Fluphenazine decanoate-induced bradycardia: A case report.

Sinus tachycardia and orthostatic hypotension have been so far reported among the negative cardiovascular complications of antipsychotic agents. This study aimed to report a case with bradycardia induced by fluphenazine decanoate administration. The patient was a 29-year-old man, admitted to the general teaching hospital in Sari, Iran, with a complaint of abdominal and gastric pain as well as weight loss following 7 months of fasting based on religious delusions. The patient developed bradycardia, 36 hours after fluphenazine decanoate administration. His pulse rate was also 46 beats per min (bpm). The antipsychotic medication was thus held and the patient did not take any drugs. On the 21st day after discontinuing this agent, the pulse rate reached 70 bpm. This case report notifies that much more attention should be paid to all patients before starting fluphenazine decanoate administration, and close cardiac monitoring must be done.

The effect of fluphenazine decanoate on glucocorticoid production, reproductive cyclicity, and the behavioral stress response in the Persian onager (Equus hemionus onager).

Artificial insemination, performed to maximize genetic diversity in populations of zoo-housed animals, requires intensive management and has been associated with low success rates in fractious species. In these species, stressors, such as frequent handling, may impact fertility. Long-acting neuroleptic pharmaceuticals (LANs) can attenuate the stress response to handling, but may also disrupt ovulation in some species, compromising their use for artificial insemination. Therefore, the goal of this study was to determine whether LANs may be used to mitigate stress during reproductive management in wild equids without inhibiting ovulation. Six female Persian onagers (Equus hemionus onager) were treated with fluphenazine decanoate (FD; 0.1 mg/kg IM) or saline control in a random crossover design study. Urinary cortisol, progesterone, estrogen metabolites and behavior were monitored, and follicular dynamics were examined using ultrasonography until ovulation. Onagers demonstrated significantly lower cortisol concentrations (P = 0.03) when treated with FD (6.61 ± 3.26 ng/mg creatinine) compared to saline (9.73 ± 3.19 ng/mg creatinine). Overall, there were no differences in peak estrogen (P = 0.51) or progesterone (P = 0.38) concentrations between the two groups, and all animals ovulated within the expected time frame following FD treatment. However, some onagers exhibited only minor reductions in cortisol secretion and one treated female demonstrated a suppressed luteal progesterone peak, indicating a possible reproductive cost to FD administration. While FD may be useful for highly fractious equids for which the stress of handling delays or inhibits ovulation, these results warrant further investigation of dosing.

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.

Synthesis, pro-apoptotic activity and 2D-QSAR studies of new analogues of fluphenazine.

A series of 10 novel analogues of fluphenazine (FPh) were synthesized. Influence of the synthesized analogues of FPh on frequency of apoptosis and necrosis in cultures of human lymphocytes genotoxically damaged in vitro with benzo[a]pyrene (B[a]P; 7,5 microM, 48 h) was compared with the effect of FPh. Activity of the tested compounds was expressed by ED50 (pro-apoptotic activity) and TD50 (pro-necrotic effect, cytotoxicity). It was noticed that compounds 3-9 and 12 exerted a pro-apoptotic effect markedly stronger than that of FPh. Additionally, compounds 3, 9 and 10 exhibited the weakest influence on frequency of necrotic lymphocyte in cultures. 2D-QSAR analysis was done in order to find quantitative relationship between structures of the tested analogues and their pro-apoptotic activity or pro-necrotic effect in B[a]P-damaged cell cultures. Several statistically significant QSAR models were generated. Information obtained from 2D-QSAR study will be used in further design of analogues of FPh more active in cancer chemoprevention.

Long-acting neuroleptic use for reproductive management of non-domestic ungulates using the domestic goat (Capra hircus) as a model.

