This is a dilemma I frequently face when I am called out to see someone with dementia on the ward or living in a nursing home. On the one hand I am thinking that anything I use can potentially have serious side-effects and will probably lead to increased health risks and increased mortality. On the other hand I have a very distressed person and a very distressed group of caregivers. I know that very soon the situation will be unsustainable if I do nothing and I just rely on the carers’ coping skills.
Screen for pain and delirium—I hear you say. You are right, of course. There have been a number of reviews looking into exactly that issue that show that this should be the first course of action (Cohen-Mansfield and Mintzer, 2005; Sink et al., 2005). Interpersonal and environmental factors can also play a role and should be ruled out (Sink et al., 2005).
OK, so now I have done all that and I still have a very distressed person and carers at the end of their tether. Now is the time to break out those non-pharmacological strategies, right? Well, maybe. Not many staff members will know about them (Conn, 1992; Burns et al., 1993; Meeks, 1996; Reichman et al., 1998; Seitz et al., 2011), their effectiveness is modest (Seitz et al., 2012), and patients may not cooperate (Cohen-Mansfield et al., 2012).
Eight in 10 people with dementia will have neuropsychiatric symptoms (Zuidema et al., 2007; Seitz et al. 2010) which means contemplating using medication in quite a few cases. Do no harm, right? Clearly, the question we need to answer is: What is the most effective, least harmful medication, for agitated or aggressive people with dementia?
Dallas Seitz from Geriatric Psychiatry Services, Providence Care – Mental Health Service in Ontario, Canada, and colleagues have published a review to try to answer that question (Seitz et al. 2013). They looked through MEDLINE, EMBASE, PsychINFO, the Cochrane Library for randomised controlled trials comparing medications with either placebo or other interventions. They also used Google Scholar as an additional search tool. On top of this, they hand searched a number of local databases and looked through references in Canadian guidelines. They used the Cochrane Collaboration risk of bias tool to measure the quality of studies and they evaluated the efficacy of medication using neuropsychiatric symptom severity rating scales. They looked at trial withdrawals, trial withdrawals due to adverse events, and mortality as measures of safety.
Using this method they identified 7,310 potential articles, of which 315 full-text references were screened for eligibility yielding a total of 29 studies included in the final synthesis.
Of those 29 studies most (15) were on antipsychotics, including risperidone (6), olanzapine (4), quetiapine (3) and aripiprazole (3).
Table 1 summarises the results.
Table 1 (the results column lists the treatment with the most benefits in the trial. The withdrawals column lists the treatment with most withdrawals due to any cause including adverse events and mortality)
|Barnes et al. 1982||Loxapine, Thioridazine, Placebo||No difference||No difference|
|De Deyn et al. 1999||Risperidone, Haloperidol, Placebo||No difference||No difference|
|Katz et al. 1999||Risperidone, Placebo||Risperidone||Risperidone|
|Street et al. 2000||Olanzapine, Placebo||Olanzapine||Olanzapine|
|Brodaty et al. 2003||Risperidone, Placebo||Risperidone||Risperidone|
|Fontaine et al. 2003||Risperidone, Olanzapine||No difference||No difference|
|De Deyn et al. 2004||Olanzapine, Placebo||Olanzapine||No difference|
|Mintzer et al. 2006||Risperidone, Placebo||No difference||No difference|
|Tariot et al. 2006||Quetiapine, Haloperidol, Placebo||No difference||No difference|
|Verhey et al. 2006||Olanzapine, Haloperidol||No difference||No difference|
|Mintzer et al. 2007||Aripiprazole, Placebo||No difference||Aripiprazole|
|Zhong et al. 2007||Quetiapine, Placebo||No difference||No difference|
|Streim et al. 2008||Aripiprazole, Placebo||Aripiprazole||Aripiprazole|
|Rappaport 2009||Aripiprazole, Placebo||No difference||No difference|
There were 3 studies on cholinesterase inhibitors, one on donepezil and 2 on rivastigmine. Unfortunately all the rivastigmine trials had antipsychotics as their controls. Table 2 summarises the results.
|Tariot et al. 2001||Donepezil, Placebo||No difference||No difference|
|Ballard et al. 2005||Rivastigmine, Quetiapine, Placebo||No difference||Quetiapine, Rivastigmine|
|Holmes et al. 2007||Rivastigmine, Risperidone||Risperidone||No difference|
There were 4 studies on anticonvulsants, two on divalproex, one on carbamazepine and 1 on oxcarbamazepine.
Table 3 summarises the results
|Tariot et al. 1998||Carbamazepine, Placebo||Carbamazepine||No difference|
|Porsteinsson et al. 2001||Divalproex, Placebo||No difference||No difference|
|Tariot et al. 2005||Divalproex, Placebo||No difference||No difference|
|Sommer et al. 2009||Oxcarbamazepine||No difference||Oxcarbazepine|
There were no trials of antidepressants versus placebo in the review. The only trial found compares Sertraline to Haloperidol and finds no difference between the treatments in terms of benefits or adverse events.
Seven studies probing a variety of other drugs also made it into the review. The summary is on table 4 below.
|Cantillon et al. 1996||Buspirone, Haloperidol||No difference||No difference|
|Kyomen et al. 1999||Estrogen, Placebo||Estrogen||No difference|
|Hall et al. 2005||Estrogen, Placebo||No difference||No difference|
|Peskind et al. 2005||Propanolol, Placebo||Propanolol||Propanolol|
|Huertas et al. 2007||Cyproterone, Haloperidol||Cyproterone||No difference|
|Gehrman et al. 2009||Melatonin, Placebo||No difference||No difference|
|Wang et al. 2009||Prazosin, Placebo||Prazosin||No difference|
Overall risperidone, olanzapine, and aripiprazole may be of benefit although the effect was small and not consistent across all trials.
There were additional single small positive studies with carbamazepine, estrogen, cyproterone acetate, propranolol, and prazosin. The effects sizes tended to be very small and only a few studies reported clinically relevant outcomes such as symptom remission. Trial withdrawals tended to be more frequent with those treatments that showed any efficacy.
From other evidence we know that antipsychotics increase the risk of death (Schneider et al., 2005) and cerebrovascular events (Herrmann and Lanctot, 2005). Antipsychotics also increase somnolence (Schneider et al., 2006a), falls (Hien Le et al., 2005), and fall-related injuries including hip fractures (Jalbert et al., 2010). There is also increasing evidence that they may accelerate cognitive and functional decline in older adults with dementia (Vigen et al., 2011).
Strengths and limitations
The main limitations of the review were the use of only English-language studies and that many articles were sponsored by pharmaceutical companies. The paper had some strengths as well. They evaluated randomised controlled trials and they looked at long term care populations. The authors assessed study quality and identified potential sources of bias in the primary studies. It was also useful to have an analysis of the safety as well as the efficacy of the treatments.
What should I do after reading this to help my distressed patient and overwhelmed carers?
- There is some evidence for the use of a few agents, but most of them can cause adverse effects to my patient
- The paper might help to talk to carers about potential pitfalls of treatment and point out the limited efficacy; that might help me persuade them to try non-pharmacological strategies. Unfortunately there is not much evidence for those that I can point to
- I can try medication with clear treatment objectives and a way to measure change in a time-limited trial with a firm commitment to stop treatment if there is no improvement. If there is improvement there is evidence that I may be able to withdraw treatment without a reoccurrence of symptoms (Declercq et al., 2013), so I will build in a withdrawal plan even as I commence treatment
From reading this review it is clear that much remains unknown about the efficacy of these agents and also the need for direct comparisons between non-pharmacological and pharmacological interventions.
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