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By M. Daro. University of Findlay.

Revascularization of the allograft by either surgical or angioplastic techniques m ay im prove renal function and am eliorate hypertension [33 purchase 500 mg amoxil with amex,34] order amoxil with paypal. Both tacrolim us and m ycophenolate m ofetil (M M F) cause bloating generic 250mg amoxil overnight delivery, nausea purchase amoxil 500mg with visa, vom iting, and diarrhea in a dose-dependent m anner, particularly when used Nausea and in combination [15,16,25]. Some authors have noted that this rather nonspecific GI toxicity occurs m ore com m only with N eoral® than Drug vomiting Diarrhea Other complications with Sandim m une® (both from Sandoz Pharm aceuticals, East Cyclosporine 4 3 Hepatotoxicity, constipation H anover, N J). Tacrolimus 30 32 Hepatotoxicity, constipation MMF 20 31 Constipation, dyspepsia Azathioprine 12 Rare Hepatotoxicity, pancreatitis FIGURE 13-21 (See Color Plate) Endoscopic image of candida esophagitis with diffuse white exudate (panel A) and colitis induced by cytomegalovirus infection with submucosal hemorrhage, ulcers, and diffuse mucosal edema (panel B). The avail- ability and common use of effective prophy- laxis against acid-peptic disease (eg, H2 block- ers, omeprazole, and antacids) have signifi- cantly reduced the frequency of upper gastrointestinal bleeding. However, infectious agents such as cytomegalovirus and candida continue to be problematic, particularly in the setting of the more intense immunosup- pression afforded by drugs such as mycophe- A B nolate mofetil (M M F) and tacrolimus. FIGURE 13-22 H istologic im age of chronic active hepatitis secondary to infection with the hepatitis C virus (H CV). N ote the periportal distribution of the lymphocytic infiltrate. Recent identification of HCV has caused intense reevaluation of the causes, frequency, and natural history of liver disease in renal allograft recipients. As the percentage of patients with end-stage renal disease who are infected with the hepatitis B virus has diminished, HCV has become the most problematic cause of liver disease. In recipients with H CV antibodies, im m unosup- pressive therapy m ay potentiate liver injury from the virus and accelerate the course of tim e over which cirrhosis develops. Nonetheless, in patients who desire transplantation and have well- preserved liver function, little evidence exists of better longevity on dialysis. HCV can be transmitted easily from donor to recipient in solid organ transplantation. Because kidney transplantation is not a life-saving procedure, m ost transplant centers choose not to use kidneys from donors who are infected with H CV. Previously, liver disease was thought to be a com m on cause of death in renal allograft recipients. As blood transfusions have becom e less com m on in the dialysis population and hepatitis B virus less prevalent, the risk of death owing to hepatic disease seems to have diminished. Unfortunately, therapies for HCV-related hepatitis (interferon- ) have proved to be of questionable efficacy and m ay stim ulate rejection of the renal allograft [35–37]. Bone densitom etry M agnetic resonance imaging of osteonecrosis. H ere, a renal transplant fem oral head but can affect any weight- early after transplantation. M etabolic bone recipient dem onstrates m arked osteoporosis, bearing bone. The m ost debilitating com pli- disease in this setting is usually multifactorial. This decrease reflects better have som e degree of renal osteodystrophy, options (including bisphosphonates, estrogens, management of calcium and bone homeostasis exacerbated in som e cases by the im pact of and thiazides) have offered hope of preserving during long-term dialysis and less intense alum inum toxicity or 2-m icroglobulin or even increasing bone m ass [38,39]. Patients with diabetes are BM D— bone m ass density. Administration of corticosteroids lim ited (pain m anagem ent while awaiting and cyclosporine also contributes to bone progression to the need for joint replacement). Although biochemical evidence of M agnetic resonance im aging is a sensitive secondary hyperparathyroidism usually diagnostic m ethod, allowing detection of resolves during the first