Showing papers in "The International Journal of Neuropsychopharmacology in 2005"

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Abstract: Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Abstract: The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.

Evidence-based pharmacotherapy of obsessive–compulsive disorder

Abstract: Obsessive-compulsive disorder is a prevalent and disabling lifespan disorder. Clomipramine and the SSRIs have been found to be effective across the range of symptoms, both in acute and longer-term studies. Meta-analyses have reported a larger treatment effect for clomipramine relative to the SSRIs, but this is not supported by evidence from head-to-head comparator studies and, based on their superior safety and tolerability, SSRIs are the preferred option for long-term treatment in most cases. The treatment-effect is usually gradual and partial, and many patients fail to respond adequately to first-line treatment. Pharmacological options for refractory cases include switching SRI, increasing the dose, or augmenting with an antipsychotic agent. Novel strategies are under investigation for this highly morbid group. This paper reviews the key questions related to OCD pharmacotherapy, synthesizing evidence derived from randomized controlled trials, meta-analyses and consensus guidelines.

Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive–compulsive disorder (OCD) and Tourette's syndrome (TS)

Abstract: There is evidence that motor and premotor cortex are hyperexcitable in obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). We tested whether low-frequency repetitive transcranial magnetic stimulation (rTMS) could normalize overactive motor cortical regions and thereby improve symptoms. Subjects with OCD or TS were treated with active rTMS to the supplementary motor area (SMA) for 10 daily sessions at 1 Hz, 100% of motor threshold, 1200 stimuli/day. Suggestions of clinical improvement were apparent as early as the first week of rTMS. At the second week of treatment, statistically significant reductions were seen in the YBOCS, YGTSS, CGI, HARS, HDRS, SAD, BDI, SCL-90, and SASS. Symptoms improvement was correlated with a significant increase of the right resting motor threshold and was stable at 3 months follow-up. Slow rTMS to SMA resulted in a significant clinical improvement and a normalization of the right hemisphere hyperexcitability, thereby restoring hemispheric symmetry in motor threshold.

The many faces of fatigue in major depressive disorder.

Abstract: Fatigue is a common complaint in the community and medical care settings. Different studies show a high comorbidity between fatigue and depressive disorder. Furthermore, fatigue is an important somatic symptom of depressive disorder and one of the main depressive presentations in primary-care medicine. Fatigue shows a slow response to antidepressant treatment and psychotherapy. Improved work performance is strongly correlated to improvement in energy. However, the assessment and treatment of fatigue in depressive disorder remains understudied. Different definitions of fatigue in depressive disorder are applied in DSM-IV and ICD-10, and depression rating scales all show a different coverage of this core depressive symptom, thereby hampering scientific research. Serotonin, norepinephrine, dopamine and histamine mediate symptoms of fatigue in depressive disorder. Although few data address the effect of antidepressants or augmentation strategies on fatigue-related symptoms, there is a pharmacological rationale for using antidepressant monotherapies, such as venlafaxine, bupropion, sertraline, fluoxetine, or augmentation of first-line treatment with stimulants or modafinil.

The antidepressant effect of running is associated with increased hippocampal cell proliferation.

Abstract: A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.

Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat.

Abstract: To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile + adulthood stress group swam faster and tended to explore the central area more than the other groups - a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.

Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials.

Abstract: Many trials of naltrexone have been carried out in alcohol-dependent patients. This paper is aimed to systematically review its benefits, adverse effects, and discontinuation of treatment. We assessed and extracted the data of double-blind, randomized controlled trials (RCTs) comparing naltrexone with placebo or other treatment in people with alcoholism. Two primary outcomes were subjects who relapsed (including heavy drinking) and those who returned to drinking. Secondary outcomes were time to first drink, drinking days, number of standard drinks for a defined period, and craving. All outcomes were reported for the short, medium, and long term. Five common adverse effects and dropout rates in short-term treatment were also examined. A total of 2861 subjects in 24 RCTs presented in 32 papers were included. For short-term treatment, naltrexone significantly decreased relapses [relative risk (RR) 0.64, 95% confidence interval (CI) 0.51-0.82], but not return to drinking (RR 0.91, 95% CI 0.81-1.02). Short-term treatment of naltrexone significantly increased nausea, dizziness, and fatigue in comparison to placebo [RRs (95% CIs) 2.14 (1.61-2.83), 2.09 (1.28-3.39), and 1.35 (1.04-1.75)]. Naltrexone administration did not significantly diminish short-term discontinuation of treatment (RR 0.85, 95% CI 0.70-1.01). Naltrexone should be accepted as a short-term treatment for alcoholism. As yet, we do not know the appropriate duration of treatment continuation in an alcohol-dependent patient who responds to short-term naltrexone administration. To ensure that the real-world treatment is as effective as the research findings, a form of psychosocial therapy should be concomitantly given to all alcohol-dependent patients receiving naltrexone administration.

