Ketamine’s Antidepressant Efficacy is Extended for at Least Four Weeks in Subjects with a Family History of an Alcohol Use Disorder

Background:

A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine’s antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine’s antidepressant efficacy.

Methods:

Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100–200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17).

Results:

FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9).

Conclusions:

Ketamine’s extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.     

Can Atypical Antipsychotic Augmentation Reduce Subsequent Treatment Failure More Effectively Among Depressed Patients with a Higher Degree of Treatment Resistance? A Meta-Analysis of Randomized Controlled Trials

Background:

Atypical antipsychotic augmentation was demonstrated to be efficacious in treatment-resistant depression (TRD) in previous meta-analyses. We investigate whether there are differences in the effect size of atypical antipsychotic augmentation in major depressive disorder according to the degree of treatment resistance.

Methods:

A comprehensive search of four databases identified 11 randomized controlled trials. The 11 trials, which included 3 341 participants, were pooled using a random-effects meta-analysis.

Results:

Atypical antipsychotic augmentation of antidepressant therapy showed superior efficacy compared to antidepressant monotherapy in TRD in terms of both response and remission rates (response, risk ratio [RR] = 1.38, 95% confidence interval [CI] = 1.25 to 1.53; remission, RR = 1.62, 95% CI = 1.42 to 1.85). In addition, regarding response rates in the TRD trials, atypical antipsychotic augmentation exhibited significantly different effect sizes according to the degree of treatment resistance (TRD 1: RR = 1.24; TRD 2: RR = 1.37; TRD 2–4: RR = 1.58). In non-TRD trials, atypical antipsychotic augmentation failed to show superior efficacy over antidepressant monotherapy in terms of remission rates (RR = 0.89; 95% CI = 0.69 to 1.14). Atypical antipsychotic augmentation of antidepressant therapy exhibits greater effect size in patients with a higher degree of treatment resistance.

Conclusions:

This finding strengthens the rationale for considering atypical antipsychotic augmentation among depressed patients with multiple previous treatment failures in clinical practice. The efficacy of atypical antipsychotic augmentation for non-TRD seems to be different from that for TRD and, thus, further studies of non-TRD populations are needed.     

Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Background:

Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).

Methods:

Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.

Results:

All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).

Conclusions:

All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.     

Extensive Gray Matter Volume Reduction in Treatment-Resistant Schizophrenia

Background:

Approximately one-third of people with schizophrenia are treatment-resistant and some do not achieve remission with clozapine, the gold-standard antipsychotic medication for treatment-resistant schizophrenia. This study compared global and regional brain volumes between treatment-respondent and treatment-resistant patients with schizophrenia, including a group of patients who were clozapine-resistant.

Methods:

T1-weighted brain MRIs were obtained on a 3T scanner in 20 controls and 52 people with schizophrenia who were selected based on their symptomatic responses to antipsychotic medication: 18 responded well to first-line atypical antipsychotics (FLR), 19 were treatment-resistant but responsive to clozapine monotherapy (TR), and 15 were ultra-treatment-resistant and did not respond to clozapine (UTR). Treatment groups were matched for disease duration and current psychopathology. SIENAX and FSL-VBM were used to investigate differences in the global brain, gray matter (GM), white matter, ventricular cerebrospinal fluid volumes, and regional GM volumes.

Results:

GM volume was significantly reduced in the TR and UTR groups compared with controls and the FLR group (p < 0.05). GM volume was significantly reduced in TR patients compared with FLRs in the superior, middle, and inferior temporal gyri, pre- and post-central gyri, middle and superior frontal gyri, right supramarginal gyrus, and right lateral occipital cortex. UTR patients showed reduced GM compared with FLRs in their right parietal operculum and left cerebellum. No significant volume differences were observed between TR and UTR groups.

Conclusions:

These differences are unlikely to be solely due to medication effects, and reduced GM volume in treatment-resistant schizophrenia may represent an accelerated disease course or a different underlying pathology.     

Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study

Background:

The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium.

Methods:

Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction.

Results:

At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with “standard” lithium levels (≥0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time.

Conclusions:

These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.     

Pharmacy Student Knowledge and Communication of Medication Errors

Objectives

To describe and evaluate pharmacy students'' knowledge of and comfort in communicating, managing, and preventing medication errors.

Methods

Using a cross-sectional design, a survey instrument was administered to fifth-year pharmacy students. The survey instrument included both open- and close-ended questions to describe and examine factors associated with knowledge and comfort in communication of medication errors.

Results

Survey instruments were completed by 93 students (90% response rate). Nearly 80% reported not having received training in communicating medication errors. The perception of having more adequate training was related to greater knowledge in the communication of medication errors (p ≤ 0.001). Knowledge was also associated with students having greater comfort in communicating medication errors (p ≤ 0.05).

