CATIE and CUtLASS: can we handle the truth?
ABSTRACT Two large, non-commercial clinical trials comparing first- and second-generation antipsychotic drugs for people with chronic schizophrenia in the US and UK have shown unexpected results. in general, the newer drugs were no more effective or better tolerated than the older drugs. Clozapine outperformed other second-gene ration drugs. The implications are considered. Declaration of interest S.L. is the Chief investigator of the CUtLASS study and J.L. is the Chief Investigator of the CATIE study, S.L. has received honoraria from several pharmaceutical companies. J.L. has received research funding from several pharmaceutical companies.
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ABSTRACT: Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMT(val158met), using Val-Val homozygotes as reference category, a protective effect for Val-Met heterozygotes (OR=0.63, 95% CI: 0.46-0.86, P=0.004) and Met carriers (OR=0.66, 95% CI: 0.49-0.88, P=0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR=1.30, 95% CI: 1.03-1.65, P=0.026), and A2-A2 homozygotes using A1-A1 as reference category (OR=1.80, 95% CI: 1.03-3.15, P=0.037); (3) in MnSOD Ala-9Val, using Ala-Ala homozygotes as reference category, a protective effect for Ala-Val (OR=0.37, 95% CI: 0.17-0.79, P=0.009) and for Val carriers (OR=0.49, 95% CI: 0.24-1.00, P=0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge. Molecular Psychiatry (2008) 13, 544-556; doi:10.1038/sj.mp.4002142; published online 8 January 2008.Molecular Psychiatry 06/2008; 13(5):544-56. DOI:10.1038/sj.mp.4002142 · 15.15 Impact Factor
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ABSTRACT: Schizophrenia is a life altering disease with a complex aetiology and pathophysiology and, although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the bio-behavioural manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g. postnatal inflammation, environmental adversity or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this review, we will discuss SIR, PPNI as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioural alterations of schizophrenia. Finally, based on these models we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways.ACS Chemical Neuroscience 03/2015; DOI:10.1021/cn5003368 · 4.21 Impact Factor
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ABSTRACT: In both clinical trials and daily practice, there can be substantial inter- and even intraindividual variability in response-whether beneficial or adverse-to antidepressants and antipsychotic medications. So far, no tools have become available to predict the outcome of these treatments in specific patients. This is because the causes of such variability are often not known, and when they are, there is no way of predicting the effects of their various potential combinations in an individual. Given this background, this paper presents a conceptual framework for understanding known factors and their combinations so that eventually clinicians can better predict what medication(s) to select and at what dose they can optimize the outcome for a given individual. This framework is flexible enough to be readily adaptable as new information becomes available. The causes of variation in patient response are grouped into four categories: (i) genetics; (ii) age; (iii) disease; and (iv) environment (internal). Four cases of increasing complexity are used to illustrate the applicability of this framework in a clinically relevant way In addition, this paper reviews tools that the clinician can use to assess for and quantify such inter- and intraindividual variability. With the information gained, treatment can be adjusted to compensate for such variability, in order to optimize outcome. Finally, the limitations of existing antidepressant and antipsychotic therapy and the way they reduce current ability to predict response is discussed.Dialogues in clinical neuroscience 12/2014; 16(4):545-54.