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The effect of sublingual atropine sulfate on clozapine-induced hypersalivation: a multicentre, randomised placebo-controlled trial.
Mubaslat, O, Lambert, T
Psychopharmacology. 2020;(10):2905-2915
Abstract
BACKGROUND Hypersalivation and drooling are commonly reported in clozapine-treated patients. Current management strategies have been evaluated using subjective measures. Many case reports describe the successful use of atropine in the treatment of the condition. AIMS To measure the effect and safety of sublingual atropine on nocturnal unstimulated saliva secretion. Secondary aims were to evaluate the patient's satisfaction with the atropine effect on hypersalivation (or sialorrhea), drooling, and sleep. METHOD Twenty-one clozapine-treated patients with hypersalivation, or drooling, were randomised to take a single 600-μg dose of sublingual atropine drops or a matching placebo. The saliva secretion was measured over 5 min at baseline and 2 h after the administration of the study medication. RESULTS Sublingual atropine reduced the saliva secretion significantly more than the placebo (mean difference = - 57.21%, 95% CI: - 104.30, - 10.11, P = 0.02). A significant decrease in standing pulse rate was recorded in the participants in the atropine group (- 5.8 (- 9.54, - 2.15), P = 0.002). Subjectively, more patients in the atropine group found their pillow to have less saliva the following morning and found their sleep to be better. CONCLUSIONS Sublingual atropine drops significantly reduces nocturnal unstimulated clozapine-induced saliva secretion. More research is required to compare the effect of sublingual atropine with other anticholinergic medications and different dosage forms. TRIAL REGISTRATION ACTRN12618000051246.
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Disparate effects of first and second generation antipsychotics on cognition in schizophrenia - Findings from the randomized NeSSy trial.
Veselinović, T, Scharpenberg, M, Heinze, M, Cordes, J, Mühlbauer, B, Juckel, G, Habel, U, Rüther, E, Timm, J, Gründer, G, et al
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2019;(6):720-739
Abstract
Cognitive impairment represents a core feature of schizophrenia. Uncertainty about demonstrable benefits of available antipsychotics on cognition remains an important clinical question relevant to patients' quality of life. The aim of our multi-center, randomized, double-blind "Neuroleptic Strategy Study" (NeSSy) was to compare the effectiveness of selected antipsychotics, conventionally classified as second- (SGAs) (haloperidol, flupentixol) and first generation antipsychotics (FGAs) (aripiprazole, olanzapine, quetiapine), on quality of life in schizophrenia. The effects on cognitive deficits represented a secondary outcome. We used an innovative double randomization for assignment of treatment group, and followed the patients with a neurocognitive test-battery upon six and 24 weeks of treatment. Psychopathology and quality of life were assessed using CGI, PANSS and SF-36. Assessment of cognitive performance was conducted in 114 of the 136 randomized patients. The SGA group (N = 62) showed beneficial effects of small to moderate effect size on cognition during the initial six weeks of treatment (executive functions, verbal fluency) and at 24 weeks (executive functions, working memory). In contrast, the FGA group (N = 52) showed moderately improved executive function, but a decline in verbal fluency at six weeks, with significant declines of moderate to large effect size in executive function, verbal learning and memory, and verbal fluency at 24 weeks. Our study indicates that SGAs present an advantage over FGAs regarding cognitive function during a medium-term treatment for schizophrenia. The results further emphasize a distinction between progression to detrimental effects of FGAs with prolonged treatment in contrast to more persistent cognitive benefits with SGA treatment.
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Prophylactic Haloperidol Effects on Long-term Quality of Life in Critically Ill Patients at High Risk for Delirium: Results of the REDUCE Study.
