Divalproex Sodium in Nursing Home Residents With Possible or Probable Alzheimer Disease Complicated by Agitation
Department of Psychiatry, The Center for Aging and Developmental Biology, Univ. of Rochester Medical Center, Rochester, NY, USA. American Journal of Geriatric Psychiatry
(Impact Factor: 4.24).
12/2005; 13(11):942-9. DOI: 10.1176/appi.ajgp.13.11.942
Three placebo-controlled clinical trials have suggested the benefit of valproate for treatment of agitation associated with dementia; one was used as the basis for this multicenter trial, conducted by the Alzheimer's Disease (AD) Cooperative Study. It addresses the efficacy, safety, and tolerability of divalproex sodium for the treatment of agitation associated with dementia.
This was a randomized, double-blind, placebo-controlled clinical trial in 153 nursing home residents with probable or possible AD complicated by agitation; 110 (72%) completed the trial. Participants were randomized to treatment with divalproex sodium at a target dose of 750 mg/day (N = 75) or placebo (N = 78) for 6 weeks. The primary outcome measure was change from baseline on the Brief Psychiatric Rating Scale (BPRS) Agitation factor. Secondary outcomes included total BPRS, Clinical Global Impression of Change, Cohen-Mansfield Agitation Inventory score, and measures of safety and tolerability.
Compliance averaged 88%. Participants receiving divalproex achieved a mean dose of 800 mg/day. Change in mean BPRS Agitation factor scores did not differ between patients treated with divalproex and placebo, nor did secondary behavioral measures. Measures of safety and tolerability did not reveal clinically important drug/placebo differences.
This multicenter trial showed no benefit of divalproex sodium for treatment for agitation in dementia at a mean dose of 800 mg/day over 6 weeks. The results do not support findings from previous trials indicating possible benefit.
Available from: Mark J Rapoport
- "The 29 studies meeting inclusion criteria encompassed 19 studies of antipsychotics (Barnes et al., 1982; Cantillon et al., 1996; De Deyn et al., 1999; 2004; Katz et al., 1999; Street et al., 2000; Gaber et al., 2001; Brodaty et al., 2003; Fontaine et al., 2003; Ballard et al., 2005; Mintzer et al., 2006; 2007; Tariot et al., 2006; Verhey et al., 2006; Holmes et al., 2007; Huertas et al., 2007; Zhong et al., 2007; Streim et al., 2008; Rappaport et al., 2009) (15 studies of atypical antipsychotics (De Deyn et al., 1999; 2004; Katz et al., 1999; Street et al., 2000; Brodaty et al., 2003; Fontaine et al., 2003; Ballard et al., 2005; Mintzer et al., 2006; 2007; Tariot et al., 2006; Verhey et al., 2006; Holmes et al., 2007; Zhong et al., 2007; Streim et al., 2008; Rappaport et al., 2009) and seven of typical antipsychotics (Barnes et al., 1982; Cantillon et al., 1996; De Deyn et al., 1999; Gaber et al., 2001; Tariot et al., 2006; Verhey et al., 2006; Huertas et al., 2007)), three studies of cholinesterase inhibitors (Tariot et al., 2001; Ballard et al., 2005; Holmes et al., 2007), four studies of anticonvulsants (Tariot et al., 1998; 2005; Porsteinsson et al., 2001; Sommer et al., 2009), one study of antidepressants (Gaber et al., 2001), and seven studies evaluating medications from other classes (Cantillon et al., 1996; Kyomen et al., 1999; Hall et al., 2005; Peskind et al., 2005; Huertas et al., 2007; Gehrman et al., 2009; Wang et al., 2009) (Table 1). Of these studies, 20 were placebo-controlled (Barnes et al., 1982; Tariot et al., 1998; 2001; 2005; De Deyn et al., 1999; 2004; Katz et al., 1999; Kyomen et al., 1999; Street et al., 2000; Porsteinsson et al., 2001; Brodaty et al., 2003; Ballard et al., 2005; Hall et al., 2005; Peskind et al., 2005; Mintzer et al., 2006; 2007; Tariot et al., 2006; Zhong et al., 2007; Streim et al., 2008; Gehrman et al., 2009; Rappaport et al., 2009; Sommer et al., 2009; Wang et al., 2009), and 11 compared two medications within the same trial (Barnes et al., 1982; Cantillon et al., 1996; De Deyn et al., 1999; Gaber et al., 2001; Fontaine et al., 2003; Ballard et al., 2005; Tariot et al., 2006; Verhey et al., 2006; Holmes et al., 2007; Huertas et al., 2007). "
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ABSTRACT: Background: Medications are frequently prescribed for neuropsychiatric symptoms (NPS) associated with dementia, although information on the efficacy and safety of medications for NPS specifically in long-term care (LTC) settings is limited. The objective of this study was to provide a current review of the efficacy and safety of pharmacological treatments for NPS in LTC.
