Propafenone effect): 12 months procyclidine 5 mg for sale, 24 months generic procyclidine 5mg overnight delivery, mean monthly progression Recurrence of AF: 2 years order procyclidine 5mg free shipping, and monthly rate Composite (Maintenance of SR and Free of adverse drug effects): 1 year, 2 years 230 Roy, 2000 403 Amiodarone vs. AF hospitalization: 12 months, Sotalol/Propafenone All-cause mortality: mean Control of AF symptoms: 3 months Recurrence of AF at mean followup of 468 days, and time to event Quality of life Stroke 245 Bellandi, 2001 300 Sotalol vs. Propafenone Maintenance of SR: 1 year Recurrence of AF: 12 months, mean time 269 Plewan, 2001 128 Sotalol vs. Bisoprolol Maintenance of SR: 12 months Recurrence of AF: 12 months, mean days to recurrence, monthly rate of recurrence Anonymous, 256 Amiodarone vs. Sotalol All-cause mortality: 5 years 241 2003 Arrhythmic deaths: 5 years Maintenance of SR: 5years Recurrence (prevalence) of AF: 4 months, 1 year 249 De Simone, 2003 324 Amiodarone vs. Flecainide AF-free survival at 90 days (amiodarone/flecainide vs. Flecainide Recurrence of AF: 3 months with Verapamil Maintenance of SR: 3 months 256 Katritsis, 2003 90 Carvedilol vs. Bisoprolol Recurrence of AF: 1 year Kochiadakis, 254 Sotalol vs. Propafenone Composite (Recurrence of AF or Adverse drug 258 2004 effect): 12 months, mean monthly progression; Composite (Maintenance of SR and Free of adverse drug effects): 30 months Kochiadakis, 146 Amiodarone vs. Composite (Recurrence or Adverse drug effect): 259 2004 Propafenone 12 months, 24 months, mean monthly progression Recurrence of AF Composite (Maintenance of SR and Free of adverse drug effects): 1 year, 2 years 180 Singh, 2005 665 Amiodarone vs. Sotalol All-cause mortality at last followup Stroke (per 100 person years) Recurrence of AF: 1 year, median days to recurrence Quality of life Vijayalakshmi, 94 Amiodarone vs. Sotalol All-cause mortality: 6 months 181 2006 Maintenance of SR: 1. Composite (Recurrence or Adverse drug effect), Dronedarone time to event Recurrence of AF: 12 months after conversion to SR All-cause mortality Abbreviations: AF=atrial fibrillation; N=number of participants; SR=sinus rhythm 83 Maintenance of Sinus Rhythm Nine studies comparing primarily pharmacological interventions reported this 181,241,245,249,258-261,269 181,241,260,261 outcome. Four studies compared amiodarone with sotalol, two of which reported a composite outcome of maintenance of sinus rhythm without adverse effects 260,261 from medication. In all four studies maintenance of sinus rhythm was greater with amiodarone than with sotalol, but the differences were statistically significant only in some studies and at some of the assessed time points (see Table 16). One of these studies showed no significant difference in the rate of this 245 outcome, while the other two found that the propafenone groups had rates of maintenance of sinus rhythm that were almost twice that of the sotalol groups, although statistical analyses 258,261 comparing the groups were not reported. Two studies compared amiodarone with propafenone and evaluated a composite outcome of 259,261 maintenance of sinus rhythm free from adverse effects from medication. In both studies, at 1 year amiodarone was better than propafenone for this outcome, but at 2 years propafenone was better. In both studies, investigators described the rate of recurrence of AF as being constant throughout followup for amiodarone, but they described the rate of recurrence of AF on propafenone as being high early on during therapy and then decreasing over time. One study compared bisoprolol with sotalol and found no significant difference in the rate of 269 maintenance of sinus rhythm. The final study found that the addition of verapamil to treatment with either amiodarone or flecainide increased the rate of AF-free survival compared with 249 treatment with either antiarrhythmic agent alone. These studies suggest that amiodarone appears to be better sotalol but no different from propafenone, but given the diversity in comparisons and the imprecision of the findings, the strength of evidence was considered low. Studies assessing maintenance of sinus rhythm with or without adverse effects Study Sample Time Point Results P-Value Size (N) a Kochiadakis, 214 1 year Amiodarone: 70. Studies assessing maintenance of sinus rhythm with or without adverse effects (continued) Study Sample Time Point Results P-Value Size (N) a Kochiadakis, 254 30 months Propafenone: 47% NR 258 2004 Sotalol: 25% a Kochiadakis, 146 12 months Amiodarone: 72% NR 259 2004 Propafenone: 56% a 24 months Amiodarone: 42% NR Propafenone: 51% Vijayalakshmi, 94 1. Abbreviations: AE=adverse event; CI=confidence interval; HR=hazard ratio; N=number of participants; NR=not reported Recurrence of AF Ten studies comparing primarily pharmacological interventions for AF included recurrence 180,224,230,241,245,249,256,259,261,269 (or prevalence) of AF as an outcome (Table 17). Three of these 180,241,261 studies compared amiodarone with sotalol. Of these three studies, one showed no 241 statistically significant difference between treatment