Comparative Effectiveness of Typical and Atypical Antipsychotics - Pediatrics (<24 years) - Comment Key Questions - AHRQ Effective Health Care Program

Comparative Effectiveness of Typical and Atypical Antipsychotics - Pediatrics (<24 years)
Background
Studies have shown that prescription patterns for use of psychotropics in children and youth under the age of 18 years has increased over the last 20 years. This includes use of antipsychotic medications.1-5 Use of antipsychotic medications in pediatric and young adult populations is controversial mainly because of limited high quality (and longitudinal) data to draw conclusive clinical practice recommendations especially with regard to safety. These medications are used for various internalizing and externalizing conditions with both on-label and off-label indications depending on the medication and/or age of the patient. Prescriptions can also be used for non-specific behavioral issues in younger children (e.g., irritability) that may be related to a diagnosable condition (i.e., disruptive behavioral disorder) or may be part of a developmental trajectory and/or an adaptive response to an environmental stressor (i.e., parental divorce).

Medication choice in children and youth is often driven by side-effect profiles and may influence normative growth and development, medication adherence and persistence, as well as other important domains such as educational performance and health related quality of life.6 Close clinical monitoring is recommended.7 There is evidence, however, of a disconnect between recent adult-based research findings of the CutLASS 18-9 and CATIE10-11 studies and meta-analyses (favoring neither atypicals nor typicals), individual efficacy trials (pharmaceutical industry trials favoring atypicals) and prescribing patterns of clinicians (favoring atypicals). In this regard, a comparative effectiveness review bringing together pediatric research of rigorous and complementary design would be beneficial for clinical decision making and policymaking.

Pervasive Developmental Disorders
The DSM-IV identifies five Pervasive developmental disorders (PDDs): autistic disorder, Rett's disorder, childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).12 PDDs are characterized by dysfunction in three symptom domains: socialization, communication, and restricted and repetitive stereotyped patterns of behavior.13 These dysfunctions can have a significant and often long-lasting negative effect on the quality of life of both the patients and their caregivers.6

While treatment often involves a multimodal approach (starting with behavioral and educational interventions), psychopharmacological therapies may be used concomitantly to reduce moderate to severe symptoms that can interfere with nonpharmacologic treatment improvements.6,14 Antipsychotics, in particular, have been reported to treat agitation, aggression, self-injurious behaviors, irritability, repetitive and compulsive behaviors, anxiety and hyperarousal.15

Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English) and the Cochrane Library (1999 to present) identified 7 reviews (of autistic disorder, Asperger's disorder, PDD-NOS) of the use of atypical antipsychotics,6,16-19 atypical and typical antipsychotics,20 and methodological processes for clinical trials21 that are relevant to PDDs in our specified age range. No reviews were identified for Rett’s disorder or childhood disintegrative disorder. The approach taken in many of the located reviews has been an overview of the state of evidence often with reference to one or two drugs as a proxy for the group (atypical or typical). We were unable to identify any reviews that directly addressed the comparative effectiveness of typical and atypical antipsychotics. The reviews varied by approach to synthesis while each presented evidence according to condition variance in conducted sub-group considerations (age, gender, co-morbidities) existed. As a collective, the reviews have included literature published from 1980 up to 2007, and have examined effectiveness/efficacy of psychiatric symptom reduction and short-term safety related to a small subset of adverse events; all have concluded the need for trials that establish long-term safety.

Also identified were a number of potential RCTs/CCTs for this topic (n≈32 trials): 24 trials of atypical antipsychotics, 5 trials of typical antipsychotics, and 3 head to head trials (atypical versus typical antipsychotics). In studies where young adults are included, it will be important to distinguish these data from adult data. Eleven trials, currently in-progress, were also identified in clinicaltrials.gov. Our literature scan also identified 158 comparative observational studies to be synthesized as well. No trials or observational studies were identified exclusively for Rett’s disorder. A synthesis of trials published after 2007 vis-à-vis previously published reviews and the inclusion of comparative observational literature will be important to identify emerging evidence on a broader range of outcomes (short- and long-term safety) as well as functional outcomes related to symptom management and quality of life.

