Bioconversion and P-gp-Mediated Transport of Depot Fluphenazine Prodrugs after Intramuscular Injection.

Fluphenazine (FPZ) decanoate, an ester-type prodrug formulated as a long-acting injection (LAI), is used in the treatment of schizophrenia. FPZ enanthate was also developed as an LAI formulation, but is no longer in use clinically because of the short elimination half-life of FPZ, the parent drug, after intramuscular injection. In the present study, the hydrolysis of FPZ prodrugs was evaluated in human plasma and liver to clarify the reason for this difference in elimination half-lives. FPZ prodrugs were hydrolyzed in human plasma and liver microsomes. The rate of hydrolysis of FPZ enanthate in human plasma and liver microsomes was 15-fold and 6-fold, respectively, faster than that of FPZ decanoate. Butyrylcholinesterase (BChE) and human serum albumin (HSA) present in human plasma, and two carboxylesterase (CES) isozymes, hCE1 and hCE2, expressed in ubiquitous organs including liver, were mainly responsible for the hydrolysis of FPZ prodrugs. FPZ prodrugs may not be bioconverted in human skeletal muscle at the injection site because of lack of expression of BChE and CESs in muscle. Interestingly, although FPZ was a poor substrate for human P-glycoprotein, FPZ caproate was a good substrate. In conclusion, it is suggested that the shorter elimination half-life of FPZ following administration of FPZ enanthate compared with FPZ decanoate can be attributed to the more rapid hydrolysis of FPZ enanthate by BChE, HSA and CESs.

Comparative effectiveness of long-acting injectable antipsychotics in patients with schizophrenia in Japan.

OBJECTIVE: To compare the effectiveness of different long-acting injectable antipsychotics (LAIs) (aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol) in patients with schizophrenia in Japan. METHODS: We conducted a retrospective cohort study using two administrative claims databases. The study population consisted of outpatients with schizophrenia who initiated LAIs between May 1, 2015, and November 30, 2019. We directly compared the risk of psychiatric hospitalization and LAI discontinuation among the LAIs based on hazard ratios (HRs) using Cox proportional hazards regression models. RESULTS: The numbers of eligible patients who initiated aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol were 303, 124, 73, and 123, respectively. Regarding psychiatric hospitalization, aripiprazole and paliperidone were associated with significantly lower risk compared to fluphenazine/haloperidol (HR of aripiprazole: 0.47, 95 % CI: 0.28-0.78, HR of paliperidone: 0.50, 95 % CI: 0.28-0.89); HR of risperidone showed the same trend as the aripiprazole and paliperidone. Regarding LAI discontinuation, aripiprazole and paliperidone were associated with significantly lower risk of LAI discontinuation compared to fluphenazine/haloperidol (HR of aripiprazole: 0.53, 95 % CI: 95 % CI: 0.35-0.80, HR of paliperidone: 0.57, 95 % CI: 0.35-0.92). Aripiprazole was also associated with a significantly lower risk compared to risperidone (HR: 0.56, 95 % CI: 0.32-0.98). CONCLUSION: Our study suggests that aripiprazole and paliperidone are superior to fluphenazine/haloperidol in the risk of psychiatric hospitalization and LAI discontinuation. Aripiprazole is superior to risperidone in the risk of LAI discontinuation.

Antipsychotic Drug Fluphenazine against Human Cancer Cells.

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy.

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

The use of carbamazepine to expedite the metabolism of a long-acting aripiprazole injection.

WHAT IS KNOWN AND OBJECTIVE: Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. CASE SUMMARY: An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. WHAT IS NEW AND CONCLUSION: Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.

Real-world effectiveness of long-acting injectable antipsychotics to reduce 90-day and annual readmission in psychotic disorders: insights from a state psychiatric hospital.

