Most patients availability of the SSRIs and behavioral treatments buy prednisone 20 mg without a prescription allergy symptoms dogs eyes. Re- In summary discount 5 mg prednisone overnight delivery allergy nasal congestion, only a handful of prospective studies of the lapses were common in those patients who discontinued course of illness in OCDare available. A significantly greater medication, which suggests that continued treatment may degree of episodic illness is seen in child and adolescent be required to maintain an improvement in OC symptoms samples than in the adult population. The earlier retrospective studies were com- was also evaluated in the prospective study conducted by pleted before the introduction of standardized diagnostic Eisen et al. Pharmacologic addition, because until recently patients with OCDwere data gathered included doses of medications and duration reluctant to seek treatment, patients with more debilitating of treatment. Patients had to have received a maximum dose symptoms may have been overrepresented in these earlier of at least one SSRI for a minimum of 12 weeks to be studies, so that the results are biased toward a worse prog- considered to have received adequate pharmacotherapy for nosis. In our pilot study, patients were followed who were OCD. Information obtained on behavior therapy included already enrolled in our clinic, a factor that potentially con- amount of time spent in sessions, time spent doing home- tributed to the chronic course noted in many of the subjects. Patients were considered tients with OCDis currently in progress. Fifty-five subjects (84% of the total sample) OCDbecame available in the late 1980s in the United received an adequate trial of at least one SSRI during the States. A follow-up study of children with OCDwas con- study period, and 12 patients (18%) received adequate be- ducted by Leonard et al. The probability of partial remission for standardized short-term treatment with clomipramine (a those patients who received an adequate trial of at least one medication known to be effective in OCD). Fifty-four chil- SSRI was 51% during the 2-year study period. Obsessive-compulsive those subjects who received an adequate trial of an SSRI symptoms were more severe in only 10 of the subjects at and those who did not receive adequate pharmacotherapy. However, only three subjects (6%) were con- subsequently underwent adequate behavior therapy during sidered to be in true remission (defined as no obsessions or the course of the study were lower than the mean GAF 1600 Neuropsychopharmacology: The Fifth Generation of Progress scores of patients who did not undergo behavior therapy. More recently, emerging data The change in GAF score at 2 years was significantly greater have clarified that OCDis a heterogeneous disorder and in the group of patients who received behavior therapy, so have begun to point to the existence of discrete subtypes that these patients in effect 'caught up'; their final GAF of illness. It will be important to determine whether these scores were similar to the scores of the patients who did not 'subtypes' influence the likelihood of remission or relapse. The most likely prediction variables are reviewed below. Although this study was conducted at a time when cur- One subtype of OCDis associated with a family or life- rent behavioral and pharmacotherapies were available, the time history of tic disorders. Although variation between results again support the findings that for the majority of studies is considerable, it is generally accepted that approxi- patients, the course of illness in OCDis continuous with mately 20% of patients with OCDhave a lifetime history of fluctuations in severity rather than episodic with clear pe- tics, and that 5% to 10% have a lifetime history of Tourette riods of remission between periods of exacerbation of symp- disorder (47,48). No longitudinal follow-up study of OCDhas systematically OCDpatients with tics appear to be less likely to respond measured psychosocial functioning and quality of life over to SSRIs, and their OCDsymptoms respond differentially time. Most treatment outcome studies have primarily fo- to augmentation of an SSRI with a neuroleptic (51). Also, no attempt has been OCDsymptoms have been shown to develop more com- made to examine the relationship between symptom severity monly in this subgroup, including the need for symmetry, and psychosocial functioning over time. For a significant ordering, arranging, and hoarding (52). The presence of a percentage of OCDpatients, impairment in function and tic disorder predicted more severe symptoms of OCDat quality of life is severe (45). It is the only major psychiatric follow-up in children (47). The predictive power of a per- disorder for which neurosurgery continues to be a treatment sonal or family history of multiple tics in regard to remission option. It will be important in future studies to gather pro- and relapse rates should be investigated. In the National Collab- been investigated in a number of acute treatment studies orative Study of Depression, even subsyndromal symptoms with inconsistent findings. In a study by Baer et suggest that psychosocial functioning continues to be im- al. A subsequent single-site study of the effect of a personality disorder on the response to fluoxetine failed to confirm that a cluster PREDICTORS OF LONG-TERM COURSE OF A diagnosis is a negative predictor of outcome (55). ILLNESS The DSM-IV field trial of OCD established that a signif- icant percentage