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By W. Marcus. Rockhurst University.

The overactive or poorly socialized child may be punished or ostracized buy tadapox 80 mg with visa erectile dysfunction yoga. Child abuse (physical 80 mg tadapox mastercard erectile dysfunction caused by herpes, emotional and sexual) is not infrequent discount 80 mg tadapox with mastercard erectile dysfunction my age is 24, and can have long-term deleterious effects on mental health. Mental illness or criminality of parents may lead to emotional neglect or periods of parental absence. While divorce is common and frequently leads to emotional trauma for the child, the experience of parental divorce is childhood is not an indicator of adult psychiatric or somatic disorder (Linberg & Wadsby, 2010). Bullying behaviors are distinct from other forms of aggressive behaviors. They are characterized by repeated hurtful actions between peers where a power imbalance exists, and being bullied is considered a significant stressful life experience. Bullying appears to be common, and is reported by 13% of children and adolescents during a school year world wide (Craig et al, 2009). Direct bullying (physical acts) is more common among boys and indirect bullying (exclusion and ostracism) is more common among girls. Genetic factors Genetic factors have been identified in many childhood psychiatric disorders. Separation anxiety, which is known to be influenced by environmental factors (including paternal absence), has significantly heritable components in large twin studies (Eley et al, 2003; Cronk et al, 2004). Attention Deficit/Hyperactivity Disorder is familial and highly heritable, and the disorder is being refined to identify phenotypes for use in the search for susceptibility genes (Thapar et al, 2006). Associations have been reported with variations in genes for the dopamine receptors 4 (DRD4) and 5 (DRD5) and a dopamine transporter (DAT1) (Collier et al, 2000). The most robust of these is the association between ADHD and a repeat within the coding region of DRD4 (Faraone et al, 2001). Twin studies report MZ concordance rates of 60-90% compared with DZ concordance of 5%, giving an estimated heritability of over 90% (Rutter et al, 1999). There is some evidence for a locus on chromosome 7 and another on chromosome 2, but multiple genes of small effect is the probable mechanism (Klauck, 2006). For the latest on the genetics of autism and Tourette syndrome, see State (2010). DNA is wrapped around histone proteins to form chromatin. The state (condensation) of the histones causes the DNA to be more tightly or loosely packed – resulting in regulation of access to particular genes, thereby influencing gene expression. Histones condensation is achieved by methylation, acetylation and other chemical changes, and may remain life-long [and in some circumstances, may be inherited]. Hoffmann and Spengler (2012) summarize, “(e)arly social life experiences become embedded in the circuitry of the developing brain and are associated with lifelong consequences”. A study (Wang et al, 2012) of the first two years of life found a range of individual variation in genome-wide methylation. It is also suggested that maltreatment of children may produce epigenetic changes which result in mental health and physical disorders later in life (Yang et al, 2013). These children may have significantly different methylation marks. Separation anxiety disorder In DSM-5, Separation anxiety disorders is listed under “Anxiety Disorders”. Separation anxiety in characterized by inappropriate or excessive anxiety which occurs when the child is separated from the people or home to which he/she has developed strong emotional attachment. It may be seen when children first begin to attend school, but may occur at other stages. There may be recurring distress at the anticipation of separation, or worry about losing the subject of attachment. There may be fear about being alone, refusal to sleep separate from the attachment figure, or nightmares about separation. There may be complaints of physical symptoms when separation is imminent. Separation anxiety is often managed by advice on parenting skills. Separation anxiety is difficult to distinguish from generalized anxiety in children (some regard these as synonymous terms). In the epidemiology study of Silva and Stanton (1997) separation anxiety was reported at 3. In a recent report (Keeton et al, 2009) generalized anxiety was reported at 10%, with a mean age of onset at 8. A combination of CBT and SSRI is recommended, with the continuation of medication