By L. Ortega. Maryville University of Saint Louis.

It is well documented in nonhuman primates that Lateral And Medial Temporal Lobe optimal dopamine function is necessary for maximal work- The temporal lobe is of interest in schizophrenia for several ing memory and DLPFC physiologic function (41) order forzest australia. Diseases of the medial temporal lobe can be associ- albeit less direct purchase generic forzest pills, evidence also exists in humans: Pharmaco- ated with psychotic symptoms discount forzest online, and some neuropsychologi- logically altering dopaminergic tone with agents such as cal aspects of schizophrenia implicate both lateral and me- amphetamine affects DLPFC activity in both healthy sub- dial temporal lobe trusted forzest 20mg. A number of neuroimaging studies have jects (42,43) and patients (44); and a relationship between reported functional abnormalities in both lateral and medial DLPFC rCBF during the WCST and CSF levels of the temporal lobe structures (47). The data as a whole, however, dopamine metabolite homovanillic acid has been found in are less compelling than for frontal lobe, and confounds schizophrenia (45). Third, converging data increasingly and potential mechanisms are less well explored. A considerable body of both hyperfunction and hypofunction have been re- of literature now documents that disruption of corticolim- ported, but the bulk of the evidence leans toward overactiv- bic connectivity in neonatal animals via hippocampal lesions ity. Heckers and colleagues (48) reported reduced hippo- models many features of schizophrenia, including working campal activation during the effort to retrieve poorly memory impairment, reduced prefrontal NAA, and dopa- encoded material; however, it is of interest that, hippocam- mine dysregulation (53). Developmental pathology with a pal activity appeared to be increased at baseline, again em- genetic basis also appears likely. A recent study links a ge- phasizing the task-dependence of neurofunctional findings netic attribute that affects prefrontal dopamine to both in general (48). Several studies point to a role for lateral working memory performance and DLPFC activation in temporal cortex in hallucinations and other positive symp- patients, their sibs, and unrelated healthy individuals (21). Investigations of this type, which explore the Miscellaneous Regional Changes interaction of genetic and neurophysiologic characteristics, hold the greatest promise for elucidating the etiology of the Functional abnormalities, primarily hypofunction, of many illness and effecting innovative treatments. Although most are unrep- licated, several are worth mentioning. Both increased and decreased basal ganglia activity have been found, but a role Other Frontal Lobe Subregions for neuroleptic treatment in such findings must be consid- Dysfunction, primarily hypofunction, of portions of the ered. Several investigators have suggested that schizophrenia frontal lobes other than the DLPFC has also been described. It may, frontal areas as well as relatively higher flow to posterior thus, be especially prone to epiphenomenologic effects. In particular, the notion tion in the face of competing information, such as the that schizophrenia may involve disordered functional later- Stroop test, complex motor control tasks, verbal fluency, alization has been explored using a variety of methods. These observations have led cognitive temporal overactivation was seen in this light in early stud- neuroscientists to propose more refined cognitive roles such ies. More recent work suggests that apparent alterations in as on line monitoring, conflict monitoring, and error detec- functional laterality in schizophrenia may not actually re- tion (46). Further research is necessary to clarify which of flect abnormal lateralization per se, but rather a failure to these putative cognitive roles, or which epiphenomena, may organize a lateralized response (6,49). For example, Mattay be linked to the finding of anterior cingulate underactiva- and associates (1997) reported less lateralized and localized tion in schizophrenia (9–11). Orbitofrontal cortex, along lateral premotor area activation in patients during a simple with the ventral portion of the anterior cingulate, has been finger movement paradigm (50). This may also be viewed 752 Neuropsychopharmacology: The Fifth Generation of Progress within the more general context of nonfocalized, less effi- ure (13,33). During working memory, Meyer-Lindenberg cient, neurophysiologic responses in schizophrenia. It has been proposed that such altered modulation) in the patients, specifically during the multiple, seemingly local changes may be indicators of more working memory condition. Friston and Frith (12), using ubiquitous dysfunction throughout widely distributed and PET data from a verbal fluency experiment and a method interactive brain networks (12,51), a heuristically appealing that allowed them to assess patterns of activation most dif- pathophysiologic model for schizophrenia given the appar- ferent between normals and patients, found that the pre- ent subtlety of the neurophysiologic abnormalities in the frontal and temporal coactivations in normals were uncou- face of the devastating and complex nature of the illness. This conceptualization is consistent with recent trends in Fletcher and colleagues (55) reported similar results, and viewing higher brain processes as parallel and distributed Jennings and co-workers (56) using structural equation functions. Disrup- its special role in schizophrenia, it is not surprising that tion of frontal–temporal connectivity has also been found many putative aberrant networks in the illness also involve using an EEG coherence measure (57). Although the specifics of this network will obviously vary Other studies have focused on medial prefrontal and cor- by task, a consistent finding in studies of working memory tical–striatal–thalamic circuit abnormalities (49); Biver and is a coactivation of prefrontal, anterior cingulate and parietal colleagues (58) and Mallet and associates (59), calculating structures. Consistent with this, Bertolino and colleagues correlations between various regions of glucose metabolic found a tight correlation between DLPFC NAA (indicative rate in PET, found decreased intrafrontal, as well as fron- of neuronal integrity) and rCBF activation during the tal–posterior connectivity. Andreasen (60) has advanced a WCST, not only in DLPFC, but also with the other nodes hypothesis implicating compromised connectivity among in the working memory pathway (39). Because this was not prefrontal regions, several thalamic nuclei, and the cerebel- evident in healthy controls, these findings appear to reflect lum as the cause of a fundamental cognitive deficit in schizo- a rate-limiting factor related to the disease process of