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By J. Jensgar. Immaculata College.

By the 1950s buy tadalafil canada, sup- ology buy tadalafil 20mg low cost, anatomy tadalafil 10 mg with mastercard, and neurochemistry of MTLE and com- port had developed among leading epilepsy researchers for pare the hippocampus with extrahippocampal limbic re- the concepts that MTLE (a) was a 'network' disorder, gions. In closing, we briefly explore how new research caused by abnormal interactions between a limited number directions resulting from recent data may lead to novel and of highly interconnected areas within the temporal lobe, improved treatments of MTLE. Thus, ir- respective of the cellular and molecular events underlying NEUROPATHOLOGY epileptogenesis and the eventual development of sponta- neously recurring seizures, which soon were to become the Hippocampus focal points of epilepsy research, brain structures such as The notion of a central role of the hippocampus in MTLE the entorhinal and perirhinal cortices and the amygdala were can be traced to a highly influential review article by Som- viewed as the critical components of the seizure network. These changes are often seen in conjunction with institution. With astounding their shape to resemble phagocytotic macrophages (mi- foresight, he concluded that the cell loss was a consequence croglia) more closely (17–19). Because of their special bio- of prolonged seizure activity and that both head trauma chemical and biophysical properties, these abnormal glial and developmental malformations ought to be considered cells are believed to play an active role in the disease process, etiologically important factors in epilepsy. Sommer also either by containing or actively enhancing seizure spread noted that neurodegenerative changes in patients with epi- (see later). He remarked that 'it is not unlikely that visualized by Timm staining or by immunohistochemistry a single underlying defect spreading through several ana- using antibodies against the neuropeptide dynorphin (20). However, axons also sprout fined by many investigators studying brain pathology post from surviving inhibitory neurons (23), and these novel mortem. This period was increasingly dominated by the axons have been proposed to impede chronic hippocampal question whether 'idiopathic' seizure activity causes neuro- hyperexcitability (24). The chicken-egg debate, which has not Extrahippocampal Areas been entirely resolved to this day, was accompanied by un- certainties about the nature of putatively epileptogenic in- Triggered by new information about the anatomic intercon- sults, such as respiratory difficulties and asphyxia, infectious nections in the normal brain and by the results of noninva- diseases leading to encephalitis, and, in particular, vascular sive imaging studies of MTLE patients (see later), the 1990s abnormalities (13). The advent, in the 1930s, of surgical also witnessed a renewed interest in the neuropathology of interventions for the treatment of MTLE revolutionized extrahippocampal temporal lobe lesions in MTLE. As men- clinical management of the disease and at the same time tioned earlier, lesions in the parahippocampal region or the provided invaluable information for research purposes (14). A and B: Nissl-stained coronal sections through the rostral portion of the hippo- campus taken from a patient with MTLE (A) and a control subject (B). Note the pronounced neuronal loss and gliosis in areas CA1 and CA3 in the patient with epilepsy. Moreover, the epileptic hippocampus is substantiallyreduced in size compared with the control. C and D: High magnifica- tion of portions of the olfactoryfield of the entorhinal cortex from a patient with MTLE (C) and a control subject (D). Note the substantiallyreduced width of layers I to III of the entorhinal cortex of the patient with epilepsy. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Because pyramidal cells of layer III normally give portion of this six-layered parahippocampal structure. Pa- rise to the monosynaptic 'temporoammonic' pathway to tients frequently present with a characteristic pattern of neu- area CA1of the hippocampus (27), their degeneration in ronal loss and associated gliosis, with layer III being prefer- MTLE may lead to deafferentation-induced changes in hip- entially affected and layer II showing pronounced pocampal excitability, and such changes have indeed been disorganization and some cell loss (26) (Fig. Neuropathologic changes in layer 1846 Neuropsychopharmacology: The Fifth Generation of Progress II of the entorhinal cortex, the origin of the major input to the granule cells of the dentate gyrus (the 'perforant path'), may also contribute to hippocampal hyperexcitabil- ity in MTLE. Neuronal loss and gliosis in the amygdala are frequently seen in MTLE and often occur in conjunction with lesions in other parts of the limbic system (29,30). Although the pattern of cell loss has so far not been analyzed in great detail, degenerative events appear primarily to affect the ventromedial aspects of the lateral amygdaloid nucleus and the parvicellular region of the basal nucleus (31). Based on published studies, this relatively restricted damage not only impedes processing of sensory information in intraamygda- loid circuits, but may also account for the impairment of memory processing in MTLE by interrupting information FIGURE 127. Imaging studies illustrating changes in extrahip- flow to the hippocampal formation (31,32). MRI scans (A and C) and fluoro- It is likely that neuropathologic changes also occur in deoxyglucose PET scans (B and D) in a patient with left MTLE. The other areas that are connected to the reverberating seizure demarcations on the two sets of scans represent the co-registra- tion of the two techniques so comparable sites are illustrated in network underlying MTLE (33). A and B show changes in hippocampus (circled include the thalamus (34), have been shown to be atrophied in white in MRI, indicated with an arrow in the PET scan) and in patients, but the precise nature and distribution of the thalamus (outlined in black) with the medial dorsal nucleus indi- catedseparatelyinA. MRIdemonstrates atrophyin theleft hippo- degenerative changes, as well as their relation to the patho- campusand theleftmediodorsal nucleus,andPET showshypome- physiology of MTLE, have not been elucidated to date. The left brain hemisphere corresponds to the right side of the images. Chugani, Wayne IN VIVO IMAGING State University, Detroit, MI. These meth- the 1990s, magnetic resonance imaging studies also revealed ods have also been, and continue to be, of critical impor- shrinkage in other areas of the seizure circuit, namely, the tance for the generation and testing of