Nefazodone (Serzone®)

Original Author: Vicki Ellingrod, Pharm.D., BCPP
Latest Reviser: Vicki Ellingrod, Pharm.D., BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed

The first available antidepressants were the tricyclics (TCAs) and the monoamine oxidase inhibitors (MAOIs). Although these medications are effective in treating major depression, their adverse drug reaction (ADR) profiles are less then desirable. Patients taking these medications often complain of sedation, dry mouth, confusion, weight gain, urinary retention, and sexual dysfunction. In addition to these ADRs, the TCAs and MAOIs may cause cardiotoxicity and can be lethal when taken as an overdose and thus are not a good therapeutic choice in a patients with active suicide ideation. In the 1980s, the introduction of the selective serotonin reuptake inhibitors (SSRIs) enabled psychiatrists to treat depressed patients without dietary restrictions, many noxious ADR, or risk of death in an overdose. The new antidepressants of the 1990s have resulted in the introduction of compounds that are neither tricyclics, MAOIs, or SSRIs. Nefazodone is a new antidepressant which may offer another treatment option for patients who are non-responsive to or are unable to tolerate currently available medications.

MECHANISM OF ACTION

That depression is the result of dysregulation of serotonin and norepinephrine neurotransmitters has been theorized for many years. It is generally concluded that dysregulation leads to a relative functional deficiency of these neurotransmitters. Nefazodone's mechanism is to increase the amount of serotonin by inhibition of reuptake and antagonism at 5HT₂ receptors. In addition, nefazodone also inhibits the reuptake of norepinephrine.

Nefazodone a phenylpiperazine antidepressant is structurally related to trazodone, another antidepressant.

EFFICACY

Typically studies with nefazodone involve outpatients, are double-blind, and are 6 weeks in duration. Overall, approximately 65% of patients will be improved with these drugs. Few studies have examined the prophylactic effect of these drugs in recurrent major depressive disorder. Many of the clinical trials for these drugs are not published and thus the majority of efficacy data is obtained from FDA reports. Due to the lack of published reports, statistical analysis of these trials is very sparse.

Nefazodone. In 5 studies, high dose nefazodone (>300 mg/day) was more effective than placebo in 4 and equal in efficacy to imipramine in 3 comparisons. In one comparison nefazodone was found to be less efficacious than amitriptyline for patients with MDD with melancholia.

In comparison to the SSRIs (sertraline and paroxetine) nefazodone was found to be just as efficacious (Feiger et al 1996, Baldwin et al 1996).

PHARMACOKINETICS

Nefazodone is extensively metabolized by the liver to weakly active or pharmacologically active metabolites. Liver disease may increase blood levels of the drugs, while renal impairment would not be expected to alter the drugs' elimination.

Absorption/Distribution

Nefazodone is rapidly absorbed after oral administration with a mean t_max of 1.2 hours (range 0.5-4 hours) ²² and an absolute bioavailability of 20%. ⁵ Food delays absorption by 20%, prolongs the t_max to 2 hours, and reduces C_max by 40% although these changes have not been regarded as clinically significant. Therefore, nefazodone may be administered with or without food. Nefazodone's metabolites appear rapidly in the plasma. The mean t_max for OH-NEF and m-CPP respectively are 1.7 hours (range 0.5-6 hours) and 2.5 hours (range 1-10 hours) ²² At steady state, nefazodone's mean half-life is dependent on dose, varying from 2 hours at 100 mg/day to 4-5 hours at 600 mg/day. The AUC and Cmax in the elderly after single doses of 300 mg have been found to be up to twice as high as the AUC and Cmax in younger patients. This result was also seen in female but not male subjects. With repeated doses only a 10-20% increase is seen. Because of these gender and age differences caution is warranted when initiating nefazodone therapy in elderly females. Nefazodone is widely distributed in the body tissues including the CNS. The volume of distribution (Vd) ranges from 0.22-0.87 L/kg. Nefazodone is also highly (>99%) protein bound which may cause clinical drug interactions with other highly protein bound medications. In vitro nefazodone did not alter the protein binding of chlorpromazine, desipramine, diazepam, phenytoin, lidocaine, prazosin, propranolol, verapamil, or warfarin but it is unknown if this occurs in vivo.

