Fluoxetine (prozac)

Prozac, one of the best known drugs in the world, is an anti-depressant medication used in the treatment of several psychological disorders. Its main use is in the treatment of major depression but many other disorders can benefit from it. Obsessive-compulsive disorder, bulimia, anorexia, obesity and premenstrual dysphoric disorder are among the best known ones. Prozac is a selective serotonin re-uptake inhibitor, which means that it slows the process of reabsorbing the chemical serotonin and increases its levels in the brain. Since most of the disorders above are believed to be caused by an imbalance of serotonin, Prozac can be very beneficial in their treatment. Hypotension and chronic headache are also believed to be helped by fluoxetine.

Zh Vyssh Nerv Deiat Im I P Pavlova. 2005 Mar-Apr;55(2):207-12.
[Effects of fluoxetine and its complexes with glycyrrizhinic acid on behavior and brain monoamine levels in rats]
[Article in Russian]
[No authors listed]

Effects of serotonin uptake inhibitor fluoxetine (F) and it's complexes with glycyrrizhinic acid (GA) in molar proportions 1GA : 1F (FGA-1) and 4GA : 1F (FGA-4) on rat behavior in elevated plus-maze and brain monoamine concentrations were studied. Drugs (25 mg/kg) were administered per os 1 h before investigations. F-treated rats showed increased anxiety and reduced locomotor activity, whereas FGA-1 and FGA-4 had no effects on the behaviors. None of the compounds modified brain tissue serotonin content, but all of them decreased the level of its metabolite 5-hydroxyindole-3-acetic acid level in the hypothalamus, and FGA-4 also decreased it in the cortex. Noradrenaline levels were increased in the hypothalamus of rats treated with F in both combinations with GA. In the striatum, F increased dopamine and its metabolite DOPAC levels, but their ratio (an indicator of the neurotransmitter turnover) was not altered by this drug. Unlike F, FGA-1 significantly activated dopamine turnover in the striatum. The data obtained suggested that application of F in complexes with GA significantly modified the drug behavioral effects and these alterations may be related to specific effects of the pure compound and its complexes on the functions of the brain monoaminergic systems that regulate investigated behavior.

Mov Disord. 2005 May 13;
Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson's disease and concurrent depression.
Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, Rumi DO, Barbosa ER, Odebrecht Rosa M, Pascual-Leone A, Rigonatti SP, Marcolin MA, Araujo Silva MT.
Department of Experimental Psychology, Institute of Psychology, University of Sao Paulo, Sao Paulo, SP, Brazil.

Previous studies show that cognitive functions are more impaired in patients with Parkinson's disease (PD) and depression than in nondepressed PD patients. We compared the cognitive effects of two types of antidepressant treatments in PD patients: fluoxetine (20 mg/day) versus repetitive transcranial magnetic stimulation (rTMS, 15 Hz, 110% above motor threshold, 10 daily sessions) of the left dorsolateral prefrontal cortex. Twenty-five patients with PD and depression were randomly assigned either to Group 1 (active rTMS and placebo medication) or to Group 2 (sham rTMS and fluoxetine). A neuropsychological battery was assessed by a rater blind to treatment arm at baseline and 2 and 8 weeks after treatment. Patients in both groups had a significant improvement of Stroop (colored words and interference card) and Hooper and Wisconsin (perseverative errors) test performances after both treatments. Furthermore, there were no adverse effects after either rTMS or fluoxetine in any neuropsychological test of the cognitive test battery. The results show that rTMS could improve some aspects of cognition in PD patients similar to that of fluoxetine. The mechanisms for this cognitive improvement are unclear, but it is in the context of mood improvement. (c) 2005 Movement Disorder Society.

Biol Psychiatry. 2005 Feb 1;57(3):301-9.
Efficacy of cognitive behavioral therapy and fluoxetine for the treatment of binge eating disorder: a randomized double-blind placebo-controlled comparison.
Grilo CM, Masheb RM, Wilson GT.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA. carlos.grilo@yale.edu
BACKGROUND: Cognitive behavioral therapy (CBT) and certain medications have been shown to be effective for binge eating disorder (BED), but no controlled studies have compared psychological and pharmacological therapies. We conducted a randomized, placebo-controlled study to test the efficacy of CBT and fluoxetine alone and in combination for BED. METHODS: 108 patients were randomized to one of four 16-week individual treatments: fluoxetine (60 mg/day), placebo, CBT plus fluoxetine (60 mg/day) or CBT plus placebo. Medications were provided in double-blind fashion. RESULTS: Of the 108 patients, 86 (80%) completed treatments. Remission rates (zero binges for 28 days) for completers were: 29% (fluoxetine), 30% (placebo), 55% (CBT+fluoxetine), and 73% (CBT+placebo). Intent-to-treat (ITT) remission rates were: 22% (fluoxetine), 26% (placebo), 50% (CBT+fluoxetine), and 61% (CBT+placebo). Completer and ITT analyses on remission and dimensional measures of binge eating, cognitive features, and psychological distress produced consistent findings. Fluoxetine was not superior to placebo, CBT+fluoxetine and CBT+placebo did not differ, and both CBT conditions were superior to fluoxetine and to placebo. Weight loss was modest, did not differ across treatments, but was associated with binge eating remission. CONCLUSIONS: CBT, but not fluoxetine, demonstrated efficacy for the behavioral and psychological features of BED, but not obesity.

