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McDonagh MS, Peterson K, Carson S, et al. Drug Class Review: Atypical Antipsychotic Drugs: Final Report Update 2 [Internet]. Portland, (OR): Oregon Health & Science University; 2008 Jun.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Drug Class Review: Atypical Antipsychotic Drugs: Final Report Update 2 [Internet].

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Introduction

, PharmD, , MS, , MPH, , MS, , MPA:HA, and , MD, MPH, Director.

Oregon Evidence-based Practice Center, Oregon Health & Science University

“Atypical” antipsychotic agents are used to treat the symptoms of schizophrenia and bipolar disorder (see Table 1 for details). In general, atypical antipsychotics produce antipsychotic responses with fewer acute extrapyramidal side effects than “conventional” antipsychotic drugs. Extrapyramidal side effects are a set of movement disorders such as akathisia, dystonia, and pseudoparkinsonism that resolve when the drug is discontinued or the dosage is lowered. Tardive dyskinesia is a movement disorder that can develop with more prolonged use and may persist even after cessation of the antipsychotic agent. Atypical antipsychotics are associated with lower rates of the development of this neurological side effect in comparison with the older, conventional agents. Atypical antipsychotics may also treat negative symptoms and improve cognitive functioning.

Table 1

Table 1

Atypical antipsychotic drug indications, doses, and mechanisms of action

Table 1 describes US Food and Drug Administration approved indications, dosing, and mechanisms of action based on the current product labels for the 7 atypical antipsychotics available in the US and Canada. Clozapine, the prototypic atypical antipsychotic, was introduced in 1989. Since then, 6 other atypical antipsychotics have been brought to market: risperidone (1993), olanzapine (1996), quetiapine (1997), ziprasidone (2001), aripiprazole (2002), and paliperidone (2006).

The atypical antipsychotics interact with more neurotransmitter receptor types than conventional antipsychotics and vary from one another in receptor interaction selection and affinity. These differences in receptor activity are hypothesized to account for differences in efficacy, safety, and tolerability among atypical antipsychotics, as well as in comparison to conventional antipsychotics. Clozapine is an antagonist at dopamine (D1–5) receptors with relatively low affinity for D1 and D2 receptors and high affinity for D4 receptors. Its greater activity at limbic (opposed to striatal) dopamine receptors and lower affinity for D2 receptors may explain the low incidence of extrapyramidal side effects. Clozapine is associated with agranulocytosis necessitating regular white blood cell counts and is available only through a distribution system that ensures such monitoring.

The antipsychotic effect of risperidone, olanzapine, quetiapine, and ziprasidone is proposed to be primarily via D2 and serotonin (5-HT2) receptor antagonism; however, each drug has varying effects on these and other receptors (see Table 1). Antagonism of the 5-HT2 receptors is thought to reduce the extent of D2 antagonism in the striatum and cortex while leaving blockade of D2 receptors in the limbic area unaffected. These properties are thought to account for fewer extrapyramidal side effects and better effects on the negative symptoms of schizophrenia compared with conventional antipsychotics. However, in doses higher than 6 mg/day, risperidone’s profile may become more similar to a conventional antipsychotic due to increased D2 receptor blockade. Ziprasidone’s product label has a warning about its relative potential to prolong the QT/QTc interval of the electrocardiogram. Some drugs that prolong this interval have been associated with the occurrence of the torsade de pointes cardiac arrhythmia and with sudden unexplained death.

Aripiprazole has unique pharmacological properties relative to the other atypical antipsychotics. Aripiprazole is a partial agonist at D2 receptors; thus it is an antagonist in the presence of high levels of endogenous dopamine and, conversely, acts as an agonist when minimal dopamine is present. Aripiprazole is also a partial agonist at 5-HT1A receptors that may contribute to improvements in anxiety, depression, negative symptoms, and lower incidence of extrapyramidal side effects.

The newest atypical antipsychotic, paliperidone, is a major active metabolite of risperidone. While risperidone is subject to drug interactions affecting the CYP2D6 enzyme, in vivo studies suggest this isozyme plays a limited role in the clearance of paliperidone. Paliperidone does not require dose adjustments in mild to moderate hepatic impairment, but awaits studies for use in patients with severe hepatic impairment.

The variation in receptor interaction among these drugs is thought to lead to differences in symptom response and adverse effects. Product labels state that antagonism of α1-adrenergic receptors may explain the orthostatic hypotension observed with aripiprazole, olanzapine, quetiapine, and ziprasidone; antagonism of H1-receptors may explain the somnolence observed with olanzapine, quetiapine, and ziprasidone; and olanzapine’s antagonism of muscarinic M1–5 receptors may explain its anticholinergic effects. However, no specific effects related to symptom response based on receptor interaction profiles are known.

