RESUMEN
BACKGROUND: Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study. METHODS: Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response. RESULTS: At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (p < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time (p < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores (p < 0.05). CONCLUSION: TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.
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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Olanzapina/uso terapéutico , Risperidona/uso terapéutico , Fumarato de Quetiapina/uso terapéutico , Haloperidol/uso terapéutico , Perfenazina/uso terapéutico , Benzodiazepinas/efectos adversos , Glucosa/uso terapéutico , Inflamación/tratamiento farmacológicoRESUMEN
Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D2 receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.
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Antineoplásicos/uso terapéutico , Antipsicóticos/uso terapéutico , Antagonistas de Dopamina/uso terapéutico , Reposicionamiento de Medicamentos , Flufenazina/uso terapéutico , Neoplasias/tratamiento farmacológico , Perfenazina/uso terapéutico , Proclorperazina/uso terapéutico , Humanos , Técnicas In VitroRESUMEN
In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.
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Antagonistas de Dopamina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Perfenazina/uso terapéutico , Antagonistas de Dopamina/farmacología , Glioblastoma/fisiopatología , Humanos , Perfenazina/farmacologíaRESUMEN
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
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Antipsicóticos/farmacología , Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Fenotiazinas/farmacología , Neumonía Viral/tratamiento farmacológico , Virus ARN/efectos de los fármacos , Animales , Antipsicóticos/uso terapéutico , Antivirales/uso terapéutico , COVID-19 , Clorpromazina/farmacología , Clorpromazina/uso terapéutico , Flufenazina/farmacología , Flufenazina/uso terapéutico , Humanos , Pandemias , Perfenazina/farmacología , Perfenazina/uso terapéutico , Fenotiazinas/uso terapéutico , Proclorperazina/farmacología , Proclorperazina/uso terapéutico , SARS-CoV-2 , Tioridazina/farmacología , Tioridazina/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect. Two different animal models including 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA)-induced dermatitis were employed. TPA and OXA-mediated ear swelling was attenuated by perphenazine. Moreover, perphenazine inhibited infiltrated mast cells into lesion area. We found levels of serum IgE, histamine and cytokines are decreased in mice cotreated with perphenazine and OXA compared to OXA-treated mice. Overall, this is a first study showing that the FDA-approved, anti-psychotic drug, perphenazine, alleviates animal models of dermatitis.
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Dermatitis Alérgica por Contacto/tratamiento farmacológico , Antagonistas de Dopamina/uso terapéutico , Perfenazina/uso terapéutico , Animales , Citocinas/metabolismo , Dermatitis Alérgica por Contacto/etiología , Antagonistas de Dopamina/farmacología , Inmunoglobulina G/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Oxazolona/toxicidad , Perfenazina/farmacología , Acetato de Tetradecanoilforbol/toxicidad , Células Th2/efectos de los fármacos , Células Th2/inmunologíaAsunto(s)
Antipsicóticos/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Adulto , Deprescripciones , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Cumplimiento de la Medicación , Pruebas de Estado Mental y Demencia , Olanzapina/uso terapéutico , Perfenazina/uso terapéutico , Modelos de Riesgos Proporcionales , Trastornos Psicóticos/fisiopatología , Trastornos Psicóticos/psicología , Fumarato de Quetiapina/uso terapéutico , Risperidona/uso terapéutico , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Resultado del TratamientoRESUMEN
Second-generation antipsychotics are associated with moderate benefits in terms of improved schizophrenia symptoms, but also with higher rates of side-effects such as excessive weight gain (WG); a consensus on their efficacy has not been reached. To date, no study has evaluated the interplay of treatments and side-effects in a single framework, which is a critical step to clarify the role of side-effects in explaining the efficacy of these antipsychotics. We used recent methods for mediation and interaction to clarify the role of WG in explaining the effects of second-generation drugs on schizophrenia symptoms. We used data from 1460 participants in the CATIE trial, assigned to either perphenazine (first-generation comparison drug), olanzapine, quetiapine, risperidone, or ziprasidone. The primary outcome was an individual's score on the Positive and Negative Syndrome Scale (PANSS) for symptoms of schizophrenia after 9â¯months, separately evaluated as positive (PANSS+), negative (PANSS-), and total PANSS score. WG after 6 months was investigated as a potential mediator and effect modifier. Results showed that, by limiting WG, patients would benefit of a considerably better improvement in terms of PANSS symptoms. In the scenario of weight change being controlled between -2% and 1% for all participants, patients assigned to olanzapine would experience the highest significant improvements in both PANSS+ (-2.66 points; 95% CI: -4.98, -0.35), PANSS- (-1.59; 95% CI: -4.31, 1.14), and total PANSS (-6.11; 95% CI: -13.13, 0.92). In conclusion, occurrence of excessive WG hampers the potentially beneficial effects of second-generation antipsychotics, thus suggesting future directions for treatment and interventions.
