Ten-year follow-up of 50 patients with bu- and are typically overweight and exhibit symptoms of anxi- limia nervosa safe 500 mg robaxin muscle relaxant prescription drugs. Bulimia nervosa: a 5- ety and depression in clinical samples buy robaxin 500 mg fast delivery spasm. Alterations in serotonin it is surprising that the response of these presumably related activity and psychiatric symptomatology after recovery from bu- symptoms to medication is at least somewhat inconsistent purchase genuine robaxin online spasms pregnancy after tubal ligation, limia nervosa. Outcome, recovery, relapse and mor- tality across six years in patients with clinical eating disorders. A major problem in the develop- Psychiatr Scand 1993;87(6):437–444. L-Dopa as treatment for anorexia ner- response of binge eating to nonspecific interventions, in- vosa. In part for this reason, the effects of medi- Press, 1977:363–372. Treatment of compulsive eating disturbances once medication has been discontinued. Am J Psychol 1974;131: the role of pharmacotherapy for BED currently unresolved, 428–432. The use of diphenylhydantoin in compulsive studies to examine the potential benefits of combining med- eating disorders: further studies in anorexia nervosa. New York: Raven Press, 1977: ication with psychological treatment, especially CBT. Naloxone in the treatment of REFERENCES anorexia nervosa: effect on weight gain and lipolysis. In: Kaplan HI, Freedman AM, noses in anorexia nervosa. Comprehensive textbook of psychiatry, vol 2, 3rd 712–718. A comparative psychometric family therapy in anorexia nervosa and bulimia nervosa. Arch study of anorexia nervosa and obsessive neurosis. Long term follow-up of therapy in the short-term treatment of anorexia nervosa. Neuroleptics in the short-term treatment of vosa in women with obsessive compulsive disorder. Int J Eating anorexia nervosa: a double-blind, placebo controlled study with Dis 1986;5:1069–1075. J Clin Psy- activity in anorexia nervosa after long-term weight restoration. Obsessive-compulsive disorder: psychobiologi- treatment of anorexia nervosa. Int J Eating Dis 2000;27(3): cal approaches to diagnosis, treatment, and pathophysiology. Antiserotonin-antihista- 9-tetrahydrocannabinol in primary anorexia nervosa. J Pharmacol Exp Ther 1961; chopharmacol 1983;3:165–171. Cyproheptatadine in an- crossover study of oral clonidine in acute anorexia nervosa. Biol Psychiatry 2001;49(7): cisapride accelerates delayed gastric emptying and increases antral 644–652. Does fluoxetine augment the Garner DM, Garfinkel PE, eds. Diagnostic issues in anorexia ner- inpatient treatment of anorexia nervosa? Effects of carbohydrate depressive illness: a review of 11 studies. Comp Psychiatry 1988; and protein meals on plasma large neutral amino acids, glucose 29:427–432. Am J Psychol weight subjects normalize after weight gain. Amitriptyline in the increases serotonin transporter (SERT) binding sites and SERT treatment of anorexia nervosa: a double-blind placebo-controlled mRNA expression in discrete regions of female rat brain. In: Schatz- trial of lithium carbonate in primary anorexia nervosa. Washington, monoamine metabolism in anorexia nervosa. Arch Gen Psychiatry DC: American Psychiatric Press, 1993:49–70. Personality and symptomatological features in young, 68. Relationship of depres- nonchronic anorexia nervosa patients. J Psychosom Res 1980;24: sion, anxiety, and obsessionality to state of illness in anorexia 353–359. Practice guideline for the treat- ship of eating disorders to major affective disorder. Psychiatry Res ment of patients with eating disorders (revision). Chapter 116: Psychopharmacology of Eating Disorders 1683 70. Intensive nutritional bulimia nervosa, and binge eating. In: Bloom FE, Kupfer DJ, counseling in bulimia nervosa: a role for supplementation with eds. Psychopharmacology: the fourth generation of progress. Flouxetine Bulimia Nervosa Collaborative Study Group. Fluoxe- pharmacological treatments of bulimia nervosa: predictors and tine in the treatment of bulimia nervosa: a multicenter, placebo- processes of change. A double-blind, placebo- treatment of bulimia nervosa. Pharmacologic and treatment of obese binge eaters and non-binge eaters. Am J Psy- cognitive-behavioral treatment for bulimia nervosa: a controlled chiatry 1990;147:876–881. Comparison of cognitive- tricyclic antidepressant and opiate antagonist on binge-eating in behavior therapy and desipramine in the treatment of bulimia normoweight bulimic and obese, binge-eating subjects. Fluvoxamine in controlled trial of fluoxetine and cognitive behavioral therapy for the treatment of binge-eating disorder: a multicenter placebo- bulimia nervosa: short-term outcome.
Cognitive functioning depends on the plasticity been an area of recent investigation cheap 500 mg robaxin visa spasms from spinal cord injuries. Glutamatergic dysfunc- mediated in part by NMDA receptors order robaxin canada muscle relaxant yellow pill with m on it, and schizophrenics tion has been hypothesized to occur in schizophrenia robaxin 500 mg with mastercard muscle relaxant flexeril, and often have cognitive deficits (11). Finally, the reduction of this has been one of the most active areas of neurotransmit- gray matter in several brain regions seen in schizophrenia has been suggested to be the result of neurotoxicity mediated ter research in this illness during the past few years. A constellation of symptoms, chapter, the glutamate hypothesis of schizophrenia is re- findings, and hypotheses of schizophrenia can be parsimon- viewed, the complexity of the molecules associated with the iously explained by NMDA-receptor dysfunction. Thus, although NMDA-re- ceptor abnormalities have been hypothesized in schizophre- nia, apparent NMDA-receptor dysregulation could be asso- GLUTAMATE AND SCHIZOPHRENIA