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d-Fenfluramine Suppresses the IncreasedCalorie and Carbohydrate Intakes andImproves the Mood of Women WithPremenstrual Depression

AMNON A. BRZEZINSKI,MD, JUDITHJ. WURTMAN, PhD,

RICHARDJ. WURTMAN,MD, RAY GLEASON, PhD,JANINE GREENFIELD,BS, AND TONY NADER, MD, PhD

The ability of d-fenfiuramine, a drug th.1 releues br.inKTCItoninand blocks its reuptake, to relieve prmlenitnaldtpression and excessive calorie and carbohydrate intaknwu eumined in 17 women with premenstrual 5Y"drome.Subjects receind d-fenfturamine (15 mg twice daily) orplKebo, in random order, during the lutul phUft of in:menstrual cycles; ie, for thrte control and three treatmentcyeln uch. Behavior was assfS!~edwith the Hamilton Rat.ing Scale for Depression and ib Addendum, and intakes ofcalorin md nutrienb were measured by allowing IUbjKtSunJimite-d access to isocaloric muland snack foods rich in

carbohydrates or protein. Pre.treatment follicular IC'Ornusing the tUmilton lUting Scale for Dtprnsion and itsAddendum were 2.0 :: 0.5 and 0.5 :: 0.5 (mun :: SEM),ftipectiftly; corT'fsponding lutul KOrn Wert n.2 :: 0.8 and10.2 :: 0.6 (P < .00011.Lutul phue intakn of kilocalories,carbohydrates, and fats wen also increased above foUiC'Ularlntll CP < .01). d-Fenfluramine decreased pmnmitnWHamilton Rating Scale for Deprel$ion and Addendum8COrftby 62.. (P < .001) and 60'1 (P < .0011,respectively;placebo reducN them by only 28'1 CP< .02)and 30.. (P <.em. d-ftnfIuramine also fully auppl'flHd the premenstrualriM in kilocalorie, carbohydrate, and fat intakes (P < .01).(Obskt GY'I~aJl 76;296, 2990)

Pnmmstrual drome (PMS), or the "late luteal.p ase dysphoric disor er, IS ractmzed by . clus-'ter of affective, appetitive, and somatic compla.ints tNtrecur each month during the late luteal phase of themmstnW cycle, In a prrnous study, direct measun-

From~ ~rtmmt t1fBroin.rui Ccgnitiw 5cimas. MassAdllI.Stftslrutitlltt t1fTtC"nol"fY' CJmrllridgt.M4sSll,InIStttS.

SlIpporfed m pm by . groFttfrOffltilt CAttr ft1rBnri1I5citrtas andMtUboliPrt Charitllblt Tnm.

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ments of food intake and mood state made during thefollicular and late luteal phases of the cyclerevealed asi!;T\ificantpremenstrual increa~ in caloricintake fromcarbohydrate-rich foods associated with abnormal de-pression scores, decreased work effidency, socialwith-drawal. and fatigue.2

A similar association of affective and appetitivesymptoms has been observed in patients with "season-al affective disorder") and in many carbohydrate-craving obese people.. In both conditions, as in PMS,patients typically complain of mood disturbances.. di-minished interest in previously enjoyed acti\ities. de-creased energy and increased fatigue, reduced produc-tivity, social withdrawal. and an increa~d appetite forcarbohydrate-rich foods leading to weight gain.) LikePMS, these disorders also recur cyclicaUy;patientsexperience seasonal affective disorder each faUas thedays grow shorter, and the syndrome disappearsspontaneously each spring as the days grow longer~Excessivecraving for carbohydntt-rich foods and theirconsumption among obese individuals usually occursonly in the late afternoon or during the evening.4Individuals suffering from seasonal affective disorderor carbohydrat~ving obesity are also similar to thosewith PMS in reporting improvement in their mood aftercarbohydrate consumption.U Because eating carbohy-drate-rich, protm-poor foods an enhance brain serot~nin synthesis,' this effect suggests an involvement ofbrain serotonin in the symptoms of these conditions.

