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    By L. Gunnar. Paul Quinn College.

    Both sertraline and paroxetine Anticonvulsants are labeled in the United States for the treatment of PD purchase kamagra super 160 mg mastercard, and citalopram is approved in several European countries Among the anticonvulsants being used in the treatment of for this indication order kamagra super 160mg. Although fluvoxamine has not been PD are valproate and carbamazepine,and the newest anti- studied in clinical trials on the scale of the other SSRIs,it convulsants gabapentin,lamotrigine,pregabalin,and viga- has been shown to be efficacious in smaller ( 100 subjects), batrin. Valproate has shown promise in several open trials randomized,placebo-controlled studies (25,44). Despite (56–58),and one small placebo-controlled study (59). It their established efficacy in the treatment of PD,there are may be particularly effective when mood instability is com- certain problems inherent in prescribing the SSRIs in pa- orbid (60). There is far less support for the use of carbamaze- tients with PD. Of primary concern on the initiation of pine in the treatment of PD,with uncontrolled studies in treatment is the commonly observed anxiogenic effect, patients with PD with EEG abnormalities demonstrating which,despite being dose-dependent,can nonetheless make some benefit from carbamazepine treatment (58). However, the initial several days of treatment a challenge for patients. Gabapentin has shown promise (62) delayed onset of anxiolytic action contributes to making the and is recognized as having a benign side-effect profile. La- period of SSRI initiation difficult for patients with PD. EFFICACY OF THE SSRIs IN THE ACUTE TREATMENT OF PANIC DISORDER BASED ON LARGE-SCALE, PLACEBO-CONTROLLED STUDIES SSRI Investigators Study Design Dose Range Outcome Fluoxetine Michelson et al. The paroxetine group had significantly greater mean reductions in HAM-A and CGI scores versus placebo Ballenger et al. Antidepressant use has two main advantages over the benzodiazepines: (a) it provides antidepressant benefits Although the beta-blockers are more commonly used in the in a population highly susceptible to depressive symptom- treatment of performance anxiety and as adjunctive treat- atology and comorbid major depression (70),and (b) it ment in PTSD,a small number of open studies suggest they eliminates the difficulties associated with withdrawal symp- may be effective in the treatment of PD (63),although they toms upon benzodiazepine discontinuation. In the case of are not considered a first-line treatment. In this regard,the SSRIs are currently considered first-line treat- Several classes of drugs,although initially viewed as promis- ment for PD,demonstrating comparable efficacy and supe- ing,have shown limited efficacy in the treatment of PD. Combination These include buspirone,bupropion,ondansetron,and the therapies are frequently used for treatment resistance,and cholecystokinin (CCK) antagonists (64–67). A number of an approach of prescribing a benzodiazepine at the initiation new classes of drugs are being studied,including the benzo- of treatment with an SSRI,and later tapering it,has proved diazepine partial agonists such as abecarnil and pagaclone, to be popular with clinicians and has recently been demon- and the corticotropin-releasing hormone (CRH) inhibitors. GENERALIZED ANXIETY DISORDER In summary,the expansion of the antipanic armamentar- ium suggests that,as with many of the psychiatric disorders, The diagnostic criteria for generalized anxiety disorder there is no single effective treatment of PD. Among the (GAD) have evolved over the past two decades,undergoing most commonly prescribed classes of drugs for the treatment substantial revision to the current definition emphasizing of PD [benzodiazepines,SSRIs,tricyclic antidepressants excessive,unrealistic worry as the cardinal feature of this (TCAs),and MAOIs],there are probably no major differ- disorder. The use of antide- R to require symptoms extended for 6 months or longer, pressants,however,and particularly the SSRIs,has sup- and an emphasis on unrealistic worry was stressed. With planted the long-term use of benzodiazepines for this DSM-IV,GAD was defined as excessive and persistent 972 Neuropsychopharmacology: The Fifth Generation of Progress worry,accompanied by three or more physical or psycholog- Tricyclic Antidepressants ical symptoms of anxiety,persisting 6 months or longer. Tricyclic antidepressants (TCAs) have been in use in the Because of the shift in diagnostic criteria and required dura- treatment of GAD for many decades; however,data sup- tion of symptoms over the years,comparison of pharmaco- porting their efficacy from controlled clinical trials are ex- logic treatment studies performed prior to the introduction tremely limited. Imipramine is the only TCA shown to be of DSM-III-R is difficult. In comparator trials, imi- sive-compulsive disorder (OCD),there are fewer publica- pramine has been shown to have clinical efficacy comparable tions devoted to GAD overall,and only a limited number to the benzodiazepines (84,86,87). Several reasons have been proposed for this deficiency,including underrepresentation in clinical settings and a view of GAD Benzodiazepines as a 'mild' disorder (72). In reality,GAD is one of the most commonly diagnosed anxiety disorders,with a lifetime Five benzodiazepines (alprazolam,chlordiazepoxide,clo- prevalence of 4. There remains substantial controversy sur- zolam are labeled specifically for the treatment of PD. There rounding the validity of GAD as a primary disorder,as are a limited number of clinical trials demonstrating the opposed to a comorbid condition or a prodromal/residual efficacy of benzodiazepines in the treatment of GAD in its phase of another disorder (78,79). Findings from epidemio- current (DSM-IV) definition (89,90); however, benzodiaze- logic studies of GAD suggest that current comorbidity with pines have been shown effective in controlled studies using other disorders is as high as 58% to 65% (73,76), and life- DSM-III criteria for GAD (91). Non-comorbid,'pure' GAD lifetime prevalence was found Buspirone to be only 0. Overall,the sum of studies examining quality of life issues Buspirone is a serotonin receptor subtype 1A (5-HT1A) par- support the idea that non-comorbid GAD is relatively rare, tial agonist with anxiolytic properties.

