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By K. Aldo. Southwest University.

Each of these sources of data ceutical outcomes of interest for a given product are expen- and type of experimentation affect the degree of evidence sive cheap vardenafil 10mg fast delivery, and data collection of all relevant information is diffi- obtained vardenafil 20mg on-line. Therefore buy vardenafil paypal, many pharmaceutical outcome studies mental health care requires careful consideration of the contribute to the body of knowledge by evaluating compo- source and strength of the evidence presented quality vardenafil 20 mg. Additionally, many pharmaco- economic analyses are based on models. These models typi- cally use published literature, expert opinion, or data from HUMANISTIC MEASURES administrative or encounter databases to get information on probabilities and costs. Humanistic measures assess how disease or treatment affects The impact of this component approach to building an patients. Humanistic measures are most important from the understanding of pharmaceutical outcomes is that data perspective of the patient. A primary goal for treatment of come from many sources ranging from experimental and any disease should be for patients to function normally, nonexperimental research designs to expert opinion and have an acceptable quality of life, and be satisfied with their models based on data from multiple and frequently diverse treatment. This is especially true for mental health disorders sources. Therefore, when reviewing pharmaceutical out- where impacts on both physical and social functioning may comes research, it is critical to understand the potential be significant. In many cases, patients and their friends and impact of the source of information on the results. Until A frequent source of outcomes data in mental health recently, humanistic measures have taken a back seat to research is randomized clinical trials conducted by the phar- traditional clinical measures and to some extent economic maceutical industry. This is in part due to greater variability from controlled and typically contain (as expected) mostly clinical patient self-reported measures compared to standard clinical information. In mental health, however, patient self-re- measures (34). The development of valid and reliable instru- ported items (i. There are also many studies that rely on chart review mon conceptualization of humanistic outcomes used in the and quasi-experimentation to document differences in re- evaluation of pharmaceuticals is health-related quality of source use for patients using various pharmaceutical agents. Examples include recent comparisons of tricyclic antide- Health-related quality of life encompasses factors such pressants and SSRIs, and atypical versus conventional anti- as functional status, physiologic status, social and emotional psychotic agents. Many of these studies were retrospective well-being, and life satisfaction (35). Health-related quality and were conducted through chart reviews or administrative of life information allows health care providers and payers data using quasi-experimental techniques. Finally, eco- to make decisions based not only on clinical effectiveness, nomic models have been built using published data or expert or costs but also on effects that are important to patients. Measurement of health-related quality of life may be espe- Historically, randomized controlled trials have been the cially important in chronic diseases for which we have no 'gold standard' (5). There are many humanistic measures available for as- and safety of a drug to be established. Unfortunately, some sessing mental health disorders. Generic and disease-specific of the strengths of such studies can also be a source of less instruments are available for a variety of disorders. This is a result of the sion of every instrument is not feasible; however, a few ex- artificial treatment environment purposefully created in effi- amples are provided. One of the most widely used generic health- 532 Neuropsychopharmacology: The Fifth Generation of Progress related quality of life instruments is the Medical Outcomes depression when comparing treatment groups (46). The MOS SF-36 cap- studies have evaluated health-related quality of life in the tures eight dimensions of health-related quality of life: phys- treatment of depression and utilized similar generic rating ical functioning, role limitations due to physical function- scales (47). However, there is a lack of understanding health (36). The tools assess functions such as daily activities, focus on dimensions that are most relevant to the particular memory, emotional well-being, and other aspects such as disease and are therefore more sensitive to subtle changes finances (48). Examples of disease specific One other area of humanistic measurement concerns the instruments used in schizophrenia include the Quality of relationship between humanistic and economic outcomes. Several review papers have utilities to combine cost information with patient prefer- been published on the use of quality of life instruments in ences. Utilities are usually measured by three techniques: mental health conditions (40–42). These articles highlight rating scales, the standard gamble, or time trade-off tech- that quality of life measurement in mental health condi- nique (49). Utility scores differ from quality of life measure- tions, and in particular specific drug comparison, is a devel- ments. While some quality of life instruments