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Soluble amyloid beta peptide ties in degenerating neurons link neuronal compromise to senile concentration as a predictor of synaptic change in Alzheimer plaque development in Alzheimer disease best dapoxetine 90mg impotence in men over 50. The pathogenesis of Alzheimer disease: an alternative 19 proven dapoxetine 60mg erectile dysfunction icd 10. J Neuropathol Exp Neurol 1996;55: cellular A beta 42 is related to apoptosis but not necrosis buy dapoxetine 60mg with amex erectile dysfunction doctor pune. Neuropathological stageing of Alzheimer- levulinic acid uptake trusted 90 mg dapoxetine impotence effects on marriage. Some cytoarchi- phism of cathepsin D is strongly associated with the risk for tectural abnormalities of the entorhinal cortex in schizophrenia. Neurosci Lett 1999; Arch Gen Psychiatry 1991;48:625–632. Alpha-2 macroglobulin high molecular mass subunit of neurofilaments in axons of reti- is genetically associated with Alzheimer disease [see Comments]. Interaction between amyloid Cell Biol 1988;107:2689–2701. The topographical and tions for the pathogenesis of Alzheimer disease. Proc Natl Acad neuroanatomical distribution of neurofibrillary tangles and neu- Sci USA 1997;94:8208–8213. Proc Natl Acad Sci USA 1999;96: ronal vulnerability in neurodegenerative diseases. Mutagenesis identifies toxicity in rat hippocampal pyramidal neuronal cultures. J Neu- new signals for beta-amyloid precursor protein endocytosis, rosci 1998;18:195–204. Eur J Biochem 1997; low density lipoprotein receptor-related protein gene. Processing of the Chapter 85: Cell and Molecular Neuropathology of Alzheimer Disease 1229 pre–beta-amyloid protein by cathepsin D is enhanced by a fa- 95. Eur J Biochem 1994;224: presenilin-1 exon 9 deletion and L250S mutations sensitize SH- 265–271. SY5Y neuroblastoma cells to hyperosmotic stress-induced 79. Impairment of glucose apolipoprotein E3 or E4 in the brains of Apoe / mice: iso- and glutamate transport and induction of mitochondrial oxida- form-specific effects on neurodegeneration. J Neurosci 1999;19: tive stress and dysfunction in synaptosomes by amyloid beta 4867–4880. Cellular actions of beta-amyloid precursor protein 1 antichymotrypsin apolipoprotein E promotes amyloid beta and its soluble and fibrillogenic derivatives. Beta-amyloid precur- (A beta) binding proteins in A beta aggregation. J Neurosci Res sor protein metabolites and loss of neuronal Ca2 homeostasis 1996;46:58–66. Calcium as sculptor and destroyer of neural circui- apolipoprotein E reduces amyloid-beta deposition in a mouse try. Lack of apolipoprotein to p25 deregulates Cdk5 activity and promotes neurodegenera- E dramatically reduces amyloid beta-peptide deposition. Immunization with human disease and transgenic mouse models. Neuron 1999;24: amyloid-beta attenuates Alzheimer-disease–like pathology in 507–510. Curr Opin Chem Biol Alzheimer disease: a potential molecular basis for neuronal de- 1997;1:260–267. Calpains and calpas- rodegeneration in Alzheimer disease. In: Terry R, Katzman R, tatin in SH-SY5Y neuroblastoma cells during retinoic acid–in- Bick K, eds. New York: Raven, 1994: duced differentiation and neurite outgrowth: comparison with 305–315. Possible role of tau toxicology of calcium-dependent protease. Loss of endo- precursor protein mutation increases amyloid beta42(43) pep- somal/lysosomal membrane impermeability is an early event tide levels and induces apoptosis. Ann Neurol 2000;47: in amyloid Abeta1–42 pathogenesis. SMALL Of the many laboratory measures and techniques available various dementia causes. The gradual onset and progressive for understanding and quantifying biological aspects of Alz- cognitive decline of AD may be difficult to distinguish clini- heimer disease (AD), imaging the structure and function of cally from other chronic dementias, including dementia the brain is a particularly attractive approach in that it can with Lewy bodies, vascular dementia, frontotemporal de- provide highly relevant and diverse information using a vari- mentia, and late-life depression. The application and interpretation of may sort out these various causes. The marginal diagnostic such information have considerable practical clinical rele- value (i. When brain imaging improves do the potential utilities of these imaging methods in ad- diagnostic homogeneity, drug efficacy and safety studies are dressing timely neuropsychopharmacologic research issues. Brain imaging techniques are often categorized as either Another application of brain imaging is in the preclinical structural or functional, based on the primary form of infor- detection of AD. This classification method breaks down, brain imaging data point to a form of gradual age-related however, when considering newer applications of these cognitive decline that precedes AD (5). For example, magnetic resonance imaging ies, particularly when coupled with data on genetic riskof (MRI) equipment is used to provide functional brain re- AD, is an emerging strategy to identify candidates for phar- sponses with functional MRI (fMRI). Moreover, both posi- macologic interventions that delay cognitive decline pro- tron emission tomography (PET) and single photon emis- gression and disease onset. A related application is the use sion computed tomography (SPECT) have the potential of brain imaging data to predict and follow treatment re- to provide visualizations of the pathognomonic structural sponse in patients with the full dementia syndrome of AD. In this chapter, I tions through brain imaging has several clinical and research review both available and developing brain imaging tech- applications for AD and other dementias. Recognition of niques and emphasize neuroimaging techniques and mea- dementia is particularly difficult in its early stages, when sures for presymptomatic AD detection and monitoring family members and physicians often incorrectly attribute pharmacologic interventions. Systematic studies indicate that the frequency of unrecognized memory impairment, beyond that associated with normal aging, or STRUCTURAL NEUROIMAGING a dementia diagnosis can range from 50% to 90% of cases TECHNIQUES (3,4). A related application is the differential diagnosis of Computed Tomography Computed tomography (CT) measures the attenuation of Gary A. Small: Department of Psychiatry and Biobehavioral Sciences, an x-ray beam through body tissues. A ring of x-ray generators and detectors radiation exposure. Disadvantages include the possibility of obtains images of multiple brain slices as the patient is ad- artifact and the fact that the measures are relatively distant vanced through the scanner (6). Moreover, the precise physiologic meaning soft tissue, fluid, and gas with spatial resolution of less than of the measure is unclear. Intravenous contrast medium enhances such patho- areas can be reduced in AD and in vascular dementia. In logic features as bleeding, neoplasm, infection, and inflam- AD, the greatest reductions in coherence occur between mation. Limitations of CT include its inability to differen- intrahemispheric parietal and prefrontal cortical areas, tiate gray and white matter and to visualize the posterior whereas in vascular dementia, this reduction occurs between fossa clearly (6).

