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Predictors of prolonged time to tant effect on the course of depression cheap 100 mg female viagra with amex. In the collaborative recovery included a longer length of the index episode cheap female viagra 100 mg without prescription, older study, it was found that patients with double depression age, and a lower family income. Relapse is also more frequent in patients with double depression than those with major depression alone—almost twice as likely in one Recurrence study of 32 double-depressed subjects followed for 2 years Angst (15), reporting on a 10-follow of patients in the Zu- (20). The MOS also found that full recovery was less likely rich study, found that only 25% of patients had only a single for patients with double depression—these patients had a episode of depression. Thus, three-fourths of the sample threefold risk of continued disease when compared with had a recurrent depression, with one or more recurrences. Though Angst examined a number of sociodemographic variables, none significantly predicted the likelihood of re- Other Psychiatric Illnesses currence. Similarly high rates of recurrence have been found in Substance Abuse other long-term studies. Weissman and Kasl (16) found that Clearly, comorbid substance abuse has a detrimental effect two-thirds of woman seen over 1 year had a recurrence of on the course of depression. Rao and Nammalvar (17), examining over 100 who were currently alcoholic were half as likely as nonalco- cases of depression in India for a follow-up of between 3 holic depressed subjects to recover from their episode of and 13 years, found that only about a fourth of the original major depression (22). Patients with a previous, but not group reported no recurrence of symptoms. The time to recurrence was The presence of such comorbid disorders appears to exert also much longer in the asymptomatic group: mean of 180 a negative effect on the course of depression. Coryell and weeks in the asymptomatic group compared with 33 weeks colleagues (23) found that depressed patients with panic in the group with residual symptoms (18). PLACEBO: with higher symptom ratings of anxiety had longer times CONTINUATION STUDIES to recovery from major depression (24). Drug Weeks of Relapse Relapse (Reference) Treatment (Drug) % (Placebo) % P Value FamilyHistory Fluoxetine (27) 52 26 57 <. Two studies have looked at the rela- Citalopram (30) 24 11 31 <. Though these studies had Mirtazapine (31) 20 4 23 <. Nefazodone has also been shown in Clearly, one of the questions of most practical interest is continuation treatment (32). These studies are summarized whether pharmacologic treatment is capable of significantly in Table 69. However, when looking beyond continua- altering the course of depression for a patient. Antidepres- tion therapy to the maintenance treatment of recurrent sants are generally used at all stages of depression—to hasten depression, much fewer data exist. However, as will be discussed, the further one looks nance trial for depression. Patients who were successfully down the course of depression, the less is really known about treated for acute depression were randomized to receive lith- the ability of antidepressant and other pharmacologic treat- ium carbonate, imipramine, both, or placebo. Of 150 patients beginning maintenance antidepressants in shortening the time to recovery from treatment, 36% were successfully treated. However, when one goes beyond the of recurrence was found it the group treated with imipra- acute phase and examines pharmacotherapy during later mine (Fig. However, even this group had a 47% points in the course of depression, the data become more recurrent rate. A second study, the Pittsburgh Study of Maintenance Data support the efficacy of most of the serotonin reup- Treatment for Recurrent Depression (34), reports on up to FIGURE 69. Pittsburgh Study of Maintenance Therapies in Recurrent Depression. Chapter 69: The Course of Depression 1013 5 years of maintenance treatment. In this study, subjects To date, there are only two published studies on the long- first underwent open treatment for acute depression, using term treatment of chronic depression. Kocsis and colleagues imipramine with interpersonal therapy (IPT). Patients who (36) report on a placebo-controlled trial of desipramine for achieved recovery for at least 4 months were then random- the treatment of chronic depression. The study included ized into one of five treatment conditions: (a) IPT alone, patients with chronic major depression (n 14). This portion of the study was contin- During this maintenance period, patients on the placebo ued for 3 years. Results from this study are summarized in had four times the recurrence rate of those receiving desipra- Fig. This rate was consistent for all diagnostic groups, The authors intentionally chose patients who had highly including those with chronic depression. They found that patients chronic depression in a larger sample of patients.