The possible involvement of serotonin in the dis-tu~ food intake and mood of patients with seasonalaffective disorder and carbohydrat~\ing obesityhas also been supported by studies using d-fenflu-

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_..~._---. - .- -- -.----

..

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ramine. a drug that selectively enhances serotonin-

mediated neurotransmission by releasing the neUro-

transmitter and blocking its reuptake.'. This drug

effectively relieved both the depressive and appetitive

symptoms ofpatientssufferingfro!1'seasonalaffectivedisorder during the annual3-month period of severestsymptoms3; it also d.iminished kilocalorie intake andbody weight among carbohydrate-craving obese. sub-jects.. - .

We examined the possibility that d-fenfluraminemight also relieve the affective and appetitive symp-toms of PMS. particularlydepression and excessivecarbohydrateintake. .

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Materials and Methods

Subjects were recruited through newspaper. radio.and television advertisements directed toward womenwhosufferedfromseverePMS.Potential subjects wereasked to complete and return a health history ques-tionnaire and a P!v1Ssymptomatology report.9 whichasked them to assess changes in their mood. appetite.sleep. and somatic symptoms during the follicularandluteal stages of their menstrual cycle. To qualify aseligible subjects. these women had to indicate signifi-cant changes in mood and appetite between the follic-ular and late luteal phases and also to state that thesesymptoms had occurred monthly during the precedingyear. Eligible subjects were then screened as outpa-tients at the Oinical Research Center during the lateluteal phase of their menstrual cycle. At that time. theywere interviewed about their premenstrual symptom-atology and underwent a physical examination by anurse and g)'necologist. Becausewe were interested inselecting subjects whose major complaints were de-pression and increased appetite for carbohydrat~richfoods. we used tests for screening (and subsequentlyduring the treatment) that specifically as~sed thesebehaviors. The Hamilton lUting Scale for Depres-sion.to which is administered by trained interviewers.was used to quantify the depressive symptoms of

PMS. According to this test. scores above 15 areconsidered diagnostic of clinical depression.1o To as-sess changes in appetite. carbohydrate craving, fa-

tigue. and sodability. a four-item Addendum wasused. This test. which is also administered by aninterviewer. was developed by Rosenthal et ai' tomeasure the symptoms of atypical depression. Bothtests ask how the individual has been feeling for thepast week; answers are rated on a three- or four-pointscale. Urine and blood samples were obtained forclinicalmeasurements(eg.completebloodcount. thy-roid indices. blood chemistry 20 profile. pregnancytest). and an electrocardiogram was performed on

VOL. 76. NO. %. AUCUST 1990

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subjects 40 years old or older. Subjects were alsoweighed and interviewed ~. a clinical nutritionist toexclude those with eating disorders. Subjects wereadmitted to the study if their Hamilton lUting Scalefor

Depression was 20 or hig.1.:erand their combinedHamilton Rating Scale for De?ression and Addendumscore was 30 or higher during the late luteal phase ofthe cycle. All subjects exhibited regular menstrualcycles ranging in periodici~' from 26 to 35 days. Aninformed consent form apprm-ed by the Massachusetts

Institute of Technology Committee on the Use ofHumans as Experimental Subjects and by the OinicalResearch Center (CRq Advisory Committee wassigned before participation in any aspect of the studies.

Before initiation of trutment. the subjects UlIder-went a baseline evaluation of menstrual-cyc1e-associated changes in mood and food intake whileinpatients at the CRC in~tient facility. During two48-houradmissions (one between'days 4-7 of their

cycle and the other 3--5 da)"5 before the expected onsetof menses). their moods were evaluated by psycho-metric testing using the Hamilton Rating Sc.aJe forDepression and its Addendum. Food intake was mea-sured concurrently. Subjects were restricted to themeals and snacks pro..-ided by the CRe. Each mealprovided unlimited quanti:ies of three high-carbohy-drate (13--15g carbohydrate) and three high-protein(13-15 g protein) foods. The high-carbohydrate foodscontained 1-2 g of protein.an amount known tobeinsufficient to block the a:ility of the carbohydrate toelevate brain tryptopha~ i::d serotonin levels.11.12Thesix food items were isoca.:.)ricand iso-fat. \-\'hen nec-essary. high-fat ingredien:s such as butter. cream. ormayonnaise were added :0 increase their caloric valueand fat content. Each food item contained about 12~

130kcal. The foods were ,,'eighed before being served.and any remaining food ,,~ reweighed after the mealwas completed.