Disruptive Behavior Disorders
Disruptive behavior disorders (DBDs) include conduct disorder, oppositional defiant disorder, and disruptive behavior disorder not otherwise specified.12 DBDs are characterized by a behavioral pattern of violating the basic rights of others and age-appropriate rules or standards and may include aggressive behavior, hostility and defiance toward authority.12,22 Pediatric DBDs are likely to be particularly disruptive, as they impair academic and social performance during a period of important mental and behavioral maturation.23

Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English) identified 5 reviews of the use of atypical antipsychotics,6,22,24-25 and atypical and typical antipsychotics26 that are relevant to DBDs in our specified age range. Similar to the PDD reviews, several provided an overview of the state of evidence often with reference to one or two drugs as a proxy for the group (atypical or typical). We were unable to identify any reviews that directly addressed the comparative effectiveness of typical and atypical antipsychotics. Meta-analysis was conducted in 3 reviews.24-26 As a collective, the reviews have included literature published from 1980 up to 2007. Evidence across reviews was presented according to condition, but there was variance in conducted sub-group considerations (age, gender, co-morbidities) and investigated outcomes (i.e., Dunbar et al. examined medication impact on growth and sexual maturation25 and Aman et al. examined medication impact on problem behavior24). Currently, research on risperidone shows it to be effective in treating aggressive behavior in this patient population, but there is limited evidence available on other antipsychotics. All reviews advocate for further research and trials designed to evaluate long-term safety with continued use through childhood and adolescence.

Also identified were a number of potential RCTs/CCTs for this topic (n≈9 trials): 8 trials of atypical antipsychotics, and 1 trial of typical antipsychotics. In studies where young adults are included, it will be important to distinguish these data from adult data. Two trials, currently in-progress, were also identified in clinicaltrials.gov. Our literature scan also identified 100 comparative observational studies. A synthesis of trials published after 2007 vis-à-vis previously published reviews and the inclusion of comparative observational literature will be important to identify emerging evidence on a broader range of outcomes (short- and long-term safety) as well as functional outcomes related to symptom management and quality of life.

Bipolar Disorder
Pediatric bipolar disorder is considered severe and chronic by some.27-30 The disorder is characterized by severe fluctuations in mood, activity, thought and behavior.12 In children, bipolar disorder may begin with a depressive episode marked by not wanting to play, chronic irritability and sadness. Mania (the activated state) may include decreased need for sleep, hyperactivity, and daredevil acts. Racing thoughts, separation anxiety and temper tantrums can occur during depression or mania. Symptoms of both states occur together in mixed states (depressed mood with high energy) or in quick succession (rapid cycling). Treatment includes nonpharmacologic and pharmacologic management, however, controversy surrounding diagnostic criteria for children and youth has limited psychopharmacology research and there are currently no accepted gold standards.31

Over the past decade the use of antipsychotics (particularly atypical antipsychotics) has increased in children and youth with bipolar disorder with reported reductions in the severity of symptoms of mania, psychosis, aggression, and depression. Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English) identified 5 reviews focused on the safety and efficacy of atypical antipsychotics.6,32-35 One other review focused on management of bipolar disorder with co-morbid substance use which will be relevant to young adult populations.36 Similar to the PDD and DBD reviews, several provided an overview of the state of evidence often with reference to one or two atypical antipsychotics. Atypicals were often compared to other medications such as mood stabilizers. Pooled analysis of multiple trials was conducted in 2 reviews.32,35 As a collective, the reviews have included literature published from 1994 up to 2006. Investigated outcomes have common foci -- i.e., reviews led by Jensen, Jolin, Hirschfeld and Brown examined safety and efficacy6,34-36 while Correll’s review focused on specific adverse events (weight gain and metabolic effects).33 Many reviews note the short duration of treatment in clinical trials and suggest the need for studies designed to evaluate long-term safety and impact on growth and maturation.