This en- has also been well described (35) cheap 100 mg female viagra free shipping, and it seems similar to zyme has been shown to enhance the aggregation of - the problems that had led to the failure of metrifonate to amyloid into the more fibrillar form that is deposited in reach the marketplace generic female viagra 50mg on-line. Antibodies to cholinesterase blocks A had a substantial association with nausea and vomiting, with aggregation in vitro (52). Whether such effects on aggrega- 47% of patients reporting these symptoms during a 12- tion are produced by cholinesterase inhibitors, as occurs week trial (31). Unless additional work is done with these with antibodies directed at the cholinesterase molecule in compounds to modify this adverse event profile, it is un- vitro, has not been shown. It is possible that the aggregating likely that either of these drugs will be available for routine effects of cholinesterase are facilitated by sites in the enzyme use in the clinic. Al- ternatively, cholinesterase inhibition could alter cholinester- ase in such a way as to diminish aggregating properties. Course-Altering Properties of Two paradigms that could offer some insight into course- Cholinesterase Inhibitors? In the delayed treatment of Alzheimer disease is now beyond question. A start paradigm, an agent that would alter the course of Alz- far more intriguing issue is whether these drugs alter the heimer disease would be expected to have a greater effect course of the disease. In of amyloid precursor proteins (APP) in various cell culture every study with cholinesterase inhibitors reported to date lines has been studied (36,37). Cholinergic stimulation ap- using a related but flawed delayed start procedure, placebo- parently increases the production of nonamyloidogenic APP treated patients who were given cholinesterase inhibitors 6 fragments. In all animals in which potentially amyloido- months after the group of patients on the drug did not genic fragments of APP are increased as a consequence of catch up on cognitive measures to the patients who were lesioning in various neuronal populations, some, but not treated with the drug from the start of the study. However, all, cholinomimetics normalize that process and diminish the interpretability of these data is limited because at the the production of amyloidogenic fragments (38). It has also time of switchover from placebo to drug, the studies were been suggested that the toxicity of beta-amyloid peptide no longer blinded. Furthermore, self-selection for switch- (A ) itself on neurons is diminished by some cholinesterase over, or retention on drug, could occur and further con- inhibitors (39,40). In the withdrawal paradigm, patients re- Nicotinic stimulation may be particularly relevant in al- ceiving the drug are randomly discontinued from the drug 1246 Neuropsychopharmacology: The Fifth Generation of Progress on the completion of the trial and compared with the pla- outcome measures were nursing home placements, death, cebo group. Occasionally, this paradigm has demonstrated or the loss of a well-defined activity of daily living. Cognitive continued efficacy for some, but not all, cholinesterase in- change was also evaluated. Here too, methodologic problems limit showed a statistically significant beneficial effect on all out- an unequivocal interpretation of these data. Surprisingly, a favorable Taken together, no carefully conducted, adequately pow- effect on cognition was not found for any agent. Unfortu- ered studies address the question of whether cholinesterase nately, despite randomization, subjects in the treatment inhibitors, at any course in the illness, delay progression. Consequently, the significant results of the puzzle are open to interpretation. However, as inter- were only obtained when a covariant technique was used esting as this question is to clinical neuroscientists, it may to adjust for the difference in baseline cognition across the be relatively moot to caregivers who struggle with patients treatment arms. This circumstance, combined with the neg- with Alzheimer disease. To such people, the nuances of ative effect on cognition, raises questions regarding the ro- whether plaque and tangle formation may be slowed, and bustness of these antioxidant treatments. Nonetheless, the neurons kept alive, are less relevant than the question inclusion of 2,000 IU per day of vitamin E in the treatment whether time to a particular milestone of the disease can regimen of patients with Alzheimer disease has become rela- be delayed by cholinesterase treatment. Coagulopathy can be another vitamin of some of these compounds, if not all, on such problematic E–associated adverse event (64–67). Interactions between noncognitive behaviors (55) can also lead to a better out- vitamin E and oral anticoagulants are a real possibility and come. This seems increasingly likely given that the cholines- emphasize the need for monitoring prothrombin times in terase inhibitors appear to have their most robust effect in patients who receive this combination. In contrast to the middle-stage disease, or perhaps even later (56–58). This widespread use of vitamin E, selegiline has not become a result is completely compatible with postmortem findings routine part of Alzheimer disease therapy because selegiline of cholinergic parameters that find the cholinergic deficit was not found to be superior to vitamin E, nor was there to be most apparent in middle- or later-stage disease and any benefit of combining vitamin E and selegiline to either to be not present in the earliest stages of illness (59). The adverse event profile for selegiline is far more extensive than vitamin E, and it includes hypotension VITAMIN E AND ANTIOXIDANTS with subsequent falls, as well as sleep disturbance, psychosis, agitation, and confusion. The potential for a serious interac- The production of free radical species has been considered tion between selegiline and antidepressants commonly used a mediating event for many forms of neuronal death or to treat comorbid depression in patients with Alzheimer damage.

