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By W. Frithjof. Cleveland Chiropractic College.

These individual differences in fear-related as an index of its level of stress discount imuran 50 mg with amex. For example imuran 50 mg on line, in the classic responses seen in the laboratory are similar to those that Geller-Seifter conflict test (29), rats are trained to press a have been observed in rhesus monkeys who inhabit Cayo lever for a food reward. Gradually, the bar press is also paired Santiago, a 45-acre island with approximately 1,000 free- with a mild foot shock, and a stable rate of responding is ranging monkeys (Kalin et al. For example, benzo- suggesting that the intensity of defensive behavior that is diazepines have been found to increase bar-pressing during displayed reflects a trait rather than a state characteristic. It the conflict schedule, putatively by decreasing the stress or was initially demonstrated that the duration of NEC- anxiety induced by the aversive stimulus. Similarly, in the induced freezing behavior remained stable in 12 animals tested twice with an interval of 4 months (r. Using Vogel punished drinking paradigm (30), thirsty rats with ac- a larger sample size, the stability of NEC-induced freezing cess to a water bottle are periodically given mild electric was confirmed; ST-induced hostility was also found to be shocks through the spout of the bottle; the extent to which relatively stable (Kalin et al. Interest- licking is decreased is used as an index of stress. Thus, monkeys that exhibited extreme INDIVIDUAL DIFFERENCES IN DEFENSIVE levels of NEC-induced freezing did not necessarily display BEHAVIORS: NATURALLY OCCURRING extreme levels of ST-induced hostility. For example, manipulations of the opiate system affect characteristic (which in part may be derived from the nature A (alone condition)–induced cooing without affecting of early postnatal maternal interactions, see below). Conversely, benzodi- individual differences detected early in life may be predictive azepines reduce the threat-related behaviors, but have little of future psychopathology. For example, extremely inhib- effect on A-induced cooing (14). Moreover, behavioral lationships between the stress-related hormone cortisol or inhibition in childhood (based on retrospective self-reports) asymmetric frontal EEG activity and individual differences is highly associated with anxiety in adulthood (35). Thus, in 28 mother- of the physiologic correlates that have been observed in ex- infant pairs, it was found that in both mothers and infants tremely inhibited children are elevated levels of the stress- freezing duration was significantly and positively correlated related hormone cortisol (36) and greater sympathetic with baseline (nonstressed) cortisol levels (38). In nonhuman primates, indi- are consistent with findings from human studies demon- vidual differences in defensive behaviors have been studied strating that extremely inhibited children have elevated lev- in an attempt to elucidate the neuroendocrine and neuro- els of salivary cortisol (36,37), and is also consistent with biological concomitants of extreme behavioral inhibition findings in rodents that corticosterone (the rodent analogue and to characterize a primate analogue of an anxiety-related of cortisol) is required for rat pups to develop the ability endophenotype. Marked individual differences among rhesus monkeys Extremely fearful monkeys (as identified by the HIP) have been noted with regard to the intensity of context- also exhibit characteristic EEG patterns. In adult humans, Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 887 asymmetric right frontal brain activity has been associated species. The examination of naturally occurring genetic with negative emotional responses (40). Our studies in rhe- variations with regard to stress reactivity may have impor- sus monkeys have demonstrated similarities in this measure tant implications for the elucidation of individual differ- between monkeys and humans (41). Thus, it has been found ences in sensitivity to stressful situations. One example of that dispositionally fearful monkeys have extreme right naturally occurring individual differences comes from the frontal brain activity, paralleling the pattern of extreme right study of different rodent strains with regard to their level of frontal activity in humans who suffer from anxiety-related stress-like behavioral responding to environmental stimuli. In addition, it was found that individual differ- Because of the important role of the CRH system in regulat- ences in asymmetric frontal activity in nonhuman primates ing defensive behaviors induced by stressful or threatening in the 4- to 8-Hz range are a stable characteristic of an situations, attention has been focused on identifying rat or animal (41,42). Furthermore, a significant positive correla- mouse strains that display differential stress reactivity and tion between relative right asymmetric frontal activity and different baseline levels of CRH gene expression. For exam- basal cortisol levels in 50 one-year-old animals was found. An extreme groups analysis re- fawn-hooded rats compared to either Sprague-Dawleys or vealed that extreme right compared to extreme left frontal Wistars (44,45). Fawn-hooded rats have also been reported animals had greater cortisol concentrations as well as in- to exhibit exaggerated behavioral responses to stress such as creased defensive responses, such as freezing and hostility. Strain differences, which right frontal animals continued to demonstrate elevated cor- essentially reflect differential genetic makeups, have also tisol levels at 3 years of age. These results are the first to link been found to influence the effects of acute environmental individual differences in asymmetric frontal activity with stressors on regulating CRH system gene expression. This finding is important be- the stress of whole-body restraint produces a much larger cause both factors have been independently associated with increase in CRH mRNA levels within the hypothalamus of fearful temperamental styles. Fisher rats than in Wistars or Sprague-Dawleys (46,47). It has recently been found that cerebrospinal fluid (CSF) Similarly, the spontaneously hypertensive and borderline levels of corticotropin-releasing hormone (CRH), a peptide hypertensive strains of rats have increased basal and stress- that mediates stress responses, are significantly elevated in induced levels of hypothalamic CRH mRNA compared to monkeys that display exaggerated defensive responses to the Wistar and Sprague-Dawley strains (48–50). As stated before, these extreme indi- In mice, it has been shown that the BALB/c strain is vidual differences in defensive behaviors are stable over time. Finally, when comparing avoidance of aversive areas in a light-dark transition test and monkeys with extreme right frontal activity (that display an open field (51,52). These mice also show high levels of exaggerated fearful responses) to those with extreme left neophobia (53). Recent genetic mapping studies in these frontal activity (that display low levels of fearful behaviors), strains have revealed that these behavioral differences may the right frontal group was found to consistently have in- be associated with differential levels of -aminobutyric acid creased CSFCRH levels over a period of 4 years (5). Thus, receptor A (GABA ) expression between the strains.