of patients with OCDhave poor insight Although a number of studies have examined predictors of (56). The validity of this new diagnostic category is still in outcome in OCD, the results have been inconsistent. Data pertaining to the effect of poor insight or have focused on identifying predictors of short-term out- overvalued ideation on behavioral treatment response have come following pharmacologic or behavioral treatment. Eisen and Rasmussen (59) retro- None of the existing studies has examined predictors of spectively assessed the course of illness in four subgroups remission or relapse rates. These studies have been methodo- of OCD: OCDand schizophrenia, OCDand schizotypal logically compromised by small sample size, inclusion or personality disorder, OCDwith poor insight, and OCD exclusion criteria that led to sample bias, and inadequate without psychotic features. A deteriorative course was noted duration of follow-up. Characteristics such as age at onset in 82% of the patients with coexisting schizophrenia, 69% of OCD, duration of illness, severity of illness at baseline, of those with coexisting schizotypal personality disorder, and phenomenologic subtype have not been associated with 17% of those with poor insight, and only 8% of those with- Chapter 111: Obsessive-Compulsive Disorder 1601 out psychotic features. This study was hampered by the lack tomography (PET) have shown that regional activation of of a valid and reliable scale to measure poor insight and by the prefrontal cortex varies according to factor (69), and the retrospective assessment of the course. We have recently emerging genetic data suggest that familial loading varies published data on the reliability and validity of a new scale, according to factor (70). Symmetry and certain obsessions, the Brown Assessment of Beliefs Scale (BABS), that has such as aggressive and sexual obsessions, are more frequent demonstrated excellent sensitivity to change with short-term in patients with OCDand chronic tics (71). The phase of a double-blinded relapse study of sertraline in analytic technique used to identify factors from the Y-BOC OCD. They found no significant correlation between de- Symptom Checklist may be fruitful in predicting the course gree of insight as measured by the BABS and outcome after of OCD. Evidence is increasing that patients in whom 16 weeks of sertraline. The role of insight in remission and hoarding is a primary obsessive-compulsive symptom are relapse deserves further scrutiny. In addition, hoarding was the only com- tions in neurologic function involving the basal ganglia after pulsion associated with a lower probability of remission in head trauma, encephalitis, and birth events (62). In a number of studies, an earlier age psychological abnormalities in comparison with a control at onset of OCDwas associated with a worse prognosis. Thomsen (36) reported that attainment ceiver operating characteristic analysis found that a cutoff of puberty by the time of referral predicted a better prog- of three or more signs yielded the minimum number of nosis than a prepubertal onset. In a reanalysis of the multi- combined errors of sensitivity and specificity in blindly dis- center efficacy and safety data for clomipramine, Ackerman tinguishing OCDsubjects from controls.

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Heterozygotes displayed a decrease in the a behavioral profile that is identical to that of the 1 subunit number of entries into and amount of time spent in the knockout mice; in normal mice buy generic prednisone on-line allergy symptoms cold symptoms, this compound decreases open arms of an elevated plus maze and the bright compart- murine anxiety-like behaviors without eliciting sedation or ment of a light-dark box discount 10mg prednisone overnight delivery allergy symptoms to peanuts. Finally, 2 heterozygotes Stress-Related Disorders were found to react to partially conditioned stimuli (only weakly paired with aversive consequences) as if they were As stated above, the most widely used GABA system-based full and potent predictors of threat; compared to wild-types, drugs for the treatment of anxiety are the benzodiazepines, which showed low levels of defensive behaviors to the par- which facilitate GABA transmission through the GABAA tially conditioned stimulus, heterozygotes displayed high receptor. As outlined in the previous section, the search for levels of conditioned freezing to the partial conditioned novel compounds that may act selectively at specific GABAA stimulus that were identical to those displayed by all animals subunits is ongoing, with the ultimate hope of discovering in response to the full conditioned stimulus. This profile ligands that produce anxiolysis but do not cause some of has been proposed to be a model for the tendency to inter- the serious side effects that are commonly associated with pret neutral situations as threatening that is seen in anxiety benzodiazepines. Taken together, the results from this extensive be- leagues (160), drugs that selectively target certain GABAA havioral profile indicate that / mice have increased receptor subunits may hold great promise for the treatment 2 neophobia and stress-like responses and may thus provide of anxiety without harmful side effects. This development a model for increased anxiety-like behaviors (154—156). The use of targeted genetic in 2 heterozygotes were blocked by the benzodiazepine alterations in identifying the roles of various GABAA sub- diazepam, suggesting that