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Buprenorphine has overdose death than is the case with methadone or LAAM female viagra 100 mg with mastercard. Most of the Antagonist Maintenance early clinical trials used a sublingual solution of buprenor- phine formulated in a hydroethanolic vehicle discount female viagra 100 mg with mastercard, although a Naltrexone is the prototypical opioid antagonist used in more commercially suitable sublingual tablet formulation abstinence maintenance therapy; this drug blocks the effects is now used. Naltrexone has no opioid agonist effects and is full agonists such as methadone and LAAM is the plateau a competitive opioid antagonist. It is orally effective and effect of -agonist activity. Parenteral doses as high as 12 can block opioid effects for 24 hours when administered as mg intravenously (28) have been given to opioid-intolerant a single daily dose of 50 to 60 mg. Higher doses usually patients with only limited adverse effects (e. Numerous large trials have con- they will provide more cross tolerance to heroin and other firmed the utility of buprenorphine for agonist maintenance opioids during the 24-hour dosing period (38). These studies have included comparisons of bu- favorable adverse event profile (nausea is typically the most prenorphine with placebo (29,30), a buprenorphine-nalox- common side effect), naltrexone is generally not favored by one combination with placebo (30), and a multiple-dose opioid addicts because, unlike opioid agonists and partial comparison study (31). In one of the most recent trials (32), agonists, it produces no positive, reinforcing effects. Fur- buprenorphine (given three times weekly) was compared thermore, it may be associated with the precipitation of an with LAAM (given three times weekly) and methadone opioid withdrawal syndrome if it is used too soon after (given daily) in a 17-week study. Mean retention in treat- opioid use stops, an effect that can be minimized by admin- ment was higher for buprenorphine, LAAM, and high-dose istering a naloxone challenge test before giving naltrexone. Opioid- more than 25 years, work continues on increasing medica- positive urine samples decreased most for the LAAM-treated tion compliance and improving outcomes. Some of these group and least for low-dose methadone. Patient self-reports more recent efforts include work to develop a depot form of opioid use did not differ among the groups, but they that will block opioid effects for 14 to 28 days. This dosage showed decreases of about 90% over the course of the study. At present, a Buprenorphine has the potential to be abused and can patient treated with naltrexone has only to stop the medica- produce addiction. However, most persons who abuse bu- tion for 1 to 3 days to experience the full effects of subse- prenorphine initiated opioid use with other drugs. A depot dosage form of naltrexone would may take the form of using greater than prescribed dosages provide more time for patients to overcome ambivalence for analgesia, using buprenorphine in place of a more de- about stopping opioid use and could result in more long- sired but less available opioid such as heroin, or using bu- term success than has currently been the case. Another var- Chapter 105: Treatment of Opioid Addiction 1511 iant on antagonist treatment is nalmefene, an orally effective weeks or months of treatment with reductions in frequency but somewhat longer-acting (about 48 hours at dosages of to biweekly or monthly depending on progress. Results showed a dence and abuse are ambivalent about stopping drug use dose–response relationship with the minimal condition (41,42). This ambivalence presents a therapeutic challenge doing significantly worse than standard and enhanced coun- because it contributes to varying levels of motivation to seling doing the best overall; however, about 30% of pa- enter and remain in treatment, to early dropout, and to tients did well in the minimal counseling condition. This partial or (in some cases) nontreatment response. Studies study clearly demonstrated the positive benefits achieved by have emphasized that treatment providers must be aware of drug counseling and showed that, for most patients, coun- this 'normal' ambivalence and make reasonable efforts to seling is necessary to bring out the maximum benefits of resolve it in favor of treatment participation and cessation agonist maintenance. Suggestions have been made regarding Most counseling is individual, one on one, but some initial steps to maximize the chances for engagement in programs use group therapy exclusively. These include avoiding programs use groups only for selected patients with focal unnecessary delays in entering treatment, expressing a hope- problems such as HIV disease, posttraumatic stress disorder, ful and nonjudgmental attitude, performing a comprehen- homelessness, loss of close personal relationships, or not at sive evaluation, and developing a treatment plan that is re- all. Some programs have self-help groups or with medical, psychiatric, legal, employment, and family that meet regularly on site. Counselors, like psychothera- or social issues that preexist or result from the addiction. This Research has found that addressing these additional prob- variability seems more related to the ability to form a posi- lems can be helpful, but they are complex and require coor- tive, helping relationship with the patient than to specific dination between agonist pharmacotherapy staff and other techniques (46). Contingency management techniques are always in- The most common type