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• W2000539903 abstract "The incidence of epilepsy is increasing among the elderly, as was demonstrated by the results of the large-scale Rochester-based epidemiologic study by Hauser et al. 1 and confirmed by subsequent studies 2. The incidence of epilepsy is now estimated to be 100/100,000 in subjects older than 60 years and 160/100,000 in those aged 80–84 years, and its prevalence is seven of 1,000 in subjects aged 55–64 and 12 of 1,000 in those aged 85–94 years 3, 4. Epilepsy in the elderly is usually associated with other organic diseases, such as vascular, degenerative (Alzheimer disease) 4, and neoplastic diseases 5. Its incidence is higher (2.5% of recurrent seizures) among patients with hemorrhagic strokes than in those with other ischemic vascular diseases 6. The majority of cases involve complex partial seizures 4, which are frequently difficult to diagnose in the elderly, but generalized tonic–clonic seizures also have been described and are probably caused by degenerative diseases or combinations of genetic and/or environmental factors. Recent studies have shown that cognitive deficits and their related disturbances also increase after a stroke 7, although the presence of deficits varies from subject to subject 8. The prevalence of behavioral disturbances is higher in the elderly than in the general population and may be associated with depression (∼2–4%) or depressive symptoms (10–25%) 9, 10, 11a. . The male/female ratio is in favor of the second, as are the costs relating to psychopharmacologic treatment and the use of medical resources 11. It has been estimated that between 5 and 50% of elderly subjects are depressed; the rate of suicide increases with age, and seems be independent of, or secondary to, stressful life events. The use of antipsychotic drugs is made particularly complex because many elderly people also are being treated for concomitant organic diseases, which gives rise to the possibility of pharmacologic interactions. In a descriptive analysis of 681 subjects with a mean age of 86.9 years, which covered the period 1994–1996, Giron et al. 12 found that the nondemented subjects were taking an average of 4.5 drugs (acting mainly on the cardiovascular system), and the demented subjects, an average of 4.8 drugs [acting mainly on the central nervous system (CNS)]. The use of drugs is therefore decidedly high in both demented and nondemented subjects. Elderly patients are frequently prescribed psychotropic agents, although these are less well tolerated and give rise to a higher incidence of adverse reactions than in the young because of age-related pharmacodynamic and pharmacokinetic changes at the level of the neurochemical processes of the CNS. The pharmacodynamic phenomena associated with the increased sensitivity of the elderly to psychoactive drugs are related to neuromorphologic modifications due to the process of aging itself. A progressive age-related loss in brain weight begins at the age 45–50 years and reaches a maximum at the age of 86 years, when the brain weighs 11% less than in young adults. There also are changes in receptor sensitivity: in comparison with the young, elderly subjects respond less to receptor agonists and β-adrenergic blockers 13 and more to benzodiazepine (BZD) sedatives, analgesics, and anticoagulants. This increased sensitivity means that the presence of 20–50% of the neurotransmitters involved is enough to obtain a response 14. Conversely, the elderly have fewer acetylcholine receptors (acetylcholine is the quantitatively most widespread neurotransmitter in the CNS), which are involved in learning, memory, motor skills, and sensation, as well as more complex functions such as the affective functions. The age-related reduction in noradrenaline (NA) and dopamine (DA) may be as much as 50%15, 16, and there is a parallel decline in tyrosine hydroxylase activity 17. As antidepressants and antipsychotics modify the equilibrium of the cholinergic and monoaminergic systems, they can give rise to clinically relevant central anticholinergic toxicity. One example of this is the dementia syndrome, which consists of mood changes (from euphoria to depression), memory deficit, and neurologic symptoms such as ataxia and akathisia. The central anticholinergic toxicity also may evolve into a form with disorientation, delirium, and hallucinations, an acute psychosis 18. All of these can lead to diagnostic errors inducing physicians to increase the dose of a drug (or change it), when what is really necessary is simply a dose reduction. The new antiepileptic and psychotropic drugs may be taken into consideration when treating the elderly, provided it is remembered that age-related physical changes often increase their adverse effects. Choosing the right drug basically depends on tolerability and the risk of drug interactions. The pharmacokinetic changes accompanying aging often lead to higher and more variable plasma drug concentrations because of modifications in drug clearance and distribution. Renal clearance steadily diminishes with age, with decreased renal blood flow, a reduced glomerular filtration rate, the loss of glomeruli in the renal cortex, and less tubular secretion, leading to impaired renal function. There also is a progressive but variable decline in creatinine clearance. These changes reduce the elimination of drugs that are partially or completely cleared by the kidney 19. It has been assumed that liver drug metabolism decreases with age, but the effect of aging on the cytochrome P-450 system and the other enzymes that metabolize psychoactive drugs have not yet been fully investigated. Sotaniemi et al. 20 demonstrated that cytochrome P-450 levels are lower in the elderly, but the results of studies of age-related changes in specific cytochrome P-450 isoenzymes are conflicting. CYP3A4 and CYP2D6 are responsible for the metabolism of an estimated 80% of the currently used drugs 21, and, although no age-related decline in CYP2D6 activity has been found 