By Z. Thorek. Lancaster Theological Seminary.

The relationship between ery after stroke: a placebo-controlled order topamax 200mg medicine hat horse, double-blind study generic topamax 100mg with mastercard medications used for fibromyalgia. Am J intellectual impairment and mood disorder in the first year after Psychiatry 2000;157:351–359 cheap 100mg topamax with mastercard medicine valium. Dementia of depres- cally ill hospitalized older adults: prevalence effective topamax 200 mg medications affected by grapefruit, characteristics, and sion or depression of dementia in stroke? Acta Psychiatr Scand course of symptoms according to six diagnostic schemes. RYAN This chapter discusses critical conceptual and practical is- events. Today, as detailed by Keller and Kovacs (3), clinical sues confronting clinicians who must distill the massive neu- depressions are now recognized as far more chronic, more roscientific, psychopathologic, and clinical research infor- often recurrent (typically with a waxing and waning course), mation about the basis for clinical depression and its and more disabling. Historically, symptom severity has been treatment and who must apply that knowledge to individual used to distinguish different forms of depression (e. This chapter does not provide an encyclopedic depressive disorder versus dysthymia). More recent evi- review of antidepressant treatments. A more chronic course and greater symptom severity ment, and on practical dilemmas encountered in daily prac- both contribute to greater levels of disability. The latter often calls for types of information not prevalence rates and the degree of disability found in non- usually provided by standard clinical research protocols de- major forms of depression provide a basis for regarding even signed to obtain regulatory approval of new antidepressant modest levels of nontransient depressive symptoms as a agents. Consequently, efficacy studies After highlighting recent revisions in our knowledge have been undertaken with more chronic forms of depres- about depressive disorders, we discuss the implications of sion (9–11) and with 'nonmajor' forms of depression (e. We conclude with suggestions for further re- such as with myocardial infarction (24,25), stroke (26), de- search. Only two decades ago, clinical depression was seen as a That is, a chronic course may entail the development of an transient, typically self-limited reaction to 'untoward' underlying neurobiology that renders treatments less effec- tive acutely or over the longer term. Such an inference is suggested by apparently longer times to develop responses A. John Rush: Department of Psychiatry, University of Texas Southwest- and remissions in studies of chronic (10,11) as opposed to ern Medical Center, Dallas, Texas. Ryan: Western Psychiatric Institute & Clinic, University of nonchronic forms of depression (32,33). This recent em- Pittsburgh Medical Center, Pittsburgh, Pennsylvania. In many such cases, patient remission and full functional restoration (not simply re- preference with careful clinical monitoring, once therapy is sponse) are the targets of treatment. This conceptual shift has profound implications for prac- tice and development and use of newer agents. It also pro- vides a rationale for combining treatments when a mono- TRANSLATING KNOWLEDGE TO PRACTICE therapy does not lead to remission. Only a few clinical clues that recommend nature of these conditions. Whether different levels of func- one treatment over another have been established scientifi- tional impairment in the context of equivalent levels of re- cally. For example, the greater acute phase efficacy of mono- sidual symptoms herald a worse prognosis has yet to be amine oxidase inhibitors (MAOIs) as compared to tricyclic demonstrated. Furthermore, recent studies (21–23) suggest antidepressants (TCAs) in depressions with atypical symp- psychotherapy that effectively removes residual symptoms tom features is well established in double-blind, placebo- also improves prognosis, which in turn may reduce the need controlled trials (44,45). Furthermore, the greater efficacy for long-term maintenance medication. The need to most On the other hand, many practical dilemmas are con- aggressively pursue full symptom remission (also called fronted in routine practice, yet knowledge is sparse to ad- complete response), rather than to accept a clinically signifi- dress these issues. This lack of practical knowledge grounded cant reduction in symptoms (a response) is now accepted in empirical evidence, can be attributed to several factors: (a) because of the worse prognosis and functional impairment insufficient investment in clinical research that goes beyond associated with residual symptoms noted in the preceding. Mainte- conducted for regulatory purposes and representative prac- nance aims at preventing a new depressive episode—a recur- tices. When continuation ends and maintenance begins for Patients with minimally treatment-resistant, or non- an individual is unclear, although classically recovery from chronic forms of depressions enter trials. These patients are: the episode is estimated by when the episode would have (a) rarely severely ill; (b) rarely inpatients; (c) never psy- spontaneously ended based on the duration of prior epi- chotic; (d) rarely encumbered by common concurrent Axis sodes, if such information is available. The need for more III (general medical) or other Axis I (psychiatric) disorders; prolonged (i. Perhaps as a consequence, placebo response rates exactly how long to provide antidepressant treatment re- are often substantial (e. Consensus strongly recommends providing a 50% to 60% response rate (34). These recommenda- proval and the procedures characteristic of current practice. Whether patients with two episodes of major fore, also to adjust dosages); (c) use more frequent treatment depression plus a risk factor for recurrence should also be visits; (d) limit acute phase trial durations (e. Furthermore, recent regulatory and mar- toms with normalization of function) to define a clinical ket forces have encouraged studies in depressed children, 'success,' contrary to clinical practice recommendations adolescents, and geriatric patients. The National Institute of Mental Health (NIMH) has Routine clinical diagnoses often sharply disagree with recently begun to address some of the knowledge gaps noted those established by structured interviews (51) (Kashner et in the preceding by emphasizing effectiveness trials of anti- al. In addition, global judg- depressant treatments in children/adolescents, adults, and ments of the severity of illness, even if codified by the Clini- geriatric patients. The emphasis (50) was based on the reali- cal Global Impression-Improvement Scale (CGI-I) (52), zation that efficacy trials for regulatory approval are only may relate only modestly to symptom severity ascertained by the first step in defining a treatment.

