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Several studies report that D2 agonists cause a in either system in response to a signal are amplified by down-regulation of glutamate-mediated EPSPs on neurons their coordinated effects on each of these interdependent in the nucleus accumbens (96–99) best 20mg levitra. Specifically purchase levitra 20mg without prescription, DA was presumed to be the glutamatergic corticostriatal afferents levitra 10mg with amex. In cases in which striatal excitatory acute depletion of endogenous DA, all corticoaccumbens amino acid afferents arising from the cortex are stimulated EPSPs are sensitive to DA (99). This suggests that under with high frequencies in the absence of magnesium (to en- normal circumstances, the presynaptic DA receptors may hance NMDA conductances), a long-term facilitation in already be saturated with DA, as suggested by the observa- synaptic transmission is induced, known as long-term po- tion that sulpiride increase EPSP amplitude in a majority tentiation. In contrast, if the stimulation is carried out at a of cases when administered alone (99). This unusual phar- low frequency, the opposite type of plasticity is induced; macology may reflect a contribution of presynaptic D4 re- that is, long-term depression (LTD) (107). These forms of ceptors on the corticoaccumbens terminals to this response synaptic plasticity have been proposed to play a major role (102). Although another group has reported a D1-mediated in learning and memory formation in other structures, such presynaptic action EPSPs evoked by intrastriatal stimulation as the hippocampus. Such plasticity within the striatum in slices, which was interpreted as a presynaptic effect on may be involved in such phenomena as the acquisition of corticostriatal terminals (103), this study employed exceed- complex motor skills. Repetitive stimulation of corticostria- ingly high doses of the D1 agonist to achieve these effects tal fibers to release glutamate is required for the induction (i. Moreover, anatomic studies have shown that D1 im- pretreatment prevents the induction of LTD (107), suggest- munoreactive axons are exceedingly rare in the striatum ing that a synergistic interaction between these receptor sub- (77). In contrast, recent studies suggest that DA acting on types is required for this process to occur. In contrast, corti- postsynaptic D1 receptors may actually cause a transsynap- cal stimulation-induced LTP is blocked selectively by D1 tic feed-forward inhibition of glutamate release. Both antagonists, but is actually enhanced by D2 antagonists or NMDA antagonists and adenosine antagonists can block in D2 receptor knockout mice (109). Thus, although studies done in vivo have consistently shown that direct DA application inhibits PFC neuron fir- ing, studies using in vitro slice preparations have found a DA-mediated increase (110,111) and a decrease (112,113) in neuronal excitability in this region. D1 stimulation has been shown to affect sodium conductances by increasing the sodium plateau potential and shifting the activation of sodium currents to more negative potentials (114). This increase in excitability was augmented by a D1-induced decrease in slow potassium conductances (110). D1 stimula- tion may also activate L-type calcium conductances located in proximal dendrites of pyramidal neurons to further in- crease excitability in these neurons (66). Such an interaction has been postulated to differentially modulate afferent input to these neurons (Fig. Indeed, the highly organized DAergic input onto virtually every dendrite of PFC pyrami- dal neurons in the primate provides a means for this neuro- transmitter to regulate nearly the entire complement of glu- tamatergic afferents to this cell type (115). In contrast, at least part of the inhibitory action of DA on PFC pyramidal neurons may occur by DA-induced excitation of GABAer- FIGURE 9. A simplified diagram illustrating the basic process- ing units within the prefrontal cortex. Each unit consists of a deep gic interneurons (116), which also receive a direct DA inner- layer pyramidal neuron that projects to the nucleus