Fluphenazine decanoate is a long-acting phenothiazine neuroleptic that attenuates the stress response and may be useful during intensive handling for reproductive procedures in non-domestic ungulates. However, phenothiazines are also associated with elevated serum prolactin, which can suppress fertility in some species. For this study, 10 female domestic goats were used as a model for non-domestic caprids to test effects of fluphenazine decanoate on serum cortisol and reproductive cyclicity following estrus synchronization. Two identical trials were conducted during the breeding season, employing a random crossover design. First, females underwent estrus synchronization using a 14-day treatment with progesterone (330 mg; CIDR). After 7 days of CIDR exposure, the treatment group (n = 5) received fluphenazine decanoate (1.0 mg/kg IM) and controls (n = 5) received an equivalent volume of 0.9% saline IM. At CIDR withdrawal (Day 14), animals received 125 mg cloprostenol sodium to lyse any luteal tissue and synchronize estrus. Blood was collected every 2 hr from 36 hr after CIDR withdrawal until 24 hr after standing estrus, or up to 5 days to monitor stress and reproductive hormones. Serum cortisol, prolactin, luteinizing hormone (LH) and progesterone concentrations were determined by enzyme immunoassay. While treatment with fluphenazine was associated with lower cortisol concentrations compared to controls (P = 0.001), 4 of the 10 treated animals experienced elevated serum prolactin, suppression of the LH surge and inhibition of ovulation. These findings suggest that long-acting neuroleptic drugs reduce the adrenal stress response, but may interfere with reproductive responses and negatively influence breeding success.

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.

Quantitation of fluphenazine in equine serum following fluphenazine decanoate administration.

Fluphenazine, a potent antipsychotic used to treat schizophrenia in humans, is used in racehorses as a performance-enhancing drug, and for that reason it has been banned by the Association of Racing Commissioners International. A liquid chromatography-tandem mass spectrometry method for detecting and quantitating fluphenazine in equine serum was developed and validated. The method was then employed to quantitate fluphenazine in serum samples collected from three study horses after intramuscular injection of fluphenazine decanoate. Stability testing showed that fluphenazine is stable in unextracted and processed samples as well as samples that have been subjected to up to three freeze-thaw cycles. The limit of detection and lower limit of quantitation of fluphenazine were determined to be 0.05 and 0.1 ng/mL, respectively. Precision was evaluated based on one-way analysis of variance of replicate quality control samples and was determined to be 27.2% at the 0.2 ng/mL level and 18.1% at the 2 ng/mL level. Bias was determined to be 0.55% at the 0.2 ng/mL level and 3.66% at the 2 ng/mL level. In two of three horses, fluphenazine was detected in serum up to 14 days post-administration. The highest detected concentration of fluphenazine in serum was 1.4 ng/mL.

Effect of Hypericum perforatum on different models of movement disorders in rats.

The effects of Hypericum perforatum, a plant with antidepressant action, were evaluated in models of abnormal movements in rats, brought about by administration of fluphenazine or reserpine. The number of vacuous chewing movements (VCMs) and locomotor activity (the number of crossings and rears in the open field test) were measured. In experiment 1, rats received a single administration of fluphenazine enanthate (25 mg/kg, intramuscular) and/or daily treatment with H. perforatum (300 mg/kg, in place of drinking water) for 7 days. Fluphenazine increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the locomotor activity. In experiment 2, rats received reserpine every 2 days for 6 days (0.5 mg/kg, subcutaneous) and/or H. perforatum (300 mg/kg, in place of drinking water) daily for 16 days beginning 10 days before the first administration of reserpine. Reserpine treatment increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the number of rears but did prevent the effect of reserpine on the number of crossings. In conclusion, H. perforatum failed to protect against orofacial movements induced by fluphenazine or reserpine in rats.

Ten year outcomes of outpatients with schizophrenia on conventional depot antipsychotics: a systematic chart review.

Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean±SD, age 44.0±13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia.

Adherence challenges and long-acting injectable antipsychotic treatment in patients with schizophrenia.

Medication nonadherence has been associated with persistence of psychotic symptoms, relapse, and hospitalization in patients with schizophrenia. Patients with untreated psychosis are significantly less likely to achieve remission, whereas antipsychotic drug adherence has been associated with recovery. As such, adherence to antipsychotic drug treatment is a key issue for nurses and treatment team members caring for patients who typically are on chronic, progressive disease course. Long-acting injectable (LAI) anti-psychotic drugs, developed to improve adherence and provide and alternative antipsychotic drug treatment fro schizophrenia, have been associated with improved treatment outcomes including reduction of relapse rates approximately 30% and reduction in hospitalizations. However, LAI antipsychotic drugs remain underutilized in the United States despite a growing body of literature supporting positive outcomes of LAI versus oral antipsychotic drugs. Mental health nurses are in a key position to support improved adherence inpatients with schizophrenia through use of practical educational strategies that help patients, family members, and health care providers better understand and manage treatment.

