Showing papers in "Journal of Clinical Psychopharmacology in 2019"

The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications.

Abstract: Purpose Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids. Methods A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies. Findings After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Δ-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely. Conclusions Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition.

Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial.

Abstract: Author(s): Evins, A Eden; Benowitz, Neal L; West, Robert; Russ, Cristina; McRae, Thomas; Lawrence, David; Krishen, Alok; St Aubin, Lisa; Maravic, Melissa Culhane; Anthenelli, Robert M | Abstract: BACKGROUND:Neuropsychiatric safety and relative efficacy of varenicline, bupropion, and transdermal nicotine patch (NRT) in those with psychiatric disorders are of interest. METHODS:We performed secondary analyses of safety and efficacy outcomes by psychiatric diagnosis in EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), a 12-week, randomized, double-blind, triple-dummy, placebo- and active (NRT)-controlled trial of varenicline and bupropion with 12-week follow-up, in a subset population, n = 4092, with a primary psychotic (n = 390), anxiety (n = 792), or mood (n = 2910) disorder. Primary end-point parameters were incidence of prespecified moderate and severe neuropsychiatric adverse events (NPSAEs) and weeks 9 to 12 continuous abstinence rates (9-12CAR). RESULTS:The observed NPSAE incidence across treatments was 5.1% to 6.3% in those with a psychotic disorder, 4.6% to 8.0% in those with an anxiety disorder, and 4.6% to 6.8% in those with a mood disorder. Neither varenicline nor bupropion was associated with significantly increased NPSAEs relative to NRT or placebo in the psychiatric cohort or any psychiatric diagnostic subcohort. There was a significant effect of treatment on 9-12CAR (P l 0.0001) and no significant treatment-by-diagnostic subcohort interaction (P = 0.24). Abstinence rates with varenicline were superior to bupropion, NRT, and placebo, and abstinence with bupropion and NRT was superior to placebo. Within-diagnostic subcohort comparisons of treatment efficacy yielded estimated odds ratios for 9-12CAR versus placebo of greater than 3.00 for varenicline, greater than 1.90 for bupropion, and greater than 1.80 for NRT for all diagnostic groups. CONCLUSIONS:Varenicline, bupropion, and nicotine patch are well tolerated and effective in adults with psychotic, anxiety, and mood disorders. The relative effectiveness of varenicline, bupropion, and NRT versus placebo did not vary across psychiatric diagnoses.

Clozapine Metabolism in East Asians and Caucasians: A Pilot Exploration of the Prevalence of Poor Metabolizers and a Systematic Review.

Abstract: PURPOSE/BACKGROUND In clozapine therapeutic drug monitoring (TDM) studies, Chinese reached the same concentrations using half the dosage Caucasians use. Defining clozapine poor metabolizers (PMs) requires stratification by ethnicity, smoking, and sex. METHODS/PROCEDURES After sex and smoking stratification in 129 Chinese inpatients (mean, 8.8 TDM samples per patient), we explored the association between the total concentration-dose (C/D) ratio and CYP1A2 (*1C, *1F, and *7) and CYP2C19 alleles (*2 and *3). A systematic literature review identified 22 clozapine TDM prior studies (13 in Caucasians and 7 in East Asians). FINDINGS/RESULTS In our Chinese sample, the mean total clozapine C/D ratio (ng/mL per mg/d) was 1.96 for 22 male smokers, 2.07 for 5 female smokers, 2.47 for 36 male nonsmokers, and 2.95 for 66 female nonsmokers. CYP1A2 *1C had no significant effects, and CYP1A2 *1F had small effects. Five clozapine PMs (4%) needed low clozapine doses of 75 to 115 mg/d to get therapeutic concentrations. Using the same methodology in a published Italian sample, we found 5 PMs (3.3% of 152). In the systematic review, the clozapine C/D ratio (ng/mL per mg/d) was higher when comparing: (1) weighted mean values of 1.57 in 876 East Asians versus 1.07 in 1147 Caucasians and (2) ranks of 8 East Asians versus 13 Caucasian samples (P < 0.001). IMPLICATIONS/CONCLUSIONS Future TDM studies need to further explore the frequency of clozapine PMs after sex and smoking stratification in East Asian and Caucasian patients. Compared with Caucasians, East Asians appear to have a clinically relevant decrease in clozapine clearance.

Zolpidem and Gender: Are Women Really At Risk?

