, Volume 4, Issue 4, pp 331-355

Trazodone

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Summary

Synopsis

Trazodone is a triazolopyridine derivative, chemically and pharmacologically unrelated to other currently available antidepressants. It possesses antidepressant, and also some anxiolytic and hypnotic activity.

Results from a small number of short term (4 to 6 weeks) comparative studies in a total of 320 evaluable elderly patients with major depression, suggest that trazodone at therapeutic doses is superior to placebo and as effective as amitriptyline, imipramine, fluoxetine and mianserin in relieving depressive symptoms. Trazodone has also been successfully used in a small number of patients with depression and pre-existing cardiovascular disease. More recently, trazodone has been used as a hypnotic for psychotropic-induced or other insomnias with some success. However, further clinical experience is needed to confirm these preliminary results.

In the elderly, maximum tolerated doses of trazodone are 300 to 400 mg/day, although higher doses of up to 600 mg/day are tolerated by younger patients. Drowsiness is commonly reported, but the incidences of both anticholinergic and cardiovascular effects were notably lower in elderly patients treated with trazodone compared with older tricyclic antidepressants. However, undesirable effects such as orthostatic hypotension, arrhythmias and priapism need to be closely monitored. In comparison with other currently available agents, particularly the tricyclic antidepressants, trazodone is relatively safe in overdose.

In terms of therapeutic efficacy, trazodone appears to confer little advantage over other available antidepressants. While limited data suggest that trazodone may be better tolerated than older tricyclic antidepressants, especially in the elderly, there is a paucity of data at present comparing trazodone with the secondary amine tricyclic agents, serotonin reuptake inhibitors or moclobemide. Bearing this in mind, trazodone may be of use in elderly patients in whom anxiety and insomnia are problematic, and in those patients who are unresponsive to or cannot tolerate therapy with other agents. Studies are also required to define the place of trazodone in long term prophylactic therapy for recurrent depression. Future trials comparing both its efficacy and tolerability with those of newer agents will ascertain whether trazodone becomes a first line agent within these subsets of elderly patients.

Pharmacodynamic Properties

Trazodone is a triazolopyridine derivative which is both chemically and pharmacologically distinct from other currently available antidepressants. Although trazodone is commonly referred to as a selective serotonin reuptake inhibitor, studies to date suggest that the pharmacological activity of trazodone may be modulated via other mechanisms such as antagonism at serotonin 5-HT1a, 5-HT1c and 5-HT2 receptor subtypes. However, its precise mechanism of action in humans is not fully understood.

Trazodone has marked soporific properties, which have been evaluated to a limited extent in elderly volunteers. In 9 elderly volunteers with insomnia, nocturnal doses of trazodone 150mg significantly reduced the duration of rapid eye movement sleep and increased the duration of slow wave sleep. The hypnotic effect was greater in the elderly when compared with young individuals.

Both cognitive performance and memory may be impaired by trazodone, although this is less pronounced with trazodone than with amitriptyline. Alertness may also be impaired for a longer period after trazodone administration in the elderly than in the young.

In comparison with the older tricyclic antidepressants, trazodone appears to have a more benign cardiovascular risk profile. In patients with pre-existing cardiac disease, postural hypotension and a tendency to lower heart rate were associated with trazodone therapy. Electrocardiographic changes were not observed. In particular, changes in cardiac conduction were not noted in these patients.

Pharmacokinetic Properties

Trazodone is a highly lipophilic compound, exhibiting linear kinetics. Following oral administration in fasted volunteers, single doses of trazodone 50 to 100mg were well absorbed from the gastrointestinal tract, with bioavailability ranging from 63 to 91%. Although the bioavailability, peak plasma concentration (Cmax) and time to reach Cmax were comparable in both the young and elderly, the area under the plasma concentration-time curve was significantly greater in the latter. Coadministration of trazodone with food has a variable affect on the amount of drug absorbed, and Cmax may decrease.

The volume of distribution following intravenous trazodone 25mg was greater in the elderly than in the young, and in women than in men.

Trazodone is extensively metabolised; less than 1% of the dose is excreted unchanged in the urine and faeces. Significant prolongation of plasma elimination half-life (13.6 vs 6 hours) and reduction in total apparent clearance (5.1 vs 10.8 L/h) were noted in fasted elderly volunteers when compared with younger individuals. Dialysis does not significantly accelerate the removal of trazodone from the body.

