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This effect of estrogen buy 80mg tadapox overnight delivery erectile dysfunction condom, however cheap tadapox 80mg with amex erectile dysfunction watermelon, does not appear to be mediated by a change in the satiating potency of CCK. Both effects of estrogen depend on binding to the estro- gen receptor because mice with this receptor knocked out do not show either effect (52). There are sex differences in the incidence or clinical course of many diseases associated with anorexia as well as in the anorectic response to many immune-system mediators, such as IL-1 and -TNF. Some of these sex differences appear to be related to estrogenic function. Crohn disease, an inflammatory bowel disease in which anorexia is an early sign (53), is one such. Anorexia caused by Gram-negative bacterial infection is also estradiol-sensitive. The effect of estradiol to increase the anorexia produced in rats by intraperitoneal administra- tion of bacterial lipopolysaccharide is expressed by a decrease in meal frequency without a change in meal size (56), indi- cating that this effect of estrogen is separate from the effects on meal size. Furthermore, endogenous CCK does not appear to contribute to Our understanding of the controls of eating in rodents has the tonic inhibitory effect of estradiol on meal size because deva- been transformed in the past 5 years. Although the relation- zepide did not increase meal size during diestrus. Data are mean ship of eating to nutritional and energetic homeostasis con- meal sizes per 3-hour quartile of the nocturnal phase. More attention to behavioral analysis not an artifact of the cyclic differences in meal size. It has meal size after devazepide larger than after vehicle, P. Re- revealed the operation of a cpg as the final common path produced from Eckel LA, Geary N. The satiating effect of cholecystokinin and The recognition that the size of a meal is under positive bombesin-like peptides. Satiation: from gut to and negative feedback controls has been exploited. Inhibition of food strated to be involved in these feedbacks. The afferent nerves intake in response to intestinal lipid is mediated by cholecystoki- that carry the peripheral information generated along the nin in humans. Cholecystokinin decreases sucrose intake in preabsorptive surface of the gut from the tip of the tongue chronic decerebrate rats. In: Bray of these peripheral mechanisms are activated in every meal, GA, Ryan DH, eds. Baton Rouge, all controls of eating not related to the food being ingested LA: Louisiana State University Press, 1999:227–245. Identification of rat brainstem multisynaptic a new theory of the controls of eating that is more biological, connections to the oral motor nuclei using pseudorabies virus. In: Adelman G, Smith The widely distributed processing of information rele- BH, eds. Systemic factors in the control of food tance and complexity of eating in omnivores such as rodents intake. Patterns of body pressing questions for rodents as well as humans. The ability temperature during feeding in rats under varying ambient tem- peratures. Recognition of this fact increasingly affects re- of food intake after 2-deoxy-D-glucose and nicotinic acid injec- search on eating. The paradigm shift that the study of eating has under- 16. Analysis of the microstructure of the rhythmic tongue movements of rats ingesting maltose and sucrose gone, that is, from viewing eating as serving only nutrient solutions. A model for the control of ingestion, 20 years later. Progress in psychobiology and ioral neuroscience (1), makes the basic science more useful physiologic psychology. Caudal brainstem participates in the distrib- uted neural control of feeding. Using the similarity in eating behavior, gastroin- of behavioral neurobiology. In: Shils ME, Olson JA, Shike as a bridge, the transfer of new information from the labora- M, et al, eds. Baltimore: tory to the clinic should accelerate markedly in the next 5 Williams & Wilkins, 1999:631–644. A direct measure of satiety disturbance in patients with bulimia nervosa. Relationship of perceived We thank Laurel Torres for assistance with processing this macronutrient and caloric content to affective cognitions about food in eating-disordered, restrained, and unrestrained subjects. We are supported by NIH grants MH40010 Am J Clin Nutr 1992;55(2):362–371. Gastric capacity, gastric emptying, and test-meal intake in normal and bulimic women. Postprandial cholecystoki- REFERENCES nin release and gastric emptying in patients with bulimia nervosa. The controls of eating: a shift from nutritional homeo- Am J Clin Nutr 1997;65:114–120. Introduction to the reviews on peptides and the con- in bulimia nervosa. The role of depot fat in the hypothalamic control limia nervosa. In: Chapter 115: The Behavioral Neuroscience of Eating 1673 Berthoud H-R, Seeley RJ, eds. Neural control of macronutrient ments to loss of physiologic postingestional stimuli. The meal patterns of the oestrous cycle and their taste elicits a preferential increase in mesolimbic dopamine re- motivational significance. CCK(A) and 5-HT3 receptors postingestive controls of sucrose licking. Physiol Behav 1997;61: interact in anorectic responses to amino acid deficiency. Serotonergic block- tion increases during estrus in female Long-Evans rats.

