Antimelanoma activity of perphenazine and prochlorperazine in human COLO829 and C32 cell lines.

Cutaneous melanoma is least common (only about 1% of skin cancers) but is the deadliest malignant tumor. Moreover, amelanotic types of melanoma are very difficult for clinical diagnosis. The standard therapy can cause a lot of side effects, e.g., nausea, vomiting, and headaches, which means that novel and effective strategies are required. Interestingly, phenothiazine derivatives possess sedative, antiemetic, and anticancer activity. Our goal was to determine the effect of perphenazine and prochlorperazine on cell viability, motility, microphthalmia-associated transcription factor (MITF) and tyrosinase content in melanotic and amelanotic melanoma cells. The viability of C32 and COLO829 melanoma cells was evaluated by the WST-1 colorimetric assay; impact on motility of human melanoma was performed by wound-healing assay, while tyrosinase and MITF content were determined by Western blot. In the present study, we explore the anticancer effect of perphenazine and prochlorperazine in human melanotic (COLO829) and amelanotic (C32) melanoma cells concluding that prochlorperazine inhibits cell viability in a concentration-dependent manner, impairs motility, and decreases tyrosinase and MITF amounts. Moreover, the analyzed drugs decrease/increase MITF amount depending on the type of melanoma. We demonstrated that the decrease of MITF and tyrosinase protein induces motility inhibition of C32 cells, which suggests the ability of those drugs to restore cancer cell sensitivity to treatment. The ability of prochlorperazine to contain the spread of the amelanotic melanoma in vivo may be helpful in the development of a new and effective antimelanoma therapies.

Postoperative nausea and vomiting in patients undergoing colorectal surgery within an institutional enhanced recovery after surgery protocol: comparison of two prophylactic antiemetic regimens.

BACKGROUND: Enhanced recovery protocols (ERP) provide optimal perioperative care for surgical patients. Postoperative nausea and vomiting (PONV) is common after colorectal surgery (CRS). We aim to compare the efficacy of aprepitant to a cost-effective alternative, perphenazine, as components of triple antiemetic prophylaxis in ERP patients. METHODS: Patients who underwent ERP CRS at a single institution from July 2015 to July 2017 were evaluated retrospectively. Only subjects who received aprepitant (Group 1) or perphenazine (Group 2) preoperatively for PONV prophylaxis were included. Patient characteristics, simplified Apfel PONV scores, perioperative medications, and PONV incidence were compared between the groups. PONV was defined as the need for rescue antiemetics on postoperative days (POD) 0-5. RESULTS: Five hundred ninety-seven patients underwent CRS of which 498 met the inclusion criteria. Two hundred thirty-one (46.4%) received aprepitant and 267 (53.6%) received perphenazine. The incidence of early PONV (POD 0-1) was comparable between the two groups: 44.2% in Group 1 and 44.6% in Group 2 (P = 0.926). Late PONV (POD 2-5) occurred less often in Group 1 than Group 2, respectively (35.9% vs. 45.7%, P = 0.027). After matching the groups for preoperative, procedural, and anesthesia characteristics (164 pairs), no difference in early or late PONV could be demonstrated between the groups. CONCLUSIONS: The incidence of PONV remains high despite most patients receiving three prophylactic antiemetic medications. Perphenazine can be considered a cost-effective alternative to oral aprepitant for prophylaxis of PONV in patients undergoing CRS within an ERP.

Perphenazine and prochlorperazine induce concentration-dependent loss in human glioblastoma cells viability.

Phenothiazine derivatives possess biological properties very useful for cancer therapy, such as antiemetic and sedative activity as well as good blood-brain barrier permeability. Our goal was to determine if perphenazine and prochlorperazine are possessing cytotoxic activity towards U87-MG cells. It has been shown that the analyzed drugs induce concentration-dependent loss in cell viability, what correlates with their chemical structure. The calculated EC50 values for perphenazine (0.98 µM) and prochlorperazine (0.97 µM) are related to their toxic concentrations in human plasma. The obtained results suggest that perphenazine and prochlorperazine may have a potential for the development of new and effective anticancer therapies.

Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

PURPOSE: Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients. METHODS: In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable. RESULTS: Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points. CONCLUSIONS: A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.

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.

Amorphous nanoparticle complex of perphenazine and dextran sulfate as a new solubility enhancement strategy of antipsychotic perphenazine.

