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Background Clozapine has demonstrated efficacy in treating treatment-resistant schizophrenia; however, it has a wide range of side effects. Sialorrhea is a common side effect of clozapine that causes the patient to withdraw from social life. This review aims to evaluate and summarize the prevalence, mechanism, risk factors, and management of clozapine-associated sialorrhea. Procedures The literature was explored for the prevalence, the mechanisms, the risk factors, and the management of sialorrhea. The following search strings and terms were used: “clozapine,” “sialorrhea,” “hypersalivation,” “clozapine induced sialorrhea,” and “clozapine induced hypersalivation”. Study Results Hypersalivation is one of the most common side effects of clozapine. Over the course of clozapine therapy, hypersalivation has been reported to have an incidence of 30% to –80%. Although different treatment approaches are applied on a case-by-case basis in the clinic, depending on the practitioners' preferences, there is a lack of clear guidelines for managing this common side effect that jeopardizes patients' social life. Conclusions It is important for healthcare professionals and patients that some clear treatment options for clozapine-associated sialorrhea are brought to the forefront and widely used, especially based on the research conducted to date.

Background Sodium valproate has been coprescribed with clozapine for seizure prophylaxis and for augmentation in treatment-refractory schizophrenia. However, the effect of valproate on clozapine metabolism and on the incidence of clozapine-related side effects is unclear. Methods We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in smokers and nonsmokers of both sexes in samples submitted for clozapine therapeutic drug monitoring, 1996–2017 in relation to valproate coprescription. Results There were 1217 (665 patients) and 3823 (1600 patients) samples from nonsmokers and from smokers, respectively, who were coprescribed valproate and clozapine. Data from 9774 (5065 patients) and 15,465 (7298 patients) samples from nonsmokers and from smokers, respectively, for whom drugs other than valproate were coprescribed were used as controls. Valproate coprescription in nonsmokers was associated with an increase in average plasma clozapine of 22.5%, suggesting moderate inhibition of clozapine metabolism, but there was no marked effect of valproate coprescription on plasma clozapine in smokers. In all the valproate-treated groups (male and female smokers and nonsmokers), the median plasma norclozapine concentration and the median plasma clozapine-to-norclozapine ratio were significantly lower and higher, respectively, as compared with the controls. Mixed-effects models showed a significant dose-response effect of valproate on lowering the plasma norclozapine concentration and on increasing the plasma clozapine-to-norclozapine ratio. Implications Given the complexity of the effect of valproate coadministration on clozapine pharmacokinetics and the possibility that the toxicity of clozapine may be enhanced in the presence of valproate, the use of these drugs in combination must now be questioned in all patients and not only in women of childbearing age.

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Purpose/Background Antipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations. Methods/Procedures This 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days. Findings/Results In a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics. Implications/Conclusions APP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.

Purpose The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty. Methods In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data. Results After the baseline height Z-score, sex, Tanner stage, daily selective serotonin reuptake inhibitor (SSRI) dose, and time were accounted for, the interaction effect of dose by time was inversely associated with height Z-score in SSRI-treated participants (β = −0.18; 95% confidence interval [CI]: −0.35, −0.02). Sertraline and fluoxetine did not differ in their effect on height growth. Compared with being unmedicated, SSRI treatment was associated with a smaller growth in height (time × dose 2-way interaction effect β = −1.30; 95% CI: −2.52, −0.09). The interaction effect of dose by time was significant for body mass index Z-score (β = 0.35; 95% CI: 0.06, 0.64) but not weight Z-score (β = 0.24; 95% CI: −0.01, 0.49). Body mass index Z-score increased more with sertraline compared with fluoxetine (time × dose × SSRI type 3-way interaction effect P < 0.05). SSRI dose was inversely associated with IGF-1 (β = −63.5; 95% CI: −112.2, −14.7) but not insulin growth factor binding protein-3 concentration (β = −207.3; 95% CI: −536.2, 121.5). Conclusions Fluoxetine and sertraline reduce height gain and IGF-1 concentration, in a dose-dependent manner. Longer-term studies are necessary.

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Purpose The efficacy and safety of valbenazine, a selective vesicular monoamine transporter 2 inhibitor, has been confirmed for treatment of tardive dyskinesia (TD) in patients aged ≥65 years in non-Asian clinical trials; however, data are lacking in elderly Asian patients. This post hoc analysis of J-KINECT aimed to evaluate the efficacy and safety of valbenazine in elderly Japanese patients with TD. Methods J-KINECT was a randomized, double-blind, placebo-controlled study with a 6-week double-blind, placebo-controlled period; 42-week double-blind, valbenazine extension period; and 4-week posttreatment observation period. Outcomes were summarized by age (≥65 years [elderly] and <65 [nonelderly]) and treatment group. Results The safety analysis set included 100 and 153 patients aged ≥65 and <65 years, respectively (intention-to-treat set: 98 and 151 patients, respectively). In the elderly group, the difference versus placebo in least-squares mean change from baseline in the Abnormal Involuntary Movement Scale total score at week 6 was −3.1 (95% confidence interval: −4.5, −1.7) and −5.5 (−7.0, −3.9) with valbenazine 40 and 80 mg, respectively; in the nonelderly group, respective differences were −1.5 (−2.6, −0.4) and −2.5 (−3.6, −1.3). Both age groups showed improvement in Clinical Global Impression of Change–Tardive Dyskinesia scores with valbenazine. The incidence of treatment-emergent adverse events (TEAEs) leading to treatment discontinuation was higher in the elderly versus nonelderly group. There was no trend toward higher incidences of TEAEs or related TEAEs in the elderly group. Conclusions The findings suggest that valbenazine may be used effectively and safely as a treatment for TD, even in elderly patients.