Out Of The Pipeline

Trazodone extended release for major depressive disorder

Current Psychiatry. 2010 December;9(12):76-84

References

1. Oleptro [package insert]. Dublin, Ireland: Labopharm Europe Limited; 2010.

2. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone. J Clin Pharmacol. 2003;43(4):414-422.

3. Beasley CM, Jr, Dornseif BE, Pultz JA, et al. Fluoxetine versus trazodone: efficacy and activating-sedating effects. J Clin Psychiatry. 1991;52:294-299.

4. Kasper S, Olivieri L, Di Loreto G, et al. A comparative, randomized double blind study of trazodone prolonged-release and paroxetine in the treatment of patients with major depressive disorder. Curr Med Res Opin. 2005;21:1139-1146.

5. Munizza C, Olivieri L, Di Loreto G, et al. A comparative, randomized double blind study of trazodone prolonged-release and sertraline in the treatment of patients with major depressive disorder. Curr Med Res Opin. 2006;22:1703-1713.

6. Cunningham LA, Borison RL, Carman JS, et al. A comparison of venlafaxine, trazodone, and placebo in major depression. J Clin Pyschopharmacol. 1994;14:99-106.

7. Weisler RH, Johnston JA, Lineberry CG, et al. Comparison of bupropion and trazodone in the treatment of major depression. J Clin Psychopharmacol. 1994;14:170-179.

8. Feighner JP. Trazodone, a triazolopyridine derivative, in primary depressive disorder. J Clin Psychiatry. 1980;41:250-255.

9. Rickels K, Case WG. Trazodone in depressed outpatients. Am J Psychiatry. 1982;139:803-806.

10. Perry PJ, Garvey MJ, Kelly MW, et al. A comparative trial of fluoxetine versus trazodone in outpatients with major depression. J Clin Psychiatry. 1989;50:290-294.

11. Sheehan DV, Croft HA, Gossen ER, et al. Extended-release trazodone in major depressive disorder: a randomized, double-blind, placebo-controlled study. Psychiatry (Edgmont). 2009;6(5):20-33.

12. Sheehan DV, Rozova A, Gossen ER, et al. The efficacy and tolerability of once-daily controlled-release trazodone for depressed mood, anxiety, insomnia, and suicidality in major depressive disorder. Psychopharmacol Bull. 2009;42(4):5-22.

13. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959-965.

14. Landén M, Högberg P, Thase ME. Incidence of sexual side effects in refractory depression during treatment with citalopram or paroxetine. J Clin Psychiatry. 2005;66(1):100-106.

15. Thompson JW, Jr, Ware MR, Blashfield RK. Psychotropic medications and priapism: a comprehensive review. J Clin Psychiatry. 1990;51:430-433.

Sleep measures. In the study sample >90% of patients had insomnia at baseline (defined as a score ≥2 in any HAM-D-17 sleep item or sum of all 3 sleep items of ≥4). Patients receiving trazodone ER had significant improvement in all 3 HAM-D-17 sleep items. Subjects reported improvement in the overall quality of sleep and awakening during the night after the first week of treatment. Investigators found no significant interaction between improvements in core symptoms of depression and baseline MADRS reduced sleep item or early changes in the HAM-D-17 sleep items. This suggests that the antidepressant effect of trazodone ER was independent of severity of sleep difficulties at baseline and of improvement in insomnia during the study.¹²

Researchers observed improvement in suicidal ideation on MADRS (item 10) and HAM-D-17 (item 3) after 8 weeks of treatment (effect size -0.2 favoring trazodone ER over placebo).¹²

In 2 European comparative, randomized, double-blind trials, trazodone prolonged release showed similar antidepressant efficacy as paroxetine⁴ and setraline⁵ as measured by HAM-D, MADRS, and CGI-S. This prolonged release formulation made in Europe is not the same technology as the ER formulation recently approved by the FDA.