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Most often purchase tadapox amex erectile dysfunction statistics canada, these enzymes are the primary Szot et al purchase tadapox 80 mg otc erectile dysfunction newsletter. Importantly, many kinases can regulate once daily) increased mRNA for the NET in the locus ceru- different and independent functions within a cell, presum- leus. This implies that drug effects on translocation of (and presumably also NET binding sites) may have impor- kinases, in addition to direct effects on their activity, may tant functional consequences relevant to the behavioral im- have important functional consequences. The changes The long-term administration of either fluoxetine or de- that acute local administration of an SSRI has on the clear- sipramine decreases the basal activity of both soluble and ance of 5-HT in vivo, measured by chronoamperometry, particulate PKC in cerebral cortex and hippocampus (281). Variable and quite small effects Because PKC may be involved in the desensitization of are produced on the peakamplitude of the electrochemical 5-HT receptors (282) and cell surface expression of the 2A signal caused by 5-HT, and clearance of the indolalkylamine SERT (283), antidepressant-induced effects on PKC activ- is inhibited by 30% to 40% (246). However, when antide- ity may cause changes in 5-HT -receptor sensitivity or 2A pressant treatment causes a marked reduction in SERT SERT expression (246,257). Similar effects on the 5-HT chrono- namely PKA in the microtubule fraction and calcium/cal- amperometric signal were also observed in rats treated with modulin-dependent protein kinase II (CaMKII) in the syn- a serotoninergic neurotoxin to cause more than a 70% loss aptic vesicle fraction. Such activation results in phosphate of SERT binding sites (279). Thus, acute blockade of the incorporation into selected substrates (284,285). With re- SERT by SSRIs may not produce the same enhancement spect to PKA, Nestler et al. They found that long-term antide- sertraline treatment has been found to cause a marked loss pressant administration decreases the activity of PKA in the of SERT binding sites only after 10 to 15 days of treatment cytosol but increases enzyme activity in the nuclear fraction. Interestingly, long-term desipramine sary to obtain marked enhancement of serotoninergic trans- treatment increases the phosphorylation of MAP-2, a sub- mission and consequent behavioral improvement. The effects Signal Transduction on PKA may be caused when long-term treatment with In recent years, there has been considerable speculation that antidepressants increases the binding of cAMP to the regula- the beneficial behavioral effects of antidepressants are a con- tory II subunit of PKA in brain homogenates (287,289). In other ment may be cAMP-dependent phosphorylation, mediated words, behavioral improvement is not a direct consequence by PKA, in microtubules. It may be speculated that such of antidepressant-induced receptor activation (which may phosphorylation causes cytoskeletal changes that result in a occur quickly); rather, it results when such receptor activa- modification of neurotransmission and antidepressant- tion alters signaling pathways to cause more slowly develop- induced changes in gene expression (see below), as PKA ing changes in gene expression. Two major areas have been translocation to the nucleus is microtubule-dependent studied. One deals with effects of antidepressants on second (290). Antidepressant-induced activation of PKA is interest- messenger-regulated protein kinases in brain. The other ing in light of findings of decreased PKA activity in cultured deals with changes in activities of protein kinases that result fibroblasts of melancholic patients with major depression in changes in gene expression and perhaps even neurogene- (291), perhaps a consequence of reduced binding of cAMP sis. Given the estab- lished facilitative function of CaMKII on neurotransmitter Protein Kinases release (293), the effect of long-term antidepressant treat- Phosphorylation of proteins may well be the primary regula- ment on CMKII, with increased phosphorylation of sub- tory mechanism for intracellular events. Such phosphoryla- strates such as synapsin 1 and synaptotagmin, may underlie Chapter 79: Mechanism of Action of Antidepressants and Mood Stabilizers 1155 the facilitation of monoamine transmitter release produced