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Unbekannt
Psychopharmacology (2004) 173:153–159DOI 10.1007/s00213-003-1711-8
O R I G I N A L I N V E S T I G A T I O N
Jessica Werth Cook · Bonnie Spring ·Dennis E. McChargue · Belinda Borrelli ·Brian Hitsman · Raymond Niaura · Nancy J. Keuthen ·Jean Kristeller
Influence of fluoxetine on positive and negative affectin a clinic-based smoking cessation trial
Received: 7 July 2003 / Accepted: 30 October 2003 / Published online: 15 January 2004 Springer-Verlag 2004
Abstract Rationale: Fluoxetine improves affect in clin-
or negative affect. Conclusions: Results indicate that
ical syndromes such as depression and premenstrual
60 mg of fluoxetine improves both positive and negative
dysphoric disorder. Little is known about fluoxetine’s
mood states after quitting smoking and that diminished
influence on mood changes after quitting smoking, which
positive affect may be an overlooked affective response to
often resemble sub-clinical depression. Objectives: The
present study, a re-analysis of previously published data(Niaura et al. 2002), examined fluoxetine’s effect on
Keywords Fluoxetine · Smoking cessation · Positive
changes in negative and positive affect following quitting
smoking. Methods: Adult smokers (n=175) withoutclinically significant depression were randomized on adouble-blind basis to receive fluoxetine hydrochloride (30
or 60 mg daily) or placebo for 10 weeks in combinationwith cognitive-behavioral therapy (CBT) for smoking
Abstaining from nicotine, even during short periods of
cessation. We postulated that fluoxetine would benefi-
time, is accompanied by a cluster of affective responses
cially influence post-cessation changes in positive and
resembling sub-clinical depression (Gilbert et al. 1998).
negative affect. Results: Mood change across treatment
Irritability, anxiety, and depressed mood, for example, are
was analyzed using mixed linear modeling controlling for
commonly reported mood disturbances that are experi-
initial level of nicotine dependence, plasma fluoxetine
enced after quitting smoking (Hughes and Hatsukami
metabolites, and change in cotinine (a nicotine metabo-
1986; American Psychiatric Association 1994; Gilbert et
lite) at each visit. Relative to placebo, those on 60 mg
al. 1998). Reductions in positive affect, however, have
fluoxetine experienced an elevation in positive affect that
largely been overlooked as a possible response to
increased across time [t(526)=2.50, P=0.01], and a
smoking cessation. That neglect is surprising, given the
reduction in negative affect that returned to baseline
integral relationship between deficient positive mood
across time [t(524)=2.26, P=0.02]. There were no differ-
states and depression (Clark and Watson 1991; Coyne
ences between 30 mg and placebo on changes in positive
1994), and evidence that quitting smoking heightens therisk of depressive episodes (Borrelli et al. 1996; Tsoh etal. 2002). Positive affect declines after quitting smoking
J. W. Cook · B. Spring ()) · D. E. McChargueDepartment of Psychology,
(Gilbert et al. 1998; Lerman et al. 2002; Cook et al. 2003)
1007 West Harrison Avenue, Chicago, IL 60607-7137, USA
and persists across 30 days of abstinence (Gilbert et al.
1998). Further, empirical evidence that positive and
negative affect are linked to different neural underpin-nings (Davidson 1992) and have different psychological
B. Borrelli · B. Hitsman · R. NiauraCenters for Behavioral and Preventive Medicine,
correlates (Watson et al. 1988) supports the independence
of these constructs. Thus, low positive affect may be an
Suite 500, One Hoppin Street, Providence, RI 02903, USA
important and neglected response to quitting smoking,which, in combination with elevated negative affect,
constitutes a distressing affective syndrome that follows
OCD Clinic, Massachusetts General Hospital,
149 13th Street, #9106, Charlestown, MA 02129, USA
Similarities between cessation-induced mood distur-
bance and other affective syndromes (e.g. depression,
Department of Psychology, Indiana State University,
premenstrual dysphoric disorder) suggest that antidepres-
sant medications might also ameliorate unpleasant mood
reinforcing value of approach behavior to rewards (Depue
states after quitting smoking. A variety of antidepressants
and Collins 1999), fluoxetine might buffer the losses in
with dopaminergic, noradrenergic, and/or serotonergic
positive affect associated with quitting smoking.
