Atypical Antipsychotic Drugs Risperidone Research Articles

Near-Infrared Fluorescent Probe for the In Situ Visualization of Oxidative Stress in the Brains of Neuroinflammatory and Schizophrenic Mice.

Schizophrenia is a common mental disorder with unclear mechanisms. Oxidative stress and neuroinflammation play important roles in the pathological process of schizophrenia. Superoxide anion (O2•-) is an important oxidative stress biomarker in vivo. However, due to the existence of the blood-brain barrier (BBB), few near-infrared (NIR) fluorescent probes have been used for the sensing and detection of O2•- in the brain. With this research, we developed the first near-infrared fluorescent probe (named CT-CF3) for noninvasive detection of endogenous O2•- in the brain of mice. Enabling fluorescence monitoring of the dynamic changes in O2•- flux due to the prolonged activation of microglia in neuroinflamed and schizophrenic (SZ) mice brains, thereby providing direct evidence for the relationship between oxidative stress, neuroinflammation, and schizophrenia. Furthermore, we confirmed the O2•- burst in the brains of first-episode schizophrenic mice and assessed the effect of two atypical antipsychotic drugs (risperidone and olanzapine) on redox homeostasis.

Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice

Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28–30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (−13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone.

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone.

N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

Risperidone accelerates bone loss in rats with autistic-like deficits induced by maternal lipopolysaccharides exposure

AimsPatients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. Materials and methodsThis study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. ResultsMaternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DiscussionsThe results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.

Inhibition by the atypical antipsychotic risperidone of voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

We evaluated the inhibitory effects of the atypical antipsychotic drug risperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Risperidone suppressed Kv currents in reversible and concentration-dependent manners with an apparent half-maximal effective concentration (IC50 value) of 5.54 ± 0.66 μM and a slope factor of 1.22 ± 0.07. The inactivation of Kv currents was significantly accelerated by risperidone. The rate constants of association and dissociation for risperidone were 0.25 ± 0.01 μM−1s−1 and 1.36 ± 0.14 s−1, respectively. Application of risperidone shifted the steady-state activation curve in the positive direction and the inactivation curve in the negative direction, suggesting that the risperidone-induced inhibition of Kv channels was mediated by effects on the voltage sensors of the channels. Application of train pulses at 1 and 2 Hz led to a progressive increase in the blockage of Kv currents by risperidone. In addition, the recovery time constants from inactivation were extended in the presence of risperidone, indicating that risperidone inhibited Kv channels in a use (state)-dependent manner. Pretreatment with the Kv1.5 subtype inhibitor reduced the inhibitory effects of risperidone on Kv channels. However, pretreatment with a Kv2.1 or Kv7.X subtype inhibitor did not affect the inhibitory effects of risperidone. Risperidone induced vasoconstriction and membrane depolarization. Based on these results, we conclude that risperidone inhibits Kv channels in a concentration-, time-, and state-dependent manners. Our results should be taken into consideration when using risperidone to study the kinetics of K+ channels in vascular smooth muscle.

Chronic Activation of the Dopaminergic Neuronal Pathway Improves Behavioral Abnormalities in the Prenatal Valproic Acid Exposure Mouse Model of Autism Spectrum Disorder

Over the last decade there has been an increase in the prevalence of autism spectrum disorder (ASD); however, its pathogenic mechanisms remain unclear. To date, no effective drug has been developed to treat the core symptoms of ASD, especially social interaction deficits. Previous studies have mainly focused on the glutamatergic, GABAergic, and serotonergic signaling pathways; however, a growing number of studies have reported abnormalities in the dopaminergic pathway, such as mutations and functional alterations of dopamine-related molecules, in ASD patients. Furthermore, atypical antipsychotic drugs risperidone and aripiprazole are prescribed for the treatment of non-core symptoms, such as irritability, in patients with ASD. These observations suggest that the dopaminergic pathway is involved in the pathogenesis of ASD. Previously, we have established a mouse model of ASD based on clinical research, which shows that exposure to valproic acid, an antiepileptic drug, during pregnancy causes an increase in the risk of developing ASD in children. This review summarizes our recent studies, which have assessed alterations in the prefrontal dopaminergic pathway. In addition, we discuss the effects of treatment with attention deficit/hyperactivity disorder drugs and atypical antipsychotic drugs, which activate the prefrontal dopaminergic pathway, on ASD-like behavioral abnormalities in the valproic acid exposure mouse model of ASD.