for 1 year following remission of symptoms. A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with function, as characterized by (1) and/or (2) 1) Inattention - six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities b) often has difficulty sustaining attention in task or play activities c) often does not seem to listen when spoken to directly d) Often does not follow through on instructions and fails to finish schoolwork, chores or duties in the workplace e) often has difficulty organizing tasks and activities f) often avoid, dislikes, or is reluctant to engage in tasks that require sustained mental effort g) often loses things necessary for tasks or activities h) often easily distracted by extraneous stimuli i) often forgetful in daily activities 2) Hyperactivity and impulsivity - six (or more) of the following symptoms have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental levels: a) often fidgets with hands or feet or squirms in seat b) often leaves seat in classroom or in other situations in which remaining seated is expected c) often runs about or climbs excessively in situations in which it is inappropriate d) often has difficulty playing or engaging in leisure activities quietly e) is often “on the go” or often acts as if “driven by a motor” f) often talks excessively g) often blurts out answer before questions have been completed h) often has difficulty awaiting turn i) often interrupts or intrudes on others B. Some hyperactive-impulsive or inattentive symptoms that caused impairment were present before age 7 years. Some impairment from the symptoms is present in two or more settings (school, work, home) D. There must be clear evidence of clinically significant impairment in social, academic or occupational functioning. These diagnostic criteria look simple but are actually difficult to use properly, and special training may be necessary. This diagnosis is frequently made incorrectly, often by teachers, parents or patients themselves. Cardinal features include inattention, hyperactivity, and impulsivity. The differential diagnosis includes age appropriate behaviour and a mismatch between parents and child (e. ADHD has recently been associated with obesity (Ptacek et al, 2010). This is somewhat counterintuitive as increased activity might be expected to cause weight loss. The explanation is unclear, but may involve impulsivity and eating habits. The prevalence is around 4% of primary school children, boys being three times more commonly affected than girls. An association between early attachment problems and ADHD is probable. A neuroimaging study (Adisetivo et al, 2013) which was careful to exclude children with co-morbid disorders reports that in pure ADHD (compared to healthy controls) showed abnormal grey and white matter changes in bilateral frontal and parietal lobes, insula, corpus callosum , and right external and internal capsules. Parents and teachers need to be educated about the disorder and involved in the designing and provision of management strategies.

Alternative definitions of pharmacogenetic poly- the related biological covariates (e discount tadapox 80 mg overnight delivery impotence reasons and treatment. At present 80mg tadapox with mastercard erectile dysfunction pump demonstration, pharmacogenomics is ex- suggested (28 generic 80mg tadapox with visa erectile dysfunction las vegas,29). For example, Harris (1980) proposed tending the early pharmacogenetic studies of drug metabo- that a genetic polymorphism occurs if the '... It was pointed out earlier that if the goal namic pharmacologic cascade, from drug absorption and of pharmacogenetic studies is to investigate the clinical rele- transport to drug–receptor interface and beyond. The vance of pharmacogenetic polymorphisms, phenotype- progress made by pharmacogenomics, in many ways, is akin based definition of polymorphisms might be more applica- to developments in the computer industry. On the other hand, if the goal is to use genetic benefits of high speed and efficient computing was self- polymorphisms as anthropological tools to study the evolu- evident early in the days of cumbersome mainframe com- tion of the species and differences in response to xenobiotics puters, but it was not until the development of low-cost and between populations, a definition incorporating both allelic proficient microcomputers that computerized information variations and phenotype may be more appropriate to allow processing could be applied in daily life (analogous to con- understanding at a molecular and mechanistic level (28). GENETIC VARIABILITY