COMPOSITIONS FOR TREATING THE PREMENSTRUAL OR LATE LUTEAL PHASE SYNDROME AND METHODS FOR THEIR USE

COMPOSITIONS POUR LE TRAITEMENT DU SYNDROME PREMENSTRUEL OU DE LA PHASE LUTEINIQUE TARDIVE, ET LEUR MODE D'EMPLOI

English Abstract

Compositions useful in the treatment of
disturbances of appetite, disturbances of mood, or
both, associated with premenstrual syndrome; as well
as methods of use therefor. The compositions
include serotoninergic drugs, such as d-fenfluramine
and fluoxetine.

Claims

-16-
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. Use of one or more serotonin-mediated
neurotransmission enhancing drugs for the
manufacture of a medicament. for treating
disturbances of mood, disturbances of appetite,
or both, associated with premenstrual syndrome
in women.
2. Use according to Claim 1 wherein the one or
more drugs is selected from the group consisting
of drugs which enhance serotonin-mediated
neurotrans-mission by increasing the quantity
of serotonin present within brain synapses;
drugs which enhance serotonin-mediated
neuro-transmission by activating brain post-synaptic
serotonin receptors; and drugs which enhance
serotonin-mediated neurotransmission by
increasing the quantity of serotonin present
within brain synapses and by activating brain
post-synaptic serotonin receptors.
3. Use according to Claim 1 wherein the one or
more drugs is selected from the group
consisting of drugs which increase serotonin
production; drugs which cause serotonin
release; drugs which suppress serotonin
reuptake; drugs which block presynaptic
serotonin receptors; and drugs which block
monoamine oxidase.

-17-
4. Use according to Claim 1 wherein the one or
more drugs is selected from the group
consisting of tryptophan, lithium,
d-fenfluramine, d,l-fenfluramine,
chlorimi-pramine, cyanimipramine, fluoxetine, paroxetine,
fluvoxamine, citalopram, femoxetine,
cianopramine, ORG 6582, RU 25591, LM5008,
1S-4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565,
indalpine, CGP 6085/A, WY 25093, alaprociate,
zimelidine, trazodone, amitriptyline,
imipramine, trimipramine, doxepin, protriptyline,
nortriptyline, dibenzoxazepine, metergoline,
methysergide, cyproheptadine, deprenyl,
isocarboazide, phenelzine, tranylcypromine,
furazolidone, procarbazine, moclobemide,
brofaromine quipazine, m-CCP, MK212 and
CM57493.
5. Use of
a. a drug which increases serotonin levels
within brain synapses and a drug which causes
serotonin release;
b. a drug which increases serotonin levels
within brain synapses and a drug which blocks
serotonin reuptake;
c. a drug which increases serotonin levels
within brain synapses and a drug which blocks
synaptic inhibition of serotonin release;

-18-
d. a drug which blocks serotonin reuptake and
a drug which blocks presynaptic inhibition of
serotonin release;
e. a drug which causes serotonin release and
a drug which blocks serotonin reuptake; or
f. a drug which causes serotonin release and
a drug which blocks presynaptic inhibition of
serotonin release; all for the manufacture of a
medicament for treating disturbances of mood,
disturbances of appetite, or both, associated
with premenstrual syndrome, in a woman having
premenstrual syndrome.
6. Use of
a. a drug selected from the group consisting
of a monoamine oxidase inhibitor, lithium and
tryptophan and a drug selected from the group
consisting of d-fenfluramine, d,l-fenfluramine,
chlorimipramine, cyanimipramine, fluoxetine,
paroxetine, fluvoxamine, citalopram,
femoxetine, cianopramine, ORG 6582, RU 25591
and LM5008, 1S-4S-N-methyl.-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-1-
naphthylamine, DU 24565, indalpine, CGP 6085/A,
WY 25093, alaprociate, zimelidine, trazodone,
amitriptyline imipramine, trimipramine,
doxepin, protiptyline, nortiptyline and
dibenzoxazepine;
b. tryptophan and a drug selected from the
group consisting of: metergoline,

