By H. Volkar. Ripon College.
Ziprasidone treatment patient with a tic and a depression discount clarinex 5 mg with amex. J Am Acad in cerebral glucose metabolic rate after successful behavior modi- Child Adolesc Psychiatry 1995;34:1140–1146 discount clarinex 5mg on-line. Paroxetine treatment of episodic rages Psychiatry 1996;53:109–113. J Neurosci 1999;19: improvement with pergolide in a randomized, double-blind, 5044–5053. D1 receptor trafficking and delivery in striatal neurons in dopa- 128. Proc Natl Acad Sci USA 2000; term potentiation of neuroleptics with transdermal nicotine in 15;97:1879–1884. A measure of striatal function predicts 35:1631–1636. Cannabis in sive-compulsive disorder and tic disorders in childhood. Toward a neuroanatomy of obsessive-compulsive dis- drome. YOUNG Over the past several decades, various animal models have (1). Moreover, there is little understanding of the biological been used extensively to characterize the activity of various factors underlying pathologic aggression in humans, so it is drugs and drug classes, and from these results, to anticipate difficult to formulate a rational research program. However, the value of animal sion of the characteristics of pathologic aggression is needed models that purport to predict the potential therapeutic for the development of animal models of this disorder. Thus, two roads are emerging: one studying the a basis for predicting responses in humans are those that fundamental causes of aggression and dysfunctions, the are homologous, that is, those in which both the condition other studying the modification of behavior by pharmaco- being observed and its origin are similar to those in humans. Examples may include suppression of bacterial infections by antibiotics or hypertension in monkeys. Few, if any, models of psychiatric dysfunction, however, can be consid- ered homologous, if only because the origin of the psychiat- CLASSIFICATION OF AGGRESSION ric condition is unknown. In the absence of homologous models, isomorphic Despite many attempts, a generally acceptable definition models (in which the observed condition is apparently simi- of aggression, particularly as it applies to individual human lar even if the cause is not) may be fairly rapidly accepted. This failure arises in part An example may be amphetamine-induced psychosis as a from the following: (a) the varying theoretic or philosophic putative model for schizophrenia. Finally, there are many persuasions of those offering definitions; (b) the inherent models in which neither the condition nor the origin can difficulty in capturing the essence of a multifaceted behav- be clearly linked with the disease being modeled, but in ior; and (c) the attempt to include within the definitions which there is empiric evidence of some predictive validity elements of motivation that cannot readily be observed or either for the disease or some aspect of its therapy. However, a generally acceptable working definition chopharmacology, the evidence is usually the discovery that from the perspective of animal research is somewhat easier agents with known therapeutic activity in humans consis- to obtain and could read 'any overt behavior that produces tently correlate with some response in an animal model. It aversive or noxious stimuli or harm to another organism. Here researchers run into trouble because the the stimuli that elicit the behavior and from the overt behav- essential features of many disorders in humans are unclear. Different types of animal aggression can be distin- Pathologic aggression is not a DSM-IV disorder for which guished based on the environmental situations eliciting criteria are set for determining what is normal or abnormal those behaviors. Moyer was the first to describe such a classi- fication (2), later followed by alternative classifications (3). All these classifications have their own inherent prob- Berend Olivier: Department of Psychopharmacology, Faculty of Phar- lems, such as to linkthe aggression to connotations of offen- macy, Utrecht University, Utrecht, Netherlands; Department of Psychiatry, sive and defensive aggression, using the ethology-derived Yale University School of Medicine, New Haven, Connecticut. Young: Departments of Psychiatry and Behavioral Sciences, term agonistic behavior as an important distinction to classify Emory University School of Medicine, Atlanta, Georgia. In ad- models is universal (4), is functional, and seems to be paral- dition, several models providing insights into novel neural leled in brain mechanisms involved in the behavior. Offen- mechanisms of aggression as well as interactions between sive behavior is characterized by the initiative of the aggressor genes and early environment are presented. Moreover, new and intended damage to the opponent (5,6). In contrast, data are introduced regarding mutant mice showing pheno- defensive behavior lacks active approach (initiative), and the typic changes in aggression, such as the serotonin (5-HT1B) defensive animal (6) inflicts no intentional damage. The informa- tory aggression represents separate classification of aggression tion coming from these new genetic models can be of help that seems to be primarily driven by appetite mechanisms in understanding possible causes of human pathologic ag- and apparently has a distinct brain system involved. Neither in humans nor in animals is agonistic behavior pathologic. In the frameworkof evolutionary theory, these Isolation-Induced Offensive Behavior behaviors are understood to encourage survival of the fittest, to disperse populations, to aid adaptation to threatening A manipulation often used to induce aggression is isolation environments, and generally to improve the probability of of male animals, typically mice, for several weeks. In humans, agonistic behav- such isolated animals, on encountering another male, will ior is considered acceptable or not based on certain predeter- reliably exhibit attackbehavior (7). Although 'aggressive' behavior is associated aggressive behavior is strain dependent (8).
