1020 Am J Clin Nutr 1995;61:1020-5. Printed in USA. © 1995 American Society for Clinical Nutrition

Fluoxetine increases resting energy expenditure and basalbody temperature in humans13

Rachelle Bross and L John Hoffer

ABSTRACT Humans lose weight when administered flu-oxetine, an inhibitor of serotonin reuptake by nerve terminals.

To determine whether increased energy expenditure contnib-utes to this weight loss we admitted 20 nondepressed obese

women to a metabolic unit where they were randomly assigned

to 3 wk of a 1.76-MJ/d formula diet and either 60 mg fluox-

etine/d or a placebo. Resting energy expenditure of the controlsubjects fell below normal after 5.6 ± 0.6 d of energy restric-tion, whereas that of the fluoxetine-treated subjects increasedby 4.4 ± 1.8% (P < 0.005) within 3 d of commencing

treatment. This increased resting energy expenditure then re-

versed and fell below normal after 9.8 ± 0.9 d of energy

restriction. Basal body temperature of the control subjects

decreased insignificantly during the period of energy restric-

tion, but that of the fluoxetine-treated subjects increased by

0.28 ± 0.10 #{176}C(P < 0.05) within 3 d of commencing diet and

drug treatment. Urinary norepinephrine excretion and the se-

rum triiodothyronine concentration decreased equally in bothgroups. Despite identical energy intakes and equal nitrogenbalance, the fluoxetine-treated subjects lost weight faster thanthe control subjects during the final week of energy restriction(P < 0.05). We propose that serotonin reuptake inhibition

increases energy expenditure by increasing basal body tem-

perature. Am J Clin Nutr 1995;61:1020-5.

KEY WORDS Energy expenditure, pharmacology, serotonin

Introduction

Fluoxetine is a widely used antidepressant drug that inhibits

neuronal serotonin reuptake (1). Unlike the tnicyclic antide-pressants, fluoxetine use is associated with weight loss in both

depressed (2) and nondepressed (3, 4) individuals, apparently

by inducing early satiety (5). To learn whether fluoxetine alsocontributes to weight loss by increasing resting energy expen-

diture (REE), by increasing the thermic effect of food, or by

blocking the adaptive reduction in REE that commonly occurs

during energy restriction (6), we combined fluoxetine admin-

istration with a very-low-energy weight-reduction diet that

normally engenders a pronounced adaptive reduction in REE

(7, 8). Urinary norepinephrine and normetanephrine excretion

and serum tniiodothyronine concentrations were measured tomonitor the altered sympathetic nervous system activity andthyroid hormone metabolism believed to mediate the hypo-

metabolic adaptation to semistarvation (6, 7). Because seroto-

nm is involved in thermoregulation (9, 10), we also monitored

basal body temperature.

Subjects and methods

Subjects, diets, and treatments

Twenty moderately obese, but otherwise healthy womenwere admitted to the Clinical Investigation Unit of the RoyalVictoria Hospital. Screening by medical history, physical ex-

amination, chest X-ray, electrocardiogram, complete bloodcount, thyroid function tests, standard biochemical screening,

and an oral-glucose-tolerance test indicated the absence ofhypertension, diabetes, or any other endocrine or significant

medical condition. All subjects were nonsmokers who hadmaintained a stable body weight for several months and hadtaken no medication in recent weeks. Written informed consentwas obtained for the study, which was approved by the Ethics

Committee of the hospital’s Department of Medicine.Each hospitalization lasted �“26 d. For the first 4-5 d all

subjects consumed a liquid-formula diet consisting of Ensurewith added Polycose glucose polymer (both from Ross Labo-ratories, Columbus, OH) to provide 150% of basal energy

expenditure (1 1) and 80 g protein. For the next 3 wk all

subjects consumed a liquid-formula diet containing 1.76 MJ(420 kcal) including 70 g protein/d and � 100% of the USrecommended dietary allowances (12; RDA) for vitamins andessential minerals (Optifast 70; Sandoz Nutrition, Minneapo-

lis). No other food or drink was consumed except for a mini-mum of 1600 mL water daily. On the day energy restrictionstarted, all subjects were randomly assigned in double-blind

fashion to receive 60 mg fluoxetine or placebo in a singlecapsule each morning before breakfast, but after any study

I From the School of Dietetics and Human Nutrition and the McGillNutrition and Food Science Centre, McGill University, Montreal, Canada.

