Benztropine and suicide attempts and intentional self-harm.

BACKGROUND: This large-scale pharmacoepidemiologic study was conducted to confirm a previous signal for decreased risk of suicide attempt following prescription fills for benztropine. METHODS: We used a within-person exposure-only cohort design to study the dynamic association between benztropine prescription fills over a 12-month period and suicidal events (suicide attempts and intentional self-harm) in 62,493 patients with private health insurance (MarketScan - MS) who filled a new benztropine prescription between 2011 and 2019. A discrete-time survival analysis was used to analyze the data, adjusting for age, sex, diagnoses related to suicidal behavior, Parkinson's disease, medical comorbidities, history of suicide attempts, concomitant CNS medications, and time-varying antipsychotic use. RESULTS: Overall, there were 486 suicidal events (0.8%) following the index end-date of the one-year baseline period. Benztropine use was associated with fewer suicidal events (HR=0.63, 95% CI = 0.50, 0.80). Patients treated with antipsychotics and benztropine had a similar reduction in suicidal events as patients treated with benztropine alone in both within-subject and between-subject analyses. Similar associations were found for patients with bipolar disorder or schizophrenia, and those treated with newer versus older generation antipsychotics. Dose-response and duration response relationships were found, with an overall 6% reduction in suicidal events per 1 mg equivalent dosage per month, that was similar in those treated and those not treated with antipsychotics. INTERPRETATIONS: Benztropine was found to lower suicidal event rates, comparably in those receiving or not receiving antipsychotic medications, regardless of the presence of major psychiatric disorders. This observation warrants testing in a randomized clinical trial. FUNDING: No funding sources were utilized for this manuscript.

FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder.

Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD. Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders. Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability. To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in two separate studies, we administered two FKBP5 inhibitors, benztropine (Study 1) or SAFit2 (Study 2). FKBP5 inhibitors were administered on the last alcohol drinking session and prior to each trauma-related behavioral assessment. We also measured plasma corticosterone to assess the actions of FKBP5 inhibitors after familiar shock stress and alcohol drinking. Benztropine reduced alcohol preference in stressed males and females, while aggressive bouts were reduced in benztropine-treated stressed females. During hyperarousal, benztropine reduced several startle response outcomes across stressed males and females. Corticosterone was reduced in benztropine-treated stressed males. The selective FKBP5 inhibitor, SAFit2, reduced alcohol drinking in stressed males but not females, with no differences in irritability. Importantly, SAFit2 decreased fear overgeneralization in stressed males and females. SAFit2 also reduced corticosterone across stressed males and females. Neither FKBP5 inhibitor changed sleep bout structure. These findings indicate that FKBP5 inhibitors modulate stress-related alcohol drinking and partially modulate trauma-related behaviors. This work supports the hypothesis that targeting FKBP5 may alleviate PTSD/AUD comorbidity.

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

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

Amisulpride withdrawal akathisia responding to aripiprazole with propranolol in first-onset psychosis: a case report.

BACKGROUND: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. CASE PRESENTATION: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100-200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. CONCLUSIONS: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia.

Unprovoked Dystonic Reaction in a Child Taking Long-Term Methylphenidate.

In this report, we discuss the case of a 9-year-old male with Attention Deficit Hyperactivity Disorder (ADHD) on long-term methylphenidate and guanfacine who experienced acute orofacial dystonia that resolved immediately with the administration of benztropine. Current literature describes various cases of methylphenidate-induced dystonia, but ours appears to be the first reported instance of spontaneous dystonia without a recent change in dose or medication change. This may suggest the possibility of methylphenidate-induced dystonia spontaneously occurring several years after initiation.

Effects of benztropine analogs on delay discounting in rats.

RATIONALE: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. OBJECTIVES: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. METHODS: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. RESULTS: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. CONCLUSIONS: AHN 1-055 may be of clinical utility in the treatment of ADHD.

Risperidone-Induced Acute Laryngeal Dystonia: A Case Report.

BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction. CASE REPORT A 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen. CONCLUSIONS ALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.

Pharmacological interventions for treating sialorrhea associated with neurological disorders: A mixed treatment network meta-analysis of randomized controlled trials.

Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.

Persistence of racial disparities in prescription of first-generation antipsychotics in the USA.

PURPOSE: The aim of this study was to estimate the prevalence of first-generation antipsychotics (FGA) prescribed for treatment of psychiatric and neurological conditions and use of benztropine to reduce extrapyramidal side effects (EPS) by patient race/ethnicity in a nationally representative sample of adult outpatient visits. METHODS: The study sample included all outpatient visits (N = 8154) among patients aged 18-69 years where a prescription for one or more antipsychotics was recorded across 6 years of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (2005-2010). Use of FGA was compared by race/ethnicity using multiple logistic regression models accounting for patient and clinical characteristics stratified by neighborhood poverty rate. Frequency of EPS was determined by use of benztropine to reduce or prevent EPS. RESULTS: Black patients were significantly more likely than White patients to use FGA (odds ratio = 1.48, p = 0.040) accounting for psychiatric and neurological diagnoses, treatment setting, metabolic factors, neighborhood poverty, and payer source. Black patients were more than twice as likely as White patients to receive higher-potency FGA (haloperidol or fluphenazine), particularly in higher-poverty areas (odds ratio = 2.50, p < 0.001). Use of FGA, higher among Black than White patients, was positively associated with use of benztropine to reduce EPS. CONCLUSIONS: Racial disparities in the pharmacological treatment of severe mental disorders persist 30 years after the introduction of second-generation antipsychotics. The relatively high frequency of FGA of use among Black patients compared with White patients despite more Food and Drug Administration-approved indications and lower EPS risk for second-generation antipsychotics requires additional research.

Benztropine for the relief of acute non-traumatic neck pain (wry neck): a randomised trial.

OBJECTIVE: The aim of this study was to determine the effect of intra-muscular benztropine on pain and range of motion in patients presenting to the emergency department with acute, non-traumatic neck pain (wry neck). METHODS: In this two-centre randomised, double-blind, placebo-controlled, parallel-group superiority trial, participants were allocated to receive 2 mg intramuscular benztropine or normal saline. Participants were aged 16-65 years, no history of neck disorders and no use of medication that cause dystonia. Randomisation was computer generated, with allocation concealment by opaque sequentially numbered sealed envelopes. Pain scores and neck range of motion were measured immediately before drug administration, and 30 min after. Pain scores, range of motion and adverse effects were compared between the groups. No funding was received. The trial was registered. RESULTS: Thirty participants were enrolled, 15 randomised to placebo and 15 to benztropine. Pain scores at 30 min were lower in those allocated to benztropine, but the difference was neither statistically nor clinically significant (0.6 points, 95% CI -0.8 to 1.8, p=0.40). The range of motion of the cervical spine was greater in those receiving benztropine, but the differences were very small and not statistically significant. Adverse events were more common in those receiving benztropine. CONCLUSIONS: Benztropine was ineffective for reducing pain or improving range of motion of the cervical spine in patients suffering from acute, non-traumatic neck pain, but frequently caused anticholinergic side effects. However, as the CI for the primary outcome included the minimum difference considered clinically significant, an important effect of benztropine cannot be ruled out. TRIAL REGISTRATION NUMBER: ANZCTR#12612000354886.

Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine.

Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chemical library of compounds approved for clinical use in humans. This system enables identifying nontoxic antiviral compounds targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this analysis, we identified 12 compounds with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by determining their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compounds. We found that both compounds effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.

Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats.

Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i.p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 µg/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((-)-3ß-(4-fluorophenyl)-tropan-2-ß-carboxylic acid methyl ester tartrate), d-amphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDA-glutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The µ-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i.p., each)] dose-dependently decreased maximal self-administration of µ-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The µ-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and σ receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of µ-agonists on µ-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse.

A regenerative approach to the treatment of multiple sclerosis.

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.