Atypical Antipsychotic Olanzapine Research Articles

Metabolic profiles differences of overweight patients on olanzapine, clozapine and risperidone

AimsWe set out to examine the differences in metabolic profiles of at risk (overweight) patients across commonly used atypical antipsychotics (Olanzapine, Risperidone, Clozapine). We hypothesized that Olanzapine and Clozapine group will have more metabolic abnormalities compared to Risperidone.BackgroundCardiovascular diseases remain the leading cause of morbidity and mortality among people with schizophrenia. Since the introduction of atypical antipsychotics, there is cumulative evidence of their association with metabolic abnormalities. Clozapine and Olanzapine are known to constitute the highest metabolic risks amongst atypical antipsychotics.MethodThis study is based on the data of 67 subjects recruited into a 12-week open-labelled trial looking at the effects of adjunctive Aripiprazole in atypical antipsychotics for weight reduction and improvement in metabolic profile. Metabolic profiles including weight, waist circumference, fasting blood glucose, HbA1c, serum total, HDL and LDL cholesterol levels and triglycerides were measured at baseline. The measurements were then compared across the different subgroups of atypical antipsychotics. The definition of metabolic syndrome proposed by the Third Report of the National Cholesterol Education Program Expert Panel (Adults Treatment Panel III) was used.ResultThe atypical antipsychotics were grouped into Olanzapine (n = 27), Risperidone (n = 24) and Clozapine (n = 16). More than 50% of clozapine-treated and Olanzapine-treated overweight patients were demonstrated to have metabolic syndrome at baseline. There was a statistically significant difference in serum triglycerides (p = 0.012), LDL (p = 0.046) and HbA1c (p = 0.045) across the three groups as demonstrated by one-way ANOVA. A Tukey post hoc test showed that both the Olanzapine (p = 0.032) and Risperidone (p = 0.013) groups demonstrated statistically significant lower serum triglycerides when compared to Clozapine. Interestingly, the mean serum HbA1c was significantly lower in Clozapine when compared to Olanzapine group (p = 0.045), perhaps reflecting the closer monitoring of fasting blood sugar in clozapine patients. When controlled for age and BMI, the significant differences in serum triglycerides remain between Clozapine and Risperidone groups [but not for serum HbA1c]. There were no statistically significant differences across the groups with respect to other metabolic parameters.ConclusionAt baseline, metabolic dysregulation was demonstrated in all subgroups of overweight patients. As hypothesized, patients on Olanzapine and Clozapine groups fared worse than Risperidone. Further studies examining long term effects of atypical antipsychotics in a larger sample of patients are warranted to confirm these findings. These findings have clinical significance in terms of choosing the first antipsychotic for drug naïve patients or where there is no clinically significant difference in efficacy.

Olanzapine Increases Neural Chemorepulsant-Draxin Expression in the Adult Rat Hippocampus.

Draxin belongs to the family of inhibitory axon-guiding factors that regulate neuronal migration and axonal spreading in the developing brain. This glycoprotein has recently been considered to play an important role both in hippocampal differentiation and adult neurogenesis in the dentate gyrus. Given that it has been reported that antipsychotic drugs may affect neurite growth and neurogenesis, we have therefore investigated whether chronic treatment with olanzapine modulates draxin immunoreactivity in the adult rat hippocampus. After analysis of local fluorescence intensity, we found a significant increase of draxin immunoexpression both in the subgranular zone (SGZ) and granular zone of the rat hippocampus following long-term olanzapine administration. This study reveals, for the first time, the modulatory effect of the atypical antipsychotic medication olanzapine on expression of the novel chemorepulsive protein draxin in the context of adult neurogenesis regulation. Moreover, this is the first report dealing with pharmacological aspects of draxin signaling. An elevated draxin expression may indirectly support a recently formulated hypothesis that olanzapine may drive adult neurogenesis via paracrine draxin-related signaling. This action of draxin is a new element in the neurogenesis mechanism that may be part of the action of second-generation antipsychotics in the treatment of schizophrenia, indicating more detailed molecular studies are urgently required to fully investigate these potential novel mechanisms of neurogenesis.

Delirium in the NICU: Risk or Reality?