hypotheses related to amygdala (38,39), the entorhinal cortex (40), and the thala- pathogenesis and disease progression. In the case of MTLE, mus (6), findings demonstrating that the extrahippocampal techniques such as computed tomography, measurements changes in tissue volume known to exist in many MTLE of regional glucose use and receptor densities by positron patients can be visualized noninvasively (Fig. Imaging test results are increasingly used for diagnostic purposes and, specifically, to provide guidance STUDIES IN EXPERIMENTAL ANIMALS for neurosurgical procedures. Kindling Improvements in the spatial resolution of most imaging techniques have made it possible to study regional brain Kindling, a phenomenon first described in 1969 (41), has abnormalities in MTLE with increasing accuracy. In early become a major research tool to study seizures involving studies, hypometabolism and decreases in cerebral blood the limbic system. In this model, a single site in the brain flow in the temporal lobe were demonstrated even when no is stimulated electrically with sufficient intensity to induce structural damage was detectable by computed tomography. With repeated focal stimulations for days or weeks, provide quantitative data adequately (8,35), but results ob- there is a gradual lengthening of the after-discharge, and tained by magnetic resonance imaging are remarkably in- behavioral seizures develop. Thus, using various modifica- behavior progresses to the point of a full convulsion. After tions of the technique, it became feasible to visualize a number of stimulations, the seizures reach a plateau of Chapter 127: Temporal Lobe Epilepsy 1847 consistent duration and behavioral severity, at which point models are commonly based on an inciting event of limbic the animal is considered fully kindled. The number of stim- status epilepticus that is precipitated by various methods, ulations required to achieve this plateau depends on several including the systemic administration of chemoconvulsants factors, such as the frequency and duration of focal stimula- (e. Studies of several limbic sites, as well lation of a limbic structure (hippocampus, perforant path, as comparisons of neocortical and subcortical regions, dem- amygdala) (51–53). In all these models, the animals recover onstrated that some extrahippocampal sites, for example, after status epilepticus and, after a latent period of weeks the amygdala, achieve the fully kindled state much faster to months, develop spontaneous seizures that continue in- than the hippocampus (43). First, seizures appear spontaneously and, certain subcortical structures, including the midline thala- like the seizures of human MTLE, have a clear predilection mus and the substantia nigra (44,45). This pattern suggests that The variable rates of kindling from different stimulation the seizures are likely to be under subcortical influence. Sec- sites suggest that some regions are more epileptogenic, that ond, as in the case of human MTLE, there is a latent period is, more able to generate and support seizure activity than during which a previously nonepileptic brain evolves into other sites. An alternative explanation is that the areas with one that generates recurring seizures. Third, the histopatho- more rapid rates of kindling are 'closer' to the pathways of logic changes in chronically epileptic animals, such as gliosis secondary generalization. This implies that seizure activity and neuronal loss in the hippocampus, amygdala, entorhinal spreads by gradual recruitment of adjacent cortex (similar cortex, and medial dorsal thalamus, closely resemble those to the classic jacksonian march), exemplified by the proposed seen in the human condition. Finally, the EEG patterns role of the perirhinal cortex as the major route from the and the locations of seizure onset are similar in human limbic system to the neocortex (46).

It is less clear what should be predicted if patients bility of a causative role of antipsychotic medications buy generic tadalafil 20 mg on-line, an (or healthy subjects) are manifestly working at a task buy tadalafil 20 mg with visa, but important consideration because the majority of functional performing it abnormally 2.5 mg tadalafil with visa. However, taken as a whole, the literature provides little healthy control subjects. Several studies have found signifi- evidence that neuroleptics generate the functional neuroim- cant correlations between prefrontal neural activity and cog- aging abnormalities. First, although additional longitudinal nitive function, suggesting that these two variables are para- investigations with newer techniques are necessary, an 18- digmatically linked, but both positive and negative (27) year follow up (15) showed that prefrontal hypofunction relationships have been described (8). The research chal- in chronic patients is remarkably stable over time and unaf- lenge has been to (a) understand this relationship and (b) fected by long-term consistent neuroleptic treatment. Sec- tease apart abnormal cognitive performance and abnormal ond, prefrontal abnormalities like those observed in schizo- brain activity in patients to determine which is primary. Third, a no single study alone can answer the question; however, study of monozygotic twins concordant for schizophrenia, convergent evidence derived from several different research 750 Neuropsychopharmacology: The Fifth Generation of Progress directions leads to the conclusion that prefrontal pathophys- described in the context of performance difficulties. Gold- iology cannot be accounted for as an epiphenomenon (8). Callicott and co- In principal, if the prefrontal physiologic deficit found in workers (1999) demonstrated that normal controls pushed patients with schizophrenia is an epiphenomenon of poor beyond their working memory capacities also demonstrate performance per se, then other subjects who perform as reduced DLPFC responses (36). Electrophysiologic record- poorly should have similar prefrontal function. These findings indicate that poor per- be seen as part of an expected curve between working mem- formance per se does not necessarily produce the pathophys- ory load and neural response—a dose–response curve that is iologic picture seen in schizophrenia. A second way to experimentally attack this 'chicken and Given the fact that other poorly performing patient popula- egg' question, and at least on the face of it the most direct tions with pathology that is different than schizophrenia do way, is to match patients and normal controls for level of not show the same prefrontal response one (28,30,31), this performance. However, ensuring good performance in pa- particular shift in the dose–response curve with poor perfor- tients (by using different