19, a substantial number of studies have shown that there are age-related decreases in the elimination of CYP3A4 substrates 21. The decline in metabolic drug clearance generally observed in the elderly also may be explained by the significant reduction in liver blood flow and liver size that occurs with age. In addition to reduced clearance, modified distribution also is responsible for the longer half-life and higher blood concentrations of drugs in the elderly. The loss of body muscle mass that occurs with aging, together with the corresponding increase in the proportion of adipose tissue, leads to proportionate increases in the distribution volume of lipid-soluble drugs (most psychotropics except lithium, lorazepam, and oxazepam), and a consequent prolongation of their half-lives. Drug distribution (and therefore half-life) also may be modified by the decreased concentration of plasma albumin observed in the elderly. Finally, the rate and completeness of oral drug absorption may be reduced by a lower gastric acid output, slower gastrointestinal motility, and diminished splanchnic blood flow. However, as the oral absorption of highly lipid-soluble psychoactive drugs depends largely on passive diffusion across a concentration gradient, their total absorption may be less affected. This section considers only the pharmacokinetic characteristics of the newer antidepressants because it is generally agreed that the use of tricyclic antidepressants (TCAs) is not advisable in subjects with epilepsy 22. Furthermore, elderly patients are more exposed to the typical adverse effects of TCAs, which are mainly due to the blockade of neurotransmitter receptors: these effects may vary from the unpleasant but harmless (such as dry mouth or sedation) to severe toxic reactions such as cardiac arrest or delirium 23. The selective serotonin receptor inihibitors (SSRIs) have similar therapeutic efficacy and adverse-effect profiles despite their relatively wide range of affinities for serotonin-uptake sites. Given their lack of receptor antagonism, they are virtually devoid of life-threatening side effects, such as cardio- or CNS toxicity 24, and have a very low seizure potential 22. The choice of the appropriate drug should therefore be based on its pharmacokinetics, potential drug–drug interactions, and any age-related changes in its metabolism (Table 1). The metabolism of fluoxetine is only minimally changed in the elderly, but the drug has a very long half-life. This may be an advantage with poor compliance (which is quite frequent in elderly patients), because blood drug concentrations decrease only slightly if a dose is missed. Conversely, it takes 4 weeks of constant fluoxetine treatment to reach steady-state levels and, if a patient does not respond, a long washout period is necessary before switching to a TCA or monoamine oxidase inhibitor (MAOI) to avoid drug interactions and adverse effects (serotonin syndrome). Although the plasma concentrations of the newer antidepressants do not seem to be closely related to efficacy or adverse events, the greater sensitivity to drug effects of elderly subjects makes it clinically undesirable to have to wait too long before achieving steady-state dosing 25. The most important characteristic of SSRIs is their potential drug–drug interactions. All of them inhibit some P-450 isoenzymes, but their effects are different. Paroxetine and fluoxetine are potent inhibitors of CYP2D6, and fluvoxamine inhibits CYP1A2 and CYP2C19, and possibly CYP3A4 and CYP2D6. This means that they may interact with many of the drugs that are frequently concomitantly administered in the elderly. It has been observed that fluoxetine inhibits the metabolism of both carbamazepine (CBZ) 26 and phenytoin (PHT) 27, and that fluvoxamine can seriously affect the blood levels of many tertiary amine antidepressants 28 and clozapine 29; clozapine metabolism is also significantly inhibited by sertraline 30. Paroxetine and citalopram can be considered the least problematic SSRIs in terms of drug–drug interactions 25. In conclusion, although some elderly patients may require doses similar to those given to younger adults, many of them have impaired drug elimination; this leads to highly variable pharmacokinetics and thus makes treatment less predictable. It is therefore better to start with low doses and make very careful dose adjustments, bearing in mind that it will take longer to reach steady-state plasma concentrations than in younger patients. The treatment of psychosis in elderly epilepsy patients is particularly difficult for a variety of reasons. The use of conventional antipsychotics has often been limited by proconvulsive 22, 31 or adverse effects. Elderly patients often have comorbid medical conditions, such as cardiovascular disease or dementia, whose symptoms may be exacerbated by antipsychotic medications. The side effects of particular concern in the elderly include anticholinergic reactions (dry mouth, constipation, blurred vision, urinary retention, confusion, and hallucinations), extrapyramidal symptoms, tardive dyskinesia, orthostatic hypotension, cardiac conduction disturbances, sedation, and cognitive slowing 32. The choice of the appropriate drug should be based on knowledge of the pharmacodynamic effects of each. The typical neuroleptics have been classified as high-, intermediate-, or low-potency agents 33. The high-potency neuroleptics (such as haloperidol and fluphenazine) have a greater affinity for dopamine receptors and less affinity for α1-adrenergic and muscarinic receptors, and consequently tend to cause extrapyramidal symptoms. The intermediate-potency neuroleptics (such as perphenazine) have a greater affinity for histaminergic, α1-adrenergic, and muscarinic receptors. Finally, the low-potency neuroleptics (chlorpromazine and thioridazine) are not usually indicated in the elderly because they more often cause peripheral and central anticholinergic side effects (confusion), sedation, and orthostatic hypotension (which can increase the risk of