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Thus imuran 50mg amex, infusion of hibited excessive burst activity in the exposed rats (40) discount imuran 50 mg mastercard. It is proposed that this subicular-driven DA re- striatum. Thus, implantation of a microdialysis probe was lease may be involved in the modulation of investigatory found to disrupt DA neuron depolarization block when DA response to novel and conditioned stimuli (45). Stimulation cell activity was assessed 24 hours following probe implanta- of the PFC also appears to result in impulse-dependent DA tion. However, if the probe was inserted via a preimplanted release in the striatum (28). On the other hand, there is guide cannula, depolarization block was maintained, and evidence suggesting that DA can be released in a manner the DA levels were found to be approximately 50% less not dependent on DA neuron firing via stimulation of the than in control conditions. Moreover, the relationship be- hippocampal afferents (46), or amygdala afferents (47) to tween DA neuron firing and release was altered. Thus, al- the accumbens, all of which use glutamate as a transmitter. There is also evidence that glutamate can release chronic antipsychotic drug (60). Thus, correlations between acetylcholine or serotonin in the striatum, which in turn cell firing patterns and DA levels postsynaptically appear to can trigger DA release (43). Glutamate may also stimulate depend on the state of the system. DA release via an action on other local systems, such as It is also possible that there may be local fluctuations in those producing NO. NO is known to be released from tonic DA stimulation that may be a consequence of in- striatal interneurons containing the enzyme NOS, and exert creases in DA neuron firing. Indeed, studies using voltamet- actions on neuronal elements in the vicinity of the release ric measures have shown that brief elevations in extracellular site. Infusion of NOS substrates or NO generator com- DA may occur as a consequence of rapid burst firing, over- pounds was found to facilitate the release of both glutamate whelming the DA uptake process (61). This relationship is and DA within the striatum in a calcium-dependent man- particularly important during administrations of drugs that ner, and is dependent on vesicular stores (52,53). Moreover, interfere with the uptake process, such as cocaine or amphet- the NO-induced efflux of striatal glutamate was found to amine (57,58). Such drugs would cause phasic DA release indirectly enhance extracellular DA levels in the striatum to rapidly augment tonic DA levels, leading to high extracel- in a manner dependent on NMDA and AMPA receptors lular DA and abnormal levels of down-regulation of spike- (53,54). Therefore, it is likely that excitatory amino acids dependent DA release. In a similar nature, in mice lacking and NO interact with DA neuron firing to regulate DA the DA transporter, the extracellular DA is already elevated release from presynaptic sites within the striatum. This tonic/ extracellular DA and glutamate within the striatum (55), phasic balance has been proposed to underlie normal and which would thereby increase in the behavioral response to dysfunctional DA regulation as it relates to the pathophysi- amphetamine (56). Thus, evidence indicates that alterations ology of schizophrenia, drug abuse, and the treatment of in tonic DA levels produced by cortical afferents can po- ADHD (44,57,58). Such tonic down- literature has emerged regarding the functional relevance of modulation of spike-dependent DA release could play a extrasynaptic DA receptors. Indeed, studies have shown that particular role when the uptake system is inactivated by in the PFC, the DA terminals located in the deep layers of psychostimulants. Thus, although the DA transporter is cortex do not contain DA transporters (63). As a conse- normally highly effective at removing DA from the synaptic quence, the DA released from these sites would be free to cleft before it can escape into the extracellular space, block- diffuse to a much greater extent than in areas such as the ade of the DA transporter would allow substantially higher striatum and accumbens. This is further substantiated by levels of DA to escape the cleft and contribute to the tonic evidence that a substantial portion of the DA that is released extracellular DA pool (57). Such a condition is thought to in the PFC is actually taken up and deaminated in norepi- underlie some of the therapeutic actions of psychostimu- nephrine (NE) terminals (64). This arrangement would lants in attention deficit/hyperactivity disorder (ADHD) have substantial functional implications. This was found to be a significant issue when testing Moreover, such a condition could imply that NE uptake Chapter 9: Dopamine 123 blockers could serve to increase the functional actions of DA in the PFC by preventing its removal via NE terminals. This may also have implications regarding the clinical ac- tions of NE-selective antidepressant drugs within this brain region. POSTSYNAPTIC EFFECTS OF DA DA exerts a myriad of actions on postsynaptic systems. These actions can occur at the level of individual cells in terms of direct postsynaptic actions, as well as altering cellu- lar interactions (via presynaptic effects and network modula- tion). Moreover, the nature of these effects can vary depend- ing on both the specific region examined and the time course of DA agonist administration. The DARPP-32 signaling pathway has a central role D1 stimulation decreases excitability of dorsal striatal and in mediating signal transduction within medium spiny neurons in the striatum. A variety of neurotransmitters act on systems accumbens neurons (67–69), although others have reported regulating the phosphorylation of DARPP-32, which in turn mod- excitation by this agonist (70). Within the dorsal striatum, ulatesthe activityof proteinphosphatase-1 (PP-1).