actions have demonstrated efficacy for promoting smok-
The present study examined the effect of 30 and 60 mg
ing cessation (Spring et al. 1995; Hurt et al. 1997; Hall et
fluoxetine, relative to placebo, on acute change in positive
al. 1998; Niaura et al. 2002). Studies on the effects of the
and negative moods during nicotine abstinence. We
agents have, for the most part, focused on the alleviation
postulated that fluoxetine would buffer the increase, or
of negative mood or depressive symptoms. Specifically,
even diminish negative affect during smoking cessation.
euthymic smokers treated with nortryptiline (catechol-
Moreover, we postulated that fluoxetine would buffer
aminergic and serotonergic actions) or bupropion (dopa-
post-cessation losses in positive affect, or, potentially,
minergic and noradrenergic actions), report lower levels
increase positive affect during smoking cessation.
of post-cessation negative affect than smokers who didnot receive these treatments (Hall et al. 1998; Shiffman etal. 2000; Lerman et al. 2002). Effects of antidepressants
on positive affect are less understood (Zald and Depue2001). Although Shiffman et al. (2000) found that
bupropion attenuated a decrease in positive affect in
Subjects were 175 euthymic male and female smokers recruited to
euthymic smokers during 72-h nicotine deprivation,
three of 16 sites in a double-blind, placebo-controlled, multicenter
Lerman and colleagues (2002) did not detect an effect
trial examining the influence of fluoxetine on smoking cessation.
of bupriopion on post-cessation positive moods.
The present study is a re-analysis of previously published data
The influence of fluoxetine, a selective serotonin
(Niaura et al. 2002), and used the three-site subset that measured
reuptake inhibiting antidepressant (SSRI), on mood
positive and negative affect across visits. Subjects’ mean age was42.6 years (SD=9.4). Most were female (57.1%), Caucasian
following smoking cessation has yet to be examined.
(94.6%), and married (52.6%). Subjects averaged 30.1 cigarettes
Although fluoxetine, given for 3 weeks prior to a quit
per day (SD=12.9) for a mean of 25.1 years (SD=9.1) prior to
attempt reduced depression among euthymic smokers
treatment. Enrollees were moderately dependent on cigarettes, as
(Dalack et al. 1995), fluoxetine’s effect on affective
indicated by a mean score of 6.8 (SD=1.8) on the FagerstromTolerance Questionnaire (Fagerstrom 1978). At entry, cotinine, a
distress during nicotine abstinence remains unknown. In
nicotine metabolite, averaged 288.7 ng/ml (SD=152.9). Subject
other clinical syndromes, including major depression
eligibility criteria, as well as the cessation outcomes of the multi-
(Gram 1994), subsyndromal depression (Gram 1994), and
center trial, are reported elsewhere (Niaura et al. 2002).
premenstrual dysphoric disorder (Cohen et al. 2002),fluoxetine has been shown to alleviate negative affect. In
depression, the drug’s mood benefit is not confined topatients who present solely with depressed mood, but
occurs also among patients with comorbid anxietydisorder (Sonawalla et al. 2002). In addition to engen-
Positive affect was assessed at each visit via the Positive andNegative Affect Scale (PANAS; Watson et al. 1988). The PANAS
dering improvements in depression, fluoxetine reduces a
is a self-report state mood questionnaire consisting of 20 adjectives
full range of negative moods, including anxiety and
that are rated on 5-point scales ranging from 1 (very slightly or not
anger-hostility (Sonawalla et al. 2002).
