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a sequential drug treatment algorithm has been applied specifically to geriatric patients with depressive disorders mulsant et al 2001 |
in updating their algorithm for treatment of geriatric depression mulsant et al |
2014 reaffirmed their view that algorithmic treatment using a sequential approach should lead to superior outcomes compared with individualized treatment in that it allows standardization of the quantity and quality of drug treatment through for example optimizing drug dosing the frequency of follow up and the length of drug treatment trials |
existing algorithms for treatment of bpsd either address symptoms other than agitation and aggression e g |
psychosis madhusoodanan and ting 2014 or where these symptoms are a focus e g |
british columbia bpsd algorithm 2014 salzman et al 2008 differ from the present algorithm in that they do not propose sequential treatment with a defined sequence of drugs with pre specified dosing schedules and decision time points |
methods an algorithm for management of agitation and aggression associated with alzheimer s and mixed alzheimer s vascular dementia was devised by an inter disciplinary team consisting of psychiatrists nurses occupational and recreational therapists and managers |
the current paper describes only the segment of the algorithm on pharmacological treatments which was designed by the psychiatrists |
the intention was to produce an algorithm that could be used after a period of drug washout and baseline assessment |
this algorithm consists of a series of drugs to be used sequentially in monotherapy over six steps |
dosing schedules have been generated for each drug which cater both to patients of normal constitution and those deemed frail because of their constitution or medical co morbidity |
the schedules were designed to provide decision points at which drugs could be held at the existing dose or titrated depending on observed response |
in addition to the main sequential algorithm we provide guidance on washing out existing psychotropic drugs at the start of the process drugs that may be used on a pro re nata prn basis e g |
trazodone and lorazepam and the role of cholinesterase inhibitors and memantine figure 1 |
summary of drugs illustrating main pathway pro re nata prn drugs and alzheimer s disease treatments |
ect electroconvulsive therapy |
methods for the main algorithm drug treatments were appraised by the psychiatrists from participating institutions using the following five criteria listed in order of importance figure 2 a strength of evidence of efficacy in agitation or aggression in alzheimer s or mixed alzheimer s and vascular dementia b time to onset of clinical effect c tolerability side effect profile d ease of use e g |
propensity to drug interactions and e efficacy of the drug or class for other relevant conditions beyond bpsd e g |
anxiety disorders assessment of sequential drug treatment algorithm medications in five domains |
key five domains are listed in descending order of importance in their contribution for ranking the drugs in the sequential medication algorithm |
efficacy strength of evidence for efficacy in agitation aggression in alzheimer s or mixed alzheimer s vascular dementia |
time to onset time to onset of clinical effect |
tolerability tolerability side effect profile |
ease of use potential for interactions disruption of co prescribed medication |
efficacy other evidence in other relevant conditions beyond behavioural and psychological symptoms of dementia bpsd including anxiety disorders |
green indicates that the drug was given the highest rating yellow intermediate rating and red the lowest rating |
for instance risperidone is rated green for efficacy due to the existence of multiple successful randomized trials while gabapentin is rated red as evidence relies on case reports case series only |
the remaining drugs are rated yellow or intermediate on efficacy since positive randomized controlled trials are more limited or evidence is based on meta analysis of randomized trials |
drugs and physical treatments included in the main sequential treatment algorithm evidence and rationale following review of patient s suitability for the algorithm baseline assessments and a clean up or washout period figure 3 the algorithm begins with trials of antipsychotic drugs figure 4 |
azermaia et al |
2012 systematically appraised existing guidelines for bpsd |
they noted that there was a broad agreement among 15 clinical guidelines that antipsychotic drugs had the strongest evidence for treating bpsd |
however the efficacy of antipsychotic drugs comes at a cost for some individuals as they carry risks of falls excessive sedation and metabolic abnormalities schneider et al 2006 |
a further concern is the reported increased risk of stroke and mortality associated with atypical antipsychotics schneider et al 2005 |
in general guidelines recommend restricting the use of antipsychotic medications to where symptoms and their potential consequences meet specific criteria |
for example recent guidance from the american psychiatric association states nonemergency antipsychotic medication should only be used for the treatment of agitation or psychosis in patients with dementia when symptoms are severe are dangerous and or cause significant distress to the patient american psychiatric association 2016 24 |
however in the hospital inpatient setting for which the algorithm was designed many patients with dementia exhibiting agitation and aggression do indeed meet these criteria for example being at significant risk of harming themselves or others and exhibiting clear evidence of distress |
where symptoms of agitation and aggression do not meet these criteria this drug treatment algorithm should not be used |
drug clean up principles |
achei acetycholinesterase inhibitor bpsd behavioural and psychological symptoms of dementia prn pro re nata |