year after transplan- osteonecrosis at a very early stage. Asterisk— values significantly different from those at the time of transplantation. Gout is the clinical m anifestation of hyperuricem ia. After transplantation, cyclosporine can exacerbate hyperuricem ia, and severe gout can be problematic even in the presence of chronic immunosuppression. M anagement of gouty arthritis usually involves some com bination of colchicine and judicious use of short courses of nonsteroidal anti-inflammatory drugs. Concomitant administration of allopurinol and azathioprine can cause profound bone m arrow suppression and is avoided by m ost physicians who treat transplant recipients. Because the m etabolism of m ycophenolate m ofetil (M M F) is not dependent on xanthine oxidase, use of allopurinol in patients treated with M M F is relatively safe [39,40]. FIGURE 13-27 FIGURE 13-28 Photograph of gingival hyperplasia. Gingival hyperplasia occurs Post-transplantation diabetes m ellitus (PTDM ). PTDM com plicates in approxim ately 10% of transplant recipients treated with the course of treatm ent in 5% to 10% of patients on cyclosporine- cyclosporine. Its severity reflects the interaction of effective dental based im m unosuppressive therapy. It is m ore com m on in blacks hygiene, cyclosporine dose, and concomitant administration of calcium and in patients with a fam ily history of glucose intolerance. This com plication does PTDM often reflects the substantial steroid-related weight gain not seem to occur with use of tacrolim us, and com plete resolution that sometimes occurs after transplantation. The severity of PTDM of gingival hyperplasia has been noted with conversion from can be attenuated by weight loss and corticosteroid withdrawal, cyclosporine-based therapy [25,41]. In a m ulticenter trial, PTDM occurred with greater frequency among patients treated with tacrolim us, particularly blacks. Although PTDM resolved over tim e in alm ost half of affected patients (as doses of tacrolim us and corticosteroids were gradually reduced), PTDM rem ained m ore com m on in patients receiving tacrolim us [25,42,43]. Ralph Crowe, Bruce Julian, Catherine Listinsky, Birmingham for contributing many of the illustrations used in this Brendan M cGuire, Klaus M onckemuller and Colleen Shimazu. United States Renal Data System : 1996 Annual Data Report. Blackstone EH , N aftel DC, Turner M E: The decom pensation of tim e Bethesda, M D: The N ational Institutes of H ealth; 1996. Suthanthiran M , M orris RE, Strom TB: Im m unosuppressants: cellular concom itant inform ation. Kershner RP, Fitzsim m ons W E: Relationship of FK506 whole blood 28:159–172. Penn I: Cancers in cyclosporine-treated versus azathioprine-treated 35:115–246. Cam pana C, Regazzi M B, Buggia I, M olinaro M : Clinically significant 10. Penn I: Occurrence of cancers in immunosuppressed organ transplanta- drug interactions with cyclosporin. Cecka JM , Los Angeles: UCLA Tissue Typing Laboratory; 1995, 99–109. M assy ZA, M a JZ, Louis TA, Kasiske BL: Lipid-lowering therapy in virus–encoded sm all RN A (by the EBER-1 gene) in liver specim ens patients with renal disease. Cockfield SM , Preiksaitis JK, Jewell LD, Parfrey N A: Post-transplan- 29. A com parison of cyclosporine and conventional Transplantation 1993, 56:88–96. Curtis JJ: H ypertension following kidney transplantation. Am J virus transform ation-associated genes in tissues of patients with EBV Kidney D is 1994, 23:471–475. Gaston RS, Curtis JJ: H ypertension in renal transplant recipients. Tricontinental M ycophenolate M ofetil Renal Transplantation Study 32. Curtis JJ, Luke RG, Jones P: H ypertension in cyclosporine-treated Group: A blinded, random ized clinical trial of m ycophenolate m ofetil renal transplantation recipients is sodium -dependent. Am J M ed 1988, for the prevention of acute rejection in cadaveric renal transplantation. Sollinger H W , US Renal Transplantation M ycophenolate M ofetil Study converting enzyme in renal transplantation recipients with hypertension. Group: M ycophenolate m ofetil for the prevention of acute rejection in N Engl J M ed 1983, 308:377–381. Gaston RS, Julian BA, Curtis JJ: Posttransplantation erythrocytosis: stenoses or renal-artery stenosis in a solitary kidney.

