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Nefazodone

A Review of its Pharmacology and Clinical Efficacy in the Management of Major Depression

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Summary

Synopsis

Nefazodone hydrochloride is a phenylpiperazine antidepressant with a mechanism of action that is distinct from those of other currently available drugs. It potently and selectively blocks postsynaptic serotonin (5- hydroxytryptamine; 5- HT) 5- HT2A receptors and moderately inhibits serotonin and noradrenaline (norepinephrine) reuptake.

In short term clinical trials of 6 or 8 weeks’ duration, nefazodone produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with imipramine, and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline. The optimum therapeutic dosage of nefazodone appears to be between 300 and 600 mg/day. Limited long term data suggest that nefazodone is effective in preventing relapse of depression in patients treated for up to 1 year. Analyses of pooled clinical trial results indicate that nefazodone and imipramine produces similar and significant improvements on anxiety- and agitation-related rating scales compared with placebo in patients with major depression.

Short term tolerability data indicate that nefazodone has a lower incidence of adverse anticholinergic, antihistaminergic and adrenergic effects than imipramine. Compared with SSRIs, nefazodone causes fewer activating symptoms, adverse gastrointestinal effects (nausea, diarrhoea, anorexia) and adverse effects on sexual function, but is associated with more dizziness, dry mouth, constipation, visual disturbances and confusion. Available data also suggest that nefazodone is not associated with abnormal weight gain, seizures, priapism or significant sleep disruption, and appears to be relatively safe in overdosage. Nefazodone inhibits the cytochrome P450 3A4 isoenzyme and thus has the potential to interact with a number of drugs.

Further long term and comparative studies will provide a more accurate assessment of the relative place of nefazodone in the management of major depression. Nonetheless, available data suggest that nefazodone is a worthwhile treatment alternative to tricyclic antidepressants and SSRIs in patients with major depression.

Pharmacodynamic Properties

In vitro studies suggest that nefazodone has potent antagonistic effects on 5-HT2A receptors and moderate serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake inhibiting properties, which together may result in an increase in 5-HT1A receptor-mediated neurotransmission. Nefazodone exhibits low affinity for 5-HT1A, muscarinic cholinergic, α-adrenergic, dopaminergic and histaminergic receptors.

Hydroxynefazodone, the primary metabolite of nefazodone, has activity equivalent to the parent compound at 5-HT2A receptors and serotonin reuptake sites. A triazoledione metabolite was found to have approximately 7-fold lower affinity for 5-HT2A receptors than nefazodone. Metachlorophenylpiperazine (mCPP), a minor metabolite, displays activity similar to the parent compound at serotonin reuptake sites and little affinity for 5-HT2A receptors.

Unlike most antidepressant agents, nefazodone appears to have minimal effect on the amount of rapid eye movement (REM) sleep and the latency period to REM sleep. Compared with placebo, nefazodone decreased nocturnal awakenings and the percentage of time awake, while paroxetine and fluoxetine significantly increased nocturnal awakenings and reduced actual sleep time.

Nefazodone is active in a number of animal models designed to predict clinical antidepressant efficacy (e.g. reserpine-induced ptosis, potentiation of yohimbineinduced lethality, learned helplessness and differential reinforcement of low rates of response). Its activity in these tests is comparable to other antidepressant agents including amitriptyline, imipramine, fluoxetine and trazodone. In addition, nefazodone shows activity in a number of analgesic screening tests in animals; these effects are thought not to be mediated by opiate mechanisms. Significant alterations in cardiovascular function have not been observed with nefazodone treatment over short periods.

Pharmacokinetic Properties

Nefazodone is rapidly and completely absorbed. Mean peak plasma concentrations (Cmax) of nefazodone are obtained approximately 1 hour (tmax) after an oral dose; tmax values for hydroxynefazodone, mCPP and the triazoledione metabolite are 1 to 2 hours, 2.5 to 4 hours and 2 hours, respectively. Because nefazodone undergoes extensive first-pass metabolism, absolute bioavailability approximates 20%. The bioavailability of nefazodone is largely unaffected by food.

Nefazodone and its main active metabolite, hydroxynefazodone, exhibit nonlinear pharmacokinetics with significant and disproportionate increases in Cmax and area under the plasma concentration versus time curve (AUC) values observed with increasing drug dosage. Nefazodone is widely distributed in body tissues and is highly plasma protein bound (>99%).