Indications Addressed

This review addresses the use of atypical antipsychotics to treat schizophrenia, bipolar disorder, behavioral and psychological symptoms of dementia (BPSD) in adults, and pervasive developmental disorders and disruptive behavior disorders in children. Descriptions of these populations are based on the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV).1 It is important to note that patients with severe symptoms of mental illness will often not be included in trials because of their inability or refusal to provide consent. Therefore, clinical trials are generally not a good source of evidence specific to this group of patients.

Schizophrenia

The essential features of schizophrenia include a constellation of positive and negative symptoms that persist for at least 6 months. Positive symptoms include distortions of thought and perception and disorganization of speech and behavior. The negative symptom spectrum is characterized by restrictions on emotions, thought processes, speech, and goal-directed behavior. Schizophrenia is prevalent in approximately 0.5% to 1.5% of the worldwide adult population and demonstrates an onset that generally occurs between the late teens and early 20s. The course of schizophrenia is variable but generally leads to marked impairment in major areas of functioning.

Mood disturbance distinguishes schizoaffective disorder from schizophrenia. In schizoaffective disorder, a major depressive, manic, or mixed mood episode must be concurrent with positive and negative symptoms characteristic of schizophrenia and must be present for a substantial portion of the duration of illness preceded or are followed by at least 2 weeks of delusions or hallucinations without prominent mood symptoms (DSM-IV). The typical age of onset for schizoaffective disorder is early adulthood. The DSM-IV suggests that schizoaffective disorder is less prevalent than schizophrenia and has a better prognosis. Schizoaffective disorder is nevertheless associated with occupational impairment and increased risk of suicide.

Clinical trials have reported that 10% to 20% of individuals with schizophrenia do not significantly benefit from conventional antipsychotic therapy.2 Subsequently, a large body of research has emerged that focuses specifically on this subgroup of individuals with treatment-resistant schizophrenia.

Schizophreniform Disorder

Schizophreniform disorder differs from schizophrenia primarily in duration of illness. Schizophreniform disorder is characterized by a course of positive and negative symptoms that resolve within a 6-month time period or when a person is currently symptomatic but less than 6 months required for a diagnosis of schizophrenia (DSM-IV). Schizophreniform disorder is less prevalent than schizophrenia. DSM-IV states that the course of schizophreniform disorder persists beyond 6 months in approximately two thirds of all cases, progressing to a diagnosis of schizophrenia.

Delusional Disorder

Delusional disorder is characterized by the presence of delusions in isolation from other positive and negative symptoms. Additionally, episodes of delusional disorder involve delusions that are more plausible than those demonstrated in the schizophrenia spectrum. Delusional disorder has a variable age of onset and a prevalence of approximately 0.03%.

Bipolar Disorder

The course of bipolar disorder is generally chronic and involves 1 or more episodes of mania or mixed mood. Bipolar disorder may also involve depressive episodes, psychotic features, or both. A purely manic episode is characterized by an excessively euphoric or irritable mood, accompanied by other symptoms that may include grandiosity, pressured speech, flight of ideas, distractibility, agitation, risky behavior, and a decreased need for sleep. Manic episodes typically have a sudden onset and can persist for several months. A depressive episode is characterized by a loss of interest or pleasure in nearly all activities. Accompanying symptoms may include changes in appetite, sleep, psychomotor activity, energy, or cognition. Individuals also may experience increased feelings of worthlessness and suicidality. Individuals experiencing a mixed mood episode have a combination of symptoms of mania and depressed mood. The prevalence of bipolar disorder is 0.4–1.6% in community samples and has an average age of onset of 20. Bipolar disorder generally results in marked distress and impairment in major areas of functioning.

Behavioral and Psychological Symptoms of Dementia

Dementia is a presentation of cognitive deficits that are common to a number of general medical, substance-induced, and other progressive conditions, including Alzheimer disease. Individuals with dementia may also demonstrate clinically significant behavioral and psychological disturbances. These can include depression/dysphoria, anxiety, irritability/lability, agitation/aggression, apathy, aberrant motor behavior, sleep disturbance and appetite/eating disturbance, delusions and hallucinations, and disinhibition and elation/euphoria.3