this animal model may also have units will undoubtedly aid in this effort to create 'designer good predictive validity for identifying clinically effective drugs' for the treatment of anxiety (158). It is also extremely important to mention the 1 subunit General Issues and Caveats of Transgenic transgenic mice, whose behavioral profiles have been thor- Animal Studies oughly and insightfully reviewed in recent articles (157, 158). In these mice, a single amino acid is altered (histidine As mentioned above, mice carrying certain mutations replaced by arginine at the 101 position of the peptide) in within either the CRH, the 5-HT, or the GABA system the 1 subunit of the GABAA receptor complex. It appears that these change does not produce any overt alterations in baseline genetically engineered mouse models also have some predic- responses to stress in the genetically altered mice; these ani- tive validity; the stress-like endophenotype observed in at mals behave similarly to wild-type controls in tests such least two of the aforementioned models is normalized by as the elevated plus maze and the fear-potentiated startle administration of a clinically effective antianxiety agent that paradigm, a measure of conditioned fear (159,160). Thus, acts within the system that was genetically targeted. It re- under drug-free, normal conditions, these animals do not mains to be determined, however, the extent to which these display a behavioral pattern that is consistent with an anxi- genetically altered models serve to identify potential anti- ety-like endophenotype. When these mice are treated with anxiety agents from different chemical classes. For example, conventional benzodiazepines, however, they react very dif- do benzodiazepines reduce stress-like effects of CRH over- ferently to the drug than their wild-type counterparts. The extent to which the stress-like endopheno- with the mutation in the 1 subunit display a normal reduc- type in these animals is altered by compounds that act on tion of stress-induced anxiety-like behaviors after benzodi- systems that were not directly targeted by the genetic muta- azepine treatment, but fail to display some of the more tion will aid in determining the generalizability and utility deleterious side effects associated with this class of drugs of these models as predictors of novel anxiolytic agents. These results indicate one assumes that these animals provide a model of inherent that the anxiolytic effects of benzodiazepines can be sepa- trait-like anxiety, they can serve as a powerful tool for Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 895 screening new potential anxiolytics. These models do pro- contributions to the development of stress and anxiety-like vide a sound approach to study the long-term effects of endophenotypes in animals, further information is needed congenital abnormalities in these neurotransmitter and neu- to understand the precise nature of gene–environment in- ropeptide systems. It is likely that a particular Several broad issues should be considered when inter- stressor results in alterations of gene expression in myriad preting studies utilizing genetically altered mice. Generally, systems and that the overall response to stress involves the the hypotheses regarding the behavioral profiles of coordination of gene activation and/or suppression within transgenic mice are based on earlier findings from psycho- these various systems. For example, within the CRH field, have recently been developed that enable the expression of the prediction that CRH overexpressers would display in- thousands of genes to be assayed at once. When the outcome of the particular environmental perturbation or disease state (163, transgenic studies agrees with the psychopharmacology- 164). This approach and its application to psychiatry re- based prediction, the findings are taken as a confirmation search have been discussed comprehensively in a recent re- of that hypothesized mechanism of action. Briefly, gene chip and DNA array tech- come of the transgenic studies disagrees with the predicted nology involve the hybridization of gene transcripts from a phenotype, however, concerns about possible develop- tissue sample onto a glass slide or filter that contains up mental confounds are raised. One of the most commonly to 10,000 different nucleotide sequences. The amount and cited drawbacks of the transgenic/knockout strategy is that pattern of the signal hybridized to the array are then as- the gene of interest is altered from the embryonic stage, sessed; this method thus permits a rapid analysis of changes therefore possibly influencing other genes involved in the in the expression of multiple genes. This technology can normal development of the animal. Thus, it is difficult to also be used to identify single nucleotide polymorphisms in tease apart the effects of under- or overexpression of that a particular gene by comparing the hybridization patterns gene on the endpoints under study from effects due to com- of samples from different candidate populations on chips pensatory or downstream developmental changes that may that contain multiple copies of the gene of interest, each have occurred as a result of the mutation (86,87,161). Theoretically, depending on the size of the excellent method for modeling a congenital abnormality that leads to a disease state, but this approach may be less gene, it would be possible to carry out a base-by-base exami- useful for identifying the discrete functions of a specific nation