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SIB is common and not necessarily associated with developmental disability (28 cheap 1mg finax with mastercard counterfeit medications 60 minutes,34) trusted 1mg finax treatment eczema. It includes skin and nose pick- ber of patients in such studies is relatively small, and the ing, nail biting, lip biting, and hair pulling (45). Patients study designs have been criticized (39,40). Indeed, in a pla- frequently have chronic skin sores. Although this finding does not entirely Both the biochemical abnormality [virtual absence of hypo- rule out a role for the opioid system, it further emphasizes xanthine-guanine phosphoribosyltransferase (HPRT)] and the need for caution in drawing conclusions from open trials the underlying genetic defect (a mutation of the HPRT of treatment for SIB. However, the mechanisms underlying neu- ing to the stage of menstrual cycle. In one study, fluctuations ropsychiatric symptoms are less clear. Nevertheless, the bio- in SIB were associated with early and late follicular phases. Animal studies with HPRT-deficient models and clini- population has not been well studied. The anticonvulsant cal studies of neurotransmitters and metabolite levels in valproic acid, however, was effective in reducing SIB and patients with the disorder support the importance of dopa- aggression in 12 of 18 patients with mental retardation and minergic mediation of symptoms (47). These BEHAVIOR differences may reflect the importance of the developmental stage at which dopaminergic deficits occur (11). Although Phenomenology dopamine supersensitivity has also been hypothesized to Lesch-Nyhan syndrome (LNS) is an X-linked recessive dis- play a role in SIB in LNS (9), and dopamine blockers have order of purine synthesis. Patients present with hyperuri- been used for their treatment, long-term treatment with cemia and neuropsychiatric symptoms including spasticity, these agents is not clearly of benefit in LNS. Further under- choreoathetosis, dystonia, mental retardation, aggression, standing of the developmental neurobiology underlying this and self-injurious behavior. SIB in LNS is dramatic, and syndrome is therefore needed. Nevertheless, there is little direct re- Cornelia de Lange syndrome (CLS) is a rare congenital search to support a dopamine hypothesis of CLS. Indeed, disorder characterized by a distinctive appearance and men- the underlying neurobiology of this interesting syndrome tal retardation. Patients with CLS manifest excessive groom- remains relatively poorly understood. Chapter 121: Compulsive and Impulsive Aspects of Self-Injurious Behavior 1747 Research has also focused on the serotonin system in duced dopamine transporters in caudate and putamen (51) LNS. Studies of cerebrospinal fluid (CSF) 5-hydroxyindol- as well as decreased dopa decarboxylase activity and dopa- eacetic acid (5-HIAA) have been inconsistent in LNS, but mine storage throughout the dopaminergic system in LNS there may be slightly increased putamen serotonin and 5- (52). It is possible that in LNS there is reorganization of HIAA (46). In addition, early reports suggested 5-HT (1 the cortical–basal ganglia–thalamic pathways during devel- to 8 mg/kg) was useful in the treatment of self-injurious opment (52). However, only a minority of subsequent Anumber of authors have suggested hypothalamic-pitui- studies have confirmed this finding (28). Again, however, further work is In an early study, CLS patients were found to have re- needed to extend these preliminary findings and to deter- duced whole blood serotonin levels (48). Several possible mine the relationship with behavioral symptoms. Indeed, at mechanisms underlying this finding were considered, in- present little is ultimately understood about the underlying cluding a dysfunction in serotonin metabolism, failure to neurobiology of self-injury and other behavioral symptoms bind to platelets, and transporter abnormalities. SMD IN INTELLECTUALLY NORMAL Serotoninergic mediation of PWS is raised by the role INDIVIDUALS of serotonin and the efficacy of serotoninergic agents in appetite control and eating disorders, compulsive skin pick- Phenomenology ing, impulsive aggression, and obsessive-compulsive–related Skin picking and scratching appear to be not uncommon disorders. Adouble-blind trial of fenfluramine found that symptoms (53). The incidence of so-called neurotic excoria- this agent was useful for weight loss and other-directed ag- tions in dermatology clinics has been estimated to be around gressive behavior in PWS patients, but did not affect SIB 2%. Medical complications of skin picking include infec- (49).