at all) to 5 (extremely). The positive affect subscale, manifested by
To our knowledge, there have been no prior studies
feelings of activation, elation, enthusiasm, and enjoyment, consistsof 10 items, with potential scores ranging from 10 to 50. The
examining whether fluoxetine can prevent the dysphoric
Positive Affect subscale has been shown to possess high internal
mood and the decreased positive affect that typically
follow nicotine abstinence. There are, however, threereasons to expect such effects. First, similar preventive
benefits have been demonstrated for fluoxetine as atreatment of premenstrual dysphoric disorder, such that
Negative affect was assessed at each visit via the negative affect
the drug prevents intermittent worsening of negative
subscale of the PANAS (Watson et al. 1988). The negative affect
mood (Cohen et al. 2002). Second, although fluoxetine
scale, encompassing feelings of distress, hostility, nervousness,
has yet to be established as a treatment for smoking
scorn, and gloominess, is comprised of ten words with scoresranging from 10 to 50. The negative affect scale possesses high
cessation, it has been shown to yield a modest cessation
internal consistency (Watson et al. 1988).
advantage to smokers who are trying to quit (Niaura et al. 2002), especially among those who have higher baselinelevels of depressive symptomatology (Hitsman et al.
1999). Such effects might partly arise from the drug’s
The eight-item Fagerstrom Tolerance Questionnaire (FTQ; Fager-
mood control properties. Third, administration of fluox-
strom 1978) was administered to measure degree of behavioral
responses suggestive of nicotine dependence (e.g. smoking many
prevents a rise in brain reward threshold during nicotine
cigarettes, smokes early in the morning). Scores ranged from 0 to11, with higher values suggesting greater nicotine dependence.
deprivation (i.e. reverses diminished responding to re-
Correlations between the FTQ and measures of nicotine intake
warding stimuli; Harrison et al. 2001). To the extent that
support the construct validity of the scale (Fagerstrom and
diminished positive affect is associated with diminished
Saliva cotinine concentration was measured at each visit. Saliva
model in a backwards manner and the model was refit. Two a-priori
cotinine samples were analyzed by SciCor Laboratory (Indianapo-
group contrasts were specified: 30 mg versus placebo; 60 mg versus
Carbon monoxide, assessed via an ecolyzer (Model EC-50,
It is important to note that mixed-effects regression modeling
Vitalograph Corporation), was also assessed at each visit.
does not place restrictions on the number of observations perindividual, so that participants with missing data at a particularassessment time were not excluded from analyses. Instead, model
parameters were estimated using all available data. Essentially, themodel assumes that the data that are present for a given subject
Compliance was verified by assays of plasma concentrations of
reasonably reflect that subject’s deviation from the usual fixed-
fluoxetine metabolites (fluoxetine and norfluoxetine) at visits 5 (3
effects regression part of the model (i.e. the regressors multiplied
weeks after starting drug) and 9 (end of medication). Assays were
by their coefficients). In the present study, the following assess-
performed after study completion using gas chromatography (Nash
ments of positive and negative affect were missing: 18 at visit 3, 24
at visit 4, 32 at visit 5, 39 at visit 6, 51 at visit 7, 62 at visit 8, 72 atvisit 9. Broken down by group, there were 116 total data pointsmissing from the placebo group, 83 from the 30 mg group, and 99
Axis I disorders were assessed via Structured Clinical Interview forDSM-IV, patient version (SCID; Spitzer et al. 1992). The SCID hasmoderate construct validity, as shown by its favorable comparison
with other diagnostic assessment methods (Williams et al. 1992). Individuals with current axis I disorders other than nicotine
dependence were excluded from the sample.
