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Developmental pathology with a pal activity appeared to be increased at baseline order 130 mg malegra dxt with visa erectile dysfunction in diabetes medscape, again em- genetic basis also appears likely cheap malegra dxt 130mg on-line erectile dysfunction doctors in alexandria va. A recent study links a ge- phasizing the task-dependence of neurofunctional findings netic attribute that affects prefrontal dopamine to both in general (48). Several studies point to a role for lateral working memory performance and DLPFC activation in temporal cortex in hallucinations and other positive symp- patients, their sibs, and unrelated healthy individuals (21). Investigations of this type, which explore the Miscellaneous Regional Changes interaction of genetic and neurophysiologic characteristics, hold the greatest promise for elucidating the etiology of the Functional abnormalities, primarily hypofunction, of many illness and effecting innovative treatments. Although most are unrep- licated, several are worth mentioning. Both increased and decreased basal ganglia activity have been found, but a role Other Frontal Lobe Subregions for neuroleptic treatment in such findings must be consid- Dysfunction, primarily hypofunction, of portions of the ered. Several investigators have suggested that schizophrenia frontal lobes other than the DLPFC has also been described. It may, frontal areas as well as relatively higher flow to posterior thus, be especially prone to epiphenomenologic effects. In particular, the notion tion in the face of competing information, such as the that schizophrenia may involve disordered functional later- Stroop test, complex motor control tasks, verbal fluency, alization has been explored using a variety of methods. These observations have led cognitive temporal overactivation was seen in this light in early stud- neuroscientists to propose more refined cognitive roles such ies. More recent work suggests that apparent alterations in as on line monitoring, conflict monitoring, and error detec- functional laterality in schizophrenia may not actually re- tion (46). Further research is necessary to clarify which of flect abnormal lateralization per se, but rather a failure to these putative cognitive roles, or which epiphenomena, may organize a lateralized response (6,49). For example, Mattay be linked to the finding of anterior cingulate underactiva- and associates (1997) reported less lateralized and localized tion in schizophrenia (9–11). Orbitofrontal cortex, along lateral premotor area activation in patients during a simple with the ventral portion of the anterior cingulate, has been finger movement paradigm (50). This may also be viewed 752 Neuropsychopharmacology: The Fifth Generation of Progress within the more general context of nonfocalized, less effi- ure (13,33). During working memory, Meyer-Lindenberg cient, neurophysiologic responses in schizophrenia. It has been proposed that such altered modulation) in the patients, specifically during the multiple, seemingly local changes may be indicators of more working memory condition. Friston and Frith (12), using ubiquitous dysfunction throughout widely distributed and PET data from a verbal fluency experiment and a method interactive brain networks (12,51), a heuristically appealing that allowed them to assess patterns of activation most dif- pathophysiologic model for schizophrenia given the appar- ferent between normals and patients, found that the pre- ent subtlety of the neurophysiologic abnormalities in the frontal and temporal coactivations in normals were uncou- face of the devastating and complex nature of the illness. This conceptualization is consistent with recent trends in Fletcher and colleagues (55) reported similar results, and viewing higher brain processes as parallel and distributed Jennings and co-workers (56) using structural equation functions. Disrup- its special role in schizophrenia, it is not surprising that tion of frontal–temporal connectivity has also been found many putative aberrant networks in the illness also involve using an EEG coherence measure (57). Although the specifics of this network will obviously vary Other studies have focused on medial prefrontal and cor- by task, a consistent finding in studies of working memory tical–striatal–thalamic circuit abnormalities (49); Biver and is a coactivation of prefrontal, anterior