Metabolism/Elimination

Nefazodone is extensively metabolized in the liver to three active metabolites, hydroxy-nefazodone (OH-NEF), triazole-dione and m-chlorophenylpiperazine (mCPP). Nefazodone's hydroxylation to OH-NEF was not found to be a saturable process.

The specific cytochrome P450 isoenzyme responsible for nefazodone's hydroxylation is unknown but in patients phenotyped for the CYP2D6 hepatic isoenzyme no differences in AUC_0-48 ratios were found between slow and extensive metabolizers, thus suggesting that CYP2D6 is not the responsible enzyme. ²² However, four poor metabolizers did exhibit a 4-5 fold greater mCPP plasma concentration than extensive metabolizers. However, since mCPP is a minor metabolite without significant clinical activity, this is an insignificant interaction.. Nefazodone has also been shown to be a potent inhibitor of CYP3A4 in vitro and will increase plasma levels of other medications metabolized by this isoenzyme if both are given concurrently. The elimination half-life of nefazodone is between 2.7±1.7 and 10.2±4.4 hours depending on dose and administration (single dose versus repeated dosing for 7 days). OH-NEF demonstrates an analogous beta elimination half-life profile ranging from 1.4±0.9 to 6.5±1.6 hours while the half lives of mCPP and triazole-dione range from 4-8 hours and 18 hours respectively. The wide range in half-life indicates that nefazodone undergoes non-linear kinetics as seen by its accumulation with continuous dosing. Due to nefazodone's short half life twice daily dosing is needed.

ADVERSE EFFECTS

Patients generally tolerate these drugs better than TCAs as more patients drop out of treatment that are receiving TCAs.

Common side effects for nefazodone include autonomic (i.e., headache, asthenia ), CNS (i.e., somnolence, dizziness, insomnia, lightheadedness, confusion), Gastrointestinal (i.e., dry mouth, nausea, constipation, dyspepsia, diarrhea), and special senses (i.e., blurred vision, abnormal vision) (See Table 1).

SEXUAL ADVERSE EFFECTS

Feiger et al (1996) looked at nefazodone's (mean dose = 456 mg/day) and sertraline's (mean dose = 148 mg/day) effects on sexual function and satisfaction in 100 patients by issuing a questionnaire. In women, nefazodone treatment resulted in superiority over sertraline treated women in achieving orgasm (p = 0.03) and satisfaction with the ability to achieve orgasm (p = 0.04). In men 67% of the sertraline group and 19% of the nefazodone group reported difficulty with ejaculation (p < 0.01). Although the author's analysis showed that nefazodone had significantly less sexual dysfunction than sertraline, the rate of dysfunction in the sertraline group may be overstated due to study flaws. Since the sexual dysfunction associated with SSRI is believed to be dose dependent, the 150 mg/day of sertraline may overestimate the rate of true sexual function. Also the end point analysis between the two groups is not valid since some patients did not fill out a baseline evaluation. It is noted that men in the sertraline group reported premature ejaculation less often than the nefazodone treated men (p< 0.02) which may indicate use of a SSRI for this condition.

Table 1: Treatment emergent ADRs (> 5%) from Nefazodone 300-600 mg/day in 6-8 weeks of placebo controlled clinical trials
Body System and ADR		Nefazodone (n=393)	Placebo (n=394)
Body as a whole
	Headache	36%	33%
	Asthenia	11%	5%
	Infection	8%	6%
Gastrointestinal
	Dry Mouth	25%	13%
	Nausea	22%	12%
	Constipation	14%	8%
	Dyspepsia	9%	7%
	Diarrhea	8%	7%
	Increased Appetite	5%	3%
Central Nervous System
	Somnolence	25%	14%
	Dizziness	17%	5%
	Insomnia	11%	9%
	Lightheadedness	10%	3%
	Confusion	7%	2%
Respiratory
	Pharyngitis	6%	5%
Special Senses
	Blurred Vision	9%	3%
	Abnormal vision	7%	1%

DOSAGE

Nefazodone is initiated at 200 mg/day given in two divided doses. This dose can then be increased by 150-300 mg/day in weekly intervals. The titration schedule may need to be lower than recommended due to increased side effects during the first 1-2 weeks of therapy. Typically 150-300 mg/day is used to treat depression. When dosing in the elderly ( > 65 years old) the initial dose should be 50 mg BID with the goal of increasing to 100-400 mg/day. The incidence of ADRs is greatest while the drug is being titrated. Once patients have received the medication for 2 or more weeks the incidence of ADRs drops in half.

