation antipsychotics dominates current inpatient practice. Total antipsychotic dosing has not increased recently, but the use of multiple psychotropics increased strikingly from 1998 to 2002.
 
Article
This study aimed to investigate the effect of dose and other factors on plasma amisulpride concentrations in clinical practice. Amisulpride therapeutic drug monitoring data 2002-2010 have been studied. There were 296 samples (196 adult patients). Amisulpride was not detected in 10% of samples. In the remainder, the mean plasma amisulpride in relation to the prescribed dose (mg/day) was as follows: 100-200 (111 µg/L), 201-400 (254 µg/L), 400-800 (421 µg/L), and 800-1200 (494 µg/L). For prescribed doses up to 800 mg/day, only 51% of results were within 100-319 µg/L. There were no significant sex differences in mean plasma amisulpride or mean dose. The mean plasma amisulpride, but not the dose, was significantly higher in smokers. Linear regression analysis showed that dose explained only 42% of the variation in plasma amisulpride after log(10) transformation of both variables. There was no significant difference in the mean dose or mean plasma amisulpride in patients co-prescribed clozapine as compared with the remaining samples. In practice, dose is a poor predictor of plasma amisulpride concentration. Therapeutic drug monitoring may not only help assess adherence, but also guide dosage. Copyright © 2012 John Wiley & Sons, Ltd.
 
Article
We tested the hypothesis that combinations and total daily doses of psychotropics for hospitalized patients diagnosed with major psychiatric disorders are rising. We evaluated McLean Hospital records of 481 consecutive inpatients with DSM-IV schizophrenia, schizoaffective, or bipolar disorders in 2004 (n = 278) or 2009 (n = 203) to compare characteristics and treatments. In 2009, Clinical Global Impression (CGI)-severity scores were 6% lower at intake and improved 1.7 times more than in 2004, as hospitalization-length decreased by 12%. Polytherapy (> or = 2 psychotropics) increased in 2009 (affective or schizoaffective disorders > schizophrenia). Total psychotropics/patient (3.1-3.2) remained stable but mood-stabilizers/patient increased markedly and antipsychotics/patient decreased somewhat in 2009. Antipsychotic-choice (2009) ranked: quetiapine, aripiprazole, risperidone, and others; mood-stabilizers ranked: lamotrigine, valproate, lithium, and others (1/4 off-label). In 2009, final total antipsychotic doses (mg/day) increased by 97%, and mood-stabilizers by 75%. Adverse-effect rates fell by half. Factors differing independently for 2009 versus 2004 ranked: (a) more CGI improvement, (b) more mood-stabilizers/patient, (c) lower admission CGI scores, and (c) higher total antipsychotic dose. Combinations and doses of antipsychotic and mood-stabilizing drugs for inpatients increased markedly (2004 vs. 2009) without consistent correspondence of agents/person and doses, without apparent increase in major adverse effects, and with possibly superior clinical improvement.
 
Article
Pharmacological treatment of schizophrenic patients in Japan is characterized by polypharmacy with high doses of antipsychotics. In this study, we examined the profiles of antipsychotic drug therapy in 2007 and 2009 to determine if there have been any recent shifts in treatment strategy. The subjects were schizophrenic inpatients (ICD-10-F20) admitted to 100 hospitals in 2007 and 152 hospitals in 2009. Information on the psychotropic agents prescribed on specified days in November 2007 and 2009 was acquired for each patient. Although no changes were observed in the rate of antipsychotic medications being prescribed, the rate of antipsychotic monotherapy in 2009 increased significantly. In 2007, among 15,761 patients, 4977 (31.6%) received antipsychotic monotherapy (i.e., administration of a single antipsychotic medication). In 2009, among 22,911 patients, 7741 (33.8%) received antipsychotic monotherapy. The rate of use of antipsychotic monotherapy has gradually increased, although the total dose has not changed significantly. The increase in the concomitant use of two or more second-generation antipsychotics is a recent trend in Japan, despite the lack of information on the efficacy and safety of this treatment strategy.
 
