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By E. Saturas. Stonehill College.

These Imaging studies have reported increased pituitary and data generally were interpreted as indicating that the de- adrenal size during depression order cheapest super avana and super avana, which appear to normalize pressed patient was highly stressed purchase 160mg super avana with amex. Increased pituitary size and ele- One method for challenging the axis is to administer the vated CSF CRH levels are associated with DEX nonsuppres- synthetic steroid dexamethasone (DEX) (104) generic super avana 160mg with amex. Elevated plasma ACTH levels have been re- pected response is to suppress the axis because the pituitary ported in psychotic depression (119) cheapest super avana. AVP neurons are increased in the PVN strate a significantly higher nonsuppression rate than do of suicide victims (120) and serum AVP has been reported controls, although the rates of nonsuppression are relatively in one study to be elevated in hospitalized depressives (121). Patients with severe or psychotic CRH is also found in extrahypothalamic brain regions. In- responses and over-activation of these systems may lead to deed, psychosis appears to be the greatest symptom or syn- panic and depression (2). Amygdala CRH has been reported Chapter 72: Molecular and Cellular Mechanisms in Depression 1045 to be under positive (stimulatory) feedback by cortisol and tissue suggestive of an autoimmune thyroiditis, often in the this observation has spurred on much research to develop face of normal T4,T,3 or TSH levels. A recent report on an open label trial suggested CSF TRH was increased in two small studies of depressed that a CRH antagonist might be effective in hospitalized patients as compared to controls (124,125), although not depressives (122). Elevated TRH levels should be ac- Although the literature has emphasized elevated CRH companied by a blunted TSH response to TRH because and cortisol activity in major depression (in part because of TRH levels in the pituitary would be expected to be down- the emphasis on DST nonsuppression), there is emerging regulated in the face of elevated TRH. Indeed, multiple evidence that CRH and cortisol activity may only be ele- studies have reported such blunting in a relatively high per- vated in some subtypes of major depression and that some centage (approximately 25%) of patients with major depres- depressed patients may actually have low HPA activity. A recent review concluded that 41 of 45 studies re- cent data suggest that depressed patients with a history of ported blunted TSH responses to TRH in major depression early abuse (as well as those with psychosis) may be most (127). Blunting of TSH responses to TRH in these patients consistently at risk for demonstrating elevated ACTH levels is not owing to clinical or subclinical hypothyroidism be- in response to social stress (123). Depressives who were not cause thyroid parameters were generally within normal lim- abused as children did not show similar responses. Similarly, low values have been responses to TRH (1). Antithyroid antibodies may be pres- reported in several other types of patients, including atypical ent. Type II hypothyroidism is characterized by normal T3 depression, posttraumatic stress disorder, so-called burn out or T4 levels but otherwise similar abnormalities as in Type syndromes, and so on. Rates of Type III or IV subclinical hypothy- HPA axis activity may be found in specific depressive sub- roidism have been reported to be elevated in depressed pa- types. In many ways this parallels the findings in catechol- tients. These syndromes are both characterized by normal amine activity in depressed patients. First, the DST as we presence of antithyroid antibodies. In one study, depressed use it may not measure cortisol overactivity as much as it patients with high normal thyroid levels were also reported does central CRH overdrive in response to suppressing the to demonstrate exaggerated TSH responses to TRH (128). Second, previous studies have often not with major depression may have subclinical hypothyroid- explored the role of psychosis or early abuse. Indeed, asymptomatic autoimmune thyroiditis with tively few studies on the HPA axis in depression have ex- positive antibodies has been reported to be relatively high plored cortisol activity over the full 24-hour period. Taken together, TSH stimulation test data suggest elevated or