IN DRUG METABOLISM: CONTRIBUTION TO PHARMACOKINETIC VARIABILITY HUMAN GENETIC VARIATION AND SINGLE NUCLEOTIDE POLYMORPHISMS Drug metabolism is one of the pivotal factors, which con- tribute to variability in pharmacokinetics. Drug metabolism The biallelic single nucleotide polymorphisms (SNPs) rep- is generally divided into two phases. Phase 1 reactions in- resent the most common DNA sequence variation in the volve oxidative, reductive, and hydrolytic reactions, which human genome. It is thought that the complete human unmask or introduce a functional group (e. This often results in an moters will contain approximately one million SNPs (26). Phase 2 reactions involve SNPs often result in predictable changes in amino acid se- conjugation (e. Although drug metabo- of common complex diseases and pharmacologic traits. In lism is necessary for the elimination of lipophilic drugs (e. A recent CYP2D6*17, occurs at high frequency in many black Afri- analysis of over 300 drugs from diverse therapeutic classes can populations and African-Americans. However, there ap- such as psychotropics, analgesics, and anti-infectious agents pears to be considerable heterogeneity in the CYP2D6 locus found that 56% of them primarily depend on CYPs for in Black populations. Among CYPs, the largest were PMs of debrisoquine, 16% carried the CYP2D6*10B contributions are made by CYP3A4 (50%), CYP2D6 allele characteristic of Asian populations, and the (20%), CYP2C9, and CYP2C19 (15%) (32). Some of the CYP2D6*17 was present in 18% of the subjects (38). The clinical signifi- POLYMORPHISM: A COMMON AND cance of reduced catalytic function associated with the CLASSICAL EXAMPLE OF A MONOGENIC CYP2D6*17 allele requires further research in patients with VARIATION IN DRUG METABOLISM African ancestry. At present, more than 50 CYP2D6 alleles were described CYP2D6 genetic polymorphism is one of the most inten- that encode an enzyme with inactive, decreased, increased, sively studied autosomal recessive monogenic defects in or normal catalytic function. Many psychotropics, including most typi- CYP2D6 genes correlates with drug and metabolite concen- cal (e. In general, PMs are at risk for drug toxicity on treatment with medications line), drugs of abuse, some of the serotonin reuptake inhibi- predominantly inactivated by metabolism via CYP2D6. For example, codeine does not poor metabolizers (PMs), whereas the rest are extensive me- produce analgesic effects in PMs or after treatment of EMs tabolizers (EMs) for CYP2D6 substrates (35). The preva- with CYP2D6 inhibitors such as quinidine. Among EMs, lence of PMs and the distribution of enzyme activity appear those with duplicated or multiduplicated CYP2D6 genes to be fairly consistent across the Western European and and ultrarapid metabolism may develop subtherapeutic North American Whites. On the other hand, the frequency plasma concentrations and inadequate clinical response and type of CYP2D6 alleles vary considerably among differ- (40). Although high doses would be necessary in such pa- ent ethnic groups. In Asians, the prevalence of PMs is only tients, an alternative strategy would be to use low subthera- 1%, owing to almost complete absence of the nonfunctional peutic doses of the CYP2D6 inhibitor quinidine, especially alleles (e. However, an for drugs with high acquisition costs, to attain therapeutic often overlooked point in comparisons of pharmacogenetic plasma concentrations (41). Overall, routine genotyping for polymorphisms between populations (e. In addi- tion) display a significant shift in the distribution of tion, the markedly increased metabolite formation in pa- CYP2D6 activity toward lower levels. The molecular basis tients with multiduplicated CYP2D6 genes may potentially of a lower CYP2D6 activity in Asian EMs is owing to a lead to qualitatively different and unexpected drug effects 188 34 C NT base change in exon 1 which leads to Pro NSer and toxicity (40). This allele was named CYP2D6*10 (51% allele fre- fractions in the brain. Hence, CYP2D6 may potentially quency in Chinese) and leads to a 10-fold decrease in activ- contribute to local clearance of psychotropics at the site of ity in vivo (35). Thus, there may be discrete interindividual action (42). Moreover, CYP2D6 in the brain is functionally differences in disposition and therapeutic/adverse effects of associated with the dopamine transporter and shares similar- Chapter 37: Pharmacogenomics and Personalized Therapeutics 499 FIGURE 37. Average plasma concentra- tions of nortriptyline and 10-hydroxynor- triptyline after a 25-mg single oral dose in