By A. Mason. Augustana College, Sioux Falls South Dakota.

Further cheap synthroid 200 mcg line, a study by Lu- (HPA) axis dysfunction can produce repeated episodes of pien and colleagues (35) demonstrated a correlation be- hypercortisolemia order 75mcg synthroid otc. Currently volume studies do not rou- tween higher cortisol levels measured longitudinally and tinely include measures of cortisol order 50 mcg synthroid with visa, nor can they ascertain greater hippocampal volume loss in normal human aging cheap 50 mcg synthroid with mastercard. However purchase synthroid 25 mcg line, several differ- Glial cell loss either directly or indirectly is another po- ent mechanisms could explain volume loss including tential mechanism for producing volume loss. Gray matter neuronal loss through exposure to repeated episodes of atrophy in the prefrontal cortex in an area ventral to the hypercortisolemia, glial cell loss, resulting in increased genu of the corpus callosum (3), an area associated in post- vulnerability to glutamate neurotoxicity, stress-induced re- mortem studies with glial cell loss (27) has been reported. A mechanism that could account for of depressed subjects in two different areas of prefrontal hippocampal, amygdala, and prefrontal cortex volume loss, cortex (26). In addition, glial cell loss has been reported in areas that have high concentrations of GC receptors is GC- postmortem studies of major depression in the amygdala mediated neurotoxicity (33), with repeated hypercortiso- and hippocampus (23). Early Through excitatory connections between the amygdala life stress may produce a permanent hypersensitivity to stress and hippocampus (36) it is possible that damage in one (34), with the production of ongoing HPA axis dysregula- structure could produce damage in the connected structure. In the Similarly, interconnections between prefrontal cortex and case of hippocampal volume loss, the inverse correlations hippocampus (37) could produce excitotoxic damage. Glial Chapter 74: Imaging of Affective Disorders 1069 cells sequester glutamate, maintain metabolic and ionic ho- LCSPT circuit. Kumar and colleagues (60), for example, meostasis, and produce trophic factors, including brain de- have found loss in prefrontal lobe volume in late-onset rived neurotrophic factor (BDNF) (38,39). Therefore, loss depression in the absence of generalized atrophy, suggesting of glial cells could increase vulnerability to neurotoxic dam- that as in early-onset depression some subjects with late- age, supporting the idea that glutamate neurotoxicity may onset depression may also have focal volume loss. It is not be involved in the volume loss in the limbic–cortical–stria- known whether this focal volume loss involves the same tal–pallidal–thalamic (LCSPT) circuit. A recently developed concept—stress-induced inhibition A well replicated finding in elderly subject groups with of neurogenesis (40)—may also explain depression-related depression is the increased numbers of hyperintensities seen volume loss, although high rates of baseline neurogenesis on T2-weighted scans (T2H) (51,61–65). Some studies would be needed to produce atrophy of the scale required that included younger subjects with depression have also by volume loss in depression. Psychosocial stress was shown found increased T2H (2,66), although negative findings to suppress neurogenesis in the tree shrew (40). Likewise, have also been reported with younger groups (5,67). The corticosterone treatment in adult rats produced suppression underlying causes of T2H are unknown, and indeed, it is of neurogenesis, which was reversed by removal of the adre- important to note that T2H also occur at rates of up to nal gland (41). More recent findings (42) indicate that neu- 60% in healthy elderly (68), in whom their significance is rogenesis may occur in the frontal cortex as well as the unknown (69). Fujikawa and associates (70,71) found a hippocampus and subventricular zone. Thus, if depression higher rate of 'silent' cerebral infarctions (T2H) in late- inhibits neurogenesis, this could potentially explain both compared to early-onset MDD. Clinical correlates of MRI- cortical and hippocampal volume loss. A subtype of 'vascular depres- Late-Onset Major Depression sion' with increased CVD risk factors and increased T2H Partly because of the increased prevalence of comorbid ill- has been proposed (47,73). Depression onset in late age frequently occurs in Structural abnormalities reported in bipolar disorder have patients with medical and neurologic disorders and com- been intermittently reported. These include diffuse gray pared with EORD it is characterized by greater medical matter tissue loss, enlarged ventricles, increased numbers of morbidity and mortality (43), higher rates of neuroradio- T2-signal hyperintensities (T2H), and regional tissue loss logic abnormalities, particularly white-matter hyperintensi- in basal ganglia, lateral and mesial temporal structures, and ties (44,45), and lower familial frequency of affective disor- cortical regions. Studies in bipolar subjects have also found ders (46). In some studies, it is associated with higher rates structural changes in the same neuroanatomic circuit of neuropsychological impairment and treatment refractori- (LCSPT) as in major depression but these changes have ness (47,48). In addition there is a substan- shown diffuse cortical and subcortical atrophy and ventricu- tial body of evidence for manic-like affective disorders fol- lar enlargement in late life depression (18,49–51). Any condition that produces recent study in geriatric bipolar disorder (79) found in- neuronal ischemia or neurotoxicity is a potential candidate creased cortical sulcal widening which was related to age of for producing brain atrophy. In a small study in middle-aged bipolar sub- Neurologic illnesses associated with both cortical and jects, Lim and co-workers (80) also found enlarged cortical subcortical atrophy are associated with unusually high rates sulci. Each of these illnesses result from differences in segmentation algorithms, differ- produces damage to brain structures critical in emotional ences in covarying the data, and a more chronically ill popu- functioning.