Fear and the human of the cognitive generation of affect cheap 30 mg dapoxetine mastercard erectile dysfunction meds online. Functional dissociation nition of fear and anger following bilateral amygdala lesions discount 30 mg dapoxetine mastercard impotence of proofreading poem. A functional anatomi- to the subiculum in the rat and cat discount dapoxetine 90 mg visa erectile dysfunction 18. J Comp Neurol 1977;172: cal study of unipolar depression 60 mg dapoxetine mastercard erectile dysfunction no xplode. Cingulate func- the perirhinal cortex but not of the frontal, medial prefrontal, tion in depression: a potential predictor of treatment response. N-methyl-D-aspartate lesions of the lat- cortex abnormalities in mood disorders. Nature 1997;386: eral and basolateral nuclei of the amygdaloid block fear-poten- 824–827. Arch Gen Psychiatry 1997;54: blood flow correlate with emotional self-rating: a PET study 233–237. Limbic connections of the orbital and late cortex volume in first-episode psychosis. Am J Psychiatry medial prefrontal cortex in macaque monkeys. Cortical inhibition and facilitation of the defense ual prefrontal cortex in mood disorders. Brain activity during ing and the orbitofrontal cortex. Cereb Cortex 2000;10: transient sadness and happiness in healthy women. Reciprocal limbic- following selective lesions of the inferior prefrontal convexity. The retrosplenial cortex and emotion: new in- 675–682. Limbic connections of the orbital and Neurosci 1999;22:310–316. The efferent projections of the medial ology of cingulate cortex and limbic thalamus Boston: Birkhauser, prefrontal cortex in the squirrel monkey (Saimiri sciureus). Individuals with socio- ity in panic disorder, a severe form of anxiety. Nature 1984; pathic behavior caused by frontal damage fail to respond auto- 310:683–685. Lateralized effects of medial prefrontal metabolic differences in patients with panic disorder. Neuropsy- cortex lesions on neuroendocrine and autonomic stress re- chopharmacology 1990;3:261–271. Neural activation during lism in women with panic disorder. Am J Psychiatry 1998;155: covert processing of positive emotional facial expressions. Regional cerebral abnormalities in drug-naive, lactate-sensitive panic patients: a blood flow changes during anticipatory anxiety. Networks within the orbital and medial prefrontal correlates of a lactate-induced anxiety attack. Reduction of pre- roanatomy of anxiety: a study of three disorders using positron frontal cortex glucose metabolism common to three types of emission tomography and symptom provocation. Functional neuroana- evidence for neuronal and glial prefrontal cell pathology in tomy of CCK4–induced anxiety in normal healthy volunteers. Louis: CV Mosby, 1997: rior parietal-temporal cortex activation after D-fenfluramine in 53–81. Psychopharmacology: the fourth bine on cerebral blood flow, symptoms, and physiological func- generation of progress. Yohimbine alters re- and prefrontal cortical structures in major depression. Prog gional cerebral blood flow in panic disorder [Letter]. Correlation of severity blood flow measured during symptom provocation in obsessive- of panic disorder and neuroanatomical changes on magnetic compulsive disorder using oxygen 15–labeled carbon dioxide resonance imaging. J Neuropsychiatry Clin Neurosci 1989;1: and positron emission tomography. PET images of fluid corticotropin-releasing hormone in healthy humans: ef- blood flow changes during anxiety: correction. Subcortical correlates differences between major depressive subtypes. J Cereb Blood of differential classical conditioning of aversive emotional reac- Flow Metab 1995;15:S93. Brain activation in PTSD changes in response to phobic anxiety and habituation. Biol Psychiatry1999;45: Blood Flow Metab 1995;15:S856. Regional cerebral Chapter 63: Neurobiological Basis of Anxiety Disorders 925 blood flow during script-driven imagery in childhood sexual HY, ed. Psychopharmacology: the third generation of progress. Neural correlates of ergic neurons in the locus coeruleus of freely moving cats. Neural correlates of noradrenergic neurons during the defense reaction. Brain Res exposure to traumatic pictures and sounds in Vietnam combat 1990;531:189–195. Biol Psychiatry 1999;45: mechanisms in stress and anxiety. Noradrenergic response to masked facial stimuli in posttraumatic stress disor- mechanisms in stress and anxiety. Dissociable effects of lesions to dorsal conditioning in trauma-exposed individuals with and without and ventral noradrenergic bundle on the acquisition, perfor- posttraumatic stress disorder. J Abnorm Psychol 2000;109: mance, and extinction of aversive conditioning. A functional neuroanatomy of anxiety ment of aversive conditioning in posttraumatic stress disorder. Stress induced sensitization of ment of hippocampal volume in combat-related posttraumatic norepinephrine release in the medial prefrontal cortex. Prior exposure surement of hippocampal volume in posttraumatic stress disor- to chronic stress results in enhanced synthesis and release of der related to childhood physical and sexual abuse: a preliminary hippocampal norepinephrine in response to a novel stressor. Presynaptic alterations asso- nance imaging study of hippocampal volume in chronic com- ciated with enhancement of evoked release and synthesis of NE bat-related posttraumatic stress disorder. Biol Psychiatry 1996; in hippocampus of chronically cold stressed rats. Altered activity of the locus coeruleus in women victimized by childhood sexual abuse. Science 1996; In: Usdin E, Kvetnansky R, Axelrod J, eds.

