Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts.

The fragment of satellite III (f-SatIII) is located in pericentromeric heterochromatin of chromosome 1. Cell with an enlarged f-SatIII block does not respond to various stimuli and are highly stress-susceptible. The fraction of f-SatIII in the cells of schizophrenia patients changed during antipsychotic therapy. Therefore, antipsychotics might reduce the f-SatIII content in the cells. We studied the action of haloperidol, risperidone and olanzapine (3 h, 24 h, 96 h) on human skin fibroblast lines (n = 10). The f-SatIII contents in DNA were measured using nonradioactive quantitative hybridization. RNASATIII were quantified using RT-qPCR. The levels of DNA damage markers (8-oxodG, γ-H2AX) and proteins that regulate apoptosis and autophagy were determined by flow cytometry. The antipsychotics reduced the f-SatIII content in DNA and RNASATIII content in RNA from HSFs. After an exposure to the antipsychotics, the autophagy marker LC3 significantly increased, while the apoptosis markers decreased. The f-SatIII content in DNA positively correlated with RNASATIII content in RNA and with DNA oxidation marker 8-oxodG, while negatively correlated with LC3 content. The antipsychotics arrest the process of f-SatIII repeat augmentation in cultured skin fibroblasts via the transcription suppression and/or through upregulated elimination of cells with enlarged f-SatIII blocks with the help of autophagy.

Designed proteinoid polymers and nanoparticles encapsulating risperidone for enhanced antipsychotic activity.

BACKGROUND: Nanoparticles (NPs) incorporating drug formulations can be used to facilitate passage through biological barriers including the blood-brain barrier (BBB) and increase drug delivery and bioavailability. Hence, NP-based administration may enhance the efficiency of current antipsychotics. Encapsulation within NPs can resolve aqueous solubility problems that not only reduce permeability through the BBB but also affect targeting. The present study describes a new drug delivery system based on proteinoid NPs to explore the possibility of improving drug efficacy. Risperidone (RSP) is a commonly used atypical antipsychotic medication, and was therefore selected for encapsulation by proteinoid NPs. RESULTS: Proteinoid polymers with high molecular weight and low polydispersity were synthesized from L-amino acids and poly-L-lactic acid (PLLA) by thermal step-growth polymerization mechanism. RSP-loaded proteinoid NPs were then prepared using a self-assembly process in the presence of RSP, followed by PEGylation. The optimal PEGylated RSP-loaded NPs were characterized in terms of diameter and size distribution, drug loading, ζ-potential, cytotoxicity, biodistribution, and psychopharmacological effects. The findings indicate significantly higher antipsychotic activity of drug-loaded proteinoid NPs compared to free RSP. CONCLUSIONS: Proteinoid NPs enhance RSP delivery and may potentially increase drug efficiency by reducing dosage and side effects.

An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis.

BACKGROUND: Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs). METHODS: PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes. RESULTS: Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect. CONCLUSIONS: Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

The clinical and economic impact of three-monthly long-acting formulation of paliperidone palmitate versus the one-monthly formulation in the treatment of schizophrenia in France: A cost-utility study.

OBJECTIVES: Schizophrenia entails a considerable humanistic and economic burden. Improved treatment continuity to antipsychotic therapy is paramount to reduce the risk of relapse. The novel three-monthly paliperidone palmitate treatment (PP3M) offers the longest dosing interval currently available in France. This study assesses its cost-effectiveness, versus the currently available one-monthly long-acting treatment (PP1M) in French schizophrenic patients. METHODS: A Markov model with monthly cycles was developed and adapted. It encompassed [a] administration of PP3M or PP1M in first-line, [b] a period where the patient does not receive any active treatment, and [c] a follow-up treatment line consisting of a treatment mix reflecting French clinical practice. Relapse rates in first-line were based on a pivotal non-inferiority head-to-head trial, and treatment discontinuation rates were based on French real-world data. Accounting for differences in drug exposure, time-dependent monthly relapse rates were applied following discontinuation to first line. The impact of a less frequent injection schedule for PP3M in QoL was accounted for through the application of a utility differential. The collective perspective was adopted throughout a 5-year time horizon. Four percent discount rates were applied on costs and outcomes. RESULTS: PP3M was dominant when compared to PP1M, featuring an incremental QALY of 0.123 and a cost saving effect (-669€) resulting from reduced therapy costs (drug acquisition, administration and monitoring) and relapse-related costs. Sensitivity analysis supported the robustness of the results. CONCLUSION: With slightly better QALY outcomes and a cost-saving effect when compared to PP1M, introducing PP3M is an improvement to the current treatment in France.

The Research and Evaluation of Antipsychotic Treatment in Community Behavioral Health Organizations, Outcomes (REACH-OUT) study: real-world clinical practice in schizophrenia.