arms at 4 months or 1 year; however, the other two studies reported a higher rate of recurrence of AF among those on sotalol compared with amiodarone—68 percent versus 33 percent at 2 years of followup in one study (no statistical 261 180 test reported), and 68 percent versus 48 percent at 1 year in the other study (p=0. The rate of recurrence of AF for sotalol versus propafenone was not statistically significantly different in 1 study at 12 months 245 (23% vs. Another study reported a higher rate with sotalol than with 261 propafenone at 2 years (68% vs. Two studies compared the effects of amiodarone versus propafenone; one found a 261 statistically significantly higher monthly rate of recurrence with propafenone; the other found 259 no significant difference in recurrence between the two drugs. In line with the results of these two studies, another study evaluated the risk of recurrence of AF for amiodarone compared with either sotalol or propafenone over approximately 1 year and found a significantly lower risk 230 among those on amiodarone, with a hazard ratio (HR) of 0. One compared amiodarone versus flecainide, with and without verapamil added to either treatment. The rate of recurrence of AF did not differ at 3 months between amiodarone and flecainide (no statistical test reported). The addition of verapamil to flecainide reduced the rate of recurrence significantly compared with flecainide alone (21% vs. One study compared amiodarone with dronedarone and found a higher rate of recurrence with 224 dronedarone, but the statistical analysis was not reported. Finally, two studies compared the beta-blocker bisoprolol with either another beta-blocker or 256,269 an antiarrhythmic agent. One study showed no significant difference between rates of 256 recurrence at 1 year between bisoprolol and carvedilol; the other showed no significant 269 difference between rates of recurrence of AF with bisoprolol versus sotalol. These findings suggest that amiodarone appears to be better than dronedarone or sotalol, but no different from propafenone (low strength of evidence). Studies assessing recurrence of AF Study Sample Time Point Results P-Value Size (N) Kochiadakis, 214 2 years Amiodarone: 33. Amiodarone + Verapamil: 20% Amiodarone + Flecainide + Verapamil: 21% Verapamil) p=0. Flecainide + Verapamil) 256 Katritsis, 2003 90 12 months Bisoprolol: 46% p=0. Three of the studies compared amiodarone with sotalol, and statistical comparisons were either not performed or treatments were not found to be statistically significantly 180,181,241 different. In one study, amiodarone was compared with sotalol or propafenone and no 230 statistical analyses were done. In another study amiodarone was compared with dronedarone 224 but no statistical analyses were done Differences in followup, comparisons, and findings resulted in insufficient strength of evidence for this outcome. Studies reporting all-cause mortality as an outcome Study Sample Time Point Results P-Value Size (N) 230 Roy, 2000 403 Mean followup 468 days Amiodarone: 4% NR Sotalol or propafenone: 4% Anonymous, 256 5 years (mean followup 3. Three studies compared amiodarone with sotalol and found no difference between these 180,241,260 treatment arms. In one study, there was no statistically significant difference in 241 arrhythmic death between those receiving amiodarone vs. Another study reported 2 percent of patients in the amiodarone group had sudden death and 3 180 percent in the sotalol group (no statistical test reported), while the third study reported no 260 deaths in either treatment arm due to proarrhythmia or sudden death. In the study comparing amiodarone with either sotalol or propafenone, 1. There was a low strength of evidence rating for there being no difference between evaluated pharmacological agents. CV Hospitalizations 230 No studies reported generally on CV hospitalizations. One study compared the proportion of patients with AF hospitalizations between amiodarone and either sotalol or propafenone. The rate of AF hospitalization was lower with amiodarone than with sotalol or propafenone (14% vs. In addition, the mean number of days to AF hospitalization was lower with amiodarone than with sotalol/propafenone (0. Control of AF symptoms 230 One study assessed control of AF symptoms using the Atrial Fibrillation Severity Scale (AFSS) and found no statistically significant difference in mean scores between amiodarone versus sotalol or propafenone arms (12. Quality of Life 180,230 Two studies reported outcomes related to quality of life. One study comparing amiodarone with sotalol found no significant changes in quality-of-life scores for any treatment group during the 1 year of followup except for a significant decrease in the mental health score 180 for patients on amiodarone, which differed significantly from those on sotalol (p=0. The 230 other study compared treatment with amiodarone versus treatment with either sotalol or 230 propafenone and found that all quality-of-life measures improved during 3 months of followup, but these improvements did not differ by treatment arm (low strength of evidence).