Delirium is a frequent complication of critical illness in adult and pediatric populations and is associated with significant morbidity and mortality. Little is known about the incidence, risk, symptoms, or treatment of delirium in the NICU. Only 4 cases of NICU delirium have been reported, but many pediatric studies include infants. The Cornell Assessment of Pediatric Delirium tool has been validated in neonatal and infant populations for identification of delirium. Initial treatment should focus on identification and reversal of the cause, with pharmacologic management reserved for patients with symptoms that do not resolve or that significantly impact medical care. Routine use of intravenous haloperidol should be avoided because of the high incidence of serious adverse effects, but it may be considered in patients with significant symptoms who are unable to take oral medications. Atypical antipsychotics (olanzapine, quetiapine, and risperidone) appear to be efficacious with a low incidence of adverse effects. Risperidone has weight-based dosing and a liquid dosage form available, making it a good option for use in the NICU. Additional data from large cohorts of NICU patients routinely screened for delirium, and treated as indicated, are needed.

Pharmacological Treatment of Agitation and/or Aggression in Patients With Traumatic Brain Injury: A Systematic Review of Reviews.

To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI), synthesize the available data, and provide guidelines. Systematic review of systematic reviews. A literature review of the following websites was performed looking for systematic reviews on the treatment of agitation and/or aggression among patients with TBI: PubMed, CINAHL, DynaMed, Health Business Elite, and EBSCO (Psychology and behavioral sciences collection). Two researchers independently assessed articles for meeting inclusion/exclusion criteria. Data were extracted on year of publication, reviewed databases, dates of coverage, search limitations, pharmacological agents of interest, and a list of all controlled studies included. The included controlled studies were then examined to determine potential reasons for any difference in recommendations. The literature review led to 187 citations and 67 unique publications after removing the duplicates. Following review of the title/abstracts and full texts, a total of 11 systematic reviews were included. The systematic reviews evaluated the evidence for safety and efficacy of the following medications: amantadine, amphetamines, methylphenidate, antiepileptics, atypical and typical antipsychotics, benzodiazepines, β-blockers, and sertraline. On the basis of the results of this literature review, the authors recommend avoiding benzodiazepines and haloperidol for treating agitation and/or aggression in the context of TBI. Atypical antipsychotics (olanzapine in particular) can be considered as practical alternatives for the as-needed management of agitation and/or aggression in lieu of benzodiazepines and haloperidol. Amantadine, β-blockers (propranolol and pindolol), antiepileptics, and methylphenidate can be considered for scheduled treatment of agitation and/or aggression in patients with TBI.

Decreased cardiovascular death in schizophrenia patients treated with antipsychotics: A Korean national cohort study

BackgroundPatients with schizophrenia have a reduced life expectancy, but the association between antipsychotic usage and cause of death is uncertain. MethodsThe authors observed associations of antipsychotic usage with the mortality rate and cause of death in a population-based cohort of the Korean National Health Insurance Service database from 2003 to 2017. A total of 86,923 patients with schizophrenia were categorized by the total duration of antipsychotic prescription after schizophrenia diagnosis into treated (n = 77,139) and untreated (n = 9784) groups. The main outcome was all-cause mortality; causes of death included cardiovascular disease, pulmonary disease, diabetes, cancer, accident, suicide and homicide. ResultsThe numbers of all-cause deaths and deaths from individual causes were significantly lower in the antipsychotic-treated group than in the untreated group (all cases, p < 10−4). When adjusted for covariates (age, sex, income, body mass index, alcohol consumption, hypertension, cancer and cerebral stroke), mortality rates due to ischemic heart disease (hazard ratio, HR, 0.38 [95% CI, 0.18–0.77]) and stroke (HR, 0.39 [95% CI, 0.19–0.80]) were significantly lower in the antipsychotic-treated group. Among 4 atypical antipsychotics (olanzapine, risperidone, aripiprazole and quetiapine), only aripiprazole was associated with a decreased mortality risk relative to olanzapine (HR, 0.55 [95% CI, 0.32–0.96]). ConclusionsSchizophrenia patients constantly prescribed antipsychotics had significantly lower rates of death from certain cardiovascular illnesses than untreated patients. Aripiprazole-treated schizophrenia was associated with a decreased risk of death compared with olanzapine-treated disease.

