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Information is not com- observed antituberculosis pharmacotherapy (71) order furosemide 100 mg mastercard blood pressure zone chart. These plete cheap furosemide 40mg mastercard arteria spinalis anterior, however generic furosemide 40 mg with amex arteria linguae profunda, and more studies are needed to map out findings have important implications for tuberculosis con- the extent of these interactions completely. One important trol policies in methadone programs because intravenous interaction is that methadone increases plasma levels of zi- drug users are at very high risk of tuberculosis infection and dovudine; the associated symptoms resemble methadone because maintenance programs provide settings in which withdrawal. There have been instances in which methadone directly observed therapy can be easily applied. Similar prin- doses have been increased in response to complaints of with- ciples apply to administration of psychotropic medication drawal, with increasing doses compounding the problem. Harm Reduction This interaction can be important if the patient discontinues either of these two drugs while taking methadone, because Harm reduction is concerned with minimizing various nega- the result may be a sudden rise in methadone blood levels tive consequences of addiction. As such, the focus is shifted with signs and symptoms of overmedication (65,66). Examples of harm reduction include seen in children born to opioid-dependent women. Perhaps needle exchange programs, efforts directed at reducing drug- the most serious is premature delivery and low birth weight, use-associated behaviors that may result in the transmission a problem that can be reduced if the mother is receiving of HIV, and making changes in policies (including increas- methadone maintenance and prenatal care (67). Another is ing treatment availability) that reduce heroin use and the physiologic dependence on opioids, seen in about half the criminal behavior associated with drug procurement. Harm infants born to women maintained on methadone or depen- reduction refers to reducing harm not only to the individual dent on heroin or other opioids. Effective treatments for addict, but also to family, friends, and society generally. For example, Reuter and The possibility that breast-feeding may cause adverse ef- Caulkins pointed out the benefit of integrating drug use fects in infants of methadone-maintained mothers was stud- reduction and harm reduction components into a single ied. It was found that methadone was present in the breast framework (74), because total harm may be lowered by re- milk of women maintained on doses as high as 180 mg, ducing either component. Roche and colleagues proposed but the concentration was very low, and no adverse effects a model for an integrated addiction treatment strategy that were observed in the infants (68). HIV infection is seen in incorporates harm reduction and use reduction with absti- about one-third of infants born to HIV-positive mothers, nence and nonuse (75), in addition to other critical elements but this incidence can be reduced to about 10% if HIV- such as factors related to culture and gender. Additionally, positive pregnant women are given zidovudine before deliv- MacCoun provided a template for integrating harm reduc- ery (69). HIV can also be transmitted by breast-feeding, tion with prevalence reduction (discouraging the engage- and thus infant formula feeding is recommended for babies ment in drug use) and quantity reduction (encouraging the of HIV-positive mothers, except in some developing coun- reduction in frequency or extent of drug use) (76). Thor- With regard to opioids, much of the health-related harm ough washing of infants born to HIV-infected mothers im- from their improper or illicit use is secondary to elements Chapter 105: Treatment of Opioid Addiction 1515 other than the substances themselves (77). Funds saved from these hygienic methods of administration and poor injection cost reductions have often not been invested in outpatient technique are typically more serious than the constipation treatment. A good example is the VA, which administers or other side effects of the drugs themselves, acute overdoses the largest network of substance abuse treatment programs notwithstanding. With regard to opioid addiction treat- in the United States. Since the application of managed care ment, medications such as methadone, LAAM, and bupre- policies, the overall amount spent on substance abuse treat- norphine, among others (including supervised heroin sub- ment declined by 41%, from $597 million in 1993 to $351 stitution) used for maintenance agonist treatment, may be million in 1999. Measured as a percentage of overall VA considered harm reduction measures. All have the potential health care costs, specialized substance abuse care decreased to reduce morbidity, mortality, and crime associated with from 4. However, in this sense they are no differ- VA health care expenditures increased 10% between 1993 ent from other medical therapies such as those used for the and 1999 (85). Most of these reductions were achieved by treatment of hypertension, diabetes, or asthma. The result has been an overall reduction cates that these types of programs may have beneficial effects in the total number of veteran patients treated and in the in numerous areas, including a reduction in the spread of amount of drug counseling provided. As a result, no new blood-borne infectious disease such as hepatitis and HIV, methadone programs were opened in the VA despite the and acting as a conduit to more comprehensive drug-abuse recent increase in heroin addiction, evidence