Pharmacopsychiatry. 2005 Jan;38(1):13-6. Related Articles, Links
Fluoxetine versus trimipramine in the treatment of depression in geriatric patients.
Wehmeier PM, Kluge M, Maras A, Riemann D, Berger M, Kohnen R, Dittmann RW, Gattaz WF.
Lilly Deutschland, Bad Homburg, Germany.
INTRODUCTION: Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), and trimipramine, a tricyclic antidepressant (TCA), were compared in terms of efficacy and tolerability in a six-week, parallel group, double-blind pilot study in 41 geriatric patients with major depression (61 - 85 years old). METHOD: The Hamilton Rating Scale for Depression (HAMD-17), the Montgomery-Asberg Rating Scale (MADRS), the Adjective Mood Scale (Bf-S), the Clinical Global Impression (CGI), and the Patients Global Impression (PGI) were used to measure changes in depressive symptoms. RESULTS: Improvement with treatment was found on all scales. Efficacy and tolerability were similar in both groups. No statistically significant differences were found. CONCLUSION: These findings suggest that fluoxetine and trimipramine are comparable in terms of efficacy and tolerability in the treatment of major depression in geriatric patients.

J Am Chem Soc. 2004 Oct 20;126(41):13335-42.
Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids.
Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP.
SSCI, Inc., 3065 Kent Avenue, West Lafayette, Indiana 47906, and Design Science Research, LLC, 1256 Briarcliff Road, Atlanta, Georgia 30306.
A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.

Cancer Res. 2004 Oct 15;64(20):7562-9.
Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models.
Peer D, Dekel Y, Melikhov D, Margalit R.
Department of Biochemistry, the George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv, Israel.
Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.

Consum Rep. 2004 Oct;69(10):22-9.
Drugs vs. talk therapy: 3,079 readers rate their care for depression and anxiety.
With or without drugs, most people who sought care for depression or anxiety gained relief. A survey of thousands of CR subscribers who recently received treatment for those conditions found that: (1) a combination of talk therapy and drugs often worked best. But "mostly talk" therapy was almost as effective if it lasted for 13 or more visits. (2) "Mostly drug" therapy was also effective for many people. Drugs had a quicker impact on symptoms than talk therapy, but it often took trial and error to find a drug that worked without unacceptable side effects. (3) Forty percent of people who took antidepressants complained of adverse sexual side effects. (4) Care from primary-care doctors was effective for people with mild problems, but less so for people with severe ones.

Arch Gen Psychiatry. 2004 Sep;61(9):877-89.
Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.
Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET.
Institute of Psychiatry, King's College London, London, England.
BACKGROUND: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing. OBJECTIVES: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response. DESIGN: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness. SETTING: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients. PATIENTS AND OTHER PARTICIPANTS: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers.Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks. MAIN OUTCOME MEASURES: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference. RESULTS: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. CONCLUSIONS: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

Clin Neurophysiol. 2004 Sep;115(9):2157-63.
Fluoxetine facilitates use-dependent excitability of human primary motor cortex.
Pleger B, Schwenkreis P, Grunberg C, Malin JP, Tegenthoff M.
Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany. burkhard.v.pleger@ruhr-uni-bochum.de
OBJECTIVES: In poststroke patients, fluoxetine, a selective serotonin-reuptake inhibitor, as an adjunct to physical therapy provided a better functional recovery from motor deficits. The aim of this study was to investigate the effect of a single dose of 20 mg fluoxetine on motor learning and associated cortical changes in healthy right-handed subjects in order to get deeper insight into its facilitating influence on human motor cortex. METHODS: Subjects performed a motor task consisting of a simultaneous co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle with and without fluoxetine in a placebo-controlled double-blinded crossover study design. Immediately before and after motor learning motor output maps of the APB muscle were assessed in order to get insight into plastic changes of the muscle representation. RESULTS: We found a significantly improved motor performance under both conditions without having substantial differences between placebo and fluoxetine. After the completion of the motor task there was a medial shift of the APB muscle motor output map. Only after the administration of fluoxetine the sum of MEP amplitudes (SOA) increased and the motor output map enlarged. CONCLUSIONS: These findings provide evidence for a use-dependent facilitating effect of fluoxetine on cortical excitability but not on motor performance. SIGNIFICANCE: Our findings are not in line with previous experiments in poststroke patients. However, long-term treatment with fluoxetine may additionally improve motor function by upregulating serotonergic receptors. Further studies investigating the influence of long-term treatment on cortical excitability and psychophysics may therefore provide deeper insight into a possible therapeutical efficiency of fluoxetine in poststroke patients.

