Uses of Anticonvulsants in the Elderly and Long-Term Care
Overview of Anticonvulsants
“The U.S. population over the age of 65 is growing at a rapid pace, and faster than the population in general,” began Lon S. Schneider, MD, Professor of Psychiatry, Neurology, and Gerontology, University of Southern California School of Medicine, Los Angeles, and Symposium Chairman. The speaker pointed out that epilepsy—often overlooked in the elderly because of the focus on dementia—has its highest incidence in the first year of life and after age 75. “The causes of seizures in the elderly include brain injury due to stroke and aneurysm, tumors, alcohol and substance abuse, infection, hyperlipidemia, and hypoglycemia,” he continued. Dr. Schneider discussed clinical considerations with anticonvulsants in the elderly. “Although thought of as a class of drugs, they differ in many ways among themselves and have different structures.” He noted that drug–drug interactions, pharmacokinetics, and effects on cognitive function are also issues of concern with regard to anticonvulsants. Common psychiatric disorders in the elderly are dementia (most common), depression, substance abuse, psychosis, schizophrenia, and developmental disabilities. “There is at least a 20% incidence of significant psychosis in the two-thirds of patients with dementia who do not have evidence of a behavioral disorder when first seen by a physician,” explained the speaker, noting that aggression is common across the psychiatric disorders, but does not meet the usual syndromal criteria. Dr. Schneider mentioned the anticonvulsants divalproex/valproic acid, carbamazepine, gabapentin, lamotrigine, and topiramate, and possible indications for use: seizures, migraine headaches, cocaine and alcohol withdrawal, cerebral malaria, preeclampsia, mania, fibromyalgia, posttraumatic stress disorder, and Huntington’s disease.
Managing Seizure Disorders: Anticonvulsant Therapy
“The incidence of seizures in the elderly is six to eight times higher than in any other age group,” stated R. Eugene Ramsay, MD, Professor of Neurology and Psychiatry, University of Miami School of Medicine, Miami, FL, and Director, International Center for Epilepsy, Miami. This statement was based on data from a Veterans Affairs (VA) cooperative study that Dr. Ramsay and two colleagues conducted. He also stated that 50% of new-onset seizures will occur in those 60 years of age and older, within 20-30 years. “Seizures have a recurrent rate of 90% if untreated, and there is a tremendous amount of concurrent neurological and medical disorders in the elderly that must be taken into account,” he continued. “Three-quarters of the elderly with psychiatric disorders have dyslipidemias,” noted Dr. Ramsay. “If vascular disease could be controlled or reduced, the incidence of epilepsy would be substantially reduced.” Most of the patients in the VA cooperative study had abnormal imaging studies, many with evidence of only small-vessel disease. Dr. Ramsay noted that one reason epilepsy is underappreciated and underdiagnosed is that two-thirds of those with the condition do not have convulsions. Many patients who do have convulsions have them when they are alone, and they are diagnosed based on inference. “The older patient is less likely to have motor phenomena because the epilepsy results mostly from vascular disease, occurring in the middle or the anterior cerebral artery,” said Dr. Ramsay. “It does not occur in the posterior cerebral artery, which supplies most of the temporal lobe. It affects the motor-sensory strip or may present only as a lapse of consciousness.” He also explained that during a seizure the elderly usually sit and stare off into the distance, as opposed to smacking their lips and rubbing their clothes, as younger patients do. “Epilepsy may present as altered mental status, confusion, or other signs or symptoms.” The VA cooperative study included 470 patients (mean age, 72.1; range, 59-93) with unprovoked seizure who were likely to live for at least one year. “One of the hardest tasks with somebody who is taking six, eight, or 10 drugs is to determine whether the seizures are provoked,” explained Dr. Ramsay. He added that finding a therapeutic range for the anticonvulsants in these patients is very difficult. “If they tolerate the anticonvulsant, they are easier to treat. In our VA study, 60% of the patients are seizure-free if they tolerate the drug.” He noted that, after three months, those not tolerating the anticonvulsant dropped out of the study—a sign that careful monitoring and drug treatment selection as well as slow titration are very important during these months. With age, lean body mass, hepatic capacity, and renal function decrease, and the volume of drug distribution increases, affecting the doses of all drugs given to the elderly. “The change in blood level is much more dramatic as doses are changed,” he said. Protein binding of drugs is also a problem in the elderly. “An