schizo- phrenia. She called the disruption in this circuitry 'cognitive phrenia. Weinberger and associates (52) found in hypothesis is based on a number of studies from her group monozygotic twins discordant for schizophrenia an inverse (61–63) in which the structures enumerated above were relationship between the volume of the hippocampus (the found to differ in activation between schizophrenics and structural variable that best differentiated well from ill controls during several unrelated tasks and in different co- twins) and the degree of dorsolateral prefrontal activation horts, and on the fact that the circuit described is anatomi- cally connected. This suggests dysfunction ing evidence is consistent with the notion that schizophrenia of neocortical–limbic connectivity in schizophrenia and is involves dissolution of neuronal interactions and that many consistent with, if not confirmatory of, a neurodevelopmen- features of schizophrenia may best be viewed as dysfunc- tal mechanism (53). It has been suggested that abnormal tional interregional circuitry. The details of this circuitry development or plasticity of hippocampal connectivity af- dysfunction differ, depending on the distributed network fects the development and function of prefrontal cortex or, called into play during the particular behavior, but prefron- alternatively, that both regions are 'put at risk' by the same tal cortex may play a special role. The new analytic tools recently developed to search more The Relationship of the Neurofunctional incisively for evidence of subtle and multidimensional ab- Abnormalities to Clinical Hallmarks normalities across the entire brain (see the foregoing) have provided results that are consistent with and extend the The importance of linking pathophysiologic findings in notion of temporohippocampal and prefrontal circuitry fail- schizophrenia to clinical aspects of the illness was recognized Chapter 54: Functional Neuroimaging in Schizophrenia 753 early on. Ingvar and Franzen (14) noted that 'hypofrontal- the future. One important advance will come from temporal ity' was most prominently seen in the most withdrawn, dissection of the abnormal neurophysiologic signals that inactive, socially isolative, and 'hypointentional' patients, have now been localized with great anatomic precision. For whereas they related the hyperfunction in posterior areas example, the particularly high degree of both segregation that they observed to a 'hypergnostic' component of the and interaction of the frontal lobe complex appears to be illness. The attempt to delineate the clinical and neurobio- essential for regulating and monitoring the functions it sup- logical implications of the physiologic abnormalities re- ports via multisynaptic feedback loops modulating posterior mains an important focus. It is likely that the functional disconnection in for neurophysiologic associations with cognitive deficits, schizophrenia described in the preceding includes abnor- symptom clusters, and individual clinical features such as malities in these feedback loops, which operate on a time hallucinations. The small sample sizes of some studies and scale less than 200 msec. Progress in understanding the eti- the necessarily phenomenologic nature of research into the ology of frontal lobe dysfunction in schizophrenia, there- neurophysiologic underpinnings of clinical symptoms fore, requires a methodology that has optimal resolution makes firm conclusions difficult, but some consistent find- both spatially (in order to reliably differentiate functionally ings have emerged. Frontal lobe dysfunction is consistently segregated areas) and temporally (to tap into the time scale linked to negative symptoms and cognitive deficits, particu- in which the feedback loop organization operates). The si- larly working memory and executive function. For example, multaneous combination of PET or fMRI studies (which Goldberg and colleagues (64) used an intra-twin pair differ- afford relatively high spatial resolution) with methods hav- ence method in which unaffected co-twins served as individ- ing excellent temporal resolution such as EEG or MEG ual controls for each patient in the NIMH monozygotic (which provide temporal resolution in the order of millisec- twin sample. Although left hippocampal size predicted a onds) will allow explicit investigation of specific hypotheses parameter of verbal memory, prefrontal blood flow and per- about prolongation of the feedback and feed-forward laten- severation on the WCST were related. These data are part cies and about disease-related changes in the order in which of a growing literature implicating medial temporal and pre- components of distributed neural systems come into play frontal regions in symptom expression and some neurocog- in schizophrenia. A second important way in which characterization of the In general, hallucinations are associated with sensory mo- abnormal neurophysiologic signals must advance is further dality-specific activation in brain regions involved in normal investigation into their relationship to other neurobiological sensory processing (65). For example, auditory hallucina- features of the illness. Silberswieg ties to dopaminergic and other neurochemical parameters. Also, the relationship of the functional abnormalities psychomotor poverty with decreased activity in DLPFC; to the neurostructural and neurochemical findings de- disorganization and impaired suppression of inappropriate scribed in other chapters must be further elucidated. Not responses with increased activity in the right anterior cingu- only does such a multimodal approach provide critical cross- late gyrus; and reality distortion, which may arise from dis- validation of the information gleaned from the different ordered internal monitoring, with increased activity medial technologies and help to rule out epiphenomena, but it is temporal lobe at a locus activated in normal subjects during also a means to more closely approach causality and mecha- internal monitoring of eye movements. For example, links with dopaminergic dysfunction has been linked to temporal lobe overactivity. Kaplan and can elucidate putative genetic mechanisms (21). Similarly, associates (68) found an association of marked psychomotor the fact that the prefrontal functional abnormalities may poverty with superior parietal as well as prefrontal areas, relate to structural pathology in other (particularly limbic) hallucinations and delusions with abnormalities in left tem- areas lends credence to the notion of a neurodevelopmental poral cortex, and disorganization with left inferior parietal mechanism, although it does not provide proof; further lobule abnormalities. Further work undoubtedly will refine work, perhaps expanding on insights from animal models these interesting clinical and pathophysiologic correlates.

