Citalopram for the Treatment of Agitation in Alzheimer Dementia

Abstract

Objective To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66-Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study—Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. Method We utilized data from the Citalopram for Agitation in Alzheimer’s Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. Results Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. Discussion Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.

The neurochemistry of agitation in Alzheimer’s disease: a systematic review

“…A significant association between 5-HTT promoter region (5-HTTPR) polymorphism and aggression was found in two studies , and between 5-HTT variable number tandem repeat (VNTR) polymorphism and aggression in another study (Ueki et al, 2007). These relationships, however, were not confirmed in several other studies (Assal et al, 2004;Ha et al, 2005;Peters et al, 2016;Pritchard et al, 2008;Proitsi et al, 2012).…”

“…Two studies found a significant association between the 5-HT2A T102C polymorphism and agitation (Assal et al, 2004;Peters et al, 2016), whilst several others, including two performed in populations of non-White ethnicity, did not support this relationship (Holmes et al, 1998;Lai et al, 2011;Lam et al, 2004;Pritchard et al, 2008;Proitsi et al, 2012). Similarly, more studies reported no significant association between 5-HT2C receptor polymorphisms and agitation (Holmes et al, 1998;Pritchard et al, 2008;Proitsi et al, 2012) than one that did (Peters et al, 2016). Genetic analysis of 5-HTT has also provided contradictory findings.…”

Psychosis in Alzheimer’s Disease

“…The CITAD trial randomized 186 people with AD to citalopram (ascending to 30 mg per day) or placebo for 9 weeks, demonstrating benefits in the primary outcome for agitation [83]. More recently, an analysis of secondary outcomes suggested benefits in both delusions and hallucinations in participants receiving citalopram compared with those receiving placebo, with the best response in individuals with psychosis and agitation [84].…”

What is the therapeutic value of antidepressants in dementia? A narrative review

“…One study (Moretti et al, 2002) had multiple elements judged as having a high risk of bias; this was largely due to the fact that it was not doubleblinded. Three studies were judged to have low risk of bias across all elements: sertraline or mirtazapine for depression in dementia (HTA-SADD; Banerjee et al, 2013Banerjee et al, , 2011, Depression in Alzheimer's Disease Study -Phase II (DIADS-II) (Drye et al, 2011;Martin et al, 2006;Rosenberg et al, 2010;Weintraub et al, 2010) and Citalopram for Agitation in Alzheimer's Disease (CitAD; Peters et al, 2016;Porsteinsson et al, 2014; Table 3).…”

“…The best trial in this area is the large (n = 186) welldesigned CitAD trial (Peters et al, 2016;Porsteinsson et al, 2014). In this 9-week RCT comparing citalopram with placebo, all the participants had probable AD and clinically significant agitation.…”