-19-
methysergide, cyproheptadine, deprenyl,
isocarboazide, phenelzine, tranylcypromine,
furazolidone, procarbazine, moclobemide and
brofaromine;
c. a drug selected from the group consisting
of fluoxetine, paroxetine, cyanimipramine,
fluvoxamine, citalopram, femoxetine, ciano-pramine,
ORG 6582, RU 25591, LM 5008, 1S-4S-N-
methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565,
indapline, CGP 6085/A, WY 25093, alaprociate,
zimelidine, trazodone, amitriptyline,
imipramine, trimipramine, doxepin, protriptyline,
nortriptyline, dibenzoxazepine, and a drug
selected from the group consisting of
metergoline, methysergide, and cyproheptadine; or
d. d-fenfluramine, d,l-fenfluramine or
chlorimipramine and a drug selected from the
group consisting of fluoxetine, fluvoxamine,
citalopram, femoxetine, paroxetine,
cianopramine, ORG 6582, RU 25591, LM5008,
1S-4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565,
indalpine, CGP 6085/A, WY 25093, alaprociate,
zimelidine, trazodone cyanimipramine,
amitriptyline, imipramine, trimipramine, doxepin,
protriptyline, and dibenzoxazepine; all for the
manufacture of a medicament for treating
disturbances of mood, disturbances of appetite,

-20-
or both, associated with premenstrual syndrome,
in a woman having premenstrual syndrome.
7. Use of at least two serotoninergic drugs for
the manufacture of a medicament for treating
disturbances of mood, disturbances of appetite,
or both, associated with premenstrual syndrome,
in women.
8. Use according to Claim 7 wherein the serotoninergic
drugs are selected from the group
consisting of tryptophan, lithium, d-fenfluramine
d,l-fenfluramine, chlorimipramine,
cyanimipramine, fluoxetine, paroxetine, fluvoxamine,
citalopram, femoxetine, cianopramine, ORG 6582,
RU 25591, LM5008, 1S-4S-N-methyl-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-1-
naphthylamine, DU 24565, indalpine, CGP 6085/A,
WY 25093, alaprociate, zimelidine, trazodone,
amitriptyline, imipramine, trimipramine,
doxepin, protriptyline, nor triptyline,
dibenzoxazepine, metergoline, methysergide,
cyproheptadine, quipazine, M-CCP, MK212,
CM57493, deprenyl, isocarboazide, phenelzine,
tranylcypromine, furazolidone, procarbazine,
moclobemide and brofaromine.
9. A composition for administration to women for
treating disturbances of mood, disturbances of
appetite, or bath, associated with premenstrual

-21-
syndrome, comprising at least two drugs which
enhance serotonin-mediated neurotransmission.
10. A composition of Claim 9 wherein the drugs are
selected from the group consisting of drugs
which enhance serotonin-mediated neurotransmisson
by increasing the quantity of serotonin
present within brain synapses; drugs which
enhance serotonin-mediated neurotransmission by
activating brain post-synaptic serotonin
receptors; and drugs which enhance
serotonin-mediated neurotransmission by increasing the
quantity of serotonin present within brain
synapses and by activating brain post-synaptic
serotonin receptors.
11. A composition of Claim 9 wherein the drugs are
selected from the group consisting of drugs
which increase serotonin production; drugs
which cause serotonin release; drugs which
suppress serotonin reuptake; drugs which block
presynaptic serotonin receptors; and drugs
which block monoamine oxidase.
2. A composition of Claim 9 wherein the drugs are
selected from the group consisting of
tryptophan, lithium, d-fenfluramine,
d,l-fenfluramine, chlorimipramine, cyanimipramine,
fluoxetine, paroxetine, fluvoxamine, citalopram,
femoxetine, cianopramine, ORG 6582, RU

-22-
25591, LM5008, 1S-4S-N-methyl-4-(3,4-dichloro-
phenyl)-1,2,3,4-tetrahydro-1-naphthylamine, DU
24565, indalpine, CGP 6085,/A, WY 25093,
alaprociate, zimelidine, trazodone, amitriptyline,
imipramine, trimipramine, doxepin, protriptyline,
nortriptyline, dibenzoxazepine, meter-goline,
methysergide, cyproheptadine, deprenyl,
isocarboazide, phenelzine, tranylcypromine,
furazolidone, procarbazine, moclobemide,
brofaromine quipazine, m-CCP, MK212 and
CM57493.
13. A composition for treating disturbances of
mood, disturbances of appetite, or both,
associated with premenstrual syndrome, in a
woman having premenstrual syndrome, comprising:
a. a drug which increases serotonin levels
within brain synapses and a drug which causes
serotonin release;
b. a drug which increases serotonin levels
within brain synapses and a drug which blocks
serotonin reuptake;
c. a drug which increases serotonin levels
within brain synapses and a drug which blocks
synaptic inhibition of serotonin release;
d. a drug which blocks serotonin reuptake and
a drug which blocks presynaptic inhibition of
serotonin release;
e. a drug which causes serotonin release and
a drug which blocks serotonin reuptake; or