Article
Antipsychotic medications are known to be commonly associated with sexual dysfunction. Sexual dysfunction is estimated to affect 30-80% of patients with schizophrenia and is a major cause of poor quality of life. However, few comparative studies on the sexual dysfunction effects associated with antipsychotic medication have been published and the effects of the newer atypical antipsychotics have been largely unexamined. This review aims to examine the latest evidence regarding the sexual function effects of different antipsychotic medications, particularly the newer prolactin-sparing drugs, quetiapine and aripiprazole, in patients with schizophrenia and schizoaffective psychosis. A literature search was conducted within PubMed/MEDLINE using the terms risperidone, haloperidol, clozapine, olanzapine, ziprasidone, quetiapine, aripiprazole; sexual dysfunction; schizophrenia. The results were limited to studies published since 2002. Recently published studies show that the relative impact of antipsychotics on sexual dysfunction can be summarised as risperidone > typical antipsychotics (haloperidol) > olanzapine > quetiapine > aripiprazole. The availability of prolactin-sparing antipsychotics should enable psychiatrists to consider and manage proactively the sexual function consequences of pharmacological intervention, thereby improving sexual side effects, which may lead to improved treatment adherence and psychiatric outcome in patients with schizophrenia.
 
Article
The aim of this study was to describe the presence and composition of cathinone derivatives (CDs) in drug samples analyzed at a Drug Testing Service. Data provided by the Drug Testing Service at Energy Control (a Spanish organization working in risk reduction among recreational drug users) were obtained from samples delivered as, or containing CDs, between January 2010 and June 2012. Specimens were identified by combining thin layer chromatography and gas chromatography associated with mass spectrometry. Two hundred and thirty-seven (3.8%) of the 6199 samples were delivered as, or contained CDs. 22 different CDs were detected, alone or in different combinations. Methylone (24.9%), mephedrone (24.5%), 4-methylethcathinone (9.28%), and methylenedioxypyrovalerone (6.8%) were the most common CDs. These substances were also found in 80 (1.3%) of 6042 samples delivered allegedly containing drugs different from CDs (such as 3,4-methylenedioxy-N-methylamphetamine (MDMA), amphetamines, ketamine…). Cathinone derivatives were markedly present in the Spanish drug market during the studied period. There is no evidence to conclude that use of CDs will become widespread or relevant for public health, but the phenomenon must be followed, as the potential risks of these new drugs of abuse are substantial. Copyright © 2013 John Wiley & Sons, Ltd.
 