Environ Toxicol Chem. 2004 Sep;23(9):2229-33.
Acute and chronic toxicity of five selective serotonin reuptake inhibitors in Ceriodaphnia dubia.
Henry TB, Kwon JW, Armbrust KL, Black MC.
Department of Environmental Health Science, University of Georgia, Athens, Georgia 30602, USA. thenry@uga.edu
Contamination of surface waters by pharmaceutical chemicals has raised concern among environmental scientists because of the potential for negative effects on aquatic organisms. Of particular importance are pharmaceutical compounds that affect the nervous or endocrine systems because effects on aquatic organisms are possible at low environmental concentrations. Selective serotonin reuptake inhibitors (SSRIs) are drugs used to treat clinical depression in humans, and have been detected in low concentrations in surface waters. In this investigation, the acute and chronic toxicity of five SSRIs (fluoxetine, Prozac; fluvoxamine, Luvox; paroxetine, Paxil; citalopram, Celexa; and sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48-h median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8-d) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48-h LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8-d chronic tests were similar to the 48-h acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubia; however, only at concentrations that are considerably higher than those expected in the environment.

J Bone Miner Res. 2004 Sep;19(9):1420-31. Epub 2004 Jun 21.
Serotonin regulates osteoclast differentiation through its transporter.
Battaglino R, Fu J, Spate U, Ersoy U, Joe M, Sedaghat L, Stashenko P.
Department of Cytokine Biology, The Forsyth Institute, Boston, Massachusetts 02115, USA.
5-HTT mediates antidepressant-sensitive clearance of 5-HT after its release into neural synapses. We found increased expression of 5-HTT in RANKL-induced osteoclast-like cells. Fluoxetine, an inhibitor of 5-HTT, reduced osteoclast differentiation but not activation. Reserpine, an inhibitor of 5-HT intracellular transport, potentiated differentiation. These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass. INTRODUCTION: Interactions between the serotonergic and skeletal systems are suggested by various clinical observations but are poorly understood. MATERIALS AND METHODS: Using gene microarrays, we found that the serotonin transporter (5-HTT) was strongly expressed in RANKL-induced osteoclasts. Using RANKL stimulation of RAW264.7 cells and mouse bone marrow cells as a model system for osteoclast differentiation, we studied the possible role/s of the different components of the serotonin (5-HT) system on the differentiation process. RESULTS: Osteoclast 5-HTT exhibited typical 5-HT uptake activity that was inhibitable by fluoxetine (Prozac). Fluoxetine reduced osteoclast differentiation but did not inhibit the activation of preformed osteoclasts, whereas the addition of 5-HT itself enhanced differentiation. Fluoxetine-treated osteoclast precursors had reduced NF-kappa B activation and elevated inhibitory protein kappa B alpha (I kappa B alpha) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-kappa B. Reserpine inhibition of intracellular transport of 5-HT into cytoplasmic vesicles potentiated RANKL-induced osteoclast formation, suggesting the importance of intracellular 5-HT in regulating osteoclast differentiation. Reserpine also modestly enhanced the expression of the osteoclast marker TRACP in the absence of RANKL. CONCLUSIONS: Taken together, these data suggest that the 5-HT system plays an important role in bone homeostasis through effects on osteoclast differentiation and implies that commonly used antidepressive agents may affect bone mass.