of psychosocial service in opioid cluded in drug counseling, if for nothing else than to fulfill agonist treatment is individual drug counseling. Counselors regulations about requiring progress in treatment as a condi- are typically persons at the masters level or below who de- tion of providing take-home doses, and studies have shown liver a behaviorally focused treatment aimed to identify spe- that they can be very helpful. For example, an opportunity cific problems, to help the patient access services that may to receive take-home medications in return for drug-free not be provided in the clinic (e. Functions that counselors perform in- a clear use in general clinical practice because it is easily clude monitoring methadone and LAAM doses and request- applied and costs little or nothing beyond standard program ing changes when needed, reviewing urine test results, re- costs. More flexibility in dispensing take-home doses as con- sponding to requests for take-homes doses, assisting with tingencies for positive behaviors could be a positive effect family problems, assessing and responding to crises, writing of the regulatory reforms described earlier. Although nicotine (tobacco) use is not always included, especially useful for patients with alcohol abuse or depen- the increased emphasis on adverse health effects of smoking dence. Maintenance, counseling, and contingency manage- has resulted in more attention to stop smoking at all levels, ment are often combined in complex ways, as seen in the including drug counseling. Counselors and patients typi- following vignette: cally have weekly, 30- to 60-minute sessions during the first A 42-year-old man presented for his sixth episode of 1512 Neuropsychopharmacology: The Fifth Generation of Progress methadone maintenance.

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Causes distress buy female viagra 50 mg on-line, impaired occupational and social functioning It is suggested generic female viagra 100 mg, “intolerance of uncertainty” (Wheaton et al, 2016) and “decreased cognitive flexibility” (Carbonella and Timpano, 2016) may be contributing factors. The media frequently report on two types of hoarders: 1) those who clutter the outside of their houses with what appears to neighbours to be unsightly rubbish, and 2) those who hoard animals. Both forms may damage real-estate values and the public health. Hoarding inside the home may leave people with almost no living space. Hoarding, with material extending outside the house. The animal welfare organization found 300 cats being kept in a residential house, 70 decomposing corpses, and surfaces covered in inches of animal waste. Animal hoarders generally have good will toward animals. As the hoarding progresses, however, these individuals are unable to care for their animals adequately, but are unable to give them up. Not all hoarding is a result of OCD, and not all hoarding reaches the extremes which makes it “newsworthy”. Hoarding is frequently associated with other psychopathology, and it is unlikely that punishment is the appropriate remedy. These ten watches, various dials, rings, notebooks (unused) and keys (to unknown locks) were among the belongings carried in a bag by an itinerant man with chronic schizophrenia. The collecting of such items may not satisfy the definition of hoarding, as they may have monetary value (although, none of watches were in working order). And further, these watches may have had delusional value to the owner. Not shown in this picture is that the bag was stuffed full of old newspaper clippings and other “rubbish”. This may qualify as “hoarding”, but was the result of a delusion. A well dressed young man with schizophrenia carried his faeces in a backpack. It was recommended by Morarji Desai (Prime Minister of India, 1977-9). However, the practice is followed by devotees in a number of countries. The author has met 2 patients who have had a strong desire (to which they yielded) to drink their own urine. In neither case was the individual psychotic and in neither case was the thought ego- alien. BODY DYSMORPHIC DISORDER DSM-5 diagnostic criteria A. Preoccupation with perceived defects in physical appearance, not apparent to others B. Repetitive behaviour – mirror checking –excessive grooming C. Clinical distress and functional impairment Pridmore S. Of adolescents with body dysmorphic disorder, 68% of those who completed a course of CBT improved (Greenberg et al, 2016). A recent study finds that the concerns about appearance held by people with dysmorphic disorder resemble the delusions of psychosis, rather than features of OCD – and this carries conceptual and therapeutic implications (Toh et al, 2017). Ms D had not completed high school, leaving at 16 years of age. Ms K, on the other hand, was very successful at school and was expecting to commence university next year. Father owned a small business and mother worked part-time in an office. Mother was described as being critical of her husband and Ms D. It was revealed that Ms D developed symmetry and ordering obsessions in school. She was slow and unable to complete tasks and left school prematurely because of the pressure to complete assignments and the disgrace of poor achievement. She did not want responsible jobs because they were more difficult for her to complete. She was an intelligent individual with a good understanding of her problems, but she felt powerless to conduct her life in the manner she wished. She was unduly concerned about her bed covers having creases, and could not leave her room until she was convinced there were none.

