Journal of Psychopharmacology

Benzodiazepines produce robust impairments of memory alongside global decreases in physiological and subjective arousal. Recently one benzodiazepine (triazolam) has been found to disproportionately impair memory for emotionally arousing material (Buchanan et al., 2003). The extent to which this effect may be mediated by the drug's sedative action is unclear. The present study aimed to assess how pharmacologically decreasing physiological arousal with a benzodiazepine and increasing arousal with a stimulant impact on memory for emotional material. A double-blind placebo controlled trial with 48 volunteers was used to investigate the effects of methylphenidate (40 mg) and Lorazepam (1.5 mg) on incidental memory for emotional material in Cahill and McGaugh's (1995) slide-story task. The slide-story was presented to participants administered either active drug or placebo and retrieval was assessed one week later. Methylphenidate produced stimulant effects and Lorazepam produced sedative effects. Significantly enhanced memory for emotional material was observed in participants given placebo, but not in those given either methylphenidate or Lorazepam. Despite producing opposite effects upon arousal, both methylphenidate and Lorazepam lessen the impact of emotionally arousing material on memory. The effects of Lorazepam add to a growing literature that benzodiazepines may exert their clinical, anxiolytic effects in part via altering emotionaL cognitive function.

We have previously shown that a single dose of intravenous citalopram in healthy volunteers enhances the detection of fearful facial expressions, suggesting an effect of acute selective serotonin re-uptake inhibitor (SSRI) treatment on the processing of anxiety-related stimuli. The aim of the present study was to confirm and extend this finding by studying the effects of a single dose of oral citalopram on a range of tasks designed to assess different aspects of emotional processing.

A total of 32 healthy volunteers were randomly allocated to double-blind treatment with either citalopram 20 mg orally or placebo. Participants then completed a series of tasks assessing emotional aspects of attention (visual-probe task), perception (categorization of facial affect), memory (emotional memory task) and reactivity to threat (emotion potentiated startle).

Relative to placebo-treated subjects, participants treated with citalopram demonstrated improved recognition of fearful faces and increased baseline startle response. However, the citalopram group also showed an attentional bias towards positive words.

Our data suggest that acute oral citalopram increases the processing of anxiety-related stimuli in healthy volunteers. This mechanism could underlie the known tendency of SSRIs to increase anxiety in patients early in treatment. Our data also suggests that some of the positive biases in emotional processing produced by SSRI treatment might be detectable at the beginning of treatment.

There is a general consensus that benzodiazepines affect attentional processes, yet only few studies have tried to investigate these impairments in detail. The purpose of the present study was to investigate the effects of a single dose of Lorazepam on performance in a target cancellation task with important time constraints. We measured correct target detections and correct distractor rejections, misses and false positives. The results show that Lorazepam produces multiple kinds of shifts in performance, which suggests that it impairs multipLe processes: (a) the evolution of performance over time was not the same between the placebo and the Lorazepam groups, with the Lorazepam affecting performance quite early after the beginning of the test. This is suggestive of a depletion of attentional resources during sequential attentional processing; (b) Lorazepam affected differently target and distractor processing, with target detection being the most impaired; (c) misses were more frequent under Lorazepam than under placebo, but no such difference was observed as far as false positives were concerned. Signal detection analyses showed that Lorazepam (d) decreased perceptual discrimination, and (e) reliably increased response bias. Our results bring new insights on the multiple effects of Lorazepam on selective attention which, when combined, may have deleterious effects on human performance.

High levels of impulsivity have adverse effects on performance in cognitive tasks, particularLy in those tasks that require high attention investment. Furthermore, both animal and human research has indicated that reduced brain serotonin (5-HT) function is associated with increases in impulsive behaviour or decreased inhibition ability, but the effects of 5-HT challenge have not yet been investigated in subjects vulnerable to impulsivity.