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Most of the subjects who dropped out open-label maintenance) cheap 90mg dapoxetine fast delivery erectile dysfunction protocol amazon, testosterone injections were effec- did so because of complaints of agitation 60mg dapoxetine free shipping erectile dysfunction protocol scam, anxiety 60 mg dapoxetine mastercard impotence prozac, and in- tive in improving both mood and libido dapoxetine 90mg lowest price erectile dysfunction treatment in urdu, energy, and body somnia during weeks 1 through 3. Both depression and muscle mass in 70 HIV-seropositive men with hypogonadal somatic symptoms perceived to be related to HIV infection symptoms who completed the trial (162). Differences in efficacy be- found that exercise may augment improvement in psycho- tween the three SSRIs could not be ascertained reliably be- logical and nutritional status in HIV-seropositive patients cause of the study design and small sample size. In an 8-week open- cently, these authors performed a small open trial label pilot study of 45 HIV-positive subjects, the adrenal comparing fluoxetine (n 21) and sertraline (n 9) in steroid dihydroepiandrosterone (DHEA) appeared promis- HIV-infected women (157). Sixty percent of the women ing for improving mood in addition to anabolic and andro- completed the trial, and of these, 78% were responders (e. Sig- and Other Psychiatric Conditions nificant improvement in HAM-Dscores was noted between weeks 2 through 6 of the study. Recently, a 73% response Antidepressant therapy is effective and can improve the rate was demonstrated with nefazodone in a small open trial quality of life of HIV-infected persons. An open-label study recently re- fection (165), although it is well established that antidepres- vealed that the efficacy of the protease inhibitor indinavir sants are effective agents for the treatment of chronic pain, (which is a metabolized by the 3A4 isoenzyme system) is particularly antidepressants with noradrenergic properties markedly reduced by the concomitant administration of St. The fects more frequently with tricyclic antidepressants than do reduction in indinavir levels was estimated to be sufficient to patients with AIDS-related complex and asymptomatic cause drug resistance and treatment failure. Better-tolerated antide- that psychotropic drugs such as antidepressants can improve pressants with effects on serotoninergic and noradrenergic the quality of life of HIV-positive persons, further research neurotransmitter systems include venlafaxine, mirtazepine, is needed to determine whether effective treatment can im- and paroxetine; these may prove useful and are awaiting prove medical outcomes in selected subsets of HIV-infected controlled studies. The multifactorial nature of HIV infection has led research- ers to examine the influence of stress, depression, and other Treatment of Psychotic Symptoms psychosocial factors on the course of this disease. A growing literature points to the potentially harmful effects of stress The treatment of psychotic disorders in HIV-infected pa- and depression on cellular immunity (173–176), and to the tients has been less well studied than the treatment of mood potentially negative impact of these psychosocial factors on disorders. Several reports have noted that HIV-seropositive the course of several types of cancer (177–180). Among patients may be more sensitive to the extrapyramidal side patients with breast cancer, severe life stress has been associ- effects associated with dopamine-receptor antagonists (149, ated with a greater probability of relapse (179), and psycho- 168). This is thought to be related to the subcortical motor social interventions to improve coping skills have resulted slowing associated with HIV infection. In a case series of in increased numbers and function of natural killer cells 21 patients with psychotic symptoms (12 had mania with and longer survival in patients with breast cancer or mela- psychotic features), risperidone was found to be efficacious noma (177,178,181). Investigators found no relationship be- antipsychotic agents may be increased (170). Controlled tween psychosocial and psychiatric factors such as depressive studies are needed in this area. However, a relationship infected patients with psychotic symptoms or mood disor- was noted between the number and severity of HIV-related ders. Pharmacologic knowledge can be used to therapeutic symptoms and levels of depressive disorders, distress, and advantage and to avoid potential untoward effects. Potential interactions commonly accepted markers of HIV disease progression. Psychotropic drugs, non-nucleoside reverse tran- Prospective studies conducted for longer time intervals scriptase inhibitors, and protease inhibitors may serve as have found that depression may significantly predict HIV substrates for various cytochrome P-450 enzymes in the disease progression. Each of these classes of compounds may possess en- Study, a 9-year longitudinal study of 395 seropositive gay zyme-inducing or enzyme-inhibiting properties, and drugs men, researchers found that subjects classified as depressed Chapter 90: Neuropsychiatric Manifestations of HIV-1 Infection and AIDS 1293 at study entry on the CES-D(186) progressed more rapidly symptoms. The small number of subjects with elevated to AIDS (187). The median time to first AIDS diagnosis scores may partially account for this outcome. This finding held the effect of stressful life events on clinical outcome. Evans after control for baseline demographic variables, CD4 T- et al. At 5 years, this cohort showed no significant sion doubled in men studied for up to 3. After 7 years of follow-up, stressful events were associated with faster progression to subjects with elevated depressive symptoms at every visit AIDS. At both time points in follow-up, every increase in had a 1. At Initial analysis of 1,809 HIV-seropositive gay men in the 7. Higher levels of serum cortisol were also associ- and progression of HIV infection during 8 years of follow- ated with faster progression to AIDS, but variations in corti- up (190). Disease progression was defined as time to AIDS, sol did not account for the stress findings (196). In a subsequent Other studies also lend support to