Baseline smoking history and sociodemographic variables
All study sites were approved by appropriate ethics committees.
were compared across conditions using one way analyses
Participants first attended a screening session where they provided
of variance for continuously scaled variables and chi-
informed consent and were assessed for axis I disorders via theSCID (Spitzer et al. 1992). Those who were eligible for the study
square tests for differences between proportions when
began the first of nine sessions of individual cognitive behavioral
variables were dichotomous. As shown in Table 1,
treatment aimed at achieving smoking cessation by the develop-
smokers randomized to the different treatment conditions
ment of coping skills and relapse prevention. Subjects were
showed no significant differences on age, gender, baseline
randomized on a double-blind basis to receive 10 weeks of placebo(n=60), 30 mg (n=57) or 60 mg (n=58) of fluoxetine, which began
positive and negative affect, nicotine dependence, number
during the second visit. Participants quit smoking 14 days after the
of years smoked, cotinine level, and history of depression.
beginning of the medication phase (just prior to visit 4), so that a
Baseline PANAS scores are comparable to those reported
therapeutic drug level would be achieved before quitting smoking.
in other euthymic samples (Watson et al. 1988).
Assessments of positive and negative affect were collected at eachvisit.
Abstinence was determined via self-report, cotinine, and
Mood change across seven time points (visits 3–9) was analyzedusing mixed linear modeling, implemented via SAS PROC
carbon monoxide assessments collected at each visit. At
MIXED. Random effects regression models used random inter-
visit 5, abstinent smokers comprised 36.7% of those of
cepts, linear and quadratic trend model with autoregressive errors.
placebo, 35.1% of those on 30 mg and 46.1% of those
As recommended, this variance covariance structure for the
taking 60 mg. At visit 6, abstinent smokers comprised
longitudinal data was selected after comparisons with several otherpotential structures (Verbecke and Molenberghs 2000). Nicotine
38.3% of those on placebo, 35.1% of the 30 mg group,
dependence, change in cotinine, and fluoxetine blood levels were
and 39.7% of the 60 mg group. At visit 7, abstinent
utilized as covariates. Change in cotinine at each visit was analyzed
smokers comprised 25% of the placebo group, 26.3% of
as a time varying covariate, which statistically removed the
the 30 mg group, and 25.9% of the 60 mg group. At visit
influence of nicotine exposure on positive and negative affect
8, abstinent smokers comprised 26.7% of those on
across time. Both time and time squared terms were included in allanalyses. Non-significant interaction terms were removed from the
placebo 19.3% of those on 30 mg, and 29.3% of those
and smoking variable meansand standard deviations by
on 60 mg. At visit 9, abstinent smokers comprised 21.7%of the placebo group, 14% of the 30 mg group, and 24.9%of the 60 mg group.
Simple change score analysis (visitbaseline) measuredchange in positive and negative affect at each visit,consistent with our interest in examining fluoxetine’sinfluence on acute changes in affect after quittingsmoking and evidence that mood change represents aclinically relevant affective disturbance during nicotineabstinence (Piasecki et al. 2000). Visits 1 and 2 wereaveraged together to create baseline positive and negativeaffect because treatment did not require smoking reduc-
Fig. 1 Regression function showing estimated positive affect
tion at these measurement points and fluoxetine was not
change by condition across time, covariate adjusted for change in
administered until after visit 2. Prior to creating baseline
cotinine, fluoxetine blood levels and nicotine dependence. Dis-
scores, it was established that positive and negative affect
tances represent real time. Participants quit smoking between visit 3
did not change across visits 1 and 2. Mean positive affect
and 4, 14 days after beginning of medication phase
at visits 1 and 2 was 32.27 and 32.79, respectively(P=0.48) and mean negative affect at visits 1 and 2 was
15.86 and 16.52, respectively (P=0.11).
