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

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

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

Driving Simulator Performance After Administration of Analgesic Doses of Ketamine With Dexmedetomidine or Fentanyl Purpose/Background As a sole agent, ketamine acutely compromises driving ability; however, performance after coadministration with the adjuvant sedating agents dexmedetomidine or fentanyl is unclear. Methods/Procedures Using a randomized within-subject design, 39 participants (mean ± SD age, 28.4 ± 5.8 years) received 0.3 mg/kg bolus followed by 0.15 mg kg−1 h−1 infusion of ketamine (3-hour duration), in addition to either (i) 0.7 μg kg−1 h−1 infusion of dexmedetomidine for 1.5 hours (n = 19; KET/DEX) or (ii) three 25 μg fentanyl injections for 1.5 hours (n = 20; KET/FENT). Whole blood drug concentrations were determined during ketamine only, at coadministration (KET/DEX or KET/FENT) and at 2 hours after treatment. Subjective effects were determined using a standardized visual analog scale. Driving performance was assessed at baseline and at posttreatment using a validated computerized driving simulator. Primary outcomes included SD of lateral position (SDLP) and steering variability (SV). Findings/Results Administration of ketamine with dexmedetomidine but not fentanyl significantly increased SDLP (F1,18 = 22.60, P < 0.001) and reduced SV (F1,18 = 164.42, P < 0.001) 2 hours after treatment. These deficits were comparatively greater for the KET/DEX group than for the KET/FENT group (t37 = −5.21 [P < 0.001] and t37 = 5.22 [P < 0.001], (respectively). For the KET/DEX group, vehicle control (SV) and self-rated performance (visual analog scale), but not SDLP, was inversely associated with ketamine and norketamine blood concentrations (in nanograms per milliliter). Greater subjective effects were moderately associated with driving deficits. Implications/Conclusions Driving simulator performance is significantly compromised after coadministration of analgesic range doses of ketamine with dexmedetomidine but not fentanyl. An extended period of supervised driver abstinence is recommended after treatment, with completion of additional assessments to evaluate home readiness.

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

The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications 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 Δ9-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. Δ9-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.

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 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.

The Use of Antidepressant Medications During Pregnancy and the Risk of Neonatal Seizures: A Systematic Review Purpose This review examined the current literature about the potential relationship between the use of antidepressants during pregnancy and neonatal seizures. Methods PubMed was searched for English language reports published between January 1, 1996, and October 31, 2018, by using combinations of the following key words: pregnancy, neonatal outcome, neonatal convulsion, neonatal seizure, SSRI, selective serotonin norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), antidepressants, sertraline, fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, venlafaxine, mirtazapine, duloxetine, bupropion, amitriptyline, imipramine, and clomipramine. Findings A total of 9 relevant studies that met the review criteria were examined. The prevalence rates of neonatal seizures in the antidepressant groups and control groups were 0.30% to 0.91% and 0.10% to 0.30%, respectively. The use of selective serotonin reuptake inhibitors was associated with up to 5-fold increase in the risk of neonatal seizures. Compared with the controls, higher risks were reported in newborns of pregnant women using any antidepressant or tricyclic antidepressants albeit in a limited number of studies. Exposure to antidepressants in the third trimester of pregnancy appeared to be associated more with neonatal seizures compared with earlier exposure. Implicatons Although an increased risk of neonatal seizures in newborns antenatally exposed to antidepressants especially selective serotonin reuptake inhibitors may be suggested, the available studies have severe methodological limitations to enable any firm conclusion.