• ARTICLE_TITLE


    By B. Pavel. Morris College.

    The critical HT6 receptor allelic variant in patients with schizophrenia role of prefrontal orbital cortex is exemplified by the case and in controls was negative for an association with aggres- of Phineas Gage order malegra dxt plus 160 mg visa, a solid generic malegra dxt plus 160 mg free shipping, upstanding railroad worker, who, sive behavior (141). NEUROPSYCHOLOGY OF AGGRESSION Other clinical cases support the central role of orbital pre- frontal cortex in regulation of aggression (153–157). Irrita- The relationship between aggression and neuropsychology bility and angry outbursts have also been associated with is in part dependent on the syndrome in which aggression damaged orbital frontal cortex in neurologic patients (158), is observed. For example, the cognitive impairment of de- and frontal and temporal hypoperfusion has been noted mentia may be associated with aggressive behavior. Lesions of prefrontal lescents with conduct disorder, verbal processing deficits are cortex, particularly orbital frontal cortex, early in childhood associated with greater aggressiveness and antisocial behav- can result in antisocial disinhibited, aggressive behavior later ior (144). Low executive cognitive function is also related in life (160). Chapter 119: Pathophysiology and Treatment of Aggression 1715 Temporal lobe lesions have also been associated with a in orbital frontal cortex (176). These deficits were more susceptibility to violent behavior, as suggested by multiple pronounced in persons without psychosocial deprivation case reports of patients with temporal lobe tumors. In a study of patients with personality disorders, an study of violent patients, many anterior inferior temporal inverse relationship was found between life history of aggres- lobe tumors were reported (161,162), and aggressive behav- sive impulsive behavior and regional glucose metabolism ior has been associated with temporal lesions (163). Al- in orbital frontal cortex and right temporal lobe. Patients though temporal disease may express itself in a variety of meeting criteria for borderline personality disorder had de- ways, there does appear to be a clear association between creased metabolism in frontal regions corresponding to temporal pathology and aggressive behavior. Single photon emission computed tomography with rage attacks, and studies of patients who have under- studies have also suggested reduced perfusion in prefrontal gone amygdalectomy (164), although destructive behaviors cortex, as well as focal abnormalities in left temporal lobe have also been observed in the context of coagulation of the and increased activity in anteromedial frontal cortex in lim- amygdala (165). Patients with bilateral amygdala damage bic system in aggressive persons with reduced prefrontal judged unfamiliar persons to be more trustworthy than con- perfusion in antisocial personality-disordered alcoholism trols, a finding consonant with the role of the amygdala in (179), and hypoperfusion in the left frontoparietal region social judgments of potential threat (166). The association of violent behavior with aggressive be- Cingulate cortex has also been implicated especially in pos- havior with localized seizure activity provides a further guide terior regions in aggressive borderline patients (178), a find- to brain regions implicated in the modulation of aggression. However, only a few patients with temporal Extensive connections between amygdala and prefrontal lobe epilepsy engage in aggressive behaviors in the interictal cortex have been described, suggesting an inhibitory influ- or periictal periods (170–172). These