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As examples buy cheapest amoxil, they also discuss the sleep switch and other operator-centered fatigue monitoring technolo- gies trusted 250 mg amoxil. Narcolepsy is frequently both overdiagnosed and un- of daytime consequences as well order amoxil with a mastercard. However purchase amoxil 500 mg otc, the condition is not rare and has into the neurobiology of insomnia are clearly needed. This a population prevalence similar to that of multiple sclerosis. Our understanding of the the relative benefits and risks of treatment in terms of symp- pathophysiology of the disorder is rapidly emerging as a tomatic relief, health-related quality of life, and morbidity re- result of the discovery that narcolepsy or cataplexy is associ- main to be defined. These issues are of considerable impor- ated with a deficiency in the hypocretin (orexin) neuropep- tance, given the potential for some insomnia treatments to tide system. The discovery that a deficit in hypocretin neu- cause significant adverse effects, such as cognitive impair- rotransmission, as revealed by cerebrospinal fluid hypocretin ment and injurious falls. The optimal duration of treatment studies, frequently causes human narcolepsy opens the door and the conceptualization of potential 'maintenance' treat- to new diagnostic and therapeutic strategies. Measuring hy- ments for insomnia are also areas open for further investiga- pocretin levels in the cerebrospinal fluid or other biological tion. With regard to behavioral treatments, one of the major fluids may soon be used as a diagnostic test for narcolepsy. Data In Chapter 132, Mendelson discusses certain basic mech- from several studies examining the optimal combination of anisms on how hypnotics act. Thus, we are beginning to behavioralandmedicationtreatmentapproachessuggestbet- have some insight into an early issue in sleep research: how ter durability of treatment effects with behavioral treatment administration of sedative-hypnotic compounds from such alone. However, sequential treatments and concurrent treat- diverse pharmacologic classes can result in sleep induction. In addition, treatment strate- It appears that most or all of them produce their pharmaco- gies for nonresponders to either behavioral or pharmacologic logic effects by altering the function of various moieties of interventions must be developed. One possibility that has received little attention our current understanding of sleep disturbances associated has been that classic hypnotics such as benzodiazepines or with neuropsychiatric disease. Nofzinger and Keshavan pro- barbiturates may alter the ascending histaminergic arousal vide a brief review of the advances relating basic research on system, which is presumably the mechanism by which anti- sleep with clinical sleep findings in major neuropsychiatric histamines produce sedating effects. As one of the which lies adjacent to the mamillary bodies, just above the earlier tools available to psychiatric research for discovering ventral surface of the hypothalamus. In this manner, the functional neu- In Chapter 133, Buysse and Dorsey provide a superb re- roanatomic basis of the electrophysiologic abnormalities view on experimental therapeutics of insomnia. Although could be determined, and interventions could be designed considerableprogresshas beenmadewithregard totheepide- targeting not only specific neurotransmitter systems but also miology of insomnia, further work needs to be done regard- systems that are specific to a discrete brain region responsi- ing its consequences for health and role functioning. The reciprocal interaction hypothesis the way in which the brainstem interacts with the forebrain. In this resonate to regulate human behavior including the intensity section, we review ongoing recent findings of the essential and form of conscious awareness. Specifically, the hypothesized self-stimula- Edward F. Allan Hobson: Laboratory of Neurophysi- ology, Department of Psychiatry, Harvard Medical School. Synaptic modifications of the original reciprocal interaction model based on recent findings. A: The original model C proposed by McCarley and Hobson (5). The originalreciprocal interactionmodel ofphys- ings of self-inhibitory cholinergic autoreceptors in mesopontine iologic mechanisms determining alterations in activation level. A: cholinergic nuclei and excitatory interactions between mesopon- Structural model of reciprocal interaction. During noncholinergic interactions taking the place of the previously waking, the pontine aminergic system is tonically activated and postulated, mutually excitatory cholinergic-cholinergic interac- inhibits the pontine cholinergic system. In the revised model, inhibitory cholinergic autoreceptors aminergic inhibition gradually wanes, and cholinergic excitation would contribute to the inhibition