Conventional Antipsychotics Research Articles

Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury.

In mature neurons, low intracellular chloride level required for inhibition is maintained by the potassium-chloride cotransporter, KCC2. Impairment of Cl- extrusion after KCC2 dysfunction has been involved in many central nervous system disorders, such as seizures, neuropathic pain, or spasticity, after a spinal cord injury (SCI). This makes KCC2 an appealing drug target for restoring Cl- homeostasis and inhibition in pathological conditions. In the present study, we screen the Prestwick Chemical Library® and identify conventional antipsychotics phenothiazine derivatives as enhancers of KCC2 activity. Among them, prochlorperazine hyperpolarizes the Cl- equilibrium potential in motoneurons of neonatal rats and restores the reciprocal inhibition post-SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the antispastic agent, baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These pre-clinical data support prochlorperazine for a new therapeutic indication in the treatment of spasticity post-SCI and neurological disorders involving a KCC2 dysfunction.

Clinically Relevant Drug Interactions with Anti-Alzheimer's Drugs.

The aging world population had led to an increase in the prevalence of Alzheimer's disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. The concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

Bipolar patients treated with long-acting injectable risperidone in Taiwan: A 1-year mirror-image study using a national claims database

ObjectiveBipolar disorder (BD) is burdensome for patients and healthcare systems. This study evaluated changes in concomitant medication patterns, healthcare utilization, and costs after the initiation of risperidone long-acting injection (RLAI) treatment among BD patients. Method287 BD patients receiving regular RLAI treatment for 1 year were identified from the Taiwan National Health Insurance Research database during 2007–2012. The bootstrapping procedure was performed to create 1000 samples to generate normally distributed data. The paired t-tests with a correction for multiple comparisons using Bonferroni correction were used to compare the proportion of patients of concomitant psychiatric medication and resource use and costs between pre- and post-RLAI periods. Rapid and non-rapid cycling stratification was performed based on the number of change-in-mood episodes within 1 year prior to the index date. ResultsThe mean annual dose of RLAI was 638.41mg, which was equal to an average dose of 24.6mg every 2 weeks. The prevalence of concomitant use of conventional antipsychotics, atypical antipsychotics, lithium, and antidepressants decreased from the pre-RLAI period to the post-RLAI period by 23.75%, 31.91%, 1.29%, and 7.08%, respectively. RLAI use decreased emergency room (ER) visits, hospital admissions, length of hospital stay, and non-medication costs (all P<0.0001). The cost savings with RLAI were attributed to lower hospitalization costs in spite of higher medication costs. Moreover, rapid cycling patients (n=36) demonstrated greater reduction in ER and inpatient services with RLAI than non-rapid cycling patients (n=251). LimitationsOf the patients who initiated RLAI, 15% of them who had regular treatment were included. Furthermore, data on measures of symptom severity, side effects, and hyperprolactinemia were not available. ConclusionBD patients had lower inpatient and ER utilization, and non-medication costs after using RLAI. In addition, RLAI use decreased the number of change-in-mood episodes in rapid cycling patients; which provides additional insights into the treatment of rapid cycling BD patients.

The Clinical Challenge of Autoimmune Psychosis: Learning from Anti-NMDA Receptor Autoantibodies.