versions of the task for patients mance is neither inevitable nor the only possible one. Thus, the strategy of employing 'easy' tasks that (27). Although this may simply represent increased 'time result in some measures of performance being 'normal' in on task,' it again provides a context in which to view recent patients is not as straightforward an approach to exploring findings of overactivation in patients. An alternative to 'matching' for good perfor- prefrontal function are discussed in the following, it remains mance is to study normal controls who perform as poorly on for future research to determine whether patients and con- a given task as the patients. This strategy at least addresses the trols share the same source for abnormal prefrontal re- question of whether normals and patients fail by the same sponses (both underactivation and overactivation) in the pathophysiologic mechanisms. In a study designed on this context of performance difficulties. Moreover, the cause of the abnormal neural function, rather it is an effect more a given normal subject activated this 'schizophrenic of that pathophysiology. Given this conclusion and the now card sort area,' the more he or she perseverated (8). In a similar example, affected members of designed to elucidate the mechanism of these linked phe- monozygotic co-twins discordant for schizophrenia showed nomena. Analogous re- Putative Underlying Mechanisms sults have been described by Friston and colleagues using paced verbal production (33) and have recently been demon- A number of clues about potential pathophysiologic mecha- strated with eigenimage analysis in a study of medication-free nisms emerge when the neuroimaging findings are consid- patients performing the N-back working memory task (34). Both underactivation and overactivation have been in DLPFC contributes to the cognitively linked dysfunc- Chapter 54: Functional Neuroimaging in Schizophrenia 751 tion. The degree of both hyperfunction and hypofunction most linked to emotion. Few studies have been carried out of DLPFC in patients are predicted by decreased n-acetyl- that formally investigate the function of these regions in aspartate (NAA), an MR spectroscopy measure of cellular schizophrenia. Second, several compelling lines of evi- dence suggest a prominent role for dopaminergic dysfunc- tion. It is well documented in nonhuman primates that Lateral And Medial Temporal Lobe optimal dopamine function is necessary for maximal work- The temporal lobe is of interest in schizophrenia for several ing memory and DLPFC physiologic function (41). Diseases of the medial temporal lobe can be associ- albeit less direct, evidence also exists in humans: Pharmaco- ated with psychotic symptoms, and some neuropsychologi- logically altering dopaminergic tone with agents such as cal aspects of schizophrenia implicate both lateral and me- amphetamine affects DLPFC activity in both healthy sub- dial temporal lobe. A number of neuroimaging studies have jects (42,43) and patients (44); and a relationship between reported functional abnormalities in both lateral and medial DLPFC rCBF during the WCST and CSF levels of the temporal lobe structures (47). The data as a whole, however, dopamine metabolite homovanillic acid has been found in are less compelling than for frontal lobe, and confounds schizophrenia (45). Third, converging data increasingly and potential mechanisms are less well explored. A considerable body of both hyperfunction and hypofunction have been re- of literature now documents that disruption of corticolim- ported, but the bulk of the evidence leans toward overactiv- bic connectivity in neonatal animals via hippocampal lesions ity. Heckers and colleagues (48) reported reduced hippo- models many features of schizophrenia, including working campal activation during the effort to retrieve poorly memory impairment, reduced prefrontal NAA, and dopa- encoded material; however, it is of interest that, hippocam- mine dysregulation (53). Developmental pathology with a pal activity appeared to be increased at baseline, again em- genetic basis also appears likely. 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.

The operation begins with a seed point vectors to produce summary statistics order tadalafil 20mg amex. In processing DTI in a voxel element and then generates a tracking sequence A C FIGURE 55 cheap 2.5mg tadalafil otc. The ver- tical line shows the approximate plane of the coronal diffusion tensor image to the right purchase cheap tadalafil on line. Note the cor- pus callosum (top blue arrow) and anterior commissure (bottom blue arrow). White matter tracts perpendicular to the plane are coded red-orange. Note the cingulum bundle (top arrows), the white matter tract within the cingulate gyrus, and the uncinate fasiculus (bottom arrows), the tract connecting anterior temporal lobe with inferior frontal lobe. Uncinate fasciculus in schizophrenia: a diffusion tensor study. American Psychiatric Association New Research Abstracts, 2000. Chapter 55: Structural MRI Studies in Schizophrenia 769 if the adjacent elements have similar linear orientation. This 90 degrees from the steady-state field orientation), followed similarity is at the voxel level, and does not, of course, permit by one or more refocusing pulses, and directed 180 degrees tracking of individual fibers; rather, it tracks groups of fi- from the orientation of the steady-state field. The reformation of phase co- CONCLUSION herence induces another signal known as a 'spin echo,' which does not have the potential confounds of magnet and A clear current and positive trend is to use as much automa- tissue inhomogeneity (they remain constant over pulses), tion as possible in structural MRI analysis because of the and thus this signal provides a better measure of T2. Currently, how- spin echo pulse sequences the repetition time (TR) is the ever, the field is still in a state of flux with respect to the time between excitation pulses, whereas the echo time (TE) validity of the new techniques, such as VBM and brain is the time from the excitation pulse to the echo maximum. Validity evaluation for new technologies is thus a produce proton density weighted images at short TE (less high priority item. Fast spin echo sequences are a variant of multiecho Similarly, as discussed in another chapter in this volume by sequences that maximize efficiency of data collection and Dr. Berman, 'functional' imaging is becoming increasingly shorten acquisition time. They are commonly used to pro- multimodal and a desideratum is the combination of struc- duce T2-weighted images. Inversion recovery pulse se- tural and functional approaches, just as anatomy and physi- quences are still another variation of the spin echo