Modified embryonic stem cells are burda and Bellugi proposed that the dorsal portions of the microinjected into a blastula that is isolated from another hemispheres safe 200 mcg synthroid, the frontal and parietal-occipital regions generic 100 mcg synthroid otc, may mouse that ordinarily has a different coat color purchase synthroid 200mcg mastercard. They noted that some language functions is then reimplanted into a female host mouse and develops are preserved that are linked to ventral systems purchase synthroid 75 mcg visa. The inserted stem cells are incorporated into the Chapter 46: Behavioral Phenotypes of Neurodevelopmental Disorders 635 developing fetuses cheap 200 mcg synthroid with amex, and progeny that contain genetically al- seen in patients with LND. Tests of both cognitive func- tered cells are chimeras that can be identified by their mosaic tions and motor functions were intact in these animals. As adults, these chimeras, in which genetically ilar findings were documented in a double knockout that modified cells have been involved in the establishment of is HPRT/APRT deficient (75). It takes several generations to produce (70) may still contribute to our understanding of LND. Because of questions be produced in the heterozygous, homozygous, or hemizy- about strain differences, Jinnah et al. Reductions of do- mal models of LND based on the use of the neurotoxin 6- pamine and also of the dopamine transporter of 35% to hydroxydopamine (6-OHDA), transgenic mouse models of 40% were found in these animals. These results indicate LND, calcium channel blocker models of self-injury, and an abnormality in the dopamine system despite apparently the mutant mouse model of fragile X syndrome. The absence of behavioral changes in the HPRT-defi- cient mice was unexpected. Originally, it was thought that Lesch–Nyhan Disease 6-OHDA uricase, which is present in rodents but is not present in (Rat Model) primates, may act in a protective manner to lessen behav- After the demonstration of dopamine deficiency in striatum ioral manifestations because uric acid, which normally in autopsies of brain in three human patients with LND builds up in the blood in LND, and hypoxanthine, which (35), Breese et al. These authors demonstrated that the sistent with the inability of treatment with allopurinol, a age at which neural function is disrupted is an important xanthine oxidase inhibitor that prevents the accumulation factor in the type of motor and behavioral symptoms ob- of uric acid, to improve the behavior disorder in patients served after a neural insult to basal ganglia structures. However, the mice were still found to have documented a relationship between dopaminergic supersen- reduced dopamine in brain (76). Thus, it is the consequence sitivity and self-injurious behavior. Rats treated with of the HPRT deficits on dopamine, and possibly other neu- 6-OHDA in the neonatal period demonstrated self-biting rotransmitter systems, that leads to the behavior in humans. Because of the self-biting, the neonatal Dopamine depletion is substantially greater in human sub- 6-OHDA–treated rat was proposed as a model for LND, jects (76) than in the mice; therefore, this difference may and dopamine deficiency was linked to self-injury. These brain regions developed supersensitive dopa- Behavior mine receptors. Self-biting was documented in the lesioned animals when they were challenged as adults with a dopa- Another approach to study self-injury is the calcium channel mine agonist; however, untreated adult rats did not show blockers model proposed by Jinnah et al. These authors showed that ad- ministration of this drug could also cause the self-injurious HPRT-Deficient Mouse biting, particularly when it was given to young mice. Self- For LND, molecular techniques were used to produce two biting was provoked by injecting small quantities of ( /-) HPRT-deficient strains of mice. One strain was produced Bay K 8644 directly into the lateral ventricle of the brain, by retroviral interruption of the human HPRT gene in the a finding indicating a central effect of the drug. Another model was produced behaviors can be elicited by administration of another L- through the selection of embryonic stem cells for sponta- type calcium channel agonist, FPL 64176. The self-biting neous mutations in the HPRT gene (70,71). In both in- elicited by ( /-) Bay K 8644 can be inhibited by pretreating stances, the mouse strains produced had nondetectable the mice with dihydropyridine L-type calcium channel an- levels of HPRT. However, neither strain showed the sponta- tagonists such as nifedipine, nimodipine, or nitrendipine. The known actions of ( /-)Bay K 8644 as an L- ing of behavioral phenotypes:self-biting in LND and learn- type calcium channel agonist, the reproduction of similar ing and fear responses in fragile X syndrome. The study of behavioral phenotypes in neurodevelopmental disorders demonstrates the complexity in mapping path- ways from genes to cognition and complex behavioral phe- Fragile X Mouse Model notypes. Behavioral phenotypes occur in disorders with The mutant mouse model of fragile X syndrome demon- mendelian inheritance (LND) and nonmendelian inheri- strates another use of an animal model for a neurogenetic tance (PWS/AS, FRX). Transgenic fragile X knockout mice were devel- demonstrates that recognition of the involved gene is only oped to provide an animal model to study the physiologic the first step. Identification of the involved protein and of function of the fragile X gene (FMR1) and to understand its expression in brain is critical. To clarify the mechanism, better the clinical phenotype caused by the absence of the the use of animal models, neuroanatomic study, brain imag- fragile X protein. The study of partial variants chidism and cognitive, affective, and behavioral features of the disorder (LND, WMS), comparison of deletion ver- similar to the human condition (79).