Whitehealthy volunteerswith0, 1,2, 3,and 13 functional copies of the CYP2D6 gene. Note that the concentration of nortripty- line and its metabolite 10-hydroxynortrip- tyline are inversely affected by the number of functional CYP2D6 gene. Reprinted with permission from Dale´n P, Dahl ML, Ruiz ML et al. Dif- IN DRUG METABOLISM ferences in personality traits between EMs and PMs were noted in both Swedish and Spanish healthy White subjects, The term 'polymorphic metabolism' is often perceived as also suggesting that there may be an endogenous substrate an alarming indication of marked variability in drug disposi- for CYP2D6 in the brain (42). Although this assertion is correct to a certain extent, The common polymorphic drug metabolizing enzymes it does not imply that a nonpolymorphic drug-metabolizing in humans and their major variant alleles are presented in enzyme is associated with reduced variability. A worldwide web page with detailed de- CYP3A4 is the most abundant CYP isoform in the adult scriptions of new alleles, nomenclature and useful references human liver with large interindividual variability in its can be found at (http://www. In vivo, CYP3A4 activity displays at least 20- TABLE 37. HUMAN POLYMORPHIC CYTOCHROME P450 ENZYMES AND THE GLOBAL DISTRIBUTION OF THEIR MAJOR VARIANT ALLELES Allele Frequencies (%) Major Variant Consequences for Ethiopians and Enzyme Alleles Mutation Enzyme Function Caucasians Asians Black Africans Saudi Arabians CYP2A6 CYP2A6∗2 Leu160His Inactive enzyme 1–3 0 ND ND CYP2A6∗del Gene deletion No enzyme 1 15 ND ND CYP2C9 CYP2C9∗2 Arg144Cys Reduced affinity for 8–13 0 ND ND P450 oxidoreductase CYP2C9∗3 Ile359Leu Altered substrate 6–9 2–3 ND ND specificity CYP2C19 CYP2C19∗2 Aberrant splice site Inactive enzyme 13 23–32 13 14–15 CYP2C19∗3 Premature stop Inactive enzyme 0 6–10 ND 0–2 codon CYP2D6 CYP2D6∗2xN Gene duplication or Increased enzyme 1–5 0–2 2 10–16 multiduplication activity CYP2D6∗4 Defective splicing Inactive enzyme 12–21 1 2 1–4 CYP2D6∗5 Gene deletion No enzyme 2–7 6 4 1–3 CYP2D6∗10 Pro34Ser, Ser486Thr Unstable enzyme 1–2 51 6 3–9 CYP2D6∗17 Thr107Ile, Arg296Cys, Reduced affinity for 0 ND 34 3–9 Ser486Thr substrates Reprinted with permission from Ingelman-Sundberg et al. Yet, the distribution GENETIC VARIABILITY IN RECEPTORS AND of CYP3A4 catalytic activity is unimodal and nonpolymor- DRUG TRANSPORTERS: CONTRIBUTION TO phic in many populations. PHARMACODYNAMIC VARIABILITY CYP3A4 contributes to disposition of more than 60 fre- quently prescribed therapeutic agents with diverse chemical Historically, the pharmacogenetic factors related to drug structures including antilipidemics, benzodiazepines, HIV efficacy and safety were mainly studied in the context of protease inhibitors, immunosuppressants, and macrolide drug metabolism (48). In the past decade, the increasing antibiotics (43,44). CYP3A4 also plays an important role for application of mathematical models for 'concentration ver- the metabolism of endogenous steroids (e.

First discount tadapox 80mg with amex erectile dysfunction and stress, DTI does not allowthe tional structure of the CNS buy discount tadapox 80 mg line erectile dysfunction treatment with exercise. Even though the identification identification of this portion of a fiber pathway clearly and reconstruction of major fiber bundles has been accom- enough to justify the application of such specific terminol- plished with the use of DTI and computational techniques cheap tadapox 80mg with mastercard erectile dysfunction doctors albany ny, ogy. Second, both the corticocortical associational and the the basic problems related to the biological sources of the commissural connections are generally bidirectional, mean- DTI signal remain to be clarified. Thus, to achieve a com- ing that within the stem of a tract fibers are running in prehensive understanding of the sensitivity and specificity both directions; thus, origins and terminations pertaining of the DTI technique, studies addressing both the gross and to the same fiber tract occur in adjacent locations. The dif- ultrastructural level of the white matter are necessary. Therefore, at a morpho- tion of the cerebrum, emphasizing the morphology and ar- logic level, a comprehensive delineation of a fiber pathway chitectonic structure of its pathways. Subsequently, we over- should include its stem, splay, and extreme periphery. A viewthe DTI technique and illustrate its use at an description of the extreme periphery of an association fiber ultrastructural and a gross neuroanatomic level. In this per- tract is related to a cortical