Schizophrenia is a heterogeneous and complex psychiatric disorder affecting up to 1% of the population worldwide (1). Although the precise development of schizophrenia is not yet fully understood, it is now admitted to be underpinned by the entanglement of genetic, environmental, and immuno-inflammatory factors. Among schizophrenic patients, it is assumed that at least 30% will not respond to conventional antipsychotics (2). These data underlie the importance of precision medicine in psychiatry, in other words, the need to identify subgroups of patients with specific signatures who will benefit from treatment targeting these specific biological pathways. Reviving an area of exploration older than a century, recent and abundant literature emphasized the importance of the immune system in the pathophysiology of schizophrenia [for review, see Ref. (3)]. In psychiatry, the link between psychotic disorders, particularly schizophrenia, and immune system deregulations, including autoimmunity, is an old concept that regained strong support; thanks to the better characterization of brain inflammation-induced psychotic symptoms and autoimmune encephalitis (3). Moreover, recent epidemiological studies evidenced a high prevalence of multiple autoimmune diseases in schizophrenic patients (4). In a recent meta-analysis, autoantibodies against neuronal receptors have indeed been identified in the circulation of patients with neuropsychiatric disorders, constituting, today, one of the hottest topics in psychiatry (5–10). This new era fosters debate on (i) how to explain the increased burden of autoimmunity in schizophrenia, (ii) what could be the precise target(s) and the pathogenic implication(s) of the autoantibodies on the disease onset and development, (iii) how to define patient subgroups carrying such autoantibodies to facilitate their diagnosis, and (iv) how should we treat these patients using appropriate protocols such as immunotherapy (i.e., corticotherapy or plasmapheresis). Several neurological autoimmune diseases are, for instance, efficiently treated once autoantibodies against neurotransmitter receptors and ion channels have been identified (11, 12). The discovery of the autoimmune encephalitis due to anti-N-methyl-d-aspartic acid receptor (NMDAR) has greatly revived the relationship between autoimmunity and psychosis. Indeed, directed against the NMDAR N-methyl-d-aspartate receptors antibodies (NMDAR-Ab), the autoantibodies are directly responsible for the psychotic symptoms and catatonia, followed by profound neurologic deterioration (13, 14). In patients with schizophrenia, the prevalence and clinical significance of circulating NMDAR-Ab remains controversial with detection prevalence rates varying considerably between studies (15–27). Inspite of such imprecisions, defining and isolating seropositive patients, suffering from “autoimmune psychosis,” is a major challenge for appropriate treatments. In this review, we focus our attention on the potential elements possibly helping to define an “autoimmune psychosis” subgroup of schizophrenic patients. Furthermore, we outline some of the specific clinical presentation of these patients that will be of great importance to optimize the diagnostic and subsequent therapies.

Predicting offense recidivism in Schizophrenia patients

IntroductionSchizophrenia increases the risk of offending. Recidivism rates are significant.AimIdentifying general and violent recidivism risk factors in schizophrenia patients.MethodsWe conducted a case control study. All included patients were admitted, at least once, to the forensic psychiatry department in Razi Hospital between January 1st, 1985 and December 31st, 2014 after a decision of irresponsibility by reason of insanity. All those who reoffended during this period were considered as cases. A draw was performed to create the control group. Both groups were matched according to their first offences’ types as well as to their ages. A multivariate analysis was performed.ResultsWe included 25 cases and 38 controls. Eight recidivism risk factors were identified. Living in urban poor neighbourhoods (P = 0.039; OR = 1.23), having been unemployed (P = 0.047; OR = 1.22) and not having lived with the family (P = 0.039; OR = 1.36) after discharge were considered as risk factors. The same applied to alcohol (P = 0.032; OR = 1.29) and cannabis use disorders (P = 0.005; OR = 1.34). A hospitalization shorter than 6 months increased the risk by 1.44 (P = 0.039). A combination of conventional antipsychotics (P = 0.003; OR = 1.36) and a poor adherence (P = 0.006; OR = 1.36) were considered as recidivism risk factors too.ConclusionsAll eight recidivism risk factors are dynamic. This makes recidivism prevention conceivable. Measures involving the patient, the health care system, patients’ families, society and the government should be taken.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Isolated rhabdomyolysis caused by olanzapine: About a clinical case

IntroductionAtypical anti-psychotics are increasingly prescribed, given their tolerance. Among these anti-psychotic olanzapine, known for its adverse metabolic effects. By against an adverse event type rhabdomyolysis with olanzapine appears uncommon (&lt;1%) and few clinical cases have been reported in the literature.AimThe aim of our study is to illustrate with a clinical case the occurrence of an isolated rhabdomyolysis with olanzapine.Materiel and methodStarting from the study of the case of a patient with rhabdomyolysis with olanzapine we studied the literature data. Clinical vignette: it is about a patient aged 25 followed for bipolar disorder type I. He responded to the association olanzapine and valproic acid then to valproic acid only. His last hospitalization for manic relapse dating to September 9, 2015 occurred in a context of treatment discontinuation. Upon admission the patient underwent an oral treatment based olanzapine and valproic acid. A dosage of creatine phosphokinase (CPK) done systematically, on September 11 showed high levels of (CPK) to 973 (U/L) without clinical signs of neuroleptic malignant syndrome. The electrocardiogram and biological tests results were normal. Other etiologies can lead to elevated (CPK) were eliminated. The persistent elevation of CPK motivated the arrest of olanzapine. The evolution was marked by a return to normal CPK rates after 15 days. The olanzapine was replaced by haloperidol and vaproic acid maintained. The pharmacovigilance investigation conclude to the accountability of olanzapine in this rhabdomyolysis.ConclusionSecond generation, anti-psychotics are known for their better tolerance compared to conventional antipsychotics. However, they are not devoid of side effects.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Clozapine efficiency in tardive syndromes induced by anti-psychotic treatment