of the entire gene on a single gene chip. However, gene product because of the problems of interpretation that it is important to realize that although a broad approach arise from the developmental confound. Indeed, with regard can be taken with this technology, it may not be sensitive to all of the studies discussed in this section on genetically enough to detect small but functionally important changes altered mice, it will be important in future studies to deline- in gene expression. This technology can be applied to pre- ate the compensatory alterations that occur in response to clinial and clinical questions regarding the complex genetic the congenital mutation, and that may indirectly contribute control of stress and anxiety by examining event-related to the adult endophenotypes that are reported for these gene expression changes and also baseline differences in gene animals. Future studies utilizing novel inducible-knockout sequences (polymorphisms) that might contribute to differ- strategies will circumvent the developmental issue; inducible ential stress responsivity (165). This technique, along with knockouts may thus become a valuable tool for exploring the recent completion of the Human Genome Project, not the functions of discrete gene products for which no selec- only raises the potential to simultaneously profile multiple tive ligands are available (123). The antisense functional role of these new genes in processes related to oligonucleotide approach, however, has been plagued with stress and anxiety. Given this daunting task, methods for a number of issues regarding toxicity, and may therefore not more specific and long-term gene targeting will increasingly represent the optimal method for studying gene function in gain importance in neuroscience research aimed at uncover- vivo (162). One technique that is likely to be helpful is that of virally me- FUTURE DIRECTIONS diated gene transfer. In this method, a gene of interest is cloned into viral vector (with most of the viral genome Although the studies summarized in this chapter have con- removed to reduce toxicity and infection) and the modified tributed a great deal of knowledge about some of the genetic vector is then infused into a particular brain region using 896 Neuropsychopharmacology: The Fifth Generation of Progress standard stereotaxic procedures (see ref. Animal models in cognitive behav- Depending on the gene insertion and the selection of the ioural pharmacology: an overview. Acta to obtain either an increase or decrease in the amount of Psychiatr Scand Suppl 1998;393:74–80. Alternative phenotypes for allows for highly selective gene regulation and thus provides the complex genetics of schizophrenia. Biol Psychiatry 1999;45: a valuable new tool with which to study the effects of a 551–558. Cerebrospinal fluid corti- particular gene product on stress-related functioning. The cotropin-releasing hormone levels are elevated in monkeys with virally mediated gene transfer approach also has certain ad- patterns of brain activity associated with fearful temperament. Linkage of a any time or into any brain region, it results in a fairly robust neurophysiologic deficit in schizophrenia to a chromosome 15 locus. Chicago: University of Chicago it can be used to insert several genes at once in the same Press, 1972. Thus, the viral gene transfer approach completely 8. Responses of black-capped chickadees avoids the issue of developmental confounds, which are per- to predators. Predator model recognition and re- transgenic and knockout approaches. A few groups have sponse habituation in shoaling minnows. Acoustic characteristics of alarm calls associated down-regulation of discrete gene products related to neuro- with predation risk in chickadees. Anim Behav 1990;39: science research applications; the behavioral effects associ- 400–401. Interactions between tit flocks and sparrowhawks not appear to be associated with the high level of toxicity Accipiter nisus.

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Effects of dehydroepian- in phospholipid fatty acid composition and monoaminergic drosterone and its sulfate on brain tissue in culture and on neurotransmission in the hippocampus of rats fed a balanced memory in mice cheap prednisone 40 mg with visa allergy zinc oxide. JNeurosci Res 1987;17: dietary deficiency alters age-related changes of dopaminergic 225–234 best buy for prednisone allergy forecast cincinnati. Do essential fatty acids play a role in brain development. The membrane phospholipid hypothesis as a 9:759–763. Potentiation of neu- sion, normalisation of blood fatty acids, reduced neuronal mem- ronal NMDA response induced by dehydroepiandrosterone and brane phospholipid turnover and structural brain changes. Int its suppression by progesterone: effects mediated via sigma re- JClin Pract 2000;54:57–63. Potentiation by de- of supplemental EPA for residual symptoms of schizophrenia. D-aspartate in the CA3 region of the rat dorsal hippocampus: 428. Implications of normal brain development for an effect mediated via sigma receptors. JEndocrinol (Suppl) the pathogenesis of schizophrenia. Selective modulation maldevelopmental hypothesis of schizophrenic psychoses. J of fibroblast growth factor-2 expression in the rat brain by the Neural Transm 1998;105:85–100. When neurotrophic factors get on your nerves: ther- 434. Iloperidone binding to apy for neurodegenerative disorders. JClin Psychiatry 1998;59: human and rat dopamine and 5-HT receptors. COVELL ECONOMICS OF MENTAL