of waiting lists treatment services (78). In one study (79), the initiation for methadone treatment, and cities (such as Portland, Ore- and continuation of syringe exchange program participation gon) with serious heroin problems but no agonist mainte- among high-risk injection drug users were independently nance programs in spite of recent increases in heroin over- associated with a cessation of syringe sharing. Not all that changes in resource allocation have caused programs findings have been positive, however. In a study designed to become vulnerable to service disruptions, poor morale, to assess the association between risk behaviors and HIV burnout, and reduced motivation and quality of perfor- seroprevalence and incidence among injection drug users, mance and characterized by failures to maintain service lev- risk elevations for HIV associated with needle exchange pro- els in accord with the mandates of law (86). However, an examination of to integrate medical and psychiatric services into agonist potential bias in nonrandomized comparisons (82) sug- maintenance programs. Thus, both old and new pharmaco- gested that injection drug users participating in needle ex- therapies for opioid addiction described earlier are un- change programs at a given point may include a high pro- derused in the VA, the largest substance abuse treatment portion of persons whose pattern of drug use puts them system. There is every indication that penetration of these at greater risk for blood-borne viral infections. Further, a new treatments into the opiate treatment field at large has prospective cohort study found no evidence of a causal asso- also been slow. Harm reduction related to psychoactive substance abuse has gone through numerous stages. The current phase has SUMMARY been described as the development of an integrated public health perspective for all drugs in which a multifaceted, New pharmacotherapies, behavioral therapies, and treat- strategic approach is taken (84). The direction of this ap- ment strategies are being developed for opioid addiction. As described earlier, various treatments can be combined to IMPACT OF MANAGED CARE produce better patient outcomes. However, the overall ef- fect of these developments on addiction treatment and pub- Efforts to control costs by managed care have resulted in a lic health is very dependent on funding support, which has marked reduction in use of inpatient or residential treat- become a serious problem. Parity legislation may help to 1516 Neuropsychopharmacology: The Fifth Generation of Progress solve funding problems and result in the expansion of treat- 19. Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone ment to meet patient needs, but the details of how and treatment for in-patient opiate detoxification. Drug Alcohol De- when more investment in substance treatment may occur pend 1998;50:227–232. The development of dose methadone in a 180-day heroin detoxification program. J medications for the treatment of opiate and cocaine addictions: issues Subst Abuse Treat 1994;11:225–232.

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Arch Gen Psychiatry raphy and 76-Br-bromospiperone in untreated patients order furosemide 40mg amex heart attack demi lovato mp3. Dopamine D2 receptor magnetic resonance spectroscopy study of schizophrenia pa- density estimates in schizophrenia: a positron emission tomogra- phy study with 11C-N-methylspiperone proven furosemide 40mg hypertension yoga exercises. No elevated D2 temporal lobe in first-onset schizophrenic patients generic 40mg furosemide amex hypertension what is it. Biol Psychia- dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methyl- try 1999;45:1403–1411. A positron emission tomography study with [11C]raclopride. In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance chiatry 1990;47:213–219. N-acetylaspartate reduction in dorsolateral characteristics in neuroleptic-naive schizophrenic patients stud- prefrontal cortex of patients with schizophrenia as revealed by ied with Positron Emission Tomography. An I-123-IBZM single photon emission computerized nia: clinical, neurodevelopmental, and cognitive correlates. Proton magnetic resonance function and negative symptoms in drug-free patients with spectroscopy: an in vivo method of estimating hippocampal neu- schizophrenia. Br J Psy- ronal depletion in schizophrenia [published erratum appears in chiatry 1997;171:574–577. Hippocampal age-related changes in schizo- with positron Emission tomography and 76Br-bromolisuride. Proton magnetic D2 receptors and negative symptoms of schizophrenia. Br J resonance spectroscopy of the left medial temporal and frontal Pharmacol 1994;164:27–34. Proton magnetic reso- studied with positron emission tomography. Am J Psychiatry nance spectroscopy in the frontal and temporal lobes of neuro- 2000;157:269–271. Biol Psychiatry 1998; lobe proton magnetic resonance spectroscopy of patients with 43:263–269. Proton lobe 1H MR spectroscopy in childhood-onset schizophrenia. J magnetic resonance spectroscopy of the temporal lobes in Magn Reson Imaging 1998;8:841–846. Psychiatry spectroscopy of the left temporal and frontal lobes in schizophre- Res 1999;92:45–56. It is in this arena that functional neuroimaging has had the broadest HISTORIC PERSPECTIVE application and greatest impact in psychiatry. This now ex- tensive body of work has left no doubt that schizophrenia Functional neuroimaging studies utilize the fact that neu- is associated with measurable, objective signs of altered brain ronal activation results in regionally increased blood flow function, and clinical and pathophysiologic correlations and metabolism. This can be measured