ciated with abnormalities of another receptor subtype that interacts with the NMDA receptor, which in turn results Several lines of evidence have implicated glutamatergic dys- in a breakdown of normal glutamatergic transmission in function in schizophrenia. Meador-Woodruff: Department of Psychiatry, University of Michigan, Ann Arbor, Michigan. Kleinman: Clinical Brain Disorders Branch, National Institutes The four classes of glutamate receptors are functionally and of Mental Health Neuroscience Center, Washington, DC. The iono- 718 Neuropsychopharmacology: The Fifth Generation of Progress FIGURE 52. Recent data suggest that glutamatergic transmission requires three cells: a presynaptic glu- tamate-releasing cell, a presynaptic glial cell that releases the endogenous agonist for the glycine co- agonist site (recently reported to be D-serine), and a postsynaptic neuron. The various glutamate re- ceptors and transporters are differentially ex- pressed by these three distinct cell populations. The glutamate uptake transporter EAAT3 (excitatory amino acid transporter 3), which is not shown on this figure, appears to be expressed primarily on the cell body and dendrites. Three families of ionotropic glutamate receptors (N-methyl-D-aspartate, AMPA, and kainate) are known, each of which is composed of distinct subunits and has identifiable binding sites. The metabotropic receptors cluster into three groups, members of which share pharmacologic and structural features. Chapter 52: Neurochemistry of Schizophrenia: Glutamatergic Abnormalities 719 tropic glutamate receptors, AMPA ( -amino-3-hydroxy-5- dynorphin, and zinc have also been identified. Additionally, methyl-4-isoxazole propionic acid), kainate, and NMDA magnesium ions blockthe ion channel of the NMDA recep- are each composed of four or five subunits that form ligand- tor complex at physiologic concentrations. The metabotropic glutamate receptors is voltage-dependent; partial depolarization of the cell mem- (mGluRs) are all seven transmembrane-domain, G protein- brane extrudes the magnesium ion. Finally, a site of four genes that have been named GluR1 through GluR4. In addition, the final subunit protein dependent (i. Thus, a potential exists for considerable petitive antagonists. The assembled AMPA receptors contain several bind- tion. NR1 homomers have been shown to form glycine ing sites: one for glutamate, another at which competitive binding sites, but an NR2 subunit appears to be required antagonists such as CNQX (6-cyano-7-nitro-quinoxalindi- to form both glutamate and MK-801 binding sites (29–32). Subunit composition appears to confer affinity for compounds that bind to the glutamate agonist site, whereas receptors with NR2A or NR2B subunits have unique pharmacologic properties to the final receptors higher affinities for MK-801 binding than do receptors with (15–19). For example, decreased calcium influx in AMPA NR2C or NR2D subunits (31). In addition, NMDA recep- receptors that contain the GluR2 subunit drastically dimin- tors containing particular NR1 splice variants have a higher ishes the electrophysiologic activity of these receptors. Receptors with NR2B sub- posed of subunits derived from genes for the low-affinity units are associated with a higher affinity for polyamine GluR5 through GluR7 and high-affinity KA1 through KA2 modulators (31,34). Therefore, differential subunit combi- subunits (13,14). The transcripts associated with these five nations confer unique binding properties to the NMDA subunits also undergo alternative splicing and editing. Final receptors and probably are associated with subtle electro- assembled kainate receptors may be composed of five identi- physiologic differences within a population of NMDA re- cal subunits, or they may be heteromers composed of low- ceptors. These mGluRs belong to a unique subset of G termed NR1 and NR2A through NR2D (13,14). An NR3 protein-coupled receptors with seven transmembrane do- gene has also been identified, although this subunit appears mains and large, extracellular amine termini. When ex- to be expressed primarily during early development pressed in heterologous systems, group I mGluRs have been (20–22). NR1 is expressed as one of eight isoforms because shown to stimulate phospholipase C, phosphoinositide hy- of alternative splicing of exons 5, 21, and 22 (13,14,23, drolysis, and the formation of cyclic adenosine monophos- 24). As in the case of the AMPA and kainate receptors, phate (cAMP) (41–44). In heterologous systems, groups II transcription of the NR1 subunit presents an important level and III mGluRs inhibit forskolin-stimulated cAMP forma- for the regulation of the expression of functional NMDA tion and adenylyl cyclase, possibly via a G protein (39,40, i receptors. This regulation can influence certain properties 45,46). The metabotropic receptors have been the target of of the final functional NMDA receptors, including the considerable recent interest because a functional relation- pharmacology of their binding sites. A primary agonist site exists for the binding of gluta- unique role in glutamatergic neurotransmission. A separate glycine co-agonist site must also be occu- receptors interact at multiple levels, as AMPA, kainate, and pied before glutamate can activate the ion channel; recent metabotropic receptors all affect NMDA-receptor activity. Modulatory bind- pothesized to be dysregulated in schizophrenia, disturbances ing sites for polyamines, protons, neuropeptides including of any of the glutamate receptors could result in a condition 720 Neuropsychopharmacology: The Fifth Generation of Progress that produces the appearance of an abnormally functioning AMPA Receptors NMDA receptor. Of all of the glutamate receptors in schizophrenia, the AMPA receptor has been studied the most, as summarized in