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There were also no significant differences cents with OCD suggest that adjunctive interventions in- between the SSRIs purchase 100mg silagra otc erectile dysfunction 7 seconds, although CMI appeared to have some cluding parent case management education and specific cog- increased efficacy but not sufficient enough to warrant fa- nitive-behavioral should be considered in the majority of voring it over other SSRIs given its side-effect spectrum cases silagra 50 mg otc erectile dysfunction instrumental. The choice between these two modalities is often dominated by the relatively limited availability of behavioral therapists and by BEHAVIOR THERAPY AND patient preference. Up to 25% of individuals refuse behav- PHARMACOTHERAPY ioral therapy, whereas others prefer a nonpharmacologic treatment. A computer program offering behavior therapy Prolonged exposure coupled with response prevention is a via 12 computer-controlled interactive phone calls was key element of behavior therapy for OCD. Exposure in- found effective in over two-thirds of the patients (136). Chapter 114: Current and Experimental Therapeutics of OCD 1655 In clinical practice, a combination of pharmacotherapy involving other neurotransmitter systems, which may con- and behavioral therapy is often employed, although avail- tribute to the pathophysiology of OCD. Serotonergic Enhancers Pharmacologic agents with serotonergic properties have shown varying utility in augmentation of SRIs. TREATMENT-RESISTANT OCD: CLINICAL AND BIOLOGICAL PREDICTORS OF Buspirone NONRESPONSE Buspirone, a 5-HT1A agonist, has been reported effective It has been recommended that a minimum of 12 weeks of in treating OC symptoms in augmentation to fluoxetine in SRI treatment is needed to evaluate treatment response. A 10-week double-blind trial of buspirone ad- beyond this period. In a double-blind, placebo-controlled study adding tine and sertraline indicated that plasma levels correlated buspirone to fluvoxamine-refractory OCD, buspirone was with dosage but there was no evidence of a concentra- not found to be significantly better than placebo in reducing tion—response relationship (75,137). Current research is investigating the connection between brain steady-state levels and treat- D-L-Fenfluramine, an indirect 5-HT agonist, added open- ment response. Poorer outcome has been associated also has been cited as potentially effective in augmenting with the presence of compulsions, the chronicity of the ill- clomipramine in OCD (148); however, these agents have ness, and a continuous as opposed to fluctuating course been removed from the market because of side-effect issues. Depression is the most common comorbid diagnosis with OCD. The pres- Tryptophan ence of concurrent depression at the start of treatment was Tryptophan, a 5-HT precursor, has shown varying degrees not found to predict whether SRIs were effective in reducing of effectiveness in case reports of SRI augmentation in OCD obsessive-compulsive symptoms (100). Hollander and asso- (68,149), but has been removed from the market because ciates (141) reported that select measures of serotonergic of side effects. They found that nonresponders to SRIs were likely to experience worsening of OCD symptoms and to have a blunted prolactin response on being challenged Lithium with the partial 5-HT agonist m-chlorophenylpiperazine Lithium, which is thought to enhance presynaptic 5-HT (m-CPP). Also, OCD release in the brain (150) and influence second messenger patients with increased neurologic soft-signs, a measure of systems coupled to 5-HT receptors, was reported to improve subtle neurologic dysfunction, had a worse response to SRIs OC symptoms in three out of four patients treated with (22). However, in a 4-week double-blind study of lithium aug- mentation to 16 OCD partial responders on clomipramine, AUGMENTATION STRATEGIES there was no further decrease in OC symptoms reported after lithium (152). In two double-blind, placebo-controlled Augmentation strategies play an important role in OCD trials of lithium, addition to ongoing fluvoxamine treatment pharmacotherapy for SRI partial and nonresponders, as in OCD nonresponders (2-week study [20 points] and 4- 40% to 60% of patients with OCD will not respond to an week study [10 points]), only a small statistically significant adequate treatment trial of an SRI. Augmentation agents reduction in OCD symptoms was reported from the 2-week added to SRIs include both serotonin enhancers and agents trial, but not from the 4-week trial (153). Other cases of risperidone augmenta- erties, has been efficacious in augmentation to SRIs in the tion reported effectiveness in reducing OC symptoms in patients with OCD in case series (154) and in a double- patients who had failed SRI trials (164,165). A chart review, blind, controlled augmentation trial with fluoxetine or including eight OCD patients treated with the combination clomipramine (155). Trazodone Trazodone, a 5-HT2 and -adrenergic blocker with weak Olanzapine 5-HT reuptake properties, which has m-CPP as a minor Case series (167,168) and open-label trials (169) have re- metabolite, was recently reported effective