CHAPTER 15

Trazodone and Nefazodone

Robert N. Golden, M.D.

Karon Dawkins, M.D.

Linda Nicholas, M.D.

Trazodone was among the earliest “second generation” antidepressants to become available for clinical use in the United States in the early 1980s. Its side-effect profile and potential toxicity were considerably different from—and in many instances preferable to—those of the original antidepressants (i.e., the monoamine oxidase inhibitors [MAOIs] and tricyclic antidepressants [TCAs]). Several years later, trazodone’s pharmacological “cousin,” nefazodone, also became available.

Trazodone

History and Discovery

Trazodone was first synthesized in Italy about four decades ago, and clinical studies began in the United States in 1978. In sharp contrast to most other antidepressants available at the time, trazodone showed minimal effects on muscarinic cholinergic receptors.

In 1982, trazodone was introduced for clinical use in the United States under the brand name Desyrel. The medication is now available in generic formulation and also in an extended-release preparation (Oleptro).

Pharmacological Profile

Trazodone is a relatively weak SSRI; however, it is relatively specific for serotonin (5-HT) uptake inhibition, with minimal effects on norepinephrine (NE) or dopamine reuptake (Hyttel 1982) (Figure 15–1). Trazodone appears to increase extracellular 5-HT concentrations through a combination of mechanisms involving the 5-HT transporter (5-HTT) and the serotonin_2A/2C (5-HT_2A/2C) receptors (Pazzagli et al. 1999). In addition, trazodone has some 5-HT receptor antagonist activity (Haria et al. 1994). Its active metabolite, m-chlorophenylpiperazine (mCPP), is a potent direct 5-HT receptor agonist. Thus, trazodone can be viewed as a mixed serotonergic agonist–antagonist, with the relative amount of mCPP accumulation affecting the relative degree of the predominant agonist activity. Sustained administration is associated with enhanced serotonergic neurotransmission in vivo in the rat brain (Ghanbari et al. 2010).

FIGURE 15–1. Chemical structure of trazodone.

In vivo, trazodone is virtually devoid of anticholinergic activity, and in clinical studies, the incidence of anticholinergic side effects is similar to that seen with placebo. Trazodone is a relatively potent antagonist of postsynaptic α₁-adrenergic receptors, and it has a propensity to cause orthostatic hypotension. Trazodone has moderate antihistaminergic (histamine₁ [H₁] receptor) activity.

Pharmacokinetics and Disposition

Trazodone is well absorbed after oral administration, with peak blood levels occurring about 1–2 hours after dosing. Trazodone is 89%–95% bound to plasma protein. Elimination appears to be biphasic; the initial alpha and subsequent beta phases have half-lives of 3–6 and 5–9 hours, respectively. Bioavailability is not influenced by age or food intake.

Trazodone undergoes extensive hepatic metabolism. The active metabolite mCPP is cleared more slowly than the parent compound (4- to 14-hour half-life) and reaches higher concentrations in the brain than in plasma (Caccia et al. 1981). The cytochrome P450 (CYP) 2D6 and 3A microsomal enzyme systems also appear to play a role in trazodone metabolism. The relation between steady-state blood levels and clinical response to trazodone is not well defined.

Mechanism of Action

The ultimate mechanism of action of trazodone remains unclear. Although the drug is described as a 5-HT reuptake inhibitor, its effects on this neurotransmitter system are complex. Trazodone has relative selectivity for 5-HT reuptake sites (Hyttel 1982); however, in vivo, it blocks the head twitch response induced by classic 5-HT agonists in animals. The potent 5-HT receptor agonist properties of trazodone’s major metabolite, mCPP, may play a role in the mechanism of action of the parent compound. Trazodone, unlike the vast majority of antidepressants, does not produce downregulation of β-adrenergic receptors in rat cortex (Sulser 1983).

Indications and Efficacy

The primary indication for trazodone is treatment of major depressive disorder. Early reviews found that trazodone’s antidepressive efficacy was similar to that of the TCAs and the tetracyclic mianserin (Lader 1987; Schatzberg (1987).