At all other times. the subjects had continuousaccess to eight snacks stored in a refrigerated vendingmachine. Four of the snacks were high-protein (11-12g) and four were high-arbohydrate (12-13 g). Thecarbohydratesnacks cor::ainedless than 1% protein.

All the snacks contained 105-110 Itcal and ~7 g of fat

andrepresented foods tr.at ue available commercially(cookies. candy) or are chen eaten as snacks at home(cheese. cold cuts). The "'ending machine was inter-faced to a miaocompu:n programmed to allow thesubject to obtain any of the eight snacks after typing apersonal access code on ~ attached kevboard. Thefoods presented at meu and snacks re~ained con-stant throughout the bseline and treatment compo-nents of the study.

Blood samples were obtained between days 4-7 of

their cycle and 3-5 days before the expected onset ofmenses to determine progesterone levels for verifica-tion of ovulation.

Subjects were admitted to the clinical trial aftercompletion of the baselineevaluation. Administrationof the drug or placebo over six menstrual cycles fol-lowed a double-blind, multiple-crossoverdesign. Eachsubject received d-fenlluramine (15 mg orally twicedaily) or its placebo during the entire luteal phase forthree cycles. Approximately hali the subjects weretreated with placebo during the first test cycle. Treat-ment was started on the 14th day of each month anddiscontinued 2 days after the onset of menses. Thus,each subject underwent I 12-14-day washout periodbefore starting the subsequent treatment. In man, thehali-life of d-fenlluramine is 18.3:: 1.1hours (mean ::SE~), with peak plasma levels occurring 3-5 hoursafter a single dose.8 Plasma levels of d-fenfluraminereach a steady-state in 4-5days and thus would be ableto exert a constant therapeutic effect by day 19-20 ofthe menstrual cycle in our study design.

Monthly assessments oi depressive and appetitivesymptoms were made byha\ing subjects rerum to theCRC outpatient clinic 2-3 days before the expectedonset of menses. At tNt time, an interviewer blindedto the treatment prognm administered the HamiltonRating Scale for Depression and its Addendum. Byhaving the subjects evaluated at the CRe. we wereable to assess mood and appetite changes under iden-tica!and controlled clirUcaJconditions each month. Thesubjects underwent a final outpatient evaluation ofmood and appetite during the follicular stage of thecycle after conclusion oi the clinica!trial.

Inpatient assessments of food intake and mood weredone twice during the study. Subjectswere readmittedto the CRC for a 48-hour period at the end of one drug~d one placebo treatment period. (A non-blindedcollaborator ensured that one pacebo and one treat-ment period would be represented.)

Two subjects were dI pon:!from the study: onebeause of prepuncy occurringduring a placebo trialand the other for failure to comply with the studyprotocol. One subject was f'Valuatedfor only two drugand two placebo months because back problems pre-vented her from puticipaling in the full study.

~ An analysis of varia~ with repeated measur~ was .performed to compare the consistency of the resultswithin uch treabnent period and the results of thedrug and placebo treatment periods with each other.

Rtsults

Sixteen subjects complewd the full clinicaltrial and onesubject completed" months of the trial. Their average

298 Brzainski d at d-FmfIuramintImprOVtSPMS

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T~bl~ 1. Prof~ oi Su~

N

A~(~T)H~lght (em)W~lght (kg!<:I:of Id~~J~.: ""p\gh~Prog~t~f r.~~.:.)

folli~rLutf~1

Ii33 :: 1.7

164 :: 2.165 :: 2.4

105:: 4.5

04 :: 0.06;.2:: 1.75

age was 33 ~ 1.7 years. and aU subjects were within105~ of ideal body weight (Table 1). Baseline measure-ments of plasma progesterone carried out 3-5 days .

before menstruation indicated that most of the subjects'had ovulatory cycles;however, two women had lutealprogesterone levels of 2 nglml or lower. suggesting~novuJation. All subjects exhibited regular menstrualcycles. ranging in perioclicity from 26 to 35 days.