Goligorsky W ilfred Lieberthal cute renal failure (ARF) is a syndrome characterized by an abrupt and reversible kidney dysfunction purchase clarinex 5 mg online. The spectrum of Ainciting factors is broad: from ischemic and nephrotoxic agents to a variety of endotoxemic states and syndrome of multiple organ failure cheap 5 mg clarinex otc. The pathophysiology of ARF includes vascular, glomerular and tubular dysfunction which, depending on the actual offending stimulus, vary in the severity and time of appearance. H emodynamic compromise prevails in cases when noxious stimuli are related to hypotension and septicemia, leading to renal hypoperfusion with sec- ondary tubular changes (described in Chapter 13). Nephrotoxic offenders usually result in primary tubular epithelial cell injury, though endothelial cell dysfunction can also occur, leading to the eventual cessation of glomerular filtration. This latter effect is a con- sequence of the combined action of tubular obstruction and activation of tubuloglomerular feedback mechanism. In the following pages we shall review the existing concepts on the phenomenology of ARF including the mechanisms of decreased renal perfusion and failure of glomerular filtration, vasoconstriction of renal arterioles, how formed elements gain access to the renal parenchyma, and what the sequelae are of such an invasion by primed leukocytes. The severe reduction in glom erular GFR by causing tubular obstruction and by allow- filtration rate (GFR) associated with established ing backleak of glom erular filtrate. Abnorm alities in ischem ic or toxic renal injury is due to the com - tubular reabsorption of solute m ay contribute to bined effects of alterations in intrarenal hem ody- intrarenal vasoconstriction by activating the tubu- nam ics and tubular injury. The hem odynam ic alter- loglom erular (TG) feedback system. GPF— glom eru- ations associated with ARF include afferent arterio- lar plasm aflow; P— glom erular pressure; Kf— lar constriction and m esangial contraction, both of glom erular ultrafiltration coefficient. FIGURE 14-2 Ischemic or toxic injury Vasoactive horm ones that m ay be responsible for the hem odynam ic abnorm alities in acute to the kidney tubule necrosis (ATN ). A persistent reduction in renal blood flow has been dem onstrated in both anim al m odels of acute renal failure (ARF) and in hum ans with ATN. The m echa- Increase in Deficiency of nism s responsible for the hem odynam ic alterations in ARF involve an increase in the vasoconstrictors vasodilators intrarenal activity of vasoconstrictors and a deficiency of im portant vasodilators. A num - ber of vasoconstrictors have been im plicated in the reduction in renal blood flow in ARF. Angiotensin II The im portance of individual vasoconstrictor horm ones in ARF probably varies to som e Endothelin extent with the cause of the renal injury. A deficiency of vasodilators such as endothelium - Thromboxane derived nitric oxide (EDN O ) and/or prostaglandin I2 (PGI2) also contributes to the renal Adenosine PGI2 EDNO hypoperfusion associated with ARF. This im balance in intrarenal vasoactive horm ones Leukotrienes Platelet-activating favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubu- factor lar injury and protracting the course of ARF. Imbalance in vasoactive hormones causing persistent intrarenal vasoconstriction Persistent medullary hypoxia Pathophysiology of Ischemic Acute Renal Failure 14. This schem atic diagram dem onstrates the anatom ic relationship between glom erular capillary loops and the m esangium. The Glomerular capillary endothelial cells m esangium is surrounded by capillary loops. M esangial cells (M ) M are specialized pericytes with contractile elem ents that can respond to vasoactive horm ones. Contraction of m esangium can close and Glomerular epithelial prevent perfusion of anatom ically associated glom erular capillary M cells loops. This decreases the surface area available for glom erular fil- tration and reduces the glom erular ultrafiltration coefficient. M esangial cell contraction Angiotensin II Endothelin–1 Thromboxane M esangial cell relaxation Sympathetic nerves Prostacyclin EDNO FIGURE 14-4 A, The topography of juxtaglom erular apparatus (JGA), including m acula densa cells (M D), extraglom erular m esangial cells (EM C), Afferent arteriole and afferent arteriolar sm ooth m uscle cells (SM C). Insets schem ati- Periportal cally illustrate, B, the structure of JGA; C, the flow of inform ation cell within the JGA; and D, the putative m essengers of tubuloglom eru- lar feedback responses. AA— afferent arteriole; PPC— peripolar cell; Extraglomerular EA— efferent arteriole; GM C— glom erular m esangial cells. Renin is released from specialized contraction reduce SNGFR back toward cells of JGA and the intrarenal renin m al kidney, the TG feedback m echanism is control levels. Step 1: An increase in SN GFR increases the am ount of sodium chloride (N aCl) delivered to the juxtaglom erular apparatus (JGA) of the nephron. Step 2: The resultant change in the com position of the filtrate is sensed by the m acula densa cells and initiates activation of the JGA. Step 3: The JGA releases renin, which results in the local and system ic generation of angiotensin II. The composition of filtrate induces vasocontriction of the glom erular 1. SNGFR increases passing the macula densa is arterioles and contraction of the m esangial causing increase altered and stimulates the JGA.