either by radiotracer have begun to emerge. Increasingly, it appears that dysfunction oglobin to oxyhemoglobin imaged by magnetic resonance of a system of functionally and/or structurally intercon- techniques (the blood oxygenation level dependent [BOLD] nected cortical and limbic brain regions is present to lesser effect). This work began in earnest some 50 years ago with or greater degrees, producing more or less psychopathology the pioneering studies of Seymour Kety and colleagues who in individual patients, and that certain brain regions, such developed the first reproducible, quantitative technique for as frontal cortex, may play a special role in this larger picture. When this method was applied to ticularly cognitive impairment. Although it is likely that at schizophrenia (1), these investigators found no alteration in least some of the functional abnormalities are generative of the overall average CBF level in patients, a result that has these features and not simply a response to them, clarifica- largely been confirmed by more recent studies; however, tion of this 'chicken versus egg' issue must be a crucial this finding did not rule out the existence of neurophysio- component of any research program in this area, and the logically meaningful changes in specific brain structures. Current functional ment of rigorous methods that could differentiate the func- neuroimaging has much to offer in guiding this quest, par- tional level of specific cortical regions, albeit with only 2- ticularly when combined with new information now avail- cm anatomic accuracy at best (2). This method, administra- able from other fields such as genetics and cognitive science. The resulting findings delineate their relationship to other neurobiological and of functional abnormality in the frontal lobe spurred a shift clinical properties of the illness, discuss conceptual issues in focus throughout many research domains in the field that and controversies, examine methodologic considerations remains a prevailing force today. In the 1980s, the advent (including technical constraints), summarize new tech- of tomographic methods, such as single photon emission computed tomography (SPECT) and PET, which both use radioactive compounds as tracers, brought improved in- Karen Faith Berman: National Institute of Mental Health, Intramural terregional spatial resolution on the order of 5 to 6 mm Research Program, Bethesda, Maryland and allowed measurement of subcortical regional function. A particular advantage ing (fMRI) has emerged as the premier technique for neu- for research in schizophrenia is that neural activity during ropsychiatric functional neuroimaging. By taking advantage correct and incorrect trials can be measured separately and of the differential paramagnetic properties of oxyhemoglo- compared, allowing more incisive study of the mechanism bin versus deoxyhemoglobin and the altered ratio between of cognitive failure and better experimental control of po- them that occurs when blood volume and blood flow change tential confounds based in performance discrepancies that in response to neural activation, BOLD fMRI uses intrinsic often occur between patient and control groups. Event- properties of the blood itself rather than an extrinsic contrast related fMRI has very recently come into wide use in neu- or tracer agent, to generate maps of brain function. It is, roimaging of cognitive systems in healthy subjects, but as thus, entirely noninvasive, and measurements can be re- of this writing has had only limited application to the study peated over time, conferring significant advantage in experi- of schizophrenia. In this approach, blood flow and other measures advance brought further improvements in spatial resolution such as MR spectroscopy, neuroreceptor measurements, and as well as enhanced temporal resolution, which, although electrophysiology (with MEG or EEG) are determined in still slow (several seconds) compared to neuronal signaling the same patients. One example of the richness of the data (on the order of 200 ms), improved to the degree that event- that can be gleaned is the use of PET or fMRI to measure related neural activity could be recorded with anatomic blood flow in conjunction with EEG or MEG. PET and precision heretofore unavailable with electrophysiologic fMRI allow localization of the brain regions that work to- methods. On the other hand, EEG and MEG TECHNICAL PERSPECTIVE have relatively poorer spatial resolution, but provide fine time resolution (i. Combining these meth- As can be seen in the preceding brief history, over the years ods, together with the application of the advanced computa- the sophistication of the questions that could be asked and tional cross-registration and source localization techniques the hypotheses about schizophrenia that could be tested that now exist, provides exponentially more information have paralleled the development of new brain imaging tech- than any of these techniques alone. For example, this allows nologies and analytic methods. This parallel development the determination of the sequence in which various finely is evident in the evolution of the science from the search localized regions are activated during cognition and the test- for regionally specific pathologic function to that in neural ing of the hypothesis that this sequence of events is altered systems, and from measures sensitive only to static patho- in schizophrenia. Although this specific multimodal ap- physiology to explorations of the dynamic interplay among proach has not been applied in schizophrenia, other exam- regions in those neural systems.

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