Pervasive Developmental Disorders

Pervasive developmental disorders include autistic disorder, Rett disorder, childhood disintegrative disorder, Asperger disorder, and pervasive developmental disorder, not otherwise specified (including atypical autism). Autistic disorder presents in childhood prior to age 3 and follows a continuous course. Individuals with autistic disorder show marked impairment in interpersonal and communication skills and emotional reciprocity, and they generally demonstrate restricted and repetitive behaviors, activities, and interests. Epidemiological study results estimate that autistic disorder occurs in 5 of every 10 000 individuals and is more common in males. A study conducted by the Centers for Disease Control and Prevention (CDC) on prevalence of autism spectrum disorders (ASD) carried across 6 sites estimated that the average prevalence was 6.7 per 1000 children aged 8 years.4 Autistic disorder generally affects development of self-sufficiency in major areas of functioning in adulthood. Medication is generally used to target reduction of the disruptive behaviors associated with autistic disorders, including hyperactivity, impulsivity, aggressiveness, and/or self-injurious behaviors.

Disruptive Behavior Disorders

Disruptive behavior disorders include oppositional defiant disorder, conduct disorder, and disruptive behavior disorder, not otherwise specified. Primary indicators of oppositional defiant disorder include hostility, negativism, and defiance toward authority. This pattern of behaviors has emerged prior to age 8 in approximately 2% to 16% of the adolescent population. In some cases, features of oppositional defiant disorder can increase in severity and become more characteristic of conduct disorder.

Individuals with conduct disorder may demonstrate a pattern of aggressiveness toward people and animals, vandalism and/or theft of property, and other serious rule violations. Conduct disorder emerges prior to the age of 16 and is more common in males. Prevalence estimates are variable and have been as high as >10%.

Oppositional defiant disorder and conduct disorder are all associated with significant impairment in home, school, and occupational settings and can lead to disciplinary, legal, and physical injury consequences. Individuals that present with patterns of behavior similar to yet do not meet DSM-IV criteria for oppositional defiant or conduct disorders can be diagnosed with disruptive behavior disorder, not otherwise specified. Psychotropic medication commonly targets reduction of aggression among individuals presenting with these conditions.

Scales and Tests Used to Measure Outcomes

There are many methods of measuring outcomes with antipsychotic drugs and severity of extrapyramidal side effects using a variety of assessment scales. Appendix A summarizes the most common scales and provides a comprehensive list of scale abbreviations. Appendix B is a glossary, such as statistical terms, and Appendix C is a list of abbreviations used in this report.

Purpose and Limitations of Evidence Reports

Systematic reviews, or evidence reports, are the building blocks underlying evidence-based practice. An evidence report focuses attention on the strength and limits of evidence from published studies about the effectiveness of a clinical intervention. The development of an evidence report begins with a careful formulation of the problem. The goal is to select questions that are important to patients and clinicians, then to examine how well the scientific literature answers those questions.

An evidence report emphasizes the patient’s perspective in the choice of outcome measures. Studies that measure health outcomes (events or conditions that the patient can feel, such as quality of life, functional status, and fractures) are emphasized over studies of intermediate outcomes (such as changes in bone density). Such a report also emphasizes measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions is dependent on the numbers of events in both groups, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant across groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than the absolute risk reduction. Another measure useful in applying the results of a study is the number needed to treat (or harm). The number needed to treat represents the number of patients who would have to be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

An evidence report also emphasizes the quality of the evidence, giving more weight to studies that meet high methodological standards that reduce the likelihood of biased results. In general, for questions about the relative benefits of a drug, the results of well-done, randomized controlled trials are regarded as better evidence than results of cohort, case-control, or cross-sectional studies. These studies, in turn, are considered better evidence than uncontrolled trials or case series. For questions about tolerability and harms, controlled trials typically provide limited information. For these questions, observational study designs may provide important information that is not available from trials. Within this hierarchy, cohort designs are preferred when well conducted and assessing a relatively common outcome. Case control studies are preferred only when the outcome measure is rare, and the study is well conducted.

An evidence report pays particular attention to the generalizability of efficacy studies performed in controlled or academic settings. Efficacy studies provide the best information about how a drug performs in a controlled setting that allows for better control over potential confounding factors and bias. However, the results of efficacy studies are not always applicable to many, or to most, patients seen in everyday practice. This is because most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, medication compliance, or severity of illness. For many drug classes, including antipsychotics, unstable or severely impaired patients are often excluded from trials. Often, efficacy studies also exclude patients who have comorbiddiseases, meaning diseases other than the 1 under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in other practice settings. They often restrict options, such as combining therapies or switching drugs that are of value in actual practice. They often examine the short-term effects of drugs that in practice are used for much longer periods of time. Finally, they tend to use objective measures of effects that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

An evidence report highlights studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, hospitalizations, and the ability to work or function in social activities. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it is neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as an efficacy or effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice, or, in the clinical setting, how relevant they are to a particular patient.