R63 Persistent invisible haematuria in the absence of proteinuria should be followed up annually with repeat testing for haematuria cheap 5 mg clarinex free shipping, proteinuria/albuminuria purchase 5mg clarinex visa, glomerular filtration rate (GFR) and blood pressure monitoring as long as the haematuria persists. Changes that occur include abnormalities of calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism; together with abnormalities of bone turnover, mineralisation, volume, linear growth, and strength; plus vascular or soft tissue calcification. However, an in-depth discussion of metabolic bone disease in CKD is beyond the scope of this guideline. This section is focussed on the changes that occur early in the course of CKD. The aim is to prevent metabolic bone disease by maintaining the blood levels of calcium and phosphate as close to normal as possible, and preventing the development of established hyperparathyroidism and parathyroid hyperplasia. Central to the prevention of these disturbances is an ability to intervene early, recognising that bone disease in people with kidney disease is often asymptomatic, and symptoms appear only late in its course, long after the opportunity for early intervention has passed. Whilst bone biopsy may be the gold standard for assessment of metabolic bone disease it is neither widely available nor widely used. Biochemical assessment is the mainstay of diagnosis and treatment. In addition to measurements of calcium and phosphate it is essential to obtain a direct index of parathyroid activity by measurement of PTH. Under certain circumstances measurement of vitamin D may also be necessary. When should these parameters be measured and at what frequency should they be repeated? Two reports from the cross-sectional US NHANES III study (N=14,679) examined changes in serum calcium and phosphate324 and 25-hydroxyvitamin D325 by level of renal function. A cross-sectional study compared levels of serum calcium, phosphate, iPTH, and vitamin D amongst stage 3, 4, and 5 CKD. The prevalence of vitamin D deficiency, hyperphosphataemia, and hypocalcaemia was examined in people with stages 3 and 4 CKD. This study also reported the prevalence of abnormal calcium, phosphate, iPTH, and vitamin D with decreasing eGFR. All of these studies were limited by the use of one serum creatinine measurement to estimate renal function. Two of these studies reported the prevalence of hypocalcaemia in a CKD population. Of people with GFR <20 ml/min, 15% had abnormal Ca levels (Ca <2. Three of these studies showed that abnormal phosphate levels were highly prevalent when eGFR was <20 ml/min. Of people with eGFR 20–29 ml/min, 15% had abnormal phosphorus levels (P >1. Of people with GFR <20 ml/min, 40% had abnormal phosphorus levels. One of these studies reported the prevalence of hyperparathyroidism in the CKD population. The prevalence of 1,25-dihydroxyvitamin D deficiency was approximately 15%, 15%, 20%, 30%, 45%, 50%, and 65% in people with eGFR 70–79, 60–69, 50–59, 40–49, 30–39, 20–29, and <20 ml/min/1. The prevalence of deficiency in serum 25-hydroxyvitamin D (<15 ng/ml) 151 Chronic kidney disease remained stable until GFR <30 ml/min/1. The prevalence of serum 25-hydroxyvitamin D deficiency was approximately 15%, 20%, and 25% in people with eGFR 39–30, 29–20, and <20 ml/min/1. CrCl >80 ml/min, N=4347 328 1,814 % Abnormal Ca <10%, GFR 15%, GFR (Ca <2. Although there were statistically significant differences in mean calcium concentrations at different levels of GFR these were unlikely to be clinically significant differences. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum calcium concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD. The GDG noted that although there were statistically significant differences in mean phosphate concentrations at different levels of GFR these values were all within the normal range. Serum phosphate concentrations generally fell within the normal range unless the GFR level was below 20 ml/min/1. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum phosphate concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD. The prevalence of hyperparathyroidism in people with a reduced GFR was higher than in healthy individuals; however, the significance of modestly elevated PTH concentrations was thought unclear and there was no consensus on whether people with concentrations elevated to this extent 154 13 Specific complications of CKD – renal bone disease benefit from treatment. On the basis of the evidence the GDG agreed that there was no requirement to routinely measure serum PTH concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD in the absence of specific indications. Specific indications to measure serum PTH would include unexplained hypercalcaemia and symptoms suggestive of hyperparathyroidism. The prevalence of abnormally low vitamin D concentrations increased once the GFR fell below 45 ml/min/1.