Nefazodone is extensively metabolised in the liver with approximately 52% and 31% of an administered dose recovered as free and conjugated metabolites in the urine and faeces, respectively; <1% of an administered dose is eliminated unchanged in the urine. Nefazodone and its metabolites appear to have a low affinity for cytochrome P450 (CYP) 2D6 and 1A2, and high affinity for CYP3A4. The plasma elimination half-lives (t½ß) of nefazodone and hydroxynefazodone at steady-state are similar, increasing from about 2 to 3.5 hours after multiple doses of nefazodone 50 to 200mg twice daily. Mean t½ß values for mCPP and the triazoledione metabolite are 4 to 8 hours and 18 hours, respectively, after twice daily administration of nefazodone 100mg.

Systemic exposure to nefazodone at steady-state, as assessed by Cmax, AUC and t½ß values, was significantly greater in healthy elderly volunteers and in patients with hepatic impairment than in healthy young volunteers. The pharmacokinetics of nefazodone were not significantly altered in patients with renal impairment.

Clinical Efficacy in Major Depression

In 6- to 8-week double-blind placebo- and/or active drug-controlled studies in outpatients with major depression, nefazodone was generally significantly more effective than placebo and at least as effective as imipramine. Analysis of pooled results from phase II or III clinical trials showed that the majority of responders to nefazodone received a daily dosage of between 300 and 600mg. Nefazodone and imipramine achieved significantly greater improvement than placebo in depressed patients with anxiety and agitation symptoms, and in patients with moderate or severe depression with or without melancholia, and in those with single or recurrent episodes of depression. Nefazodone has demonstrated effectiveness in patients who continued their treatment for up to 1 year in double-blind placebo-controlled studies.

Nefazodone showed efficacy similar to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline in short term double-blind studies in outpatients with major depression. Both nefazodone and the SSRIs achieved consistent and continuous improvement over the 6- to 8-week treatment periods.

Pharmacoeconomic Considerations

The pharmacoeconomics of nefazodone have been assessed in 2 recent studies that used clinical decision models. Annual direct costs per successfully treated patient in the UK were 25% lower for nefazodone than imipramine (£242 vs £323; 1994 pounds sterling). Costs associated with treatment failure and drug acquisition accounted for 31 vs 56% and 26 vs 11% of total treatment costs for nefazodone versus imipramine. The lifetime cost of nefazodone to save an additional quality-adjusted life year was $Can2010 lower than that of imipramine and $Can 127 lower than that of fluoxetine (1993 Canadian dollars). Extensive sensitivity analysis confirmed that cost-utility ratios generally favoured nefazodone over imipramine and fluoxetine, although the differences between nefazodone and fluoxetine were usually small.

Tolerability

In placebo-controlled studies, nausea (21 vs 15%), somnolence (19 vs 13%), dry mouth (19 vs 13%), dizziness (12 vs 6%), constipation (11 vs 7%), asthenia (11 vs 6%), light-headedness (10 vs 4%) and blurred vision (6 vs 3%) occurred significantly more frequently with nefazodone than with placebo. Anticholinergic adverse events normally associated with tricyclic antidepressants (dry mouth, constipation, blurred vision, urinary retention and tachycardia) were relatively common in nefazodone recipients, but occurred at lower frequencies than in imipramine recipients; urinary retention and tachycardia were reported significantly more frequently with imipramine than nefazodone.

Adverse event data from manufacturer databases and comparative studies show different adverse event profiles for nefazodone and SSRIs. SSRIs are generally associated with a higher incidence of activating symptoms (agitation, anxiety, tremor, insomnia, nervousness), diarrhoea, sweating, anorexia, nausea and male sexual dysfunction than nefazodone while nefazodone is generally associated with a higher incidence of dizziness, dry mouth, constipation, visual disturbances and confusion than SSRIs. Specifically, questionnaire results showed that nefazodone had little negative effect on sexual function and satisfaction, whereas sertraline negatively affected a number of measures of sexual satisfaction in both men and women.