-23-
f. a drug which causes serotonin release and
a drug which blocks presynaptic inhibition of
serotonin release.
14. A composition for treating disturbances of
mood, disturbances of appetite, or both,
associated with premenstrual syndrome, in a
woman having premenstrual :syndrome, comprising:
a. a drug selected from the group consisting
of a monoamine oxidase inhibitor, lithium and
tryptophan and a drug selected from the group
consisting of d-fenfluramine, d,l-fenfluramine,
chlorimipramine, cyanimipramine, fluoxetine,
paroxetine, fluvoxamine, citalopram,
femoxetine, cianopramine, ORG 6582, RU 25591
and LM5008, 1S-4S-N-methyl-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-1-
naphthylamine, DU 24565, indalpine, CGP 6085/A,
WY 25093, alaprociate, zimelidine, trazodone,
amitriptyline imipramine, trimipramine,
doxepin, protiptyline, nortiptyline and
dibenzoxazepine;
b. tryptophan and a drug selected from the
group consisting of: metergoline,
methysergide, cyproheptadine, deprenyl, isocarboazide,
azide, phenelzine, tranylcypromine, furazolidone,
procarbazine, moclobemide and
brofaromine;
c. a drug selected from the group consisting
of fluoxetine, paroxetine, cyanimipramine,

-24-
fluvoxamine, citalopram, femoxetine,
cianopramine, ORG 6582, RU 25591, LM 5008,
1S-4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565,
indapline, CGP 6085/A, WY 25093, alaprociate,
zimelidine, trazodone, amitriptyline,
imipramine, trimipramine, doxepin, protriptyline,
nortriptyline, dibenzoxazepine, and a drug
selected from the group consisting of
metergoline, methysergide, and cyproheptadine; or
d, d-fenfluramine, d,l-fenfluramine or
chlorimipramine and a drug selected from the
group consisting of fluoxetine, fluvoxamine,
citalopram, femoxetine, paroxetine,
cianopramine, ORG 6582, RU 25591, LM5008,
1S-4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565,
indalpine, CGP 6085/A, WY 25093, alaprociate,
zimelidine, trazodone cyanimipramine,
amitriptyline, imipramine, trimipramine, doxepin,
protriptyline, and dibenzoxazepine.
15. A composition for administration to women for
treating disturbances of mood, disturbances of
appetite, or both, associated with premenstrual
syndrome, comprising at least two
serotoninergic drugs.
16. A composition of Claim 15 wherein the
serotoninergic drugs are selected from the
group

-25-
consisting of tryptophan, lithium, d-fenfluramine
d,l-fenfluramine, chlorimipramine, cyanimipramine,
fluoxetine, paroxetine, fluvoxamine, citalopram,
femoxetine, cianopramine, ORG 6582, RU 25591, LM5008,
1S-4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-1-naphthylamine, DU 24565, indalpine, CGP
6085/A, WY 25093, alaprociate, zimelidine, trazodone,
amitriptyline, imipramine, trimipramine, doxepin,
protriptyline, nor triptyline, dibenzoxazepine,
metergoline, methysergide, cyproheptadine, quipazine,
M-CCP, MK212, CM57493, deprenyl, isocarboazide,
phenelzine, tranylcypromine, furazolidone,
procarbazine, moclobemide and brofaromine.
17. Use of a drug which selectively enhances
serotoninmediated neurotransmission for treating
disturbances of mood, disturbances of appetite, or
both, associated with premenstrual syndrome.