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Therapies as complex interventions Our opening sections of Chapter 6 presented the notion of physiotherapy best imuran 50mg, occupational therapy and speech and language therapy as complex interventions generic imuran 50 mg on line,31 and described the existing conceptualisations of the active ingredients of non-pharmacological interventions. Both have highlighted the challenges of identifying, defining and measuring the active ingredients of complex, non-pharmacological interventions, and this offers an explanation of why, to date, the active ingredients have been poorly reported. In essence, the argument is made that the following interconnecting features of complex, non-pharmacological interventions make it difficult and complicated to identify their active ingredients. First, there was clear consensus that a therapy intervention comprises the therapist, the work that therapist does and the work that others do under the training or supervision of the therapist. This includes the overall approach that they adopt (deficit vs. We used this term to define elements such as the capacity of the wider therapeutic team (e. Certainly, both the lack of an understanding of active ingredients, which ones matter most, 94 NIHR Journals Library www. Findings relating to this objective were presented in Chapter 7, with relevant material also appearing in Chapters 4 and 5. Although these outcomes were global, parents strongly believed in the potential of therapy interventions in supporting their achievement. Thus, improvements in physical functioning, acquiring new motor skills and having access to equipment were regarded as necessary, but intermediate, outcomes to the achievement of higher-level outcomes. 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 95 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. However, as we reported in Chapter 5, some parents reported that therapists may not explicitly refer to these higher-level goals, and can appear to be focused on specific aspects of functioning, etc. As reported in Chapter 4, the ICF framework16 and the concept of participation were adopted by the professions a number of years ago, although understanding of the meaning of the concept varied. The specifics of definition aside, participation was consistently regarded as a complex and multifaceted concept. Furthermore, it was clear that some study participants felt that further critical, conceptual work was required to clarify its definition, and the way in which it should be operationalised by the therapies. Some helpful developments to the concept were, however, offered during our interviews. There was also a clear view that participation had to be something defined by the child and/or their wider family, and that assumptions should not be made about what constitutes participation for an individual child. Another thread in our discussions with professionals were concerns about the extent to which participation can be operationalised, or applied, to some groups of children with neurodisability, including neonates and very young children, children with disordered states of consciousness, children with multiple and profound disabilities, and typically developing children who have recently sustained a severe brain injury. Participation as an outcome measure A second, separate question explored in our interviews with study participants was to ask whether participation is an appropriate or meaningful concept to use with respect to the evaluation of interventions. A number of significant issues were raised and we will not rehearse them fully here. First, therapy interventions are often one aspect of a multifaceted, multidisciplinary programme of interventions that a child may be receiving. Second, any evaluation of intervention outcomes needs to take account of the impact of any age-/development-related changes in the child. There was greater engagement with the notion of participation as an outcome indicator if the evaluation concerned the whole approach of services, or particular service models. However, questions about when, and what, to measure were still raised, and similar arguments rehearsed regarding the challenges and complexities of outcome measurement. A recently completed NIHR HSDR project55 on meaningful health outcomes for paediatric neurodisability – incorporating the collection and collation of the views of families and professionals, as well as a systematic review of existing outcome measures – makes an important contribution to moving forward on this issue. In addition, a similar project but specific to young children with autism has also been published recently. It was also regarded as having the potential to be implemented routinely, and, if standardised and used routinely, could lead to the development of very useful data sets for cohort studies. To date, this approach has predominantly been confined to adult rehabilitation,57 although its use in paediatrics has been critically evaluated. A useful piece of work going forward would be to review evidence on this. Finally, before this discussion is concluded, it is important to return to the issue of multiple definitions and understandings, which introduced this section. Other child outcomes Interviewees readily identified other outcomes that they believed to be appropriate and meaningful, and that should be considered when designing evaluations. These included measures of body structure and functioning, engagement in/achievement of activities, emotional well-being, quality of life, acceptance of impairment and engagement with interventions.