A “reversible” inhibitor of MAO-A (RIMA) is available (moclobemide) buy clarinex 5mg amex. RIMAs have relatively little effect on MAO-B buy clarinex 5mg, they can be displaced by other substances such as tyramine, and their inhibitory effects are lost within hours of the last dose. Moclobemide has a benign side-effect profile and has the advantage of not interfering with sexual function – it has a place in modern therapy. Moclobemide is not available in the USA, which may explain a relative lack of interest in the scientific literature. TRICYCLIC ANTIDEPRESSANTS (TCAs) For decades, the TCAs were the most commonly used antidepressants. They continue to have a place in unresponsive depression. Imipramine (first developed) is the less sedating and is appropriate when the patient is already “slowed-down” by the disorder. Amitriptyline (second developed) is the more sedating and is appropriate when the patient is anxious (agitated) or suffering insomnia. Clomipramine is a more active serotonin reuptake inhibitor than the other TCAs and was found especially effective in OCD. While the SSRIs are now also used in OCD, many experts still regard clomipramine as the most effective drug. Nortriptyline (the N-demethylated metabolite of amitriptyline) has the most benign side-effect profile of the TCAs, and is often used in the elderly. Generally characterized as antidepressants, the SSRIs have multiple uses. SSRI actions are helpful: 1) prefrontal cortex (low mood), 2) basal ganglia (OCD), 3) limbic system (panic and anxiety), and 4) hypothalamus (eating disorders). SSRI actions are unhelpful in 1) mid-brain structures (may cause insomnia), and 2) spinal cord (may cause sexual dysfunction) The SSRIs are the most widely used antidepressants (at present) - fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram and escitalopram. Vortioxetin was recently released in Australia, Canada and the UK. It inhibits the reuptake of serotonin and acts as an agonist or antagonist at various 5-HT receptors. Five to 20 mg daily may lower depression scores, and provide some relapse prevention (Boulenger et al, 2012). Nausea is the most common side-effect, and abrupt discontinuation is well tolerated (McIntyre, 2017). Agomelatine is an agonist of melatonin receptors (MT1 & 2) – and it was proposed that this action had antidepressant effects. There is some evidence of antidepressant action, however, this is now attributed to SSRI effects. It suffers extensive first- pass metabolism - an intranasal administration method has recently been devised which enhances both absolute bioavailability and brain delivery (Fatouh et al, 2017). This compound is not yet available in clinical practice. SELECTIVE NORADRENERGIC REUPTAKE INHIBITOR (NARI) Reboxetine is a selective noradrenergic reuptake inhibitor (NARI). In 2010, the German Institute for Quality and Efficiency in Health Care (IQEHC) published results of a meta-analysis which found that reboxetine was not more effective than placebo. MULTIPLE/DUAL ACTION ANTIDEPRESSANTS The dual action antidepressants may be more effective antidepressant than the SSRIs; remission is achieved by venlafaxine in 45% of cases, and by SSRIs in 35% of cases (Thase et al, 2001). And, mirtazapine may have a more rapid onset than many of the newer antidepressants (Gartlehner et al, 2008). Venlafaxine (and desvenlafaxine) is described as a selective noradrenalin and serotonin reuptake inhibitor. Mirtazapine has a range of actions, central is alpha-2 antagonism which disinhibits 5HT and NA neurons causing release of these transmitters. In addition, mirtazapine blocks most 5HT receptors, which results in the release of DA. Duloxetine has a range of actions impacting on synaptic 5HT, NA and DA. AUGMENTATION OF ANTIDEPRESSANTS The response rate to antidepressants is poor. Unresponsive depression may be managed by combining antidepressants. Another strategy is augmentation of an antidepressant with a non-antidepressant. Lithium is the most extensively reported antidepressant augmenter (Bauer et al, 2010). Thyroxine has also been widely used, even in the presence of normal thyroid function (Kaira and Balhara, 2014).
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