Questions have been raised about the effectiveness of trazodone in treating severely ill depressed patients, especially those with prominent psychomotor retardation. Shopsin et al. (1981) pointed out that in several unpublished double-blind, controlled studies, the rates of clinical response to trazodone were low (i.e., 10%–20%).

The performance of trazodone, in direct comparisons with other second-generation antidepressants, has been mixed. In a double-blind, placebo-controlled comparison with venlafaxine, the final response rates were 55% for placebo, 60% for trazodone, and 72% for venlafaxine. Trazodone was more effective than venlafaxine in ameliorating sleep disturbances and was associated with the most dizziness and somnolence (Cunningham et al. 1994). In a double-blind comparison with bupropion, response rates were 46% for trazodone and 58% for bupropion (Weisler et al. 1994). In a double-blind study of 200 hospitalized patients experiencing a moderate to severe major depressive episode, mirtazapine yielded greater reductions in depression ratings than did trazodone (van Moffaert et al. 1995).

Three double-blind studies reported that trazodone had antidepressant efficacy similar to that of other antidepressants in geriatric patients (Gerner 1987). However, trazodone’s association with orthostatic hypotension may increase the risk of falls, with devastating consequences in elderly patients. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia. A survey of British geropsychiatrists identified trazodone as one of their most popular adjuncts or alternatives to atypical antipsychotics in the management of behavioral symptoms in the elderly (Condren and Cooney 2001). A Cochrane Database review found insufficient evidence to support trazodone as a treatment for the behavioral and psychological symptoms of dementia, although the review could not conclude that trazodone was ineffective, given the limited number of eligible studies (Martinon-Torres et al. 2004). A recent study of 30 patients with Alzheimer’s disease found that trazodone produced a normalization of circadian rhythms, which are often disturbed in this patient population (Grippe et al. 2015)

In a randomized, double-blind, placebo-controlled trial, the anxiolytic efficacy of trazodone was comparable to that of diazepam in weeks 3–8 of treatment for generalized anxiety disorder, although patients treated with diazepam had greater improvement during the first 2 weeks of treatment (Rickels et al. 1993).

Many clinicians use low-dose trazodone as an alternative to benzodiazepines for the treatment of insomnia. Trazodone is the second most prescribed agent for primary insomnia, even though there is minimal evidence to support its use for this indication (Mendelson 2005; Rosenberg 2006). Controlled trials have confirmed trazodone’s efficacy (at doses of 50–100 mg) in treating antidepressant-associated insomnia (Nierenberg et al. 1994). A retrospective analysis at a Department of Veterans Affairs (VA) medical center found that approximately 24% of patients receiving trazodone were taking other primary antidepressants (Clark and Alexander 2000). Another VA study of patients with posttraumatic stress disorder (PTSD) found that of those patients who were able to tolerate trazodone (60 of 72 patients), 92% reported that it improved sleep onset and 78% reported that it improved sleep maintenance (Warner et al. 2001). A recent study found that trazodone improved the Apnea-Hypopnea Index in patients with obstructive sleep apnea (OSA) without any deleterious effects on oxygen saturation or non–rapid eye movement (REM) arousal threshold, suggesting that the drug might have potential as a treatment for OSA (Smales et al. 2015).

Trazodone is more effective than placebo when added to antipsychotic medication in the treatment of the negative symptoms of schizophrenia (Singh et al. 2010; Watanabe 2011). A double-blind, placebo-controlled trial found trazodone to be effective in treating antipsychotic-induced akathisia (Stryjer et al. 2010).

A recent review highlighted the common off-label use of trazodone in a number of conditions, including bulimia, fibromyalgia, chronic pain, and diabetic neuropathy (Bossini et al. 2015). We agree with the authors’ conclusion that large randomized controlled trials are needed to determine whether there is adequate scientific evidence to support trazodone’s use for any of these indications.

Trazodone should be initiated at a low dose and increased gradually, based on clinical response and tolerance to side effects. For the treatment of a major depressive episode, the suggested initial dosage is 150 mg/day, with increases of 50-mg increments every 3–4 days. Doses may be divided, although many patients prefer bedtime dosing because of the sedating effects. The maximum dosage recommended for outpatients is 400 mg/day, although for inpatients with more severe depression, dosages up to 600 mg/day have been used. When trazodone is prescribed as a hypnotic agent, the usual dose is 50 mg at bedtime, although some patients may require as little as 25 mg or as much as 200–300 mg.