2 Supported by a grant from Eli Lilly Canada, Inc. RB received partial

support from the Fonds pour la Formation de Chercheurs et l’Aide a laRecherche. LJH is a chercheur-boursier of the Fonds de la Recherche en

Sante du Qu#{233}bec.The Clinical Investigation Unit of the Royal VictoriaHospital is supported by a grant from the Fonds pour la Recherche en Santedu Qu#{233}bec.Optifast-70 was donated by Sandoz Nutrition Canada, Inc.

3 Address reprint requests to U Hoffer, McGill Nutrition and Food

Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Room

H6.90, Montreal, Quebec H3A 1A1, Canada.

Received October 25, 1994.Accepted for publication January 9, 1995.

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THERMIC EFFECT OF FLUOXETINE 1021

‘ S ± SEM; ,z = 10 subjects per group.

measurement was completed on that day. Activity was limited

to walking on the hospital ward.

Measurements and calculations

Body weight was measured each morning with the subjects

wearing light bedclothes, after voiding, and before breakfast,

by using a high-precision digital platform scale (Scale-Tronix;

Ingram & Bell-Meditron, LeGroupe, Inc, Don Mills, Canada).

REE was measured by ventilated-hood indirect calorimetry(Deltatrac; SensorMedics, Yorba Linda, CA), using calibration,

measurement, and subject training procedures described previ-

ously (13). The training procedure included at least two com-

plete REE measurement sessions for which the data were

disregarded before admission to the clinical investigation unit

for the formal protocol. On the unit, three formal REE mea-

surements were obtained during the baseline period and every

second or third day during the low-energy period. Before that

morning’s dose of study medication was given, each subject’s

measurements were obtained in a semidarkened room with the

temperature maintained between 21 and 24 #{176}C.Only results

from the final 15 mm of each formal 20-mm determination

were analyzed. Steady state, defined as having a CV < 5% for

both oxygen consumption and carbon dioxide production, was

usually achieved. If a steady state was not achieved, the mea-

surement was repeated the next day, but this occurred only

rarely. REE was calculated as kcal/min from the oxygen and

carbon dioxide results according to the Weir equation (14).

The thermic effect of a glucose load was assessed at the end

of the baseline diet and after 3 wk of energy restriction. After

a standard REE measurement, subjects consumed a test drink

composed of 1 12.5 g glucose in 450 mL carbonated water

(Glucodex; Rougier Inc, Chambly, Canada) over 15 mm, thenimmediately reclined under the ventilated hood. Energy expen-

diture was measured for 210 mm, which included three 10-mm

interruptions at 55, 120, and 165 mm to break the monotony or

for voiding. Control experiments with sham glucose loads

indicated no change in REE using this protocol. The thermic

effect of glucose was obtained by subtracting from total energy

expenditure the contribution due to REE as determined at the

outset.

Serum thyroxine (14) and triiodothyronine (13) were mea-sured by automated radioimmunoassay (ARIA II; Becton Dick-

inson Immunodiagnostics, Baltimore) on the first and last day

of the baseline period and on days 7, 14, and 21 of energy

restriction. All urine was collected in serial 24-h aliquots. Each

subject’s collection bottles (containing 15 mL 12 mol HC1/L as

a preservative) were kept in a bedside refrigerator during each

collection period. Samples of the resulting collection were

analyzed daily for creatinine, sodium, and potassium (Beckman

Syncron CX4 and CX5 Systems, Brea, CA) and three times

during the baseline diet and for norepinephrine and normeta-

nephrine by using an automated HPLC system (Bio Rad,

Richmond, CA) on the last 2 d of each week during the energyrestriction period. Other aliquots were frozen at -25 #{176}Cfor

later nitrogen analysis. Urine total nitrogen was determined

colonimetrically after Kjeldahl digestion (15) by using a Tech-

nicon Autoanalyzer II (Chauncey, NY). Daily nitrogen balance

was calculated as nitrogen intake minus the sum of urinary and

estimated fecal (0.6 g/d) and miscellaneous losses

(8 mg . kg’ . d’) (16, 17). Urine creatinine excretion wasmeasured to verify completeness of the urine collections,

and potassium and sodium excretion were measured to

verify adherence to the diets.

