By F. Ramirez. Hendrix College.

Clozapine buy 0.5 mg colchicine mastercard infection preventionist, risperidone purchase colchicine 0.5mg amex antibiotics before dental work, 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). In addition, the done treatment has been associated with minimal weight atypical antipsychotics have been associated with new onset gain, which could distinguish it among other atypical agents type II diabetes mellitus (82). The FDA delayed ziprasidone approval because of effects are secondary to weight gain, independent, or causa- concern about its ability to prolong the Q-T interval (90), tive. Atypical drugs are also associated with increases in cho- but an FDA Advisory Committee recommended its ap- lesterol and lipids, the long-term medical consequences of proval for the treatment of schizophrenia in July 2000, and which are largely unknown (78). It appears prudent to mon- the FDA issued an approval letter in September 2000. The new atypical drugs also have their Effectiveness own individual and idiosyncratic side-effect profiles (Table 56. Thus, each new drug should be evaluated individually Considerable evidence indicates that relapse and rehospital- in terms of side effects and safety (39). The decreased EPS liability of the atyp- zapine can cause serious side effects that impose substantial ical drugs will make it easier to prescribe more effective limitations on its use. Patient-based measures as sedation, hypotension, hypersalivation, and weight gain of quality of life show improvement with the atypical drugs (8). The frequency of agranulocytosis with clozapine is such over the conventional neuroleptics (45). In one randomized controlled trial comparing clozapine Risperidone has a favorable side effect profile in compari- with standard neuroleptic therapy for treatment-resistant son to haloperidol (84). Risperidone can produce dose-re- schizophrenic inpatients, the actual hospital discharge rates lated EPS ( 6 mg per day), but the rate of TD is low at 1 year were 27% for clozapine and 29% for standard (0. The clozapine group, however, had decreased re- 85).

The newer medication involving 4 million residents of the United Kingdom indi- 'broke even' on costs proven 0.5 mg colchicine antibiotic resistance review article, in that the higher acquisition costs cated the rate of death by suicide in patients receiving fluox- of fluoxetine were balanced by the lower costs of other ser- etine to be no lower than the rate of death by suicide in vices generic colchicine 0.5 mg fast delivery antibiotics for uti elderly, but did not result in an overall savings to the health patients receiving TCAs (54). On the other hand, a formulary policy of re- appeared to substitute violent methods or carbon monoxide quiring failure of a tricyclic before access to the newer medi- poisoning for overdoses. Such complete method substitu- cation was granted would not have saved money in this tion would suggest that SSRIs do not save lives and that particular primary care practice. The authors concluded that saving lives cannot therefore be used to justify their added 1134 Neuropsychopharmacology: The Fifth Generation of Progress expense. These data, however, are based on only 11 suicides This is especially true for psychiatric practices and for prac- among a limited number of fluoxetine cases. This analysis produced a very wide range of estimates, the simulations and none of the administrative database primarily because of uncertainty regarding whether SSRI- studies focus exclusively on psychiatric practice. Many fea- treated patients would substitute other methods of suicide tures distinguish the treatment of depression in primary care for overdoses. As part of a simulation, another study in- fromthe treatment of depression in psychiatric practice, cluded suicide as part of the cost of treatment dropout (56). For example, the direct costs of latter study were very high, and few costs were considered treatment failure may be higher in psychiatric practice than in the analysis. On the other hand, the tendency of psychiatrists to data are needed about the extent to which patients, knowing use higher and possibly more effective doses of TCAs than that the pills are not lethal, might substitute methods of primary care prescribers do would likely favor the cost-effec- suicide that are even more deadly than TCA overdoses. Simi- However, recently emerging epidemiologic data appear to larly, it may be less likely in psychiatric practice than in suggest that newer antidepressants may have a favorable im- primary care that the greater tolerability of SSRIs and the pact on death by suicide when all methods, not just over- reduced requirement for dose titration would offset costs doses, are taken into account (57–60). Prospective randomized cost- The available data that may be confidently brought to bear effectiveness experiments in psychiatric practice could ad- on the two cost-effectiveness questions