Side Effects and Toxicology

Because of its lack of anticholinergic side effects, trazodone is especially useful for patients with prostatic hypertrophy, closed-angle glaucoma, or severe constipation. Trazodone’s propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for others, including those with psychomotor retardation and low energy, trazodone may not be tolerable.

Trazodone was found to be among the top three medications associated with orthostatic hypotension in patients attending a VA geriatric clinic (Poon and Braun 2005). More than 200 cases of trazodone-associated priapism have been reported (Thompson et al. 1990), and the manufacturer estimates that the incidence of any abnormal erectile function is approximately 1 in 6,000 male patients. The risk appears to be greatest during the first month of treatment at low dosages (<150 mg/day). Early recognition of any abnormal erectile function is important and should prompt immediate discontinuation of trazodone treatment.

In overdose situations, trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg (Ayd 1984). When trazodone overdoses occur, clinicians should carefully monitor for hypotension.

In common with several other sedative-hypnotics, trazodone has the potential to impair driving skills, especially in new users, who have been shown to have an increased risk of motor vehicle crashes. The risk estimate for trazodone is roughly comparable to that of blood alcohol concentration levels of 0.09% (Hansen et al. 2015).

Drug–Drug Interactions

Trazodone can potentiate the effects of other central nervous system (CNS) depressants. Patients should be warned about increased drowsiness and sedation when trazodone is combined with other CNS depressants, including alcohol.

The combination of trazodone with an MAOI, as with other antidepressants, should be handled with great caution, although there are case reports of the successful combination of trazodone with an MAOI. Development of the serotonin syndrome has been associated with the combination of trazodone with other proserotonergic agents. Trazodone inhibits the antihypertensive effects of clonidine. Trazodone can cause hypotension, especially orthostatic hypotension, and concomitant administration of trazodone with antihypertensive therapy may require a reduction in the dose of the antihypertensive agent.

Clinically significant cases of suspected trazodone–warfarin interactions have been described.

Nefazodone

History and Discovery

Trazodone’s sedative properties and association with orthostatic hypotension inspired an effort to discover a modified molecule that would possess a more desirable pharmacological profile. This led to the development of nefazodone (Figure 15–2), which became available in the United States in 1994. Nefazodone and trazodone share a common active metabolite.

FIGURE 15–2. Chemical structure of nefazodone.

In 2004, the manufacturer of Serzone (nefazodone) announced that it was discontinuing the drug’s sale in the United States, citing declining sales. The drug had been banned in many countries because of its association with liver toxicity, and lawsuits against that manufacturer and the FDA had been initiated in this country. Nefazodone continues to be available in the United States as a generic medication.

Pharmacological Profile

Nefazodone is a 5-HT₂ receptor antagonist and a weak inhibitor of 5-HT and NE reuptake (Figure 15–2). It has little affinity for α₂-adrenergic, β-adrenergic, or serotonin_1A (5-HT_1A) receptors, and its affinity for the α₁-adrenergic receptor is less than that of trazodone. Nefazodone is inactive at most other receptor-binding sites (Taylor et al. 1986).

Nefazodone demonstrates several of the classic preclinical characteristics of antidepressants. In humans, nefazodone does not suppress REM sleep, in contrast to most other antidepressants (Sharpley et al. 1996).