can be used oping science. Many of the available studies are observa- to capture utilities, most cannot. Utilities are a measure of tional or cross-sectional. However, quality of life overall patient well-being that lie on a scale between 0and measurement is increasingly being built into clinical trials. Unfortunately, utility values are difficult and expen- ment of instrument validity and reliability. They require detailed patient interviews articles have shown that it is possible for patients with severe with large numbers of subjects with and without the disease. While these tech- posed the conceptually challenging task of the standard niques have been used in mental health care, more wide- gamble, patients with mental illness have been able to per- spread use is dependent on the development of reliable and form adequately. It is important to note that although agree- valid measures of utility or preference for alternative health ment is not universal, there are many researchers who be- states in mental health diseases. Much has been pub- USING OUTCOMES DATA IN PRACTICE lished on this subject and in particular on the issue of whose values to use in creation of reference case analyses (to be The use of outcomes data in practice is not about applying used for comparisons across studies). But rarely is the view the results of a single study. Instead, using outcomes data of the health care provider or other proxy considered supe- typically requires synthesis across a body of literature. Out- rior to that of either the patient or of society in general. The study took place within a staff decisions will be made even if all these data are not available. Patients starting new Uses of outcomes data in practice include reimbursement antidepressant therapy were randomized to an SSRI or TCA decisions, internal practice decisions, external or regulatory for 24 months. The primary care providers were allowed to decisions, and marketing of pharmaceutical products. Phar- adjust doses and medications or discontinue medications as macy and therapeutics committees are using outcomes data they deemed appropriate. The quality of life outcome was as a component of the formulary decision. Where these measured using the Medical Outcomes Study SF-36 Health decisions were once made almost entirely on clinical param- Survey at 6, 9, 12, 18, and 24 months. The results indicated eters, the use of economic and humanistic data is becoming no significant difference in quality of life or severity of more common. Chapter 39: The Role of Pharmaceuticals in Mental Health Care Outcomes 533 In practice, the use of terminology such as evidence- trials that are commonly performed for regulatory purposes. The evaluation of a body of literature conditions of treatment and limits treatment to optimal to make decisions about best practice is the goal of evidence- patients, conditions that can be difficult or impossible to based medicine. Evidence-based medicine involves explicit duplicate in regular practice. Blind, prospective randomiza- use of what can be identified as the best evidence in making tion of an adequate number of patients to a study in which decisions about the care of both individual patients and outcomes are assessed by raters blind to treatment is in- populations of patients (Fig. This philosophy tended to minimize observer bias and confounding, and extends into treatment guidelines that are often established maximize internal validity. Accordingly, clinical trials are by expert panels that have reviewed the available evidence excellent for providing confidence that there is a causal rela- in the literature regarding effectiveness of alternative treat- tionship between drug use and the measured endpoint. While these efforts rely most heavily on clinical in- Once confidence in this relationship is established, however, formation, economic and humanistic data are being in- questions of use in the real world arise, which beg the ques- cluded in these considerations. Efficacy results, generally using highly Outcomes data is beginning to be considered in the ac- select, often healthier, patient populations (not least because creditation of health care organizations. Although the mea- informed consent is required) under different practice con- sures currently used are more process than outcomes ori- ditions (tertiary vs.

A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study buy vardenafil 20 mg with mastercard. Radiofrequency Catheter Ablation and Antiarrhythmic Drug Therapy: A Prospective cheap vardenafil 10mg fast delivery, Randomized 4-Year Follow-Up Trial - The APAF Study purchase vardenafil 10 mg amex. Ventricular pacing vs dual chamber pacing in patients with persistent atrial fibrillation after atrioventricular node ablation: open randomized study buy 20mg vardenafil fast delivery. The cost comparison of rhythm and rate control strategies in persistent atrial fibrillation. Comparison of surgical cut and sew versus radiofrequency pulmonary veins isolation for chronic permanent atrial fibrillation: a randomized study. Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol. Prophylactic cavotricuspid isthmus block during atrial fibrillation ablation in patients without atrial flutter: a randomised controlled trial. Effect of shock polarity on the efficacy of transthoracic atrial defibrillation. Efficacy of transthoracic cardioversion of atrial fibrillation using a biphasic, truncated exponential shock waveform at variable initial shock energies. Signal-averaged P wave reflects change in atrial electrophysiological substrate afforded by verapamil following cardioversion from atrial fibrillation. Improvements in symptoms and quality of life in patients with paroxysmal atrial fibrillation treated with radiofrequency catheter ablation versus antiarrhythmic drugs. External cardioversion of atrial fibrillation: comparison of biphasic vs monophasic waveform shocks. Enhanced cardiovascular morbidity and mortality during rhythm control treatment in persistent atrial fibrillation in hypertensives: data of the RACE study. Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study. Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study). Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. Circumferential pulmonary vein ablation with additional linear ablation results in an increased incidence of left atrial flutter compared with segmental pulmonary vein isolation as an initial approach to ablation of paroxysmal atrial fibrillation. Comparison of monophasic and biphasic shocks for transthoracic cardioversion of atrial fibrillation. Surgical treatment of permanent atrial fibrillation using microwave energy ablation: a prospective randomized clinical trial. Pulmonary vein isolation and linear lesions in atrial fibrillation ablation. A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study). Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Impact of biphasic electrical cardioversion of atrial fibrillation on early recurrent atrial fibrillation and shock efficacy. Randomized comparison of anterolateral versus anteroposterior electrode position for biphasic external cardioversion of atrial fibrillation. Clinical assessment of clonidine in the treatment of new-onset rapid atrial fibrillation: a prospective, randomized clinical trial. Systematic electrocardioversion for atrial fibrillation and role of antiarrhythmic drugs: a substudy of the SAFE-T trial. Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation. Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study. Efficacy of three different ablative procedures to treat atrial fibrillation in patients with valvular heart disease: a randomised trial. Catheter ablation treatment in patients with drug- refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. The effect of rate versus rhythm control strategy on the left ventricular function in patients with persistent atrial fibrillation: Results of one year follow-up. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study. Rapid loading of sotalol or amiodarone for management of recent onset symptomatic atrial fibrillation: a randomized, digoxin-controlled trial. Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study. Antiarrhythmic drug therapy after radiofrequency catheter ablation in patients with atrial fibrillation. A prospective randomized multicenter comparison on health-related quality of life: the value of add-on arrhythmia surgery in patients with paroxysmal, permanent or persistent atrial fibrillation undergoing valvular and/or coronary bypass surgery. Lenient versus strict rate control in patients with atrial fibrillation. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies. VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. A randomized trial of prophylactic antiarrhythmic agents (amiodarone and sotalol) in patients with atrial fibrillation for whom direct current cardioversion is planned. Effects of diltiazem pretreatment on direct-current cardioversion in patients with persistent atrial fibrillation: a single-blind, randomized, controlled study. Mitral valve surgery plus concomitant atrial fibrillation ablation is superior to mitral valve surgery alone with an intensive rhythm control strategy. Control of heart rate versus rhythm in rheumatic atrial fibrillation: a randomized study. Control of rate versus rhythm in rheumatic atrial fibrillation: a randomized study. Prospective randomized comparison of left atrial and biatrial radiofrequency ablation in the treatment of atrial fibrillation. Pulmonary vein isolation combined with superior vena cava isolation for atrial fibrillation ablation: a prospective randomized study. Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein- left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial.

Cost-effectiveness of repetitive transcranial magnetic stimulation versus antidepressant therapy for treatment-resistant depression 20mg vardenafil visa. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multi-site randomized controlled trial buy 10 mg vardenafil. Pascual-Leone A discount 10 mg vardenafil otc, Cohen L order 20 mg vardenafil free shipping, Wassermann E, Vallas-Sole J, Brasil-Neto J, Hallet M. Lack of evidence of auditory dysfunction dure to transcranial magnetic stimulation. Pascual-Leone A, Valls-Sole J, Brasil-Neto J, Cammarota A, Grafman J, Hallett M. Effects of subthreshold repetitive transcranial motor cortex stimulation. Pascual-Leone A, Valls-Sole J, Wassermann E, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Motor threshold in transcranial magnetic stimulation: a comparison of a neurophysiological method and a visualization of movement method. Transcranial magnetic stimulation (TMS) in chronic pain: studies in waiting. Journal of the Neurological Sciences 2000; 182: 1-4. Transcranial magnetic stimulation and chronic pain: current status. Transcranial magnetic stimulation: potential treatment for tinnitus? Psychiatry and Clinical Neuroscience 2006; 60:133-138. Therapeutic use on non-invasive brain stimulation in dystonia. Rossini P, Barker A, Berardelli A, Caramia M, Caruso G, Cracco R, Dimitrijevic M, Hallett M, Katayama Y, Lucking C. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical Pridmore S. Electroencephalography and Clinical Neurophysiology 1994; 91:79-92. Physical principles for transcranial magnetic stimulation. Effectiveness of repetitive transcranial magnetic stimulation in patients with fibromyalgia: a meta-analysis. Short E, Borckardt J, Anderson B, Frohman H, beam W, Reeves s, George M. Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study. Siebner H, Tormos J, Ceballos-Baumann A, Auer C, Catala M, Conrad B, Pascual- Leone A. Efficacy toward negative symptoms and safety or repetitive transcranial magnetic stimulation treatment for patients with schizophrenia: a systematic review. Shanghai Arch Psychiatry 2017; 29: 61-76 Wassermann E. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalography and Clinical Neurophysiology 1998; 108:1-16. Short- and long-term effects of repetitive transcranial magnetic stimulation on upper limb motor function after stroke: a systematic review and meta- analysis. An updated meta-analysis: short-term therapeutic effects of repeated transcranial magnetic stimulation in treating obsessive-compulsive disorder. Only the first four (memory, orientation, concentration, language) are components of the regular psychiatric assessment. Language is a component in so far as we focus particular attention on the form of thought. It is also a focus of attention in the Mini Mental State Examination (MMSE; Folstein et al, 1975, see Chapter 20), the most widely used screening test for cognition/HCF. Some additional aspects of language are listed toward the end of this chapter for reference purposes. Recognition of stimuli (gnosis) and performance of skilled movements (praxis) are not components of the regular psychiatric assessment; they are traditionally part of the neurological exam, and may be used in the examination of a psychiatric patient when a neurological or other medical condition is being excluded. That is, the HCFs are examined in detail when the clinical findings suggest an “organic” disorder. It was coined at a time when investigative st technologies were crude (compared to those of the early 21 century). At the time, it was assumed that if no organic basis could be demonstrated (with the technology of the day), none existed. Those conditions for which no physical explanation could be Pridmore S. With technological advances, the boundaries of “organic” should be moved. Schizophrenia, for example, was considered to be a functional disorder, but imaging and genetic studies have clearly demonstrated a physical basis. The same applies to many other psychiatric disorders. The term organic, therefore, says more about the technology of the day than the existence of pathology. It can be argued that psychiatry is generally concerned with pathology at a molecular level (e. Putting confusing terminology aside: HCF testing is a valuable means of detecting conditions which may present as psychiatric disorders but which require the services of other branches of medicine. For example, patients may present with a picture suggestive of schizophrenia or depression which is secondary to space occupying lesions, toxic, endocrine or metabolic abnormalities, and in such circumstances, HCF testing frequently reveals abnormalities. In general, if memory, orientation, concentration and language are intact, the performance of learned skilled movements and recognition of stimuli will also be intact. Thus, the former may be regarded as a screening test, such that if they are intact, the latter need not be tested. This is a standardised, widely employed screening test of HCF. It examines orientation in some detail and then briefly touches on registration and recall, attention/concentration, language and constructional abilities. Brevity is its strength (allowing wide breadth examination) and its weakness (not providing a comprehensive assessment). This is a screening test which may be used to indicate whether more extensive (time consuming) examination is necessary. Memory Memory is the ability to revive past thoughts and sensory experiences. It includes three basic mental processes: registration (the ability to perceive, recognise, and establish information in the central nervous system), retention (the ability to retain registered information) and recall (the ability to retrieve stored information at will). Short-term memory (which for this discussion includes what has been called immediate memory by others) has been defined as the recall of material within a period of up to 30 seconds after presentation. Intuitively, there is something different between short tem and long term memory. At the library, there is something different Pridmore S. Long term memory can be split into recent memory (events occurring during the past few hours to the past few months) and remote memory (events occurring in past years). In addition to physical lesions, intoxication, emotional arousal, psychomotor retardation, thought disorder and motivation must be considered. Tests of memory During the psychiatric interview good information about memory is available. Memory testing provides quantification (but this may not be necessary). After some general conversation, the examiner may say something like, “Thank you Mr X, I understand what you have been saying. When a patient who has been treated respectfully but makes excuses or refuses cognitive testing, there is probably cognitive impairment.