posed in the intro- dress the substantially different environment of specialty duction are surprisingly sparse. Similarly, although the data on the treatment of depres- More prospective studies are clearly needed. Most of the sion in the United States are limited, those on the cost- retrospective studies and the simulations contain methodo- effectiveness of the newer antidepressants in other countries, logic limitations sufficient to generate significant concern especially developing countries, are still more limited. Additionally, the studies include randomized studies outside the United States have com- diverse variations in almost all the elements of cost-effective- pared newer and older antidepressants. Some of the simula- ness analysis, so that cross-comparisons and aggregate con- tions and none of the administrative database studies focus clusions are very difficult to make. However, if we must on other developed countries, such as Canada and the Euro- draw conclusions fromthe current data, we would suggest pean nations. The many ways in which the treatment of the following tentative conclusions. Acquisition costs for the newer medications are newer antidepressants cost-effective as first-line treatment generally lower in countries other than the United States fromthe health care systemperspective? Nevertheless, price may still put the newer antidepres- use of the newer antidepressants within primary care prac- sants out of reach for most of the population in some devel- tice in the United States may be roughly equally effective oping countries (64). The organization of health care sys- and also cost-neutral in terms of direct medical resource tems varies greatly, and the potential of the newer costs to the health care system. The recently published long- antidepressants to offset costs could also vary greatly across termdata fromthe only randomized study support this view countries. Prospective randomized cost-effectiveness experi- (26), and the simulations and retrospective studies, with all ments in countries other than the United States would make their limitations, do not contradict it. However, because it possible to evaluate whether cost-effectiveness conclusions the data are sparse and contain multiple methodologic prob- are widely applicable. Economic comparisons of the pharmacotherapy and none of the studies is prospective. Acta Psychiatr Scand 1998;97: costs were not comprehensive in some studies, being limited 241–252. Mirtazapine—a pharmacoeco- porting QALYs, the outcome rates were taken from expert nomic review of its use in depression. Pharmacoeconomics 2000; opinion panels, or utility determinations were uncertain. Fluoxetine—a pharmacoeconomic review Most of these studies have numerous other methodologic of its use in depression. Sertraline—a pharmacoeconomic evaluation substitution of suicide methods, enhancement of work pro- of its use in depression—reply.

These assessments involved have come under scrutiny in epidemiologic research cheap colchicine 0.5mg otc antibiotics for uti for sale, most private face-to-face interviews with each child discount 0.5mg colchicine with amex antibiotics for acne safe while breastfeeding, in which recently an observed co-occurrence involving the anxiety standardized survey research methods with blinding (asses- disorders, especially phobic disorders (61). One can expect sors did not know which children had received which inter- a more rapid acceleration of epidemiologic attention to the vention) and teacher ratings were used. Once the children linkof anxiety disorders to alcohol or other drug depen- were old enough, they were allowed to marktheir answers dence, with time from the first nonexperimental observa- on an answer sheet that could not be read by the assessor tions to the first indirect randomized, controlled trial mea- and was sealed in an envelope for later data entry. The sured in years rather than in decades, as was the case for assessments also involved ratings by the teachers in these the linkof childhood deviance and antisocial behavior to later grades; the middle school teachers knew that the chil- drug dependence. In this context, it may be important to dren had been in a prevention experiment, but they did not note another feature of the Woodlawn Project findings, know which of the three conditions the child might have which drew attention to the combination of shyness and received during the first 2 years of primary school. The Woodlawn Life table and regression analyses of the follow-up teacher Project report noted an interaction of shyness and aggres- Chapter 109: Epidemiology of Drug Dependence 1567 sion, directing attention mainly to the excess riskfor heavy gets identified and characterized through elaborations of drug use among boys who were rated in first grade as being the human genome project. For example, one can imagine both shy and aggressive. However, careful inspection of the research on parental influences