By B. Murat. Fayetteville State University.
In summary order provera 2.5 mg, in most studies that assessed tical thickness cheap 5 mg provera, neuronal size decrease, and loss of glial cells depression severity in unipolar subjects and used high-reso- in layers II to IV. In caudal orbitofrontal cortex there were lution MRI techniques (Fig. Reductions in glial and neuronal cells The significance and source of the volume loss has not been throughout all layers as well as reduction in cell size were demonstrated. It is intriguing that a recent postmortem reported in dorsolateral prefrontal cortex. Glial cell loss in study (23) has found glial cell loss in the dentate gyrus the subgenual region of prefrontal cortex has also been re- of the hippocampus as well as in the amygdala in major ported in major depression (27). The prefrontal cortex is particu- with depressed subjects exhibiting an increase in volume in larly important as a target of monoamine projections. Ab- the right amygdala (12), loss of normal asymmetry (13), or normalities in monoamine receptors, transporters, and sec- reduction in the bilateral core nuclei (15). The amygdala is ond messenger systems (28–32) are reported to occur in a difficult structure to measure, because in many areas the major depression. It is also possible that overactivation in 'cortical amygdala' merges with surrounding cortex. Partic- one part of the interconnected LCSPT neuroanatomic cir- ular boundaries selected can vary widely. The orbitomedial prefron- basal ganglia structures in major depression, particularly tal cortex has high concentrations of glucocorticoid recep- late-onset depression (1,4,5,24), as further discussed. One tors, potentially rendering it vulnerable to stress-mediated study has reported negative findings in caudate and puta- damage (see the following). Orthogonal views (coronal, sagittal, and transverse) represent hippocampal and amygdala volumes as they are shown using stereological techniques. Labels for orientation of the hippocampus are included on the sagittal view. These measurements are derived from a cubic subvolume depicted in the last panel. Potential Mechanisms for Volume Loss in between the total amount of time patients have been de- Early-Onset Recurrent Depression pressed and hippocampal volume (9,11) found in some studies but not all (12) supports recurrent depressive epi- It has been proposed that hypothalamic–pituitary–adrenal sodes having a causal relationship. Further, a study by Lu- (HPA) axis dysfunction can produce repeated episodes of pien and colleagues (35) demonstrated a correlation be- hypercortisolemia. Currently volume studies do not rou- tween higher cortisol levels measured longitudinally and tinely include measures of cortisol, nor can they ascertain greater hippocampal volume loss in normal human aging. However, several differ- Glial cell loss either directly or indirectly is another po- ent mechanisms could explain volume loss including tential mechanism for producing volume loss. Gray matter neuronal loss through exposure to repeated episodes of atrophy in the prefrontal cortex in an area ventral to the hypercortisolemia, glial cell loss, resulting in increased genu of the corpus callosum (3), an area associated in post- vulnerability to glutamate neurotoxicity, stress-induced re- mortem studies with glial cell loss (27) has been reported. A mechanism that could account for of depressed subjects in two different areas of prefrontal hippocampal, amygdala, and prefrontal cortex volume loss, cortex (26). In addition, glial cell loss has been reported in areas that have high concentrations of GC receptors is GC- postmortem studies of major depression in the amygdala mediated neurotoxicity (33), with repeated hypercortiso- and hippocampus (23). Early Through excitatory connections between the amygdala life stress may produce a permanent hypersensitivity to stress and hippocampus (36) it is possible that damage in one (34), with the production of ongoing HPA axis dysregula- structure could produce damage in the connected structure. In the Similarly, interconnections between prefrontal cortex and case of hippocampal volume loss, the inverse correlations hippocampus (37) could produce excitotoxic damage. Glial Chapter 74: Imaging of Affective Disorders 1069 cells sequester glutamate, maintain metabolic and ionic ho- LCSPT circuit. Kumar and colleagues (60), for example, meostasis, and produce trophic factors, including brain de- have found loss in prefrontal lobe volume in late-onset rived neurotrophic factor (BDNF) (38,39). Therefore, loss depression in the absence of generalized atrophy, suggesting of glial cells could increase vulnerability to neurotoxic dam- that as in early-onset depression some subjects with late- age, supporting the idea that glutamate neurotoxicity may onset depression may also have focal volume loss. It is not be involved in the volume loss in the limbic–cortical–stria- known whether this focal volume loss involves the same tal–pallidal–thalamic (LCSPT) circuit. A recently developed concept—stress-induced inhibition A well replicated finding in elderly subject groups with of neurogenesis (40)—may also explain depression-related depression is the increased numbers of hyperintensities seen volume loss, although high rates of baseline neurogenesis on T2-weighted scans (T2H) (51,61–65). Some studies would be needed to produce atrophy of the scale required that included younger subjects with depression have also by volume loss in depression. Psychosocial stress was shown found increased T2H (2,66), although negative findings to suppress neurogenesis in the tree shrew (40). Likewise, have also been reported with younger groups (5,67). The corticosterone treatment in adult rats produced suppression underlying causes of T2H are unknown, and indeed, it is of neurogenesis, which was reversed by removal of the adre- important to note that T2H also occur at rates of up to nal gland (41). More recent findings (42) indicate that neu- 60% in healthy elderly (68), in whom their significance is rogenesis may occur in the frontal cortex as well as the unknown (69).
