Mohammed T. Abou-Saleh

MANAGEMENT OF DEMENTIA SYMPTOMS 243Olanzapine. Street et al. 22 studied 206 nursing home patientswith a mean MMSE of 7.3 in a trial of six weeks of olanzapine orplacebo. The main outcome measure was a 50% reduction in theNeuropsychiatric Inventory (NPI) score for a newly definedcluster of symptoms (hallucinations, delusions, agitation). Theoptimal dose (5 mg) was as effective as typical neuroleptic(NNT=3.3) but seemed to be associated with relatively highrates of adverse reactions. The response rates (66% on 5 mg, 52%on 10 mg, 43% on 15 mg and 36% on placebo) suggest that doseshigher than 5 mg are likely to be suboptimal. Somnolence and gaitabnormality were the commonest side effects (NNH=5.4 and 5.7,respectively) This study illustrates the difficulties that occur incomparing adverse drug reactions (ADRs) across studies, since itis very likely that ADRs were more assiduously sought in thisstudy than earlier studies of typical neuroleptics. The lower doseof 2.5 mg, which is now available—and which one would expect tobe associated with fewer ADRs than 5 mg—was not tested.Carbamazepine. Few trials have published significant differencesin responder rates on measures of Global Clinical Impression(CGI). One exception is the study of Tariot et al. 23 . At least minimalimprovement on the CGI was apparent in 77% of those takingcarbamazepine compared to 22% on placebo (NNT=1.8).Furthermore, the reduction in the number of cases requiring ‘‘agreat deal’’ or ‘‘almost constant’’ extra nursing time to deal with theagitation was 37% in those taking carbamazepine and 8% in thosetaking placebo (NNT=3.4). This was a relatively small (ca. 25subjects in each arm) 6 week study of predominantly female nursinghome residents with severe dementia (mean MMSE 6.0), 92% ofwhom were aggressive. Carbamazepine was started at 100 mg/day.The modal dose reached was 300 mg/day. The NNH for any ADRwas 3.3, although these were considered clinically significant in only2 of 16 cases. The large effect size may have been at least partlyattributable to the fact that a non-blind physician adjusted the doseof carbamazepine—a strategy which, of course, parallels the clinicalsituation, but is not commonly employed in more recent studies.Trazodone. Trazodone is widely used for BPSD, although therehas only been a single small randomized trial of its effectiveness, inwhich it was shown to be comparable in effect to haloperidol 24 .The CGI was ‘‘much improved’’ or ‘‘very much improved’’ atweek 9 in 57% of cases on haloperidol and 71% on trazodone.However, trazodone was associated with fewer side effects (14%,mean dose 218 mg) than haloperidol (50%, mean dose 2.5 mg).Interestingly, post hoc analyses suggested that those who wereverbally aggressive or had repeated behaviours or mannerismswere more likely to respond to trazodone. Those who paced, weregenerally restless or made unwarranted accusations were morelikely to respond to haloperidol. This raises the possibility of twosyndromes of behavioural change in dementia, one associated withabnormalities of dopaminergic function and one associated withserotonergic dysfunction. The replicated finding that thosewith depression early in dementia are more likely to go on to bephysically aggressive is also consistent with the possibility thatthere is a distinct serotonergic syndrome of behavioural change indementia 25,26 . It is not necessary for other signs of depression to bepresent to justify a trial of an antidepressant for aggressivebehaviour.Xanomeline. Xanomeline is a cholinomimetic with agonistactivity at postsynaptic muscarinic M1 and M4 receptors.Bodick et al. 27 presented data from a large (87 in each arm), 6month study of patients with mild to moderate AD. Three dosesof xanomeline were compared with placebo. The dropout rate washigh, ranging from 35% in the placebo group to 59% at thehighest dose of active drug (NNH=4.2), precluding its further usein the formulation used. However, there was a dose-relatedresponse to xanomeline of hallucinations (NNT=2.1 at thehighest dose) and a variety of other behaviours (e.g. vocaloutbursts, delusions and mood swings; NNT=2.7–6.4).Rivastigmine. The cholinergic nucleus basalis of Meynert is indouble jeopardy in patients with dementia with Lewy bodies(DLB) because it is likely to degenerate as a result of both Lewybody and neurofibrillary change. Cortical cholinergic parametersshow even more marked depletion in DLB than in AD. There isnow evidence showing that patients with DLB are preferentialresponders to cholinesterase inhibitors. McKeith et al. 28conducted a 20 week placebo-controlled study of 3–12 mgrivastigmine in 120 patients with probable or possible DLB ofmild to moderate severity. The main outcome measure was a 30%reduction on a newly defined cluster of symptoms derived fromthe NPI: hallucinations, delusions, depression and apathy. A 30%reduction was chosen because it was comparable to the effect sizeseen with neuroleptics. The main result was based on the observedcase analysis: 63% of those on rivastigmine responded, comparedto 30% on placebo (NNT=3.0). Although there was no overalldifference in the number of ADRs (59 vs. 61%), those takingrivastigmine were significantly more likely to drop out (31% vs.16%; NNH=7.1). As well as improvements in the pre-definedcluster, there were also marked improvements in a computer testof attention in those on rivastigmine.These two studies provide good evidence that hallucinations inparticular, and possibly other BPSD, respond well to cholinergicagonism.When to Consider a Trial without MedicationNeuroleptics have unpleasant side effects. Sedation, falls, hipfractures and tardive dyskinesia are common sequelae. Indeed, theprescription of typical, rather than atypical, neuroleptics is likelyto be a false economy, particularly if there is any risk that the drugwill be taken for more than a brief period. Trials withoutneuroleptics are a legal requirement in nursing homes in the USA,following the OBRA-1987 regulations. What is the optimalduration of treatment before a trial without medication isindicated?Since evanescent symptoms do not require long periods oftreatment, an important related question is ‘‘How often would thesymptom normally be expected to resolve without drug treatmentwithin a given time?’’ Levy et al. 29 assessed 181 outpatients andfound that 60–70% of those with agitation or psychosis still hadthe symptom 3 months later. Persistence was more commonamongst those with low MMSE scores (12–17). Devanand et al. 30in an outpatient study of 235 patients with early AD, found that74% of those with wandering or agitation had the symptom 6months later. Comparable figures for other behaviours were:physical aggression 53%, hallucinations 52%, paranoid ideas45%, misidentification 56%. In a group of 48 patients withautopsy-confirmed AD, Hope et al. 31 found that aggression andhyperactivity were both still present in 75% of cases after 8months, and hallucinations were still present in 75% of cases at 11months. All these studies were potentially directly or indirectlyconfounded by the effect of psychotropics on the natural historyof behaviour. Nevertheless, these data suggest that BPSD mayendure for up to 8 months in approximately 75% of cases and beevanescent in 25%.How often will trials without treatment succeed and how oftenwill they fail? Cohen-Mansfield et al. 4 studied the effect ofwithdrawal of drugs from nursing home residents, many of whomwill have had dementia. The doses of haloperidol (mean=0.9–1.3 mg), thioridazine (25–27 mg) and lorazepam (0.7–0.9 mg) thatwere being used were within current standards of care. The design