Atypical Antipsychotics Drug Scan 091911 PDF

Drug Class Review of Atypical Antipsychotic Drugs
Update #4: Scan Report 1 August 2011
Oregon Health & Science University 3455 SW US Veterans Hospital Road Mailstop SN-4N, Portland, OR 97239-2941 Phone: 503.494.2182 Fax: 503.494.3807 http://www.ohsu.edu/xd/research/centers-institutes/evidence-based-policy-center/
Center for Evidence-based Policy
OBJECTIVE
The purpose of this drug class literature scan is to provide a preview of the volume and nature of new research that has emerged after the search dates of the Drug Effectiveness Review Projects systematic review and scan reports for a specified drug class. ACKNOWLEDGEMENTS
This report was prepared by: Kathryn Clark, BA Alison Little, MD, MPH Valerie King, MD, MPH The MEDLINE search was performed by: Andrew Hamilton, MS, MLS
This document was prepared by the Center for Evidence-based Policy at Oregon Health & Science University (the Center). This document is intended to support participant organizations and their constituent decision-making bodies to make informed decisions about the provision of health care services. The document is intended as a reference and is provided with the understanding that the Center is not engaged in rendering any clinical, legal, business or other professional advice. The statements in this document do not represent official policy positions of the Center. Researchers and authors involved in preparing this document have no affiliations or financial involvement that conflict with material presented in this document.
Table of Contents
Key Questions ................................................................................................................................. 1 Date of Last DERP Report Update ....................................................................................... 2 Methods .......................................................................................................................................... 2 Search Strategy ............................................................................................................................... 2 Inclusion Criteria ................................................................................................................. 2 Exclusion Criteria................................................................................................................. 4 Results ............................................................................................................................................. 4 New FDA Approved Drugs .................................................................................................. 5 New FDA Indications ........................................................................................................... 5 New FDA Safety nformation ............................................................................................... 5 New Cochrane or AHRQ Systematic Reviews ................................................................... 12 New RCTs .......................................................................................................................... 14 Appendix A. Search Strategy ......................................................................................................... 18 Appendix B. New Literature from Current Search ........................................................................ 20
KEY QUESTIONS In 2005, the Drug Effectiveness Review Project (DERP) commissioned a report on Atypical Antipsychotic Drugs. The Oregon Evidence-based Practice Center drafted preliminary key questions, identifying the populations, interventions, and outcomes of interest. The key questions were reviewed and revised by representatives of organizations participating in DERP. The participating organizations had responsibility for ensuring that the scope of the review reflected the populations, drugs, and outcome measures of interest for both clinicians and patients. The participating organizations approved the following key questions to guide the review. These key questions have also guided this scan for new literature on this topic. Key Question #1: For adults and adolescents with schizophrenia and other psychotic disorders, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? a. For adults and adolescents experiencing a first episode of schizophrenia, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #2: For adults, children and adolescents with bipolar disorder, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #3: For adults with major depressive disorder, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #4: For adults and adolescents with schizophrenia (including first-episode) and other psychotic disorders, adults, children and adolescents with bipolar disorder, or adults with major depressive disorder, what is the comparative evidence that differences in adherence or persistence among the atypical antipsychotic drugs correlate with a difference in clinical outcomes? Key Question #5: For children and adolescents with pervasive developmental disorders, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #6: For children and adolescents with disruptive behavior disorders, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #7: For older adults with behavioral and psychological symptoms of dementia, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms? Key Question #8: Are there subgroups of patients based on demographics (age, racial groups, gender), socioeconomic status, other medications, or co-morbidities for which one atypical antipsychotic drug is more effective or associated with fewer harms?
Atypical Antipsychotic Drugs
Date of Last Atypical Antipsychotic Drugs DERP Report Update July 2010 METHODS Search strategy A MEDLINE (Ovid) search was conducted to identify new randomized controlled trials (RCTs) published since the last search on this drug class. The MEDLINE (Ovid) for RCTs was completed by a medical librarian and a clinical epidemiologist. Please see Appendix A for the full MEDLINE search strategy. An additional search for recent SRs, using the terms atypical antipsychotic, and atypical was conducted using Cochrane Library (Wiley Interscience) and the Agency for Health Research and Quality (AHRQ) websites. The Food and Drug Administrations (FDA) website was searched for new FDA approved drugs, indications, and safety alerts. All searches were limited to publications published between February 2010 and week 2 of August 2011. Inclusion criteria Table 1. Inclusion Criteria Population 1. Adults (age 18 years or older) and adolescents (age 13 to 17 years) with a DSM III-R or DSM-IV diagnosis of schizophrenia, including other psychotic disorders such as schizophreniform, delusional, and schizoaffective disorders, and including: o First episode schizophrenia o Patients refractory to treatment 2. Adults (age 18 years or older) and adolescents (age 1317years) and children (under 13 years) with bipolar disorder (manic or depressive phases, rapid cycling, mixed states) 3. Adults with major depressive disorder 4. Older adults ( 65 years of age) with behavioral and psychological symptoms of dementia 5. Children (under age 13 years) and adolescents (age 13-17 years) with a DSM-III-R or DSM-IV diagnosis for a pervasive developmental disorder, including: o Autistic disorder o Aspergers disorder o Pervasive developmental disorder not otherwise specified (including atypical autism) 6. Children (under age 13 years) and adolescents (age 13-17 years) with a DSM-III-R or DSM-IV diagnosis of a disruptive behavior disorder, including: o Conduct disorder
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Intervention
Outcomes For patients with schizophrenia (including patients with a first episode and treatment-resistance), bipolar disorder, major depressive disorder, and behavioral and psychological symptoms of dementia, effectiveness outcomes included in this review are:
o Oppositional defiant disorder o Disruptive behavior disorder not otherwise specified Aripiprazole (Abilify) Asenapine (Saphris) Clozapine (Clozaril) Iloperidone (Fanapt) Lurasidone (Latuda) Olanzapine (Zyprexa) Paliperidone (Invega) Quetiapine (Seroquel) Risperidone (Risperdal) Ziprasidone (Geodon) 1. Mortality 2. Quality of life 3. Functional capacity (for example, employment or encounters with legal system) 4. Hospitalization (for psychiatric and other causes), emergency department visits, etc. 5. Efficacy as measured by symptom response (for example, global state, mental state, positive symptoms, or negative symptoms): response rates, duration of response, remission, relapse, speed of response, time to discontinuation of medication, etc. 6. Adherence, the ability to take medication as prescribed, also known as compliance 7. Persistence, the ability to continue taking medication over time 8. For patients with behavioral and psychological symptoms of dementia, care-giver burden was also included as an outcome of interest. 1.Functional capacity (social, academic, and occupational) 2.Quality of life 3. Hospitalization, emergency department visits, etc. 4. Efficacy as measured by symptom response (for example, global state, irritability, aggressiveness, or self-injurious behavior), response rates, duration of response, remission, relapse, speed of response, time to discontinuation of medication. For children and adolescents with disruptive behavior disorders, additional symptom response outcomes included disciplinary consequences (detention, suspension,
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For children and adolescents with pervasive developmental disorders and disruptive behavior disorders, effectiveness outcomes included in this review are:
encounters with the legal system) and property damage or theft. 5. Caregiver burden 6. Adherence (the ability to take medication as prescribed), also known as compliance 7. Persistence (the ability to continue taking medication over time) For all patient populations, outcomes measuring harms included in this review are: 1. Overall adverse events 2. Withdrawals due to adverse events and time to withdrawal due to adverse events 3. Specific adverse events o Major: Those that are life-threatening, result in longterm morbidity, or require continuing medical intervention to treat (for example, death, cerebrovascular disease-related events, development of diabetes mellitus, diabetic ketoacidosis, weight gain, neuroleptic malignant syndrome, seizures, tardive dyskinesia, cardiomyopathies and cardiac arrhythmias, or agranulocytosis) o General: extrapyramidal effects, weight gain, agitation, constipation, somnolence, hypersalivation, hypotension, elevated serum lipids, sexual dysfunction, and others
Exclusion criteria Studies were excluded if they: Were not published in English, Were not SRs (Cochrane and AHRQ searches) or head-to-head RCTs (Medline search)
RESULTS The MEDLINE search retrieved 341 full citations. After a full review of citations and abstracts, 24 head-to-head RCTs were included. The search of the Cochrane and AHRQ websites identified 10 relevant systematic reviews and protocols. The search on the FDA website identified one new approved drug, no new drug indications, and a variety of safety warnings (see Table 2). The citations and abstracts for all relevant studies are listed in Appendix B.
New FDA Approved Drugs Lurasidone (Latuda) is an atypical antipsychotic agent indicated for the treatment of patients with schizophrenia. The recommended starting dose of LATUDA is 40 mg once daily. Lurasidone is available in tablet form (40 mg and 80 mg). New FDA Indications None New FDA Safety Alerts Table 2. FDA Safety Information - Extracted verbatim from the FDAs MedWatch Website, available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
Drug Aripiprazole (Abilify), Clozapine (Clozaril and Fazaclo), Iloperidone (Fanapt), Ziprasidone HCL (Geodon), Paliperidone (Invega), Asenapine (Saphris), Quetiapine fumarate (Seroquel), Olanzapine (Zyprexa and Zyprexa Relprevv), Risperidone (Risperdal) Asenapine (Saphris) Modification Date December 2010 Product Label Sections Modified Precautions Details of Modifications SPECIFIC POPULATIONS/Pregnancy Non-teratogenic Effects
Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. These products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
September 2011
Contraindications, warnings and precautions, adverse reactions, patient counseling information
CONTRAINDICATIONS
Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine. Therefore, SAPHRIS is contraindicated in patients with a known hypersensitivity to the product
WARNINGS AND PRECAUTIONS Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.
ADVERSE REACTIONS
Hypersensitivity reactions
PATIENT COUNSELING INFORMATION Hypersensitivity Reactions
Patients should be informed of the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms.
Olanzapine (Zyprexa)
April 2010 May 2010
Adverse reactions, warnings and precautions
ADVERSE REACTIONS Vital Signs and Laboratory Studies
Within the larger premarketing Zyprexa Relprevv database of 1886 patients with baseline ALT 90 IU/L, the incidence of ALT elevation to >200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while Zyprexa Relprevv treatment was continued.
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Olanzapine Monotherapy in Adults: An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT 90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.
USE IN SPECIFIC POPULATIONS Pediatric Use
Compared to patients from adult clinical trials, adolescents treated with oral ZYPREXA were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.
WARNINGS AND PRECAUTIONS Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Longstanding hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and
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male subjects. Paliperidone (Invega) May 2010 April 2011 June 2011 Drug interaction, use in specific populations, adverse reactions, post-marketing experience, warnings and precautions DRUG INTERACTION Potential for Invega to Affect Other Drugs