BACKGROUND: To evaluate the effectiveness of long-acting injectable antipsychotics (LAI-a) in reducing the 90-day and annual readmission rates in schizophrenia inpatients. METHODS: We conducted a cross-sectional study and included 180 adult patients with psychotic disorders discharged from 2018 to 2019 at a state psychiatric hospital. Descriptive statistics were used to measure the differences between the readmit and nonreadmit cohorts. Logistic regression model was used to measure the odds ratio (OR) for 90-day and annual readmission and was controlled for potential readmission risk factors. RESULTS: A lower proportion of patients receiving LAI-a were readmitted within 90-day (28.6%) and 1-year (32.4%) periods. Patients receiving LAI-a had lower odds of association for 90-day (OR 0.36, 95% confidence intervals [CI] 0.139-0.921) and annual (OR 0.35, 95% CI 0.131-0.954) readmissions compared to those discharged on oral antipsychotics. A higher proportion of inpatients who received fluphenazine LAI had 90-day (25%) and annual (18.2%) readmissions compared to other LAI-a. CONCLUSION: Utilization of LAI-a in patients with psychotic disorders can decrease both 90-day and annual psychiatric readmissions by 64% to 65%. Physicians should prefer LAI-a to reduce the readmission rate and improve the quality of life, and decrease the healthcare-related financial burden.

In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review.

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.

Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review.

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.

Eficácia, segurança e efetividade comparada de palmitato de paliperidona e outros antipsicóticos injetáveis de efeito prolongado para tratamento de esquizofrenia: revisão rápida de evidências / Efficacy, safety and effectiveness in the real world for paliperidone palmitate compared to the others long acting injectable antipsychotics for schizophrenia treatment: rapid review of evidence

Tecnologia: Palmitato de Paliperidona (PP) é um antipsicótico injetáveis de efeito prolongado (AIEP). Indicação: Tratamento sintomático da esquizofrenia. Objetivo: Comparar a eficácia, segurança e efetividade terapêutica entre PP e outros AIEP para o tratamento de esquizofrenia em adultos. Pergunta: O PP é mais eficaz e seguro que os outros AIEP (Decanoato de Haloperidol, Enantato de Flufenazina, Decanoato de Zuclopentixol, Risperidona-IEP) para o tratamento sintomático de esquizofrenia em adultos? Métodos: Levantamento bibliográfico, com estratégias estruturadas de busca, na base de dados PUBMED. Foi feita avaliação da qualidade metodológica das revisões sistemáticas (RS), ensaios clínicos randomizados (ECR) e dos estudos observacionais de efetividade no mundo real (EOEMR) com as ferramentas Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List e Newcastle-Ottawa Scale (NOS), respectivamente. Resultados: Foram selecionadas 3 RS, 1 ECR e 3 EOEMR. Conclusão: PP (de aplicação mensal) tem similar eficácia e segurança com a Risperidona-IEP para o tratamento de esquizofrenia, exceto que provoca menor incidência de sintomas extrapiramidais. PP e Decanoato de Haloperidol são similares na eficácia e segurança para o tratamento de esquizofrenia, inclusive no risco de sintomas extrapiramidais (discinesias tardias e parkinsonismo), exceto que PP tem menor incidência de acatisia. PP é similar aos outros AIEP nos vários desfechos de eficácia e segurança terapêutica, inclusive mortalidade

Technology: Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotics. Indication: Symptomatic treatment of schizophrenia. Objective: To compare the therapeutic efficacy, safety and effectiveness in the real world between PP and other LAI antipsychotics for the treatment of schizophrenia in adults. Question: Is PP more effective and safer than other LAI antipsychotics (Haloperidol Decanoate, Fluphenazine Enanthate, Zuclopentixol Decanoate, Risperidone-LAI), for the symptomatic treatment of schizophrenia? Methods: Bibliographic survey, with structured search strategies, in the PUBMED database. Na evaluation was made of the methodological quality of systematic reviews (SR), randomized clinical trials (RCT) and observational studies (OS) of effectiveness in the real world with Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List and Newcastle-Ottawa Scale (NOS) tools, respectively. Results: 3 SR, 1 RCT and 3 OE were included. Conclusion: PP (monthly dose presentation) has similar efficacy and safety with Risperidone-LAI for the treatment of schizophrenia, except that it causes a lower incidence of extrapyramidal symptoms. PP and Haloperidol Decanoate are similar in efficacy and safety for the treatment of schizophrenia, including the risk of extra-pyramidal symptoms (tardive dyskinesias and parkinsonism), except that PP has a lower incidence of akathisia. PP has similar outcomes of efficacy and safety to the other LAI antipsychotics, including mortality risk

Impulsivity moderates the effects of dopamine D2 and mixed D1-D2 antagonists in individuals with gambling disorder.

