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Determinants of antipsychotic selection and response include parameters of the primary disorder, psychiatric and physical comorbidities, past treatment effects, patient preferences, availability and acceptability of different treatments and formulations, as well as expected efficacy and safety. In the absence of consistent and sufficiently large efficacy differences among antipsychotics (except for clozapine in refractory patients), and in view of a greater focus on physical health, functional outcomes and quality of life, relatively more predictable differences in adverse events have become an important management consideration. Treatments are often selected because of a relatively lower propensity for extrapyramidal and sexual side effects, sedation, and, especially, the reduced development of cardiometabolic risk states and disorders. In this context, differences in receptor binding affinity, intrinsic activity and in the half life of antipsychotics are crucial to adopt adequate dosing and switching strategies. Dopamine rebound phenomena can occur when the level of dopamine blockade is not kept relatively constant during the switch process. This can happen when the new antipsychotic is underdosed or not fully absorbed, the switch is too abrupt from an antipsychotic with a short half life to one with a much longer half life, or when a dopamine antagonist is switched too fast to an antipsychotic with markedly less dopamine affinity or to a partial dopamine agonist. Intra-switch destabilization can also occur when changing too quickly from antipsychotics with strong histaminergic and/or cholinergic blockade to ones with lower affinity to these receptors. Overlapping " plateau" switch strategies and transient co-treatment with calming medications, such as benzodiazepines, have emerged as potential solutions to these rebound phenomena that can complicate the early switch period. To optimize outcomes, antipsychotic treatment should be pharmacologically informed and measurement based, combining both acute and long-term management goals and balancing efficacy and adverse effect considerations. © 2010 Elsevier Masson SAS.

Correll C.U.,Psychiatry Research | Correll C.U.,Yeshiva University | Correll C.U.,Feinstein Institute for Medical Research
Dialogues in Clinical Neuroscience | Year: 2011

State-of-the art clinical trial design and methodology are enormously important for the advancement of the field. In contrast, the critical relevance of trial conduct and implementation have only more recently been the focus of discussion and research. Although randomized controlled trials are generally considered the gold standard for the assessment of pharmacologic and nonpharmacologic interventions in medicine, trials are vulnerable to complications and influences that can seriously compromise their success, Like interventions, trial design and conduct are also contextual. They need to be individualized and adapted to a number of relevant variables, such as setting, population, illness phase, interventions, patient and rater expectations and biases, and the overall aims of the investigation. While this means that there is no unified approach possible, certain general principles and guidelines require careful consideration. Knowledge of basic solutions and alternatives, and the recognition of the complex challenges that need to be addressed proactively can help to minimize unwanted outcomes, including trial failure and uninformative or falsely negative outcomes. Moreover, novel design alternatives need to be explored that target sample enrichment according to the study question and enhancement of precision in the measurement of relevant outcomes. We propose two novel design strategies that take advantage of the recently validated early antipsychotic response paradigm (that has also been observed with antidepressants and mood stabilizers). In the "early responder randomized discontinuation design" all patients are assigned to the active drug, and only those who had at least a minimal response at 2 weeks are enrolled in a double-blind, placebo-controlled discontinuation trial, enriching the placebo controlled trial portion with true drug responders. In the mirror image "early nonresponder randomized dose increase or augmentation design," early nonresponders at 2 weeks are assigned to staying on the medication or going either to a higher dose or an augmentation agent. It is hoped that through increased attention to the issues raised in this article and further refinement of trial methodology and conduct, the field will make much needed additional progress in the prevention and treatment of schizophrenia.