decreased TRH activity could be involved in HPT Axis major depression, depending on whether patients met crite- The overlap in symptoms between patients with hypothy- ria for subclinical hypothyroidism. Patients with a history of thyroid yielded intriguing, although at times, conflicting results. One possible explanation which in turn stimulates specific receptors in the pituitary to for the differential effects of T4 and T3 on mood rests with release triiodothyronine (T3) and thyroxine (T4) hormones. Depressed patients have been reported to demon- Activity of the axis can be measured in several ways: strate increased reversed T3 levels in CSF (130), which sug- circulating levels of T3 and T4—both bound and unbound; gests inhibition of the Type II 5′ deiodinase and subsequent TRH levels in the CSF; TSH responses to TRH administra- increased activity of the Type III of the enzyme. Cortisol tion (TRH-stimulation test); and circulating TSH levels. Of interest is a recent report (133) 1046 Neuropsychopharmacology: The Fifth Generation of Progress that in depressed patients low T3 levels predicted earlier tems and their complex interactions in depression. Also, relapse, pointing further to an important role for T3 in research has tended to emphasize cross-sectional rather than mood relation. Future research that Transthyretin levels have been reported to be low in refrac- combines genetic risk factors with longitudinal study of tory depressed patients (134). This may also help explain multiple systems will likely lead to breakthroughs in our possible CNS enhancing effects of T3 in the face of normal understanding of the biology of the disorder. However, there are still a number of seeming contradictions regarding the direc- tion and specific nature of HPT alterations in depression. REFERENCES Data point to both elevations in central TRH activity and subtle forms of hypothyroidism (suggestive of low T3 and 1. Biology of TRH activity) as playing potential roles in major depression. Washington, DC: The Ameri- can Psychiatric Press, 1998:549–588. Growth hormone (GH) is synthesized in the anterior pitui- New York: Oxford University Press, in press. Two hypothalamic hormones, growth hormone releas- 3. The catecholamine hypothesis of affective disor- ders: a review of supporting evidence. Am J Psychiatry 1965; ing factor (GRF) and somatostatin modulate its release from 122:509–522. Somatostatin is also found in extra-hypotha- Arch Gen Psychiatry 1965;13:137–152. Toward a major neurotransmitters involved in mood regulation (e. X: Urinary catecholamines, their metabolites, and D-type scores in norepinephrine, serotonin, and dopamine) all affect GH subgroups of depressive disorders. Arch Gen Psychiatry 1989; release, and these systems can be challenged by specific com- 46(3):260–268. Catecholamine metab- Diurnal rhythms of GH, as measured in plasma, are dis- olism, depressive illness and drug response. Nocturnal GH is elevated in depres- 1972;26:252–262. Toward a bio- sion (135), but daylight-stimulated GH levels are increased chemical classification of depressive disorders. I: Differences in in both unipolar and bipolar depressives (136). GH responses to GRF have also been ex- chiatry 1978;35(12):1427–1433. Urinary 3-methoxy- 4-hydroxyphenylglycol and major affective disorders: a replica- not all, groups reporting blunted GH responses (137–139). CSF levels of somatostatin, which inhibits GH, CRH, and 9. Toward a ACTH release, are also reduced in depression (140,141), biochemical classification of depressive disorders. V: Heteroge- such that somatostatin does not appear to provide an expla- neity of unipolar depressions. Toward a Low somatostatin levels in depression may reflect increased biochemical classification of depressive disorders. VII: Urinary cortisol activity (1,142) and appear to normalize with treat- free cortisol and urinary MHPG in depressions. Low CSF somatostatin has also been observed in 1983;140:314–318. Plasma cortisol, catechol- amine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity in manic-depressive patients. Lithium carbonate Proliferation of research into the biology of depression has treatment of mania. Catecholamine metab- focused on single biological systems such that there is a olism, depressive illness and drug response. Arch Gen Psychiatry dearth of studies that simultaneously explore multiple sys- 1972;26:252–262. Chapter 72: Molecular and Cellular Mechanisms in Depression 1047 15.