Randomized controlled trial of the cognitive side-effects of magnetic seizure therapy (MST) and electroconvulsive shock (ECS).

Abstract: Magnetic seizure therapy (MST) is under development as a means of improving the cognitive side-effect profile of electroconvulsive therapy (ECT) by inducing more spatially delimited seizures that spare cortical regions involved in memory. We tested whether MST had a cognitive side-effect profile distinct from electroconvulsive shock (ECS) in a non-human primate model, using the Columbia University Primate Cognitive Profile, which has been shown to be sensitive to the cognitive effects of ECS. Using a within-subject cross-over design, daily ECS, MST, and sham (anaesthesia-only) interventions were administered in 5-wk blocks. Rhesus macaques ( n = 2) were trained on a long-term memory task, an anterograde learning and memory task, and a combined anterograde and retrograde task where learning and memory were evaluated for new and previously learned 3-item lists. Acutely following each intervention, monkeys were tested on the cognitive battery twice daily, separated by a 3-h retention interval. Overall, monkeys were least accurate following ECS ( p 's<0.05) compared to sham and MST. This effect was most marked for long-term memory of a constant target, short-term memory of a variable target and recall of previously learned 3-item lists. Monkeys were slowest to complete all tasks following ECS ( p 's=0.0001). Time to task completion following MST did not differ from sham. These findings suggest that MST results in a more benign acute cognitive side-effect profile than ECS in this model, consistent with initial observations with human MST.

Prefrontal grey-matter changes in short-term and long-term abstinent methamphetamine abusers.

Abstract: Authors explored grey-matter density in 29 methamphetamine abusers and 20 healthy comparison subjects using voxel-based morphometry. Grey-matter density changes and performances on the Wisconsin Card Sorting test (WCST) were also compared between 11 short-term ( or=6 months) abstinent methamphetamine abusers. Methamphetamine abusers had lower grey-matter density in the right middle frontal cortex (corrected p<0.05) and more total errors in the WCST (p<0.01) relative to healthy comparison subjects. Grey-matter density decrease in the right middle frontal cortex correlated with total errors in the WCST in methamphetamine abusers (r=-0.45). Long-term abstinent abusers had significantly less right middle frontal grey-matter density decrease (p<0.01) and total errors in the WCST (p<0.01) than short-term abstinent abusers, but more than the healthy comparison subjects. We report that methamphetamine abusers have prefrontal grey-matter deficit, which may, in part, recover with long-term abstinence.

Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans.

Abstract: Functional abnormalities in muscarinic and nicotinic receptors are associated with a number of disorders including Alzheimer's disease and schizophrenia. While the contribution of muscarinic receptors in modulating cognition is well established in humans, the effects of nicotinic receptors and the interactions and possible synergistic effects between muscarinic and nicotinic receptors have not been well characterized in humans. The current study examined the effects of selective and simultaneous muscarinic and nicotinic receptor antagonism on a range of cognitive processes. The study was a double-blind, placebo-controlled, repeated measures design in which 12 healthy, young volunteers completed cognitive testing under four acute treatment conditions: placebo (P); mecamylamine (15 mg) (M); scopolamine (0.4 mg i.m.) (S); mecamylamine (15 mg)/scopolamine (0.4 mg i.m.) (MS). Muscarinic receptor antagonism with scopolamine resulted in deficits in working memory, declarative memory, sustained visual attention and psychomotor speed. Nicotinic antagonism with mecamylamine had no effect on any of the cognitive processes examined. Simultaneous antagonism of both muscarinic and nicotinic receptors with mecamylamine and scopolamine impaired all cognitive processes impaired by scopolamine and produced greater deficits than either muscarinic or nicotinic blockade alone, particularly on working memory, visual attention and psychomotor speed. These findings suggest that muscarinic and nicotinic receptors may interact functionally to have synergistic effects particularly on working memory and attention and suggests that therapeutic strategies targeting both receptor systems may be useful in improving selective cognitive processes in a number of disorders.

Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder

Abstract: Autism is a neurodevelopmental disorder characterized by impairment in three core symptom domains: socialization, communication, and repetitive/stereotyped behaviours. Other associated symptom domains are also affected including impulsivity/aggression, self-injury, anxiety, and mood lability. Divalproex has been shown to have efficacy in treating epilepsy, bipolar disorder, mood lability, and impulsive aggression. The present study evaluated the use of divalproex in the treatment of repetitive, compulsive-like symptoms of autism spectrum disorder (ASD). Thirteen individuals with ASD participated in an 8-wk, double-blind, placebo-controlled trial of divalproex sodium vs. placebo. There was a significant group difference on improvement in repetitive behaviours as measured by the Children's Yale-Brown Obsessive Compulsive Scale (C-YBOCS) (p=0.037) and a large effect size (d=1.616). This study provides preliminary support for the use of divalproex in treating repetitive behaviours in ASD. Further research is needed to evaluate the specificity and mechanism of action of these findings.

Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder (ADHD) – the spontaneously hypertensive rat (SHR)

Abstract: The spontaneously hypertensive rat (SHR) is generally considered to be a suitable genetic model for the study of attention deficit hyperactivity disorder (ADHD), since it displays hyperactivity, impulsivity, poorly sustained attention, and deficits in learning and memory processes. Converging evidence suggests a primary role of disturbance in the dopaminergic neurotransmission in ADHD patients and in SHR, and in addition, some studies have also demonstrated alterations in adenosinergic neurotransmission in SHR. In the present study, adult female Wistar (WIS) and SHR rats received caffeine (1-10 mg/kg i.p.) 30 min before training, immediately after training, or 30 min before a test session in the spatial version of the Morris water maze. The effect of caffeine administration on WIS and SHR blood pressure was also measured. SHR needed significantly more trials in the training session to acquire the spatial information, but they displayed a similar profile to that of WIS rats in the test session (48 h later), demonstrating a selective deficit in spatial learning. Pre-training administration of caffeine (1-10 mg/kg i.p.) improved this spatial learning deficit in SHR, but did not alter the WIS performance. In contrast, post-training administration of caffeine (3 mg/kg i.p.) did not alter the SHR test performance, but increased memory retention in WIS rats. No dose of caffeine tested altered the mean blood pressure of WIS or SHR. These results demonstrate a selective spatial learning deficit in SHR which can be attenuated by pre-training administration of caffeine. In addition, the present findings indicate that the spatial learning deficit in SHR is not directly related to hypertension.

Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia

Abstract: Serotonin 5-HT1A receptors are promising targets in the management of schizophrenia but little information exists about affinity and efficacy of novel antipsychotics at these sites. We addressed this issue by comparing binding affinity at 5-HT1A receptors with dopamine rD2 receptors, which are important targets for antipsychotic drug action. Agonist efficacy at 5-HT1A receptors was determined for G-protein activation and adenylyl cyclase activity. Whereas haloperidol, thioridazine, risperidone and olanzapine did not interact with 5-HT1A receptors, other antipsychotic agents exhibited agonist properties at these sites. E(max) values (% effect induced by 10 microM of 5-HT) for G-protein activation at rat brain 5-HT1A receptors: sarizotan (66.5), bifeprunox (35.9), SSR181507 (25.8), nemonapride (25.7), ziprasidone (20.6), SLV313 (19), aripiprazole (15), tiospirone (8.9). These data were highly correlated with results obtained at recombinant human 5-HT1A receptors in determinations of G-protein activation and inhibition of forskolin-stimulated adenylyl cyclase. In binding-affinity determinations, the antipsychotics exhibited diverse properties at r5-HT1A receptors: sarizotan (pK(i)=8.65), SLV313 (8.64), SSR181507 (8.53), nemonapride (8.35), ziprasidone (8.30), tiospirone (8.22), aripiprazole (7.42), bifeprunox (7.19) and clozapine (6.31). The affinity ratios of the ligands at 5-HT1A vs. D2 receptors also varied widely: ziprasidone, SSR181507 and SLV313 had similar affinities whereas aripiprazole, nemonapride and bifeprunox were more potent at D2 than 5-HT1A receptors. Taken together, these data indicate that aripiprazole has low efficacy and modest affinity at 5-HT1A receptors, whereas bifeprunox has low affinity but high efficacy. In contrast, SSR181507 has intermediate efficacy but high affinity, and is likely to have more prominent 5-HT1A receptor agonist properties. Thus, the contribution of 5-HT1A receptor activation to the pharmacological profile of action of the antipsychotics will depend on the relative 5-HT1A/D2 affinities and on 5-HT1A agonist efficacy of the drugs.

Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei.

Abstract: The pharmacological efficacy of serotonergic-acting drugs suggest that patients with obsessive–compulsive disorder (OCD) may have alterations in their cerebral serotonergic (5-HT) receptor system, and previous neuroimaging studies of OCD patients have shown abnormalities in several fronto-subcortical regions. In this study we investigated cerebral 5-HT2A receptor binding in 15 untreated OCD patients and in 15 age- and gender-matched healthy volunteers by magnetic resonance imaging and [18F]altanserin positron emission tomography (PET). Eleven of the patients were rescanned with PET after receiving treatment with a selective serotonin reuptake inhibitor (SSRI). The distribution volumes of specific tracer binding (DV3′) were calculated for 12 brain regions, and comparisons were made between: (1) healthy volunteers vs. untreated OCD patients, (2) healthy volunteers vs. treated OCD patients, and (3) OCD patients before and during treatment. When comparing the distribution volume for specific fronto-subcortical brain regions, significantly higher values were recorded in the caudate nuclei in OCD patients (DV3′: 0.24±0.14) compared to the healthy control group (DV3′: 0.15±0.13) ( p <0.05, Wilcoxon matched-pairs test). This difference between groups was not present after treatment with SSRIs. There was no correlation between the severity of OCD symptoms and 5-HT2A receptor binding. An increase in 5-HT2A receptor binding is found in the caudate nuclei of untreated patients with OCD. The up-regulation in 5-HT2A receptors might be compensatory for a lack of serotonin in the feedback loop between the thalamus and orbito-frontal cortex, the caudate nuclei, and the globus pallidus.

Evidence-based pharmacotherapy of generalized anxiety disorder

Abstract: Generalized Anxiety Disorder (GAD) is a common and often disabling disorder. This paper reviews the pharmacological treatment of GAD, based on the findings of published meta-analyses and randomized placebo-controlled studies. In doing so, it aims to address three fundamental questions: What is the first-line treatment for GAD? How long should treatment continue? What is the best intervention in patients who do not respond to first-line and second-line treatments? Due to their efficacy in GAD and comorbid anxiety and depressive disorders, their tolerability and safety, certain selective serotonin re-uptake inhibitors (escitalopram, paroxetine, sertraline) should be considered the first-line treatment for most patients, although the serotonin-noradrenaline re-uptake inhibitor venlafaxine is a reasonable alternative. Little is known about the optimal length of therapy after response to acute treatment but relapse-prevention studies with paroxetine suggest that continuation treatment should last for at least 6 months. The management of patients who do not respond to first-line treatment is uncertain, but some patients may benefit from certain tricyclic antidepressants, buspirone, or pregabalin.

Focus on Protein kinase A and protein kinase C, critical components of signal transduction system, in mood disorders and suicide

Abstract: Depression is among the most prevalent forms of mental disorders, affecting 10–15% of the US population, with high rates of comorbidity and frequent suicidal behaviour. Tragically, about 30000 lives are lost each year by suicide (Minino and Smith, 2001). Despite significant progress in research, the pathophysiology of depression and suicide is poorly understood. A number of studies suggest that abnormalities in signalling mechanisms may be crucial to various psychiatric disorders, including depression and suicide (Dwivedi et al., 2002, 2003; Jope et al., 1998; Pacheco et al., 1996; Pandey et al., 2002a). Particular attention has been paid to examining protein phosphorylation and dephosphorylation and the activation and repression of transcription factors, which are key processes in signalling mechanisms, and ultimately in modulating the expression of genes involved in various neuronal functions. Two important protein phosphorylating enzymes, protein kinase A (PKA) and protein kinase C (PKC), are components of the adenylyl cyclase-cyclic AMP (AC-cAMP) and the phosphoinositide (PI) signalling systems respectively. Activation of PKC by diacylglycerol is associated with the translocation of the enzyme from the cytoplasm to the membrane and then causes phosphorylation of important proteins and transcription factors such as cAMP response element-binding (CREB) protein, which regulates the expression of genes containing CRE consensus in their promoters. As is the case with PKC, the activation of PKA by cAMP also phosphorylates a diverse number of target proteins in both cytoplasm and the nuclear compartment. One such target in the nucleus is CREB.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Abstract: Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0002) over and above the effect of population group, also when controlling for age and gender (p=00008), but not with His452Tyr genotype The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0001) but not orofacial TD By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 164 A T102C-His452Tyr haplotype was significantly associated with TD (p=00008) These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications

Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia.