accumbens vation (115,117). The apical and basal dendrites of the pyramidal neu- ron receive functionally segregated inputs from various cortical membrane potentials, which alternate between a hyperpo- and subcortical regions, whereas the GABAergic interneuron, larized, nonfiring condition and a depolarized plateau state which is also modulated by DA, exerts inhibitory influences over where they fire action potentials. Moreover, studies have both the apical dendrite and soma of the pyramidal neuron. By acting on both the interneuron and pyramidal neuron dendrites, shown that the effects of DA vary depending on the state the DA input has the capacity to modulate the integration of the of the membrane potential at which it is administered. In functionally diverse array of inputs to this neuron. DA activation of the GABAergic interneuron can also serve bining in vivo microdialysis administration of drugs with to suppress information input from the apical dendrites. In con- trast, DA modulation of conductances at the somatodendritic re- intracellular recording (119) found that DA could poten- gion amplifies low-level afferent inputs from neighboring pyra- tiate glutamate-driven bistable states of PFC neurons (Fig. Therefore, the state of the membrane may significantly change the pyramidal neuron from responding primarily to long- loop afferents to a state in which it responds primarily to local influence the response to DA observed. Dopamine receptors for the in several of the behavioral aspects of DA system function D1 and D2 class have been identified in the ventral pal- (121), particular related to drug sensitization (122). DA causes an overall de- crease in the firing rate of presumed projection neurons by two mechanisms: (a) a direct effect on the projection neu- ron, and (b) an activation of the firing of putative interneur- ons, which may be analogous to the interactions occurring in the PFC. In addition, DA produced effects on afferent drive of these neurons that was dependent on the origin of the projection system. Thus, DA attenuates afferents from limbic structures such as the PFC and MD thalamus, whereas afferent input from auditory association cortex (Te3) is potentiated (Fig. Intracellular recordings re- vealed that this was a consequence of a D1-mediated de- crease in PFC-evoked EPSP amplitude, combined with a D2-mediated increase in BLA input resistance that poten- FIGURE 9. In vivo intracellular recordings from a pyramidal tiated Te3 afferent drive (129). PFC stimulation also caused neuron in the frontal cortex of a chloral hydrate anesthetized rat an excitation of BLA interneurons, which lead to a subse- is illustrated. The neuron was located near a microdialysis probe quent attenuation of input arising from Te3; however, in implanted to deliver the compounds to be tested by reverse di- alysis to the environment of the cell. Administration of NMDA (20 the presence of DA stimulation, the ability of the PFC stim- M) increases the number of spikes evoked by brief depolarizing ulation to attenuate responses from Te3 was diminished pulses. Following washout, administration of NMDA DA (30 (129). These data suggest that the PFC is normally capable M) greatly increases the spikes evoked per unit current. This occurs despite the fact that DA did not appear to significantly of attenuating amygdala responses to sensory inputs, which affect current threshold. In the case of NMDA alone, the increase could be a mechanism for decreasing emotional responses to in the number of spikes per unit current occurs with (and may be familiar or nonthreatening stimuli. However, with excessive secondary to) a decrease in current threshold; that is, the cell is simply more excitable. In the case of DA added to NMDA, the cell DA stimulation, the ability of the PFC to suppress amyg- fires more spikes during the current-induced depolarization, but dala-mediated emotional responses may be lost. Because the VP is positioned anatomically at the crossroads of the limbic and extrapyramidal system, DA modulation in this area has the ability to potently influence motivated behavior by its actions in this region (121).