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Latent variable modeling high school interventions: community action to reduce adoles- of longitudinal and multilevel alcohol use data generic procyclidine 5mg without a prescription. Clusters of marijuana use in the misuse: the impact of refusal skills and norms generic 5mg procyclidine amex. Treatment and prevention of use and experience with cocaine: do they cluster within U order 5 mg procyclidine otc. Introduction: commu- New York: Oxford University Press, 1998. Policy options for prevention: the and environmental contributions. Br J Psy- tobacco control: a review of smoking prevention and control chiatry 2001;178(Suppl 40): S8–S11. Socioeconomic efficacy of interventions for the primary prevention of alcohol status and psychiatric disorders: the causation–selection issue. Addicted patients describe the craving as a power- ent scales. For example, craving may be reported in associa- ful, 'must-have' pull that causes them to risk, and some- tion with cocaine cessation (3), but also in association with times lose, their relationships, families, money, possessions, cocaine administration (4) and cues signaling cocaine (5,6). Interest- greatly needed, but despite intensive research efforts since ingly, changes in the mesolimbic dopamine (DA) systems the mid-1980s, such agents have remained elusive (1,2). Diversity in possible (tonic) decrease in mesolimbic (nucleus accum- measurement may well account for some of the variability bens) DA has been proposed in the case of cessation/func- in the data collected, as described below. In part, the prob- tional depletion (7–9), whereas an (episodic) increase in DA lem is our nascent understanding of which brain substrate(s) has been hypothesized in the case of cocaine administration an 'anticraving' medication should address. Until recently, (10) and response to cocaine cues (11,12). Of course, these the activity of the brain during cocaine craving was a matter differing DA-related states are not mutually exclusive and of inference rather than direct observations. The increased may interact in important ways; for example, a dose of co- availability of powerful tools for brain imaging in vivo has caine or a cocaine-related cue may have a different brain thrust research on drug craving forward into a new era. The possible during cocaine-craving states directly. If the same brain substrates are responsible for the craving associated IS THERE MORE THAN ONE KIND OF with DA deficiency and the craving associated with DA COCAINE CRAVING? We will return to this ques- Despite sophisticated tools for brain imaging, the study of tion after a review of the neuroimaging evidence for craving cocaine craving is complicated by the fact that desire for across the conditions. Neurotransmitter systems other than DA are likely to be involved in cocaine reward and motivation (13,14). Acton, and example, serotonin (15,16), glutamate (17), corticosteroids Charles P. However, in the neu- 1576 Neuropsychopharmacology: The Fifth Generation of Progress roimaging of cocaine craving, many of the studies have used Data a DA-related framework for their hypotheses, interpreta- The results of several neuroimaging studies are consistent tions, or both. The emphasis on a dopaminergic system with the notion of DA dysregulation in cocaine cessation; reflects not only a long literature on DA involvement in we review here the studies that have also included craving stimulant reward and motivation (23–25) but also the avail- measures. Imaging studies testing the role of other neurotransmitters and neuromodulators in cocaine craving will be a welcome Early Cessation (1 Week or Less post Cocaine) addition to the field. The only currently available study in this category is included in the current review (27). In this patients in early cessation viewing cocaine cues), this is study, craving ('none,' 'mild,' 'moderate,' or 'severe') noted, as it may be helpful in the final integration of craving during the week before the scan was positively correlated results across studies and paradigms. DAT increases of tion of mood, motivation, thought, and concentration. An inverse relationship was noted between DAT surements in long-term users (or laboratory animals main- level and depression scores, but no relationship of DAT tained on cocaine) have revealed differences from controls, level to craving scores (on the Cocaine Craving Scale) was such as reduced DA synthesis (30), reduced cocaine uptake found (3). Long-term cocaine use can alter -opioid binding (34–36), DA transporters (DATs) in the long-term user of cocaine which indicates an interaction of DA and endogenous opi- may also be dysregulated, although the direction of observed oid systems. Given the role of endogenous opioids in mood change varies across studies (35,37–40), potentially reflect- modulation, up-regulated -opioid receptors may contrib- ing the oscillating nature of re-regulation (see also refs. These studies have found alterations in accumbens DA in cocaine patients at 1 to 4 days, and then at 4 weeks post levels (7), the threshold for rewarding brain self-stimulation cocaine. In comparison with controls, the cocaine patients (42), the metabolism of reward-relevant regions (43), DA showed up-regulation of -opioid receptors in the caudate, synthesis (44), and postsynaptic DA receptors (44). Thus, thalamus, anterior cingulate, frontal, and