flow chart illustrating sequential medication algorithm |
av atrioventricular bpsd behavioural and psychological symptoms of dementia cgi clinical global impression ect electroconvulsive therapy epse extrapyramidal side effect po per os oral rct randomized controlled trial se side effect ssri selective serotonin reuptake inhibitor |
drugs and physical treatments included in the main sequential treatment algorithm evidence and rationale while the recommended treatment sequence begins with antipsychotic agents we have acknowledged that a minority of patients or their families and caregivers may not agree with the use of antipsychotic drugs in which case drug treatment may need to start lower down the algorithm at step 3 |
while several antipsychotic drugs have trial or meta analytic evidence of efficacy for agitation and aggression associated with alzheimer s disease seitz et al 2013 we selected three atypical antipsychotic drugs risperidone quetiapine and aripiprazole |
step 1 risperidone risperidone neuroscience based nomenclature nbn dopamine serotonin noradrenaline receptor antagonist nutt and blier 2016 has the strongest evidence base for treatment of bpsd symptoms in alzheimer s or mixed dementia through several large randomized trials brodaty et al 2003 de deyn et al 1999 dur谩n et al 2005 schneider et al 2006 suh et al 2006 |
in canada risperidone has approval for symptomatic management of aggression or psychosis restricted to severe dementia of the alzheimer s type health canada 2015 while in the uk it is licensed for short term treatment of aggression in bpsd up to six weeks |
in the usa the use of risperidone is not approved for any bpsd related indication |
as all antipsychotics risperidone carries cardiovascular and metabolic risks |
a relationship between antipsychotics and stroke has been suggested herrmann and lanct么t 2005 |
in a large retrospective case control study of patients with dementia antipsychotics conferred an excess risk of mortality from all causes over 180 days compared with matched controls on no psychotropic drug treatment maust et al 2015 with a number needed to harm nnh of 27 for risperidone 95 confidence interval 19 46 |
olanzapine and quetiapine had slightly but not significantly higher nnhs but the risk of mortality for all three atypical antipsychotics studied had a significant relationship to dose |
thus the algorithm allows for the scenario that a patient or their caregivers may be unwilling to agree to the use of atypical antipsychotics whereby the medication algorithm may be started at step 3 |
step 2 a quetiapine the evidence base for quetiapine nbn dopamine and serotonin receptor antagonist and noradrenaline reuptake inhibitor is considerably weaker than that for risperidone |
however a meta analysis cheung and stapelberg 2011 combining five randomized trials reported a statistically significant effect relative to placebo on neuropsychiatric symptoms neuropsychiatric inventory scores cummings et al 1994 and overall improvement clinical global impression cgi scores |
while these effects were modest quetiapine ranked well for time to onset of effect with cgi change score reported to be significantly greater than placebo after one week zhong et al 2007 tolerability and its evidence of efficacy in other disorders such as generalized anxiety disorder for review see baldwin et al 2014 |
quetiapine was therefore included alongside aripiprazole as an option for the algorithm s second step |
step 2 b aripiprazole again aripiprazole nbn dopamine serotonin receptor partial agonist has a smaller evidence base than risperidone |
however there is randomized trial evidence suggesting a statistically significant effect for agitation in patients with alzheimer s disease where bpsd symptoms included psychosis mintzer et al 2007 with superiority over placebo detected as early as week 2 for some outcomes |
aripiprazole was superior to placebo in a meta analysis schneider et al 2006 both on outcome measures specific to agitation and on the more wide ranging neuropsychiatric inventory |
aripiprazole was included as an alternative to quetiapine due to its differing mechanism of action which involves partial d2 receptor antagonism |
although this has not been demonstrated the panel of psychiatrists believed this different mechanism of action might confer a greater efficacy in risperidone non responders than the remaining atypical antipsychotics |
step 3 carbamazepine carbamazepine nbn glutamate voltage gated sodium and calcium channel blocker is used in many forms of epilepsy and as a mood stabilizer for bipolar disorder |
case reports support its use to control aggressive outbursts in episodic dyscontrol syndrome lewin and sumners 1992 |
the panel ranked carbamazepine below the antipsychotics |
it has one successful but small randomized trial olin et al 2001 in patients with bpsd who were resistant to treatment with antipsychotics with efficacy demonstrated over a six week treatment period but also several other negative trials in bpsd for review see konovalov et al 2008 |
carbamazepine presents several issues to prescribers including potential for drug interactions given its known induction of the cyp 3a4 enzyme which plays a role in the metabolism of numerous psychotropic drugs davies et al 2004 and rare but potentially dangerous side effects including severe skin reactions aplastic anemia and agranulocytosis |
however the panel considered carbamazepine as a drug that still had potential for efficacy in the psychopathology of bpsd within a short time scale in patients resistant to or unable to take antipsychotics |
by step 3 patients may already have been hospitalized for six weeks or more and in ontario patients admitted to an inpatient psychiatric unit may be forced to relinquish their place in long term care homes after 60 days in hospital |
thus the panel regarded it as essential that prescribers had the option around this deadline of using a drug with the potential to deliver a marked improvement within a few weeks in at least a minority of cases |