Abstract: BACKGROUND In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. METHODS Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. RESULTS Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. CONCLUSIONS Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13

Abstract: Purpose/Background: Clozapine clearance is influenced by sex, smoking status, ethnicity, co-prescription of inducers or inhibitors, obesity and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 standard deviations beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalences of PMs and UMs using data from 4 already-published Asian samples. Three samples were East Asian (Beijing 2, Taipei and Seoul); one was from South India (Vallore). Findings/Results: The prevalence of phenotypical PMs ranged from 2-13%, but inflammation was not excluded. The prevalence was 7.3% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypical PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0-1.6%, but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. Implications/Conclusions: Around 10% of Asians may be clozapine PMs and may only need 50-150 mg/day to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings and multiple serum concentrations.

Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study.

Abstract: Background Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure μ-opioid peptide receptor agonists. Methods We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 μg; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. Results Forty-two subjects completed the study. Cebranopadol 200 and 400 μg did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 μg were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. Conclusions These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure μ-opioid peptide agonist.

Effects of Repeated Intravenous Ketamine in Treatment-Resistant Geriatric Depression: A Case Series.

Abstract: Purpose There is an immediate need for more sustainable, effective therapies for treatment-resistant depression in patients who do not respond to traditional psychopharmacology. The aim of this study was to determine the efficacy and safety of intravenous ketamine infusions on the elderly population by using a case series of 6 geriatric patients with treatment-resistant depression. Methods Eligible patients aged 65 to 82 were given a subanesthetic ketamine hydrochloride dose of 0.5 mg/kg delivered intravenously over 40 minutes twice weekly for an acute series. If patients reported a 50% decrease in depression symptoms after the acute series of 2 to 4 infusions, they would be moved to a maintenance series of infusions, which would occur every 2 to 6 weeks on an individual basis. Results Of the 6 patients given ketamine, 1 failed to respond to the acute treatment phase, 4 responded to the acute infusion phase but failed to sustain a response after a range of 8 to 22 maintenance infusions, and 1 responded to the infusions but relapsed into alcohol use; therefore, treatment was discontinued. Conclusions The relative safety of intravenous ketamine in the elderly was demonstrated by the mild, transient adverse effects seen by this patient group. The geriatric population is unable to maintain an antidepressant response to intravenous ketamine over time, signifying that ketamine has low efficacy for the elderly.

Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies.

Abstract: Purpose/background N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonists are potential agents for the treatment of several central nervous system disorders including major depressive disorder. Racemic methadone, L-methadone, and D-methadone all bind the NMDAR with an affinity similar to that of established NMDAR antagonists, whereas only L-methadone and racemic methadone bind to opioid receptors with high affinity. Therefore, D-methadone is expected to have no clinically significant opioid effects at therapeutic doses mediated by its NMDAR antagonism. Methods We conducted 2 phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose studies to investigate the safety and tolerability of oral D-methadone and to characterize its pharmacokinetic profile in healthy opioid-naive volunteers. Results D-Methadone exhibits linear pharmacokinetics with dose proportionality for most single-dose and multiple-dose parameters. Single doses up to 150 mg and daily doses up to 75 mg for 10 days were well tolerated with mostly mild treatment-emergent adverse events and no severe or serious adverse events. Dose-related somnolence and nausea occurred and were mostly present at the higher dose level. There was no evidence of respiratory depression, dissociative and psychotomimetic effects, or withdrawal signs and symptoms upon abrupt discontinuation. An overall dose-response effect was observed, with higher doses resulting in larger QTcF (QT interval corrected using Fridericia formula) changes from baseline, but none of the changes were considered clinically significant by the investigators. Mild, dose-dependent pupillary constriction of brief duration occurred particularly at the 60-mg dose or above in the single-ascending-dose study and at the dose of 75 mg in the multiple-ascending-dose study. No detectable conversion of D-methadone to L-methadone occurred in vivo. Conclusions These results support the safety and continued clinical development of D-methadone as an NMDAR antagonist for the treatment of depression and other central nervous system disorders.

Effect of Brexpiprazole on Prolactin: An Analysis of Short- and Long-Term Studies in Schizophrenia.

