Lessons to take home from CATIE

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Psychiatric Services (Impact Factor: 2.41). 06/2008; 59(5):523-5. DOI: 10.1176/
Source: PubMed


The publicly funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) did not support superiority hypotheses for second-generation antipsychotic drugs in schizophrenia. Instead, the study supported the view that first- and second-generation antipsychotics have similar therapeutic properties and diverse adverse effect profiles. This emphasizes the importance of designing pharmacotherapy for the individual in order to optimize the benefit-to-risk profile. First- and second-generation antipsychotic drugs are extensively similar in mechanism of action, efficacy for psychosis, and lack of efficacy for avolition and impaired cognition. However, adverse effect profiles vary between drugs. The authors review the clinical implications of these data, with an emphasis on individualizing pharmacotherapy in an effort to reduce risk. Rather than selecting drugs on the basis of unfounded expectations of superior efficacy, clinicians can focus on selecting drugs and optimizing dosages to minimize adverse effects without sacrificing efficacy. Tardive dyskinesia may be a good reason to avoid a high dosage of first-generation antipsychotics, although the evidence for differential risk is less compelling for a modest dosage of low-affinity first-generation antipsychotics. Similarly, the metabolic effects of some second-generation antipsychotics can be decisive in considering risks. In either case, the clinician should detect earliest signs and take action while dyskinetic or metabolic effects are most reversible. Bottom line: the dichotomy between first- and second-generation antipsychotics was not supported by efficacy data (and now, is not supported effectiveness data). Only clozapine has documented superiority in treatment-resistant cases.

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    • "Moreover, we lack efficient tools for its treatment or prevention. For example, the multicenter, NIMH-funded Clinical Antipsychotic Trials in Intervention Effectiveness project recently found that newer atypical antipsychotics are not significantly more effective for treating psychosis than older typical antipsychotic medications and showed little benefit for improving cognitive symptoms [2] [3]. These findings highlight the need to develop novel therapeutic interventions for schizophrenia [4] [5]. "
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    ABSTRACT: Schizophrenia is a brain disorder associated with cognitive deficits that severely affect the patients' capacity for daily functioning. Whereas our understanding of its pathophysiology is limited, postmortem studies suggest that schizophrenia is associated with deficits of GABA-mediated synaptic transmission. A major role of GABA-mediated transmission may be producing synchronized network oscillations which are currently hypothesized to be essential for normal cognitive function. Therefore, cognitive deficits in schizophrenia may result from a GABA synapse dysfunction that disturbs neural synchrony. Here, we highlight recent studies further suggesting alterations of GABA transmission and network oscillations in schizophrenia. We also review current models for the mechanisms of GABA-mediated synchronization of neural activity, focusing on parvalbumin-positive GABA neurons, which are altered in schizophrenia and whose function has been strongly linked to the production of neural synchrony. Alterations of GABA signaling that impair gamma oscillations and, as a result, cognitive function suggest paths for novel therapeutic interventions.
    Neural Plasticity 09/2011; 2011(3):723184. DOI:10.1155/2011/723184 · 3.58 Impact Factor
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    • "In the face of recent doubts about the cost-effectiveness of second-generation antipsychotics informed by controversial findings from various trials and meta-analyses (Rosenheck, 2006; Rosenheck et al., 2006; Jones et al. 2006; Davies et a.l. 2008; Zhu et al. 2008; Carpenter & Buchanan 2008), quantitative data in this field are fundamental to the ongoing transformation of community care systems. To bridge this gap, we analysed the total cost of care for patients with a diagnosis of schizophrenia in six countries as a part of a randomised controlled European trial, in which particular emphasis was put on the prospective recording of the cost of psychopharmacologic drug use on the patient level. "
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    ABSTRACT: As part of an RCT in six European sites, the direct mental health care cost for 422 patients with schizophrenia was analysed according to how total and medication costs differed across sites and which variables were likely to predict total or service-specific costs. Service use was recorded continuously during a 12-month follow-up. Prescribed psychotropic medication was recorded at baseline and 12 months later. Service use data were transformed into EURO, log-transformed and analysed using linear regression models. Although samples were homogeneous, large inter-site cost differences were found (annual means ranging from 2958 euro in Spain up to 36978 euro in Switzerland). Psychopharmacologic costs were much more constant across sites than costs for other services. Total costs were associated more with region or socio-demographic characteristics than with disorder related parameters. The findings confirm remarkable differences in direct costs of patients with schizophrenia across Europe. However, the relative stability of medication costs suggests a need to analyse mechanisms that influence service-specific costs for schizophrenia.
