Clinical Reviews

Use of Nefazodone for Depression in the Elderly in Long-Term Care Settings

William Simonson

Objective: To evaluate the appropriateness of nefazodone use in elderly patients in long-term care settings.

Data Sources: Search of Medline and Adisearch using the terms depression, elderly, nefazodone, nursing homes, diagnosis, epidemiology, and treatment. English language articles and papers published within the last 10 years were further search criteria.

Study Selection: Letters to the editor and case reports were excluded from this review.

Data Extraction: Material was considered if it contributed generally to the understanding of the drug treatment of depression in the elderly in long-term care settings or in particular to the role of nefazodone treatment for depression in this population.

Data Synthesis: Nefazodone potently antagonizes post synaptic serotonin-2 receptors and presynaptically inhibits serotonin reuptake. A major active metabolite contributes to nefazodone's pharmacologic activity. Dose increases should be made more slowly in older individualsand those with hepatic dysfunction. Its therapeutic efficacy and favorable side effect profile have been demonstrated in double-blind clinical trials. The risk of adverse effects during nefazodone therapy is not increased in elderly patients. Clinically important drug interactions occur with alprazolam, triazolam, terfenadine, astemizole, cisapride, and digoxin.

Conclusion: The pharmacologic, efficacy, and safety profiles ofnefazodone suggest that it is a viable alternative for treatment of depressed elderly patients in long-term care.

Key Words: Depression, Antidepressants, Nefazodone, Elderly, Long-term Care

Abbreviations Used: SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants; 5-HT = serotonin; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D = Hamilton Rating Scale for Depression.

Consult Pharm 1997; 12: 67-71.

As was demonstrated in the national drug-use evaluation published in the December 1996 issue of The Consultant Pharmacist,¹ selectives erotonin reuptake inhibitors and tricyclic antidepressants are used to treat depression in a substantial number of elderly nursing home residents. Use of SSRIs is a result of clinicians' perceptions that these agents have a more favorable safety and tolerability profile for the elderly than other agents. TCAs continue to be used because of their lower cost and prescribers' familiarity with the drugs.

In this article, I review the newer antidepressant nefazodone, with emphasis on its appropriateness for the nursing home resident. In analyzing nefazodone, rely on the criteria and concepts presented by Mandos et al. in the November 1996 issue of The Consultant Pharmacist.²

Mechanism of Action

Nefazodone has pharmacologic actions within the serotonin and norepinephrine systems. It potently antagonizes post synaptic serotonin-2(5-HT₂) receptors and presynaptically inhibits serotonin (5-HT) reuptake, which together increase the availability of serotonin to interact with other serotonin receptors.^3,4 Down-regulation of 5-HT₂ receptors occurs when nefazodone is given chronically.⁴ Nefazodone also inhibits norepinephrine reuptake.⁴

Nefazodone antagonizes alpha-1-adrenergic receptors but demonstrates little or no activity at muscarinic cholinergic, histaminic, alpha-2-and beta-adrenergic, 5HT1A, dopamine D1, or benzodiazepine receptors.^3,4

Pharmacokinetic Characteristics

Oral absorption of nefazodone is rapid. Food delays the absorption of nefazodone and decreases its bioavailability by approximately 20%.⁵ Peak plasma nefazodone concentrations are reached at about one hour after oral administration and steady state concentrations are achieved within four to five days of initiation of therapy.⁵ The drug has a large volume of distribution (0.22 to 0.87 L/kg)and is highly (> 99%) but loosely bound to plasma proteins.

Nefazodone has a short mean elimination half-life of two to four hours, indicating removal is prompt following withdrawal. Like other antidepressants, nefazodone is metabolized in the liver, and the pharmacokinetics of three of its metabolites have been determined. A major active metabolite is alpha-hydroxynefazodone, with an area under the curve (AUC) approximately 40% that of theparent compound and a similar half-life (1.5-4.0 hours) and pharmacologicprofile.⁴ The pharmacologic profile of the other major metabolite, triazoledione, has not yet been well characterized. The AUC for the triazoledione metabolite is approximately four times thatof the parent compound, with an elimination half-life of approximately18 hours. Meta-chloro-phenylpiperazine is a minor active metabolite, with an AUC approximately 7% that of the parent compound and ahalf-life of 48 hours.⁴ Less than 1% of the administered dose of nefazodone is excreted in urine as unchanged drug. Approximately 55% is excreted in urine and about 20%-30% in feces.⁵