unbound fraction of 10% in a younger patient and 30% in an older one would present as the same total blood levels. Unbound fractions are needed, especially with the protein-bound drugs carbamazepine and phenytoin.” Cognitively impaired patients experienced 134 of the total 428 epileptic incidences in the study (one-third undiagnosed). Another 41 incidences were multi-infarct, 13 were alcohol-related, four were experienced by patients with Parkinson’s disease, 36 were of other origins, and 53 were of unknown origin. Target daily doses for the study were carbamazepine 600 mg, gabapentin 1500 mg, and lamotrigine 150 mg. Dr. Ramsay listed the drug-induced side effects that are influenced by age: gait (in already unstable persons), tremor, posture, sedation, rash, gastrointestinal disturbance, and weight changes. The speaker reviewed the use of carbamazepine, phenytoin, and valproate. “Unfortunately, they are all high protein-bound, and their pharmacology is not ideal. The major advantage is that no physician in the world has not used one of them. Phenytoin and valproate can be delivered in more ways than any of the others.” He then discussed gabapentin, lamotrigine, tiagabine, and topiramate. “Very few people know about tiagabine. There are concerns about the dose-dependent absorption of gabapentin, but it has no drug interactions and works on pain, as do tiagabine and valproate. Topiramate has some drug interactions.” Dr. Ramsay then noted that there is no information on the elderly in regard to the use of oxcarbazepine, levetiracetam, and zonisamide. “Levetiracetam may have the best potential because it resembles gabapentin pharmacokinetically, with no drug interactions. However, to date, only 10,000 patients have used it, and there have been some reports of behavioral disturbances. Zonisamide enhances free radical trapping. There are many unknowns, and caution must be taken until there are data on these drugs in the elderly. Establish the need for them, start at a low dose, and titrate slower than normal,” he cautioned. Dr. Ramsay concluded by discussing the length of treatment in the elderly. “Low doses can be used, but I do not think they can ever safely be taken off drugs. More evaluation is also needed at onset to examine the adverse side effects of these drugs.”
New Frontiers: Treatment of Agitation and Aggression in Elderly Patients
Anton Porsteinsson, MD, Assistant Professor of Psychiatry, University of Rochester School of Medicine, Rochester, NY, and Associate Director, Program in Neurobehavioral Therapeutics, Monroe Community Hospital, Rochester, spoke of the treatment of agitation and aggression in elderly patients with dementia. “Neuropsychiatric disturbances have an estimated prevalence of 60-80% at any given time with a lifetime risk of approximately 100% in persons with dementia,” Dr. Porsteinsson began. “They are the main reason persons with dementia are admitted to nursing homes due to significant caregiver distress.” He also stated that behavioral disturbances exacerbate functional and cognitive deficits, noting that patients with these disturbances may have a more rapid progression of dementia and can be difficult to care for. “Neuropsychiatric disorders tend to occur in fairly predictable patterns and have a high rate of co-occurrence,” he added. “Agitation and psychosis have incidence rates that increase from approximately 20-40% at one year to 50-60% at two years. There is also a high rate of persistence, and combining prevalence and persistence predicts the magnitude of the problem.” Dr. Porsteinsson discussed a general approach to treating behavioral complications of dementia. “Characterize target symptoms, and provide a standard medical evaluation to identify any possible medical disorders. If a medical disorder exists, treat and monitor target symptoms. Provide a standard psychiatric evaluation. If a psychiatric disorder exists, treat and monitor target symptoms.” The speaker also outlined a general approach to pharmacotherapy:
• Use psychotropics where appropriate, once nonpharmacologic interventions fail
• Use empirical trials of symptomatic pharmacotherapy for remaining symptoms
• Start at a low dose, and titrate slowly
• Assess response of target symptoms versus toxicity
• Increase dose until benefit or toxicity is seen
• Hold at nontoxic efficacious dose or subtoxic dose
• If effective, continue for several weeks to months, taper, and re-evaluate
• If ineffective, taper and reevaluate; consider second agent
• Medications do not always work