Also identified were a number of potential RCTs/CCTs for this topic (n≈38 trials): 30 trials of atypical antipsychotics, 4 trials of typical antipsychotics, and 4 head to head trials (atypical versus typical antipsychotics). In studies where young adults are included, it will be important to distinguish these data from adult data. Ten trials, currently in-progress, were also identified. Our literature scan also identified 206 comparative observational studies. A synthesis of trials published after 2006 vis-à-vis previously published reviews and the inclusion of comparative observational literature will be important to identify emerging evidence on a broader range of outcomes (short- and long-term safety) as well as functional outcomes related to symptom management and quality of life.

Schizophrenia/Schizophrenia related psychoses
Schizophrenia and related psychoses impact all psychological functions including perception, mood, thoughts, and cognition.12 Symptoms include positive (i.e., delusions, hallucinatory behavior) and negative (i.e., passive/apathetic social withdrawal, blunted affect) symptoms, and general psychopathology (i.e., preoccupation, motor retardation).12 Elementary auditory hallucinations are the most frequent positive symptom, and delusions are less complex than in adolescents and are usually related to childhood themes. Negative symptoms are largely predominant, namely flat or inappropriate affect.37 Onset of symptoms typically occurs in late adolescence/young adulthood.38 Understanding symptom complexity in relation to short- and long-term outcomes continues to challenge clinical management with antipsychotic medications, which are the first line of treatment in combination with other therapies (both pharmacological and nonpharmacological).39 Treatment resistance and unsatisfactory functional outcomes, for example, continue to burden those diagnosed, families, and health care provided.

Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English) identified 14 reviews of the use of atypical antipsychotics (indirect comparisons and direct comparisons of atypical versus atypical and atypical versus typical) that are relevant to the topic of schizophrenia and related psychoses.6,39-51 In studies where young adults are included, it will be important to distinguish these data using discrete age parameters (e.g., ages <6yrs, 6-12yrs, 13-17yrs, 18-24yrs). For example, several trials and observational studies included an age range of 16 to 65 years. A number of reviews provided an overview of the state of evidence often with reference to one or two drugs as a proxy for the group (atypical or typical). We identified reviews that directly addressed the comparative effectiveness of typical and atypical antipsychotics. Meta-analysis was conducted in 11 reviews.39-41,43-46,48,49-51 As a collective, the reviews have included literature published from 1955 up to 2007.

Reviews have focused on safety and efficacy, but a few have investigated other novel outcomes including genetic association with treatment outcomes,40 co-treatment versus monotherapy,41 and outcomes for treatment resistant schizophrenia.48 Many reviews note the short duration of treatment in clinical trials and suggest the need for studies designed to evaluate long-term safety and effectiveness on health related quality of life outcomes, and well as special groups including those with first-episode psychosis.42

Also identified were a number of potential RCTs/CCTs for this topic (n≈270 trials): 135 trials of atypical antipsychotics, 33 trials of typical antipsychotics, and 102 head to head trials (atypical versus typical antipsychotics). In studies where young adults are included, it will be important to distinguish these data from adult data. Eighteen trials, currently in-progress, were also identified in clinicaltrials.gov. Our literature scan also identified 834 comparative observational studies. A synthesis of trials published after 2007 vis-à-vis previously published reviews and the inclusion of comparative observational literature will be important to identify emerging evidence on a broader range of outcomes (short- and long-term safety) as well as functional outcomes related to symptom management and quality of life.

Summary
Availability of evidence varies on the efficacy and effectiveness of antipsychotics for use with children, youth, and young adults, and depends on the medical condition. Based on our preliminary literature scan, a comparative effectiveness review (using indirect and direct comparisons when available) on this topic would be useful for (1) updating previously published reviews to weigh benefits and harms associated with medication use (short- and long-term), (2) synthesizing comparative observational studies vis-à-vis reviews to establish medication impact on functional outcomes, and (3) synthesizing evidence for specific sub-groups (i.e., age, gender, co-morbidities).

