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Such individuals may abuse alcohol in families with an odds ratio of 1 purchase propranolol 80mg mastercard. Alcoholism is today among the most holic parent is a significant risk factor for the development pervasive psychiatric disorders cheap propranolol 40mg on-line. In the United States order propranolol 80mg otc, the of the disease; children of alcoholics are five times more lifetime prevalence of alcohol dependence, the severe form likely to develop alcohol-related problems than children of of alcoholism, is 8% to 14% (1). It has been shown that the transmission dence to abuse is 1. Individuals often maintain a pattern of the vulnerability to alcoholism from parents to their of alcohol abuse without dependence for many years (2). Serious drinking frequently begins in adolescence, and ap- Studies of heritability, a measure of the genetic compo- proximately 40% of alcoholics develop their first symptoms nent of variance in interindividual vulnerability, indicate of addiction between the ages of 15 and 19 years (3). As that genetic influences are substantially responsible for the discussed in this chapter, heritability studies suggest that an observed patterns of familiality. Comparative studies across populations suggest holism in children even when the child is reared by unre- that sociocultural factors determine differences in thresholds lated adoptive parents (7,8). Large, well-constructed twin above which an individual is likely to go beyond social studies (8–10) have demonstrated that genetic factors are drinking and slip into abuse or addiction. Is the develop- important in determining vulnerability to alcoholism, par- ment of alcoholism due to a unique set of biochemical and ticularly in the more severe forms of the disease (11). Are there preexisting behav- been performed using the population-based Virginia Twin ioral traits that predispose to alcoholism? Caucasian female twin pairs of the questions addressed by this chapter. Some of the environmental influences are uniquely nonshared environmental factors, which is most accurately experienced by the individual (nonshared) and some are labeled as 'other,' including as it does other sources of variance such as measurement error (12). The results of these two studies were confirmed in a recent analysis of 5,091 U. This study also added the information Health, Bethesda, Maryland. Compared recent evaluation of the co-inheritance of alcoholism and with the expected genetic correlations of 0. Female twins from the Virginia Twin dence interval (CI) 4% to 45%] for opposite-sex pairs. Registry were evaluated for alcoholism, MD, BN, phobia, Although the heritability value of approximately 0. Alcoholism cohol dependence in men and women was replicated in emerged as the one disorder with a large disease-specific an analysis of 2,685 male and female twin pairs from the genetic component: approximately 75% of the genetic vari- Australian twin registry (10), no evidence was found for sex ance. In addition, smaller components of the genetic liabil- differences in sources of genetic influence. It may be that ity to alcoholism also loaded onto a factor common to MD the relatively small number of opposite sex pairs—592—in and GAD as well as a factor common to phobia, panic, and the Heath et al. COMORBIDITY OF ALCOHOLISM WITH OTHER SUBSTANCE ABUSE: GENETIC GENETIC HETEROGENEITY IN ALCOHOLISM DIATHESES? Although there is good evidence for substantial heritability Alcohol, cocaine, opiate, and tobacco (nicotine) depen- for alcoholism, individual differences in clinical presenta- dency co-occur more often in the population than would tion suggest variation in origins of vulnerability. This raises the pos- vary in their drinking patterns, the severity of their symp- sibility that there may be substance-general, as well as sub- toms, and in behavioral, physical, and psychiatric sequelae. Vulnerability factors found in some, but by hol and drug dependence (22,23). Both studies found that no means all, alcoholics include attentional deficits reflected relatives of drug-disorder probands across a wide range of by low amplitude of the P300 event-related potential (14), substances, including opioids, cocaine, and cannabis, had a anxiety reflected by the low-voltage alpha EEG trait (15), greater rate of drug disorders themselves than relatives of and diminished subjective response to alcohol (16). However, this comorbidity occurred largely inde- pendently from cotransmission of alcoholism, suggesting