Description

-1-
TREATING PREMENSTRUAL OR LATE LUTEAL PHASE SYNDROME
Description
Background
Each month, for a few days prior to the onset
05 of menstruation, many millions of otherwise-healthy
American women develop symptoms of disturbed mood
and appetite that can be strikingly similar to those
reported by,patients with Seasonal Affective
Disorder (SAD), carbohydrate-craving obesity, or -the
non-anorexic variants of bulimia. This syndrome was
first termed "premenstrual tension" by R. T. Frank
in 1931 and' is a very common phenomenon. According .
to Guy Abraham of UCLA, "...of every ten patients to
walk into a,gynecologist's affice, three or four
will suffer from premenstrual tensipn...", and in
some the symptoms will be of such severity as to
include attempts at suicide. Current Progress in
Obstetrics and Gynecalog~, 3:5-39 (1980)
Initial descriptions of the Premenstrual
Syndrome (PMS) focused on its association with
"nervous tension", headache; and weight gain. The
weight gain observed was initially attributed to
excessive retention of salt and Taater, which does
indeed occur in some PMS patients: However,'it soon
became evident that it..was also a consequence of the
widespread tendency of PMS individuals to crave and
overconsume carbohydrates; particularly foods with a
sweet taste. PMS is also now referred to as late

-2-
luteal phase syndrome. D.N.S. III, Revised,
American Psychiatric Association (1987).
There have. been numerous suggestions made about
the etiology of PMS. For example, some hypothesized
05 that it was caused by a uterine toxin. Others
suggested its cause was overconsumption of sweets,
which was presumably followed by excessive insulin
secretion, hypoglycemia, and inadequate brain
glucose and resulted in the often observed depres-
lion and anxiety. It has also been postulated that
the behavioral symptoms result from the tissue edema
often observed and that the psychological changes
result from feelings of loss or the social complex-
ities generated by the discomforts of menstruation.
However, none of these theories has been
substantiated: PMS can persist after hysterectomy
and, hence, uterine toxins cannot be its cause; the
hyperinsulinism of PMS is not associated with low
blood glucose levels, and is probably the con-
sequence of a behavioral aberration (i.e., the
tendency of premenstrual women to choose high-
carbohydrate diets, which potentiate insulin secre-
tion)--rather than the cause; the moodwand ap-
petitive changes of PMS are poorly correlated with
the tissue swelling; and subhuman primates who are
presumably exempt from the psychodynamic or social
complexities of human life, also exhibit character-
istic behavioral changes premenstrually.
There have been many treatments suggested for
3p overcoming-or reducing the symptoms of PMS. These

-3-
include carbohydrate-free diets, vitamin supple-
ments, ovarian hormones, detoxifying agents, ir-
radiation of the ovaries and pituitary, and use of
diuretics. These approaches have all had limited
05 success, however, and a means of treating the mood
and appetite disturbances commonly experienced on a
recurring basis by a large number of women would be
of great benefit.
Summary of the Invention
The present invention is based on the discovery
that administration of an agent which selectively
enhances sero~tonin-mediated neurotransmission is
useful in the treatment of disturbances of mood
(e. g., depression, anxiety) and of appetite (e. g.,
carbohydrate craving, weight gain) commonly
associated with the premenstrual Syndrome (PMS).
Agents or drugs useful in enhancing serotonin-
~r,ediated neurotransmission, or the effect of
serotonin within the brain synapses, are ref2rr~d'to
as serotoninergic drugs and include 1) drugs which
act to increase the quantity of serotonin present
within the synapses and 2) drugs which act to
enhance the effects of serotonzn present with brain
syna~ses, generally by activating post-synaptic
serotonin receptors.
Drugs which act to increase the quantity of
serotonin with~.n brain synapses include those which
act to increase serotonin production, cause its
release, or suppress its reup~ake; those which block

-4-
presynaptic receptorst and those which block the
activity of monoamine oxidase. Related drugs, the
serotonin agonists, share with these drugs the
ability to enhance serotonin-mediated neuro-
05 transmission.
One or more of these serotoninergic drugs can
be administered to an individual in an amount
effective to reduce or prevent the mood and/or
appetite disturbances which would otherwise be
observed in the individual prior to onset of men-
struation. The drug (or drugs) can be administered,
for example, orally, by subcutaneous, or other
injection-, intravenously, parenterally, trans-
dermally; or rectally and can be given in various
forms, such as a powder, tablet, capsule, solution
or emulsion. In these various dorms, the sero-
toninergic drug or drugs can be combined with
additional substances, such as those needed to serve
as fillers, diluents, binders, flavorings or color-
ing agents or coating materials.
The length of time during which a serotonin-
ergic drug or drugs will be given varies on an
individual basis, but will generally begin 1 to 14
days prior to menstruation and may continue for
several days (e. g., 3 days) after onset. of men-
struation.
In one'embodiment of the present invention,
d-fenfluramine, or d,l-fenfluramine, which act to
release serotonin and inhibit its inactivation by
reuptake, is administered to an individual, prior to