Dr. Porsteinsson noted that no therapy for behavioral disturbances in any disorder has been approved by the Food and Drug Administration (FDA). “The FDA has asked for more data, and there may be more openness on their part if clinicians can provide good data for such an indication,” he stated. “I think this may happen soon. Alternatives to antipsychotics are needed—even the atypicals, which are better tolerated in the elderly. Antipsychotics are meant for people who have true psychotic symptoms, something hard to define in dementia.” Dr. Porsteinsson mentioned various mood stabilizers and anticonvulsants—lithium, carbamazepine, valproate, gabapentin, lamotrigine, topiramate, and oxcarbazepine—and spoke of a carbamazepine-in-dementia study on which he worked. “We included 26 subjects and found that carbamazepine showed evidence of efficacy along with minimal side effects,” he explained. A best-dose study1 of carbamazepine versus placebo was conducted by the speaker and his colleagues, which recruited 51 agitated patients with dementia in nursing homes (mean age, mid-80s). The mean dose was 300 mg for six weeks, with the Brief Psychiatric Rating Scale (BPRS) as the main outcome measure. “The group on medication had a greater improvement in BPRS scores, which was statistically significant,” the speaker noted. “However, in this study, we became more and more convinced that carbamazepine is not the optimal drug for this population. We were concerned with the drug–drug interactions, as each patient in this age group (those in the study) seems to be on many medications. Carbamazepine may decrease serum levels of warfarin, theophylline, many conventional and atypical antipsychotics, valproate, zaleplon, nefazodone, alprazolam, and even of itself. In total, with carbamazepine, there are eight uncontrolled studies of 68 subjects that all suggest efficacy, one controlled but flawed negative study, and two positive, controlled studies.”2-11 Because of the prominent side effects of carbamazepine, Dr. Porsteinsson and colleagues looked for another anticonvulsant with better tolerability and fewer drug–drug interactions. They chose to look at divalproex, before it was approved for acute mania. “It is effective in a broad range of psychiatric conditions characterized by agitation, and the safety profile looked reasonable,” he explained.
He also mentioned that divalproex had been used successfully to treat agitation associated with dementia, had a relatively benign side-effect profile, and also had few drug–drug interactions. The possible mechanisms of divalproex sodium were discussed: inhibition of limbic kindling; enhancement of central g-aminobutyric acid transmission; augmentation of serotonergic function; inhibition of corticotropin-releasing factor, glycogen sythase kinase 3 (GSK3), and protein kinase C; and neuroprotection. “These mechanisms have raised the issue of whether valproate can offer some degree of neuroprotection through modulation of cell survival pathways.” Dr. Porsteinsson and associates12 conducted a randomized, double-blind, placebo-controlled, best-dose study of divalproex in 56 agitated nursing home patients with dementia. A mean dose of divalproex 826 mg was found to reduce the agitation factor of the BPRS more effectively than placebo. Those who responded to the drug responded well (39% had a marked response; only 10% had this response with placebo). The investigators found that a large confirmatory follow-up study was needed. A multicenter divalproex study in dementia was conducted by Tariot and colleagues,13 looking at 172 nursing home residents who met the criteria for secondary mania. The target dose was 20 mg/kg/day for 10 days. The study was suspended due to side effects (mostly sedation) but had 100 completers. “We found there was no specific effect on the usual mania scale, but there was statistically significant improvement on the Cohen-Mansfield Agitation Inventory,” Dr. Porsteinsson reported. “A follow-up study was needed with lower doses and slower titration. Two divalproex studies for agitation and dementia are ongoing,” he added. He then summarized the use of divalproex. “It is theoretically attractive, as it is better tolerated and has clinical effects similar to carbamazepine.” He also noted that divalproex has a decreased risk of drug–drug interaction and a more benign side-effect profile. It needs to be further studied in controlled trials and is being used clinically now. Dr. Porsteinsson spoke about extended-release divalproex and its benefits, noting that the once- daily dosing improves patient compliance and treatment. “With conventional-release divalproex, there is concern about plasma concentration peak-related side effects, but the extended-release formulation ‘flattens the concentration curves,’” he explained. “These data are from young persons, and it needs to be looked at more specifically in the elderly. It cannot be predicted that the elderly will react in the same way as younger patients in regard to pharmacokinetics.” The speaker concluded by mentioning that agitation and aggression are common clinical challenges in dementia; alternatives to antipsychotics are needed; and new data about potential novel mechanisms of action for anticonvulsants, specifically with valproate, offer exciting, new research and treatment opportunities.
References
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