Earlier this month there was a request for information on the antidepressant
known as Serzone.  Following are three articles on this drug.
 
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** INFORMATION ON SERZONE  -  ARTICLE 1 OF 3 **
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 NEW ANTIDEPRESSANT UNVEILED
 
WASHINGTON (AP) -- A new type of anti depressant was unveiled Thursday by
Bristol-Myers Squibb with claims that it combines the best benefits of Prozac
with an additional boost, fewer side effects -- and a lower price.
 
Serzone, already approved by the Food and Drug Administration, is chemically
different from other depression medications.
 
Serzone combines the main mechanisms of the two major classes of
antidepressants with fewer of at least two troublesome side effects --
insomnia and sexual dysfunction, Bristol-Myers said.
 
I would suspect it will take off relatively quickly and will be found to be
effective for a goodly percentage of patients,'' said Dr.Sheldon Preskorn of
the University of Kansas, who tested the drug.
 
Depression is the nation's most prevalent mental health problem, afflicting
about 15 million Americans at some point in their lives and costing $44
billion a year in medical bills and lost productivity. Americans spend about
$3 billion a year on drugs to battle it.
 
The world's leading antidepressant is Prozac, the first of a class of drugs
called selective serotonin reuptake inhibitors, or SSRIs, that boost the
brain levels of serotonin, which regulates moods. An older class of
antidepressant, called tricyclics, blocks serotonin receptors in the brain.
 
Serzone is the first drug to do both, said Dr.Jan Fawcett, psychiatry
chairman at Rush Presbyterian-St. Luke's Medical Center in Chicago.  It
specifically blocks one of the most important depression receptors, one
called 5HT2, he said.
 
Clinical trials show Serzone is as effective at alleviating depression as
other drugs.
 
But Serzone shows little sign of sleep disturbance, while as many as one in
five patients taking an SSRI drug also are prescribed a sleepaid, Preskorn
said.
 
And the labels of the three SSRI drugs say the incidence of sexual problems,
ranging from abnormal ejaculation to decreased libido, vary from 1.9 percent
to 15 percent. Some studies indicate the problems may really hit up to 40
percent of patients, Bristol-Myers argued. The incidence of sexual problems
among Serzone patients is 1.5 percent, the company said.
 
To boost Serzone, Bristol-Myers is undercutting competitors' prices. Serzone
will cost $1.66 a day wholesale regardless of whether the patient needs 300
milligrams or 600, said Samuel Barker, president of U.S. pharmaceuticals for
Bristol-Myers.
 
Prozac, in contrast, costs $2.165 a day wholesale, and most manufacturers
increase the price for higher doses of medicine, Barker noted.
 
Prozac maker Eli Lilly & Co. didn't immediately comment on the new
competition.
 
And while Bristol-Myers denied that it was trying to lure away Prozac users
in favor of newly diagnosed patients, it does hope to make Serzone the drug
of choice for insurance companies.
 
"Part of our pricing issue here is getting the attention of managed care
early ... because one things they do focus on is cost,'' Barker said.
 
One drug analyst said Bristol-Myers was hyping Serzone too much. Ira Loss of
NatWest Securities said patients on successful drugs will be reluctant to
switch despite side effects, particularly since other antidepressants are
taken once a day while Serzone is a twice-a-day drug.
 
"This is going to be a tough one for this drug,'' Loss said. ``I wouldn't
expect it would bea first-line therapy.''
 
But Barker noted that only about half of depression patients now get
medication. ``With Serzone, competitively priced, we will help this market
grow,'' he said. ``We believe Serzone will be a significant drug for us.''
 
 Copied from the PRODIGY(R) service 01/05/95 16:48
 
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** INFORMATION ON SERZONE - ARTICLE 2 OF 3 **
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 MESSAGE FROM  IVAN GOLDBERG, M.D.
 
1. What is nefazodone (Serzone)?
 
2. How does nefazodone differ from other antidepressants?
 
3. What kinds of depression can be treated with nefazodone?
 
4. What are the side-effects of nefazodone?
 
5. Which side effects force people to stop taking nefazodone?
 
6. Are there any special hazards for people with bipolar disorder?
 
7. Does nefazodone interact with other medications?
 
8. Does nefazodone interact with alcohol?
 
9. Is nefazodone safe for a woman who is pregnant, about to become pregnant,
or nursing an infant?
 
10. Is nefazodone a satisfactory antidepressant for children and
 adolescents?
 
11. Is nefazodone a satisfactory antidepressant for the elderly?
 
12. How is treatment with nefazodone initiated?
 
13. What is the usual final dose of nefazodone?
 
14. How long does it take nefazodone to relieve depression.
 
15. Are there withdrawal effects if nefazodone is suddenly discontinued?
 
16. Is nefazodone toxic if an overdose is taken?
 
17. What precautions are necessary when switching between nefazodone and an
MAO inhibitor?
 
18. What does nefazodone cost?
 
19. Might nefazodone be effective when a person has not responded to other
antidepressants?
 
20. What are the advantages of nefazodone?
 
21. Has nefazodone been available in other countries? What do
psycho-pharmacologists from               those countries think of the drug?
 