Pharmacokinetic interaction between Invega Sustenna and lithium is unlikely. In a drug interaction study, coadministration of oral paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steadystate pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing valproate treatment.
Potential for Other Drugs to Affect Invega Sustenna
Pharmacokinetic interaction between lithium and Invega Sustenna is unlikely.
USE IN SPECIFIC POPULATIONS Pediatric Use
In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.
ADVERSE REACTIONS Commonly-Observed Adverse Events in DoubleBlind, Placebo-Controlled Clinical Trials
(updated) Table 2. Incidence if Treatment Emergent Adverse Events in 2% of Invega Sustenna-Treated Subjects with Schizophrenia in Four Fixed- Dose, DoubleBlind, Placebo-Controlled Trials
Adverse Reactions Observed During the Clinical Trial Evaluation of Invega Sustenna and Not Listed in Table 2
section updated
Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

Cardiac disorders: bundle branch block left Gastrointestinal disorders: flatulence, small intestinal obstruction General disorders and administration site conditions: edema peripheral Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, torticollis, trismus Nervous system disorders: cogwheel rigidity, grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders: hypotension
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, priapism, swollen tongue, urinary incontinence, urinary retention.
WARNINGS AND PRECAUTIONS Metabolic Changes
...Weight Gain information added
Quetiapine fumarate (Seroquel), quetiapine fumarate (Seroquel XR)
MAY 2011 JULY 2011
Warnings and precautions
WARNINGS AND PRECAUTIONS Tardive Dyskinesia
Addition of text regarding tardive dyskinesia syndrome may arise after discontinuation of treatment
Withdrawal
Addition of the incidence rates of discontinuation symptoms
Drug Interactions
False positive urine drug screens using immunoassays for methadone or tricyclic antidepressants have been reported in patients taking quetiapine.
Adverse Reactions
Decreases in hemoglobin to 13 g/dl (males) and 12 g/dl (females)
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WARNINGS AND PRECAUTIONS 5.12 QT Prolongation
In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect.....
5.21 Use in Patients with Concomitant Illness
see changes to section 5.12
ADVERSE REACTIONS 6.3 Postmarketing Experience
hypothermia added
DRUG INTERACTIONS
The use of quetiapine should be avoided in combination with drugs known to increase QT interval, and caution should be exercised when quetiapine is used in combination with drugs known to cause electrolyte imbalance
USE IN SPECIAL POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers MEDICATION GUIDE
bullet added to 'tell your healthcare provider if' ..... for "abnormal heart beats or rhythm"
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New Cochrane or AHRQ Systematic Reviews Five systematic reviews were identified through the Cochrane Library and the Agency for Effective Health Care website. Five review protocols were also identified. Characteristics of the five reviews and five protocols are outlined in Table 3.
Table 3. Characteristics of New Systematic Reviews Author, Year AHRQ Protocol (Posted 2010) AHRQ Protocol (Posted 2010) Drug Name(s) First and Second Generation Antipsychotics Selectiveserotonin reuptake inhibitors, serotoninnorepinephrine reuptake inhibitors, monoamine oxidase inhibitors, non-ssri antidepressants, augmenters (including various atypical antipsychotics) All atypical antipsychotics (exluding luradisone and clozapine) Population Description Pts with bipolar disorder and schizophrenia Adolescents and adults with major depressive disorder, dysthymia, or subsyndromal depression Main Outcome Functional outcomes, relapse and remission rates Partial or complete response, remission, speed of response or remission, relapse Comments
AHRQ Protocol (Posted 2010)
Adults, 18 years old and older with obsessive-compulsive disorder, posttraumatic stress disorder, personality disorders, agitation in dementia, major depressive disorder Children, youth, and young adults ( 24 years) with pervasive developmental Disorder, ADHD, disruptive behavior disorders, pediatric bipolar disorder,
Efficacy and effectiveness of off-label use of atypical antipsychotics
AHRQ Protocol (Posted 2010)
All atypical antipsychotics (exluding luradisone and clozapine)
Efficacy and effectiveness of off-label use of atypical antipsychotics
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schizophrenia / schizophrenia-related psychosis, obsessive compulsive disorder, post traumatic stress disorder, anorexia nervosa, Tourettes syndrome or behavioral issues Warren et al. (2011) AHRQ review Antipsychotics, psychostimulants, and serotonin reuptake inhibitors (SRIs), and modalities such as therapeutic diets, supplements, hormonal supplements, immunoglobulin, hyperbaric oxygen, and chelating agents Olanzapine vs. other atypical antipsychotics Children ages 2-12 with autism spectrum disorders Changes in core autism spectrum symptoms and in commonly associated symptoms
Komossa et al. (2010) Cochrane Review Komossa et al. (2010) Cochrane Review Komossa et al. (2011) Cochrane Review Lobos et al. (2010) Cochrane Review
Pts with schizophrenia
Efficacy and tolerability
Quetiapine vs. other atypical antipsychotics
Risperidone vs. other atypical antipsychotics
Clozapine vs. other atypical antipsychotics
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Preda et al. Cochrane Protocol (Posted 2010)
Asenapine vs. other atypical antipsychotics
New RCTs Twenty-four new head-to-head trials were identified in our MEDLINE search and are outlined in Table 4.
Table 4. Characteristics of New Head-to-Head Trials Author, Year Drug Name(s) Addington et Perphenazine al. (2011) vs olanzapine, quetiapine, risperidone, or ziprasidone Bitter et al. (2010) Olanzapine orodisperisble tablet vs. oral conventional tablet Four unspecified atypical antipsychotics Population Description Pts with DSM-IVdefined schizophrenia Main Outcome Impact of atypical antipsychotic medications on symptoms of depression Compliance and drug attitude Comments Post hoc analysis of CATIE trial
Outpatients with stable schizophrenia
Caroff et al. (2011)
Pts with DSM-IV defined schizophrenia both with and without tardive dyskinesia (TD) Schizophrenic pts with tardive dyskinesia
Time to all-cause treatment discontinuation
Assessed course of TD using change in Abnormal Involuntary Movement Scale (AIMS)
Chan et al. (2010)
Risperidone vs. olanzapine
Comparison in the change in total scores on the Abnormal Involuntary Movement Scale (AIMS) Long-term safety and efficacy Maintenance safety & effectiveness
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Findling et al. (2010)
Olanzapine vs. risperidone vs. molindrone
Pts (8 to 19 years old) with earlyonset
(plus benztropine)
schizophrenia spectrum disorders
findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study Time to relapse, adverse events
Gaebel et al. (2011)
Long-acting injectable risperidone vs. quetiapine Quetiapine vs. risperidone Ziprasidone vs. olanzapine
Pts with schizophrenia or related disorders First-episode schizophrenia pts Pts with recentonset schizophrenia Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder Agitated pts with psychosis during first 24 hours of treatment in an acute care psychiatric ward
Gafoor et al. (2010) Grootens et al. (2011)
Efficacy and adverse effect profiles Efficacy and tolerability Cognitive functioning
Harvey et al. Lurasidone vs. (2011) ziprasidone
Hsu et al. (2010)
Intramuscular olanzapine, intramuscular haloperidol, orally disintegrating olanzapine tablets and oral risperidone solutions Olanzapine vs. quetiapine vs. risperidone vs. ziprasidone
Efficacy and safety
Johnsen et al. (2010)
Pts admitted to the emergency ward for psychosis
Effectiveness, e.g., time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes
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Kinon et al. (2010) Kuwilsky et al. (2010)
Risperidone vs. other atypical antipsychotics Clozapine in combination with ziprasidone vs. risperidone Asenapine vs. placebo or olanzapine Olanzapine vs. quetiapine vs. risperidone vs. ziprasidone vs. perphenazine
Pts with schizophrenia Pts with treatmentresistant schizophrenia
Early response/ non response to treatment Comparable efficacy and differential side effects Safety and tolerability Family burden, e.g., problem behavior, resource demands and disruption, impairment in act ivies of daily living and pt helpfulness Assess noninferiority of paliperidone palmitate for tolerability and safety Predictors of adherence Changes in cognition Adherence to treatment, hospitalization, symptoms, quality of life Long-term safety and efficacy 40-week extension study Longitudinal results of CATIE trial