clinical correlations, ence of frontal cortex on the amygdala (181). Amygdalo- although pointing to regions of interest for imaging studies, tomy has been associated with reduced aggressive outbursts cannot directly address the circuitry involved in impulsive in patients with intractable aggression (182), but there have aggression in the absence of specific neurologic disease. Imaging Neurotransmitter Systems in Structural Imaging and Aggression Aggression Reduced prefrontal gray matter has been associated with Serotonin autonomic deficits in patients with antisocial personality disorders characterized by aggressive behaviors (173). Al- Ascending serotonergic neurons from the raphe nuclei though these deficits are not visually perceptible, they reach project widely throughout the brain, including projections statistical significance and are consistent with the neurologic to dorsolateral prefrontal cortex and medial temporal lobe. Diffuse tracts extend from dorsal and medial raphe project Functional Imaging and Aggression to frontal lobe. Both 5-HT2A and 5-HT1A receptors are One technique used to identify brain activity in individuals found in high concentrations in human prefrontal cortex, as displaying aggressive behavior is the assessment of in vivo are 5-HT transporter sites (183), and patients with localized cerebral glucose metabolism through positron emission to- frontotemporal contusions show significantly lower 5-HT mography. Studies of this type tend to implicate brain hypo- metabolites in CSF than patients with diffuse cerebral con- metabolism in a variety of regions but particularly frontal tusions (184). Greater -CIT binding to 5-HT transporters and temporal cortex. In psychiatric patients with a history has also been reported in nonhuman primates with a higher of repetitive violent behavior, decreased blood flow consis- -CIT binding associated with greater aggressiveness (185). In a study of homicide gressive behavior in posterior orbital frontal cortex and me- offenders, bilateral diminution of glucose metabolism was dial frontal cortex in the amygdala, whereas increased 5- observed in both medial frontal cortex and at a trend level HT2A number in orbital frontal cortex, posterior temporal 1716 Neuropsychopharmacology: The Fifth Generation of Progress cortex, and amygdala have been correlated with prosocial may have a disinhibiting effect on the generation of aggres- behavior in primates (186). Thus, serotonergic modulation sion by amygdala and related structures. The administration of FEN has been shown to increase In animal studies, 1-methyl-4-phenyl-1,2,3,6-tetrahydro- cortical metabolism in frontal, temporal, and parietal cortex pyridine–induced unilateral striatal dopamine deficiency in (187–189). In a study of depressed patients that included vervet monkeys was associated with increased frequency of patients with a comorbid diagnosis of borderline personality aggressive behaviors toward other members of the group in disorder and a history of suicide attempts, activation of cor- the monkey colony (193). Greater heterogeneity was also tex including orbital and cingulate cortex was significantly found in striatal dopamine transporter density, as assessed by 123I( -CIT distribution) of impulsive violent offenders blunted in the depressed patients, particularly in those who attempted suicide, compared with the control subjects. The than controls (88), a finding possibly consistent with hy- depressed patients showed no significant changes in their potheses that aggressive behavior is associated with increased glucose metabolic response to FEN compared with placebo, dopaminergic transmission in contrast to the controls (189).