No 157 adverse reactions were reported by patients receiving amiodarone order discount forzest line. One study using rate- 160 control drugs reported adverse events cheap 20mg forzest free shipping, finding three hematomas in the ablation arm 20mg forzest free shipping, as well as one pulmonary embolus 20 mg forzest amex. During long-term followup of this study, two patients who received ablation plus pacing developed heart failure, one patient who received ablation plus pacing developed failure to capture related to malfunction of their pacemaker, and one patient in the medication arm experienced prolonged pauses with their AF and required pacemaker 163 placement. One Procedure Versus Another In the study comparing AVN ablation plus biventricular pacing versus AVN ablation plus RV pacing, overall numbers of complications were reported for a 3-year period and included adverse events related to pacemaker dysfunction, such as diaphragmatic stimulation, lead dislodgement, and oversensing, as well as adverse events related to pacemaker placement 162 including pneumothorax, hematoma, and infection. There was no significant difference in overall complication rates between treatment arms, with rates of 15 and 6 percent (p=0. This study found that the results of heart rate changes or exercise capacity by treatment group did not differ from the main 160 study for this subgroup. One Procedure Versus Another The study comparing AVN ablation plus biventricular pacing versus AVN ablation plus RV pacing also evaluated 6-month outcomes of subgroups of participants based on LVEF. This study found that among participants with an LVEF >45 percent (n=89), both treatment arms had improvements in 6-minute walk distance, and there was no significant difference between treatment groups in this improvement. However, among participants with an LVEF ≤45 percent (n=76), those participants receiving biventricular pacing had significantly greater improvements in their 6-minute walk distance compared with those receiving RV pacing, with improvements of 96. This study also compared outcomes for patients with different functional classes of heart failure based on New York Heart Association (NYHA) symptoms. Similar to the pattern observed for patients by LVEF, those with NYHA class I symptoms demonstrated similar improvements in 6-minute walk distance (p=0. Strength of Evidence Tables 8 and 9 summarize the strength of evidence for the various comparisons and outcomes of interest. Studies varied in the type of procedures and drugs that were tested, limiting our ability to synthesize evidence across studies. Studies that explored the impact of procedures versus drugs on ventricular rate control demonstrated a significantly lower heart rate in patients in the procedural intervention arms. Other outcomes assessed either found no differences by treatment arm (exercise capacity, mortality) or were inconsistent (quality of life). Studies that evaluated one rate-control procedure versus another did not find differences in rate control or all- cause mortality but did demonstrate an improvement in exercise capacity among those in a biventricular pacing group compared with right ventricular pacing. Our findings underscore the need for additional studies to compare rate-control procedures with rate-control drugs or other procedural interventions with in relation to these outcomes. Although based on direct and mostly consistent evidence, the low number of studies, imprecise findings, and inability to determine a summary effect given the variability in study design and population lowered our confidence in the evidence. Strength of evidence domains for rate-control procedures versus drugs Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Ventricular 3 (175) RCT/Low Consistent Direct Imprecise SOE=Moderate Rate Control Using different metrics, all 3 studies found that patients in the procedure arm had a significantly lower heart rate at 12 months than those on drugs All-Cause 2 (201) RCT/Low Consistent Direct Imprecise SOE=Low Mortality No significant difference CV Mortality 1 (102) RCT/Low NA Direct Imprecise SOE=Low No significant difference Exercise 2 (135) RCT/Low Consistent Direct Imprecise SOE=Low Capacity Studies did not show significant differences between procedure and drug arms Quality of Life 2 (135) RCT/Low Inconsistent Direct Imprecise SOE=Insufficient Abbreviations: CI=confidence interval; NA=not applicable; RCT=randomized controlled trial; SOE=strength of evidence 39 Table 9. Strength of evidence domains for one rate-control procedure versus another Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Ventricular 1 (40) RCT/Low NA Direct Imprecise SOE=Low Rate Control No difference between those assigned to anterior vs. Antiarrhythmic Drugs and Electrical Cardioversion for Conversion to Sinus Rhythm KQ 4: What are the comparative safety and effectiveness of available antiarrhythmic agents and electrical cardioversion for conversion of atrial fibrillation to sinus rhythm? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points • Based on 4 RCTs (2 good, 2 fair quality) involving 411 patients, use of a single biphasic waveform is more effective in restoring sinus rhythm than use of a single monophasic waveform in patients with persistent AF (high strength of evidence). Description of Included Studies A total of 42 RCTs involving 5,780 patients were identified that assessed the use of antiarrhythmic drugs or electrical cardioversion for the conversion of AF to sinus rhythm 140,170-181 (Appendix Table F-4). Thirteen studies were considered to be of good quality, 27 of fair 144,145,147,149,182-204 205,206 quality, and 2 of poor quality. The studies were published from the years 170,171,188,196 2000 through 2011; however, all but four studies were published in 2007 or earlier. Only 7 studies included sites in the United States; 25 140,144,145,147,170,175-179,187,188,191-196,200-206 included sites in Europe. The study population consisted 144,145,147,170-172,175-178,183,185-187,192-195,197-199,202- entirely of patients with persistent AF in 25 studies, 204,206 189 entirely of patients with paroxysmal AF in 1 study, and entirely of patients for whom 174,195 prior rate- or rhythm-control therapy had been ineffective in 2 studies. Funding was unclear 140,144,147,170,172,173,175,179,181,183,185-188,190-206 or not reported in 31 studies. Seven studies used 145,171,174,176,178,180,184 industry funding, none was government-only funded, and eight were funded 145,149,171,174,177,178,182,189 by nongovernment/nonindustry