Pharmacokinetics and Disposition

Nefazodone is rapidly and completely absorbed and is then extensively metabolized, resulting in a low (about 20%) and variable absolute bioavailability. The plasma half-life is only 2–4 hours. Nefazodone has three active metabolites: triazole dione, hydroxynefazodone, and mCPP. Triazole dione is a specific 5-HT₂ receptor antagonist with weaker affinity for that receptor than the parent compound and no appreciable effects on 5-HT reuptake. With a plasma half-life of 18 hours, triazole dione predominates in the plasma, occurring at concentrations approaching four times that of the parent compound. Hydroxynefazodone has affinities for the 5-HT₂ receptor and 5-HT reuptake site that are similar to those of the parent compound. Its plasma half-life is between 1.5 and 4 hours, and at steady state, plasma concentrations are approximately 40% of those of the parent compound. mCPP is a direct agonist at the 5-HT₁, 5-HT₂, and serotonin₃ (5-HT₃) receptors, with one order of magnitude higher affinity for 5-HT_2C receptors. mCPP has a plasma half-life of 4–8 hours, and its plasma concentrations are only 7% of those seen with the parent compound (DeVane et al. 2002). However, the ratios of mCPP to nefazodone concentrations in the brain are 47:1 and 10:1 in the mouse and rat, respectively. Brain concentrations of hydroxynefazodone in the rat are less than 10% of those in plasma, suggesting very poor blood–brain barrier penetration. Thus, despite its relatively lower plasma concentrations, mCPP has substantial presence in the brain, whereas the in vivo activity of hydroxynefazodone may be mostly the result of its biotransformation to mCPP (Nacca et al. 1998).

Nefazodone has nonlinear kinetics, which results in greater than proportional mean plasma concentrations with higher doses. Nefazodone is extensively (99%) but loosely protein bound (Bristol-Myers Squibb 2003). In patients with hepatic cirrhosis, single-dose nefazodone and hydroxynefazodone levels are about twice as high as in healthy volunteers, but the difference decreases to approximately 25% at steady state. Exposure to mCPP is about two- to threefold greater in patients with cirrhosis, and exposure to triazole dione is similar after a single dose and at steady state (Barbhaiya et al. 1995).

Mechanism of Action

The mechanism of action of nefazodone is poorly understood. The manufacturer has indicated that nefazodone antagonizes 5-HT₂ receptors and also inhibits neuronal uptake of both 5-HT and NE (Bristol-Myers Squibb 2003). Several reviews refer to nefazodone as a “dual acting” antidepressant, suggesting that it enhances both serotonergic and noradrenergic neurotransmission via uptake blockade. Although nefazodone has similar effects on the 5-HT and NE transporters, this observation is potentially misleading. Nefazodone’s inhibition of NE reuptake is weaker than that of the SSRI fluoxetine and is approximately three orders of magnitude weaker than what is seen with conventional NE reuptake inhibitors. Furthermore, nefazodone’s inhibition of 5-HT reuptake is nearly identical to that of desipramine and more than 100-fold less than that of fluoxetine (Bolden-Watson and Richelson 1993). Thus, the “dual action” of nefazodone refers to minimal, albeit equal, effects on 5-HT and NE reuptake inhibition.

In humans, therapeutic doses of nefazodone do not cause sustained 5-HT uptake inhibition at the platelet 5-HTT (Narayan et al. 1998). The active metabolite m-CCP, which appears to predominate in the brain because of greater penetration of the blood–brain barrier (Nacca et al. 1998), may play an important role in the mechanism of action.

Indications and Efficacy

In three of four Phase III imipramine- and placebo-controlled studies, nefazodone was found to be an effective antidepressant with similar efficacy to imipramine; in one of these studies, neither active drug had significantly greater efficacy than did placebo. The incidence of premature treatment discontinuation and side effects was higher for the imipramine group than for the nefazodone treatment group (Rickels et al. 1995). In double-blind studies without placebo control groups, there were no significant differences in the clinical responses to nefazodone and sertraline or paroxetine in outpatients with depression (Feiger et al. 1996). Hospitalized patients with severe major depressive disorder had higher response rates to nefazodone compared with placebo (Feighner et al. 1998). In patients with moderate to severe major depression, the efficacy of amitriptyline was clearly superior to that of nefazodone (Ansseau et al. 1994). Keller et al. (2000) compared nefazodone, cognitive-behavioral therapy (CBT), and a combination of these two treatments in a double-blind study of patients with chronic major depressive disorder. Each monotherapy yielded a response rate of 48%, whereas the combined treatment had a greater efficacy (73%). When patients who failed to respond to 12 weeks of treatment with either nefazodone or cognitive-behavioral analysis system psychotherapy are then switched to the other treatment, significant symptom improvement is achieved (Schatzberg et al. 2005). Nefazodone has also been shown to be effective in the continuation phase of treatment in double-blind studies (Baldwin et al. 2001; Feiger et al. 1999).