the hypothesis that report on years 2 through 6, a robust increase of 30% to stressful events may hasten the progression of HIV infec- 104% above baseline levels (depending on CES-Ddepres- tion. In the study of Kemeny and Dean (197), the stress sion cut point) was noted in self-reported depressive symp- of bereavement before study entry was associated with a toms beginning 1. Bereavement did not predict authors interpreted these findings as an indication that progression to AIDS or mortality rate. However, a subsequent survival analysis of these data, development of HIV-related clinical symptoms at 2-year in which the level of depressive symptoms during the 6 follow-up was greater. In a recent study of 67 asymptomatic months before AIDS diagnosis was used, showed no rela- HIV-infected African-American women, trauma (e. A death of child, assault, rape), particularly among those with limitation of both these prospective cohort studies is the posttraumatic stress disorder, was associated with a greater method of ascertainment of depression. The CES-Dis not decrease in the CD4 /CD8 ratio during 1 year of follow- a clinical diagnostic tool; its sensitivity for DSM-III major up (199). Stud- gay men who are followed every 6 months; extensive clinical ies that examine actual stressors (e. An analysis of this cohort at study entry showed a are more likely to show such results than studies based on significant effect of stress on parameters of cellular immu- questionnaire assessments of stress. These findings echo symptoms, measured by a modified Hamilton Depression those of some earlier research showing potentially harmful Rating Scale (HDRS) excluding somatic symptoms that effects of denial and potentially beneficial effects of social could be related to HIV disease. In the study of Antoni and colleagues severe depressive symptom (3-point increment on the (203), HIV-infected gay men scoring above, rather than HDRS), the risk for AIDS doubled (194). This result, how- below, the median on passive coping strategies (e. An increase in denial from before to after sero- erate the progression of HIV-1 disease. However, these stud- status notification was also associated with a greater proba- ies require confirmation by comprehensive, longitudinal in- bility of development of symptoms and AIDS during a 2- vestigations in which similar methodologies are used. In the study of study is also necessary to increase our understanding of the Solano and colleagues (201) of 100 male and female HIV- neuropsychiatric manifestations of HIV-1 infection in infected subjects, those who became symptomatic after 1 women and its special effects on neurologic development year had shown more denial and less 'fighting spirit' at in infants and children. Recent controlled trials of psychopharmacologic treat- The findings of other studies regarding the effects of ment have yielded positive results for the alleviation of social support have been less consistent. Larger social net- depression, and preliminary evidence also indicates a reduc- works and greater emotional support predicted longer sur- tion in neurocognitive impairment. Future neuropsycho- vival during 5 years in men who were symptomatic or had pharmacologic approaches will likely focus on both direct AIDS; however, larger social networks were associated with and indirect effects of HIV-1 in the brain in an effort to faster progression to AIDS in those who were asymptomatic develop novel interventions that may alter the course of at entry (202). Loneliness was associated with a more rapid disease and symptomatic treatments to improve clinical out- decline in CD4 levels but was unrelated to AIDS or mor- come and quality of life. The long-term impact of HAART tality during 3 years of follow-up in 205 symptomatic HIV- on HIV-related CNS disease and associated neuropsychia- infected men (204). Other prospective studies have reported tric manifestations will also be extensively studied. In summary, the evidence is substantial that psychosocial ACKNOWLEDGMENTS factors such as depression and stressful life events may ad- versely affect disease progression in persons infected with The authors thank Carol Roberts, B.

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Proc Natl through a flexible array of distributed weak sites discount dapoxetine 90mg without a prescription kidney transplant and erectile dysfunction treatment. Identification of a novel microtubule in human buy discount dapoxetine 60 mg on-line impotence effects on marriage, primate 30mg dapoxetine sale ketoconazole impotence, and rat brain: evidence that a pool of tau binding and assembly domain in the developmentally regulated is highly phosphorylated in vivo and is rapidly dephosphorylated inter-repeat region of tau cheap dapoxetine 90mg fast delivery erectile dysfunction teenager. Biopsy-derived between the proline-rich and repeat regions of tau enhance mi- adult human brain tau is phosphorylated at many of the same crotubule binding and assembly. Proc Natl Acad Sci USA 1992;89:1983– phosphorylation at specific sites. Sequen- specific functional impairments in distinct tau isoforms of he- tial phosphorylation of tau by glycogen synthase kinase-3beta reditary FTDP-17. Somatodendritic locali-¨ mer-specific epitope of antibody AT100 and requires a paired- zation and hyperphosphorylation of tau protein in transgenic helical filament-like conformation. Eur J Biochem 1998;252: mice expressing the longest human brain tau isoform. Protein kinase I converts normal tau protein into A68-like component sequence and mass spectrometric analyses of tau in the Alzhei- of paired helical filaments. Evidence for cdk5 line-directed and non-proline-directed phosphorylation of as a major activity phosphorylating tau protein in porcine brain PHF-tau. Insulin and insulin-like growth factor-1 comes long and stiff upon phosphorylation: correlation between regulate tau phosphorylation in cultured human neurons. J Biol paracrystalline structure and degree of phosphorylation. Phosphorylation of Ser262 synthase kinase-3/factor A. A brain-specific activator of opment and contributes to reduced microtubule binding. Tau in paired helical filaments is function- to p25 deregulates Cdk5 activity and promotes neurodegenera- ally distinct from fetal tau: assembly incompetence of paired tion. Phosphorylation of Ser262 ylation of tau protein at Ser202/Thr205 in response to microtu- strongly reduces binding of tau to microtubules: distinction bule depolymerization in cultured human neurons involves pro- between PHF-like immunoreactivity and microtubule binding. Phosphorylation affects the ability of tau hyperphosphorylated forms of tau protein in human brain slices. Modulation of of protein phophatase 2A is associated with microtubules and the dynamic instability of tubulin assembly by the microtubule is regulated during the cell cycle. Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, et al. Progressive su- proteins differentiate corticobasal degeneration and Pick disease. Different distribution caused by tau gene mutations. Vulnerable neuronal tion study of frontotemporal dementia in the Netherlands. Autosomal domi- in familial frontotemporal dementia (FTD-Kumamoto). Ann nant dementia with widespread neurofibrillary tangles. Pathogenic implica- exon 10 splice site region in familial frontotemporal dementia. Tau proteins with FTDP- families and kindreds with late-onset FAD. Neurology 1997;48: 17 mutations have a reduced ability to promote microtubule 949–954. Splice junctions, branch autosomal dominant parkinsonism and dementia with pallido- point sites, and exons: sequence statistics, identification, and ponto-nigral degeneration. The cardiac troponin T alternative parkinsonism-amyotrophy complex. Neurology 1994;44: exon contains a novel purine-rich positive splicing element. The role of exon sequences and parkinsonism linked to chromosome 17: a new group of tauopathies. A splicing enhancer of a chromosome 17-linked autosomal dominant parkinsonism in the human fibronectin alternate ED1exon interacts with SR and dementia ('pallido-ponto-nigral degeneration'). The regulation of splice-site selection, tau gene in familial multiple system tauopathy with presenile and its role in human disease. Polymerization tauopathy with presenile dementia is localized to chromosome of tau peptides into fibrillar structures. Accelerated filament disinhibition dementia: a frontotemporal dementia linked to formation from tau protein with specific FTDP-17 missense 17q21-22. Somatodendritic locali-¨ and 5′-splice-site mutations in tau with the inherited dementia zation and hyperphosphorylation of tau protein in transgenic FTDP-17. FTDP-17: an early- ing the shortest human tau isoform. Neuron 1999;24:751– onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Prominent axon- dementia with a novel missense mutation in the tau gene. Neu- opathy in the brain and spinal cord of transgenic mice overex- roreport 1999;10:497–501. Axonopathy and amy-¨ Natl Acad Sci USA 1999;96:55598—55603. Tau gene mutation Acta Neuropathol (Berl) 2000;99:469–481. G389R causes a tauopathy with abundant pick body-like inclu- 179. Characterization of pathol- sions and axonal deposits. J Neuropathol Exp Neurol 1999;58: ogy in transgenic mice over-expressing human genomic and 1207–1226. Alzheimer-type neu- loss in the human amyloid precursor protein V717F (PDAPP) ropathology in transgenic mice overexpressing V717F beta-am- transgenic mouse. Correlative memory defi- ease and transgenic models. Annu Rev Neurosci 1998;21: cits, Abeta elevation, and amyloid plaques in transgenic mice. Abeta deposition dence for the involvement of tau in progressive supranuclear is associated with neuropil changes, but not with overt neuronal palsy. Alois Alzheimer in suggest directions for future investigation or are the only 1907 (1) was remarkable for both her progressive cognitive studies available. Clinical interest in the noncognitive abnormali­ ties in Alzheimer disease (AD) has been substantial because DEPRESSION IN ALZHEIMER DISEASE of their high prevalence (2–4) and because noncognitive behavioral problems complicate patient management and Diagnostic Challenges often precipitate institutionalization (3,5–12). The real or The diagnosis and treatment of depression complicating the apparent resemblance of delusions, hallucinations, de- course of AD have received considerable attention. Because pressed mood, agitation, hostility, and other noncognitive depression per se can impair cognitive function (17), it is behavioral abnormalities of AD to the signs and symptoms reasonable to hypothesize that effective treatment of depres­ expressed in such classic psychiatric disorders as depression, sion in the patient with AD may maximize potential cogni­ schizophrenia, and mania has prompted the widespread use tive capacity. Furthermore, the consensus is that reduction of psychotropic drugs in the management of AD (13–16). Unfortunately, the apparently straightforward goal of cacy.

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 buy dapoxetine 30mg mastercard erectile dysfunction massage. Pharmacologic addition order 90 mg dapoxetine amex erectile dysfunction drugs mechanism of action, because until recently patients with OCDwere data gathered included doses of medications and duration reluctant to seek treatment best 30mg dapoxetine erectile dysfunction age at onset, patients with more debilitating of treatment discount 30 mg dapoxetine overnight delivery erectile dysfunction drugs over the counter uk. 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. A second study of OCDadolescents for confounds, found a later age at onset to be a strong found a high frequency of age-inappropriate synkinesias and predictor of response. Skoog and Skoog (42) reported that lateralization of deficits to the left side of the body (64). In onset of OCDbefore age 20 was related to a poorer out- a nonblinded study in which a clinical neurologic examina- come, especially in men. In other studies, age at onset did tion was performed in childhood and adolescent OCDsub- not predict severity of illness at follow-up. Adolescents in jects, most of the patients had abnormal neurologic find- the study of Berg et al. It seems likely sided signs that were suggestive of right-sided dysfunction. However, in the only study we could locate that type in OCD. Thus far, specific obsessions and compulsions have not predicted outcome in the vast majority of follow- examined level of functioning in OCD, pretreatment func- up studies.