Rood, PJT, Zegers, M, Slooter, AJC, Beishuizen, A, Simons, KS, van der Voort, PHJ, van der Woude, MCE, Spronk, PE, van der Hoeven, JG, Pickkers, P, et al
Anesthesiology. 2019;(2):328-335
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Abstract
BACKGROUND Delirium incidence in intensive care unit patients is high and associated with impaired long-term outcomes. The use of prophylactic haloperidol did not improve short-term outcome among critically ill adults at high risk of delirium. This study evaluated the effects of prophylactic haloperidol use on long-term quality of life in this group of patients and explored which factors are associated with change in quality of life. METHODS A preplanned secondary analysis of long-term outcomes of the pRophylactic haloperidol usE for DeliriUm in iCu patients at high risk for dElirium (REDUCE) study was conducted. In this multicenter randomized clinical trial, nondelirious intensive care unit patients were assigned to prophylactic haloperidol (1 or 2 mg) or placebo (0.9% sodium chloride). In all groups, patients finally received study medication for median duration of 3 days [interquartile range, 2 to 6] until onset of delirium or until intensive care unit discharge. Long-term outcomes were assessed using the Short Form-12 questionnaire at intensive care unit admission (baseline) and after 1 and 6 months. Quality of life was summarized in the physical component summary and mental component summary scores. Differences between the haloperidol and placebo group and factors associated with changes in quality of life were analyzed. RESULTS Of 1,789 study patients, 1,245 intensive care unit patients were approached, of which 887 (71%) responded. Long-term quality of life did not differ between the haloperidol and placebo group (physical component summary mean score of 39 ± 11 and 39 ± 11, respectively, and P = 0.350; and mental component summary score of 50 ± 10 and 51 ± 10, respectively, and P = 0.678). Age, medical and trauma admission, quality of life score at baseline, risk for delirium (PRE-DELIRIC) score, and the number of sedation-induced coma days were significantly associated with a decline in long-term quality of life. CONCLUSIONS Prophylactic haloperidol use does not affect long-term quality of life in critically ill patients at high risk for delirium. Several factors, including the modifiable factor number of sedation-induced coma days, are associated with decline in long-term outcomes.
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Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial.
Lin, CH, Lin, CH, Chang, YC, Huang, YJ, Chen, PW, Yang, HT, Lane, HY
Biological psychiatry. 2018;(6):422-432
Abstract
BACKGROUND Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of N-methyl-D-aspartate receptors, including inhibition of D-amino acid oxidase that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a D-amino acid oxidase inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine. METHODS We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for 6 weeks' add-on treatment of 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, and Global Assessment of Functioning. Side effects and cognitive functions were also measured. RESULTS Both doses of sodium benzoate produced better improvement than placebo in the Scale for the Assessment of Negative Symptoms. The 2 g/day sodium benzoate also produced better improvement than placebo in PANSS-total score, PANSS-positive score, and Quality of Life Scale. Sodium benzoate was well tolerated without evident side effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS-total score and PANSS-positive score in the sodium benzoate group. CONCLUSIONS Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.
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Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.
Wilcock, GK, Gauthier, S, Frisoni, GB, Jia, J, Hardlund, JH, Moebius, HJ, Bentham, P, Kook, KA, Schelter, BO, Wischik, DJ, et al
Journal of Alzheimer's disease : JAD. 2018;(1):435-457
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BACKGROUND LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
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Superwellness Program: a cognitive-behavioral therapy-based group intervention to reduce weight gain in patients treated with antipsychotic drugs.
Magni, LR, Ferrari, C, Rossi, G, Staffieri, E, Uberti, A, Lamonaca, D, Boggian, I, Merlin, S, Primerano, G, Mombrini, A, et al
Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2017;(3):244-251
Abstract
OBJECTIVE To assess the effectiveness of a cognitive-behavioral therapy-based intervention (Superwellness Program) on weight gain compared with a treatment-as-usual (TAU) approach in patients treated with antipsychotics, and to evaluate the relationship between body mass index (BMI) variation and clinical variables. METHOD Eighty-five patients treated with antipsychotics were allocated across two groups, experimental (n=59) and control (n=26). The Superwellness Program (experimental group) consisted of 32 twice-weekly 1-hour sessions, conducted by a psychologist and a nutritionist/nurse, concurrently with moderate food intake and moderate physical activity plans. Sociodemographic, clinical, and biological variables were collected at baseline, at the end of intervention (16 weeks), and after 6 months. RESULTS BMI change from baseline differed significantly between the experimental and control groups, with a larger decrease in the experimental group (F = 5.5, p = 0.021). Duration of illness moderated the effect of treatment on BMI (p = 0.026). No significant (p = 0.499) effect of intervention during the follow-up period was found. Interestingly, the intervention indirectly induced a significant (p = 0.024) reduction in metabolic risk by reducing BMI. CONCLUSION A cognitive-behavioral therapy-based intervention could be useful in reducing weight in a clinical population taking antipsychotics, with consequent benefit to physical and mental health.
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Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia.