Article
We investigated whether micronutrients given acutely following the Christchurch earthquakes continued to confer benefit 1 year following the treatment. Sixty-four adults from the original 91 participants experiencing heightened anxiety or stress 2-3 months following the 22nd February 2011 earthquake and who had been randomized to receive three different doses of micronutrients completed on-line questionnaires assessing mood, anxiety, stress, and symptoms associated with post-traumatic stress disorder 1 year after completing the initial study. Twenty-one out of 29 nonrandomized controls who did not receive the treatment also completed the questionnaires. Both the treated and control groups experienced significant improvement in psychological functioning compared with end-of-trial. However, treated participants had better long-term outcomes on most measures compared with controls (ES = 0.69-1.31). Those who stayed on micronutrients through to follow-up or stopped all treatment reported better psychological functioning than those who switched to other treatments including medications. About 10% of the sample continued to have post-traumatic stress disorder symptoms. Disaster survivors improve psychologically over time regardless of receiving intervention; however, those taking micronutrients during the acute phase following a disaster show better outcomes, identifying micronutrients as a viable treatment for acute stress following a natural disaster with maintenance of benefits 1 year later. ACTRN 12611000460909 Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
Parrott recently published a review of literature on MDMA/ecstasy. This commentary is a response to the content and tenor of his review, which mischaracterizes the literature through misstatement and omission of contrary findings, and fails to address the central controversies in the literature. The review makes several erroneous statements concerning MDMA-assisted psychotherapy, such as incorrect statements about research design and other statements that are baseless or contradicted by the literature. Though it critiques an attempt by other authors to characterize the risks of MDMA, the review fails to produce a competing model of risk assessment, and does not discuss potential benefits. Parrott does not represent an even-handed review of the literature, but instead recites dated misconceptions about neurotoxicity concerns involving the recreational drug ecstasy, which do not relate directly to the use of pure MDMA in a therapeutic setting. Unchallenged, Parrott's report may deter researchers from further investigating an innovative treatment that in early clinical trials has demonstrated lasting benefits for people with chronic, treatment-resistant post-traumatic stress disorder. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
Human Psychopharmacology recently published my review into the increase in empirical knowledge about the human psychobiology of MDMA over the past 25 years (Parrott, 2013a). Deficits have been demonstrated in retrospective memory, prospective memory, higher cognition, complex visual processing, sleep architecture, sleep apnoea, pain, neurohormonal activity, and psychiatric status. Neuroimaging studies have shown serotonergic deficits, which are associated with lifetime Ecstasy/MDMA usage, and degree of neurocognitive impairment. Basic psychological skills remain intact. Ecstasy/MDMA use by pregnant mothers leads to psychomotor impairments in the children. Hence, the damaging effects of Ecstasy/MDMA were far more widespread than was realized a few years ago. In their critique of my review, Doblin et al. (2014) argued that my review contained misstatements, omitted contrary findings, and recited dated misconceptions. In this reply, I have answered all the points they raised. I have been able to refute each of their criticisms by citing the relevant empirical data, since many of their points were based on inaccurate summaries of the actual research findings. Doblin and colleagues are proponents of the use of MDMA for drug-assisted psychotherapy, and their strongest criticisms were focused on my concerns about this proposal. However, again all the issues I raised were based on sound empirical evidence or theoretical understanding. Indeed I would recommend potentially far safer co-drugs such as D-cycloserine or oxytocin. In summary, MDMA can induce a wide range of neuropsychobiological changes, many of which are damaging to humans. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
The aim of this observational study was to evaluate the effectiveness of escitalopram in a naturalistic sample of employed people with mood and anxiety disorders. Days on sick leave 3 months prior and 3 months during treatment with escitalopram were recorded and compared (mirror study design) in 2378 patients (949 men and 1376 women). A further clinical examination including the clinical global impression of severity (CGI-S) and improvement (CGI-I) scales and assessments of tolerability were used to evaluate treatment effects in a subgroup of 807 study subjects. Escitalopram treatment (mean final daily dosage: 12.4+/-5.0 mg) led to a significant reduction (baseline versus end of study) of sick leave (11.0+/-12.8 days versus 5.4+/-11.0 days; p<0.001). CGI-S scores decreased from 4.7+/-0.9 at baseline to 2.4+/-1.1 after 3 months (p<0.001), the CGI-I after 3 months was 1.9+/-0.9. The incidence of adverse events after initiation of treatment with escitalopram was 13.1%, with only 1.3% of patients experiencing severe adverse events interfering with patient functioning. Our results suggest that escitalopram is an efficacious and overall well-tolerated treatment in a naturalistic sample of working patients. A decrease in the days on sick leave is indicative of indirect cost-effectiveness of this treatment.
 
Article
Previous studies tested the efficacy of sertraline in Binge Eating Disorder (BED) over a period of 6 weeks. The present open study assesses the efficacy of sertraline over a period of 24 weeks in obese persons with binge eating behaviour (with or without the full criteria for BED) confirmed by high scores on the Binge Eating Scale (BES). Thirty-two obese outpatients (14 with BED and 18 without full criteria for BED), without co-occurring psychiatric comorbidities, were treated with sertraline (dose range 100-200 mg/d). Subjects were assessed at baseline and at 8, 12 and 24 weeks of treatment for number of binges, weight and psychopathology. After 8 weeks of treatment a significant improvement in the BES score and a significant weight loss emerged. These results were maintained over 24 weeks. A moderate drop out rate was detected, but no significant association with the severity of side effects was found. Further studies are needed to confirm the usefulness of sertraline in the treatment of patients with BED and also in binge eaters with a less severe eating psychopathology.
 
