nefazodone in the treatment of elderly patients with depressive disorders

Nefazodone in the Treatment of Elderly Patients with Depressive DisordersA Prospective, Observational Study

Jerónimo Saiz-Ruiz,1 Angela Ibañez,1 Marina Díaz-Marsá,1 Francisco Arias,1 José L. Carrasco,1 David Huertas,1 Manuel Martín-Carrasco,1 Isabel Moreno1 and Fernando Rico-Villademoros2

1 Department of Psychiatry, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain2 Medical Department, Biometrica, Madrid, Spain

Abstract Objectives: The aim of this study was to evaluate the clinical effectiveness andtolerability of nefazodone for the treatment of depression in elderly patients inclinical routine practice.

Patients and study design: Seventy-nine patients with a mean age of 72.81 years,who had major depression or dysthymia according to DSM-IV criteria, wereenrolled into this open label study. Patients were prescribed nefazodone startingat 50 mg/day, increasing every 4 days until a dosage of 200 mg/day was attained,and subsequently upward to 600 mg/day if no dose-limiting adverse effects ap-peared. Effectiveness was evaluated at the end of weeks 2, 4, 8 and 12 by com-pletion of the Hamilton Depression Rating Scale (HAM-D), the GeriatricDepression Scale (GDS) and the Clinical Global Impressions scale. The HamiltonAnxiety Rating Scale (HAM-A), the sleep satisfaction item of the Oviedo SleepQuestionnaire (OSQ) and the Short Portable Mental Status Questionnaire(SPMSQ) were used to assess the patients at the end of week 12. Primary efficacyanalysis was based on an intention-to-treat, last-observation-carried-forward data set.

Results: HAM-D scores decreased progressively from a baseline mean of 22.3to 14.2 at the study endpoint; although this was a significant reduction, the end-point score indicates that a significant residual symptomatology remained in thepatients. Similarly, the GDS and HAM-A scores had decreased significantly byweek 12. Response and remission rates were 47 and 37.5%, respectively. Thepercentage of patients who were satisfied, much satisfied or very much satisfiedwith their sleep according to the OSQ increased from 4.2% at baseline up to 62.2%at the study endpoint. A significant reduction in the SPMSQ total score wasobserved at the study endpoint, although the clinical relevance of this finding isdoubtful. Forty-two (53.2%) patients completed the study. The most commonreasons for withdrawal from the study were a lack of efficacy and adverse effects.Most adverse reactions were mild to moderate in severity and included dizziness,dry mouth, gastrointestinal distress, sedation, anxiety and malaise.

ORIGINAL RESEARCH ARTICLE CNS Drugs 2002; 16 (9): 635-6431172-7047/02/0009-0635/$25.00/0

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Conclusion: Our results suggest that nefazodone may be a well tolerated andeffective alternative for treating elderly patients with depression. Although theHAM-D score at study endpoint indicated significant residual symptomatology,a similar finding has been described in several meta-analyses of antidepressanttreatment in the elderly. Further research is needed to evaluate a differentnefazodone dose regimen, especially a slower dose titration rate, which couldresult in a reduced discontinuation rate and thus a better treatment outcome.

Depression is not a normal response to aging,but it remains underdiagnosed and undertreated ingeriatric patients. Major depression is a serious dis-order in late life causing significant morbidity andmortality and a decrease in quality of life; it is alsoassociated with an increased use of medical ser-vices.[1]

Although common, the most severe forms of de-pression occur less frequently in elderly adults thanin younger adults. In 1991, the EpidemiologicalCatchment Area (ECA) study[2] estimated that the1-year prevalence rates of major depression anddysthymic disorder among community-dwellingpersons aged 65 years or older were approximately1 and 2%, respectively. As part of the ECA project,Regier et al.[3] reported a 1-month prevalence ratefor any affective disorder of 5.1% in the generalpopulation compared with 2.5% in the elderly (≥65years). Significant depressive symptoms without amajor depression diagnosis occur in approximately8 to 15% of community residents over 65 years ofage; rates of depression in nursing homes rangefrom 20 to 50%.[4-6]