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    However order kamagra super 160 mg with amex, these work- chosis had the highest scores (149) kamagra super 160 mg generic. However, perhaps of ers studied a small sample that included few adults, and in greater interest, those without psychosis had intermediate 680 Neuropsychopharmacology: The Fifth Generation of Progress scores in comparison with controls (149). If schizotypy is are clinical symptoms—so-called intermediate phenotypes a trait marker for increased liability to psychosis, this sug- or endophenotypes. Work in this area is developing fast; for gests that the majority if not all of those with 22q11 dele- example, candidate trait markers for schizophrenia include tions are at increased risk for psychosis, but that other ge- schizotypal personality traits, measures of cognitive process- netic or environmental factors are required for this risk to ing, brain evoked potentials, and abnormalities in eye move- be expressed. The genetic loci involved may reside elsewhere ments (163). It is also hoped that advances in brain imaging in the genome and include those involved more widely in will lead to the identification of genetically valid trait mark- psychosis, or lie within 22q11. However, it seems unlikely that these phenotypes will does not appear to be related to the size of the deletion provide a rapid solution to the problem. However, it is possible that susceptibility to psychosis to ensure that the measures used are stable and determine reflects allelic variation of a hemizygous gene or genes within the extent to which they are affected by state. The gene encoding catechol-O-methyltransfer- be of use in gene mapping, such measures will have to be ase (COMT), an enzyme involved in the catabolism of cate- practicably applied to a sufficient number of families or cholamine neurotransmitters, maps to the VCFS region and unrelated patients. Third, we will need to ensure that the is therefore an obvious candidate for influencing the expres- traits identified are highly heritable, which will itself require sion of psychosis in VCFS probands. This gene exists in a return to classic genetic epidemiology and model fitting. However, concerned with enhancing the traditional categoric ap- Murphy and colleagues (149) found no evidence for an proach to defining psychiatric disorders by identifying ge- association between the allele for low-activity COMT and netically valid phenotypes that can be measured quantita- either schizophrenia or schizotypy in patients with VCFS. These can be used in quantitative trait locus approaches to gene mapping. Work in this area has begun but still faces problems, particularly those relating to the FUTURE DIRECTIONS confounding influence of state-related effects. Perhaps the best hope of taking account of the complexity and heteroge- Refining the Phenotype for Molecular neity of the schizophrenia phenotype comes from new Genetic Studies methods of analysis in which aspects of the phenotype can The effectiveness of molecular genetic studies depends on be entered as covariates in linkage analyses (164). Perhaps if we were better at defining phenotypes, we would be better Genome-wide Association Studies at finding genes. It is worth reiterating at this point that the commonly used diagnostic criteria define phenotypes In recent years, interest has increased in the possibility of with high heritability. In principle, therefore, it should be systematic, genome-wide association studies (109,165). However, perhaps genetic validity been fueled by the fact that the most abundant form of could be improved by focusing on aspects of clinical varia- genetic variation, the single-nucleotide polymorphism, is tion, such as age at onset or symptom profiles, or by identi- usually bi-allelic and potentially amenable to binary, high- fying biological markers that predict degree of genetic risk throughput genotyping assays such as microarrays (so-called or define more homogeneous subgroups. Moreover, as sequence data accumulate, it spite much work, it has not been possible to identify geneti- has become possible to contemplate the construction and cally distinct subtypes of schizophrenia. Instead, clinical application of very dense maps of hundreds of thousands variation is likely to reflect at least in part a combination of single-nucleotide polymorphisms (165). In the former, asso- sion rather than the risk for illness per se. Examples of this ciation is sought between a disease and a comprehensive phenomenon are probably age at onset and symptom pat- catalogue of every variant that can alter the structure, func- tern in schizophrenia (161,162). In contrast, indirect The search for trait markers aims to move genetic studies studies seek associations between markers and disease that beyond the clinical syndrome by identifying indices of ge- are caused by linkage disequilibrium between the markers netic risk that can be measured in asymptomatic persons or and susceptibility variants. The hope is that if sufficiently by identifying markers of pathophysiologic processes that dense marker maps can be applied, it will be possible to are closer to the primary effects of susceptibility genes than screen the whole genome systematically for evidence of link- Chapter 49: Molecular and Population Genetics of Schizophrenia 681 age disequilibrium without actually having to screen every chiatry (170), although with some trait markers, we need functional single-nucleotide polymorphism in the genome. We should also not forget that there is no a priori functional single-nucleotide polymorphisms in regulatory reason why responses to behavioral and psychological treat- rather than coding regions of the genome, uncertainty about ments should be less influenced by genetic factors than by the distances over which linkage disequilibrium is main- pharmacologic treatments. Animal Models Given these considerations, it seems clear that the era of genome-wide association studies, direct or indirect, is not Another important challenge will be the development of yet at hand. Instead, studies in the next few years should suitable animal models to allow functional studies of puta- probably focus mainly on the direct approach utilizing sin- tive disease loci (165). Disorders that predominantly involve gle-nucleotide polymorphisms from the coding sequence higher cognitive function, such as schizophrenia, are likely that actually alter protein structure in a wide range of func- to prove difficult to model in animals. However, certain tional and positional candidate genes.

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