sequence, ology are inextricably linked in basic neuroscience studies. It is clear that functional studies have defined more prominent abnormalities in frontal lobe than in tem- poral lobe, whereas structural studies have tended to show Gradient Echo Pulse Sequences a greater degree of abnormality in temporal lobe. The mis- These sequences do not use 180-degree refocusing pulses. Functional neuroimaging 'ac- GRASS (SPGR) in GE imagers and FLASH in Siemens tivation' in a region primarily represents postsynaptic po- imagers. This pulse sequence uses a 'spoiling scheme' to tentials; these and not action potentials constitute the major dephase the transverse (x-y plane) magnetization following metabolic and energetic load and hence the main signals signal detection, commonly using 'spoiler' (also called used in functional analysis. It is consequently often very 'crusher') gradient pulses that have the same duration and difficult to disambiguate abnormalities in input to frontal magnitude as the first excitation pulse, but the opposite lobe from intrinsic abnormalities. This has as a consequence that, at the time of poral lobe gray matter volume changes appear quantitatively the next excitation, only the longitudinal direction (vertical larger than those in frontal cortex, no brain region acts on direction in our analogy) has any remaining coherence. If its own and interconnections and abnormalities of intercon- the first pulse has a low excitation angle (small 'tilt' of the nections, as well as intrinsic volume changes must be consid- tops in our analogy) this allows shorter repetition times to ered in the explanation of the features of schizophrenia. Signal Intensity of Tissue Elements and T1 and T2 Weighting APPENDIX A: STRUCTURAL MRI PULSE SPGR pulses lead to proton density-weighted images, be- SEQUENCES cause the small 'tilt' and short TR diminishes any T1 or T2 effects. In a proton density image produced by the SPGR Spin echo pulse sequences use at least two pulses. The first is sequence most commonly used in schizophrenia research, an initial excitation pulse (tilting the magnetization vector CSF appears dark, gray matter is gray, and white matter 770 Neuropsychopharmacology: The Fifth Generation of Progress has the most signal (is brightest). Metaanalysis, decision analysis, and cost-effectiveness produce proton density, T2- or T1-weighted images. Hippocampal vol- longer T1 relaxation time than white matter and thus shows ume reduction in schizophrenia as assessed by magnetic resonance a brighter signal with sequences allowing longer T1 relaxa- imaging: a meta-analytic study. Because the ability to capture relatively complete 433–440. MRI anatomy of T1 relaxation depends on longer TRs, longer TRs thus give schizophrenia. The neuropathology of schizophrenic diseases: histori- The tissue intensity in T2-weighted images depends on the cal aspects and present knowledge. Eur Arch Psychiatry Clin Neu- TE in spin echo sequences. CSF has longer T2 values than rosci 1999;249(Suppl 4):2–13. A critical review of the data and their interpretation. Brain 1999;122: weighted acquisitions with the long TE values commonly 593–624. Cell biology of the hippocampal formation in TR allows more time for T1 relaxation and produces more schizophrenia. Elevated neu- allows more time for T2 relaxation and produces more sig- ronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional stereologic counting nal from tissues with long T2 values. Temporal lobe sulco- gyral pattern anomalies in schizophrenia: an in vivo MR three- ACKNOWLEDGMENTS dimensional surface rendering study. An automated Supported in part by VA Medical Research Service, Depart- registration algorithm for measuring MRI subcortical brain struc- ment of Veterans Affairs Center for Clinical and Basic Neu- tures. Adapting multi-grid methods to the class 52807 (RWM). Parts of the introduction are adapted from of elliptic partial differential equation appearing in the estimation of displacement vector fields. In: Cantoni V, Creutzburg R, Levi- a previous review: McCarley RW, Wible C, Frumin M, et aldi S, et al, eds. Biol Psychiatry 1999;45: Berlin: Springer, 1989:266—274. Automatic identification of grey matter structures from MRI to improve the segmentation of white matter lesions. Proceedings of Medical Robotics and Com- puter Assisted Surgery (MRCAS), November, 1995;140–47. New York: New York: Churchill Livingstone, 1971 (German 23. Model based segmentation edition published in 1899).

SSRIs are inhibitors of cyto­ the HAD compared with the LAD rats (86) order tadalafil overnight. Smith and chrome P-450 isoenzymes order tadalafil without prescription, with paroxetine an especially Weiss (87) have recently shown that ethanol-naive P rats strong inhibitor of the P-450-2D6 isoenzyme purchase tadalafil 10mg without a prescription, whereas flu­ have higher basal levels 5-HT release compared with NP voxamine is an especially potent inhibitor of P-450-1A2. How- SSRIs are combined with medications that are metabolized ever, although acute administration of alcohol results in in- by the P-450 system. Despite their common mechanism of creased levels of serotonin in the brain and periphery of action, there are important pharmacokinetic and pharmaco­ alcohol-naive animals, this release is not altered by a genetic dynamic differences. Despite their name, SSRIs are not predisposition toward high alcohol drinking (88). For The evidence on densities of serotonin receptors in rats example, sertraline and to a lesser extent fluoxetine are rela­ with a genetic predisposition to alcohol drinking is contro­ tively potent dopamine reuptake inhibitors, and the various versial. Alcohol-preferring (P) rats have higher 5-HT1A SSRIs can also block the reuptake of norepinephine (95). In contrast, minic receptors leading to anticholinergic and sedative side the replicate HAD and LAD lines do not display the same effects. Of the most disturbing side effects to SSRIs, initial differences in receptor densities, and in the alcohol-drinking nausea and sexual dysfunction are the most common. Preclini­ cal studies indicate that 5-HT1A agonists and serotonin None of the SSRIs is currently approved for the treatment reuptake inhibitors reduce ethanol intake in P and HAD of alcoholism. The results of several placebo-controlled dou­ rats as well as in unselected rat lines (86,91). In contrast, ble-blind studies using SSRIs for the treatment of alcohol the role of the 5-HT2and 5-HT3receptor systems in alcohol dependence have led to conflicting results. In an Italian drinking behavior is controversial (see ref. Similarly, in a Finnish study of 62 randomized HT2 receptors. Similarly, the role of the 5-HT3 receptor subjects, citalopram was more effective then placebo in alco­ system in mediating ethanol drinking is also controversial, hol drinking outcomes (97). These studies are not consistent with reductions in drinking seen in paradigms using contin­ with two American trials. For example, in a 12-week trial uous access to alcohol, but little efficacy being observed in using fluoxetine in a general sample of alcohol-dependent paradigms using limited access to alcohol. In contrast, stud­ subjects, there were no overall differences between the medi­ ies using serotonin uptake inhibitors such as fluoxetine re- cation and placebo groups (98). At doses of up to 60 mg ported robust decreases in alcohol drinking in the P rats per day in a group of 101 subjects who also received weekly (86,92). Although the overall results of SSRIs for alcoholism treat­ Pharmacodynamics, Pharmacokinetics, and ment are generally negative, there may be subtypes of pa­ Safety tients who benefit from treatment with SSRIs and other There are currently five Food and Drug Administration serotoninergic medications (Table 101. For example, in (FDA) approved selective serotonin reuptake inhibitors a study of 51alcoholics with severe comorbid major depres- 1452 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 101. DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS OF SEROTONINERGIC AGENTS FOR THE TREATMENT OF ALCOHOL DEPENDENCE Results No. Minus sign means a significant difference in favor of the placebo group. A plus/minus sign is a trend in favor of the medication group or a significant difference in a subsample. AD, alcohol dependence; GAD, generalized anxiety disorder; MD, mood disorder; NR, result not reported. At 1-year follow-up the results for both subgroup of alcoholics showed a favorable response to ser­ depression and alcohol continued to favor the fluoxetine traline in several drinking measures. Given that there may be important subgroups of alcohol­ Other Serotoninergic Medications ics who self-medicate with alcohol, Kranzler and colleagues (Buspirone, Ritanserin, Ondansetron) (102) subsequently reanalyzed their data after using a k- cluster technique to identify type A and type B alcoholics. There are a variety of other medications that affect the sero­ Type B alcoholics are thought to reflect some underlying tonin system but work through different mechanisms than serotoninergic dysfunction because they tend to be more the reuptake inhibitors. The results are mixed and suggest impulsive, have more emotional distress, and have increased that these medications may be effective only for certain sub- severity of alcohol dependence. There were no Buspirone medication differences in type A alcoholics. Similarly, Petti­ nati and colleagues (103) found that in a 14-week placebo- The results of buspirone, a serotonin 1A partial agonist, on controlled trial of sertraline (200 mg per day), there was no alcohol drinking are mixed and may depend on the main effect of sertraline on any alcohol drinking measure, subgroup of alcoholics studied (104–108). Subjects with presumed serotoninergic dysfunctions little evidence of clinical efficacy. In anxious alcoholics, Chapter 101: Alcoholism Pharmacotherapy 1453 however, studies consistently show that buspirone reduces mood and anxiety disorders. This class of medications, like anxiety in subjects and may reduce alcohol drinking and, the SSRIs, blocks the reuptake of serotonin but are far less in one study, days in which alcohol was craved (107). They also block the reuptake of norepinephine and dopamine, and antagonize muscarinic and histaminic receptors to varying degrees. The effect of Ritanserin TCAs on antagonizing muscarinic receptors and histaminic In a large multicentered placebo-controlled trial, 493 sub­ receptors give TCAs substantial anticholinergic and sedative jects were randomized to receive placebo or one of three effects. These anticholinergic effects include dry mouth, doses of ritanserin, a 5-HT2 receptor antagonist, with a constipation, and tachycardia. The antihistamine effects in­ treatment duration of 6 months. The results of the study clude drowsiness and sedation. The TCAs are metabolized showed no differences between the placebo group and any in the liver by the cytochrome P-450-2D6. Of note, alcohol can induce liver enzyme activity and reduce plasma TCA levels. Ondansetron More encouraging are the results of the 5-HT3 antagonist Efficacy ondansetron. A 6-week placebo-controlled study of 71pa- tients, found that 0. Johnson and colleagues (111) TCAs effectively reduce symptoms of depression but have found that among early-onset alcoholics (onset prior to age little effect of alcohol drinking. For example, Mason and 25), 4 �g/kg reduced the intensity of drinking compared colleagues (112) tested the effectiveness of desipramine in to placebo. Among subjects receiving ondansetron, the per- a double-blind, placebo-controlled trial of 71alcohol-de- cent of days abstinent was about 70% compared to 50% pendent subjects with (28 subjects) or without (41subjects) for those subjects treated with placebo (111). Overall, desipra­ no differences between the medication and placebo groups mine did not reduce alcohol drinking, but it was effective in for late-onset alcoholics. In this Although there are suggestions that serotoninergic mecha­ double-blind, placebo-controlled study, imipramine com­ nisms are involved in excessive drinking, the results of using bined with relapse prevention therapy was effective in im­ serotoninergic medications for alcoholism treatment are in- proving depression but had little effect on alcohol drinking. An understanding of which patients may be Among subjects who showed a good clinical response on helped by which serotoninergic medications is complicated depressive symptoms, there was evidence that imipramine by the heterogeneous nature of alcohol-dependent patients was associated with greater reductions in alcohol drinking and the subtle pharmacokinetic and pharmacodynamic dif­ compared to placebo. In summary, the results of these small- ferences among serotoninergic medications. The finding scale studies provide suggestive evidence that there is a that some subtypes of alcoholics may do worse while taking subgroup of patients with coexisting depression who may serotoninergic medications is of considerable clinical inter­ benefit from TCAs. Given the widespread use of SSRIs and other serotoninergic medications, it is likely that there are more The use of lithium for the treatment of alcoholism was alcoholics patients taking serotoninergic medications than suggested on the basis of clinical observations that many those taking all the medications specifically approved for patients with mood disorders, particularly bipolar disorder, the treatment of alcohol dependence combined.