Table 52. When the AMPA-associated subunits were ABNORMALITIES OF GLUTAMATE first cloned, Harrison et al. A consistent decrease Given the possibility of glutamate-receptor dysfunction in in the expression of this subunit transcript was found in schizophrenia, the expression of all four families of the gluta- hippocampal regions, an abnormality that was statistically mate receptor have been studied in schizophrenic brain. These investigators sub- As would be expected, these investigations have primarily sequently extended their finding and demonstrated that targeted limbic regions that have been implicated in schizo- GluR1-subunit mRNA is decreased in multiple hippocam- phrenia, particularly limbic cortex, striatal areas, medial pal subfields (dentate gyrus, CA3, and CA4) and also in temporal lobe structures, and, more recently, the thalamus. They also reported that GluR2-subunit These investigations have also targeted multiple levels of mRNA is decreased in the medial temporal lobe in schizo- gene expression, including subunit messenger RNA phrenia, particularly in the parahippocampal gyrus (49), (mRNA) and protein levels, and final binding sites have and continued their examination of AMPA-receptor expres- been studied. In the following sections, the studies that have sion in the medial temporal lobe by determining the pat- been published for each receptor subtype in postmortem terns of expression of the flip and flop isoforms of the GluR1 brain in schizophrenia are reviewed. AMPA RECEPTOR BINDING AND SUBUNIT EXPRESSION IN SCHIZOPHRENIA Ligand or Subunit Findings Brain Regions Studied Reference Receptor binding sites [3H]CNQX caudate 57 [3H]CNQX none putamen, nucleus accumbens 57 [3H]AMPA none caudate, putamen, nucleus accumbens 55 [3H]CNQX CA4, CA3 53 [3H]AMPA none frontal cortex, putamen, nucleus accumbens 58 [3H]AMPA none caudate, putamen, nucleus, accumbens 56 [3H]AMPA CA2 54 [3H]AMPA none dentate gyrus, CA1, CA3, subiculum 54 [3H]AMPA none thalamus 61 Subunit protein expression GluR1 parahippocampal gyrus 50 none CA1, CA3, CA4, subiculum 50 GluR2/3 CA4 50 none dentate gyrus, CA1, CA3, subiculum 50 parahippocampal gyrus GluR1 none hippocampus 52 GluR2, GluR3 none cingulate cortex 52 Subunit mRNA expression GluR1 dentate gyrus, CA3, CA4, subiculum 49 none CA1, parahippocampal gyrus 49 GluR2 dentate gyrus, CA3, CA4, subiculum 49 none CA1 49 GluR1, GluR2, GluR3, GluR4 none caudate, putamen, nucleus accumbens 55 GluR1 CA3 48 none dentate gyrus, CA1, CA4, subiculum 48 GluR1, GluR2, GluR3, GluR4 none caudate, putamen, nucleus accumbens 56 GluR1, GluR3 thalamus 61 GluR2, GluR4 none thalamus 61 GluR1 frontal cortex 59 GluR1 none frontal cortex 59 GluR2flip none hippocampus 51 GluR2flop hippocampus 51 flip-flop ratio hippocampus 51 AMPA, -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; CNQZ, 6-cyano-7-nitro-quinoxalindione Chapter 52: Neurochemistry of Schizophrenia: Glutamatergic Abnormalities 721 unit mRNA was again found in hippocampal structures, human thalamus. In a recent report (61), although and both the flip and flop variants were reduced, the flop [3H]AMPA binding was not different in limbic thalamic to a greater extent (50). Using quantitative immunocytochemical results suggest that alterations in the stoichiometry of sub- analyses, Eastwood et al. In particular, GluR1 immunoreactivity was noted to be sig- nificantly reduced in the parahippocampal gyrus, and com- bined GluR immunoreactivity was decreased in the CA4 KainateReceptors 2/3 subfield of the hippocampus. On the other hand, Breese The kainate receptor has been the subject of study in the and co-workers (52) found no differences in GluR1, GluR2, brain in schizophrenia, as summarized in Table 52.
Cranial Nerve V – Individual branch testing of the trigeminal nerve is unnecessary buy robaxin with paypal muscle relaxant pakistan, as central nervous system lesions affecting CN V usually involve all three branches 500mg robaxin otc muscle relaxant phase 2 block. Cranial Nerve VII – The facial nerve innervates motor function to the face order 500mg robaxin spasms 2, and sensory function to the ear canal, as well as to the anterior two-thirds of the tongue. Central lesions cause contralateral weakness of the face muscles below the eyes. Cranial Nerve VIII – The acoustic nerve has a vestibular and a cochlear component. An easy screening test for hearing defects is accomplished by speaking in graded volumes to the patient. Motor exam Motor system assessment focuses on detecting asymmetric strength deficits, which may indicate an acute CNS lesion. Testing motor power can be difficult or impossible in the uncooperative patient. It is not mandatory to test different muscle groups but instead just test for the presence of a “drift”. In diseased patients, the hand and arm on the affected side will slowly drift or pronate when they try to hold their arm out horizontally, palms up with eyes closed. Reflexes For rapid assessment of reflexes, major deep tendon reflexes and the plantar reflex must be elicited. Major deep tendon reflexes include the patellar reflex, the Achilles reflex, the biceps reflex, and the triceps reflex. Response can be graded from 0 (no reflex) to 4+ (hyperreflexia). Asymmetrical reflexes are the most important as they are considered pathologic. Sensory exam For rapid assessment of the sensory system, pain and light touch sensations should be done. Testing for other sensory modalities is reserved for patients with suspected neuropathies or for further evaluation of sensory complaints. Coordination and balance Coordination depends on functional integration of the cerebellum and sensory input from vision, proprioception, and the vestibular sense. Coordination assessment is an important part of neurological assessment, as many central lesions may present only