Tenormin

By K. Keldron. Benedict College.

A circuitry model of the expression of schizophrenia buy discount tenormin 100 mg on line. The pharmacology and neu- of psychotic symptoms in schizophrenia cheap tenormin 50mg otc. Am J Psychiatry 1997; ral circuitry of sensitization to psychostimulants. Dextroamphetamine: SPECT benzodiazepine receptor imaging in schizophrenia. Dysfunctions in multiple interrelated altered in vivo benzodiazepine receptor binding in schizophre- systems as the neurobiological bases of schizophrenic symptom nia. Benzodiazepine receptor¨ 852 Neuropsychopharmacology: The Fifth Generation of Progress distribution and diazepam binding in schizophrenia: an explora- ceptor occupancy levels. Time course of of GABA(A) and benzodiazepine receptor binding activity in central nervous dopamine-D2 and 5-HT2 receptor blockade the hippocampal formation of schizophrenic brain. Brain Res and plasma drug concentrations after discontinuation of quetia- 1997;755:121–129. Serotonin receptors as target of anti- cology (Berl) 1998;135:119–126. A positron emission tomog- ceptors in actions of antipsychotic medications. Boca Raton, FL: raphy study of quetiapine in schizophrenia: a preliminary find- CRC Press LLC, 2000:79–107. Serotonin 5-HT2 receptors mine D2 receptor occupancy. Arch Gen Psychiatry 2000;57: in schizophrenia: a PET study using [18F]setoperone in neuro- 553–559. Trichard C, Paillere-Martinot ML, Attar-Levy D, et al. A PET study of [C-11]FLB tonin 5-HT2A receptor density abnormality in the cortex of 457 binding to extrastriatal D-2-dopamine receptors in healthy schizophrenic patients studied with PET. Schizophr Res 1998; subjects and antipsychotic drug-treated patients. In vivo occupancy in schizophrenic patients studied by positron emission tomogra- of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs. Decreased serotonin 2A emission tomography (SPET) study. Br J Psychiatry 1999;175: receptor densities in neuroleptic-naive patients with schizophre- 231–238. Measurement risperidone, and olanzapine in schizophrenia. Am J Psychiatry of striatal and extrastriatal D-2 receptor occupancy by clozapine 1999;156:286–293. Regionally specific effects occupancy in patients treated with classical neuroleptics and of atypical antipsychotic drugs on striatal fos expression: the clozapine. Clozapine, single photon bic and nigro-striatal dopamine systems in humans. J Nucl Med emission tomography, and the D2 dopamine receptor blockade 2000;41:105P. Central D2-dopamine phetamine-induced dopamine release in ventral versus dorsal receptor occupancy in relation to antipsychotic drug effects: a striatum. Predicting haloperi- ble-blind PET study of first-episode schizophrenia. Am J Psy- dol occupancy of central dopamine D2 receptors from plasma chiatry 2000;157:514–520. N-[11C]methylspi- receptor occupancy in relation to clozapine serum concentra- perone PET, in contrast to [11C]raclopride, fails to detect D2 tion: a PET study of schizophrenic patients [see comments]. Imaging of cAMP- receptor occupancy in the living human brain. A PET study specific phosphodiesterase-IV:comparison of [11C]rolipram and with risperidone. An acute effect of receptor occupancy of risperidone and its relationship to extra- triazolam on muscarinic cholinergic receptor binding in the pyramidal symptoms: a PET study. Dopamine receptor-mediated Chapter 59: Neurochemical and Neuropharmacological Imaging in Schizophrenia 853 regulation of striatal cholinergic activity: positron emission to- 31PMRS of the schizophrenic brain in vivo. J Comput Assist mography studies with norchloro[18F]fluoroepibatidine. MR image segmenta- of the prefrontal cortex of schizophrenic patients at different tion and tissue metabolite contrast in 1H spectroscopic imaging stages of illness via phosphorus magnetic resonance spectros- of normal and aging brain. Proton MR spectroscopic imaging with- ment of improved homogeneity using higher-order shims for out water suppression.