Depression in the geriatric population is ahighly recurrent disease with relapse occurring in40 to 80% of patients.[7] Major depressive disorderis an independent risk factor for mortality amongthe elderly and increases the likelihood of death by59% in the first year after diagnosis. Death ratesamong institutionalised elderly individuals whoare depressed are between 1.5 and 3 times those ofnondepressed institutionalised elderly individu-als.[8,9]

Elderly patients with depression are more diffi-cult to treat than their younger counterparts. Phar-macokinetic changes that accompany aging resultin higher and more variable drug concentrations.

In addition, age-related pharmacodynamic changesoccur. The reduced plasticity of the brain and theimpairment of the central serotonergic system, forinstance, could contribute to a delayed and/or re-duced response to antidepressants in the elderly.Elderly patients with depression are also particu-larly sensitive to the motor, cardiovascular and an-ticholinergic effects of antidepressants.[10,11]

Common adverse effects of tricyclic antidepres-sants (TCAs) that are particularly hazardous in theelderly include orthostatic hypotension, sedation,cardiac toxicity and anticholinergic reactions.These adverse effects limit the use of TCAs in theelderly, although nortriptyline and desipraminehave fewer of these adverse effects than otherTCAs. The use of monoamine oxidase inhibitorshas been limited because of the risk of hyperten-sive emergencies. Selective serotonin reuptake in-hibitors (SSRIs) cause fewer sedative, anticholin-ergic and hypotensive effects than the TCAs, andare unlikely to affect cardiac conduction; however,they may cause gastrointestinal distress, agitation,insomnia and sexual dysfunction.[12,13]

Nefazodone is an antidepressant with a uniquepharmacology, characterised by potent antago-nism of serotonin 5-HT2 receptors combined withinhibition of the reuptake of serotonin and, to aminor extent, noradrenaline (norepinephrine).[14]

Controlled clinical trials with nefazodone that in-volved patients of various ages, including some el-derly, have demonstrated that it is associated withsimilar antidepressant response rates to those ofimipramine[15-17] and the SSRIs.[18,19] Nefazodonealso has favourable effects on anxiety[20] and sleepdisruption[21,22] in patients with depression; in ad-dition, it seems to cause fewer activating adverseeffects and sexual dysfunction compared with the

636 Saiz-Ruiz et al.

© Adis International Limited. All rights reserved. CNS Drugs 2002; 16 (9)

SSRIs and venlafaxine.[23] However, several casesof severe hepatic failure have been recently re-ported with nefazodone,[24,25] which has led the USFood and Drug Administration (FDA) to include awarning in the package insert.

Most research studies include primarily pa-tients who are medically healthy. This is a crucialdimension where research studies differ from clin-ical practice; the clinician must treat many patientswith depression who have concurrent medical con-ditions.[26] In a recent review of the newer non-tricyclic antidepressants, Livingston and Living-stone[27] found that 60% of trials of antidepressantsspecifically excluded patients with a history of car-diovascular, renal, hepatic and prostatic disease,and 37% excluded patients with organic brain dis-ease. In order to adequately test antidepressants inthis group, they advocate more naturalistic trials.

The following is a report of the results of a pro-spective, observational and naturalistic study of theuse of nefazodone in elderly patients meeting DSM-IV[28] criteria for nonpsychotic mood disorders.

Patients and Methods

This was an open evaluation of nefazodone inthe treatment of elderly (≥65 years) outpatientswho met DSM-IV criteria for nonpsychotic mooddisorders (major depression, dysthymia or depres-sive disorders not otherwise specified). Patientsfor whom the investigators had decided to pre-scribe nefazodone as part of their normal clinicalpractice were evaluated at baseline and, after ful-filment of eligibility criteria was ensured, patientsreceived 12 weeks of open treatment with oralnefazodone. The dosage used was 50 to 600mg/day, titrated according to therapeutic responseand tolerability.