with coordination disturbance, such as cerebellar infarction, hemorrhage or cerebellar connections insult. Assessment of Patients in Neurological Emergency | 19 By the end of the examination, you should reach a clinical diagnosis, which includes answers to the two critical questions, what is the lesion? Neuroanatomical localization Some knowledge of neuroanatomy is essential for correct localization. The first step in localizing neurological lesions should be to determine if it is a central (upper motor neuron) lesion (i. The hallmark of upper motor neuron lesions is hyperreflexia with or without increased muscle tone. Central (upper motor neuron) lesions are localized to: Brain – Cortical brain (frontal, temporal, parietal, or occipital lobes) – Subcortical brain structures (corona radiata, internal capsule, basal ganglia, or thalamus) – Brainstem (medulla, pons, or midbrain) – Cerebellum Spinal cord – Cervicomedullary junction – Cervical – Thoracic – Upper lumbar The hallmark of a lower motor neuron (LMN) lesion is decreased muscle tone, leading to flaccidity and hyporeflexia. Peripheral LMN lesions are localized to: – Anterior horn cells – Nerve root(s) – Plexus – Peripheral nerve – Neuromuscular junction – Muscle 20 | Critical Care in Neurology Conclusions 1. The neurological screening examination provides the clinician with the necessary data to make management decisions. A cranial nerve examination gives plenty of data in the emergency setting and is a critical component of the screening exam. How to Approach an Unconscious Patient Magdy Khalaf, Nabil Kitchener Coma (from the Greek κώμα [koma], meaning deep sleep) is a state of unconsciousness lasting more than 6 hours, in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. All unconscious patients should have neurological examinations to help determine the site and nature of the lesion, to monitor progress, and to determine prognosis. Neurological examination is most useful in the well-oxygenated, normotensive, normoglycemic patient with no sedation, since hypoxia, hypotension, hypoglycemia and sedating drugs profoundly affect the signs elicited. Therefore, immediate therapeutic intervention is a must to correct aberrations of hypoxia, hypercarbia and hypoglycemia. Medications recently taken that cause unconsciousness or delirium must be identified quickly followed by rapid clinical assessment to detect the form of coma either with or without lateralizing signs, with or without signs of meningeal irritation, the pattern of breathing, the size and reactivity of pupils and ocular movements, the motor 22 | Critical Care in Neurology response, the airway clearance, the pattern of breathing and circulation integrity, etc. Special consideration must be given to neurological causes which may lead to unconsciousness like status epilepticus (either convulsive or non-convulsive), locked-in state, persistent vegetative state and lastly brain stem death. Any disturbances of thermoregulation must be measured. Coma may result from a variety of conditions including intoxication, metabolic abnormalities, central nervous system diseases, acute neurologic injuries such as stroke, hypoxia or traumatic injuries including head trauma caused by falls or vehicle collisions. Looking for the pathogenesis of coma, two important neurological components must function perfectly that maintain consciousness. The first is the gray matter covering the outer layer of the brain and the other is a structure located in the brainstem called the reticular activating system (RAS or ARAS), a more primitive structure that is in close connection with the reticular formation (RF), a critical anatomical structure needed for maintenance of arousal. It is necessary to investigate the integrity of the bilateral cerebral cortices and the reticular activating system (RAS), as a rule. Unilateral hemispheric lesions do not produce stupor and coma unless they are of a mass sufficient to compress either the contralateral hemisphere or the brain stem (Bateman 2001). Metabolic disorders impair consciousness by diffuse effects on both the reticular formation and the cerebral cortex. Coma is rarely a permanent state although less than 10% of patients survive coma without significant disability (Bateman 2001); for ICU patients with persistent coma, the outcome is grim. Maneuvers to be established with an unconscious patient include cardiopulmonary resuscitation, laboratory investigations, a radiological examination to recognize brain edema, as well as any skull, cervical, spinal, chest, and multiple traumas. Intracranial pressure and neurophysiological monitoring are important new areas for investigation in the unconscious patient. How to Approach an Unconscious Patient | 23 Diagnosis In the initial assessment of coma, it is common to judge by spontaneous actions, response to vocal stimuli and response to painful stimuli; this is known as the AVPU (alert, vocal stimuli, painful stimuli, unconscious) scale. The most common scales used for rapid assessment are: 1. The Glasgow Coma Scale (GCS), which aims to record the conscious state of a person, in initial as well as continuing assessment. Pediatric Glasgow Coma Scale: The Pediatric Glasgow Coma Scale (PGCS) is the equivalent of the Glasgow Coma Scale used to assess the mental state of adult patients. As with the GCS, the PGCS comprises three tests: eye, verbal and motor responses. The three values separately as well as their sum are considered (Holmes 2005). The lowest possible PGCS is 3 (deep coma or death) whilst the highest is 15 (fully awake and aware) (Holmes 2005). Diagnosis of coma is simple; but determining the cause of the underlying pathology may prove to be challenging. As in those with deep unconsciousness, there is a risk of asphyxiation as control over the muscles in the face and throat is diminished, so those in a coma are typically assessed for airway management, nasopharyngeal airway or endotracheal intubation to safeguard the airway (Formisano 2004). Following the previous assessment patients with impaired consciousness can be classified according to their degree of consciousness disturbance into lethargic, stuporous or comatose.