increase in BDNF can oppose and perhaps overcome the by these drugs. Indeed, long-term anti- depressant treatment has been shown recently to increase neurogenesis of dentate gyrus granule cells (312). Gene Expression/Neuroplasticity Although the precise mechanism is not understood, long- term but not acute treatment with antidepressants has ef- CONCLUSION fects on the expression of specific genes that may be a conse- quence of the activation of protein kinases, particularly Our understanding of the mechanism of action of drugs PKA. It is known, for example, that PKA can phosphorylate that treat mood disorders such as depression and manic- the transcription factor CREB. CREB binds to specific pro- depressive illness derives for the most part from their inter- moter sites (cAMP response elements) to produce changes action with known signaling systems within the brain. It is in the expression of specific genes, such as those for brain- evident that intracellular effects initiated by antidepressant derived neurotrophic factor (BDNF) and its receptor, trkB. Al- of antidepressants increases the mRNA for CREB in addi- though much more research is needed to test this hypothesis tion to CREB protein in brain (294; see 221,295). More and establish whether and how such long-term changes are recently, it was shown that such treatments increase CREB of physiologic significance, current evidence suggests that expression and CREB phosphorylation, indicative of func- such changes in brain may be quite important for the now tional activation of CREB (296). Furthermore, long-term well-established prophylactic effects of mood stabilizers and antidepressant treatment increases BDNF and trkB expres- antidepressants in the treatment of recurrent mood disor- sion in hippocampus (294,297). Finally, exogenous BDNF has that use gene expression arrays, we have the opportunity been shown to have antidepressant-like activity in behav- to examine multiple targets in the brain, both known and ioral tests sensitive to antidepressant treatment (301). Within this chapter, Such results are viewed as evidence that long-term antide- we have tried to identify the most promising of the candi- pressant treatment causes sustained activation of the cAMP date targets of mood stabilizers and antidepressants. The noradren- ever, research to determine which current and future targets ergic and serotoninergic receptors producing increases in constitute a profile that is most relevant to the therapeutic cAMP are -adrenoceptors and 5-HT4, 5-HT6, and 5-HT7 action of these agents will continue to be hampered by a receptors. If such intracellular effects are responsible for clin- lackof animal models for these complex behavioral disor- ical improvement, then these receptors may be the impor- ders that have strong construct and predictive validity. The hypothesis which new mood stabilizers can be discovered has proved is fundamentally different from earlier views of antidepres- more challenging. We suggest that the creation of models sant action, in which depression was a problem of synaptic with both construct and predictive validity to permit the transmission and drugs acted within the synapse to improve discovery of novel targets directly related to therapeutic effi- behavior directly (301,302). The new view is more morpho- cacy will be significantly enhanced by the identification of logic in nature. It posits that depression may be caused by susceptibility and protective genes for these illnesses. It is well established that such atrophy occurs (303,304). Further, more recent REFERENCES data indicate a decrease in hippocampal volume in some 1. In: Nemeroff CB, Schatzberg depressive patients (305–307), although this need not indi- AF, eds. American Psychiatric Association textbook of psychophar- cate a loss of neurons. However, postmortem studies have macology, second ed. Washington DC: American Psychiatric revealed a loss of glia and neurons in the cortex of depressed Association, 1998:303–349. New York: the differentiation and growth of neurons in the developing McGraw-Hill, 1996:461–486. Thus, the antidepressant-induced port in the psychoses. In: ometry of Na-dependent Li transport in human red blood cells. Psychopharmacology: the fourth gener- J Gen Physiol 1978;72:249–265. American Psychiatric Association textbook of psychopharma- dietary lithium on activity and regulation of [Na,K]-adeno- cology.