IntroductionTardive syndromes (TS) resulting from prolonged exposure to dopamine receptor blocking agents are frequent. Clozapine is considered to have a low risk of causing new onset TS and accounts therefore as an interesting option in patients with invalidating TS.ObjectivesOur study aims to describe clozapine indications in patients experiencing TS.MethodsPresentation of the clinical cases of five patients, who experienced different kinds of TS secondary to 1st and 2nd generation anti-psychotic treatment.ResultsWe present the cases of AB aged 41, MJ aged 40, HM aged 31 and AS aged 30, diagnosed with schizophrenia; and FB aged 24,diagnosed with schizoaffective disorder. Adverse side effects to conventional anti-psychotics such as limb and trunk tremors were described for AB, choreic limb movements, axial and segmental dystonia for MJ, AS, FB and oculogyration for FB. All patients were switched to atypical anti-psychotics without improvement of the TS. The switch to clozapine, associated with abotulinum injection for MJ, led to regression of the TS and improvement of clinical signs. In fact, according to several studies, clozapine seems to be an interesting option when invalidating TS occurs. The low prevalence of TS under clozapine can be explained by its low affinity for striatal-D2 receptors, its anti-serotonin and anti-cholinergic effects.ConclusionsClozapine should be considered in symptomatic patients who develop TS while receiving other anti-psychotics. Further research on mechanism of TS and clozapine effect on TS is needed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Predicting offense recidivism in Schizophrenia patients

IntroductionSchizophrenia increases the risk of offending. Recidivism rates are significant.AimIdentifying general and violent recidivism risk factors in schizophrenia patients.MethodsWe conducted a case control study. All included patients were admitted, at least once, to the forensic psychiatry department in Razi Hospital between January 1st, 1985 and December 31st, 2014 after a decision of irresponsibility by reason of insanity. All those who reoffended during this period were considered as cases. A draw was performed to create the control group. Both groups were matched according to their first offenses’ types as well as to their ages. A multivariate analysis was performed.ResultsWe included 25 cases and 38 controls. Eight recidivism risk factors were identified. Living in urban poor neighbourhoods (P = 0.023; OR = 4.86), having been unemployed (P = 0.042; OR = 2.18) and not having lived with the family (P = 0.039; OR = 1.36) after discharge were considered as risk factors. The same applied to alcohol (P = 0.026; OR = 4.89) and cannabis use disorders (P = 0.018; OR = 6.01). A hospitalization shorter than 6 months increased the risk by 1.79 (P = 0.046). A combination of conventional antipsychotics (P = 0.023;OR = 4.81) and a poor adherence (P = 0.001; OR = 10.42) were considered as recidivism risk factors too.ConclusionsAll eight recidivism risk factors are dynamic. This makes recidivism prevention conceivable. Measures involving the patient, the health care system, patients’ families, society and the government should be taken.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Differentiated psychopharmacological treatment in three genetic subtypes of 22q11.2 deletion syndrome