Abstract: Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4-5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 receptor occupancy ranged from 25-48%, 59-83% and 62-72% respectively, while plasma active-moiety levels ranged from 4.4-8.8, 15.0-31.1 and 22.5-26.3 ng/ml respectively. The results indicate that brain D2 receptor occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2-6 mg of oral risperidone.

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures.

Abstract: Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

Obesity among outpatients with major depressive disorder.

Abstract: Studies focusing on the prevalence of obesity in Major Depressive Disorder (MDD), or the impact of excess body fat on the treatment of MDD are lacking. The aim of the present work is to systematically study obesity in MDD outpatients. A total of 369 MDD outpatients enrolled in an 8-wk trial of 20 mg fluoxetine had height and weight measured at baseline. We then examined: (1) the prevalence of being overweight or obese, (2) the relationship between obesity and a number of demographic and clinical variables, and, (3) the relationship between relative body weight and obesity with clinical response. We found that more than 50% of patients were overweight [body mass index (BMI) > or =2 5 kg/m2], while 20% were obese (BMI > or = 30 kg/m2). Obese patients presented with worse somatic well-being scores than non-obese MDD patients, but they did not differ with respect to depression severity, anxiety, somatic complaints, hopelessness or hostility. Greater relative body weight, but not obesity, predicted non-response. In conclusion, greater relative body weight was found to place MDD outpatients at risk for fluoxetine resistance.

Decreased frontal white-matter volume in chronic substance abuse.

Abstract: There is quite a body of work assessing functional brain changes in chronic substance abuse, much less is known about structural brain abnormalities in this patient population. In this study we used magnetic resonance imaging (MRI) to determine if structural brain differences exist in patients abusing illicit drugs compared to healthy controls. Sixteen substance abusers who abused heroin, cocaine and cannabis but not alcohol and 16 age-, sex- and race-matched controls were imaged on a MRI scanner. Contiguous, 5-mm-thick axial slices were acquired with simultaneous T2 and proton density sequences. Volumes were estimated for total grey and white matter, frontal grey and white matter, ventricles, and CSF using two different methods: a conventional segmentation and a stereological method based on the Cavalieri principle. Overall brain volume differences were corrected for by expressing the volumes of interest as a percentage of total brain volume. Volume measures obtained with the two methods were highly correlated (r=0.65, p<0.001). Substance abusers had significantly less frontal white-matter volume percentage than controls. There were no significant differences in any of the other brain volumes measured. This difference in frontal lobe white matter might be explained by a direct neurotoxic effect of drug use on white matter, a pre-existing abnormality in the development of the frontal lobe or a combination of both effects. This last explanation might be compelling based on the fact that newer concepts on shared aspects of some neuropsychiatric disorders focus on the promotion and inhibition of the process of myelination throughout brain development and subsequent degeneration.

Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram

Abstract: Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response.

Prevalence of sexual dysfunction in patients with schizophrenia: international variation and underestimation.

Abstract: The prevalence of sexual dysfunction in schizophrenia patients was investigated as part of this large (n = 7655), prospective, international (27 countries) study. Based on patient reports, sexual dysfunction affected approx. 50% of patients and the prevalence of complaints varied significantly between regions (p < 0.0001). The prevalence of sexual dysfunction, as perceived by psychiatrists, also varied significantly across regions (p < 0.0001). Psychiatrists significantly underestimated the presence of impotence/sexual dysfunction (p < 0.0001) and loss of libido (p < 0.0001), compared to reports from patients. The frequency of sexual dysfunction was significantly higher in patients who had been using prolactin-elevating antipsychotics prior to study entry, compared to those who had been treated with prolactin-sparing antipsychotics (patient reports, p = 0.002; psychiatrist perception, p = 0.0004). This study has shown that the prevalence of sexual dysfunction is high in both male and female patients with schizophrenia and frequently underestimated by psychiatrists. Regional variation is evident in both psychiatrist perceptions and patient reports of sexual dysfunction. Given the importance of sexual function to quality of life and treatment compliance, proactive assessment of sexual function is required to optimize schizophrenia management.

