Background

Trazodone is a phenyl piperazine derivative with agonist and antagonist activity at serotonin receptors, in addition to adrenergic and histaminergic activity and serotonin uptake inhibition. It was approved more than 40 years ago to treat major depressive disorder. It is widely used off-label for insomnia and anxiety disorders, and to treat agitation and sleep disturbances in people with Alzheimer’s disease. Taken as a tablet, trazodone is available as a generic.

Recent interest in trazodone is focused on its potential to slow cognitive loss by improving sleep in people with early stage memory loss or dementia. Compared to other sleep medications, trazodone has a unique effect of prolonging and deepening slow-wave sleep. Disruption of slow-wave sleep by amyloid and tau deposition appears to contribute to cognitive problems (e.g., Mander et al., 2015; Lucey et al., 2019).

In an observational study of people with AD, MCI, or normal cognition but attending a sleep clinic, those using trazadone showed significantly slower decline in MMSE scores over four years than a matched group who did not take the drug (La et al., 2019; commentary by Ashford, 2019; also Burke et al., 2018). Slowing of cognitive decline was associated with subjective reports of sleep improvement.

There is also emerging evidence from preclinical studies for a possible disease-modifying effect due to trazodone’s ability to enhance proteostasis and protect against neurodegeneration in models of prion disease and frontotemporal dementia (Halliday et al., 2017; also see review by Sidhom et al., 2022). In rTg4510 tau mice, it reduced neuroinflammation and tau pathology, and improved sleep and olfactory memory (de Oliveira et al., 2022).

For treatment of depression, doses range from 150-300 mg per day, and can go up to 600 mg. Common side effects include dry mouth, feeling faint, hypotension, vomiting, and headache. Trazodone is moderately sedating. This drug can increase the risk of falling, but is nonetheless used for older people with depression, and for severe agitation or insomnia in AD patients (e.g. see Ringman and Schneider 2019).

A placebo-controlled study at Colorado State University Veterinary Teaching Hospital is evaluating trazodone for age-related cognitive dysfunction in dogs (TRAC study).

Findings

Following anecdotal reports of trazodone’s effectiveness for agitation in people with AD, a Phase 3 trial was run in the late 1990s at 21 sites in the U.S. It compared 16 weeks of trazodone (average mean dose 200 mg daily) to haloperidol, behavior management techniques, or placebo in 149 AD patients with moderate to severe cognitive impairment and agitation. Participants had to be living at home, or not in an institution. None of the interventions changed agitation compared to placebo. There was a slight worsening of cognition and function in medicated groups (Teri et al., 2000; Feb 2001 news). Side effects in the trazodone group were similar to placebo, with few dropouts in the trazodone arm.

In other, smaller trials, trazodone did improve agitation better than placebo in institutionalized AD dementia patients (Sultzer et al., 2001), and reduced irritability, agitation, depression, and disordered eating in people with frontotemporal dementia (Lebert et al., 2004).

Between 2010 and 2012, a low dose of trazodone was tested to treat sleep disorders in people with AD at a single center in Brasilia, Brazil. The trial randomized 36 patients with dementia and sleep problems to 50 mg trazodone or placebo at bedtime for two weeks. The primary outcome was change from baseline in total sleep time; secondary outcomes measured nighttime waking and daytime sleep, as well as cognitive function, dementia rating, and functional and behavioral measures. According to published results, the trazodone group slept 42.5 minutes longer than the placebo group at night, with no increase in daytime sleepiness or naps. The study found neither improvement nor impairment in cognition (Camargos et al., 2014; Carmargos et al., 2105).

In March 2022, Johns Hopkins investigators registered a Phase 2 clinical trial, called REST, to evaluate trazodone for its ability to improve sleep and cognition in people with mild cognitive impairment. Participants will have a subjective memory complaint and/or evidence of memory problems, a Clinical Dementia Rating of 0.5, and sleep complaints. In a crossover design, 100 participants will get 50 mg trazodone or placebo at bedtime for four weeks, separated by a four-week washout period. Primary outcomes are measures of sleep duration, slow-wave sleep duration and intensity, time to sleep onset, sleep fragmentation, self-reported sleep quality, and sleepiness. Secondary measures are memory performance and fMRI measures of hippocampal activation. The trial is to run from June 2022 to May 2028.

In May 2022, a one-year trial is to start in Hong Kong, enrolling 124 people with mild cognitive impairment due to AD and sleep apnea, to evaluate effects of 50 mg trazodone daily or placebo on plasma biomarkers of inflammation and neurodegeneration, and CDR global score. Completion is expected for December 2026.

A Phase 2/3 study in the U.K. is comparing trazodone or memantine to placebo in people with amyotrophic lateral sclerosis or other motor neuron disease. Called MND-SMART, the multicenter, adaptive trial is enrolling 750 patients for 18 months of treatment. Results are expected in 2026. 

Other ongoing studies are assessing the ability of trazodone to enhance overnight memory consolidation in healthy or depressed people, to treat insomnia or sleep apnea in a variety of settings, and to treat delirium in intensive care. A small study in Brazil is assessing the effects on motor symptoms in 30 people with Parkinson’s disease.

For details on trazodone trials, see clinicaltrials.gov.