Analytic Framework
Figure 1. Provisional analytic framework for evaluating the comparative effectiveness of atypical and typical antipsychotics for use in children, youth and youth adults diagnosed with pervasive developmental disorder (PDD), disruptive behavioral disorder (DBD), bipolar disorder (BPD), schizophrenia or other psychotic illnesses (Sz).

hacer doble click sobre la imagen para ampliarla



Population(s)
Children, youth and young adults (≤ 24 years) with a DSM-III-R or DSM-IV diagnosis of:

Pervasive Developmental Disorder
Including autistic disorder, Rett’s disorder, childhood disintegrative disorder, Asperger’s disorder, pervasive developmental disorder not otherwise specified (including atypical autism)

Disruptive Behavior Disorder
Including conduct disorder, oppositional defiant disorder, disruptive behavior disorder not otherwise specified

Bipolar Disorder
Including manic or depressive phases, rapid cycling, mixed states

Schizophrenia/Schizophrenia related psychoses
Including first episode

Interventions
Antipsychotic medications currently available on the market in the United States:

Atypical Antipsychotics (brand names in brackets): aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozapine, Clozaril), iloperidone (Fanapt), olanzapine (Olanzapine, Zyprexa, Zyprexa Zydis), paliperidone (Invega, Invega Sustenna), quetiapine (Quetiapine Fumarate, Seroquel, Seroquel XR), risperidone (Risperidone, Risperdal, Risperdal Consta), ziprasidone (Ziprasidone Hydrochloride, Geodon)

Typical Antipsychotics (brand names in brackets): chlorpromazine (Chlorpromazine Hydrochloride, Chlorpromazine Hydrochloride Intensol, Promapar, Sonazine, Thorazine), fluphenazine (Fluphenazine, Fluphenazine Decanoate, Fluphenazine Hydrochloride, Permitil, Prolixin, Prolixin Decanoate, Prolixin Enanthate), haloperidol (Haloperidol, Haldol, Haldol Solutab, Haloperidol Decanoate, Haloperidol Intensol, Haloperidol Lactate), loxapine (Loxapine, Loxapine Succinate, Loxitane, Loxitane C, Loxitane IM), molindone (Moban), perphenazine (Perphenazine, Trilafon) pimozide (Orap), prochlorperazine (Prochlorperazine, Prochlorperazine Edisylate, Prochlorperazine Maleate, Compazine, Compro), thiothixene (Thiothixene, Thiothixene Hydrochloride, Thiothixene Hydrochloride Intensol, Navane), thioridazine (Thioridazine Hydrochloride, Thioridazine Hydrochloride Intensol, Mellaril, Mellaril-S), trifluoperazine (Trifluoperazine Hydrochloride, Stelazine)

Outcomes
Adverse events (overall events, specific events, withdrawals due to adverse events, time to withdrawal due to adverse events, persistence and reversibility of adverse events). Adverse events to include:
Major: mortality, cerebrovascular disease-related events, development of diabetes mellitus, diabetic ketoacidosis, neuroleptic malignant syndrome, seizures, tardive dyskinesia, cardiomyopathies and cardiac arrhythmias, agranulocytosis
General: extrapyramidal effects, weight gain (e.g., using BMI growth charts), agitation, constipation, sedation, elevated cholesterol, adverse events related to prolactin elevations, galactorrhea/bloody galactorrhea, exercise intolerance, precocious puberty
Symptom response (e.g., non-specific behavioral issues, core features of the disorder/illness)
Response rates with corresponding dose, duration of response, remission, relapse, speed of response, time to discontinuation of medication
Growth (using BMI growth charts) and maturation (Tanner stage)
Cognitive and emotional development
Suicide-related behaviors, death by suicide
Medication adherence and persistence
School performance/attendance
Health related quality of life via levels of physical activity/inactivity, diet (i.e., caloric intake, food preferences)
Legal/justice system interaction (i.e., arrests, detention)
Health care system utilization (e.g., protective services, social services)
Timing
Short-term outcomes will be defined as outcomes occurring within 6 months.
Long-term outcomes will be defined as outcomes occurring post-6 months.

Setting
No limitations have been set for clinical setting.