All subjects exhibited significantly elevated depres-sion scores during the late lute.a.1baseline measure-ment period using both the Hamilton Rating Scale forDepression and its Addendum as test instruments(Table 2). The late luteal Hamilton Rating Scale forDepression and Addendum scores (mean :: SEM)were 21.2 = 0.6 and 10.2 ~ 0.6, respectively; follicularphase Hamilton Rating Sale for Depression and Ad-dendum scores were 2.0 :: 0.5 and 0.5 :: 0.5, respec-tively. Scoreson the Hamilton Rating Scale for Depres-sion and Addendum subscales that assess symptomscharacteris::icof PMS were also changed significantlyduring the la~elu!eal test period; work efficiency de-creased (P < .QX)}) J-.Jeanxjety, fatigue, social v.ith-drawal. genenl appetite, and carbohydrate craving aUincreased (p < .000l) (Table 2).

Kilocalo~. arbohydrate. and fat intakes increasedsignificantly during the late luteal phase (Table 3). Lateluteal phase JQ]oc.aJorieintake from meals increasedfrom follicular Je.\'elsby about 300 kcal (P < .01), andintak~ from snacks increased from follicular levels by

T~bl~ 1. PmnenstnW Symptom Profile

Fo1licu1&r Lut~&I

HAmilton RAt::\1 SeW for

~presIIO!IAdd~ndwn

Subscales

worit c:f5oencyf.tiprSoci.a.I."'i:..~.~-a..-a1AnxXtyA~Ca.~hy:..-a~ o'"::-,~

2.0 :: 0.5 21.2 : 0.8"

0.5 : 0.5 10.2 : 0.6.

0.0 : 0.00.0 :: 0.00.0 : 0.0

0.12: 0.10.0 : 0.00.1 :: 0.1

2.9 : 0.1.2.6:0.2"2.5 : 0.2"2.0 : 0.4.1.7 : 0.2"2.5 :: 0.2"

D.u .rt ~~~ as ~L- : SE.'-!..Nm frc!='. tc:::C\Ik: \-a];Jft. P < .0001.

Obstttria & Gyntcology

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..-' -..-..- _. - ....

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T.ble 3. Effect of d-FenBuramine and I'Ixeboon Ulone

Ind NutrientIn\Ues .=~ ;:;,..= ~ _ .

BiseliM -:-:-.-::-:-.-TreAtrlmt

Follicular lutul

Mewl<aJProtein (g)Urbohydn~ (g)FAt(g)

SMCksI<aI 0) : (I) 606 = 71'Protein (g) 19: 5.. Z3: 3Uzbohydrate (g) 32: 7 53 = 8' .Fat (g) 25 : 4 34 = ...Dilfen from follicWar values. P < .01..DiHeD &om lutu! and pl.acebo values.' < .01., Differs from follicubr values. P < .003.. DilfeD from follicWar values. P < .05.

lW = 11217-&0: 129".15U: 116 l362 : l27"76 = 5 74 : 5 . 63: 5 71 = 9

110: 13 151: 16' 131: U 'UI3: U'78 = 6 93 = r . 12 : 6 74 : 7"

778= 15628: 668:1543:9

415 : 72'16: 334=7"24 : 4'

about 180 kcal (P < .003). Carbohydrare intake frommeals increased by 37% (P < .01)and from snacks by65% (P < .003). Of necessity. fat intake increased inproportion to calorie intake. inasmuch as the fat con-tents of all of the foods were similar. No changeassociated with the menstrual cyclewas noted in theconsumption of protein-rich foods (Table3).

d-Fenfluramine suppressed the late luteal phaseincreases in kilocalorie, carbohydrate, and fat intakes(P < .01) in all of the subjects. Kilocalorieand nutrientintakes did not differ from tM subjects' follicularlevels. Placebo treatment had no effect;kilocalorie andnutrient intakes on placebo were similar to thoseobserved during the baseline luteal phase (Table 3).