In a double-blind, placebo-controlled study, nefazodone was found to be safe and effective in the treatment of depression in patients with alcohol dependence, although it did not add any advantage over psychoeducational group intervention in terms of drinking outcomes (Roy-Byrne et al. 2000). A double-blind, controlled study found that nefazodone was not efficacious for the treatment of alcohol dependence (Kranzler et al. 2000). A randomized, placebo-controlled, double-blind multicenter study compared nefazodone versus placebo and CBT versus nondirective group counseling (GC) for relapse prevention in alcohol dependence. Two hundred forty-two male patients received either nefazodone plus GC or CBT or placebo plus GC or CBT. There were no differences among the four groups in cumulative days of abstinence or amount of alcohol consumed during specified time periods during the initial 12-week study phase. After 1 year, the only significant difference among the groups was higher alcohol consumption in the nefazodone plus GC group, raising concerns that nefazodone may potentially increase the risk of relapse (Wetzel et al. 2004). Other potential clinical applications for nefazodone have been explored, including treatment of PTSSD (for which it is considered a second-line agent) (Jeffreys et al. 2012); however, nefazodone’s current use is relatively limited.

The usual starting dosage of nefazodone is 200 mg/day in two divided doses. The suggested dosage range is 300–600 mg/day. Increases should be in increments of 100–200 mg/day at weekly intervals. The starting dosage in elderly or debilitated patients should be lowered to 100 mg/day, taken in two divided doses, and the rate of titration should be adjusted accordingly (Bristol-Myers Squibb 2003). Zajecka et al. (2002) reported that in studies comparing low-dosage (50–250 mg/day) and high-dosage (100–500 mg/day) nefazodone, better clinical response was obtained in the latter group, and the mean effective dosage ranged from 375 mg/day to 460 mg/day. A lower starting dose should be considered when switching to nefazodone from an SSRI if a full washout has not been completed. Once-daily bedtime dosing appears to be well tolerated and effective.

Side Effects and Toxicology

In initial clinical trials that included approximately 2,250 patients, side effects more frequently associated with nefazodone than with placebo included dizziness, asthenia, dry mouth, nausea, and constipation (Fontaine 1993).

Preskorn (1995) found that the total cumulative incidence of treatment-emergent adverse effects for nefazodone was lower than that of imipramine or fluoxetine. The most common placebo-adjusted adverse effects associated with nefazodone were dry mouth, somnolence, dizziness, nausea, constipation, blurred vision, and postural hypotension. Nefazodone appears to have advantages over SSRIs in terms of treatment-associated sexual dysfunction (Clayton et al. 2014; Ferguson et al. 2001).

There are now well-publicized concerns regarding the association of nefazodone with liver toxicity and liver failure, including fatalities (Choi 2003; Voican et al. 2014). In 2001 the manufacturer added a black box warning to the package insert, describing a reported rate of life-threatening liver failure in the United States of 1 case per 250,000–300,000 patient-years of nefazodone treatment. In 2004 Serzone was withdrawn from the U.S. market, following its withdrawal from several international markets. The generic drug remains available in the United States. In a review of 1,338 humans with exposure to nefazodone overdoses, there were no reported deaths. The most common serious clinical effect was hypotension, reported in 1.6% of cases (Benson et al. 2000).

Drug–Drug Interactions

The manufacturer of triazolam warns that its concurrent use with nefazodone is contraindicated. Increases in the plasma concentration of digoxin occur with concurrent nefazodone administration. Nefazodone increases the plasma concentrations of terfenadine and loratadine (with associated QTc prolongation), carbamazepine, and cyclosporine.

Conclusion

Trazodone was one of the earliest second-generation antidepressants. Its lack of anticholinergic effects provided an advantage over the TCAs for many patients; its sedative properties are helpful for some patients but problematic for others; and orthostatic hypotension is a concern for elderly patients. Nefazodone is related to trazodone, and the two drugs share an active metabolite, mCPP, that may play an important role in their mechanism of action. The risk of serious liver damage led to Serzone’s removal from the market in several countries, although generic nefazodone is currently available in the United States.

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