temporal brain on cocaine cessation, the DA systems of some cocaine users regions; these changes persisted for 4 weeks in all but the may be in a neurologically adapted, dysregulated state. On the early cessation scan, craving (Min- lowered mood, energy, and concentration experienced by nesota Craving Scale on the prior evening, 100-mm visual some cocaine patients during abstinence may be related, at analogue scale just before the PET, or both) was positively least in part, to a dysfunction in brain DA systems. Accord- correlated with -opioid binding in the amygdala and the ing to this general view, the craving that arises during absti- anterior cingulate, frontal, and temporal cortex. These four nence may also reflect DA system dysregulation (8). Do regions all receive significant DA projections, consistent neuroimaging studies support this hypothesis? Scores on the Beck Depres- Chapter 110: Neuroimaging of Cocaine Craving States 1577 sion Inventory did not correlate with -opioid-receptor lism and rCBF) in DA projection areas, such findings would availability, which indicates that the early cessation craving have implications for both theory and treatment. None of the correlations ple, if low DA tone is not associated with craving, then of craving with -opioid binding were significant for the enhancing DA activity might not help craving, and could later, 4-week scan. Even if unrelated to craving, the differences between co- caine patients and controls that are evident at both early Later Cessation and later time points (e. They may reflect other weeks, and again at 3 to 4 months post cocaine), neuroimag- functional consequences of cocaine use, or group differences ing studies from the laboratory of Volkow et al. The latter possibility has received very recent cocaine users in comparison with that in controls. In a further study of the related to D2-receptor availability. The D2-receptor levels same patient sample, reductions in orbitofrontal cortex and for normal subjects who liked methylphenidate were signifi- cingulate metabolism were particularly profound, and these cantly lower than those for normal subjects who did not reductions were correlated with reductions in (striatal) DA like the drug, and they were strikingly similar to those of D2-receptor availability (33). However, craving (on a scale long-term cocaine users in earlier studies by the same inves- of 0 to 10) during the week of the study did not correlate tigators (51). Reduced D2 receptors may thus be a marker with striatal D2-receptor availability; correlations of craving for vulnerability to stimulant misuse in addition to, or per- with metabolic rates were not reported. Paralleling the metabolic findings of Volkow, Childress et al. However, neither baseline cocaine crav- Administering cocaine in the laboratory is a reliable and ing nor withdrawal (self-rated on a scale of 0 to 9) at the robust trigger of cocaine desire (4), and cocaine users com- time of the scan correlated with rCBF in these regions. Almost two decades ago, Eikelboom and Stew- art (52) modeled this behavior in rats, showing that small The neuroimaging data clearly show a number of differences drug 'primes' could motivate drug seeking and reinstate between the brains of cocaine patients undergoing cessation extinguished responding for drug. According to the priming in comparison with controls not using drugs. The observed hypothesis, the initial drug effect always precedes the full differences often are clearly linked to brain DA systems. The state has powerful positive tion craving' has been variable. At this time, correlative incentive properties, 'pulling' the organism back to the evidence from studies in early ( 1 week) cessation, but not drug. In this 'opponent frontal and prefrontal cortex metabolism, -opioid process' view, the brain responds to cocaine with homeo- binding). The opponent re- often conducted in separate populations, and with impor- sponse (i. Clinically, patients do complain about the jittery offset must be drawn with caution. Powerful within-subject de- of the cocaine high, and they recognize that taking another signs, including frequent scans and subjective measures dose of the drug will alleviate this state. If such istration more closely related to a brain state that occurs at longitudinal studies were to confirm a lack of a relationship the onset or at the offset of the drug response? Although the between craving and later resting hypoactivity (by metabo- question is posed as a choice, these possibilities (unfortu- 1578 Neuropsychopharmacology: The Fifth Generation of Progress nately for the task of developing medications) are not mu- anterior cingulate). Signal change in the amygdala during tually exclusive. Craving of the positive, appetitive, cocaine administration was initially reported as heterogene- 'primed' variety may map onto brain responses associated ous (some patients showed increases and others showed de- with the initial effect of the drug and be followed shortly creases), not correlated with rush, and negatively correlated thereafter by the dysphoric craving of offset, which may with craving ratings. However, in a follow-up study with map onto a later set of brain responses that are opposite in cardiac gating of the fMRI signal (see below), the direction direction to those of drug. The exquisite temporal sensitivity of signal change in amygdala was positive for all subjects.