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Rhythm Control Using AADs Maintenance of 7 (1 discount synthroid 25mcg free shipping,473) RCT/Low Consistent Direct Precise SOE=High Sinus Rhythm OR 0 generic 100 mcg synthroid overnight delivery. Since 6 of the 8 studies had ORs that crossed 1 (including 95% of the patients) quality synthroid 100mcg, and given significant heterogeneity buy 25 mcg synthroid fast delivery, we assessed these studies as demonstrating no difference between rate- and rhythm-control strategies purchase synthroid 75 mcg mastercard. CV Mortality 5 (2,405) RCT/Low Inconsistent Direct Precise SOE=Moderate OR 0. Strength of evidence domains for rhythm versus rate control (continued) Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) CV 3 (439) RCT/Low Consistent Direct Precise SOE=High hospitalizations OR 0. Rhythm Control Using PVI Maintenance of 2 (122) RCT/Moder Consistent Direct Imprecise SOE=Low Sinus Rhythm ate Significantly better in rhythm-control strategies (OR not reported) Quality of Life 2 (122) RCT/Moder Inconsistent Direct Imprecise SOE=Insufficient ate Abbreviations: AAD(s)=antiarrhythmic drug(s); CI=confidence interval; CV=cardiovascular; OR=odds ratio; NA=not applicable; PVI=pulmonary vein isolation; RCT=randomized controlled trial; SOE=strength of evidence 108 Discussion Key Findings and Strength of Evidence In this comparative effectiveness review (CER), we reviewed 148 studies represented by 182 publications and involving 25,524 patients that directly compared rate- and rhythm-control strategies in patients with atrial fibrillation (AF). Rate-Control Drugs 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. Table 23 summarizes the strength of evidence for the most commonly used classes of therapies and evaluated outcomes. Details about the specific components of these ratings (risk of bias, consistency, directness, and precision) are available in the Results chapter. For ventricular rate control, most comparisons were evaluated in one small study, resulting in insufficient evidence to support conclusions about comparative effectiveness. Exceptions were as follows: There was low strength of evidence that amiodarone was comparable to the calcium channel blocker diltiazem, and that amiodarone controlled ventricular rate better than digoxin, and there was high strength of evidence for a consistent benefit of verapamil or diltiazem compared with digoxin for rate control. There was insufficient evidence regarding the effect of rate-control therapies on quality of life. Summary of strength of evidence and effect estimate for KQ 1 Treatment Comparison Ventricular Rate Control Quality of Life Beta Blockers vs. Digoxin SOE=Insufficient (1 study, 47 SOE=Insufficient (No studies) patients) Beta Blockers vs. Calcium Channel SOE=Insufficient (1 study, 40 SOE=Insufficient (No studies) Blockers patients) Beta Blockers vs. Calcium Channel SOE=Insufficient (1 study, 29 SOE=Insufficient (1 study, 29 Blockers in Patients Taking Digoxin patients) patients) Sotalol vs. Metoprolol in Patients SOE=Insufficient (1 study, 23 SOE=Insufficient (No studies) Taking Digoxin patients) Amiodarone vs. Calcium Channel SOE=Low (3 studies, 271 patients) SOE=Insufficient (No studies) Blockers Amiodarone is comparable to the calcium channel blocker diltiazem for rate control Amiodarone vs. Digoxin SOE=Low (3 studies, 390 patients) SOE=Insufficient (No studies) Amiodarone controlled ventricular rate better than digoxin across 2 studies (both p=0. Summary of strength of evidence and effect estimate for KQ 1 (continued) Treatment Comparison Ventricular Rate Control Quality of Life Calcium Channel Blockers Plus SOE=Insufficient (1 study, 52 SOE=Insufficient (No studies) Digoxin vs. Digoxin Alone patients) Calcium Channel Blockers vs. SOE=High (4 studies, 422 patients) SOE=Insufficient (No studies) Digoxin Consistent benefit of verapamil or diltiazem compared with digoxin (p<0. Strict Versus Lenient Rate-Control Strategies 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. Table 24 summarizes the strength of evidence for strict versus lenient rate control and the outcomes of interest. Details about the specific components of these ratings (risk of bias, consistency, directness, and precision) are available in the Results