Article
Previous studies suggest possible modulatory effects of progesterone on nicotine addiction. The goal of this study was to determine the effects of progesterone, on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent male and female smokers. Twelve smokers, six males and six females, participated in a double-blind, placebo-controlled, crossover study, which consisted of two experimental sessions. Before each session, subjects were treated orally with a single dose of either 200 mg progesterone or placebo. Starting 2 h following the medication treatment, subjects received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. Progesterone treatment, compared to placebo, enhanced the ratings of "bad effects," from IV nicotine and attenuated the rating of "drug liking." Progesterone also enhanced suppression of smoking urges by nicotine as assessed by the Brief Questionnaire on Smoking Urges (BQSU). These results suggest that progesterone may alter the subjective effects of nicotine as well as urges to smoke cigarettes. Further studies are warranted to examine the modulation of nicotine's effects by gonadal hormones.
 
Article
Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits. Copyright © 2014 John Wiley & Sons, Ltd.
 
Article
The effect of antipsychotics (APs) on negative symptoms is controversial. The present study assessed negative symptoms in healthy volunteers without any source of primary negative symptoms after single doses of haloperidol and risperidone. Twenty-five healthy subjects were included in this randomized, placebo-controlled, single-dose (haloperidol 5 mg and risperidone 2.5 mg) crossover and double-blind clinical trial. Negative symptoms were assessed by observer-rated scales and with a self-report scale. Possible confounding effects considered were extrapyramidal symptoms (EPS) and sedative effects. The occupation of striatal dopamine D2 receptors was also determined. Risperidone induced a wide range of negative symptoms such as alogia, blunted affect, avolition/apathy, and attention impairment, whereas haloperidol only induced the avolition/apathy subdomain. Most of the effects of risperidone in healthy volunteers, with the exception of its effects on avolition/apathy, were attributable to AP-induced EPS. Haloperidol did not cause significant EPS after administration. No effect of sedation or psychomotor performance was observed on negative symptoms. Single doses of both haloperidol and risperidone induced nonmotor secondary negative symptoms in healthy volunteers. The clinical findings are especially relevant in view of the impact of negative symptoms on poor functioning. They may help to guide clinicians in their choice of APs (http://clinicaltrials.gov/ct2/show/NCT01259973). Copyright © 2013 John Wiley & Sons, Ltd.
 
Article
Antagonism at the serotonin receptor 2A by the atypical antipsychotics clozapine and olanzapine has been suggested to be linked to these drugs' adverse effects on glucose-insulin homeostasis. Therefore, the aim of this study was to evaluate the impact of haplotypes based on the main functionally characterized polymorphisms of the serotonin receptor 2A (HTR2A) gene on parameters related to the glucose metabolism in clozapine- and olanzapine-treated patients. Forty-nine patients, with schizophrenia or schizoaffective disorder and treated with clozapine (n = 22) or olanzapine (n = 27), were evaluated for fasting levels of C-peptide, insulin and blood glucose, homeostasis model assessment index for insulin resistance (HOMA-IR) and body mass index (BMI), and genotyped for the -1438A/G, -783A/G, 102T/C, and His452Tyr polymorphisms of the HTR2A gene. About 50% of the patients had elevated levels of C-peptide (>0.68 nmol/L) and insulin (>or=79 pmol/L). However, patients carrying the haplotype [-1438A, -783A, 102T, 452Tyr] had significantly lower C-peptide levels compared with patients not carrying this haplotype (p = 0.039), despite no differences in blood glucose, HOMA-IR or BMI between the patient groups. Our results indicate that patients with the HTR2A haplotype [-1438A, -783A, 102T, 452Tyr] are less likely to develop metabolic abnormalities like C-peptide and insulin elevations during clozapine and olanzapine treatment.
 
