Out Of The Pipeline

Trazodone extended release for major depressive disorder

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

Once-daily dosing eliminates peaks and troughs in serum concentration seen with the immediate release formulation

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.

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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.

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Extended-release (ER) trazodone—FDA-approved in February 2010—improves symptoms of major depressive disorder (MDD) and allows once-daily dosing (Table 1). Trazodone immediate release (IR) was developed in 1960 and approved by the FDA for treatment of MDD in December 1981. Trazodone IR is now mainly prescribed off-label as a hypnotic at lower-than-antidepressant doses, such as 50 to 100 mg/d at bedtime. The dose needed to achieve antidepressant effect is believed to be ≥300 mg/d. Use of the IR formulation for treating depression has been limited by the need for 3-times-a-day dosing and daytime sedation associated with peaks in serum concentration.

Table 1

Trazodone extended release: Fast facts

Brand name: Oleptro
Class: Triazolopyridine-derived antidepressant
Indication: Major depressive disorder
Approval date: February 2, 2010
Availability date: August 10, 2010
Manufacturer: Labopharm, Inc.
Dosage forms: 150 mg and 300 mg bisectable tablets
Starting dose: 150 mg at bedtime
Target dose: 300 mg/d; maximum dose 375 mg/d

Clinical implications

Trazodone ER was designed to eliminate the peaks and troughs in serum concentration seen with trazodone IR. It was hypothesized that by reducing the maximum concentration (Cmax) peaks, trazodone ER would permit higher doses to be better tolerated and help patients to more easily reach target antidepressant doses (≥300 mg/d). Trazodone ER’s once-daily dosing also may increase patient adherence.

How it works

The exact mechanism of action through which trazodone treats depression is not completely understood, but is likely related to enhancing serotonergic activity in the CNS. Trazodone is a triazolopyridine antidepressant, inhibits the serotonin transporter, and is a 5-HT2A and 5-HT2C antagonist. This is why it is sometimes referred as a serotonin antagonist/reuptake inhibitor, but regulatory agencies do not accept this class name. Trazodone is an antagonist at both histamine (H1) and α1-adrenergic receptors, which may mediate trazodone’s sedating properties (H1) and hypotensive (α1-adrenergic) effects.

The ER formulation employs a cross-linked, high-amylose starch excipient that provides controlled release of trazodone over an extended period.

Pharmacokinetics

Trazodone ER has linear pharmacokinetics in doses from 75 to 375 mg. Trazodone ER, 300 mg/d, provides a steady-state exposure equivalent to 100 mg of trazodone IR given 3 times daily, while having a lower Cmax. A high-fat meal can increase Cmax of trazodone ER by 1.9-fold. Trazodone is extensively biotransformed in the liver via the cytochrome P450 (CYP) 3A4 pathway and its metabolites are eliminated within 72 hours. Elimination is predominantly renal, with 70% to 75% of an oral dose being recovered in the urine within 72 hours.¹ This formulation maintains its controlled-release properties if bisected.

Because trazodone is a substrate of the CYP3A4 enzyme, its metabolism can be inhibited by CYP3A4 inhibitors. Exercise caution when coadministering medications that cause CYP3A4 inhibition with trazodone ER. The effect of short-term administration of ritonavir (4 doses of 200 mg) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects.² The Cmax of trazodone increased by 34%, area under the curve increased 2.4-fold, half-life increased by 2.2-fold, and clearance decreased by 52%. There is no difference in the half-life between the IR and ER formulations because the ER formulation influences only the release kinetics of the drug, not the half-life of the medication.

Efficacy

Clinical Point

Compared with placebo, trazodone ER resulted in a statistically significant difference in change in HAM-D-17 score

Efficacy of trazodone for MDD initially was established in trials conducted with trazodone IR.^3-10 The efficacy of the ER formulation was established in a multi-center randomized, double-blind, placebo-controlled trial with 412 patients (age 18 to 80). Patients who met DSM-IV criteria for MDD were randomly assigned to trazodone ER (n=206) or placebo (n=206) for 8 weeks.¹¹ This study showed a statistically significant difference between trazodone ER and placebo after 8 weeks of treatment on the primary outcome measure, which was a change in score on the 17-item Hamilton Depression Rating scale (HAMD-17). HAM-D-17 scores decreased 11.4 points in the trazodone ER group and 9.3 points in the placebo group (P=.012 in the modified intent to treat [ITT] population; P=.009 in the completer analysis). This difference was seen from week 1 and throughout the study. Efficacy of trazodone ER was further supported by statistically significant differences between the drug and placebo in 7 of 13 secondary efficacy endpoints in both the modified ITT and per protocol (PP) populations (HAM-D-17 mood item, mean Montgomery-Åsberg Depression Rating Scale [MADRS] total score, mean Clinical Global Impressions Severity of Illness [CGI-S] score, percentage of HAM-D-17 responders, and 3 quality of sleep items [overall quality of sleep, trouble falling asleep, and awakening during the night]). Overall effect sizes for the HAM-D-17 were -0.26 (modified ITT-last observation carried forward [LOCF] dataset) and -0.33 (PP/observed cases [OC] dataset). The effect sizes in MADRS scores were -0.22 and -0.29 for the modified ITT-LOCF and the PP/OC analyses, respectively.¹²