This DA hypothesis of schizophrenia is substantiated by the observation that positive symptoms of schizophrenia abate when DA receptor blocking drugs cheap 10mg provera visa, IMAGING STUDIES such as neuroleptics purchase provera 5mg without a prescription, occupy the postsynaptic DA receptors. In 1988, Farde and colleagues demonstrated the concept Measures of Substrate Metabolism that effective neuroleptic dosages for schizophrenia corre- Regional cerebral blood flow (rCBF) is a well-established spond to 80% to 90% occupancy of DA type-2 receptors surrogate marker widely used for both clinical diagnostic (D2Rs) by the drug (95). Thus, occupancy of 80% to 90% procedures and new drug development. Furthermore, clinically 123 99m equivalent doses of neuroleptics are estimated by comparing with radioligands labeled with Ior Tc; for example, [123I]iodoamphetamine, [99mTc]ethylenediylbis-L-cystein proportions of receptors occupied by various psychothera- diethylester (ECD), and [99mTc]hexamethylpropylenea- peutic agents (93,94). Several examples of this approach are mine oxime (HMPAO). Although repeated assessments given in the following. Furthermore, Tc is relatively available in practically every hospital with a radiology or The occupancy of D2Rs by neuroleptics has been extensively nuclear medicine department worldwide; therefore, SPECT evaluated by PET and SPECT. Historically, this began with procedures can be performed widely on a clinical basis. On the other tients with schizophrenia utilizing [11C]raclopride (95,96), hand, doses of greater than 30 mg/day olanzapine are associ- spiperone derivatives, including [11C]N-methyl-spiperone ated with greater than 80% D2R occupancy as well as dyski- (NMSP) (97), [18F], or 76Br (98). This research has estab- nesias and prolactin elevation. Olanzapine exhibits 59% to lished that a therapeutic response corresponds to occupancy 63% D2Rs occupancy after single 10-mg dosing. Further- of 65% to 90% of the D2Rs by the drug; however, occu- more, olanzapine shows a greater (68% to 84%) occupancy pancy of greater than 90% of the D2Rs is not associated of D2Rs than clozapine (20% to 67%) after 10 to 20 mg with a greater therapeutic effect. Therefore, occupancy of daily dosing in patients (60). These characteristics suggest 65% to 90% of D2R2 is correlated with a therapeutic dose that olanzapine differs from clozapine. Additionally, quetia- of typical neuroleptics as well as other clinical manifestations pine is characterized by abatement of psychotic symptoms of pharmacologic efficacy. For example, patients with acute in association with a transient increase in D R occupancy 2 extrapyramidal side effects were found to have higher DA (62). Wolkin and colleagues (1989) found a comparable occupancy of haloperidol in responders versus nonrespond- Receptor Occupancy as a Surrogate ers indicating that treatment nonresponse is not a function Marker of Clinical Efficacy? Kapur and colleagues recently confirmed that the D2 One of the most important questions about D2R and occupancy is an important mediator of beneficial and ad- 5HT2A receptor occupancy is the prediction of doses yield- verse effects (101) in a study of first episode schizophrenia ing clinical efficacy. D2R occupancy predicted the clinical and haloperidol. Although the patients showed a wide range improvement of 22 first episode schizophrenic patients ran- of D2R occupancy (38% to 87%), the degree of D2R occu- domly assigned to 1 or 2. Thus, D2R occupancy is related to the clinical and extrapyramidal side effects. Also, Daskalakis and associ- response to antipsychotics (99,109,110). D R occupancy occur at very low haloperidol doses (111). Kapur Receptor Occupancy by Atypical and colleagues (1997) also showed D2 occupancies between Neuroleptics of 53% to 88% for haloperidol doses of 1 to 5 mg. Thus, the conventional therapeutic practice of haloperidol doses of D2R occupancy has been determined for humans treated greater than 10 mg/day is too high for many schizophrenic with atypical neuroleptics. For example, receptors of people patients because there is no increase in beneficial effect, treated with clozapine exhibit low (20% to 65%) D2R occu- pancy and high serotonin type 2A (5HT ) receptor occu- whereas the riskof adverse effects increases in