Article
The sum of the serum levels of risperidone (RIS) and 9-hydroxyrisperidone (9-OH-RIS), which is the active moiety serum level, could be important for estimating the clinical effects of RIS. However, there have been no consistent results reported about the relationship between cytochrome P450 (CYP) 2D6*10 allele and plasma 9-OH-RIS or active moiety levels. We investigated the effect of the number of CYP2D6*10 alleles on steady-state plasma RIS, 9-OH-RIS, and active moiety levels in Japanese patients. Steady-state plasma RIS, 9-OH-RIS, and active moiety levels were measured in 64 patients treated with an average dosage of 4.6 mg/day. The number of CYP2D6*10 alleles significantly affected dose-corrected plasma RIS levels (p = 0.001), and the median concentrations in ng/ml/mg were 0.94 (0 allele) vs. 1.73 (1 allele) vs. 3.05 (2 alleles). The number of CYP2D6*10 alleles did not affect plasma 9-OH-RIS or active moiety levels. The present study shows that the number of CYP2D6*10 alleles affected plasma RIS levels but not plasma 9-OH-RIS and plasma active moiety levels. Because the plasma active moiety levels can influence antipsychotic effects or side effects, the genetic screening of the CYP2D6*10 allele for RIS in Asian populations may not be clinically important.
 
Article
The aims of this study were to determine if patients with SSRI-related hyponatraemia were (1) genetically poor metabolizers of CYP2D6, and/or (2) had excessive plasma concentrations of the SSRI antidepressant. Plasma DNA from 20 people with hyponatraemia attributable to fluoxetine or paroxetine was analysed for the CYP2D6 alleles *1-*16. Trough plasma concentrations of fluoxetine and norfluoxetine, or paroxetine were assayed in nine people who remained on the antidepressant. Genotype results were compared with those published in a large population study. The poor metabolizer PM/PM genotype was present in one subject only, or 5% of the study population, compared with 7.2% of a general population. The 95% Cl of this result was 0-21%, suggesting that it is most unlikely that hyponatremia is related to the PM/PM genotype. The intermediate IM/PM genotype was present in 5% compared with 19.7% of a general population. All differences were not statistically significant. Antidepressant concentrations of fluoxetine (n = 5, all EM) and paroxetine (n = 1 IM/PM and n = 3 EM) were all within the lower half of the reference range. These results do not support the hypothesis that SSRI-related hyponatraemia is linked to genetically poor metabolizers, or excessive drug concentrations.
 
Article
'Ecstasy' (3,4-methylenedioxymethamphetamine) induces impaired functioning in the serotonergic system, including the occipital lobe. This study employed the 'tilt aftereffect' paradigm to operationalise the function of orientation-selective neurons among ecstasy consumers and controls as a means of investigating the role of reduced serotonin on visual orientation processing. The magnitude of the tilt aftereffect reflects the extent of lateral inhibition between orientation-selective neurons and is elicited to both 'real' contours, processed in visual cortex area V1, and illusory contours, processed in V2. The magnitude of tilt aftereffect to both contour types was examined among 19 ecstasy users (6 ecstasy only; 13 ecstasy-plus-cannabis users) and 23 matched controls (9 cannabis-only users; 14 drug-naive). Ecstasy users had a significantly greater tilt magnitude than non-users for real contours (Hedge's g = 0.63) but not for illusory contours (g = 0.20). These findings provide support for literature suggesting that residual effects of ecstasy (and reduced serotonin) impairs lateral inhibition between orientation-selective neurons in V1, which however suggests that ecstasy may not substantially affect this process in V2. Multiple studies have now demonstrated ecstasy-related deficits on basic visual functions, including orientation and motion processing. Such low-level effects may contribute to the impact of ecstasy use on neuropsychological tests of visuospatial function.
 
Top-cited authors
Andrew C Parrott
  • Swansea University
Ian Hindmarch
  • University of Surrey
Brian Leonard
  • National University of Ireland, Galway
Ornella Corazza
  • University of Hertfordshire
Andrew Scholey
  • Monash University (Australia)