Adherence to depot versus oral antipsychotic medication in schizophrenic patients during the long-term therapy.

BACKGROUND/AIM: There is a high rate of schizophrenic patients who do not adhere to their prescribed therapy, despite the implementation of antipsychotic long-acting injections and the introduction of atypical antipsychotics. The aim of this study was to investigate the differences in sociodemographic, clinical and medication adherence variables between the two groups of schizophrenic patients on maintenance therapy with depot antipsychotic fluphenazine decanoate and oral antipsychotics only as well as a correlation between the medication adherence and other examined variables. METHODS: A total of 56 patients of both genders, aged < 60 years, with the diagnosis of schizophrenia (F20) (ICD-10, 1992) clinically stable for at least 6 months were introduced in this cross-sectional study. The patients from the depot group (n = 19) were on classical depot antipsychotic fluphenazine decanoate administering intramuscularly every 4 weeks (with or without oral antipsychotic augmentation) and the patients from the oral group (n = 37) were on oral therapy alone with classical or atypical antipsychotics, either as monotherapy or combined. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Item G12 of the PANSS was used to assess insight into the illness. The patients completed the Medical Adherence Rating Scale (MARS) was used to assess adherence to the therapy. A higher MARS score indicates behavior [Medical Adherence Questionnaire (MAQ subscale)] and attitudes toward medication [Drug Attitude Inventory (DAI subscale)] that are more consistent with treatment adherence. The exclusion criteria were determined. The Pearson's chi2 test was used to compare categorical variables, Student's t-test to compare continuous variables and Pearson's correlation to test the correlation significance; p = 0.05. RESULTS: Significant between-group differences in age, illness duration, chlorpromazine equivalents, PANSS score and DAI subscore were found. Item G12 of the PANSS subscore and MARS score correlated significantly negatively. A significant positive correlation between receiving depot antipsychotic and DAI subscore as well as between illness duration and both DAI subscore and MARS score were also found. CONCLUSION: Schizophrenic patients on classical depot antipsychotic maintenance therapy might present subpopulation of patients with significantly longer illness duration, more favorable medication attitude and outcome in relation to those on oral antipsychotics alone.

[Tardive dyskinesia induced by classical antipsychotic drugs: a Tunisian sample of schizophrenics]. / Dyskinésies tardives sous neuroleptiques classiques: à propos d'une population tunisienne de schizophrènes.

INTRODUCTION: The term tardive dyskinesia (TD) is used to describe abnormal movement, primarily associated with typical antipsychotic drugs, which are used to treat psychotic states such as schizophrenia. TD is characterised by repetitive involuntary purposeless muscle contractions that force parts of the body into abnormal, and sometimes painful, movements or postures. These movements are involuntary and are difficult or impossible to control. TD usually begins with the face, mouth, lips and tongue, and includes grimacing, lip-smacking, tongue movements and rapid blinking. It may also involve the rest of the body and produce involuntary gestures, tics and writhing movements. TD is severe physically and socially disabling. Schizophrenia is thought to be the psychiatric diagnosis the most frequently associated with TD. MATERIALS AND METHODS: The purpose of this article is to study the characteristics of TD in a Tunisian sample of 157 schizophrenics. A variety of demographic and clinical information was obtained by a questionnaire. Diagnoses of schizophrenia and TD were determined by using DSM-VI-R criteria. TD was assessed using the Abnormal Involuntary Movements Scale (AIMS). RESULTS: The average age in this sample was 37 ± 6 years. The intermediate duration of evolution of the disease was 8 ± 3 years with a medium full number of hospitalizations of 4 ± 3. We found 58% of the paranoid sub-type. The intermediate duration of exposure to classical neuroleptics was 7 ± 3 years. The average of daily neuroleptic amount was 572.9 ± 145.3 equivalent milligrams of chlorpromazine. Extended release antipsychotics were used in 64.3% of cases, with fluphenazine deaconate in 90% and haloperidol deaconate in 10%. Anticholinergics were used by 74.5% of patients, with use of biperidene in 96% of cases. Therapeutic observance was good in 89.2% of patients. The prevalence of TD was an estimated 35%. The average of AIMS score was 17 ± 9, with a minimal score of 3 and a maximal one of 34. The distribution of patients according to severity found a prevalence of 52.7% of subjects with moderate TD, 38.2% with light TD and 9.1% with severe TD. The distribution of patients according to type, according to DSM-IV criteria, found 78.4% of cases with choreiform TD, 17.5% of cases with athetosic TD and 4.1% of cases with rhythmic TD. The intermediate duration of evolution of TD was estimated at 18 ± 6 months with a minimal duration of 3 months and a maximum of 72 months. The distribution of subjects according to duration of evolution of TD found that approximately three quarter of patients presented with TD that had evolved since one duration, lower or equal to one year. The average age of patients at the moment of installation of TD was estimated at 36 ± 6 years with 22 years as a minimal and 46 years as a maximal age. Among them, 81.8% of patients were aged over 30 at the time of the installation of TD. CONCLUSION: The majority of patients with schizophrenia in Tunisia are still treated with typical antipsychotic drugs, and that's why the prevalence of TD remains relatively high.

