By F. Gelford. University of Texas at Dallas. 2019.
Consistent evidence for a biological J Clin Psychiatry 2000;61(Suppl 6):7–11 purchase propranolol 80 mg on-line. Arch Gen Psychiatry 1994;51: effects of intravenous clomipramine in depressed patients and 865–874 cheap 80mg propranolol visa. Regulation of nora- increases dopamine D1 receptor antagonist [3H]SCH 23390 drenergic coerulean neuronal firing mediated by 5-HT2 recep- binding and dopamine-stimulated adenylate cyclase in the rat tors: involvement of the prepositus hypoglossal nucleus buy discount propranolol 80mg line. Effects of chronic antidepressant drug 1A receptor binding in depression purchase 80mg propranolol with amex. Biol Psychiatry 1999;46: administration and electroconvulsive shock and locus ceruleus 1375–1387 generic 40mg propranolol fast delivery. Prazosin modulates the firing pattern theory of depression [see comments]. Arch Gen Psychiatry 1997; of dopamine neurons in rat ventral tegmental area. Lesioning of serotoninergic the nucleus accumbens may be implicated in the mode of action and noradrenergic nerve fibres of the rat brain does not decrease of antidepressant drugs. Distinct mechanism tral tegmental area increases accumbens dopamine release. Brain for antidepressant activity by blockade of central substance P Res Bull 1989;23:541–547. Suppression of nigrostri- cleus locus ceruleus by substance P and related peptides. Brain atal and mesolimbic dopamine release in vivo following nora- Res 1977;136:178–184. Modulation of the firing freely moving rats as assessed by microdialysis. J Neurochem activity of noradrenergic neurones in the rat locus ceruleus by 1993;60:602–612. Stress-induced C-fos expression in the excitatory amino acids. Induction of burst firing in ventral teg- 1896–1897. Depression as a spreading neuronal adjust- (5-HT)1A receptors: WAY 100,635-reversible actions of the ment disorder. Origin and organization of brain stem in depressed patients and healthy subjects. Arch Gen Psychiatry catecholamine innervation in the rat. Serotonin transporter in the ventral tegmental area of the rat: fine structure and synap- binding sites and mRNA levels in depressed persons committing tic input to dopaminergic neurons. Autoradiographic localization of sub- release in the locus ceruleus on dorsal raphe neuronal activity. Neurokinin innervation of the jection to the rostral raphe nuclei: lesion-induced decrease of rat median raphe nucleus does not originate in the brain stem. Monoaminergic interaction ing the translation of motivational stimuli into adaptive motor in the central nervous system: a morphological analysis in the responses. Comp Biochem Physiol C 1991;98: and neuropsychiatry. Neurochemical and behav- pressant drugs increases the behavioural response to apomor- ioral effects of corticotropin-releasing factor in the ventral teg- phine. Effects of amitripty- enhances behavioural effects of dopamine and d-amphetamine line on serum glutamate and free tryptophan in rats. Eur J Pharmacol 1987; atr Nervenkr 1982;232:391–394. Reduced brain seroto- releasing factor on neuronal activity in the serotonergic dorsal nin transporter availability in major depression as measured by raphe nucleus. Repeated administration of antidepressants single photon emission computed tomography [see comments]. Role of the serotonergic system in the pathogenesis 79. Brain noradrenergic of major depression and suicidal behavior. Neuropsychopharma- receptors in major depression and schizophrenia. Reduced levels characteristics and cerebrospinal fluid amine metabolites of norepinephrine transporters in the locus ceruleus in major in depressed inpatients. Neuropeptides are present in projection doclonidine binding to 2-adrenoceptors in the locus ceruleus neurones at all levels in visceral and taste pathways: from periph- in major depression. Fluoxetine treat- ylase in the locus ceruleus of suicide victims. Clinical effects, drug concentrations and 62:680–685. Limbic-cortical dysregulation: a proposed model locus ceruleus and raphe nuclei.