in augmentation ported benefits of adding titrated doses of olanzapine (10 to various SRIs in five cases of refractory OCD (156). Thus, olanzapine might also be considered in the augmenta- Pindolol tion of severe forms of OCD, although careful monitoring of the potential interaction with SSRIs is suggested because Pindolol is a -adrenergic blocker with 5-HT1B and 5- this combination may produce idiosyncratic effect on HT1A receptor antagonist activity. One study of pindolol augmentation to GABA/Second Messenger Systems paroxetine in resistant OCD resulted in mild improvement Gabapentin, a -aminobutyric acid (GABA) analogue, was (158), whereas another report found that pindolol did not reported to improve OC symptoms in 5/5 partial responders shorten the latency of fluvoxamine antiobsessional response in a 6-week pilot study of fluoxetine augmentation within (159). Thus, the utility of pindolol in non-depressed OCD 2 weeks of treatment (170). Dopamine antagonist/SRI combina- tions have been reported to be effective in OCD. NOVEL PHARMACOTHERAPIES Haloperidol Some individuals with OCD remain refractory even to aug- In a double-blind, placebo-controlled study of OCD pa- mentation strategies. For them, alternate pharmacotherapy tients on fluvoxamine monotherapy, haloperidol augmenta- may provide relief. Intravenous clomipramine was first reported successful in treating obsessive symptoms in 1967 (46). A review of the literature found over 100 cases of successful treatment with Pimozide intravenous clomipramine (172). In a double-blind, pla- Open case series have shown the effectiveness of pimozide/ cebo-controlled trial of intravenous versus oral pulse loading SRI combinations in OCD patients with and without com- of clomipramine in 15 OCD patients, six of seven patients orbid tic-related disorders (161).

Improvement by H3 receptor responsiveness in mouse brain discount 100mg silagra with visa impotence from alcohol. J Neurochem 2000; FUB 181 generic 100 mg silagra mastercard impotence kit, a novel histamine H3-receptor antagonist, of learning 74:339–346. Facilitation of learning¨ sured by in vivo microdialysis. Minireview: the role of histamine in the neuronal histamine as a target of leptin in feeding behavior. Dehydration stimulates continuous histamine release in the striatum of conscious freely hypothalamic gene expression of histamine synthesis enzyme: moving rats produced by middle cerebral artery occlusion. J importance for neuroendocrine regulation of vasopressin and Cereb Blood Flow Metab 1992;12:477–483. Evidence for the involvement of hista- histamine using ion-pair HPLC coupled with postcolumn fluo- minergic neurones in the regulation of the rat oxytocinergic rescent derivatization: its application to biological specimens. Dehydration-induced mine release from the rat hypothalamus as measured by in vivo renin secretion: involvement of histaminergic neurons. Estrogen re- of neuronal histamine in the hypothalamus of rats measured by ceptor immunoreactivity is present in the majority of central 190 Neuropsychopharmacology: The Fifth Generation of Progress histaminergic neurons: evidence for a new neuroendocrine path- mine H3 receptor antagonist, attenuates stimulant-induced lo- way associated with luteinizing hormone—releasing hormone- comotor activity in the mouse. Eur J Pharmacol 1994;259: synthesizing neurons in rats and humans. Hypothalamic neuronal lites in cerebrospinal fluid of patients with chronic schizophre- histamine: implications of its homeostatic control of energy me- nia: their relationship to levels of other aminergic transmitters tabolism. Histamine H2 receptor gene in the amygdaloid kindling rats. Behavioural characterization 301 U, in rodent antinociception. Recent progress in the development of molecular genetic tations may resemble features of human neuropsychiatric methods enables the manipulation of genes in intact mam- diseases, providing animal models for studying neural pro- malian organisms. The power of such techniques to eluci- cesses relevant to such disorders. Furthermore, as genes that date complex biological systems was initially recognized and confer susceptibility to human diseases are identified, it will exploited by developmental biologists and immunologists. Finally, genetic models has led to their use in neuropsychopharmacology. Since the will be useful for investigating mechanisms through which publication of the previous edition of this book, there has nonselective drugs influence neural function and behavior. We have divided these techniques into three of such organisms for research in neuropsychopharmacology categories: (a) transgenic technologies, in which exogenous arise from the marked organizational differences between gene sequences are inserted into the mouse genome; (b) the mammalian brain and the systems that govern behavior gene targeting technologies, in which mutations are targeted in these organisms. By contrast, a substantial degree of ho- to inactivate or otherwise modify an endogenous gene of mology exists in the organization of the central nervous interest; and (c) conditional genetic manipulations, in system (CNS) and in the complement of genes expressed which