Among these is whether schizotaxia degree of genetic relatedness decreases generic 160mg super avana overnight delivery, is also compatible always or even usually progresses to schizotypal personality with a model of multiple loci with epistasis (interaction disorder or schizophrenia order 160 mg super avana visa. Our empiric analyses suggest that between genes) (79) buy generic super avana canada. However buy super avana 160 mg without prescription, the number of susceptibility the basic symptoms of schizotaxia occur in 20% to 50% of loci, the disease risk conferred by each locus, and the degree adult relatives of patients with schizophrenia (68,69). This of interaction between loci all remain unknown. The contri- rate is considerably higher than the rates of schizophrenia bution of individual genes to the familiality of a disorder or schizotypal personality disorder likely to develop in first- can be expressed in terms of (s (i. The false-positives were largely the patible with the existence of a single locus having a value consequence of a combination of multiple testing and the of (s greater than 3. Unless extreme epistasis (interaction use of statistical methodology and significance levels derived between loci) exists, models with two or three loci having from work on single-gene disorders. It should be Despite the failure to identify regions of unambiguous emphasized that these calculations are based on the assump- linkage in multiply affected families, modest evidence for tion that the effects of genes are distributed equally across several regions has been reported in more than one data set. It is quite possible that genes of larger Areas implicated for which supportive data have also been effect are operating in a subset of patients—for example, obtained from international collaborative studies include those from families with a high density of illness. A number of other promising evidence that genetic factors increase the risk for schizophre- areas of putative linkage are also currently under investiga- nia. However, although it is possible to state that, as a group, tion by international consortia. However, in each general population, it is not currently possible to translate case, both negative and positive findings have been ob- this figure to the level of risk for a particular sibling in a tained, and in only two cases, those of chromosomes particular family. Another These positive findings contrast with those from a large important point is that risk to related individuals does not systematic search for linkage in which a sample of 196 af- directly equate with genetic risk because some relatives carry fected sibling pairs, drawn typically from small nuclear fami- one or more susceptibility alleles for schizophrenia but re- lies rather than extended pedigrees, was used (101). In other words, the results of simulation studies suggest that the power of this accumulation of susceptibility alleles, environmental risk study is greater than 0. This study yielded evidence at the level of the definition of Lander and Kruglyak (102) of 'suggestive' linkage to chromosomes 4p, 18p, and Xcen. However, none MOLECULAR GENETICS: LINKAGE STUDIES of the findings approached a genome-wide significance of 0. This was done in the hope that such families, in the search for genes for complex traits (103–106). First, or at least a proportion of them, were segregating genes of no finding is replicated in all data sets. Second, levels of sufficiently large effect that they could be detected unequiv- statistical significance are unconvincing and estimated effect ocally in this way. This approach has been successful in sizes are usually modest. Third, chromosomal regions of other complex disorders—Alzheimer disease, for example, interest are typically broad [often 20 to 30 centimorgan in which mutations in three genes, APP, PS1, and PS2, are (cM)]. In such At the present time, therefore, the linkage literature sup- cases, the disease is of unusually early onset and is transmit- ports the predictions made by Risch (79); it is highly un- ted through multiplex pedigrees in an autosomal dominant likely that a commonly occurring locus of effect size [(s] fashion (80–82). Studies of such large families also initially gions suggest that rarer alleles of larger effect may be segre- produced positive findings in schizophrenia (83), but unfor- gating in some large, multiply affected families. The reasons for this Linkage methods in sample sizes that are realistically have become clear as data from systematic genome scans achievable can detect smaller genetic effects than those in have accumulated; highly penetrant mutations causing the studies to date. For example, it is possible to detect schizophrenia are at best extremely rare and quite possibly alleles with values of (s of 1. However, the purpose of experiment is to reject that priority should now be given to collecting such samples a null hypothesis, and in the face of uncertainty, the burden with a robust clinical methodology that is comparable across of proof remains with the proponents of a particular candi- all interested research groups. Overall, the results in this extensive literature CANDIDATE GENE ASSOCIATION STUDIES are disappointing, but it should be noted that the sample sizes in many of the older studies would now generally be Once genes of smaller effect than (s 1. For this reason, many research- represent functional variants and that few genes have been ers have tried to take advantage of the potential of candidate systematically screened even for common functional var- gene association studies to identify such loci (109,110). However, more promising reports of candidate gene though a potentially powerful means of identifying genes associations have recently appeared, three of which are con- of small effect, association studies are not without their sidered here. First, for a complex and poorly understood disor- der such