on drug taking that includes Woodlawn Project study data indicated that the observed measurement of parenting behaviors in addition to inher- interaction depended heavily on a quite low occurrence of ited determinants of persistent drug use, such as the alleles drug use among the boys who were shy but not aggressive. The link to current anxiety disorders and comorbidity research involves the RUBRIC 4, MECHANISMS: 'HOWDO prominence of phobias in the observed association with al- SEQUENCES OF CIRCUMSTANCES, cohol and other drug dependence, and the Woodlawn CONDITIONS, AND PROCESSES LEAD TO Project measurement of shyness as a trait that encompasses DISEASE? Epidemiology as a discipline places emphasis on studies of Before we leave the rubric of causes, several recent studies the 'natural history' of disease, in part because of its early merit special mention because of their pertinence in the confluence with clinical medicine, bacteriology, and virol- genetic epidemiology of drug dependence. Here, natural history may be understood as the out- Veteran twin study is especially noteworthy because it is ward manifestations of an evolving causal process and the seeking to partition genetic, shared and nonshared environ- expression of causal mechanisms that lead toward the fatal mental influences across a sequence of transitions leading or nonfatal resolution of the condition under study. Unique to this study is its attention study of diseases, 'clinical course' can be differentiated to the transition from before to after the first exposure to from 'natural history' once clinical attention can make a opportunities to try drugs (62). The importance of this tran- fundamental difference. Before then, what we see is natural sition in etiologic research on drug dependence is discussed history. Once effective treatment maneuvers have been in the next section, under the heading of causal mechanisms. This workis leading us to applied in the epidemiology of drug dependence, most at- a better understanding of how genetic predispositions may tention was given to observable 'stages' and 'develop- have an important influence on entry into risk-laden envi- mental sequences. They specified a pre-initiation stage that involved characteristics on responses to drug exposure. In a related first exposure to an opportunity to try a drug. Thereafter, line of workon parent–child interactions, Kendler et al. Among those who actually try the ness or aloofness may affect the occurrence of alcohol or drug, the drug-using stage may or may not be followed by other drug dependence, but the evidence is not generally another stage—transition into drug dependence. Some supportive of an influence of active parenting styles (e. Soon, results will be available from indirect random- mental sequence in which different drugs are tried, first ized, controlled trials in which interventions have been used legally available beer or wine, then hard liquor or tobacco, to increase the aspects of parenting behavior suspected of then marijuana as the first 'illicit' drug in the sequence, being most influential in early drug involvement (e. Here, the causal inference is sup- sequence is use of prescription psychotherapeutic medicines ported by a fairly solid body of observational evidence con- (Fig. Nonetheless, as in the linkbetween sociopathy and drug Nonetheless, some observers have argued that this 'gate- dependence, replications from indirect randomized, con- way description' of sequences from drug to drug may rest trolled trials are apt to provide the most definitive evidence solely on different levels of availability or opportunity to regarding these issues of causal inference. Other investigators have challenged the randomized, controlled trials with large epidemiologic sam- stage transition concept as applied to drug dependence and ples will probably be performed, possibly with specific tar- youthful tobacco smoking (77). They have advocated an 1568 Neuropsychopharmacology: The Fifth Generation of Progress century, a new type of professional emerged—a public STAGE 1 health officer equipped with newly found knowledge of epi- BEER OR WINE demiology and armed with police powers necessary to pro- tect the larger population from the threat of infectious dis- STAGE 2 eases. In twentieth century efforts to mount an effective TOBACCOTOBACCOTOBACCO societal response to drug dependence, the police authority HARD LIQUOR CIGARETTESCIGARETTESCIGARETTES was split from the public health authority. As a result, when most people now thinkof the prevention of drug depen- dence, what comes to mind are health education classes for TOBACCO young people of school age or mass media campaigns to HARD LIQUOR CIGARETTES publicize the hazards one faces once drug use starts. We do not tend to thinkof the international, federal, state, and local laws or police actions as societal instruments for pre- STAGE 3 vention.

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