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Clinical Note

Objective: To compare nefazodone to three selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, sertraline) in the treatment of depression with agitation or depression with anxiety.

Design: Over 10,000 charts were reviewed in 60 nursing facilities. Eighty residents were identified as having either a diagnosis of depression with agitation or depression with anxiety. Presence or absence of side effects was noted, and type and number of concomitant medications were considered.

Setting: Sixty long-term care facilities in New Jersey and Pennsylvania.

Results: Of the 50 residents receiving an SSRI, 98.0% also received a benzodiazepine or another antidepressant. Only 26.7% of the 30 residents receiving nefazodone had such concomitant therapy. Residents treated with nefazodone had fewer side effects than residents treated with selective serotonin reuptake inhibitors.

Abbreviations: BZD = benzodiazepine, SSRI = selective serotonin reuptake inhibitor, LTC = long-term care

Key Words: Depression, Anxiety, Agitation, Nefazodone, Elderly.

Consult Pharm 1998;6:701-4

During routine drug regimen review, pharmacy consultants employed by Pharm Rx Consultants observed that some patients for whom selective serotonin reuptake inhibitor (SSRI) antidepressants were prescribed were also taking adjunctive benzodiazepines or additional antidepressants. Many of these residents had diagnoses of depression with anxiety or depression with agitation. Consultant pharmacists also observed that many patients who were receiving nefazodone did not require adjunctive therapy. Their observation prompted this retrospective study, which compared the use of nefazodone with three SSRIs in the treatment of depression with either agitation or anxiety in residents of long-term care (LTC) facilities.

Methods

Over 10,000 charts in 60 LTC facilities in New Jersey and Pennsylvania were screened. Pharmacists identified residents with diagnoses of depression with anxiety or depression with agitation who were being treated with either an SSRI (fluoxetine, paroxetine, or sertraline) or nefazodone. Additionally, pharmacists noted concurrent medications and any side effects reported in the clinical record. All data were obtained from record review; no interview of clinical staff or residents was conducted. A copy of the standard collection tool is presented in Figure 1.

Figure 1. Serzone Alone Vs Combo Therapy (SSRI + BZD or SSRI + Tricyclic)

Nursing Home

Sex, age

Diagnosis*

Serzone (1)

SSRI Antidep. (2)

BZD or Antihist (3) (during day)

Tricylic Antidep. (4)

Hypnotic (5) (any type at HS)

Other psych med (6)

Side effects from meds (7)

Therapy changes, from what to what and why (8)

Length of current therapy in months

Efficacy (9)

Where info gotten from

Results

Eighty residents with either of the target diagnoses were identified. The residents were distributed throughout the nursing facilities; no large clusters were found. Of these, 50 (62.5%) were receiving an SSRI, and 30 (37.5%) were receiving nefazodone. Adjunctive agents, either benzodiazepines or other antidepressants, were prescribed for 49 (98.0%) of the residents receiving SSRIs. Adjunctive agents were prescribed for eight (26.7%) of the 30 nefazodone patients. Table 1 describes the various combinations of medications used.

Table 1. Number of Residents Taking Various Combinations of Medications for Depression with Agitation/Anxiety
Antidepressant med	Alone	Plus BZD* during day	Plus BZD** HS	Plus 2nd anti- depressant ***HS	Plus BZD during day & HS	Plus 2nd anti- depressant during day & BZD HS	Plus 2nd anti- depressant and BZD HS	Total number of patients
Sertraline	1	10	4	2	1	0	0	18
Fluoxetine	0	11	1	0	1	1	0	14
Paroxetine	0	11	3	2	0	0	2	18
Paroxetine	0	11	3	2	0	0	2	18
Nefazondone	22	4	2	0	2	0	0	30

Data concerning other side effects were also collected from residents' charts and reviewed. In the SSRI group, five patients had increased sedation from combination therapy (SSRI plus a benzodiazepine or additional antidepressant), four residents continued to have anxiety, and three complained of sleep disturbances. In the nefazodone group, neither insomnia nor anxiety was reported. One patient had increased lethargy.

Discussion

The efficacy of fluoxetine, sertraline, paroxetine, and nefazodone is established in the literature. All agents currently approved for treatment of depression have response rates of 60%-70%. Further study of efficacy was not conducted.