mutations are restricted to particular stages of devel- across mammalian species. Currently, the mouse genome is opment or to particular regions of the CNS. In addition to by far the most accessible mammalian genome to manipula- a brief description of these technologies, examples of their tion. Procedures exist in the mouse for introducing new application to neuropsychopharmacology are provided, as genes, expressing elevated levels of endogenous genes, and well as discussions of the benefits and limitations of each eliminating or altering the function of identified target approach. Mutant mouse models may be used for a number of purposes relevant to neuropsychopharmacologic research. TRANSGENIC PROCEDURES For example, the impact of genetic mutations on the behav- ior of mutant mice may be examined, providing insights The ability to insert an exogenous (or foreign) gene into into the functional significance of particular gene products. The term transgenic was applied to mice expressing exogenous DNA that had been produced using this technique (2). With this method, the gene of interest is inserted into a random locus Laurence H. The techniques required for intro- 242 Neuropsychopharmacology: The Fifth Generation of Progress ducing transgenes into the mouse genome have been highly rates of integration of transgenes than other known methods refined, permitting their widespread use. After microinjection, the embryos are ment of this technique, many thousands of lines of surgically transferred into the oviduct of pseudopregnant transgenic mice have been generated, and it has been the mice. Pseudopregnant females are generated by matings most widely utilized technique of genetic manipulation in with vasectomized males. The foster mothers give birth 19 Methods of Production of Transgenic to 21 days after oviduct transfer. For genotyping, DNA is Mice typically isolated from mouse tail biopsies and screened for Techniques for producing transgenic mice involve the mi- the presence of the transgene by Southern blotting or poly- croinjection of DNA constructs into fertilized mouse eggs merase chain reaction (PCR).

One that and long-term effect of clozapine treatment on neuropsycho- has been implicated is the glutamate system (78) 50 mg silagra amex erectile dysfunction medicine from dabur. N-methyl-D-aspartate (NMDA) subtype of glutamate re- 6 buy silagra 100mg low cost erectile dysfunction treatment in thane. Neuropsychological functioning in siblings discordant for schizophrenia and healthy ceptor, such as phencyclidine and ketamine, it has been volunteers. Because the NMDA receptor is modu- on neuropsychological function in chronic schizophrenic pa- lated by glycine, glycinergic agents can provide a useful tients. Neuropsychological means for manipulating glutamate function. Glycine itself evidence supporting a neurodevelopmental model of schizo- has been utilized by Javitt et al. Sustained attention deficit partial glycine agonist, resulted in a benefit in choice reac- and schizotypal personality features in nonpsychotic relatives of tion time when it was utilized in conjunction with conven- schizophrenic patients. Verbal working mem- tional antipsychotic medications (32), but not when added ory impairment in schizophrenia patients and their first-degree to clozapine (33). A full glycine agonist, D-serine, demon- relatives: evidence from the digit span task. Am J Psychiatry strated some success in improving WCST performance 2000;157:275–277. If these studies of adjunctive agents result in reliable 11. Psychiatr Q 1997;68: improvement in neurocognition in schizophrenia, it may 343–359. Functional mechanisms under- cation for each of the major domains of illness, clinical lying impaired recognition memory and conscious awareness symptoms and neurocognitive deficits. IQ and risk for schizo- phrenia: a population-based cohort study. Severity of symp- toms in chronically institutionalized geriatric schizophrenic pa- tients. In the lay imagination, schizophrenic patients experience 15. Behavioral selves, out of touch with reality, and disorganized. The view and intellectual markers for schizophrenia in apparently healthy of scientists, once not altogether different, has changed. Neurocognitive defi- cits and social functioning in outpatients with schizophrenia. Human memory and the cholinergic impairments may be a relatively central feature of the disor- system. Cognitive impairments are involved in the genetic etiol- 19. Relative risk of attention deficits in siblings of patients with schizophrenia. They seem enduring in that they are J Psychiatry 2000;157:1309–1316. Cognitive impairments also may have a rela- cognitive impairments in siblings of patients with schizophrenia tively well-delineated profile in which executive, memory, Biol Psych 2001;50:98–107. Neuropsychological ments should be considered target symptoms in the same evidence for frontostriatal dysfunction in schizophrenia. Psychol way as hallucinations, delusions, and anergia. Chapter 48: Neurocognitive Functioning in Patients with Schizophrenia 667 22. The use of cognitive and functional outcome in schizophrenia: are we measuring the context in schizophrenia: an investigation.