Abstract: Background Hyperprolactinemia is an undesirable effect of most antipsychotics because of D2-receptor blockade. We assessed the effect of the D2-receptor partial agonist brexpiprazole on prolactin, based on pooled data from three 6-week, randomized, placebo-controlled studies and two open-label extension studies in patients with schizophrenia. Methods In the short-term studies, patients received 0.25, 1, 2, 4 mg brexpiprazole or placebo; or flexible-dose brexpiprazole (2-4 mg/d), placebo, or active reference. The extension studies were 52-week, flexible-dose (1-4 mg/d) studies. We studied changes from baseline and shifts in prolactin status in patients with normal or elevated prolactin levels at baseline, and prolactin-related treatment-emergent adverse events (TEAEs). Results Median changes from baseline to week 6 in brexpiprazole-treated patients in short-term studies were as follows: 3.63 ng/mL (females), 0.26 ng/mL (males); placebo: -2.15 ng/mL (females), -1.08 ng/mL (males).Median changes from baseline to week 52 in long-term studies were 0.60 ng/mL (females) and 0.18 ng/mL (males). Prolactin levels in patients with baseline values greater than 1× upper limit of normal tended to decrease over time regardless of previous treatment.The proportions of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies were as follows: 1.5% (females), 1.6% (males); placebo: 3.6% (females), 3.4% (males). Corresponding figures in long-term studies were 5.3% (females) and 2.0% (males).In short-term studies, the incidence of prolactin-related TEAEs was 1.8% for brexpiprazole and 0.6% for placebo. In long-term studies, the incidence of prolactin-related TEAEs was 1.7%. Conclusions Small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, and low incidence of prolactin-related TEAEs were observed after treatment with brexpiprazole.

Antipsychotic Use During Pregnancy and the Risk of Gestational Diabetes Mellitus: A Systematic Review.

Abstract: Purpose This study aimed to review the current literature examining a potential relationship between the use of antipsychotic drugs during pregnancy and gestational diabetes mellitus (GDM). Methods PubMed was searched for English language reports between January 1, 1996, and March 31, 2018, by using combinations of the following key words: antipsychotics, pregnancy, FGAs, SGAs, GDM, obstetric outcomes, pregnancy outcomes, obstetric complications, maternal complications, clozapine, olanzapine, risperidone, aripiprazole, amisulpirde, ziprasidone, quetiapine, haloperidol, chlorpromazine, zuclopenthixol, and flupenthixol. Studies but not case reports, case series, or reviews published in a peer-reviewed journal were eligible for inclusion. Results A total of 10 relevant studies that met the review criteria were examined. Data from these studies indicated that the prevalence rates of GDM in pregnant women using antipsychotic drugs and the nomedication group were 2.6% to 22% and 0.95% to 10.7%, respectively. Most comparative studies reported that antipsychotic treatment during pregnancy was not significantly associated with increased in risk of GDM. In addition, the study results also suggested that underlying maternal psychopathologies might affect the risk of GDM. Implications Findings from some studies suggesting a higher risk of GDM in pregnant women who were administered antipsychotic drugs were not confirmed by results of many other studies. The current evidence suggests no significant relationship between antipsychotic drugs, including second- and first-generation antipsychotics, and the risk of GDM.

Serotonin Toxicity: Associated Agents and Clinical Characteristics.

Abstract: Background Serotonin toxicity is a common cause of drug-induced altered mental status. However, data on the causes of serotonin toxicity, symptomatology, complications, and rate of antidotal treatment are limited. Methods This study evaluated cases of serotonin toxicity in the ToxIC registry, an international database of prospectively collected cases seen by medical toxicologists. Serotonin toxicity was diagnosed by bedside evaluation of medical toxicology specialists and explicit criteria were not used. The database was searched for "serotonin syndrome" between January 1, 2010, and December 31, 2016. Results There were 1010 cases included. Females made up 608 (60%) cases. Ages are as follows: younger than 2 years (3, 0.3%), 2 to 6 years (8, 0.8%), 7 to 12 years (9, 0.9%), 13 to 18 years (276, 27.3%), 19 to 65 years (675, 67%), older than 66 years (33, 3.4%), unknown (6, 0.6%). Reasons for encounter: intentional (768, 76%), adverse drug event/reaction (127, 12.6%), unintentional (66, 6%), and unknown (55, 5.4%). Signs/symptoms: hyperreflexia/clonus/myoclonus (601, 59.5%), agitation (337, 33.4%), tachycardia (256, 25.3%), rigidity (140, 13.9%), seizures (139, 13.7%), and hyperthermia (29, 2.9%). Complications rhabdomyolysis (97, 9.7%), dysrhythmias (8, 0.8%), and death (1, 0.1%). Treatments benzodiazepines 67% (677/1010), cyproheptadine 15.1% (153/1010). There were 192 different xenobiotics reported with 2046 total exposures. Antidepressants were most common (915, 44.7%) with bupropion the most frequent overall (147, 7.2%). Common non-antidepressants were dextromethorphan (95, 6.9%), lamotrigine (64, 3.1%), and tramadol (60, 2.9%). Discussion Serotonin toxicity most often occurred in adult patients with intentional overdose. Antidepressants were the most common agents of toxicity. Interestingly, bupropion, a norepinephrine/dopamine reuptake inhibitor, was the most frequently mentioned xenobiotic. Though often cited as a potential antidote, only 15% of patients received cyproheptadine. Severe toxicity was rare. A single death was reported.