however prescribers can skip steps in the algorithm and when they consider carbamazepine unsuitable they may move straight to step 4 citalopram |
step 4 citalopram citalopram nbn serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor ssri antidepressant |
ssris are the most widely used antidepressants and also have efficacy for most anxiety disorders baldwin et al 2014 |
the use of citalopram in bpsd has various pros and cons |
in favor of the inclusion of citalopram is the recent successful placebo controlled randomized trial known as citad in which citalopram titrated to a target of 30 mg day was effective in reducing bpsd symptoms porsteinsson et al 2014 and three previous trials pollock et al 1997 2002 2007 |
against the use of citalopram are the recent concerns of qtc prolongation which prompted the us food and drug administration and health canada to restrict its use to a maximum of 20 mg day in people aged over 65 years health canada website 2012 |
there is also the possibility that despite the data from the citad trial treatment with ssris may initially cause increased agitation through jitteriness anxiety syndrome sinclair et al 2009 |
a recent analysis of citad data weintraub et al 2015 concludes that at least nine weeks are required for full response with citalopram |
thus in the time sensitive context of treatment of bpsd in inpatient settings the panel consensus was that prescribers should have the option of undertaking a trial of carbamazepine for which both benefits and adverse effects may be realized more quickly before a trial with citalopram |
the panel considered a variety of pharmacologic agents for possible fifth and sixth steps see below given that some or all of the standard agents recommended for the first four steps may not be appropriate for example through issues relating to consent or previous intolerance to one or more of the recommended drugs prior to being admitted to an inpatient unit |
it selected two agents that have different mechanisms of action gabapentin and prazosin |
step 5 gabapentin originally developed for treatment of epilepsy gabapentin nbn glutamate voltage gated calcium channel blocker has only case reports and case series suggesting effectiveness for bpsd symptoms covering agitation and aggression with or without sexual disinhibition kim et al 2008 |
it was included at this point in the medication algorithm due to its versatility in treating allied conditions such as anxiety disorders baldwin et al 2014 its lack of potential cytochrome p 450 based pharmacokinetic interactions since it is excreted unchanged by the kidney and good tolerability |
some case reports indicate a relatively rapid time to onset of effect within two weeks cooney et al 2013 although this remains to be assessed in a randomized placebo controlled trial |
step 6 prazosin prazosin nbn noradrenaline receptor antagonist is an alpha adrenoceptor blocking drug originally used as an antihypertensive |
it has more recently been used in psychiatry to reduce distressing dreams of post traumatic stress disorder de berardis et al 2015 |
prazosin has one small randomized placebo controlled trial reporting a significant impact on agitation and aggression in alzheimer s dementia using doses between 1 mg and 6 mg day wang et al 2009 |
it should be avoided in individuals who have experienced postural hypotension and it is advised to give the first dose at bedtime to reduce the impact of hypotensive effects |
step 7 a combination of any two drugs which have produced partial response or step 7 b electroconvulsive therapy ect ect is included at the last treatment step in the algorithm |
a recent review of studies in which ect was given to people having a mood disorder in the presence of dementia did not identify clear evidence of excess safety risks compared with non demented individuals |
however data was acknowledged to be limited with some suggestions of cognitive decline in late stage dementias or in vascular dementia oudman 2012 necessitating careful discussion with patients where possible and family members |
although there are no published controlled trials of ect in bpsd rapid resolution of agitation and aggression has been reported in small case series carlyle et al 1991 grant and mohan 2001 and safety and efficacy has been documented in two retrospective case note reviews isserles et al 2017 ujkaj et al 2012 |
isserles et al |
2017 report a clinically meaningful response of bpsd in 72 of cases with maintenance ect sustaining the response in 87 but all observations were uncontrolled |
drugs included for prn use evidence and rationale while the above sections describes steps the panel endorsed for sequential treatment of agitation and aggression in alzheimer s and mixed alzheimer s vascular dementia it was recognized that at times the regular treatments cannot offer adequate protection from the impact of these symptoms |
accordingly the algorithm allows for the possibility of supplementing medication given in the main sequence with drugs to be given on a prn basis |
the main drug selected for this purpose was trazodone with use of lorazepam considered acceptable in certain circumstances |
prn drug 1 trazodone trazodone nbn serotonin receptor antagonist and receptor agonist is an effective antidepressant |
although it was developed and entered the market concurrently to tricyclic agents such as clomipramine desipramine and nortriptyline it differs markedly from these drugs in its mechanism of action and receptor binding profile |
its main antidepressant action is thought to be through direct blockade of certain serotonin receptors while weak serotonin reuptake inhibition and receptor agonism are adjunctive effects |
it lacks affinity for cholinergic receptors thereby avoiding many of the unwanted side effects associated with tricyclics but does produce a strong histaminergic effect which directly promotes sedation |