as schizophrenia, the choice of candidate genes Serotonin 5-HT2A-Receptor Gene is limited largely by the imagination and resources of the researcher. This places a stringent burden of statistical proof Many novel antipsychotic drugs affect the serotoninergic on positive results because of low prior probability and mul- system. The first genetic evidence that serotoninergic recep- tiple testing (111). Second, case–control association studies tors may play a role in schizophrenia came from a Japanese have the potential to generate false-positives because of pop- group reporting an association between a T-to-C polymor- ulation stratification. This problem can be addressed by phism at nucleotide 102 in the 5-HT2A-receptor gene in a using family-based association methods (112), but because small sample (114). A large European consortium compris- of stigma, adult age at onset, and the disruptive effects of ing seven centers and involving 571 patients and 639 con- mental illness on family relationships, family-based samples trols then replicated this finding (115), which was further may be unrepresentative in addition to limited in size. Con- replicated with use of a family-based design (116). Although sequently, family-based studies may introduce more spu- many other studies followed with mixed results, a recent rious results than do case–control studies (113). It would metaanalysis of all available data from more than 3,000 seem unwise, therefore, to discard the case–control study subjects supports the original finding (p. A third problem common to all molecular genetic (117). If we assume homogeneity and studies, larger sample sizes are required than have typically if the association is true, the putative odds ratio (OR) for the been used to date in psychiatric genetics (111). Fourth, even C allele can be expected to be around 1. Sample sizes of 1,000 subjects are then be required replication study will be sufficiently powered to replicate a for 80% power to detect an effect of this size, even at a particular effect. This is because variations may be noted in relaxed criterion of p. Thus, the negative studies are the contribution of a given susceptibility allele in different effectively meaningless, but it is also true that the evidence patient populations as a result of different allele frequencies for association, even in the metaanalysis (p. Further poten- not definitive if genome-wide significance levels are required tial for heterogeneity occurs if the association with the (109). At present, all we can conclude is that the evidence marker is a result of tight linkage with the true susceptibility favors association between the T102C 5-HT2A polymor- allele, or if different subtypes of the disease exist. Given that phism and schizophrenia, but the most stringent burden of all the above factors may influence power, and that none proof has not yet been met. T102C is 678 Neuropsychopharmacology: The Fifth Generation of Progress in complete linkage disequilibrium with a polymorphism tance of schizophrenia is at least consistent with the presence in the promoter region of this gene, but no evidence has as of anticipation, although ascertainment biases offer an alter- yet been found that this has a functional effect either (116). Because pathogenic expanded tri- Recent evidence of polymorphic monoallelic expression of nucleotide repeats are the only known genetic mechanisms the 5-HT2Agene points to the possible existence of sequence for anticipation, these findings have been taken as suggest- variation elsewhere that influences gene expression (118), ing that such mutations may account for at least some of and this may be the true susceptibility variant. This hypothesis was supported by two groups who observed that the maximum length of the most common D3 Dopamine-Receptor Gene known pathogenic trinucleotide repeat, CAG/CTG, was Association has been reported between schizophrenia and greater in patients with schizophrenia than in unaffected homozygosity for a Ser9Gly polymorphism in exon 1 of the controls (125,126). These findings were later replicated in a D3 dopamine-receptor gene (DRD3) (119). Unfortunately, the early HT2A association, the results have now been confirmed in repeat expansion detection (RED) studies were followed by several independent samples, including one family-based a series of unsuccessful attempts to identify the relevant study (120), but several negative studies have also been re- repeat-containing loci by a variety of methods, and by sev- ported. Metaanalysis of data from more than 5,000 individ- eral failures to replicate the RED findings (128–130), thus uals has revealed a small (OR 1. Again, this cannot easily be as- however, with the report of an association between schizo- cribed to selective publication (120). Because it is a fairly phrenia and alleles of a member of the family of calcium- uncommon genotype, we cannot be certain that homozy- activated potassium channel genes, KCa3 (hKCa3/KCCN3) gosity for the 9Gly allele alone is not associated with an (131). For several reasons, KCa3 seemed a remarkable can- increased risk for schizophrenia, and therefore it is not cer- didate gene for schizophrenia. First, the gene contained two tain that the findings at D3 are an example of heterosis. Second, However, a plausible biological explanation for D3 heterosis the family of genes to which it belongs is thought to play has been put forward in that possession of two different an important role in regulating neuronal activity, and it was molecular forms of the receptor may allow the dopaminergic therefore considered a functional candidate gene. Ironically, KCa3 gene is similar to that of the 5-HT2A-receptor gene—that maps not to 22q11 but to 1q21 (132), which is also a region is, the balance of evidence at present favors association, but implicated by linkage studies as possibly containing a sus- the null hypothesis still cannot be confidently rejected.