sources. In the majority of studies, the 145,179,181,183-187,193,195,197-203,206 setting was not reported (18 studies ). Of the remaining studies, 7 140,144,174,177,182,191,205 149,170,173,189,190 were inpatient, 5 were in the emergency room, 10 were 147,171,172,175,176,178,180,192,194,204 188,196 outpatient, and 2 were in more than one setting. Figure 5 represents the treatment comparisons evaluated for this KQ. Overview of treatment comparisons evaluated for KQ 4 aLines running from one oval back to the same oval (e. Abbreviations: KQ=Key Question; J=Joules; Tx=treatment Twenty-one studies compared methods of external electrical cardioversion, four studies 178 199,205 compared electrical cardioversion augmented by medications (metoprolol, verapamil, 195 and ibutilide ) with electrical cardioversion alone, and eight studies evaluated the efficacy of drugs used both prior to and after external electrical cardioversion (amiodarone [five 144,149,180,181,204 144,204 145,147,149,204,206 studies ], diltiazem [two studies ], digoxin [five studies ], 145,147,206 149,180,181 verapamil [three studies, ], sotalol [three studies ]). Nine studies compared drugs 140,170,177,188-193 without (or prior to) external electrical cardioversion. No study compared electrical cardioversion directly with pharmacological cardioversion. Of the 42 studies, 3 had a 170,180,193 181,192 placebo arm, and 2 had a “control” arm that was not included in this review. The remaining 36 studies had 2 intervention arms each. The primary outcome reported for this KQ was restoration of sinus of rhythm within a specified time period following the intervention. This time period ranged from immediately following the intervention to 6 weeks following the intervention. Several studies presented outcome data at multiple time points following the intervention, while others assessed time to outcome within a prespecified time frame. Only three studies did not report restoration of sinus 194,199,205 rhythm. Of these, one assessed maintenance of sinus rhythm at 1 week following 199 electrical cardioversion or verapamil plus electrical cardioversion, another reported 42 194 maintenance of sinus rhythm 1 month after electrical cardioversion, and the third reported recurrence of AF within 1 week following verapamil with electrical cardioversion versus 205 electrical cardioversion alone. Three studies reported an outcome relevant to this KQ in addition to restoration of sinus rhythm. One study reported all-cause mortality, mixed embolic events, and maintenance of sinus 185 191 rhythm at 6 weeks; one reported recurrence of AF within 24 hours after cardioversion; and 202 one reported recurrence of AF within 1 minute of electrical cardioversion. Detailed Synthesis Comparisons of Various Methods for External Electrical Cardioversion Overview Twenty-one studies (2,996 patients) compared different methods of external electrical cardioversion. Nine studies (1,219 patients) compared a biphasic waveform with a monophasic waveform (Table 10), and 4 studies (393 patients) compared anterolateral versus anteroposterior positioning of the defibrillation electrodes (paddles in 2 studies, paddles and/or gel pads in 1 175,183,187,202 study, and pads in 1 study). Three studies (432 patients) included a comparison of an 172,185,186 initial 200 J shock with an initial 360 J shock. The remaining five studies addressed 197 182 comparisons in polarity (one study ), shapes of the biphasic waveform (one study ), 176 composition of the cardioversion electrodes (one study ), and different amounts of energy 171,198 delivered (two studies ). Among the 9 studies comparing a biphasic waveform with a monophasic waveform, 8 assessed restoration of sinus rhythm at 0 or 30 minutes after cardioversion, and 1 assessed 194 maintenance of sinus rhythm at 1 month following electrical cardioversion. Only two studies 194,203 included only patients with persistent AF, and one study included only patients for whom a 174 prior rate- or rhythm-control therapy was ineffecitve. One study also included an assessment 203 of recurrence of AF within 1 minute following initial cardioversion. Three studies were of good quality, and six were of fair quality. Among these nine studies, mean/median population age ranged from 55–70 years; data on AF type and heart failure prevalence were generally not reported. Studies evaluating biphasic versus monophasic waveform Study Biphasic Protocol Monophasic N Outcomes Assessed Protocol 184 Ambler, 2006 100 J, 200 J, 300 70 J, 110 J, 150 J, 128 − Restoration of SR J, 360 J, 360 J 200 J, 360 J immediately − Restoration of SR at 30 minutes Kawabata, 50 J, 100 J, 150 J, 100 J, 200 J, 300 154 − Restoration of SR after 173 2007 175 J J, 360 J cumulative shocks (IV amiodarone) (IV amiodarone) − Restoration of SR after 1st shock 174 Khaykin, 2003 150 J, 200 J, 360 J Single 360 J 56 − Restoration of SR 194 Marinsek, 2003 70 J, 100 J, 150 J, 100 J, 200 J, 300 83 − Maintenance of SR at 1 200 J J, 360 J month Mortensen, 75 J, 100 J, 150 J, 100 J, 150 J, 200 95 − Restoration of SR 196 2008 200 J J, 300 J, 360 J immediately after cumulative shocks − Restoration of SR after 1st shock 179 Page, 2002 100 J, 150 J, 200 100 J, 150 J, 200 203 − Restoration of SR after 4 J, 200 J biphasic J, 200 J biphasic shocks or 360 J or 360 J − Restoration of SR after 3 monophasic monophasic shocks − Restoration of SR after 2 shocks − Restoration of SR after 1 shock 200 Ricard, 2001 150 J, 150 J 150 J, 360 J 57 − Restoration of SR after all shocks − Restoration of SR after 1 shock 201 Scholten, 2003 120–200 J 200–360 J 277 − Restoration of SR after 1st sequence sequence shock − Restoration of SR after 2nd shock Siaplaouras, 120 J, 150 J, 200 200 J, 300 J, 360 216 − Restoration of SR 203 2004 J, 200 J J, 360 J − Recurrence of AF within 1 minute Abbreviations: AF=atrial fibrillation; J=Joules; N=number of patients; SR=sinus rhythm Four studies (393 patients) compared anterolateral vs. One study was of 175 183,187,202 good quality, and three were of fair quality. One study was conducted in the outpatient 175 setting; the other three did not specify the setting. All four studies included only patients with persistent AF. The mean age of patients receiving the anterolateral approach ranged from 58–68 years, and the mean age of patients receiving the anteroposterior approach ranged from 62–67 years. All four studies assessed restoration of sinus rhythm immediately after the external electrical cardioversion, all four were conducted in Europe, and all four were single-center studies.