Neuropsychopharmacology. 2004 Sep;29(9):1752-61.
Dichotic listening tests of functional brain asymmetry predict response to fluoxetine in depressed women and men.
Bruder GE, Stewart JW, McGrath PJ, Deliyannides D, Quitkin FM.
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. bruderg@pi.cpmc.columbia.edu
Patients having a depressive disorder vary widely in their therapeutic responsiveness to a selective serotonin reuptake inhibitor (SSRI), but there are no clinical predictors of treatment outcome. Studies using dichotic listening, electrophysiologic and neuroimaging measures suggest that pretreatment differences among depressed patients in functional brain asymmetry are related to responsiveness to antidepressants. Two new studies replicate differences in dichotic listening asymmetry between fluoxetine responders and nonresponders, and demonstrate the importance of gender in this context. Right-handed outpatients who met DSM-IV criteria for major depression, dysthymia, or depression not otherwise specified were tested on dichotic fused-words and complex tones tests before completing 12 weeks of fluoxetine treatment. Perceptual asymmetry (PA) scores were compared for 75 patients (38 women) who responded to treatment and 39 patients (14 women) who were nonresponders. Normative data were also obtained for 101 healthy adults (61 women). Patients who responded to fluoxetine differed from nonresponders and healthy adults in favoring left- over right-hemisphere processing of dichotic stimuli, and this difference was dependent on gender and test. Heightened left-hemisphere advantage for dichotic words in responders was present among women but not men, whereas reduced right-hemisphere advantage for dichotic tones in responders was present among men but not women. Pretreatment PA was also predictive of change in depression severity following treatment. Responder vs nonresponder differences for verbal dichotic listening in women and nonverbal dichotic listening in men are discussed in terms of differences in cognitive function, hemispheric organization, and neurotransmitter function.

Psychosomatics. 2004 Sep-Oct;45(5):438-44.
Change in psychosocial functioning and quality of life of patients with body dysmorphic disorder treated with fluoxetine: a placebo-controlled study.
Phillips KA, Rasmussen SA.
Butler Hospital, Providence, RI, USA. Katharine_Phillips@brown.edu
In a 12-week placebo-controlled study of fluoxetine in the treatment of body dysmorphic disorder, the authors investigated change in psychosocial functioning and mental health-related quality of life in 60 subjects. The subjects were assessed with the LIFE-RIFT (a measure of impaired functioning), Social and Occupational Functioning Scale (SOFAS), and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) before and after receiving fluoxetine or placebo. At baseline, the patients had impaired psychosocial functioning and markedly poor mental health-related quality of life. Compared to placebo, fluoxetine was associated with significantly greater improvement in LIFE-RIFT and SOFAS scores and with improvement on the mental health subscale of the SF-36 that approached significance. Decrease in the severity of body dysmorphic disorder, as measured by the Yale-Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder, was significantly correlated with improvement in functioning and quality of life.

Psychosomatics. 2004 Sep-Oct;45(5):419-25.
Comorbid medical illness and relapse of major depressive disorder in the continuation phase of treatment.
Iosifescu DV, Nierenberg AA, Alpert JE, Papakostas GI, Perlis RH, Sonawalla S, Fava M.
Depression Clinical and Research Program, Psychiatry Department, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. diosifescu@partners.org
The authors examined the impact of comorbid medical illness on the rate of relapse of major depressive disorder during continuation therapy. Subjects (N = 128) with major depressive disorder (according to DSM-III-R criteria) achieved clinical remission (a 17-item Hamilton Depression Rating Scale score < or = 7) after 8 weeks of treatment with fluoxetine and entered the continuation phase of antidepressant treatment. They used the Cumulative Illness Rating Scale to measure the severity of comorbid medical illness. Eight patients (6.3%) relapsed during the 28-week continuation phase. With logistic regression, the total burden and the severity of comorbid medical illness significantly predicted the relapse of major depressive disorder during continuation therapy with fluoxetine. Greater medical comorbidity was also associated with higher increases in self-reported symptoms of depression, anxiety, and anger during the follow-up.

J Neurosci Methods. 2004 Aug 30;137(2):161-5.
Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex.
Williams JM, Steketee JD.
Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA. jmwilliams@utmem.edu
Accumulating evidence suggests that dopamine (DA) uptake into mesocortical neurons may be regulated through mechanisms that are markedly different from those observed in nigrostriatal or mesoaccumbens systems. The current studies were conducted to develop a rapid and sensitive DA uptake assay in crude synaptosomes prepared from the medial prefrontal cortex (mPFC) of a single animal. Uptake of DA into the mPFC was saturable, linear with respect to protein concentration, time dependent, and sensitive to the effects of monoamine transport inhibitors. Saturation analysis revealed the K(m) and V(max) values for DA transport in the mPFC were approximately 60 nM and 6.5 pmol/min mg protein, respectively. A significant amount of DA uptake in the mPFC was more sensitive to inhibition by nisoxetine compared to GBR12909, fluoxetine (FLX), and cocaine (COC), suggesting the norepinephrine transporter (NET) plays an important role in the clearance of DA within this region. The described assay conditions would be useful in examining DA uptake within specific brain regions obtained from a single animal.