While the pharmacokinetics of nefazodone are unaltered in patients with renal impairment (creatinine clearance 7-60 mL/min/1.73 m²), plasma concentrations and half-lives of nefazodone and alpha-hydroxynefazodone are increased in the elderly and in patients with hepatic dysfunction as a result of decreased metabolic clearance.⁶ It is therefore recommended that the initial dose of nefazodone be 50 mg twice daily and dose titration be slower in the latter two groups of patients.⁵ The final target dose for the elderly should be based on careful assessment of the patient's clinical response and maybe similar in healthy younger and older patients. In controlled clinical trials, the effective dose range for nefazodone was generally300-600 mg/day for all patients.⁵

Clinical Efficacy and Tolerability

The therapeutic efficacy and favorable side effect profile of nefazodone has been compared in double-blind clinical trials compared with placebo⁷ and placebo or imipramine.^8,9

In one study, the superiority of nefazodone (100-600 mg/day) over placebo was evidenced by significantly greater reductions in depressive symptoms as assessed by improvement in Hamilton Rating Scale for Depression (HAM-D) scores and clinician- and patient-rated Inventory for Depressive Symptomatology scores in nefazodone-treated patients, compared with scores in placebo-treated patients after six weeks of treatment. The therapeutic benefit of nefazodone was seen as early as two weeks after the start of treatment. After six weeks, the nefazodone-treated patients experienced significantly greater improvement in mood, concentration and decision-making, energy, sexual interest, psychomotor agitation, and future outlook. There were no significant differences in the rates of withdrawal due to adverse events in nefazodone- and placebo-treated patients.⁷

Six- and eight-week double-blind, placebo-controlled trials demonstrated the antidepressant efficacy of nefazodone at dosages ranging from100 to 500 or 600 mg/day, and the efficacy of imipramine at dosages ranging from 50 to 250 or 300 mg/day in the treatment of depression. In both of these studies, nefazodone was better tolerated, as indicated by lower overall incidences of adverse events and lower rates of drug discontinuation due to adverse events.^8,9

Nefazodone has also been shown to be effective in relieving symptoms of anxiety and agitation,¹⁰ which co-exist with depression in approximately 50%-70% of patients.^10,11 A meta-analysis of six placebo-controlled, double-blind studies in patients with moderate to severe depression (n = 817) revealed significant improvement in concomitant anxiety symptoms, as judged by significant improvement in several measures of anxiety, including mean Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression anxiety factor, HAM-D psychic anxiety item, HAM-D anxiety factor, and HAM-D agitation item scores, compared with placebo by the fourth week of treatment with nefazodone.¹⁰ Nefazodone-treated patients also experienced significant relief from agitation symptoms as early as week one.¹⁰

Thus far, no published studies have specifically evaluated nefazodone in the treatment of depression in the elderly. However, published clinical trials that have reported the successful use of nefazodone have included elderly depressed patients (> 60 years of age);in one study, patients up to 75 years of age were treated withnefazodone.^10,12

Tolerability

At the recommended dosages of 100-600 mg/day, nefazodone has been well-tolerated in clinical trials. Most adverse events were mild to moderate, reversible, and only occasionally led to drug withdrawal. After adjustment for withdrawal rates in placebo-treated patients, the discontinuation rates caused by specific nefazodone-induced adverse events did not exceed 1.6%.¹³ Placebo-adjusted rates of adverse events that occurred significantly more often with nefazodone than with placebo were 7.5% for dry mouth, 5.8% for somnolence, 5.6% for dizziness, 5.5% for nausea, 4.2% for lightheadedness, 3.3% for constipation, 3.2% for blurred vision, and 2.6% for postural hypotension. As expected, imipramine, which was generally the active reference drug, was associated with a higher overall placebo-adjusted incidence of anticholinergic-type side effects, including dry mouth (47.1%); constipation (17.4%); somnolence (12.0%); and cardiovascular effects, including postural hypotension (10%).¹³

Importantly, nefazodone does not induce agitation, anxiety, orinsomnia.¹³ Nefazodone also improves sleep quality. Depressed patients treated with nefazodone have experienced significantly decreased arousals, decreased wakefulness during sleep, and increased stage two sleep.¹⁴ Nefazodone also does not cause weight changes.⁵