A significant group by time interaction was present in thelongitudinal analysis of change in positive affect (see
Pearson correlations were computed to identify appropri-
Table 2). Specifically, the 60 mg versus placebo com-
ate covariates. The association between change in positive
and negative affect and the following potential covariates
[t(526)=2.50, P=0.01]. Relative to placebo, those on
were examined: history of depression, nicotine depen-
60 mg fluoxetine experienced an increase in positive
dence (FTQ), number of cigarettes smoked daily, gender,
affect that grew across time (see Fig. 1). There were no
plasma concentrations of fluoxetine metabolites (com-
significant differences between 30 mg and placebo.
posite average of visits 5 and 9), and change in cotinine
Parallel analyses using residualized positive affect as an
from baseline to each visit. Only nicotine dependence,
outcome variable yielded the same results.
fluoxetine blood levels, and change in cotinine weresignificantly correlated with change in positive andnegative affect after cessation (all r<0.05), and were
therefore retained as covariates. Associations betweenchange in positive and negative affect at each visit were
The negative affect model showed a significant linear
also examined. Correlation analysis showed that the
association between change in positive and negative
P=0.02] interaction with time (see Table 3). Relative to
affect was moderate and significant at all time points
placebo, those on 60 mg fluoxetine experienced a
[r=0.21 to 0.41, P<0.05], although not to the extent that
decrease in negative affect. Across time, however, this
they appeared to reflect the same construct.
advantage appeared to diminish (see Fig. 2). There were
positive affect from visit 3through visit 9, determined by
negative affect from visit 3through visit 9, determined by
negative affect (linear, P=0.04; quadratic, P=0.04). Re-sults suggest that positive and negative affect changes areinfluenced by fluoxetine rather than feelings of successafter quitting smoking.
The current results are the first to show that fluoxetineimproves post-quit positive and negative mood states. Thefindings accord with growing evidence that antidepres-sants may be used to reduce affective distress followingquitting smoking (Hall et al. 1998; Shiffman et al. 2000;Lerman et al. 2002). Notably, fluoxetine produced areduction in negative affect and a rise in positive affect. That observation is particularly noteworthy when consid-
Fig. 2 Regression function showing estimated negative affect
ering that other antidepressants have simply attenuated
change by condition across time, covariate adjusted for change in
increases in negative affect (nortriptyline, bupropion) and
cotinine, fluoxetine blood levels and nicotine dependence. Dis-
decreases in positive affect (bupropion) while abstaining
tances represent real time. Participants quit smoking between visit 3
from nicotine. The current results showing that fluoxetine
and 4, 14 days after beginning of medication phase
increased post-cessation positive affect suggest that thedrug may be unique in not only buffering against an
no significant differences between 30 mg and placebo.
aversive mood response to nicotine abstinence, but
Parallel analyses using residualized negative affect as an
actually producing improvement in positive affect fol-
outcome variable yielded the same results.
Fluoxetine’s enhancement of positive affect is inter-
esting to consider given that human pharmacology studies
have focused primarily on SSRI modulation of negativeaffect (Zald and Depue 2001). The dearth of research
We ran parallel analyses among continuous abstainers
examining SSRI influences on positive affect may
versus non-continuous abstainers to examine whether
partially result from the view that positive mood states
fluoxetine’s beneficial mood effects were secondary to
reflect little more than the opposite of negative moods
feelings of success associated with quitting smoking.
along a single affective dimension (Russell and Carroll
Those identified as continuous abstainers were abstinent
1999). Our data, however, showed that changes in post-
at visit 6 and maintained continuous abstinence through
quit positive and negative affect were only moderately
visit 9. Fluoxetine produced similar trends in positive and
intercorrelated. That fluoxetine exerted a more sustained
negative affect in both groups. That is, 60 mg fluoxetine
influence on positive affect than on negative affect also
increased positive affect and decreased negative affect
suggests that these two parameters of affective responses
after quitting, regardless of smoking status. To examine
are at least partially independent. Although those on
the impact of smoking cessation on changes in affect
60 mg fluoxetine experienced reductions in negative
further, continuous abstinence was statistically controlled
affect during the first few weeks after quitting smoking,
in both regression models. Even after controlling for
improvements in negative affect dissipated by end of
abstinence, those taking 60 mg fluoxetine experienced a
treatment (see Fig. 2). In contrast, fluoxetine’s influence
linear increase in positive affect (P=0.01) and decrease in
on positive affect grew stronger across time (see Fig. 1),
resulting in assessments of positive mood that exceeded
(Clark and Watson 1991; Coyne 1994). In the context of
pre-quit levels. The positive affect pattern that emerged
smoking cessation, our data show that 60 mg fluoxetine,
for the 60 mg group is strikingly different than reported
relative to placebo, improved positive and negative affect
losses in positive affect in the placebo group and in others
during nicotine abstinence. In view of prior findings that
abstaining from nicotine (Gilbert et al 1998; Lerman et al.