Brain Res. 2004 Aug 27;1018(2):201-7.
Fluoxetine inhibits A-type potassium currents in primary cultured rat hippocampal neurons.
Choi JS, Choi BH, Ahn HS, Kim MJ, Han TH, Rhie DJ, Yoon SH, Jo YH, Kim MS, Hahn SJ.
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
The effects of fluoxetine (Prozac) on the transient A-currents (IA) in primary cultured hippocampal neurons were examined using the whole-cell patch clamp technique. Fluoxetine did not significantly decrease the peak amplitude of whole-cell K+ currents, but it accelerated the decay rate of inactivation, and thus decreased the current amplitude at the end of the pulse. For further analysis, IA and delayed rectifier K+ currents (IDR) were isolated from total K+ currents. Fluoxetine decreased IA (the integral of the outward current) in a concentration-dependent manner with an IC50 of 5.54 microM. Norfluoxetine, the major active metabolite of fluoxetine, was a more potent inhibitor of IA than was fluoxetine, with an IC50 of 0.90 microM. Fluoxetine (3 microM) inhibited IA in a voltage-dependent manner over the whole range of membrane potentials tested. Analysis of the time dependence of inhibition gave estimates of 34.72 microM(-1) s(-1) and 116.39 s(-1) for the rate constants of association and dissociation, respectively. The resulting apparent Kd was 3.35 microM, similar to the IC50 value obtained from the concentration-response curve. In current clamp configuration, fluoxetine (3 microM) induced depolarization of resting membrane potential and reduced the rate of action potential. Our results indicate that fluoxetine produces a concentration- and voltage-dependent inhibition of IA, and that this effect could affect the excitability of hippocampal neurons.

JAMA. 2004 Aug 18;292(7):807-20.
Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial.
March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team.
Duke Clinical Research Institute, Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. jsmarch@acpub.duke.edu
CONTEXT: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. OBJECTIVE: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. INTERVENTIONS: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. MAIN OUTCOME MEASURES: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. RESULTS: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. CONCLUSION: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.

Eur Neuropsychopharmacol. 2004 Aug;14(4):274-81.
Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test.
Harkin A, Connor TJ, Burns MP, Kelly JP.
Department of Pharmacology, National University of Ireland, Galway, Ireland. andrew.harkin@nuigalway.ie
The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor NG-nitro-L-arginine (L-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion L-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between L-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.

J Clin Psychiatry. 2004 Aug;65(8):1096-8.
Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy.
Papakostas GI, Petersen T, Mischoulon D, Green CH, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M.
Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. gpapakostas@partners.org
OBJECTIVE: In the present study, we assessed the relationship between serum folate, vitamin B12, and homocysteine levels on the rate of relapse in outpatients with remitted major depressive disorder (MDD) during a 28-week continuation phase of treatment with fluoxetine. METHOD: Seventy-one outpatients (mean +/- SD age = 40.2 +/- 11.1 years; 56.3% women) with MDD (as assessed with the Structured Clinical Interview for DSM-III-R) who had remitted and who were enrolled in the continuation phase of treatment with fluoxetine had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to acute-phase treatment). Patients were followed for 28 weeks of continued treatment with fluoxetine 40 mg/day to monitor for depressive relapse. Folate levels were classified as either low (< or = 2.5 ng/mL) or normal. Vitamin B12 levels were classified as either low (< or = 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (> or = 13.2 micromol/L) or normal. With the use of separate logistic regressions, we then assessed the relationship between folate, vitamin B12, and homocysteine level status and relapse. The study was conducted from November 1992 to January 1999. RESULTS: The presence of low serum folate levels (p =.004), but not low B12 (p >.05) or elevated homocysteine levels (p >.05), was associated with relapse during continuation treatment with fluoxetine. The relapse rates for patients with (N = 7) and without (N = 64) low folate levels were 42.9% versus 3.2%, respectively. CONCLUSION: Low serum folate levels were found to place patients with remitted MDD at risk for depressive relapse during the continuation phase of treatment with fluoxetine.