For the RCT discount 20mg forzest visa, significance data were presented separately for stroke and systemic embolism; a statistically significant difference in stroke rate was observed buy cheap forzest 20mg on line, with a HR of 0 quality 20mg forzest. However buy discount forzest 20mg online, although it was a good quality study, this RCT used a prespecified 90 percent CI, and it is not clear whether this conclusion of noninferiority for stroke would be equally valid using a statistical significance of p<0. Bleeding Events 17 152 The RCT and one observational study examined incidence of bleeding events among patients receiving strict and lenient rate control. No statistically 27 significant difference in the incidence of bleeding events between strict and lenient rate control was observed in either study (insufficient strength of evidence). Composite Outcomes The included studies examined a variety of composite outcomes as primary outcomes. As described in the articles, these included: (1) death from cardiovascular causes, hospitalization for heart failure, stroke, systemic embolism, major bleeding, arrhythmic events (including syncope), sustained ventricular tachycardia, cardiac arrest, life-threatening adverse effects of rate-control 17 drugs, and implantation of a pacemaker or cardioverter-defibrillator; (2) all-cause death, 153 cardiovascular hospitalization, and myocardial infarction; and (3) cardiovascular death, heart failure, thromboembolic complications, bleeding, severe adverse effects of antiarrhythmic drugs, 152 and pacemaker implantations. The single available RCT showed a nonsignificant hazard ratio (HR) of 0. No statistically significant difference in composite primary outcome between strict and lenient rate control was observed in any of the included studies, despite the use of distinct composite outcomes and unique definitions for strict and lenient rate control. Other Outcomes Other outcomes were reported infrequently. Two observational studies also reported data on pacemaker implantation for patients with refractory rate control; one reported an incidence of pacemaker implantation of 11 percent in the strict rate- 153 control group and 1 percent in the lenient rate-control group (p=0. One observational study reported data on myocardial infarction, with an incidence of 2 percent in the strict rate-control group and 1 percent in the lenient rate- 153 control group (p=NS). Adverse Events Reporting of adverse events attributable to rate-controlling drugs was inconsistent across studies. Strength of Evidence Our review identified only one RCT and two observational studies representing secondary analyses of RCTs exploring the comparative safety and effectiveness of strict versus lenient rate- control strategies. In general, these studies were consistent in showing no significant difference between strict and lenient rate control with respect to mortality, cardiovascular hospitalizations, heart failure symptoms, quality of life, thromboembolic events, bleeding events, and composite outcomes. However, the RCT differed from the observational studies in showing a statistically significantly lower stroke rate with lenient rate control. By emphasizing the limitations in the available data and the paucity of data on lenient versus strict rate control, our findings highlight the need for more research in this area. Table 6 summarizes the strength of evidence for the outcomes of interest and illustrates how the current evidence base is insufficient to provide conclusive estimates of the effect of strict and lenient rate-control strategies. Note that because the one RCT was powered as a noninferiority trial the risk of bias was estimated to be moderate rather than low. Strength of evidence domains for strict versus lenient rate-control strategies Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) All-Cause 1 (614) RCT/ NA Direct Imprecise SOE=Insufficient Mortality Moderate CV Mortality 2 (828) RCT/ Consistent Direct Imprecise SOE=Insufficient Moderate Observa- tional/ Moderate CV Hospitaliza- 2 (1,705) RCT/Moder Consistent Direct Imprecise SOE=Insufficient tions ate Observa- tional/ Moderate Heart Failure 2 (828) RCT/ Consistent Direct Imprecise SOE=Insufficient Symptoms Moderate Observa- tional/ Moderate Quality of Life 2 (828) RCT/ Consistent Direct Imprecise SOE=Insufficient Moderate Observa- tional/ Moderate Thrombo- 2 (828) RCT/ Consistent Direct Precise SOE=Low embolic Events Moderate HR 0. Rate-Control Procedures Versus Drugs or Versus Other Procedures in Patients for Whom Initial Pharmacotherapy Was Ineffective KQ 3: What are the comparative safety and effectiveness of newer procedural and other nonpharmacological rate-control therapies compared 30 with pharmacological agents in patients with atrial fibrillation for whom initial pharmacotherapy was ineffective? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points Procedures versus drugs: • Based on 3 studies (1 good, 2 poor quality) involving 175 patients, patients undergoing a procedural intervention had a significantly lower heart rate at 12 months than those receiving a primarily pharmacological intervention (moderate strength of evidence). One procedure versus another: • Based on 1 study (fair quality) involving 40 patients, there was no difference in ventricular rate control between those assigned to an anterior versus posterior ablation approach (low strength of evidence). Description of Included Studies Six RCTs (2 good, 3 fair, and 1 poor quality) involving a total of 537 patients met the inclusion criteria for KQ 3 (Appendix Table F-3), evaluating the comparative effectiveness of a procedural intervention versus a primarily pharmacological intervention for rate control of 157-160 161,162 AF, or comparing two primarily procedural interventions. We also included data from 163 160 a separately published subgroup analysis of one of the RCTs. One study each was based in 158 159 161 the UK, continental Europe, and Asia; one was a multicenter trial based in Australia (Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial 160 162 [AIRCRAFT]); one was a multicenter trial in the United States and Canada; and one did not 157 specify the geographical location. All studies were unblinded due to the nature of the 162 interventions, although one was described to be patient-blinded. Four studies recruited patients 158,160,162 159 with only one specific type of AF, either permanent or persistent; one study recruited 157 patients with “resistant chronic” AF; and one study recruited patients with