Effect of aripiprazole as an adjunct to atypical antipsychotics on weight and metabolic profile: a 12-week open-label trial.

Background:Atypical antipsychotics are widely prescribed, yet have been associated with weight gain and metabolic syndrome.Aim:To study the effect of adjunct low-dose aripiprazole on weight and metabolic parameters of subjects on atypical antipsychotics (olanzapine, clozapine or risperidone).Methods:The study was carried out as an open-label trial with a fixed dose of 5 mg aripiprazole added to the patient’s current antipsychotic for 12 weeks. The primary outcome measure was mean change in weight, while secondary outcome measures included change in waist circumference; fasting blood glucose; HbA1c; triglycerides; total, HDL and LDL cholesterol levels; functioning; and neurocognition.Results:For the overall study (n = 55), there was no significant effect of adjunct aripiprazole on the weight of the subjects. However, the clozapine group achieved significant weight loss (p = 0.002) and also had significant improvements in total cholesterol (p < 0.001), HDL (p = 0.016), LDL (p = 0.044) and triglyceride levels (p = 0.038). The olanzapine group had significant improvement in triglycerides (p = 0.001), and other metabolic parameters for this group showed improvement trends, but did not reach statistical significance. The risperidone group did not show any significant improvement in weight or metabolic parameters.Conclusions:The study adds support to the adjunctive use of aripiprazole to clozapine for weight loss and improvement in metabolic profile, and for reduction in cardiometabolic risk for patients on olanzapine.Trial Registration:Clinicaltrials.gov identifier: NCT02949752

Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments.

The cannabinoid type 1 (CB1 ) receptor and the dopamine type 2 (D2 ) receptor are co-localized on medium spiny neuron terminals in the globus pallidus where they modulate neural circuits involved in voluntary movement. Physical interactions between the two receptors have been shown to alter receptor signaling in cell culture. The objectives of the current study were to identify the presence of CB1 /D2 heteromers in the globus pallidus of C57BL/6J male mice, define how CB1 /D2 heteromer levels are altered following treatment with cannabinoids and/or antipsychotics, and determine if fluctuating levels of CB1 /D2 heteromers have functional consequences. Using in situ proximity ligation assays, we observed CB1 /D2 heteromers in the globus pallidus of C57BL/6J mice. The abundance of the heteromers increased following treatment with the nonselective cannabinoid receptor agonist, CP55,940. In contrast, treatment with the typical antipsychotic haloperidol reduced the number of CB1 /D2 heteromers, whereas the atypical antipsychotic olanzapine treatment had no effect. Co-treatment with CP55,940 and haloperidol had similar effects to haloperidol alone, whereas co-treatment with CP55,940 and olanzapine had similar effects to CP55,940. The observed changes were found to have functional consequences as the differential effects of haloperidol and olanzapine also applied to γ-aminobutyric acid release in STHdhQ7/Q7 cells and motor function in C57BL/6J male mice. This work highlights the clinical relevance of co-exposure to cannabinoids and different antipsychotics over acute and prolonged time periods.

Effect of psychotropic drugs on cortical excitability of patients with major depressive disorders: A transcranial magnetic stimulation study

Transcranial magnetic stimulation (TMS) can be used to evaluate the effects of pharmacological interventions. The aim of this study was to assess the impact of the selective serotonin reuptake inhibitor, sertraline, and the atypical antipsychotic drugs quetiapine and olanzapine, on cortical excitability in unmedicated patients with major depressive disorder (MDD). The study included 45 medication-free MDD patients diagnosed according to DSM V. They were divided randomly into three groups who received a single oral dose of one of the three drugs sertraline (50 mg), quetiapine (100 mg) and olanzapine (10 mg). Psychological evaluation was conducted using the Mini-Mental State Examination (MMSE) and Beck Depression Inventory Scale (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant before and at the time of maximum concentration of drug intake. There was significant increase in excitability of motor cortex after sertraline without changes in GABAB neurotransmission. Quetiapine and olanzapine potentiated inhibitory GABAB neurotransmission (prolongation of cSP); olanzapine additionally prolonged the iSP. Thus TMS can differentiate between the impact of different psychotropic drugs on excitatory and inhibitory transmission in motor cortex.