Basal body temperature was measured each morning by the

subjects by holding a digital basal thermometer (Becton-Dick-

inson, Toronto) under the tongue with the mouth closed and

recording the final temperature indicated. Mean daily basal

temperature was calculated in two ways: first, according to the

study protocol day; and second, according to the day of the

menstrual cycle as determined from the first day of menstrual

flow. For the latter calculation, each subject’s lowest recordedbasal temperature was set at zero and all other values plotted in

degrees Celsius above this. Because the analysis of fluoxetine’s

effect in relation to the days of the menstrual cycle should not

include data from the 4 baseline days when no drug was

administered, the temperatures for these days were set equal to

each subject’s mean temperature over the 3 wk of fluoxetine

administration.

Statistical analysis

The sample size of 10 in each group was chosen in accor-dance with a and �3 probabilities of0.05 and 0.10, respectively,

a predicted 3-4% within-subject SD in REE, and the judgmentthat a 5% increase in REE would be of physiologic interest

(18). Treatment and control data for REE, body weight, tem-perature, nitrogen balance, thyroid hormone indexes, and un-

nary catecholamines were compared by two-classification re-

peated-measures analysis of variance using PC SAS (version

6.01; SAS Institute, Inc, Cary, NC). Temperature, body weight,

and energy expenditure data were expressed as changes from

each subject’s baseline value. When significant (P � 0.05)

time or treatment effects were indicated, a contrast was done

against the baseline variable to determine the time points

responsible for significance. P values reported in the text are

for these contrasts. Baseline subject characteristics or biochem-

ical measurements were compared by the two-sample two-

tailed t test. All results are expressed as mean ± SEM.

ResultsSubject characteristics and clinical response

Random assignment of the 20 subjects resulted in well-

matched groups with no significant differences in any of the

measured variables (Table 1). No adverse events occurred.

Body weight was constant during the baseline period, anddecreased steadily and equally in both groups for the first 2 wk

of energy restriction. During the final week, however, weight

loss was faster in the fluoxetine group (0.25 ± 0.01 compared

TABLE 1

Baseline subject characteristics’

. .

CharacteristicFluoxetine

groupPlacebo

group

Age (y) 32.0 ± 3.2 33.0 ± 3.9Weight (kg) 91.5 ± 3.7 92.8 ± 3.2

Height (m) 1.64 ± 0.02 1.65 ± 0.01Body mass index (kg/m2) 34.0 ± 1.3 34.1 ± 1.3Waist-hip ratio 0.86 ± 0.02 0.83 ± 0.01Resting energy expenditure (kJ/min) 4.69 ± 0.11 4.56 ± 0.15

Basal body temperature (#{176}C) 36.5 ± 0.1 36.5 ± 0.1First day of menstruation (study day) 16.1 ± 9.5 12.2 ± 6.8

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Study Day

1022 BROSS AND HOFFER

with 0.22 ± 0.01 kg/d, P = 0.049), as shown in Figure 1.Average nitrogen balance was slightly positive and similar forboth groups during the baseline period (0.4 ± 0.5 and 0.8 ± 0.3

g N/d for the fluoxetine and placebo groups, respectively),

becoming negative during consumption of the very-low-energydiet (Figure 2). During the third week of energy restrictiondaily nitrogen losses were constant and not significantly dif-

ferent in the two groups (-2.87 ± 0.52 g/d in the fluoxetinegroup and -3.43 ± 0.37 g/d in the placebo group; P = 0.39).