Efficacy of risperidone and haloperidol in treatment of schizophrenia in tertiary care hospital

Background: Schizophrenia is a chronic debilitating disease with significant morbidity and mortality that often requires either typical or atypical antipsychotic pharmacotherapy. Atypical antipsychotic drugs are preferred over typical because of lower risk of extra pyramidal side effects. As there is paucity of data in Indian population, the present study was taken up to evaluate the efficacy of haloperidol and risperidone in the treatment of schizophrenia.Methods: It was a comparative study conducted on 60 patients of Schizophrenia for one year in a tertiary care hospital. The study subjects were randomly assigned into 2 groups of 30 patients each, where group 1 were treated with atypical antipsychotic drug risperidone and group 2 with typical antipsychotic drug Haloperidol and both groups received the treatment for one year. Efficacy was measured using positive and negative syndrome scale (PANSS), clinical global impression - severity of illness (CGI-S), clinical global impression - improvement (CGI-I) scales.Results: Both haloperidol and risperidone were associated with comparable baseline to endpoint reduction in symptom severity. However, risperidone treated subjects had significantly greater decrease in symptom severity as measured by PANSS score and total score, CGI-S scale. However, there is no significant difference between two groups in terms of CGI-S score.Conclusions: The reduction in positive, negative and general scores in risperidone treated patients were significant with that of haloperidol treated patients.

A comparative study of metabolic side effects of risperidone and olanzapine in the treatment of schizophrenia

ABSTRACTBackground: Schizophrenia is one of most serious chronic psychiatric disorder, which affects about 1% of population. Treatment of schizophrenia comprises of typical antipsychotics and or atypical antipsychotics. Typical antipsychotics like haloperidol have extrapyramidal side effects which limit their use in chronic cases. Atypical antipsychotics though have better treatment response, they have metabolic side effects like hypercholesteremia, hypertriglyceridemia and hyperglycaemia. As there is paucity of data in Indian population the present study has been taken up to compare the metabolic side effects of risperidone and olanzapine in the treatment of schizophrenic patients in a tertiary care hospital.Methods: It was a comparative study conducted on 60 patients of Schizophrenia for one year in a tertiary care hospital. The study subjects were randomly assigned into 2 groups of 30 patients each, where group 1 were treated with atypical antipsychotic drug risperidone and group 2 with Olanzapine and both groups received the treatment for one year. Metabolic side effects like hypercholesteremia, hypertriglyceridemia and hyperglycaemia were evaluated and compared over a period of one year.Results: Both risperidone and olanzapine were associated with comparable baseline to endpoint increase in metabolic side effects. However, risperidone treated subjects had significantly less metabolic side effects compared to olanzapine.Conclusions: Apart from total cholesterol and triglycerides, other metabolic side effects were less in risperidone treated patients than olanzapine treated patients.

Serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

SummaryDopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases ranging from schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, nausea and vomiting, among others. Dopamine’s actions are mediated by a family of five G-protein coupled receptors (GPCRs) (viz. D1, D2, D3, D4 and D5)1. The D2 dopamine receptor (DRD2) is the primary target for both typical2 and atypical3,4 antipsychotic drugs, and for Parkinson’s disease drugs. Unfortunately, many drugs targeting DRD2 frequently suffer from serious and potentially life-threatening side effects due to promiscuous activities against related receptors4,5. Accordingly, a molecular understanding of DRD2 structure and function could provide a template for the design of safer and more effective medications. Here we provide the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and illuminates structural determinants essential for the actions of risperidone and related drugs at DRD2.