Blood plasma proteomic modulation induced by olanzapine and risperidone in schizophrenia patients

Antipsychotics are the main line of treatment for schizophrenia. Even though there are significant rates of medication drop out due to side effects and limited response of approximately 50% of patients. This is likely due to incomplete knowledge in how these drugs act at the molecular level. To improve treatment efficacy during the critical early stages of schizophrenia, we aimed to identify molecular signatures at baseline (T0) for prediction of a positive response to the atypical antipsychotics olanzapine and risperidone after 6 weeks (T6) treatment. Blood plasma samples were processed and analyzed by label-free quantitative shotgun proteomics using two-dimensional nano-liquid chromatography, coupled online to a Synapt G2-Si mass spectrometer. Data were obtained in MSE mode (data-independent acquisition) in combination with ion-mobility (HDMSE). We were able to identify a potential panel of proteins that might predict a positive outcome to olanzapine and risperidone treatment. The proteins found to be differentially abundant between T0 and T6 in good responders compared to poor responders were analyzed in silico for enrichment pathways and found to be mostly involved with immune system functions. This data can contribute to better understand the biochemical signaling mechanisms peripherally triggered by antipsychotic medication and eventually used to develop surrogate biomarker tests to help improve treatment outcomes and guide development of new treatment approaches. SignificanceThe application of proteomics to the study of the atypical antipsychotic effects on the blood plasma proteome from schizophrenia patients could help in the search for new targets to improve the current therapies, as well as in the development of new therapeutic strategies. In this original article, we provided clues that atypical antipsychotics might be associated with good response by modulating proteins that play a role in inflammation and/or immune system pathways. In addition, the proteins with differential abundance found in the comparison between good and poor responders at the baseline might compose a signature for prediction of response effectiveness.

T96. RESULTS OF THE HUMMINGBIRD STUDY A MULTICENTRE, PRAGMATIC TRIAL OF A DIGITAL MEDICINE SYSTEM

BackgroundThis was a multicentre, 8-week, single-arm, open-label, pragmatic trial to explore the acceptance and performance of using the Digital Medicine System (DMS) with health care professionals (HCPs) and adult subjects with schizophrenia, schizoaffective disorder (SAD), or first episode psychosis (FEP) on an oral atypical antipsychotic (aripiprazole, olanzapine, quetiapine, or risperidone).MethodsSubjects received an initial introduction to the DMS, and had HCP visits at screening/baseline, Week 4, Week 8/early termination (ET), and as directed by the HCP for the duration of the subject’s participation in the trial. Safety and tolerability data was collected and evaluated on an ongoing basis, as assessed by the frequency and severity of serious adverse events (SAEs), and device-related non-serious adverse events (AEs). Subjects were monitored on the DMS technology by the HCPs through review of the HCP dashboard data at a minimum of every 2 weeks and to make changes to the current treatment plan and therapy at their discretion. The study initiated in May 2018 and concluded in September 2019. NCT03568500ResultsFifty-five (55) subjects were screened, and forty-three (43) subjects were treated and included in the sample analysis. Subjects enrolled were on average 34.4 years old. There were twenty-eight (28) male and fifteen (15) female subjects in the study. The most common reasons for discontinuation was subject withdrawal of consent (5 subjects, 11.6%), loss to follow-up (4 subjects, 9.3%), and adverse events (4 subjects, 9.3%). The primary endpoint was the proportion of days with good patch coverage during the trial, calculated by the number of days with good patch coverage divided by the total number of trial days for each subject. Over the duration of the study, subjects had 63.4 % (SD = 26.6%) of days with good patch coverage during the trial time. No notable differences were observed across the disease types, with schizophrenic subject 64.3% (SD=20.2%), FEP subject 62.5% (SD = 27.5%), and SAD subject 63.0% (SD = 37.7%). The secondary endpoint was subject adherence, defined as the proportion of detected ingestible events markers (IEM) over the expected during the trial days with good patch coverage. Overall, subjects had a mean of 86.6% (SD = 14.5%) IEMs detected during the good patch coverage days. The proportion of IEM detected by disease type were: FEP 91.0% (SD = 7.4%), schizophrenic 88.9% (SD = 8.1%), and SAD 72.3% (SD=25.7%). There were nine (9) subjects (20.9%) who had eleven (11) AEs during the study, all were non-serious. Out of all the AEs, nine (9) subjects had nine (9) treatment emergent adverse events (TEAE) that were all reported as medical device site irritation, and four (4) subjects discontinued the study due to AEs.DiscussionIn conclusion, during the 8-week treatment with the DMS, subjects reported good patch coverage 63.4% of the time on average for this pragmatic study. Using the DMS, subjects’ medication adherence reached 86.6% on average when subjects were having good patch coverage. The acceptance and performance of DMS is considered safe and there were no SAEs associated with its use.FundingThis study was supported by Otsuka Pharmaceutical Development & Commercialization, Inc.