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.

Fluphenazine (oral) versus placebo for schizophrenia.

BACKGROUND: Fluphenazine is one of the first drugs to be classed as an 'antipsychotic' and has been widely available for five decades. OBJECTIVES: To compare the effects of oral fluphenazine with placebo for the treatment of schizophrenia. To evaluate any available economic studies and value outcome data. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (23 July 2013, 23 December 2014, 9 November 2016 and 28 December 2017 ) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There is no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We sought all randomised controlled trials comparing oral fluphenazine with placebo relevant to people with schizophrenia. Primary outcomes of interest were global state and adverse effects. DATA COLLECTION AND ANALYSIS: For the effects of interventions, a review team inspected citations and abstracts independently, ordered papers and re-inspected and quality assessed trials. We extracted data independently. Dichotomous data were analysed using fixed-effect risk ratio (RR) and the 95% confidence interval (CI). Continuous data were excluded if more than 50% of people were lost to follow-up, but, where possible, mean differences (MD) were calculated. Economic studies were searched and reliably selected by an economic review team to provide an economic summary of available data. Where no relevant economic studies were eligible for inclusion, the economic review team valued the already-included effectiveness outcome data to provide a rudimentary economic summary. MAIN RESULTS: From over 1200 electronic records of 415 studies identified by our initial search and this updated search, we excluded 48 potentially relevant studies and included seven trials published between 1964 and 1999 that randomised 439 (mostly adult participants). No new included trials were identified for this review update. Compared with placebo, global state outcomes of 'not improved or worsened' were not significantly different in the medium term in one small study (n = 50, 1 RCT, RR 1.12 CI 0.79 to 1.58, very low quality of evidence). The risk of relapse in the long term was greater in two small studies in people receiving placebo (n = 86, 2 RCTs, RR 0.39 CI 0.05 to 3.31, very low quality of evidence), however with high degree of heterogeneity in the results. Only one person allocated fluphenazine was reported in the same small study to have died on long-term follow-up (n = 50, 1 RCT, RR 2.38 CI 0.10 to 55.72, low quality of evidence). Short-term extrapyramidal adverse effects were significantly more frequent with fluphenazine compared to placebo in two other studies for the outcomes of akathisia (n = 227, 2 RCTs, RR 3.43 CI 1.23 to 9.56, moderate quality of evidence) and rigidity (n = 227, 2 RCTs, RR 3.54 CI 1.76 to 7.14, moderate quality of evidence). For economic outcomes, we valued outcomes for relapse and presented them in additional tables. AUTHORS' CONCLUSIONS: The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. Fluphenazine's global position as an effective treatment for psychoses is not threatened by the outcome of this review. However, fluphenazine is an imperfect treatment and if accessible, other inexpensive drugs less associated with adverse effects may be an equally effective choice for people with schizophrenia.

Long-acting formulation leading to severe long-term adverse effects: a case report of fluphenazine and persistent extrapyramidal symptoms.

WHAT IS KNOWN AND OBJECTIVE: Long-acting formulations are an important therapeutic option for non-adherent patients with schizophrenia. There is a commonly held view that management of long-acting formulation-induced side effects is difficult. CASE DESCRIPTION: We present a patient with schizophrenia who developed acute and persistent extrapyramidal symptoms requiring tracheostomy and long-term rehabilitation after long-acting injections of fluphenazine decanoate. Extrapyramidal symptoms improved with declining fluphenazine concentration and antiparkinsonian drug therapy with bromocriptine. WHAT IS NEW AND CONCLUSION: Long-acting formulations may lead to severe persistent adverse effects. For preventing fluphenazine-induced side effects, a possible option might be the antiparkinsonian drug therapy with bromocriptine.

Modulating cancer cell survival by targeting intracellular cholesterol transport.

BACKGROUND: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. METHODS: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs. RESULTS: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects. CONCLUSIONS: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.

Fluphenazine (oral) versus atypical antipsychotics for schizophrenia.