d-Fenfluramine treatment signifiantly redu~ boththe mean Hamilton Rating ScaleforDepression and itsAddendum scores compared with ~ observed dur-ing the baseline cycle or with plKebo treatment. Themean Hamilton Rating Scalefor Depression score withd-fenfluramine was 8 ~ 1and with placebo, 16 ~ 1 (P< .001) (Table 4). SubscaJes on the Hamilton RatingScale for Depression that meas1lftCldepressed mood,anxiety, and work impairment were significantly im-proved (P < .01)(Table4).The Addendum scores werealso significantly lower with dnas treatment than withplacebo (P < .05). This was due primarily to significantdecreases in the appetite and cubohydnte cravingsubscales. No significant changes were found in thefatigue and social withdnwal subsa1es (Table 4).

Individual subjects varied in the consistency of theirresponses to placebo and ciJu, ~atment (Table 5).Nine subjects demonstrated significant improvementor a total reversal of their PMSsymptoms during eachof the three drug treatment months; of these, eightnever responded to placeboand one subject improvedonly during her first placebo trial. One subject in this

VOL. 76. NO. 2. AUGUST 1990

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T.ble .. E5ectofd-FenBunmine .nd PL1ceboonPremenstnul Mood Scores

Drug

fU~iJt.oc':lY:1tIgSale for _ 8 : l'~

Addend-.= 4 = l'SV :-

~~n 0.5: 0.1'Worit eSdcncy 1 : 0.2'AzuXty 0.7: 0.1'F.tipIt 1 = 0.25aaA1widldnwal 1 : 0.2

~IZ 0.6 : 0.1'CutdI~~ cnving 0.8 : 0.1'

. Di&D &am pIKtbo values. P < .001..Difes &am pIac:cbo values. P < .(15.

'Difes &am pUabo values. P < .01.

PtA~bo-16: 1

6 = 1

1 = 0.22: 0.22: 0.11: 0.21: 0.21: 0.\2: 0.1.

group reported considerable fatigue during the drugtreatment months; her elevated Addendum score mayhave been due to this side effect of d-fenflu ramine.(This subject participated in only two placebo and twodrug trials because back problems prevented her fromcoming to the CRC for evaluation.) Three subjectsdemonstrated positive mood responses during boththe drug and placebo trials. Five subjects had incon-sistent responses to both the placebo and the drug and

T.ble 5. Effectof Tre.tments on Hamilton Rating Sale forDep~sion Scores and Addendum Scores ofIndividual Subjects

PtAcebo d-Fentluranune

fUmeD fUmeDAdd Add

Reponde:1'i19&S6815789191398399909:012

~on-~deni!C

20.6 = l.4513 : 2.5U: 0.917 : 8.026:1.219 : 1.7

15.3 = 6.020 : 2.626 : 4.0

8.3 : 2.7 2.6: 0.89 1: 1.06.3 : 2.3 6 = 2.5 3 = 1.35.3 : 1.2 0.7: 0.7 1.7: 0.96.6 : 3.5 6.3: 1.8 1.3 = 099.3 : 1.2 11.3 : 2.6 6.6 = 0.6

11.3 : 0.9 1: 1.0 3 : 1.08 : 3.0 5.6 = 5.2 2.6 = 2b

11 : 0.7 4.3: 0.89 2.3 = 0891 : 1.2 13: 2.0 10 = 5.0

7.3 : 2.3 14.3 : 7.56.3 : 2.0 15.3 : 6.25.3 : 1.6 13.3 : 1.4

6 : 0.7 17 = 2.45 = 1.8 18: 2.6

9.6 : 4.017 : 4.59 = 3.5

10 : 4.015 = 2.0

4.3 = U'5.6 : 1 4

6.3: \16 = \1

9.3 : ~O

~8:4!::9138

Respcn.:r.5 on bothtnA:=wntS

IkJ3 6.3 : U 1.3 : 0.9 6.7: 3.2 2.6 = 16Q30 4.6 : 3.7 2.0 : 1.0 9 : 5.3 4.3: 3 3C':'!I 9.0 = 5.0 5.3 : 2.7 6.6: 6.6 4 = 2.1>

HL~ . Hanulton JUang Sale for ~p~sion; Add . Add~n'dIU:\.