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Clinical studies in PCP users order imuran 50mg mastercard, like those previously con- Efforts to determine whether selective serotonin neuro- ducted in MDMA users purchase 50mg imuran, should be directed toward deter- toxicity develops in human MDMA users, as in animals mining whether humans, like rodents, are susceptible to exposed to MDMA, have been limited by the paucity of PCP neurotoxic injury and defining the functional conse- available methods for assessing the status of central nervous quences of such injury if it occurs. MDMA research during the next decade should also At present, two methods for detecting MDMA-induced yield significant advances. Preclinical studies aimed at deter- brain 5-HT neurotoxicity in living humans have been vali- mining the mechanism of MDMA-induced 5-HT neuro- dated. These include measurement of spinal fluid 5-HIAA toxicity may not only increase our understanding of seroto- and PET neuroimaging of the SERT. Both of these methods nin neuronal function but also provide insight into have demonstrated capability for detecting MDMA- idiopathic neurodegenerative illnesses and neuronal re- induced neurotoxic injury in nonhuman primates (128, sponses to injury. With these methods, two studies have shown decre- and humans will be essential to learn whether recovery from ments in human cerebrospinal fluid 5-HIAA that are similar MDMA-induced 5-HT neurotoxicity can occur (and if so, to those seen in monkeys with known MDMA-induced 5- under what conditions), and will be useful in defining the HT neurotoxic damage (92,130). Similarly, imaging studies functional consequences of MDMA-induced neurotoxicity. Further, reductions in the SERT could be correlated with Increased efforts should be directed toward identifying those the extent of previous MDMA use. Finally, cost-effective methods quences of MDMA neurotoxicity in humans suggest that should be devised to detect MDMA-induced neurotoxicity, brain serotonin function is abnormal in human MDMA so as to identify those who may benefit from alternative, users. In particular, as previously described, abnormal neu- science-based treatment strategies. Schematic diagramof putative electrophys- iologic mechanism of action of hallucinogenic drugs. De- picted are serotoninergic hallucinogenic inputs at the raphe nuclei and locus ceruleus projecting to the vicinity of apical dendrites of layer V pyramidal cells in the neocortex. Hallu- cinogens, acting as partial agonists at 5-hydroxytryptamine subtype 2A (5-HT2A) receptors, induce the release of gluta- mate from excitatory nerve terminals. Also shown are inhib- itory modulators of 5-HT2A-induced glutamate release: - aminobutyric acid, opiate, group II and III metabotropic glutamate, and possibly 5-HT1B receptors. NE, noradrener- gic input; alpha1, 1-adrenergic receptor; mGluR II/III, group II and III metabotropic glutamate receptor; GABA, -amino- butyrate. Washington, DC: American Psychiatric Association, 1999:103–116. J Pharma- results on drug use from the Monitoring the Future Study, col Exp Ther 1961;134:160–166. Mescaline and lysergic acid diethyl- National Institute on Drug Abuse, 1999. Dissociations between the effects of hallucinogens 3. Consumption of psilocybin-con- on behavior and raphe unit activity in behaving cats. Pharmacol taining hallucinogenic mushrooms by young people [in Dan- Biochem Behavior 1986;24:351–357. Monitoring the future: 3 3 tial binging of [ H]5-hydroxytryptamine, [ H]lysergic acid di- national survey results on drug use, 1975–1999. Antagonism between lysergic acid diethylamide types and signal transduction mechanisms. Psychopharmacology: the fourth generation of progress. Chemical, pharmacological and medical aspects lus effects of the hallucinogen DOM and the purported seroto- of psychotomimetics. Electrophysiological analysis of psychotogenic dence implicates the brain 5-HT2 receptor as a site of action drug action I. Bristol, ville, MD: National Institute on Drug Abuse, 1994:4–32. In: Lin GC, Glennon of information processing in animals: relevance to schizophre- RA, eds. Animal models of human Institutes of Health, 1994:52–73. Structure and function of sero- phencyclidine with ion channels of nerve and muscle: behavioral tonin 5-HT2 receptors. Psy- diethylamide, but not its nonhallucinogenic congeners, is a po- chopharmacology 1998;138:89–95. A 5-hydroxytryptamine2agonist aug- J Subst Abuse Treat 1993;10:523–527. Activation-related and noradrenergic locus coeruleus neurons. Neuroscience 1993;54: activation-independent effects of polyamines on phencyclidine 409–420. Antidotal strategies in involvement of a 5-HT2-activated interneuron. Role of serotonergic neurons and 5-HT receptors search Monograph Series. In: Baumgarten HG, Gothert Washington, DC: US Government Printing Office, 1986.

