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Christoph U Correll – 1st expert on this subject based on the ideXlab platform
national trends in the office based treatment of children adolescents and adults with AntipsychoticsArchives of General Psychiatry, 2012Co-Authors: Mark Olfson, Carlos Blanco, Shuai Wang, Christoph U CorrellAbstract:
sonsincreasedfrom0.24to1.83forchildren,0.78to3.76 for adolescents, and 3.25 to 6.18 for adults. The proportion of total visits that included a prescription of Antipsychotics increased during this period from 0.16% to 1.07% for youths and from 0.88% to 1.73% for adults. From 2005 to 2009, disruptive behavior disorders were the most common diagnoses in child and adolescent antipsychotic visits, accounting for 63.0% and 33.7%, respectively, while depression (21.2%) and bipolar disorder (20.2%) were the 2 most common diagnoses in adult antipsychotic visits. Psychiatrists provided a larger proportion of the antipsychotic visits for children (67.7%) andadolescents(71.6%)thantoadults(50.3%)(P.001). From2005to2009,Antipsychoticswereincludedin28.8% of adult visits and 31.1% of youth visits to psychiatrists. Conclusions: On a population basis, adults make considerably more medical visits with a prescription of Antipsychotics than do adolescents or children. Yet antipsychotic treatment has increased especially rapidly among young people, and recently Antipsychotics have been prescribed in approximately the same proportion of youth and adult visits to psychiatrists.
Antipsychotic drugs and obesityTrends in Molecular Medicine, 2010Co-Authors: Christoph U Correll, Todd Lencz, Anil K. MalhotraAbstract:
Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk Antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naive samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) Antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naive/first episode samples, are needed to further advance the field.
Antipsychotics associated with the development of type 2 diabetes in antipsychotic naive schizophrenia patientsNeuropsychopharmacology, 2010Co-Authors: Jimmi Nielsen, Christoph U Correll, Soren SkadhedeAbstract:
Diabetes mellitus occurs in schizophrenia patients at higher rates than in the general population. Reasons for this elevated risk are poorly understood and have not been examined prospectively in antipsychotic-naive, first-episode patients. This study aims to determine which Antipsychotics are associated with diabetes development in antipsychotic-naive schizophrenia patients. All antipsychotic-naive patients diagnosed with schizophrenia in Denmark between 01 January 1997 and 31 December 2004, followed until 31 December 2007, allowing for ⩾3 years follow-up, unless death or diabetes onset occurred. Risk factors for the time to diabetes onset were assessed, including Antipsychotics taken for at least 180 defined daily doses in the first year after first antipsychotic prescription (‘initial treatment’). Risk factors for diabetes incidence were assessed, including antipsychotic use within 3 months before diabetes onset or study end (‘current treatment’). Of 7139 patients, followed for 6.6 years (47 297 patient years), 307 developed diabetes (annual incidence rate: 0.65%). Time to diabetes onset was significantly shorter in patients with higher age (hazard ratio (HR): 1.03, confidence interval (CI): 1.02–1.03) and those with ‘initial’ treatment of olanzapine (HR: 1.41, CI: 1.09–1.83), mid-potency first-generation Antipsychotics (FGAs) (HR: 1.60, CI: 1.07–2.39), antihypertensive (HR: 1.87, CI: 1.13–3.09), or lipid-lowering drugs (HR: 4.67, CI: 2.19–10.00). Significant factors associated with diabetes within 3 month of its development included treatment with low-potency FGAs (odds ratio (OR): 1.52, CI: 1.14–2.02), olanzapine (OR: 1.44, CI: 1.98–1.91), and clozapine (OR: 1.67, CI: 1.14–2.46), whereas aripiprazole was associated with lower diabetes risk (OR: 0.51, CI: 0.33–0.80). In addition to general diabetes risk factors, such as age, hypertension, and dyslipidemia, diabetes is promoted in schizophrenia patients by initial and current treatment with olanzapine and mid-potency FGAs, as well as by current treatment with or low-potency first-generation Antipsychotics and clozapine, whereas current aripiprazole treatment reduced diabetes risk. Patients discontinuing olanzapine or mid-potency FGA had no increased risk of diabetes compared with patient not treated with the drugs at anytime.
Shitij Kapur – 2nd expert on this subject based on the ideXlab platform
from dopamine to salience to psychosis linking biology pharmacology and phenomenology of psychosisSchizophrenia Research, 2005Co-Authors: Shitij Kapur, Romina Mizrahi, Ming LiAbstract:
Abstract How does an excess in a neurochemical lead someone to being paranoid about the intentions of their neighbour? And why does blocking a dopamine receptor improve this symptom? In this article we present a heuristic framework which attempts to link the biology, phenomenology and pharmacology of psychosis. Focussing on dopamine’s role in reward prediction and motivational salience we propose that psychosis arises from an aberrant assignment of novelty and salience to objects and associations. Antipsychotics block dopamine receptors and decrease dopamine transmission, which leads to the attenuation of aberrant novelty and salience. This ‘salience’ framework accounts for existing data and questions several current assumptions about the speed of onset phenomenological effects of Antipsychotics and their behavioral effects in animal models. We review new data to show that in contrast to the prevailing idea of a “delayed onset” of antipsychotic action, the improvement is evident in the first few days. Antipsychotics do not eradicate symptoms, but create a state of “detachment” from them. And the actions of Antipsychotics in the conditioned avoidance response model, one of the best established animal models for identifying antipsychotic action, are consistent with the idea that they dampen aberrant as well as normal motivational salience. The article discusses the caveats, limitations as well as the clinical implications of the salience framework.