The present study aimed to investigate whether subjects with high trait impulsivity perform worse than low impulsive subjects in a task switching paradigm in which they have to rapidly shift their attention between two response rules, and to investigate the influence of a 5-HT enhancing diet. Healthy subjects with high ( n = 19) and low (n = 18) trait impulsivity scores participated in a double-blind placebo-controlled study. All subjects performed the attention switch task in the morning following breakfast containing either tryptophan-rich alpha-lactalbumin (4.8 g/100 g TRP) or placebo protein (1.4 g/100 g TRP).

Whereas there were no baseline differences between high and low impulsive subjects in task switching abilities, high impulsive subjects made significantly more switch errors and responded slower after dietary 5-HT stimulation, whereas no dietary effects were found on task switching performance in low-impulsive subjects. The deterioration in task switching performance induced by the 5-HT enhancing diet in high impulsive subjects was suggested to be established by general arousal/attention-reducing effects of 5-HT, which might have a larger impact in high impulsive subjects due to either different brain circuitry involved in task switching in this group or lower baseline arousal levels.

Recent research suggests that not only does the use of recreational drugs impact on working memory functioning, but more `everyday' aspects of memory (e.g. remembering to do something in the future) are also affected. Forty-three ecstasy-polydrug users and 51 non-ecstasy users were recruited from a university population. Each participant completed the Cognitive Failures Questionnaire (CFQ) and Everyday Memory Questionnaire (EMQ). Of these, 28 ecstasy-polydrug users and 35 non-ecstasy users completed the Prospective Memory Questionnaire (PMQ). In addition, an objective measure of cognitive failures (the CFQ-for-others) was completed by friends of participants. With the exception of the CFQ-for-others, in each regression equation, cannabis emerged as the only significant predictor of everyday and prospective memory deficits. Significant correlations were found between the different indicators of everyday memory and various measures of illicit drug use. Cannabis featured prominently in this respect. The present study provides further support for cannabis related deficits in aspects of everyday memory functioning. Ecstasy may aLso be associated with cognitive slips, but not to the same extent as cannabis.

Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/— and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (—48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings.

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely IKr (IKr: rapid component of the delayed rectifier potassium current).

Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150—250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 µM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 ± 0.7 msec at 3 µM but by 26.0 ± 4.3 msec at 100 µM (250 msec cycle length). Increase in MAPD₉₀ was also reverse frequency dependent; 30 µM olanzapine increased MAPD90 by 28.0 ± 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 ± 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 µM.

Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients.

Rhodiola rosea l. is one of the most popular adaptogen and anti-stress plants in European and Asiatic traditional medicine. Its pharmacological properties appear to depend on its ability to modulate the activation of several components of the complex stress-response system. Exposure to both physical and psychological stress reduces feeding in rodents. The aim of this work was thus to determine whether in rats an hydroalcoholic R. rosea extract standardized in 3% rosavin and 1% salidroside (RHO) reverses hypophagia induced by (1) physical stress due to 60 min immobilization; (2) intracerebroventricular injection of corticotrophin-releasing factor (CRF, 0.2 μg/rat), the major mediator of stress responses in mammals; (3) intraperitoneal injection of Escherichia coli Lipopolysaccharide (LPS, 100 μg/kg); (4) intraperitoneal administration of fluoxetine (FLU, 8 mg/kg). The effect of the same doses of the plant extract was also tested in freely-feeding and in 20 h food-deprived rats. RHO was administered acutely by gavage to male Wistar rats 1 h before the experiments. The results show that at 15 and 20 mg/kg, RHO reversed the anorectic effects induced both by immobilization and by intracerebroventricular CRF injection. Moreover, at the same doses, RHO failed to reduce the anorectic effect induced both by LPS and FLU, and did not modify food intake in both freely-feeding and food-deprived rats. These findings strongly demonstrated that RHO is able selectively to attenuate stress-induced anorexia, providing functional evidence of claimed adaptogen and anti-stress properties of Rhodiola rosea L.

Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPTAUC % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPTAUC % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPTAUC %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood—placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.

