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Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia purchase 100mg viagra with mastercard. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes cheap viagra 50 mg mastercard. Iloperidone binding to human and rat dopamine and 5-HT receptors. However, as well as H1 and 1-adrenergic receptors (55) (Table 56. Aripiprazole is distinct from the other atypical useful for treating cognitive deficits of the disease (50). Olanzapine is more potent at 5-HT2A than D2 drugs (56,57). Clozapine, however, does not exhibit high receptors (Table 56. 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 (20,58, two drugs. 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.

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In the ability of agonist maintenance treatment with a relatively United States quality viagra 50mg, buprenorphine is currently approved only low risk for abuse or diversion cheap viagra 50 mg with amex. In addition, the partial ago- as an analgesic for parenteral administration; approval for nist activity of buprenorphine results in a much lower risk of opioid addiction treatment is pending. Buprenorphine has overdose death than is the case with methadone or LAAM. Most of the Antagonist Maintenance early clinical trials used a sublingual solution of buprenor- phine formulated in a hydroethanolic vehicle, 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.

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It has into the clinical characteristics and prognosis of the illness been described in children as young as age 2 (7) and also (3) viagra 25 mg otc. Improvements in methodology generic 50mg viagra fast delivery, including the develop- in the very elderly (8). Evidence supports the hypothesis ment of structured interviews with proven reliability and that OCDis a heterogeneous disorder with multiple causes validity, the application of survival analysis and other statis- (9). Neurobiologic studies have demonstrated abnormalities tical techniques to assess longitudinal variables, and more in frontostriatal–basal ganglia circuitry (10). Like any organ sophisticated database management systems, have been in- system, these neural circuits are susceptible to a variety of strumental in these advances. Identifying homogeneous subgroups of patients with OCDshould help in unraveling its neurobiologic pathogen- Steven A. Rasmussen: Brown University, Butler Hospital, Providence, esis and developing more specific and effective treatment Rhode Island. Eisen: Department of Psychiatry and Human Behavior, Brown strategies. This chapter reviews data related to the clinical features 1594 Neuropsychopharmacology: The Fifth Generation of Progress and course of OCDduring the lifespan. It focuses on the dren of parents with OCDfor subsequent development of heterogeneity and comorbidity of the disorder in relation the disorder is poorly defined. No data are available that to its course, and points to a new wave of studies that should would make it possible to predict this transition. Similarly, complement neurobiologic and genetic studies of the patho- almost no data are available relating the effect of continuing genesis of OCD, lead to fuller recognition of its impact on subthreshold symptoms during a period of remission to the society, and help to measure the effectiveness of behavioral likelihood of relapse in adults. Prospective quantitative lon- and pharmacologic treatment strategies that have been de- gitudinal assessment of probands with subthreshold symp- veloped during the past two decades. SUBTHRESHOLD SYMPTOMS DEVELOPMENTAL PSYCHOPATHOLOGY It is generally agreed that it is the frequency of obsessions Little systematic study of the developmental antecedents of and compulsions, in addition to the degree with which they OCDhas been carried out since Janet. In his Obsessions interfere with function, that distinguishes normal from ab- and Psychasthenia, Janet (19) postulated that obsessions and normal. A patient must have had an hour of obsessive-com- compulsions are the most severe stage of an underlying pro- pulsive symptoms daily for a period of 6 months that inter- dromal state that he called psychasthenia, a syndrome charac- fere with social or occupational function to meet DSM-IV terized by feelings of incompleteness and imperfection. This requirement has tradi- hypothesized that all patients in whom obsessions and com- tionally been thought to translate to a score of 16 or higher pulsions develop pass through a prodromal stage of psychas- on the Yale–Brown Obsessive-Compulsive Scale (Y- thenia. His clinical descriptions of the temperamental fea- BOCS). Like symptoms of anxiety, obsessive-compulsive tures of psychasthenics coincide remarkably well with our symptoms are present to some degree in most people. Rach- preliminary findings of the prodromal symptoms of patients man and Hodgson (12) found that a high percentage of the with OCD. His description of the patient who 'finds on normal population report some obsessions and compul- the stairway the word that needed to be said in the parlor' sions. Similarly, after screening 861 Israeli military recruits is an astute clinical description and close analogue of the at 16 years of age, Apter et al. It is worth noting that Janet included three of the toms and severe impairment on the other. The receiver op- five elements of DSM-III compulsive personality disorder in erating characteristics that would best distinguish the clini- his description of the psychasthenic state: perfectionism, cal from the subthreshold syndrome of OCDhave yet to restricted emotional expression, and indecisiveness. Goodman (15) screened 958 college students and pean diagnostic schema for anacastic personality is more identified 23 subjects with subclinical OCD. Deter- A retrospective study of 90 of our OC probands in which mining where the clinical syndrome begins and ends is im- a semistructured format was used was designed to elicit pro- portant for pharmacologic and genetic studies. For example, dromal personality traits or temperamental factors com- the multicenter collaborative studies of the selective seroto- monly found in OCD(22). During this study, we identified nin reuptake inhibitors (SSRIs) in OCDnoted a higher 10 factors commonly found in our adult OC probands as rate of response to placebo in patients with Y-BOCS scores children (Table 111. These traits tended to vary mini- between 16 and 20, a finding that prompting some investi- mally during the childhood and adolescent years. Family genetic cantly with the behavioral inhibition syndrome in children studies have shown a higher risk for both subthreshold and that Kagan et al. Four of the developmental clinical OCDin OCDprobands (18). The clini- tance to change or novelty, risk aversion, and submissive- cal significance of subthreshold symptoms in childhood ness.