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Al- Glutamatergic Models though they also increase dopamine neurotransmission in Dysfunctional glutamate neurotransmission has been impli- limbic regions (82) cheap procyclidine 5 mg fast delivery, their motor-activating effects appear to cated in schizophrenia discount 5mg procyclidine otc, primarily because noncompetitive be dopamine-independent (83) purchase procyclidine 5mg fast delivery. At rather low doses, PCP antagonists of the NMDA subtype of glutamate receptors, retards habituation of the startle response without affecting including PCP and ketamine, produce a behavioral syn- startle reactivity (84), a pattern similar to that seen in paral- drome in healthy humans that closely resembles symptoms lel studies in schizophrenic patients (9). Also as in schizo- of schizophrenia and is frequently misdiagnosed as acute phrenia, PCP-treated rats exhibit marked deficits in social schizophrenia (77,78). Although typical antipsychotics have no reliable symptoms, such as paranoia, agitation, and auditory halluci- effect on the PCP-induced disturbance in social behavior nations; negative symptoms, such as apathy, poverty of in rats, the atypical antipsychotics clozapine, sertindole, and thought, and social withdrawal; and cognitive deficits, such olanzapine appear to reverse the effects partially (22). The remarka- terms of sensorimotor gating measures, PPI is reduced or ble similarity of PCP-precipitated behaviors with the diverse eliminated in rats by psychotomimetic noncompetitive array of symptoms associated with schizophrenia has NMDA antagonists, including PCP, dizocilpine (MK-801), prompted the use of PCP (and its analogue ketamine) in and ketamine (14,15). As with apomorphine and as in schiz- pharmacologic models of schizophrenia in both basic and ophrenia, both intramodal and cross-modal PPI is sensitive clinical studies. Notably, whereas psychotic episodes are to noncompetitive NMDA antagonists (59). In contrast to 696 Neuropsychopharmacology: The Fifth Generation of Progress the effects of dopamine agonists on PPI, but in keeping with Isolation rearing of rats has also been used as a manipula- the results of studies of the subjective effects of ketamine in tion to generate models related to schizophrenia and models humans, the PPI-disruptive effects of NMDA antagonists of depression and attention-deficit/hyperactivity disorder are not reversed by typical antipsychotics such as haloperidol (ADHD). In the context of schizophrenia, the focus has or selective D1 or D2 antagonists. Importantly, these effects been on the disruptions of PPI rather than the locomotor are reversed by the atypical antipsychotics clozapine, olan- hyperactivity observed in isolation-reared rats. Indeed, com- zapine, quetiapine, and remoxipride (14,15). These findings parisons among different strains of rats indicate that both raise the possibility that the PCP-induced disruption of PPI effects are strain-dependent but appear in different strains may be a useful model for identifying compounds with atyp- (91–93). Thus, as with a variety of pharmacologic manipu- ical antipsychotic potential. Although this model lacks some of the impor- to exhibit a neuroleptic-reversible deficiency in PPI in com- tant characteristics of acute models, such as lack of an effect parison with group-reared controls (91,94). This effect of on PPI, it produces an enduring cognitive impairment that isolation rearing appears to be specific to development; simi- is highly relevant to schizophrenic symptomatology. Furthermore, as in the most common form of schizophrenia, the PPI deficits DEVELOPMENTAL MODELS are not evident before puberty but emerge at about that time (96). Converging evidence for an influence of isolation The best-characterized animal model in this class is that rearing on gating mechanisms in adulthood stem from the proposed by Lipska and Weinberger (86,87), which involves observation that the rat analogue of the P50 sensory gating neonatal excitotoxic lesions of the ventral hippocampus. Because these deficits in PPI and P50 gating are not such as increased spontaneous, amphetamine-induced, and associated with concomitant deficits in latent inhibition NMDA antagonist-induced locomotion. They also produce (95), which occurs only in acutely ill schizophrenic patients potentiated apomorphine-induced stereotypies, disruption (19), it would appear that the isolation-rearing model is of PPI, reduced cataleptic response to haloperidol, impaired more relevant to chronic than to acute schizophrenia. In working memory, and hypersensitivity to stressful stimuli. Thus, PPI deficits in isolation-reared rats may be a 1 (EAAT1) and glutamic acid decarboxylase (GAD67). To valuable paradigm that—like the apomorphine-induced the limited extent that they have been tested, dopamine disruption of PPI—is sensitive, but not specific, in its ability antagonists, including classic and atypical antipsychotic to identify compounds with atypical antipsychotic proper- drugs, ameliorate the behavioral abnormalities produced by ties. The potential advantage of the isolation-rearing model, neonatal ventral hippocampal lesions. It will be important as of other models involving developmental perturbations, in the future to examine the predictive power of this model is that it does not rely on the administration of a drug or for the identification of antipsychotic drugs more thor- the introduction of an artificial lesion to produce the behav- oughly with measures that are not sensitive to the effects ior of interest. When the behavior studied in the model is of antipsychotic drugs in sham-lesioned rats. Indeed, most of the animal models of nine, a nitric oxide synthase inhibitor that disrupts neuronal schizophrenia have relied on dopaminergic psychostimu- maturation (89), or the antimitotic agent methyazoxymeth- lants and have proved to be largely limited to the detection anol (54,90). These models produce morphologic changes of dopamine antagonists. The major message of the fact relevant to schizophrenia, such as altered neurogenesis and that clozapine is effective, even at doses that achieve low reduced cortical volume. They also produce some of the levels of dopamine