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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conventional neuroleptics can further reduce cognitive function, which is already impaired in most patients with schizophrenia. Although some areas of cognition may remain relatively well preserved in schizophrenia, it has been suggested that the origins of a neurocognitive decline in schizophrenia may be related to a reduction in dopamine activity in the prefrontal cortex. If this is the case, dopamine D2 blockade would be expected to impair some aspects of neurocognitive function further. The level of neurocognitive function in schizophrenia is related to vocational and social ability, and the course of cognitive decline appears to be consistent with a static encephalopathy, rather than progressive dementia. Intensive cognitive retraining in patients with schizophrenia may improve, but not normalize, some aspects of cognitive performance. Most cognitive deficits remain stable, even when improvements in symptoms are obtained with antipsychotic treatment. Drugs such as risperidone, one of the newer serotonin-dopamine antagonists (SDAs), have a better effect on cognitive function than conventional antidopaminergic neuroleptics, and are therefore more likely to enable the patient to benefit from cognitive and other forms of training. Anticholinergic drugs used to treat EPS, or drugs with anticholinergic activity, also impair cognitive function. Consequently, because the need to use anticholinergic drugs is less with the SDA antipsychotics, the cognitive function of patients treated with drugs such as risperidone is likely to be better than it would be if they took a conventional neuroleptic.
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PMID:The role of cognition in the risk--benefit and safety analysis of antipsychotic medication. 898 71

Relapse is the "return of a disease after partial recovery", and is a major feature of schizophrenia disorder. It can be defined in terms of need for change in treatment, including rehospitalization or crisis intervention, the re-emergence of florid psychotic features, or gross social decompensation. Relapse is best viewed as continuum of severity rather than as discrete "attacks". Factors influencing relapse include major life events and the family constellation. Antipsychotic drugs protect against the latter but not the former, and relapse may be mediated by non-specific arousal mechanisms. The efficacy of drug treatment in postponing rather than preventing relapse is well established. The interval between relapses is prolonged at least two-fold, but in the long run most patients relapse. Unwanted effects of antipsychotic drugs can be a burden to patients, impairing quality of life. In particular, movement disorders and subjective dysphoria may be marked, as may compliance. Of these EPS, tardive dyskinesia is the most serious on long term use. Non-EPS long term effects include weight gain and endocrine changes. Depot medication has advantages over oral medication in the more ill, less compliant patients. Side effects may, however, be more marked. The greatest pain is in improved compliance but the regular supervision of the patient is also helpful. Pharmacokinetic issues are poorly understood. High and mega-dose strategies have been advocated. High doses may be needed in some patients, but megadoses are rarely justified and may be hazardous. Low dose and intermittent therapy have been evaluated but are not as successful as hoped. Some less ill patients may benefit. These schedules depend on the identification of prodromata of relapse which is not always easy, nor are relapses necessarily preceded by prodromata. Newer drugs are being developed rapidly in the search for a safer clozapine, the only antipsychotic with definitely enhanced efficacy. Other drugs which have been re-evaluated include the benzodiazepines. However, the area of greatest priority in research is that of interactions, particularly potentiation, between drug and non-drug treatments.
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PMID:Pharmacological prevention of relapse. 973 77

Conventional antipsychotics were the first treatments effective in controlling psychotic symptomatology and revolutionized management of psychotic disorders when introduced in the 1950's. The use of these agents has, however, been marked by several shortcomings, including limited efficacy in treating the negative and cognitive symptoms of schizophrenia, and by significant extrapyramidal and other side-effects. There appears to be justifiable excitement about the introduction of the newer atypical antipsychotics, which may represent the second pharmacological revolution in the treatment of psychotic disorders. But how are these agents really different from their neuroleptic predecessors? How is their pharmacological profile different? Are there clear differences in efficacy? How do side-effect profiles differ? These issues are reviewed in this manuscript. Atypical agents are pharmacologically distinct from their neuroleptic predecessors. Their primary advantage is their superior side effect profiles, particularly with regard to EPS. The implications of EPS reduction touch virtually every domain of pathology in schizophrenia, including short- and long-term movement disorders, negative symptoms, noncompliance, relapse rate, cognitive dysfunction, and dysphoria. It should be emphasized that while atypical antipsychotics share some clinical attributes, there are substantial clinical differences between them as well. These differences are reviewed in this article as well. The drugs' unique profiles with regard to other side effects may make it possible to tailor treatment more individually to patients. Further refinement of our understanding of the clinical utility of these drugs awaits their widespread use in mainstream clinical settings. Controlled studies comparing them to one another should be of particular interest.
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PMID:New atypical antipsychotic medications. 979 75