permanent or 161 paroxysmal AF. These studies, however, evaluated and compared different types of treatments, preventing conclusions about whether effectiveness varied by type of AF. Treatment 31 158,160,162 arms ranged in size from 18–103 patients. One study reported outcomes with a mean followup period of approximately 26 months. Finally, one study reported outcomes at an unclear time point, which is presumed to be immediately after the 161 procedure was completed, as well as at 14 months. Three studies reported their funding 160,162 source, which was from industry for two studies, and at least partially from a governmental 161 organization in the other. In line with our a priori definition of rate-control procedures, all studies included at least one treatment arm with radiofrequency ablation of either the atrioventricular node (AVN) or His bundle, most often in conjunction with pacemaker placement. The comparison arms included a pharmacological intervention whose main purpose was to control ventricular heart rate rather than converting the underlying rhythm of AF, based on the description of outcomes; this was combined with a procedure in some studies. One study compared AVN ablation plus pacing of 157 the His bundle area versus treatment with amiodarone at a dose of 200–400 mg a day. Another study compared AVN ablation plus ventricular demand rate-responsive (VVIR) pacing versus a pharmacological intervention for ventricular rate control, including digoxin, beta blockers, and calcium channel blockers, alone or in combination, as selected by the treating health care 160 provider. In one study, all patients had placement of a VVIR-programmed pacemaker, followed by randomization to either a His bundle ablation or pharmacological treatment to assist with ventricular heart rate control, with medications including calcium channel blockers, 158 digoxin, or beta blockers. In two studies, all patients had AVN ablation, but were randomized to different types of pacing strategies. In one of these studies, all patients underwent AVN ablation for chronic AF 162 and were randomized to chronic biventricular pacing versus right ventricular (RV) pacing. In the other study, in addition to AVN ablation, participants were randomized to dual chamber demand rate-responsive (DDDR) pacing in conjunction with antiarrhythmic therapy with medicines such as propafenone, sotalol, or amiodarone, versus VVIR pacing with no additional 159 antiarrhythmic therapy. Finally, one study compared anterior and posterior approaches to 161 AVN ablation for rate control. Detailed Synthesis Ventricular Rate Control Four studies reported outcomes related to ventricular rate control based on 24-hour Holter 157,158,160,161 monitor, but only three of these presented actual measures of heart rates achieved 158,160,161 with the different treatments (Table 7). Three studies compared a primarily procedural 157,158,160 intervention with a primarily pharmacological intervention; one compared two primarily 161 procedural interventions with one another. Heart rate results (24-hour Holter monitor) Study Sample Timing of Interventions Minimum Mean Heart Maximum a a a Size (N) Outcome Heart Rate Rate Heart Rate Procedures vs. Abbreviations: AVN=atrioventricular node; VVIR=ventricular demand rate-responsive 33 Procedures Versus Drugs Three studies found that patients in the primarily procedural intervention arm had a significantly lower heart rate at 12 months than those receiving the primarily pharmacological intervention (moderate strength of evidence). The studies used different measures based on 24- hour Holter monitor—either maximal heart rate or mean heart rate. One study comparing AVN ablation plus pacing of the His bundle area versus amiodarone found that after 3 weeks of treatment, 100 percent of the patients who had undergone AVN ablation with pacemaker achieved a normal ventricular rate, defined as 50–90 bpm, compared with only 57. Also, none of the patients who received AVN ablation with pacemaker had an uncontrolled heart rate, defined as >90 bpm at rest or >130 bpm on exertion, while 42. In this same study, 100 percent of patients who had undergone AVN ablation with pacemaker achieved a normal ventricular rate at 12 months, compared with only 33. Also, none of the patients who received AVN ablation with pacemaker had an uncontrolled heart rate at 12 months, while 66. In the study comparing VVIR pacing plus His bundle ablation versus VVIR pacing plus rate- control medications, at 1-month followup, those receiving the ablation had a lower mean heart rate over 24 hours, based on 24-hour Holter recordings, with a mean heart rate of 71±6 bpm 158 compared with 83±8 bpm in the medication arm (p<0. Mean heart rates were described as being similar to these values through 1 year of followup. Resting heart rates also differed between groups, but this difference was thought to be due to the fact that the lower heart rate was programmed on the pacemakers differently in the two groups, with the ablation group having the lower heart rate set at 60 bpm and the medication group having the lower heart rate set at 70 bpm. The maximum heart rate, as measured on the 24-hour Holter recordings, did not differ significantly between the two groups. In another study, at 12 months, based on 24-hour ambulatory electrocardiograms (ECGs), those receiving AVN ablation plus VVIR pacing compared with those on medication alone had significantly higher minimum heart rates (70±9 vs. However, those receiving the ablation had significantly lower maximum heart rates compared with those on medication alone on 24-hour tapes (117±16 vs. For this subgroup, investigators reported that at approximately 5 years of followup, minimum heart rate (assessed by 24-hour Holter monitor) was still higher in those receiving AVN ablation plus VVIR pacing than in those receiving medication alone (60±9 bpm vs. Mean heart rates were not significantly different, but maximum heart rate was again lower in those receiving ablation plus VVIR pacing than in those receiving medication alone (108±12 vs. One Procedure Versus Another The study that compared two different approaches for performing AVN ablation—an anterior approach and a posterior approach—defined immediate success of the procedure with reference to heart rate parameters including a heart rate of approximately 120–130 bpm during infusion of isoproterenol (4 mcg/min) or an average ventricular rate of approximately 70–75 percent of the 34 161 baseline ventricular rate during infusion of isoproterenol (4 mcg/min).