BACKGROUND: Outpatient facilities, such as community behavioral health organizations (CBHOs), play a critical role in the care of patients with serious mental illness, but there is a paucity of "real-world" patient outcomes data from this health care setting. Therefore, we conducted The Research and Evaluation of Antipsychotic Treatment in Community Behavioral Health Organizations, Outcomes (REACH-OUT) trial, a real-world, prospective, noninterventional observational study of patients with mental illness treated at CBHOs across the United States. We describe demographic and clinical characteristics, antipsychotic therapy (APT) treatment patterns, and health care resource utilization in patients with schizophrenia undergoing medical care as usual. METHODS: This study enrolled adults with schizophrenia or bipolar I disorder who initiated APT treatment at various time points: 1) within 8 weeks of initiating risperidone long-acting injectables (RLAIs) or other APTs except paliperidone palmitate (PP), 2) after more than 24 weeks of continuous RLAI treatment, or 3) at any time after initiating PP LAI treatment (schizophrenia only). Study assessments were performed via participant interview, medical chart abstraction, and clinical survey at enrollment and at month 12. RESULTS: A total of 1065 patients from 46 CBHOs were enrolled. Of these, 944 (88.6%) had a diagnosis of schizophrenia and 121 (11.4%) had bipolar I disorder. At enrollment, 599 (63.5%) of patients with schizophrenia were receiving RLAIs or PP LAI, 281 (29.8%) were receiving oral APTs, and 64 (6.8%) were receiving other injectable APTs. A number of differences in patient characteristics and outcomes were observed between patients in the LAI APT cohort and the oral APT cohort. CONCLUSION: Descriptive analyses from this observational study suggest differences in the patient characteristics, treatment patterns, and clinical and economic outcomes among those with schizophrenia treated at CBHOs with LAI APT or oral APTs. Additional analyses will be conducted to delineate the impact of LAI APT versus oral APTs on patient outcomes. TRIAL REGISTRATION: Clinical Trial Registry: NCT01181960 . Registered 12 August 2010.

Dual Atypical Antipsychotics in Treatment-Resistant Schizophrenia: A Correctional Case Report and Review of Literature.

Treatment-resistant schizophrenia (TRS) is a challenging condition to treat for the correctional psychiatrist. Guidelines from the American Psychiatric Association indicate that the first-line pharmacotherapy for TRS is the use of the atypical antipsychotic clozapine. The use of clozapine is unique in that it requires patient adherence with weekly blood draws as a prophylactic measure against agranulocytosis and leukopenia. In the correctional setting, patients with severe and persistent schizophrenia are frequently nonadherent due to lack of insight and anemic access to health care resources, specifically as these pertain to clozapine. Therefore, an alternative treatment option would be a welcome solution for this demographic. Our literature review demonstrates a limited number of studies documenting the successful use of clozapine alternatives or combination antipsychotic therapy for treatment of TRS. In this article, we present a putative case where we believe that a combination regimen of paliperidone palmitate, oral aripiprazole, and escitalopram led to a notable mitigation of both positive and negative symptoms of psychosis in the case of an incarcerated patient with TRS, as well as an improvement in functional stability, which was conducive to housing in a less restrictive setting. A brief review of the published literature follows the report.

The Effect of Switching to Long-Acting Injection (LAI) Antipsychotic Therapy on Patients with Schizophrenia.

MATERIAL AND METHOD: We analyzed 362 patients with schizophrenia admitted during 2016 in an acute psychiatric ward and in a chronic psychiatric ward, diagnosed with paranoid or other schizophrenia, according to DSM-IV-TR, which, after remission of the symptoms of the acute episode, they benefited from antipsychotic therapy only in oral formulation. For some of these patients we instituted maintenance therapy with depot formulas. Patients were followed for up to two years. RESULTS: Comparing the level of adherence to therapy, we found a statistically significant improvement, from 42.96% to 76.30%. Although we estimate that adherence to LAI therapy is over 90%, almost a quarter of patients have given up this type of treatment at some point due to side effects. Carrying out the comparative analysis of the number of hospitalizations per year, from the past and from the follow-up period, as well as of the scores registered at the scales used (PANSS, CGI, GAS, WHOQOL), in dynamics, we demonstrated the appearance of statistically significant changes. CONCLUSIONS: the administration of antipsychotic therapy through LAI-type depot formulas can improve the therapeutic adherence of the patient with schizophrenia, thus improving the evolution of the disease and the quality of life.

[Using Lurasidone in the treatment of mental illness in childhood]. / Primenenie Lurazidona pri lechenii psikhicheskikh zabolevanii v detskom vozraste.

Lurasidone is one of the newest antipsychotics approved for use in childhood. The review presents generalized data on the pharmacological profile of Lurasidone, preclinical and clinical studies of the drug with an analysis of the parameters of pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability and safety of therapy for schizophrenia and bipolar disorder in children. It also provides data on the off-lable use of Lurasidone in childhood for autism spectrum disorders, Tourette's syndrome, hypomania in the structure of bipolar affective disorder. The data on the efficacy of Lurasidone in a wide range of psychopathological disorders, including positive, negative, affective and cognitive domains, as well as a favorable tolerability profile of the drug, including long-term therapy, are presented.

