Citalopram significantly reduces agitation in patients with Alzheimer’s disease, an American and Canadian multicentre study has found.

Participants were recruited from a number of different settings, including memory clinics, community outreach and nursing homes. They had probable Alzheimer’s disease, as defined by national criteria, they did not meet DSM IV criteria for major depression and had clinically significant agitation (defined by frequency and severity).¹

A total of 186 participants were randomised to receive a psychosocial intervention plus either citalopram or placebo for nine weeks.

The psychosocial intervention consisted of a 20-30 minute counselling session at each of the scheduled study visits, educational materials, and 24-hour availability for crisis management. The starting dose of citalopram was 10 mg and this was titrated up to 30 mg over three weeks if tolerated.

Two primary outcome measures were used. Agitation was measured at baseline and nine-week follow-up using the agitation subscale of the Neurobehavioral Rating Scale (NBRS-A), which has a range of 0-18. Clinically relevant improvement or worsening of agitation over the nine-week study period was assessed by a clinician using the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC).

• At nine weeks’ follow-up, the citalopram group had significantly lower NBRS-A scores than the placebo group: adjusted treatment difference

- 0.93 (95% CI: – 1.80 to – 0.06, P = 0.04). The mADCS-CGIC showed that 40% of those receiving citalopram had a moderate or marked improvement during the study period compared with 26% of those receiving placebo. The estimated treatment effect was 2.13 (95% CI:1.23-3.69, P = 0.007).

• However, citalopram was associated with significant adverse effects. Compared with the placebo group, the citalopram group experienced

a statistically significant cognitive decline: MMSE difference –1.05 points (95% CI: – 1.97 to – 0.13, P = 0.03), although this may not have been clinically significant.

The FDA warning of QT interval prolongation with citalopram was published partway through the trial. ECG screening and monitoring was introduced for the remaining 48 participants and a significant increase in the corrected QT interval was observed in the citalopram group: 18.1 ms (95% CI:6.1-30.1, P = 0.004).

Agitation is characterised by inappropriate verbal, vocal or motor activity which is not explained by needs or confusion.² It is often treated with antipsychotic drugs but these are associated with an increase in long-term mortality³ and there is a specific risk of stroke with risperidone and olanzapine. Only risperidone is licensed, for the short-term (up to six weeks) treatment of persistent aggression not responsive to non-pharmacological approaches and where there is risk of harm to the patient or others.⁴

Therefore, there is a need for alternative pharmacological therapies. There is evidence that agitated patients with Alzheimer’s disease have serotonergic dysfunction but a Cochrane review found only limited evidence to support the use of antidepressants for this indication.⁵

The main problem with the present study is that the 30 mg target dose of citalopram, which was achieved by 78% of those in the citalopram group, is no longer recommended for patients over 65 years because of the risk of QT interval prolongation. Unfortunately, there were insufficient patient numbers to determine the efficacy of a 20 mg dose.

SSRIs are associated with other side effects, including falls, hyponatraemia and upper GI bleeding, and a recent cohort study suggested that tricyclics were safer drugs in the elderly.6 However, tricyclics may adversely affect cognition through their anticholinergic effect and NICE recommends that they should not be used in patients with dementia.⁷

Trazodone is a tricyclic-related antidepressant with minimal cholinergic effects which is recommended for the treatment of agitated dementia patients who have depressive symptoms.8 However, at the present time there are no high quality studies to support its use in agitated patients who are not depressed.⁵

An alternative pharmacological approach is the stepwise use of analgesia. A Norwegian trial reported a seven point reduction in the Cohen-Mansfield Agitation Inventory (CMAI) score after pain treatment for eight weeks.9 This is much greater than the CMAI treatment difference of –2.38 reported in the present study. However, agitation is more commonly caused by psychosocial distress rather than pain, and analgesia should not be used indiscriminately.

It is essential to identify and treat underlying causes of agitation, such as boredom or pain, before considering drug therapy. When there is evidence that agitation is associated with underlying depression, we should certainly consider prescribing antidepressant medication, and trazodone may be the treatment of choice.

In view of the risks associated with antipsychotic medication, I think it is also reasonable to consider antidepressant medication as an alternative for patients with significant agitation who do not have depression. However, the evidence to support this practice remains limited.

Dr Phillip Bland