The 'pre- are caused by specific discount 100 mg silagra with amex, not generalized buy 50mg silagra otc, deficits (51). Given the known role of subcortical networks as These studies have also shown adults with ADHD to be modulators of prefrontal functioning, the term frontosubcor- impaired in other functions known to affect children with tical seems appropriate for ADHD. These include the following: perceptual-motor behavioral or cognitive dysfunction that looks 'frontal' but speed as assessed by the digit symbol/coding tests (54,55); may be influenced by subcortical projections. For example, the cingulate cortex influences mo- Test (57,58). Because neuropsychological tests are free of tivational aspects of attention and in response selection and the potential biases of self-reported symptoms, the finding inhibition. The brainstem reticular activating system regu- that the neurocognitive profiles of adults with ADHD are lates attentional tone and reticular thalamic nuclei filter in- similar to those of children with ADHD suggests that the terference. Working memory deficits implicate a distributed diagnosis of ADHD is valid as applied in adulthood. Moreover, the atten- literature, not findings that have been consistently repli- tional problems of children with ADHD may implicate a cated. Although there are inconsistencies among studies, it wider distribution of neural networks. A system mainly in- is notable that the pattern of deficits that has emerged is volving right prefrontal and parietal cortex is activated dur- similar to what has been found among adults with frontal ing sustained and directed attention across sensory modali- lobe damage. The inferior parietal lobule and superior temporal support the hypothesis that the frontal cortex or regions sulcus are polymodal sensory convergence areas that provide projecting to the frontal cortex are dysfunctional in at least a representation of extrapersonal space and play an impor- some children with ADHD. Because neuropsychological tests provide indirect mea- sures of brain function, we must be cautious in using them Neuroimaging Studies to make inferences about the locus of brain impairment in ADHD. Yet because many of these tests have been standard- Fortunately, hypotheses based on neuropsychological infer- ized on normative populations and administered extensively ence can be tested with neuroimaging paradigms. Because to brain-damaged populations, observed deficits tests can neuroimaging studies provide direct assessments of brain Chapter 43: Pathophysiology of ADHD 581 TABLE 43. STRUCTURAL NEUROIMAGING STUDIES OF ADHD Study Diagnosis Method Findings Shaywitz et al. First, and adults with ADHD that used computed tomography the adolescent samples studied may have been more hetero- or magnetic resonance imaging. Among these studies, the geneous than the adult samples. Although all the adults had most consistent findings implicated frontal cortex, usually persistent ADHD, some of the adolescent cases may have limited to the right side, cerebellum, globus pallidus, cau- remitted by adulthood. Thus, frontal dopaminergic hypoac- date, and corpus callosum. Several other regions were less tivity may be associated with persistent ADHD only. Consistent with these findings, the natively, Ernst et al. These mice shift from the midbrain in childhood to the prefrontal cor- show learning impairments, impulsiveness, and hyperactiv- tex in adults. Metabolic mapping studies suggest that their behavioral Anterior cingulate cortex, lying on the medial surface deficits are associated with lower 2-deoxyglucose uptake in of the frontal lobe, has strong connections to dorsolateral the left striatum and the frontal and parietal cortex (61). In contrast to sion tomography, single photon emission tomography, controls, the adults with ADHD failed to activate the ante- functional magnetic resonance imaging, or electroencephal- rior cingulate cortex. The most consistent findings were hypoactivity of kin et al. The neurochemical basis of brain dysfunction in ADHD found gender differences in lateralization (63), future stud- was studied by Dougherty et al. They measured DAT ies will need to assess gender differences and to determine density by single photon emission computed tomography how they may be related to the male predominance of the with the radiopharmaceutical iodine 123–labeled altropane. Their findings were consistent with the catecholamine hy- 582 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 43. FUNCTIONAL NEUROIMAGING STUDIES OF ADHD Study Diagnosis Method Findings Lou et al. Taken together, the brain imaging anomalies and malformations of the posterior fossa were studies fit well with the idea that dysfunction in frontosub- more common among patients with ADHD compared with cortical pathways occurs in ADHD. How- with the report of a father and son, both having methyl- ever, given that several other studies showed partial agenesis phenidate-responsive ADHD secondary to frontal lobe epi- of the corpus callosum or anomalies of the cerebellar vermis lepsy (68). Notably, the frontosubcortical systems that con- (also formed before birth), it seems reasonable to conclude trol attention and motor behavior are rich in that at least some children with ADHD have a very early catecholamines, which have been implicated in ADHD by onset of brain abnormalities. In a novel approach to assessing brain regions implicated in ADHD, Herskovits et al. Compared with head-injured children who did not develop Figure 43. To address this issue, Nopoulos et diagnosis is valid. These studies leave no doubt that ADHD Chapter 43: Pathophysiology of ADHD 583 Faraone et al. These investigators reasoned that cases that remit before adolescence could have a smaller genetic component to their disorder than persistent cases.