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Increase of extracellular emission computerized tomography (SPECT) buy dapoxetine 90mg fast delivery erectile dysfunction causes smoking. Am J Drug Alco- corticotropin-releasing factor-like immunoreactivity levels in hol Abuse 1995;21:47–63 buy cheap dapoxetine 30 mg line impotence 20s. Opioid receptor imaging with PET and [18F]cyclofoxy in long-term methadone-treated withdrawal as measured by microdialysis effective dapoxetine 90 mg erectile dysfunction over 50. Activation of reward circuitry ing factor from the rat amygdala after repeated administration in human opiate addicts purchase dapoxetine 90mg with mastercard erectile dysfunction doctor boston. Mol Fischer rats following chronic cocaine treatment using a recently Psychiatry 1997;2:430–434. Co-occurrence of ceptor up-regulation during binge cocaine administration. Arch Gen Psychiatry 1998;55: Pharmacol Exp Ther 1994;270:1387–1396. Mu-Opioid recep- receptor binding detected by PET in cocaine-dependent men tor knockout mice do not self-administer alcohol. WOODY Currently, numerous effective pharmacologic and behav- ing treatment have been addicted to heroin or other opioids ioral therapies are available for the treatment of opioid ad- for 2 to 3 years, some for 30 years or more. Newer therapeutic op- generally ineffective in producing sustained remission unless tions may take various forms. For example, methadone combined with long-term pharmacologic, psychosocial, or maintenance is an established treatment modality, whereas behavioral therapies, detoxification alone continues to be the use of buprenorphine and naloxone in an office-based widely used and studied. It is sometimes the only option setting represents a new variation on that theme. Clonidine available for patients who do not meet United States Food has been used extensively to ameliorate opioid withdrawal and Drug Administration (FDA) criteria for, do not desire, signs, whereas lofexidine is a structural analogue that ap- or do not have access to agonist medications such as metha- pears to have less hypotensive and sedating effects. The done or methadyl acetate (L- -acetylmethadol or LAAM). In almost oid alternatives such as clonidine, benzodiazepines, or non- every treatment episode using pharmacotherapy, it is com- steroidal antiinflammatory agents. In many cases, one or bined with some type of psychosocial or behavioral treat- more medications are combined, such as naloxone with ment. Recent research has documented the value of these clonidine and a benzodiazepine. The choice of detoxifica- additional treatments and has provided insight into the ones tion medication and the duration of the process depend that are the most effective. This chapter reviews current on numerous factors including patient preference, clinician and experimental treatments for opioid addiction with an expertise and experience, type of treatment facility, li- emphasis on some of the newer, more promising, and inter- censing, and available resources. Unfortu- nately, however, detoxification for some patients appears to be used in a punitive manner or as an expedient means to TREATMENT PARADIGMS achieve a drug-free state rapidly with no follow-up pharma- Long-Term, Short-Term, Rapid, and cologic or behavioral therapy. Ultrarapid Opioid Detoxification Opioid detoxification paradigms are frequently catego- rized according to their nominal duration: long-term (typi- Detoxification from opioids, for most patients, is only the cally 180 days), short-term (up to 30 days), rapid (typically first phase of a longer treatment process. Most patients seek- 3 to 10 days), and ultrarapid (1 to 2 days). These temporal modifiers provide only a coarse description of the paradigm; they do not provide other important information such as Paul J. Fudala: Department of Psychiatry, University of Pennsylvania, the medications used or whether postdetoxification pharma- Philadelphia, Pennsylvania; Department of Behavioral Health Service, Veter- cologic (e. Woody: Substance Abuse Treatment Unit, VA Medical Center, havioral therapy is provided. However, some general guide- Philadelphia, Pennsylvania. Unfortunately, these particular is the occurrence of potentially serious adverse strategies have not generally been associated with acceptable effects, such as respiratory distress (7), or other pulmonary treatment response using relapse to opioid use as an out- and renal complications (8), during or immediately after come criterion. For example, one study reported that more the procedure. A high frequency of vomiting has also been than half the patients participating in a 180-day detoxifica- reported (9). The degree to which serious adverse effects tion program were using opioids illicitly during the medica- occur has not yet been determined; however, there have tion-taper phase of the protocol (1). Six-month follow-up been press reports of sudden death occurring shortly after indicated that 38. Results from more rapid detoxification highly selected patients based on considerations of previous evaluations using short- or even intermediate-term (up to treatment history, economic factors, and patient choice. However, oughly informed that serious adverse effects, including sud- provision of additional services such as counseling, behav- den unexpected deaths, have occurred in association with ioral therapy, treatment of underlying psychopathologies, this procedure, and its use should probably be limited to job skills training, and family therapy to address concomi- inpatient settings where monitoring by anesthesiologists and other highly trained staff is available. Results from inpatient Rapid detoxification involves the use an opioid antago- (10–12) and outpatient (13,14) studies have shown that it nist, typically naltrexone or naloxone, in combination with is safe and well tolerated, and it mitigates opioid withdrawal other medications (such as clonidine and benzodiazepines) signs and symptoms over a range of doses and detoxification to mitigate the precipitated withdrawal syndrome. Clonidine, an 2-adrenergic agonist, has been cedure is intended to expedite and compress the withdrawal shown to suppress many of the autonomic signs and symp- process to minimize discomfort and to decrease treatment toms of opioid withdrawal. Ultrarapid detoxification also uses other medications, tion and hypotension but has been used with few problems along with an opioid antagonist, to moderate withdrawal when appropriate monitoring is available. However, rather than being awake as they are during press the subjective discomfort of withdrawal, and probably the rapid detoxification process, patients are placed under for that reason, it is not well accepted by most opioid ad- general anesthesia or, alternatively, are deeply sedated. Rapid detoxification less sedation and hypotension than clonidine. Lofexidine, studies were conducted in inpatient facilities, outpatient a medication that was originally promoted as an antihyper- substance abuse treatment settings, and outpatient primary tensive, has been the most thoroughly studied. When com- care facilities; ultrarapid ones were confined to inpatient pared with clonidine, it was found to suppress autonomic settings. Patients included those who were heroin depen- signs and symptoms of opioid withdrawal equally, but with dent as well as those in methadone maintenance treatment. When compared Only four of the studies reviewed provided follow-up with methadone dose tapering, lofexidine detoxification was beyond the initial detoxification. Retention on postdetoxifi- associated with opioid withdrawal effects that peaked cation naltrexone maintenance in one rapid detoxification sooner, but resolved to negligible levels more rapidly (18). In another study (19), an accelerated 5-day lofexidine treat- Only one of the ultrarapid detoxification studies provided ment regimen attenuated opioid withdrawal symptoms follow-up information indicating that all patients (11 of 11) more rapidly than 10 days of either lofexidine or metha- were taking naltrexone 30 days after detoxification (5). A done, with similar blood pressure responses observed for more recently published study (6), in which ultrarapid de- the two lofexidine groups. Data regarding the potential ef- toxification was followed by naltrexone maintenance and fectiveness of guanabenz and guanfacine have also been re- supportive psychotherapy, indicated that 49 of 72 patients ported, but further studies are required to assess the poten- were opioid abstinent 12 months after detoxification. All tial utility of these medications for detoxification treatment. The overall effect has been cacy approximates that of clonidine but with fewer side a widening gap between treatment need and availability, effects. As a result, the Institute of Medicine and the National Institutes of Health each made recommendations for regula- Opioid Agonist Pharmacotherapy tory reform (23,24). Many of these recommendations are Methadone maintenance was developed by Dole and Nys- in the process of being carried out and include an overall wander and has become the most commonly used pharma- reduction in regulations and transfer of oversight to accredi- cotherapy for opioid dependence (20). Methadone acts as tation bodies that are approved by the Center for Substance the -opioid receptor, and its ability to suppress opioid Abuse Treatment, rather than the FDA. Other recommen- withdrawal for 24 to 36 hours after a single oral dose makes dations include allowing long-term, stable patients to be it an ideal medication for this purpose. Another -opioid treated in settings other than methadone clinics where they agonist, LAAM, received FDA approval for maintenance can receive up to 30 days of take-home medications (medical treatment in 1993. LAAM is a long-acting congener of maintenance), allowing take-home doses for LAAM, and methadone that suppresses withdrawal for 48 to 72 hours allowing more clinical judgment in determining dosages and and thus has the advantage of requiring less frequent clinic take-home schedules.

