The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD.

BACKGROUND AND OBJECTIVE: Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods. METHODS: The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration. RESULTS: Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance. CONCLUSIONS: Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

Apathy after hip fracture: a potential target for intervention to improve functional outcomes.

The authors examined apathy symptoms, their improvement, and their association with functional recovery after a hip fracture. Of 126 participants, 37% had clinically significant apathy symptoms, which predicted functional outcome (i.e., poorer recovery from the fracture among those with higher baseline apathy). Of participants with high baseline apathy, approximately one-third improved; these participants had a better functional outcome than those with persistently high apathy scores. It is concluded that apathy symptoms are common after a hip fracture, but improve in one-third of individuals, with a concomitant functional recovery after hip surgery. Interventions to prevent or improve apathy in elderly persons deserve further attention.

Recovery from major depression in older adults receiving augmentation of antidepressant pharmacotherapy.

OBJECTIVE: Few data are available concerning the utility of augmentation in late-life depression treatment. The authors examined likelihood, speed, and predictors of recovery in older adults receiving augmentation pharmacotherapy after inadequate response to standardized treatment with paroxetine plus interpersonal psychotherapy. METHOD: Depression levels were monitored during open treatment in 195 adults age 70 or older. Patients were grouped by whether they required augmentation (bupropion, nortriptyline, or lithium) and compared on likelihood, time, and predictors of recovery. RESULTS: Augmentation was required for 105 patients (53.8%) because of inadequate treatment response (N=77) or response followed by relapse (N=28). Of these patients, 69 received augmentation and 36 did not (primarily because of consent withdrawal or comorbid medical conditions). Patients receiving augmentation showed lower recovery rates than patients never requiring augmentation: recovery occurred in 50.0% of patients receiving it because of inadequate response, 66.7% of those receiving it after early relapse, and 86.7% of patients never requiring augmentation. Patients receiving augmentation because of inadequate response recovered more slowly, with modestly more side effects than other patients. Greater medical burden and anxiety predicted slower recovery. CONCLUSIONS: Despite a lower likelihood of recovery in elderly people receiving augmentation, the recovery by over one-half of such patients suggests the value of augmentation for those able to tolerate it. Need for augmentation presages slower recovery in patients showing initial inadequate response; those requiring it after early relapse recovered more quickly. Strategies to further improve the likelihood and speed of recovery after initial treatment failure are needed.

Impact of prior treatment exposure on response to antidepressant treatment in late life.

OBJECTIVE: The objective of this study was to describe the correlates of prior antidepressant exposure and its association with response to protocolized treatment in older patients with major depression. METHODS: Based on their prior antidepressant treatment exposure, 193 elderly patients with a major depressive episode were divided into three groups: those with no prior treatment for their current episode (not treated [TN]), those with antidepressant trials of inadequate dose or duration ("treatment-inadequate" [TI]), and those with at least one adequate trial but persisting depression ("treatment-resistant" [TR]). All patients then received protocolized treatment with interpersonal psychotherapy (IPT) and paroxetine plus pharmacologic augmentation if needed. The demographic, clinical, and outcome information were compared among these three groups. RESULTS: Approximately one-third of the patients referred to the study had been adequately treated (TR), one-third had been inadequately treated (TI), and one-third were not treated for the current episode (TN). Treatment completion rates and reasons for dropping out did not differ statistically among TR, TI, and TN patients. TR patients took longer to respond (13.0 weeks) than either TI or TN patients (7.6 and 8.0 weeks, respectively). TR and TI patients had lower response rates (67% and 71%) than TN patients (86%). CONCLUSIONS: Prior treatment exposure is an important correlate of course and outcome in late-life depression. Most TR and TI patients eventually respond, but TR patients may require more intensive and longer courses of treatment than TI and TN patients.

CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly.

INTRODUCTION: The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability. METHODS: Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined. RESULTS: Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects. CONCLUSIONS: Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.

Depression after stroke: a prospective epidemiological study.

OBJECTIVES: To elucidate the relationship between stroke and depressive symptoms and to determine whether disability or cerebrovascular risk factors mediate that relationship. DESIGN: A prospective longitudinal epidemiological survey. SETTING: The mid-Monongahela Valley, a rural, nonfarm, low-socioeconomic-status community. PARTICIPANTS: Random sample of 1,134 subjects aged 65 and older. MEASUREMENTS: The dependent variable was clinically significant depressive symptoms, as defined by five or more symptoms on the modified Center for Epidemiological Studies Depression scale. The independent variables were demographics (age, sex, education), stroke, number of impaired instrumental activities of daily living (IADLs), diabetes mellitus, hypertension, atherosclerotic heart disease, and smoking. Logistic regression analyses were conducted for cross-sectional and longitudinal models examining whether stroke was associated with or predicted depressive symptoms, with other associated factors included as covariates. RESULTS: Clinically significant depressive symptoms were cross-sectionally associated with stroke (odds ratio (OR)=3.5, 95% confidence interval (CI)=1.4-8.3), diabetes mellitus (OR=2.8, 95% CI=1.7-4.6; P

Geriatric depression treatment in nonresponders to selective serotonin reuptake inhibitors.

BACKGROUND: Up to a third of elderly patients with major depressive disorder are treatment resistant, yet little objective evidence is available to guide the clinician in managing these patients. We report here our experience with elderly subjects with prospectively defined treatment-resistant depression in 2 separate research studies: one entailing an augmentation strategy, the other a change to venlafaxine extended release (XR). METHOD: Fifty-three elderly subjects with major depressive disorder according to DSM-IV criteria who failed treatment with paroxetine plus interpersonal psychotherapy received 1 to 3 trials of augmentation with bupropion sustained release, nortriptyline, or lithium. Successively fewer subjects entered each sequential trial of augmentation. Twelve subjects subsequently received venlafaxine XR monotherapy. Response to treatment was defined as a 17-item Hamilton Rating Scale for Depression score of < 10 for 3 weeks. RESULTS: Sixty percent of subjects (N = 32) responded to some form of augmentation, with 45% (24/53), 31% (5/16), and 43% (3/7) responding to the first, second, and third augmentation trials, respectively. The mean time to response after starting the first augmentation trial was 6.0 (SD = 5.8) weeks. Forty-two percent (N = 5) of the venlafaxine XR-treated subjects responded with the mean time to response of 6.4 (SE = 0.9) weeks. Adverse effects leading to treatment discontinuation and falls were more common in the augmentation subjects than in the venlafaxine XR subjects. CONCLUSION: We observed similar rates and speed of response with an augmentation strategy and a strategy of switching to venlafaxine XR in elderly subjects with prospectively defined treatment-resistant major depressive disorder. Venlafaxine XR was generally better tolerated than the augmentation strategies. Further investigation of venlafaxine XR as a preferred strategy for treatment-resistant geriatric depression is warranted.