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The first of during fluvoxamine treatment were of only mild intensity these studies involved a 31-year-old woman with PG and and were consistent with SSRI treatment order silagra 50mg overnight delivery, and they were not comorbid social phobia and OC personality traits who had associated with early withdrawal from the study discount 100 mg silagra with mastercard. Outcome been gambling persistently despite multiple prior treatments measures included scores from the PG-CGI and PG- (140). Clomipramine was administered in double-blind, YBOCS, as earlier. Data from the investigation demon- placebo-controlled fashion in a crossover design. Minimal strated active drug to be superior to placebo in targeting improvement was seen after 10 weeks of placebo treatment. Both the groups receiving After initiation of active drug at 25 mg per day with an active medication and placebo showed improvement in con- increase up to 175 mg per day, gambling behavior was dis- trol of gambling behaviors during the first 8 weeks, and the continued at week 3, with absence of gambling remaining most significant difference in response was observed at the at 38 weeks. The adverse effect of increased irritability was end of the second 8-week block (Fig. In other words, effectively treated with a temporary decrease in dose. Sixteen group were more likely to persist over time, whereas initial subjects entered the 16-week trial (8-week placebo lead-in, gains observed in the fluvoxamine-placebo treatment group 8-week active), with seven of ten completers judged to be declined. These findings are consistent with a high initial responders by (a) a score of 'much improved' or 'very rate of placebo responders and suggest that acute trials of much improved' on the Clinical Global Impression score longer duration may be important in better distinguishing for gambling severity (PG-CGI) and (b) greater than 25% response to placebo and active drug. Of the the treatment of PG was reported by an independent group completers, four were female and six were male. In their study, 34 patients were treated for 6 months cation was well-tolerated, and the average dose for complet- with placebo or fluvoxamine at 200 mg per day. Outcome ers was 220 mg per day at endpoint, with responders tend- was measured by quantification of time and money spent ing to be treated with a slightly lower dose (207 mg per on gambling. The authors found no statistically significant day on average). Noncompleters left the study during the differences in response rates to placebo as compared with placebo phase (four for noncompliance, two for lack of re- active drug for the overall sample. Of the three nonresponders, two were the only observing a statistically significant superiority of fluvoxa- completers with histories of cyclothymia, a finding raising mine as compared with placebo in the male and younger- the possibility that individuals with a comorbid cycling aged subgroups of individuals with PG in the study. Strik- Chapter 120: Pathologic Gambling and Impulse Control Disorders 1733 FIGURE 120. Changes in gambling symptom severity of patients with pathologic gambling (PG) in response to fluvoxamine. Changes in PG–Clinical Global Impression (CGI) scores are shown for subjects completing a 16-week pla- cebo-controlled, double-blind study of fluvoxa- mine for the treatment of PG. Measures are shown for individuals receiving placebo in phaseIfollowedbyfluvoxamine inphaseII(dia- monds) or fluvoxamine in phase I followed by placebo in phase II (squares). The study com- promising results and to define better the short- and long- pared the results of treatment with fluoxetine at 20 mg per term efficacies and tolerabilities of specific SRIs in groups day with support psychotherapy (n 11) as compared of individuals with PG. Measures of outcome included scores on the CGI and Ludo-Cage test. The treat- Opioid-Receptor Antagonists ment group receiving fluoxetine showed significantly im- The mOR, involved in regulation of DA reward- and rein- proved outcomes as measured by CGI scores (fluoxetine forcement-related pathways, has been the target for pharma- plus psychotherapy: 1. Individuals in the combined intake and alcohol cravings in the treatment of alcohol de- fluoxetine and psychotherapy treatment group also demon- pendence (146–148), as well as to target impulsive, self- strated better adherence to treatment guidelines. Two case reports described a potential role for of a third SSRI, paroxetine, was performed (145). The study naltrexone in the treatment of individuals with PG (152, used a parallel group design with each group receiving a 1- 153). In an open-label case series of individuals with ICDs, week placebo lead-in followed by 8 weeks of either placebo Kim described a 55-year-old man with PG and CB (152). Dosing was initiated at 20 mg per day Naltrexone at 50 mg per day was initiated with no clinical with increases up to 60 mg per day as clinically indicated. Several days after an increase Forty-one patients meeting the criteria for PG and no other to 100 mg per day, a significant decrease in gambling urge axis I diagnosis participated in the study (20 paroxetine, 21 intensity was reported by the patient. Adverse effects were observed with greater fre- followed by elimination of gambling and excessive buying, quency in the paroxetine-treated group (2. The treatment- treatment of a 49-year-old man with comorbid PG, depres- emergent symptoms were consistent with SSRI treatment, sion, and alcohol dependence (153). The patient was ini- most frequently involving reports of headaches, fatigue, and tially treated with fluoxetine (dose and duration not speci- dry mouth. Outcome was measured by scores on the pa- fied), with improvements in mood and persistence in urges tient- and clinician-rated CGI and the Gambling Symptom to drink and gamble.