For example order imuran 50 mg mastercard, clozapine validity has in no way weakened its utility in neurobiological fails to reverse amphetamine- and apomorphine-induced research order imuran 50 mg overnight delivery, which is based on the etiologic and predictive va- stereotypy in rats, or apomorphine-induced emesis in dogs lidity of the model. The ability of antipsychotics, including atypical antipsy- effects of amphetamine in rodents, including either locomo- chotics, to restore PPI in apomorphine-treated rats strongly tor hyperactivity or stereotypy, have a high degree of phar- correlates with their clinical potency (r. In macologic isomorphism as models for the efficacy of dopa- addition to its sensitivity, the specificity of the PPI model mine-antagonist treatments for schizophrenia (4,5); thus, for compounds with antipsychotic efficacy is supported by 694 Neuropsychopharmacology: The Fifth Generation of Progress the fact that it predicts no such efficacy for a wide variety Serotonin-Agonist Models of other psychiatric drugs. Thus, the PPI paradigm appears Soon after the initial reports of the behavioral effects of to be sensitive to both typical and atypical antipsychotics, lysergic acid diethylamide (LSD), researchers began to ex- but—when used with the dopamine agonist apomor- plore the idea that the class of drugs represented by LSD phine—this paradigm clearly fails to make the important might appropriately be called psychotomimetics, or even psy- distinction between these two classes of antipsychotic chotogens. This hypothesis was engendered by the similarities agents. Thus, converging evidence indicates the important between the effects of LSD on perception and affective labil- involvement of dopaminergic systems, acting via D2-family ity and the symptoms of the early stages of psychoses such as receptors, in the control of PPI. Recent studies systematically comparing lel the deficits in PPI observed in schizophrenic patients hallucinogen-induced psychotic states with the early stages (58), which are also reported to be corrected by both typical of psychotic disorders have confirmed substantial overlap and atypical antipsychotics (62,63). Despite many clear similarities, It has been suggested that the increased stereotypy and two major differences prompted the dubious albeit widely submissive behavior produced by amphetamine in monkeys accepted conclusion that this class of drugs does not provide may mimic the stereotypy and paranoid ideation in schizo- a useful model of schizophrenia (67,68). Accordingly, both these behavioral effects found to develop rapidly to the subjective effects of LSD- can be prevented by pretreatment with the antipsychotics like drugs, whereas the symptoms of schizophrenia persist haloperidol and chlorpromazine (21). Second, the hallucinations produced by LSD isolation induced by amphetamine in monkeys is generally and related drugs are typically visual rather than auditory, regarded as related to the social withdrawal seen in patients as is characteristic of schizophrenia. As in schizophrenic patients, the ani- weaken the predictive validity of the hallucinogen model of mals actively avoid other animals, and these effects cannot the syndrome of schizophrenia. Although few novel antipsy- bility that abnormalities of biochemistry might lead to the chotics have been tested in this model, both clozapine and endogenous production of such compounds and hence be quetiapine have been shown to reverse amphetamine- responsible for some psychotic symptomatology. Initially, this etiologically based model was dismissed chotic-like behavior in psychiatrically healthy humans. Nevertheless, re- psychosis is produced only by repeated exposure to the drug cent studies indicate that no tolerance occurs to the subjec- (6,64), many preclinical researchers have directed their at- tive effects of DMTin humans (69), which suggests that tention to the behavioral effects of amphetamine that are DMTmay differ from other hallucinogens and that this augmented or sensitized by repeated administration of the model may still be viable. A review of the available clinical literature, however, may be involved in the various actions of the different hallu- reveals that chronic exposure is not required and that psy- cinogenic drugs, as suggested by the lack of cross-tolerance chotic episodes can be produced by acute administration of to DMTin human subjects made tolerant to LSD (70). The complex and limited Hence, further studies are warranted to provide the objec- nature of the clinical data seems to have led to mistaken tive evidence needed to evaluate adequately the model of interpretations that have inordinately influenced a large pro- psychosis based on the hypothesis of an endogenous psy- portion of the basic research in this area. Hence, although an ani- of some aspects of psychotic episodes in humans. Recent mal model based on the effects of chronic amphetamine suggestions of serotoninergic abnormalities in schizophrenia could be invalidated if tolerance were observed, the develop- (71) and of 5-HT2A-receptor contributions to the clinical ment of sensitization does not provide evidence supporting efficacy of atypical antipsychotics (72) have revitalized inter- the relevance of the model to schizophrenia. Hallucinogens are now believed to pears that the animal models having the greatest amount produce their characteristic subjective effects by acting as of predictive validity are those based on the effects of the 5-HT2A agonists (73). Many of the newer atypical antipsy- psychostimulant that are evident after acute administration chotic drugs are clearly potent 5-HT2A antagonists (72). With regard to specific abnormalities exhibited by patients Chapter 50: Animal Models Relevant to Schizophrenia Disorders 695 with schizophrenia, evidence indicates that the study of hal- generally associated with prolonged abuse of amphetamine, lucinogen action may provide useful animal models. For a single exposure to PCP or ketamine can produce the cog- example, both schizophrenic and schizotypal patients ex- nitive deficits and several