Alette M. Wessels

Diabetes and cognitive decline in elderly African Americans: A 15-year follow-up study

Diabetes mellitus is associated with an increased risk for cognitive impairment and vascular factors seem to play a role in this relationship. In a sample involving elderly African Americans, we tested the hypothesis that diabetes accelerates cognitive decline and explored possible mediating mechanisms within a follow‐up period of 15 years.

Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia.

BACKGROUND Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting. DESIGN A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates. SETTING Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007. PARTICIPANTS Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril). MEASUREMENTS A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder. RESULTS A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years. CONCLUSIONS Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

Population Pharmacokinetic Modeling of Ziprasidone in Patients With Schizophrenia From the CATIE Study

1587 2011 51 1587-1591 Z is a second-generation antipsychotic drug used for the treatment of schizophrenia. Ziprasidone has combined dopamine, serotonin, and histaminergic receptor antagonist activity, and because of the high 5-HT2A to dopamine D2 ratio, there is a low propensity for extrapyramidal adverse effects. Approximately two-thirds of the metabolic clearance of ziprasidone occurs via aldehyde oxidase-mediated reduction, and less than one-third of the metabolic clearance of the drug is accounted for by cytochrome P450 (CYP)–mediated oxidation. CYP3A4 is the principal enzyme thought to be responsible for the formation of ziprasidone sulfoxide and ziprasidone sulfone, 2 of the major ziprasidone metabolites. However, these metabolites are unlikely to contribute to the antipsychotic effect of ziprasidone. In healthy fasting male participants, it was shown that the bioavailability is increased 2-fold in the presence of food. In fed patients, the maximum plasma concentration (Cmax) is generally achieved at 6 to 8 hours postdose, and the mean terminal elimination half-life (t1/2) is approximately 7 hours. 6

Association of 9-hydroxy risperidone concentrations with risk of switching or discontinuation in the clinical antipsychotic trial of intervention effectiveness-alzheimer's disease trial

Risperidone has been used to treat behavioral symptoms, such as delusions and agitation, in people with Alzheimers disease. The relationship between magnitude and variability of risperidone and 9-hydroxy risperidone exposure and the relationship with time to discontinuation of the medication were explored. Sixty-five subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimers Disease Trial that received risperidone were included in this study. Eighteen subjects completed the study without switching medication (completers on risperidone), whereas 47 discontinued the medication. Those who discontinued were divided into 2 groups according to responsiveness to therapy. Using Cox proportional survival regression analysis, we estimated time to discontinuation and factors associated with treatment discontinuation including age, dose, body mass index, neuropsychiatric inventory baseline score, and average exposure (area under the curve [AUC]) to risperidone and 9-hydroxy risperidone. Twenty-four and 17 subjects discontinued therapy because of inadequate therapeutic effect and side effects, respectively (6 subjects were excluded because of missing information about reason for switching or discontinuation). Discontinuation hazards for those with a higher than median AUC of the metabolite were 2.54 (P = 0.029; inadequate and side effect group combined) and 3.48 (P = 0.025; inadequate effect group) times that of those in the lower than median AUC group. None of the other covariates contributed significantly to the switching hazard. Risperidone metabolite, 9-hydroxy risperidone concentrations, correlated with the risk of switching or discontinuing the medication, suggesting that 9-hydroxy risperidone contributes to adverse events and intolerability in dementia patients.

Adherence to escitalopram treatment in depression: a study of electronically compiled dosing histories in the 'Depression: the search for phenotypes' study

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram. Participants were randomly assigned to interpersonal psychotherapy (IPT) or pharmacotherapy. Participants assigned to IPT who did not evidence a response or remission had escitalopram added to their treatment. Adherence to pharmacotherapy was assessed using an electronically monitored pill cap (MEMS). Fifty-four participants on escitalopram alone and 32 on escitalopram+IPT were monitored. After 200 days, 71.7% of the participants in the escitalopram group and 54.8% of those in the escitalopram+IPT group were still engaged with the dosing regimen. Of those engaged in the dosing regimen, 17.9% (average over 210 days) of the participants did not take their medication (nonexecution). In 69% of the days participants took the correct dosage required. On average, participants had three drug holidays and the mean length of a holiday was 7 days per patient. No difference in adherence patterns was observed between patients receiving escitalopram alone vs. IPT+escitalopram. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimen are the most common facets of poor adherence in this study population.

IC-P1-054: Comparison of manual and automated determination of hippocampal volumes in MCI and older adults with cognitive complaints

of language and semantic memory testing. Results: As a group, patients with progressive fluent aphasia demonstrated prominent left-greater-thanright temporopolar thinning, while patients with progressive non-fluent aphasia demonstrated thinning in left-greater-than-right inferior frontoinsular cortex. Yet there were notable individual differences in anatomic abnormalities that corresponded with differences in language, cognition, and behavior. Within the group of patients with fluent aphasia, the patient with the most prominent semantic impairment had the greatest degree of thinning of the left temporopolar cortex (31%) as compared to a group of controls; this patient also had prominent abnormalities of affective and social behavior, which may relate to prominent right temporopolar thinning (29%). Within the group of patients with non-fluent aphasia, the patient with non-fluent progressive aphasia and apraxia of speech had thinning not only in left inferior frontal gyrus (19%) but also in ventral precentral gyrus (26%) and supplementary motor area (24%). Conclusions: Quantitative cortical thickness analysis of MRI data shows promise in applications to individual subjects with progressive aphasia for localizing regional cortical thinning that may underlie specific language and behavioral abnormalities. Further investigation will determine whether this approach will be helpful in more detailed subtyping of these patients, in differential diagnosis, or as an imaging biomarker for monitoring the effects of potential future therapies. Supported by NIA R01-AG29411, K23-AG22509, NCRR P41RR14075, U24-RR021382, and the MIND Institute.