J Clin Psychiatry. 2004 Aug;65(8):1090-5.
Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression.
Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M.
Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. gpapakostas@partners.org
OBJECTIVE: In the present study, we assessed the relationship between serum folate, vitamin B12, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. METHOD: Fifty-five outpatients (mean +/- SD age = 41.7 +/- 10.6 years; 50.9% women) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to fluoxetine treatment initiation). Folate levels were classified as either low (< or = 2.5 ng/mL) or normal. Vitamin B12 levels were classified as either low (< or = 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (> or = 13.2 micromol/L) or normal. With the use of a logistic regression, we then assessed the relationship between (1) low or normal folate levels, (2) normal or low B12 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. RESULTS: Low serum folate levels (chi2=3.626, p =.04), but not elevated homocysteine (p >.05) or low vitamin B12 levels (p >.05), were associated with poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. CONCLUSION: Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD.

J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1171-4.
Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease.
Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA.
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ffregni@bidmc.harvard.edu
OBJECTIVE: To study the efficacy of 15 Hz repetitive transcranial magnetic stimulation (rTMS) in treating depression in patients with Parkinson's disease. METHODS: 42 patients were enrolled into two groups: group 1, active rTMS (15 Hz rTMS for 10 days) and placebo drug treatment; group 2, sham rTMS and fluoxetine 20 mg/day. A specially designed sham coil was used for sham stimulation. The unified Parkinson's disease rating scale (UPDRS), activities of daily living (ADL), Hamilton rating scale for depression (HRSD), Beck depression inventory (BDI), and mini-mental state examination (MMSE) were assessed by a rater blinded to treatment arm. RESULTS: HRSD and BDI were improved to the same extent in both groups after two weeks of treatment (38% and 32% for group 1, 41% and 33% for group 2, respectively). At week 8 there was a tendency for worse motor UPDRS scores in group 2 (NS). ADL showed improvement at week 8 only in group 1. MMSE improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. CONCLUSIONS: rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.

Expert Opin Pharmacother. 2003 Oct;4(10):1659-78.
Towards the pharmacotherapy of eating disorders.
Pederson KJ, Roerig JL, Mitchell JE.
The Neuropsychiatric Research Institute, 700 First Avenue South, Fargo, ND 58103, USA.
The purpose of this review is to discuss pharmacological options for the treatment of patients with eating disorders. Sequentially described are pharmacotherapy studies of anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). The quantity of drug trials performed with AN patients has been very limited. While the majority of studies have failed to show medication efficacy for the acute treatment of AN, there is data which suggests that fluoxetine hydrochloride may play a role in preventing relapse during maintenance therapy. Atypical antipsychotics, most often olanzapine, have shown promise in a number of uncontrolled studies. BN has been most extensively studied, with the majority of pharmacological trials focusing on antidepressants. Fluoxetine, at a dose of 60 mg/day, is FDA-approved for the treatment of BN. Psychotherapy, particularly cognitive behavioural therapy (CBT) is of well-established utility in BN and data suggests that the combination of an antidepressant plus CBT is superior to either treatment alone. Recently, there has been interest in the 5-HT3 antagonist, ondansetron, and the anticonvulsant, topiramate. BED investigators have focused largely on antidepressants, which may reduce symptoms of depression and augment psychotherapy. While sibutramine and topiramate have both been associated with weight loss in controlled trials, the former appears to be fairly well-tolerated and the latter appears to be responsible for the emergence of significant cognitive and peripheral nervous system side effects in some patients. Further pharmacological research with eating disorder patients is needed, particularly in the areas of AN and BED. Also, pharmacological augmentation strategies for those not responding to primary therapies should be explored.

Int J Eat Disord. 2004 Jan;35(1):10-5.
Use of nutritional supplements to increase the efficacy of fluoxetine in the treatment of anorexia nervosa.
Barbarich NC, McConaha CW, Halmi KA, Gendall K, Sunday SR, Gaskill J, La Via M, Frank GK, Brooks S, Plotnicov KH, Kaye WH.
Department of Psychiatry, University of Pittsburgh Medical School, Anorexia and Bulimia Nervosa Research Module, Pittsburgh, Pennsylvania.
OBJECTIVE: Selective serotonin reuptake inhibitor (SSRI) medication does not appear to be effective in ill, malnourished anorexia nervosa (AN) patients. However, it may be effective in preventing relapse after weight restoration. The purpose of this study was to determine whether nutritional supplements could potentiate the effects of fluoxetine in underweight AN subjects. METHOD: Twenty-six subjects with AN participated in a trial of fluoxetine. In a double-blind, placebo-controlled manner, subjects received either nutritional supplements or a nutritional placebo. The nutritional supplement included tryptophan (the precursor of serotonin), vitamins, minerals, and essential fatty acids believed to influence serotonin pathway function. RESULTS: There was no significant difference in weight gain between subjects treated with fluoxetine plus nutritional supplements versus fluoxetine plus a nutritional placebo. Moreover, there were no significant differences between groups on mean changes in anxiety or obsessive and compulsive symptoms. DISCUSSION: The results of this study suggest that supplement strategies are not a substitute for adequate nutrition and are ineffective in increasing the efficacy of fluoxetine in underweight AN subjects. Copyright 2003 by Wiley Periodicals, Inc. Int J Eat Disord 35: 10-15, 2004.