McIntyre et al. (2010) Perlick et al. (2010)
Pts with bipolar 1 disorder Family caregivers of pts diagnosed with schizophrenia
Pandina et al. (2011)
Paliperidone palmitate and risperidone
Adult pts with schizophrenia
Ritchie et al. (2010) Robles et al. (2011) Rosenheck et al. (2011)
Risperidone vs olanzapine Quetiapine vs. risperidone Long-acting injectable risperidone vs. other atypical antipsychotics
Pts over 60 with schizophrenia Pts with early onset psychosis VA pts who had schizophrenia or schizoaffective disorder and who have been hospitalized Pts with schizophrenia or schizoaffective disorder Chronic
Schoemaker Asenapine vs. et al. (2010) Olanzapine
Smith et al.
Olanzapine vs.
Lipid metabolism
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(2010) Strom et al. (2011) van Veelen et al. (2010) Vieta et al. (2010)
risperidone Ziprasidone vs olanzapine Ziprasidone vs. olanzapine Paliperidone ER vs. quetiapine
schizophrenic pts Pts with schizophrenia Pts with recent onset schizophrenia Pts with bipolar 1 disorder
Nonsuicide mortality
Short-term neurocognitive effects Antimanic efficacy and safety of paliperidone ER
NOTE: There are now a total of 24 relevant head-to-head trials and 47 placebo-controlled and activecontrolled trials that may be relevant to these topics that have been published since the date of the last report. 47 RCTs that compared an atypical antipsychotic(s) to placebo or a drug other than an atypical antipsychotic were identified, but are not included in this scan. Additionally, two Cochrane reviews and one Cochrane protocol that compared an atypical antipsychotic(s) to placebo, were identified but are not included in this scan.
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APPENDIX A. SEARCH STRATEGY Database: Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) <1946 to August Week 2 2011> Search Strategy: -------------------------------------------------------------------------------1 aripiprazole.mp. (1500) 2 abilify.mp. (24) 3 Clozapine.mp. or exp Clozapine/ (8632) 4 clozaril.mp. (65) 5 fazaclo.mp. (1) 6 olanzapine.mp. (5355) 7 zyprexa.mp. (48) 8 quetiapine.mp. (2469) 9 seroquel.mp. (109) 10 paliperidone.mp. (165) 11 invega.mp. (5) 12 risperidone.mp. or exp Risperidone/ (6005) 13 risperdal.mp. (43) 14 ziprasidone.mp. (1199) 15 geodon.mp. (12) 16 lurasidone.mp. (15) 17 latuda.mp. (2) 18 iloperidone.mp. (69) 19 Fanapt.mp. (2) 20 asenapine.mp. (60) 21 Saphris.mp. (5) 22 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (17859) 23 exp Schizophrenia/ or schizophren$.mp. (96779) 24 exp Psychotic Disorders/ (34625) 25 schizophreniform$.mp. (848) 26 (delusion$ adj3 disorder$).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] (756) 27 schizoaffectiv$.mp. (3519) 28 bipolar disorder$.mp. or exp Bipolar Disorder/ (30011) 29 bipolar$.mp. (47898) 30 dementia$.mp. or exp Dementia/ (122370) 31 (autism or autistic$).mp. or exp Autistic Disorder/ (17614) 32 rett syndrome.mp. or exp Rett Syndrome/ (1984) 33 rett.mp. (2074) 34 childhood disintegrative disorder.mp. (48)
Atypical Antipsychotics 18
35 exp Asperger Syndrome/ or asperger.mp. (1425) 36 pervasive development disorder.mp. or exp Child Development Disorders, Pervasive/ (15793) 37 exp Conduct Disorder/ (1812) 38 exp Conduct Disorder/ or conduct disorder$.mp. (3786) 39 oppositional defiant disorder$.mp. (928) 40 disruptive behavior disorder$.mp. (1936) 41 major depressive disorder$.mp. or exp Depressive Disorder, Major/ (18949) 42 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 (312975) 43 22 and 42 (11808) 44 limit 43 to (english language and humans) (9989) 45 ((2010$ not 201001$) or 2011$).ed. (1342937) 46 44 and 45 (1067) 47 limit 46 to (controlled clinical trial or randomized controlled trial) (185) 48 random$.mp. (690525) 49 46 and 48 (338) 50 47 or 49 (341)
Atypical Antipsychotics
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APPENDIX B. NEW LITERATURE FROM CURRENT SEARCH Systematic Reviews and Protocols (Cochrane and AHRQ) Agency for Healthcare Research and Quality (AHRQ). (2011). Therapies for children with autism spectrum disorders (Review). Rockville, MD: AHRQ. Retrieved August 22, 2011, from http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-andreports/?pageaction=displayproduct&productID=656 Agency for Healthcare Research and Quality (AHRQ). (2010). Efficacy and comparative effectiveness of off-label use of atypical antipsychotics update (Protocol). Rockville, MD: AHRQ. Retrieved August 22, 2011, from http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-andreports/?pageaction=displayproduct&productid=443 Agency for Healthcare Research and Quality (AHRQ). (2010). Comparative effectiveness of first and second generation antipsychotics in the adult population (Protocol). Rockville, MD: AHRQ. Retrieved August 22, 2011, from http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviewsandreports/?pageaction=displayproduct&productid=583 Agency for Healthcare Research and Quality (AHRQ). (2010). Comparative effectiveness of first and second generation antipsychotics in the pediatric and young adult populations (Protocol). Rockville, MD: AHRQ. Retrieved August 22, 2011, from http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-andreports/?pageaction=displayproduct&productid=453 Agency for Healthcare Research and Quality (AHRQ). (2010). Depression treatment after unsatisfactory response to SSRIs when used as first-line therapy (Protocol). Rockville, MD: AHRQ. Retrieved August 22, 2011, from http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-andreports/?pageaction=displayproduct&productid=455 Komossa, K., Rummel-Kluge, C., Hunger, H., Schmid, F., Schwarz, S., Duggan, L., et al. (2010). Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews, Issue 3. Komossa, K., Rummel-Kluge, C., Schmid, F., Hunger, H., Schwarz, S., Srisurapanont Manit, K. W., et al. (2010). Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews, Issue 1. Komossa, K., Rummel-Kluge, C., Schwarz, S., Schmid, F., Hunger, H., Kissling, W., et al. (2011). Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews, Issue 1.
Lobos, C.A., Komossa, K., Rummel-Kluge, C., Hunger, H., Schmid, F., Schwarz, S., et al. (2010). Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews, Issue 11. Preda, A., Faziola, L. (2010). Asenapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews, Issue 12. This is the protocol for a review and there is no abstract. The objectives are as follows: To review the effects of asenapine compared to other second generation/atypical antipsychotics for people with schizophrenia.
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Head to Head RCTs Addington, DE., Mohamed, S., Rosenheck, RA., Davis, SM., Stroup, TS., McEvoy, JP., et al. (2011). Impact of second-generation antipsychotics and perphenazine on depressive symptoms in a randomized trial of treatment for chronic schizophrenia. Journal of Clinical Psychiatry. 72(1), 75-80. BACKGROUND: According to the American Psychiatric Association Clinical Practice Guidelines for schizophrenia, second-generation antipsychotics may be specifically indicated for the treatment of depression in schizophrenia. We examined the impact of these medications on symptoms of depression using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), conducted between January 2001 and December 2004. METHOD: Patients with DSM-IV-defined schizophrenia (N = 1,460) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of 4 second-generation drugs (olanzapine, quetiapine, risperidone, or ziprasidone) and followed for up to 18 months (phase 1). Patients with tardive dyskinesia were excluded from the randomization that included perphenazine. Depression was assessed with the Calgary Depression Scale for Schizophrenia (CDSS). Mixed models were used to evaluate group differences during treatment with the initially assigned drug. An interaction analysis evaluated differences in drug response by whether patients had a baseline score on the CDSS of >= 6, indicative of a current major depressive episode (MDE). RESULTS: There were no significant differences between treatment groups on phase 1 analysis, although there was a significant improvement in depression across all treatments. A significant interaction was found between treatment and experiencing an MDE at baseline (P = .05), and further paired comparisons suggested that quetiapine was superior to risperidone among patients who were in an MDE at baseline (P = .0056). CONCLUSIONS: We found no differences between any second-generation antipsychotic and the first-generation antipsychotic perphenazine and no support for the clinical practice recommendation, but we did detect a signal indicating a small potential difference favoring quetiapine over risperidone only in patients with an MDE at baseline. Bitter, I., Treuer, T., Dilbaz, N., Oyffe, I., Ciorabai, EM., Gonzalez, SL., et al. (2010). Patients' preference for olanzapine orodispersible tablet compared with conventional oral tablet in a multinational, randomized, crossover study. World Journal of Biological Psychiatry, 11(7), 894903. OBJECTIVES: The aim of this study was to compare patients' preference for olanzapine orodispersible tablet (ODT) with oral conventional tablet (OCT). METHODS: A 12-week randomized, crossover, multinational, open-label study was conducted to estimate the proportion of patients preferring ODT or OCT. Outpatients with stable schizophrenia on OCT monotherapy were randomly assigned 1:1 to ODT or OCT. Compliance and drug