The Act makes no distinction between failure of a study to find a drug placebo difference is owing the value of symptomatic treatments and those that are ad- to the inability of the sample of patients randomized in the vanced as cures for a disease buy generic super avana 160 mg on line. Almost any claim can be made super avana 160 mg low cost, study to respond to drug order 160 mg super avana with mastercard. The agency is mindful super avana 160 mg generic, of course, that a tion of the effectiveness of new drug products. In light of single dose is unlikely to be the best choice for all patients; the variability in course and outcome among samples of nonetheless, for dose evaluation purposes, a fixed-dose de- patients assigned the same psychiatric diagnosis, it is highly sign is more likely to be interpretable than a dose titration unlikely that either the historic control or the no control design. Clinicians often find this assertion counterintuitive, designs would ever be deemed acceptable for the evaluation but designs allowing up-titration for therapeutic nonre- of a drug for a psychiatric indication. To the contrary, the for data that might better inform the use of prescription choice of patient subject is almost always based on the spon- drug products in children. This sampling strategy is not of investigational drugs in children a premarket obligation. In some patients with the condition for which the treatment 1998, however, the agency issued new regulations (21 CFR will be marketed. For example, prior to the of the patient samples that had been employed in them promulgation of DSM-III in 1980, sedatives, as they were and whether or not long-term maintenance trials had been then known, were granted broad and nonspecific claims for conducted. The strategy employed was intended to reserve anxiety, anxiety neurosis, etc. In recent years, claims have been chotic conditions other than schizophrenia. In dealing with these drugs shown to be effective in studies enrolling schizo- issues, the agency has to consider whether or not already phrenic patients will get claims for use in schizophrenia, approved older claims subsume the new entities. Incidentally, the newly announced approach claim simply a re-expression of a previous one, a claim for to product labeling is perfectly reasonable and certainly con- a subset of the patients covered by the previously approved sistent with the requirements of law, although it is obviously claimed use, or an entirely new claim for a previously nonex- not the one that the author prefers. Drugs are administered to individ- of related claims may be. For example, sponsors often seek uals, not diagnoses. There is advantage in knowing, there- to define a claimed use in a way that will allow the unique fore, whether, and if so how and to what extent, various promotion of their drug product (i. Claims advanced by sponsors for the use of sponse rates among samples of patients assigned identical marketed antipsychotic drug products in the management psychiatric diagnoses documents that our current psychiat- of psychotic demented patients are a case in point. As a consequence, to dem- regularly deemed to be pseudospecific, in the absence of onstrate that their products are effective in use, sponsors evidence to prove the contrary. As discussed, from a far as the author can determine, came about because the strictly regulatory perspective such criticisms are irrelevant. Support for other and/or more demanding standards for establishing the existence of this entity derived primarily from the testi- drug effectiveness, but it did not. Although there is little doubt that the algo- rather than a true drug effect, accounts for the positive study rithm endorsed by the PDAC does capture demented indi- reports submitted in the application. Reviewers search for evidence that classes of drugs to be something else: nutriceuticals, botani- the randomization process failed, the treatment mask was cals, food supplements, etc. These substances escape the penetrated, subjects failed to comply with protocol require- premarket drug clearance requirements of the FDDCA be- ments, etc. The extent, pattern, and timing of premature cause they are deemed by DSHEA not to be drugs. Subsumed within the ill-described mix of botanicals, equal). The lack of data bearing on the safety and efficacy of THE FUTURE OF DRUG REGULATION these drug