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Transcript of Fluoxetine Increases Resting Energy Expenditure
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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