22. Additions and corrections.
 
-------------------
 
 1. What is nefazodone (Serzone)?
 
Nefazodone (Serzone) is a new antidepressant with a chemical structure that
is somewhat similar to that of psenylpiperazine antidepressant, trazodone
(Desyrel). 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 administration 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%
 
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 (Depakote), or
carbamazepine (Tegretol), 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, SeldaneD, and Hismanal to
possibly life threatening levels. These antihistamines should never be taken
while taking nefazodone. Claritin and ClaritanD can be substituted, as they
are very similar to Seldane and SeldaneD, although they are chemically
different, and therefore safe to take with Serzone.
 
The blood levels of Halcion and Xanax are also increased by nefazodone. If
Xanax is taken with nefazodone, daily dosage must be decreased by at least
50%, although it is preferable to stop taking Xanax and substitute that with
a different minor tranquilizer, such as Valium or Ativan. If Halcion is taken
with nefazodone, its dose should be reduced by 75%.
 
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 any alcohol 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 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. A few patients of all ages find that starting
does of 50 mg. twice a day is too strong, and in those situations it is
appropriate to begin dosage at 25 mg. twice a day for the first week. When
nefazodone is given to elderly patients the starting dose is usually 50 mg
twice a day.
 
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. Most patients require between 300 mg.
per day and 600 mg. per day. As with most medications, the lowest dosage that
provides effective treatment is the appropriate dosage
 
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 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 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 o nefazodone's short half-life.nefazodone's
short half-life.
 
18. What does nefazodone cost?
 
Nefazodone is supplied in tablets ranging from 100 mg to 250 mg in strength.
The 100 mg tablets cost pharmacies nearly as much as the 250 mg tablets. It
is expected that all strengths of nefazodone will be sold for between $0.80
and $1.25 per tablet.
 
19. 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.
 
20. What are the advantages of nefazodone?
 
The low incidence of sexual side effects and disturbed sleep are possible
advantages of nefazodone.
 
21. 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. Psychiatrists in Canada, however, are
prescribing nefazodone to many patients, and their patients report good to
excellent results with nefazodone. .
 
20. Additions and corrections to:.
 
Ivan Goldberg, MD
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** INFORMATION ON SERZONE - - ARTICLE 3 OF 3 **
 
SERZONE INFO
 
One of the best information available from a neutral source is from The
Medical Letter on Drugs and Therapeutics, which is available in most medical
libraries and hospital libraries.  In Volume 37 (Issue 946) for April 14,
1995 under the title of Nafazodone for Depression, Serzone is fully
discussed.
 
Serzone inhibits neuronal reuptake of serotonin (5-HT) and norepinephrine and
also acts as an antagonist atalpha1-adrenergic and 5-HT2 receptors.  It is
rapidly  and completely absorbed after oral administration, reaching peak
plasma concentrations in one to three hours.  Food delays absorbtion and
decreases bioavailability by about 20%.
 
Serzone undergoes extensive first-pass metabolism in the liver, resulting in
three active metabolites, one of which is also a major metabolite of
trazodone (Desyrel) and acts as an agonist at some seroitonergic receptors.
 Half life of Serzone is 2-4 hours, but the active metabolites last longer.
 Accumulation of the drug occurs with multiple doses, but plasma levels of
Serzone and its active metabolites reach a steady state in 4-5 days.
 
Clearance may decrease in elderly and those with liver dysfunction.  Clinical
trials showed effectiveness similar to imipramine (Tofranil).  There have
been no clinical trials comparing Serzone with Prozac, Zoloft, Paxil,
Desyrel, Welbutrin, or Effexor.  Adverse effects were slightly less than
imipramine with headache, sleepiness, dry mouth, nausea, dizziness and
blurred vision reported.
 
Serzone inhibits the cytochrome P450 3A4 isoenzyme and thus could have an
interaction with such drugs as Halcion, Xanax, Seldane, and Hismanal.
 
Recommended dosage starts at 100 mg twice daily increasing gradually at
intervals of no less than one week to 150-300 mg twice daily.  In patients
past 65 the initial dose is 50 mg twice daily and effective therapeutic range
is 50-200 mg twice daily.
 
The conclusion of the Medical Letter article is that available data is
inadequate to determine how Serzone compares with other antidepressants at
this time.  However, both Bristol Myers/Squibb and the FDA anticipaate that
Serzone will prove to be just as successful for treatment of depression as
are the well established SSRIs, including the best-selling  three, Prozac,
Zoloft, and Paxil.
 
** END **
 
Regards,
Alan Bonander
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