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By Z. Spike. Concordia College, Saint Paul Minnesota.

Am ping of the human and mouse VCFS/DGS syntenic region dis- J Hum Genet 1998;62:1189–1197 buy anacin 525 mg otc. QTLs for general cognitive ability in children on chromosome 173 purchase anacin 525mg overnight delivery. GEYER BITA MOGHADDAM Animal models used to study schizophrenia include both effects of antipsychotic treatments anacin 525mg without a prescription. Here order anacin 525 mg mastercard, the behavior of models of the full syndrome and models of specific signs the model is intended to reflect only the efficacy of known or symptoms buy anacin 525mg lowest price. As reviewed elsewhere (1), models are com- therapeutic agents and so lead to the discovery of related monly explored initially because of indications of so-called pharmacotherapies. Because the explicit purpose of the face validity, but they are evaluated scientifically in terms model is to predict treatment efficacy, the principle guiding of their construct and etiologic and predictive validity with this approach has been termed pharmacologic isomorphism respect to both clinical phenomena and responsiveness to (2). The fact that such models are developed and validated antipsychotic drugs. Here, models are organized by the ma- by reference to the effects of known therapeutic drugs fre- nipulations used to mimic the clinical phenomena. Thus, quently limits their ability to identify new drugs with novel in some of these models, only specific dependent measures mechanisms of action. Similarly, an important limitation are utilized, whereas others are evaluated by using a range inherent in this approach is that it is not designed to identify of dependent measures. Typically, models are animal proach to the development of relevant animal models relies preparations that attempt to mimic a human condition, in on focusing on specific signs or symptoms associated with our case the human psychopathology associated with the schizophrenia, rather than mimicking the entire syndrome. In developing and assess- In such cases, specific observables that have been identified ing an animal model, it is important to specify the purpose in schizophrenic patients provide a focus for study in experi- intended for the model because the intended purpose deter- mental animals. The particular behavior being studied may mines the criteria that the model must satisfy to establish or may not be pathognomonic for or even symptomatic of its validity. At one extreme, one can attempt to develop an schizophrenia, but it must be defined objectively and ob- animal model that mimics the schizophrenia syndrome in served reliably. It is important to emphasize that the reliance its entirety. In the early years of psychopharmacology, the of such a model on specific observables minimizes a funda- term animal model often denoted such an attempt to repro- mental problem plaguing animal models of the syndrome duce a psychiatric disorder in a laboratory animal. Specifically, the difficulties inherent in nately, the group of schizophrenia disorders is characterized conducting experimental studies of schizophrenic patients by considerable heterogeneity and a complex clinical course have limited the number of definitive clinical findings with that reflects many factors that cannot be reproduced readily which one can validate an animal model of schizophrenia. Thus, the frequent attempts to model the syn- The validation of any animal model can only be as sound dromes of schizophrenia in animals usually met with failure as the information available in the relevant clinical literature and so prompted skepticism regarding this entire approach. By focusing on specific signs or symptoms rather than At the other extreme, a more limited use of an animal syndromes, one can increase the confidence in the cross- model related to schizophrenia is to study systematically the species validity of the model. The narrow focus of this ap- proach generally leads to pragmatic advantages in the con- duct of mechanistic studies addressing the neurobiological Mark A. Geyer: Department of Psychiatry, School of Medicine, Univer- substrates of the behavior in question. By contrast, in sity of California at San Diego, La Jolla, California. Bita Moghaddam: Departments of Psychiatry and Neurobiology, Yale models intended to reproduce the entire syndrome of schiz- University School of Medicine, New Haven, Connecticut. Another approach to the development of animal models is based more theoretically on psychological constructs be- lieved to be affected in schizophrenia. Such identification Behavioral Phenotypes of underlying psychological processes or behavioral dimen- Locomotor and Stereotypy sions (2,3) involves the definition of a hypothetical con- struct and the subsequent establishment of operational defi- Changes in locomotor activity in rodents have often been nitions suitable for experimental testing of the validity of used to assess both models of schizophrenia and the effects the construct. Constructs such as selective attention, persev- of antipsychotic treatments. The original impetus for the eration, sensorimotor gating, and working memory have use of locomotor activity measures was derived from the been used in this manner in schizophrenia research. This psychostimulant models based on the dopamine hypothesis approach is most fruitful when conceptually or procedurally of schizophrenia, as reviewed elsewhere (3–5). These related experiments are undertaken in both the relevant pa- models arose because of the apparent similarity (i. In other validity') between the symptoms of schizophrenia and the words, studies of appropriate patients are needed to establish effects of high doses of amphetamine in presumably normal the operational definitions of the hypothetical construct and humans (6). Cross-species studies in animals treated with the relevance of the construct to schizophrenia. In concert, psychostimulants revealed both locomotor hyperactivity parallel studies of the potentially homologous construct, and, at higher doses, striking stereotyped or perseverative process, or dimension are required to determine the simi- behaviors, which were seen as having face validity for the larity of the animal model to the human phenomena.

