N -N-Butyl Haloperidol Iodide Mitigates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1-Nrf2 Signaling Loop.

ABSTRACT: N -n-butyl haloperidol iodide (F 2 ), a derivative of haloperidol developed by our group, exhibits potent antioxidative properties and confers protection against cardiac ischemia/reperfusion (I/R) injury. The protective mechanisms by which F 2 ameliorates I/R injury remain obscure. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor transactivating many antioxidative genes, also attenuates I/R-induced myocardial damage. The present study investigated whether the cardioprotective effect of F 2 depends on Nrf2 using a mouse heart I/R model. F 2 (0.1, 0.2 or 0.4 mg/kg) or vehicle was intravenously injected to mice 5 minutes before reperfusion. Systemic administration of 0.4 mg/kg F 2 led to a significant reduction in I/R injury, which was accompanied by enhanced activation of Nrf2 signaling. The cardioprotection conferred by F 2 was largely abrogated in Nrf2-deficient mice. Importantly, we found F 2 -induced activation of Nrf2 is silent information regulator of transcription 1 (SIRT1)-dependent, as pharmacologically inhibiting SIRT1 by the specific inhibitor EX527 blocked Nrf2 activation. Moreover, F 2 -upregulated expression of SIRT1 was also Nrf2-dependent, as Nrf2 deficiency inhibited SIRT1 upregulation. These results indicate that SIRT1-Nrf2 signaling loop activation is indispensable for the protective effect of F 2 against myocardial I/R injury and may provide new insights for the treatment of ischemic heart disease.

Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors.

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.

N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice.

N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2 (0.75, 1.5 or 3 mg·kg-1·d-1, ip) for 4 weeks of fibrosis induction. We showed that F2 administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-ß receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-ß1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2 (0.1, 1, 10 µM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2 inhibited TGF-ß/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-ß signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-ß1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-ß signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-ß signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-ß1. F2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

SYA 013 analogs as moderately selective sigma-2 (σ2) ligands: Structure-affinity relationship studies.

Several lines of evidence suggest that selective sigma-2 (σ2) ligands might be useful for the treatment of solid tumors. However, very few selective σ2 ligands have been identified. This study was aimed at identifying new selective σ2 receptor ligands using a previously identified agent, SYA 013 as a lead. Four groups, homopiperazine, piperazine, tropane and selected oxime analogs of the homopiperazines were identified, synthesized and subsequently screened at the σ1 and σ2 receptors. The results demonstrate that these scaffolds can be modified to obtain selective σ2 receptor ligands. 1-(5-Chloropyridin-2-yl)-4-(3-((4-fluorophenyl)thio)propyl)-1,4-diazepane, 7 and 3-(4-chlorophenyl)-8-(3-((2-fluorophenyl)thio)propyl)-8-azabicyclo[3.2.1]octan-3-ol, 21 were identified as the highest binding affinity ligands (σ2Ki = 2.2 nM) and (4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-butan-1-one oxime, 22 as a high affinity and the most selective ligand for the σ2 receptor (σ1Ki/σ2Ki = 41.8).

New analogs of SYA013 as sigma-2 ligands with anticancer activity.

Our previous study has revealed 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one·2HCl (SYA013) 1 as a sigma ligand with moderate selectivity for the sigma-2 receptor. Given the overexpression of sigma receptors in solid tumors and reports of sigma ligands with anticancer activities, we selected 1 for evaluation in several solid tumor cell lines. In addition, we have synthesized new analogs of 1 and now report that several of them bind preferentially at the sigma-2 receptor and have shown inhibition of several cancer cell lines including MDA-MB-231, MDA-MB-486, A549, PC-3, MIA PaCa-2 and Panc-1 cells. In particular, compounds 1 and 12 have demonstrated sub-micromolar activity against the Panc-1 cell line. It has also been observed that several of these compounds demonstrate selective toxicity toward cancer cells, when compared to normal cells.

Real-life persistence of long-acting injectable antipsychotics in schizophrenic patients: A retrospective observational study in France
.