receptor occupancy, is that new treat- behavioral characteristics associated with schizophrenia, ments can be identified for patients with schizophrenia, and such as stereotypy, cognitive impairments, and deficits in that these novel treatments may not involve dopamine an- PPI. As yet, the predictive validity of this model in terms tagonism. The isolation-rearing manipulation presumably of sensitivity to antipsychotic treatments remains to be de- produces a deficit in PPI by virtue of a substantial reorgani- termined. Chapter 50: Animal Models Relevant to Schizophrenia Disorders 697 Hence, such a model has the potential to identify completely receptor transduction) are associated with substrates that novel antipsychotic treatments simply because it does not regulate both PPI and latent inhibition, which are transmit- require the administration of a drug. In another approach, comparisons of several inbred strains of rats identified some strains that exhibit deficits in PPI (103). Because these strains did not exhibit GENETIC MODELS hearing impairments, the genetically determined deficit in PPI likely represents a deficit in sensorimotor gating pro- Genetic contributions to schizophrenia have been clearly cesses. Although the focus of consid- erable research, the application of linkage analyses to schizo- GeneticallyModified Animals phrenia has not generally proved successful, perhaps because schizophrenia does not represent a single phenotype. Never- Other examples of nonpharmacologically based models rele- theless, it remains possible that genetic approaches will lead vant to schizophrenia are emerging from the field of molecu- to etiologically based models lar biology, in which genetic engineering is being used to generate transgenic and knockout animals. In the absence of established candidate genes, the use of mutant animals Strain Differences in models of schizophrenia has focused on the identification Genetic factors appear to be critical determinants of both of phenotypic differences in behaviors considered relevant sensory and sensorimotor gating in rats. For example, schizophrenia-like deficits in PPI of of the P50 gating deficit seen in schizophrenia. Indeed, a startle have been observed in specific strains of mice (104) linkage between the P50 gating deficit in patients with and in 'knockout' mice in which specific genes have been schizophrenia and a specific chromosomal marker associated deleted (105). The focus of genetic engineering in the with the gene for the 7 subunit of the nicotinic acetylcho- mouse is beginning to prompt extensions of pharmacologic line receptor has been demonstrated in a series of elegant studies from the rat to the mouse. The potential power of cross-species studies of such work is needed, it is already abundantly clear that specific behavioral abnormalities in psychiatric disorders is species differences in pharmacologic effects between mice exemplified by the parallel between these human linkage and rats will complicate the application of some schizophre- studies and the observation that the strain of mice that is nia-related rat models to mice. For example, in rats, antipsy- most deficient in gating of the N40 event-related potential chotic drugs by themselves have minimal effects on PPI, in is also the most deficient in 7-nicotinic receptors (17). Hence, rat PPI an exemplar for the application of modern molecular bio- models can identify antipsychotic effects only if a drug re- logical techniques to the generation and validation of animal verses the effects of a disruption in PPI produced by another models of psychiatric disorders. However, this genetically drug, a lesion, or a developmental manipulation such as related deficit in sensory gating does not extend to studies isolation rearing. In mice, however, it appears that antipsy- of sensorimotor gating as measured by PPI of the startle chotics improve PPI in mice that have not been manipulated response. Thus, mice in which the 7-nicotinic receptors (106). This important difference means that it may be easier have been deleted by genetic engineering exhibit normal to detect antipsychotic effects in mice, but also that it will levels of PPI (99). Nevertheless, other evidence indicates be much more difficult to demonstrate a reversal of a PPI that PPI is regulated by genetic factors. For example, strain- deficit produced by an experimental manipulation. More relevant to the recent indi- date gene approach, genetically modified mice have been cations that PPI deficits are evident in family members of used to test specific hypotheses of relevance to animal schizophrenia patients (101), Ellenbroek et al. For example, although most phar- pharmacogenetic selective breeding to produce strains of macologic evidence in rat had implicated the D2 subtype rats that were either sensitive (APO-SUS) or insensitive of the family of dopamine receptors in the PPI-disruptive (APO-UNSUS) to the effects of apomorphine on gnawing effects of dopamine agonists, gene knockout mice proved behavior. Within either a single generation or after many useful in testing this conclusion more definitively. Ralph et generations of selective breeding, APO-SUS rats and their al. Only the mice lacking the D2 subtype of logic substrates that regulate behavioral sensitivity to apo- receptor failed to show the normal effect of amphetamine morphine (presumably some feature related to dopamine- on PPI. Although knockout manipulations are confounded 698 Neuropsychopharmacology: The Fifth Generation of Progress by developmental adaptations, such a study takes advantage cal Center (MG); and the Veterans Administration National of the specificity that represents the fundamental strength Center for Schizophrenia (BM). Another model with relevance to the etiology and patho- 1. Psychopharmacology: the fourth 1 1 generation of progress. Prog Brain display exaggerated spontaneous locomotion and stereotypy Res 1986;65:259–270. In: estingly, preliminary studies indicate that some of these be- Judd LL, Groves PM, eds. Psychobiological foundations of clinical havioral abnormalities may be ameliorated with a single dose psychiatry. Stimulants: neurochemical, behavioral, and clinical per- of haloperidol or clozapine.