BACKGROUND: Fluphenazine is a typical antipsychotic drug from the phenothiazine group of antipsychotics. It has been commonly used in the treatment of schizophrenia, however, with the advent of atypical antipsychotic medications, use has declined over the years. OBJECTIVES: To measure the outcomes (both beneficial and harmful) of the clinical effectiveness, safety and cost-effectiveness of oral fluphenazine versus atypical antipsychotics for schizophrenia. SEARCH METHODS: We searched the Cochrane Central Register of Studies (25 April 2013). For the economic search, we searched the Cochrane Schizophrenia Group Health Economic Database (CSzGHED) on 31 January 2014 SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing fluphenazine (oral) with any other oral atypical antipsychotics. DATA COLLECTION AND ANALYSIS: Review authors worked independently to inspect citations and assess the quality of the studies and to extract data. For homogeneous dichotomous data we calculated the risk ratio (RR) and 95% confidence interval (CI), and calculated the mean differences (MDs) for continuous data. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the quality of the evidence. MAIN RESULTS: Four studies randomising a total of 202 people with schizophrenia are included. Oral fluphenazine was compared with oral amisulpride, risperidone, quetiapine and olanzapine.Comparing oral fluphenazine with amisulpride, there was no difference between groups for mental state using the Brief Psychiatric Rating Scale (BPRS) (1 RCT, n = 57, MD 5.10 95% CI -2.35 to 12.55, very low-quality evidence), nor was there any difference in numbers leaving the study early for any reason (2 RCTs, n = 98, RR 1.19 95% CI 0.63 to 2.28, very low-quality evidence). More people required concomitant anticholinergic medication in the fluphenazine group compared to amisulpride (1 RCT, n = 36, RR 7.82 95% CI 1.07 to 57.26, very low-quality evidence). No data were reported for important outcomes including relapse, changes in life skills, quality of life or cost-effectiveness.Comparing oral fluphenazine with risperidone, data showed no difference between groups for 'clinically important response' (1 RCT, n = 26, RR 0.67 95% CI 0.13 to 3.35, very low-quality evidence) nor leaving the study early due to inefficacy (1 RCT, n = 25, RR 1.08 95% CI 0.08 to 15.46, very low-quality evidence). No data were reported data for relapse; change in life skills; quality of life; extrapyramidal adverse effects; or cost-effectiveness.Once again there was no difference when oral fluphenazine was compared with quetiapine for clinically important response (1 RCT, n = 25, RR 0.62 95% CI 0.12 to 3.07, very low-quality evidence), nor leaving the study early for any reason (1 RCT, n = 25, RR 0.46 95% CI 0.05 to 4.46, very low-quality evidence). No data were reported for relapse; clinically important change in life skills; quality of life; extrapyramidal adverse effects; or cost-effectiveness.Compared to olanzapine, fluphenazine showed no superiority for clinically important response (1 RCT, n = 60, RR 1.33 95% CI 0.86 to 2.07, very low-quality evidence), in incidence of akathisia (1 RCT, n = 60, RR 3.00 95% CI 0.90 to 10.01, very low-quality evidence) or in people leaving the study early (1 RCT, n = 60, RR 3.00 95% CI 0.33 to 27.23, very low-quality evidence). No data were reported for relapse; change in life skills; quality of life; or cost-effectiveness. AUTHORS' CONCLUSIONS: Measures of clinical response and mental state do not highlight differences between fluphenazine and amisulpride, risperidone, quetiapine or olanzapine. Largely measures of adverse effects are also unconvincing for substantive differences between fluphenazine and the newer drugs. All included trials carry a substantial risk of bias regarding reporting of adverse effects and this bias would have favoured the newer drugs. The four small short included studies do not provide much clear information about the relative merits or disadvantages of oral fluphenazine compared with newer atypical antipsychotics.

Pharmacological interventions for self-harm in adults.