Methods: We searched MEDLINE, EMBASE, PsychINFO, and the Cochrane Library for randomized controlled trials comparing medications with either placebo or other interventions in LTC. Study quality was described using the Cochrane collaboration risk of bias tool. The efficacy of medications was evaluated using NPS symptom rating scales. Safety was evaluated through rates of trial withdrawals, trial withdrawals due to adverse events, and mortality.
Results: A total of 29 studies met inclusion criteria. The most common medications evaluated in studies were atypical antipsychotics (N = 15), typical antipsychotics (N = 7), anticonvulsants (N = 4), and cholinesterase inhibitors (N = 3). Statistically significant improvements in NPS were noted in some studies evaluating risperidone, olanzapine, and single studies of aripiprazole, carbamazepine, estrogen, cyproterone, propranolol, and prazosin. Study quality was difficult to rate in many cases due to incomplete reporting of details. Some studies reported higher rates of trial withdrawals, adverse events, and mortality associated with medications.
Conclusions: We conclude that there is limited evidence to support the use of some atypical antipsychotics and other medications for NPS in LTC populations. However, the generally modest efficacy and risks of adverse events highlight the need for the development of safe and effective pharmacological and non-pharmacological interventions for this population.
Available from: Heinz Grunze
- "A large placebo-controlled study included 153 nursing home residents with probable or possible AD complicated by agitation . Patients receiving a mean dose of 800 mg/d VPA over a period of 6 weeks did not differ from patients treated with placebo. "
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ABSTRACT: Complex psychopathological and behavioral symptoms, such as delusions and aggression against care providers, are often the primary cause of acute hospital admissions of elderly patients to emergency units and psychiatric departments. This issue resembles an interdisciplinary clinically highly relevant diagnostic and therapeutic challenge across many medical subjects and general practice. At least 50% of the dramatically growing number of patients with dementia exerts aggressive and agitated symptoms during the course of clinical progression, particularly at moderate clinical severity.
Commonly used rating scales for agitation and aggression are reviewed and discussed. Furthermore, we focus in this article on benefits and limitations of all available data of anticonvulsants published in this specific indication, such as valproate, carbamazepine, oxcarbazepine, lamotrigine, gabapentin and topiramate.
To date, most positive and robust data are available for carbamazepine, however, pharmacokinetic interactions with secondary enzyme induction limit its use. Controlled data of valproate do not seem to support the use in this population. For oxcarbazepine only one controlled but negative trial is available. Positive small series and case reports have been reported for lamotrigine, gabapentin and topiramate.
So far, data of anticonvulsants in demented patients with behavioral disturbances are not convincing. Controlled clinical trials using specific, valid and psychometrically sound instruments of newer anticonvulsants with a better tolerability profile are mandatory to verify whether they can contribute as treatment option in this indication.
- "In that context, other non-neuroleptic drugs such as anticonvulsants and antidepressants have been tested over the last few years for the treatment of BPSD (Schneider and Sobim, 1991). Divalproex (Tariot et al., 2005) and trazodone (Lawlor et al., 1994; Sultzer et al., 2001; Lebert et al., 2004) have been advocated as useful in treating certain BPSD but have not been as well studied. Trazodone is a triazolopyridine-derivative phenylpiperazine with combined properties as 5HT agonist and antagonist, antidepressant and sedative effects and no anticholinergic effects (Brogden et al., 1981). "
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ABSTRACT: This study intended to provide a patient profile for trazodone (a triazolopyridine-derivative of phenylpiperazine) prescription in everyday clinical practice in patients with Alzheimer's disease (AD), and to describe clinical evaluation and the impact on caregiver burden at a 6-month follow-up. A naturalistic, prospective and observational study was performed, with a 6-month follow-up in 396 patients with probable AD, according to the NINCDS-ARDRA criteria. At the baseline and at the 6-month visit, patients were administered the Neuropsychiatric Inventory (NPI) to determine their Behavioral and Psychological Symptoms of Dementia (BPSD), and the Zarit Burden Interview (ZBI) to assess the impact on caregiver burden. Trazodone was prescribed for 6.1% of patients. With respect to the baseline visit, the untreated group showed an increased global NPI score (3.1 points; 95% CI=1.9-4.2; p=0.001) and ZBI score (2.2 points; 95% CI=0.9-3.4; p=0.001). At 6 months, the global NPI and ZBI scores remained unchanged for the treated group. The treated group showed a significant reduction in the NPI irritability subscale score (2.1 points; 95% CI=0.4-3.7; p=0.015). In the clinical practice, trazodone treatment was prescribed for patients with irritability, agitation and disinhibition. After 6 months, patients treated with trazodone exhibited no increase in BPSD frequency or severity, nor was an increase noted in the caregiver burden.
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