Given their apparently favorable side- 1746 Neuropsychopharmacology: The Fifth Generation of Progress effect profile generic tenormin 100 mg line, controlled trials with such agents are war- ing behavior (hand licking and hair stroking) and SIB in- ranted purchase tenormin 100 mg on line. Increased plasma enkephalin levels in patients with devel- Prader-Willi syndrome (PWS) is a congenital disorder opmental disability compared with normal controls have that affects approximately 1 in 10,000 newborns and is one been reported (38). Although this may support the excessive of the five commonest abnormalities seen in birth defect opioid hypothesis, it is also possible that decreased endoge- clinics (53a,53b). PWS is associated with marked hyper- nous brain opioid levels ultimately lead to compensatory phagia, and the disorder is the most common dysmorphic overproduction (39). It has also been argued, however, that form of obesity. In addition, PWS is characterized by behav- opioid effects on self-injury may be primarily mediated via ioral disturbances, mental retardation, sleep disturbances, the dopamine or serotonin system (28). Behavioral distur- There is some evidence that the opiate antagonists nalox- bances include compulsive self-mutilation, impulsive tem- one and naltrexone lead to a reduction in frequency of self- per outbursts, and classic obsessive-compulsive behaviors injury in different patient populations, including those with (44,45). SIB is common and not necessarily associated with developmental disability (28,34). It includes skin and nose pick- ber of patients in such studies is relatively small, and the ing, nail biting, lip biting, and hair pulling (45). Patients study designs have been criticized (39,40). Indeed, in a pla- frequently have chronic skin sores. Although this finding does not entirely Both the biochemical abnormality [virtual absence of hypo- rule out a role for the opioid system, it further emphasizes xanthine-guanine phosphoribosyltransferase (HPRT)] and the need for caution in drawing conclusions from open trials the underlying genetic defect (a mutation of the HPRT of treatment for SIB. However, the mechanisms underlying neu- ing to the stage of menstrual cycle. In one study, fluctuations ropsychiatric symptoms are less clear. Nevertheless, the bio- in SIB were associated with early and late follicular phases. Animal studies with HPRT-deficient models and clini- population has not been well studied. The anticonvulsant cal studies of neurotransmitters and metabolite levels in valproic acid, however, was effective in reducing SIB and patients with the disorder support the importance of dopa- aggression in 12 of 18 patients with mental retardation and minergic mediation of symptoms (47). These BEHAVIOR differences may reflect the importance of the developmental stage at which dopaminergic deficits occur (11). Although Phenomenology dopamine supersensitivity has also been hypothesized to Lesch-Nyhan syndrome (LNS) is an X-linked recessive dis- play a role in SIB in LNS (9), and dopamine blockers have order of purine synthesis. Patients present with hyperuri- been used for their treatment, long-term treatment with cemia and neuropsychiatric symptoms including spasticity, these agents is not clearly of benefit in LNS. Further under- choreoathetosis, dystonia, mental retardation, aggression, standing of the developmental neurobiology underlying this and self-injurious behavior. SIB in LNS is dramatic, and syndrome is therefore needed. Nevertheless, there is little direct re- Cornelia de Lange syndrome (CLS) is a rare congenital search to support a dopamine hypothesis of CLS. Indeed, disorder characterized by a distinctive appearance and men- the underlying neurobiology of this interesting syndrome tal retardation. Patients with CLS manifest excessive groom- remains relatively poorly understood. Chapter 121: Compulsive and Impulsive Aspects of Self-Injurious Behavior 1747 Research has also focused on the serotonin system in duced dopamine transporters in caudate and putamen (51) LNS. Studies of cerebrospinal fluid (CSF) 5-hydroxyindol- as well as decreased dopa decarboxylase activity and dopa- eacetic acid (5-HIAA) have been inconsistent in LNS, but mine storage throughout the dopaminergic system in LNS there may be slightly increased putamen serotonin and 5- (52). It is possible that in LNS there is reorganization of HIAA (46). In addition, early reports suggested 5-HT (1 the cortical–basal ganglia–thalamic pathways during devel- to 8 mg/kg) was useful in the treatment of self-injurious opment (52). However, only a minority of subsequent Anumber of authors have suggested hypothalamic-pitui- studies have confirmed this finding (28). Again, however, further work is In an early study, CLS patients were found to have re- needed to extend these preliminary findings and to deter- duced whole blood serotonin levels (48). Several possible mine the relationship with behavioral symptoms. Indeed, at mechanisms underlying this finding were considered, in- present little is ultimately understood about the underlying cluding a dysfunction in serotonin metabolism, failure to neurobiology of self-injury and other behavioral symptoms bind to platelets, and transporter abnormalities.

Berman purchase 100mg tenormin otc, 'functional' imaging is becoming increasingly shorten acquisition time effective tenormin 50mg. 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).