Cumulative nitrogen losses over the entire 21-d period wereslightly, but not significantly greater in the placebo group (71.5

± 6.6 compared with 61.1 ± 4.8 g; P = 0.21).

Biochemical responses

REE was constant (within-subject CV: 2.2 ± 0.3%) and

closely similar in both treatment groups during the baseline

period (P = 0.51; Table 1). During the first week of energy

restriction a significant treatment effect became evident (P =

0.041), with REE increasing in the fluoxetine group (P =

0.003) but falling below the baseline value in the placebo group

after 5.6 ± 0.6 d of energy restriction (P = 0.035; Figure 3).After first increasing, REE in the fluoxetine group returned to

baseline, then fell below it after 9.8 ± 0.9 d of energy restnic-tion. The delay in the reduction of REE in the fluoxetine groupis significant (P = 0.001). By the end of the study REE had

decreased by 6.7 ± 1.2% in the fluoxetine group and by9.7 ± 1.5% in the placebo group.

The thermic effect of an oral glucose load was similar in both

groups under baseline conditions (8.1 ± 0.8% of 24-h REE or

4.5 ± 0.4% of the energy consumed for the fluoxetine group,and 8.7 ± 1.4% of 24-h REE or 4.5 ± 0.5% of energy

consumed in the placebo group; P = 0.71). After 3 wk of

Study Day

FIGURE 2. Mean (± SEM) daily nitrogen balance in the fluoxetine (#{149})and placebo (0) groups. The curves are not significantly different.

energy restriction, the response to the same glucose challengewas unchanged (7.6 ± 0.8% of 24-h REE or 4.0 ± 0.4% of the

energy consumed in the fluoxetine group and 8.8 ± 1.1% of24-h REE or 4.2 ± 0.5% of energy consumed in the placebogroup).

Serum thyroid hormone concentrations were similar at base-line in both groups. During energy restriction, serum 14

0 3 6 9 12 15 18 21

Study Day

FIGURE 1. Change from baseline in mean (± SEM) body weight of 20

women randomly assigned to consume a 1.76-MJ/d weight-reduction dietand either fluoxetine (#{149})or placebo (0). Initial body weight was 91.5 ±3.7 kg in the fluoxetine group and 92.8 ± 3.2 kg in the placebo group.

Weight loss by the fluoxetine group was significantly faster during the

third study week (P 0.049).

FIGURE 3. Change from baseline in mean (± SEM) resting energy

expenditure (REE) in the fluoxetine (#{149})and placebo (0) groups. BaselineREE was 4.69 ± 0.11 kJ/min in the fluoxetine group and 4.56 ± 0.15kJ/min in the placebo group.

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Study Day

‘;t ± SEM.2.3 Significantly different from treatment group’s baseline value: 2 p < 0.05, -‘ p < 0.01.

ThERMIC EFFECT OF FLUOXETINE 1023

remained constant, apart from a transient, clinically insignifi-

cant increase observed at 7 d of energy restriction. Serum 13

decreased equally in both treatment groups (P = 0.0007), as

did urinary norepinephnine and normetanephnine excretion

(P = 0.001; Table 2).Changes in basal body temperature are illustrated in Figures

4 and 5. Basal temperature was constant and equal in the twogroups under baseline conditions (Table 1). With the onset of

drug and diet treatment, a significant treatment effect became

evident (P = 0.026). Basal temperature decreased by 0.12 ±

0. 10 #{176}Cin the placebo group, an insignificant change(P = 0.37), but increased by 0.28 ± 0.10 #{176}Cin the fluoxetine

group (P = 0.025). The temperature increase in the fluoxetinegroup was significant by day 2 of treatment and was sustainedthroughout the treatment period (Figure 4). As illustrated in

Figure 5, basal temperature in the placebo group increased in

the middle of the menstrual cycle (P = 0.002), suggesting the

“thermal nadir” that has been reported to occur just before the

onset of the luteal phase (19, 20). No change in basal temper-

ature occurred over the period of fluoxetine administration

however (P = 0.87). Thus, basal body temperature of the

fluoxetine-treated subjects was significantly higher during the

first, but not the second half of their menstrual cycles.