In this case order 30 mg dapoxetine mastercard erectile dysfunction treatment blog, the cated because purchase 30 mg dapoxetine erectile dysfunction treatment in uae, since the markers are so closely spaced cheap dapoxetine 30 mg overnight delivery erectile dysfunction in diabetes mellitus pdf, one implicated allele would be both associated and linked to the cannot assume that these markers are not in LD with each disorder buy dapoxetine 60 mg line erectile dysfunction medication ratings, obviating the possibility that the allele is falsely other independent of the disease phenotype. Multipoint LD associated through population stratification. Other ap- methods such as AHR will need to take into account the proaches for analyzing family-based association data use possibility that significant background LD could occur be- 236 Neuropsychopharmacology: The Fifth Generation of Progress tween closely spaced markers in order to distinguish this variation than highly conserved coding sequence. One pos- background LD from what may be a very subtle increment sible strategy in this situation is to search for an orthologous of LD surrounding the true disease locus. Com- In summary, the ability to localize disease genes using parison of these sequences may highlight strongly conserved LD methods in a given population sample depends on the regions of DNA outside of coding sequence that may be amount and extent of LD present, the number of disease functionally relevant and important to examine closely for predisposing alleles at a given locus (allelic complexity), the disease predisposing variants (42). Provision of the complete degree to which the disease locus increases the likelihood sequences of the genomes of model organisms amenable to of manifesting the affected phenotype, and the power of genetic manipulations such as flies, mice, roundworms, and current statistical methods to measure existing LD. For an yeast by the HGP could speed understanding of comparable excellent review of the strengths and weaknesses of current gene structure and function in humans and serve as a molec- statistical approaches for analyzing LD, see ref. Identification of a Disease Gene Should psychiatric geneticists overcome the many obstacles PHARMACOGENOMICS facing them and succeed in mapping a disease locus to a specific interval, the next step would be to identify the dis- As genes contributing to the development of psychiatric ease gene within it, a process termed positional cloning or, disorders are discovered, they will be added to the known given the completion of genome sequencing, the positional array of neurotransmitters, receptors, and transporters that candidate approach (41). Positional cloning in its purest are already considered candidate genes for pharmacogenetic sense is the process of identifying a disease gene based only analysis. This process involves laborious ef- pathways and sites of action, or disease processes if known, forts to build a physical map and sequence the region. Physi- are examined for naturally occurring variants or polymor- cal maps are made by isolating and linking together yeast phisms, which may then be shown to affect the expression and/or bacterial artificial chromosomes (YACs, BACs) con- of that gene. This effect on gene function may then be taining fragments of human DNA from the region. These linked to the efficacy of the drug and/or a predisposition fragments are then sequenced and ordered so that the geno- to particular side effects in individuals with that genotype. Then comes the arduous process of identifying all E locus has been shown to be associated with late-onset AD, the genes in the interval and performing mutation detection. The downside of this strategy is that gies arising from the HGP have greatly speeded up this it is limited by the paucity of candidate genes with proven process, however. For instance, near-complete genomic se- association to psychiatric phenotypes. Fortunately, investi- quence data for the region of interest may already have been gators in the emergent field of pharmacogenomics are seek- deposited in the public databases, obviating the need for ing to identify previously unsuspected genetic markers of extensive genomic sequencing. In addition, there are already a multitude of Web- macogenetics and pharmacogenomics (see ref 47. This computer exercise is part of the positional proach we currently employ. Once all the ESTs have been identified, The impact of genetic variation on drug response is char- the complete sequence of the corresponding genes (includ- acterized broadly by changes in pharmacokinetic and phar- ing definition of intron/exon boundaries and the promotor, macodynamic parameters. Pharmacokinetic studies assess if possible) are elucidated and mutation detection begins. Transport pro- however, it can be very difficult to detect disease-causing cesses in renal, intestinal, and hepatic epithelia and drug mutations in the surrounding noncoding DNA or introns, metabolizing enzymes exhibit genetic variability, which will as these regions are large and likely to display more natural in many cases be likely to influence the pharmokinetics of 18: Using Human Genomics to Advance Neuropsychopharmacology 237 relevant drugs. In the latter situation, the cytochrome P- referred to now as the long (versus the short) allele. Lesch 450 system has been best studied (48) beginning with the et al. Since then, investigators have studied depressed metabolism of roughly a quarter of all drugs including most patients to see if they can correlate SSRIresponse with alleles antipsychotics and antidepressants (49). About 7% of Caucasians suggesting that patients with delusional depression re- and an even greater percentage of Asians are poor metabol- sponded better to fluvoxamine if they were homozygous for izers of such drugs due to polymorphisms in this enzyme. Other investigators On the other hand, some persons carry different alleles and/ have obtained similar findings in a samples of depressed or multiple copies of this gene, which predispose to more patients treated with paroxetine (57), although in this study rapid metabolism; up to 13 copies have been documented rapidity of response was improved in persons homozygous in a single individual. A study of nortriptyline metabolism for the long allele, while overall outcome at 12 weeks was in these individuals clearly demonstrated that clearance of the same for all genotypes. Knowledge that a person has a genotype predispos- been cloned and expressed in some type of