Proc Natl Acad Sci ent regulation of the basal forebrain by telencephalic and brain- USA1997;94:13311–13316 forzest 20mg with amex. Modification of neocortical cologic deficits in M2 muscarinic acetylcholine receptor knock- acetylcholine release and electroencephalogram desynchroniza- out mice cheap forzest 20mg line. Arousal: revisiting the reticular activating system buy discount forzest 20mg on line. Brainstem afferents to ciation between locomotor activity and the acquisition of re- the magnocellular basal forebrain studied by axonal transport purchase 20 mg forzest overnight delivery, sponding for conditioned reinforcement stimulated by d-am- immunohistochemistry, and electrophysiology in the rat. Common aspects of the action of nicotine and pedunculopontine tegmental nucleus increase sucrose consump- other drugs of abuse. Frontal syndrome as a consequence of lesions in the nicotine. Preferential stimulation of loco- (Review; 141 refs. 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Removal of cholinergic efflux in the nucleus accumbens after cholinergic stimulation input to rat posterior parietal cortex disrupts incremental pro- of the ventral tegmental area in intact, pedunculopontine teg- cessing of conditioned stimuli. Basal forebrain lesions in monkeys disrupt attention but not learning and mem- lesioned rats. The pedunculopontine in J Neurosci 1995;15(3 Pt 2) following table of contents. Selective immuno- tine self-administration in the rat: a correlative neuroanatomical toxic lesions of basal forebrain cholinergic cells: effects on learn- and behavioral study. A re-examination of culopontine tegmental nucleus lesions on responding for intra- the role of basal forebrain cholinergic neurons in spatial working venous heroin under different schedules of reinforcement. 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AGHAJANIAN AND ELAINE SANDERS-BUSH Serotonin, or 5-hydroxytryptamine (5-HT), has been impli- cellular aspects of individual 5-HT receptor subtypes and cated in almost every conceivable physiologic or behavioral their transduction mechanism, in addition to interactions function—affect, aggression, appetite, cognition, emesis, between different receptor subtypes within a single neuron endocrine function, gastrointestinal function, motor func- or region. The implications of this work in understanding tion, neurotrophism, perception, sensory function, sex, the global functions of the 5-HT system are discussed. Moreover, most drugs that are currently used for the treatment of psychiatric disorders (e. How is it possible for 5-HT to be involved in so many different processes? One answer lies in In the first half of the last decade, the cloning of the major the anatomy of the serotoninergic system, in which 5-HT known families of 5-HT receptors was accomplished. More cell bodies clustered in the brainstem raphe nuclei are posi- recently, attention has turned to issues of transcriptional tioned through their vast projections to influence all regions and post-transcriptional regulation. Another answer lies in the molecular diver- sity and differential cellular distribution of the many 5- RNA Processing HT receptor subtypes that are expressed in brain and other tissues. The 5′-flanking region of several 5-HT-receptor genes has During the past decade, molecular cloning techniques been cloned, and consensus sequences for transcription fac- have confirmed that putative 5-HT receptor subtypes, pre- tors have been identified in the promoter region (2–4). The dicted from radioligand binding and functional studies identification of these potential regulatory sites sets the stage (e. This knowledge has revolution- tion of gene transcription in vivo (5). A prominent form of ized contemporary research on the serotoninergic system.

FGF-2 generic forzest 20mg with mastercard, however generic 20 mg forzest free shipping, is mem- tal order 20 mg forzest amex, behavioral buy discount forzest 20 mg line, genetic, neuroendocrine, and neurochemical ber of a family of 10 related, but genetically and functionally factors can regulate adult neurogenesis. Among those, only FGF-2 and FGF- cesses that lead to neurogenesis, cell proliferation and the 4 are mitogens for neural progenitor cells. Moreover, a com- subsequent differentiation and survival of newborn neurons, parison of amino acid sequences between the FGFs revealed can undergo differential regulation by these factors (Table a striking similarity between a 10-amino acid sequence of 8. This 10-amino acid sequence was been shown to elicit the mitogenic effects of FGF-2 and FGF-4 Genetics on neural progenitor cells, whereas similar regions in FGF- 1 and -5 were found to be inactive (35). In 1997 Kempermann and colleagues found that strains of Several factors have been found to be important for neu- mice differ with respect to rate of cell division and amount ronal differentiation in cultured progenitor cells. Comparisons were made lar, retinoic acid and cAMP increase neuronal differentia- among C57BL/6, BalB/c, CD1, and 129/SVJ strains. In addition, neurotrophins such as NGF, liferation was found to be highest in C57BL/6 mice; how- BDNF, and NT-3 have been found to influence neuronal ever, net neurogenesis was highest in the CD1 strain. Indeed, exposure to an Transplanted Cells and Responses to enriched environment (18)had different effects on two of Local Cues these strains of mice, C57BL/6 and 129/SVJ, respectively. Progenitor cells may play an important role in brain or In C57BL/6 mice enrichment promoted the survival of pro- spinal cord repair. In particular, grafting of progenitor cells genitor cells but did not affect proliferation, whereas the into degenerated or injured areas may be used to replace net increase in neurogenesis in 129/SVJ mice was accompa- cells that are no longer functional. The phenotype and func- nied by a twofold increase in proliferation (18). Thus, strain tion that these cells acquire appears to be very much depen- differences not only influence the baseline rate of adult hip- dent on the specific environment into which they are trans- pocampal neurogenesis, but also influence how adult hippo- planted. Thus, cultured hippocampal progenitors become campal neurogenesis is regulated in response to environ- granule cell neurons when grafted into the dentate gyrus, mental stimulation. Indeed, proliferation, survival and tyrosine hydroxylase, and calbindin positive neurons in the differentiation of progenitor cells and their progeny are each olfactory bulb after grafting into the rostral migratory separately influenced by inheritable traits and are not uni- 112 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 8. REGULATION OF CELL PROLIFERATION AND NEUROGENESIS IN THE DENTATE