This suggests that a partial agonist purchase 80 mg propranolol free shipping, demonstrated that 8-OH-DPAT enhanced the antipsy- acting as an antagonist discount propranolol 40 mg online, may sometimes be of benefit with chotic-like effect of the D2/D3 antagonist raclopride (129) regard to effects relevant to schizophrenia order propranolol 80 mg online. The THE ROLE OF SEROTONIN RELEASE IN ability of clozapine to reverse olanzapine-induced catalepsy ANTIPSYCHOTIC DRUG ACTION is blocked by the selective 5-HT1Aantagonist WAY 100635 generic propranolol 80mg line, suggesting the effect of clozapine was mediated by stimula- tion of 5-HT1A receptors buy 40mg propranolol with mastercard. The beneficial effect of 5-HT1A The antagonism of multiple 5-HT receptors by clozapine agonists appears to be mediated by inhibition of median would be expected to enhance the release of 5-HT by feed- raphe serotoninergic neurons (132). Thus, it is surprising that Ferre and Arti-´ 5-HT1A agonists have different regional effects on DA gas (136) reported that clozapine decreased 5-HT release release in the rat brain. Thus, Ichikawa reported that clozapine (20 mg/kg) and risperidone (1 mg/ et al. The effect of 5-HT1A receptor stimu- tracellular 5-HT levels in both regions. If so, this is not the explanation for the effects including clozapine, ziprasidone, quetiapine, and tiospi- of clozapine or olanzapine on negative symptoms because rone, are partial agonist at the 5-HT1A receptor. Their affin- olanzapine, sulpiride, haloperidol, and M100907 had no ities for the 5-HT1A receptor are similar to their affinities effect on extracellular 5-HT levels in either region. The enhance- agonist properties, as it could be blocked by WAY-100635, ment of 5-HT efflux in the prefrontal cortex may contribute a 5-HT1A antagonist. These findings suggest that the 2-AND 1-ADRENERGIC MECHANISMS combination of D2 antagonism and 5-HT1A agonism pro- AND ATYPICAL ANTIPSYCHOTIC DRUGS vides some of the key features of atypical antipsychotic agents. S16924, a 5-HT1A partial agonist D2 antagonist, is an example of a putative atypical antipsychotic drug based Most of the atypical antipsychotic drugs are potent antago- on this model. It has atypical antipsychotic properties very nists of the 1 or 2 adrenoceptors, or both. Thus, risperi- similar to those of clozapine in a variety of relevant animal done 9-hydroxyrisperidone, clozapine, olanzapine, zotep- models (64). Whether this or similar compounds will have ine, quetiapine, ORG-5222, sertindole and ziprasidone are the same spectrum of efficacy and side effect advantages as potent 1 antagonists (22). Prazosin, an 1 adrenoceptor the multireceptor antagonists that are relatively more potent antagonist, has, like clozapine and other atypical antipsy- 5-HT2A than D2 antagonists remains to be determined. It is noteworthy but not the core of the nucleus accumben, signifying a lim- that clozapine has both relatively more potent 5-HT2A an- bic rather than a striatal effect of 1 antagonism (91). These tagonism than D2 antagonism as well as 5-HT1A partial authors also suggested that 1 antagonism may explain the agonism. This may be part of the mixture that accounts for atypical properties of sertindole, which has been reported its particular advantages over other atypical antipsychotic to achieve as high an occupancy of D2 receptors as typical drugs. All of the atypical agents men- 5-HT1A antagonist, attenuated the effect of MK-801, an tioned above are also potent 2 antagonists, with the excep- NMDA antagonist on locomotor activity, prepulse inhibi- tion of zotepine and sertindole (22). They cite other evidence that 5-HT1A an- of clozapine and iloperidone. However, McAllister and Rey tagonists may improve learning and memory in animal (139) were unable to reverse the effects of loxapine or halo- Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 827 peridol on catalepsy with 2 antagonists and showed that the role of 5-HT2A receptors and suggestive evidence of the the effect of clozapine to reverse loxapine-induced increase roles of the 5-HT1A, 5-HT2C, and 1 receptors in various in catalepsy was due to its anticholinergic rather than its actions of clozapine, risperidone, olanzapine, quetiapine, zi- adrenoceptor blocking properties. Clozapine produces mas- prasidone, iloperidone, sertindole, and related atypical anti- sive increases in plasma norepinephrine, which may indicate psychotic drugs. Atypical antipsychotic drugs that are po- that it can cause effective stimulation of -adrenoceptors tent 5-HT2A antagonists relative to their D2 receptor receptors in brain (140). The addition of idazozan, an 2 blocking property appear to potentiate 5-HT1A-mediated antagonist, to fluphenazine, a typical neuroleptic, was re- effects on dopaminergic neurons in the mesocortical, meso- ported by Littman et al. The effects in the mesocor- to clozapine in a small group of neuroleptic-resistant pa- tical regions appear to be mediated by modulation of gluta- tients with schizophrenia. These results need to be repli- mate release from pyramidal neurons. Idazoxan has also been shown to improve attentional been found to preferentially increase DA efflux in the mPFC and executive dysfunction in patients with dementia of the compared to limbic and striatal regions. They also increase frontal type (142), suggesting that some of the cognitive acetylcholine release in the PFC. Effects on 5-HT2C, enhancing effects of the atypical antipsychotic drugs might 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors may also be be related to their blocking properties. Another antag- relevant to some of their actions, e. Other models of atypicality appear performance in aged rats (143). Polymorphisms of the to be effective, including partial DA agonists such as aripi- 1 and receptors have been reported not to predict response prazole. Selective D2/D3 antagonists such as amisulpride 2 to clozapine (144). At this time, multirecep- In this regard, it is of interest that idazoxan has been tor agents appear to be more promising as antipsychotic shown to preferentially increase DA efflux in the rat mPFC agents for the majority of psychiatric patients because of by an action at the terminal area (145). This effect appears important interactions between neural circuits that employ multiple neurotransmitters. This effect was closely coupled to the increase in DA efflux.
