Drug Whisperer (May-June 2016)

1. If You Have To Prescribe A 2nd Generation Antidepressant, Make Your Choice Based Only On The Onset Of Action And Side-Effect Profile

BACKGROUND: Second-generation antidepressants dominate the management of major depressive disorder (MDD), but evidence on the comparative benefits and harms of these agents is contradictory. 

PURPOSE: To compare the benefits and harms of second-genera- tion antidepressants for treating MDD in adults.

DATA SOURCES: English-language studies from PubMed, Embase, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to August 2011 and reference lists of pertinent review articles and gray literature.

STUDY SELECTION: 2 independent reviewers identified ran- domized trials of at least 6 weeks’ duration to evaluate efficacy and observational studies with at least 1000 participants to assess harm. 

DATA EXTRACTION: Reviewers abstracted data about study design and conduct, participants, and interventions and outcomes and rated study quality.A senior reviewer checked and confirmed extract- ed data and quality ratings.

DATA SYNTHESIS: Meta-analyses and mixed-treatment compari- sons of response to treatment and weighted mean differences were conducted on specific scales to rate depression. On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and mainte- nance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, eth- nicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life.

LIMITATIONS: Most trials were conducted in highly selected populations. Publication bias might affect the estimates of some com- parisons. Mixed-treatment comparisons cannot conclusively exclude differences in efficacy. Evidence within subgroups was limited. 

CONCLUSION: Current evidence does not warrant recommend- ing a particular second-generation antidepressant on the basis of dif- ferences in efficacy. Differences in onset of action and adverse events may be considered when choosing a medication.

PRIMARY FUNDING SOURCE: Agency for Healthcare Re- search and Quality.

Gartlehner G, et al. Comparative benefits and harms of second-gen- eration antidepressants for treating major depressive disorder: an up- dated meta-analysis. Ann Intern Med. 2011 Dec 6;155(11):772-85. doi: 10.7326/0003-4819-155-11-201112060-00009.

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2. Calcium Channel Blocker May Not Be A Good Antihy- pertensive For Patients With Chronic Kidney Disease

BACKGROUND/AIMS: The use of antihypertensive medicines has been shown to reduce proteinuria, morbidity, and mortality in pa- tients with chronic kidney disease (CKD).A specific recommendation for a class of antihypertensive drugs is not available in this population, despite the pharmacodynamic differences.We have therefore analysed the association between antihypertensive medicines and survival of pa- tients with chronic kidney disease.

METHODS: Out of 2687 consecutive patients undergoing kidney biopsy a cohort of 606 subjects with retrievable medical therapy was included into the analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy. Main outcome variable was death.

RESULTS: Overall 114 (18.7%) patients died. In univariate regres- sion analysis the use of alpha-blockers and calcium channel antagonists, progression of disease, diabetes mellitus (DM) type 1 and 2, arterial hypertension, coronary heart disease, peripheral vascular disease, male sex and age were associated with mortality (all p<0.05). In a multi- variate Cox regression model the use of calcium channel blockers (HR 1.89), age (HR 1.04), DM type 1 (HR 8.43) and DM type 2 (HR 2.17) and chronic obstructive pulmonary disease (HR 1.66) were associated with mortality (all p < 0.05).

CONCLUSION: The use of calcium channel blockers but not of other antihypertensive medicines is associated with mortality in pri- marily GN patients with CKD.

Haider DG, et al. Use of Calcium Channel Blockers is Associated with Mortality in Patients with Chronic Kidney Disease. Kidney Blood Press Res. 2015;40(6):630-7. doi: 10.1159/000368539. Epub 2015 Dec 17.

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3. Histamine Receptor H1 Antagonists May Have A Role In The Management Of Irritable Bowel Syndrome.

BACKGROUND & AIMS: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. 

METHODS: By using live calcium imaging, we compared activation of submucosal neu- rons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects.The sensitization of TRPV1 by hista- mine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons.We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis.The pri- mary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension.

RESULTS: TRPV1 responses of submu- cosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their preincubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidaz- ole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22;P = .0004). 

CONCLUSIONS: In studies of rectal biopsy specimens from patients, we found that HRH1- mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and ab- dominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS.

Wouter MM, et al. Histamine Receptor H1- Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome. Gas- troenterology. 2016 Apr;150(4):875-887.e9. doi: 10.1053/j.gastro.2015.12.034. Epub 2016 Jan 2.