attitude were measured using the Drug Attitude Inventory (DAI-10) and Medication Adherence Form (MAF) scales; tolerability and safety by Association for Methodology and Documentation in Psychiatry (AMDP-5) questionnaire and adverse event summary. RESULTS: A total of 175 patients answered a preference question: 106 (61%) preferred ODT and 48 (27%) preferred OCT (P<0.001 adjusted for treatment sequence); 21 (12%) expressed no preference. There was no significant change in DAI-10 with either formulation. MAF was above 75% in 94% vs. 93% of patients on ODC and OCT, respectively. Compliance as measured by tablet count was above 98% on both formulations. The adverse event profiles did not differ between formulations. Mean weight increase over 6 weeks on ODT was 0.8 kg and on OCT was 0.6 kg. CONCLUSIONS: Given the importance of patients' preference for treatment planning and success, the ODT formulation should be routinely considered as a treatment option. Caroff, SN., Davis, VG., Miller, del D., Davis, SM., Rosenheck, RA., McEvoy, JP., et al. (2011). Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia. Journal of Clinical Psychiatry, 72(3), 295-303. OBJECTIVE: We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD.METHOD: This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 secondgeneration antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with chi(2) tests. Data were collected from January 2001 to December 2004. RESULTS: Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (chi(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a >= 50% decrease in AIMS score, and 7% showed a >= 50% increase in AIMS score. CONCLUSIONS: Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between
treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. Chan, HY., Chiang, SC., Chang, CJ., Gau, SS., Chen, JJ., Chen, CH., et al. (2010). A randomized controlled trial of risperidone and olanzapine for schizophrenic patients with neurolepticinduced tardive dyskinesia. Journal of Clinical Psychiatry, 71(9), 1226-33. OBJECTIVE: To compare the efficacy of risperidone and olanzapine in schizophrenic patients with tardive dyskinesia on treatment with first-generation antipsychotics. METHOD: We conducted a 24-week, rater-blinded, flexible-dose study. Sixty patients with DSM-IV schizophrenia (n=58) or schizoaffective disorder (n=2) met the DSM-IV research criteria for neuroleptic-induced tardive dyskinesia and were randomly assigned to a risperidone or olanzapine group. The primary outcome was a comparison of the change in the total scores on the Abnormal Involuntary Movement Scale (AIMS) from baseline to study end point between the groups. The study was conducted from July 2000 to June 2004. RESULTS: The mean +/- SD doses of risperidone and olanzapine from baseline to study end point were 1.9+/-0.7 to 4.1+/-1.4 mg/d and 8.1+/-2.0 to 12.6+/-5.4 mg/d, respectively. There were no statistically significant differences in demographic data, severity of tardive dyskinesia, or psychotic symptoms between risperidone and olanzapine groups at baseline assessment. Both groups showed significant improvement in mean +/- SD AIMS total scores (risperidone: -7.4 +/- 6.9, P<.0001; olanzapine: -6.2 +/8.0, P = .0002). However, there was a more statistically significant change in the slope of AIMS total scores in the risperidone group than in the olanzapine group (P = .0001). CONCLUSIONS: Our findings demonstrated that olanzapine may not have better potential for tardive dyskinesia improvement than risperidone did. Double-blinded, fixed dose studies with a larger sample size on schizophrenic patients with tardive dyskinesia from different ethnic groups are needed to confirm the results of our study. Findling, RL., Johnson, JL., McClellan, J., Frazier, JA., Vitiello, B., Hamer, RM. (2010). Doubleblind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study. Journal of the American Academy of Child & Adolescent Psychiatry, 49(6), 583-94. OBJECTIVE: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. METHOD: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. RESULTS: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three
treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. CONCLUSIONS: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Gaebel, W., Schreiner, A., Bergmans, P., de Arce, R., Rouillon, F., Cordes, J., et al. (2011). Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology, 36(2), 548. Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan-Meier estimate of time-to-relapse was significantly longer with RLAI (p<0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25+/-6.61 and 0+/-6.55[THIN SPACE]kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.
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Gafoor, R., Landau, S., Craig, TK., Elanjithara, T., Power, P., McGuire, P. (2010).Esquire trial: efficacy and adverse effects of quetiapine versus risperidone in first-episode schizophrenia. Journal of Clinical Psychopharmacology, 30(5), 600-6. OBJECTIVE: To compare the efficacy and adverse effect profiles of 2 widely used atypical antipsychotics in the short-term phase of first-episode schizophrenia in patients who were treatment-naive. A secondary objective was to establish the effective dose of these drugs in this context. METHODS: A total of 72 patients with a first episode of schizophreniform psychosis (schizophrenia spectrum disorder) with less than 2 weeks of exposure to antipsychotic medication were randomized to quetiapine or risperidone in a single-blind 12-week controlled trial. Psychopathologic diagnoses and adverse effects were assessed by blinded raters at 4 weekly intervals. Medication was administered by a specialized clinical team following dosing guidelines. Data were analyzed using an intention-to-treat paradigm. RESULTS: Both quetiapine and risperidone were associated with a reduction in immediate symptoms and relatively few adverse effects other than weight gain. There was no statistically significant difference between the 2 compounds in adverse effects, relative efficacies, or adherence to treatment. The median (SD) time to cessation for patients randomized to quetiapine was 65.3 (41.85) days and that for risperidone was 82.5 (44.88) days. There was no statistically significant difference between time to discontinuation for the 2 compounds. The mean daily doses prescribed were 375 mg of quetiapine and 2.72 mg of risperidone. CONCLUSIONS: Quetiapine and risperidone are both effective treatments in first-episode schizophrenia at doses lower than those used in patients with long-term schizophrenia and are similar in efficacy and the incidence of adverse effects.
Grootens, KP., van Veelen, NM., Peuskens, J., Sabbe, BG., Thys, E., Buitelaar, JK., et al. (2011). Ziprasidone vs. olanzapine in recent-onset schizophrenia and schizoaffective disorder: results of an 8-week double-blind randomized controlled trial. Schizophrenia Bulletin, 37(2), 352-61. INTRODUCTION: Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia. METHODS: The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram. RESULTS: Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However,
mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05). DISCUSSION: The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms. Harvey, PD., Ogasa, M., Cucchiaro, J., Loebel, A., Keefe, RS. (2011).Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. Schizophrenia Research, 127(1-3), 188-94. BACKGROUND: Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes. METHODS: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007. RESULTS: There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within groupimprovement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms. CONCLUSIONS: These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures. Hsu, WY., Huang, SS., Lee, BS., Chiu, NY. (2010). Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol
in the management of acute agitation in an acute care psychiatric ward in Taiwan. Journal of Clinical Psychopharmacology, 30(3), 230-4. INTRODUCTION: The purpose of this study was to compare efficacy and safety among intramuscular olanzapine, intramuscular haloperidol, orally disintegrating olanzapine tablets, and oral risperidone solution for agitated patients with psychosis during the first 24 hours of treatment in an acute care psychiatric ward. METHODS: Forty-two inpatients from an acute care psychiatric ward of a medical center in central Taiwan were enrolled. They were randomly assigned to 1 of the 4 treatment groups (10-mg intramuscular olanzapine, 10-mg olanzapine oral disintegrating tablet, 3-mg oral risperidone solution, or 7.5-mg intramuscular haloperidol). Agitation was measured by using the excited component of the Positive and Negative Syndrome Scale (PANSS-EC), the Agitation-Calmness Evaluation Scale, and the Clinical Global Impression--Severity Scale during the first 24 hours. RESULTS: There were significant differences in the PANSS-EC total scores for the 4 intervention groups at 15, 30, 45, 60, 75, and 90 minutes after the initiation of treatment. More significant differences were found early in the treatment. In the post hoc analysis, the patients who received intramuscular olanzapine or orally disintegrating olanzapine tablets showed significantly greater improvement in PANSS-EC scores than did patients who received intramuscular haloperidol at points 15, 30, 45, 60, 75, and 90 minutes after injection. CONCLUSIONS: These findings suggest that intramuscular olanzapine, orally disintegrating olanzapine tablets, and oral risperidone solution are as effective treatments as intramuscular haloperidol for patients with acute agitation. Intramuscular olanzapine and disintegrating olanzapine tablets are more effective than intramuscular haloperidol in the early phase of the intervention. There is no significant difference in effectiveness among intramuscular olanzapine, orally disintegrating olanzapine tablets, and oral risperidone solution. Johnsen, E., Kroken, RA., Wentzel-Larsen, T., Jorgensen, HA. (2010). Effectiveness of secondgeneration antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone. BMC Psychiatry, 10(26). BACKGROUND: No clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line secondgeneration antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes. METHODS: Patients >or= 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years. RESULTS: A total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naive. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until
discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups. CONCLUSIONS: Quetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis. Kinon, BJ., Chen, L., Ascher-Svanum, H., Stauffer, VL., Kollack-Walker, S., Zhou, W., et al. (2010). Challenging the assumption that improvement in functional outcomes is delayed relative to improvement in symptoms in the treatment of schizophrenia. Schizophrenia Research, 118(1-3), 176-82. OBJECTIVES: Functional improvement is generally thought to be distal to improvement in psychiatric symptoms in patients with schizophrenia. In this study, we assessed the effects of early response/non-response to an atypical antipsychotic across multiple outcome measures. METHODS: This was a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients (n=628) diagnosed with schizophrenia or schizoaffective disorder who were experiencing acute symptom exacerbation. Patients were initially assigned to risperidone drug therapy (2-6 mg/day), and their response status at 2 weeks was determined. Early responders (ERs) continued with risperidone therapy, whereas early non-responders (ENRs) were randomized (1:1) in a double-blind manner to either continue on risperidone or switch to another atypical antipsychotic for 10 additional weeks of therapy. Subsequent treatment outcomes were measured by the Quality of Life Scale (QLS), Schizophrenia Objective Functioning Instrument (SOFI), and Subjective Well-being under Neuroleptics (SWN-K) scale. RESULTS: Compared to ENRs, ERs to risperidone showed significantly more improvement from baseline to endpoint on the QLS total score and all 4 categories (p<.01), the SOFI overall global score and all 4 domains (p<.001), and the SWN-K total score and all 5 subscales (p<.05). Among ERs, the majority of improvement had already been attained by Week 2. There was concordance among clinician- and patient-rated scales across outcomes. CONCLUSION: Improvement across multiple outcome dimensions was not delayed relative to improvement in psychiatric symptoms. Rather, patients who showed an early response to antipsychotic treatment as defined by improvement in psychiatric symptoms also showed early and consistent improvement in functioning, quality of life, and subjective well-being.
Kuwilsky, A., Krumm, B., Englisch, S., Dressing, H., Zink, M., et al. (2010). Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry, 43(6), 216-20. INTRODUCTION: Treatment resistance in schizophrenia often leads to add-on of atypical antipsychotics to clozapine. METHODS: In a randomized trial, we recently obtained evidence for comparable efficacy and differential side effects of clozapine in combination with ziprasidone (CZ, N=12) versus risperidone (CR, N=12). Here, we present the open-label, long-term evaluations of these patients after 26 and 52 weeks. RESULTS: Sustained improvements of psychopathology as assessed by PANSS (positive and negative syndrome scale), SANS (scale for the assessment of negative symptoms), and HAMD (Hamilton depression scale) were documented in both subsamples being treated according to protocol, while dropouts reduced the study sample after 26 (CZ: reduced by -4; CR: -2) and 52 weeks (CZ: -0; CR: -5). We observed a slight increase of akathisia in the CZ group whereas general clozapine-associated side effects improved. DISCUSSION: The combinations of clozapine with ziprasidone or risperidone exhibit long-term efficacy, but the level of evidence is limited. Further head-to-head comparisons of atypical antipsychotics as add-on to clozapine are necessary. McIntyre, RS., Cohen, M., Zhao, J., Alphs, L., Macek, TA., Panagides, J., (2010). Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. Journal of Affective Disorders, 126(3), 358-65. BACKGROUND: Asenapine is approved in the United States for acute treatment of manic or mixed episodes of bipolar I disorder with or without psychotic features. We report the results of long-term treatment with asenapine in patients with bipolar I disorder. METHODS: Patients completing either of two 3-week efficacy trials and a subsequent 9week double-blind extension were eligible for this 40-week double-blind extension. Patients in the 3-week trials were randomized to flexible-dose asenapine (5 or 10mg BID), placebo, or olanzapine (5-20mg QD; included for assay sensitivity only). Patients entering the extension phase maintained their preestablished treatment; those originally randomized to placebo received flexible-dose asenapine (placebo/asenapine). Safety and tolerability endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory values, and anthropometric measures. Efficacy, a secondary assessment, was measured as change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline to week 52 with asenapine or olanzapine; the placebo/asenapine group was assessed for safety only. RESULTS: Incidence of treatment-emergent AEs was 71.9%, 86.1%, and 79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most frequent treatment-emergent AEs were headache and somnolence with placebo/asenapine; insomnia, sedation, and depression with asenapine; and weight gain, somnolence, and sedation with olanzapine. Among observed cases, mean +/- SD changes in YMRS total score at week 52 were -28.6 +/- 8.1 and -28.2 +/- 6.8 for asenapine and olanzapine, respectively. LIMITATIONS: The study did not have a long-term placebo group.