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Functional MRI changes in patients with sensory conversion disorder purchase silagra 50mg without a prescription. Gungor S order 50mg silagra visa, Aiyer Rl Postoperative transient blindness after general anaesthesia and surgery: a case report of conversion disorder. Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder. Assessment and management of medically unexplained symptoms. Attribution theory: social and functional extensions. Intelligence is negatively associated with the number of functional somatic symptoms. Clinical lessons from anthropologic and cross- cultural research. Efficacy of treatment of somatoform disorders: a review of randomized controlled trials. Beyond the unexplained pain: relational world if patients with somatization syndromes. Journal of Nervous and Mental Disease 2012; 200:413-422. Somatization: the concept and its clinical applications. American Journal of Psychiatry 1988, 145, 1358-1368. Attributions about common body sensations: their associations with hypochondriasis and anxiety. An attachment-based model of the relationship between childhood adversity and somatization in children and adults. Clin Psychol Psychother 2013; Oct 9 [Epub ahead of print]. DSM-5 illness anxiety disorder and somatic symptom disorder: comorbidity, correlates, and overlap with DSM-IV hypochondriasis. Antidepressant therapy for unexplained symptoms and symptom syndromes. British Journal of Medical Psychology 1969, 42, 347-351. Childhood abuse in adults in primary care: empirical findings and clinical implications. Somatization disorder from a cognitive-psychobiological perspective. Transcranial magnetic stimulation in motor conversion disorder: a short case series. Journal of Clinical Neurophysiology 2006; 23:472-475. Long-term follow-up of hypochondriasis after selective serotonin reuptake treatment. Journal of Clinical Psychopharmacology 2011; 31: 365-368. American Journal of Psychiatry 1996, 153 (7 Suppl), 137-142. Terluin B, van Marwijk H, Ader H, de Vet H, Penninx B, Hermens M, van Boeijen C, van Balkom J, van der Klink J, Stalman W. The Four-Dimensional Symptom Questionnaire (4DSQ): a validation study of a multidimensional self-report questionnaire to assess distress, depression, anxiety and somatization. Clinical and cost-effectiveness of cognitive behaviour therapy for health anxiety. Post-traumatic neurosis: form railway spine to the whiplash. Common limbic and frontal- striatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis. Von Korff M, Gruman J, Schaefer J, Curray S, Wagner E. Culture and mental illness: a social labelling perspective. Journal of Nervous and Mental Diseases 1974, 159, 379-395. Cognitive therapy and exposure therapy for hypochondriasis (health anxiety): A 3-year naturalistic follow-up. Suicidality in primary care patients with somatoform disorders.