Long-Acting Injectables Versus Oral Antipsychotics: A Retrospective Bidirectional Mirror-Image Study.

Abstract: Purpose Mirror-image studies, which compare equal periods of time before and after a new treatment is introduced, may reflect the real-world impact of that treatment. However, most mirror-image studies that have investigated the impact of long-acting injectable antipsychotics (LAIs) were unidirectional in design, for patients switching from oral antipsychotics (OAPs) to LAIs. Therefore, we conducted a bidirectional mirror-image study comparing LAIs and OAPs. Methods We included 126 schizophrenia or schizoaffective disorder patients' LAI treatment data from 3 psychiatric hospitals. Patients took OAPs for 6 months or more before initiating LAIs, or the reverse. We obtained data on the number of hospitalizations as a primary outcome, plus the total duration and mean duration of hospitalization as secondary outcomes during the 6 months of the patients' first treatment, and the 6 months after the patients started their second type of treatment. Results The results indicated that there was no significant difference in any outcomes between LAI and OAP treatment when going from LAIs to OAPs (n = 59). However, when patients started with OAPs and switched to LAIs (n = 67), they were hospitalized a significantly fewer number of times, and the duration of their stays was shorter in the LAI phase than in the OAP phase. When combined with bidirectional data, LAI superiority was still observed. Conclusions The findings endorse the relative effectiveness of LAIs over OAPs in the real world, although the inherent flaws of mirror-image studies such as expectation bias and having no parallel comparator should be considered.

Prodopaminergic Drugs for Treating the Negative Symptoms of Schizophrenia: Systematic Review and Meta-analysis of Randomized Controlled Trials.

Abstract: Background The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments. Methods We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder.Medline, EMBASE, and several other databases as well as trial registries were searched for placebo-controlled trials. Results Ten randomized controlled trials were included in the meta-analysis, 6 trials on modafinil, 2 on armodafinil, 1 on L-dopa, and 1 on pramipexole. Overall, prodopaminergic agents did not significantly reduce negative symptoms. Restricting the analysis to studies requiring a minimum threshold for negative symptom severity, modafinil/armodafinil showed a significant but small effect on negative symptoms. A subset of studies allowed for calculating specific effects for the negative symptom dimensions diminished expression and amotivation, but no significant effect was found. Prodopaminergic agents did not increase positive symptom scores. Conclusions The currently available evidence does not allow for formulating recommendations for the use of prodopaminergic agents for the treatment of negative symptoms. Nevertheless, the observed improvement in studies defining a minimum threshold for negative symptom severity in the absence of an increase in positive symptoms clearly supports further research on these agents.

A Novel Text Message Intervention to Improve Adherence to Stimulants in Adults With Attention Deficit/Hyperactivity Disorder.

Abstract: BACKGROUND Attention deficit/hyperactivity disorder (ADHD) is a prevalent neurobiological disorder associated with a wide range of adverse outcomes. Although large data sets document that stimulants decrease the risks for many ADHD-associated adverse outcomes, compliance with stimulants remains very poor. The main aim of this study was to assess the effectiveness of a novel text messaging-based intervention aimed at improving the poor rate of adherence to stimulant medications in adults with ADHD. METHODS Subjects were adults with ages 18 to 55, prescribed a stimulant medication for ADHD treatment. For comparators, we identified at a 5-to-1 ratio (age and sex matched) adult patients from the Partners HealthCare electronic medical record who had been prescribed stimulant medications over a 1-year period. We determined whether patients had timely prescription refills, defined as refilled within 37 days, using prescriptions documented in their electronic medical record. RESULTS Our results showed that 68% of the SMS intervention group refilled their prescriptions in a timely manner. In contrast, only 34% of patients receiving treatment as usual refilled their prescriptions in a timely fashion (odds ratio, 4.04; 95% confidence interval, 2.49-6.56; P < 0.001). CONCLUSIONS These data indicate that an innovative ADHD-centric text messaging intervention significantly improved patient engagement to treatment with stimulants in adults with ADHD. Findings provide strong support for the use of a readily accessible, inexpensive, and widely available technology to improve the poor rate of adherence to stimulant treatment in adults with ADHD. To the best of our knowledge, this study is the first digital health intervention aimed at improving adherence to stimulant medication for adults with ADHD.