Conclusions

The need and value of additional training for pharmacy students in communicating medication errors was demonstrated. Educational interventions should be developed to provide consistent instruction on these communication issues.     

Danthron activates AMP-activated protein kinase and regulates lipid and glucose metabolism in vitro

Aim:

To discover the active compound on AMP-activated protein kinase (AMPK) activation and investigate the effects of the active compound 1,8-dihydroxyanthraquinone (danthron) from the traditional Chinese medicine rhubarb on AMPK-mediated lipid and glucose metabolism in vitro.

Methods:

HepG2 and C2C12 cells were used. Cell viability was determined using MTT assay. Real-time PCR was performed to measure the gene expression. Western blotting assay was applied to investigate the protein phosphorylation level. Enzymatic assay kits were used to detect the total cholesterol (TC), triglyceride (TG) and glucose contents.

Results:

Danthron (0.1, 1, and 10 μmol/L) dose-dependently promoted the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in both HepG2 and C2C12 cells. Meanwhile, danthron treatment significantly reduced the lipid synthesis related sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthetase (FAS) gene expressions, and the TC and TG levels. In addition, danthron treatment efficiently increased glucose consumption. The actions of danthron on lipid and glucose metabolism were abolished or reversed by co-treatment with the AMPK inhibitor compound C.

Conclusion:

Danthron effectively reduces intracellular lipid contents and enhanced glucose consumption in vitro via activation of AMPK signaling pathway.     

Glutamatergic Neurometabolites in Clozapine-Responsive and -Resistant Schizophrenia

Background:

According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated.

Methods:

Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects.

Results:

Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η² = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η² = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected).

Conclusions:

Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.     

Polymorphisms in the HOXD4 gene are not associated with peak bone mineral density in Chinese nuclear families

Aim:

To determine the associations between HOXD4 gene polymorphisms with peak bone mineral density (BMD) throughing measuring three tagging single nucleotide polymorphisms (tagSNPs), including rs1867863, rs13418078, and rs4972504, in HOXD4.

Methods:

Four hundred Chinese nuclear families with male offspring (1215 subjects) and 401 Chinese nuclear families with female offspring (1260 subjects) were recruited. BMD of the lumbar spine 1-4 (L1-4) and left proximal femur including total hip and femoral neck were measured by dual-energy X-ray absorptiometry. The quantitative transmission disequilibrium test (QTDT) was performed to investigate the association among the tagging SNPs, haplotypes and peak BMD.

Results:

Only the CC genotype was identified in rs13418078 in the Chinese population, unlike other populations. We failed to find significant within-family association among these SNPs, haplotypes and peak BMD at any bone site in either male- or female-offspring nuclear families.

Conclusion:

The results suggest that genetic polymorphisms in HOXD4 may not be a major contributor to the observed variability in peak BMD in the lumbar spine and the hip in Chinese men and women.     

Neural Correlates of Suicidal Ideation and Its Reduction in Depression

Background:

The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion.

Methods:

Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5mg/kg for 40 minutes).

Results:

Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=−.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression.

Conclusion:

The infralimbic cortex may be implicated in suicidal ideation.     

Inpatient prescribing errors and pharmacist intervention at a teaching hospital in Saudi Arabia

Background

Prescribing errors phenomena are very common within health care practice. These errors could result in adverse events and harm to patients. Pharmacist has an identified role in minimizing and preventing such errors.

Objectives

To detect the incidence of prescribing errors for hospitalized patient, to evaluate the clinical impact of pharmacist intervention on the detection of these errors, and to propose a program to overcome this problem in a teaching hospital.

Methods

For one month period starting November until December 2009, the inpatient medication charts and orders were identified and rectified by ward and practicing pharmacists within inpatient pharmacy services in a teaching hospital at King Khalid University Hospital (KKUH) at King Saud University, Riyadh, Kingdom of Saudi Arabia on routine daily activities. Data were collected and evaluated. The causes of this problem were identified.

Results

Approximately 113 (7.1%) prescribing errors were detected during the study period out of 1580 medication orders. Wrong strength and wrong administration frequency of the prescribed drug were the most errors encountered in the study, which were 35%, and 23%, respectively. Other errors such as wrong patient, wrong drug, and wrong dose were also encountered. Lack of knowledge of prescribing skill was the main cause of such errors.

Conclusion

Prescribing errors in teaching hospital within inpatient pharmacy services were noticed. The applied method in this project might be implemented as part of pharmacy quality assurance program for ongoing detection and monitoring of such errors. Technology in prescribing process will support the practitioner to reduce the incidence of these errors. Forcing ongoing professional communication and education within the medical team about prescribing errors now appear warranted.     