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The potential with an increased risk of relapse (68) generic 1 mg finax fast delivery medicine 5 rights. Another aspect of the for abuse with CNS depressant drugs in general and benzo- tolerance model is the possibility of replacing one type of diazepines in particular is well known discount 1 mg finax with visa medications breastfeeding, as is the interaction GABAR subunit with another that still responds to GABA 164 Neuropsychopharmacology: The Fifth Generation of Progress but not to the chronically administered modulatory drug lite is the endogenous steroid that appears to be the most (69,70). Pregnenolone sulfate, a biosynthetic intermediate in the synthesis of all GABAA RECEPTORS ARE THE TARGETS OF the steroid hormones, present in high levels in the CNS, ALCOHOL, GENERAL ANESTHETICS, AND has weak activity as an antagonist of GABA function, but NEUROSTEROIDS this appears to involve another mechanism and is unlikely to be biological (85). Neurosteroid action apparently has Alcohols are CNS depressants with a pharmacologic spec- relevance to alcohol action. GABA-active steroids can sub- trum of action overlapping those of the benzodiazepines stitute for ethanol in discriminative stimulus testing in rats and barbiturates, known to act by enhancement of GABAR. The neurosteroid-GABA ing effects at lower concentrations (10 to 100 mM) have connection potentially may be fruitful for new applications been suggested to involve blockade of N-methyl-d-aspartate in psychopharmacology. As the endogenous functions of (NMDA)–type glutamate receptors (71) or enhancement neurosteroids in stress control, seizure protection, attention of GABAR (72–74). Because the latter effect varies consid- and learning, and possibly even sleep, become better deline- erably among, for example, laboratories, preparations, as- ated, additional therapeutic approaches may arise. Alternatively, and most popular currently, is the hypothesis is currently the major candidate molecular mechanism for that ethanol acts on GABAR indirectly to produce impor- a generalized theory of general anesthesia. Everyone agrees tant aspects of its pharmacologic actions in cells and in that the anesthetic action of the steroid alphaxalone occurs animals (75). For example, ethanol may interact with mem- by enhancement of GABAR (84,85), and many investiga- brane signaling proteins that regulate GABAR and NMDA tors believe that the actions of high-dose ethanol and other receptors. Further, GABAA receptor function appears to be modulated by the sedative-hypnotic effects, and possibly anesthetic effects, an endogenous substance: not a benzodiazepine-like or a of barbiturates and related drugs are considered to act picrotoxin-like peptide, but a barbiturate-like steroid. Anesthetics are now believed to have neurosteroids are endogenous steroid hormone metabolites a greater effect on membrane ion channels than on many that have direct and rapid actions on cells not involving other biological systems and to affect synaptic transmission steroid hormone receptors or regulation of gene expression. Ligand-gated ion Progesterone was shown to produce rapid sedative activity, channels, especially receptors for glutamate, glycine, and a finding that led to the development of the clinical intrave- GABA, are most sensitive (89). All general anesthetics en- nous steroid anesthetic, alphaxalone. Progesterone has anxi- hance GABA function at anesthetic concentrations (36,75). The neuroactive steroids act principally by for many drugs with respect to potency as a general anes- binding directly to membrane GABAA receptors and en- thetic and partition in an oil-water biphasic system. The hancing their function in a manner resembling the barbitu- Meyer-Overton correlation has been found wanting, be- rates (79,80). Whether these com- dipole moment, such as halogenated cyclobutane isomers, pounds are biologically relevant is uncertain, but this is sug- that differ in anesthetic potency: only the anesthetic isomers gested by considerable evidence. Endogenous steroids reach enhance GABAA receptors (91). Volatile anesthetics and levels sufficient to modulate GABAA receptors during con- alcohols (87), as well as intravenous agents such as barbitu- ditions of stress and anxiety, and during pregnancy (82,83). The progesterone metabo- receptor function in cells (36,88). Chapter 12: GABA 165 GABAA RECEPTORS ARE THE TARGETS OF both GAD67 and GABAA receptor subunit 3 lead to cleft MANY CNS EXCITANTS palate and early neonatal lethality (100–102). GAD65 knockout mice show increased anxiety, increased sensitivity Many naturally occurring and synthetic convulsive agents to benzodiazepines, and impaired developmental plasticity are blockers of GABA-mediated inhibition (46). Epilepsy results from knockout typic GABAA channel blocker picrotoxinin (Fig. Other isolated from plants of the moonseed family, Menisperma- phenotypic deficits include motor incoordination, move- ceae, and its close relatives tutin and coriamyrtin, from the ment disorders, cognitive defects, and other CNS circuitry New Zealand tutu plant Coriaria arborea (92), known as a problems resulting from lack of inhibitory synaptic trans- loco weed, which causes occasional poisonings in cows and mission. In particular, the GABAR 3 subunit is implicated even in people. A major category of synthetic potent neu- in the human genetic disease Angelman syndrome, associ- rotoxic chemicals (93), comprising the cage convulsants, ated with mutation in maternal chromosome 15q and typi- was discovered to consist of noncompetitive GABAA recep- fied by severe mental retardation, epilepsy, motor incoordi- tor antagonists acting at the picrotoxinin site (93–95). Mice targeted for this of these drugs, t-butyl bicylcophosphorothionate (Fig.