GABA neurons in the striatum have the tracer and the displacer have achieved equilibrium bind- inhibitory effects on nigral dopamine neurons vardenafil 10 mg lowest price, nigral dopa- ing conditions order 10 mg vardenafil mastercard. However discount 10mg vardenafil with amex, if either the radiotracer (as in the mine neurons have inhibitory effects on striatal ACh neu- bolus injection paradigm) or endogenous dopamine (as in rons buy vardenafil with amex, and striatal ACh neurons have facilitating effects on stimulant-induced release) changes dynamically over time, striatal GABA neurons. By estimating dopamine levels in the equilibrium condition is not achieved, and the apparent striatum as described above, Dewey and collaborators sensitivity of the radioligand to endogenous dopamine levels showed in human or anesthetized nonhuman primates that is determined by the kinetic properties of the radioligand the blockade of cholinergic transmission by benztropine 11 (34,35). Equilibrium conditions can be achieved for both (44) or scopolamine (45) decreased [ C]raclopride binding tracer and displacer in the dopamine depletion paradigm. The high-af- pine agonist) increased [ C]raclopride binding (decrease 123 finity D2 radioligand [ I]epidepride provides an instruc- in dopamine levels) (46). In addition, they showed that tive example of the differences seen in kinetic and equilib- a dopamine antagonist, N-methylspiroperidol, induced a rium studies. The kinetics of its uptake in brain are slow decrease in [N-11C-methyl]benztropine binding, indicating and do not show displacement by transiently increased do- an increase in ACh levels (44). However, Other interactions have also been studied with PET. In stable low levels of dopamine induced with AMPT show two human studies, an N-methyl-D-aspartate (NMDA) an- unmasking of D2 receptors (37). In two human studies with similar tech- niques, the binding of [11C]raclopride was decreased by In Vivo Confounding Factors stimulation of 5-hydroxytryptamine (5-HT) transmission Although the displacement of radioligand binding by neu- with fenfluramine (a 5-HT releaser) (49) or psilocybin (a rotransmitter can be simply described with in vitro tissue mixed 5-HT2A and 5-HT1A agonist) (50). However, these homogenates, several factors complicate the interpretation results are discordant with those of previous studies in ba- of in vivo experimental results. Key aspects of the by the receptor to guanyl nucleotide-binding proteins (38). For example, typical antipsychotic limitation of these studies is that no useful glutamatergic agents occupy 50% to 80% of striatal D2 receptors (54). PET probes have been developed to examine this important Thus, a new typical antipsychotic agent should show a rea- mediating neurotransmitter system. Furthermore, the link- sonably acceptable side effect profile when given at doses age of pharmacologic challenges can be difficult to interpret. With regard to dos- For example, if a disorder is associated with an abnormal ing interval, the drug may be retained in tissue much longer dopamine outcome measured with PET in response to a 5- than in plasma, and, therefore dosing intervals based on HT challenge, is the abnormal response caused by altered plasma pharmacokinetics may be too frequent. Such a situa- sensitivity of the dopamine or 5-HT system? This kinetics in brain combined with the evaluation of adverse simple assumption has been questioned by elaborate studies reactions in a small number of healthy subjects may provide by Tsukada et al. If targeted receptor occupancy [ -11C]methyldopa (L-[ -11C]DOPA), [11C] -CIT, and is achieved without causing adverse reactions, studies in pa- [11C]raclopride, respectively, in combination with microdi- tients are justified. If not, further studies may not be indi- alysis in conscious rhesus monkeys. Even in the absence of a target level for receptor change extracellular dopamine levels in the striatum but occupancy, it is reasonably safe to assume that doses associ- increased [11C]raclopride binding by decreasing its affinity ated with greater than 95% occupancy are unnecessarily at the dopamine D2 receptor (52) Furthermore, ketamine high, and that those with less than 10% occupancy are un- decreased [11C]raclopride binding in the striatum without likely to be efficacious. By measur- the pharmacokinetics of either the tracer or displacer and ing receptor occupancy with [11C]N-methylspiperone in changes in the synthesis and reuptake of neurotransmitters healthy human subjects, initially an appropriate amount of and affinity of receptor binding may complicate the experi- a single dose (57) and then an appropriate dose and dosing ment, the authors feel that challenges linked with radio- interval were determined (56). Further, a similar level of tracer imaging are likely to provide useful information to receptor occupancy was recently confirmed with allow a better understanding of the pathophysiology of neu- [11C]M100907 in a small number of patients with schizo- ropsychiatric disorders. Dopamine Transporter Imaging as a USE OF RADIOTRACER IMAGING IN Biological Marker in Parkinson Disease THERAPEUTIC DRUG DEVELOPMENT Imaging of a biological marker may provide information Radiotracer imaging can provide useful information about that is useful either for diagnosis or as a monitor of disease molecules that are either the direct target of or indirect progression. In Parkinson disease, the two most successful markers for the effects of therapeutic drugs. For example, imaging targets used as biological markers are measures of if both the tracer and therapeutic drug competitively bind dopamine synthesis with [18F]FDOPA and of dopamine to the same target, then imaging can provide direct informa- terminal innervation with ligands for dopamine transporter. In addition, the molecular target mea- progressive loss of dopamine neurons in the nigrostriatal sured by the tracer (e. Such measurements are possible with in vivo deposition). However, these tracers do not detect the