IntroductionThe 22q11.2 deletion syndrome (22q11DS), mostly caused by the common deletion including the TBX- and COMT-genes (LCR22A-D), is highly associated with somatic anomalies. The distal deletion (distal of LCR22D) comprises the MAPK1-gene and is associated with specific heart defects. The rare central deletion (LCR22B-D) encompasses the CRKL-gene and shows predominantly urogenital anomalies. 22q11DS also differs in its neuropsychiatric profile: common deletion accompanied by schizophrenia-like psychoses and autism spectrum disorders, distal deletion by anxiety disorders, and central deletion by autistic-like behaviours.ObjectivesInvestigating genetic subtypes of 22q11DS.AimsAchieving a targeted pharmacological treatment based on genetic sub-typing.MethodsThirty-two patients with genetically proven 22q11DS, referred for detailed neuropsychiatric analysis.ResultsApart from two patients with distal deletion and one with central deletion, common 22q11.2 deletion was detected in 29 patients. Those with the common deletion were typified by a history of relapsing schizophrenia-like psychoses and partial non-response to conventional antipsychotics. In most patients, anxieties and mood instability were also manifest. The two patients with a distal deletion predominantly showed anxiety symptoms, while the behaviour of the patient with a central deletion was characterized by symptoms from the autism spectrum. Most patients with a common deletion could successfully be treated with clozapine or quetiapine, often combined with valproic acid. One patient with a distal deletion showed full remission upon treatment with citalopram (the second refused such a pharmacological intervention). The behaviour of the patient with central deletion improved upon contextual measures only.ConclusionsThe genetic subtype of 22q11DS enables targeting of treatment strategy.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Antipsychotic Augmentation with Venlafaxine for Treatment of Negative Symptoms in Chronic Schizophrenia - A Case Series

Negative symptoms represent a core feature in schizophrenia and the deficit syndrome in chronic schizophrenic patients is closely related to their poor outcome and global failure in community adaptation. Atypical antipsychotics have been widely used in the treatment of negative symptoms in schizophrenia, and tend to produce a better response when used in association with antidepressants. We describe a case series of patients with a clinical diagnosis of residual type of schizophrenia, who have undergone an augmentative treatment of antipsychotic medication with venlafaxine. Both primary and secondary negative symptoms, as well as the overall functioning in these patients were substantially improved following this treatment. This is the first clinical study describing the combination of venlafaxine with both conventional antipsychotics and novel antipsychotics, such as risperidone, to treat successfully both secondary and primary negative symptoms in schizophrenia. We also discuss possible modes of action of the joint use of this particular antidepressant with antipsychotic medication.

Antipsychotic drug use associated with urinary tract infections in older women

ObjectivesAntipsychotic drugs are frequently prescribed to elderly patients, but they are associated with serious adverse effects. The objective of the current study was to investigate the association between use of antipsychotics by elderly women and the risk of urinary tract infections (UTIs). Cohort study settingDispensing data were obtained from the PHARMO Database Network for the period 1998–2008. ParticipantsAmbulatory Dutch women (≥65 years) with current and past use of antipsychotics. MeasurementsIncidence rates of UTIs, as defined by use of nitrofurantoin, was calculated within and outside the period of exposure to antipsychotic drugs. Cox proportional hazard regression analysis with Andersen-Gill extension for recurrent events was used to calculate crude and adjusted hazard ratios (HRs). ResultsDuring the study period, 18,541 women with a first prescription of an antipsychotic were identified. Current use of antipsychotics was associated with an increased risk of UTI compared to past use: HR, adjusted for age and history of UTIs, 1.33, 95% CI 1.27–1.39. A strong temporal relationship was found: the risk of being treated for a UTI was higher in the first week after the start of the treatment (adjusted HR 3.03, 95% CI 2.63–3.50) and decreased after 3 months (adjusted HR 1.22, 95% CI 1.17–1.28). Cumulative exposure was not associated with an increased risk of UTIs. There was no difference in effect between conventional and atypical antipsychotics. ConclusionOur results show an increased risk of uncomplicated UTIs during antipsychotic use in older female patients, especially in the first week of treatment.