The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis.

Abstract: BACKGROUND Animal models and human studies have identified the potential of modafinil as a cognitive enhancing agent, independent of its effects on promoting wakefulness in sleep-deprived samples. Given that single-dose applications of other putative memory enhancers (eg, D-cycloserine, yohimbine, and methylene blue) have shown success in enhancing clinical outcomes for anxiety-related disorders, we conducted a meta-analytic review examining the potential for single-dose effects for modafinil on cognitive functioning in non-sleep-deprived adults. METHODS A total of 19 placebo-controlled trials that examined the effects of single-dose modafinil versus placebo on the cognitive domains of attention, executive functioning, memory, or processing speed were identified, allowing for the calculation of 67 cognitive domain-specific effect sizes. RESULTS The overall positive effect of modafinil over placebo across all cognitive domains was small and significant (g = 0.10; 95% confidence interval, 0.05-0.15; P < 0.001). No significant differences between cognitive domains were found. Likewise, no significant moderation was found for modafinil dose (100 mg vs 200 mg) or for the populations studied (psychiatric vs nonpsychiatric). CONCLUSIONS In conclusion, the available evidence indicates only limited potential for modafinil to act as a cognitive enhancer outside sleep-deprived populations.

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia.

Abstract: Background Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia. Methods The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18-65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability. Results At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively. Conclusions Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.

An 8-Week, Randomized, Phase 2, Double-Blind, Sequential Parallel-Group Comparison Study of Two Dose Levels of the GABAA Positive Allosteric Modulator PF-06372865 Compared With Placebo as an Adjunctive Treatment in Outpatients With Inadequate Response to Standard of Care for Generalized Anxiety Disorder.

Abstract: Background Generalized anxiety disorder (GAD) is a common psychiatric disorder, but many patients experience only partial relief of symptoms with existing therapies. Benzodiazepines are effective in many cases but are limited by a number of significant adverse effects. PF-06372865 is a subtype-selective gamma-aminobutyric acid A (GABAA)-positive allosteric modulator lacking in functional activity at alpha 1-containing receptors that are believed to mediate many of these adverse effects. Methods PF-06372865 was evaluated as an adjunct to current GAD treatment in a double-blind, placebo-controlled, sequential parallel comparison study in patients with GAD who showed an incomplete response to current standard-of-care pharmacotherapy. A total of 90 subjects (of the planned 384) were randomized into the study before the decision to terminate the study. Two doses of PF-06372865 (2.5 mg twice daily and 7.5 mg twice daily) were compared with placebo. Results Neither dose of PF-06372865 differentiated from placebo on week 4 Hamilton Anxiety Inventory total (primary end point) or on the Sheehan Disability Scale total score (secondary end point). Adverse events including dizziness, headache, and somnolence were observed, and the 7.5 mg dose demonstrated some impairment on the Digit Symbol Substitution test and the Epworth Sleepiness Scale relative to placebo and the 2.5 mg dose. Conclusions Factors contributing to the negative results include the limited sample size and failure to explore a broader range of doses.

Monthly Extended-Release Risperidone (RBP-7000) in the Treatment of Schizophrenia: Results From the Phase 3 Program.

Abstract: Purpose/background The Phase 3 program for RBP-7000, a once-monthly subcutaneous (SC) extended-release risperidone formulation approved for treatment of schizophrenia, consisted of a double-blind placebo-controlled trial (previously reported) and a 52-week open-label study of monthly RBP-7000 120 mg. The primary objective of the open-label study was to evaluate the long-term safety and tolerability of RBP-7000 in adults with schizophrenia. A secondary objective was to assess long-term maintenance of effectiveness. Methods/procedures The 52-week Phase 3 open-label study (NCT02203838) enrolled 92 rollover participants from the double-blind trial (NCT02109562) and 408 stable (Positive and Negative Syndrome Scale [PANSS] total score, ≤70) de novo participants. Participants received up to 13 monthly SC injections of RBP-7000 120 mg. Safety assessments included treatment-emergent adverse events, injection-site assessments, vital signs, laboratory and ECG parameters, extrapyramidal symptoms, and suicidality. Clinical outcomes included the PANSS and Clinical Global Impression-Severity. Findings/results Overall, 367 participants (73.4%) reported 1 or more treatment-emergent adverse event; the most common were injection-site pain (13.0%) and weight increase (12.8%). Most participants (>80%) experienced no injection-site reactions. No clinically meaningful changes were observed in laboratory or electrocardiogram values, vital signs, extrapyramidal symptoms, or suicidality. Over 12 months of exposure, mean PANSS scores continued to improve in rollover participants and remained stable among de novo participants. Mean Clinical Global Impression-Severity scores remained stable among all participants. Implications/conclusions Except for anticipated injection-site reactions, RBP-7000 demonstrated a favorable safety and tolerability profile similar to oral risperidone. Notably, PANSS scores continued to improve for participants from the pivotal study and remained stable for de novo participants.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Adjunctive Therapy in Adults With Major Depressive Disorder.