Elevated plasma ACTH levels have been re- pected response is to suppress the axis because the pituitary ported in psychotic depression (119) order robaxin 500mg line muscle relaxant non-prescription. AVP neurons are increased in the PVN strate a significantly higher nonsuppression rate than do of suicide victims (120) and serum AVP has been reported controls order robaxin 500 mg free shipping spasms calf muscles, although the rates of nonsuppression are relatively in one study to be elevated in hospitalized depressives (121) discount 500 mg robaxin amex spasms muscle. Patients with severe or psychotic CRH is also found in extrahypothalamic brain regions. In- responses and over-activation of these systems may lead to deed, psychosis appears to be the greatest symptom or syn- panic and depression (2). Amygdala CRH has been reported Chapter 72: Molecular and Cellular Mechanisms in Depression 1045 to be under positive (stimulatory) feedback by cortisol and tissue suggestive of an autoimmune thyroiditis, often in the this observation has spurred on much research to develop face of normal T4,T,3 or TSH levels. A recent report on an open label trial suggested CSF TRH was increased in two small studies of depressed that a CRH antagonist might be effective in hospitalized patients as compared to controls (124,125), although not depressives (122). Elevated TRH levels should be ac- Although the literature has emphasized elevated CRH companied by a blunted TSH response to TRH because and cortisol activity in major depression (in part because of TRH levels in the pituitary would be expected to be down- the emphasis on DST nonsuppression), there is emerging regulated in the face of elevated TRH. Indeed, multiple evidence that CRH and cortisol activity may only be ele- studies have reported such blunting in a relatively high per- vated in some subtypes of major depression and that some centage (approximately 25%) of patients with major depres- depressed patients may actually have low HPA activity. A recent review concluded that 41 of 45 studies re- cent data suggest that depressed patients with a history of ported blunted TSH responses to TRH in major depression early abuse (as well as those with psychosis) may be most (127). Blunting of TSH responses to TRH in these patients consistently at risk for demonstrating elevated ACTH levels is not owing to clinical or subclinical hypothyroidism be- in response to social stress (123). Depressives who were not cause thyroid parameters were generally within normal lim- abused as children did not show similar responses. Similarly, low values have been responses to TRH (1). Antithyroid antibodies may be pres- reported in several other types of patients, including atypical ent. Type II hypothyroidism is characterized by normal T3 depression, posttraumatic stress disorder, so-called burn out or T4 levels but otherwise similar abnormalities as in Type syndromes, and so on. Rates of Type III or IV subclinical hypothy- HPA axis activity may be found in specific depressive sub- roidism have been reported to be elevated in depressed pa- types. In many ways this parallels the findings in catechol- tients. These syndromes are both characterized by normal amine activity in depressed patients. First, the DST as we presence of antithyroid antibodies. In one study, depressed use it may not measure cortisol overactivity as much as it patients with high normal thyroid levels were also reported does central CRH overdrive in response to suppressing the to demonstrate exaggerated TSH responses to TRH (128). Second, previous studies have often not with major depression may have subclinical hypothyroid- explored the role of psychosis or early abuse. Indeed, asymptomatic autoimmune thyroiditis with tively few studies on the HPA axis in depression have ex- positive antibodies has been reported to be relatively high plored cortisol activity over the full 24-hour period. Taken together, TSH stimulation test data suggest elevated or decreased TRH activity could be involved in HPT Axis major depression, depending on whether patients met crite- The overlap in symptoms between patients with hypothy- ria for subclinical hypothyroidism. Patients with a history of thyroid yielded intriguing, although at times, conflicting results. One possible explanation which in turn stimulates specific receptors in the pituitary to for the differential effects of T4 and T3 on mood rests with release triiodothyronine (T3) and thyroxine (T4) hormones. Depressed patients have been reported to demon- Activity of the axis can be measured in several ways: strate increased reversed T3 levels in CSF (130), which sug- circulating levels of T3 and T4—both bound and unbound; gests inhibition of the Type II 5′ deiodinase and subsequent TRH levels in the CSF; TSH responses to TRH administra- increased activity of the Type III of the enzyme. Cortisol tion (TRH-stimulation test); and circulating TSH levels. Of interest is a recent report (133) 1046 Neuropsychopharmacology: The Fifth Generation of Progress that in depressed patients low T3 levels predicted earlier tems and their complex interactions in depression. Also, relapse, pointing further to an important role for T3 in research has tended to emphasize cross-sectional rather than mood relation. Future research that Transthyretin levels have been reported to be low in refrac- combines genetic risk factors with longitudinal study of tory depressed patients (134). This may also help explain multiple systems will likely lead to breakthroughs in our possible CNS enhancing effects of T3 in the face of normal understanding of the biology of the disorder. However, there are still a number of seeming contradictions regarding the direc- tion and specific nature of HPT alterations in depression. REFERENCES Data point to both elevations in central TRH activity and subtle forms of hypothyroidism (suggestive of low T3 and 1. Biology of TRH activity) as playing potential roles in major depression. Washington, DC: The Ameri- can Psychiatric Press, 1998:549–588. Growth hormone (GH) is synthesized in the anterior pitui- New York: Oxford University Press, in press. Two hypothalamic hormones, growth hormone releas- 3. The catecholamine hypothesis of affective disor- ders: a review of supporting evidence. Am J Psychiatry 1965; ing factor (GRF) and somatostatin modulate its release from 122:509–522. 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The inclusive Melancholia Scale scores were significantly better after 3 approach is favored because of its ease of use and practical and 6 weeks of treatment in the 33 patients given citalopram applicability discount 500 mg robaxin free shipping muscle relaxant constipation, and it appears to be sufficient discount 500mg robaxin spasms stomach. It is also more (under age 65 purchase 500 mg robaxin with amex muscle relaxant generic, 20-mg dose; over age 65, 10-mg dose) than sensitive and relates well to functional impairment (75). In summary, evidence is increasing that depression in The most recent of the four studies compared nortripty- patients with vascular disease can be successfully treated line (n 16) with fluoxetine (n 23) and placebo (n with pharmacologic agents. 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A temperature probe is also indicated for purposes of monitoring core temperature purchase robaxin with a mastercard back spasms 36 weeks pregnant. Subsequent fluid management should be based upon urine output and maintaining central venous pressure between 5 and 10 mmHg discount robaxin 500 mg fast delivery spasms under left rib. Monitor potassium robaxin 500 mg amex muscle relaxant wiki, sodium, glucose and arterial blood gases every 4 hours. Especially if there is respiratory embarrassment at initial evaluation, measurement of hematocrit, magnesium, blood urea nitrogen, creatinine, calcium, liver function tests, urine analysis, prothrombin, partial thromboplastin times and phosphate levels are mandatory. If hematocrit is below 30%, transfuse cross-matched blood (Amin 1993). Common indications for central venous cannulation: measurement of mean central venous pressure, large bore venous access, administration of irritating drugs and or parenteral nutrition, hemodialysis, placement of a pulmonary artery catheter. Placement of a pulmonary artery catheter is indicated to obtain direct and calculated hemodynamic data that cannot be obtained through less invasive means (Sakr 2005). The goal for all critically ill patients is to provide adequate oxygen for cellular use through suitable oxygen consumption, which is variable between tissues, and the changes of the basal or active metabolic rate for each cell. Basic Hemodynamic Monitoring of Neurocritical Patients | 57 Oxygen delivery to tissues and organs responds to many local systemic variables to keep cellular homeostasis. Pulmonary artery balloon flotation catheter insertion may be necessary for full assessment of these parameters, and of evaluation of determinants of cardiac output and the oxygen content of circulating blood, on which oxygen delivery is dependent. In the presence of positive pressure ventilation with PEEP, central venous and pulmonary artery occlusion pressures may be falsely elevated and need to be interpreted with caution. The fluid challenge is the only way to interpret Central Venous Pressure (CVP) or Pulmonary Artery Occlusion Pressure (PAOP). Assessment of the determinants of cardiac output will proceed as follows: a. Heart rate and rhythm assisted by pulse oximeter and electrocardiogram. Preload assessed right and left heart; right heart through neck vein distension, liver enlargement and central venous pressure assessment; left heart through dyspnea on exertion, orthopnea, arterial blood pressure; pulmonary artery occlusion pressure and arterial pressure through waveform analysis (Sakr 2005). Afterload assisted by mean arterial blood pressure and systemic vascular resistance; contractility can be assessed by ejection fraction and echocardiography. As discussed earlier, the goal of hemodynamic monitoring in neurocritical care units is to assess the magnitude of physiological derangements in critically ill patients and to institute measures to correct the imbalance. Basic hemodynamic monitoring consists of clinical examination, invasive arterial monitoring, central venous pressure monitoring, hourly urine output, central venous oxygen saturation and echocardiography. Dynamic indices of fluid responsiveness such as the pulse pressure variation and stroke volume variation can guide 58 | Critical Care in Neurology decision making for fluid resuscitation. Cardiac output is traditionally measured using the pulmonary artery catheter; less invasive methods now available include the pulse contour analysis and arterial pulse pressure derived methods. It is essential to determine whether the hemodynamic therapy is resulting in an adequate supply of oxygen to the tissues proportionate to their demand. Mixed and central venous oxygen saturation and lactate levels are commonly used to determine the balance between oxygen supply and demand (Walley 2011). Neurocritical Monitoring Mervat Wahba, Nabil Kitchener, Simin Mansoor Neurocritical care relies on monitoring cerebral