Sensitive Liquid Chromatography/Tandem Mass Spectrometry Method for the Simultaneous Determination of Risperidone, Olanzapine, Quetiapine, Clozapine, Ziprasidone, Perospirone, Aripiprazole and Blonanserin in Human Serum

The sensitive method for the simultaneous determination of eight atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, clozapine, ziprasidone, perospirone, aripiprazole and blonanserin) in human serum has been developed based on a high-performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) with electrospray ionization (ESI). The chromatographic separation was performed on a Mightysil-RP-18 MS column (2.0 mm × 150 mm, particle size 3 μm). The mobile phase consisted of 10 mM formic ammonium buffer (pH 6.0) and acetonitrile and was delivered at a flow rate of 0.20 mL/min. The triple quadrupole mass spectrometer was operated in positive ion mode, and multiple reaction monitoring was used for drug quantification. Solid-phase extraction of the eight antipsychotic drugs added to the human serum was performed with an Oasis®HLB extraction cartridges column. The method was linear for the investigated drugs over the concentration range of 20 - 100 ng/mL. The recoveries of these drugs were in the range of 81.3% - 140%. The intraday and inter day standard deviation (SD) values for all analytes were <0.10. Therefore, the selectivity, accuracy and precision of this method are sufficient for clinical and forensic studies. This simultaneous screening method will be also applicable to analyze other atypical antipsychotic drugs.

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice.

Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.

Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs—risperidone, olanzapine, aripiprazole, and quetiapine—differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined—risperidone, olanzapine, aripiprazole and quetiapine—quetiapine has the strongest effect on ANS activity.

A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice

Atypical antipsychotic (AA) drugs, including risperidone (RIS), are used to treat schizophrenia, bipolar disorder, and autism, and are prescribed off-label for other mental health issues. AA drugs are associated with severe metabolic side effects of obesity and type 2 diabetes. Cross-sectional and longitudinal data also show that risperidone causes bone loss and increases fracture risk in both men and women. There are several potential mechanisms of bone loss from RIS. One is hypogonadism due to hyperprolactinemia from dopamine receptor antagonism. However, many patients have normal prolactin levels; moreover we demonstrated that bone loss from RIS in mice can be blocked by inhibition of β-adrenergic receptor activation with propranolol, suggesting the sympathetic nervous system (SNS) plays a pathological role. Further, when, we treated ovariectomized (OVX) and sham operated mice daily for 8weeks with RIS or vehicle we demonstrated that RIS causes significant trabecular bone loss in both sham operated and OVX mice. RIS directly suppressed osteoblast number in both sham and OVX mice, but increased osteoclast number and surface in OVX mice alone, potentially accounting for the augmented bone loss. Thus, hypogonadism alone cannot explain RIS induced bone loss. In the current study, we show that dopamine and RIS are present in the bone marrow compartment and that RIS can exert its effects directly on bone cells via dopamine receptors. Our findings of both direct and indirect effects of AA drugs on bone are relevant for current and future clinical and translational studies investigating the mechanism of skeletal changes from AA drugs.

Effect of risperidone on serum homocysteine levels in first-episode, drug-naïve patients with schizophrenia