A true understanding of the pathophysiology on therapeutic doses of lithium cheap tenormin 100mg without a prescription, VPA cheap 50mg tenormin overnight delivery, or the combination, of an illness as complex as BD must clearly address its neuro- were randomized to adjunctive treatment with gabapentin biology at different physiologic levels (i. Abnormalities in gene expres- Chapter 77: Treatments for Acute Mania and Prophylaxis for Bipolar Disorder 1115 sion undoubtedly underlie the neurobiology of the disorder for the action of lithium has been identified. Klein and at the molecular level; this will become evident as we iden- Melton (51) were the first to demonstrate that lithium, at tify the susceptibility and protective genes for BD in the therapeutically relevant concentrations, inhibits glycogen coming years. Once this has been accomplished, however, synthase kinase 3 (GSK3 ). GSK3 is now known to play the even more difficult work must begin to examine the a critical role in the CNS, by regulating various cytoskeletal impact of the faulty expression of these gene products (pro- processes, synaptic plasticity, and long-term gene expression teins) on integrated cell function. Interestingly, VPA (but not CBZ) also concentra- critical signaling molecules recently have been identified as tion-dependently inhibits GSK-3 in vitro, with significant candidate targets for the development of truly novel agents effects observed at concentrations of VPA similar to those for the treatment of BD. Most recently, it has been dem- Multicomponent, cellular signaling pathways interact at onstrated that the chronic (3- to 4-week) administration of various levels, thereby forming complex signaling networks lithium and VPA also increase -catenin levels in rodent that allow the cell to receive, process, and respond to infor- brain (Chen and Manji, unpublished observations), com- mation (58). The high degree of complexity generated by patible with inhibition of GSK3 during chronic in vivo these signaling provides neurons with the flexibility to gen- administration of the agents under therapeutic paradigms. These pathways are undoubtedly involved in regu- neuroplastic events in the CNS, and there is considerable lating such diverse vegetative functions as mood, appetite, excitement about the possibility of developing novel GSK- and wakefulness, as well as higher cognitive functions—sys- 3 modulators as potential new therapeutics for both BD tems that are all affected in BD—and thus represent attrac- and neurodegenerative diseases (60). Over the last decade, there have been major advances in our understand- ing of the critical role of the protein kinase C (PKC) signal- NEUROTROPHIC AND NEUROPROTECTIVE ing pathway as a therapeutically relevant target for the long- AGENTS FOR THE OPTIMAL LONG-TERM term actions of mood stabilizers (57,59). The preponder- TREATMENT OF BD ance of the data indicates that chronic lithium attenuates PKC responses and down-regulates specific PKC isozymes Recent studies investigating potential structural brain (57). Studies in rodents and cultured cells have demon- changes in mood disorders have demonstrated reductions strated that chronic (but not acute) lithium produces an in regional CNS volume and cell numbers (both neurons isozyme-selective reduction in PKC and. It is thus noteworthy that structurally highly dissimilar antimanic agent VPA produces lithium and VPA have recently been demonstrated to ro- strikingly similar effects on the PKC signaling pathway, as bustly increase the expression of the cytoprotective protein does lithium (17,57). In view of the pivotal role of the PKC bcl-2 in the CNS (59,61). Chronic lithium not only exerts signaling pathway in the regulation of neuronal excitability, neuroprotective effects in several preclinical paradigms, but and neurotransmitter release (57), it was postulated that the also enhances hippocampal neurogenesis (61). VPA robustly attenuation of PKC activity might play a major role in the promotes neurite outgrowth and activates the ERK MAP antimanic effects of lithium and VPA. There is currently kinase pathway, a signaling pathway utilized by many only one relatively selective PKC inhibitor available for endogenous neurotrophic factors (61). Tamoxifen, a synthetic non- preclinical neurotrophic/neuroprotective effects, chronic steroidal antiestrogen, is also a potent PKC inhibitor at ther- lithium treatment of patients with BD increases brain N- apeutically relevant concentrations (20). Therefore, a pilot acetylaspartate (NAA, a putative marker of neuronal viabil- study was initiated to investigate the efficacy of tamoxifen ity and function) levels, effects that are localized almost in the treatment of acute mania, and it was found that exclusively to gray matter (61). To determine if lithium was tamoxifen did indeed possess antimanic activity (57,58). Nevertheless, the signifi- chronic lithium significantly increases total gray matter vol- cant (and in some cases rapid and striking) results that have ume in the human brain of patients with BD (61). In view of the preliminary data evidence demonstrating the neurotrophic effects of lithium, suggesting the involvement of the PKC signaling system in VPA, and antidepressants, the enhancement of hippocam- the pathophysiology of BD (17,57), these results suggest pal neurogenesis in the adult mammalian brain, as well as that PKC inhibitors may be very useful agents in the treat- the growing appreciation that mood disorders are associated ment of BD. Larger, double-blind placebo-controlled stud- with cell loss and atrophy, suggest that these effects may be ies of tamoxifen and novel selective PKC inhibitors in the very relevant for the long-term treatment of mood disorders. It is perhaps useful to conceptualize the cell death and atro- In recent years, a hitherto completely unexpected target phy that occurs in mood disorders as arising from an impair- 1116 Neuropsychopharmacology: The Fifth Generation of Progress ment of 'cellular resiliency. Therapeutic effects of CBZ in affective death pathways are currently under investigation. Response to clozapine CONCLUDING REMARKS in acute mania is more rapid than that of chlorpromazine. Olanzapine compared to lithium The growing body of data implicating signaling pathways in mania: a double-blind randomized controlled trial. Int Clin in the pathophysiology and treatment of BD suggests that Psychopharmacol 1999;14: 339–343. Efficacy of dival- represent truly novel treatments for BD. A randomized, enhanced our ability to understand the complexities of the placebo-controlled 12-month trial of divalproex and lithium regulation of neuronal function; these advances are leading in treatment of outpatients with bipolar I disorder. Arch Gen to an increasing number of avenues to modulate transmem- Psychiatry 2000;57:481–489. Illness characteristics of patients in clinical drug development of truly novel and improved therapeutics. Emerging results from a variety of clinical and preclinical 11. Use of sodium VPA in experimental and naturalistic paradigms also suggest that the management of affective disorders: basic and clinical aspects. Anticonvulsants in by the early use of agents with neurotrophic/neuroprotective affective disorders. A double-blind, effects, irrespective of the primary, symptomatic treatment.