OBJECTIVE: The objective of this study is to develop a new solubility enhancement strategy of antipsychotic drug - perphenazine (PPZ) - in the form of its amorphous nanoparticle complex (or nanoplex) with polyelectrolyte dextran sulfate (DXT). SIGNIFICANCE: Poor bioavailability of PPZ necessitated the development of fast-dissolving PPZ formulations regardless of delivery routes. Existing fast-dissolving formulations, however, exhibited low PPZ payload. The high-payload PPZ-DXT nanoplex represents an attractive fast-dissolving formulation, as dissolution rate is known to be proportional to payload. METHODS: The nanoplex was prepared by electrostatically driven complexation between PPZ and DXT in a simple process that involved only ambient mixing of PPZ and DXT solutions. We investigated the effects of key variables in drug-polyelectrolyte complexation (i.e. pH and charge ratio RDXT/PPZ) on the physical characteristics and preparation efficiency of the nanoplex produced. Subsequently, we characterized the colloidal and amorphous state stabilities, dissolution enhancement, and supersaturation generation of the nanoplex prepared at the optimal condition. RESULTS: The physical characteristics of nanoplex were governed by RDXT/PPZ, while the preparation efficiency was governed by the preparation pH. Nanoplex having size of ≈80 nm, zeta potential of ≈(-) 60 mV, and payload of ≈70% (w/w) were prepared at nearly 90% PPZ utilization rate and ≈60% yield. The nanoplex exhibited superior dissolution than native PPZ in simulated intestinal juice, resulting in high and prolonged apparent solubility with good storage stabilities. CONCLUSIONS: The simple yet efficient preparation, excellent physical characteristics, fast dissolution, and high apparent solubility exhibited by the PPZ-DXT nanoplex established its potential as a new bioavailability enhancement strategy of PPZ.

NNMT Silencing Activates Tumor Suppressor PP2A, Inactivates Oncogenic STKs, and Inhibits Tumor Forming Ability.

Purpose: To identify potential molecular hubs that regulate oncogenic kinases and target them to improve treatment outcomes for glioblastoma patients.Experimental Design: Data mining of The Cancer Genome Atlas datasets identified nicotinamide-N-methyl transferase (NNMT) as a prognostic marker for glioblastoma, an enzyme linked to the reorganization of the methylome. We tested our hypothesis that NNMT plays a crucial role by modulating protein methylation, leading to inactivation of tumor suppressors and activation of oncogenes. Further experiments were performed to understand the underlying biochemical mechanisms using glioblastoma patient samples, established, primary, and isogenic cells.Results: We demonstrate that NNMT outcompetes leucine carboxyl methyl transferase 1 (LCMT1) for methyl transfer from principal methyl donor SAM in biological systems. Inhibiting NNMT increased the availability of methyl groups for LCMT1 to methylate PP2A, resulting in the inhibition of oncogenic serine/threonine kinases (STK). Further, NNMT inhibition retained the radiosensitizer nicotinamide and enhanced radiation sensitivity. We have provided the biochemical rationale of how NNMT plays a vital role in inhibiting tumor suppressor PP2A while concomitantly activating STKs.Conclusions: We report the intricate novel mechanism in which NNMT inhibits tumor suppressor PP2A by reorganizing the methylome both at epigenome and proteome levels and concomitantly activating prosurvival STKs. In glioblastoma tumors with NNMT expression, activation of PP2A can be accomplished by FDA approved perphenazine (PPZ), which is currently used to treat mood disorders such as schizophrenia, bipolar disorder, etc. This study forms a foundation for further glioblastoma clinical trials using PPZ with standard of care treatment. Clin Cancer Res; 23(9); 2325-34. ©2016 AACR.

Electrospun fibers as potential carrier systems for enhanced drug release of perphenazine.