Potentiating effect of fluphenazine decanoate and risperidone on development of neuroleptic malignant syndrome.

We present the case of a woman with paranoid schizophrenia who was receiving oral risperidone. She developed neuroleptic malignant syndrome (NMS) following the addition of depot fluphenazine for the treatment of refractory delusions. NMS subsided and psychotic features were controlled after both antipsychotics were discontinued and the patient was treated instead with olanzapine.

The challenge of patients with severe psychiatric illness who do not access care - a way forward.

Psychiatric illnesses are a significant cause of morbidity all over the world. In India many people with mental disorders are unable to access psychiatric care for a variety of reasons. This article describes the successful management of a person with schizophrenia in the community through a primary care team in liaison with psychiatrist services.

Treatment of schizophrenia with depot preparations of fluphenazine, haloperidol, and risperidone among inpatients at state-operated psychiatric facilities.

BACKGROUND: This study aimed to characterize the inpatient utilization of depot antipsychotics. METHOD: The characteristics of adults with schizophrenia or schizoaffective disorder, hospitalized for at least 28 days, and who were prescribed depot antipsychotics were examined from 2004 to 2006 using a database from a large state-operated psychiatric hospital system. Demographic and clinical characteristics of patients receiving depot fluphenazine or haloperidol were compared to those prescribed depot risperidone. RESULTS: We identified 2210 unique patients who initiated treatment with a depot antipsychotic (after receiving oral antipsychotics). Of these, 1484 (67.1%) received depot fluphenazine or haloperidol, and 726 (32.9%) received risperidone as their initial depot antipsychotic. Patients who received depot risperidone did not differ from those receiving depot fluphenazine or haloperidol with regard to demographics, diagnosis of schizoaffective disorder, number of comorbid psychiatric or medical diagnoses, or diagnosis of substance abuse. Patients started on depot risperidone during the observation period had a longer length of stay prior to initiation of depot than those started on depot fluphenazine or haloperidol (583 days vs. 237 days, t=5.489, p<.001). Patients who started on depot risperidone were less likely to be discharged on that medication than were patients who started on depot fluphenazine or haloperidol (odds ratio from Cox regression model=0.846 [95% CI 0.745-0.960]). CONCLUSIONS: Patients initiated on depot risperidone had a longer length of stay prior to their first injection and were less likely to be discharged on that medication compared to patients initiated on depot fluphenazine or haloperidol, possibly indicating that patients initiating depot risperidone had a more severe or treatment-resistant course of illness and/or that there were reimbursement barriers for the outpatient utilization of depot risperidone, or that efficacy differences exist between the depot antipsychotics at the doses used in this population.

Stimulation of neuronal KATP channels by cGMP-dependent protein kinase: involvement of ROS and 5-hydroxydecanoate-sensitive factors in signal transduction.