The following patients were excluded from thestudy: (i) patients who met DSM-IV criteria forany significant psychoactive substance use disor-der; (ii) patients with a concurrent Axis I disordersuch as organic mental syndromes and disorders,schizophrenia, delusional disorders or psychoticdisorders; (iii) patients with a known allergy orhypersensitivity to phenylpiperazine antidepres-

sants or m-chlorophenylpiperazine (a metabolite ofnefazodone); and (iv) patients who were anticipatedto require treatment with prohibited concomitantmedication listed in the nefazodone package insert.

Following the Spanish regulations on post-marketing studies, the study was reported to theMinistry of Health.

Baseline evaluations included the Spanish valid-ated versions of the 17-item Hamilton DepressionRating Scale (HAM-D),[29] the Geriatric Depres-sion Scale (GDS),[30] the Hamilton Anxiety RatingScale (HAM-A),[31] the Clinical Global Impres-sions (CGI) severity of illness scale,[32] item 1 ofthe Oviedo Sleep Questionnaire (OSQ)[33] and theSpanish validated version of the Short PortableMental Status Questionnaire (SPMSQ).[34]

Medical evaluations included an assessment ofmedical and psychiatric history, physical examina-tion and recording of vital signs (heart rate andblood pressure, because nefazodone has been as-sociated with postural hypotension[35]). Because ofthe naturalistic style of the study, no routine elec-trocardiogram (ECG) or laboratory tests were per-formed.

Patient visits were scheduled at the end ofweeks 2, 4, 8 and 12. Efficacy was assessed bycompletion of the HAM-D, GDS and CGI im-provement scale at each visit. In addition, theHAM-A and the sleep satisfaction item of the OSQand the SPMSQ were used at the end of week 12.Patients were also monitored for adverse events.

The dose regimen and intervals between dosetitration were individualised for each patient. Med-ication was started at 50 mg/day as a single doseat bedtime, increasing by 50 mg/day every 4 daysto a dosage of 200 mg/day (100mg twice daily) bythe end of week 2. Subsequently, if a patient didnot experience dose-limiting adverse effects, thedosage could be increased up to 600 mg/day.

Statistical Analysis

All the efficacy measures were analysed on thebasis of an intention-to-treat (ITT), last-observation-carried-forward (LOCF) approach and includedthose patients who were dispensed the medication

Nefazodone in Elderly Patients with Depressive Disorders 637


and had an efficacy evaluation during treatment. Inaddition, a per protocol (PP) analysis was per-formed and included those patients who receivedat least 6 weeks of treatment with nefazodone.Analyses were performed for each study visit andwere two-tailed; they were considered significantif the p value was ≤0.05.

Demographic data were described by means,medians, ranges and standard deviations. ForHAM-D, GDS, HAM-A and SPSMQ scores andblood pressure, the significance of changes frombaseline to endpoint was calculated with the Stu-dent’s t-test. A CGI global improvement rating ofat least ‘much improved’ or a decrease greater than50% in the total score on the HAM-D constitutedevidence of a therapeutic response. Remission wasdefined as a HAM-D score ≤10.

Results

A total of 79 patients were enrolled in the study.Demographic and clinical characteristics of thesample are shown in table I.

Forty-two (53.2%) patients completed the study.Of the 37 patients who withdrew, ten (12.7%) did sobecause of adverse reactions, ten (12.7%) becauseof lack of efficacy, 14 (17.7%) were lost to follow-up and three (3.7%) for other reasons.

The ITT sample for the study included all 79patients recruited. The mean daily dose at week 12was 292mg (SD ± 122.25). The PP sample com-prised 50 patients who received a mean dosage of305 mg/day (SD ± 109.85).