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Calcium Channel Blockers Plus Digoxin Versus Digoxin Alone The calcium channel blocker diltiazem in combination with digoxin was compared with 151 digoxin alone in patients with AF and rapid ventricular response in one study discount levitra 20mg otc. Successful rate control was defined as ventricular rate <100 bpm persisting for at least 1 hour or conversion to sinus rhythm cheap levitra 10mg amex. All patients achieved successful rate control at 12 hours levitra 10 mg visa. The ventricular rates were comparable in both treatment arms throughout the study period (insufficient strength of evidence). The time taken to achieve successful rate control was shorter in patients receiving diltiazem plus digoxin than in patients receiving digoxin alone although was not statistically significant (p=NS). The loss of rate control in the combination treatment arm was significantly less than in the diltiazem alone arm (14 episodes vs. Among patients with episodes of loss of rate control, the combination treatment caused less loss of rate control when compared with digoxin alone (2 episodes vs. The only adverse event observed was an episode of sinus pause for 2. Calcium Channel Blockers Versus Digoxin 143,145,147,148 145 Four studies compared calcium channel blockers with digoxin. In one, verapamil was compared with digoxin in patients undergoing elective cardioversion. At 2 weeks after inclusion, the mean heart rate was comparable between patients receiving verapamil and digoxin (82 vs. In order to obtain adequate rate control, more patients in the digoxin arm were treated with additional beta blocker therapy than in the verapamil arm (60% vs. In the second study, sustained ventricular rate (<90 bpm) within 24 hours was compared between patients receiving digoxin or diltiazem. Patients receiving diltiazem were more likely to achieve sustained heart rate control (90%) than patients receiving digoxin (74%; p=0. The median time to ventricular rate control was also significantly shorter in patients receiving diltiazem (3 hours) than in patients receiving digoxin (6 hours; p<0. Patients receiving diltiazem had lower mean ventricular rate after the first hour of drug administration 147 compared with patients receiving digoxin (p<0. In a third study, patients were more like to have a ventricular rate >90 bpm at 4 weeks when receiving digoxin (15 patients) than when receiving verapamil (5 patients; p<0. Importantly, five patients in the verapamil group 148 required concomitant use of digoxin to reach ventricular rate control. Finally, in the last study, digoxin was compared with the calcium channel blocker verapamil in patients with new onset AF with rapid ventricular response. The mean reduction in heart rate over 6 hours was 52. At 6 hours, there was no difference in the rates of sinus rhythm between the two groups (p=0. Conversion to sinus rhythm tended to be achieved more quickly in the digoxin group than in the verapamil group, although this difference was not statistically significant. Among patients remaining in AF, the reduction in heart rate was greater in patients receiving digoxin (mean reduction 47 bpm) than in patients receiving verapamil (mean reduction 21. Patients receiving verapamil had a greater reduction in heart rate compared with patients receiving digoxin at 0. There were no clear adverse events related to the treatments in this study. Some of the symptoms that were reported, such as lightheadedness and palpitations, seem to have been related to AF and not to the study treatments. In summary, there was a consistent benefit of verapamil or diltiazem compared with digoxin across studies (high strength of evidence). Results in Specific Subgroups of Interest One study compared combined treatment with the beta blocker carvedilol plus digoxin with 141 carvedilol alone and with digoxin alone in patients with AF and heart failure in one study. The combination of digoxin plus carvedilol was superior to digoxin alone for rate control at 4 months. At 6 months, there was no difference in rate control between digoxin alone and carvedilol alone. The improvement of AF symptoms was greater in patients receiving combined treatment than in patients receiving digoxin alone. The included studies did not allow a direct comparison of these findings with those in other populations. Other subgroups of interest were not specifically evaluated. Strength of Evidence Our review of rate-control drugs explored the comparative effectiveness of beta blockers, calcium channel blockers, digoxin, and other antiarrhythmics in controlling ventricular rate. The 14 included studies varied in terms of the drugs involved, and the lack of multiple studies exploring similar comparisons decreased our ability to quantitatively synthesize their findings. Our findings highlight the lack of definitive data on the superiority of one beta blocker over another or against calcium channel blockers. Our findings underscore the importance of conducting studies comparing the effectiveness, tolerability and safety of different beta blockers and calcium channel blockers and in different patient populations. Based on a limited number of comparative studies, our analysis suggests that either a calcium channel blocker (verapamil or diltiazem) or amiodarone is beneficial compared with digoxin for rate control. Evidence exploring adverse events and safety and effectiveness of the available agents in specific subgroups of interest was insufficient. Table 4 summarizes the strength of evidence for the studied rate-control drugs and outcomes of interest. In general, the limited number of studies exploring specific comparisons, along with the various metrics used to assess outcomes of interest, reduced our confidence in the findings. Strength of evidence domains for rate-control drugs Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Beta Blockers vs. Digoxin Ventricular 1 (47) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Beta Blockers vs. Calcium Channel Blockers Ventricular 1 (40) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Beta Blockers vs. Calcium Channel Blockers in Patients Taking Digoxin Ventricular 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Exercise 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Capacity Moderate Quality of Life 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Moderate Sotalol vs. Metoprolol in Patients Taking Digoxin Ventricular 1 (23) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Amiodarone vs.