Definition of Terms
There is no consensus on how to define the medications to be included in this review (e.g., use of the terms first and second generation antipsychotics, typical and atypical antipsychotics). For the purposes of this review, the terms typical and atypical antipsychotics will be used.

References
Zito JM, Safer DJ, Sai D, Gardner JF, Thomas D, Coombes P, Dubowski M, Mendez-Lewis M. Psychotropic medication patterns among youth in foster care. Pediatrics 2008;121:e157-63.
Zito Jm, Safer DJ, Berg LT, Janhsen K, Fegert JM, Gardner JF, Glaeske G, Valluri SC. A three-country comparison of psychotropic medication prevalence in youth. Child Adolesc Psychiatry Ment Health 2008;25:26.
Pathak S, Arszman SP, Danielyan A, Johns ES, Smirnov A, Kowatch RA. Psychotropic utilization and psychiatric presentation of hospitalized very young children. J Child Adolesc Psychopharmacol 2004;14:433-42.
Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;283:1025-30.
Zito JM, Safer DJ, dosReis S, Gardner JF, Magder L, Soeken K, Boles M, Lynch F, Riddle MA. Psychotropic practice patterns for youth: A 10-year perspective. Arch Peditr Adolesc Med 2003;157:17-25.
Jensen PS, Buitelaar J, Pandina GJ, et al. Management of psychiatric disorders in children and adolescents with atypical antipsychotics: A systematic review of published clinical trials. Eur Child Adolesc Psychiatry 2007;16(2):104-20.
Zito JM, Derivan AT, Kratochvil CJ, Safer DJ, Fegert JM, Greenhill LL. Off-label psychopharmacologic prescribing for children: History support close clinical monitoring. Child Adolesc Psychiatry Ment Health 2008;2:24.
Lewis SW, Barnes TR, Davies L, et al. Randomized controlled trial of effect of prescription of clozapine vs other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006;32:715-23.
Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-87.
Lieberman JA, Stroup S, McEvoy J, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23.
McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine vs olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163:600-10.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edition). Washington, DC: Author; 1994.
Leskovec TJ, Rowles BM, Findling RL. Pharmacological treatment options for autism spectrum disorders in children and adolescents. Harv Rev Psychiatry 2008;16(2):97-112.
Volkmar F, Cook EH, Pomeroy J, et al. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues. J Am Acad Child Adolesc Psychiatry 1999;38(Suppl 12):32S-54S.
Findling RL. Pharmacologic treatment of behavioral symptoms in autism and pervasive developmental disorders. J Clin Psychiatry 2005;66Suppl10:26-31.
Dinca O, Paul M, Spencer NJ. Systematic review of randomized controlled trials of atypical antipsychotics and selective serotonin reuptake inhibitors for behavioural problems associated with pervasive developmental disorders. J Psychopharmacol 2005;19(5):521-32.
Erickson CA, Stigler KA, Posey DJ, McDougle CJ. Risperidone in pervasive developmental disorders. Expert Rev Neurother 2005;5(6):713-9.
Barnard L, Young AH, Pearson J, et al. A systematic review of the use of atypical antipsychotics in autism. J Psychopharmacol 2002;16(1):93-101.
Jesner OS, Aref-Adib M, Coren E. Risperidone for autism spectrum disorder. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD005040. DOI: 10.1002/14651858.CD005040.pub2.
Broadstock M, Doughty C, Eggleston M. Systematic review of the effectiveness of pharmacological treatments for adolescents and adults with autism spectrum disorder. Autism 2007;11:335-48.
Scahill L, Lord C. Subject selection and characterization in clinical trials in children with autism. CNS Spectr 2004;9(1):22-32.
Findling RL. Atypical antipsychotic treatment of disruptive behavior disorders in children and adolescents. J Clin Psychiatry 2008;69:9-14.
Burke JD, Loeber R, Birmaher B. Oppositional defiant disorder and conduct disorder: A review of the past 10 years, part II. J Am Acad Child Adolesc Psychiatry 2002;41:1275-1293.