Effect of Antipsychotic Drugs on Body Composition in Patients Attending Psychiatry Clinic, Jimma, Ethiopia

Despite their irrevocability in the therapeutics of mental illness, an antipsychotic drug has many side effects including change in the body composition. More specifically, atypical antipsychotics, such as, Olanazapin, were often associated with increased weight gain compared to conventional antipsychotics, risking patients to metabolic syndrome. Generally, there is lack of study concerning effects of antipsychotic drugs on body composition in low income setting. The aim of this study was to assess changes in body composition among psychiatric patients taking antipsychotic drugs. A longitudinal study was conducted among 74 clients attending psychiatric clinic at Jimma university specialized hospital. A consecutive sampling method was applied. Body weight, height, waist and hip circumferences and skin fold thickness were measured before and after 12 weeks of therapy. A structured questionnaire was used to assess socio-demographic and socio-economic factors. The data were analysed using SPSS Version 20 for Windows. One way ANOVA, paired t-test, and independent t-test were applied to examine mean change in body composition indicators across the variables. The mean ± SD of body weight, Body mass index, waist to hip ratio, Percent body fat of patients taking antipsychotic drugs were significantly higher by 4.16 kg ± 2.78, 1.54 kg/m2 ± 1.08, 1.27 ± 0.781 and 0.02 ± 1.08 respectively. Increment of body composition was not even among different types of drugs used. The mean change in weight for Risperidone, Haloperidol, and Chlorpromazine were 4.3, 3.4, 5.4 kg, respectively. The increase in body composition observed in this study was irrespective of socio-demographic and behavioral characteristics of the patients. Significant increment in body weight, BMI, waist to hip ratio and percent body fat was observed among psychotic patients who took Risperidone, Haloperidol, and Chlorpromazine. Efforts to mitigate the untoward effects of these drugs should begin early before evident metabolic risk profile changes become evident. Despite their irrevocability in the therapeutics of mental illness, an antipsychotic drug has many side effects including change in the body composition. More specifically, atypical antipsychotics, such as, Olanazapin, were often associated with increased weight gain compared to conventional antipsychotics, risking patients to metabolic syndrome. Generally, there is lack of study concerning effects of antipsychotic drugs on body composition in low income setting. The aim of this study was to assess changes in body composition among psychiatric patients taking antipsychotic drugs. A longitudinal study was conducted among 74 clients attending psychiatric clinic at Jimma university specialized hospital. A consecutive sampling method was applied. Body weight, height, waist and hip circumferences and skin fold thickness were measured before and after 12 weeks of therapy. A structured questionnaire was used to assess socio-demographic and socio-economic factors. The data were analysed using SPSS Version 20 for Windows. One way ANOVA, paired t-test, and independent t-test were applied to examine mean change in body composition indicators across the variables. The mean ± SD of body weight, Body mass index, waist to hip ratio, Percent body fat of patients taking antipsychotic drugs were significantly higher by 4.16 kg ± 2.78, 1.54 kg/m2 ± 1.08, 1.27 ± 0.781 and 0.02 ± 1.08 respectively. Increment of body composition was not even among different types of drugs used. The mean change in weight for Risperidone, Haloperidol, and Chlorpromazine were 4.3, 3.4, 5.4 kg, respectively. The increase in body composition observed in this study was irrespective of socio-demographic and behavioral characteristics of the patients. Significant increment in body weight, BMI, waist to hip ratio and percent body fat was observed among psychotic patients who took Risperidone, Haloperidol, and Chlorpromazine. Efforts to mitigate the untoward effects of these drugs should begin early before evident metabolic risk profile changes become evident.

Cognitive effects of adjunctive N-acetyl cysteine in psychosis.

Cognitive deficits are predictors of functional outcome in patients with psychosis. While conventional antipsychotics are relatively effective on positive symptoms, their impact on negative and cognitive symptoms is limited. Recent studies have established a link between oxidative stress and neurocognitive deficits in psychosis. N-acetylcysteine (NAC), a glutathione precursor with glutamatergic properties, has shown efficacy on negative symptoms and functioning in patients with schizophrenia and bipolar disorder, respectively. However, there are few evidence-based approaches for managing cognitive impairment in psychosis. The present study aims to examine the cognitive effects of adjunctive NAC treatment in a pooled subgroup of participants with psychosis who completed neuropsychological assessment in two trials of both schizophrenia and bipolar disorder. A sample of 58 participants were randomized in a double fashion to receive 2 g/day of NAC (n = 27) or placebo (n = 31) for 24 weeks. Attention, working memory and executive function domains were assessed. Differences between cognitive performance at baseline and end point were examined using Wilcoxon's test. The Mann-Whitney test was used to examine the differences between the NAC and placebo groups at the end point. Participants treated with NAC had significantly higher working memory performance at week 24 compared with placebo (U = 98.5, p = 0.027). NAC may have an impact on cognitive performance in psychosis, as a significant improvement in working memory was observed in the NAC-treated group compared with placebo; however, these preliminary data require replication. Glutamatergic compounds such as NAC may constitute a step towards the development of useful therapies for cognitive impairment in psychosis.