that the transmission of alcoholism and other drug disorders COMORBIDITY OF ALCOHOLISM AND is largely independent. OTHER PSYCHIATRIC DISORDERS: GENETIC The strongest evidence of a shared, as well as a specific, DIATHESES? It has long been observed that there is a relationship between Alcohol dependence is often comorbid with other psychiat- smoking and alcoholism. More than 80% of alcoholics ric disorders, including drug abuse, major depression (MD), smoke cigarettes and 70% are heavy smokers, compared anxiety disorders (ADs), and bulimia nervosa (BN), or anti- with 30% of the general population who smoke and 10% social personality disorder (ASPD) (17,18). In a multivariate genetic analysis currence is more common among women than men and is of the use of tobacco and alcohol in 774 MZ and 809 DZ positively associated with the persistence of alcohol depen- male and female twin pairs from the Virginia Twin Registry, dence in both men and women (18). Population comorbid- the univariate heritability of alcohol consumption was 0. Tobacco use had epidemiologic studies is their ability to detect evidence of a stronger loading on this shared genetic factor (0. However, the precise level of coexist in the same individuals, usually male. The relative the co-inheritance is less certain than the existence of co- risk of alcoholism is significantly increased in males with inheritance, and the level of genetic sharing may depend either ASPD, attention-deficit/hyperactivity disorder, or on how the phenotypes are determined. In an analysis of childhood conduct disorder, and there is evidence of co- 2,220 MZ and 2,373 DZ U. These data notwithstanding, a alcohol genetic factor accounted for 0. A study opioids are enhanced by activation of (and possibly also of 3,356 male twin pairs from the U. Registry found a substantial genetic correlation (r 0. Of the total vari- paminergic, opioid peptide, and serotoninergic neurotrans- ance in risk for alcohol dependence, 0. In contrast to opioids, which bind to specific receptors, ethanol appears to act on a variety of targets THE NEUROBIOLOGY OF ALCOHOL within the cell membrane in a less specific manner, inducing ADDICTION effects on neurotransmitter and neurohormone membrane receptors and receptor-gated and voltage-activated ion The essential features of addiction are loss of control over channels as well as modulating neurotransmitter release consumption, compulsion to obtain the next stimulus, and (34). Alterations in calcium channels may be a major com- continuation of abuse despite knowledge of negative health ponent of the changes that occur in the physical dependence and social consequences. Processes of reward and reinforcement GABA is the major inhibitory neurotransmitter in brain. It is likely that genetic variation in this neurobi- GABAA receptors are the primary site of action of benzodi- ology predisposes some individuals to a pattern of increased azepines and barbiturates, which are used in the treatment craving and loss of control. However, a path- of the glutamatergic neurotransmitter pathways, especially way that appears to be crucial to the action of all addictive at the level of the postsynaptic N-methyl-D-aspartate drugs is the mesolimbic dopamine system, which originates (NMDA) receptor, may be an important cause of its neu- in the ventral tegmental area (VTA) of the midbrain and rotoxic effects (36). Glutamate is the major excitatory brain projects to the nucleus accumbens (NAC), with projections neurotransmitter with up to 40% of all synapses being gluta- also to the limbic system and the orbitofrontal cortex (28). The mesolimbic in disinhibition of forebrain glutamatergic neurons that dopamine pathway is associated with the ability to feel plea- augment dopamine release (37). Serotoninergic neurons originating in the dorsal and receptor system may underlie intoxication and withdrawal median raphe nuclei project to mesolimbic structures, in- symptoms (38) as well as 'blackouts' (36). Homotarrine cluding the VTA and NAC, and may exert inhibitory con- (Acamprosate), a structural analogue of glutamate and an trol on mesolimbic dopamine neuron activity (29) (see NMDA-receptor antagonist, has been shown to almost dou- Chapter 95). Alcohol, psychostimulants, opiates, and nicotine (as well Some of the rewarding effects of ethanol result from acti- as tetrahydrocannabinol and phencyclidine) exert their pri- mary reinforcing or reward effects by releasing dopamine vation of opioid receptors in the VTA and/or receptors (DA) in the NAC.