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Thus when morphine is given while GluR1 of the transcription factor CREB (cAMP response element expression in the VTA is elevated order topamax 200 mg with amex symptoms narcolepsy, increased sensitivity to binding protein) in the NAc order 200mg topamax with visa medications of the same type are known as. These data suggest that altered expression of GluR1 in the VTA underlies topamax 100 mg cheap medications like xanax, at least in part topamax 200mg with visa symptoms definition, the development and GluRs in the VTA expression of sensitized behavioral responses to morphine. AMPA receptors are made up of various combinations of The effect of elevated GluR1 expression in the VTA on the subunits GluR1, GluR2, GluR3, and GluR4 (collec- the rewarding effects of morphine was examined using place tively called GluRs) (38,39). Repeated intermittent expo- conditioning, a classic conditioning procedure in which rats sure to morphine selectively elevates expression of GluR1 learn to associate the rewarding effects of a drug with a in the VTA (40). Relative levels of GluR1 and GluR2 distinctive environment. Rats given HSV-GluR1 into the expression in the dopamine neuron-rich VTA are important rostral (anterior) portion VTA spent more time in mor- because the subunit composition of AMPA receptors con- phine-associated environments than did control rats, indi- 258 Neuropsychopharmacology: The Fifth Generation of Progress Exposure to cocaine and other drugs of abuse causes the rapid and transient expression of the immediate-early gene c-fos in the striatum (including the NAc) (48,49). Repeated drug exposure decreases expression of the transient forms of c-fos, but increases expression of a more stable and long- lasting form of the transcription factor, FosB (50,51). The accumulation and sustained transcriptional activity of FosB in the NAc could mediate long-lasting neural and behavioral adaptations that accompany repeated drug expo- sure (37). Consistent with this notion, inducible transgenic mice that express FosB spontaneously (i. Simplified schematic of putative reward circuitry; seeref. Treatments thatincreaseexcita- drug treatment) in the NAc during adulthood have in- tion in the ventral tegmental area (VTA)(A)are rewarding, pre- creased sensitivity to the locomotor-stimulating and reward- sumably because they promote the inhibitory actions of dopa- ing effects of cocaine (46). The proximal cause of the in- mine (a D2-like receptors)in the nucleus accumbens (NAc)(B). Inhibition of NAc GABAergic output neurons, in turn, decrease crease in drug sensitivity is presumably not increased inhibitory influences on reward processes in other areas of brain expression of FosB per se, but rather increased expression reward circuitry (C), including the ventral pallidum (VP) and pe- of a target gene (or genes) whose transcription is regulated duncular pontine nucleus (PPN)(63). Elevations in GluR1 expres- sion in the VTA (A)increase drug reward, presumably because by this factor. The FosB-overexpressing mice also had the accompanying changes in Ca2 flux increase the excitability large increases in GluR2 expression in the NAc, implicating and/or neuronal function of VTA dopaminergic neurons (as in ref. Conversely, elevations in GluR1 in the NAc decrease drug reward (B), presumably because the accompanying changes in ity. To examine whether elevated GluR2 expression in the Ca2 flux increase the excitability of NAc GABAergic neurons that NAc was sufficient to cause increases in sensitivity to the normally inhibit reward processes in distal regions (C). This treatment dramatically increased sensitivity to the rewarding effects of cocaine, mimicking the effects of increased expression of FosB. Since prior Together, these findings provide strong evidence that the treatment with morphine intensifies its rewarding actions increase in cocaine sensitivity seen in FosB transgenic mice in the place-conditioning paradigm (33), these data suggest is attributable, at least in part, to elevated expression of that the behavioral consequences of morphine preexposure GluR2 in the NAc. Rats given mi- in motivational states can result from altered expression of croinjections of HSV-GluR1 into the NAc spent dramati- a single, localized gene product. Drug-related increases in cally less time than control rats in the cocaine-associated GluR1 expression in the VTA, a region