Safety

The risk of adverse events during nefazodone therapy is not increased in elderly patients as compared with younger patients. Treatment with nefazodone is associated with a low incidence of orthostatic hypotension (2.8% versus 0.8% for placebo); events characterized as syncope occurred in 0.2% of patients receiving nefazodone and 0.3% of those on placebo. Nefazodone has not been associated withclinically important hepatic, renal, or cardiac toxicity except for sinus bradycardia, which was observed in 1.5% of nefazodone recipients and 0.4% of placebo recipients. Blood pressure monitoring is not required during nefazodone therapy.⁵ Nefazodone has not been evaluated in patients with a recent history of myocardialinfarction or unstable heart disease.

None of the seven reported cases of overdose with nefazodone (upto 11.2 g, either alone or with other drugs) was fatal or life-threatening, had serious sequelae, or required specific treatment.⁵

Nefazodone demonstrated no carcinogenic, mutagenic, or genotoxic potential in animals.

An analysis of long-term data (from more than 250 patients treated for one year or more) indicates that nefazodone has an excellent safety and tolerability profile during long-term treatment ofdepression.⁵

Drug Interactions

No clinically important interactions occur between nefazodone and theophylline,¹⁵ phenytoin,¹⁶ lorazepam,^17,18 propranolol,¹⁹warfarin,^20,21 cimetidine,²² or haloperidol,²³ and nefazodone does not potentiate the central nervous system effects of alcohol when given concomitantly.²⁴

Coadministration of nefazodone with alprazolam or triazolam results in significant elevation of plasma concentrations of alprazolamand triazolam, prolonged triazolam half-life, and potentiation of the psychomotor effects of these two benzodiazepine compounds.^5,17,25,26 Thus, a 50% and 75% reduction in the initial dosage of alprazolamand triazolam, respectively, are recommended when these drugs are administered together with nefazodone. In addition, concomitant use of triazolam and nefazodone should be avoided in the elderly.⁵

Nefazodone has been shown in vitro to be an inhibitor of the cytochromeP450IIIA4 isoenzyme.⁵ This explains the pharmacokin-etic interactions with alprazolam and triazolam, both of which are metabolized by this isoenzyme. Because of inhibition of P450IIIA4, coadministration of terfenadine, astemizole, or cisapride with nefazodone is contraindicated. Nefazodone has been shown to be an extremely weak inhibitor ofP450IID6, and it does not inhibit P450IA2.⁵ Thus, it is unlikely that nefazodone will decrease the clearance of drugs metabolized by these isoenzymes.

Plasma concentrations of digoxin are elevated somewhat (Cmax by29%, Cmin by 27%, and AUC by 15%) during concurrent administration of nefazodone.²⁷ While the precise mechanism of this interaction has not been defined, caution should be exercised when nefazodone and digoxin are coadministered because of digoxin's narrow therapeutic range. As with all patients receiving digoxin, periodic plasma level monitoring of digoxin is recommended.²⁸

Although their combined use has not been directly evaluated, nefazodone should not be used in combination with monoamine oxidase inhibitors or within 14 days of discontinuing MAOI treatment. This is because of reports of serious, sometimes fatal, reactions in patients receiving MAOIs in combination with antidepressants pharmacologically similar to nefazodone. At least one week should be allowed after stopping nefazodone before starting therapy with a MAOI.⁵

Dosage and administration

In elderly patients in whom the clearance of drugs may be reduced, nefazodone treatment should be initiated at a dosage of 50 mg twice daily, followed by dosage increases to 100 mg twice daily after at least one week. The final therapeutic dose should be based on individual patient response. The dose may be similar in healthy younger and older patients (300-500 mg/day in two divided doses).

In younger patients with normal hepatic function, nefazodone treatment is generally initiated at a dosage of 100 mg twice daily, followed by a dosage increase to 150 mg twice daily after one week. Most patients should respond to daily dosages between 300 and 500 mg. The maximum recommended daily dosage is 600 mg in two divideddoses.⁵

Patients may experience early improvement in depression-associated anxiety symptoms¹⁰ and depression-associated sleep disturbances,¹⁴ while the full antidepressant effect generally occurs after several weeks of treatment.