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Pharmacological conversion of recent atrial fibrillation: a randomized generic propranolol 80 mg online, placebo-controlled study of three antiarrhythmic drugs discount 80mg propranolol with amex. Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation purchase 80 mg propranolol fast delivery. Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. Success of serial external electrical cardioversion of persistent atrial fibrillation in maintaining sinus rhythm; a randomized study. Randomized study comparing duty-cycled bipolar and unipolar radiofrequency with point-by-point ablation in pulmonary vein isolation. Blomstrom-Lundqvist C, Johansson B, Berglin E, et al. A randomized double-blind study of epicardial left atrial cryoablation for permanent atrial fibrillation in patients undergoing mitral valve surgery: the SWEDish Multicentre Atrial Fibrillation study (SWEDMAF). Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST): A 2-Center Randomized Clinical Trial. DC cardioversion of persistent atrial fibrillation: a comparison of two protocols. Higher energy monophasic DC cardioversion for persistent atrial fibrillation: is it time to start at 360 joules?. Anterior-posterior versus anterior-lateral electrode position for biphasic cardioversion of atrial fibrillation. An evaluation of the strategy of maintenance of sinus rhythm by antiarrhythmic drug therapy after ablation and pacing therapy in patients with paroxysmal atrial fibrillation. Catheter ablation for paroxysmal atrial fibrillation: a randomized comparison between multielectrode catheter and point-by-point ablation. Atrial fibrillation among African Americans, Hispanics and Caucasians: clinical features and outcomes from the AFFIRM trial. Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation: a prospective and randomized study. Oral amiodarone increases the efficacy of direct- current cardioversion in restoration of sinus rhythm in patients with chronic atrial fibrillation. Confounding factors in rate versus rhythm control trials in patients with atrial fibrillation: lessons from the strategies of treatment of atrial fibrillation (STAF) pilot study. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. Randomized comparison between pulmonary vein antral isolation versus complex fractionated electrogram ablation for paroxysmal atrial fibrillation. Left atrial radiofrequency ablation during mitral valve surgery: a prospective randomized multicentre study (SAFIR). Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. Impact of systematic isolation of superior vena cava in addition to pulmonary vein antrum isolation on the outcome of paroxysmal, persistent, and permanent atrial fibrillation ablation: results from a randomized study. Clinical factors that influence response to treatment strategies in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Randomized study of surgery for patients with permanent atrial fibrillation as a result of mitral valve disease. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Effect of verapamil on secondary cardioversion in patients with early atrial fibrillation recurrence after electrical cardioversion. Does electrogram guided substrate ablation add to the success of pulmonary vein isolation in patients with paroxysmal atrial fibrillation? Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management of rapid ventricular rate in atrial fibrillation. Efficacy of an additional MAZE procedure using cooled- tip radiofrequency ablation in patients with chronic atrial fibrillation and mitral valve disease. Atrial fibrillation ablation strategies for paroxysmal patients: randomized comparison between different techniques. Comparison of cool tip versus 8-mm tip catheter in achieving electrical isolation of pulmonary veins for long-term control of atrial fibrillation: a prospective randomized pilot study. Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: a prospective randomized study. Randomized Ablation Strategies for the Treatment of Persistent Atrial Fibrillation: RASTA Study. Quality of life variables in the selection of rate versus rhythm control in patients with atrial fibrillation: observations from the Canadian Trial of Atrial Fibrillation. Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). Left atrial radiofrequency ablation during mitral valve surgery for continuous atrial fibrillation: a randomized controlled trial. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Left mitral isthmus ablation associated with PV Isolation: long-term results of a prospective randomized study. Pulmonary vein isolation using segmental versus electroanatomical circumferential ablation for paroxysmal atrial fibrillation: over 3-year results of a prospective randomized study. Catheter ablation of atrial fibrillation in patients with diabetes mellitus type 2: results from a randomized study comparing pulmonary vein isolation versus antiarrhythmic drug therapy. Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate. Long-term clinical results of 2 different ablation strategies in patients with paroxysmal and persistent atrial fibrillation. Pulmonary venous isolation versus additional substrate modification as treatment for paroxysmal atrial fibrillation. Biphasic energy selection for transthoracic cardioversion of atrial fibrillation. Does intensity of rate control influence outcome in persistent atrial fibrillation? The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. Impact of rate versus rhythm control on quality of life in patients with persistent atrial fibrillation. Sinus rhythm is associated with fewer heart failure symptoms: insights from the AFFIRM trial. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation.

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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 purchase propranolol 80 mg fast delivery,58 order propranolol discount, two drugs buy 80mg propranolol mastercard. 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). 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).