However buy tadalafil toronto, large sample sizes are with schizophrenia are also similar to those in patients with required to distinguish between models order 20 mg tadalafil, especially the poly- schizophrenia generic tadalafil 5mg with amex, but are generally of lesser severity (67–71). In addition However, it has not been possible to distinguish between a to specifying the clinical consequences of schizotaxia more polygenic and a mixed model (77). Among these is whether schizotaxia degree of genetic relatedness decreases, is also compatible always or even usually progresses to schizotypal personality with a model of multiple loci with epistasis (interaction disorder or schizophrenia. Our empiric analyses suggest that between genes) (79). However, the number of susceptibility the basic symptoms of schizotaxia occur in 20% to 50% of loci, the disease risk conferred by each locus, and the degree adult relatives of patients with schizophrenia (68,69). This of interaction between loci all remain unknown. The contri- rate is considerably higher than the rates of schizophrenia bution of individual genes to the familiality of a disorder or schizotypal personality disorder likely to develop in first- can be expressed in terms of (s (i. The false-positives were largely the patible with the existence of a single locus having a value consequence of a combination of multiple testing and the of (s greater than 3. Unless extreme epistasis (interaction use of statistical methodology and significance levels derived between loci) exists, models with two or three loci having from work on single-gene disorders. It should be Despite the failure to identify regions of unambiguous emphasized that these calculations are based on the assump- linkage in multiply affected families, modest evidence for tion that the effects of genes are distributed equally across several regions has been reported in more than one data set. It is quite possible that genes of larger Areas implicated for which supportive data have also been effect are operating in a subset of patients—for example, obtained from international collaborative studies include those from families with a high density of illness. A number of other promising evidence that genetic factors increase the risk for schizophre- areas of putative linkage are also currently under investiga- nia. However, although it is possible to state that, as a group, tion by international consortia. However, in each general population, it is not currently possible to translate case, both negative and positive findings have been ob- this figure to the level of risk for a particular sibling in a tained, and in only two cases, those of chromosomes particular family. Another These positive findings contrast with those from a large important point is that risk to related individuals does not systematic search for linkage in which a sample of 196 af- directly equate with genetic risk because some relatives carry fected sibling pairs, drawn typically from small nuclear fami- one or more susceptibility alleles for schizophrenia but re- lies rather than extended pedigrees, was used (101). In other words, the results of simulation studies suggest that the power of this accumulation of susceptibility alleles, environmental risk study is greater than 0. This study yielded evidence at the level of the definition of Lander and Kruglyak (102) of 'suggestive' linkage to chromosomes 4p, 18p, and Xcen. However, none MOLECULAR GENETICS: LINKAGE STUDIES of the findings approached a genome-wide significance of 0. This was done in the hope that such families, in the search for genes for complex traits (103–106). First, or at least a proportion of them, were segregating genes of no finding is replicated in all data sets. Second, levels of sufficiently large effect that they could be detected unequiv- statistical significance are unconvincing and estimated effect ocally in this way. This approach has been successful in sizes are usually modest. Third, chromosomal regions of other complex disorders—Alzheimer disease, for example, interest are typically broad [often 20 to 30 centimorgan in which mutations in three genes, APP, PS1, and PS2, are (cM)]. In such At the present time, therefore, the linkage literature sup- cases, the disease is of unusually early onset and is transmit- ports the predictions made by Risch (79); it is highly un- ted through multiplex pedigrees in an autosomal dominant likely that a commonly occurring locus of effect size [(s] fashion (80–82). Studies of such large families also initially gions suggest that rarer alleles of larger effect may be segre- produced positive findings in schizophrenia (83), but unfor- gating in some large, multiply affected families. The reasons for this Linkage methods in sample sizes that are realistically have become clear as data from systematic genome scans achievable can detect smaller genetic effects than those in have accumulated; highly penetrant mutations causing the studies to date. For example, it is possible to detect schizophrenia are at best extremely rare and quite possibly alleles with values of (s of 1. However, the purpose of experiment is to reject that priority should now be given to collecting such samples a null hypothesis, and in the face of uncertainty, the burden with a robust clinical methodology that is comparable across of proof remains with the proponents of a particular candi- all interested research groups. Overall, the results in this extensive literature CANDIDATE GENE ASSOCIATION STUDIES are disappointing, but it should be noted that the sample sizes in many of the older studies would now generally be Once genes of smaller effect than (s 1. For this reason, many research- represent functional variants and that few genes have been ers have tried to take advantage of the potential of candidate systematically screened even for common functional var- gene association studies to identify such loci (109,110). However, more promising reports of candidate gene though a potentially powerful means of identifying genes associations have recently appeared, three of which are con- of small effect, association studies are not without their sidered here. First, for a complex and poorly understood disor- der such as schizophrenia, the choice of candidate genes Serotonin 5-HT2A-Receptor Gene is limited largely by the imagination and resources of the researcher. This places a stringent burden of statistical proof Many novel antipsychotic drugs affect the serotoninergic on positive results because of low prior probability and mul- system. The first genetic evidence that serotoninergic recep- tiple testing (111). Second, case–control association studies tors may play a role in schizophrenia came from a Japanese have the potential to generate false-positives because of pop- group reporting an association between a T-to-C polymor- ulation stratification. This problem can be addressed by phism at nucleotide 102 in the 5-HT2A-receptor gene in a using family-based association methods (112), but because small sample (114). A large European consortium