Solubility represents an important challenge for formulation of drugs, because the therapeutic efficacy of a drug depends on the bioavailability and ultimately on its solubility. Low aqueous solubility is one of the main issues related with formulation design and development of new molecules. Many drug molecules present bioavailability problems due to their poor solubility. For this reason there is a great interest in the development of new carrier systems able to enhance the dissolution of poorly water-soluble drugs. In this work, fibers containing an insoluble model drug and prepared by an electrospinning method, are proposed and evaluated to solve this problem. Two hydrophilic polymers, polyvinylpyrrolidone (Plasdone® K29/32) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used to increase the water solubility of perphenazine. The physico-chemical characterization suggests that the drug loaded in the fibers is in the amorphous state. Both polymeric carriers are effective to promote the drug dissolution rate in water, where this active pharmaceutical ingredient is insoluble, due to the fine dispersion of the drug into the polymeric matrices, obtained with this production technique. In fact, the dissolution profiles of the fibers, compared to the simple physical mixture of the two components, and to the reference commercial product Trilafon® 8mg tablets, show that a strong enhancement of the drug dissolution rate can be achieved with the electrospinning technique.

Evaluation of NADPH oxidases as drug targets in a mouse model of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and oxidative stress. The aim of this study was to evaluate the involvement of NADPH oxidases (NOX) in the oxidative damage and progression of ALS neuropathology. We examined the pattern of NOX expression in spinal cords of patients and mouse models of ALS and analyzed the impact of genetic deletion of the NOX1 and 2 isoforms as well as pharmacological NOX inhibition in the SOD1(G93A) ALS mouse model. A substantial (10-60 times) increase of NOX2 expression was detected in three etiologically different ALS mouse models while up-regulation of some other NOX isoforms was model-specific. In human spinal cord samples, high NOX2 expression was detected in microglia. In contrast to previous publications, survival of SOD1(G93A) mice was not modified upon breeding with constitutive NOX1 and NOX2 deficient mice. As genetic deficiency of a single NOX isoform is not necessarily predictive of a pharmacological intervention, we treated SOD1(G93A) mice with broad-spectrum NOX inhibitors perphenazine and thioridazine. Both compounds reached in vivo CNS concentrations compatible with NOX inhibition and thioridazine significantly decreased superoxide levels in the spinal cord of SOD1(G93A) mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1(G93A) mice. Thioridazine induced an immediate and temporary enhancement of motor performance (rotarod) but its precise mode of action needs further investigation. Additional studies using specific NOX inhibitors will provide further evidence on the relevance of NOX as drug targets for ALS and other neurodegenerative disorders.

Identification and management of tardive dyskinesia: A case series and literature review.

Tardive dyskinesia (TD) is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking dopamine receptor-blocking agents. The pathophysiology of TD is complex, multifactorial and still not fully understood. Although there is no identified effective and standard treatment for TD, several agents have been tried for the management of this motor disturbance. The aim of this case series is to review the literature in regard to the identification, diagnosis and the treatment of TD with anticholinergics, anticholinergic medication withdrawal, cholinergic agents, botulinum toxin intramuscular injections, tetrabenazine, levetiracetam, propranolol and zolpidem, and to describe one case of TD that responded favorably to clonazepam and two cases of TD that responded favorably to Ginkgo biloba.

PLGA biodegradable nanoparticles containing perphenazine or chlorpromazine hydrochloride: effect of formulation and release.

In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles.

Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: an analysis of the CATIE data.

OBJECTIVE: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia. METHOD: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy-Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/tolerability-Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group. RESULTS: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate. CONCLUSIONS: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001.

Extrapyramidal symptoms following administration of oral perphenazine 4 or 8 mg: an 11-year retrospective analysis.

BACKGROUND: Perphenazine is a treatment option in postoperative nausea and vomiting (PONV) prophylaxis. Chronic administration and high dose are known to cause extrapyramidal system (EPS) dysfunction at a frequency of 8%, but the incidence of acute EPS after a single 4 or 8 mg dose is unknown. OBJECTIVE: A retrospective analysis of patient medication billing data and departmental quality records was performed (January 2001 to 10 July 2012) to identify patients who experienced EPS dysfunction after oral perphenazine. DESIGN: A retrospective analysis. SETTING: Surgical outpatients presenting to any one of 10 hospitals in the area of Pittsburgh, Pennsylvania, USA. PATIENTS: Overall, 45 766 patients received 4 or 8 mg of perphenazine before same-day surgery. MAIN OUTCOME MEASURES: EPS dysfunction was defined as acute dystonia, akathisia or pseudoparkinsonism. Records were reviewed to determine the likely number of reactions to perphenazine, the nature of these reactions and impact on patient care. RESULTS: There were four 'likely' cases of EPS dysfunction, and two 'possible' cases. Five reported events were consistent with akathisia, with the sixth being a dystonic reaction. All six patients had resolution of symptoms, with five receiving intravenous diphenhydramine for treatment. The incidence of EPS dysfunction was 1.3 events per 10 000 patients (95% confidence interval (CI) 0.4 to 3.0, based on six events). All patients who experienced reactions pre-operatively were able to proceed to surgery without complications or delay. One patient required unplanned admission and 3-h observation owing to sedation from diphenhydramine. The incidence of EPS dysfunction after oral perphenazine is low. Reactions that did occur were mild and easily treated. CONCLUSION: Given the infrequent side effects, this single, low dose of perphenazine should be encouraged as a low-risk adjunct to any multimodal PONV prophylaxis regimen, based on the selection criteria described.