HEALTH AND economists indicate the range of activities in the field of SCHIZOPHRENIA mental health economics, including the economics of schiz- ophrenia. This chapter focuses on two aspects of the eco- Prior to the 1980s, economists paid scant attention to schiz- nomics of schizophrenia: cost studies and cost-effectiveness ophrenia, or indeed to mental health in general (1). Studies of the cost of mental illnesses appeared be- work in the field included efforts to consider the impact fore other types of work in the economics of mental health, of organization and financing on system efficiency and to and they have continued throughout the past two decades. For example, McGuire (2) reviewed the mar- cost-benefit studies because they identify the range of re- ket for psychotherapy and the insurability of mental health sources that are consumed as a result of an illness. Cost- care, and Frank (3) examined the supply of psychiatrists. The use of diagnosis- brod and colleagues (14) on the cost-benefit of assertive related groupings to pay for care under prospective payment community treatment teams. Collectively, studies of costs was considered by Taube and his colleagues (5). Dickey and cost-effectiveness are perhaps the most important foci and Goldman (6) reviewed the impact of various funding of the economics of schizophrenia. First, the sizable cost to mechanisms in public mental health. Observers of systems change consid- ered major reorganizational efforts, such as those imple- mented through the Robert Wood Johnson Program on Costs Of Schizophrenia Chronic Mental Illness (8) and other types of organizational reforms (9–12). The 1990s also brought analysis of the Early studies of the costs of mental illness (15–17) did not increasing implementation of managed care with behavioral distinguish between the costs of different diagnostic categor- health carve-outs (13). More recent studies have estimated specific costs These examples of the contributions of mental health for schizophrenia and other illnesses. Rice has estimated the cost of schizophrenia in the United States at $32. Goeree and colleagues (21) have calculated costs in Canada in 1996 to Susan M. Essock: Department of Psychiatry, Mount Sinai School of be approximately $2. However, But no study of the cost of schizophrenia can claim to cap- new strategies for improving the employment outcomes for ture all costs. As noted by McGuire (18), even comprehen- persons with serious mental illness, such as Individual Place- sive studies of the cost of schizophrenia often underestimate ment and Support (29), have made employment a realistic two types of costs: the costs to families and the costs of goal of rehabilitation. These new successes suggest that loss publicly owned capital. Economic, or social, costs are the costs of re- Capital Costs sources consumed because of an illness. Cost-effectiveness and cost-benefit analysis should always state the perspective Economic cost studies appropriately study the opportunity from which the study is undertaken. Although a societal costs of all resources, that is, the value of those resources perspective presumably provides the balanced view of the in their best alternative use. In a cost-effectiveness study of neutral scientist, it is also helpful to examine costs from a new residential model for persons with serious mental perspectives of particular stakeholders. For example, in an illness, Cannon and her colleagues (31) carefully considered analysis of the impact of Assertive Community Treatment the value of capital costs of a public hospital, which would in Connecticut, Essock and colleagues (25) present costs have been underestimated if valued through traditional from the perspectives of society, the state, and the Depart- methods of depreciation. Capital costs can be large enough ment of Mental Health. Comparison of the results from to change the most basic findings of a cost study, as shown multiple perspectives may identify areas of cost-shifting that by Rosenheck and colleagues (32). Public administrators results from certain programs and policies. For example, a may not consider the value of buildings and property to be treatment that reduces hospital days may shift costs from part of a cost equation because it is not always part of the state-run inpatient facilities to private nonprofit outpatient operating costs, but the value of the property in alternative settings. Cost Components Other Components Especially where an intervention is expected to have an im- Costs of Treatment and other Services pact on co-occurring substance use disorders, it is important The examples provided by Rice and Knapp are instructive to attend to criminal justice costs (33). Another neglected for those conducting cost-of-illness studies and cost-effec- aspect of cost studies is the costs of administering transfer tiveness studies in the area of schizophrenia. Although disability pay- there are many ways in which the illness is associated with ments themselves do not represent the use of new resources, greater costs. First are the costs of treatment, including med- the cost of administering these payments is a cost that ication. Treatment may be offered by public, private, or should be counted, especially if the intervention could voluntary sector settings, and many persons with schizo- change the rate of receipt of disability payments or other phrenia receive care in multiple places.

K. Denpok. Teikyo Post University.

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