A Review of Adverse Outcomes Associated with Psychoactive Drug Use in Nursing Home Residents with Dementia.

Treatment guidelines generally recommend careful assessment and non-pharmacological treatment approaches for behavioural and psychological symptoms of dementia. However, the inappropriate use of psychoactive drugs in patients with dementia in nursing homes is still prevalent. The aim of this narrative review is to summarise and criticize the most recent data investigating the adverse outcomes related to psychoactive drug use, specifically antipsychotics, antidepressants and benzodiazepines, in patients with dementia living in nursing homes. Searches of PubMed® and Web of Science® identified 790 potentially relevant articles, 23 of which were retained in this review. All studies investigated adverse outcomes of antipsychotics compared with non-use, or with antidepressants and/or benzodiazepine anxiolytic or hypnotic drugs. Several studies focused on the comparison between atypical and conventional antipsychotics, risperidone often being the reference. The most frequently reported outcomes were mortality (all-cause or cardiovascular), falls and/or fractures, and cardiovascular or cerebrovascular events. Overall, for mortality or falls, the highest risk is for benzodiazepines, followed by conventional antipsychotics, antidepressants and atypical antipsychotics. Whatever the drug, the patient must be carefully monitored during the first days of treatment, which needs to be initiated at the lowest possible dose and for the shortest duration. In light of the high risk of adverse outcomes (falls, cardiovascular events, infections, mortality) for patients with dementia living in nursing homes, all drugs must be carefully prescribed. However, further studies comparing pharmacological with non-pharmacological interventions, with a realistic consideration of the structural nursing home organisation, would be welcome.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside.

The cognitive symptoms observed in schizophrenia are not consistentlyalleviated by conventional antipsychotics. Following a recent pilot study, sodium nitroprusside (SNP) has been identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients. The present experiments were designed to explore the effects of SNP on the highly translatable trial-unique, delayed nonmatching-to-location (TUNL) task in rats with and without acute MK-801 treatment. SNP (0.5, 1.0, 2.0, 4.0, and 5.0mg/kg) and MK-801 (0.05, 0.075, and 0.1mg/kg) were acutely administered to rats trained on the TUNL task. Acute MK-801 treatment impaired TUNL task accuracy. Administration of SNP (2.0mg/kg) with MK-801 (0.1mg/kg) failed to rescue performance on TUNL. SNP (5.0mg/kg) administration nearly 4h prior to MK-801 (0.05mg/kg) treatment had no preventative effect on performance impairments. SNP (2.0mg/kg) improved performance on a subset of trials. These results suggest that SNP may possess intrinsic cognitive-enhancing properties but is unable to block the effects of acute MK-801 treatment on the TUNL task. These results are inconsistent with the effectiveness of SNP as an adjunct therapy for working memory impairments in schizophrenia patients. Future studies in rodents that assess SNP as an adjunct therapy will be valuable in understanding the mechanisms underlying the effectiveness of SNP as a treatment for schizophrenia.

P.1.j.051 - Effects of atypical and conventional antipsychotics on cognition in schizophrenia

P.1.j.051 - Effects of atypical and conventional antipsychotics on cognition in schizophrenia

P.1.g.034 - Analysis of Homer1a expression levels as a tool to investigate antipsychotic-related perturbation of synaptic plasticity: translational implications for schizophrenia treatment strategies

Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome.To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms.A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact.There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, l-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms.Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed.

WITHDRAWN: Risperidone versus other atypical antipsychotic medication for schizophrenia.