Therapeutic Efficacy

To date, the efficacy of trazodone has been assessed in a limited number of elderly patients. In comparative trials, short term therapy (4 to 6 weeks) with trazodone at therapeutic doses appeared to be superior to placebo, and as effective as amitriptyline, imipramine, mianserin and fluoxetine in a total of 320 evaluable elderly depressed patients (divided over 14 groups) aged 51 to 90 years. Where numerical data were available, reductions in total Hamilton Depression Rating Scores were 39 to 64% for trazodone, 63% for amitriptyline, 58% for fluoxetine and 53 to 78% for mianserin. Alleviation of other symptoms such as insomnia and anxiety was observed early with trazodone therapy. Trazodone was also noted to reduce both depression and anxiety in 67 patients with pre-existing cardiovascular disease.

More recently, low doses of trazodone 25 to 200 mg/day in combination with monoamine oxidase inhibitors (MAOIs), fluoxetine or other psychotropic agents, have been used to alleviate psychotropic-induced or other insomnias with some success. Severe behavioural problems were also resolved or became manageable in a small number of patients with dementia. However, these results at present should be considered as preliminary.

Tolerability

In elderly patients, maximum tolerated doses of trazodone are generally 300 to 400 mg/day, although in younger patients trazodone appears to be tolerated in larger doses (up to 600 mg/day). Long term experience with trazodone suggests that significant adverse events are more likely to occur within the first 3 months of treatment. In a review of 58 studies, in which 1621 patients received trazodone at doses of 75 to 500 mg/day, the most commonly reported adverse events were drowsiness (5.6%), tiredness (3.1%), gastrointestinal disorders (3%), dizziness (2.6%), dry mouth (2.5%), insomnia (1.6%), headache (1.6%), hypotension (1.2%), agitation (1.1%) and tachycardia (1%). Both anticholinergic and cardiovascular adverse effects were notably lower in elderly patients treated with trazodone than in patients receiving amitriptyline, imipramine or mianserin. Concern has, however, been expressed regarding its propensity to cause orthostatic hypotension and arrhythmias, the incidence of both being comparable to that of tricyclic antidepressants.

Other adverse effects associated with trazodone therapy include priapism, which should be considered a urological emergency. In addition, while the incidence of seizures is relatively low, patients with predisposing conditions may be at risk.

In comparison with other antidepressants, trazodone is relatively safe in overdose. Where deaths have resulted from overdosage, trazodone was taken in conjunction with other agents and/or alcohol.

Dosage and Administration

Dosage guidelines for the elderly patient with depression recommend initial trazodone dosages of 100 mg/day in divided doses after food or as a single night-time dose. This may be slowly titrated according to efficacy and tolerability with doses rarely needing to exceed 300 mg/day in this population. Trazodone therapy should be continued for several months after symptom remission, and cessation of treatment should be gradual.

Concomitant therapy with antihypertensives, MAOIs and other CNS depressants, including alcohol, should be initiated cautiously.

Various sections of the manuscript reviewed by: D.R. Abernethy, Division of Clinical Pharmacology, Rhode Island Hospital, Providence, Rhode Island, USA; A.C. Altamura, Istituto di Clinica Psichiatrica, Universita Degli Studi di Cagliari, Cagliari, Italy; A. Bayer, University Department of Geriatric Medicine, Cardiff Royal Infirmary, Cardiff, Wales; H.V. Curran, Clinical Psychopharmacology Section (MRC), Institute of Psychiatry, London, England; F. de Jonghe; Algemeen Psychiatrisch Centrum, Amsterdam, The Netherlands; S. Gershon, Office of Research Health Sciences, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; K. Ghose, National Toxicology Group, University of Otago Medical School, Dunedin, New Zealand; S.B. Lippmann, Department of Psychiatry, Humana Hospital-University of Louisville School of Medicine, Louisville, Kentucky, USA; L.H. Price, Clinical Neuroscience Research Unit, Yale University School of Medicine, New Haven, Connecticut, USA; R.G. Priest, Academic Department of Psychiatry, St Mary’s Hospital, London, England.