    Schizophrenia Research 05/2009; 111(1-3):70-7. DOI:10.1016/j.schres.2009.03.027 · 3.92 Impact Factor
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    • "Clozapine is the most effective antipsychotic compound in treating therapyresistant schizophrenia (Lewis et al. 2006a, Nasrallah 2007, Kane et al. 1988, Tauscher et al. 2004, Kane et al. 2001, Chakos et al. 2001). In addition, clozapine can improve cognitive deficits (Lewis et al. 2006b, Kane et al. 2001, Peuskens et al. 2005, McGurk 1999), has shown superior efficacy over other antipsychotics for positive symptoms (Carpenter and Buchanan 2008), causes a three-fold reduction in the risk of suicidal behavior in schizophrenic patients (Hennen and Baldessarini 2005) and may be associated with a lower mortality than any other antipsychotics (Tiihonen et al. 2009). "
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    ABSTRACT: Clozapine is the most effective drug in treating therapy-resistant schizophrenia and may even be superior to all other antipsychotics. However, its use is limited by a high incidence (approximately 0.8%) of a severe hematological side effect, agranulocytosis. The exact molecular mechanism(s) of clozapine-induced agranulocytosis is still unknown. We investigated the mechanisms behind responsiveness to clozapine therapy and the risk of developing agranulocytosis by performing an HLA (human leukocyte antigens) association study in patients with schizophrenia. The first group comprised patients defined by responsiveness to first-generation antipsychotics (FGAs) (n= 19). The second group was defined by a lack of response to FGAs but responsiveness to clozapine (n=19). The third group of patients had a history of clozapine-induced granulocytopenia or agranulocytosis (n=26). Finnish healthy blood donors served as controls (n= 120). We found a significantly increased frequency of HLA-A1 among patients who were refractory to FGAs but responsive to clozapine. We also found that the frequency of HLA-A1 was low in patients with clozapine-induced neutropenia or agranulocytosis. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and therefore HLA typing may aid in the selection of patients for clozapine therapy. Furthermore, in a subgroup of schizophrenia, HLA-A1 may be in linkage disequilibrium with some vulnerability genes in the MHC (major histocompatibility complex) region on chromosome 6. These genes could be involved in antipsychotic drug response and clozapine-induced agranulocytosis. In addition, we investigated the effect of clozapine on gene expression in granulocytes by performing a microarray analysis on blood leukocytes of 8 schizophrenic patients who had started clozapine therapy for the first time. We identified an altered expression in 4 genes implicated in the maturation or apoptosis of granulocytes: MPO (myeloperoxidase precursor), MNDA (myeloid cell nuclear differentiation antigen), FLT3LG (Fms-related tyrosine kinase 3 ligand) and ITGAL (antigen CD11A, lymphocyte function-associated antigen 1). The altered expression of these genes following clozapine administration may suggest their involvement in clozapine-induced agranulocytosis. Finally, we investigated whether or not normal human bone marrow mesenchymal stromal cells (MSC) are sensitive to clozapine. We treated