field of origin or termination spective, we elaborate on three representative white matter (Fig. Additionally, we discuss the utility, potential, and limita- Architectonic Connections tions of the DTI technique in the context of its applications and its integration within a larger neurofunctional MRI The detailed characterization of a fiber pathway in terms examination. For this purpose, we present a case of amyotro- of its cytoarchitectonic correlates is a fundamental step for phic lateral sclerosis that we studied with MRI, DTI, MRS, the understanding of cerebral structural and functional or- and fMRI. These issues have been addressed at the architec- tonic level in experimental animals and in human postmor- OVERVIEW OF WHITE MATTER PATHWAYS tem material. In particular, cerebral cytoarchitecture has been described precisely in both the human and the experi- Anatomic Connections mental animal, such as the macaque. In the experimental The white matter of the CNS contains axons serving corti- nonhuman primate, the white matter fiber pathways have cocortical, commissural, cortico-subcortical, and cerebellar been delineated precisely and comprehensively (i. With this technique, a number of studies of the fiber connections between the different lobes of the cerebral cortex, between the two hemispheres, and between the cerebral cortex and subcortical regions have been carried out in the monkey. These studies have demon- strated that the various fiber bundles are distinct and occupy unique trajectories from origin to termination. In Material to Human Material this lateral preparation of Ludwig and Klingler (53), the sample tract is the human superior longitudinal fasciculus, which is a In the monkey, it is known how different pathways correlate long, associational, corticocortical connection. Its three compo- with radioactively labeled material, so that their origin and nents are (a) the stem, where axons run compactly and in a bidi- termination can be delineated. Because the stems of the rectional fashion;(b) thesplays or sprays,where theaxons diverge or converge; and (c) the extreme peripheries, the cortical regions major pathways are similar in the monkey and the human, within which the axons originate or terminate. Arrows denote one can extrapolate the origins and terminations of the ob- the bidirectionality of axons within the stem and the splays of served pathways in the human to correlate specific fiber the fiber tract as they run from origin to termination. Drawing these inferences, we can formulate for each individual fiber bun- dle a specific map that characterizes the tract in terms of its connections. Al- though this is currently the case for the nonhuman primate, the status of research in human brain anatomic connectivity Maps of Anatomic Connectivity is very different. A map of anatomic connectivity (MAC) is a set of neuroana- tomic regions interconnected by a particular white matter fiber Studies in Human Postmortem Material pathway, and we can symbolize it as PATHWAYMAC. For instance, the MAC for cingulum bundle (CB) would be In human postmortem material, traditional techniques such CB (Fig. Whereas in the human we have precise MAC as myelin stain, bichromate fixation, and gross anatomic knowledge only of the stem of this bundle, the architectonic dissection allowvisualization of the stems of these fiber bun- connections in the nonhuman primate are well docu- dles (10). With very fewexceptions, in which dyes such as mented. A comprehensive description of maps for anatomic the carbocyanine dye (DiI) were used for very short connec- cerebral connectivity has been formulated, derived from an- tions (13), histologic description of human fiber pathways atomic studies in the human and by extrapolation from is incomplete because it does not provide a detailed under- experimental material, and has been integrated in the con- standing of their origins and terminations, and no technique text of a methodology for topographic characterization and is available that can identify with certainty the origin and quantification of human forebrain white matter (16,17). The closest inferences at this level of description formulation of more sophisticated tractographic experi- are obtained from white matter degeneration studies of ments and in interpreting neurofunctional data. Most of these stud- the neuroanatomic knowledge of fiber tracts within an ies deal with cortico-subcortical connections and are not fMRI experiment is an additional challenge, but at the same specific because the cortical lesions that cause the remote time it seems to be