    This could be mediated by a blockade of serotonin treatment in humans discount 160 mg malegra dxt plus free shipping. Alternatively order malegra dxt plus 160 mg with amex, the newer drugs may modulate dopamine blockade regionally to attenuate TREATMENT APPROACHES the cellular changes produced by the drugs. The results of the chronic treatment experiments in rat would favor this There is still no definitive treatment for TD. Additional possibilities exist, including therapeutic strategies are often used for patients with TD a thalamic or cortical action of the drug at the serotonin symptoms. Prevention, reversal, and suppression or (clinical 2A receptor. Prevention and reversal used to be only theoretic possibilities, but this is no longer the case. The newer generation of antipsychotic Reversal drugs, with their low TD incidence, has introduced these Clinical data with traditional antipsychotic treatment sug- various new options. Data suggest that this reversal may hap- pen faster with newer drug treatment than with the contin- Patients who require antipsychotic treatment for extended ued use of traditional drugs. TD reversal occurs frequently, times today have the opportunity of treatment with one of although not inevitably, with cessation of antipsychotic the newer antipsychotic drugs and thus are at reduced risk treatment (43). This reversal appears to be more likely in of developing TD, probably at considerably reduced risk. The reversal oc- tiapine (67) all have been reported to have reduced associa- curs over the course of months to years, not in the range tion with TD. Data are not yet available for new antipsy- of weeks, so the phenomenon is challenging to document. Clozapine has been tested in a double-blind protocol the use of the newer drugs. Very low-dose traditional drug comparing dyskinesia scores between two treatment popula- treatment, such as haloperidol, 2 to 3 mg/day, is being tested tions during ongoing drug treatment (haloperidol versus in several centers for efficacy in psychosis and for side effects. Dyskinesia However, low-dose haloperidol at 4 mg/day has the same in the clozapine-treated group tended to be reduced after incidence of acute parkinsonism and akathisia as a haloperi- clozapine compared with haloperidol treatment (p. Nonetheless, the economic advantage of significant, whereas after a year of clozapine treatment, the traditional antipsychotic treatments, when necessity de- previously sensitive group failed to show any dyskinesia re- mands it, deserves thorough testing. Olanzapine is currently being tested in been inferred from what is known of their pharmacology. The possibilities include a D1 antagonist action, a serotonin2A antagonist action, an anti- Suppression muscarinic action, particularly at the M1 receptor, and even the antihistaminic action that can spare drug-induced TD. The feature that most consistently characterizes the results Parsimoniously, because this TD advantage appears to be of suppression trials in TD is the variability within patients Chapter 126: Tardive Dyskinesia 1839 and among clinical centers conducting trials. No drugs have ganglia circuits: neural substrates of parallel processing [Review]. Parallel organization of groups and ages, although some drug classes show more functionally segregated circuits linking basal ganglia and cortex promise and consistency in this regard than other ap- [Review]. Receptor activity Benzodiazepines most reliably reduce the dyskinesias of and turnover of dopamine and noradrenaline after neuroleptics. TD, even at doses that do not produce sedation (64). A controlled trial of amanta- nazepine has been widely used and seems to be one of the dine hydrochloride and neuroleptics in the treatment of tardive more effective benzodiazepines (51,64,72). Striatal meta- continual dose increases to sustain efficacy. Thus, treatment bolic rate and clinical response to neuroleptics in schizophrenia. Neuro- to its effects for treatment to sustain action. The mechanism chemical evidence for antagonism by olanzapine of dopamine, of therapeutic action has always been thought related to the serotoin, adrenergic and muscarinic receptors in vivo in rats. Because the biology of TD Psychopharmacology (Berl) 1996;124:87–94. Extrapyramidal syndromes in nonhuman primates: Based on a continuation of this reasoning, other GA- typical and atypical neuroleptics. Psychopharmacol Bull 1991; BAmimetics have been tested in TD (60).