The objective of this meta-analysis is to summarize the efficacy and tolerability of the new antipsychotics risperidone, olanzapine, sertindole and quetiapine in schizophrenia compared to placebo and conventional antipsychotics. The main results are: (1) All of the 4 new drugs are more effective than placebo, but the magnitude of the effect is only moderate [mean effect size, r, of all antipsychotics vs. placebo = 0.25, with a 95% confidence interval (CI) = 0.22-0.28, n = 2477]. (2) According to the studies published to date, sertindole and quetiapine are as effective as haloperidol, and risperidone and olanzapine are slightly more effective than haloperidol in the treatment of global schizophrenic symptomatology. (3) With respect to negative symptoms, all new antipsychotics are more effective than placebo. However, contrary to widespread opinion, so is the 'conventional' antipsychotic haloperidol. Risperidone and olanzapine are slightly superior, sertindole is as effective and--according to the only study fully published to date--quetiapine is even slightly less effective than haloperidol in this regard. (4) All new antipsychotics are associated with less frequent use of antiparkinson medication than haloperidol, with risperidone appearing to have a slightly less favourable EPS-profile than the other new antipsychotics. The methodological limitations of this review, the generalizability of the results and expectations from future research are discussed.
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PMID:Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. 998 41

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptor which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.
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PMID:The role of serotonin in antipsychotic drug action. 1043 96

On the heels of clozapine, we now have a number of newer agents (risperidone, olanzapine, quetiapine, sertindole, and ziprasidone). Are they all the same? What are the differences? How do we best understand them? In this article we review current clinical evidence to compare these issues on four measures of atypicality: EPS, prolactin elevation, superior efficacy in refractory/positive symptoms and efficacy against negative symptoms. All the newer agents are superior on EPS and, with the exception of risperidone, avoid prolactin elevation. Clozapine shows the most convincing efficacy in refractory schizophrenia, although comparative data concerning risperidone's benefit in this respect are also emerging. It is unclear, however, whether any of the agents produce a greater effect than conventional antipsychotics against positive symptoms in responsive patients. Both clozapine and olanzapine have demonstrated superior efficacy against negative symptoms, although it remains controversial whether this is an effect on primary or secondary symptoms. The precise pharmacologic mechanisms underlying "atypicality" remain unclear, but several conceptual frameworks are highlighted that characterize, and perhaps differentiate, these newer agents.
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PMID:Atypical antipsychotics: are some more atypical than others? 1214 Dec 76

Olanzapine is a new atypical antipsychotic (Weaver, 1997). Both early development and clinical studies support its safe use. Clinical trials suggest that it is efficacious in treating positive symptoms in schizophrenia, and more efficacious for negative symptoms and depressive symptoms than traditional antipsychotics. In addition, the side-effect profile of olanzapine is favourable, with a low incidence of EPS and little increase in prolactin during acute-phase trials. At present, olanzapine appears broadly as good as the other novel atypical drugs. As a group, the atypical antipsychotics have been recommended for use as first-line therapy, in acute schizophrenic relapse, and for those who are responsive, but intolerant, to classical antipsychotic medication (Kerwin, 1994; Lieberman, 1996). The role of olanzapine in treating treatment-resistant patients is unproven, and data is awaited comparing olanzapine directly with clozapine. The current era of development of drugs for schizophrenia holds great promise, and it is the duty of all doctors to make patients aware of the benefits and risks of available treatments, and to enable them to choose.
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PMID:Psychopharmacology of olanzapine. A review. 1088

Preclinical studies have shown that quetiapine (Seroquel, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150-750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of EPS and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer's disease and Parkinson's disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.
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PMID:Review of quetiapine and its clinical applications in schizophrenia. 1124 16