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For this reason 1mg finax visa symptoms xanax, many research- represent functional variants and that few genes have been ers have tried to take advantage of the potential of candidate systematically screened even for common functional var- gene association studies to identify such loci (109 discount finax 1 mg with visa medicine misuse definition,110). However, more promising reports of candidate gene though a potentially powerful means of identifying genes associations have recently appeared, three of which are con- of small effect, association studies are not without their sidered here. First, for a complex and poorly understood disor- der such as schizophrenia, the choice of candidate genes Serotonin 5-HT2A-Receptor Gene is limited largely by the imagination and resources of the researcher. This places a stringent burden of statistical proof Many novel antipsychotic drugs affect the serotoninergic on positive results because of low prior probability and mul- system. The first genetic evidence that serotoninergic recep- tiple testing (111). Second, case–control association studies tors may play a role in schizophrenia came from a Japanese have the potential to generate false-positives because of pop- group reporting an association between a T-to-C polymor- ulation stratification. This problem can be addressed by phism at nucleotide 102 in the 5-HT2A-receptor gene in a using family-based association methods (112), but because small sample (114). A large European consortium compris- of stigma, adult age at onset, and the disruptive effects of ing seven centers and involving 571 patients and 639 con- mental illness on family relationships, family-based samples trols then replicated this finding (115), which was further may be unrepresentative in addition to limited in size. Con- replicated with use of a family-based design (116). Although sequently, family-based studies may introduce more spu- many other studies followed with mixed results, a recent rious results than do case–control studies (113). It would metaanalysis of all available data from more than 3,000 seem unwise, therefore, to discard the case–control study subjects supports the original finding (p. A third problem common to all molecular genetic (117). If we assume homogeneity and studies, larger sample sizes are required than have typically if the association is true, the putative odds ratio (OR) for the been used to date in psychiatric genetics (111). Fourth, even C allele can be expected to be around 1. Sample sizes of 1,000 subjects are then be required replication study will be sufficiently powered to replicate a for 80% power to detect an effect of this size, even at a particular effect. This is because variations may be noted in relaxed criterion of p. Thus, the negative studies are the contribution of a given susceptibility allele in different effectively meaningless, but it is also true that the evidence patient populations as a result of different allele frequencies for association, even in the metaanalysis (p. Further poten- not definitive if genome-wide significance levels are required tial for heterogeneity occurs if the association with the (109). At present, all we can conclude is that the evidence marker is a result of tight linkage with the true susceptibility favors association between the T102C 5-HT2A polymor- allele, or if different subtypes of the disease exist. Given that phism and schizophrenia, but the most stringent burden of all the above factors may influence power, and that none proof has not yet been met. T102C is 678 Neuropsychopharmacology: The Fifth Generation of Progress in complete linkage disequilibrium with a polymorphism tance of schizophrenia is at least consistent with the presence in the promoter region of this gene, but no evidence has as of anticipation, although ascertainment biases offer an alter- yet been found that this has a functional effect either (116). Because pathogenic expanded tri- Recent evidence of polymorphic monoallelic expression of nucleotide repeats are the only known genetic mechanisms the 5-HT2Agene points to the possible existence of sequence for anticipation, these findings have been taken as suggest- variation elsewhere that influences gene expression (118), ing that such mutations may account for at least some of and this may be the true susceptibility variant. This hypothesis was supported by two groups who observed that the maximum length of the most common D3 Dopamine-Receptor Gene known pathogenic trinucleotide repeat, CAG/CTG, was Association has been reported between schizophrenia and greater in patients with schizophrenia than in unaffected homozygosity for a Ser9Gly polymorphism in exon 1 of the controls (125,126). These findings were later replicated in a D3 dopamine-receptor gene (DRD3) (119). Unfortunately, the early HT2A association, the results have now been confirmed in repeat expansion detection (RED) studies were followed by several independent samples, including one family-based a series of unsuccessful attempts to identify the relevant study (120), but several negative studies have also been re- repeat-containing loci by a variety of methods, and by sev- ported. Metaanalysis of data from more than 5,000 individ- eral failures to replicate the RED findings (128–130), thus uals has revealed a small (OR 1. Again, this cannot easily be as- however, with the report of an association between schizo- cribed to selective publication (120). Because it is a fairly phrenia and alleles of a member of the family of calcium- uncommon genotype, we cannot be certain that homozy- activated potassium channel genes, KCa3 (hKCa3/KCCN3) gosity for the 9Gly allele alone is not associated with an (131). For several reasons, KCa3 seemed a remarkable can- increased risk for schizophrenia, and therefore it is not cer- didate gene for schizophrenia. First, the gene contained two tain that the findings at D3 are an example of heterosis. Second, However, a plausible biological explanation for D3 heterosis the family of genes to which it belongs is thought to play has been put forward in that possession of two different an important role in regulating neuronal activity, and it was molecular forms of the receptor may allow the dopaminergic therefore considered a functional candidate gene. Ironically, KCa3 gene is similar to that of the 5-HT2A-receptor gene—that maps not to 22q11 but to 1q21 (132), which is also a region is, the balance of evidence at present favors association, but implicated by linkage studies as possibly containing a sus- the null hypothesis still cannot be confidently rejected.