chapter. Across outcomes, data were limited by the number of studies and the imprecision of their findings. We based our findings on the evidence from the one RCT and then evaluated whether the observational studies were consistent or not with these findings. In general, the included 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. Summary of strength of evidence and effect estimate for KQ 2 Outcome Strength of Evidence and Effect Estimate All-Cause Mortality SOE=Insufficient (1 study, 614 patients) CV Mortality SOE=Insufficient (2 studies, 828 patients) CV Hospitalizations SOE=Insufficient (2 studies, 1,705 patients) Heart Failure Symptoms SOE=Insufficient (2 studies, 828 patients) Quality of Life SOE=Insufficient (2 studies, 828 patients) Thromboembolic Events SOE=Low (2 studies, 828 patients) HR 0. Rate-Control Procedures Versus Drugs or Versus Other Procedures in Patients Failing Initial Pharmacotherapy Our review identified six RCTs evaluating the comparative effectiveness of a procedural intervention versus a primarily pharmacological intervention for rate control of AF, or comparing two primarily procedural interventions.

But when they are assessed synthroid 200 mcg, the previous weekcan be the focus of the assessment purchase synthroid 100 mcg with visa. Improvement of phase III psychotropic drug trials by intensive phase II work purchase synthroid 75 mcg fast delivery. Neuropsychopharmacology 1991;4: ASSESSMENT OF ADVERSE EXPERIENCES 251–257 buy synthroid 200mcg fast delivery. Antipsychotic-induced The two major goals of drug development—to enhance weight gain: a comprehensive research synthesis buy discount synthroid 125mcg on-line. Am J Psychiatry therapeutic efficacy and to improve tolerability—go hand 1999;156(11):1686–1696. The placebo control in clinical trials (a view from the clinical signs and symptoms of psychiatric illnesses. Biol Psychiatry 2000;47: ance and determining the overall benefit-to-riskratio. Does short term placebo In general, the methods for detecting adverse events have treatment of chronic schizophrenia produce long term harm? Br been given far less attention than the methods for evaluating Med J 1986;293:726–728. The long-term effects of placebo accurately estimating the incidence of adverse effects. Biol Psychiatry 1999;46: clinical trials rely on patient self-report, with some specific 1092–1105. Duration of psychosis queries or rating scales used to assess known adverse effects and outcome in first episode schizophrenia. Predictors of relapse many adverse events, there is a concern that detailed, specific following response to first episode schizophrenia or schizoaffec- queries across a broad range of possible symptoms will result tive disorder. Placebos, active control groups, and in the elicitation of far more symptoms than an unstruc- the unpredictability paradox. Statistical ap- A methodologic comparison study (27) suggested that proaches to trial durations in episodic affective illness. Psychiatry the general elicitation of adverse events is more practical Res 1998;78:71–87. A case study of an and appropriate for routine clinical trials than a comprehen- adaptive clinical trial in the treatment of outpatients with depres- sive and lengthy interview. Control, dose- response study of sertindole and haloperidol in the treatment of take inhibitor (SSRI) antidepressants. There is a strong argument for the use of data and safety 15. Antiepileptic drugs, clinical trials, and the market- monitoring boards when large and/or long-term studies are place. Methodological issues in maintenance therapy clinical trials. Fluphenazine versus placebo CONCLUSION in patients with remitted, acute first episode schizophrenia. The clinical trial remains the mainstay of treatment develop- 18. Prevention of relapse in chronic schizophrenic pa- ment. It is always hoped that further advances will evolve tients. Low and conventional more rapidly than they do, but there is reason for considera- dose maintenance therapy with fluphenazine decanoate. Two- ble optimism that over the next decade there will be impor- year outcome. In: Kaplan drug response whether via functional neuroimaging, phar- HI, SadockBJ, eds. Balti- macogenomics, or other potential developments.

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