cingulate and parietal colleagues (58) and Mallet and associates (59), calculating structures. Consistent with this, Bertolino and colleagues correlations between various regions of glucose metabolic found a tight correlation between DLPFC NAA (indicative rate in PET, found decreased intrafrontal, as well as fron- of neuronal integrity) and rCBF activation during the tal–posterior connectivity. Andreasen (60) has advanced a WCST, not only in DLPFC, but also with the other nodes hypothesis implicating compromised connectivity among in the working memory pathway (39). Because this was not prefrontal regions, several thalamic nuclei, and the cerebel- evident in healthy controls, these findings appear to reflect lum as the cause of a fundamental cognitive deficit in schizo- a rate-limiting factor related to the disease process of schizo- phrenia. She called the disruption in this circuitry 'cognitive phrenia. Weinberger and associates (52) found in hypothesis is based on a number of studies from her group monozygotic twins discordant for schizophrenia an inverse (61–63) in which the structures enumerated above were relationship between the volume of the hippocampus (the found to differ in activation between schizophrenics and structural variable that best differentiated well from ill controls during several unrelated tasks and in different co- twins) and the degree of dorsolateral prefrontal activation horts, and on the fact that the circuit described is anatomi- cally connected. This suggests dysfunction ing evidence is consistent with the notion that schizophrenia of neocortical–limbic connectivity in schizophrenia and is involves dissolution of neuronal interactions and that many consistent with, if not confirmatory of, a neurodevelopmen- features of schizophrenia may best be viewed as dysfunc- tal mechanism (53). It has been suggested that abnormal tional interregional circuitry. The details of this circuitry development or plasticity of hippocampal connectivity af- dysfunction differ, depending on the distributed network fects the development and function of prefrontal cortex or, called into play during the particular behavior, but prefron- alternatively, that both regions are 'put at risk' by the same tal cortex may play a special role.

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J Comp Neurol 1982; sion and anxiety in mentally retarded patients: a multiple base- 205:63–76 order malegra dxt 130mg on-line impotent rage definition. Pharmacotherapy of borderline per- beta-adrenergic receptor binding sites in the brain of suicide sonality disorder: alprazolam buy 130mg malegra dxt otc erectile dysfunction gnc products, carbamazepine, trifluroperazine, victims. Efficacy and tolerability ence in neurotransmitter metabolism in fronto-temporal-lobe of carbamazepine for agitation and aggression in dementia. In vivo association between gressive children with conduct disorder: a double-blind and pla- alcohol intoxication, aggression, and serotonin transporter avail- cebo-controlled study. J Am Acad Child Adolesc Psychiatry 1996; ability in nonhuman primates. An open trial of valproate Chapter 119: Pathophysiology and Treatment of Aggression 1723 in borderline personality disorder. Divalproex sodium as a treatment for borderline 217. Divalproex treatment J Clin Psychiatry 1993;54:219–223. Propranolol in the treat- ropsychiatry Clin Neurosci 1995;7:314–319. Open assessment orbitofrontal dysfunction in elderly demented patients. Alzhei- of the safety and efficacy of thioridazine in the treatment of patients with borderline personality disorder. Psychopharmacol mer Dis Assoc Disord 1995;9:233–237. Amitriptyline versus control of aggressive behaviors in patients with chronic schizo- haloperidol in borderlines: final outcomes and predictors of re- phrenia. Borderline and sion and psychiatric symptomatology in chronic psychiatric in- schizotypal personality disorders treated with low-dose thiothix- patients: a double-blind, placebo-controlled study, J Clin Psy- ene versus placebo. Medroxyprogester- phrenia: clozapine as a specific antiaggressive agent. Bull Am Acad Psychiatry Law Acad Psychiatry Law 1995;23:607–611. POTENZA ERIC HOLLANDER Impaired regulation of impulse is a central feature in several Theoretic Conceptualizations psychiatric disorders and behaviors, including drug use dis- PG has been described as sharing features with several orders, cluster B