Discussion

Our results indicate that ingestion of 60 mg fluoxetine/dpromptly increases the REE of obese women and significantly

delays the reduction in their REE that normally occurs during

severe energy restriction. Fluoxetine also increases basal body

temperature and slightly, but significantly increases the rate of

weight loss above that associated with energy restriction alone.

The observation that fluoxetine promptly increases REE in

humans is novel, as is the subsequent return of REE to normal

and then below normal after several days of energy restriction.

It is possible that REE would have returned to normal againeven without energy restriction, and indeed, this possibility wassuggested by a recent report that the REE of obese subjects was

unchanged from baseline when measured after 14 d of fluox-

etine treatment with no formal energy restriction (21). The

observation that fluoxetine promptly induces and sustains an

TABLE 2

FIGURE 4. Change from baseline in mean (± SEM) basal body

temperature in the fluoxetine (#{149})and placebo (0) groups. Baseline basal

temperature was 36.5 ± 0. 1 #{176}Cin both treatment groups.

increase in basal body temperature is also novel. Serotoninagonists change body temperature by activating specific centraland peripheral receptors (9, 10), and although fluoxetine re-

duces hypothalamic temperature in Syrian hamsters (22), this

may not be relevant to humans. Central serotonin receptors

mediate a hyperthermic response whereas peripheral receptorsmediate a hypothermic one (9, 10, 23, 24), perhaps by increas-ing heat loss through vasodilation (25). Therefore, observationsin Syrian hamsters could represent the net effect of a prepon-

derance of peripheral effects over central ones in that species.By contrast, the serotonin-releasing drug fenfluramine has re-

cently been shown to increase the body temperature of normal

humans during acute administration (26). Ours is the first

observation that a serotonin-active drug may induce a sustained

Serum thyroid hormone concentrations and daily urinary catecholamine excretion’

Clinical chemistry index and group Control diet

Very-low-energy diet

Day 7 Day 14 Day 21

Thyroxine (nmol/L)

Fluoxetine 111 ± 4 119 ± �2 111 ± 3 112 ± 4

Placebo 109±6 116±72 118±7 106±7

Triiodothyronine (nmol/L)

Fluoxetine 2.0 ± 0.1 1.6 ± 0.i3 1.4 ± O.i� 1.2 ± 0.i�

Placebo 2.1 ± 0.1 1.7 ± 0.i’ 1.5 ± 0.i’ 1.5 ± 0.i�

Norepinephrine (nmol/d)

Fluoxetine 294 ± 31 239 ± 28� 200 ± 24� 194 ± 20’

Placebo 265 ± 39 218 ± 27� 158 ± 24� 134 ± 20�’

Normetanephrine (nmol/d)

Fluoxetine 1718 ± 185 1155 ± 107� 842 ± 933 799 ± 743Placebo 1574 ± 233 1181 ± ii5’ 848 ± 773 694 ± 72�

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Specific hormonal measurements would be required to deter-

mine whether ovulation and progesterone-mediated thermo-

genesis occur normally during the initial weeks of severe

energy restriction, with or without fluoxetine.

Despite their energy intake being equal to that of the control

group, the fluoxetine-treated women lost weight significantly

faster than those in the placebo group during the third week of

the study. Weight loss in the early days of semistarvation is

mostly due to the mobilization of extracellular water, glycogen,

and lean tissues (30), and would not be expected to reveal any

difference in the rate of fat loss. By the third week of energy

restriction, however, weight loss is mostly due to lean and

adipose tissue loss (31), and because nitrogen balance was, if

anything, slightly more positive for the fluoxetine-treated sub-

jects the possibility cannot be disregarded that the greater daily

weight loss during the final week of energy restriction was due

a faster dissolution of adipose tissue. This is in general agree-

ment with the observation that their REE was greater. Never-

theless, it remains true that although the REE in the fluoxetine

group remained higher than in the placebo group at this stage,

the difference was small and of only borderline significance

(P = 0.07). It is possible, therefore, that factors other than a

higher REE might have accounted for a greater daily total

energy expenditure-and hence faster fat loss-in the fluox-

etine group. First, REE and the thermic effect of glucose were

measured =24 h after the previous dose of medication; energy

expenditure might have been greater immediately after drug

ingestion.