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Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Aumento de Peso , Adulto , Trayectoria del Peso Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Olanzapina/uso terapéutico , Perfenazina/uso terapéutico , Piperazinas/uso terapéutico , Fumarato de Quetiapina/uso terapéutico , Risperidona/uso terapéutico , Tiazoles/uso terapéutico , Resultado del TratamientoAsunto(s)
Antipsicóticos/orina , Fenciclidina/orina , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/orina , Triazinas/orina , Adulto , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Ensayos Clínicos como Asunto , Reacciones Falso Positivas , Femenino , Humanos , Inmunoensayo , Lamotrigina , Espectrometría de Masas , Perfenazina/farmacología , Perfenazina/uso terapéutico , Perfenazina/orina , Fenciclidina/farmacología , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVE: Today, the role of oxidative stress in development of schizophrenia has gained attention. Also, some atypical antipsychotic agents showed antioxidant properties. Therefore, in this study, we evaluated the level of oxidative stress parameters between patients treated with perphenazine, clozapine and risperidone and their relationship with schizophrenia symptoms' severity. MATERIALS AND METHODS: This was a descriptive study on 100 patients with chronic schizophrenia. Patient selection was done based on the DSM-IV-TR criteria for at least 3 months regular use of clozapine or risperidone or perphenazine and a minimum period of 2 years of schizophrenia. Ten ml of patient's blood samples were used to assess serum levels of glutathione (GSH), protein carbonyl, lipid peroxidation (LPO), superoxide dismutase (SOD) and Ferric Reducing Ability of Plasma (FRAP). Also, the severity of symptoms was assessed with the positive and negative syndrome scale (PANSS scale). P-values of less than 0.05 were considered significant. RESULTS: The results showed a significant difference between clozapine and risperidone with perphenazine in all subscales of PANSS. Also, there was a positive correlation between MDA and PANSS all subscales in risperidone and perphenazine groups and a negative correlation between MDA and PANSS in all subscales in the clozapine group. Serum level of GSH and negative symptoms in patients receiving clozapine showed a negative correlation. The results also represented that clozapine significantly increased SOD levels in comparison to perphenazine and risperidone and reduced LPO in comparison to perphenazine and risperidone, While the protein carbonyl level did not show a significant difference between three groups (p-valueâ¯=â¯0.8). CONCLUSION: This study showed that clozapine, as an atypical antipsychotic agent, has significant antioxidant effects compared to risperidone and perphenazine. Especially, it increased SOD and GSH levels and reduced LPO in patients with schizophrenia. Therefore, clozapine's antioxidant effect may be contributive to improving negative symptoms of schizophrenic patients.