SSRIs inhibit presynaptic reuptake of neuronal serotonin (5HT) and potentiate the action of 5HT released by neuronal activity.¹ This action appears to relieve depression, but anxiety, agitation, nervousness, or sleeplessness may also occur. Sleeplessness may be due to an increase in rapid eye movement (REM) sleep; it may manifest as failure to fall asleep or as an increased number of nighttime awakenings or periods of sleeplessness that are longer than those experienced prior to use of the specific SSRI.

Fluoxetine, sertraline, and paroxetine can potentially cause anxiety, nervousness, or agitation. These symptoms are collectively referred to as "activating effects." A review of these products' Food and Drug Administration-approved labeling provides estimates of the incidence with which these side effects occur (Table 2). Thus use of these agents to treat depression may induce or aggravate behavior problems (such as agitation) or insomnia.

Nefazodone has a dual effect; it blocks serotonin reuptake and it has potent pharmacological action as a 5-HT2 receptor antagonist.³ Researchers propose that it is this action that alleviates depression without concurrent disturbance to sleep⁴ or drug-induced agitation or anxiety.⁵ Nefazodone can cause somnolence, and antagonism of 5-HT2 receptors is suspected as the mechanism of action for this side effect.⁶

In clinical trials, incidence of agitation or anxiety associated with nefazodone was comparable to placebo, and the incidence of insomnia was 11% in nefazodone-treated patients compared to an incidence of 9% with placebo.⁷

This retrospective study did not attempt to determine what proportions of nursing facility residents also had independent diagnoses of agitation or anxiety, but other studies estimate that approximately 65% of patients with depression also have moderate anxiety symptoms, and 20%-25% have severe anxiety symptoms.⁸

Recognition and treatment of anxiety associated with depression can ameliorate symptoms and promote compliance with antidepressant therapy.⁹ This is especially important in LTC facilities, where a resident's expression of anxiety or agitation can be disruptive to the environment and sleep disturbances can affect not only the resident, but others as well.

Of the 50 residents in this study receiving SSRIs, 17 (34%) received either a benzodiazepine or a second antidepressant at bedtime (as opposed to divided doses throughout the day or in a single dose earlier in the day). Consultant pharmacists postulated that this adjunctive therapy was used to treat insomnia. In the nefazodone group, four patients (13.3%) required bedtime adjunctive medication.

Researchers have found that sleep patterns of patients with clinical depression differ from those of people who do not. Electroencephalogram abnormalities commonly found in people with depression include increased REM sleep in the early part of the night; shortened REM latency (a shortened period from the beginning of sleep to the first REM period of the night); and decreased slow-wave sleep.^10-12

In depressed patients, nefazodone improves depression-related insomnia with a decrease in arousal, nighttime and early morning wakenings, and light sleep. Thus it contributes to overall sleep efficiency, which is important for nursing facility residents. In addition, two randomized, double-blind studies compared nefazodone with fluoxetine and paroxetine, respectively; these studies demonstrated that nefazodone is associated with more normal sleep than either of these SSRIs.^15,16 Normal sleep patterns can improve resident quality of life.

Study Limitations

A small number of patients with the target diagnoses were identified. Further study in larger populations is needed to confirm these findings.

Concurrent benzodiazepines may have been used for other diagnoses rather than SSRI-induced anxiety or agitation. However, the absence of concurrent benzodiazepines or antidepressants in the nefazodone-treated group is noteworthy and suggests a possibility that the adjunctive treatment was related to SSRI use.

Conclusions were drawn on the basis of the educated assumption that all agents used were equally effective in treating depression.

Quality of life improvements are difficult to measure. Conclusions are based on the educated assumption that fewer side effects and concomitant medications increase quality of life.

Conclusion

The results of this study indicate that nefazodone may be preferable to the SSRIs in elderly residents who are diagnosed with depression with agitation or depression with anxiety. The nefazodone-treated group had fewer side effects, and required fewer concomitant medications.

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Address for Reprints: I. Barton Frenchman, Pharm Rx Consultants, 1238 Stuyvesant Avenue, Union, NJ 07083

Acknowledgment: This study was funded by an unrestricted educational grant from Bristol-Myers Squibb, Princeton, New Jersey.

Copyright © 1998, American Society of Consultant Pharmacists, Inc. All rights reserved.