cultures of human MSCs and human skin fibroblasts with 10 µM of unmodified clozapine and with clozapine bioactivated by oxidation. We found that, independent of bioactivation, clozapine was cytotoxic to MSCs in primary culture, whereas clozapine at the same concentration stimulated the growth of human fibroblasts. This suggests that direct cytotoxicity to MSCs is one possible mechanism by which clozapine induces agranulocytosis. Klotsapiini on tehokkain lääke hoidolle vastaamattomassa skitsofreniassa. Sen käyttöä rajoittaa kuitenkin vakava verenkuvaan liittyvä haittavaikutus, agranulosytoosi, jonka esiintyvyys on noin 0.8%. Klotsapiinin aiheuttaman agranulosytoosin tarkkaa molekyylitason syntymekanismia tai mekanismeja ei tunneta. Tutkimme liittyvätkö immuunivastetta säätelevät HLA-molekyylit klotsapiinivasteeseen ja klotsapiinin aiheuttamaan agranulosytoosiin kolmessa skitsofreniapotilasryhmässä. Ensimmäisessä ryhmässä oli 19 hyvin ensimmäisen polven psykoosilääkkeelle vastannutta potilasta. Toisessa oli 19 potilasta, jotka eivät saaneet vastetta ensimmäisen polven psykoosilääkkeelle mutta sen sijaan klotsapiinille. Kolmannessa oli 26 klotsapiinihoidon yhteydessä granulosytopenian tai agranulosytoosin saanutta potilasta. Terveet verenluovuttajat olivat kontrolleina. HLA-A1 esiintyi merkitsevästi useammin klotsapiinille mutta ei ensimmäisen polven psykoosilääkkeelle vastanneilla potilailla. Sen sijaan HLA-A1 liittyi harvoin verenkuvamuutokseen. HLA-A1 voi ennustaa hyvää klotsapiinivastetta ja alhaista agranulosytoosin riskiä. Siksi HLA-tyypitys voisi auttaa valittaessa potilaita klotsapiinihoitoon. Skitsofrenian alaryhmässä HLA-A1 voi olla kytkentäepätasapainossa joidenkin altistavien geenien kanssa kromosomi 6:n MHC (major histocompatibility complex) -aluella. Nämä geenit voivat osaltaan säädellä klotsapiinivastetta ja klotsapiinin aiheuttamaa agranulosytoosia. Teimme mikrosiruanalyysin kahdeksan skitsofreniaa sairastavan potilaan veren granulosyyteistä, kun he aloittivat ensimmäistä kertaa klotsapiinihoidon. Tunnistimme neljä geeniä, joiden ilmentymistaso oli muuttunut ja jotka liittyvät granulosyyttien kypsymiseen tai apoptoosiin: MPO (myeloperoxidase precursor), MNDA (myeloid cell nuclear differentiation antigen), FLT3LG (Fms-related tyrosine kinase 3 ligand) ja ITGAL (antigen CD11A, lymphocyte function-associated antigen 1). Geenien ilmentymismuutokset klotsapiinin aloittamisen jälkeen voivat viitata niiden osallisuuteen agranulosytoosissa. Tutkimme ovatko luuytimen stroomasolut herkkiä klotsapiinille. Viljelimme normaaleja ihmisen luuytimen mesenkymaalisia stroomasoluja ja ihmisen ihofibroblasteja soluviljelmässä, jossa oli 10 µM muuntumatonta klotsapiinia tai hapettamalla bioaktivoitua klotsapiinia. Havaitsimme, että klotsapiini riippumatta bioaktivaatiosta oli sytotoksinen luuytimen stroomasoluille primääriviljelmässä, kun taas samalla annoksella klotsapiini jopa kiihdytti fibroblastien kasvua. Löydös viittaa siihen, että suora luuytimen stroomasoluihin kohdistuva haittavaikutus voi olla eräs agranulosytoosin mekanismeista. Tulokset rohkaisevat lisätutkimuksiin, joissa voidaan tarkemmin selvittää klotsapiinin aiheuttaman agranulosytoosin mekanismeja ja löytää uusia mahdollisuuksia sen estämiseksi.
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