personality disorders such as borderline groups of disorders (Fig. Some authors have hypoth- personality disorder, bipolar disorders, and suicide attempts. Consistent with the classification than other psychiatric conditions. This heterogeneous of PG as an OC-spectrum disorder, individuals with PG group of illnesses includes intermittent explosive disorder, kleptomania, pyromania, pathologic gambling (PG), tri- engage in repetitive (gambling-related) behaviors, often in chotillomania, and ICDs not otherwise specified. We review response to overwhelming thoughts to engage in the behav- the neurobiology and treatment of one of these ICDs, PG, ior (11). Studies of comorbidity between OC disorder and describe the nature and treatments of several other po- (OCD) and PG have yielded mixed results, with some stud- tentially related conditions that have recently received in- ies finding rates of OCD in individuals with PG higher creased attention: (a) compulsive buying (CB); (b) compul- than in the general population (12,13), whereas others have sive sexual behavior (CSB); and (c) compulsive computer not found elevated rates of comorbidity (14–17) or elevated use (CCU). These disorders, linked by a failure to resist rates of positive family histories for PG in patients with urges to engage in ultimately self-destructive behaviors, ap- OCD (18). A direct investigation into OC characteristics pear to be relatively common, frequently go unrecognized of individuals with PG found that those with PG scored for considerable periods, and may constitute greater threats significantly higher than those without on the Padua Inven- to personal health than is often appreciated. The differences clustered within two factors corre- sponding to obsessive qualities of impaired control over mental activity and worries of losing control over motor PATHOLOGIC GAMBLING behavior, respectively (19). Although the findings support the notion that PG lies toward the impulsive end of a com- Descriptions of gambling and gambling disorders are found pulsive-impulsive spectrum, the authors cite a central differ- in some of the earliest human records (2,3). Historically, ence between gambling in PG and repetitive behaviors in gambling has been viewed as a sin and later as a vice (2–5). Namely, gambling and actions in other ICDs More recently, disordered gambling has been seen as an are often related as pleasurable or egosyntonic, whereas per- illness determined by genetic and environmental factors and formance of repetitive activities in OCD is generally de- individual decision making. The most extreme form of dis- scribed as egodystonic. Although one study reported the ordered gambling, PG, was first included in the DSM in possibility of the association of PG and OCD with the Hun- 1980 (1). Since that time, there has been increasing research tington disease mutation in a family with PG, OCD, and into the clinical features and neurobiological causes of PG. Huntington disease (20), the neurobiological similarities and differences between PG and OCD remain to be defined more clearly, to explore their relatedness further.

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Naltrexone at 50 mg per day was Assessment Scale (G-SAS) buy cheap malegra dxt 130 mg erectile dysfunction journal. The paroxetine treatment as added to the fluoxetine with a cessation in gambling and compared with placebo resulted in statistically significant alcohol cravings observed over a 4-week period cheap malegra dxt 130 mg otc erectile dysfunction due to diabetes. Given the improvement as determined by the clinician-rated CGI data supporting gambling-induced opioidergic changes (random regression analysis: z 1. COMPULSIVE BUYING Selective Serotonin Reuptake Inhibitors Although recognized by Kraeplin and Bleuler a century ago, Given the repetitive, ritualistic buying behaviors and the CB, then termed oniomania and more recently compulsive intrusive preoccupations with buying associated with CB, shopping or impulsive or addictive buying, has been rela- the efficacy of SSRIs in the treatment of OCD, and the tively understudied in psychiatry (154–156). Although not initial findings with SSRIs described earlier, an open-label formally listed in the DSM-IV (1), CB has a set of proposed trial of fluvoxamine in CB was undertaken (165). The ten diagnostic criteria (157), which include maladaptive preoc- participants in the study met the criteria