same biological process. Whereas Measurement of Receptor Occupancy 18 [ F]FDOPA detects metabolic activities at dopamine nerve Molecular imaging can provide useful guidance for two as- terminals, the tracers for dopamine transporter simply mea- pects of drug administration: dose and dosing interval. Because of this differ- dose is most easily chosen with a known target occupancy ence, the sensitivity to detect the decrease in dopamine neu- 420 Neuropsychopharmacology: The Fifth Generation of Progress rons may be different. In fact, both human and animal ing mood disorders (67) and drug addiction (68). However, studies have indicated that the imaging of dopamine trans- only a small number of PET and SPECT studies have been porter is more sensitive to dopamine neuronal loss (59). Although tracers have been Dopamine transporter can be quantified with SPECT developed to image three major biochemical cascades [i. Therefore, imaging of the dopamine transporter in tide (PI), and arachidonate pathways], all existing ligands movement disorders is widely performed in many developed have moderate to significant technical limitations, and bet- countries. Some of these tracers are lipids, It is clinically important but sometimes difficult to differ- and their nonspecific binding is too high. In addition, be- entiate essential tremor and Parkinson disease. Dopamine cause most of these tracers do not bind to a single type of transporter imaging clearly distinguishes these two groups, protein but are metabolized by several enzymes, the inter- with only a small overlap (60,61). However, dopamine pretation of the results is not clear. Further, these techniques have shown bilateral loss of dopamine transporter in hemi- Imaging of this signal transduction system was initially at- Parkinson disease (i. The binding of [11C]forskolin may be correlated with the Restoring dopamine levels with L-DOPA is still the core activation of adenylate cyclase (71). However, brain uptake medication treatment of Parkinson disease. Although palliative treat- PDE-IV is the major subtype in brain of PDE, which hydro- ment with L-DOPA is clearly of significant clinical benefit, lyzes cAMP into 5′-AMP. PDE-IV is composed of four current drug development is oriented toward neuroprotec- major enzyme subtypes, PDE-IV A, B, C, and D, and all tive treatments designed to slow the loss of dopamine neu- four subtypes are found in human brain (73). Rolipram rons and the consequent progression of symptoms. As a binds to and inhibits all four PDE-IV subtypes with high biological marker of dopamine terminal innervation of the affinity. In one report of a rat ex vivo study, [11C]rolipram striatum, dopamine transporter imaging may well be useful was a promising tracer exhibiting high specific brain uptake to monitor whether such new therapies actually slow the loss (72). Further evaluation of the binding selectivity and kinet- of dopamine neurons. In fact, SPECT imaging is sensitive to ics must be performed in nonhuman primates and humans and can quantify dopamine transporter loss in longitudinal subjects. Therefore, with appropriate Phosphoinositide System sample sizes, this imaging technique can quantify a relevant biological marker as a surrogate measure of the efficacy of Imahori and colleagues have studied the PI system in vivo putative neuroprotective therapies. They showed specific incorporation of the tracer in the chemical components of the rat PI system, such as phos- IMAGING POST-RECEPTOR SIGNAL phatidic acid, phosphatidylinositol, phosphatidylinositol 4- TRANSDUCTION phosphate, and phosphatidylinositol 4,5-bis-phosphate (74). Further, the tracer uptake was increased by an agonist The majority of the imaging studies performed to date have at the muscarinic ACh receptor, which is known to be cou- focused on the synapse: transporters as presynaptic targets, pled with the PI system (74). Therefore, two promising areas for expansion in the near Under these circumstances, intersubject variability in the future are post-receptor signal transduction and subsequent amount of tracer delivered to brain may be primarily deter- changes in gene expression. Abnormalities in second mes- mined by its binding to plasma components and not by senger systems have been postulated to play important neuronal activity of the PI system. If intersubject variability pathophysiologic roles in many psychiatric illnesses, includ- in f1 (the free fraction of tracer in plasma) is noted, tracer Chapter 31: In Vivo Molecular Imaging 421 uptake cannot be compared among different subjects. Several modalities are applied in cancer did indeed show such behavior (76). Further, whatever imaging, including (a) imaging oncogene products with ra- amount of a highly lipophilic tracer actually crosses the dioactively labeled antibodies, (b) imaging messenger RNAs blood–brain barrier tends to exhibit a high rate of nonspe- with labeled antisense oligonucleotides (81), (c) imaging cific binding. In summary, because of the difficulty in abso- reporter gene products with labeled reporter probes (82, lute quantification, the utility of this tracer as a quantitative 83), and (d) applying conventional techniques with labeled measure may be significantly limited. Because the blood–brain barrier presents a special obsta- cle in neuroimaging, most techniques successfully used in Arachidonate cancer imaging are difficult to apply in brain imaging. For The utility of [11C]arachidonate to detect in vivo activity this reason, the first approach with antibodies is not possible of phospholipase A2 has been studied rigorously. After intra- in brain imaging unless the integrity of the blood–brain venous injection, [11C]arachidonate is readily taken up barrier is disrupted, as in the case of brain tumors. By stimu- used, is also difficult because these multiply charged com- lating receptors that are linked to phospholipase A2, proba- pounds do not cross the blood–brain barrier in any appre- bly via the PI pathway, the labeled phospholipids are ciable amount.