known to be in- environments, suggesting that elevated expression of this volved in the induction of sensitization (42,44), may them- AMPA receptor subunit in this region increases sensitivity selves be sufficient to explain sensitization (13,41), or they 2 to the aversive effects of the drug. Additionally, some rats may lead to Ca -dependent adaptations (45) that also con- were tested after intra-NAc microinjections of HSV- tribute to changes in drug sensitivity (Fig. This form of studies have added strength to the hypothesized association GluR2 lacks the final transcriptional edit (Q N R) that between the VTA and sensitization, and identified biobe- 2 produces the motif that blocks Ca flux (38,39). Use of havioral relevance for the drug-induced regulation of the this construct showed that the ability of GluR2 to increase GluR1 protein in the VTA. First, GluR2 is a target gene of FosB, a stable Ca2 flux in the NAc might influence drug reward, consid- and long-lasting variant of the fos family of transcription ering the role of Ca2 in cellular functions including mem- factors that is regulated in the Nac by drugs of abuse (46). Certainly, cocaine-induced sensitized rats during long-term drug withdrawal (47). Studies with FosB (46) sug- Dose-response analyses revealed that microinjections of gest that these electrophysiologic adaptations are associated HSV-mCREB and HSV-CREB in the NAc were produc- with increases in the rewarding efficacy of cocaine, because ing, respectively, approximately parallel leftward (more re- elevations in GluR2 expression (which would be expected to warding) and rightward (less rewarding) shifts in the effects minimize Ca2 flux and/or neuronal excitability) increase of cocaine. At a high dose of cocaine, there were no differ- cocaine reward, whereas elevations in GluR1 (which would ences in the preferences for the drug-associated environment be expected to increase Ca2 flux and/or neuronal excitabil- between rats given HSV-mCREB and those given vehicle, ity) decrease (or oppose) cocaine reward. Treatment with high doses of cocaine established place NAc has important consequences on motivated behaviors preferences in some rats given HSV-CREB, suggesting that (Fig. Moreover, they suggest that altered GluR1 the aversive consequences of increased levels of CREB in expression in this region seen during long-term (3-week) the NAc can be counteracted by more drug. Re- expression in the NAc increases local dynorphin function. To determine if dy- norphin is involved in the cocaine aversion caused by HSV- CREB, brain receptors for dynorphin were blocked with CREB in the NAc the long-lasting receptor antagonist norBNI. Treatment Chronic cocaine exposure increases 3′,5′-cyclic adenosine with norBNI [intracerebroventricular (ICV)] before cocaine monophosphate (cAMP) formation and protein kinase A place conditioning blocked the aversive effects associated (PKA) activity in the NAc (37). Direct stimulation of PKA with cocaine in animals given HSV-CREB into the NAc, in the NAc counteracts the rewarding properties of cocaine but not in rats given microinjections of vehicle or HSV- (56), suggesting that drug-induced up-regulation of the mCREB. The fact that only the aversive properties of co- cAMP system is a neural mechanism of drug tolerance. In- caine are altered significantly by nor-Binaltorphimine (nor- creased PKA activity leads to increased CREB phosphoryla- BNI) suggests that microinjections of HSV-CREB into the tion, which activates CREB-mediated gene transcription NAc enhance the aversive aspects of cocaine via increased and could be an important step in producing long-lasting stimulation of opioid receptors by dynorphin. To determine the functional role of These results suggest that drug-induced increases in CREB and its transcriptional consequences in the NAc, its CREB activity (62) is a homeostatic change that opposes expression in this region was increased directly by microin- drug reward. Mimicking increases in CREB activity by in- jecting HSV-CREB (57). In other rats, a dominant negative creasing levels with HSV-CREB or by stimulating PKA- mutant CREB (mCREB) was overexpressed, which is tran- induced phosphorylation (56) decreases the rewarding ef- scriptionally inactive and competes with endogenous CREB fects of cocaine. Moreover, these data implicate opioid for cAMP response element binding sites (CREs) (58).

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