The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine

Abstract: The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation) Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8 Patients with low folate levels ( 005) In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 15 wk

Involvement of nitric oxide-cGMP pathway in the antidepressant-like effects of adenosine in the forced swimming test.

Abstract: We have previously shown that an acute administration of adenosine produces an antidepressant-like effect in the forced swimming test (FST) and in the tail suspension test in mice. In this work we investigated the contribution of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway to adenosine's antidepressant-like effect in the FST since this signalling pathway is assumed to play an important role in depression. The effect of adenosine (10 mg/kg i.p.) was prevented by pre-treatment with L-arginine (750 mg/kg i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25 microg/site i.c.v), or sildenafil (5 mg/kg i.p.), but not with D-arginine (750 mg/kg i.p.). Treatment of mice with N(G)-nitro-L-arginine ( L-NNA, 0.03 and 0.3 mg/kg i.p.), Methylene Blue (18 mg/kg i.p.), or ODQ (30 pmol/site i.c.v.) potentiated the effect of adenosine (1 mg/kg i.p.) in the FST. The reduction of immobility time elicited by adenosine (10 mg/kg i.p.) in the FST was prevented by pre-treatment with sildenafil (0.5 and 5 mg/kg i.p.). Together the results indicate that the effect of adenosine in the FST appears to be mediated through an interaction with the NO-cGMP pathway.

Associations between serotonin-related gene polymorphisms and panic disorder.

Abstract: Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD.

Combined alpha2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat.

Abstract: The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse.

Abstract: Alcoholism is a lifelong disease often associated with emotional disturbances and a high risk of relapse even years after detoxification. To explore if cell proliferation in the dentate gyrus of the hippocampus might be important for alcohol-induced brain adaptation, we analysed hippocampal neurogenesis and gliogenesis in adult C57BL/6 mice that consumed moderate levels of ethanol (~6 g/kg.d) in a two-bottle free-choice model during ~10 wk. The mice developed a 53% preference for ethanol vs. water and displayed a blood ethanol concentration of 0.24 per thousand at the time of sacrifice. Bromo-deoxy-uridine (BrdU) was administered in different regimes to analyse proliferation, survival, cell distribution and differentiation of new cells in the dentate gyrus. Moderate ethanol consumption increased the proliferation of cells, which survived and developed a neural phenotype. Ethanol consumption did not induce apoptosis, neither did it change differentiation or the distribution patterns of the newly formed cells. The cell proliferation rate in the dentate gyrus returned to basal levels 3 d after ethanol withdrawal. We conclude that voluntary ethanol intake by mice can change the rate of cell proliferation in the dentate gyrus. These observations add to the emerging picture of dentate gyrus neurogenesis as a highly regulated process. Since there was no increase in apoptosis concomitant with the ethanol-induced increase in neurogenesis, it is possible that the new cells in the dentate gyrus may contribute to the long-lasting changes of brain function after ethanol consumption.

Bupropion SR for the treatment of postpartum depression: a pilot study.

Abstract: Despite the prevalence of postpartum depression, few studies have assessed the efficacy of antidepressants for the treatment of this disorder. Failure to treat postpartum depression (PPD) places the woman at risk for chronic depression and may have adverse effects on child wellbeing and development. Eight female outpatients aged 18-45 yr were enrolled in an 8-wk open-label trial of bupropion SR for PPD. All patients met DSM-IV criteria for major depression with onset within 3 months of delivery and scored 17 or greater on the Hamilton Depression Rating Scale (HAMD) at baseline. Those with onset of depressive symptoms during pregnancy, psychotic symptoms, or significant medical illness were excluded. Median scores on the HAMD declined from 20.5 (range 15-38) at baseline to 10.0 (range 1-20) at end-point (p or =50% decrease in HAMD scores from baseline; three subjects achieved remission (HAMD score of < or =7) at week 8. Median final dosage of bupropion SR was 262.5 (range 37.5-300). Bupropion SR was well tolerated, and no subjects discontinued treatment as a result of medication side-effects. Bupropion SR represents an effective and well-tolerated antidepressant for the treatment of PPD.