compris- of stigma, adult age at onset, and the disruptive effects of ing seven centers and involving 571 patients and 639 con- mental illness on family relationships, family-based samples trols then replicated this finding (115), which was further may be unrepresentative in addition to limited in size. Con- replicated with use of a family-based design (116). Although sequently, family-based studies may introduce more spu- many other studies followed with mixed results, a recent rious results than do case–control studies (113). It would metaanalysis of all available data from more than 3,000 seem unwise, therefore, to discard the case–control study subjects supports the original finding (p. A third problem common to all molecular genetic (117). If we assume homogeneity and studies, larger sample sizes are required than have typically if the association is true, the putative odds ratio (OR) for the been used to date in psychiatric genetics (111). Fourth, even C allele can be expected to be around 1. Sample sizes of 1,000 subjects are then be required replication study will be sufficiently powered to replicate a for 80% power to detect an effect of this size, even at a particular effect. This is because variations may be noted in relaxed criterion of p. Thus, the negative studies are the contribution of a given susceptibility allele in different effectively meaningless, but it is also true that the evidence patient populations as a result of different allele frequencies for association, even in the metaanalysis (p. Further poten- not definitive if genome-wide significance levels are required tial for heterogeneity occurs if the association with the (109). At present, all we can conclude is that the evidence marker is a result of tight linkage with the true susceptibility favors association between the T102C 5-HT2A polymor- allele, or if different subtypes of the disease exist. Given that phism and schizophrenia, but the most stringent burden of all the above factors may influence power, and that none proof has not yet been met. T102C is 678 Neuropsychopharmacology: The Fifth Generation of Progress in complete linkage disequilibrium with a polymorphism tance of schizophrenia is at least consistent with the presence in the promoter region of this gene, but no evidence has as of anticipation, although ascertainment biases offer an alter- yet been found that this has a functional effect either (116). Because pathogenic expanded tri- Recent evidence of polymorphic monoallelic expression of nucleotide repeats are the only known genetic mechanisms the 5-HT2Agene points to the possible existence of sequence for anticipation, these findings have been taken as suggest- variation elsewhere that influences gene expression (118), ing that such mutations may account for at least some of and this may be the true susceptibility variant.

Mood symp- zapine exert direct effects on negative symptoms indepen- toms in schizophrenia patients have tended to be relatively dent of differences in psychotic purchase tadalafil with amex, depressive cheap tadalafil 20 mg with mastercard, or extrapyrami- Chapter 56: Therapeutics of Schizophrenia 787 dal symptoms (212 discount tadalafil online mastercard,213). Recently, Volavka and colleagues augmentation of an atypical agent, fluoxetine at a mean dose (74) preliminarily reported a prospective double-blind ran- of 49 mg per day produced no improvement in negative domized study, comparing the effects of clozapine, olanza- symptoms when added to clozapine in 33 patients (223). Clozapine (mean dose 527 tional antipsychotics for control of EPS (224). The atypical mg per day) and olanzapine (mean dose 30 mg per day), but agents vary substantially in their muscarinic anticholinergic not risperidone (mean dose 12 mg per day), demonstrated activity; clozapine is strongly anticholinergic, whereas queti- significantly greater efficacy than haloperidol (mean dose apine and risperidone exhibit very low affinity for muscar- 26 mg per day) in reducing negative symptoms (74). Whether primary negative symptoms are Few data are available from controlled trials to guide treat- improved by anticholinergics, as suggested by Tandon and ment of negative symptoms that persist despite optimal colleagues (229), cannot be answered by studies in which treatment with atypical agents (215). Clinicians commonly subjects are treated with conventional agents; by attenuating employ augmentation strategies, but evidence supporting psychomotor side effects of the neuroleptic, the anticholin- this practice is derived mostly from an older literature de- ergic may be improving secondary negative symptoms only. Although the efficacy of augmenta- 5-HT2 receptors, investigators combined haloperidol with tion with muscarinic anticholinergic agents for negative ritanserin, a relatively selective 5-HT2Aand 5-HT1Cantago- symptoms remains poorly established, the potential cogni- nist (216). In a 6-week, placebo-controlled trial, addition tive impairment that these agents can produce is well de- of ritanserin to haloperidol produced significant reductions scribed (232,233). Three of four placebo-con- blockade may improve negative symptoms by enhancing trolled trials demonstrated improvement of negative symp- mesocortical dopamine release. Svensson and colleagues toms following a single dose of amphetamine given orally or demonstrated that 5-HT2 blockade increases firing of mid- intravenously (234–237); in one study efficacy for negative brain dopamine neurons and reverses the effects of N- symptoms was not affected by coadministration with pi- methyl-D-aspartate (NMDA) antagonism (217) and hypo- mozide (236). However, Casey and colleagues (238) found frontality (218) on A10 dopamine neuronal firing. Because no clinical benefit in an extended, 20-week placebo-con- the available atypical agents achieve maximal occupation of trolled trial of amphetamine augmentation of chlorproma- 5-HT2 receptors at usual therapeutic doses (57), it is un- zine. Augmentation trials of psychostimulants added to likely that augmentation with 5-HT2 antagonists (e. Fluoxetine and fluvoxamine signifi- NMDA receptor activity (239). Significant improvements cantly improved negative symptoms when added to conven- in negative symptoms consistently have been produced in tional neuroleptics in three of four controlled trials, placebo-controlled trials by the addition to conventional producing generally modest effects (220). In one study, flu- antipsychotics of agonists at the glycine site of the NMDA oxetine 20 mg per day added to depot neuroleptics de- receptor. D-cycloserine, a partial agonist at the glycine site, creased ratings of negative symptoms by 23% compared to produced a selective, 23% mean improvement of negative a 12% reduction with placebo; this improvement occurred symptoms at 6 weeks that, compared to placebo (7% reduc- despite a mean 20% elevation in haloperidol serum concen- tion), represented a large effect size (. The full trations and a 65% increase in fluphenazine levels (221). Aug- cebo-controlled trial in 36 chronic inpatients with