OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use

AIM: This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. METHODS: This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of > or = 3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). RESULTS: A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (< 12%) but statistically significant (P = 0.02) increase in donepezil C(max) was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the t(max) or AUC(0-24 h) of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone. CONCLUSIONS: The co-administration of once-daily oral donepezil HCl 5 mg for 15 days and once-daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed

Donepezil and paroxetine: possible drug interaction

OBJECTIVE: To describe a case of fulminant hepatitis possibly related to concomitant donepezil and seratriline therapy. PATIENT AND SETTING: An 83-year-old woman treated in a dementia care facility and later in a tertiary medical center. INTERVENTION AND MANAGEMENT: Discontinuation of donepezil and sertraline therapy with subsequent improvement evidenced by liver biopsy and liver function tests. RESULTS: An older woman with Alzheimer´s disease was admitted to a dementia care facility because of aggressive behavior. Treatment with sertraline was initiated in February 1998. Sertraline doses were increased gradually to 200 mg daily by May 1998, and some improvement in behavior was seen. Concomitant therapy with donepezil 5 mg qhs was initiated June 26, 1998. Ten days later, confusion and jaundice were noted. Total bilirubin was 5.6 mg/dL, GGTP was 1,208 IU/L, and alkaline phosphatase was 369 IU/L. Computed tomography revealed cholelithiasis without ductal dilation. Liver, spleen, and pancreas seemed normal. Donepezil and sertraline were discontinued. The patient was admitted to our institution and treated for dehydration. A liver biopsy revealed scattered portal eosinophils and prominent cholestasis consistent with acute chemical hepatitis. The GGTP and total bilirubin of this patient peaked at 2,235 IU/L and 22.6 mg/dL, respectively. The patient improved, and her liver function tests normalized over the next 2 months