Cytochrome P450 Polymorphisms and their Relationship with Premature Ovarian Failure in Premenopausal Women with Breast Cancer Receiving Doxorubicin and Cyclophosphamide

To the Editor: About 200,000 new breast cancer cases were expected to be diagnosed in 2009 (1), of which approximately 25% would occur in premenopausal women. Adjuvant chemotherapy prolongs overall survival in patients with breast cancer and because of its common application in cancer care, long-term sequelae of treatment are becoming increasingly important. In addition to the acute toxicities of anthracycline and cyclophosphamide-based regimens (2), one side effect with both psycho-social and physical implications is premature menopause (3,4). The frequency of polyagent chemotherapy-induced amenorrhea (CIA) ranges from 34% to 89% (4,5) and multiple factors (both patient and drug-related) play a role in explaining this large variability. The age of the patient (at time of therapy) (3,5,6), type of chemotherapy drugs (7), and duration and intensity (8) of therapy all influence the overall likelihood of a patient prematurely entering menopause after therapy. As inheritance is recognized to play a role in natural menopause (9), it is also likely that intrinsic host genetic variability plays a role in that chemotherapy-induced menopause. The variable ability to metabolize and clear a drug may, in part, affect its efficacy and toxicity and ultimately impact the effect on ovarian function. Cyclophosphamide is a pro-drug that requires activation by cytochrome P450 (CYP) enzymes to 4-hydroxycyclophosphamide (10). Multiple CYP450 enzymes have been implicated in this activation, including CYP2B6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. Several studies have demonstrated single nucleotide polymorphisms (SNPs) in these enzymes with decreased metabolic activity of the expressed proteins as a result (11,12). This, then, may result in wide inter-patient variability in exposure to cyclophosphamide which may subsequently impact patient response and toxicity to therapy. In this pilot study, we tested the effects of common variant polymorphisms in CYP450 enzymes as they relate to CIA in a cohort of premenopausal women with early stage breast cancer being treated with the combination of doxorubicin and cyclophosphamide. Participants included women between the ages of 18 and 45 with histologically or cytologically confirmed adenocarcinoma of the breast and who were planning to receive treatment with doxorubicin and cyclophosphamide. At enrollment, all women were premenopausal as defined by regularly occurring menstrual cycles and serologic estradiol and FSH levels consistent with premenopausal status. Pharmacogenetic assessment included common variant alleles for CYP450 enzymes; 2C19*3, 3A4*1b, 3A5*3, 2C19*2, 2C9*3, and 2C9*2. Treatment with doxorubicin and cyclophosphamide was given concurrently and either in neoadjuvant or adjuvant fashion per the plans of the treating physician. Formal serologic assessment of menopausal status was performed at baseline, and 1 month and 12 months from the time of chemotherapy treatment completion. Menopausal status was also documented at these time points using a menopause form, used in our prior studies (13,14). Throughout the study, menstrual cycle was documented by the patient in a previously validated diary (15). We considered women to have CIA if they did not resume bleeding within 12 months after the completion of chemotherapy. Twenty subjects with intact data were included in this analysis. All patients received a standard doxorubicin ⁄ cyclophosphamide regimen (60 ⁄ 600 mg ⁄ m for 4 cycles). Eleven subjects (55%) remained premenopausal throughout the study, whereas 9 (45%) Address for correspondence and reprint requests to: Alette M. Wessels, PhD, Division of Clinical Pharmacology, Wishard Memorial Hospital, 1001 West 10th Street, WD Meyers Building, W7123, Indianapolis, IN 46202, USA, or e-mail: awessels@iupui.edu.

THE INTEGRATED ALZHEIMER’S DISEASE RATING SCALE (IADRS): FINDINGS FROM THE EXPEDITION3 TRIAL

annually according to a standardized protocol, the Uniform Data Set. Eligible subjects were aged 60 years or older, cognitively normal but depressed at baseline, and had at least 3 in-person visits from 2005 through 2016. Depression was defined as any two of the five aspects: self-reported depression history which was active in the last 2 years, depression in the last month assessed by Neuropsychiatric Inventory Questionnaire, depressed mood judged by the clinician, active depression diagnosis based on the clinician’s best judgement, or baseline Geriatric Depression Scale score at least 6.MCIwas diagnosed if one didn’t have dementia but had cognitive complaint not normal for his or her age, and had cognitive decline but essentially normal functional activities. Those who progressed from normal to dementia were assumed to have passed through MCI. Time-dependent Cox proportional hazard models examined the association between self-reported antidepressant use and risk of MCI. Results:Out of 669 eligible participants, 488 reported antidepressant use at least once. Of the antidepressant users, 126 (25.82%) eventually developed MCI. A larger number of participants who never used antidepressant eventually developed MCI (61 out of 181, 33.70%). A log rank test indicated that unadjusted MCI-free survival rate was better for antidepressant users (P 1⁄4 0.051). However, after adjusting for covariates and accounting for time-dependent antidepressant use, the relationship no longer attained statistical significance (HR: 0.89; 95% CI: 0.70-1.14; P 1⁄4 0.36).Conclusions:We did not find a significant association between antidepressant use and incident MCI in adjusted models. This result may be partly due to modeling that can account for a participant’s variation in antidepressant use prior to onset of MCI.