BACKGROUND: Self-harm (SH; intentional self-poisoning or self-injury) is common, often repeated, and strongly associated with suicide. This is an update of a broader Cochrane review on psychosocial and pharmacological treatments for deliberate SH, first published in 1998 and previously updated in 1999. We have now divided the review into three separate reviews. This review is focused on pharmacological interventions in adults who self harm. OBJECTIVES: To identify all randomised controlled trials of pharmacological agents or natural products for SH in adults, and to conduct meta-analyses (where possible) to compare the effects of specific treatments with comparison types of treatment (e.g., placebo/alternative pharmacological treatment) for SH patients. SEARCH METHODS: For this update the Cochrane Depression, Anxiety and Neurosis Review Group (CCDAN) Trials Search Co-ordinator searched the CCDAN Specialised Register (September 2014). Additional searches of MEDLINE, EMBASE, PsycINFO, and CENTRAL were conducted to October 2013. SELECTION CRITERIA: We included randomised controlled trials comparing pharmacological treatments or natural products with placebo/alternative pharmacological treatment in individuals with a recent (within six months) episode of SH resulting in presentation to clinical services. DATA COLLECTION AND ANALYSIS: We independently selected trials, extracted data, and appraised trial quality. For binary outcomes, we calculated odds ratios (ORs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and 95% CI. Meta-analysis was only possible for one intervention (i.e. newer generation antidepressants) on repetition of SH at last follow-up. For this analysis, we pooled data using a random-effects model. The overall quality of evidence for the primary outcome was appraised for each intervention using the GRADE approach. MAIN RESULTS: We included seven trials with a total of 546 patients. The largest trial included 167 participants. We found no significant treatment effect on repetition of SH for newer generation antidepressants (n = 243; k = 3; OR 0.76, 95% CI 0.42 to 1.36; GRADE: low quality of evidence), low-dose fluphenazine (n = 53; k = 1; OR 1.51, 95% CI 0.50 to 4.58; GRADE: very low quality of evidence), mood stabilisers (n = 167; k = 1; OR 0.99, 95% CI 0.33 to 2.95; GRADE: low quality of evidence), or natural products (n = 49; k = 1; OR 1.33, 95% CI 0.38 to 4.62; GRADE: low quality of evidence). A significant reduction in SH repetition was found in a single trial of the antipsychotic flupenthixol (n = 30; k = 1; OR 0.09, 95% CI 0.02 to 0.50), although the quality of evidence for this trial, according to the GRADE criteria, was very low. No data on adverse effects, other than the planned outcomes relating to suicidal behaviour, were reported. AUTHORS' CONCLUSIONS: Given the low or very low quality of the available evidence, and the small number of trials identified, it is not possible to make firm conclusions regarding pharmacological interventions in SH patients. More and larger trials of pharmacotherapy are required. In view of an indication of positive benefit for flupenthixol in an early small trial of low quality, these might include evaluation of newer atypical antipsychotics. Further work should include evaluation of adverse effects of pharmacological agents. Other research could include evaluation of combined pharmacotherapy and psychological treatment.

Fluphenazine decanoate (depot) and enanthate for schizophrenia.