Efficacy results for the ITT analysis at endpointare shown in table II. HAM-D scores for the pa-tients decreased progressively from a baselinemean score of 22.3 to 14.2 at the study endpoint(LOCF analysis). Also, GDS scores had decreasedsignificantly by week 12. Similarly, HAM-Ascores decreased from a baseline mean score of22.0 to 13.6 at the end of treatment. Figure 1 (PPanalysis) and figure 2 (ITT analysis) illustrate thereductions in the HAM-D total score over time;significant differences were seen as early as the

Table I. Baseline demographic characteristics and psychiatry his-tory of 79 elderly patients treated for 12 weeks with nefazodone 50to 600 mg/day

Characteristic

Age, y (mean ± SD) 72.81 ± 6.46

Gender, n (%)

women 61 (77.2)

men 18 (22.8)

Diagnosis, n (%)

major depression, single 22 (27.9)

major depression, recurrent 25 (31.6)

dysthymia 17 (21.5)

other 15 (19.0)

Number of prior depressive episodes(mean ± SD)

3.37 ± 3.8

Patients who had received a previousantidepressant for the current episode, n (%)

44 (55.7)

CGI severity of illness, n (%)

mildly ill 8 (10.1)

moderately ill 28 (35.4)

markedly ill 36 (45.6)

severely ill 7 (8.9)

CGI = Clinical Global Impressions scale; n = number of patients;SD = standard deviation.

Table II. Summary of efficacy results at endpoint in 79 elderlypatients treated for 12 weeks with nefazodone 50 to 600 mg/day

Assessment Baseline End oftreatment

p-Valuea

HAM-D-17 score

total (mean ± SD) 22.3 ± 4.2 14.2 ± 8.9 <0.0001

% remitters NA 37.5 NA

GDS total score(mean ± SD)

23.7 ± 3.2 16.3 ± 8.7 <0.0001

HAM-A total score(mean ± SD)

22 ± 6.1 13.6 ± 9 <0.0001

CGI improvementscoreb

% responders NA 47 NA

SPMSQ total score(mean ± SD)

0.95 ± 1.34 0.82 ± 1.7 <0.01

a Change from baseline, intent-to-treat data set, last-observation-carried-forward approach, t-test.

b n = 76.

CGI = Clinical Global Impressions scale; GDS = Geriatric Depres-sion Scale; HAM-A = Hamilton Anxiety Rating Scale; HAM-D-17 =17-item Hamilton Depression Rating Scale; NA = not applicable;SD = standard deviation; SPMSQ = Short Portable Mental StatusQuestionnaire.



end of week 2 and continued through to the end oftreatment.

Response and remission rates were 47 and37.5%, respectively, in the LOCF analysis, and 68and 58%, respectively, in the PP analysis. Al-though the clinical relevance is doubtful, a signif-icant reduction in the SPMSQ total score was ob-served at the endpoint (table II). At baseline, thepercentage of patients who were satisfied, muchsatisfied or very much satisfied with their sleepaccording to the OSQ was 4.2%; this increased to62.2% at the study endpoint.

Overall, 41 (51.9%) patients receiving nefazo-done reported at least one adverse reaction. Mostadverse reactions were mild to moderate in sever-ity (77.5%), and most did not result in study dis-continuation, although nine patients reported se-vere adverse reactions. Bearing in mind that apatient could report more than one reaction, severeadverse reactions reported included malaise (n =6), dizziness (n = 3), somnolence (n = 2), anxiety(n = 1), diarrhoea (n = 1), skin reaction (n = 1) andgastrointestinal distress (n = 1). Table III summa-rises the most frequent adverse events (i.e. thosereported by at least 5% of the patients). Ten of thepatients (12.7%) discontinued treatment becauseof adverse reactions.

There were no significant changes from base-line to endpoint in systolic or diastolic blood pres-sure or heart rate (table IV). Moreover, in thosepatients treated concomitantly with antihyperten-sives (n = 20, 25.3%) blood pressure at the end-point did not significantly differ from baseline val-ues (Wilcoxon test).

