Focus on Nefazodone

Nefazodone is a relatively new antidepressant with a chemical structure that is somewhat similar to that of the phenylpiperazine antidepressant, trazodone.

The antidepressant action of nefazodone is thought to be dependent on its ability to block postsynaptic serotonin type-2 receptors and inhibit presynaptic serotonin reuptake. Nefazodone also blocks norepinephrine reuptake. Nefazodone does not have a chemical structure similar to the SSRIs, tricyclic anti- depressants, monoamine oxidase inhibitors, bupropion, or venlafaxine.

2. How does nefazodone differ from other antidepressants?

One possibly important way in which nefazodone differs from other SSRIs is that while use of SSRIs is often associated with sexual dysfunction, and sleep disturbances, these side effects have been reported infrequently in people taking nefazodone.

3. What kinds of depression can be treated with nefazodone?

While the pre-marketing studies were restricted to patients with a DSM-III-R diagnosis of non-melancholic Major Depressive Disorder, it is expected that nefazodone will be prescribed for patients with Dysthymia, Major Depression, and Bipolar Disorder.

Although nefazodone has mostly been studied for periods of admin- istration of up to 8-weeks, it is expected that patients with long-standing depressions will take the drug for longer periods of time. Data on about 250 patients who took nefazodone for 12 or more months, did not reveal any problems with administration for that length of time.

As yet, there is no data on the effectiveness of nefazodone when used to treat patients whose depressions were so severe as to make hospitalization necessary

4. What are the side-effects of nefazodone?

The side-effects that occurred significantly more commonly in people taking nefazodone as compared to placebo are:

Side effect % of nefazodone treated patients Dry mouth 25% Sleepiness/sedation 25% Nausea 22% Dizziness 17% Visual problems 16% Weakness 11% Lightheadedness 10% Confusion 7%: Orthostatic hypotension 5% Note: The Psychopharmacology Forum of InterPsych has received one report of inappropriate erections in a patient taking nefazodone. It is expected that priapism will be reported shortly as inappropriate erections and priapism are often associated.

5. Which side effects force people to stop taking nefazodone?

In the premarketing studies 16% of the 3496 depressed patients taking nefazodone discontinued the medication because of side- effects. The side effects, that the patients cited as the reason they dropped out that were mentioned at least twice as often for nefazodone as compared to placebo are:

Nausea	3.5%
Dizziness	1.9%
Insomnia	1.5%
Weakness	1.3%
Agitation	1.2%

6. Are there any special hazards for people with bipolar disorder?

As with other antidepressants, people with bipolar disorder who are not being treated with a mood regulator such as lithium, valproate, or carbamazepine, may be pushed into a manic episode when treated with nefazodone. In the pre- marketing studies, the rate of manic episodes in patients with bipolar disorder was 1.6%

7. Does nefazodone interact with other medications?

Nefazodone increases the blood level of Seldane and Hismanal to possibly life-threatening levels. These antihistamines should never be taken while taking nefazodone.

The blood levels of Halcion and Xanax are also increased by nefazodone. If Halcion is taken with nefazodone, its dose should be reduced by 75%. A reduction of 50% in the dose of Xanax is suggested if it is taken with nefazodone.

8. Does nefazodone interact with alcohol?

Although nefazodone has not been found to increase the impairment of cognitive or motor skills caused by alcohol, the manufacturer warns against drinking while taking nefazodone.

9. Is nefazodone safe for a woman who is pregnant, about to become pregnant, or nursing an infant?

There is no data to establish the safety of nefazodone for the fetus or nursing infant.

10. Is nefazodone a satisfactory antidepressant for children and adolescents?

Although here have been no published studies on the use of nefazodone for the treatment of children and adolescents with depression, it is expected that the drug will be prescribed for depressed children and adolescents.

11. Is nefazodone a satisfactory antidepressant for the elderly?

No special problems were encountered when nefazodone was studied in a group of 500 people over the age of 65 with depression. As with most drugs, when administered to the elderly, it is useful to start low and go slow.

12. How is treatment with nefazodone initiated?

Most psychiatrists start people with depression on 50 mg or 100 mg of nefazodone twice a day. At intervals of about one-week, the dose can be increased by 100 mg per day.

When nefazodone was first was released in the US the usual starting dose for adults was 100 mg twice a day. As many people found this dose to be too high, it has been replaced by a lower initial dose

When nefazodone is given to elderly patients the starting dose is usually 50 mg twice a day.

13. What is the usual final dose of nefazodone?

While doses up to 600 mg per day are approved by the FDA, some severely depressed patients have been treated with higher doses. Most depressed people respond to doses under 600 mg per day.

14. How rapidly may a person with depression feel some relief from taking nefazodone?

While most people taking nefazodone become aware of some lessening of depression within two to four weeks, there are some who experience relief within the first week and others who only experience relief after a many weeks of therapy.

15. Are there withdrawal effects if nefazodone is suddenly discontinued?

A withdrawal syndrome following the abrupt discontinuation of nefazodone has not been described. Because the half-life of nefazodone and its active metabolites are 18-hours or less, it is prudent to taper nefazodone than abruptly discontinue it.

16. Is nefazodone toxic if an overdose is taken?

Seven overdoses of nefazodone have been reported. The highest reported overdose was 11,200 mg. In some cases nefazodone was taken along with alcohol and/or other medications. All seven people who took an overdose recovered.

17. What precautions are necessary when switching between nefazodone and a MAO inhibitor?

When switching from an MAO inhibitor to nefazodone, there should be a 14-day interval between the discontinuation of the MAOI and the initiation of nefazodone therapy. When switching from nefazodone to an MAOI a 7-day interval is adequate, because of nefazodone's short half-life.

18. Might nefazodone be effective when a person has not responded to other antidepressants?

Although there is no data on this, it is expected that some individuals who have failed to be helped by other antidepressants will be helped by nefazodone.

19. What are the advantages of nefazodone?

The low incidence of sexual side effects and disturbed sleep are possible advantages of nefazodone.

20. Has nefazodone been available in other countries? What do psycho- pharmacologists from those countries think of the drug?

Nefazodone has been available in Canada for over six months. Most of the psychopharmacologists to whom I have spoken think that it is less effective than the SSRIs, and some have stopped writing prescriptions for it. Most of the nefazodone being prescribed in Canada is prescribed by nonpsychiatric physicians, not by psychiatrists.

21. What did the Medical letter conclude about nefazodone?

The Medical Letter [1995, 37 (946), 33-35] concluded its review of nefazodone with the words: "Available data are inadequate to determine how nefazodone compares with other antidepressants. Better established drugs are preferred."

22. Additions and corrections to:Dr Ivan Goldberg, MD

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