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Clomipramine parallel group cheap tadapox 80 mg with mastercard impotence definition inability, randomized study (104) cheap tadapox 80mg amex erectile dysfunction exercises treatment. Both groups Chapter 114: Current and Experimental Therapeutics of OCD 1653 showed steady improvement throughout the study; no dif- SRIS IN CHILDHOOD AND ADOLESCENT ferences were observed between the groups for any efficacy OCD variable at any time and both clomipramine and fluvoxa- mine were equally effective in reducing OCD symptoms; The clinical presentation of OCD in children and adoles- they displayed differences in the profiles but not severity of cents resembles that observed in adults (113). Clomipra- mine has been well studied in the treatment of OCD in LONG-TERM TREATMENT AND this population. An 8-week multicenter double-blind study DISCONTINUATION (115) found clomipramine to be effective and superior to placebo (mean Y-BOCS scores decreased by 37% versus OCD is a chronic disorder; therefore, long-term treatment 8%). These findings led to FDA approval of clomipramine is often required. Although this research has methodologic for the treatment of OCD in children and adolescents. The limitations, data on long-term SSRI treatment (fluoxetine, side-effect profile in this sample included anticholinergic, sertraline, and paroxetine) suggests that efficacy is main- antihistaminic, and -adrenergic effects such as dry mouth, tained and sometimes increases over time. Still more infor- tremor, sedation, dizziness, sweating, and insomnia. No se- mation is needed on the long-term efficacy and safety of rious adverse events were reported; however, some patients SRIs in OCD treatment. SRIs have been proved effective were withdrawn owing to hepatic enzyme elevations and in the acute treatment of OCD; double-blind substitution cardiac palpitations. Electrocardiographic monitoring trials with clomipramine have shown that symptoms fre- should be undertaken because tricyclic antidepressants have quently recur after discontinuation of treatment (108,109). A retrospective follow-up study of 85 patients with OCD Fluvoxamine is an FDA-approved SSRI for the treatment reported that most of the patients treated with SSRIs for 1 to of pediatric OCD. In an 8-week open-label trial of fluvoxa- 3 years had maintained or increased symptom improvement mine with adolescents (100 to 300 mg per day), the majority (110). Two double-blind and/or placebo-controlled long- of patients showed significant improvement in their OCD term SSRI continuation studies have reported continued symptomatology (117). The side-effect profile was similar efficacy and tolerability (74,75). Although valuable, these to that reported in adults, including hyperactivity, anxiety, studies had no effective control group for the maintenance sedation, dizziness, headache, tremor, and nausea. A large phase: Because only responders to an acute trial continued (N 120) double-blind placebo-controlled 10-week study into long-term maintenance, there were only a handful of of fluvoxamine (50 to 200 mg per day) with children and placebo patients in maintenance and there was no other adolescents (ages 8 to 17) found the drug to be significantly control group. To date, no long-term, double-blind substi- superior to placebo (118). Side effects were described as tution trials have been published. An open-label discontin- mild; those that were more commonly reported in the flu- uation trial (111) followed 130 responders to 6 months of voxamine group included insomnia, agitation, hyperactiv- acute treatment with an SRI: clomipramine, fluoxetine, or ity, somnolence, and dyspepsia. This occurred for 2 years of treatment (or until There have been four small prospective studies investigat- they experienced a recurrence) with the same medication at ing the efficacy of fluoxetine in pediatric OCD. Three of the same dose, the same medication at half the dose, or no these were open design (119–121). The study showed a superior therapeutic effect (122) conducted a double-blind crossover trial of fluoxetine for both medication conditions compared to discontinua- (N 14; mean age 11. One controlled, long term, dou- and reported it to be superior to placebo as measured by ble-blind