Aman M, Buitelaar J, De Smedt G, et al. Pharmacotherapy of disruptive behavior and item changes on a standardized rating scale: Pooled analysis of risperidone effects in children with subaverage IQ. J Child Adolesc Psychopharmacol 2005;15:220-32.
Dunbar F, Kusumakar V, Daneman D, Schulz M. Growth and sexual maturation during long-term treatment with risperidone. Am J Psychiatry 2004;161:918-20.
Ipser J, Stein DJ. Systematic review of pharmacotherapy of disruptive behavior disorders in children and adolescents. Psychopharmacol 2007;191:127-40.
Duffy A. The early course of bipolar disorder in youth at familial risk. J Can Acad Child Adolesc Psychiatry 2009;18:200-5.
Biederman J, Mick E, Faraone SV, et al. Pediatric mania: A developmental subtype of bipolar disorder? Biol Psychiatry 2000;48:458-466.
Geller B, Craney JL, Bolhofner K, et al. Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002;159:927-933.
Wozniak J, Biederman J, Kiely K, et al. Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 1995;34:867-876.
Biederman J, McDonnell MA, Wozniak J, et al. Aripiprazole in the treatment of pediatric bipolar disorder: A systematic chart review. CNS Spectr 2005;10(2):141-8.
Kryzhanovskaya LA, Robertson-Plouch CK, Xu W, et al. The safety of olanzapine in adolescents with schizophrenia or bipolar I disorder: a pooled analysis of 4 clinical trials. J Clin Psychiatry 2009;70(2):247-58.
Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: A systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry 2007;46(6):687-700.
Jolin EM, Weller EB, Weller RA. Prepubertal bipolar disorder: Proper diagnosis should lead to better treatment response. Curr Psychiatry Rep 2005,7:104-11.
Hirschfeld RM, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry 2003;64(7):841-6.
Brown ES. Management of comorbid bipolar disorder and substance abuse. J Clin Psychiatry 2006;67(8):e05.
Masi G, Mucci M, Pari C. Children with schizophrenia: Clinical picture and pharmacological treatment. CNS Drugs 2006;20:841-66.
Bhugra D. The global prevalence of schizophrenia. PLoS Medicine 2006;2(5):372-73.
Janicak PG, Glick ID, Marder SR, et al. The acute efficacy of aripiprazole across the symptom spectrum of schizophrenia: A pooled post hoc analysis from 5 short-term studies. J Clin Psychiatry 2009;70(1):25-35.
Campbell DB, Ebert PJ, Skelly T, et al. Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia. Bio Psychiatry 2008;63(1):32-41.
Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 2009;35(2):443-57.
Johnsen E, Jorgensen HA. Effectiveness of second generation antipsychotics: A systematic review of randomized trials. BMC Psychiatry 2008;8:31.
Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone: Results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S29-35.
Adams CE, Rathbone J, Thornley B, et al. Chlorpromazine for schizophrenia: A Cochrane systematic review of 50 years of randomized controlled trials. BMC Med 2005;3:15.
Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179:290-299.
Volavka J, Czobor P, Citrome L, et al. Efficacy of aripiprazole against hostility in schizophrenia and schizoaffective disorder: Data from 5 double-blind studies. J Clin Psychiatry 2005;66(11):1362-6.
Lemieux AA, Goldman-Levine JD, Goren JL. Aripiprazole: An Antipsychotic with a Novel Mechanism of Action. Journal of Pharmacy Technology 2003;19(6):365-372.
Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: A review and meta-analysis of randomized trials. Am J Psychiatry 2001;158(4):518-26.
Moller HJ. Amisulpride: Efficacy in the management of chronic patients with predominant negative symptoms of schizophrenia. Eur Arch Psychiatry Clin Neurosci 2001;251(5):217-24.
Peuskens J, Van Baelen B, De Smedt C, Lemmens P. Effects of risperidone on affective symptoms in patients with schizophrenia. Int Clin Psychopharmacol 2000;15(6):343-9.
Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine's effectiveness in schizophrenia: A systematic review and m

abrir aquí para acceder al documento AHRQ completo con sus vínculos y accesos:
Comment Key Questions - AHRQ Effective Health Care Program