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By C. Taklar. McMurry University.

We observed no diagnosis-related differ- hormone by more than 10% cheap plaquenil 200mg mastercard, the cycle with the lower levels ences in plasma levels purchase 200mg plaquenil otc, areas under the curve, or patterns of allopregnanolone and higher levels of estradiol, pregna- of hormone secretion for estradiol, progesterone, follicle- nolone, and pregnenolone sulfate was accompanied by more stimulating hormone (FSH), or luteinizing hormone (LH) severe symptoms. In sum, then, no consistent or convincing evidence is (170) in a comparison of patients with high and low degrees available that PMS is characterized by abnormal circulating of cyclic mood change. Results of studies of androgen levels have been one is never certain that the response seen is causally related similarly inconsistent, demonstrating both normal and de- to the pharmacologic (contrasted with the nonspecific) creased testosterone levels (174–176) and elevated and de- properties of the intervention employed. Therefore, we at- creased free testosterone levels (175,176). We administered a proges- tions central to these speculations include the following: (a) terone receptor blocker (RU 486) with or without human the GABA receptor (the presumed mediator of anxiolysis) chorionic gonadotropin (hCG) to women with PMS during is positively modulated by the 5- and 5- reduced metabo- the early luteal to midluteal phase. Within 2 days of admin- lites of progesterone (allopregnanolone and pregnanolone, istration, RU 486 caused menses (by blocking the endome- respectively) (25); (b) withdrawal of progesterone in rats trial progesterone receptors) and luteolysis and advanced produces anxiety and insensitivity to benzodiazepines sec- the onset of the follicular phase of the next cycle. Addition ondary to withdrawal of allopregnanolone, with consequent of hCG does not alter the RU 486-induced menses but induction of GABAA 4 subunit levels and inhibition of 'rescues' or preserves the corpus luteum and permits a lu- GABA currents (177,178); (c) decreased plasma allopregna- teal phase of normal length. Consequently, after women nolone levels are seen in major depressive disorder and in experienced an RU 486-induced menses, they did not know depression associated with alcohol withdrawal, with in- whether they were in the follicular phase of the next cycle creased levels seen in plasma and cerebrospinal fluid follow- (RU 486 alone) or in the preserved luteal phase of the first ing successful antidepressant treatment (179–182); (d) allo- cycle (RU 486 plus hCG). Women in both groups experi- pregnanolone has anxiolytic effects in several animal models enced typical PMS symptoms despite the fact that the of anxiety (183–185) and may be involved in the stress women receiving RU 486 were now symptomatic in the response (186); (e) antidepressants may promote the reduc- context of an experimentally advanced follicular phase. This suggested two possibilities: mood velocity and sedation in the luteal phase in comparison with symptoms in women with PMS were entrained to the men- controls (188) (although the reported differences seem at- strual cycle but not caused by it, or mood symptoms might tributable to a saccadic eye velocity response to vehicle in be triggered in the luteal phase by reproductive endocrine those with PMS and a blunted sedation response in the events occurring earlier in the menstrual cycle, a possibility follicular phase in controls); (g) patients with severe PMS that was examined in a second study. Although one investigator observed decreased serum study to 20 women with PMS. Women receiving Lupron, allopregnanolone levels in women with PMS in comparison but not those receiving placebo, demonstrated a significant with controls on menstrual cycle day 26 (190), other studies decrease in symptom severity and cyclicity, consistent with Chapter 80: Hormonal and Gender Influences on Mood Regulation 1171 several earlier demonstrations of the efficacy in PMS of gonadal steroids and a consequent Lupron-induced hypo- medical or surgical oophorectomy (197,198). This protocol was performed in two groups: cycle, therefore, appears to be necessary for the expression euthymic women with a history of PPD occurring no more of PMS (199). In the first 2 weeks that when removed resulted in the elimination of PMS, we following withdrawal, the women with a history of PPD added back estradiol and progesterone separately to women experienced a significant increase in measures of depression who continued to take Lupron and for whom Lupron alone relative to baseline, with several subjects experiencing an successfully eliminated symptoms of PMS. Both estradiol increase in symptoms during the last few weeks of addback. Symptoms were precipitated within 7 to ing a history of PPD. Both the levels of hormones achieved 10 days and largely remitted by the end of the 4-week phase and the change from peak to withdrawal-induced hypogo- of addback. It does appear, therefore, that gonadal steroids nadism were comparable in the two groups. It appears, can trigger symptoms of PMS, an observation that at first therefore, that like women with PMS, women with a history glance appears discordant with the lack of differences in of PPD experience mood state destabilization in association gonadal steroid levels between women with PMS and con- with changes in levels of gonadal steroids that are without trols. The reconciliation of these observations is found in effect on mood in women lacking a history of PPD. The the second part of the aforementioned study, in which a hormonal changes can trigger the mood state change, but comparison group of women with confirmed absence of only in a context of increased susceptibility to affective dys- PMS received the same protocol of Lupron and hormone regulation. The control women showed no perturbation of mood during Lupron-induced hypogonadism or during Context hormone addback with either progesterone or estradiol, de- spite