BACKGROUND: Intramuscular injections (depot preparations) offer an advantage over oral medication for treating schizophrenia by reducing poor compliance. The benefits gained by long-acting preparations, however, may be offset by a higher incidence of adverse effects. OBJECTIVES: To assess the effects of fluphenazine decanoate and enanthate versus oral anti-psychotics and other depot neuroleptic preparations for individuals with schizophrenia in terms of clinical, social and economic outcomes. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (February 2011 and October 16, 2013), which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. SELECTION CRITERIA: We considered all relevant randomised controlled trials (RCTs) focusing on people with schizophrenia comparing fluphenazine decanoate or enanthate with placebo or oral anti-psychotics or other depot preparations. DATA COLLECTION AND ANALYSIS: We reliably selected, assessed the quality, and extracted data of the included studies. For dichotomous data, we estimated risk ratio (RR) with 95% confidence intervals (CI). Analysis was by intention-to-treat. We used the mean difference (MD) for normal continuous data. We excluded continuous data if loss to follow-up was greater than 50%. Tests of heterogeneity and for publication bias were undertaken. We used a fixed-effect model for all analyses unless there was high heterogeneity. For this update. we assessed risk of bias of included studies and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to create a 'Summary of findings' table. MAIN RESULTS: This review now includes 73 randomised studies, with 4870 participants. Overall, the quality of the evidence is low to very low.Compared with placebo, use of fluphenazine decanoate does not result in any significant differences in death, nor does it reduce relapse over six months to one year, but one longer-term study found that relapse was significantly reduced in the fluphenazine arm (n = 54, 1 RCT, RR 0.35, CI 0.19 to 0.64, very low quality evidence). A very similar number of people left the medium-term studies (six months to one year) early in the fluphenazine decanoate (24%) and placebo (19%) groups, however, a two-year study significantly favoured fluphenazine decanoate (n = 54, 1 RCT, RR 0.47, CI 0.23 to 0.96, very low quality evidence). No significant differences were found in mental state measured on the Brief Psychiatric Rating Scale (BPRS) or in extrapyramidal adverse effects, although these outcomes were only reported in one small study each. No study comparing fluphenazine decanoate with placebo reported clinically significant changes in global state or hospital admissions.Fluphenazine decanoate does not reduce relapse more than oral neuroleptics in the medium term (n = 419, 6 RCTs, RR 1.46 CI 0.75 to 2.83, very low quality evidence). A small study found no difference in clinically significant changes in global state. No difference in the number of participants leaving the study early was found between fluphenazine decanoate (17%) and oral neuroleptics (18%), and no significant differences were found in mental state measured on the BPRS. Extrapyramidal adverse effects were significantly less for people receiving fluphenazine decanoate compared with oral neuroleptics (n = 259, 3 RCTs, RR 0.47 CI 0.24 to 0.91, very low quality evidence). No study comparing fluphenazine decanoate with oral neuroleptics reported death or hospital admissions.No significant difference in relapse rates in the medium term between fluphenazine decanoate and fluphenazine enanthate was found (n = 49, 1 RCT, RR 2.43, CI 0.71 to 8.32, very low quality evidence), immediate- and short-term studies were also equivocal. One small study reported the number of participants leaving the study early (29% versus 12%) and mental state measured on the BPRS and found no significant difference for either outcome. No significant difference was found in extrapyramidal adverse effects between fluphenazine decanoate and fluphenazine enanthate. No study comparing fluphenazine decanoate with fluphenazine enanthate reported death, clinically significant changes in global state or hospital admissions. AUTHORS' CONCLUSIONS: There are more data for fluphenazine decanoate than for the enanthate ester. Both are effective antipsychotic preparations. Fluphenazine decanoate produced fewer movement disorder effects than other oral antipsychotics but data were of low quality, and overall, adverse effect data were equivocal. In the context of trials, there is little advantage of these depots over oral medications in terms of compliance but this is unlikely to be applicable to everyday clinical practice.

Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between any other antipsychotic compounds, however, low-potency antipsychotic drugs are often perceived as less efficacious than high-potency compounds by clinicians, and they also seem to differ in their side effects. This review examined the effects of the high-potency antipsychotic fluphenazine compared to those of low-potency antipsychotics. OBJECTIVES: To review the effects of fluphenazine and low-potency antipsychotics for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (November 2010). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing fluphenazine with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. 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 based on a random-effects model. MAIN RESULTS: The review currently includes seven randomised trials and 1567 participants that compared fluphenazine with low-potency antipsychotic drugs. The size of the included studies was between 40 and 438 participants. Overall, sequence generation, allocation procedures and blinding were poorly reported. Fluphenazine was not significantly different from low-potency antipsychotic drugs in terms of response to treatment (fluphenazine 55%, low-potency drug 55%, 2 RCTs, n = 105, RR 1.06 CI 0.75 to 1.50, moderate quality evidence). There was also no significant difference in acceptability of treatment with equivocal numbers of participants leaving the studies early due to any reason (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, n = 1532, RR 1.00 CI 0.88 to 1.14, moderate quality evidence). There was no significant difference between fluphenazine and low-potency antipsychotics for numbers experiencing at least one adverse effect (fluphenazine 70%, low-potency antipsychotics 88%, 1 RCT, n = 65, RR 0.79 CI 0.58 to 1.07, moderate quality evidence). However, at least one movement disorder occurred significantly more frequently in the fluphenazine group (fluphenazine 15%, low-potency antipsychotics 10%, 3 RCTs, n = 971, RR 2.11 CI 1.41 to 3.15, low quality of evidence). In contrast, low-potency antipsychotics produced significantly more sedation (fluphenazine 20%, low-potency antipsychotics 64%, 1 RCT, n = 65, RR 0.31 CI 0.13 to 0.77, high quality evidence). No data were available for the outcomes of death and quality of life. The results of the primary outcome were robust in a number of subgroup and sensitivity analyses.Adverse effects such as akathisia (fluphenazine 15%, low-potency antipsychotics 6%, 5 RCTs, n = 1209, RR 2.28 CI 1.58 to 3.28); dystonia (fluphenazine 5%, low-potency antipsychotics 2%, 4 RCTs, n = 1309, RR 2.66 CI 1.25 to 5.64); loss of associated movement (fluphenazine 20%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 11.15 CI 3.95 to 31.47); rigor (fluphenazine 27%, low-potency antipsychotics 12%, 2 RCTs, n = 403, RR 2.18 CI 1.20 to 3.97); and tremor (fluphenazine 15%, low-potency antipsychotics 6%, 2 RCTs, n = 403, RR 2.53 CI 1.37 to 4.68) occurred significantly more frequently in the fluphenazine group.For other adverse effects such as dizziness (fluphenazine 8%, low-potency antipsychotics 17%, 4 RCTs, n = 1051, RR 0.49 CI 0.32 to 0.73); drowsiness (fluphenazine 18%, low-potency antipsychotics 25%, 3 RCTs, n = 986, RR 0.67 CI 0.53 to 0.86); dry mouth (fluphenazine 11%, low-potency antipsychotics 18%, 4 RCTs, n = 1051, RR 0.63 CI 0.45 to 0.89); nausea (fluphenazine 4%, low-potency antipsychotics 15%, 3 RCTs, n = 986, RR 0.25 CI 0.14 to 0.45); and vomiting (fluphenazine 3%, low-potency antipsychotics 8%, 3 RCTs, n = 986, RR 0.36 CI 0.18 to 0.72) results favoured fluphenazine with significantly more events occurring in the low-potency antipsychotic group for these outcomes. AUTHORS' CONCLUSIONS: The results do not show a clear difference in efficacy between fluphenazine and low-potency antipsychotics. The number of included studies was low and their quality moderate. Therefore, further studies would be needed to draw firm conclusions about the relative effects of fluphenazine and low-potency antipsychotics.

Va'a fakalelei 'atamai: restoring the mind in the Kingdom of Tonga.

OBJECTIVE: We aim to report on the practice of psychiatry in the Kingdom of Tonga. METHOD: We provide a description of the findings from a visit to Vaiola Hospital and data provided by the chief psychiatrist of Tonga. RESULTS: The practice of psychiatry in Tonga reflects the difficulties of providing health care in a middle-income micro state. Interesting features include the use of kava as a calmative for some acutely disturbed and anxious patients, the high proportion of patients receiving treatment with fluphenazine decanoate and the possibility that the observed increase in psychosis among Tongan migrants to Australia is at least partly due to a high prevalence of psychosis in Tonga itself. CONCLUSIONS: A prevalence of psychosis study would need to be undertaken to confirm the report of a higher rate of psychosis in Tonga compared with that in Australia.

Berberine inhibits fluphenazine-induced up-regulation of CDR1 in Candida albicans.

Over-expression of the Candida drug resistance gene CDR1 is a common mechanism generating azole-resistant Candida albicans in clinical isolates. CDR1 is transcriptionally activated through the binding of the transcription factor Tac1p to the cis-acting drug-responsive element (DRE) in its promoter. We previously demonstrated that the combination of fluconazole (FLC) and berberine (BBR) produced significant synergy when used against FLC-resistant C. albicans in vitro. In this study, we found that BBR inhibited both the up-regulation of CDR1 mRNA and the transport function of Cdr1p induced by fluphenazine (FNZ). Further, electrophoretic mobility shift assays suggested that the transcription activation complex of protein-DRE was disrupted by BBR, and electrospray ionization mass spectrometry analysis showed that BBR bound to the DRE of CDR1. Thus we propose that BBR inhibits the FNZ-induced transcriptional activation of CDR1 in C. albicans by blocking transcription factor binding to the DRE of CDR1. These results contribute to our understanding of the mechanism of synergistic effect of BBR and FLC.