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Antipsicóticos/farmacología , Clozapina/farmacología , Estrés Oxidativo/efectos de los fármacos , Perfenazina/farmacología , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antipsicóticos/uso terapéutico , Biomarcadores/sangre , Clozapina/uso terapéutico , Humanos , Persona de Mediana Edad , Perfenazina/uso terapéutico , Escalas de Valoración Psiquiátrica , Risperidona/uso terapéutico , Esquizofrenia/sangre , Adulto JovenRESUMEN
Importance: Mood stabilizers and antipsychotics are the main maintenance treatments for bipolar disorder. Lithium is considered to be the most effective mood stabilizer, but very little is known about overall health outcomes associated with specific treatments and the comparative long-term effectiveness of specific psychotropics or routes of administration in the prevention of rehospitalizations. Objective: To study the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in a nationwide cohort of patients with bipolar disorder. Design, Setting, and Participants: This cohort study examined the risk of psychiatric, cardiovascular, and all-cause hospitalization from January 1, 1987, to December 31, 2012, among all patients in Finland who had been hospitalized for bipolar disorder (N = 18â¯018; mean follow-up time, 7.2 years) using prospectively gathered nationwide databases for hospitalization and dispensed medications. The primary analysis was within-individual analysis, in which each individual was used as his or her own control to eliminate selection bias. The study adjusted for the effect of concomitant psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods. Statistical analysis was conducted from January 1, 1996, to December 31, 2012. Main Outcomes and Measures: Adjusted hazard ratios (HRs) for rehospitalization were calculated. Results: Among the cohort (9558 women and 8460 men; mean [SD] age, 46.6 [17.0] years), 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. In comparison between use and no use among specific agents reaching nominal statistical significance, risperidone long-acting injection (HR, 0.58 [95% CI, 0.34-1.00]), gabapentin (HR, 0.58 [95% CI, 0.44-0.77]), perphenazine long-acting injection (HR, 0.60 [95% CI, 0.41-0.88]), and lithium carbonate (HR, 0.67 [95% CI, 0.60-0.73]) were associated with the lowest risk of psychiatric rehospitalization. Concerning all-cause hospitalization, lithium (HR, 0.71 [95% CI, 0.66-0.76]) was associated with the lowest risk. The most frequently used antipsychotic treatment, quetiapine fumarate, showed only modest effectiveness (risk of psychiatric rehospitalization: HR, 0.92 [95% CI, 0.85-0.98]; risk of all-cause hospitalization: HR, 0.93 [95% CI, 0.88-0.98]). Long-acting injections were associated with substantially better outcomes compared with identical oral antipsychotics (risk of psychiatric rehospitalization: HR, 0.70 [95% CI, 0.55-0.90]; risk of all-cause hospitalization: HR, 0.70 [95% CI, 0.57-0.86]). Results from sensitivity analyses showed consistent beneficial effects only for lithium and for long-acting injections compared with their oral counterparts. Conclusions and Relevance: Lithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness.
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Trastorno Bipolar/tratamiento farmacológico , Readmisión del Paciente/estadística & datos numéricos , Psicotrópicos/uso terapéutico , Administración Oral , Adulto , Estudios de Cohortes , Preparaciones de Acción Retardada , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Gabapentina/uso terapéutico , Humanos , Inyecciones Intramusculares , Carbonato de Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Perfenazina/uso terapéutico , Estudios Prospectivos , Fumarato de Quetiapina/uso terapéutico , Riesgo , Risperidona/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI. OBJECTIVES: To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse. SEARCH METHODS: On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers). SELECTION CRITERIA: We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data. DATA COLLECTION AND ANALYSIS: We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 294, RR 0.96, 95% CI 0.86 to 1.07, low-quality evidence).For risperidone versus ziprasidone, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 240, RR 0.96, 95% CI 0.85 to 1.10, low-quality evidence).For many comparisons, important outcomes were missing; and no data were reported in any study for metabolic disturbances, global impression of illness severity, quality of life or mortality. AUTHORS' CONCLUSIONS: There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.
