Alzheimer’s Therapy: Antidepressants

By | April 15, 2015

Overview. Major depression affects approximately 15% of Alzheimer’s disease patients. By comparison, 5-12% of the general population aged 15 years or older in the major pharmaceutical markets experience at least one episode of major depression per year. Because depression itself may lead to declines in cognition and function, treatment of depression in Alzheimer’s disease patients is seen as an important aspect of therapy; depression appears to be an early sign of Alzheimer’s disease because it is more common in mild to moderate Alzheimer’s disease patients than in patients with severe Alzheimer’s disease. Tricyclic antidepressants (TCAs) were once the preferred treatment for depressive symptoms in Alzheimer’s disease, but selective serotonin reuptake inhibitors (SSRIs) have largely replaced these agents. Citalopram (Lundbeck’s Cipramil, Forest Laboratories’ Celexa, generics) is one of the most frequently prescribed SSRIs in the treatment of Alzheimer’s disease because of its favorable side-effect profile. The SSRI paroxetine (GlaxoSmifhK-line’s Paxil/Seroxat) is becoming less popular in the treatment of Alzheimer’s disease because it causes mild anticholinergic side effects. Other commonly prescribed SSRIs include sertraline (Pfizer’s Zoloft), fluvoxamine (Solvay/Fujisawa’s Luvox, Meiji Seika’s Depromel, generics), and fluoxetine (Eli Lilly’s Prozac, generics). The noradrenergic and specific serotonergic antidepressant mirtazapine (Organon’s Remeron/Remergil) is another commonly used antidepressant for the treatment of depression in Alzheimer’s disease because of its favorable tolerability and faster onset of action than SSRIs. The discussion here focuses on the most commonly used SSRI for Alzheimer’s disease patients, citalopram.

Mechanism of Action. Although depression in Alzheimer’s disease patients can be a reaction to the diagnosis of the disease, it is also part of the disease itself; neuropathogenic features of Alzheimer’s disease can be responsible for the onset of depression. It has been suggested that the death of cholinergic neurons in the basal forebrain interrupts their transmission to postsynaptic monoaminergic (noradrenergic and serotonergic) neurons in the limbic, paralimbic, and cortical regions (). In addition, a loss of noradrenergic neurons in the locus coeruleus and of serotonergic neurons in the dorsal raphe nuclei has been observed in brain autopsies of Alzheimer’s disease patients affected by depression (). Antidepressant effects of SSRIs in Alzheimer’s disease probably occur because these agents compensate for the loss of cholinergic neuron signaling to serotonergic neurons (or loss of serotonergic neurons) in Alzheimer’s disease patients by effectively increasing levels of serotonin present in synaptic clefts. SSRIs selectively inhibit the presynaptic reuptake of serotonin while exerting little effect on norepinephrine reuptake. SSRIs as a class have little effect on histaminergic, dopaminergic, or alpha-adrenergic () receptors — hence their lower incidence of side effects as compared with older antidepressants (TCAs and monoamine oxidase inhibitors [MAOIs]). Side effects of SSRIs, such as bradycardia or hyponatremia, are not common in other populations, but they occasionally arise in elderly patients treated with antidepressants ().


Citalopram (Lundbeck’s Cipramil, Forest Laboratories’ Celexa, generics) () is available for depression and panic disorder in the United States and Europe. No development has been reported in Japan. This agent is a popular choice for elderly depressed patients because of its low incidence of side effects (). Of note, citalopram’s s-enantiomer, escitalopram (Lundbeck’s Cipralex, Forest’s Lexapro), was launched in the United States in September 2002 for depression. Escitalopram has also been approved for depression in France, Germany, Italy, Spain, and the United Kingdom. Theoretically, escitalopram is associated with fewer side effects than citalopram because it is more potent and more selective than citalopram (). Data from a comparator trial in depression suggest that escitalopram (10 mg daily) is similar to citalopram (40 mg daily) in tolerability, with similar incidence of discontinuation due to adverse events ().

Citalopram shows the high selectivity for serotonin over norepinephrine (the only SSRI that is more selective is escitalopram). SSRIs as a class have little effect on histaminergic, cholinergic, dopaminergic, or a-adrenergic receptors — hence their lower incidence of side effects compared with older antidepressants (TCAs, MAOIs, and second-generation agents). Historically, citalopram has been touted for its lack of drug interactions and low incidence of side effects compared with other SSRIs. With the launch of citalopram, Forest and Lundbeck are marketing this new drug as the most tolerable SSRI.

Citalopram has shown efficacy in the treatment of acute behavioral and psychotic symptoms in patients with Alzheimer’s disease, and it may have modest effects on cognition in nondepressed Alzheimer’s disease patients as well. The drug is used in clinical practice, but few trial data exist to support its therapeutic effects in depressed Alzheimer’s disease patients. In a double-blind, placebo-controlled study, the ability of citalopram and the antipsychotic perphenazine (generics) to treat psychosis and behavioral symptoms of nondepressed Alzheimer’s disease patients were compared (). In the study, 85 hospitalized patients with dementia were treated with citalopram, perphenazine, or placebo for up to 17 days. The short duration of the trial was intended to represent the length of time for which patients are hospitalized for an acute psychotic episode in Alzheimer’s disease. Sixty-one of the patients met the DSM-IV criteria for Alzheimer’s disease, with at least one moderate to severe behavioral symptom on the Neurobehavioral Rating Scale (NRS, a 28-item observer-rated test that assesses multiple types of psychopathologies including a comprehensive assessment of dementia-specific impairments). Moderate to severe behavioral symptoms were defined as a score of 3 or more on the NRS. Patients treated with citalopram (20mg/day) showed statistically significant improvement in their behavior, as assessed by NRS scores, versus placebo. Moreover, citalopram-treated patients showed significant improvement from baseline with respect to agitation/aggression and psychosis. In addition, the citalopram-treated group displayed significant improvement on cognition, as measured by the MMSE. Patients treated with perphenazine did not display NRS scores significantly higher than placebo. Finally, although perphenazine-treated patients showed improvement from baseline for agitation and psychosis, there was no significant improvement in this group with respect to cognitive symptoms.

Like all SSRIs, citalopram is contraindicated for patients taking MAOIs and should be used with caution in conjunction with TCAs. The most frequent adverse events reported with citalopram versus placebo in clinical trials include nausea (21% versus 14%), dry mouth (20% versus 14%), and somnolence (18% versus 10%).