PRECAUTIONS/CONTRAINDICATIONS

It should be assumed that nefazodone will interact with MAOIs and at least 7 days after nefazodone's discontinuation should be allowed before administration of an MAOI. Likewise, nefazodone should not be started within 14 days of discontinuation of a MAOI.

Nefazodone should be used with caution in patients that are extremely sensitive to possible hypotensive episodes. The incidence of hypotension (SBP > 90 mmHg) is 5.1% for nefazodone and for bradycardia ( < 50 bpm) is 1.5%.

DRUG INTERACTIONS

Nefazodone is an inhibitor of the CYP3A4 enzyme and has been found to increase the serum concentrations of alprazolam and triazolam by 1.5-4 fold. When using these medications concurrently with nefazodone an initial dosage reduction of the benzodiazepine is needed. Nefazodone is also contraindicated with the non-sedating antihistamines terfenadine and astemizole due to inhibition of their metabolism and the possible resulting fatalities.

Numerous other drug interactions have been reported with nefazodone. These include increased haloperidol concentrations of 36%, decreased propranolol concentrations by 30%, and a decrease in the total body clearance of digoxin with an elongation of its half life to > 100 hours. When these two medications are used together, routine monitoring of digoxin levels is warranted.

COST COMPARISONS

Average wholesale price (AWP) for a month's supply of drug provides a relative cost comparison.

The average wholesale price per 60 tablets for the 100 mg (scored), 150 mg (scored), 200 mg and 250 mg strengths are all $51.75. A months supply of nefazodone 450 mg/day costs $77.00.

In comparison, the cost for sertraline 50 and 100 mg/d is $47.00 and $49.00. Fluoxetine for 10 mg, 20 mg, and liquid is $59.00, $58.00, and $107.00 (20 mg/d), respectively. Paroxetine for the 20 mg and 30 mg doses is $52.00 and $53.00, respectively.

Depending on the dose prescribed, these agents are approximately equivalent price. Splitting tablets of sertraline 100 mg or dosing fluoxetine 20 mg QOD can reduce the cost by approximately 50%.

CONCLUSIONS/RECOMMENDATIONS

1. All antidepressants are equally effective in treating depression.
2. Nefazodone may not be drugs of choice in patients with cardiovascular problems.
3. More studies need to be conducted to look at the side effect profile for nefazodone.
4. Dosage titration may need to be done slowly so as to avoid potential side effects.
5. Nefazodone is more expensive compared to generically prescribed TCAs.
6. Nefazodone's places in therapy for the treatment of depression need to be defined.
7. The incidence of sexual side effects associated with Nefazodone needs to be better defined.