Effect of storage on the dissolution rate of a fast-dissolving perphenazine/ß-cyclodextrin complex.

OBJECTIVE: In general, the chemical and physical stability of amorphous cyclodextrin complexes and how storage affects their dissolution rate have not been widely reported. The aim of this study was to evaluate the solid-state stability of a fast-dissolving perphenazine/ß-cyclodextrin (ß-CD) complex, which has been found to be well absorbed after sublingual administration to rabbits. In addition, the dissolution rate of plain ß-CD in crystalline and amorphous forms was determined. METHODS: The amorphous perphenazine/ß-CD complex powders were prepared by spray-drying and freeze-drying, and their stability was examined after storage at 40°C, 75% relative humidity (RH) or at room temperature, 60% RH for up to 82 days. KEY FINDINGS: Perphenazine was found to be chemically stable in all samples. The dissolution rate of perphenazine remained practically unchanged at both storage conditions, although partial crystallization was observed in both spray-dried and freeze-dried samples at 40°C, 75% RH. Interestingly, it was also observed that the dissolution rates of crystalline and amorphous ß-CD were similar. CONCLUSION: The results suggest that CD complexation may represent a suitable alternative for preparing intraorally dissolving formulations because the fast dissolution rate of the drug was maintained even though changes in the crystal structure were observed during storage.

Noninferiority of perphenazine vs. three second-generation antipsychotics in chronic schizophrenia.

Noninferiority analysis is a statistical method of growing importance in comparative effectiveness research that has rarely been used in psychopharmacology. This method is used here to evaluate whether first-generation antipsychotics are clinically not inferior to second-generation antipsychotics (SGAs) using data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). A conservative noninferiority margin (NIM) on the Positive and Negative Syndrome Scale (PANSS) was derived from the smallest published value for the minimal clinically important difference, further reduced by 25%. This NIM was used to assess whether perphenazine is noninferior to olanzapine, risperidone, and quetiapine on the basis of the 95% confidence intervals of differences in mean PANSS outcomes (N = 1049). Perphenazine was noninferior to all three SGAs during 18 months of intention-to-treat analysis and in several subanalyses. Noninferiority can be evaluated from studies designed as superiority trials. Power was available in the CATIE to conduct noninferiority analysis.

Pharmacokinetics of orally disintegrating tablets of perphenazine/hydroxypropyl-beta-cyclodextrin inclusion complex in rabbits.

We investigated the pharmacokinetic behavior of orally disintegrating tablets (ODTs) containing perphenazine/hydroxypropyl-beta-cyclodextrin inclusion complex (PPZ/HP-beta-CD) in rabbits and evaluated their bioequivalence with conventional tablets. In this study, a simple, sensitive and accurate high performance liquid chromatography method was developed for the determination of perphenazine concentration in rabbit plasma. The pharmacokinetic parameters were calculated by non-compartmental methods and the bioequivalence between PPZ/HP-beta-CD ODTs with conventional tablets was determined by calculating 90% confidence interval (CI) for the ratio of logarithmic transformed C(max), AUC(0-t), AUC(0-infinity) values. The pharmacokinetic parameters of test ODTs and reference tablets were as follows: C(max), 82.86 and 62.71 ng/mL; AUC(0-24), 480 and 397.56 ng/mL/h; AUC(0-infinity), 505 and 400.12 ng/mL/h; T(max), 1.04 and 3.83h. The relative bioavailabilities of two formulations for AUC(0-t) and AUC(0-infinity) were 120.77% and 126.37%, respectively. The 90% CI statistical analysis demonstrated the two formulations were not bioequivalence. In conclusion, the ODTs showed faster absorption and higher peak concentration when compared with conventional tablets, which suggests ODTs could be promising oral formulations for PPZ.