Effect of Clozapine on Anti-N-Methyl-D-Aspartate Receptor Encephalitis With Psychiatric Symptoms: A Series of Three Cases.

The main clinical manifestations of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis are acute or subacute seizures, cognition impairment, and psychiatric symptoms. Nowadays, the scheme of antipsychotic therapy for this disease has not been established. This study reports three cases of anti-NMDAR encephalitis with psychiatric symptoms. The anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum were positive. The psychiatric symptoms still existed after intravenous immunoglobulin (IVIG) treatment; thus, clozapine was used for antipsychotic therapy. Case 1 was a 37-year-old man who suffered from bad mood and suicide behaviors for 1 month. Hallucination and delusion still existed after IVIG treatment and hormone therapy, and the symptoms were relieved when given clozapine for 12 months. Case 2 was a 28-year-old man who was admitted to our hospital due to injuring other people and destructive behaviors for 2 days. He showed irritability, bad temper, declined cognition, and severe delusion of persecution after IVIG treatment and hormone therapy, but the psychiatric symptoms disappeared when given clozapine for 3 months. Case 3 was a 23-year-old man who suffered from headache and babbing for 7 days. Symptoms such as irritability, bad temper, babbing, and injuring other people still existed after IVIG treatment and hormone therapy, but they disappeared when given clozapine for 2 months. Therefore, we suggest that during the treatment of anti-NMDAR encephalitis with psychiatric symptoms, if the anti-NMDAR antibodies in CSF and serum were positive, and psychiatric symptoms could not be controlled after IVIG and hormone therapy, clozapine may work.

Switching from oral atypical antipsychotic monotherapy to paliperidone palmitate once-monthly in non-acute patients with schizophrenia: A prospective, open-label, interventional study.

RATIONALE: Long-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia. OBJECTIVE: This study aimed to explore the safety, tolerability, and treatment response of paliperidone palmitate once-monthly in non-acute but symptomatic adult patients switched from previously unsuccessful monotherapy with frequently used oral atypical antipsychotics. METHODS: This was a post hoc analysis of a prospective, interventional, single-arm, international, multicenter, open-label, 6-month study. RESULTS: The patients (N = 472) were switched to paliperidone palmitate once-monthly (PP1M) from daily oral treatment with either aripiprazole (n = 46), olanzapine (n = 87), paliperidone extended-release (n = 104), quetiapine (n = 44), or risperidone (n = 191). In all groups, mean Positive and Negative Syndrome Scale total (p < 0.0001) and Clinical Global Impression-Severity scores improved significantly (p = 0.0004 to p < 0.0001). An improvement of ≥50 % in the Positive and Negative Syndrome Scale total score was observed in 21.7 % (aripiprazole), 29.9 % (olanzapine), 29.8 % (paliperidone extended-release), 27.3 % (quetiapine), and 37.2 % (risperidone) of patients. The patients showed significant improvements in the Personal and Social Performance score (aripiprazole p = 0.0409, all others p ≤ 0.0015); Mini International Classification of Functionality, Disability and Health Rating for Activity and Participation Disorders in Psychological Illnesses total scores (all p < 0.01); and Treatment Satisfaction Questionnaire for Medication Global Satisfaction score (olanzapine and risperidone p < 0.0001, quetiapine p = 0.0465, paliperidone extended-release p = 0.0571, aripiprazole p = NS). Paliperidone palmitate once-monthly was well tolerated, presenting no new safety signals. CONCLUSIONS: These data illustrate that stable, non-acute but symptomatic patients on oral antipsychotic monotherapy may show clinically meaningful improvement of symptoms, functioning, and treatment satisfaction after direct transition to PP1M. The findings are limited by the naturalistic study design; thus, further studies are required to confirm the current findings.

Long-term survival in a patient with glioblastoma on antipsychotic therapy for schizophrenia: a case report and literature review.

Glioblastoma is not only the most common primary brain tumor, but also the most aggressive. Currently, the most effective treatment of surgery, chemotherapy and radiation therapy allows for a modest median survival of 15 months. Here, we report a case of a 57-year-old male with histologically confirmed glioblastoma with unfavorable prognostic characteristics (poor performance status and persistent neurological symptoms after surgery), whose expected 5-year survival is 0%. Further genetic analysis offered a mixed prognostic picture with positive methylation of 0-6-methylguinine-DNA (deoxyribonucleic acid) methyltransferase (MGMT; favorable prognosis) and wild-type isocitrate dehydrogenase 1 (IDH-1; unfavorable prognosis). Remarkably, the patient showed a progression-free survival of 5.5 years and a total survival of 6.5 years. In the context of recently published literature, the authors hypothesize that the patient's use of the antipsychotic medication risperidone may have had a potential antitumor effect. Risperidone antagonizes the dopamine-2 receptor and the serotonin-7 receptor, both of which have been individually implicated in the growth and progression of glioblastoma. To the authors' knowledge, this is the first clinical case in the literature to explore this association.

Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update.

BACKGROUND: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. METHODS: An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. RESULTS: Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043-0.972, I(2) = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. CONCLUSION: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.