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Antipsicóticos/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , Risperidona/uso terapéutico , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Benzodiazepinas/uso terapéutico , Clozapina/uso terapéutico , Diagnóstico Dual (Psiquiatría) , Humanos , Olanzapina , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Perfenazina/uso terapéutico , Piperazinas/uso terapéutico , Fumarato de Quetiapina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Esquizofrenia/tratamiento farmacológico , Trastornos Relacionados con Sustancias/psicología , Tiazoles/uso terapéuticoRESUMEN
OBJECTIVE: This analysis of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study (NCT01157351) compared outcomes after administration of once-monthly paliperidone palmitate (PP) vs conventional oral antipsychotics (COAs) or atypical oral antipsychotics (AOAs). METHODS: PRIDE was a 15-month study of 444 individuals with schizophrenia and a history of incarceration. They were randomly assigned to PP or to 1 of 7 commonly prescribed OAs. Primary endpoint was time to first treatment failure (TF). Event-free probabilities were estimated using the Kaplan-Meier method; treatment group differences (PP vs COAs, PP vs AOAs, and PP vs oral paliperidone/risperidone) were assessed using a log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. No adjustment was made for multiplicity. RESULTS: Compared with PP, risk for first TF was 34% higher with COAs (HR: 1.34; 95% CI: 0.80-2.25), 41% higher with AOAs (HR: 1.41; 95% CI: 1.06-1.88), and 39% higher with paliperidone/risperidone (HR: 1.39; 95% CI: 0.97-1.99). Incidences of extrapyramidal symptom-related adverse events (AEs) were 45.7%, 13.7%, and 10.6% in the COA, AOA, and oral paliperidone/risperidone groups vs 23.9% in the PP group. Incidences of prolactin-related AEs were 5.7%, 3.8%, and 3.5% vs 23.5%, and incidences of ≥7% weight increase were 11.4%, 14.9%, and 16.0% vs 32.4%. CONCLUSIONS: Results suggest a lower risk of TF but a higher rate of some AEs after treatment with PP vs COAs, AOAs, and paliperidone/risperidone. Deselection of specific OAs and low patient-compliance rates with OAs likely biased the safety results.
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Antipsicóticos/administración & dosificación , Palmitato de Paliperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Administración Oral , Adulto , Antipsicóticos/uso terapéutico , Aripiprazol/uso terapéutico , Enfermedades de los Ganglios Basales/inducido químicamente , Benzodiazepinas/uso terapéutico , Preparaciones de Acción Retardada , Femenino , Haloperidol/uso terapéutico , Humanos , Hiperprolactinemia/inducido químicamente , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Olanzapina , Palmitato de Paliperidona/uso terapéutico , Perfenazina/uso terapéutico , Modelos de Riesgos Proporcionales , Fumarato de Quetiapina/uso terapéutico , Risperidona/uso terapéutico , Psicología del Esquizofrénico , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. Perphenazine (PPZ) is one of the phenothiazines and widely used as an antipsychotic drug. Recently, it is reported that PPZ directly binds with scaffolding subunit of PP2A complex and exerts anti-tumor effects on human T cell acute lymphoblastic leukemia. However, the effect of PPZ on canine lymphoma has not been studied. Here, we investigated the potential therapeutic role of PPZ and its molecular mechanism in canine T-cell lymphoma. In canine T-cell lymphoma cell lines, UL-1 and Ema, PPZ decreased cell survival in a dose-dependent manner. Increased caspase 3 activity and Annexin V positive cells suggested that PPZ induced apoptosis. PPZ dephosphorylated Akt, MEK1/2 and ERK1/2. Akt inhibitor, but not MEK1/2 inhibitor and ERK1/2 inhibitor, induced cell death, indicating the importance of Akt dephosphorylation for the anti-tumor effect of PPZ. Finally, we observed enhanced PP2A activity by PPZ treatment. The present results for the first time revealed that PPZ induced canine lymphoma cells apoptosis through Akt dephosphorylation via PP2A activation. Our study suggests the possible therapeutic application of phenothiazines for canine T-cell lymphoma.