In another approach buy discount anacin 525 mg on-line, comparisons of several inbred strains of rats identified some strains that exhibit deficits in PPI (103) anacin 525 mg on-line. Because these strains did not exhibit GENETIC MODELS hearing impairments discount 525 mg anacin, the genetically determined deficit in PPI likely represents a deficit in sensorimotor gating pro- Genetic contributions to schizophrenia have been clearly cesses buy 525 mg anacin free shipping. Although the focus of consid- erable research order anacin 525 mg overnight delivery, 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. Stimulant-induced psychosis: standing of the long-term effects of congenital NMDA- an evaluation of animal models.

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Although some cases are asymptomatic generic 525 mg anacin otc, others are not diagnosed because the patient or the health-care provider fails to recognize the 64 MMWR December 17 anacin 525mg visa, 2010 implications of mild or nonspecifc symptoms or signs (e cheap 525 mg anacin fast delivery. Because discharge or evidence of WBCs on a microscopic evaluation of the difculty of diagnosis and the potential for damage to of a saline preparation of vaginal fuid (i 525 mg anacin with visa. If the the reproductive health of women (even by apparently mild or cervical discharge appears normal and no WBCs are observed subclinical PID) anacin 525 mg cheap, health-care providers should maintain a low on the wet prep of vaginal fuid, the diagnosis of PID is unlikely, threshold for the diagnosis of PID (382). A wet Te optimal treatment regimen and long-term outcome prep of vaginal fuid ofers the ability to detect the presence of of early treatment of women with asymptomatic or subclini- concomitant infections (e. Te following recommendations for Te most specifc criteria for diagnosing PID include: diagnosing PID are intended to help health-care providers rec- • endometrial biopsy with histopathologic evidence of ognize when PID should be suspected and when they need to endometritis; obtain additional information to increase diagnostic certainty. Several antimicrobial Te requirement that all three minimum criteria be pres- regimens have been efective in achieving clinical and micro- ent before the initiation of empiric treatment could result in biologic cure in randomized clinical trials with short-term insufcient sensitivity for the diagnosis of PID. However, only a limited number of investigations of signs of lower-genital–tract infammation (predominance of have assessed and compared these regimens with regard to leukocytes in vaginal secretions, cervical exudates, or cervical elimination of infection in the endometrium and fallopian friability), in addition to one of the three minimum criteria, tubes or determined the incidence of long-term complications increases the specifcity of the diagnosis. All regimens used to treat PID should also be efective More elaborate diagnostic evaluation frequently is needed against N. One or more of the following upper-reproductive-tract infection. Te need to eradicate additional criteria can be used to enhance the specifcity of the anaerobes from women who have PID has not been determined minimum criteria and support a diagnosis of PID: defnitively. Anaerobic bacteria have been isolated from the • oral temperature >101° F (>38. Treatment should be initiated as soon as the presumptive Oral and IV administration of doxycycline provide similar diagnosis has been made because prevention of long-term bioavailability. When selecting a treatment regimen, health-care cal improvement, but oral therapy with doxycycline (100 mg providers should consider availability, cost, patient acceptance, twice a day) should continue to complete 14 days of therapy. When tubo-ovarian abscess is present, clindamycin or metron- In women with PID of mild or moderate clinical severity, idazole with doxycycline can be used for continued therapy outpatient therapy yields short- and long-term clinical out- rather than doxycycline alone because