Perphenazine suspension: a new, old treatment, side effects and continuous use.

A number of innovative delivery systems for acute antipsychotic pharmacotherapy have been developed over the years which include oral suspensions, rapidly dissolving wafers and acute intramuscular preparations. Currently, the availability of first generation antipsychotic (FGA) formulations is limited to two high potency agents: haloperidol and fluphenazine. At Yale New-Haven Psychiatric Hospital, the hospital pharmacy was able to create perphenazine suspension, a mid-potency FGA, with a record of effectiveness and tolerability that was no worse than that of second generation antipsychotics (SGAs) in the CATIE trial. In this study we compare perphenazine suspension to other first and SGAs in the risk of extrapyramidal reactions and whether or not patients were continued on the same antipsychotic they were started with at the time of discharge. Medical records of patients who received acute pharmacotherapy in a unique form while hospitalized at Yale New Haven Psychiatric Hospital from July 2009 to December 2009 were examined. All data were collected thru a chart review using a form that was created to systematically document experiences. A total of 229 patients were included in the study. There were no significant differences between treatment groups on gender, age, race or diagnosis. In the entire samples 1.75% had pseudo-parkonisnism, 1.31% had acute dystonia, 0.04% had tardive dyskinesia, 1.31% akithesia, and 4.8% any neurological side effects. There were no significant differences between agents in the likelihood of any of these side effects or of having any side effect. Higher use of anticholinergics was found in patients treated with FGAs. We also found that 77% were discharged on the same antipsychotic agent they received when they were initially hospitalized. A wide range of acute oral pharmacoptherapy in non-tablet formulations of first and SGAs should be available in psychiatric hospital formularies. FGAs seems to be as well tolerated as SGAs.

Concomitant psychotropic medication use during treatment of schizophrenia patients: longitudinal results from the CATIE study.

OBJECTIVE: This study is a post hoc analysis of additions of antidepressants, anxiolytics, and sedative/hypnotics in treatment of patients randomized to antipsychotic treatment in the CATIE study, which recruited a chronic, "real world" schizophrenia sample and followed patients for up to eighteen months. We examined baseline predictors of initiation, time until initiation, and duration of treatment with antidepressants, anxiolytics, and sedative/hypnotics in CATIE study participants. METHODS: Psychotropic medication use by 1,449 CATIE study participants was documented at each study visit. Baseline demographic and clinical predictors of initiation, of time to initiation, and of duration of treatment of Concomitant Psychotropic Medications (CPMs) in each category (antidepressant, anxiolytic, and sedative/hypnotics) were identified through multiple regression analyses. RESULTS: Initiation of new CPMs post baseline by CATIE clinicians was moderately frequent, with 14.6% of patients receiving antidepressants, 13.7% receiving anxiolytics, and 11.2% receiving sedative/hypnotics. Predictors of antidepressant initiation (14.6% of group) were being female or white, and having a prior diagnosis of depression or symptoms of depression at baseline. Patients with higher positive symptom scores and younger patients were started on antidepressants sooner. Duration of antidepressant treatment was longer in patients with less education and in those with a history of alcohol abuse/dependence. Predictors of anxiolytic initiation (13.7% of group) were not being of African-American race, being separated/divorced, younger age, higher body mass index, and akathisia. Time to anxiolytic initiation was shorter in patients who were separated or divorced and in patients with better neurocognitive functioning. Duration of anxiolytic treatment was shorter for African Americans and longer in patients with better instrumental role functioning. Predictors of sedative/hypnotic use (11.2% of group) were depressive symptoms and prior diagnosis of an anxiety disorder. Time to initiation of sedative/hypnotics was longer for those with depressive symptoms and shorter for those with a history of alcohol abuse/dependence. CONCLUSIONS: Sedative/hypnotics, anxiolytics, and antidepressants were commonly used CPMs in schizophrenia during the CATIE trial, where patients were being seen frequently and antipsychotic treatment was optimized. Randomized, controlled clinical trials examining adjunctive use of antidepressants, anxiolytics and sedative/hypnotics to target symptoms of anxiety, depression, and insomnia in patients with schizophrenia are needed to adequately address the efficacy of these interventions.