of laterodorsal tegmental nu- reciprocally waxes. C: Acti- linergic neurons that is also caused by noradrenergic and seroto- vation level. As a consequence of the interplay of the neuronal nergic inputs to these nuclei. Additional synaptic details of the revised recipro- cal interaction model shown in Fig. For ex- as other neurotransmitters such as adenosine and nitric oxide (see ample, although type I bursting neurons are noncholinergic, text), may contribute to the modulation of these interactions. A selection of the many recent be blocked by scopolamine. In addition to brainstem- induced atonia of hypoglossal motor neurons (44). For example, in vitro studies in the rat suggested the Modification of the Original Reciprocal following modification of reciprocal interaction (58) (Fig. Representative hypothetical tion that can be triggered by cholinergic stimulation in di- cholinergic-noncholinergic mechanisms are illustrated in verse mesopontine and medial pontine sites (1–4) may in- Figs. The illustration of a particular Status of Reciprocal Interaction synaptic interaction in a schematic of a particular behavioral state (i. Illustrated circuits are those hypothe- sized to play executive roles in state initiation or maintenance or to mediate cardinal physiologic signs of that state (e. The major defining neuromodulatory features of each state are described, and the most important of these are depicted with the heaviest lines in diagrams. Details of neuronal interactions are provided in the text and are cross-referenced using lower-case letters appearing adjacent to the excitatory or inhibitory synaptic interaction illustrated in A–C. These neuronal interactions are also summarized at the end of each sublegend with a representative citation. During the wake state, the full complement of ascend- ing arousal systems classified by Saper et al. Specific brainstem and basal forebrain circuits promoting the (Figure continues. These other neuromodulatory sys- sification of nightmares (60). Such in the section on modification of the original reciprocal excitatory signals may include corollary discharge from ocu- interaction hypothesis, such glutamatergic excitation (Figs. In brief, pro- Three findings highlight the importance of neuropep- jections of this system innervate the entire forebrain (Fig. The third finding has come from studies on the genetic and galaninergic projections from the anterior hypothalamus basis of narcolepsy using animal models. Adenosinergic Systems Adenosine has received much experimental attention as a Second Messengers and Intranuclear probable physiologically important endogenous somnogen (84). Adenosine has been shown to exert multiple effects Events on behavioral state (18,84). Results of the molecular genetic approach to sleep research 128. The picture that we are input originates in the periaqueductal gray, the midbrain attempting to sketch is designed to provide an integrating reticular formation, and various medullary sites (e. A major magnus, gigantocellular , paragigantocellular nuclei) (Fig. This work provides still another bridge for (56) (Fig. For ex- tures in a manner consistent with connectivity studies (48). These include noncholinergic spread areas of the forebrain. We focus here on findings in the cycle, detailed here and illustrated in Fig. In contrast, tonic firing of histaminergic arousal systems (Fig.

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Another limitation of this paradigm is that ophrenia purchase amoxil online. Both studies reported no differences in DAT it measures changes in synaptic DA transmission following binding between patients and controls buy amoxil 250 mg low cost. In addition cheap amoxil 500mg fast delivery, Laruelle a nonphysiologic challenge (i buy amoxil now. Subcortical DA Dysregulation as a Failure of The failure of glutamatergic control of DA release might Inhibitory Pathways stem from mechanisms other than NMDA hypofunction. Although the studies reviewed above generally confirmed For example, glutamatergic projections from the PFC to the classic DA hypothesis of schizophrenia, it is important the ventral tegmental area (VTA) are under tonic inhibition to examine these results in light of the more recent views by prefrontal GABA and DA activity (see ref. It follows that deficits in GABAergic or do- dysconnectivity of multiple cortico-subcortical and intra- paminergic function in the PFC (both deficits also impli- cortical networks. Although it cannot be definitively ruled cated in schizophrenia) are expected to have similar out that the DA dysregulation revealed by these studies consequences to an NMDA deficiency on the subcortical would stem from a primary abnormality of DA neurons, it DA response to amphetamine. Thus, in patients with schiz- seems more likely that these abnormalities are a consequence ophrenia, various or multiple