Effect of verapamil on the pharmacokinetics of pasireotide in healthy volunteers.

We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 µg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15-24). On day 18, subjects also received pasireotide SC 600 µg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were superimposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91-1.06) for C(max), 0.97 (0.90-1.04) for AUC(last), and 0.98 (0.92-1.05) for AUC(inf). Exploratory analyses showed a 17% (90% CI, 0.72-0.94) reduction in C(trough) and 31% (0.58-0.82) reduction in C(max) (8 hours post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil.

An examination of 26,168 Hamilton Depression Rating Scale scores administered via interactive voice response across 17 randomized clinical trials.

This article presents descriptive and psychometric data from 26,168 Hamilton Depression Rating Scale (HAM-D) scores administered via Interactive Voice Response (IVR) in 17 randomized clinical trials sponsored by 6 pharmaceutical companies. To provide evidence for construct validity, the IVR HAM-D scores before and after randomization are compared, and the change in the IVR HAM-D scores over time after randomization are examined. In addition, the evidence for the reliability of the IVR-administered HAM-D is presented. An examination of the distribution of first-time IVR HAM-Ds before randomization may provide useful information to researchers planning to use the IVR HAM-D as a screening tool for entry or to verify baseline severity in randomized clinical trials.

Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression.

BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

Open-label study of mirtazapine orally disintegrating tablets in depressed patients in the nursing home.

OBJECTIVE: To evaluate the efficacy and tolerability of mirtazapine orally disintegrating tablets in depressed, elderly nursing home residents, under naturalistic study conditions. METHODS: In this open-label 12-week study, mirtazapine orally disintegrating tablets (15-45 mg/day) were administered to patients > or =70 years old with physician-diagnosed depression and a Mini-Mental State Examination (MMSE) score > or =10. Patients with medical comorbidities, cognitive impairment and/or concomitant medications were enrolled if they met study inclusion criteria and had illnesses and/or medication dosages that were considered stable. Assessments were performed at baseline by physicians and at days 14, 28, 56, and 84 (or early termination) by physicians or nurse coordinators using the Clinical Global Impression (CGI) scale, the 16-item Hamilton Rating Scale for depression (Ham-D-16 (the standard 17-item scale minus item 14)), and the Cornell Scale for Depression in Dementia (CSDD). Tolerability was evaluated based on treatment-emergent adverse events. RESULTS: A total of 119 patients in the intent-to-treat (ITT) group were treated with mirtazapine orally disintegrating tablets (mean daily dose: 19.4 mg) and evaluated for efficacy. At endpoint, 54% of patients in the ITT group showed CGI-I response (defined as a CGI-I score of 1 or 2 ('very much' or 'much' improved) and 47% were Ham-D-16 responders (defined as decrease from baseline of at least 50% in Ham-D-16 total score). CSDD mean scores and Ham-D-16 mean total scores demonstrated a progressive decrease from baseline to trial completion. The decrease in Ham-D scores from baseline to day 84 was statistically significant (p < 0.0001). Mean changes from baseline to day 84 were -6.6 +/- 6.9 (CSDD score) and -7.9 +/- 7.4 (Ham-D-16 total score). Ham-D Factor I, Factor VI and item 1 scores also decreased. Fourteen of 124 patients in the all-subjects-treated (AST) group (11.3%) discontinued prematurely due to adverse events. The most frequently occurring adverse events were urinary tract infection (19%), accidental injury (18%), fall (18%), somnolence (12%), and upper respiratory infection (12%). Mean body weight increased by 0.7 +/- 2.25 kg (1.54 +/- 5 lb) from baseline to day 28, and by 1.3 +/- 3.36 kg (2.86 +/- 7.4 lb) from baseline to day 84. CONCLUSIONS: The results suggest that mirtazapine orally disintegrating tablets provide antidepressant efficacy and are a relatively well-tolerated treatment for depression in this patient population of elderly nursing home residents with medical and cognitive comorbidities.

The apolipoprotein E epsilon4 allele and antidepressant efficacy in cognitively intact elderly depressed patients.

BACKGROUND: Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response. METHODS: The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping. RESULTS: Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age. CONCLUSIONS: The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.

Pharmacogenetics of antidepressant medication intolerance.

OBJECTIVE: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). METHOD: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. RESULTS: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. CONCLUSIONS: Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients.

OBJECTIVE: Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks). METHODS: Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events. RESULTS: Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events. CONCLUSION: During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.