Our longitudinal path analysis contained data from three time points: (1) at baseline buy discount propranolol 80mg, including the demographic variables gender discount propranolol 40mg free shipping, baseline BMI SDS cheap propranolol 40 mg with mastercard, school size and school-level deprivation buy 80mg propranolol visa, with direct paths to the outcome variable as well as the baseline scores of the outcome and demographic variables; (2) the 12-month mediating variables; and (3) the 18-month outcome data generic propranolol 40mg without a prescription. The model shows that baseline composite variables predicted scores on these same variables at 12 months, which in turn predicted the outcome variable at 18 months. The intervention versus control variable also predicted the scores on the five composite variables at 12 months. Several of the composite variables were correlated at baseline (guided by modification indices of > 10). The error variances of the mediating variables at 12 months were correlated in an identical pattern to those pairs of mediating variables at baseline. Table 49 shows the goodness-of-fit indices for the two longitudinal path analysis models (with energy-dense snacks and negative food markers as outcome variables). Overall, the model fits were acceptable for both outcome variables, and although the CFI results were slightly below the 0. Path analysis for weekday energy-dense snacks (18 months) Figure 10 presents a diagram of the path analysis for energy-dense snacks. Not shown are the correlations of the variables at baseline, error covariances and non-significant regression weights (dashed lines). TABLE 48 Summary of Pearson correlation coefficient between the outcome variables energy-dense snacks and negative food makers with the mediating variables at 12 months Variable Energy-dense snacks Negative food markers Knowledge –0. TABLE 49 Goodness-of-fit indices for the longitudinal path analysis models with energy-dense snacks and negative food markers at 18 months as outcome variables Goodness-of-fit indices Energy-dense snacks Negative food markers Satorra–Bentler scaled χ2/df 4. B&S, behaviours and strategies; C&M, confidence and motivation; EDS, energy-dense snacks; FAB&CA, family approval/behaviours and child attitudes; NFM, negative food markers; PN, peer norms; SES, socioeconomic status. The following composite variables were significantly (p < 0. All paths shown in the diagram were significant (p < 0. The direct effect of the intervention on energy-dense snacks (18 months) was significant (p = 0. Of these three mediating variables, the effect of family approval/behaviours and child attitudes was the strongest, with a standardised regression weight of –0. 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 97 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. PROCESS EVALUATION Path analysis for weekday negative food markers (18 months) Figure 11 shows the full mediation model with significant standardised regression weights of pathways for weekday negative food markers at 18 months. Not shown are the correlations of the variables at baseline, error covariances and non-significant regression weights (dashed lines). The results for negative food markers were generally similar, with the same variables correlated at baseline and at 12 months. Similar to the results for energy-dense snacks, there were no significant associations between gender and negative food markers (18 months), between school-level deprivation and negative food markers (18 months) and between peer norms and negative food markers (18 months). However, the association between behaviours and strategies and negative food markers (18 months) was significant (p < 0. Additionally, the direct effect of the intervention on negative food markers (18 months) was not significant (p = 0. Gender BMI SDS baseline Number of Year 5 classes School SES NFM baseline Intervention or control NFM 18 months 0. B&S, behaviours and strategies; C&M, confidence and motivation; EDS, energy-dense snacks; FAB&CA, Family approval/behaviours and child attitudes; NFM, negative food markers; PN, peer norms; SES, socioeconomic status. Overall, the effects of the composite mediating variables on the outcome variables were fairly small. The largest association was between family approval/behaviours and child attitudes at 12 months and the outcome variables. For both paths (between family approval/behaviours and child attitudes and energy-dense snacks and between family approval/behaviours and child attitudes and negative food markers), β was –0. Additionally, the results of the behaviours and strategies variable need to be interpreted with caution. As outlined in Appendix 18,this variable was the least psychometrically robust of MLQ variables. The path between behaviours and strategies at 12 months and energy-dense snacks was not significant, but the path between behaviours and strategies at 12 months and negative food markers resulted in a significant change in the opposite direction to those of the other mediating variables. This counterintuitive result is most likely a result of collinearity; as shown in Table 48, behaviours and strategies was negatively correlated with negative food markers. However, in the context of the other MLQ variables, this association became positive (β was 0. Such seemingly paradoxical cases have been described in the literature134 and are most likely due to collinearity with other predictor variables or the operation of suppressor variables. Table 47 shows that behaviours and strategies and confidence and motivation were correlated to an extent (r = 0.