-5-
the onset of her menstrual period, in a quantity
sufficient to ameliorate or prevent the mood dis-
turbances and/or to suppress the weight gain and the
increased appetite which otherwise would be evident.
05 In a further embodiment, fluoxetine, which acts to
inhibit reuptake of serotonin, is administered in a
quan~.ity sufficient to suppress these effects.
Administration of a serotoninergic drug accord-
ing to the method of the present invention is of
l0 great benefit to women who experience disturbances
of mood and/or appetite prinr,to onset of their
menstrual period because the drug or drugs admini-
stered act to alleviate or prevent such adverse
premenstrual~symptoms.
15 Detailed Description of the Invention
The present invention relates to compositions
useful in alleviating or preventing disturbances of
mood and/or appetite which occur prior to onset of
menstruation; as well as ~o methods of their use in
20 treating such disturbances. Such compositions
include one or more serotoninergic agents ordrugs
(i.a., one or more agents or drugs which selectively
enhance serotonin-mediated neurotransmission).
Serotoninergic drugs included in compositions
25of the present invention act to enhance serotonin-
mediated neurotransmission by increasing the,quan-
tity of serotonin present within brain synapses, by
activating post-synaptic serotonin receptors, or
both. One 'or more of such serotoninergic drugs may

be present in a composition of the present invention
and may be present alone (i.e., only serotoninergic
drug(s)) or in combination with other substances
which function in another capacity (e.g., as a
05 filler, binder, etc.), as described below.
The neurotransmitter serotonin (5-hydroxytryp-
tamine or 5-HT)Yis 3-(beta-aminoethyl)-5-hydroxyin-
dole. 2t stimulates or inhibits a variety of smooth
muscles and nerves and, among others, has effects on
secretion by both exocrine and endocrine glands and
on functioning of the respiratory, cardiovascular
and central nervous systems. Within the central
nervous system (CNS), serotonimserves as a neuro-
transmitter in the brain and spival cord, where it
l5 is the chemical transmitter of neurons referred to
as tryptaminergic or serotoninergia neurons. These
neurons are involved in control of sleep, appetite,
nutrient selection, blood pressure; mood, endocrine
secretion, aggressivity and numerous other sensitiv-
ities to external stimuli.
Numerous substances or drubs have been shown to
affect serotonin activity. For example, endogenous
serotonin levels can be increased by administering
_ tryptophan, the precursor of sero~t~nin: Fernstrom,
~'~' and Wurtman; R.J., Science, 173:1~I9-152 (1971).
It has now been discovered that adr~tinistration
of an agent or a drug which selectively enhances
serotonin-mediated neurotransmission suppresses the
weight gain and the increased appetite; part2cularly
for carbohydrates, as well as decreasing the

depression and other negative mood states, which
many women experience prior to onset of
menstruation. An agent or a drug which selectively
enhances serotoninmediated neurotransmission has
05 been shown to be particularly effective in having
these effects.
Administration of a drug (or drugs) which
enhances serotonin-mediated neurotransmission by
increasing the quantity of serotonin caithin brain
synapses or by activating post-synaptic serotonin .
receptors results in amelioration or elimination of
these commonly-experienced adverse effects.
For example, it has been shoran that adminis-
tration of d-fenfluramine (an anorectic drug) to
women prior to onset of their menstrual period
results in a decrease in depression and other
negative mood states.(e.g., tension, anger, con-
fusion, irritability), as assessed using recogni2ed
tests (see Example 1) and,in lower consumption of
high-carbohydrate foods than observed when they were
not given the drug (i:.a.; were given a placebo). A
d-fenfluramine analogue, d,'1-fenfluramine, has the
same effect.
Similarly, administration of fluoxetine, which
suppresses reuptake of serotonin and, thus, in-
creases the quantity of-serotonin available at brain
synapses, has been shown to ameliorate the depressed
moods and carbohydrate craving othercaise seen in
subjects prior to their menstrual period. In
addition, it was effective in suppressing the weight