key if we are to study behavior in normal degeneration are very large (10,14). Studies in the Experimental Nonhuman Primate In Vivo Analysis of Fiber Pathways Experimental approaches with available techniques have ad- The capability of studying tracts in the living human brain dressed the problem of origin and termination of fiber path- opens up a newwindowin structural–functional and ana- ways in the monkey. The injection of radioactively labeled tomic–clinical relationships. Currently, the detection of 360 Neuropsychopharmacology: The Fifth Generation of Progress fiber tracts in vivo has been addressed by MRI techniques such as DTI. DTI analysis enables us to characterize a white matter fiber pathway in terms of its orientation, location, and size. To date, tractography has been performed in two different ways. Using manual or model-independent methods, we can derive the trajectory of the fiber bundle and approxi- mate its extreme peripheries (12). Using mathematically driven model-based methods, we can also trace a fiber path- way (18–20). In the section on applications, we give exam- ples in which both methods are used and different tracts A are visualized in two and three dimensions. Although the field of DTI-based brain tractography is expanding rapidly with impressive results, it has to be pointed out that certain basic conceptual obstacles still need to be overcome. For instance, in this stage, it has not been demonstrated that we are able to delineate completely and precisely a fiber tract in the brain by means of any DTI analysis technique. At the most, we can identify and characterize the stems of the major fiber tracts (12,21); however, the problem of elucidating the splays and extreme peripheries of the bun- dles remains to be solved reliably. Therefore, when we use the term pathway, tract, or bundle, we currently refer to its B stem. Map of cortical anatomic connectivity (MAC) for the cingulum bundle (CB), or CBMAC. The connections of the CB Self-diffusion of molecules has been studied with magnetic are represented in the mesial (A), lateral (B), and ventral (C) views of the human brain on a cortical parcellation system (46). The resonance methodologies for several decades (22,23). For shaded area in blue within the frontal pole in the ventral view comprehensive reviews of the use of diffusion in nuclear corresponds approximately to the rostralpart of the frontoorbital cortexthat is anterior to the transverse orbital sulcus. AG, angular magnetic resonance, we refer the reader to other sources gyrus; CALC, intracalcarine cortex; CGa, cingulate gyrus, anterior; (24–26). With respect to the physical principles underlying CGp, cingulate gyrus, posterior; CN, cuneiform cortex; CO, central diffusion (also known as brownian motion), water in tissues operculum; F1, superior frontal gyrus; F2, middle frontal gyrus; F3o, inferior frontal gyrus, pars opercularis; F3t, inferior frontal with an oriented structure tends to diffuse more along the gyrus, pars triangularis; FMC, frontal medial cortex; FO, frontal orientation of the tissue structure (Fig. The incoher- operculum;FOC, frontalorbitalcortex; FP,frontalpole; H1,Heschl gyrus; INS, insula; JPL, juxtaparacentral cortex; LG, lingual gyrus; ent motion of the diffusing water, when it occurs in the OP, occipital pole; OF, occipital fusiform gyrus; OLi, lateral occipi- presence of a magnetic field gradient, leads to dephasing of tal cortex, inferior; OLs, lateral occipital cortex, superior; PAC, the MR signal. This dephasing produces signal attenuation paracingulate cortex; PCN, precuneus; PHa, parahippocampal gyrus, anterior; PHp, parahippocampal gyrus, posterior; PO, pari- (SA), which is related to the magnitude of diffusivity of the etal operculum; POG, postcentral gyrus; PP, planum polare; PRG, water along the direction and magnitude of the applied precentral gyrus; PT, planum temporale; SC, subcallosal cortex; SCLC, supracalcarine cortex; SGa, supramarginal gyrus, anterior; gradient in an exponential fashion. For anisotropic gaussian 2 2 T SGp, supramarginal gyrus, posterior; SPL, superior parietal lobule; diffusion, the SA is proportionate to e ( 3)g Dg. For T1a, superior temporal gyrus, anterior; T1p, superior temporal isotropic diffusion, this reduces to the Stejskal–Tanner rela- gyrus, posterior; T2a, middle temporal gyrus, anterior; T2p, mid- bD dle temporal gyrus, posterior; T3a, inferior temporal gyrus, ante- tion: SA SA0 e , where D is the diffusion coefficient rior; T3p, inferior temporal gyrus, posterior; TFa, temporal fusi- and b is the diffusion sensitivity factor.