Prevalence estimates have design included a 1-week placebo lead-in followed by an 8- been made at 1% to 8% of the general population week period of treatment with fluvoxamine and a subse- (157–159) purchase levitra 10 mg. Initial reports describe individuals with CB as quent drug taper and discontinuation (over 3 to 4 days) generally in their thirties and predominantly female cheap levitra 10 mg line, with and reassessment off medication at the end of week 13 cheap 20mg levitra with visa. Indi- Responses were measured with the YBOCS modified for viduals with CB are reported to have elevated rates of psychi- CB (YBOCS-SV), the CGI, patient self-rating, and other atric comorbidity, particularly anxiety disorders, mood dis- standardized scales for depression, disability, and OC symp- orders, substance abuse or dependence, eating disorders, toms. Nine of ten individuals were deemed responders, hav- ICDs, and personality disorders (157,159,161). Highly significant im- provements were observed at week 9 as compared with base- Pharmacotherapy line in scores on both the obsession and compulsion sub- scales of the YBOCS-SV, the National Institute of Mental Thymoleptic Treatment Health OC scale, patient self-rating reports, subscales of the Some authors have proposed depression as a significant un- Sheehan Disability Scale, and the CGI severity and im- derlying motivational factor related to engagement in CB provement scales. Symptoms appeared to worsen but often (158,162,163). An early description of pharmacotherapeu- remained improved from baseline during the 4-week dis- tic interventions in PG described the use of three antidepres- continuation phase. Each of the three patients receiving the medi- with sedation, headache, dry mouth, and gastrointestinal cations reported a partial or complete reduction in CB disturbances reported most frequently. In a larger study of 20 individuals with CB, nine adverse effects did not result in discontinuation of the drug of 13 patients who had received thymoleptic pharmacother- for any of the participants. The results from this initial study apy while they were symptomatic (69%) reported their CB of fluvoxamine in the treatment of CB suggest it to be to be in full (n 5) or partial (n 4) remission (157). The effective drugs used varied widely and included buprop- Opioid Antagonists ion, lithium, valproate, nortriptyline, desipramine, fluoxe- tine, sertraline, trazodone, clonazepam, diazepam, levothyr- Given data supporting efficacy of the -opioid antagonist oxine, and methylphenidate, often used in combination of naltrexone in urge regulation and the role of -opioid func- two or more drugs simultaneously (157). Doses and dura- tion in modulating MCL DA pathways, a trial of naltrexone tions of pharmacotherapy were not clearly defined in the in the treatment of ICDs (including CB) was reported report. The authors described full remissions up to only 7 (152). Two patients with CB treated with naltrexone were months and partial remissions up to 13 months and noted described in detail in a series of 15 individuals with ICDs, that several of the drug trials were terminated after only a with an additional three responders with CB mentioned in short period secondary to intolerable adverse effects (n 2) the report. One of the two responders had comorbid PG or hypomania (n 1). Although the relationship between and CB, and this response is described earlier (in the PG Chapter 120: Pathologic Gambling and Impulse Control Disorders 1735 section). A second individual, a 46-year-old woman with Selective Serotonin Reuptake Inhibitors comorbid CB and bulimia nervosa, was started on naltrex- Initial studies into the efficacy and tolerability of SSRIs in one at 50 mg per day. She initially developed diarrhea, the treatment of paraphilic and nonparaphilic CSBs have which later resolved without discontinuation of the drug. In one study, 20 men with CSB After not experiencing improvement in target symptoms, were entered into a 12-week open-label trial of fluoxetine her dose was increased to 100 mg per day at week 2. Ten of the men had solely nonparaphilic CSBs, and this dose, she reported a significant decrease in thoughts the other ten had both paraphilic and nonparaphilic CSBs. She maintained her gains at 7 months and tolerated for current major depression. Outcome measures included the medication with normal liver function tests and without the Inventory to Diagnose Depression (IDD) and the Sexual adverse effects. The results from this initial report of open- Outlet Inventory (SOI). IDD scores were obtained at base- label, high-dose naltrexone administration suggest that the line and weeks 4, 8, and 12. Of the 20 entered