OBJECTIVE: Antipsychotics exhibit different profiles of efficacy and safety in patients with schizophrenia. It has recently been reported that the risk of rehospitalization was the lowest with paliperidone palmitate (PP), a long-acting injectable (LAI), when compared with other LAIs (of zuclopenthixol, perphenazine, and olanzapine). We aimed to investigate whether treating patients with PP was also associated with improved real-life treatment persistence. MATERIALS AND METHODS: We conducted a retrospective observational study of the LAI antipsychotics (LAIAs) dispensed in French retail pharmacies. Treatment persistence was defined as the non-discontinuation of LAIAs for ≥ 5 months after LAIA initiation (and was also analyzed by Kaplan-Meier persistence curves). RESULTS: A total of 4,492 patients were included in the study. The persistence rate was significantly greater for LAI-PP (64.5%) than for either LAI haloperidol decanoate (HD) or LAI risperidone microspheres (R) (46.4% and 35.4%, respectively). Multivariate Cox analyses illustrated that LAIA initiation with HD or R significantly increased the risk of discontinuation when compared with PP. CONCLUSION: PP demonstrated a significantly higher persistence rate than HD or R. Moreover, LAIA initiation with HD or R significantly increased the risk of treatment discontinuation relative to PP. Further comparative studies are required to comprehensively determine whether PP has a better efficacy and/or safety profile than other LAIs.

In silico repurposing of antipsychotic drugs for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. RESULT: A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule. CONCLUSION: The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Potent haloperidol derivatives covalently binding to the dopamine D2 receptor.

The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.

An acute oral intoxication with haloperidol decanoate.

Haloperidol decanoate is a typical antipsychotic drug used as maintenance therapy for schizophrenia and mood disorders formulated as an ester for intramuscular injection. Cases of oral haloperidol decanoate intoxications have not been described in literature. In this report, we present for the first time a case of an oral ingestion of haloperidol decanoate of a young woman who presented to the emergency department following an intentional oral ingestion of 1 ampoule of haloperidol decanoate 100mg. At presentation, she had a bilateral rest tremor of both hands and mild hypothermia. No other obvious signs of an intoxication were observed. She was treated with a single dose of activated charcoal and laxative and was admitted to the intensive care for rhythm monitoring and observation. During the night the QTc interval increased to 453ms, but stayed within the normal range. Haloperidol plasma levels increased as well, but also stayed within therapeutic ranges. These findings indicate that treatment with oral activated charcoal was sufficient to prevent any serious events.

Depot antipsychotics: Where do we stand?

BACKGROUND: Nonadherence to medication is a major problem for patients with schizophrenia. To counter this problem, pharmaceutical companies began developing depot antipsychotics. Although there are currently 5 first-generation and 6 second-generation depot antipsychotics available worldwide, many physicians are still reluctant to use this category of drug initially. This review provides the latest information about the use of depot antipsychotics in schizophrenia treatment as well as several studies in support of depot antipsychotic use as first-line treatment for patients with schizophrenia. METHODS: A systematic review of 4 milestone schizophrenia studies was performed to provide an aggregate analysis of the history and use of depot antipsychotics. Results and findings from several clinical trials--the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), European First Episode Schizophrenia Trial (EUFEST), A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS), and Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE)--were summarized to provide more information on the development and evolution of depot antipsychotics, common factors that contribute to nonadherence, and guidelines for each long-acting injectable currently available. RESULTS: The CATIE schizophrenia study revealed a 74% rate of discontinuation of oral antipsychotics within 6 months of use. Similar findings from the EUFEST study indicated that 42% of participants discontinued oral medications after 12 months of use. The ACLAIMS study reported no statistically significant difference in efficacy failure rate between haloperidol decanoate and paliperidone palmitate. The PRIDE study found that first hospitalization or arrest was 43% higher among patients in the oral antipsychotic group vs the depot group during the study. CONCLUSIONS: This review provides clinical evidence to support the use of depot formulations as first-line treatment for patients with schizophrenia, which may improve adherence and thereby lower risk of relapse, suicide, rehospitalization, and incarceration.

Vitamin E and essential polyunsaturated fatty acids supplementation in schizophrenia patients treated with haloperidol.