substitution trial (71) has shown that paroxetine CGI scores for global improvement. The most commonly is superior to placebo in preventing OCD relapse during a reported adverse effects included insomnia, motor activa- 6-month discontinuation trial (which followed 12 weeks of tion, fatigue, and nausea. In general, the side effects were acute treatment in a double-blind placebo-controlled pa- reasonably well tolerated and did not result in withdrawal roxetine dose finding trial and 6 months of open-label pa- from the study, except for a 13-year-old boy who developed roxetine treatment). In addition, treatment effects appeared suicidal ideation in the third week of fluoxetine treatment. In addition, following the double-blind discon- EKG, weight, pulse, or blood pressure. Major limitations tinuation phase, subjects switched to placebo had a signifi- of the study were the small sample size and the fixed dosage. One study (123), fluoxetine led to moderate to marked improvement suggested that long-term maintenance therapy might be in OCD symptoms in 74% of patients (N 38); mean provided with lower dosages of antiobsessional drugs, with age 12. Relatively high doses of the drug were required, a clear advantage for tolerability and compliance (112). Long-term 1654 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 114. CONTROLLED TRIALS OF SEROTONIN REUPTAKE INHIBITOR THERAPY FOR OBSESSIVE-COMPULSIVE DISORDER IN CHILDREN AND ADOLESCENTS Study (Ref. Fluoxetine was generally well tolerated and obsessional thoughts or compulsive behaviors. Patients adverse effects were less marked than those associated with agree not to engage in their usual ritualistic behavior or clomipramine. Despite this apparent tolerability of high cognitions and to remain in the situation until their discom- doses, it has been recommended that, for children, an appro- fort wanes. Homework is generally prescribed outside the priate starting dose of fluoxetine is 10 mg per day or less therapist contact. Some studies suggest that up to 90% of patients The FDA has also approved sertraline for the treatment have achieved clinically significant benefits from behavior of child and adolescent OCD, which has been shown to be therapy (130). Generally, 70% to 80% of these patients safe and effective in this population (124). In a randomized, maintain their acute gains at 1-year follow-up (131). Foa randomized to receive either sertraline titrated to a maxi- and colleagues (132) reported that 51% of patients experi- mum of 200 mg per day (53 children, 39 adolescent) or ence at least a 70% drop in symptoms, with 35% experienc- placebo (54 children, 41 adolescents). These gains are generally of the patients receiving sertraline and 26% of those receiv- (75%) maintained at 12-month follow-up. It is often diffi- ing placebo were very much or much improved on CGI cult to arrange such extensive exposure in an outpatient ratings. The incidence of side effects was similar to that setting, however. Recent results in one trial suggest that reported in adults; sertraline appears to be a safe and effec- providing this treatment in a group setting may be effective tive antiobsessional agent in children and adolescents. Relapse prevention programs have In an open-label trial, the adverse effects and potential proved beneficial in maintaining the gains of acute treat- clinical efficacy of citalopram (10 to 40 mg) were examined ment (134). After 10 weeks, over 75% of these youths showed a moderate or Comparisons marked improvement and adverse effects appeared to be minor and transient, suggesting that citalopram might be A metaanalysis comparing behavioral treatments and SSRIs well tolerated in children and adolescents (Table 114. There were also no significant differences cents with OCD suggest that adjunctive interventions in- between the SSRIs, although CMI appeared to have some cluding parent case management education and specific cog- increased efficacy but not sufficient enough to warrant fa- nitive-behavioral should be considered in the majority of voring it over other SSRIs given its side-effect spectrum cases. The choice between these two modalities is often dominated by the relatively limited availability of behavioral therapists and by BEHAVIOR THERAPY AND patient preference.