Tolerability

Clinical Point

The most common side effects leading to discontinuation were dizziness, sedation, and somnolence

In the pivotal registration study, trazodone ER was well tolerated at a mean dose of 310 mg/d.¹¹ Twenty-five patients (12.4%) in the trazodone ER group discontinued the drug because of side effects. The most common side effects leading to discontinuation in the active treatment group were dizziness (n=7), sedation (n=5), and somnolence (n=3).¹¹ The most frequent adverse events reported at any study time point were headache (33%), somnolence (31%), dry mouth (25%), dizziness (25%), nausea (21%), sedation (17%), and fatigue (15%) (Table 2).¹¹ In general, these adverse events were mild to moderate and short-lived; most side effects resolved within the first 2 to 3 weeks of treatment with trazodone ER.¹¹

Sexual side effects—delayed ejaculation, delayed time to orgasm, or orgasmic blockade—are common with many anti-depressants. In the pivotal registration study, the incidence of sexual side effects was low (4.9% with trazodone ER vs 2.5% with placebo).¹¹ This is much lower than the rates typically found with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, which range from 17% to 41%.^13,14 This benefit is thought to be mediated through 5-HT2A and 5-HT2C antagonism. Priapism has been reported in trazodone IR at rates ranging from 1 in 1,000 to 1 in 10,000 and does not appear to be dose-related.¹⁵ The rate of priapism in persons using agents for erectile dysfunction ranges from .05% to 6%.¹⁵ No case of priapism was seen in the trazodone ER study; however, with its sample size of 412 patients this study was not powered to adequately detect this adverse event.¹¹

There was no significant weight gain difference between the active drug and placebo groups over 8 weeks of treatment.

Safety. Trazodone ER should not be used within 14 days of taking a monoamine oxidase inhibitor.¹ Trazodone carries a pregnancy category C, meaning that it should be used only if the potential benefit justifies potential risk to the fetus. In animal studies, trazodone has been shown to cause increased fetal resorption and congenital anomalities with doses up to 50 times the maximum human dose (375 mg/d). Trazo-done may be secreted in breast milk. The drug is best avoided in patients with recent myocardial infarction.

Table 2

Trazodone extended release treatment-emergent adverse events*

	Trazodone ER (n=202)	Placebo (n=204)
Headache	67 (33%)	55 (27%)
Somnolence	63 (31%)	32 (16%)
Dry mouth	51 (25%)	26 (13%)
Dizziness	50 (25%)	25 (12%)
Nausea	42 (21%)	26 (13%)
Sedation	34 (17%)	7 (3%)
Fatigue	30 (15%)	17 (8%)
Diarrhea	19 (9%)	23 (11%)
Constipation	16 (8%)	4 (2%)
Back pain	11 (5%)	7 (3%)
Blurred vision	11 (5%)	0 (0%)
Reported by ≥5% of patients Source:* Reference 11

Dosing

Clinical Point

The recommended starting dose is 150 mg/d at bedtime; it may be increased by 75 mg/d every 3 days, but should not exceed 375 mg/d

The recommended starting dose is 150 mg/d at bedtime. The dose may be increased by 75 mg/d every 3 days, but the maximum dose should not exceed 375 mg/d.¹ Trazodone ER is available in 150 mg or 300 mg bisectable tablets. Breaking the tablets in half does not affect the controlled release, but they should not be chewed or crushed.

Related Resource

Extended-release trazodone (Oleptro) prescribing information. www.oleptro.com/images/9379.pdf.

Drug Brand Names

Paroxetine • Paxil
Ritonavir • Norvir
Sertraline • Zoloft
Trazodone • Desyrel
Trazodone extended-release • Oleptro

Disclosures

Dr. Hidalgo receives grant/research support from AstraZeneca, CeNeRx Biopharma, Centers for Disease Control and Prevention, Dainippon Sumitomo Pharma America, Inc., Eli Lilly and Company, Forest Laboratories, Indevus Pharmaceuticals, Janssen Pharmaceuticals, Labopharm, Otsuka, Pfizer, Inc., Repligen Corp., Sanofi-Synthelabo, Sepracor, and the University of South Florida, and is consultant to the MAPI Institute.