proportion to 2A pancy (94,99,103). In studies directly comparing clozapine the dose (112). Nevertheless, Volavka and colleagues (113) (450 mg/day) and haloperidol (5 mg/day), there was a rever- (1995) showed that antipsychotic efficacy of haloperidol sal of receptor occupancy producing high D blockade with increases with plasma levels up to 12 ng/mL, plasma levels 2 haloperidol and high 5HT blockade with clozapine. In- that would predict almost completely saturated D2 receptors 2A deed PET imaging has been an important approach for according to the Kapur and associates (1997) data (112). Risperidone has been shown to block40% to 60% with haloperidol plasma levels up to 15 ng/mL and almost of D receptors at only 1 mg (104) with even higher 5HT complete D2R occupancy saturation with haloperidol 2 2A receptor occupancy. Indeed, in patients with schizophrenia, plasma levels above 15 to 20 ng/mL (100). These differences oral dose of 6 mg risperidone, 75% to 80% of D2Rs and could be explained partly by the differences in radioligands 78% to 88% of 5HT2Areceptors are occupied (106). Further research by other investi- levels of risperidone correlate with D2R occupancy (107). The probability of acute dyskinesias is directly pro- of olanzapine (10 to 20 mg/kg) produce 71% to 80% D2R portional to the proportion of D2Rs occupied by the drug occupancy. These doses usually do not result in the adverse (99,110,115).
Acyclovir 200 mg orally fve times a day for 7–10 days Most persons with HSV-1 antibody have oral HSV infection OR acquired during childhood discount provera 2.5 mg without a prescription, which might be asymptomatic cheap provera 10mg overnight delivery. Famciclovir 250 mg orally three times a day for 7–10 days However, acquisition of genital HSV-1 appears to be increas- OR ing, and genital HSV-1 also can be asymptomatic (147–149). Valacyclovir 1 g orally twice a day for 7–10 days Lack of symptoms in an HSV-1 seropositive person does not *Treatment can be extended if healing is incomplete after 10 days of therapy. Established HSV-2 Infection Type-specifc HSV serologic assays might be useful in the Almost all persons with symptomatic frst-episode genital following scenarios: 1) recurrent genital symptoms or atypical HSV-2 infection subsequently experience recurrent episodes of symptoms with negative HSV cultures; 2) a clinical diagnosis of genital lesions; recurrences are less frequent after initial genital genital herpes without laboratory confrmation; or 3) a partner HSV-1 infection. Intermittent asymptomatic shedding occurs with genital herpes. HSV serologic testing should be considered in persons with genital HSV-2 infection, even in those with for persons presenting for an STD evaluation (especially for longstanding or clinically silent infection. Antiviral therapy for those persons with multiple sex partners), persons with HIV recurrent genital herpes can be administered either as suppres- infection, and MSM at increased risk for HIV acquisition. Many persons might prefer symptomatic patients and is the mainstay of management. Suppressive Therapy for Recurrent Genital Herpes Systemic antiviral drugs can partially control the signs and Suppressive therapy reduces the frequency of genital herpes symptoms of herpes episodes when used to treat frst clinical recurrences by 70%–80% in patients who have frequent recur- and recurrent episodes, or when used as daily suppressive rences (166–169); many persons receiving such therapy report therapy. However, these drugs neither eradicate latent virus nor having experienced no symptomatic outbreaks. Treatment also afect the risk, frequency, or severity of recurrences after the is efective in patients with less frequent recurrences. Randomized trials have indicated that and efcacy have been documented among patients receiving three antiviral medications provide clinical beneft for genital daily therapy with acyclovir for as long as 6 years and with herpes: acyclovir, valacyclovir, and famciclovir (160–168). Quality of life Valacyclovir is the valine ester of acyclovir and has enhanced is improved in many patients with frequent recurrences who absorption after oral administration. Famciclovir also has high receive suppressive therapy rather than episodic treatment. Topical therapy with antiviral drugs ofers The frequency of recurrent genital herpes outbreaks minimal clinical beneft, and its use is discouraged. Terefore, Newly acquired genital herpes can cause a prolonged periodically during suppressive treatment (e. Even persons with frst-episode herpes who have the patient. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use Severe Disease and avoidance of sexual activity during recurrences. Suppressive Intravenous (IV) acyclovir therapy should be provided for antiviral therapy also is likely to reduce transmission when patients who have severe HSV disease or complications that used by persons who have multiple partners (including MSM) necessitate hospitalization (e. Te recommended regimen is acyclovir 5–10 mg/ Recommended Regimens kg IV every 8 hours for 2–7 days or until clinical improvement Acyclovir 400 mg orally twice a day is observed, followed by oral antiviral therapy to complete at OR least 10 days of total therapy. Acyclovir dose adjustment is Famiciclovir 250 mg orally twice a day recommended for impaired renal function. OR Counseling Valacyclovir 500 mg orally once a day* OR Counseling of infected persons and their sex partners is Valacyclovir 1 g orally once a day critical to the management of genital herpes. Te goals of counseling include 1) helping patients cope with the infection * Valacyclovir 500 mg once a day might be less efective than other vala- cyclovir or acyclovir dosing regimens in patients who have very frequent and 2) preventing sexual and perinatal transmission (174,175). Although initial counseling can be provided at the frst visit, many patients beneft from learning about the chronic aspects Acyclovir, famciclovir, and valacyclovir appear equally efec- of the disease after the acute illness subsides. Multiple resources, tive for episodic treatment of genital herpes, but famciclovir including websites (http://www. Ease of administration and cost also are clinicians who become involved in counseling. Although the psychological efect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecog- Episodic Therapy for Recurrent Genital Herpes nized genital herpes appears minimal and transient (176), some Efective episodic treatment of recurrent herpes requires HSV-infected persons might express anxiety concerning genital initiation of therapy within 1 day of lesion onset or during the herpes that does not refect the actual clinical severity of their prodrome that precedes some outbreaks. Te patient should disease; the psychological efect of HSV infection frequently be provided with a supply of drug or a prescription for the is substantial. Common concerns regarding genital herpes medication with instructions to initiate treatment immediately include the severity of initial clinical manifestations, recurrent when symptoms begin. Te misconception that HSV causes cancer should be dispelled. Acyclovir 400 mg orally three times a day for 5 days Te following recommendations apply to counseling of OR persons with genital HSV infection: Acyclovir 800 mg orally twice a day for 5 days • Persons who have genital herpes should be educated OR concerning the natural history of the disease, with Acyclovir 800 mg orally three times a day for 2 days emphasis on the potential for recurrent episodes, asymp- OR tomatic viral shedding, and the attendant risks of sexual Famciclovir 125 mg orally twice daily for 5 days transmission. OR • Persons experiencing a frst episode of genital herpes Famciclovir 1000 mg orally twice daily for 1 day should be advised that suppressive therapy is available and OR Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days efective in preventing symptomatic recurrent episodes OR Vol. Patients should • All persons with genital HSV infection should be encour- be informed that suppressive antiviral therapy does not aged to inform their current sex partners that they have reduce the increased risk for HIV acquisition associated genital herpes and to inform future partners before with HSV-2 infection (177,178). Management of Sex Partners • Sexual transmission of HSV can occur during asymp- tomatic periods. Asymptomatic viral shedding is more Te sex partners of patients who have genital herpes can frequent in genital HSV-2 infection than genital HSV-1 beneft from evaluation and counseling.