These latter studies are faxine produces NE reuptake inhibition (8 generic 80mg tadapox how to get erectile dysfunction pills,9 quality 80mg tadapox zma impotence,36) proven tadapox 80mg kidney transplant and erectile dysfunction treatment. Because powered to detect a clinically significant improvement, usu- NE metabolism varies according to whether it occurs inside ally over placebo, often utilizing multiple dose arms (each or outside neurons (37), a more definitive and perhaps more with at least 50 or more patients) and multiple clinical sites. However, all of these measures reflect instance, if one had an ampakine such as CX-516 that im- functional changes in the peripheral sympathetic nervous proved learning in rats, then one might show enhancement system; therefore, they are at best surrogates for effects in of some aspects of cognition in healthy volunteers after safe the brain. The improved Some of these same measures have been applied to study performance in healthy subjects would then be a surrogate other compounds, which are predicted to affect NE func- for improvement in AD to identify the appropriate dose. These In the more usual case of a variation on an existing mech- include bupropion, clozapine, alpha 2 antagonists, and anism (e. Interest- produces the desired biochemical effect so as to move as ingly, such studies are not yet available to support or refute quickly as possible into Phase II trials with doses that one claims that the relatively new antidepressant mirtazapine is confident will work(25,26). In this latter instance, the produces alpha 2 antagonism in humans. Some of these studies been used in enough instances over the last two decades to were clearly done prior to Phase II trials so they can be qualify as surrogate markers. There is no available literature inferred to have influenced the selection of dose. Doses of as to the extent to which these measures actually drove deci- SSRIs known to inhibit platelet uptake in humans have also sions about what doses to use in Phase II trials, but one can been shown to reduce the turnover of 5HT in the CNS as assume that they must have been influential in some cases. Similarly, MAOIs of polysomnography (for sleep-related disorders) and EEG reduce both platelet MAO and 5-HIAA in CSF (51,52). Assessments of decrements in performance compare the sensitivity of the peripheral and central mea- (especially ability to concentrate, recall, and carry out motor sures. Moreover, 5HIAA in CSF obtained by a lumbar tasks) and measures of cognitive enhancement all seem to puncture reflects a complicated process of all sources of for- be better classified as direct measures of an intended or mation and clearance of the metabolite. This leaves DA has been studied almost exclusively in terms of its mainly biochemical measures, which can be broadly classi- metabolite, homovanillic acid (HVA) in blood and CSF. Decreased HVA in CSF can be expected after a compound in advance. It is doubtful that any substantial mixed Types A and B MAO inhibition in the brain (52) decisions concerning doses of compounds affecting either and might be relevant to assessing DA uptake inhibition. DA uptake inhibition, did not decrease HVA in the CSF (40,44). ACTH/Cortisol Prolactin Stimulation of the hypothalamic–pituitary–adrenal axis as reflected by increases of ACTH and/or cortisol has also been Prolactin has the potential to be used as a marker for drugs used as a marker of drug action in the CNS. This approach affecting these systems, because either DA or 5HT can affect has been most extensively applied to evaluation of putative this circulating hormone. In the simplest and most wide- 5HT agonists, sometimes coupled with pretreatment with spread instance, it has been used as an index of D2 antago- whatever antagonists were available (e. Unlike typical neuroleptics, atypical neuroleptics pro- dolol) (63). Such studies can generate evidence of apparent duce no elevations of prolactin at therapeutic dosages (59, selectivity in postsynaptic receptor responses to indirect and 60). By extension, absence of prolactin elevation after anti- direct agonists. ACTH release induced by 5-hydroxy-L- psychotics could be considered a surrogate of low D2 recep- tryptophan (5HTP) is argued to occur through indirect acti- tor occupancy in the striatum and, hence, imply low to vation of 5HT2 receptors because it is antagonized by ri- absent motor side effects (61,62). Pindolol does, however, antagonize ACTH re- to increase extracellular 5HT in the brain including sponses to a variety of agents classified as partial to full fenfluramine, clomipramine, l-tryptophan, and 5- 5HT1A agonists (64,79,80). Again, given the complexities hydroxytrytophan; and (b) those that stimulate various of the ACTH/cortical response and the imperfect selectivity types of 5HT receptors, including meta-chlorophenylpiper- of the pharmacologic