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Antineoplásicos/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Linfoma/veterinaria , Perfenazina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Perros , Relación Dosis-Respuesta a Droga , Citometría de Flujo/veterinaria , Immunoblotting/veterinaria , Linfoma/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/veterinaria , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Oncogénica v-akt/efectos de los fármacos , Proteína Oncogénica v-akt/metabolismo , Fosforilación , Proteína Fosfatasa 2/efectos de los fármacosRESUMEN
RATIONALE: The effect of long-term treatment with the atypical antipsychotic clozapine on the serum amino acid profile in schizophrenia patients has not previously been studied. OBJECTIVES: The aim of this study was to compare serum amino acid patterns in patients on long-term clozapine treatment with long-term conventional antipsychotic treatment, and their relationships to insulin resistance and antipsychotic serum concentrations. METHODS: Thirty-three patients with schizophrenia or schizoaffective disorder on long-term treatment (mean 8.3 years) with clozapine (n=20) or conventional antipsychotics (n=13) were studied. Amino acids were quantified in fasting serum samples by ion exchange chromatography and markers of insulin resistance and antipsychotic drug concentrations were determined by standard methods. RESULTS: Several amino acids, most notably tyrosine and glutamic acid, were elevated above the reference range in several patients receiving clozapine. Additionally, significantly higher mean values of tyrosine (1.5-fold, p=0.001), glutamic acid (2-fold, p=0.0005) and six other amino acids were observed in the clozapine group than in the conventional antipsychotic group. Several amino acids were related to insulin resistance in both treatment groups. CONCLUSIONS: In this study, we show that serum tyrosine and glutamic acid concentrations are markedly elevated in patients on long-term clozapine treatment, compared to patients on long-term conventional antipsychotic treatment. These findings are of importance since these two amino acids have been implicated in the pathophysiology of schizophrenia.
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Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Ácido Glutámico/sangre , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Tirosina/sangre , Adulto , Aminoácidos/sangre , Cromatografía por Intercambio Iónico , Clopentixol/uso terapéutico , Estudios de Cohortes , Femenino , Haloperidol/uso terapéutico , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Perfenazina/uso terapéutico , Estudios Prospectivos , Esquizofrenia/sangre , Tioridazina/uso terapéuticoRESUMEN
No large-scale randomized trial has compared the effect of different second-generation antipsychotic drugs and any first-generation drug on alcohol, drug and nicotine use in patients with schizophrenia. The Clinical Antipsychotic Trial of Intervention Effectiveness study randomly assigned 1432 patients formally diagnosed with schizophrenia to four second-generation antipsychotic drugs (olanzapine, risperidone quetiapine, and ziprasidone) and one first-generation antipsychotic (perphenazine) and followed them for up to 18 months. Secondary outcome data documented cigarettes smoked in the past week and alcohol and drug use severity ratings. At baseline, 61% of patients smoked, 35% used alcohol, and 23% used illicit drugs. Although there were significant effects of time showing reduction in substance use over the 18 months (all p < 0.0001), this study found no evidence that any antipsychotic was robustly superior to any other in a secondary analysis of data on substance use outcomes from a large 18-month randomized schizophrenia trial.
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Alcoholismo/epidemiología , Alcoholismo/rehabilitación , Antipsicóticos/uso terapéutico , Drogas Ilícitas , Esquizofrenia/epidemiología , Esquizofrenia/rehabilitación , Prevención del Hábito de Fumar , Fumar/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/rehabilitación , Adolescente , Adulto , Anciano , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Enfermedad Crónica , Comorbilidad , Estudios Transversales , Dibenzotiazepinas/efectos adversos , Dibenzotiazepinas/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Olanzapina , Perfenazina/efectos adversos , Perfenazina/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Escalas de Valoración Psiquiátrica , Fumarato de Quetiapina , Risperidona/efectos adversos , Risperidona/uso terapéutico , Psicología del Esquizofrénico , Tiazoles/efectos adversos , Tiazoles/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Perphenazine is an old phenothiazine antipsychotic with a potency similar to haloperidol. It has been used for many years and is popular in the northern European countries and Japan. OBJECTIVES: To examine the clinical effects and safety of perphenazine for those with schizophrenia and schizophrenia-like psychoses. SEARCH METHODS: We updated our original search using the Cochrane Schizophrenia Group's register (September 2013), references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials that compared perphenazine with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. We excluded trials of depot formulations of perphenazine. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected citations and, where possible, abstracts. We ordered papers, inspected and quality assessed them. We extracted data, again working independently. If loss to follow-up was greater than 50% we considered results as 'prone to bias'. For dichotomous data, we calculated risk ratios (RR) and for continuous data we calculated mean differences (MD), both with the 95% confidence intervals (CI). We assessed quality of data using the GRADE (Grading of Recommendations Assessment, Development and Evaluationtool) and assessed risk of bias for included studies. MAIN RESULTS: Thirty-one studies fulfilled the inclusion criteria, with a total of 4662 participants (of which 4522 were receiving the drugs relevant to our comparison) and presented data that could be used for at least one comparison. The trial centres were located in Europe (especially Scandinavia), Japan and Northern America.When comparing perphenazine with placebo, for our primary outcome of clinical response, results favoured perphenazine with significantly more people receiving placebo rated as either 'no better or deterioration' for global state than people receiving perphenazine (1 RCT, n = 61 RR 0.32 CI 0.13 to 0.78, very low quality evidence). More people receiving placebo relapsed, although not a statistically significant number (1 RCT, n = 48, RR 0.14 CI 0.02 to 1.07, very low quality evidence). Death was not reported in the perphenazine versus placebo comparison. Experiences of dystonia were equivocal between groups (1 RCT, n = 48, RR 1.00 CI 0.07 to 15.08, very low quality evidence); other outcomes not reported in this comparison include serious adverse events, economic outcomes, and service use and hospitalisation.For the comparison of perphenazine versus any other antipsychotic drugs, no real differences in effect between the drugs were found. There was no significant difference between groups for those considered 'no better or deterioration' (17 RCTs, n = 1879, RR 1.04 CI 0.91 to 1.17, very low quality evidence). For mental state outcome of 'no effect' of the study drug, there was again no significant difference between groups (4 RCTs, n = 383, RR 1.24 CI 0.61 to 2.52, very low quality evidence). Death was not reported in any of the included studies. There was no significant difference in rates of dystonia with perphenazine versus any other antipsychotic drugs (4 RCTs, n = 416, RR 1.36 CI 0.23 to 8.16, very low quality evidence), nor was there a significant difference between groups for serious adverse events (2 RCTs, n = 1760, RR 0.98 CI 0.68 to 1.41, very low quality evidence). AUTHORS' CONCLUSIONS: Although perphenazine has been used in randomised trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes in this review were of very low quality evidence. At best we can say that perphenazine showed similar effects and adverse events as several of the other antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.
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Antipsicóticos/uso terapéutico , Perfenazina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Humanos , Trastornos Mentales/tratamiento farmacológico , Perfenazina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: There are limited evidences reported of temporal lobe epilepsy associated with active cysticercosis in cystic stage. The objective is to present the correlation between active cysticercosis in topographical zones associated with temporal lobe epilepsy, with neuropsychiatric manifestations and pattern of secondarily generalized partial seizures. CASE REPORTS: Two cases of adult patients with neuropsychiatric manifestations of one year evolution, refractory to antipsychotic drug treatment, and who subsequently appear late onset partial-secondarily generalized seizures. Cysticercosis active presence in the temporal lobe in one patient, and the insula in the other, is identified. A better clinical control after albendazol treatment and subsequently anticonvulsant therapy only remained to evaluate pertinence of pharmacological withdrawal criteria. CONCLUSIONS: Active neurocysticercosis, may be the cause of acquired neuropsychiatric disorders and temporal lobe epilepsy of late onset when the topography is in the mesolimbic circuit. Early etiologic diagnosis and appropriate treatment allows adequate control of their symptoms and potentially final cure.
TITLE: Epilepsia del lobulo temporal y neurocisticercosis activa: dos casos representativos.Introduccion. Existen pocas evidencias notificadas de casos de epilepsia del lobulo temporal asociadas a cisticercosis activa en su fase quistica. El objetivo es presentar la correlacion entre cisticercosis activa en zonas topograficas asociadas a epilepsia del lobulo temporal, con las manifestaciones neuropsiquiatricas y el patron de crisis parciales secundariamente generalizadas. Casos clinicos. Dos casos de pacientes adultos con manifestaciones neuropsiquiatricas de un año de evolucion, refractarios a tratamiento farmacologico antipsicotico, y en quienes posteriormente aparecen crisis convulsivas parciales secundariamente generalizadas de inicio tardio. Se identifica la presencia de cisticercosis activa en el lobulo temporal en un paciente, y en la insula, en el otro. Buen control clinico posterior al tratamiento con albendazol, pero se mantiene el mismo tratamiento anticonvulsionante para considerar la pertinencia de su retirada farmacologica. Conclusiones. La neurocisticercosis activa puede ser causa de trastornos neuropsiquiatricos adquiridos y de epilepsia del lobulo temporal de inicio tardio cuando su topografia se encuentra en el circuito mesolimbico. El diagnostico etiologico oportuno y el tratamiento apropiado permiten el control adecuado de su sintomatologia y, potencialmente, su curacion definitiva.