Use in Long-Term Care Patients

While to date no efficacy studies have focused specifically on the elderly, the pharmacologic, efficacy, and safety profiles of nefazodone suggest that it is suitable for treatment of depressed elderly patients in long-term care settings. Indeed, no unusual adverse age-related phenomena were identified in a cohort of more than 500 patients 65 years of age or older who participated in nefazodone clinical trials.⁵

The features of nefazodone that make it especially appropriate for use in elderly depressed patients in long-term care settings include the following:

• Early relief of anxiety and agitation symptoms in depressed patients.¹⁰
• Potential for improving sleep quality and sleep efficiency.¹⁴ Insomnia is a common symptom of depression and is potentially disruptive in long-term care settings.^29,30
• Relative lack of cardiovascular effects. This is particularly favorable since many elderly patients have cardiovascular diseases. However, nefazodone has not been evaluated specifically in patients with concurrent cardiovascular disorders. In addition, it should be noted that postural hypotension was observed at a rate of 2.8%during placebo-controlled premarketing studies of nefazodone. Thus, postural hypotension may occur in association with nefazodone use, and caution should be exercised in patients with known cardiovascularor cerebrovascular disease that could be exacerbated by hypotension or conditions that would predispose patients to hypotension.⁵
• Minimal central nervous system activating effects. This is a benefit in depressed patients with associated anxiety and agitation symptoms.
• Safety during long-term use. This is important since some clinicians may be hesitant to prescribe antidepressants or may prescribe less than effective dosages in elderly depressed patients because of the long-term risk of adverse effects.³¹
• Lack of effect on weight. Which is important with patients for whom weight gain or loss is of concern.

Conclusion

A substantial number of elderly residents in nursing facilities or other long-term care settings have major depression, many of whom may not have been properly diagnosed or are being undertreated.^1,2 Further, many of the residents who are being treated may be receiving inappropriate pharmacotherapy (tertiary amine TCAs)¹; as a consequence, they may be suffering from adverse effects that could have been avoided or at least minimized by selection of a newer and safer antidepressant agent.

Several treatment issues are involved in the care of elderly depressed nursing facility residents. These include co-existing medical conditions and their pharmacotherapy (raising issues of illness-or drug-induced depression as well as the potential for drug interactions),side effects of antidepressant agents, and age-related alteration of pharmacokinetic and pharmacodynamic effects.

Nefazodone is an effective antidepressant with an excellent safety profile that appears to be appropriate for the treatment of major depression in elderly residents of nursing facilities or other long-term care environments. The favorable pharmacologic profile of nefazodone makes it an appropriate alternative to other antidepressant agents, especially TCAs, as nefazodone is better tolerated and is associated with a lower risk of sedation and adverse anticholinergic or cardiovascular effects. The anxiolytic effects of nefazodone, combined with its low potential for inducing anxiety, agitation, or insomnia, offer additional therapeutic benefits. In addition, nefazodone appears to have an excellent safety profile for long-term use.

References

1. Simonson W, Bauwens SF, Cali TJ et al. Drug-use evaluation of antidepressant agents in long-term care. Consult Pharm; 11:1241-60.

2. Mandos LA. Current issues in the diagnosis and management of depression in the elderly in the long-term care setting. ConsultPharm 1996; 11: 1328-38.

3. Taylor DP, Carter RB, Eison AS et al. Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. J Clin Psychiatry1995; 56(suppl 6): 311.

4. Eison AS, Eison MS, Torrente JR et al. Nefazodone: preclinicalpharmacology of a new antidepressant. Psychopharm Bull 1990; 26:3115.

5. Nefazodone prescribing information, Princeton, NJ: BristolMyersSquibb Company, January 1995.

6. Barbhaiya RH, Shukla UA, Greene DS. Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment. Eur J Clin Pharmacol 1995; 49:2218.

7. Mendels J, Reimherr F, Marcus RN et al. A double-blind, placebo-controlled trial of two dose ranges of nefazodone in the treatment of depressed outpatients. J Clin Psychiatry 1995; 56(suppl 6): 306.

8. Fontaine R, Ontiveros A, Elie R et al. A double-blind comparison of nefazodone, imipramine, and placebo in major depression. JClin Psychiatry 1994; 55: 23441.