Discussion

Despite the major limitation of the lack of acontrol group, our study provides some evidencefor the efficacy of nefazodone in the treatment ofmood disorders in the elderly, as shown by a re-duction of the HAM-D and GDS total scores at thestudy endpoint. The relatively low rates of re-sponse and remission in the ITT analysis group (47and 37.5%, respectively) are influenced by thehigh number of patients who withdrew from thestudy. The higher proportion of response and re-mission found in the PP analysis group (68 and58%, respectively) supports this statement. On theother hand, 54.5% of the patients were markedlyor severely depressed at baseline, and it has beenrecognised that patients who were initially themost depressed prior to treatment are still likely tobe depressed at the end of the treatment course,with final HAM-D scores often >10.[13] The end-point HAM-D score of 14.2 indicates that a signif-

0

5

10

15

20

25

30

HA

M-D

sco

re

Baseline 2 4 8 12

Week

*

** *

Fig. 1. Mean change in the 17-item Hamilton Depression RatingScale (HAM-D) total score by visit for the per protocol analysisin 50 elderly patients treated for 12 weeks with nefazodone 50to 600 mg/day. * p < 0.001 (t-test).

Baseline 2 4 8 12

HA

M-D

sco

re

0

5

10

15

20

25

30

Week

** * *

Fig. 2. Mean change in the 17-item Hamilton Depression RatingScale (HAM-D) total scoreby visit for the intention-to-treat analysisin 79 elderly patients treated for 12 weeks with nefazodone 50to 600 mg/day. * p < 0.001 (t-test).



icant residual symptomatology remained in the pa-tients, a finding described in several meta-analysesof antidepressant treatment in the elderly (see re-view by Salzman et al.[13]).

Despite the advantages that observational stud-ies offer regarding knowledge on how a certaindrug acts under clinical conditions, our study hasseveral limitations in addition to the lack of a con-trol group: (i) the large number of patients whowithdrew from the study; (ii) the relatively lownumber of patients included; and (iii) the patientselection bias (noteworthy, a female bias). In addi-tion, the low dosage used could have contributedto the modest outcome.

In order to put our results into perspective, fol-lowing is a brief review of the data available withnefazodone and other new antidepressants in thetreatment of late-life depression. Since remissionrate is a better indicator of how many patients re-cover when given a certain treatment,[26] we haveincluded only studies that report this efficacy cri-terion.

Two studies of nefazodone in the treatment ofelderly patients have been presented in scientificmeetings (but have not been published yet in peer-reviewed journals). Medori et al.[36] reported on adouble-blind comparison of nefazodone andmaprotiline in 105 patients who met DSM-III-R[37]

criteria for a moderate to severe nonpsychotic ma-jor depressive episode. Only CGI response rates atthe end of 6 weeks of therapy are provided; theseresponse rates were 71% in the patients treatedwith maprotiline and 60% in the patients treatedwith nefazodone, a difference that was not signif-icant (the type of analysis is not specified). The

second study[38] compared the efficacy and toler-ability of nefazodone in 50 patients <65 years and40 patients ≥65 years. The ITT CGI response rateat week 8 was 55% in the elderly group, comparedwith 57% in the younger group (patient withdrawalrates were 22.5 and 18%, respectively).

In our review of the literature, we found morethan 20 studies on the use of new antidepressantsin the elderly. Although well designed (i.e.randomised and controlled), these trials had differ-ent methodologies as well as many pitfalls in re-porting, making it difficult to compare the resultswith those of our study. Only a few studies clearlystate whether ITT analysis was used, and only aminority report remission rates. Bearing in mindthese limitations, remission rates reported forsertraline (45 to 54%)[39-41] and citalopram (53.6and 57%)[42,43] seem to be consistently good andbetter than those observed in our study. Althoughsignificantly better than placebo, remission ratesreported in two large trials of fluoxetine[44,45] aresomewhat low (21 and 31%, respectively); how-ever, trial duration was shorter and harder remissioncriteria were used in both trials than in our studyof nefazodone. In two controlled studies,[46,47] re-ported remission rates for paroxetine were 29.2 and44%, compared with 38.1 and 57% for mirtazapineand nortriptyline, respectively. Although good re-mission rates have been reported with venlafaxinein younger adults,[48] data in the elderly are limitedto a small, open label study[49] where a remission rateof 75% was found. Data on the extended-releaseformulation of bupropion and reboxetine are scarce,and no remission rates are reported.[50,51] In a re-cent trial,[52] 347 elderly patients with depressionwere randomised to receive reboxetine or imipra-mine, resulting in a comparable efficacy as mea-sured by reductions in mean total HAM-D scores.