Finally generic propranolol 40mg overnight delivery, CM is not builds on a rapidly evolving field of stroke pharmacother- effective for all patients—for example discount 80mg propranolol fast delivery, 10 of 19 (53%) CM- apy order 80 mg propranolol with amex. Although increasing the value purchase 40mg propranolol mastercard, schedule buy cheap propranolol 80mg online, cocaine administration as a surrogate efficacy assessment. Considering that drug-dependent tient randomized clinical trials, these laboratory settings patients continue illicit drug use despite extremely high im- have been helpful in assessing medical safety during cocaine mediate and longer-term costs, increasing patient internal interactions. Neuroimaging of cerebral blood flowand of Chapter 102: Pathophysiology and Treatment of Cocaine Dependence 1471 'receptor' binding also holds promise for medication devel- dependence: neurobiology and pharmacotherapy. Elevated striatal With all of these pharmacotherapies the behavioral plat- dopamine transporters during acute cocaine abstinence as mea- form for their delivery is critical in retaining the patient in sured by [123I]beta-CIT SPECT. Am J Psychiatry 1998;155(6): treatment and maintaining compliance with the medica- 832–834. As a behavioral disorder, stimulant dependence is 8. Effect of chronic cocaine quite responsive to contingency management using a variety abuse on postsynaptic dopamine receptors. Serotonergic mecha- purchase prosocial goods and services are the most common nisms of cocaine effects in humans. Psychopharmacology 1995; reinforcer used to initiate and maintain stimulant-free ur- 119:179–185. Dopaminergic one-to-one fixed ratio initially, with a progressive increase responsivity during cocaine abstinence. Noradrenergic dys- as longer periods of abstinence are attained. The major regulation during discontinuation of cocaine use in addicts. Arch problem with this approach has been maintaining absti- Gen Psychiatry 1994;51:713–719. The pharmacology of cocaine developing a mechanism to obtain these types of reinforcers related to its abuse. A more typical time limited between dopamine transporter protein alleles and cocaine- therapy for clinical programs is cognitive behavioral therapy. Neuropsychopharmacology 1994;11(3): Cognitive behavioral therapies have been examined in con- 195–200. Elevated central pressants, and have shown interesting additive effects (32). Am J Psychiatry 2000;157: For example, at 1-year follow-up after a 3-month treatment 1134–1140. Regional cerebral and the cognitive therapy showed more sustained abstinence blood flowimproves with treatment in chronic cocaine polydrug than those who got either therapy alone. Pharmacotherapy of cerebral ischemia in cocaine treatments may also be most useful for abstinence initiation, dependence. Cerebral blood flow havioral therapy approaches (32). Overall, the long-term in chronic cocaine users: a study with positron emission tomog- outcome at 1 year is substantially enhanced by the use of raphy. Selective inhibition of cocaine seeking behavior by a partial dopamine D3 receptor agonist. Proc Coll Prob Drug Depend This work was supported by the National Institute on Drug 2000;60(Suppl. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Clinical management of acute and chronic cocaine poisoning. National Survey Results on iant of the neuroleptic malignant syndrome? Am J Drug Alcohol Drug Use from Monitoring the Future Survey. In: Bloom FE, Kupfer In: Lowinson JH, Ruiz P, Millman RB, et al. Psychopharmacology: the fourth generation of progress. Baltimore: Williams & NewYork: Raven Press, 1995:1685–1697. N Engl J Med 1988;318(18): and subject effects of intravenous cocaine administration in hu- 1173–1181. Ethical and practical issues in- in the treatment of cocaine addiction. J Clin Pharmacol 1991; volved in behavioral pharmacology research that administers 11:374–378.