GYRUS IN VIVO Factor Proliferation Glia Neurons References FGF 44,46 EGF 44 IGF 47 Estrogen 67 Serotonin G n. G Enriched environment 17,18,80 Wheel running 55,56 Learning n. Both running and enrichment increase net neurogenesis (17,55,56). The ef- fects of intracerebral administration of trophins such as Growth Factors BDNF, NT-3, and GDNF remain to be determined; how- ever, it appears that growth factors do play a role in in vivo During development, growth factors provide important ex- regulation of proliferation and neurogenesis in the adult tracellular signals for regulating the proliferation and fate hippocampus. Better understanding of their mechanisms of determination of stem and progenitor cells in the CNS (43). Intra- cerebroventricular infusion of EGF and FGF-2 in adult rats increased proliferation in the subventricular zone (44). Nei- Neuroendocrine Factors and Stress ther EGF nor FGF enhanced proliferation in the subgranu- lar zone of the dentate gyrus. With regard to differentiation, McEwen and Gould at Rockefeller University first in- EGF promoted glial differentiation, whereas FGF-2 did not vestigated the effects of glucocorticoids or stress on adult influence phenotype distribution (44). The initial study reported that experiments, FGF was administered systemically during the adrenalectomy, which leads to a reduction in serum gluco- first postnatal weeks and in the adult rat. Cell proliferation corticoid levels, elicits cell division in the dentate gyrus. Conversely, stress or increased levels of glucocorticoid intracerebral infusion of IGF increases both cell prolifera- hormones inhibit proliferative activity in the dentate gyrus tion and neurogenesis in hypophysectomized rats (47). For example, administration of high levels of corti- songbirds, seasonal regulation of adult neurogenesis de- costerone diminishes cell division in the adult rat hippocam- pends on testosterone levels that mediate their effect pus (59). In addition, exposure of a rat to the odor of a through BDNF (48). In addition, IGF-1, FGF mRNA, and natural predator (fox), causing stress and elevated corticoste- BDNF mRNA are elevated in rodents by exercise (49–52). Thus, monoamines can affect cell gene- moset monkeys to a resident intruder causes stress and re- sis in the dentate gyrus. The receptors and mechanisms by sults in a decrease in cell proliferation (61). In a recent which they exert their effects as well as possible interactions study, rats that are highly reactive to novelty and exhibit a with other classes of neurotransmitters and/or growth fac- prolonged corticosterone secretion in response to novelty tors remain to be determined. Aging is accompanied by a reduction in neuro- Experience genesis (63), which may be caused in part by elevated gluco- As mentioned, stress (19)and depression may reduce the corticoid levels. Adrenalectomy in aged rodents has been birth of new neurons. In addition, the aging process is ac- shown to increase cell proliferation and neurogenesis (64). Thus, glucocorticoids and stress associated permann and colleagues carried out the first of these studies with increased corticosterone secretion inhibit cell genesis in comparing mice living under standard conditions with those the hippocampus. Enhanced stress or glucocorticoid levels housed in an enriched environment (17). Exposure to an therefore may impair hippocampal function, and lead to enriched environment, consisting of larger housing; toys; deficits in learning and memory. In contrast to the glucocor- and more opportunity for social stimulation, physical activ- ticoids, other steroid hormones, such as testosterone, en- ity, and learning than standard laboratory conditions (79), hance neurogenesis in birds (66), whereas estrogen results resulted in a significant increase in neurogenesis, without in a transient increase in proliferation in rats (67). Thyroid affecting cell proliferation in mice and rats (17,80). Subse- hormone can affect neuronal differentiation of hippocampal quent studies showed that the age-related decline in neuro- progenitor cells in vitro (27). In vivo, hypothyroidism inter- genesis could be attenuated by enrichment (81). In addition, feres with cell migration (68), but does not affect postnatal it was shown that enrichment inhibits cell death by cell proliferation (69). Moreover, it was deter- mined that the most important components of enrichment Neurotransmitters are increased physical activity and possibly learning. Similar to enrichment, voluntary exercise in a running wheel in- Neurotransmitters have also been suggested to play a role creases net neurogenesis (55). In addition, running increases in adult dentate gyrus neurogenesis. Systemic injection of glutamate analogs inhibits birth of new cells, whereas an antagonist, such as MK801, enhances cell division (65,70). Recently, another class of neurotransmitters, the mono- amines, has been suggested to be important as well. Pro- longed administration of fluoxetine, as well as therapeutic agents acting on norepinephrine and dopamine receptors, and electroconvulsive shock enhance the number of BrdU- positive cells in rats (71–73). Acute administration of fluox- etine did not affect cell genesis (73). Grafting of fetal raphe neurons also stimulated granule proliferation in the hippo- campus, whereas embryonic spinal tissue had no effect (74). Furthermore, depletion of serotonin reduces stem cell pro- liferation in the dentate gyrus (75). It is possible that these effects are mediated by the 1A receptor, because administra- tion over 4 days of a specific 1A receptor antagonist (WAY) reduced basal rate of cell proliferation (Jacobs et al. Taken together, these findings suggest that induction of cell proliferation is dependent on chronic administration of monoamines, consistent with the thera- FIGURE 8. Proliferation and neurogenesis in the dentate peutic time course for antidepressant treatments. Photomicrographs of BrdU-positive cells 1 day (a–c) and 4 these studies have led to the hypothesis that therapeutic weeks (d–f) after the last injection in control (a,d), running (b,e), and enriched (c,f) mice. Confocal images of BrdU positive cells in interventions that increase serotonergic transmission may control (g), running (h), and enriched (i) mice, 4 weeks after the act in part by augmenting dentate neurogenesis, promoting last injection. Sections were immunofluorescent triple labeled for recovery from depression (76,77). It is of interest to note BrdU (red), NeuN indicating neuronal phenotype (green), and s100 selective for glial phenotype (blue). Orange (arrow, new- in this context that voluntary exercise increases cell prolifera- born neuron) is red green.

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