CONCLUSIONS: In this 52-week extension in patients with bipolar mania, asenapine was well tolerated and long-term maintenance of efficacy was supported. Pandina, G., Lane, R., Gopal, S., Gassmann-Mayer, C., Hough, D., Remmerie, B., et al. (2011). A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35(1), 21826. This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N=1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25mg), days 36, 50 (25 or 37.5mg) and days 64, 78 (25, 37.5 or 50mg). RIS-LAI-treated patients received oral supplementation with RIS 1-6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n=1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (-18.6 [15.45]) and RIS-LAI (-17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [-1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings. Perlick, DA., Rosenheck, RA., Kaczynski, R., Swartz, MS., Canive, JM., Lieberman, JA., et al. (2010). Impact of antipsychotic medication on family burden in schizophrenia: longitudinal results of CATIE trial. Schizophrenia Research, 116(2-3), 118-25. BACKGROUND: This study evaluated the effectiveness of first- and second-generation antipsychotics in reducing family burden associated with schizophrenia.METHODS: The family caregivers of 623 SCID-diagnosed patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) randomly assigned to a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetiapine, risperidone or ziprasidone) were interviewed about resources provided and stresses experienced at baseline and followed for 18 months. Patient symptoms, side effects and service use were assessed as well. Hierarchical regression analyses evaluated the effect of treatment assignment on four burden factors: problem behavior, resource demands and disruption, impairment in activities of daily living and patient helpfulness. Intention-to-treat analyses with all available observations classified based on initial treatment assignment, including observations after medications changed were followed by secondary analyses excluding observations after the first medication change, i.e. only considering initial medication.RESULTS: Despite significant reductions on the problem behavior and resource demands/disruption factors, there were no significant
differences between perphenazine and any of the second-generation medications. When only initial treatment period observations were included, patients were perceived as more helpful when medicated with perphenazine as compared to risperidone. In comparisons between second-generation drugs, patients on quetiapine were perceived as more helpful than those on risperidone (p=0.004). CONCLUSION: In this 18-month randomized trial, there was no evidence of superiority of second-generation antipsychotics in relieving family burden. Ritchie, CW., Harrigan, S., Mastwyk, M., Macfarlane, S., Cheesman, N., Ames, D. (2010). Predictors of adherence to atypical antipsychotics (risperidone or olanzapine) in older patients with schizophrenia: an open study of 3(1/2) years duration. International Journal of Geriatric Psychiatry, 25(4), 411-8. OBJECTIVE: Although the evidence base for the use of antipsychotics in older people with schizophrenia is generally of low quality, it tends to support the use of atypical antipsychotics. Only limited information regarding longer term adherence to these apparently more effective drugs is available. The aim of this study was to determine predictors of adherence to risperidone or olanzapine in patients over 60.METHODS: Patients receiving care from old age psychiatrists for their schizophrenia were randomised to treatment with olanzapine or risperidone and were followed for up to 3(1/2) years. Kaplan-Meier curves were generated to assess the univariate effect of randomisation drug on long-term adherence and Cox regression adjusted for baseline variables which may have affected adherence. RESULTS: In total, 60.6% of the 66 patients in the study were still taking their randomised drug by the end of the interval in which they remained under observation (64.7% olanzapine and 56.3% risperidone). This difference was non-significant. No baseline variable was associated with an increased risk of non-adherence, though the delivery form of pre-randomisation drug (oral or depot) was weakly (p = 0.054) associated with patients originally on depot being less likely to be adherent to an atypical drug. CONCLUSIONS: Overall adherence with atypical medication was good with almost two-thirds of the patients remaining on their randomisation drug for the interval in which they were under observation. Patients taken off depot were less likely to be adherent but there was no significant difference in adherence between olanzapine and risperidone. Scrutiny of the survival curves suggested that non-adherence is an early event in treatment and patients adherent at 6 months were likely to remain adherent over a longer time period. Robles, O., Zabala, A., Bombin, I., Parellada, M., Moreno, D., Ruiz-Sancho, A., et al. (2011). Cognitive efficacy of quetiapine and olanzapine in early-onset first-episode psychosis. Schizophrenia bulletin, 37(2), 405-15. The primary purpose of this study was to compare changes in cognition in early-onset psychosis after 6-months treatment with quetiapine or olanzapine. This is a randomized, single-blind, 6-month study in 50 adolescents with a diagnosis of early-onset psychosis.
Patients were randomized to quetiapine (n = 24) or olanzapine (n =26). A thorough neuropsychological battery was administered at baseline and after 6-month treatment. Out of the total sample included in the study, 32 patients completed at least 6-months treatment with the assigned medication (quetiapine, n =16; olanzapine, n = 16). No changes were observed in cognitive performance after 6-month treatment with quetiapine or olanzapine. Although some trends toward cognitive improvement were observed for the olanzapine group after 6-month treatment, neither group showed statistically significant gains. Furthermore, there was no evidence of any differential efficacy of olanzapine or quetiapine on cognitive improvement in this sample of adolescents with psychosis. Rosenheck, RA., Krystal., JH., Lew, R., Barnett, PG., Fiore, L., Valley, D., et al. (2011). Long-acting risperidone and oral antipsychotics in unstable schizophrenia. New England Journal of Medicine, 364(9), 842-51. BACKGROUND: Long-acting injectable risperidone, a second-generation antipsychotic agent, may improve adherence to treatment and outcomes in schizophrenia, but it has not been tested in a long-term randomized trial involving patients with unstable disease. METHODS: We randomly assigned patients in the Veterans Affairs (VA) system who had schizophrenia or schizoaffective disorder and who had been hospitalized within the previous 2 years or were at imminent risk for hospitalization to 25 to 50 mg of long-acting injectable risperidone every two weeks or to a psychiatrist's choice of an oral antipsychotic. All patients were followed for up to 2 years. The primary end point was hospitalization in a VA or non-VA psychiatric hospital. Symptoms, quality of life, and functioning were assessed in blinded videoconference interviews. RESULTS: Of 369 participants, 40% were hospitalized at randomization, 55% were hospitalized within the previous 2 years, and 5% were at risk for hospitalization. The rate of hospitalization after randomization was not significantly lower among patients who received long-acting injectable risperidone than among those who received oral antipsychotics (39% after 10.8 months vs. 45% after 11.3 months; hazard ratio, 0.87; 95% confidence interval, 0.63 to 1.20). Psychiatric symptoms, quality of life, scores on the Personal and Social Performance scale of global functioning, and neurologic side effects were not significantly improved with long-acting injectable risperidone as compared with control treatments. Patients who received long-acting injectable risperidone reported more adverse events at the injection site and more extrapyramidal symptoms. CONCLUSIONS: Long-acting injectable risperidone was not superior to a psychiatrist's choice of oral treatment in patients with schizophrenia and schizoaffective disorder who were hospitalized or at high risk for hospitalization, and it was associated with more local injection-site and extrapyramidal adverse effects. Schoemaker, J., Naber, D., Vrijland, P., Panagides, J., Emsley, R. (2010). Long-term assessment of asenapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry, 43(4), 138-46.