Although the mechanism of action of acetaminophen (AAP) is not fully understood, some studies suggest that AAP and phenacetin (PHE) are selective cyclooxygenase (COX)-3 inhibitors. To examine the participation of COX-3 in memory formation, water maze performance was studied in mice treated with AAP, PHE or other COX inhibitors. Mice received intraperitoneal injections of drugs immediately after each training session. Administration of high-dose AAP [302.3 mg/kg (IC50 for COX-2)] or PHE [179.2 mg/kg (IC50 for COX-2)] and of non-specific (indomethacin: 20 mg/kg) or specific COX-2 (NS-398: 10 mg/kg) inhibitor impaired the performance in hidden platform (HP) not visible platform (VP) tasks, whereas low-dose (15.1 mg/kg) AAP facilitated performance in HP and VP tasks. The facilitation of performance by low-dose AAP was reversed by co-administration with a 5-HT1/2 receptor antagonist (methysergide: 0.47 mg/kg). The middle-dose [69.5 mg/kg (IC50 for COX-3)] of AAP, the PHE [17.9 mg/kg (IC50 for COX-3)] and a specific COX-1 inhibitor (piroxicam: 10—20 mg/kg) did not influence performance in either task. These results suggest that the memory impairment by high-dose AAP and PHE and facilitation of performance by low-dose AAP could involve endogenous COX-2 and serotonergic neuronal activity, but not COX-3, respectively.

Hyperprolactinaemia is a common finding in patients treated with antipsychotics. A complete cohort of 194 schizophrenia and bipolar disorder patients receiving antipsychotics in a single community mental health trust in Halifax UK underwent routine prolactin screening in the absence of any reLevant symptomatoLogy. Values above the upper limit of normal were measured in 38% of the cohort and were more common in females (52%) than males (26%). Significantly elevated levels (>1000 mIU/l) were measured in 21% of the cohort. Risperidone monotherapy treatment was associated with hyperprolactinaemia in 69% of patients ( n = 35) and in 100% of female patients (n = 16) and amisulpride monotherapy in 100% (n = 7). Prolactin screening is not currently undertaken routinely in the UK. These data give some indication of prevalence of varying degrees of hyperproLactinaemia that might be found when screening an asymptomatic cohort of schizophrenia and bipolar outpatients. Clinicians may be helped by the reporting of such categorical data from clinical trials in addition to mean cohort values of prolactin. Long-term hyperprolactinaemia may be associated with clinical sequeLae in some patients.

No systematic review or meta-analysis using a hard outcome has been conducted on the role of benzodiazepines for generalized anxiety disorder (GAD). The objective of this study was to assess the effectiveness and efficacy of benzodiazepines in the treatment of GAD based on trial drop-out rates. We used a systematic review of randomized controlled trials that compared any of the three best established benzodiazepines (diazepam, Lorazepam and aLprazolam) against placebo. Our primary outcome for effectiveness was withdrawal for any reason. Our secondary outcome tapping efficacy was withdrawal due to lack of efficacy, and that tapping side effects was withdrawals due to adverse events.

We included 23 trials. Pooled analysis indicated less risk of treatment discontinuation due to lack of efficacy for benzodiazepines, compared to placebo, relative risk (RR) 0.29 (95% CI 0.18—0.45; p < 0.00001). Nevertheless, pooled analysis showed no conclusive results for risk of all-cause patient discontinuation, RR 0.78 (95% CI 0.62—1.00; p = 0.05). Meta-regression model showed that 74% of the variation in logRR across the studies was explained by year of publication (p <0.001).

This systematic review did not find convincing evidence of the short-term effectiveness of the benzodiazepines in the treatment of GAD. On the other hand, for the outcome of efficacy, this review found robust evidence in favour of benzodiazepines. Due to the heterogeneity induced by year of publication, three hypotheses are plausibLe when it comes to being able to account for the differences between efficacy and effectiveness observed in the outcomes (publication bias, quality of the trial literature and a non-differential response to the placebo effect).