this regimen provides comes similar to inpatient therapy. Te decision of whether more efective anaerobic coverage. However, these cephalosporins are less active than • the patient is pregnant; cefotetan or cefoxitin against anaerobic bacteria. Single daily dosing high fever; or (3–5 mg/kg) can be substituted. No evidence is available to suggest that adolescents beneft from hospitalization for treatment of PID. Te decision to Although use of a single daily dose of gentamicin has not hospitalize adolescents with acute PID should be based on been evaluated for the treatment of PID, it is efcacious in the same criteria used for older women. Parenteral therapy can be discontinued mild-to-moderate acute PID have similar outcomes with either 24 hours after clinical improvement; ongoing oral therapy outpatient or inpatient therapy, and clinical response to outpa- should consist of doxycycline 100 mg orally twice a day, or tient treatment is similar among younger and older women. When tubo-ovarian abscess is present, Parenteral Treatment clindamycin should be continued rather than doxycycline, For women with PID of mild or moderate severity, paren- because clindamycin provides more effective anaerobic teral and oral therapies appear to have similar clinical efcacy. Many randomized trials have demonstrated the efcacy of both Alternative Parenteral Regimens parenteral and oral regimens (390,391,393). Clinical experi- Limited data are available to support the use of other paren- ence should guide decisions regarding transition to oral therapy, teral regimens. Te following regimen has been investigated in at which usually can be initiated within 24–48 hours of clinical least one clinical trial and has broad-spectrum coverage (394). In women with tubo-ovarian abscesses, at least 24 hours of direct inpatient observation is recommended. Alternative Parenteral Regimens Ampicillin/Sulbactam 3 g IV every 6 hours Recommended Parenteral Regimen A PLUS Cefotetan 2 g IV every 12 hours Doxycycline 100 mg orally or IV every 12 hours OR Cefoxitin 2 g IV every 6 hours PLUS Ampicillin/sulbactam plus doxycycline is efective against Doxycycline 100 mg orally or IV every 12 hours C. One trial demonstrated high short-term clinical cure rates with azithromycin, either as monotherapy 66 MMWR December 17, 2010 for 1 week (500 mg IV for 1 or 2 doses followed by 250 mg trial and have demonstrated broad spectrum coverage. In a orally for 5–6 days) or combined with a 12-day course of single clinical trial, amoxicillin/clavulanic acid and doxycycline metronidazole (395). Azithromycin has demonstrated Outpatient, oral therapy can be considered for women short-term efectiveness in one randomized trial (395), and in with mild-to-moderately severe acute PID, because the clinical another study, it was efective when used combination with outcomes among women treated with oral therapy are similar ceftriaxone 250 mg IM single dose and azithromycin 1 g orally to those treated with parenteral therapy (390). When considering alternative regimens provide coverage against the frequent etiologic agents regimens, the addition of metronidazole should be considered of PID. Patients who do not respond to oral therapy within because anaerobic organisms are suspected in the etiology of 72 hours should be reevaluated to confrm the diagnosis and PID and metronidazole will also treat BV. If parenteral Recommended Regimen cephalosporin therapy is not feasible, use of fuoroquinolones Ceftriaxone 250 mg IM in a single dose (levofoxacin 500 mg orally once daily or ofoxacin 400 mg PLUS twice daily for 14 days) with or without metronidazole (500 Doxycycline 100 mg orally twice a day for 14 days mg orally twice daily for 14 days) can be considered if the WITH or WITHOUT community prevalence and individual risk for gonorrhea are Metronidazole 500 mg orally twice a day for 14 days low. Diagnostic tests for gonorrhea must be performed before OR instituting therapy and the patient managed as follows if the Cefoxitin 2 g IM in a single dose and Probenecid, 1 g orally test is positive.