INTRODUCTION: We conducted a double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. METHODS: Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. RESULTS: Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in PANSS total score with asenapine and olanzapine were 21.0 and -27.5 ( P<0.0001); the exclusion of patients who had previous poor experience with olanzapine may have biased the results in favor of olanzapine. Scores on the subjective well-being on neuroleptics scale and functionality measures were similar between groups. CONCLUSION: Asenapine was well tolerated over 1 year of treatment, causing less weight gain than olanzapine but more frequent extrapyramidal symptoms. PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis. Smith, RC., Lindenmayer, JP., Hu, Q., Kelly, E., Viviano, TF., Cornwell, J., et al. (2010). Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with longterm antipsychotic treatment: a randomized five month study. Schizophrenia Research, 120(13), 204-9. OBJECTIVE: Metabolic syndrome and elevated lipids, related to cardiovascular risk factors, are more prevalent in schizophrenia and there has been much debate about the extent to which specific antipsychotics contribute more to the increased risk of developing hyperlipidemia and metabolic syndrome. Most studies have concentrated on fasting levels in patients recently started on medication. Randomized prospective studies of metabolic effects of 2nd generation antipsychotics using both fasting measures and provocative tests may provide results that are more informative. We present results of a randomized prospective study of lipid metabolism and metabolic syndrome in chronic schizophrenic patients using both fasting and post-prandial lipid measures. METHOD: Hospitalized patients with chronic schizophrenia, most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting levels of lipids, free fatty acid (FFA) and leptin were assessed. At baseline and end of month 2 of treatment patients had a fatty meal test (FMT) in which postprandial lipids were measured at several time points before and after meal ingestion. Weight was assessed monthly and waist measures were taken at baseline and month 5. Data was analyzed on 23 patients randomized to risperidone and 23 patients randomized to olanzapine. RESULTS: Overall, there were no differential drug effects on any fasting lipid measure and fasting triglycerides did not increase in olanzapine treated patients after 5 months of treatment. However, at 2 months of drug treatment the FMT revealed a significantly
greater increase in triglycerides, and very low density (VLDL) cholesterol and triglycerides, in olanzapine compared to risperidone patients (Ps=.05-.01). There was no difference between treatments with olanzapine vs. risperidone on development of metabolic syndrome during the 5 month treatment period. CONCLUSIONS: Chronic schizophrenic patients treated for years with first and second generation antipsychotics may have developed tolerance to the effects of olanzapine on increasing fasting triglycerides and other lipids, but some underlying metabolic abnormalities may be revealed in postprandial tests of lipid metabolism. These findings suggest that the development of standardized tests and criteria for measurement of postprandial triglycerides and related lipid levels, in addition to fasting levels, may be helpful in identifying metabolic effects of olanzapine and other second generation antipsychotics in chronically treated schizophrenics. In some reports postprandial increases in triglycerides have been identified as important risk factors for cardiovascular disease, but the actual differential consequences of these lipid metabolic differences for development of atherosclerosis and cardiovascular disease in patients treated with different antipsychotics need more objective outcome measures to determine and quantify cardiovascular risk outcomes. Strom, BL., Eng, SM., Faich, G., Reynolds, RF., D'Agostino, RB., Ruskin, J., et al. (2011). Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). American Journal of Psychiatry, 168(2), 193-201. OBJECTIVE: The authors compared 1-year mortality rates associated with ziprasidone and olanzapine in real-world use. METHOD: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was an open-label, randomized, postmarketing large simple trial that enrolled patients with schizophrenia (N=18,154) in naturalistic practice in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of assigned treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for 1 year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was collected and reported by treating psychiatrists. Post hoc analyses of sudden death, a secondary endpoint, were also conducted. RESULTS: The incidence of nonsuicide mortality within 1 year of initiating pharmacotherapy was 0.91 for ziprasidone (N=9,077) and 0.90 for olanzapine (N=9,077). The relative risk was 1.02 (95% CI=0.76-1.39). This finding was confirmed in numerous secondary and sensitivity analyses. CONCLUSIONS: Despite the known risk of QTc prolongation with ziprasidone treatment, the findings of this study failed to show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use; the study excludes a relative risk larger than 1.39 with a high probability. However, the study was neither powered nor designed to examine the risk of rare events like torsade de pointes.
van Veelen, NM., Grootens, KP., Peuskens, J., Sabbe, BG., Salden, ME., Verkes, RJ., et al. (2010). Short term neurocognitive effects of treatment with ziprasidone and olanzapine in recent onset schizophrenia. Schizophrenia Research, 120(1-3), 191-8. BACKGROUND: Cognitive deficits are a core feature in schizophrenia. Cognitive deficits appear to be present at the onset of schizophrenia and persist after remission of psychotic symptoms. As cognitive deficits are associated with poor functional outcome, they form an important focus of treatment. There are relatively few head-to-head comparisons of the effects of second generation antipsychotics on cognition in recent onset schizophrenia. This is the first study to compare the effects of a short term treatment of olanzapine versus ziprasidone on cognitive functioning in recent onset schizophrenia. An earlier study conducted in chronic patients revealed an enhancement of cognition after treatment for both agents, but the extent of improvement was not significantly different between ziprasidone and olanzapine. METHOD: Patients with recent onset schizophrenia with limited previous exposure to medical treatment underwent a double blind randomized controlled treatment trial. Fifty-six patients completed the neuropsychological testing procedure prior to randomization and after eight weeks of treatment and were included in the analysis. We tested cognitive functioning in general and verbal memory in particular. We calculated a single unweighted composite score based on nine cognitive tests to determine general cognitive functioning. RESULTS: Cognition appeared enhanced after treatment, but was not significantly different between treatment groups, neither for the verbal memory measures, nor for the neurocognitive composite score. Furthermore, cognitive enhancement did not correlate to clinical improvement. CONCLUSION: Cognitive deficits are not a reason for preferentially prescribing one of the two second generation antipsychotics tested over the other. (c) 2010 Elsevier B.V. All rights reserved. Vieta, E., Nuamah, IF., Lim, P., Yuen, EC., Palumbo, JM., Hough, DW., et al. (2010). A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disorders, 12(3), 230-43. OBJECTIVES: To evaluate the antimanic efficacy and safety of paliperidone extendedrelease (ER) tablets in patients with bipolar I disorder. METHODS: This study included a 3-week, double-blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9-week, double-blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score >or= 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3-12 mg/day), quetiapine (400-800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. RESULTS: Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome; least-squares mean difference in change from baseline in
YMRS scores [95% confidence interval (CI)]: -5.5 (-7.57; -3.35); p < 0.001} and noninferior to quetiapine at the 12-week endpoint [least-squares mean difference (95% CI): 1.7 (-0.47; 3.96)]. The median mode dose during the 12-week treatment period was 9 mg for paliperidone ER and 600 mg for quetiapine. The most common (>or= 10%) treatment-emergent adverse events during the 12-week period were: headache (16%), somnolence (10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight increase >or= 7% from baseline to 12-week endpoint was 8% with paliperidone ER and 17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus quetiapine patients (7.5%) 'switched to depression' at the12-week endpoint. CONCLUSIONS: Paliperidone ER (3-12 mg/day) was efficacious and tolerable in the treatment of acute mania.
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Drug Class Review of Atypical Antipsychotic Drugs