In our study, nefazodone improved symptomsof anxiety and sleep quality as measured by theHAM-A and the OSQ, which is consistent with theknown profile of the drug. Nefazodone has beenshown to be effective in relieving symptoms ofanxiety and agitation.[20] Importantly, nefazodonedoes not induce agitation, anxiety or insomnia.[23]

Table III. Adverse reactions reported by ≥5% of 79 elderly patientstreated with nefazodone 50 to 600 mg/day for 12 weeks

Adverse reaction No. ofpatients

% ofpatients

Dizziness 21 26.6

Dry mouth 14 17.7

Gastrointestinal distress 12 15.2

Sedation 10 12.7

Anxiety 9 11.4

Malaise 6 7.6



In fact, patients treated with nefazodone experi-enced significantly decreased arousals, decreasedwakefulness and improved sleep quality comparedwith fluoxetine.[21,22] In addition, nefazodone didnot impair cognitive function in our study.

Nefazodone antagonises α1-adrenergic recep-tors, a property that may be associated with pos-tural hypotension.[35] Therefore, the nefazodonepackage insert recommends caution when it is usedin patients with known cardiovascular or cerebro-vascular conditions that could be exacerbated byhypotension and conditions that would predisposepatients to hypotension (e.g. treatment with anti-hypertensive medication). Although in our study46.4% of the patients were diagnosed with hyper-tension and 25.3% were currently receiving anti-hypertensives, there were no significant changesin systolic or diastolic blood pressure, including inthe subset of patients who were treated with anti-hypertensives.

The adverse reaction profile seen in our studyis similar to that of placebo-controlled studies inyounger adults (see review by Davis and Whitting-ton[53]), although the patients in our study had aslightly higher rate of dizziness. Although withinthe rates found with other antidepressants,[25] wedo think that the overall rate of patient withdrawalfrom our study was relatively high and could beminimised with a slower dose escalation to avoidadverse effects; starting with 50 mg/day and in-creasing by 50 mg/day every 7 days instead of ev-ery 4 days could be a better strategy.

Conclusion

Nefazodone appeared to be effective and welltolerated in elderly patients with depression in this

study. These findings, together with the improve-ment on anxiety and sleep measures, suggest thatit may be a useful alternative for treating elderlypatients with depression. However, further double-blind, clinical trials are needed to evaluate a differentdose regimen (especially a slower dose titrationrate that could result in a reduced discontinuationrate and thus in a better treatment outcome) as wellas to confirm the clinical effectiveness of nefazo-done in this population.

Acknowledgements

This study was supported by a grant from Bristol-MyersSquibb, Spain. The authors thank Diego Jiménez MD, JoséM. Montes MD, Francisco Vicente MD, and Rosa Viñas MDfor their participation in this study. Dr J. Saiz-Ruiz is amember of the Speaker’s Bureau of Lundbeck andGlaxoSmithKline and has received grant and research sup-port from Wyeth, Organon and Eli Lilly.

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Table IV. Changes in blood pressure and heart rate in elderly patients treated with nefazodone 50 to 600 mg/day for 12 weeks

Assessment All patients (n = 79) Patients receiving concomitantantihypertensives (n = 20)

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Heart rate (± SD) [beats per minute] 76.2 ± 10.2 73.2 ± 8 81.1 ± 11.8 74.2 ± 7.6

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Correspondence and offprints: Dr Jerónimo Saiz-Ruiz, De-partment of Psychiatry, Hospital Ramón y Cajal, Ctra Col-menar, Km 9.1, Madrid, 28034, Spain.E-mail: [email protected]



nefazodone in the treatment of elderly patients with depressive disorders

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