mechanisms (NMDA recep- of cortico-subcortical dysconnectivity. Moreover, given the tor hypofunction, GABAergic or dopaminergic deficits in weight of evidence implicating PFC connectivity as a central the PFC) may lead to the dysregulation of subcortical DA deficient node in the schizophrenic brain, it is tempting to revealed by the amphetamine challenge. In fact, it has long been hypothesized that dysregula- with prefrontal pathology in schizophrenia. In patients with tion of subcortical DA function in schizophrenia may be schizophrenia, low N-acetylaspartate (NAA) concentration secondary to a failure of the PFC to adequately control in the dorsolateral prefrontal cortex (DLPFC), a marker of subcortical dopaminergic function (53,54). DLPFC pathology, is associated with increased amphet- Activity of midbrain DA neurons is under dual influence amine-induced DA release (63). Studies in primates have of PFC via an activating pathway (the 'accelerator') and documented the consequences of neurodevelopmental alter- an inhibitory pathway ('the brake'), allowing fine-tuning ation in PFC connectivity on subcortical DA release (64, of dopaminergic activity by the PFC (55). Adult rhesus monkeys with neonatal ablation of the pathway is provided by direct glutamatergic projections amygdala-hippocampal formation within 3 weeks of birth onto the dopaminergic cells. The inhibitory pathway is pro- exhibit lower NAA concentration in the PFC and abnormal vided by glutamatergic projections to midbrain -aminobu- relationships between prefrontal and subcortical DA func- tyric acid (GABA)ergic interneurons or striatomesencepha- tions; whereas local perfusion of amphetamine into the PFC lic GABA neurons. The inhibition of dopaminergic cell induced a decrease in striatal DA in control monkeys and firing following amphetamine is an important feedback in monkeys with adult lesions, PFC amphetamine perfusion mechanism by which the brain reduces the effect of amphet- increased striatal DA release in monkeys with neonatal le- amine on DA release. This study documents that dysregulation of subcorti- firing induced by amphetamine is mediated both by stimu- cal DA function might be a delayed and enduring conse- lation of presynaptic D2 autoreceptors and by stimulation quence of neurodevelopmental abnormalities of PFC of this inhibitory pathway (56). Neurochemical sensitization of trol conditions to 12. The increase in amphetamine- thors as one mechanism that might underlie the progression induced DA release induced by ketamine (greater than two- of a 'silent' vulnerability into an overt symptomatology fold) was comparable in magnitude to the exaggerated re- (67–71). Sensitization of DA systems is a positive feedback sponse seen in patients with schizophrenia. These data are loop, in which increased DA activity leads to more DA 840 Neuropsychopharmacology: The Fifth Generation of Progress activity (70,72). During late adolescence, the failure of cor- thermore, a deficient prefrontal DA function is a potential tical development associated with schizophrenia liability mechanism to account for the subcortical DA disinhibition might limit the brain capacity to modulate stress-related discussed above, as cortical DA function has an inhibitory increased activity of mesolimbic DA neurons. This failure impact on subcortical DA function (18,19). In vivo mea- of normal homeostatic and buffering mechanisms would surement of prefrontal DA function would provide the tools result in an increased vulnerability of DA neurons to de- to directly test these hypothesis. At the ultrastructural level, they are mostly dogenous sensitization process drives the prodromal and located on pyramidal spines, and are mostly abundant on initial phases of the illness, characterized by increased DA the distal dendrites (78–80). In postmortem studies, no activity and culminating in the expression of positive symp- evidence was found of an alteration in D1 receptors in the toms. Sustained D2 receptor blockade interrupts this posi- DLPFC of patients with schizophrenia (81,82), and the tive feedback loop. Upon neuroleptic discontinuation, the expression of the D1 receptor gene is unaltered (83). In brain becomes again vulnerable to the stress-induced re- contrast, a PET study with [11C]SCH 23390 reported de- emergence of this endogenous sensitization process and clin- creased density of D1 receptors in younger patients with ical relapse. No significant differences were found It should be emphasized that the relationship between in the other regions examined (anterior cingulate, temporal, stimulation of D2 receptors and psychotic symptoms is occipital, and striatum). In addition, low-PFC D1 density complex and presumably also involves neuroplasticity. This finding is important, because it represents symptoms in healthy subjects immediately upon drug expo- the first direct evidence