Children were encouraged to set three goals based on snacking generic silagra 50mg mastercard do erectile dysfunction pills work, fizzy drink consumption and physical activity cheap 100mg silagra otc erectile dysfunction pills review, depending on the area in which they needed to make changes. Table 42 shows the number and percentage of goals set for each target behaviour by gender. As Table 42 shows, the majority of goals set by both genders were focused on increasing their physical activity and snacking. No marked differences were observed in the type of goal set by gender or engagement. Children reported mixed feelings about setting goals, with some finding it easy and others finding it more challenging for various reasons: I felt setting the goals, um one of my goals is really easy to set but the other two were really hard. Male EC, school 9 TABLE 42 Number and percentage of goalsa set for each target behaviour by gender Number (%) of goals set by Goal type Boys Girls Snacking 251 (26) 276 (28) Drinks Fizzy 60 (6) 74 (8) Other 8 (1) 16 (2) Physical activity 391 (40) 336 (35) Other 265 (27) 267 (28) a Each child could set a maximum of three goals. Overall, 1944 goals were set (975 by boys and 969 by girls). 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 85 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. Female LEC, school 1 I found it quite easy because my mum was really supportive. And because we especially did it over the weekend and the holidays, I found that extremely hard because in the holidays and that, I kind of let myself go and like, have a lot of chocolate, that sort of thing. So if we had done it during the week I think I would have found it a lot easier, so maybe next time. P, school 9 Yeah so she really owned her goals as well. She was very responsible about it which was good because it gave her something to be responsible for and it was only kind of small changes so um. Male LEC, school 7 Sometimes I found it hard, but sometimes it was quite easy because when I got more in to the programme I found it easier because I started doing it more, in the beginning I found it really hard to make any changes. Specific to the goal-setting phase, it was hoped that the children would use a number of strategies they had learnt during phase 2 to help them achieve their goals (e. It was also hoped that parents would support them by increasing access to and availability of healthy snacks and physical activity, and enforcing rules about screen time. When the children discussed their experiences of making changes in the focus groups, some commented that their parents had supported them in this way: My parents helped a lot with my goals because my mum made a rota which is so I only get an hour or half an hour on screen time every day. 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 87 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. Female EC, school 12 We know that changes at a family level can have a positive impact on children making changes to their eating and activity behaviours,128 and there was strong evidence for this from parents and children alike. The results of the parent questionnaire indicated that 74% of families had made changes (see Appendix 17), with 78% of parents providing further details. P, school 13 Yeah definitely yeah because like you know if she would get a snack and she has a carrot, and then thinks oh yeah you will all have carrots, so in that respect you know she has pulled the whole family to a healthier snack rather than just herself. P, school 7 Yes we definitely decreased the fruit juice that we have. Male LEC, school 9 Um yeah, we started doing more as a whole family together and going out more, like going on family walks on the weekend, instead of just having one person go out by themselves, and literally just going out all together. The focus group and interviews suggested that children had made changes to their diet and/or activity/ sedentary behaviours: The one area that I did really notice that he picked up on is looking at ingredients of food. P, school 4 Teachers also reported being aware of changes the children had made: It was perfect timing, to have that farm trip after the 80 : 20 programme to see if they had adjusted their lunchboxes to be a little bit more, there was more water and less fizzy drinks, less sweets, more fruit. Because I went around looking at the packed lunches as we were sitting on these bales of hay, and it was a kind of relaxed fashion, and the children were just openly talking about it straight away. T, school 13 The evidence from the focus groups and interviews of reported changes was supported by data from the parent questionnaire. Fifty-five per cent of parents noticed changes to screen time, with 67% reporting changes to physical activity. In response to the question asking whether or not any observed changes had been maintained, 78% reported that they had (see Appendix 17). When given the opportunity to provide details of these changes, 89% of parents responded and provided a brief description of the change they had observed in their child.