Cereb Cortex. 2004 Feb;14(2):224-229.
Acute Stress-induced Changes in Hippocampal/Prefrontal Circuits in Rats: Effects of Antidepressants.
Rocher C, Spedding M, Munoz C, Jay TM, .
NAMC, CNRS UMR 8620, Bat. 446, Universite Paris-Sud, 91405 Orsay, France. I.R.I.SERVIER, 31 rue du Pont, 92578, Neuilly sur Seine Cedex, France Present address: E0117 INSERM-Paris 5, Hopital Sainte-Anne, 2ter rue d'Alesia, 75014 Paris, France.
Acute stress inhibits long-term potentiation (LTP) at synapses from the hippocampus to prefrontal cortex in the rat, a model of the dysfunction in the anterior cingulate/orbitofrontal cortices which has been observed in human depression. We demonstrate that the antidepressants tianeptine and, to a lesser extent, fluoxetine, are able to reverse the impairment in LTP, a measure of frontal synaptic plasticity, caused by stress on an elevated platform. LTP was induced by stimulation of hippocampal outflow. Beneficial effects on neuronal plasticity, defined as a reversal of the effects of stress in this paradigm, can be considered as a new animal model for the impact of stress on hippocampal/frontal circuits, a key target in psychiatric diseases

Ann Pharmacother. 2003 Dec;37(12):1800-3.
Memory loss in a patient treated with fluoxetine.
Joss JD, Burton RM, Keller CA.
Jacqueline D Joss PharmD, Clinical Pharmacy Specialist, Ambulatory Services, Good Samaritan Regional Medical Center, Corvallis, OR.

OBJECTIVE: To report a case of severe memory loss in an elderly patient after initiation of fluoxetine.CASE SUMMARY: An 87-year-old white woman was started on fluoxetine for depression, and the dose was titrated to 20 mg/d. She developed progressive memory loss over the next 6 weeks for which she ultimately was hospitalized. Other potential causes for her memory loss were ruled out. After fluoxetine was discontinued, the patient's memory improved significantly over the next 2 months. An objective causality assessment indicated a possible relationship between the memory loss and fluoxetine in this patient.DISCUSSION: Our report documents a case of severe reversible memory deterioration after initiating fluoxetine. Fluoxetine has a favorable adverse effect profile when compared with older classes of antidepressants. Postmarketing studies and isolated case reports, however, suggest that fluoxetine may harm memory in some patients. Some selective serotonin-reuptake inhibitors (SSRIs) appear to cause memory loss more frequently than others.CONCLUSIONS: Clinicians should be aware of the possible effects of fluoxetine (and possibly other SSRIs) on memory.

J Clin Psychopharmacol. 2003 Dec;23(6):549-52.
Department of Psychiatry, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Moosa MY, Panz VR, Jeenah FY, Joffe BI.

African women with depression: the effect of imipramine and fluoxetine on body mass index and leptin secretion.
SUMMARY: Treatment of depression is often accompanied by weight changes. Previous studies indicate that leptin plays no role in this change despite showing a strong correlation with body mass index (BMI) in healthy people. The aim of this study was to evaluate the effect of imipramine and fluoxetine on BMI and its correlation with leptin. Eighteen depressed female patients randomly received either drug for 3 months. BMI was calculated and fasting blood samples were assayed for glucose, leptin, insulin, free fatty acids (FFA), and lipids. The difference between the changes in BMI (imipramine + 1.0 kg/m2, fluoxetine -0.5 kg/m2) was statistically significant (P < 0.05, t = 2.106). There was a significant positive correlation between overall BMI and leptin (r = 0.784, P < 0.001) but not between BMI and insulin or FFA. However, fasting insulin levels and calculated insulin resistance levels dropped substantially in the imipramine group. We conclude that the use of tricyclic antidepressants (TCAs) in depressed patients at risk for developing type 2 diabetes remains unresolved at this stage.

Pediatrics. 2003 Nov;112(5):e425.
Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs.
Epperson CN, Jatlow PI, Czarkowski K, Anderson GM.
Department of Psychiatry, Yale University School of Medicine, Connecticut, USA.