Tolerability data from nearly 3500 patients from mostly short term clinical trials indicated that nefazodone was not associated with abnormal weight gain, seizures or priapism. Data from different studies suggest that the percentage of nefazodone-treated patients withdrawing because of adverse events was similar to that for SSRI (fluoxetine, paroxetine and sertraline) recipients and lower than that for imipramine recipients.

Assessment of approximately 250 patients who received nefazodone treatment for at least 1 year showed a similar pattern of adverse events to that seen with short term treatment and no evidence of late-emerging adverse events.

Nefazodone does not appear to differ from imipramine with respect to rates of emergence of suicidal ideation. Nausea, vomiting and somnolence were experienced in 7 patients taking an overdosage (up to a dose of 11 200mg) of nefazodone; all patients recovered without sequelae with supportive care. Nefazodone was not associated with clinically relevant changes in laboratory parameters.

Drug Interactions

Nefazodone and its metabolites appear to have a high affinity for the CYP3A4 isoenzyme which is involved in the metabolism of a number of drugs; therefore, caution is advised when nefazodone is coadministered with such agents. Importantly, coadministration of terfenadine, astemizole or cisapride with nefazodone is contraindicated.

Concurrent administration of nefazodone with alprazolam or triazolam increased systemic exposure to the latter 2 drugs, resulting in significant negative effects on psychomotor performance. Thus, dosage reduction of these benzodiazepines is warranted with concomitant use of nefazodone. No pharmacokinetic or pharmacodynamic interactions were observed following coadministration of nefazodone and lorazepam. Elevated plasma carbamazepine concentrations with associated toxicity have been reported in a patient with epilepsy after initiation of nefazodone. Coadministration of nefazodone may slightly elevate plasma digoxin concentrations (by ≈25%) necessitating plasma concentration monitoring of this drug under these circumstances.

Dosage and Administration

The effective therapeutic dosage range of nefazodone appears to be 300 to 600 mg/day. The recommended starting dosage of nefazodone is 50 to 100mg twice daily, with dosage increases after a minimum 7 days. In elderly, debilitated or drug-sensitive patients, careful assessment of starting dosage and subsequent dose titration is required; the recommended starting dosage in these patients is 50mg twice daily. However, the therapeutic dosage range is likely to be similar in younger and elderly patients. Nefazodone should not be administered with or within 14 days after discontinuation of a monoamine oxidase inhibitor (MAOI). After discontinuation of nefazodone, at least 7 days should be allowed before initiating therapy with an MAOI.

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    Rick Davis, Ruth Whittington & Harriet M. Bryson

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  1. Rick Davis
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Correspondence to Rick Davis.

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Various sections of the manuscript reviewed by: M. Ansseau, Psychiatric Unit, Centre Hospitalier Universitaire de Liège, Liège, Belgium; R. Armitage, Department of Psychiatry, University of Southwestern Medical Center at Dallas, Dallas, Texas, USA; W.A. Brown, Department of Veterans Affairs Medical Center, Providence, Rhode Island, USA; F. de Jonghe, Algemeen Psychiatrisch Centrum, Amsterdam, The Netherlands; A. Feiger, Feiger PsychMed Center, Wheat Ridge, Colorado, USA; N. Ferry, Department of Physiology and Clinical Pharmacology, Hospices Civils de Lyon, Lyon, France; M. Lader, Institute of Psychiatry, London, England; J. Lundmark, Department of Psychiatry, Motala Hospital, Motala, Sweden; J. Mendels, Therapeutics P.C., Wynnewood, Pennsylvania, USA; D.B. Menkes, Department of Psychological Medicine, University of Otago Medical School, Dunedin, New Zealand; S.A. Montgomery, Department of Psychiatry, St Mary’s Hospital Medical School, London, England; M.J. Owens, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA; L.H. Price, Department of Psychiatry, Brown University School of Medicine, Providence, Rhode Island, USA; A.L. Sharpley, Psychopharmacology Research Unit, Littlemore Hospital, Oxford, England; M.W. van Laar, Department of Psychopharmacology, University of Utrecht, Utrecht, The Netherlands; J.C. Ware, Sleep Disorders Center, Sentara Norfolk General Hospital, Eastern Virginia Medical School, Norfolk, Virginia, USA.

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Davis, R., Whittington, R. & Bryson, H.M. Nefazodone. Drugs 53, 608–636 (1997). https://doi.org/10.2165/00003495-199753040-00006

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