half a century of Antipsychotics and still a central role for dopamine d2 receptorsProgress in Neuro-psychopharmacology & Biological Psychiatry, 2003Co-Authors: Shitij Kapur, David C MamoAbstract:
A review of the history of Antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical Antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most Antipsychotics, including atypical Antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical Antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of Antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and Antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, Antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of Antipsychotics may need to move away from a “one-size-fits-all polypharmacy-in-a-pill” approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients’ presenting psychopathology.
does fast dissociation from the dopamine d2 receptor explain the action of atypical Antipsychotics a new hypothesisAmerican Journal of Psychiatry, 2001Co-Authors: Shitij Kapur, Philip SeemanAbstract:
OBJECTIVE: Although atypical Antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic “atypical” is not clear. This article provides a new hypothesis about the mechanism of action of atypical Antipsychotics. METHOD: Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical Antipsychotics were reviewed to develop this hypothesis. Particular attention was paid to data regarding the role of the serotonin 5-HT2 and dopamine D4 receptors in atypicality. RESULTS: Neuroimaging data show that optimal dopamine D2 occupancy is sufficient to produce the atypical antipsychotic effect. Freedom from motor side effects results from low D2 occupancy, not from high 5-HT2 occupancy. If D2 occupancy is excessive, atypicality is lost even in the presence of high 5-HT2 occupancy. Animal data show that a rapid dissociation from the D2 receptor at a molecular level produces the atypical antipsychotic effect. In vitro data show that …
John M Kane – 3rd expert on this subject based on the ideXlab platform
Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical AntipsychoticsBMC Psychiatry, 2005Co-Authors: Douglas E. Faries, Christoph U Correll, Haya Ascher-svanum, John M KaneAbstract:
Antipsychotic monotherapy is recognized as the treatment of choice for patients with schizophrenia. Simultaneous treatment with multiple Antipsychotics (polypharmacy) is suggested by some expert consensus guidelines as the last resort after exhausting monotherapy alternatives. This study assessed the annual rate and duration of antipsychotic monotherapy and its inverse, antipsychotic polypharmacy, among schizophrenia patients initiated on commonly used atypical antipsychotic medications. Data were drawn from a large prospective naturalistic study of patients treated for schizophrenia-spectrum disorders, conducted 7/1997–9/2003. Analyses focused on patients (N = 796) who were initiated during the study on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276). The percentage of patients with monotherapy on the index antipsychotic over the 1-year post initiation, and the cumulative number of days on monotherapy were calculated for all patients and for each of the 3 atypical antipsychotic treatment groups. Analyses employed repeated measures generalized linear models and non-parametric bootstrap re-sampling, controlling for patient characteristics. During the 1-year period, only a third (35.7%) of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients. Despite guidelines recommending the use of polypharmacy only as a last resort, the use of antipsychotic polypharmacy for prolonged periods is very common during the treatment of schizophrenia patients in usual care settings. In addition, in this non-randomized naturalistic observational study, the most commonly used atypical Antipsychotics significantly differed on the rate and duration of antipsychotic monotherapy. Reasons for and the impact of the predominant use of polypharmacy will require further study.
lower risk for tardive dyskinesia associated with second generation Antipsychotics a systematic review of 1 year studiesAmerican Journal of Psychiatry, 2004Co-Authors: Christoph U Correll, Stefan Leucht, John M KaneAbstract:
OBJECTIVE: Based on lower rates of acute extrapyramidal side effects associated with second-generation Antipsychotics, compared to first-generation Antipsychotics, and based on preliminary data, second-generation Antipsychotics are expected to cause less tardive dyskinesia than first-generation Antipsychotics. This hypothesis was examined in a systematic review of studies involving open or controlled treatment with any second-generation antipsychotic. METHOD: Studies of treatment with second-generation Antipsychotics lasting ≥1 year and reporting on new cases of tardive dyskinesia or dyskinesia were systematically reviewed. RESULTS: In 11 studies, 2,769 patients received treatment with risperidone (five studies, N=1,235), olanzapine (two studies, N=610), quetiapine (two studies, N=386), amisulpride (one study, N=331), or ziprasidone (one study, N=207) for a weighted mean and median duration of 263 and 306 days, respectively. Study designs were double blind and randomized (N=3); open-label extensions of do…
relapse prevention in schizophrenia with new generation Antipsychotics a systematic review and exploratory meta analysis of randomized controlled trialsAmerican Journal of Psychiatry, 2003Co-Authors: Stefan Leucht, Christoph U Correll, Thomas R E Barnes, Werner Kissling, Rolf R Engel, John M KaneAbstract:
Objective: The authors performed a systematic review and meta-analysis of studies of the potential of new-generation antipsychotic drugs to improve adherence and decrease relapse rates in patients with schizophrenia. Method: Randomized, controlled trials comparing new-generation antipsychotic drugs with placebo and/or conventional Antipsychotics were identified. Data on relapse, general treatment failure, and dropout due to adverse events were extracted and combined in a meta-analysis. Results: Because few trials were available for each individual drug, the effects of new-generation antipsychotic drugs as a group were analyzed. The analysis of six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional Antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified. Conclusions: Overall, the currently available data suggest that new-generation Antipsychotics have the potential to reduce relapse rates. Methodological issues to be addressed in future trials include the choice of comparator, use of appropriate doses, application of clinically relevant relapse criteria, monitoring of adherence, and minimization of dropouts.