Dunayevich, E, Buchanan, RW, Chen, CY, Yang, J, Nilsen, J, Dietrich, JM, Sun, H, Marder, S
Schizophrenia research. 2017;:90-97
Abstract
OBJECTIVE To determine the safety and efficacy of AMG 747, an oral inhibitor of glycine transporter type-1 (GlyT1), as an add-on to antipsychotic therapy in clinically stable people with schizophrenia with enduring negative symptoms. METHOD Analysis of pooled data from two phase 2 studies. Adults diagnosed with schizophrenia stabilized on antipsychotic medication randomized (2:2:2:3) to orally receive daily AMG 747 (5mg, 15mg, or 40mg) or placebo. Primary endpoint was Negative Symptom Assessment (NSA)-16 total score change from baseline to week 12. RESULTS Studies were terminated early after a report of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in one participant (40-mg AMG 747). At termination, 232 participants had enrolled and 153 completed 12weeks of treatment. At week 12, change from baseline NSA-16 total score showed no differences between groups. Mean decrease in Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) and NSA-16 global score were greater with 15-mg AMG 747 than placebo (p<0.05). Changes in PANSS-Positive Symptom Factor Scale were not significantly different for any group. Changes in patient-reported outcomes (Sheehan Disability Scale and Quality of Life Enjoyment and Satisfaction Questionnaire) showed trends consistent with greater efficacy of 15-mg AMG 747 compared with placebo (p≤0.1). Adverse event rates were similar among all groups, with no clear differences observed. CONCLUSIONS Significant treatment effects of 15-mg AMG 747, but not higher or lower doses, were observed on secondary endpoints but not on the primary outcome. These results replicate previous reports of an inverted-U dose response curve and suggest further evaluation of GlyT1 inhibitors in schizophrenia negative symptoms is warranted. TRIAL REGISTRATION Clinicaltrials.govNCT01568216 (https://clinicaltrials.gov/ct2/show/NCT01568216) and NCT01568229 (https://clinicaltrials.gov/ct2/show/NCT01568229?term=NCT01568229&rank=1); EudraCT number 2011-004844-23 and 2011-004845-42.
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Electrocardiogram Alterations Associated With Psychotropic Drug Use and CACNA1C Gene Variants in Three Independent Samples.
Fabbri, C, Boriani, G, Diemberger, I, Filippi, MG, Ravegnini, G, Hrelia, P, Minarini, A, Albani, D, Forloni, G, Angelini, S, et al
Basic & clinical pharmacology & toxicology. 2017;(5):482-490
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Several antipsychotics and antidepressants have been associated with QTc prolongation or other electrocardiogram (ECG) alterations, but their impact is still debated and other risk factors are known to affect QTc. We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n = 145 and prospective sample n = 68, naturalistic treatment) and a replication prospective sample (Clinical Antipsychotic Trials of Intervention Effectiveness, n = 515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated. There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥20 msec.) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular comorbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs.
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Improvement in Body Image, Perceived Health, and Health-Related Self-Efficacy Among People With Serious Mental Illness: The STRIDE Study.
Yarborough, BJ, Leo, MC, Yarborough, MT, Stumbo, S, Janoff, SL, Perrin, NA, Green, CA
Psychiatric services (Washington, D.C.). 2016;(3):296-301
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OBJECTIVE The authors examined secondary outcomes of STRIDE, a randomized controlled trial that tested a weight-loss and lifestyle intervention for individuals taking antipsychotic medications. METHODS Hierarchical linear regression was used to explore the effects of the intervention and weight change at follow-up (six, 12, and 24 months) on body image, perceived health, and health-related self-efficacy. RESULTS Participants were 200 adults who were overweight and taking antipsychotic agents. Weight change × study arm interaction was associated with significant improvement in body image from baseline to six months. From baseline to 12 months, body image scores of intervention participants improved by 1.7 points more compared with scores of control participants; greater weight loss was associated with more improvement. Between baseline and 24 months, greater weight loss was associated with improvements in body image, perceived health, and health-related self-efficacy. CONCLUSIONS Participation in STRIDE improved body image, and losing weight improved perceived health and health-related self-efficacy.
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The ASCOMALVA (Association between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in Alzheimer's Disease) Trial: interim results after two years of treatment.
Amenta, F, Carotenuto, A, Fasanaro, AM, Rea, R, Traini, E
Journal of Alzheimer's disease : JAD. 2014;:S281-8
Abstract
Cholinesterase inhibitors (ChE-Is) are used for symptomatic treatment of mild-to-moderate Alzheimer's disease (AD), but long-term effects of these compounds are mild and not always obvious. Preclinical studies have shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. The trial has recruited AD patients suffering from ischemic brain damage documented by neuroimaging and has completed 2 years of observation in 113 patients of the 210 planned. Patients were randomly allotted to an active treatment group (donepezil + choline alphoscerate) or to a reference group (donepezil + placebo). Cognitive functions were assessed by the Mini-Mental State Evaluation and Alzheimer's Disease Assessment Scale Cognitive subscale. Daily activity was evaluated by the basic and instrumental activities of daily living tests. Behavioral symptoms were assessed by the Neuropsychiatric Inventory. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the different items analyzed. These findings suggest that the combination of choline alphoscerate with a ChE-I may prolong/increase the effectiveness of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.