of an association between negative sure. In contrast, sustained administration of DA agonists symptoms, working memory deficits, and selective alter- is required to induce psychotic symptoms in healthy subjects ation in prefrontal DA function. This observation suggests that sustained overstimu- in this study had a limited resolution, and the low specific lation of D2 receptors leads to remodeling of prefrontal- to nonspecific ratio of [11C]SCH3390 makes the measure- ventrostriatal-thalamic-prefrontal loops and their modula- ment of D1 receptor in PFC with this ligand quite vulner- tion by hippocampal afferents projections, neuronal ensem- able to noise (85). Several groups are currently attempting bles that are believed to underlie the psychotic experience to replicate this finding, using better cameras and a superior (74,75). In the amphetamine studies, DA-mediated stimu- D1 receptor radiotracer, [11C]NNC 112 (86). As D1 receptors are tients with schizophrenia (41), indicating that factors down- the most abundant DA receptors in the PFC, the availability stream from the DA synapse play a role in the exacerbation of a D1 receptor radiotracer vulnerable to competition by of these symptoms following amphetamine. Unfortunately, such a ligand is currently lacking gesting that, in some patients, the experience of positive (87,88). Patients with psychotic symptoms in Studies of Nondopaminergic Receptors the presence of apparently normal DA function failed to in Schizophrenia show significant improvement in these symptoms following 6 weeks of D2 receptor blockade (45). Thus, although these Receptors related to the GABA and 5-HT systems have imaging studies have generally confirmed the time-honored been studied in vivo in schizophrenia. Postmortem studies dopamine hypothesis of schizophrenia, they also contrib- reported abnormalities of both systems in schizophrenia. A uted to pointing out the limitations of an oversimplified robust body of findings suggests deficiency of GABAergic model linking psychosis and excess DA activity. In vivo evaluation of GABAergic systems in schizophrenia has so far been limited to evaluation of benzo- Prefrontal DA D1 Receptor Density 123 diazepine receptor densities with SPECT and [ I]ioma- As discussed above, several lines of evidence from preclini- zenil, and three out of three studies comparing patients with cal, clinical, and postmortem studies converge to suggest schizophrenia and controls reported no significant regional that a deficiency in DA transmission in the prefrontal cortex differences (91–93). Although some significant correlations is involved in the pathophysiology of negative symptoms with symptoms clusters and regional benzodiazepine densi- and cognitive impairment in schizophrenia (14,16). Fur- ties have been observed (91,92,94,95), these relationships Chapter 59: Neurochemical and Neuropharmacological Imaging in Schizophrenia 841 have not been replicated by other studies. Thus, together, selective D2 receptor antagonists (haloperidol and raclo- these studies are consistent with an absence of marked ab- pride) suggested that 50% to 60% occupancy was required normalities of benzodiazepine receptor concentration in the to observe a rapid clinical response (107,108). Alterations of GA- pine, at clinically therapeutic doses, achieved only 40% to BAergic systems in schizophrenia might not involve benzo- 60% D2 receptor occupancy (104,106,109), which, in con- diazepine receptors (96), or be restricted to certain cortical junction with its anticholinergic properties, accounts for layers or classes of GABAergic cells that are beyond the its low liability for extrapyramidal symptoms (EPSs). Recent developments in GABA imaging with MRS antagonists' such as risperidone does not confer protection (described below) are a promising new avenue to study in against EPS, because the threshold of D2 receptor occu- vivo GABAergic function in schizophrenia. Given the relatively recent development tors might be sufficient to elicit clinical response (114,115). The concentra- 123 degree of occupancy achieved by atypical antipsychotic tion of SERT in the midbrain measured by [ I] -CIT is drugs in striatal and extrastriatal areas. Studies with reported lower occupancy of striatal D2 receptors compared more specific ligands are warranted to assess the distribution to temporal cortex D2 receptors in seven patients treated of SERT in other brain areas, such as the PFC, where their density has been reported to be reduced in three out of four with clozapine, using the high-affinity SPECT ligand [123I]epidipride. In contrast, typical antipsychotics were re- postmortem studies (97). Decrease in 5-HT2A receptors has been reported in the PFC in four out of eight postmortem ported to achieve similar occupancy in striatal and extras- triatal areas, as measured with [11C]FLB 457 (117) or studies (97,98). Three