Abstract: Background Long-term treatment is recommended in major depressive disorder (MDD) to prevent relapse and to restore functioning. The aim of this study (Orion; NCT01360866) was to assess the long-term safety, tolerability, and efficacy of open-label treatment with adjunctive brexpiprazole in adult patients with MDD. Methods Patients rolled over into this 52-week study (amended to 26 weeks) from 3 randomized, double-blind, placebo-controlled studies. Patients received brexpiprazole 0.5 to 3 mg/d (flexible dose) adjunct to their current antidepressant treatment. The primary outcome variable was the frequency and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed as a secondary objective using clinical rating scales. Results A total of 2944 patients were enrolled (1547 for 52 weeks, 1397 for 26 weeks), of whom 1895 (64.4%) completed the study. The TEAEs with incidence of 5% or greater were weight increase (17.7%), somnolence (8.0%), headache (7.2%), akathisia (6.7%), increased appetite (6.3%), insomnia (6.3%), fatigue (6.1%), viral upper respiratory tract infection (5.4%), and anxiety (5.2%). Most TEAEs were mild or moderate in severity. The mean increase in body weight was 2.7 kg to week 26 and 3.2 kg to week 52; 25.8% of patients had a weight increase of 7% or greater at any postbaseline visit. There were no clinically relevant findings related to extrapyramidal symptoms, prolactin, lipids, or glucose. Patients' symptoms and functioning showed continual improvement. Conclusions Adjunctive treatment with open-label brexpiprazole 0.5 to 3 mg/d was generally well tolerated for up to 52 weeks in patients with MDD and was associated with continued improvement in efficacy measures and functional outcomes.

Systematic Review of Gender Bias in the Clinical Trials of New Long-Acting Antipsychotic Drugs.

Abstract: Purpose/background This article evaluates gender bias in the published clinical trials of new long-acting antipsychotics. Methods/procedures We conducted a review of controlled clinical trials of the new prolonged-release antipsychotics (aripiprazole, risperidone, or paliperidone) for the treatment of schizophrenia published in MEDLINE over the last 10 years and available in full text in English. The study followed the corresponding international recommendations. Results We identified 132 trials, and of these, 40 met the inclusion and exclusion criteria. We found that only 36.41% of the total patients were women. The separate analysis of the main variable between the subpopulations of men and women was carried out in only 6 of the 40 works included. In contrast, in 15 trials, this analysis was performed on secondary variables, generally related to safety. Only 3 of the 40 trials discussed the results separately according to sex. Conclusions The clinical trials of long-acting atypical antipsychotic drugs show a far-from-negligible gender bias. Women are underrepresented, and the main and secondary variables are not analyzed separately according to gender. This is despite international recommendations establishing these criteria as part of a package of minimum requirements for meeting scientific validity and making results apt to extrapolate to the general population of patients.

Effects of Curcumin on Cognitive Functioning and Inflammatory State in Schizophrenia: A Double-Blind, Placebo-Controlled Pilot Trial.

Abstract: Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons AttributionNon Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Smoking Is Associated With Lower Dose-Corrected Serum Concentrations of Escitalopram.

Abstract: BACKGROUND Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. METHODS A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. RESULTS Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. CONCLUSIONS Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.

Mortality Risk of Atypical Antipsychotics for Behavioral and Psychological Symptoms of Dementia: A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis of Randomized Controlled Trials.