_g_
gain usually associated with the premenstrual phase
in the subjects studied.
In place of, ar in addition to, d-fenfluramine,
d,l-fenfluramine and fluaxetine, other drugs which
05 have the effect of enhancing serotonin-mediated
neurotransmission can be administered. For example,
the quantity of serotonin present at a given time or
over a period of time can be enhanced by admini-
stering a drug which has any o.f the follo:aing
effects:
1. increases serotonin production (e. g.,
tryptophan lithium);
2. causes serotonin release, e.g.,
d-fenfluramine, d,l-fenfluramine
chlorimipramine (also known as
~clomipromine);
3. suppresses serotonin reuptake; e.g.,
fluoxetine, fluvoxamine, citalopram,
femoxetine, cianopramine, ORG 6582,
RU 25591, LM5008, sertraline or
1S-4S-N-methyl-4-(3,4 dichlorophenyl)-
1,2,3,4,-tetrahydro-1-naphthylamine,
paroxetine, DU 24565, indalpzne,
CGP 6085/A, wY 25093, alaprociate,
zimelidine, cyanimipramine; desyrel
(trazodone hydrochloride) ar trazodone
amitriptyline-or elavil (amitriptyline
hydrochloride), imipramine or tofranil
(imipramine hydrochloride); trimipramine
or surmontil, doxepin or sinequan (doaepin

-9-
hydrochloride), protriptyline or vivactil
(protriptyline hydrochloride), nor-
triptyline or aventyl (nortriptyline
hydrochloride), dibenzoxazepine (also
05 known as amoxapine or asendin);
4. blocks .presynaptic receptors, e.g.,
metergoline, methysergide, cyproheptadine
(which can also block postsynaptic
receptors); or
5~ blocks monoamine oxidase, e.g., deprenyl,
marplan or isocarboazide, nardil
(phenelzine sulfate) or phenelzine,
parnate (tranylcypromine sulfate) or
tranylcypromine, furazalidone,
procarbazine, moclobemide or aurorix,
brofaromine).
The chemical names of DU 24565, CGP 6085/A, and ~dY
25093 are, respectively, 6-nitroquipazine, 4-(5,6-'
dimethyl-2-benzofuranyl) pi.peridine HCl,.and 1-[1-
([idol-3-yl]methyl) piperid-4-yl]-3-benzoylurea,
respectively. Classen; K., et al.; NaunYn
Schmiedeberqs Arch. Pharmacol., 326(3): 198°202
(1984); Kulakowski, E:C. et al., Clin. Exp. Hy~=
tens. [A); 7(4): 585-604 (1985): Di9gorY: G.L. et
al., Areh. rnt: Pharacodyn. Ther., 248(1): 86-104
(1980) .
alternatively, serotonin-mediated neurotrans-
mission can be enhanced by administering a drug,
such as quipazine, m-CPP, MK212 or CP~I57493, which
activates post~synaptic serotonin receptors:

-10-
In either case, such agents or drugs can be
administered individually or in combination. The
quantity of an individual drug to be administered
will be determined on an individual basis and will
05 be .based at least in part on consideration of the
individual's size., the severity of symptoms to be
treated and the result sought.
The agents) or drugs) can be administered
orally, by subcutaneous or other injection,
l0 intravenously, parenterally, transdermally, or
rectally. The form in which the drug caill be
administered (e. g., powder, tablet, capsule,
solution, emulsion) will depend on the route by,
which it is administered.
15 The composition of the present invention can
optionally include, in addition to the sero-
toninergic drug,or drugs, other components. The
components included in a particular composition are
determined primarily by the manner in which the '
20 composition is to be administered: For example, a
composition to be administered orally in tablet form
can include, in addition to ome or more sero-
toninergic drugs, a filler (e. g.lactose); a binder
(e. g:, carboxymethyl-cellulose, gum arabic; gel-
25 atinj, an adjuvant, a flavoring agent, a coloring
agent anda coating material (e.g, wax or'a pla -
icizer): A composition to be administered or.allx,
but in liquid form;' can include':one or more sero-
toninergic drugs, and, optionally; an emulsifying
agent, a flavoring anent and/or a'coloring agent.