These results suggest that volatile anes- these agents have been widely used in surgery for over a thetics interfere with synaptic transmission through direct century buy silagra 100mg low cost erectile dysfunction latest medicine, their mechanism of action remains poorly under- interaction with one or more members of the SNARE com- stood discount silagra 100 mg impotence 19 year old. General anesthesia appears to result from defects in plex. Interest- ber of receptors and channels, including the N-methyl-D- ingly, none of the synaptic mutations affecting the low- aspartate (NMDA), serotonin, and -aminobutyric acid concentration effects on coordinated movements affect this (GABA) receptors and various voltage-gated ion channels, high-concentration paralytic response. However, a different, appear to be modulated by the presence of ethanol (45). Several of these genes have been cloned, in- choactive effects of ethanol; however, a variety of experi- cluding unc-1, which encodes a homologue of stomatin ments in cultured cells suggest that a critical short-term (41), and unc-8, which encodes a subunit of the degenerin/ effect of ethanol is to enhance receptor-mediated synthesis ENaC family of passive sodium channels (42,43). Both unc- of the second messenger 3′,5′-cyclic adenosine monophos- 1 and unc-8 are expressed in neurons, and both genes can phate (cAMP). Conversely, long-term ethanol exposure ap- be mutated to confer either resistance or hypersensitivity to pears to decrease intracellular cAMP levels. Allele-specific genetic interactions between and chronic effects of ethanol have also been linked to unc-1, unc-8, and the yet uncloned unc-79 and unc-80 genes changes in dopaminergic neurotransmission (46). In partic- suggest that their products may physically interact in a mul- ular, ethanol has been shown to promote release of dopa- timeric channel complex specifically involved in anesthetic mine in the mesolimbic pathways of the brain, in particular responses. Since stomatin has been shown to function as the so-called reward pathway synapses between the ventral a negative regulator of cation channels in erythrocytes, a tegmental area (VTA) and the nucleus accumbens (NAc). Homologues of both stomatins remains to be determined. Moreover, although sensitivity and ENaC channels have been identified in mammals, and to both the acute and chronic effects of ethanol are clearly are known to be expressed in the central nervous system; affected by genetic factors, the nature of the genes affecting thus, in principle stomatin-regulated ENaC channels could human ethanol sensitivity are not known. Recent work in Drosophila has provided support for both In summary, there are two distinct sets of genes that the dopamine and cAMP hypotheses of ethanol action. At present, it is not clear which of and ultimately immobilization. Using an instrument called the two (or whether both) might encode homologues of an inebriometer (47), lines of mutant flies have been identi- biologically relevant human anesthetic targets. Although the fied that exhibit abnormal sensitivity to volatilized ethanol. Conversely, although the stomatin/de- lian pituitary adenylyl cyclase activating peptide (PACAP) generin genes affect a paralytic response that closely resem- (48,49). Consistent with the implications of this homology, bles anesthesia, the response also has a relatively long time the effects of amnesiac on ethanol response appeared to delay and occurs at concentrations well above those clini- involve the adenylyl cyclase pathway, since the adenylyl cy- cally relevant in humans. Given the effective drug concen- clase activator foskolin blocks the ethanol sensitivity associ- trations for these two behavioral responses, it is possible that the synaptic genes might encode targets relevant to ated with amnesiac loss-of-function mutations. Moreover, anesthesia, while the stomatin/degenerin genes might en- several other loss-of-function mutations affecting cAMP code targets relevant for side effects of anesthetics. Alterna- pathway components, including the adenylyl cyclase gene tively, it is possible that genes affecting high-concentration rutabaga and the cAMP-dependent protein kinase gene anesthetic responses do define molecules involved in anes- DCO, also conferred ethanol sensitivity. Although one thesia, especially since the nematode cuticle is relatively im- might suppose based on these results that the response to permeant and presents a significant barrier for the entry of ethanol is simply a function of the level of cAMP signaling many drugs. Since well-defined mammalian homologues in the relevant neuronal targets (with increased ethanol re- exist for both classes of anesthetic response genes, it should sponse corresponding to low cAMP signaling), a variety of be possible in the future to examine these issues directly in data are inconsistent with this simple model. Nonetheless, these ge- Drugs of Abuse netic data provide the first conclusive link between the activ- ity of the cAMP pathway and the behavioral effects of Ethanol ethanol in an intact organism; the precise nature of that Unlike many neuroactive substances, ethanol is not believed link remains to be determined, but should be accessible to to have a single molecular target in neurons; rather, a num- further genetic analysis. During the first 7 to 10 minutes of Genetic analysis in C. When flies are depleted of dopamine through traction of body wall muscles, stimulation of egg laying, ingestion of a tyrosine hydroxylase inhibitor, they become and increased pharyngeal pumping. The effects of nicotine significantly less susceptible to this stimulation of motor on the body and egg-laying muscles are mediated through activity by ethanol. However, these dopamine-depleted flies a nicotinic receptor known as the levamisole receptor (57, exhibited no abnormalities in their sensitivities to ethanol- 58). The antihelminthic drug [and ganglionic nAChR ago- induced uncoordination or immobilization. Thus, the stim- nist (59)] levamisole is a potent agonist of this receptor; like ulation of motor activity by ethanol may involve ethanol- nicotine, levamisole causes body muscle hypercontraction induced enhancement of dopaminergic transmission in and (at high doses) spastic paralysis.