cellular system ing to unusually slow or rapid metabolism could guide ap- and that are viable candidates for drug targets (58). Unfortunately, cogenomic technologies may aid in prioritizing these candi- despite intensive study, no definitive relationship between dates for examination, or identifying yet more candidates, polymorphisms in cytochrome P-450 enzymes and drug by determining those genes that are activated or deactivated efficacy or predisposition to side effects of antidepressant in tissues during an acute psychiatric episode and in re- drugs has yet been discovered (52). One approach to evaluating gene Pharmacodynamics concerns the relationship between expression involves hybridization of fluorescent or radioac- the concentration of a drug and response at its site of action, tively labeled messenger RNA (mRNA) samples taken from for example at receptors and transporters for neurotransmit- the relevant cell population to cDNA arrays. Pharmacodynamic effects may also vary temporally, gene expression (up, down, or none) can then be compared and so both the acute and chronic nature of response to between different samples at a single time point or within the drug must be considered. This technique is known as serial analysis siveness, receptor polymorphisms could alter any of the of gene expression (SAGE) (59). However, if the changes myriad steps in a pathway from receptor-drug binding in gene activation induced by disease or by drugs are local- through the cascade of signals that result; such variants may ized to a specific population of cells in inaccessible tissues determine who is more prone to immediate drug reactions, such as that of the brain, rather than, say, in fibroblasts for example the malignant hyperthermia that may occur in from skin biopsies, the SAGE technique will not be helpful. Genetic variation could also play Alternatively, large-scale analysis of proteins within clinical a role in the drug-induced neural plasticity that occurs as samples is also predicted by some to become a useful means a result of the chronic treatment required for alleviation of of identifying biological markers indicative of a response to psychiatric symptomatology as well as chronic use of addic- drugs (60). Again, any changes in protein expression would tive substances. Adaptive responses to drugs will vary among need to be detectable in easily obtainable fluids such as individuals, and genetic factors may predict such phenom- blood or urine to be of use in the evaluation of psychiatric ena as waning of drug response over time, and proneness disorders, and the process of informed consent for such to side effects such as tardive dyskinesia induced by antipsy- experimentation would need to be reviewed thoroughly. From a pharmacogenetic perspective, one of the most obvious candidates for studying psychiatric drug responsive- SUMMARY ness identified to date is the serotonin (5-hydroxytrypta- mine, 5-HT) transporter (5-HTT) (52). This transporter Genomics has great potential to advance the field of psychia- plays a critical role in the termination of serotoninergic try in general and neuropsychopharmacology in particular. Although we have not made much insertion within the promoter region, which is commonly headway as of yet in either of these fields, impressive ad- 238 Neuropsychopharmacology: The Fifth Generation of Progress vances in our knowledge of the genomes of human and 15. Elementary phenotypes in the neurobiological and genetic study of schizophrenia. The central nervous system (CNS) spans across different ments were designed in such manner that information re- levels of organization, covering the gamut from genes to lated to structure was gathered along with behavioral behavior. It is the aim of neuroscience to elucidate all these information, we would have an ideal setting for struc- levels at a gross and an ultrastructural resolution and to tural–functional or, in the case of disease, anatomic–clinical define the relationships among them. This can be done in the domain of neuroimag- levels of organization is the systems level, which includes ing by using currently available technology in an unprece- the motor, sensory, and central neural systems. In the past two centuries, functional–structural central systems are included those related to cognitive func- correlations were derived mostly from experimental nonhu- tion, such as attention, memory, language, and executive man material, whereas anatomic–clinical correlations were function. Each system can be considered as a set of intercon- derived principally from human behavioral and, eventually, nected processors or centers constituted by nerve cells. With the tremendous develop- physical connections are composed of axons of different ment of magnetic resonance imaging (MRI) technol- lengths that can form fascicles as they run from origin to ogy—both structural and functional MRI (fMRI) and mag- destination. Within the neocortex, these connections are netic resonance spectroscopy (MRS)—the study of the selective and architectonic (1). Howcytoarchitecture, con- structure, function, and metabolism of the living human is nections, and function relate within the neocortex is a fun- an ongoing reality. This question addresses One of the latest advancements of MRI technology has basic organizational principles of the nervous system and been diffusion tensor imaging (DTI), a technique capable of aims to elucidate the mechanisms through which the cere- measuring the diffusivity of water molecules and rendering brum mediates behavior (2,3). Behavior, to a large extent visible the preferential orientation of their movement. On the other hand, within a strongly ori- ented tissue such as a white matter tract, water diffusion is Nikos Makris, G. Jenkins, not equal in all directions but is instead anisotropic, specifi- L. Wu, cally predominant along the direction of the tissue. Ken- nedy: Massachusetts General Hospital, Harvard Medical School, Boston, strongly parallel axonal arrangement within a fiber bundle Massachusetts. These connections can be categorized in three and orientation of a tissue, and because brain white matter principal classes—namely, associational, commissural, and can be characterized to a large extent by its orientation and projectional. Intrahemispheric associational corticocortical anisotropy, the detection of white matter fiber pathways has connectivity in particular is accomplished in general by (a) become feasible in the living brain.

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