Individual schizophrenic patients are sometimes reported to benefit from unusually high doses of neuroleptics. Such patients may have poor drug penetration into the brain or ultra-rapid metabolism. Alternately, very high doses may be required to induce occupancy of 5-HT(2) receptors, which have been suggested as mediators of atypical effects. Five schizophrenic patients treated with high doses of fluphenazine decanoate (100-250 mg/wk) and adjunct medications were examined with positron emission tomography and [(11)C]raclopride to measure D(2) receptor occupancy and [(11)C]NMSP to measure 5-HT(2) receptor occupancy. All patients were rated globally as 'markedly' to 'severely' ill and had high scores on all subscales of the Positive and Negative Syndrome Scale for schizophrenia. However, according to retrospective clinical evaluation, there was improved social function and reduced distress following high-dose treatment, an effect that deteriorated after previous explorative dose reduction. Extrapyramidal symptoms were modest. D(2) receptor occupancy was very high (89-97%). 5-HT(2) receptor occupancy was also high (76-105%). Plasma concentrations of fluphenazine were 5-37 nm. No patient had a cytochrome P450 CYP2D6 genotype associated with ultra-rapid drug metabolism. The findings suggest almost complete saturation of D(2) receptors, and do not support poor drug availability in the brain as the basis of the apparent high-dose requirement. The high 5-HT(2) receptor occupancy may have contributed to the apparent clinical improvement and modest degree of EPS. However, it is likely that the treatment used also induced occupancy of other neuroreceptors.
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PMID:D(2)- and 5-HT(2) receptor occupancy in high-dose neuroleptic-treated patients. 1128 52

One of the major clinical challenges in the treatment of schizophrenia is the treatment of negative symptoms, which are particularly associated with poor long-term outcome. Clozapine is often effective in the treatment of a great proportion of previously neuroleptic refractory patients. Its utility is, however, limited by the high risk of agranulocytosis. Depressive and negative symptoms such as anhedonia, lack of interest, motor retardation and social withdrawal show some overlap. Because of the similarities between negative and depressive symptoms in schizophrenic patients and the success of antidepressants in the treatment of depressive symptoms in schizophrenic disorders, the augmentation of antipsychotics by SSRI antidepressants has repeatedly been suggested as a promising strategy in schizophrenic patients with negative symptoms. Besides several open studies, five controlled trials of the effect of SSRI addition to current treatment with classic neuroleptic agents, have been published. They reveal some evidence for increased efficacy of conventional antipsychotics after addition of SSRIs. Neither placebo-controlled studies nor open trials have revealed additional efficacy of antipsychotic/SSRI combination on the positive symptoms or depressive symptoms in comparison with antipsychotic treatment alone, but the patients in the reviewed studies had been generally selected for their prominent negative symptoms, their neuroleptic resistance or their chronicity. There seems to be, however, clear evidence supporting the efficacy of SSRI augmentation of conventional antipsychotics in the treatment of negative schizophrenic symptoms. The data on clozapine reveal no additional therapeutic potential if pharmacokinetic interactions are controlled for. Path analysis allows an estimate whether, and to which degree, the effect of a treatment on a symptom is mediated by effects on other symptoms. Path analysis has, though, not been reported for antipsychotic/SSRI combinations until now. Nevertheless, SSRI augmentation in the treatment of schizophrenia seems to act directly, has only limited efficacy in treating depressive symptoms, and does not seem to have an effect on positive symptoms or EPS. Furthermore, there is no evidence for an increased efficacy due to increased plasma levels of typical neuroleptics. A paradox exists, as both the serotonin-agonists and antagonists produce similar effects in combination with dopamine-blocking drugs. As reasons for this paradox have been proposed: the complexity of multiple 5HT receptor types, their differing distribution, their different serotonin-affinity and their partly divergent postsynaptic effects. In conclusion, some inferences can be made despite the limitations of the data. There is some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs, and, whereas path analyses are still lacking, this seems to be a direct effect. SSRIs may be an alternative to clozapine, especially in patients for whom there are contraindications for a clozapine treatment. As yet, there is no convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms.
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PMID:[The place of SSRIs in the treatment of schizophrenia]. 1238 45

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