Update #4: Scan Report 1 August 2011

Center for Evidence-based Policy

Center for Evidence-based Policy

Center for Evidence-based Policy

Center for Evidence-based Policy

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Contraindications, warnings and precautions, adverse reactions, patient counseling information

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions

PATIENT COUNSELING INFORMATION Hypersensitivity Reactions

April 2010 May 2010

Adverse reactions, warnings and precautions

ADVERSE REACTIONS Vital Signs and Laboratory Studies

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

USE IN SPECIFIC POPULATIONS Pediatric Use

WARNINGS AND PRECAUTIONS Hyperprolactinemia

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Potential for Other Drugs to Affect Invega Sustenna

Pharmacokinetic interaction between lithium and Invega Sustenna is unlikely.

USE IN SPECIFIC POPULATIONS Pediatric Use

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

ADVERSE REACTIONS Commonly-Observed Adverse Events in DoubleBlind, Placebo-Controlled Clinical Trials

Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

WARNINGS AND PRECAUTIONS Metabolic Changes

...Weight Gain information added

Quetiapine fumarate (Seroquel), quetiapine fumarate (Seroquel XR)

MAY 2011 JULY 2011

Warnings and precautions

WARNINGS AND PRECAUTIONS Tardive Dyskinesia

Addition of the incidence rates of discontinuation symptoms

Decreases in hemoglobin to 13 g/dl (males) and 12 g/dl (females)

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

WARNINGS AND PRECAUTIONS 5.12 QT Prolongation

5.21 Use in Patients with Concomitant Illness

see changes to section 5.12

ADVERSE REACTIONS 6.3 Postmarketing Experience

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

AHRQ Protocol (Posted 2010)

Efficacy and effectiveness of off-label use of atypical antipsychotics

AHRQ Protocol (Posted 2010)

All atypical antipsychotics (exluding luradisone and clozapine)

Efficacy and effectiveness of off-label use of atypical antipsychotics

Atypical Antipsychotic Drugs

Center for Evidence-based Policy

Pts with schizophrenia

Efficacy and tolerability