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

Prescription patterns of antipsychotics in the management of first episode psychosis at three psychiatric hospitals in Khartoum, 2018: A descriptive cross-sectional study

Background:First-Episode Psychosis (FEP) is defined as the first treatment contact with psychiatric service, regardless of the duration of symptoms. This study aims to determine the antipsychotics prescription patterns in FEP patients at three psychiatric hospitals in Khartoum.Method:A descriptive cross-sectional retrospective hospital-based study was conducted at Eltigani Elmahi, Taha Baasher, and Abd Elaal Aledrissi Psychiatric hospitals in Khartoum State, Sudan, during the period March to July 2018. Medical records of patients with FEP were identified and reviewed to look for demographic data, the onset of symptoms, investigations requested, and medications prescribed. Data were recorded and subjected to statistical analysis using the Statistical Package for Social Sciences.Result:Reviewing the medical records of the 98 FEP patients (66 males and 32 females) included in the study showed that the majority of patients (94.8%) were medicated with combinations of psychotropic medications. The most commonly used combination was Haloperidol, Olanzapine, Promethazine, and Benzodiazepines. And only 5.1% of the whole population was treated with an atypical antipsychotic (Olanzapine) as a monotherapy.Conclusion:Based on prescription patterns and requested investigations, there was a wide gap between the actual practice regarding antipsychotics prescriptions for FEP at the three psychiatric hospitals and the evidence-based guidelines in this respect.

Voltammetric Analysis of Atypical Antipsychotic Drugs with Solid Electrodes

Background: Qualitative and quantitative analysis of atypical antipsychotic drugs used for the treatment of schizophrenia, depression, anxiety, and bipolar disorder obtaining satisfactory results can be ensured by voltammetric techniques. The aim of this review is to present the application of voltammetric techniques developed for the determination of the atypical antipsychotic drugs, which are amisulpride, aripiprazole, clozapine, olanzapine, quetiapine fumarate, risperidone, sertindole, and ziprasidone, in pharmaceutical dosage forms and biological samples. Methods: Studies in the literature published between 2004 and 2017 based on the voltammetric determination of atypical antipsychotic drugs were gathered using scientific databases. The results obtained from these studies were combined and interpreted. Results: oltammetric techniques applied for the sensitive determination of trace amounts of the selected atypical antipsychotic drugs in their pharmaceutical dosage forms and biological fluids were compared. The best analysis conditions were obtained after the optimization of some parameters such as buffer type, pH, and scan rate. For diffusion controlled electrode processes, it was observed that differential pulse and square wave voltammetry methods were generally used for the sensitive quantitative determination of the drugs, whereas stripping methods were used for the adsorption controlled electrode processes. Detection limits were between 1.53×10-3 µM for clozapine and 0.97 µM for risperidone. Conclusion: The electrodes used in the studies showed high selectivity, sensitivity, and good accuracy with precision. The developed methods were also applied to pharmaceutical preparations of the drugs and biological fluids with satisfactory results, without any interference from inactive excipients.

Olanzapine: A potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics.

Designer receptors exclusively activated by designer drugs (DREADDs) derived from muscarinic receptors not only are a powerful tool to test causality in basic neuroscience but also are potentially amenable to clinical translation. A major obstacle, however, is that the widely used agonist clozapine N-oxide undergoes conversion to clozapine, which penetrates the blood-brain barrier but has an unfavorable side effect profile. Perlapine has been reported to activate DREADDs at nanomolar concentrations but is not approved for use in humans by the Food and Drug Administration or the European Medicines Agency, limiting its translational potential. Here, we report that the atypical antipsychotic drug olanzapine, widely available in various formulations, is a potent agonist of the human M4 muscarinic receptor-based DREADD, facilitating clinical translation of chemogenetics to treat central nervous system diseases.