This process results in the enzymatic levels of polyunsaturated fatty acids buy silagra 100 mg low cost, which provide an index production of H2O2 purchase 100mg silagra otc, which, while itself not a free radical, of the amount of substrate available for lipid peroxidation, can nevertheless react nonenzymatically with ferrous or cu- and an increase in levels of malondialdehyde, an intermedi- pric ions via Fenton-type reactions to form highly reactive ate in the lipid peroxidation process. Second, DA can react nonenzymatically dialdehyde was regionally specific for the SN. These workers with oxygen to form quinones and semiquinones, with the subsequently confirmed evidence for abnormal lipid peroxi- production of superoxide, hydrogen peroxide, and hydroxyl dation in PD by identifying a tenfold increase in cholesterol radicals. Third, the SN, particularly the SN pars reticulata, lipid hydroperoxide, an early marker in the lipid peroxida- is rich in iron, which as mentioned above, may in its ferrous tion process (25). Free radicals are also capable of directly state catalyze the formation of hydroxyl radicals from H2O2. The possibility that such stated above, it remains the foremost and most widely tested protein changes may also occur in PD brain is supported hypothesis of neural degeneration in PD. Nevertheless, it by the demonstration that protein adducts of 4-hydroxy-2- remains only a hypothesis, and it has its shortcomings (17). In addition, it must be remembered that nonaminergic neu- Postmortem studies have also revealed neurochemical ronal groups, such as the nucleus basalis, which is choliner- features that may predispose the PD brain to oxidative dam- gic, also degenerate in PD, and aspects of the free radical age. Reduced glutathione is an important endogenous anti- hypothesis that are dependent on catecholamine metabo- oxidant, and it has been reported to be reduced in the SN lism are not relevant to the degeneration of these structures. Jenner and colleagues (80) have confirmed low levels of reduced glutathione in the SN of PD patients, Programmed Cell Death and have shown that the alteration is disease-specific. Inter- estingly, they have also shown that reductions are observed The concept that a genetically regulated cell death process in patients with incidental Lewy body disease, which may may underlie the neuron-specific degenerations of later life be a preclinical form of PD (49). This finding suggests that has gathered great attention in recent years. The pro- the reduced levels of glutathione may be a fundamental and grammed cell death hypothesis in fact may be related to primary abnormality in PD, rather than a secondary change. Although A number of postmortem studies have also suggested traditional concepts of free radical injury have centered on that abnormalities of iron metabolism may underlie the neu- the ability of toxic molecules to directly injure cellular con- rodegeneration of PD. It is also apparent that in some settings Dexter and colleagues (26) reported increased levels of iron programmed cell death may be carried out by the controlled in the SNpc of PD patients. This observation took on po- production of free radicals. As predicted by classic neu- However, it has become apparent that increased iron levels rotrophic theory, some natural cell event does occur during may be observed in many brain regions demonstrating neu- development in the SNpc, with typical light microscopic ral degeneration in a variety of diseases of the basal ganglia morphology of apoptosis, demonstrated both by Nissl stain (22), so the specificity of changes in iron levels in PD is and suppressed silver staining (79), and we used a double- less clear. Nevertheless, the possible relationship of altered labeling technique to identify apoptotic natural cell death iron metabolism to the pathogenesis of PD remains of inter- in phenotypically defined dopaminergic neurons (123). There is an initial, major peak that begins on embry- (35). This finding suggests that lactoferrin receptors, which onic day 20, and largely abates by the eighth postnatal day regulate intraneuron iron content, may be overly expressed (PND). There is a second, minor peak of natural cell death in vulnerable dopaminergic neurons in PD. The presence of a postnatal cell death event Another postmortem finding in PD patients that is com- is in keeping with the demonstration by Tepper and col- patible with the free radical hypothesis is that of a deficiency leagues (151) that there is a decrement in the number of in mitochondrial complex I. Such a defect could either result TH-positive neurons in SN postnatally, particularly in the in the abnormal production of free radicals, or be the result first postnatal week. Although there is evidence that the of free radical injury (137). This defect takes on particular magnitude of the natural cell death event in DA neurons interest in light of the observation that MPP , the toxic is regulated by interactions with the target striatum (see oxidative product of MPTP, inhibits complex I (121). The below), as classic neurotrophic theory would predict, it re- defect in complex I in PD patients has been demonstrated mains unknown which neurotrophic factors are involved. This decrease appears to be both regionally spe- neurons that GDNF is uniquely able to support viability by 1788 Neuropsychopharmacology: The Fifth Generation of Progress suppressing spontaneous apoptotic death (16) as well as cell but they were not clearly characteristic of apoptosis. Whether glial cell TUNEL labeling (45) has been demonstrated in PD brains line-derived neurotrophic factor (GDNF) plays such a role (115). However, the terminal deoxynucleotidyl transferase in vivo remains to be determined. Excitotoxic injury to the striatum on PND 7 results in an Thus, it is essential to co-identify not only TUNEL labeling eightfold increase in the number of apoptotic profiles (102). Tompkins and co-workers (153) and Tatton and served during natural cell death, and meet ultrastructural colleagues (150) have both achieved this more specific dem- and 3′ end-labeling criteria for apoptosis. However, many other investigators have been induction of cell death is identified within phenotypically unable to identify specific TUNEL labeling in PD brains defined dopaminergic neurons. Thus, a consensus has not been achieved, Programmed cell death also occurs in DA neurons in and further investigation will require methods beyond these animal models of parkinsonism. Intrastriatal injection of 6- morphologic techniques, such as the utilization of specific OHDA results in an induction of apoptotic death in pheno- biochemical markers for programmed cell death. Hartmann typically defined DA neurons of the SN (106). This induc- and colleagues (58) have made such an effort utilizing an tion is most pronounced in a developmental setting, antibody that is specific for the activated form of caspase- through PND 14, but it can also be demonstrated, at a 3. They have shown that activated caspase-3 could be identi- lower level, in mature animals.

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