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It will be important to determine whether specific drugs differ in prophylactic efficacy against relapse trials did not extend beyond 1 year cheap female viagra 50mg otc. Research comparing when compliance is controlled and issues of dosing equiva- low and standard-dose maintenance with depot neuroleptics lence are addressed order 50 mg female viagra amex. It is possible that clozapine and perhaps has demonstrated a trade-off between adverse effects with other atypical agents are more effective in suppressing re- higher doses, including neurologic side effects and dys- lapse; this effect may be relatively independent of antipsy- phoria, versus increased relapse rates with lower doses (122, chotic efficacy and mediated by different neurotransmitter 124). Continued development of psychosocial interven- with an unacceptable rate of hospitalizations, whereas re- tions to improve compliance and monitor and respond to lapses associated with low-dose depot medication generally early signs of relapse will be equally important. Carpenter and colleagues (125) reported that adminis- A diverse range of psychosocial interventions has been tration of diazepam at the earliest sign of exacerbation in shown to reduce relapse rates. In over 20 controlled trials, medication-free patients was more effective than placebo family therapies emphasizing psychoeducation and support and comparable to fluphenazine in preventing relapse. This have reduced relapse rates for schizophrenia patients who work suggests that lower doses of depot neuroleptic may have regular contact with family members (129,130). Al- provide acceptable protection against relapse if accompanied though differences in theoretical orientations and intensity of treatment have not produced consistent differences in by close monitoring and rapid psychosocial and pharmaco- efficacy, recent evidence has suggested that multiple-family logic intervention at the first sign of relapse. These measures psychoeducation groups may be particularly effective (131). Social skills training improves role functioning trial, Essock and colleagues (126) found that chronically of patients with schizophrenia, but has not substantially hospitalized patients randomized to clozapine were not reduced symptoms or reduced relapse rates compared to more likely to be discharged than patients receiving treat- control conditions in most studies (134). In an illuminating ment as usual, but once discharged, relapse rates were signif- study, Herz and colleagues (135) found that a relatively icantly lower with clozapine. Pooled results from three dou- simple, weekly monitoring of schizophrenia patients in psy- ble-blind extension studies revealed that relapse rates were choeducation groups in conjunction with the availability of significantly lower with olanzapine (20%) compared to rapid pharmacologic and psychosocial interventions at the haloperidol (28%) in patients with schizophrenia and re- first sign of decompensation substantially reduced relapse lated psychoses (97). Until depot preparations of atypical rates, by approximately fourfold, compared to treatment as agents are available for study, it will be difficult to determine usual. It is clear from depot Pharmacotherapy neuroleptic studies that large numbers of patients relapse despite adequate compliance; relapse in medication-com- Cramer and Rosenheck (136) surveyed the literature on pliant patients is often associated with depression and re- antipsychotic medication and found that compliance rates 784 Neuropsychopharmacology: The Fifth Generation of Progress averaged 42%. Similar surveys have not been conducted hospitalizations. In a randomized, controlled trial, compli- looking specifically at atypical agents, although it is gener- ance therapy was found to improve insight and observer- ally believed that reduced relapse rates reported with olan- rated adherence to treatment over an 18-month treatment zapine and clozapine may reflect, in part, improved compli- period (147). Patients in the compliance therapy group also ance (97,126). Compliance can be compromised by Cramer and Rosenheck (148) demonstrated that interven- psychosis, agitation, and comorbid substance abuse (137, tions that assist patients in remembering to take medica- 138). Van Putten (139) studied compliance in 85 schizo- tions, such as placing microchip schedulers on pill bottles, phrenia patients chronically treated with conventional neu- can also substantially improve compliance. Medication refusal was associ- Treatment Resistance ated with an early dysphoric response, which Van Putten attributed to subtle akathisia. Analysis