for CB, as proposed cupation with or engagement in buying and the preoccupa- by McElroy et al. Additionally, the behavior cannot be better the average age of the group was 41. Prevalence estimates have design included a 1-week placebo lead-in followed by an 8- been made at 1% to 8% of the general population week period of treatment with fluvoxamine and a subse- (157–159). Initial reports describe individuals with CB as quent drug taper and discontinuation (over 3 to 4 days) generally in their thirties and predominantly female, with and reassessment off medication at the end of week 13. Indi- Responses were measured with the YBOCS modified for viduals with CB are reported to have elevated rates of psychi- CB (YBOCS-SV), the CGI, patient self-rating, and other atric comorbidity, particularly anxiety disorders, mood dis- standardized scales for depression, disability, and OC symp- orders, substance abuse or dependence, eating disorders, toms. Nine of ten individuals were deemed responders, hav- ICDs, and personality disorders (157,159,161). Highly significant im- provements were observed at week 9 as compared with base- Pharmacotherapy line in scores on both the obsession and compulsion sub- scales of the YBOCS-SV, the National Institute of Mental Thymoleptic Treatment Health OC scale, patient self-rating reports, subscales of the Some authors have proposed depression as a significant un- Sheehan Disability Scale, and the CGI severity and im- derlying motivational factor related to engagement in CB provement scales. Symptoms appeared to worsen but often (158,162,163). An early description of pharmacotherapeu- remained improved from baseline during the 4-week dis- tic interventions in PG described the use of three antidepres- continuation phase. Each of the three patients receiving the medi- with sedation, headache, dry mouth, and gastrointestinal cations reported a partial or complete reduction in CB disturbances reported most frequently. In a larger study of 20 individuals with CB, nine adverse effects did not result in discontinuation of the drug of 13 patients who had received thymoleptic pharmacother- for any of the participants. The results from this initial study apy while they were symptomatic (69%) reported their CB of fluvoxamine in the treatment of CB suggest it to be to be in full (n 5) or partial (n 4) remission (157). The effective drugs used varied widely and included buprop- Opioid Antagonists ion, lithium, valproate, nortriptyline, desipramine, fluoxe- tine, sertraline, trazodone, clonazepam, diazepam, levothyr- Given data supporting efficacy of the -opioid antagonist oxine, and methylphenidate, often used in combination of naltrexone in urge regulation and the role of -opioid func- two or more drugs simultaneously (157). Doses and dura- tion in modulating MCL DA pathways, a trial of naltrexone tions of pharmacotherapy were not clearly defined in the in the treatment of ICDs (including CB) was reported report. The authors described full remissions up to only 7 (152). Two patients with CB treated with naltrexone were months and partial remissions up to 13 months and noted described in detail in a series of 15 individuals with ICDs, that several of the drug trials were terminated after only a with an additional three responders with CB mentioned in short period secondary to intolerable adverse effects (n 2) the report. One of the two responders had comorbid PG or hypomania (n 1). Although the relationship between and CB, and this response is described earlier (in the PG Chapter 120: Pathologic Gambling and Impulse Control Disorders 1735 section). A second individual, a 46-year-old woman with Selective Serotonin Reuptake Inhibitors comorbid CB and bulimia nervosa, was started on naltrex- Initial studies into the efficacy and tolerability of SSRIs in one at 50 mg per day. She initially developed diarrhea, the treatment of paraphilic and nonparaphilic CSBs have which later resolved without discontinuation of the drug. In one study, 20 men with CSB After not experiencing improvement in target symptoms, were entered into a 12-week open-label trial of fluoxetine her dose was increased to 100 mg per day at week 2. Ten of the men had solely nonparaphilic CSBs, and this dose, she reported a significant decrease in thoughts the other ten had both paraphilic and nonparaphilic CSBs. She maintained her gains at 7 months and tolerated for current major depression.