PET studies in drug-naive or drug- [123I]epidipride (118). It should be noted, however, that free patients with schizophrenia reported normal cortical 5-HT2A receptor binding (98–100), whereas one study re- these very high affinity ligands do not allow accurate deter- ported a significant decrease in PFC 5-HT2A binding in a mination of D2 receptor availability in the striatum. In con- trast, [18F]fallypride enables accurate determination of D2 small group (n 6) of drug-naive schizophrenic patients (101). The most consistent abnormality of 5-HT param- receptor availability in both striatal and extrastriatal areas eters reported in postmortem studies in schizophrenia is an (119), and preliminary PET experiments in primates with increase in the density of 5-HT receptors in the PFC, [18F]fallypride indicate that clozapine and risperidone 1A reported in seven out of eight studies (97). Several groups achieve similar D2 receptor occupancy in striatal and extra- are currently evaluating the binding of this receptor in vivo striatal regions (120). Finally, it is important to point out with PET and [11C]WAY100907. Improved resolution of PET cameras cur- Maybe the most widespread use of neuroreceptor imaging rently allows dissociating signals from ventral and dorsal in schizophrenia over the last decade has been the assessment striatum (123,124), and it is now feasible to specifically of neuroreceptor occupancy achieved by typical and atypical study the clinical correlates of D2 receptor occupancy in antipsychotic drugs, a topic that has been the subject of ventral striatum in humans. Neuroreceptor studied included Another unresolved question is the discrepant values of essentially D2 receptors, but also 5-HT2A and D1 receptors. The haloperidol plasma concentration as- sociated with 50% inhibition of [11C]NMSPbinding (3 to threshold of occupancy of striatal D2 receptors (about 80%) above which extrapyramidal side effects are likely to occur 5 mg/mL) (125) is ten times higher than that associated with 50% inhibition of [11C]raclopride binding (0.

Polymerization tauopathy with presenile dementia is localized to chromosome of tau peptides into fibrillar structures generic amoxil 500mg on-line. Accelerated filament disinhibition dementia: a frontotemporal dementia linked to formation from tau protein with specific FTDP-17 missense 17q21-22 order amoxil online. Somatodendritic locali-¨ and 5′-splice-site mutations in tau with the inherited dementia zation and hyperphosphorylation of tau protein in transgenic FTDP-17 order generic amoxil on-line. FTDP-17: an early- ing the shortest human tau isoform generic amoxil 250mg otc. 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. In fact, data establishing the efficacy of psychotropic treating depression complicating AD becomes complex drugs for noncognitive behavioral problems in AD and when the problems involved in the diagnosis of depression other dementing disorders remain limited. Although reports in the context of AD or other dementing illnesses are consid­ of treatment outcome studies incorporating reliable and ered. A fundamental problem is the substantial overlap of valid outcome measures, well-defined patient samples, and signs and symptoms between depression and AD. Common randomization to an adequate trial of active medication or to both disorders are apathy and loss of interest, impaired placebo continue to appear, their number remains small. The macologic management of noncognitive behavioral prob- ability to diagnose depression in AD is further compromised lems in AD. Placebo-controlled studies are emphasized, but re- Even if investigators agreed on uniform diagnostic criteria sults of other studies and reports are discussed when they for syndromal depression in AD and used uniform assess­ ment instruments and interviews, discrepant prevalence rates would likely arise from the differential characteristics of the samples of AD patients studied. Raskind: Veterans Administration Northwest Network Men- AD with concurrent depression derived from clinical popu­ tal Illness Research Education and Clinical Center, Seattle, Washington. Barnes: Department of Psychiatry and Behavioral Sciences, lations are higher than those derived from research registries University of Washington School of Medicine, Seattle, Washington. For example, in an outpatient geriatric study carefully documented the presence of major depressive clinic, Reifler et al. Patients were treated for a mean duration contrast, Burke et al. HAM-D scores significantly and substantially de- included a longitudinally followed normal control group creased from a mean of 19 on admission to a mean of 5 matched for age, sex, race, and social position. This degree of improvement did not differ symptoms of depression occurred in both patients with AD significantly from that in an elderly, nondemented, de- and