Da:a ..~ prncnted ASmean: SEM of 3-month tnAtments eAch on~ And dnlg.

Brzezinski et II d-Fmflu'GmilV ImprOfJt$ PMS 299

were not shown to be helped by drug treatmenL How-ever, even these subjects significantly decreased theirsubjective reports of increased appetite and carbohydratecraving while on drug treatment, and they all consumedsignificantly fewer calories and carbohydrates while onthe drug than they did while on the placebo.

With the exception of the subject who experienced

fatigue, none of the subjects reported any consistentside effects other than dry mouth. (d-Fenflurarrune

appears to induce fewer side effects than the racemiccompound dl-fenfluramine because the levolsomer hasa direct antidopaminergic action not found with thedextroisomer. Thus, although drowsiness has been

reported for d-fenfJuramine, sedation and depression- h"ve not.13.1.)Measurements of moodduring the first

follicular stage after completion of the overall studywere not significantly different from pre-treatmentfollicular levels.

Discussion

We found that d-fenfluramine. a drug that selectivelyenhances serotonin-mediated neurotransmission,I canbe effective in relieving the excess1Vefood intake andcravings for carbohydrate-rich foods that characterizePMSI.2;moreover, in the majorityof subjects, the drugalso relieved the premenstrual symptoms of depres-sion, anxiety, and inability to work. The subjectsreportrd no side effects other than dry mouth, andthere were no differences in the incidence of drowsi-ness between the placebo- and drug-treated groups.

The UIiliorm effectiveness of the drug in redudrlgsubjective feelings of increased appetite and carbohy-drate craving and in preventing the luteal increase incarbohydrate consumption is of ~rticuLu interest.These responses to d-fenfluramine are consistent withthe known roles of serotoninergic neurons in thecontrol of appetite...15 Transmitter release from theseneurons is affected by food consumption and, in turn,may inf]uence subsequent food choice. Consumptionof carbohydrate-rich, protein-poor foods can enhanceserotonin synthesis via insulin-me<iYteddanges inthe p~SrN amino acid pattern wtUchfacilitates theuptake of circulating tryptophan, SftOtonin's pl'KU1-sor, into the brain.7.11Subsequently, the substratesaturation of tryptophan hydroxylase facilitates theproduction and' release of serotonin. Drugs such as .d-fenfluramine or norfenfluramine that selectively re-lease brain serotonin or block its reuptake also dimin-ish electjYecarbohydra~ intake in normal rats.1.5

The selective effectof d-fenfluraminein reducing theexcessive intake of carbohydrate-rich. protein-poorfoods by premenstrual patients is similar to its pmi-ously described effect among obese indi\iduals who

claim to be carbohydrate-cravers" In a series of inpa-bent studies in which the overeating of carbohydrate-rich foods by obese subjects was quantified usingmethods for measuring food intake similar to thosedesaibed herein, d-fenfluramine selectively dimin-ished carbohydrate intake without significantly de-creasing prot~in consumption" Similarly, admi~istra-tion of d-fenfluramineto subjectssufferingfromseasonalaffectivedisorder alsodecreased their excessivecarbohv-drate cra\-mg and prevented the weight gain that th;yotherwise would have experienced.3Thedrug's abilitytocoJTectabnonnahties in food intake among the premen-strual women in the present study suggests its utility inhelping such women maintain body weight. That thedrug restored food and nutrient intake to follicularlevelsrather than depressing intakes below what the subjectswould normally haveconsumed maymake itparticularlyvaluable in sustaining adequate nutrient intake, es~ci.aJlyof protein-rich foods.