    discount 160 mg malegra dxt plus with amex

    160mg malegra dxt plus visa

    Replacement of sine wave stimuli onstrated to cause down-regulation of B-adrenoreceptors with machines that provide a brief pulse stimuli cheap 160mg malegra dxt plus otc, and the (101) and buy malegra dxt plus 160 mg low price, as has been shown in ECS, rTMS up-regulates elucidation of the appropriate stimulus parameters that in- astroglial gene expression in the CNS (102). Preliminary crease the efficacy of safer treatments (suprathreshold right data support rTMS in the treatment of a number of psychi­ unilateral versus threshold bilateral ECT) have both been atric disorders including depression, schizophrenia, obses­ important contributions to the decrease in the ECT associ­ sive-compulsive disorder, and posttraumatic stress disorder ated memory loss over the past few decades. From the outset it should oxone (84), and thyrotropin releasing hormone (TRH) (85) be stressed that the efficacy of rTMS in the treatment of all hold promise for further decreasing ECT-associated depression is modest and much of the research has been memory loss. Double-blind placebo controlled trials using focused narrowly on a relatively restricted group of treat­ with intranasal vasopressin (86,87), ACTH (88,89), dexa­ ment parameters. The majority of rTMS studies use set methasone (90), and nimodipine (91) have not shown the parameters: high frequency or fast stimulations (�10 Hz) active drug to be more effective than placebo. Twice-weekly These parameters are based on PET data (104) and ECT ECT is associated with an antidepressant response as good data (34) demonstrating hypofunctioning of the left pre- as thrice-weekly ECT, but with less adverse memory effects frontal cortex in depression as well as two pivotal early stud­ (and a slower rate of antidepressant response) (92,93). Re­ ies demonstrating an antidepressant effect of fast left cently, the issue of optimal electrode placement has been DLPFC rTMS (105,106). Although one recent parallel reopened with isolated enthusiasm for bifrontal stimulating group sham controlled study found no treatment effect electrode placement or an asymmetric placement (a right (107), most open (105,108,109) and double-blind studies fronto-temporal electrode referenced to a left frontal elec­ (106,110,111) have confirmed a relatively modest antide­ trode). Preliminary reports suggest that these novel electrode pressant response for fast left DLPFC. When directly com­ placements are associated with an antidepressant efficacy pared to ECT, 4 weeks of rTMS appears to be as effective comparable to standard bilateral placement, with fewer cog­ as ECT in nonpsychotic, but not psychotic, depression nitive side effects, but there are insufficient data thus far to (112). In this study there may have been a bias for the ECT recommend them as a replacement for standard BL or RUL group because over half of the patients in the ECT group placements (94,95). Two weeks of either RUL ECT or one ECT treatment followed by four rTMs NONCONVULSIVE STIMULI IN THE sessions were also shown to be equivalent in the treatment TREATMENT OF DEPRESSION of 22 depressed outpatients (113). To date there have been no seizures reported using fast Repetitive transcranial magnetic stimulation (rTMS) and rTMS within the established safety guidelines (114) and no vagal nerve stimulation (VNS) are two new treatments for cognitive side effects in patient populations (109). The most depression that, unlike ECT, use subconvulsive stimuli to common side effects are pain at the treatment site and head- treat depressive symptoms. Compared to ECT, these treat­ aches usually relieved by acetaminophen. Although early studies using slow TMS demon­ rTMS was first used in 1985 as a noninvasive method strated poor outcomes (115–117), and are often cited as of stimulating brain neurons (96). More recent trials of slow rTMS have different effects on neuronal firing, depending on the over the right DLPFC have shown benefit. Klein and col- 1104 Neuropsychopharmacology: The Fifth Generation of Progress leagues (118) randomized 71 depressed patients to 2 weeks effective in given individuals by evaluating the functional of slow, active or sham treatment over the right prefrontal neuroimaging before and after rTMS stimulation. Speer and cortex and 41% of active-treatment subjects had a 50% or associates have shown that patients with hypometabolism greater drop in Hamilton depression scores compared to on baseline PET scans utilizing [18F]-Fluorodeoxyglucose only 17% of sham-treatment subjects. Similarly, Tormos in the left prefrontal cortex responded preferentially to 2 and associates (119) showed a significant antidepressant re­ weeks of fast rTMS (20 Hz) as compared with patients with sponse to fast left DLPFC stimulation and slow right DLPFC hypermetabolism who responded at a higher rate to slow stimulation, but not fast right DLPFC stimulation or sham. Individual characteristics may be a key Slow left stimulation was not administered. Trials of slow factor in determining treatment response. Padb­ Vagal nerve stimulation (VNS) is another new and prom­ erg and colleagues (120) randomized 18 nonpsychotic pa­ ising treatment for major depression. VNS has been success- tients to treatment over the left DLPFC using fast, slow, fully used to treat patients with intractable seizures since or sham treatments. They showed a statistically significant 1994 and was noticed to have positive effects on mood (but clinically insignificant) response to fast and slow stimu­ that were not simply secondary to the decrease in seizure lation compared to placebo. The VN has both parasympathetic efferent and Nahas demonstrated that lower frequency stimulation fibers to the heart and GI tract and sensory afferent fibers (5 Hz) might be more effective at 20 Hz TMS. Patients (approximately 20% and 80% of the fibers, respectively). The fibers passing 10 versus 3/10 responders, respectively) and placebo (0/10 through the PN/LC (which are adjacent to one another) responders) (121,122). Slow TMS (�1 Hz) has never been connect to the hypothalamus and thalamus and, central to associated with seizures or any other adverse consequences the antidepressant properties of VNS, the bed nucleus of in neurologically normal individuals; therefore, it is poten­ the stria terminalis and amygdala.