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Genetics screens have Several other HD mouse models have been constructed buy viagra 75 mg line. A transgene consist- ing of a full-length huntingtin cDNA driven by the CMV A MODEL OF POLYGLUTAMINE promoter resulted in a line of mice with a rather different PATHOGENESIS phenotype discount viagra 75 mg with mastercard, characterized by early weight gain and hyperac- tivity followed later by hypoactivity. These mice have both A model for HD pathogenesis is depicted in Figure 125. Several of the steps are speculative, and, as has been evident Perhaps the most promising mouse model of HD in- in this summary, the data supporting the model are at times volves the use of YAC constructs, so the transgene consists conflicting. Here we highlight areas of uncertainty: of the entire human HD gene, including the human HD Evidence for pathogenetically significant proteolytic promotor and all introns, with an expanded repeat. The finding that mice develop neurologic signs, electrophysiologic abnormal- nuclear inclusions can be labeled for N-terminal epitopes, ities, and a shortened life span (92). A single founder with but not for internal or C-terminal epitopes, is consistent a long repeat had striking evidence of selective striatal neuro- with proteolytic cleavage, but it could also result from mask- degeneration and nuclear localization of N-terminal epi- ing of epitopes. In addition, details of the cleavage, includ- topes of huntingtin in striatal neurons. If additional lines ing whether it is processive or endoproteolytic and where can be generated, this model may be the closest to the in the cell it may occur, are uncertain. The figure shows human disease of any model yet generated. It seems ingtin gene, thus avoiding the confounding factor of the likely that the mutant protein adopts an abnormal confir- presence of the human transgene. So far, these mice have mation and that this is a necessary step in pathogenesis. There is evidence of translocation of copy may represent a downstream event, an epiphenome- huntingtin into the nucleus in striatal neurons. Thus, these non, or even a protective reaction, and therefore they may mice may model early aspects of HD pathogenesis and could not be directly tied to pathogenesis. Our hypothesis is that provide a useful model for studying the early features of the mutant huntingtin adopts an abnormal confirmation, lead- disease. An example of such protein is CREB binding pro- containing exon 1of huntingtin with an expanded gluta- tein, an important transcriptional regulator; sequestration mine repeat under the control of the tet-off system was of this and similar proteins could have marked effects on inserted so that the timing of transgene expression could neuronal function and survival. With the transgene on, mice events also remains unclear. In our model, the location of developed neurologic signs and neuropathologic changes in- huntingtin in the nucleus leads to altered gene transcription. Remarkably, when the expres- However, huntingtin could act also within the cytoplasm sion of huntingtin was turned off, these abnormalities par- to interfere with proteins that could otherwise be imported tially reversed. This surprising result suggests that the brain into the nucleus. Furthermore, huntingtin may interact may have more restorative and plastic ability than previously with cytoplasmic molecules, including microtubules or mi- appreciated, and that if the pathologic changes of HD could crotubule motors, caspase adaptors, and other proteins, to be halted, substantial repair would perhaps be possible. We propose that HD pathogenesis begins with altered conformation of the protein con- taining the expanded polygluta- mine repeat. Proteolysis generates a fragment that leads to toxicity through several pathways. Nuclear importation may lead to altered gene transcription with a detri- mental effect on cell survival. Inclu- sions also form in the nucleus but may not be a major cause of cell death. Huntingtin fragments may interfere with mitochondrial en- ergy metabolism, either directly, or more likely indirectly, perhaps by altered gene transcription. Micro- aggregation of the fragment may lead to caspase activation and the consequent initiation of cell death pathways. Fragments maybe trans- ported into neurites, interfering with cytoskeletal function. Toxicity may also be mediated by the full- length huntingtin protein with the expanded repeat.

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