Postpartum major depression, a frequently (10%) occurring complication of childbirth, adversely affects the mother's functioning, the mother-infant relationship, and the child's subsequent development and propensity for later psychopathology. Although selective serotonin reuptake inhibitors (SSRIs) are effective in treating postpartum depression, concerns have been raised regarding their use in lactating women. Although plasma drug levels of infants who are exposed to SSRIs through breast milk are low compared with those typically seen in patients, infant levels in some reports do seem to be at or near the drugs' reported affinities (K(D)s) and IC(50)s for inhibition at the serotonin (5-hydroxytryptamine [5-HT]) transporter. The impact of central serotonin 5-HT modulation by SSRIs during critical periods of brain development is unknown. These concerns have led our group to examine whether exposure through breast milk has a discernible effect on platelet 5-HT uptake. Taking advantage of the similarities between platelet and neuronal serotonin transporters, we previously used measurements of platelet 5-HT before and during maternal sertraline treatment to determine the degree of 5-HT transporter blockade in breastfed infants. We found that infants who were exposed to sertraline through their mothers' breast milk experienced little to no change in platelet 5-HT levels, suggestive of minimal effects on peripheral and central 5-HT transporter blockade. Compared with sertraline and most other SSRIs, fluoxetine and its active metabolite, norfluoxetine, have substantially longer plasma half-lives, and both compounds have been found in measurable quantities in plasma of nursing infants. Thus, to extend our previous work in this area, we measured platelet 5-HT levels and plasma drug levels in breastfeeding mother-infant pairs before and during maternal treatment with fluoxetine. METHODS: Maternal and infant transporter blockade was assessed by measurement of platelet 5-HT in 11 breastfeeding mother-infant pairs before and after 4 to 12 weeks of maternal fluoxetine (20-40 mg/d) treatment for postpartum depression. The study was approved by the Human Investigation Committee of Yale University School of Medicine, and each mother (mean age: 34.5 years; standard deviation [SD]: 5.3) gave written informed consent. Whole-blood 5-HT levels and plasma fluoxetine and norfluoxetine levels were determined by high-performance liquid chromatography. RESULTS: Five mothers were taking 20 mg of fluoxetine daily, 4 were taking 30 mg daily, and 2 were taking 40 mg daily. Mean infant age at the start of the study was 16.8 (SD: 8.8) weeks. All infants except 1 were <6 months of age and 4 were <3 months of age when their mothers began treatment. Six infants were breastfed exclusively; the remaining were breastfed between 3 and 8 times daily and were given supplemental feedings. Mean maternal postexposure 5-HT levels of 22.9 ng/mL (SD: 12.5) were markedly lower than mean preexposure (baseline) levels of 156.6 ng/mL (SD: 71.4; paired t = 6.9, df = 10). In contrast, the mean infant pre- and postexposure 5-HT concentrations of 217.1 (SD: 66.5) and 229.9 (SD: 83.5) ng/mL, respectively, were similar (paired t = -0.24, df = 10). However, the 1 infant with measurable plasma fluoxetine had a substantial decline in 5-HT to 40% of baseline. In samples obtained from the same infant 4 months later, plasma drug levels were undetectable (<1 ng/mL) and the platelet serotonin levels were no longer reduced (12% increase from baseline). CONCLUSIONS: The marked declines (to 9%-28% of baseline) in platelet 5-HT concentrations seen in mothers who were treated with the SSRI fluoxetine were similar to those observed in our study of sertraline in breastfeeding and other previous studies. In contrast, all but 1 infant experienced little or no decline in whole-blood (platelet) 5-HT concentrations after exposure to fluoxetine through breast milk. The substantial drop in platelet 5-HT seen in 1 infant and the coupling of this drop with measurable plasma fluoxetine leves drop with measurable plasma fluoxetine level raises some concern. Possible reasons for the infant's measurable plasma fluoxetine level include his mother's high plasma drug level and his being breastfed exclusively. However, the observations may be coincidental, and the infant experienced no discernible adverse effects. These data suggest that most infants may continue to breastfeed without experiencing meaningful changes in platelet 5-HT transport while their mothers are treated with 20 to 40 mg of fluoxetine daily. Given the limited data regarding occurrence and extent of SSRI exposure and the uncertainties concerning the possible effects of exposure, it is premature to propose treatment guidelines. Our own advice to women who are thinking of combining breastfeeding and SSRI treatment will weigh a range of factors, including severity of postpartum depression, any demonstrated preferential response to a specific SSRI, and the mother's commitment to breastfeeding. Additional research is needed to establish more definitively the frequency of physiologically meaningful infant SSRI exposure during breastfeeding and to determine the behavioral consequences of such exposure.