of responses by 150 Estimates of the incidence of treatment resistance have var- schizophrenia patients to a 'Drug Attitude Inventory' re- ied with changes in the diagnostic classification of schizo- vealed that, based on responses to 10 items, 89% of patients phrenia and definitions of treatment response (149), which could be correctly assigned to compliant versus non- have tended to obscure potential improvements in outcome compliant categories as determined by clinician assessment associated with advances in pharmacologic and psychosocial of compliance (140). For example, Hegarty and colleagues (150) re- was a positive experience with medication—this factor ac- viewed results of 320 clinical trials and found that, since the counted for 60% of the total variance, whereas the factor introduction of modern antipsychotics in the mid-twentieth representing a negative subjective experience accounted for century, about 50% of patients were improved at follow- 12%. Factors representing attitudes and beliefs about medi- up, whereas the rate of improvement dropped to 35% in cation had minimal predictive power. Rates of response have tended to be higher in first- Whereas many clinicians expect atypical agents to achieve episode psychosis, although dropout rates have been high higher levels of compliance by virtue of reduced or absent in this population, particularly with conventional agents EPS, this view may seriously underestimate the impact of (102,107). Persistence of psychotic symptoms is more com- other side effects. Two studies have found that clinicians mon in drug trials involving chronic patients, presumably tend to misjudge the relative distress produced by different reflecting progression of the illness as well as a possible selec- medication side effects (142,143). Side effects associated tion bias favoring participation by more refractory patients. The advan- or failure to achieve premorbid levels of functioning, treat- tage of atypical agents in terms of compliance may stem ment resistance can be considered the rule rather than the less from their reduced EPS and more from their improved exception. Whether targeting cognitive deficits and impairment in in- Psychotic Symptoms sight will improve compliance remains to be seen. Antipsychotic Monotherapy Response of psychotic symptoms to conventional antipsy- Psychosocial Interventions chotics, risperidone, and olanzapine has been associated Most approaches to noncompliance involve psychoeduca- with D2 receptor occupancy in excess of 65% (18,57), al- tion, supervision, and supportive therapy in which the bene- though persistence of psychotic symptoms has been shown fits of treatment are emphasized, whereas barriers to adher- to occur despite adequate D2 blockade in a subgroup of ence and medication side effects are minimized (145). As noted, only clozapine has con- Family therapy and social skills training may also exert a sistently demonstrated efficacy for psychotic symptoms in positive impact on compliance. Cognitive behavioral ap- treatment of refractory patients; the mechanism responsible proaches have recently been applied to noncompliance by for this therapeutic advantage remains uncertain. In a sam- Kemp and colleagues (146,147), who developed 'compli- ple of 268 patients prospectively established to be neurolep- ance therapy,' a four- to six-session intervention based on tic resistant, 30% in the clozapine group met criteria for motivational interviewing techniques that targets attitudes response at 6 weeks compared to 7% treated with chlorpro- towards medication and discharge planning during acute mazine (11). Response rates as high as 60% have been re- Chapter 56: Therapeutics of Schizophrenia 785 ported after 6 months in open trials with clozapine in pa- therapy as an intervention for neuroleptic-resistant patients; tients less rigorously defined as treatment refractory (152). Given the risk mine efficacy of clozapine and other atypical agents is the of agranulocytosis, the burden of side effects, and the re- subject of debate (153,154). Marder and colleagues (155) found that priate first choice among these agents is unclear; two con- schizophrenia patients presumed to be treatment-resistant trolled studies that compared olanzapine and risperidone on the basis of having been hospitalized for 6 months or have produced divergent results, probably reflecting differ- longer at the time of study entry did not respond to haloper- ences in dosing of the two agents and the use of intent-to- idol 20 mg per day but significantly improved with risperi- treat versus completer analyses (63,163).

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