substances did not deter the Congressional Lead- ership, however; to the contrary, when Senator Orin Hatch, These are, at once, the best of times and the worst of times a sponsor of DSHEA, introduced the bill he asserted that for medical therapeutics. In my own hold sanguine expectations for the future in regard to the state of Utah, healthy life-styles, coupled with common use discovery and development of effective new treatments. On of dietary supplements have made a real difference. Our the other hand, the armamentarium stands at increasing state is one of the healthiest in the nation and we enjoy one risk of being polluted by worthless, even unsafe drugs. Signs of the lowest incidence rates for cancer and heart disease. In Utah, the use of herbs is a well-accepted practice that The public is gullible and uncritical where therapeutic has passed from generation to generation (18). Even more alarming is the infer- lars on unproved, perhaps unsafe, remedies and nostrums. It is arguable whether such dual demonstrated that it can, with the limited authority it has expectations truly advance the interests of the public health, under the FFDCA, serve as an effective guardian of the however. As the former head of the FAA noted when she drug supply. An egregious and illuminating example of its scientific, and health care communities. Princeton, NJ: Princeton University Press, By what is as close to an Orwellian 1984-like maneuver 1970:151–174. Berkeley: University of psychiatric drugs: an historical context. Biol Psychol 2000;47: California Press, 1974:107–137. Factors influencing clinical evaluation absolutely safe drug. Berkeley: Univer- of drugs with special reference to the double-blind technique. The extent of population exposure to assess clinical 12. Hazards of inference: the active control investigation. Is there an alternative to the randomized controlled 5. Symptom reduction and suicide York: Guilford Press, 1992:3–12. Thrombotic thrombocytopenic purpura and Clopi- trials: an analysis of the FDA database. Arch Gen Psychiatry 2000; dogrel—a need for new approaches to drug safety. Statistical power analysis for the behavioral sciences, rev employing enrichment strategies for sample selection. DSM-III and the transformation of American psy- DG, Cooper FM, Kahan JS, eds. Guidance for industry: providing clinical evidence of 18. Supplement Health andEducation Act: a legislative history and 10. The use of placebo control groups in the assessment of analysis. KENNEDY The advances in molecular medicine are taking place at a (xenobiotics) or environmental factor including foodstuffs, hitherto unprecedented pace. Genetics has come of age and pesticides, infectious diseases, and ionizing radiation (5–7). It is clear that these advances will 40 years ago to emphasize the role of heredity in person- soon lead to identification of many genes causing common to-person differences in drug response (1,2). The focus of complex diseases, thereby creating numerous new potential drug targets. This will also present a bioinformatics and pharmacogenetic investigations has traditionally been unu- data analysis challenge for lead optimization among numer- sual and extreme drug responses resulting from a single gene ous new chemical entities (NCE) directed to such disease effect. Pharmacogenomics is a recently introduced concept targets for therapeutic purposes. Pharmacogenomics is a hy- that attempts to explain the hereditary basis of both mono- brid research field that bridges the knowledge gained from genic as well as subtler and continuous variations in drug the Human Genome Project with existing principles of pop- responses that are under multigenic control (3). Although ulation genetics, pharmacokinetics, pharmacodynamics, cell the two terms are often used interchangeably, the scope physiology, proteomics, and bioinformatics. It is expected of pharmacogenomic investigations follows a genome-wide that pharmacogenomics will importantly contribute to de- approach and also aims to identify novel biological targets velopment of guidelines for rational and personalized drug for drug discovery, with use of the new affordable high- treatment; it should also expedite the drug discovery, devel- throughput molecular genetic technologies (4). In theory, opment, and approval process in the pharmaceutical indus- pharmacogenomics can assist in clinical decision making to try (8).