9. Rickels K, Schweizer E, Clary C et al. Nefazodone and imipramine in major depression: a placebo-controlled trial. Br J Psychiatry1994; 164: 8025.

10. Fawcett J, Marcus R, Anton S et al. Response of anxiety and agitation symptoms during nefazodone treatment of major depression. J Clin Psychiatry 1995; 56(suppl 6): 3742.

11. DeGruy F. Management of mixed anxiety and depression. Am FamPhysician 1994; 49: 8606.

12. Feighner JP, Pambakian R, Fowler RC et al. A comparison of nefazodone, imipramine, and placebo in patients with moderate to severe depression. Psychopharmacol Bull 1989; 25: 21921.

13. Preskorn SH. Comparison of the tolerability of nefazodone, imipramine, fluoxetine, sertraline, paroxetine, and venlafaxine. J Clin Psychiatry 1995; 56(suppl 6): 1221.

14. Armitage R, Rush AJ, Trivedi M et al. The effects of nefazodone on sleep architecture in depression. Neuropsychopharmacology 1994;10: 1237.

15. Dockens RC, Rapoport D, Roberts DS, Greene DS. Lack of an effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline during concurrent administration in patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol 1995;40: 598601.

16. Marino MR, Langenbacher KM, Hammett JL et al. The effect of nefazodone on the single dose pharmacokinetics of phenytoin in healthy male subjects. J Clin Pharmacol. In Press.

17. Kroboth PD, Folan MM, Lush RM et al. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessments. J Clin Psychopharmacol1995; 15: 30619.

18. Greene DS, Salazar DE, Dockens RG et al. Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic interaction study with lorazepam. J Clin Psychopharmacol 1995; 15: 40916.

19. Salazar DE, Marathe PH, Fulmor IE et al. Pharmacokinetic andpharmacodynamic elevation during coadministration of nefazodoneand propanolol in healthy man. J Clin Pharmacol 1995; 35: 1109-18.

20. Fulmor IE, Dockens RC, Chaikin P et al. Effect of nefazodone on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Abstract presented at the New Clinical Drug EvaluationUnit Meeting, 1994.

21. Salazar DE, Dockens RC, Milbrath RL et al. Pharmacokineticand pharmacodynamic evaluation of warfarin and nefazodone coadministrationin healthy subjects. J Clin Pharmacol 1995; 35: 7308.

22. Barbhaiya RH, Shukla UA, Greene DS. Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans. Br J Clin Pharmacol 1995; 40: 1615.

23. Barbhaiya RH, Shukla UA, Greene DS et al. Investigation of pharmacokinetic and pharmacodynamic interactions following coadministration of nefazodone and haloperidol. J Clin Psychopharmacol 1996; 16:2634.

24. Frewer LJ, Lader M. The effects of nefazodone, imipramine and placebo, alone and combined with alcohol, in normal subjects. Int Clin Psychopharmacol 1993; 8: 1320.

25. Greene DS, Salazar DE, Dockens RC et al. Coadministrationof nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 1995; 15: 399-408.

26. Barbhaiya RH, Shukla UA, Kroboth PD, Greene DS. Coadministration of nefazodone and benzodiazepines: II. A pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol 1995; 15: 3206.

27. Dockens RS, Greene DS, Barbhaiya RH. Assessment of pharmacokinetic and pharmacodynamic drug interaction between nefazodone and digoxinin healthy male volunteers. J Clin Pharmacol 1995; 35: 160-7.

28. Lanoxin prescribing information. Research Triangle Park, NC:Glaxo Wellcome Inc., 1991 Sept.

29. Mendels J. Clinical management of the depressed geriatric patient: current therapeutic options. Am J Med 1993; 94(suppl5A): 13S18S.

30. Mandos LA. Treatment of depression. Am Drug 1989; 199: 5360.

31. Kanowski S. Depression in the elderly: clinical considerations and therapeutic approaches. J Clin Psychiatry 1994; 55: 16673.

37. von Moltke LL, Greenblatt DJ, Shader RI. Clinical pharmacokineticsof antidepressants in the elderly. Clin Pharmacokinet 1993; 24:14160.

38. Ghose K. Prescribing CNS drugs for elderly patients. Drugs Aging 1994; 4: 27584.

Copyright © 1997, American Society of Consultant Pharmacists,Inc. All rights reserved.