Analysis of phenformin hydrochloride and atypical antipsychotics in plasma using surface-enhanced Raman scattering

The increasing number of deaths caused by drug poisoning indicates that a rapid and accurate method to identify the type of drugs is critically needed to provide a real-time and effective treatment for poisoned patients. In this report, a surface-enhanced Raman scattering (SERS) analysis method for the detection of phenformin hydrochloride and atypical antipsychotics in plasma was successfully developed. Colloidal silver, prepared by a redox reaction of hydroxylamine and silver nitrate, was used as a SERS substrate. The pH condition and the sample incubation time for each drug were also explored to improve SERS enhancement factor. Based on these, phenformin hydrochloride and atypical antipsychotics (quetiapine fumarate, risperidone, olanzapine and clozapine) in plasma at concentration of 10−6 M were detected successfully. Thus, we provided a potentially method for rapid diagnosis of acute drugs poisoning.

Journal Digest

Journal Digest

Neutropenia and leukopenia protective intranasal olanzapine-loaded lipid-based nanocarriers engineered for brain delivery

Possible risk of leukopenia is one of the drug-induced adverse effects of the atypical antipsychotic agent olanzapine (OLZ). Hence, to prevent the peripheral exposure and related side effects of the agent, the present research was aimed to prepare and investigate safety and efficacy of OLZ-loaded lipid nanocarriers in the therapy of CNS disorders via intranasal (i.n.) delivery. The OLZ-loaded nanostructured lipid carriers (NLC) and microemulsion (ME) were prepared by melt emulsification and aqueous titration methods, respectively. Optimized formulation was evaluated for the particle size, zeta potential and entrapment efficiency were found to be 88.95 ± 0.8 and 24.80 ± 0.5 nm, -22.21 ± 1.9 and − 20.84 ± 1.3 mV, and 88.94 ± 1.6 and 98.40 ± 0.95%, respectively for the two nanocarriers (NLC and ME). Alternatively, ex vivo permeation of OLZ mucoadhesive NLC (OLZ-MNLC) and OLZ mucoadhesive ME (OLZ-MME) was observed 820 ± 7.2 and 940 ± 8.9 µg/cm2, respectively. Finally, Cmax values calculated for OLZ in brain through administration of 99MTc-OLZ-MNLC (i.n.), 99MTc-OLZ-MME (i.n.) and 99MTc-OLZ-NLC (i.v.) and it was found to 9.33 ± 0.65% radioactivity/gram (RA/g), 1.06 ± 0.26% RA/g and 0.082 ± 0.004% RA/g, respectively. Therefore, 99MTc-OLZ-MNLC formulation through i.n. delivery showed superior brain uptake than OLZ-MME formulation. Simultaneously, the nanoformulations didn’t reflect any gross changes in biomarkers and hematological toxicity when compared with control. Hence, it can be inferred that the nose-to-brain delivery of OLZ-MNLC can be considered as effective and safe delivery for brain therapy.

Second generation atypical antipsychotics olanzapine and aripiprazole reduce expression and secretion of inflammatory cytokines in human immune cells

Schizophrenia and major depression are associated with alterations in peripheral inflammatory markers, and anti-inflammatory therapy has been proposed as a promising add-on approach in the pharmacologic treatment of both disorders. Second-generation atypical antipsychotics are currently first-line drugs in the treatment of schizophrenia and are also used as augmentation strategies in treatment-resistant major depression. Furthermore, these drugs have been reported to exhibit distinct metabolic side effects and to influence inflammatory processes.In this study, we used ex vivo stimulation of primary human peripheral blood mononuclear cells (PBMC) from healthy blood donors with atypical antipsychotics olanzapine or aripiprazole to examine effects on cytokine production independent from metabolic side effects and disease status.Both olanzapine and aripiprazole stimulation decreased mRNA levels of IL-1β, IL-6, and TNF-α and resulted in diminished protein concentrations of IL-6 and TNF-α in conditioned medium of stimulated PBMC. A multiplex approach revealed additional downregulation of IL-2; MIP-1β and IP-10 secretion. Similarly, olanzapine and aripiprazole stimulation of the human monocytic cell line THP-1 resulted in a significant decrease in expression and secretion of IL-1β and TNF-α. Our results suggest that atypical antipsychotics directly influence immune cell function and thereby highlight the importance to factor in potential side effects of drugs routinely used in treatment of schizophrenia and major depression on inflammatory processes when considering anti-inflammatory drug therapy as an additional treatment option.

