Treatment of behavioral symptoms related to demen4a Behavioral symptoms in Alzheimer disease (AD) and other types of demen8a are extremely common and o;en much more troubling than amnes8c symptoms. This topic will review the causes and treatment of behavioral disturbance and symptoms related to demen8a
An4psycho4c drugs Atypical neurolep4cs have been the agents of choice for trea4ng hallucina4ons in pa4ents with demen4a. However, these drugs may increase mortality, and are not approved for the treatment of behavioral disorders in pa8ents with demen8a by the US Food and Drug Administra8on (FDA). Nonetheless, their beneﬁts o;en s8ll outweigh their risks in pa8ents with demen8a when treatment of hallucina8ons and delusions is cri8cal. In the absence of other eﬀec4ve agents, we con4nue to use them cau4ously, a>er informing the pa4ents and families of the poten4al risks Typical an4psycho4cs — A systemic review of typical an8psycho8cs included two meta-‐analyses of 12 trials plus two addi8onal studies of haloperidol, thioridazine, thiothixene, chlorpromazine,triﬂuoperazine and acetophenazine, and concluded that, in the aggregate, there was no clear evidence of beneﬁt for these agents in pa8ents with demen8a . A Cochrane review concluded that haloperidol may help control aggression, but not other neuropsychiatric manifesta8ons of demen8a . No trials compared agents with one another Atypical an4psycho4cs — These agents include clozapine, olanzapine, risperidone, and que4apine and have been somewhat more extensively studied. Two independently conducted systema8c reviews have concluded that these agents have, at most modest eﬃcacy [42,44]. Of seven trials studied, four found a sta8s8cally signiﬁcant beneﬁt for the primary endpoint with olanzapine or risperidone; there were no studies of clozapine and que8apine for this indica8on at the 8me of this analysis.
Side eﬀects The choice of speciﬁc an8psycho8c drug used to treat hallucina8ons is driven by drug side eﬀects such as seda8on or extrapyramidal disturbances. The older low potency typical(conven4onal) neurolep4cs (eg, chlorpromazine and thioridazine) are highly seda8ng, and their an8cholinergic ac8vity can worsen memory and cogni8on. High potency neurolep8cs (eg, haloperidol and ﬂuphenazine) are associated with an o;en unacceptable incidence of extrapyramidal side eﬀects. In a trial of haloperidol, for example, there was a high rate of extrapyramidal side eﬀects and decline in cogni8ve func8on even at rela8vely low doses of 1 to 5 mg.Intravenous haloperidol has been associated with clinically signiﬁcant QT prolonga8on requiring addi8onal precau8ons regarding its use. While the atypical neurolep4cs are perceived to have a lower incidence of adverse eﬀects, this may be true only with low doses. Systema8c reviews and clinical trials ﬁnd that adverse events with these agents in pa8ents with demen8a are common and dose related. These include extrapyramidal symptoms, confusion, somnolence, and falls. The addi8onal risk of agranulocytosis with clozapine and the necessity for frequent blood tests make this agent less a`rac8ve.
Mortality risk The US Food and Drug Administra8on (FDA) reported in a public health advisory that the use of second genera8on an8psycho8c medica8ons, aripiprazole, olanzapine, que4apine, and risperidone, for the treatment of behavioral symptoms in elderly pa8ents with demen8a is associated with increased mortality [49,50]. Their ﬁndings were conﬁrmed in an independently conducted meta-‐ analysis, as well as a subsequent randomized, placebo-‐controlled study. The reported odds ra8o for increased mortality in these analyses ranged from 1.54 to 1.7.
Clinical use Given the risk of increased mortality associated with the use of atypical neurolep8cs in elderly pa8ents with demen8a , we reserve their use for pa8ents who have neuropsychiatric symptoms, par4cularly psychosis, that are severe and debilita4ng and inform pa4ents and families of the risks. There is o;en no good alterna8ve. Somnolence is also concern with all of these agents, and may be dose limi8ng. Olanzapine (Zyprexa cpr 2.5 , 5, 10 mg CLASSE A NOTA A8 PIANO TERAPEUTICO) can be started at a dose of 2.5 mg daily and 4trated up to a maximum of 5 mg twice a day. This drug appears to be at least modestly eﬀec8ve for trea8ng the neuropsychiatric symptoms of demen8a in pa8ents with AD or vascular demen8a. The incidence of extrapyramidal symptoms is low at this dose. Que4apine (Seroquel cpr 25, 50, 100, 150, 200, 300, 400 mg CLASSE A NOTA A8 PIANO TERAPEUTICO) is an alterna8ve, star8ng at a dose of 25 mg at bed4me and 4tra4ng up to a maximum of 75 mg twice a day. There is li`le data regarding the eﬀec8veness of que8apine in this seeng. Risperidone (Risperdarl cpr1,2,3,4,mg CLASSE A NOTA A8 PIANO TERAPEUTICO) at no more than 1 mg daily also appears to be at least modestly eﬀec8ve, but higher doses are associated with increased side eﬀects. Treatment should be maintained only if beneﬁts are apparent, and discon8nua8on should be a`empted at regular intervals.
Neuropsychiatric symptoms are common in demen8a and contribute to nursing home admission and caregiver stress. When a pa8ent develops neuropsychiatric symptoms, the ﬁrst step is to rule out and treat a medical cause or superimposed delirium
Environmental, behavioral, and other nonpharmacologic therapies can be eﬀec8ve in this popula8on and, when appropriate, are preferred over medica8ons, which have a high rate of adverse eﬀects. Cholinesterase inhibitors do not produce clinically signiﬁcant improvement in neuropsychiatric symptoms in pa8ents with demen8a. However, many such pa8ents are s8ll treated with these drugs because of modest improvement in cogni8on. An8psycho8c agents have limited eﬃcacy and are associated with increased mortality in pa8ents with demen8a. We suggest the use of low doses of olanzapine or que8apine in pa8ents with severe, disabling symptoms a;er informing families of the mortality risk (Grade 2B). Short term use when possible, with regular reassessments of risks and beneﬁts, is advised. A trial of selec8ve serotonin reuptake inhibitors (SSRIs) is suggested for the treatment of depression in Alzheimer disease (Grade 2C). Citalopram is o;en used because of its possible addi8onal beneﬁts for neuropsychiatric symptoms. Sertraline is a well studied alterna8ve to citalopram. A trial of trazodone may also be considered to treat psycho8c symptoms, especially when they interfere with sleep. Tricyclics should be avoided because of side eﬀects and drug interac8ons. Agita8on may be due to unrecognized depression and respond to an SSRI. Because of the risk of side eﬀects with long-‐term use, we recommend reserving benzodiazepines for acute stressful episodes