There is no single stan- dard set of sleep hygiene recommendations; a sample of Lie down intending to go to bed only when you are sleepy generic 5 mg procyclidine visa. Do not watch commonly reported elements is included in Table 133 cheap 5mg procyclidine otc. Get out of bed if you cannot fall asleep or go back to sleep within 10–15 minutes; return to bed only when you feel sleepy trusted procyclidine 5mg. Stimulus Control Therapy If you still cannot fall asleep, repeat the processing step as often Stimulus control techniques (36) are based on the premise as is necessary during the night. Set your alarm and maintain a regular arising time in the morning, that insomnia is exacerbated or maintained by a maladaptive irrespective of how much sleep you got during the night. Whatever the initial cause of the insomnia, when Adapted from refs. Chapter 133: Current and Experimental Therapeutics of Insomnia 1935 Sleep Restriction Therapy sense for some of the approaches to be combined, such as stimulus control and sleep restriction. The change in behav- Patients with insomnia often try to compensate for lost sleep ior advocated and the net result of each are similar, although by getting into bed early or remaining in bed after awaken- the rationales are different. Many individuals assume that bed rest can be accomplished with cognitive restructuring,can be may be restorative, even if no sleep is achieved. Unfortu- helpful for successful completion of any behavioral or cogni- nately, the excess time in bed results in increased wakeful- tive treatment. Effective, circumscribed, multicomponent ness in bed, which causes more frustration about difficulty therapies, such as that developed by Morin (39) combine sleeping and leads to even more pronounced insomnia. In- several different treatment approaches within a limited creased time awake in bed can thus contribute to condi- number of treatment sessions to treat insomnia. The treatments are integrated in a later session, and bed. Unlike stimulus control, sleep restriction addresses relapse prevention is addressed, promoting an overall focus only the amount of time one spends in bed, rather than how on self-efficacy. From the existing literature, it is not clear the time in or out of bed is spent. This approach involves an that such combined approaches are more effective than the initial curtailment of time in bed to the amount of time most effective of the individual techniques (e. Average sleep efficiency, which may have the added benefit of treating a broader range of represents the proportion of time in bed spent asleep, is patients without having to individualize treatment. After sleep efficiency reaches desired levels (typically 90%), time allowed in bed can be increased by increments of 15 minutes until desired total Other Nonpharmacologic Treatments sleep time at night is reached. If sleep efficiency remains Phototherapy low ( 80%), after the initial restriction, time in bed is further curtailed by 15-minute increments until sleep conti- As noted, insomnia associated with circadian rhythm sleep nuity improves sufficiently. Time in bed is not changed if disorders results from problems related to the timing of sleep efficiency is between 80% and 90%. Because light is the most potent zeitgeber, or time cue, for the circadian timing system, pho- totherapy can be used as part of a treatment regimen to Relaxation and Biofeedback Therapies adjust the timing of the sleep/wake cycle and address a corre- sponding complaint of insomnia and/or sleepiness. Relaxation techniques target the cognitive or physiologic Exposure to bright light shifts circadian phase in a time- arousal that interferes with sleep, as discussed. In general, bright light in the early relaxation therapies have been used for insomnia, including morning hours shifts sleep and circadian rhythms to an ear- progressive muscle relaxation and biofeedback to diminish lier time (i. Phototherapy can be deliv- ation treatments may be most useful for sleep onset insom- ered through artificial light, or by exposure to diffuse natural nia. In general, the magnitude of improvement seen with outdoor light. Artificial bright light has been shown to im- relaxation is smaller than for other behavioral approaches prove sleep maintenance insomnia in older adults (41) and (37). These phototherapy in the treatment of sleep disorders, including dysfunctional beliefs can cause emotional arousal and exac- recommendations for light intensity and duration (43). Cognitive restructuring has been used to help patients question the validity of auto- Exercise matic, maladaptive thoughts and reformulate them to make them more realistic and adaptive. The effects of exercise on sleep have been reviewed elsewhere Many cognitive and behavioral techniques share com- (35,44). Exercise can increase sleep quality and slow-wave mon elements, and they are increasingly being used together sleep, and reduce sleep latency in some individuals, includ- within