schizo- mentation with another endogenous full agonist, D-serine phrenia (222). In the only reported controlled trial of SSRI 30 mg per kg per day, was associated with significant im- 788 Neuropsychopharmacology: The Fifth Generation of Progress provements in negative, positive, and cognitive symptoms phoric reactions to high-potency conventional agents, al- when added to conventional agents and to risperidone in an though generally not meeting criteria for major depression, 8-week trial (242). Consistent with evidence that clozapine can closely resemble the depressive symptoms often associ- differs from conventional agents in its effects on NMDA ated with the illness (254,259,260). Clozapine, olanzapine, receptor responsiveness, glycine, D-cycloserine, and D-ser- and risperidone have all demonstrated significantly greater ine did not improve negative symptoms when added to efficacy for depressive symptoms compared to conventional clozapine (242–245). Whether strategies that enhance neuroleptics in large, double-blind trials (64,211,261). Path NMDA receptor activation will improve response to other analysis suggested that 57% of the superior response of de- atypical agents remains uncertain, although both olanzapine pressive symptoms to olanzapine compared to haloperidol and quetiapine resemble clozapine in certain models of was a direct effect, whereas effects on negative symptoms NMDA receptor responsivity. Antidepressant activity of the atypical agents may have Existing psychosocial approaches have not achieved notable important clinical consequences because perceived improve- success in the treatment of negative symptoms. Negative ment in anxiety and depression is a strong predictor of com- symptoms are substantially less responsive to CBT than are pliance and emergence of depressive symptoms often ac- psychotic symptoms and patients with prominent negative companies relapse. Adjunctive Agents Similarly, in a pilot study, Kopelowicz and colleagues (246) In a placebo-controlled trial reported in 1989, Kramer (258) found that patients meeting criteria for the deficit syndrome found that addition of desipramine or amitriptyline 5 weeks were relatively less likely to benefit from a program of psy- after initiating haloperidol to acutely decompensated pa- choeducation and social skills training than patients without tients with schizophrenia and depression was associated with prominent negative symptoms. The presence of negative poorer antipsychotic response and did not improve depres- symptoms also predicts poor outcome in vocational rehabil- sive symptoms. Subsequently, Siris and colleagues (262, itation programs for patients with schizophrenia (247). Al- 263) demonstrated that imipramine added to conventional though most forms of outreach and involvement of deficit agents in stable outpatients significantly improved depres- syndrome patients in psychosocial programs may improve sion without adversely affecting psychotic symptoms. In a their quality of life by reducing social isolation and coun- carefully controlled trial, imipramine 200 mg per day was tering apathy, negative symptoms constitute a serious obsta- associated with substantial improvement in depressive cle to participation in such programs and are unlikely to symptoms in 42% of patients compared to 12% with pla- improve with psychosocial treatment. Hogarty and colleagues (176) found that desipramine improved symptoms of depression, anxiety, and psychosis Mood Symptoms when added to fluphenazine decanoate in a placebo-con- trolled trial. Benefits of desipramine were only significant Antipsychotic Monotherapy in female patients and did not achieve significance until Depressive symptoms are common during all stages of schiz- week 12. The investigators noted that improvement of psy- ophrenia and are associated with poor outcome, including chotic symptoms might have resulted from successful pro- relapse and suicide (248–250). It is not uncommon for phylaxis against depressive episodes, which were associated patients to present initially with depression during the pro- with worsening of psychosis. Several trials of tricyclic antide- dromal stage, prior to the appearance of psychotic symp- pressants added to conventional agents have been reported; toms (251). Approximately 25% of first-episode patients this literature generally supports their use for acute and exhibit depression, although estimates of the incidence of maintenance treatment of depressive symptoms in stable comorbid depression vary widely according to choice of di- patients (264,265). Augmentation with selective serotonin agnostic criteria (251–253). The prevalence of depression reuptake inhibitors has been studied primarily as a treat- as defined by moderate scores on depression rating scales ment for negative symptoms—use of these agents in schizo- ranges between 25% and 50% in chronic patients (252, phrenia patients with depression is not well studied. Although considerable overlap exists between symp- larly, addition of antidepressants to atypical agents has not toms of depression and certain negative symptoms (e. Cognitive Symptoms Conventional antipsychotics tend to have little effect on comorbid depression, although anxiety and depression asso- Antipsychotic Monotherapy ciated with acute psychotic exacerbation frequently respond A wide range of cognitive deficits are usually present at the to neuroleptic monotherapy (257,258). However, dys- time of the first psychotic episode (266) and remain stable Chapter 56: Therapeutics of Schizophrenia 789 or only slowly progressive during the course of the illness, effects of atypical agents, particularly because excessive dos- independent of psychotic symptoms (267–269). Cognitive ing can impair performance on time-sensitive tasks and in- deficits are particularly prominent in patients meeting crite- crease anticholinergic exposure. The latter association may indicate Adjunctive Agents that cognitive deficits are a risk factor for tardive dyskinesia, Augmentation with glutamatergic agents has shown prom- or alternatively, that the neurotoxic mechanism responsible ise for cognitive deficits in schizophrenia (279). As noted, for irreversible motoric deficits also compromises cognitive glycine and D-serine improved ratings of cognitive func- functioning. Targeting cognitive impairments is now a tioning when added to conventional neuroleptics (241, major focus of drug development because cognitive deficits 280). Both agents improved the 'cognitive subscale' of the are powerful determinants of vocational and social function- PANSS compared to placebo, and D-serine was also associ- ing and may influence quality of life (36) more than psy- ated with improved performance on the Wisconsin Card chotic symptoms. These findings are of interest given that NMDA antag- The conventional neuroleptics produce small and incon- onists produce in normal subjects deficits in attention and sistent effects on cognitive functioning; sustained attention memory similar to those found in schizophrenia (281,282).

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