    order malegra dxt plus 160mg amex

    order malegra dxt plus 160mg with amex

    In the PRISMATIC trial our evaluation of PRISM became an evaluation of PRISM alongside incentivisation of targeted care for those at highest risk through QOF targets order malegra dxt plus 160 mg amex. The PRISM tool itself can only be part of a wider intervention purchase 160 mg malegra dxt plus mastercard. PRISM was not designed to be used with such a focus on the highest level of risk, but UK health policy has focused on these patients and PRISM was used to identify patients to meet these targets. We do not know what effects would be found if efforts – and resources – were to be targeted at those at a slightly lower-risk level, and whether or not the generation of a risk score per se can have the effects that we found. This will require a new study based on an experimental design – preferably a randomised trial clustered by practice to exclude biases caused by changing policy and practice within the study time frame. This study must be underpinned by theory and a logic model, and include a strong process evaluation to understand mechanisms of change. We recommend also that this study should be carried out in sites across England and Wales and that longer-term outcomes are included. Investigation of effects on vulnerable populations, health inequalities and by health condition type; in the PRISMATIC trial we have detected effects at aggregate and risk group levels, but have not delved into differential effects within the general practice population. This could partially be achieved by secondary analysis of the PRISMATIC trial data set, but some new investigation would also be required. Acceptability of predictive risk stratification and communication of scores to patients and practitioners is an important topic to explore, but it is more important at this stage to establish effects, costs and mechanisms of change. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 111 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Although we specifically acknowledge the following parties, we would like to extend our thanks to all of those who supported this work. We would particularly like to thank the following staff members: Ken Leake, Dave Price, Mick Kelly, Cecilia Jones, David Leach, Tracey Taylor, Claire John and Simon Scourfield. In particular, for their support with practice engagement and research tasks, we thank Kathy Malinovszky, Carol Thomas, Zoe Abbott and Rachel McGrath. In particular, we would like to thank Cynthia McNerney, Caroline Brooks, Dan Thayer and Ronan Lyons and members of the Information Governance Review Panel. Contributions of authors Helen Snooks (Professor of Health Services Research), chief investigator, led the development of the research question, study design, and was responsible for trial delivery and conduct. Kerry Bailey-Jones (GP) and Deborah Burge-Jones (GP) acted as study GP champions, offering general practice insight and experience throughout. Jeremy Dale (Professor of Primary Care), co-applicant, provided expertise in primary and emergency care research. Jan Davies (Service User Representative), RMG member and service user advisor. Bridie Evans (Research Officer), service user involvement lead and qualitative support. Angela Farr (Researcher in Swansea Centre for Health Economics) helped prepare implementation costs section. Deborah Fitzsimmons (Professor of Health Outcomes Research) supported the management of the health economic analysis and contributed to the draft of the cost-effectiveness chapter. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 113 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ACKNOWLEDGEMENTS Jane Harrison (Public Health Wales, previously ABM UHB Assistant Medical Director for Primary Care) led the introduction of PRISM in ABM UHB. Martin Heaven (Senior analyst at FARR Institute @ CIPHER) provided expertise and support for data linkage. Helen Howson (Welsh Government) advised on policy concerning chronic conditions management throughout the study. Hayley Hutchings (Professor of Health Services Research and Deputy Director of STU), research manager, supervised staff, and led the writing of the study protocol and methods chapter. Gareth John (Information Manager at NWIS) supported implementation of PRISM, advised and facilitated data linkage, and was key liaison for NWIS throughout the study. Mark Kingston (Research Officer), project and data manager, co-ordinated the day-to-day delivery of the trial, including site liaison, and wrote first drafts of the introduction and systematic review.

    Malegra DXT Plus
    8 of 10 - Review by B. Pavel
    Votes: 86 votes
    Total customer reviews: 86