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Techniques that provide information on the Careful observations of behavior are necessary when consid- three-dimensional structure of the HPRT protein make it ering intervention for neurogenetic disorders buy malegra dxt 130mg with amex impotence tcm. Although possible to correlate structure and function of the enzyme standardized rating scales and personality profiles have been (26) generic malegra dxt 130 mg without a prescription erectile dysfunction natural treatment options. Besides The gene involved in LND is on the X chromosome, so behavioral phenotypes, isolated special abilities that occur the disorder occurs almost entirely in males; occurrence in in genetically based syndromes require assessment. The metabolic abnormality is the include special abilities in calculation and in music (24). This enzyme is normally present in each posed modular organization of the central nervous system. Its absence prevents the normal metabolism of hypoxanthine and results in excessive uric acid production BEHAVIORAL PHENOTYPES OF SPECIFIC and manifestations of gout without specific drug treatment NEURODEVELOPMENTAL DISORDERS (i. The full disease requires the virtual ab- sence of the enzyme. Other syndromes with partial HPRT The sections that follow discuss four syndromes in which deficiency are associated with gout without the neurologic behavioral phenotypes have been identified:LND, PWS/ and behavioral symptoms. Page and Nyhan reported that AS, fragile X syndrome, and WMS. Characteristic behaviors HPRT levels are related to the extent of motor symptoms, Chapter 46: Behavioral Phenotypes of Neurodevelopmental Disorders 629 the presence or absence of self-injury, and possibly the level findings was documented on quantitated neurologic exami- of cognitive function (27). The study of variant cases with motor symptoms but with no self-injurious be- Self-injurious behavior usually is expressed as self-biting; havior suggests that reductions in dopamine receptor den- however, other patterns of self-injurious behavior may sity are not a sufficient explanation of the self-injury. It is not uncommon for self-injury to progress to deliberate self-harm (19,28). Characteristically, ever, these authors found that HPRT level and the extent the fingers, mouth, and buccal mucosa are mutilated. The of motor deficit were correlated with dopamine transporter biting pattern is often asymmetric, so the patient may muti- binding in caudate and putamen in the nine cases. Dopa- late the left or right side of the body and may become anx- mine transporter binding was significantly correlated with ious if he perceives that this side of the body is threatened. Moreover, when the movement Other associated maladaptive behaviors include head or disorder was rated on the Fahn-Marsden dystonia rating limb banging, eye poking, pulling of fingernails, and psy- scale, putamen dopamine transporter density was signifi- chogenic vomiting (28). These findings Self-mutilation in LND is conceptualized as a compul- suggest that dopamine reduction is linked to the extent of sive behavior that the child tries to control but generally the movement disorder, but it may not be a sufficient expla- is unable to resist. With increasing age, the affected child nation for self-injurious behavior, and other neurotransmit- becomes more adept at finding ways to control his self- ters need to be examined. He may enlist the help of others to protect him with levels from 2% to 20% showed cognitive deficit pro- against these impulses or may learn self-restraint. A language pattern that consists of repeated ambivalent Future investigation will need to take into account the statements with anxiety and coprolalia (vulgar speech) is existence of a variety of mutations in the HPRT gene struc- characteristic. Why partial HPRT deficiency does not lead to neuro- aggressive and may inflict injury on others through pinch- logic and behavioral symptoms remains unclear; perhaps ing, grabbing, or using verbal forms of aggression. Fre- neurotrophic factors are active with minute amounts of the quently, he will apologize for this behavior immediately enzyme. It is advisable to study combined drug and behav- afterward and will say that the behavior was out of his con- ioral treatment. As in other inborn errors, continuous Etiologic Factors family support is essential. Harris provides a description of a comprehensive treatment program for LND (19). The cause of the neurologic and behavioral symptoms is not clearly established; however, abnormalities in dopamine function have been demonstrated in three autopsied cases Prader–Willi Syndrome (29). The behavior is not caused by either hyperuricemia PWS is a neurodevelopmental disorder characterized by or by excess hypoxanthine because LND partial variants whose HPRT levels are greater than 2 do have hyperuri- obesity, short stature, cryptorchidism, mental retardation, cemia but they do not self-injure. Moreover, infants treated hyperphagia, learning disability, short stature, hypogonad- for hyperuricemia from birth whose uric acid level is nor- ism, hypotonia, small hands and feet, and dysmorphic fa- malized still develop self-injury despite having normal levels cies. Patients have an increased prevalence of daytime sleepi- of uric acid.

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