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Figure 25 shows that the OR of rate control versus rhythm control for mixed embolic events (including stroke) was 1 buy discount finax 1 mg line medicine just for cough. There was significant heterogeneity driven by a poor-quality study which lacked sufficient detail to evaluate the applicability of the findings to our population of interest purchase finax 1 mg amex medicine you cant take with grapefruit, which therefore lowered the strength of evidence rating. Forest plot of mixed embolic events for rate- versus rhythm-control strategies Study name Odds ratio and 95% CI Odds Lower Upper ratio l imit l imit Van Gelder, 2002 0. Figure 26 shows that the OR of rate control versus rhythm control for bleeding 1. Forest plot of bleeding events for rate- versus rhythm-control strategies Study name Odds ratio and 95% CI Odds Lower Upper ratio l imit l imit Van Gelder, 2002 1. Because the components of 296 these outcomes differed across studies, combining them was deemed inappropriate. One study examined a composite of all-cause mortality, stroke, embolic events other than stroke, and cardiopulmonary resuscitation, and found no significant difference in this outcome between patients managed with a rate-control strategy (10%) and those managed with a rhythm-control 299 strategy (9%; p=0. Another study examined a composite of all-cause mortality, mixed embolic events including stroke, and bleeding events including hemorrhagic stroke. One study found that time to the composite outcome of all-cause mortality, heart failure symptoms, and stroke was not significantly different between the rate- control group and the rhythm-control group (HR 0. In another 156 study, the risk of the combined outcome of cardiovascular mortality, mixed embolic events including stroke, bleeding events (including hemorrhagic stroke), heart failure, need for a permanent pacemaker, and severe adverse events from antiarrhythmic medications was not significantly different between the rate-control group and the rhythm-control group (17. Finally, one study compared the rate of the combined outcome of all-cause mortality, stroke, bleeding events (including hemorrhagic stroke) and adverse drug reactions in patients treated with rate-control and patients treated with rhythm 104 control and found no significant difference between the two groups over a mean followup of 3. Adverse Events Reporting of adverse events was inconsistent across studies. Hypotension and hypothyroidism were not reported as adverse events in any of the studies. Adverse events that 299 were reported included: hyperthyroidism (0 in rate control vs. Proarrhythmia 299 155 was reported (0 in rate control 4 in rhythm control, p=NS). In one study, 10 patients (4%) developed ocular toxicity, all in the 155 rhythm-control arm. In the same 155 study, corrected QT interval prolongation >520 ms occurred in 0. Comparison 2: Rate-Control Strategy Versus Rhythm-Control Strategy Using PVI Maintenance of Sinus Rhythm 305 In one poor-quality study, after 6 months of followup, PVI resulted in maintenance of sinus rhythm in only 50 percent of patients (compared with none in the medical treatment arm). Quality of Life/Functional Status 304 In one study, functional capacity was measured by the 6-minute walk test, and investigators found that the distance increased from 269±54 m at baseline to 340±49 m at 6 months in the group that underwent PVI as compared with 281±44 m to 297±36 m in the group that underwent AVN with biventricular pacing (p<0. In the group that underwent PVI, the mean MLWHF score improved, with a reduction from 89±12 at baseline to 60±8 at 6 months. In the group that underwent AVN ablation with biventricular pacing, a reduction was observed from 89±11 at baseline to 82±14 at 6 months (p<0. PVI did not improve quality of life as assessed by the 6-minute walk distance (mean change of 20. The SF-36 physical component was significantly better in the PVI group than in the 105 rate-control group (mean within-group change 4±9. Composite Outcomes 304 One study compared the composite outcome of quality of life/functional status as defined by the 6-minute walk distance, Minnesota Living With Heart Failure (MLWHF) questionnaire, and LVEF in patients who received PVI as the rhythm-control strategy versus patients who underwent AVN ablation and pacemaker as the rate-control strategy. After 6 months of followup, this outcome was significantly better in the PVI group (p=0. Reported separately, the components of the primary outcome were as follows: For PVI as compared with AVN ablation with biventricular pacing, the LVEF was significantly higher (35±9% vs. Adverse Events 305 In one poor-quality study, within 6 months of followup, the rate of serious complications related to PVI was 15 percent versus 0 percent in the rate-control group. These complications included: one stroke, two cardiac tamponades, and one readmission to the hospital within 1 week 304 after the procedure. In the other study, bleeding occurred in 4 patients (9.

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