Effects of smoking cessation, acute re-exposure and nicotine replacement in smokers on AIR inhaled insulin pharmacokinetics and glucodynamics

Aims

To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR® inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT).

Methods

Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8–12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD.

Results

Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced.

Conclusion

Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.

What is already known about this subject

• Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers.

What this study adds

• This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR® inhaled insulin pharmacokinetics and glucodynamics.
• We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable.
• Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response.

     

A Computer-based Module for Prescribing Error Instruction

Objective

To evaluate an instructional module''s effectiveness at changing third-year doctor of pharmacy (PharmD) students'' ability to identify and correct prescribing errors.

Design

Students were randomized into 2 groups. Using a computer-based module, group 1 completed worksheet A, watched a presentation on medication errors, and then completed worksheets B and C. Group 2 completed worksheets A and B, watched the presentation, and then completed worksheet C.

Assessment

Both groups scored a median 50% on worksheet A and 66.7% on worksheet C (p < 0.001). Median scores on worksheet B differed between groups (p = 0.0014). Group 1 viewed the presentation before completing worksheet B and scored 62.5%, while group 2 viewed the presentation after scoring 50% on worksheet B.

Conclusion

The module effectively taught pharmacy students to identify and correct prescribing errors.     

Clinical and Financial Impact of Pharmacist Involvement in Discharge Medication Reconciliation at an Academic Medical Center: A Prospective Pilot Study

Background:

Medication reconciliation is one of the more challenging aspects of inpatient care, and its accuracy is paramount to safe transitions of care. Studies have shown that pharmacists have a role in medication reconciliation through improving patient safety and avoiding costs associated with medication errors. The wide-scale use of pharmacists in this process has been limited by time constraints, cost, and lack of resources.

Objective:

This study evaluates the impact of pharmacists in resolving medication errors, decreasing readmission rates, and reducing institutional costs during the discharge medication reconciliation process.

Methods:

Pharmacists evaluated discharge medication reconciliation documentation for patients to determine its accuracy, the accuracy of the admission reconciliation documentation, and any potential issues unrelated to accuracy. Analysis of these data determined the time required for pharmacist involvement, the number of errors identified by pharmacists, the quality of pharmacist interventions, the cost avoidance for each error, and the overall impact on hospital readmission.

Results:

During the 7-week study period, pharmacists performed 67 discharge medication reviews and identified 84 errors. Seventy-five percent were considered to be significant and 6% were considered to be serious. The 30-day readmission rate in the study cohort was 18% compared with 20% in the control group. Based on the clinical severity scale and pharmacist salaries, pharmacist interventions resulted in $42,300 in cost avoidance.

Conclusion:

Pharmacists involved in this pilot discharge process identified and resolved significant errors on medication reconciliation orders that resulted in a financial benefit to the institution.     

Development of a simplified protocol for administration of 20% magnesium sulphate for prophylaxis and treatment of eclampsia

Background:

Magnesium sulphate is a high-risk medication that is used extensively for prophylaxis and treatment of eclampsia. To accommodate recommendations related to fluid restrictions and patient safety, a protocol was developed for the administration of 20% magnesium sulphate.

Objectives:

To determine whether administration of 20% magnesium sulphate increased the risk of phlebitis relative to 2% to 8% magnesium sulphate solutions, to determine if the institution’s protocol for administration of 20% magnesium sulphate reduced errors during administration, and to identify strategies to further reduce potential errors.

Methods:

A retrospective chart audit was undertaken for patients who had received magnesium sulphate for prophylaxis of eclampsia from December 2004 to December 2007. A failure mode and effect analysis was used to identify additional safety strategies.

Results:

A total of 47 patients received magnesium sulphate according to the old administration protocol (2% to 8% solution) and 29 according to the new protocol (20% solution). No evidence of phlebitis was documented for any of these 76 patients. A few errors occurred with changes in rates or concentrations and because of failure to reset the pump after the loading dose, but there was no documented harm to any of the patients. Strategies to further reduce errors in the administration of magnesium sulphate included development of preprinted orders, use of 20% magnesium sulphate for all infusion rates, changes to pump settings to enable use of fractional infusion rates, preparation of magnesium sulphate in mini-bags in the pharmacy, double-check of pump settings by nurses, anesthesiology consult, and distribution of protocols to all areas in the hospital (to limit errors associated with patient transfers).

Conclusions:

There was no documented phlebitis, and fewer errors occurred when 20% magnesium sulphate was used. Several additional strategies were identified to reduce errors in the administration of this high-risk medication.