Abstract: BACKGROUND Evidence suggests that atypical antipsychotics (AAPs) exert a short-term mortality risk in people with dementia. We assessed whether additional randomized clinical trials influence the current evidence and the potential effect modifiers. METHODS Electronic databases were systematically searched for randomized controlled trials from their inception through March 2018. A random-effects model was used for analysis. Potential effect modifiers were examined through meta-regression. Trial sequential analysis was performed to quantify the statistical reliability of data in the cumulative meta-analysis with adjustment of significance levels for sparse data and repetitive testing on accumulating data. Certainty of evidence and risk of bias were also evaluated. RESULTS We found that compared with placebos, AAPs may increase the risk of mortality (odds ratio [OR], 1.536; 95% confidence intervals [CIs], 1.028-2.296; P = 0.036, high certainty). In the subgroup analysis, the estimated ORs were the highest for olanzapine (1.919; P = 0.232), followed by those for quetiapine (1.663; P = 0.506), aripiprazole (1.649; P = 0.297), and risperidone (1.354; P = 0.277); however, the mortality risk presented by individual AAPs did not exhibit between-group differences. The meta-regression did not identify any effect modifiers, including the chlorpromazine equivalent dose, trial duration, and cognitive status. The trial sequential analysis revealed that future similar trials are unlikely to alter our findings. CONCLUSIONS Atypical antipsychotics are associated with increased short-term mortality risk, although a disease-drug interaction may contribute to such risk in people with dementia. Patients with dementia may still benefit by AAPs after appropriate assessment of the disease severity as well as the dosage of AAPs, treatment duration, and monitoring of AAPs.

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia

Abstract: PURPOSE/BACKGROUND Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

Adverse Drug Reactions Related to Mood and Emotion in Pediatric Patients Treated for Attention Deficit/Hyperactivity Disorder: A Comparative Analysis of the US Food and Drug Administration Adverse Event Reporting System Database.

Abstract: Background Attention deficit/hyperactivity disorder (ADHD) can be comorbid with frequent anxiety and mood disorders, as well as emotional symptoms (anxiety, irritability, mood lability). These may also be triggered by drugs and appear as adverse drug reactions (ADRs). Methods We mined data from the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database, focused on methylphenidate, atomoxetine, amphetamine, lisdexamfetamine, and their derivatives. We collected reports of ADRs connected with mood or emotional symptoms in pediatric patients, excluding drug abuse/accidents. Reporting odds ratios (RORs) were calculated and compared between drug classes and children/adolescents. Results We collected 6176 ADRs of interest of which 59% occurred in children. Atomoxetine accounted for 50.7% of reports, methylphenidate for 32.5%, lisdexamfetamine for 14.2%, and amphetamine for 2.6%. Irritability, anxiety, obsessive thoughts, depressed mood, and euphoria scored significant RORs for all drugs, overall with an increasing risk from methylphenidate to atomoxetine, lisdexamfetamine, and amphetamine. Apathy regarded mostly atomoxetine, and crying regarded all drugs except methylphenidate. Several age-based differences were found. Notably, affect lability hit only adolescents. All drugs scored significant self-injury RORs, except lisdexamfetamine in adolescents, with an increasing risk from methylphenidate to lisdexamfetamine, atomoxetine, and amphetamine. For suicidality, all drugs had significant RORs in children, and methylphenidate was better than atomoxetine and lisdexamfetamine. In adolescents, only methylphenidate and atomoxetine scored significant RORs. Conclusions We conclude that real-world data from the US Food and Drug Administration Adverse Event Reporting System are consistent with previous evidence from meta-analyses. They support a hierarchy of drug safety for several ADRs (except self-injury/suicidality) with methylphenidate as safest, followed by atomoxetine, lisdexamfetamine, and amphetamine last. Self-injury and suicidality RORs were overall higher in children.

A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia.

Abstract: Background Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study. Methods The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points. Results Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed. Conclusions Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.

Is Antipsychotic Treatment Associated With Risk of Pneumonia in People With Serious Mental Illness?: The Roles of Severity of Psychiatric Symptoms and Global Functioning.