agents, quantitative conclusions as to azine (mCPP) and some, but not all, putatively selective degree of specific receptor activation or antagonism are not 5HT1A agonists (63–66). Growth Hormone Temperature decreases are consistently observed follow- ing 5HT1A agonists (63,83), and hence can serve as a surro- There was a period in which plasma growth hormone (GH) gate marker of 5HT1A agonist effects in the CNS. Evaluat- was used as a surrogate for increased noradrenergic transmis- ing the ability of a novel compound to antagonize the sion in human brain (presumably at the level of the hypo- hypothermia produced by a 5HT1A agonist may be the easi- thalamus) after, for instance, the 2 agonist, clonidine, or est way to see if it antagonizes 5HT1A receptors in the an NE uptake inhibitor (71,72). More recently, stimulation of plasma GH has been con- sidered evidence of activation of both 5HT1A and 5HT1B/ LIMITATIONS OF CURRENT SURROGATE 1Dreceptors (see Table 34. Sumatriptan MARKERS increases GH, apparently through activation of the 5HT1B/ 1D receptors (73,74), with the most recent evidence using As described, there is no validated linkbetween the concen- the more brain penetrant, zolmitriptan, implicating 5HT1D tration of drug in blood (or even CSF) and a specific bio- postsynaptic receptors (75). It has been suggested that stim- chemical effect in human brain (not to mention a specific ulation of the 1B/1D receptors inhibits somatostatin release brain region). Thus, even in the case of SSRIs, the most Chapter 34: Proof of Concept 463 widely prescribed class of drugs in neuropsychopharmacol- By contrast, positron emission tomography (PET), an- ogy, we do not know how closely platelet 5HT depletion other procedure to estimate rCBF, requires an onsite cyclo- reflects 5HT uptake inhibition in brain. Although known tron, so it is not available in many areas. Recent third-party therapeutic doses of SSRIs invariably have been shown to camera reimbursement of some PET procedures (primarily deplete platelet 5HT, the converse is not clear; that is, any [18F]fluorodeoxyglucose (FDG)) are making PET cameras dose that is effective in platelets will be therapeutic. Matters more available, but cyclotrons are still relatively scarce. The are even less certain when it comes to using available surro- two most widely used radioisotopes used in PET are 11C gates of NE uptake inhibition to establish the dose of a with a half-life of 20 minutes and 18F with a half-life of drug. And, as already noted, primary dosing decisions are 110 minutes. Additionally, 15O, with a half-life of 2 minutes not made on the basis of whether compounds affect prolac- is primarily employed in brain perfusion studies. The most tin, growth hormone, or ACTH/cortisol responses. The problem is that even in vantage is lackof specificity. Furthermore, in vivo ani- ies demonstrate increases in rCBF in the limbic system and mal studies raise questions about species differences; there- decreases in the basal ganglia as manifestations of craving fore, how does one select the dose for clinical studies when for cocaine following exposure to videotapes suggesting co- testing a new compound that is well tolerated with a wide caine use (91). How does one know that the target in question has been blocked ESTIMATION OF DOPAMINE RECEPTOR or stimulated so as be sure that one is testing the hypothesis OCCUPANCY BY ANTIPSYCHOTIC DRUGS that such an effect produces therapeutic benefit? The answer is, one does not know with the surrogates (discussed in the It has been hypothesized that positive symptoms of schiz- preceding). This brings us to a discussion of the promise ophrenia, such as hallucinations and delusions, result from of direct measures of drug effect in the brains of living increased stimulation of postsynaptic dopamine (DA) re- humans. This DA hypothesis of schizophrenia is substantiated by the observation that positive symptoms of schizophrenia abate when DA receptor blocking drugs, IMAGING STUDIES such as neuroleptics, occupy the postsynaptic DA receptors. In 1988, Farde and colleagues demonstrated the concept Measures of Substrate Metabolism that effective neuroleptic dosages for schizophrenia corre- Regional cerebral blood flow (rCBF) is a well-established spond to 80% to 90% occupancy of DA type-2 receptors surrogate marker widely used for both clinical diagnostic (D2Rs) by the drug (95). Thus, occupancy of 80% to 90% procedures and new drug development. Furthermore, clinically 123 99m equivalent doses of neuroleptics are estimated by comparing with radioligands labeled with Ior Tc; for example, [123I]iodoamphetamine, [99mTc]ethylenediylbis-L-cystein proportions of receptors occupied by various psychothera- diethylester (ECD), and [99mTc]hexamethylpropylenea- peutic agents (93,94). Several examples of this approach are mine oxime (HMPAO). Although repeated assessments given in the following.