symptoms listed above in healthy hibit deficits in startle habituation (9,11–13). Thus, acute exposure to these compounds is con- genic 5-HT2A agonists such as LSD and mescaline produce sidered a useful pharmacologic tool for producing some as- similar deficits in startle habituation in rats (59,74). Con- pects of schizophrenic symptomatology in the laboratory versely, opposite behavioral effects are produced by 5-HT2A animal. Simi- Several interesting aspects of this model distinguish it larly, the PPI-disruptive effects of hallucinogenic 5-HT2- from monoamine-based models. For example, the behav- receptor agonists are blocked by the selective 5-HT2A antag- ioral effects of PCP and related compounds are not, for the onist M100907, but not by the dopamine blocker haloperi- most part, mediated by increased dopamine transmission dol (74). Furthermore, in keeping with the similarities be- and therefore are not blocked by typical antipsychotics (see tween acute psychotic states and the syndrome induced by below). Similarly, in normal human volunteers, the psy- hallucinogens, latent inhibition is also disrupted by LSD chotomimetic effects of ketamine are not blocked by typical and other serotoninergic hallucinogens (75), as it is in antipsychotics, but they are reduced significantly by the pro- acutely ill schizophrenic patients. These effects can be totypal atypical antipsychotic clozapine (79). Therefore, this blocked by the putative antipsychotic M100907 (75). Thus, model may be especially useful for testing the effectiveness the effects of hallucinogens on habituation, PPI, and latent of atypical and perhaps even novel antischizophrenia drugs. The construct validity of this model is based been based on preclinical PCP models (41,80). Another on compelling evidence that both the symptoms of schizo- attractive aspect of the NMDA antagonist model is that, phrenia and the effects of hallucinogens reflect exaggerated unlike the dopamine-based models, it has strong construct responses to sensory and cognitive stimuli, theoretically re- validity for studying the cognitive and attentional deficits sulting from failures in normal filtering or gating processes in schizophrenia. In laboratory animals, NMDA antagonists such as habituation, PPI, or latent inhibition (1,3,9). Ac- impair working memory, set shifting, and other cognitive cordingly, 5-HT2A antagonism by itself might be effective functions that are related to schizophrenia (31). More im- in the treatment of certain forms of schizophrenia. Indeed, portantly, in clinical studies, direct comparison of schizo- a rather selective 5-HT2A antagonist, M100907, appears phrenic patients with healthy volunteers receiving subanes- to have efficacy as an antipsychotic in some patients with thetic doses of ketamine have indicated no significant schizophrenia, despite having negligible affinity for dopa- difference in scores for thought disorder between the two mine receptors (76).

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Van Putten (139) studied compliance in 85 schizo- tions buy cheap imuran 50mg online, such as placing microchip schedulers on pill bottles trusted imuran 50mg, phrenia patients chronically treated with conventional neu- can also substantially improve compliance. Medication refusal was associ- Treatment Resistance ated with an early dysphoric response, which Van Putten attributed to subtle akathisia. Analysis of responses by 150 Estimates of the incidence of treatment resistance have var- schizophrenia patients to a 'Drug Attitude Inventory' re- ied with changes in the diagnostic classification of schizo- vealed that, based on responses to 10 items, 89% of patients phrenia and definitions of treatment response (149), which could be correctly assigned to compliant versus non- have tended to obscure potential improvements in outcome compliant categories as determined by clinician assessment associated with advances in pharmacologic and psychosocial of compliance (140). For example, Hegarty and colleagues (150) re- was a positive experience with medication—this factor ac- viewed results of 320 clinical trials and found that, since the counted for 60% of the total variance, whereas the factor introduction of modern antipsychotics in the mid-twentieth representing a negative subjective experience accounted for century, about 50% of patients were improved at follow- 12%. Factors representing attitudes and beliefs about medi- up, whereas the rate of improvement dropped to 35% in cation had minimal predictive power. Rates of response have tended to be higher in first- Whereas many clinicians expect atypical agents to achieve episode psychosis, although dropout rates have been high higher levels of compliance by virtue of reduced or absent in this population, particularly with conventional agents EPS, this view may seriously underestimate the impact of (102,107). Persistence of psychotic symptoms is more com- other side effects. Two studies have found that clinicians mon in drug trials involving chronic patients, presumably tend to misjudge the relative distress produced by different reflecting progression of the illness as well as a possible selec- medication side effects (142,143). Side effects associated tion bias favoring participation by more refractory patients. The advan- or failure to achieve premorbid levels of functioning, treat- tage of atypical agents in terms of compliance may stem ment resistance can be considered the rule rather than the less from their reduced EPS and more from their improved exception. Whether targeting cognitive deficits and impairment in in- Psychotic Symptoms sight will improve compliance remains to be seen. Antipsychotic Monotherapy Response of psychotic symptoms to conventional antipsy- Psychosocial Interventions chotics, risperidone, and olanzapine has been associated Most approaches to noncompliance involve psychoeduca- with D2 receptor occupancy in excess of 65% (18,57), al- tion, supervision, and supportive therapy in which the bene- though persistence of psychotic symptoms has been shown fits of treatment are emphasized, whereas barriers to