participants, drug may be effective in targeting symptoms of CB. Larger- four discontinued (three nonparaphilic and one paraphilic, scale, placebo-controlled, double-blind studies are war- one each for alcohol abuse, no change in CSB, increase in ranted to define better the efficacy and tolerability of the CSB after initial remission, and increased anxiety and CSB). Significant reductions in both depressive and CSB symptoms were observed, with improvement in sexual symptoms independent of baseline depression scores. Sexual symptoms showing significant improvement included total COMPULSIVE SEXUAL BEHAVIOR sexual outlet and unconventional forms of masturbation, sexual activity, desire intensity, and sexual interests. Con- Traditionally, the majority of attention given to disordered ventional sexual symptoms were not adversely effected. The sexual behaviors has arguably been focused on the paraphil- promising results of this open-label study warrant larger, ias. These disorders involve sexual arousal from inappro- placebo-controlled, double-blind studies of specific priate objects or partners and include fetishism, exhibition- subgroups of individuals with CSB to determine further the ism, voyeurism, sadomasochism, pedophilia, and zoophilia. Nonparaphilic excessive sexual behavior, currently classified as an 'ICD not otherwise specified' in the DSM, involves repetitive, interfering sexual behavior without the use of Dopamine Augmentation inappropriate objects or partners (166). The term CSB has In individuals who respond incompletely to SSRIs, trials of been used to encompass both paraphilic and nonparaphilic augmentation with the DA-enhancing drugs methylpheni- sexual disorders (167). CSB has been estimated to affect date or bupropion have been described. The rationale for 3% to 6% of individuals in the United States (167–169), use of these drugs has been described as related to multiple with most of those with the disorder thought to be male findings, including the efficacy of similar augmentation (167,170,171). Given the relatively high estimated preva- strategies in depressive disorders, improvement of SRI- lence rates and the clinical or social impairment often expe- induced adverse effects with these DA 'agonists,' and com- rienced with CSB, there exists a need for further well-de- orbidity and similarities with attention-deficit/hyperactivity fined studies into the epidemiology and treatment of CSB. One investigator reports having treated more than 30 patients with the combination of an SRI and a DA drug (172). Further studies are needed to both explore Pharmacotherapy possible DA dysfunction in CSB and to determine the effi- cacies and tolerabilities of DA drugs in CSB. Thymoleptics High rates of mood disorders have been reported in individ- uals with CSB (167,172). Case reports have been described Hormone System Treatments supporting the efficacy of multiple thymoleptics in the treat- Several classes of drugs modulating hormonal systems, in- ment of CSB. Specifically, the following have been reported: cluding antiandrogens, estrogens, and gonadotropin-releas- electroconvulsive therapy (173) and treatments with lithium ing hormone (GnRH) analogues, have been investigated in (174–176), buspirone (177), imipramine (178,179), desi- the treatment of CSBs (187–193). The group of antiandro- pramine (180), clomipramine (180), and the SSRIs (172, gens includes medroxyprogesterone acetate (MPA) and cy- 178,181–187), particularly fluoxetine and sertraline. MPA, a potent progestogen lack- following section, we describe one of the larger, systematic ing antiandrogen effects at the androgen receptor level, has investigations performed to date. CPA, also a potent progestogen but also with testos- forms as well as stock trading), shopping, and sexual behav- terone antagonist activity at the receptor level, has also been iors, and it may be associated with an increase in the preva- studied in the treatment of CSB (190,194). Individuals with excessive and inter- placebo-controlled trials of MPA, CPA, or both (190,194, fering computer use have been termed 'webaholics' or 195), as well as data from a large number of open-label trials 'cyberholics,' and their computer-related behaviors have and case reports (reviewed in refs. Given the recent emergence of CCU, formal uals with aggressive sexual behaviors. Although these agents diagnostic criteria have not been developed or endorsed, are not effective for all patients (196), accumulating data pharmacologic treatment studies have not been reported, suggest this family of drugs may be effective in subgroups and its relationship with other disorders (e.

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