functions. Intracranial pressure monitoring may indicate high pressure in several acute neurological conditions. Massive stroke may cause life-threatening brain edema and occur in about 10% of patients with supratentorial stroke. Massive brain edema usually occurs between the second and the fifth day after stroke onset. Neuro-Specific Monitoring Accurate neurological assessment is fundamental for the management of patients with intracranial pathology. This consists of repeated clinical examinations (particularly GCS and pupillary response) and the use of specific monitoring techniques, including serial CT scans of the brain. This chapter provides an overview of the more common monitoring modalities found within the neurocritical care environment. A drop of two or more GCS points (or one or more motor points) should prompt urgent re-evaluation and a repeat CT scan. Eye opening is not synonymous with awareness, and can be seen in both coma and persistent vegetative state (PVS). The important detail is that the patients either open their eyes to a specific command or shows ability to fix eye on a specific target or follows a visual stimulus. Pupillary response Changes in pupil size and reaction may provide useful additional information: – Sudden unilateral fixed pupil: Compression of the third nerve, e. A reduction in sedation level will usually be at the suggestion of the Regional Neurosurgical Center (RNC) and its timing will depend upon a number of factors. Responses such as unilateral pupillary dilatation, extensor posturing, seizures, or severe hypertension should prompt rapid re-sedation, repeat CT scan, and contact with the RNC. In the patient with multiple injuries, consideration must be given to their analgesic requirements prior to any decrease in sedation levels. Invasive Monitoring Cerebral perfusion pressure (CPP) reflects the pressure gradient that drives cerebral blood flow (CBF), and hence cerebral oxygen delivery. Measurement of intracranial pressure (ICP) allows estimation of CPP. Sufficient CPP is needed to allow CBF to meet the metabolic requirements of the brain. An inadequate CPP may result in the failure of autoregulation of flow to meet metabolic needs whilst an artificially induced high CPP may result in hyperemia and vasogenic edema, thereby worsening ICP. The CPP needs to be assessed for each individual and other monitoring modality (e. Despite its almost universal acceptance, there are no properly controlled trials demonstrating improved outcome from either ICP- or CPP-targeted therapy. As such, ICP- and CPP- targeted therapy have become an accepted standard of care in head injury management. The 2007 Brain Trauma Foundation Guidelines (Brain Trauma Foundation 2007) recommend treating ICP values above 62 | Critical Care in Neurology 20 mmHg and to target CPP in the range of 50-70 mmHg. Patients with intact pressure autoregulation will tolerate higher CPP values. Aggressive attempts to maintain CPP >70 mmHg should be avoided because of the risk of ARDS. Although associated with a higher incidence of infection and greater potential for brain injury during placement, this remains the gold standard. Historically, saline could be injected to assess brain compliance.
Moreover generic robaxin 500 mg with amex muscle relaxant gi tract, at this point it is have discontinued their medication is 11 discount robaxin amex muscle relaxant cvs. Often purchase robaxin 500 mg on-line xanax muscle relaxant dosage, when considering the best dose of a conven- potential therapeutic significance of the adrenergic receptor tional antipsychotic, there is a trade-off between maximizing blocking properties of clozapine and risperidone is uncer- relapse prevention and optimizing comfort (46). Addition of the 2-antagonist idazoxan to the regime there has been substantial progress in understanding main- of patients treated with the typical neuroleptic fluphenazine tenance dosing, for most patients with schizophrenia, this resulted in improved treatment responses in patients refrac- 778 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 56. AFFINITY OF ANTIPSYCHOTIC DRUGS FOR HUMAN NEUROTRANSMITTER RECEPTORS (Ki, nM)a Receptor Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Iloperidone Haloperidol D 290 580 52 1,300 130 410c 320 120 1 D 130 2. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Iloperidone binding to human and rat dopamine and 5-HT receptors. However, as well as H1 and 1-adrenergic receptors (55) (Table 56. Aripiprazole is distinct from the other atypical useful for treating cognitive deficits of the disease (50). Olanzapine is more potent at 5-HT2A than D2 drugs (56,57). Clozapine, however, does not exhibit high receptors (Table 56. The low occupancy of striatal D2 receptors by but there are also some notable distinctions between the clozapine could account for its low EPS liability (20,58, two drugs. For example, clozapine has substantially higher 59). Although 5-HT2A receptor an- for 5-HT2A than for D2 receptors, but also some affinity tagonism is likely to be associated with the low EPS liability for 1-adrenergic and H1 receptors (53) (Table 56. Inter- of risperidone and olanzapine, the role of this molecular estingly, quetiapine produces only transiently high striatal action in the superior therapeutic responses to clozapine is D2 occupancy in schizophrenic patients, although the study unclear (13). Ziprasidone has potent 5-HT2A and D2 affinities, and like clozapine, it Efficacy shows 5-HT1A agonist properties that could potentially act as protective effects on the development of EPS. Ziprasi- Although the proportion of patients who improve and the done also has significant affinity for 5-HT1D and 5-HT2C, magnitude of therapeutic effects vary greatly, atypical anti- Chapter 56: Therapeutics of Schizophrenia 779 psychotics