controls, but criterion-based major depression could pressed inpatient group treated in a similar naturalistic man­ not be diagnosed. However, the mean length of stay to achieve compara­ depression in a sample of subjects with AD screened to ble improvement in the elderly nondemented, depressed exclude those with a past history of major psychiatric disor­ group was substantially shorter than that in the demented, ders was reported by Kumar et al. Possible differential treatment responses mood was more frequent in the AD subjects than in age- between AD subjects with major depression and MID sub­ matched normal controls, depressed mood in the AD sub­ jects with major depression were not reported. Both Rey­ jects was unaccompanied by classic vegetative signs and nolds et al. These investigators, therefore, in­ results as suggesting that major depression complicating de­ terpreted depressed mood as reflecting 'demoralization' mentia is responsive to somatic antidepressant treatments, rather than major depressive disorder. Given these prob­ but both investigators acknowledged that standardized, lems, it is not surprising that estimates of the prevalence of double-blinded, placebo-controlled studies of antidepres­ depression in AD are widely disparate. Perhaps the true sants in dementia patients with major depression are prevalence of concurrent depression in AD lies somewhere needed. As early as 1955, Sir Mar- The SSRI antidepressants are theoretically attractive tin Roth (21) addressed the issue of differentiating the com­ drugs for the treatment of depression in AD. Decreased mon 'affective coloring' seen in dementia patients from numbers of serotoninergic neurons in the dorsal raphe nu­ the relatively uncommon 'sustained depressive symptom cleus and decreased concentrations of the serotonin metabo- complex. Enhancing serotoninergic neurotransmission by inhib­ iting serotonin reuptake theoretically might alleviate depres­ sion in AD. Furthermore, the adverse effect profile of SSRIs Psychopharmacologic Approaches is relatively benign compared with those of the tricyclics It continues to be disappointing that the extensive interest and MAOIs. SSRIs are not anticholinergic, nor do they in defining the prevalence of depression complicating AD produce orthostatic hypotension. These theoretic advan­ has generated few interpretable studies evaluating the out- tages likely account for the increasing use of SSRIs in elderly come of antidepressant treatment in such patients. These reports Placebo-Controlled Outcome Trials suggest that depression complicating AD may respond to tricyclic antidepressants (22,23), monoamine oxidase inhib­ Despite the widespread use of antidepressants in patients itor (MAOI) antidepressants (24), or selective serotonin with AD and other dementing disorders (32), it is clear that reuptake inhibitors (SSRI) (25). In an open trial of nortrip­ this use is not grounded in an adequate empiric database. Depression Scale (HAM-D) scores (27) from 17 before Reifler et al. Although the reduction in (n � 13) or placebo (n � 12) subjects who met DSM­ depressive signs and symptoms was substantial in AD pa­ III criteria for both primary degenerative dementia of the tients with concurrent depression, it was less robust than in Alzheimer type and major depressive episode. AD outpa­ a similarly treated group of elderly nondemented depressed tients (mean age, 72) had a mean Mini-Mental State Exami­ patients. Another open trial of 'naturalistic' somatic antide- nation (MMSE) score of 17 [very comparable with the mean pressant treatment of inpatients with dementia and concur- MMSE scores of the demented, depressed patients studied rent depression was reported by Greenwald et al. Imipramine (mean depression have several implications. First, the robust re­ dose, 83 mg/d; mean plasma level of imipramine plus des­ sponses of the placebo group make it essential to include a methylimipramine, 116 ng/mL) or placebo was prescribed placebo group in future antidepressant drug outcome trials for 8 weeks. Substantial, highly significant, and almost iden­ in dementia patients if the results are to be interpretable. Imipramine was controlled trial demonstrating efficacy of behaviorally based generally well tolerated in these subjects. However, its cen­ psychotherapy for depression in AD outpatients is consis­ tral anticholinergic effect likely accounted for subtle decre­ tent with this interpretation (38). Second, the absence of ments in cognitive function in the imipramine group. The SSRI adverse effects on cognitive function or blood pressure improvement in HAM-D scores was similar to that achieved regulation is an advantage for this class of antidepressant in the open inpatient studies reported by Greenwald et al. More placebo-controlled trials of (28) and Reynolds et al.

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