Abstract: BACKGROUND Most pneumonia-related researches in people with severe mental illness were based on insurance claims data. This study aimed for a comprehensive analysis of factors potentially associated with risk of pneumonia in psychiatric inpatients. METHODS Inpatients at a large psychiatric hospital diagnosed with pneumonia during the course of hospitalization were enrolled as cases. Controls were matched by ward and date. The diagnosis of pneumonia was confirmed by physicians based on clinical features, chest radiographs, and blood tests. A stepwise conditional logistic regression model was used to identify potential risk factors for pneumonia. RESULTS Seventy-five pneumonia cases and 436 matched controls were enrolled. Conditional logistic regression revealed 3 variables significantly associated with an increased risk of pneumonia: a higher score on the Clinical Global Impression-Severity scale (adjusted odds ratio [aOR], 3.7; 95% confidence interval [CI]. 1.5-9.1), a higher score on the Charlson comorbidity index (aOR, 2.2; 95% CI, 1.5-3.2), and a longer duration of antipsychotic treatment (aOR, 1.0; 95% CI, 1.0-1.0). Two variables were significantly associated with a decreased risk of pneumonia: a higher score on the Global Assessment of Functioning scale (aOR, 0.9; 95% CI, 0.8-0.9) and an older age of onset (aOR, 0.9; 95% CI, 0.9-1.0). After adjusting for potential confounders, use of antipsychotic or other psychotropic medications was not found to be a significant risk factor for pneumonia. CONCLUSIONS Physical comorbidities, long duration of antipsychotic treatment, early onset, severe psychiatric symptoms, and poor global functioning are associated with pneumonia in people with serious mental illness.

Characteristics of Patients Experiencing Extrapyramidal Symptoms or Other Movement Disorders Related to Dopamine Receptor Blocking Agent Therapy.

Abstract: Purpose/background Dopamine receptor blocking agents (DRBAs), also known as antipsychotics, are medications widely used to treat a growing number of mental health diagnoses. However, their utility is limited by the potential to cause serious adverse movement reactions. Akathisia, dystonia, parkinsonism, and tardive dyskinesia (collectively known as extrapyramidal symptoms or EPSs) are associated with reduced social and occupational functioning, negative patient attitudes toward treatment, and nonadherence to pharmacotherapy. Neuroleptic malignant syndrome is a life-threatening reaction that can result from DRBA use and cause musculoskeletal dysfunction. The aim of this study is to profile patients who have developed DRBA-related movement adverse effects and identify risk factors significantly associated with each subtype of EPSs or other movement disorders (OMDs) such as neuroleptic malignant syndrome. Methods/procedures A report of all potential DRBA-related EPSs or OMDs occurrences within a large community hospital network was generated using International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) billing codes. Each patient encounter was manually reviewed to confirm that a documented case of DRBA-related EPSs or OMDs had indeed occurred and subsequently determine the likely causative agent(s). Findings/results The resultant cohort of 148 patients experiencing unique DRBA-related EPS or OMD events was analyzed. The average patient was female, middle-aged, and overweight. The most common DRBAs precipitating EPSs or OMDs were haloperidol and quetiapine. In the population studied, age was significantly associated with the subtype of EPSs experienced such that those patients with akathisia and dystonia tended to be younger, whereas those with tardive dyskinesia tended to be older. Body mass index (BMI) category was also negatively correlated with the incidence of dystonia. In addition, it was observed that exposure to specific DRBAs, classes, and routes of administration significantly affected the risk of developing different subtypes of EPSs or OMDs in the study population. Implications/conclusions To our knowledge, this is the first study to describe an association between age and BMI with the risk of akathisia and dystonia, respectively, in patients taking DRBAs. Other trends observed with age and BMI in patients developing DRBA-related EPSs support previously reported findings. Expanding the knowledge base of individual characteristics associated with the risk of developing different subtypes of EPSs or OMDs can help providers and patients anticipate and attempt to mitigate these reactions, and may ultimately improve adherence to DRBA therapy.

Clozapine-Associated Myoclonus and Stuttering Secondary to Smoking Cessation and Drug Interaction: A Case Report.

Abstract: Copyright given the expanse of medications used. Bowen et al reported a case where lithium levels were between 0.2 and 0.6 mmol/L (reference range, 0.5–0.8 mmol/L) during a complicated treatment course, with authors commenting that the normal lithium levels themselves did not exclude lithium toxicity, formulating clozapine toxicity and associated renal damage best characterized the case. Clinical details, treatment courses, and outcomes of the prior cases, including the 8 reports without lithium use, are summarized (Table 1). The presented case and all those reviewed describe symptomatic improvement and partial or complete return of renal functioning. It is important to recognize the plausibility of dehydration as potentially contributory in this scenario, especially in the setting of fever, a common finding in the reviewed cases, which should be a consideration for relative dehydration furthering renal compromise. Lithium use in clozapine-associated kidney injury has been reported rarely with scant discussion of the risk of secondary toxicity. This potential complication warrants vigilant assessment to guide appropriate management, such as lithium avoidance or interruption.