are at least as effective for psychotic symptoms and clozapine in treatment-resistant patients. Well-controlled double-blind was found to be more effective than haloperidol (74,76), studies of atypical antipsychotics suggest that clozapine, but not chlorpromazine (77), in treatment-refractory pa- risperidone, and olanzapine may be superior to haloperidol tients. In a recent randomized double-blind study of treat- for controlling psychotic symptoms (61). At selected doses, ment-resistant schizophrenia, olanzapine and clozapine had risperidone appears to be more effective than haloperidol similar antipsychotic efficacy (74). Additional studies are in treating positive and negative symptoms (53). Olanza- needed to reach definitive conclusions regarding efficacy pine has been demonstrated to be effective for positive, neg- of the newer atypical antipsychotics in treatment-resistant ative, and depressive symptoms (62), and in some studies schizophrenia. Results of studies investigating the effects the drug was superior to haloperidol and risperidone in of atypical antipsychotics in treatment-resistant patients are terms of negative symptoms and long-term efficacy (63,64). However, in a recent large double-blind study (that has The efficacy of atypical antipsychotics in treating primary only been preliminarily reported), risperidone demonstrated negative symptoms has not been clearly demonstrated (61). Quetiapine inantly negative symptoms is less clear (8). In addition, the appears to be comparable to chlorpromazine and haloperi- effects of atypical antipsychotics on cognitive impairment dol in treating both positive and secondary negative symp- have not yet been clearly proved. Similarly, ziprasidone appears to be as effective ies (only three of which were double-blind) of atypical anti- as haloperidol in alleviating positive and negative signs in psychotics and cognitive impairment in patients with schiz- an acute treatment study (66), whereas a 52-week placebo- ophrenia suggests that they may improve attention and controlled maintenance study found primary and secondary executive function (37). Available results, however, are rela- negative symptom efficacy for ziprasidone (67). Furthermore, To date, clozapine is the only drug that has proven effi- there are statistical limitations and a lack of standard con- cacy in treatment-refractory schizophrenia (68,69). It appears that ficacy rates for clozapine in treatment-refractory patients there could be significant differences among the atypical vary from 20% to more than 70% (11,70,71). In some drugs in terms of what types of cognition they improve. Clozapine, risperidone, and olanzapine, in particular, resistant patients. In this latter study, certain methodologic appear to have beneficial effects on the depressive compo- issues may have led to an overestimation of the efficacy of nent of schizophrenia (6,65) (Table 56. Further investigation is necessary they are not effective in all patients and against all symptom to adequately compare the relative efficacy of risperidone dimensions of psychotic disorders (Table 56. CLINICAL AND SIDE-EFFECT PROFILE OF ATYPICAL ANTIPSYCHOTIC DRUGS Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Clinical effect Psychotic symptoms +++ +++? Side effect EPS — ++a +a — +a TD — Prolactin elevation — +++ — — — aDose dependent. EPS, extrapyramidal side effects; TD, tardive dyskinesia; + to +++, weakly (for clinical effect) or active (for side effect) to strongly active; – to —, weak to little activity;? National Institute of Mental Health, Division of Services and Intervention Research Workshop, July 14, 1998. Thus, the possi- zapine-related TD is low (1%) (87). There is a risk of mild ble use of these agents in the prodromal period of schizo- sedation and mild anticholinergic side effects, and the risk phrenia, before the emergence of psychosis, is an important of weight gain appears greater than with risperidone, but issue to address in the next decade (79). Quetiapine is associated with very low levels of EPS and its prolactin level elevation is indistinguishable from that Safety of placebo (88). The incidence of TD with quetiapine is Although atypical antipsychotics were developed to improve reportedly low or virtually nonexistent, although this re- on the shortcomings of conventional drugs it has already mains to be demonstrated prospectively. There is a potential become apparent that they also have significant limitations risk of lenticular opacities that were associated in one pre- in terms of side effects in the relatively brief period that clinical study in beagles (89), but have not been found in they have been in general clinical use (3). As a class, and nonhuman primates or patients, yet monitoring is recom- with some variation between the individual drugs (Table mended until additional data are available. They do, however, with olanzapine and clozapine (78). Although quetiapine produce side effects, including sedation, hypotension, dry has virtually no cholinergic activity, tachycardia is a possible mouth, constipation, sedation, and some types of sexual side effect, perhaps secondary to its adrenergic effects on dysfunction (3). Neuroleptic malignant syndrome has also blood pressure (39). There are several other side effects with been reported with atypical antipsychotics such as clozapine, quetiapine such as decrease in T3 and T4, orthostatic hypo- risperidone, and olanzapine (80). Weight gain is the most tension, and sedation, necessitating gradual dose titration worrisome and potentially serious side effect that appears (39). The risk of TD is including aripiprazole and iloperidone (81). Ziprasidone is associated with mild dyspepsia, weight gain and sedation are common reasons for drug dis- nausea, dizziness, and transient somnolence (90).