The ATP-sensitive potassium (K(ATP)) channel couples intracellular metabolic state to membrane excitability. Recently, we demonstrated that neuronal K(ATP) channels are functionally enhanced by activation of a nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) signaling cascade. In this study, we further investigated the intracellular mechanism underlying PKG stimulation of neuronal K(ATP) channels. By performing single-channel recordings in transfected HEK293 and neuroblastoma SH-SY5Y cells, we found that the increase of Kir6.2/SUR1 (i.e., the neuronal-type K(ATP)) channel currents by PKG activation in cell-attached patches was diminished by 5-hydroxydecanoate (5-HD), an inhibitor of the putative mitochondrial K(ATP) channel; N-(2-mercaptopropionyl)glycine, a reactive oxygen species (ROS) scavenger, and catalase, a hydrogen peroxide (H(2)O(2))-decomposing enzyme. These reagents also ablated NO-induced K(ATP) channel stimulation and prevented the shifts in the single-channel open- and closed-time distributions resulting from PKG activation and NO induction. Bath application of H(2)O(2) reproduced PKG stimulation of Kir6.2/SUR1 but did not activate tetrameric Kir6.2LRKR368/369/370/371AAAA channels. Moreover, neither the PKG activator nor exogenous H(2)O(2) was able to enhance the function of K(ATP) channels in the presence of Ca(2+) chelators and calmodulin antagonists, whereas the stimulatory effect of H(2)O(2) was unaffected by 5-HD. Altogether, in this report we provide novel evidence that activation of PKG stimulates neuronal K(ATP) channels by modulating intrinsic channel gating via a 5-HD-sensitive factor(s)/ROS/Ca(2+)/calmodulin signaling pathway that requires the presence of the SUR1 subunit. This signaling pathway may contribute to neuroprotection against ischemic injury and regulation of neuronal excitability and neurotransmitter release by modulating the function of neuronal K(ATP) channels.

Calmodulin inhibition contributes to sensitize TRAIL-induced apoptosis in human lung cancer H1299 cells.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells. However, TRAIL alone is not effective in treating TRAIL-resistant tumors. We evaluated the effect of 180 enzyme inhibitors on TRAIL-induced apoptosis in human lung cancer H1299 cells, and found fluphenazine-N-2-chloroethane (a calmodulin (CaM) antagonist) sensitized TRAIL-induced apoptosis. Interestingly, in the presence of TRAIL, it increased caspase-8 binding to the Fas-associated death domain (FADD), but decreased binding of FADD-like interleukin-1beta-converting enzyme inhibitory proteins (FLIPs). Additionally, its combination with TRAIL inhibited Akt phosphorylation. These results were consistently observed in cells treated with CaM siRNA. We suggested the blockade of CaM could sensitize lung cancer cells to TRAIL-induced apoptosis in at least 2 ways: (i) it can activate death-inducing signaling complex mediated apoptosis by inhibiting TRAIL-induced binding of FLIP and TRAIL-enhanced binding of caspase-8 to FADD; (ii) it can inhibit Akt phosphorylation, consequently leading to decreased expression of anti-apoptotic molecules such as FLIP and members of the inhibitor of apoptosis protein family. This study suggests the combination of CaM antagonists with TRAIL may have the therapeutic potential to overcome the resistance of lung cancers to apoptosis.

Use of aripiprazole in tardive dyskinesia: an open label study of six cases.

Aripiprazole, a partial dopamine agonist has been reported to help reduce symptoms of tardive dyskinesia (TD). In a prospective, open label study of a series of cases, we examined the effectiveness of aripiprazole in reducing TD symptoms. Six clinically stable patients with schizophrenia or Schizoaffective disorder and a moderate to severe TD participated in this study. They were systematically cross-titrated from their current medication to aripiprazole and maintained for 16 weeks. The mean extra pyramidal symptom score measured by Abnormal Involuntary Movement Scale (AIMS) improved from a baseline score of 15.8 to final score of 5 (paired t-test; P=0.0009). The severity of psychiatric symptoms remained unchanged. This study supports our hypothesis that clinically stable patients with moderate tardive dyskinesia who are under treatment with other first- or second-generation antipsychotics may benefit from switching to aripiprazole with a reduction of TD symptoms but with out any significant benefit in psychiatric symptoms. The results need to be viewed with caution and not considered as indicative of a viable treatment option for TD as this is an open label study, and a small sample size.