adher- to occur despite adequate D2 blockade in a subgroup of ence and medication side effects are minimized (145). As noted, only clozapine has con- Family therapy and social skills training may also exert a sistently demonstrated efficacy for psychotic symptoms in positive impact on compliance. Cognitive behavioral ap- treatment of refractory patients; the mechanism responsible proaches have recently been applied to noncompliance by for this therapeutic advantage remains uncertain. In a sam- Kemp and colleagues (146,147), who developed 'compli- ple of 268 patients prospectively established to be neurolep- ance therapy,' a four- to six-session intervention based on tic resistant, 30% in the clozapine group met criteria for motivational interviewing techniques that targets attitudes response at 6 weeks compared to 7% treated with chlorpro- towards medication and discharge planning during acute mazine (11). Response rates as high as 60% have been re- Chapter 56: Therapeutics of Schizophrenia 785 ported after 6 months in open trials with clozapine in pa- therapy as an intervention for neuroleptic-resistant patients; tients less rigorously defined as treatment refractory (152). Given the risk mine efficacy of clozapine and other atypical agents is the of agranulocytosis, the burden of side effects, and the re- subject of debate (153,154). Marder and colleagues (155) found that priate first choice among these agents is unclear; two con- schizophrenia patients presumed to be treatment-resistant trolled studies that compared olanzapine and risperidone on the basis of having been hospitalized for 6 months or have produced divergent results, probably reflecting differ- longer at the time of study entry did not respond to haloper- ences in dosing of the two agents and the use of intent-to- idol 20 mg per day but significantly improved with risperi- treat versus completer analyses (63,163). The focus of this done 6 mg per day or 16 mg per day compared to placebo. Many clinicians response of psychotic symptoms to olanzapine (mean dose express the impression that certain patients do respond pref- 11 mg per day) than haloperidol (mean dose 10 mg per erentially to a single agent of this class. Sequential controlled day); this difference was significant in the intent-to-treat trials of the newer agents in treatment-resistant patients will analysis but not in a comparison of completers (76). In 67 schizophrenia patients with his- The practice of combination therapy is gaining widespread tories of neuroleptic resistance, risperidone 6 mg per day popularity in the absence of controlled data in its support significantly improved total BPRS scores compared to halo- (164). In part based on empirical experience and the dem- peridol 15 mg per day at 4 weeks, but response did not differ onstration that clozapine at optimal doses achieves relatively between groups at 8 weeks (156). In contrast, risperidone low degrees of D2 occupancy, European clinicians com- produced significantly higher response rates than haloperi- monly add low-doses of neuroleptics to clozapine in par- dol in a large, randomized open trial involving 184 schizo- tially responsive patients (165). Uncontrolled trials and case phrenia patients with a history of poor response (157). Rela- reports have described benefits associated with the addition tive response of psychotic symptoms to risperidone of risperidone (4 mg per day) (159,166) and pimozide (167) increased over time and reached a maximum improvement to clozapine in partially responsive patients. In a small, pla- compared to haloperidol at the final 12-month assessment. The same group cians perceive improved response during the cross-tapering reported that 41% of 44 patients identified as unresponsive phase of switching from one to the other. A theoretical to olanzapine in the preceding study or in an open trial rationale for this combination is less apparent, given that subsequently exhibited a response to clozapine (158). In each agent produces maximal D2 and 5-HT2 occupancy addition, open trials in which patients have been switched when appropriately dosed (57). If combined treatment with from clozapine to olanzapine or risperidone have reported olanzapine and risperidone is found in suitably controlled a high incidence of clinical deterioration, casting doubt on study designs to offer advantages over optimal monotherapy claims for therapeutic equivalence between clozapine and with either agent, such a finding would argue in favor of the second-generation agents, at least at the doses tested the existence of additional contributory receptor actions (159,160). Of interest, two controlled trials have found unique to each drug. How- ever, in one 4-week trial, the 59 participants were not Adjunctive Treatments screened for treatment resistance at baseline and, despite A diverse range of adjunctive treatments has been proposed equivalence in outcomes between groups using an LOCF for antipsychotic-resistant schizophrenia, although thera- analysis, 25% of the risperidone group dropped out owing peutic effects generally have been small or inconsistent in to lack of efficacy compared to only 5% in the clozapine controlled trials. Very little data are available from con- group (161). Lithium augmentation frequently has been cited as 786 Neuropsychopharmacology: The Fifth Generation of Progress the best-established intervention based on positive results unresponsive to ECT and a diagnosis of schizoaffective dis- from three small studies (170–172); however, two recent order did not predict a favorable response (192–195). Cases placebo-controlled studies found no benefit when well-char- describing the successful combination of ECT with cloza- acterized neuroleptic-resistant patients were treated with pine in refractory patients have also been reported, suggest- lithium (approximately 1. Recently, interest has fo- lithium may enhance response of some patients, particularly cused on the potential use of transcranial magnetic stimula- in the presence of affective symptoms or excitement (175, tion (TMS) as an alternative to ECT in schizophrenia.