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The unilateral tive and could not examine compliance rates or the ade­ seizure at or near the seizure threshold used during the initial quacy of either the initial (pre-ECT) or continuation medi­ treatment setting to determine seizure threshold probably cation trial cheap anacin 525 mg mastercard. However discount anacin 525mg free shipping, the potential advantages of In a prospective study anacin 525mg with mastercard, Sackeim and co-workers (63) fol­ determining the seizure threshold and adjusting the subse­ lowed 58 patients for 1 year after ECT buy anacin 525 mg with amex. They examined a quent seizures to the threshold has advantages in maximiz­ number of clinical variables including a retrospective review ing benefit and decreasing the potential for future ineffective of the adequacy of the pre-ECT medication trial anacin 525mg without a prescription. The most treatments (if the energy delivered is too low) and cognitive important factor in determining relapse on maintenance side effects (if the energy is too high). Patients (with and without ment for depression (55,58) and this data could obviate the psychotic features) who were rated as receiving a therapeutic need to determine seizure threshold. Because the majority medication trial(s) prior to their acute course of ECT re- of patients treated with ECT are older and older patients lapsed at a rate that was twice the rate found in patients have very high seizure thresholds, dose titrations at eight to who did not receive an adequate pre-ECT medication trial ten times threshold are generally at or above the 400-mC (64% versus 32%). The maintenance medication was not range used by McCall and associates. In fact, in some older standardized but the results indicated that the adequacy of 1102 Neuropsychopharmacology: The Fifth Generation of Progress the post-ECT medication trial was only marginally related senting for ECT after multiple failed medication trials and to the relapse rate and then primarily in patients who did there may be little benefit from yet another trial of an SSRI. The pa­ In fact the one medication regimen that has been shown tients who were not determined to be medication resistant to be effective in maintenance therapy is a combination of prior to ECT had a lower relapse rate when they received lithium and nortriptyline (discussed in the following). Sackeim and as­ benefit of this combination therapy may be owing to the sociates argue that many of these patients may have re­ fact that few patients had been given lithium augmentation sponded to antidepressant medication prior to ECT if they prior to their acute course of ECT. The overall relapse rate re­ Finally, maintenance ECT is similar to depot haloperidol mained very high (approximately 50%) and most of the in the treatment of schizophrenia and may provide prophy­ patients who relapsed did so in the first 4 months of this lactic benefit from improved compliance in patients who 1-year follow-up study. This finding indicates that the effi­ might otherwise not comply with their maintenance medi­ cacy of ECT may be relatively transient. Most studies of maintenance ECT only report pa­ ing medication resistance found in most ECT patient popu­ tients who complied with the treatment regimen. The expe­ lations, the clinical challenge is increasingly to determine rience at the Emory University Outpatient ECT program the most effective maintenance treatments and increasingly is similar to the data reported by Clarke and colleagues (67). There is ance with antidepressant medications; (c) can comply with clear evidence that these treatments are being used increas­ the overall treatment plan including behavioral restrictions ingly in clinical practice, yet there is a lack of guidelines to (i. The NIMH is presently funding three studies The guidelines for the use of C-ECT have been actively that will add significantly to our understanding of mainte­ discussed but there are little prospective data on which to nance ECT. Two multicenter trials are examining the effi­ base recommendations on frequency of treatments and how cacy of different maintenance strategies after an acute re­ long they should be continued or the nature of the potential sponse to ECT. Sackeim and colleagues are comparing cognitive side effects. A majority of the studies are case re- maintenance placebo, nortriptyline versus nortriptyline and ports and many predate antidepressant medication (66). Preliminary results More recent reports in patients with depression (66–74), from this line of investigation show that nortriptyline pro­ mania (75,76), and schizophrenia (77) describe a marked vides only marginally greater protection against relapse dur­ decrease in the number of hospitalizations, hospital days, ing the post-ECT period than does placebo, with relapse depressive symptoms, increased functional status, and stable rates of approximately 70% during the first year. The addi­ cognitive functioning for the period of continuation ECT. Charles Kellner is the principal investigator on a nance medication. First, maintenance ECT may be effective trial comparing maintenance medication and maintenance because the ECT treatments are gradually tapered rather ECT. The authors are currently examining the cost effec­ than abruptly discontinued. During this taper, most clinical tiveness of maintenance medication compared to mainte­ protocols decrease the interval between the maintenance nance ECT in elderly patients with recurrent major depres­ treatments if the patient shows signs of relapse. These last two trials do not yet have preliminary data schedule over this period may be critical because most pa­ available, but together they will provide prospective data on tients relapse within 3 months of stopping the treatments. ECT The second potential therapeutic benefit may be the fact that ECT has a different mechanism of action than the The one significant remaining ECT-related morbidity is the antidepressant medications. Increasingly patients are pre­ potential for cognitive side effects. Although there is little Chapter 76: Electroconvulsive Therapy 1103 scientific literature supporting permanent brain damage frequency in which it is administered.

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