link mood problems during smoking cessation with
2002; Cook et al. 2003). Fluoxetine appears to have not
relapse, it is plausible that beneficial effects of antide-
only reversed typical reported losses in positive affect
pressants on smoking cessation (Spring et al. 1995; Hurt
following smoking, but stimulated a positive mood
et al. 1997; Hall et al. 1998; Niaura et al. 2002) may be
improvement that continued to grow 8 weeks after
modulated via effects on positive and negative affect.
Clinically, the current findings indicate that fluoxetine is
Animal models of brain reward function are relevant to
helpful in alleviating affective distress triggered by
understanding positive mood effects in humans to the
quitting smoking, and might therefore prove helpful in
extent that positive emotions can be viewed as subjective
preventing post-cessation decline into depression (Bor-
cues that motivate approach behavior toward rewards
relli et al. 1996; Tsoh et al. 2002). An important question
(Depue and Collins 1999). Findings from animal studies
that remains to be examined in future research is whether
indicate that fluoxetine heightens responsivity to rewards,
fluoxetine’s effects on post-cessation affect mediate
and suggest dopaminergic (DA) and serotonergic (5-HT)
mechanisms of action. In animal studies, nicotine absti-nence leads to a decrement in reward functioning that is
Acknowledgements This study was supported in part by DA14144
reversed or prevented by fluoxetine (Harrison et al. 2001),
to Jessica Werth Cook, VA Merit Review, NIH HL63307and HL59348 to Bonnie Spring, 1 K08 DA00467 to Dennis
a finding analogous to fluoxetine’s enhancement of
McChargue, NHLBI R01 62165 to Belinda Borrelli, National
positive affect in the present study. Fluoxetine’s positive
Cancer Institute, Transdisciplinary Tobacco Use Research Center
mood enhancing effects might plausibly come about via
Grant, P50 CA84719 to Brian Hitsman and Raymond Niaura,
5-HT/DA interaction. Fluoxetine administration directly
Forest Laboratories, Pfizer Inc. to Nancy Keuthen, NIH-NCCAM-R21AT00416-01, Metanexus Institute, NIDA, and Fetzer Institute
enhances 5-HT activity, which has been shown to
Grant to Jean Kristeller. Additional funding provided by the
facilitate dopamine release in the nucleus accumbens
National Institute on Drug Abuse, and the Robert Wood Johnson
(Benloucif and Galloway 1991; De Deuwaerdere et al.
1996), and increase sensitivity to reward (Sasaki-Adamsand Kelley 2001). Conversely, decreased 5-HT releaseinhibits DA activity (Ichikawa et al. 1995), a mechanism
that has been linked with acquisition of anhedonia(Harrison et al. 2001; Zagen et al. 2001). Plausibly,
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LACTAÇÃO: não se deve amamentar durante o tratamento com metronidazol visto que o mesmo é excretado no leite materno. O tratamento deve ser descontinuado em caso de ataxia, vertigem, alucinações ou confusão mental. Deve-se empregar precauções apropriadas em pacientes com neuropatias periféricas ou centrais, severas, estáveis ou em evolução, benzoilmetronidazol devido ao risco