-11-
In general, the composition of tk~e present
invention is administered to an individual prior to
the expected onset of her menstrual period. The
length of time during which the drug (or drugs) is
05 administered varies on an individual basis, but in
general will be from l to 14 days prior to onset of
menstruation and might continue (e.g.,,3 days) after
its onset. The dose of serotoninergic drug admini-
stered daily will also vary on an individual basis
,10 and to some extent will be determined by the type
and severity of symptoms to be treated. If the
serotoninergic drug administered is d-fenfluramine
or d;l-fenfluramine, a dose of from approximately 7
mg/day to approximately 60 mg/day is administered.
15 ~s described in Example I, a dose of 30 mg/day.of
d-fenfluramine has been shown to lie effective ih .
decreasing depression and other negative mood states
in 'subjects. In the case of fluoxetine admini-
stration; a dose of from approximately 5 mg/day to
20 apps°ximately 120 mg/day is administered. ~s
described in Example ILa dose of 40 mg/day, given
on alternate days; has been shown to be effective in
ameliorating the depressed mood and carbohydrate
craving reported by ubjects not given fluoxetine.
25 It was also effective in suppressing the ~neight gain
usually experienced. (See Example II): The sero-
toninergic drug can be administered in a single close
or in a number of smaller doses over a period oz
time; for example; the 30 mg/day dose of d-

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fenfluramine can be administered in a series of
smaller doses over the course of the day.
The present invention will now be illustrated
by the following examples, which are not to be taken
OS as limiting in any way.
Example I Assessment of effect of d-fenfluramine
on Mood and Appetite Disturbances Associated with
pMS
Seventeen women received either d-fenfluramine
(30 mg/day) or a placebo for l5 days prior to their
expected menstrual period. Each subject partici-
pated in 6 randomized test'periods; in 3 of the test
periods, each was given d-fenfluramine and in the
other 3 test periods, was given a placebo. Mood was
assessed 1-3 days before the onset of menses, using -
the Hamilton Depression Scale and the PMS Symptom
Rating Scale, for mood and appetite symptoms.
Hamilton, N., Journal of Neurosurgery and
Psychiatry, 23;56-62 (1960); Steiner, M: et al.,
ACta Psychiatrica Scandinavia; 62:177-190 (1980).
Food intake was measured through the use of self-
reports (when subjects were aut-patients), and
directly (while subjects were inpatients), during
one drug and'one placebo period; subjects also were
weighed. As shown in Table 1; 15 of the 17 patients
reported a decrease in depression and other negative
mood states (such as°tensionanger, confusion,,and.
irritability) following drug treatment, but not
following placebo treatment.

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TABLE 1
Effect of D-fenfluramine on PMS
Symptoms of Mood
(Hamilton Depression Scale*)
p5 Patient No. Placebo D-fenfluramine
1 7 1
2 11 2
3 12 . 2
4 10 14
5 12 20
14 t 6
14 9
g 17 10
9 17 9 '
10 la 15
11 18 p
12 21 4
13 22 S
14 23 6
15 26 15
16 27 12
17 29 1
Mean Score: 18 8
*Higher scpres on these tests indicate greater
severity of symptoms. .
Lt was found that consumption of high carbo-
hydrate foods increased for patients taking the

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placebo, but not for patients treated caith d-
fenfluramine. Appetite and mood (meausured by the
"PMS Symptoms Checklist" described by Steiner et
al., ibid.) were assessed 1-3 days before the onset
0~ of menses. The results are shown in Table 2, cahich
reflect mean scores for eleven of the seventeen
women tested:
TABLE 2
Effect of D-fenfluramine on PMS Svmptoms of
Mood and Appetite
Mood Scores Placebo D-fenfluramine
mean score
' CMS Sympt. Checklist
Mood 3a 0
Appetite a 1
Food Intake
Calories 3300 1660
CHO(g)* 232, 130
Protein ~a d5
(Higher scores on these tes s indicate, greater
severity,
of symptoms)
*CHO = carbohydrates

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Example II Assessment of Effect of Fluoxetine on
Mood and Appetite Disturbance Associated ~~~ith FDIS
Fluoxetine (40 mg/day) was given on alternate
days,' starting two caeeks prior to the expected onset
05 of a subject's menstrual period. Amelioration of
the depressed mood and the carbohydrate cravings was
reported (using the PPQS Symptom Rating Scale): ~~Iean
scores for subjects taking the placebo were 36 and
(for mood and appetite, respectively), and 9 and
10 3 for subjects taking fluoxetine. Fluoxetine also
suppressed the usual weight gain associated with the
premenstrual phase in these particular subjects.
Eauivalents
Those skilled in the art will recognize, or be
able to ascertain using no more than routine
experimentation, many equivalents to the specific
embodiments of the invention described specifically
herein. Such equivalents are intended to be
encompassed in the scope of the following claims.