Some studies have shown that homocysteine (Hcy) levels are increased in patients with schizophrenia, and may be involved in its pathophysiology. The purpose of this study was to investigate the effect of the atypical antipsychotic drug risperidone on serum Hcy levels and to explore the relationship between the changes in Hcy levels and the therapeutic outcome, which, to our best knowledge have not been investigated.Fifty-six first-episode and drug-naïve inpatients with schizophrenia were assigned to a 12-week treatment regime with risperidone. Clinical efficacy was determined with the Positive And Negative Syndrome Scale (PANSS). Serum Hcy levels were measured by sandwich enzyme-linked immunosorbent assay in schizophrenia patients before and after the 12-week treatment, and the values were compared with those of fifty-six age- and gender- matched healthy controls.Serum Hcy levels were significantly higher in first-episode and drug-naïve patients than in control subjects (11.18±4.53 vs. 5.99±3.61μmol/L, F=37.195, df=1, p=1.73×10−8). Moreover, a significant positive correlation between Hcy levels and PANSS negative sub-score was observed (r=0.515; p=4.81×10−5). Serum Hcy levels were significantly decreased in patients after risperidone treatment (baseline: 11.18±4.53μmol/L vs. post-treatment: 8.98±4.07μmol/L, t=3.857, p=3.034×10−4). At post-treatment, there was a significant negative relationship between serum Hcy levels and PANSS negative sub-scores (r=−0.288, p=0.032).High Hcy levels at the onset of psychosis suggests that it may contribute to the pathogenesis of schizophrenia and is related to clinical psychopathology. Serum Hcy levels were significantly decreased in schizophrenia patients after risperidone treatment.

Efficacy and Safety of Bitopertin in Patients with Schizophrenia and Predominant Negative Symptoms: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 2 Trial.

ObjectiveThe aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl-D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizophrenia and predominant negative symptoms.MethodsPatients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS).ResultsThe efficacy of bitopertin (10 mg and 30 mg) was similar between Japanese and non-Japanese patients. In the bitopertin 60-mg group, no difference from the placebo group was observed in Japanese or non-Japanese patients. The response to placebo was lower in Japanese patients, and there was a trend towards a greater difference in the change in PANSS NSFS between the placebo group and the 10-mg and 30-mg groups among Japanese patients. The safety profile of bitopertin was favorable in Japanese and non-Japanese patients.ConclusionAccording to this subgroup analysis from a global phase II study of bitopertin, there was no difference in terms of efficacy and safety between Japanese and non-Japanese patients.

Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study

Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

Retraction Note: Efficacy and safety of atypical antipsychotic drug treatment for dementia: a systematic review and meta-analysis.

A wide variety of atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone and clozapine) are widely used in the management of neuropsychiatric symptoms, which are commonly seen in dementia, but results from randomised controlled trials (RCTs) on the efficacy and safety of these agents are conflicting. We aimed to quantify the efficacy and safety of atypical antipsychotic drugs on neuropsychiatric symptoms in dementia patients. PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of Systematic Reviews for reports published before August 2014 were searched for eligible randomized controlled trials of atypical antipsychotic drugs therapy in patients with psychotic symptoms of dementia. Two reviewers independently assessed the quality of the trials and extracted information. Overall, 23 relevant RCTs with 5,819 participants were identified. This meta-analysis demonstrated a significant efficacy of atypical antipsychotics on psychiatric symptoms and cognitive functions compared to placebo. In the meta-analysis, the weighted mean differences (WMDs) in change scores for psychiatric symptoms were in favor of aripiprazole (−4.4, 95% confidence interval (CI) – 7.04 to −1.77) and risperidone (−1.48, 95% CI −2.35 to −0.61) compared to placebo. In cognitive effects, WMDs in change scores for the Clinical Global Impression-Change (CGI-C) were in favor of aripiprazole, risperidone, olanzapine and quetiapine which ranged from a −0.30 points mean difference (95% CI:-0.59 to −0.01) in the aripiprazole trials to −0.43 (95% CI:-0.62 to −0.25) in the risperidone group. Patients receiving atypical antipsychotics showed no difference in risk for injuries or falls (P > 0.05), significantly higher risks (P < 0.05) for somnolence, urinary tract infection, edema and abnormal gait. However, there was no significant evidence for death reported. Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognition function at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse events may offset the efficacy of atypical antipsychotics in dementia.

Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels.

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. The aim of this study was to find out whether elevated serum levels (≥5mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5mg/l) and pathological (>5mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0% (clozapine), 11.9% (quetiapine), and 24.2% (active moiety of risperidone), respectively. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.