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Anomia/etiología , Epilepsia del Lóbulo Temporal/etiología , Neurocisticercosis/complicaciones , Trastorno de Pánico/etiología , Albendazol/uso terapéutico , Anomia/tratamiento farmacológico , Antihelmínticos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antipsicóticos/uso terapéutico , Carbamazepina/análogos & derivados , Carbamazepina/uso terapéutico , Citalopram/uso terapéutico , Diagnóstico Tardío , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/etiología , Resistencia a Medicamentos , Quimioterapia Combinada , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Cefalea/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neurocisticercosis/diagnóstico , Neurocisticercosis/tratamiento farmacológico , Neurocisticercosis/psicología , Oxcarbazepina , Trastorno de Pánico/tratamiento farmacológico , Perfenazina/uso terapéutico , Prednisona/uso terapéuticoRESUMEN
Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18 months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.
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Antipsicóticos/uso terapéutico , Receptores de Glucagón/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Adulto , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Benzodiazepinas/uso terapéutico , Biomarcadores Farmacológicos , Dibenzotiazepinas/efectos adversos , Dibenzotiazepinas/uso terapéutico , Femenino , Técnicas de Genotipaje , Receptor del Péptido 1 Similar al Glucagón , Haplotipos , Humanos , Masculino , Modelos Genéticos , Olanzapina , Perfenazina/efectos adversos , Perfenazina/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Polimorfismo de Nucleótido Simple , Fumarato de Quetiapina , Análisis de Regresión , Risperidona/efectos adversos , Risperidona/uso terapéutico , Tiazoles/efectos adversos , Tiazoles/uso terapéutico , Resultado del Tratamiento , Aumento de Peso/efectos de los fármacos , Aumento de Peso/genética , Población Blanca/genéticaRESUMEN
BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects. OBJECTIVES: To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (October 2010). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis and using a random-effects model. MAIN RESULTS: The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high.The effects of perphenazine and low-potency antipsychotic drugs seemed to be similar in terms of the primary outcome - response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 - moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence).There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89).There were three deaths in the low-potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care.The event rates reported quote simple aggregates and are not based on the RRs. AUTHORS' CONCLUSIONS: The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.
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Antipsicóticos/uso terapéutico , Perfenazina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: Effects of conventional and atypical antipsychotics on bone mineral density (BMD) and serum prolactin levels (PRL) were examined in patients with schizophrenia. METHODS: One hundred and sixty-three first-episode inpatients with schizophrenia were recruited, to whom one of three conventional antipsychotics (perphenazine, sulpiride, and chlorpromazine) or one of three atypical antipsychotics (clozapine, quetiapine, and aripiprazole) was prescribed for 12 months as appropriate. BMD and PRL were tested before and after treatment. Same measures were conducted in 90 matched healthy controls. RESULTS: Baseline BMD of postero-anterior L1-L4 range from 1.04 ± 0.17 to 1.42 ± 1.23, and there was no significant difference between the patients group and healthy control group. However, post-treatment BMD values in patients (ranging from 1.02 ± 0.15 to 1.23 ± 0.10) were significantly lower than that in healthy controls (ranging from 1.15 ± 0.12 to 1.42 ± 1.36). The BMD values after conventional antipsychotics were significantly lower than that after atypical antipsychotics. The PRL level after conventional antipsychotics (53.05 ± 30.25 ng/ml) was significantly higher than that after atypical antipsychotics (32.81 ± 17.42 ng/ml). Conditioned relevance analysis revealed significant negative correlations between the PRL level and the BMD values after conventional antipsychotics. CONCLUSION: The increase of PRL might be an important risk factor leading to a high prevalence of osteoporosis in patients with schizophrenia on long-term conventional antipsychotic medication.