OBJECTIVES: Previously, oxidative damage has been associated with severity of clinical symptoms and supplementation with antioxidants and essential polyunsaturated fatty acids (EPUFAs) was proposed to have beneficial effects in schizophrenia. We evaluated the effects of supplementation with EPUFAs and vitamin E in patients treated with haloperidol depot injection. DESIGN: This was a double-blind randomized placebo-controlled study with four arms (Placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were assessed at baseline and after 4 months. RESULTS: In EPUFAs group of patients, reduced glutathione concentration was increased compared to placebo. Concentration of oxidized glutathione was decreased in patients receiving vitamin E. In addition, compared to placebo a non-significant trend of increased activity of catalase and superoxide dismutase was observed in all three treatment groups. Patients receiving vitamin E experienced less motor retardation. No difference in extrapyramidal symptoms was found. DISCUSSION: Our study indicates that supplementation with vitamin E and EPUFAs may improve the antioxidative defense, especially glutathione system, while there is no major effect on symptoms severity. Supplemental treatment with EPUFAs and vitamin E in schizophrenia patients treated with haloperidol is potentially beneficial and a larger independent study appears warranted.

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives.

The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing.

The effectiveness of psychoeducational family intervention for patients with schizophrenia in a 14-year follow-up study in a Chinese rural area.

BACKGROUND: It is unclear if the impact of psychoeducational family intervention for patients with schizophrenia can be sustained over 10 years. In this study, we explored the 14-year effect of psychoeducational family intervention for patients with schizophrenia in a Chinese rural area. METHOD: The data from a cluster randomized control trial (CRCT) study of psychoeducational family intervention in a 14-year follow-up was analyzed. All patients with schizophrenia (n = 326) who participated in the CRCT drawn from six townships in Xinjin County of Chengdu in 1994, of whom 238 (73.0%) who were still alive, and their informants were followed up in 2008. The Patients Follow-up Scale, the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning were used in the follow-up study. RESULTS: There were no significant differences of marital status, mean scores of PANSS positive symptoms, negative symptoms, general mental health, and total scores among the psychoeducational family intervention, medication, and control groups in 2008. The psychoeducational family intervention group had a significantly higher rate of antipsychotic medication and a higher level of work ability than other two groups. The control group had a significantly higher rate of never-treated (26.0%) than psychoeducational family intervention group (6.5%). CONCLUSION: Psychoeducational family intervention might be still effective in the 14-year follow-up, especially in patients' treatment adherence/compliance and social functioning. Psychoeducational family intervention might be more effective in places where family members frequently participated in patients' care and had a lower level of knowledge on mental illness. Family intervention should be considered when making mental health policy and planning mental health services.

Invariom based electron density studies on the C/Si analogues haloperidol/sila-haloperidol and venlafaxine/sila-venlafaxine.

The subjects of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1a·HCl), haloperidol hydropicrate (1a·HPic) and sila-haloperidol hydrochloride (1b·HCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2a·HCl; as orthorhombic (2a·HCl-ortho) and monoclinic polymorph (2a·HCl-mono)) and sila-venlafaxine hydrochloride (2b·HCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader's quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues.

MRJF4, a novel histone deacetylase inhibitor, induces p21 mediated autophagy in PC3 prostate cancer cells.

Autophagy is a cellular defense mechanism which occurs through degradation and recycling of cytoplasmic constituents and represents a caspase—independent alternative to cell death by apoptosis. It is generally accepted that the suppression of autophagy in many cancer cells is directly correlated to malignancy; hence, the control of autophagy genes could represent a target for cancer therapy. The inhibition of cell proliferation through autophagy activation could be an important mechanism for many anti—tumor drugs. Here we report the effects of a novel histone deacetylase inhibitor MRJF4 (racemic mixture) and of its two enantiomers [(+)—MRJF4 and (—)—MRJF4] on the morphological and molecular mechanisms causing death and migration of PC3 prostatic cancer cells. In particular, we investigated the occurrence of the autophagic process, both at morphological and molecular levels (LC3 expression), and its relationship with p21, a key molecule which regulates cell cycle and autophagy cell death. Moreover, pERK/Nf—kB driven intracellular signaling, the expression of MMP9 protein — a key component of cell migration — invasion, and metastasis were assayed. Our results showed that the anti—proliferative effects of MRJF4 due to autophagy occurrence, documented by LC3 increase and ultrastructural modifications, and the reduction of invasiveness seem to be mediated by the down—regulation of pERK/NF—kB signaling pathway, along with p21 up—regulation.

Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders.

BACKGROUND: Haloperidol is worldwide one of the most frequently used antipsychotic drugs with a very high market share. Previous narrative, unsystematic reviews found no differences in terms of efficacy between the various first-generation ("conventional", "typical") antipsychotic agents. This established the unproven psychopharmacological assumption of a comparable efficacy between the first-generation antipsychotic compounds codified in textbooks and treatment guidelines. Because this assumption contrasts with the clinical impression, a high-quality systematic review appeared highly necessary. OBJECTIVES: To compare the efficacy, acceptability, and tolerability of haloperidol with other first-generation antipsychotics in schizophrenia and schizophrenia-like psychosis. SEARCH METHODS: In October 2011 and July 2012, we searched the Cochrane Schizophrenia Group's Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. To identify further relevant publications, we screened the references of all included studies and contacted the manufacturers of haloperidol for further relevant trials and missing information on identified studies. Furthermore, we contacted the corresponding authors of all included trials for missing data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared oral haloperidol with another oral first-generation antipsychotic drug (with the exception of the low-potency antipsychotics chlorpromazine, chlorprothixene, levopromazine, mesoridazine, perazine, prochlorpromazine, and thioridazine) in schizophrenia and schizophrenia-like psychosis. Clinically important response to treatment was defined as the primary outcome. Secondary outcomes were global state, mental state, behaviour, overall acceptability (measured by the number of participants leaving the study early due to any reason), overall efficacy (attrition due to inefficacy of treatment), overall tolerability (attrition due to adverse events), and specific adverse effects. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data from the included trials. The methodological quality of the included studies was assessed using The Cochrane Collaboration`s 'Risk of bias' tool.We analysed dichotomous outcomes with risk ratios (RR) and continuous outcomes with mean differences (MD), both with the associated 95% confidence intervals (CI). All analyses were based on a random-effects model and we preferably used data on an intention-to-treat basis where possible. MAIN RESULTS: The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69).Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. AUTHORS' CONCLUSIONS: The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.

Further evaluation of the tropane analogs of haloperidol.

Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.

Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.

IMPORTANCE: Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE: To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS: Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS: Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES: Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS: There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE: In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01136772.

Pharmacoeconomics of depot antipsychotics for treating chronic schizophrenia in Sweden.

AIMS: To determine the cost-effectiveness of long-acting injectable (LAI) antipsychotics for chronic schizophrenia in Sweden. METHODS: A 1-year decision tree was developed for Sweden using published data and expert opinion. Five treatment strategies lasting 1 year were compared: paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), haloperidol decanoate (HAL-LAI) and olanzapine tablets (oral-OLZ). Patients intolerant/failing drugs switched to another depot; subsequent failures received clozapine. Resources and employment time lost (indirect costs) were costed in 2011 Swedish kroner (SEK), from standard government lists. The model calculated the average cost/patient and quality-adjusted life-years (QALYs), which were combined into incremental cost-effectiveness ratios. Multivariate and 1-way sensitivity analyses tested model stability. RESULTS: PP-LAI followed by OLZ-LAI had the lowest cost/patient (189,696 SEK) and highest QALYs (0.817), dominating in the base case. OLZ-LAI followed by PP-LAI cost 229,775 SEK (0.812 QALY), RIS-LAI followed by HAL-LAI cost 221,062 SEK (0.804 QALY), HAL-LAI followed by oral-OLZ cost 243,411 SEK (0.776 QALY), and oral-OLZ followed by HAL-LAI cost 249,422 SEK (0.773 QALY). The greatest proportions of costs (52.5-83.8%) were for institutional care; indirect costs were minor (2.4-3.8%). RESULTS were sensitive to adherence and hospitalization rates, but not drug cost. PP-LAI followed by OLZ-LAI dominated OLZ-LAI followed by PP-LAI in 59.4% of simulations, RIS-LAI followed by HAL-LAI in 65.8%, HAL-LAI followed by oral-OLZ in 94.0% and oral-OLZ followed by HAL-LAI in 95.9%; PP-LAI followed by OLZ-LAI was dominated in 1.1% of the 40,000 iterations. CONCLUSION: PP-LAI followed by OLZ-LAI was cost-effective in Sweden for chronic schizophrenia and cost-saving overall to the healthcare system.