Identifying the In Vivo Cellular Correlates of Antipsychotic Drugs.

GPCRs such as 5-HT2A and D2 are implicated in the therapeutic and the side effects of antipsychotics. However, the pattern of brain activity that leads to the behavioral effects of antipsychotics is poorly understood. To address this question, we used the transgenic ‘FosTRAP’ mice (Mus musculus), where a fluorescent reporter marks the cells responsive to the stimulus of interest. Here, the stimulus was an administration of various antipsychotic drugs. In case of typical antipsychotics such as Haloperidol, the c-fos active cells were predominantly found in the striatum, whereas in case of the atypical antipsychotics (Clozapine and Olanzapine), c-fos-induced cells were more numerous in the cortical regions, e.g., orbital cortex, piriform cortex. Curiously, we also observed ependymal cells to be a novel cellular target of atypical antipsychotics. 5-HT2A is considered to be a major target for atypical antipsychotics. Therefore, we bred ‘FosTRAP’ mice with 5-HT2A knock-out (KO) mice and tested their response to the prototype of atypical antipsychotics, Clozapine. Interestingly, the absence of 5-HT2A did not significantly affect the number of c-fos-induced cells in the cortical regions. However, the ependymal cells showed a dramatically reduced response to Clozapine in the absence of 5-HT2A. In summary, the TRAP system has allowed us to identify various region-specific activity induced by antipsychotics and novel cellular targets of the antipsychotics. These results serve as a “proof of principle” study that can be extended to explore the biochemical and physiological changes brought about by antipsychotics and specifically identify antipsychotic-responsive cells in the live tissue.

Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper.

Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life. This paper provides the American Academy of Sleep Medicine (AASM) position regarding various treatments of nightmare disorder in adults. A literature search was performed based upon the keywords and MeSH terms from the Best Practice Guide for the Treatment of Nightmare Disorder in Adults that was published in 2010 by the AASM. The search used the date range March 2009 to August of 2017, and sought to find available evidence pertaining to the use of behavioral, psychological, and pharmacologic therapies for the treatment of nightmares. A task force developed position statements based on a thorough review of these studies and their clinical expertise. The AASM Board of Directors approved the final position statements. Positions of "recommended" and "not recommended" indicate that a treatment option is determined to be clearly useful or ineffective/harmful for most patients, respectively, based on a qualitative assessment of the available evidence and clinical judgement of the task force. Positions of "may be used" indicate that the evidence or expert consensus is less clear, either in favor or against the use of a treatment option. The interventions listed below are in alphabetical order within the position statements rather than clinical preference: this is not meant to be instructive of the order in which interventions should be used. The following therapy is recommended for the treatment of PTSD-associated nightmares and nightmare disorder: image rehearsal therapy. The following therapies may be used for the treatment of PTSD-associated nightmares: cognitive behavioral therapy; cognitive behavioral therapy for insomnia; eye movement desensitization and reprocessing; exposure, relaxation, and rescripting therapy; the atypical antipsychotics olanzapine, risperidone and aripiprazole; clonidine; cyproheptadine; fluvoxamine; gabapentin; nabilone; phenelzine; prazosin; topiramate; trazodone; and tricyclic antidepressants. The following therapies may be used for the treatment of nightmare disorder: cognitive behavioral therapy; exposure, relaxation, and rescripting therapy; hypnosis; lucid dreaming therapy; progressive deep muscle relaxation; sleep dynamic therapy; self-exposure therapy; systematic desensitization; testimony method; nitrazepam; prazosin; and triazolam. The following are not recommended for the treatment of nightmare disorder: clonazepam and venlafaxine. The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, accessible treatment options, and resources.