Risperidone is one of a number of 'atypical antipsychotics' which are currently being marketed for the treatment of those with schizophrenia, largely on the basis of claims of improved tolerability and effectiveness compared to much cheaper conventional antipsychotics. The efficacy of risperidone has already been compared to conventional drugs, but it remains unclear how risperidone compares with other atypical antipsychotic drugs such as clozapine. To determine the effects of risperidone compared with other atypical antipsychotic drugs for schizophrenia. Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 2000), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. All randomised controlled clinical trials that compared risperidone to other atypical antipsychotic treatments for schizophrenia and schizophrenia-like psychoses were included by independent assessment. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, standardised and weighted mean differences were calculated (SMD, WMD). All data were inspected for heterogeneity. Nine studies were obtained, comparing risperidone with clozapine (five studies - largely amongst treatment resistant patients); olanzapine (three studies); and amisulpiride (one study). The research was beset by problems of high attrition rates and short term follow up.Clozapine does seem equally acceptable to risperidone in the short term (leaving the study early, n=466, RR 1.00 CI 0.73-1.37). For most other outcomes wide confidence intervals were obtained, which meant that it was impossible to judge whether the two compounds were equally effective, or whether one was in fact superior to the other.Olanzapine and risperidone seem broadly similar according to numbers of patients responding to treatment (40% reduction in PANSS scores: n=339, RR 1.14, CI 0.99-1.32). Olanzapine caused fewer people to leave the study early (n=404, RR 1.31 CI 1.06-1.60; NNT 8 CI 4-32) and fewer extrapyramidal side effects (n=339, RR 1.67 CI 1.14-2.46; NNH 8 CI 5-33), although comparative doses of risperidone were higher than those recommended in practice.In one single study (n=228) amisulpiride seemed broadly similar to risperidone in most respects.There were no useful data presented relating to service use and costs. Very few data relating to quality of life were presented. The equivalence of clozapine and risperidone for treatment resistant schizophrenia cannot yet be assumed and there seems to be little to chose between risperidone and both olanzapine and amisulpiride. The research is limited in many respects, and longer term studies measuring clinically important outcomes, including service use and quality of life are needed to judge the comparative value of the various atypical drugs.

The Effect of Safety Warnings on Antipsychotic Drug Prescribing in Elderly Persons with Dementia in the United Kingdom and Italy: A Population-Based Study

Antipsychotic (AP) drugs are commonly used to manage the behavioural symptoms of dementia. Nevertheless, international (i.e. the European Medicines Agency in Europe) and national (i.e. the Medicines and Healthcare products Regulatory Agency in the UK and the Italian Drug Agency) regulatory agencies issued safety warnings against AP use in dementia in 2004 and 2009. The aim of this study is to investigate the short- and long-term impact of safety warnings on the use of APs in UK and Italian persons with dementia using two nationwide databases: The Health Improvement Network (THIN) from the UK and the Health Search Database-Cegedim-Strategic Data-Longitudinal Patient Database (HSD-CSD-LPD) from Italy. We calculated the overall quarterly prevalence of AP use by class and by individual drug in persons with dementia aged ≥65years and used generalized linear models to explore the effect of the safety warnings. We identified 58,497 and 10,857 individuals aged ≥65years with dementia from the THIN and HSD-CSD-LPD databases, respectively, over the period 2000-2012. After the 2004 warnings, the use of atypical APs decreased, whereas the use of conventional APs increased, in Italy and the UK until 2009. However, the trend for APs individually showed that the use of risperidone/olanzapine decreased, whereas the use of quetiapine increased in both countries. After the 2009 warnings (until 2012), the use of atypical and conventional APs decreased in the UK (from 11 to 9 and 5 to 3%, respectively), but such use increased in Italy (from 11 to 18 and 9 to 14%, respectively). The 2004 warnings led to a reduction in the use of olanzapine and risperidone and increased the use of quetiapine/conventional APs in both countries. From 2009, the use of APs decreased in persons with dementia in the UK but not in Italy. Possible reasons for the difference in AP use between the two countries include a more proactive approach towards reducing the use of APs in the UK than in Italy.

PM527. Higher serum concentrations of tyrosine and glutamate in schizophrenia patients treated with clozapine, compared to in those treated with conventional antipsychotics

PM527. Higher serum concentrations of tyrosine and glutamate in schizophrenia patients treated with clozapine, compared to in those treated with conventional antipsychotics