multimodal treatment protocols. In summary, these agents bind at a proximity to bedtime, or by individuals who are unaccus- specific recognition site in the benzodiazepine- aminobu- tomed to such exercise, can cause arousal. In particu- specifically zolpidem, may be relatively more specific for lar, a rise in core body temperature with exercise may be hypnotic effects relative to anticonvulsant and anxiolytic followed by an exaggerated temperature decline during early effects; this may be related to greater specificity for benzodi- sleep. This temperature decline may promote slow-wave azepine type I receptors. Finally, these during the early evening also increases slow-wave sleep in agents differ in terms of active metabolites, which may have both young and older individuals, and improves sleep conti- longer half-lives than the parent compound. For each of these outcomes, the effect size d ranged between. For instance, treatment with zopiclone for both 14 days and 8 weeks of treatment was associated Several medication classes are used for the treatment of in- with greater improvements in quality of life measures, social somnia, although the strength of evidence regarding their activities, and professional activities compared to placebo efficacy and tolerability varies considerably. In particular, For instance, zaleplon, with its very short half-life, has not prescriptions for trazodone increased sixfold. Some patients clearly developed tolerance studies failing to show such improvement (72). In particu- studies show continued efficacy over several nights of con- lar, risk seems to be increased with the use of long-acting tinued nightly administration. For instance, triazolam, zol- agents, high doses, multiple agents, and cognitive impair- pidem, and zaleplon have shown continued efficacy over a ment in patients (73,74). Data regarding automobile crashes period of 4 to 5 weeks in double-blind, placebo-controlled are somewhat mixed. Other studies have shown risk associated with stance, double-blind studies have shown continued efficacy long half-life drugs and recent initiation of treatment, but for up to 24 weeks with no evidence of tolerance according not with longer-term treatment (76). In fact, examination of two specific benzo- common of these is a continuation of their desired therapeu- diazepine agents in this cohort did not show an elevated tic effect, sedation during the daytime. The behavioral aspect of taking a pill may contribute of the drug is more controversial, with some studies noting to rebound insomnia. Venlafaxine Cognitive and behavioral treatments can help patients dis- Trazodone, to to ↑ continue chronic benzodiazepine use (83). Recurrence is another potential discontinuance syndrome ↑, Increase. Although data are difficult to obtain, Studies with small numbers of subjects and diverse inclu- benzodiazepines may be used by. A over time as well as a tendency to intermittent rather than more recent 2-week double-blind placebo-controlled study consistent dosing (86). This study showed improvements in subjective sleep latency and sleep duration with both active drugs, although there was some evidence for superiority of zolpidem during Antidepressant Drugs the second treatment week. Finally, somnia include trazodone, tertiary tricyclic agents, and mir- a recent open-label trial of paroxetine for primary insomnia tazapine. These drugs clearly have diverse effects on neuro- in the elderly showed significant improvement in a multi- transmission, as reviewed in Chapter 79. In general, the variate measure of sleep quantity based on both diary and sedating properties of antidepressants are related to antago- polysomnographic sleep measures (96). For instance, fluvoxamine the treatment of insomnia. Some antidepressant drugs also has a relatively alerting effect relative to desipramine that can cause or exacerbate insomnia problems. Selective seroto- in turn is more alerting than amitriptyline (97,98). In addition, serotonergic specific antide- comparison of fluoxetine with trazodone showed that the pressants can lead to anomalous sleep stages characterized later drug was associated with more improvements in in- Chapter 133: Current and Experimental Therapeutics of Insomnia 1939 somnia symptoms, but also with a greater percentage of specific receptors in the suprachiasmatic nucleus of the hy- sedating events during the daytime (100). In addition, melatonin shifts circadian parisons between fluoxetine and nefazodone has consis- rhythms according to a phase response curve (110,111). Doses greater than 1 mg are likely to induce supraphysiologic concentrations. Clinical trials have Antihistamines employed doses ranging from. Antihistamines such as diphenhydramine and doxylamine During daytime administration, melatonin causes sleepi- are the most widely available over-the-counter preparations ness in fatigue and healthy subjects (112,113).

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