Table 2. Clinical efficacy of nefazodone according to published studies.
Author (Patient Number)	Study Design (Patient Population)	Mean drug dose (± s.d. or range) and study duration		Outcome measures	Results
Placebo
D'Amico et al 1990 (n=222)	Phase II, PLBb controlled, fixed dose (outpts-MDD-RDCc)		NEFa: 50, 100, 200 or 300 mg/d. 6 weeks	HAMDc	LOCFe HAMD NEF 100 mg/d and 200 mg/d >PLB at week 5 and 6 (p<0.05). LOCF NEF 50 mg/d and 300 mg/d = PLB at week 6 (p>0.05).
D'Amico et al 1990 (n=218/240 preliminary analysis)	Phase II, PLB controlled, fixed dosage range (MDEf- DSM-IIIg)		L-NEF: 50-300 mg/d H-NEF: 100-600 mg/d 2 weeks	Unknown	Doses >300 mg/d well tolerated. Modal dose for L-NEF = 300 mg and modal dose for H-NEF = 600 mg.
Imipramine
Feighner et al 1989 (n= 45)	randomized DBb, PLB controlled (outpts-MDDf with melancholia-DSM-III for 4 wks)		NEF: 180 mg/d (modal dose) IMIa: 158 mg/d (modal dose) 6 weeks	HAMD, CGIc (patient and clinician)	LOCF HAMD NEF=IMI=PLB (p>0.05). HAMDd NEF = IMI>PLB at week 5 (p<0.05). LOCFe CGI-patient NEF>IMI>PLB at week 6 (p<0.01). LOCFe CGI-clinician NEF=IMI=PLB at week 6 (p>0.05).
Rickels et al 1994 (n=283)	randomized DB, PLB controlled (outpts-MDD or BPAD- DSM-III-Rg)		NEF: 375 mg (100-600 mg/d) IMI: 174 mg (50-300 mg/d) 8 weeks	HAMD, CGI, HSCL-depression factor	LOCF HAMD NEF>IMI at week 4,6, and 8 (p<0.01). HAMDd NEF=IMI at week 8 (p<0.01). CGId NEF=IMI>PLB at week 3 (p<0.05). HSCLd NEF = IMI>PLB at week 8 (p<0.02).
Fontaine et al 1994 (n=180)	randomized DB, PLB controlled (outpts-MDD-RDC with dysphoric features for 4 wks)		H-NEFc: 25-250 mg/d (242±4.7) L-NEFc: 100-500 mg/d (460±11.1) IMI: 50-250 mg/d (214±7.8) 6 weeks	HAMD, CGI (clinician), PGAc, HSCL-90, and HAMAc	LOCF HAMD, CGI-clinician, HAM-A: H-NEF=IMI> L-NEF=PLB at week 6 (p<0.05). HSCL H-NEF>IMI=L-NEF=PLB at week 6 (p<0.05). PGA H-NEF=L-NEF=IMI>PLB at week 6 (p<0.05).
Anton et al 1994 (n= 276)	randomized DB, PLB controlled extension of efficacy trials		NEF: 100-600 mg/d IMI: 50-300 mg/d 1 year maximum	HAMD, CGI	Relapse rates: NEF (9%), IMI (8%), PLB (25%) Prevention of relapse NEF> PLB (p< 0.01), IMI > PLB (p< 0.05)
Amitriptyline
Ansseau et al 1994 (n=106)	randomized, DB (inpts-MDD-DSM-III-R for 6 wks)		NEF: 242 ± 86.5 mg/d (100-400 mg) AMI: 124.4 ± 38.5 mg/d (50-200 mg) 6 weeks	MADRSc, CGI (clinician), PGA, HAMD	MADRS: AMI>NEF (p<0.0001) starting at week 2. HAMD: AMI> NEF (p<0.0006) starting at week 4. CGI: AMI>NEF (p<0.0001) starting at week 3. PGA: AMI>NEF (p<0.01) starting at week 4.

a: NEF = nefazodone, H-NEF = higher dosage nefazodone, L-NEF = lower dosage nefazodone, IMI = imipramine, AMI = amitriptyline, PLB = placebo
b: DB = double blind, PLB controlled = placebo controlled
c: HAMD = Hamilton Rating Scale for Depression (Total score), CGI = Clinical Global Improvement, HSCL = Hopkins Symptom Checklist, HAMA = Hamilton Rating scale for Anxiety, PGA = Patient Global Assessment, MADRS = Montgomery and Asberg depression rating scale
d: Complete analysis
e: LOCF = last observation carried forward
f: MDD = Major depressive disorder, BPAD = Bipolar Affective Disorder, MDE = Major depressive episode
g: RDC = Research Diagnostic Criteria, DSM-III = Diagnostic Statistical Manual III, DSM-III-R= Diagnostic Statistical Manual III-Revised

REFERENCES

Baldwin DS, Hawley CJ, Abed RT et al (1996). A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression. J Clin Psychiatry 57[suppl 2]: 46-52.

Ellingrod VL and Perry PJ (1995). Nefazodone: a new antidepressant or another me too drug? Am J Health Systems Pharmacy ( in press).

Feiger A, Kiev A, Shrivastava RK et al (1996). Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry 57[suppl 2]: 53-62.

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