Ideally buy 10 mg vardenafil fast delivery, persons referred to such services tion services varies by locale and by STD purchase vardenafil 20 mg on line. Some programs should also receive health counseling and should be referred have considered partner notifcation in a broader context purchase vardenafil 10mg on-line, for other health services as appropriate vardenafil 20mg mastercard. Prospective evaluations efectively decreases exposure to STDs and whether it reduces incorporating the assessment of venues, community structure, the incidence and prevalence of these infections in a com- and social and sexual contacts in conjunction with partner munity. Nevertheless, evaluations of partner notification notifcation eforts have improved case-fnding and illustrated interventions have documented the important contribution transmission networks (74,75). While such eforts are beyond this approach can make to case-fnding in clinical and com- the scope of individual clinicians, support of and collaboration munity contexts (65). When partners are treated, index patients with STD programs by clinicians are critical to the success of have reduced risk for reinfection. Terefore, providers should social network-based interventions. Further, tate partner notifcation (76), especially among MSM and providers can ask patients to bring partners with them when in cases where no other identifying information is available, returning for treatment. Time spent with index patients to and many health departments now conduct formal internet counsel them on the importance of notifying partners is associ- partner notifcation (IPN) (http://www. Clinical When patients diagnosed with chlamydia or gonorrhea providers are unlikely to participate directly in IPN. However, indicate that their partners are unlikely to seek evaluation and when discussing partner notifcation approaches with patients, 8 MMWR December 17, 2010 they should be aware of the value of the internet in this type pregnant women and treating those who are infected are of communication and should know where to refer patients vital not only to maintain the health of the patient, but to who are interested in using the internet to notify partners reduce perinatal transmission of HIV through available about their diagnosis. STD/HIV and acquired immunodefciency syndrome should be performed on any woman in labor who has an (AIDS) cases should be reported in accordance with state and undocumented HIV status unless she declines. Syphilis, gonorrhea, chlamydia, HIV test result is positive in these women, antiretroviral chancroid, HIV infection, and AIDS are reportable diseases in prophylaxis should be administered without waiting for every state. Because the requirements for reporting other STDs the results of the confrmatory test (78). Clinicians populations in which the amount of prenatal care deliv- who are unsure of state and local reporting requirements should ered is not optimal, rapid plasma reagin (RPR) card test seek advice from state or local health departments or STD screening (and treatment, if that test is reactive) should programs. In most jurisdictions, such reports are protected by statute Women who are at high risk for syphilis, live in areas from subpoena. Some states require all women to be screened at deliv- ery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has Special Populations been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a Pregnant Women stillborn infant should be tested for syphilis. Intrauterine or perinatally transmitted STDs can have • All pregnant women should be routinely tested for hepa- severely debilitating efects on pregnant women, their titis B surface antigen (HBsAg) during an early prenatal partners, and their fetuses. Women the possibility of perinatal infections, and provided access to who were not screened prenatally, those who engage in treatment, if needed. Screening should be conducted after the woman be retested at the time of admission to the hospital for is notifed that she will be screened for HIV as part of delivery. Pregnant women at risk for HBV infection the routine panel of prenatal tests, unless she declines also should be vaccinated. For women who decline HIV transient positive HBsAg result during the 21 days after testing, providers should address their objections, and vaccination, HBsAg testing should be performed before when appropriate, continue to encourage testing strongly. Testing including testing of initially reactive specimens with a Vol. When pregnant • Evidence does not support routine screening for women are tested for HBsAg at the time of admission Trichomonas vaginalis in asymptomatic pregnant women. Diagnostic Considerations) during the frst prenatal visit other Concerns (81). Women aged ≤25 years and those at increased risk for chlamydia (e. Women found and that timely and appropriate prophylaxis is provided to have chlamydial infection during the frst trimester for their infants. Screening during the pital in which delivery is planned and to the health-care frst trimester might prevent the adverse efects of chla- provider who will care for the newborn. In