Second, the higher basal body temperature in the fluoxetine

group was sustained throughout the period of adaptation to

energy restriction despite the progressive reduction of their

REE. Because we measured energy expenditure and body

temperature only under ideal conditions of patient comfort, we

cannot rule out the possibility that energy expenditure wasgreater than this under the thermally unregulated conditions

that prevailed most of the time, and might have been greater yet

for the fluoxetine-treated subjects because their temperature set

point was higher.

A third conjecture is that fluoxetine may stimulate physical

activity. Even substantial increments in energy expenditure

caused by physical activity, such as those due to “fidgeting,”

may be difficult to perceive unless special measurementtechniques are used (32).

As a final remark, we suggest that the present observations

with fluoxetine-a drug that induces early satiety-could

prove relevant to the thermostatic theory of weight regulation.

This theory holds that the increase in body temperature asso-

ciated with food ingestion helps limit the total amount eaten

(33, 34). If this theory is correct, a higher basal temperature

preceding a meal could also limit food consumption, because insuch a situation the thermic effect of food will increase body

temperature to the satiety level earlier in the course of a meal.

In agreement with this prediction, fluoxetine’s anorexiant ef-

fect is relatively specific for carbohydrate (4), the nutrientwhich, when consumed in customary amounts, has the most

immediate and pronounced thermic effect (35). U

We thank Mi Myers for assisting with many of the resting energy

expenditure measurements, MG Shingler for assisting in patient care, and

S Solomon and I Niarri for the catecholamine measurements.

4 8 12 16 20 24 28

Day of Menstrual Cycle

FIGURE 5. Mean (± SEM) difference in basal body temperature from

each subject’s lowest recorded value in relation to the day of the menstrual

cycle in the fluoxetine (#{149})and placebo (0) groups. Basal body temperature

was significantly higher in the fluoxetine group during the first, but not the

second half of the menstrual cycle.

increase in human body temperature during continued

administration.

Unlike previous studies, this one combined both REE andbody temperature measurements and indicated a closely similartime course of increasing REE and body temperature in sub-jects administered fluoxetine, at least until the hypometabolic

adaptation to semistarvation became established. The magni-tude of the temperature increase was in good agreement with

earlier evidence that each degree (Celsius) increase in body

temperature brings about a 13% increase in REE in the absenceof increased thermal insulation (27). REE in the fluoxetine

group increased at a time when serum 13 and urinary norepi-

nephnine and normetanephrine excretion were steadily decreas-ing. Although crude, these indicators provide no evidence

favoring a thyroid- or sympathetic nervous system-mediated

mechanism to account for fluoxetine’s effect. It is reasonable,

therefore, to suggest that fluoxetine increased REE indepen-

dently of the mechanisms that govern the hypometabolic ad-aptation to energy restriction by raising the body temperatureset point. REE ultimately decreased in both treatment and

control groups despite a continuing normal body temperature inthe control subjects and a sustained temperature elevation in

the fluoxetine-treated ones. Such constancy of basal body tem-

perature despite a lowered REE indicates that the subjects in

both groups voluntarily increased their thermal insulation to

maintain the constancy of their respective temperature set

points. Although we did not systematically record this, the

subjects in both groups noted mild cold intolerance, a common

complaint of severely energy-restricted individuals (28, 29).The strategy of increasing thermal insulation will, of course,

reduce or eliminate the need for increased basal thermogenesis

to maintain a higher temperature set point.It is well known that basal body temperature increases during

the luteal phase of the normal menstrual cycle and this phe-nomenon appeared to persist during energy restriction of the

placebo-treated subjects (Figure 5). By contrast, the basal tem-perature of the fluoxetine-treated subjects remained constant at

a value equal to that of the luteal phase of the control subjects.

1024 BROSS AND HOFFER

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THERMIC EFFECT OF FLUOXETINE 1025

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