achieving hormone levels comparable with those seen The differential sensitivity to gonadal steroids seen in in the women with PMS. Women with PMS, therefore, are women with a history of PMS or PPD emphasizes that the differentially sensitive to gonadal steroids such that they response to a biological signal cannot be inferred absent an experience mood destabilization with levels or changes in understanding of the context in which the signal occurs. Gonadal steroids, then, ronments, prior experience, past history of exposure to the are necessary but not sufficient for PMS. With the imminent mapping PMS, but only in women, who, for undetermined reasons, of the human genome, this last contextual determinant be- are otherwise vulnerable to experience mood state destabili- comes of great practical interest as a potential explanation zation (199). In other words, PMS represents an abnormal for the differential response to steroids. Data already exist response to normal hormone levels. Similarly, strain/genetic (and task-dependent) differ- PMS. This literature, however, may be similarly distilled; ences in behavioral sensitivity to allopregnanolone were ob- the evidence for a reproductive hormone abnormality in served by Finn et al. Nonetheless, demonstrated not only intraperson stability of baseline cor- it is difficult to regard as irrelevant the enormous hormonal tisol and feedback sensitivity (to dexamethasone), which excursions occurring during the puerperium (with precipi- suggests a genetic influence (209), but also a higher sensitiv- tous drops of estradiol and progesterone from levels of up ity to exogenously administered glucocorticoid (dexametha- to 15,000 pg/mL and 150 ng/mL, respectively, to hypogon- sone) in association with a polymorphism in exon 2 of the adal levels in just 1 to 3 days). Analagous to our observations glucocorticoid receptor. Association studies suggest a pro- with PMS, it is possible that women with and those without gressively increased rate and severity of prostate cancer as PPD differ in sensitivity to puerperal hormone changes, not the number of cytosine–adenine–guanosine (CAG) tri- in the degree to which they occur. To test this hypothesis, nucleotide repeats in exon 1 of the androgen receptor de- we created a scaled-down model of the puerperium in which creases (210). This observation is accompanied by the recent women received high-dose estradiol and progesterone for 2 observation that androgen receptors with decreased CAG months (superimposed on Lupron-induced gonadal repeats demonstrate increased transcriptional efficiency suppression to permit comparability and stability of levels (211). Steroid receptor polymorphisms, then, may alter the achieved), followed by a blinded, precipitous withdrawal of steroid signaling pathway in such a way as to produce or 1172 Neuropsychopharmacology: The Fifth Generation of Progress contribute to a different behavioral/phenotypic response to forts to illuminate the neurobiology of mood and mood a hormone signal. Androgens: biochemistry, physiology, and clinical significance.

For example plaquenil 200 mg on-line, some structural MRI studies have revealed a In contrast buy 200 mg plaquenil otc, parvalbumin-labeled varicosities were not de- reduction in thalamic volume in subjects with schizophrenia creased in layers 2 to superficial 3, suggesting that the reduc- (103–106). In addition, thalamic volume was correlated tion in layers deep 3 and 4 might not be attributable to with prefrontal white matter volume in schizophrenic sub- changes in the axon terminals of the parvalbumin-contain- jects (107), suggesting that a reduction in thalamic volume ing subset of cortical GABA neurons present in cortical was associated with fewer axonal projections to the PFC. Thus, the laminar-specific reduction of Consistent with these observations, postmortem studies have revealed reductions of 17% to 25% in volume and 27% to 40% in total neuron number of the medial dorsal thalamic nucleus (MDN), the principal source of thalamic projections to the PFC (108–110). Interestingly, the avail- able data suggest that these abnormalities exhibit topo- graphic specificity. For example, reduced cell numbers have been reported in the MDN and the anterior thalamic nuclei (which project to the PFC and anterior cingulate cortex), whereas the ventral posterior medial nucleus, a sensory relay nucleus, appears to be unaffected (109,110). In addition, within the MDN, one study indicates that neuron number is significantly decreased in the parvocellular subdivision (which projects principally to the dPFC), but not in the magnocellular subdivision (which projects principally to the ventral PFC) (110). Finally, studies in both subjects with schizophrenia who never received antipsychotic medications (111) and monkeys treated for 1 year with haloperidol (112) suggest that these medications do not account for the reduc- tion in MDN neuron number. However, despite the appar- ent consistency of the published studies, a deficient number of MDN neurons in schizophrenia must still be considered a preliminary finding given the relatively small sample sizes reported to date, and the fact that potential confounds, such FIGURE 53. Schematic diagram summarizing disturbances in as comorbid conditions (e. Catching up Certainly, a reduction in cell number in the MDN could on schizophrenia: natural history and neurobiology. Neuron contribute both to the decrease in synaptic markers in the 2000;28:325–334. Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia 737 parvalbumin varicosities in schizophrenia is consistent with distinctive vertical arrays (termed cartridges) that synapse a decreased number of MDN terminals in the dPFC, al- exclusively on the axon initial segment of pyramidal neurons though a laminar-specific reduction in the axon terminals (126). Interestingly, expression of the mRNA for GABA of local circuit neurons cannot be conclusively excluded. In laminar distribution similar to the neurons with undetect- experimental animals, the elimination of presynaptic axon able GAD67 mRNA expression (127). In addition, the den- terminals leads to a resorption of the postsynaptic dendritic sity of GAT-1 immunoreactive chandelier neuron axon car- spine (117), suggesting that a reduction in MDN projection tridges is decreased in the dPFC of schizophrenic subjects, neurons would be associated with decreased dendritic spine with the reduction most evident in the middle cortical layers density in the dPFC. Thus, given the powerful inhibitory control that this issue both found decreased spine density on the basilar chandelier neurons exert over pyramidal cell output, de- dendrites of PFC layer 3 pyramidal neurons (94,118), with creased excitatory thalamic drive to the PFC may be partially this decrease most marked for pyramidal neurons located compensated for by a reduction in chandelier cell-mediated in deep layer 3 (94), those most likely to be targeted by inhibition at the axon initial segment of layer 3 pyramidal projections from the thalamus. This effect could occur via the local axon collaterals mented, remarkable plasticity of dendritic spines must be of layer 3 pyramidal cells, approximately 50% of which considered when interpreting these findings, these observa- target the dendritic shafts of GABA neurons (79). However, tions are consistent with a reduction in MDN–dPFC con- it is important to note that other causes and consequences nectivity in schizophrenia. However, the presence of more of the observed alterations in chandelier neurons have not modest reductions in spine density on pyramidal neurons been excluded. Although mal thalamocortical projection is paralleled by a disturbance the possible relationship of these findings to a decrease in in the corticothalamic projection. Studies that have exam- MDN inputs is less clear, studies in animals have provided ined PFC neurons in layers 5 and 6, the principal location evidence of denervation atrophy of layer 3 pyramidal cells of corticothalamic projection neurons, have generally not following the loss of other afferent inputs (120). Al- cells are the principal synaptic targets of DA axon terminals though the experimental manipulation of the visual system in layer 6, and DA appears to play a critical role in regulating did not involve a partial reduction in thalamic neuron num- the influence of other inputs on pyramidal cell activity ber, if these findings in the visual cortex can be generalized (130). Thus, a shift in DA neurotransmission in dPFC layer to a deficient number of MDN projections to the dPFC, 6 could reflect a change in the modulation of corticotha- a reduction in GAD67 in the dPFC of schizophrenic subjects lamic feedback in response to abnormal thalamocortical might be expected. GAD67 mRNA and protein levels have been reported to be The significance of these findings depends, in part, on reduced in the dPFC of schizophrenic subjects (26,123, the extent to which they are unique to the diagnosis of 124), observations supported by other evidence of reduced schizophrenia, and not a consequence of other factors asso- GABA neurotransmission in the PFC of schizophrenic sub- ciated with schizophrenia, such as antipsychotic drug treat- jects. Some of these findings have been examined for diag- Finally, the reduction in GAD67 mRNA expression in nostic specificity, whereas others have not. For example, schizophrenia appears to be restricted to a subpopulation the reduction in dendritic spine density on deep layer 3 of PFC GABA neurons (approximately 25% to 30%), espe- pyramidal neurons was not found in subjects with major cially those neurons located in the middle cortical layers depressive disorder (94), and the reduction in density of (124). Consistent with this finding, other studies suggest GAT-1 immunoreactive axon cartridges was not apparent in that the affected subpopulation of GABA neurons includes subjects with nonschizophrenic psychiatric disorders (129). The axon terminals of chandelier cells form Similarly, to the extent to which it has been examined, these 738 Neuropsychopharmacology: The Fifth Generation of Progress findings do not appear to be attributable to the abuse of Distinguishing among these three possibilities for each com- alcohol or other substances, which frequently accompanies ponent of a neural network will be necessary for understand- the diagnosis of schizophrenia, although further studies in ing the pathophysiology of the disease as well as for develop- this area certainly are needed. Globally, phrenia requires several additional types of investigations. For treated for 6 months with a variety of antipsychotic agents example, what patterns of connectivity within the dPFC (131). Similarly, treatment of monkeys for 12 months with link inputs from the MDN to the neurons that provide haloperidol and benztropine at blood levels known to be outputs to the MDN or to other brain regions such as the therapeutic in humans was not associated with a reduction striatum? Second, MDN–dPFC circuitry needs to be fur- in the size or total neuron number of the MDN (112). For exam- 1–labeled axon cartridges has been examined in several ways ple, what are the postsynaptic consequences in pyramidal with interesting results (129). The density of labeled car- neurons of the apparent alterations in GABA neurotrans- tridges was greater in schizophrenic subjects who were on mission in chandelier cells? Third, the direction of the than off antipsychotic medications at the time of death (al- pathophysiological changes in MDN–dPFC circuitry in though both groups showed reduced levels compared to schizophrenia need to be assessed in experimental animal normal controls). For example, can the observations of altered spine animals, the density of GAT-1-positive cartridges was ele- density and decreased GAD67 mRNA expression in the vated in monkeys treated for 1 year with haloperidol. Thus, dPFC be replicated by partial lesions of the MDN in mon- the convergence of these findings suggests both that the keys?

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