Hirota T.,Vanderbilt University | Schwartz S.,Psychiatry Research | Correll C.U.,Yeshiva University | Correll C.U.,Feinstein Institute for Medical Research
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective To meta-analyze the efficacy and safety of α-2 agonists in pediatric attention-deficit/hyperactivity disorder (ADHD). Method We searched MEDLINE, EMBASE, Cochrane Library, CINAHL, and PsycINFO until May 2013 for randomized trials comparing α-2 agonists with placebo in ADHD youth. Primary outcome was reduction in overall ADHD symptoms. Secondary outcomes included hyperactivity/impulsivity, inattentiveness, oppositional defiant disorder symptoms (ODD symptoms), all-cause discontinuation, specific-cause discontinuation, and adverse effects. Standardized mean differences (SMD), relative risk (RR), and number-needed-to-treat/number-needed-to-harm (NNT/NNH) were calculated. Data were analyzed separately in monotherapy and as add-on to psychostimulants. Results Altogether, 12 studies (N = 2,276) were included. Across 9 studies (n = 1,550), α-2 agonist monotherapy significantly reduced overall ADHD symptoms (SMD = -0.59, p <.00001), hyperactivity/ impulsivity (SMD = -0.56, p <.00001), inattention (SMD = -0.57, p <.00001), and ODD symptoms (SMD = -0.44, p =.0004). Similarly, α-2 agonist add-on treatment (3 studies, n = 726) significantly reduced overall ADHD symptoms (SMD = -0.36, p <.0001), hyperactivity/impulsivity (SMD = -0.33, p <.0001), and inattention (SMD = -0.34, p <.0001), but effect sizes were lower than in monotherapy trials (p =.03-0.04). As monotherapy, α-2 agonists had lower all-cause (RR = 0.70, p =.01, NNT = 10) and inefficacy-related (RR = 0.39, p <.0001) discontinuations than did placebo; however, intolerability-related discontinuation was similar, despite significantly more common fatigue (NNH = 10), sedation (NNH = 17), and somnolence (NNH = 4) and significantly greater hypotensive (clonidine-IR), bradycardic (clonidine-IR), and QTc prolonging (guanfacine-XR) effects. Added to stimulants, α-2 agonists had all-cause and specific-cause discontinuations that were comparable to those of placebo, but somnolence (NNH = 10) was more common, and hypotensive and bradycardic effects (clonidine-XR and guanfacine-XR) were greater than with placebo. Conclusions α-2 Agonist monotherapy and, possibly to a lesser extent, co-treatment, are significantly superior to placebo for overall, hyperactivity, and inattentive ADHD symptoms. Efficacy advantages need to be balanced against fatigue, somnolence/sedation, hypotension, bradycardia, and possibly QTc prolongation. © 2014 American Academy of Child and Adolescent Psychiatry.

Nielsen J.,Aarhus University Hospital | Skadhede S.,Aarhus University Hospital | Correll C.U.,Psychiatry Research | Correll C.U.,Yeshiva University
Neuropsychopharmacology | Year: 2010

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-naïve, first-episode patients. This study aims to determine which antipsychotics are associated with diabetes development in antipsychotic-nave schizophrenia patients. All antipsychotic-naïve 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. © 2010 Nature Publishing Group.

Leucht C.,TU Munich | Heres S.,TU Munich | Kane J.M.,Psychiatry Research | Kissling W.,TU Munich | And 2 more authors.
Schizophrenia Research | Year: 2011

Objective: Non-adherence is a major problem in the treatment of schizophrenia. Depot antipsychotic drugs are thought to reduce relapse rates by improving adherence, but a systematic review of long-term studies in outpatients is not available. Method: We searched the Cochrane Schizophrenia Group's register, ClinicalTrials.gov, Cochrane reviews on depot medication, and the reference sections of included studies for randomised controlled trials lasting at least 12 months in outpatients that compared depot with oral antipsychotics in schizophrenia. Data on relapse (primary outcome), rehospitalisation, non-adherence, and dropout due to any reason, inefficacy of treatment and adverse events were summarised in a meta-analysis using a random-effects model. Study quality was assessed with the Cochrane collaboration's risk of bias tool, and publication bias with funnel plots. Results: Ten studies with 1700 participants met the inclusion criteria. Depot formulations significantly reduced relapses with relative and absolute risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57-0.87, NNT 10, CI 6-25, P = 0.0009), and dropout due to inefficacy (RR 0.71, CI 0.57-0.89). Limited data on non-adherence, rehospitalisation and dropout due to any reason and adverse events revealed no significant differences. There were several potential sources of bias such as limited information on randomisation methods, problems of blinding and different medications in the depot and oral groups. Other studies reduced a potential superiority of depot by excluding non-adherent patients. Discussion: Depot antipsychotic drugs significantly reduced relapse. Due to a number of methodological problems in the single trials the evidence is, nonetheless, subject to possible bias. © 2010 Elsevier B.V.

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