Our observaton that d-fenfJuramine, which selec-tively enhances serotoninergic neurotransmission. .11-leviates premenstrual depression in the majority ofsubJects supports the hypothesis that serotonin-releasing raphe neurons are involved in producing theaffective and ap~ntive symptoms characteristic of thisdisorder. An involvement of peripheral serotonin haspreviously been proposed. based on the observationsthat platelet serotonin uptakel6 and blood serotoninlevelsl7 were depressed in subjects with PMS duringthe luteal phase of the cycle. However, circulatingserotonin is not thought to cross the blood-brain bar-rier and there is no reason to believe a priori that themechanisms controlling the synthesis of peripheralserotonin within enterochromaffin cells, or its storage

;thin platelets. are at all related to those regulating itsproduction in and release from brain ~urons.

We reported pre\iously that subjKts with severepremenstrual depression demonstrated significant im-provements in mood after consuming a carbohydrate-rich, protein-poor test meal.2 These changes wereobserved only during the ~te luteal stage of the cycleand were not found among symptom-free controls.Because dieury arbohydJ:ate an accelerate brain se-rotonin synthesis,7.11these observations also supportthe possible involvement of serotonin in the premen-strual mood disorder.

The range of responsiveness of our subjects wasconsiderable. 1':ine demonstrated a total reversal of

their symptoms or considerable improvement while ondrug treatment, with no or ahnost no responses toplacebo (Table 4). In contrast, five showed no patternof consistent responsiveness to placebo or to drugtreatment, and three responded to both. We examinedthe influence of treatment order and found that only

Obstttria b GyratCDlogy

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-one subject responded positively to the placebo when

itwas the firsttreatment given;-hence. expectationsthat the initial treatment would be.'eff'ective we!'e not a

factor. We also looked at the influence of time of yearbecause subjects were entered individu.illy into thestudy. and thus the 6-month treatment phase followeddifferent seasonal patterns for each subject. There wasno effect of time of year on responsivenesS tc eitherdrug or placebo. What we did note was an unpredict-able variety of non-study-related problems' amongthenon-responders: One experienced an unrelenting se-ries of social, financial. and housing crises; two othersexperienced family or financial crises (including abankruptcy); and one encountered un~ jobstress. Of anecdotal interest was the benign accrptanceby a patienton drug treatment of a household of child..'en

infectedwithchickenpoxduringa familycelebration.This study used standardized observer-rated tes~ oi

mood and appetite. These tests asked the subject toevaluate her mood. work activity. fatigue. apperite.and sociabilityover the immediate past 7-day period.Such tests may prevent the reporting of !>ymptomsoccurring only infrequently during the past w~k. It ispossible that only those symptoms with the greatestseVl"ritywere remembered and described and that theuse of daily ratings may have revealed less severe orinfrequent changes in mood. fatigue. or appetite.However, the observer-rated assessments permittedthe investigators to see the subject in the researchfacility at the end of each treatment. allo ing antValuation of her premenstrual symptomatology underidentical clinicalconditions each month. Moreover. byhaving a tRined observer rate the symptoms. weavoided the possibility that the mood of the subjectmight itseUhave an effect on the care and accuracy ofa self-assessment report,

Our daQ suggest that d~fenfluramine and otherdrugs that increaseserotoninergic transmission may beuseful in treating premenstrual disorders of appetiteand mood. Drugs such as d-fenfluramine, which pro-duce their clinicaleffects within a few days of initialadministRtion and which can be withdrawn abruptlywithout risk during the nonsymptomatic sta~es of thecycle. have obvious advantages in the long-term ~at.ment of this cyclicdisorder. Their use may be particu-larly valuableto patients who are engaged in long-termweight loss programs and whose ability to maintaincontrol OWl' caJorie intake is impaired because ofpremenstrual depression.

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Address reprint requnts to:ludith I. Wurtman. PhDDtpartmmt of Bl'IJinand CognitirJtScimCtSMAsS4ChusntsInstilldt of TtChnology.E2S-604CIImbridgt. MA 02139

R«maI Deambfor 7. 1989.R.tcnwrl i" rtWGI ft1mrMardt 16. 1990.Accqnal Mardt 22. 1990.

Copyri~t C 1990 by 1M AlMrian CoIIerr of Obst~mcuns otndG~.

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VOL. 76. NO. 1. AUGUST 1990