Many insults are associated with hypertension purchase imuran 50 mg otc, which may be a physiologic compensation order imuran 50mg line, so excessive lowering of blood pressure may induce secondary ischemia. In general, systolic pressure should be treated when more than 200 mmHg or MAP when more than 125 mmHg. Cautious reduction in mean arterial pressure by only 25% is recommended (Adams 2007). Avoiding prophylactic or routine hyperventilation - a decrease in extracellular brain pH may produce vasoconstriction in responsive vessels and reduce CBF to already ischemic zones. This applies to patients with head trauma in whom routine hyperventilation is no longer considered desirable; brief hyperventilation may be lifesaving in the patient with herniation, pending the institution of other methods to lower elevated ICP. Hypervolemia may also be helpful when vasoconstriction is suspected, as in the setting of subarachnoid hemorrhage. Consideration should be given to administering intravenous lidocaine 1. Nimodipine should be instituted immediately in patients with SAH and is advocated by some in patients with subarachnoid bleeding after head trauma. Nimodipine probably improves outcome by decreasing calcium- mediated neuronal toxicity. Using normal saline as the primary maintenance fluid; dextrose administration is usually avoided unless the 44 | Critical Care in Neurology patient is hypoglycemic; hypotonic solutions should also be avoided. Sedation and/or neuromuscular blockade after intubation may be required to control harmful agitation. If seizure occurrs, it should be aggressively treated. Titration of the ICP and cerebral perfusion pressure. Management of Special Issues Traumatic brain injury Outcome after traumatic brain injury depends upon the initial severity of the injury, age, the extent of any subsequent complications, and how these are managed. Much of the early management of traumatic brain injury falls upon emergency room staff, primary care and ambulance services prior to hospital admission. Most patients who attend hospital after a traumatic brain injury do not develop life-threatening complications in the acute stage. However, in a small but important subgroup, the outcome is made worse by failure to detect promptly and deal adequately with complications. A traumatic brain injury should be discussed with neurosurgery when a. Persistent coma (GCS <9, no eye opening) after initial resuscitation ii. Confusion persisting for more than 4 hours Brain Injuries | 45 iii. Deterioration in level of consciousness after admission (a sustained decrease of one point in the motor or verbal GCS subscores, or 2 points on the eye opening subscale of the GCS) iv. A CSF leak or other sign of base of skull fracture 2. A fall in serum sodium produces an osmotic gradient across the blood–brain barrier, and aggravates cerebral edema. Avoid hyperglycemia (treat blood glucose >11 mmol/L). Hyperglycemia increases cerebral lactic acidosis, which may aggravate ischemic brain injury. Apply 15–30° head-up tilt with head kept in neutral position; this may improve CPP. Acute stroke The World Stroke Organization declared a public health emergency on World Stroke Day (WSO 2010). There are 15 million people who have a stroke each year. According to the World Health Organization, stroke is the second leading cause of death for people above the age of 60, and the fifth leading cause in people aged 15 to 59. Stroke also happens to children, including newborns. Each year, nearly six million people die from stroke. In fact, stroke is responsible for more deaths annually than those attributed to AIDS, tuberculosis and malaria put together. Stroke is also the leading cause of long-term disability irrespective of age, gender, ethnicity or country. Yet for many healthcare staff it remains an area of therapeutic nihilism and thus uninteresting and neglected (WSO 2010). This 46 | Critical Care in Neurology negative perception is shared by the general public, who often has a poor understanding of the early symptoms and significance of a stroke. Yet within the last few years there have been many important developments in the approach to awareness and caring for stroke patients, for both the acute management and secondary prevention. Clinical research and interest in stroke has increased greatly in the last few years.