falls). Four atypical antipsychotics have recently been approved by the American Food and Drug Administration (Table 2). Clozapine is almost exclusively used in patients with treatment-refractory schizophrenia because of its potentially fatal side effect of agranulocytosis; the other three—risperidone, olanzapine, and quetiapine—have a much better side-effect profile 32, and a series of controlled studies showed that they are efficacious and well tolerated in elderly psychotic patients 34, 35. The clinical efficacy of atypical antipsychotics has been attributed to their combined serotonin 5-HT2A and DA D2-receptor antagonism. It has been hypothesized that their action on the serotonin 5-HT2A receptor counteracts the negative symptoms of schizophrenia, whereas their occupation of DA D2 receptors may have beneficial effects on the positive symptoms. The better tolerability profile of this new drug class also may be explained by receptor affinities 36. Extrapyramidal symptoms and tardive dyskinesia (antipsychotic-induced oral–buccal dyskinesia) are caused by DA D2-receptor blockade in the nigrostriatal system, whereas antipsychotic efficacy is associated with D2-receptor blockade in the mesolimbic system: as all of the new antipsychotic drugs are less active on D2 receptors than the typical antipsychotics, and are mainly selective for the mesolimbic system, they are much less associated with such adverse events 32. Furthermore, the adverse anticholinergic effects that are so important in elderly patients with cognitive decline also are less frequent. Adrenergic α1-receptor blockade can cause orthostatic (postural) hypotension and may therefore have serious consequences for older patients (falls with possible fractures). Expert consensus guidelines have recently been published concerning the treatment of agitation in demented patients 37: risperidone and the high-potency typical antipsychotics were elected the first-line drugs for the long-term treatment of agitated patients with prominent psychotic symptoms; olanzapine the second-line agent; and low-potency antipsychotics or quetiapine, the third choice. High-potency typical antipsychotics were selected as the first-line treatment for the short-term management of agitation related to psychosis because of the availability of an injectable administration route. Olanzapine was considered first choice for patients with Parkinson disease and psychosis. Risperidone, which is the first-line drug for elderly patients, is metabolized mainly by P-450 enzymes (particularly the CYP2D6 isoform). Its major metabolite (9-hydroxy-risperidone) is active, present in the plasma at concentrations that are 3–5 times higher than those of the parent drug, has a high affinity for serotonin 5-HT receptors, and is eliminated primarily by renal excretion. Elderly patients require one-third the risperidone dose used in younger patients to achieve similar plasma concentrations of both 9-hydroxy-risperidone and the parent drug 38. Consequently, the usual starting dose in the elderly is 0.25–0.5 mg/day administered as a single daily dose. It should be noted that, at doses marginally higher than optimal doses, the drug loses its atypical nature and causes extrapyramidal symptoms as often as do typical neuroleptics 36. Olanzapine may be the second-choice drug in elderly epilepsy patients. Despite its activity on a broad range of neurotransmitter receptors (in particular, its very high affinity for muscarinic M1 receptors) and reduced clearance in the elderly, it seems to be very well tolerated 36. As it is metabolized mainly by CYP1A2 and CYP2D6, it may interact with SSRIs and other antipsychotics. In comparison with young individuals, its elimination half-life in elderly men and women is longer by 68 and 42%, respectively 36. There are few clinical data concerning the use of quetiapine in the elderly, although it does seem to be effective and well tolerated in patients with Parkinson disease 39. In comparison with younger patients, drug clearance in nine elderly patients was found to be reduced by 30–50%. In terms of drug interactions, it has been observed that PHT treatment increases quetiapine clearance fivefold 40. Quetiapine is metabolized by P-450 enzymes, principally CYP3A4 with less dependence on CYP2D6, but it does not seem to inhibit a number of P-450 isoenzymes 41. In the elderly, the indicated total daily oral dose is 50% that used in younger patients. Finally, quetiapine has a high affinity for histamine and α1-adrenergic receptors. In conclusion, the limited clinical data available indicate that, as a class, atypical antipsychotics are likely to be equally efficacious and better tolerated by elderly epilepsy patients with psychoses than are classic neuroleptics. One major exception to this may be clozapine: the risks of agranulocytosis, autonomic adverse events, and possible seizure worsening suggest that it should be used to treat only patients who have not responded to classic or other atypical antipsychotics. This is particularly true in the case of older patients, as the elderly appear to be more likely to develop agranulocytosis with clozapine treatment and may be more likely to die when agranulocytosis occurs 36. Finally, in elderly epilepsy patients, all of the newer antipsychotics should initially be administered at a very low dose (Table 2), and a minimum of 4–7 days should be allowed before changing a drug because of inadequate response. Consideration also should be given to tapering the drug after a certain time of improved behavior. Acknowledgment: Professor Trimble and the members of The Commission for the Psychobiology of Epilepsy are very grateful to the International League Against Epilepsy for their financial support of the commission and for their help with the publication of this supplement." @default.
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• W2000539903 title "The Use of Antidepressant and Antipsychotic Drugs in Elderly Epilepsy Patients" @default.
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