addition, mydia during pregnancy, but supportive evidence for household and sex contacts of women who are HBsAg such screening is lacking. Women aged <25 years are at high- should receive information regarding hepatitis B that est risk for gonorrhea infection. Other risk factors for addresses: gonorrhea include a previous gonorrhea infection, other – modes of transmission; STDs, new or multiple sex partners, inconsistent con- – perinatal concerns (e. Pregnant contraindicated); women found to have gonococcal infection during the – prevention of HBV transmission, including the frst trimester should be retested within approximately importance of postexposure prophylaxis for the new- 3–6 months, preferably in the third trimester. Uninfected born infant and hepatitis B vaccination for household pregnant women who remain at high risk for gonococ- contacts and sex partners; and cal infection also should be retested during the third – evaluation for and treatment of chronic HBV trimester. However, all women with Hepatitis C, Diagnostic Considerations) at the frst HCV infection should receive appropriate counseling and prenatal visit. Women at high risk include those with a supportive care as needed (see Hepatitis C, Prevention). Prophylactic cesarean delivery is not indicated for women who do not have active genital other Tests lesions at the time of delivery. Symptomatic women should references: Prenatal screening for HIV: A Review of the evidence be evaluated and treated (see Bacterial Vaginosis). Preventive Services Task Force (86); Revised 10 MMWR December 17, 2010 Recommendations for HIV Testing of Adults, Adolescents, and covered by the health plan (i. Pregnant Women in Health-Care Setting (77); Guidelines for In addition, federal laws obligate notices to benefciaries when Perinatal Care (87); Rapid HIV Antibody Testing During Labor claims are denied, including alerting consumers who need to and Delivery for Women of Unknown HIV Status: A Practical pay for care until the allowable deductable is reached. For STD Guide and Model Protocol (88); Viral Hepatitis in Pregnancy detection- and treatment-related care, an EOB or medical bill (89); Hepatitis B Virus: A Comprehensive Strategy for Eliminating that is received by a parent might disclose services provided Transmission in the United States — Recommendations of and list any laboratory tests performed. Tis type of mandated the Immunization Practices Advisory Committee (ACIP) (4); notifcation breeches confdentiality, and at a minimum, could Screening for Chlamydial Infection: U. Preventive Services Task prompt parents and guardians to question the costs and reasons Force Recommendation Statement (81); Canadian guidelines on for service provision. Preventive Services about sexual behaviors, assess STD risks, provide risk reduc- Task Force Recommendation Statement (85). Te screening recommendations in this oral, anal, or vaginal sex and drug-use behaviors). Screening Recommendations Adolescents Routine laboratory screening for common STDs is indi- In the United States, prevalence rates of many sexually cated for sexually active adolescents. Te following screening acquired infections are highest among adolescents (92,93). Factors on feasibility, efcacy, and cost-efectiveness. However, contributing to this increased risk during adolescence include screening of sexually active young men should be consid- having multiple sexual partners concurrently, having sequential ered in clinical settings associated with high prevalence of sexual partnerships of limited duration, failing to use barrier chlamydia (e. Women aged <25 years are at highest risk minors to consent for their own health services for STDs. Other risk factors that place state requires parental consent for STD care or requires that women at increased risk include a previous gonorrhea providers notify parents that an adolescent minor has received infection, the presence of other STDs, new or multiple STD services, except in limited or unusual circumstances. After a claim has been reported, many states and encouraged for those who are sexually active and mandate that health plans provide a written statement to a those who use injection drugs (77,95). USPSTF recom- BV, HSV, HPV, HAV, and HBV) is not recommended. Ofcial investigations, when indicated, adolescents (98). However, the American Cancer Society should be initiated promptly. Primary prevention and anticipatory guidance to recognize symptoms and behaviors associated with STDs are strategies Persons in Correctional Facilities that can be incorporated into any or all types of health-care Multiple studies have demonstrated that persons enter- visits. Te following recommendations for primary prevention ing correctional facilities have high rates of STDs (including of STDs (i. Te vaccine series sex; having multiple sexual partners; using drugs and alcohol; can be started at 9 years of age. Catch-up vaccination is and engaging in commercial, survival [prostitution to earn recommended for females aged 13–26 years who have money for food, shelter, or drugs], or coerced sex) are com- not yet received or completed the vaccine series (16).