Studies across the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard to determine whether the characteristics of different drugs are related to their effects on disease. An evidence report reviews the efficacy data thoroughly to ensure that decision-makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how much there is of it, may have limited applicability to practice. Clinicians can judge the relevance of the study results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs, there are few or no effectiveness studies and many efficacy studies. As a result, clinicians must make decisions about treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. An evidence report indicates whether or not there is evidence that drugs differ in their effects in various subgroups of patients, but it does not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these are decisions that must be informed by clinical judgment.

In the context of developing recommendations for practice, evidence reports are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. By themselves, they do not tell you what to do: Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is not true. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policies. Additional criteria include acceptability to physicians or patients, the potential for unrecognized harms, the applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The purpose of this review is to help policy makers and clinicians make informed choices about the use of atypical antipsychotics. Given the prominent role of drug therapy in psychiatric disease, our goal is to summarize comparative data on the efficacy, effectiveness, tolerability, and safety of atypical antipsychotics.

The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients.

The participating organizations approved the following key questions to guide this review:

Key Question 1. For adults with schizophrenia, related psychoses, or bipolar disorder (manic or depressive phases, rapid cycling, mixed states), do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms?

  1. For adults experiencing a first episode of schizophrenia, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms?
  2. For adult patients with schizophrenia, related psychoses (including first episode), or bipolar disorder, what is the comparative evidence that differences in adherence or persistence among the atypical antipsychotic drugs correlates with a difference in clinical outcomes?

Key Question 2. For children and adolescents with pervasive developmental disorders or disruptive behavior disorders, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms?

Key Question 3. For older adults with behavioral and psychological symptoms of dementia, do the atypical antipsychotic drugs differ in benefits (efficacy, effectiveness) or harms?

Inclusion Criteria

Populations

Adult patients (age 18 years or older) with a DSM III-R or DSM-IV diagnosis of:

  • Schizophrenia, schizophrenia-related psychoses (schizophreniform, delusional, and schizoaffective disorders), including:
    1. first-episode schizophrenia
    2. patients refractory to treatment
  • Bipolar disorder (manic or depressive phases, rapid cycling, mixed states)

Older Adults (≥ 65 years of age)

  • Behavioral and psychological symptoms of dementia

Children and adolescents (under age 18) with a DSM-III-R or DSM-IV diagnosis of:

  • Pervasive developmental disorders
    • - Autistic disorder
    • - Rett disorder
    • - Childhood disintegrative disorder
    • - Asperger disorder
    • - Pervasive developmental disorder not otherwise specified (including atypical autism)
  • Disruptive behavior disorders
    • - Conduct disorder
    • - Oppositional defiant disorder
    • - Disruptive behavior disorder not otherwise specified

Interventions

Interventions included in this review are Aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. All formulations are included in this review. Information on formulations available can be found in Table 1.

Outcomes

For patients with schizophrenia (including patients with a first episode and treatment-resistance), bipolar disorder, and behavioral and psychological symptoms of dementia, effectiveness outcomes included in this review are:

  • Mortality
  • Quality of life
  • Functional capacity (for example, employment or encounters with legal system)
  • Hospitalization (for psychiatric and other causes), emergency department visits, etc.
  • 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.
  • Adherence, the ability to take medication as prescribed, also known as compliance
  • Persistence, the ability to continue taking medication over time
  • For patients with behavioral and psychological symptoms of dementia care-giver burden was also included as an outcome of interest.

For patients with pervasive developmental disorders and disruptive behavior disorders, effectiveness outcomes included in this review are:

  • Functional capacity (for example, activities of daily living)
  • Quality of life
  • Hospitalization, emergency department visits, etc.
  • 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, etc.
  • Caregiver burden
  • Adherence, the ability to take medication as prescribed, also known as compliance
  • Persistence, the ability to continue taking medication over time

For all patient populations, outcomes measuring harms included in this review are:

  • Overall adverse events
  • Withdrawals due to adverse events, time to withdrawal due to adverse events
  • Specific adverse events
    • - Major: Those that are life-threatening, result in long-term 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)
    • - General: extrapyramidal effects, weight gain, agitation, constipation, somnolence, hypersalivation, hypotension, elevated serum lipids, sexual dysfunction, and others

Study Designs

For all patient populations, the following study designs are included in this review:

  • Effectiveness outcomes: Randomized controlled effectiveness trials,5, 6 good quality systematic reviews, and comparative observational studies (cohort studies, including database studies, and case-control studies) were sought.
  • Efficacy outcomes and general adverse events: Head-to-head randomized controlled trials, good-quality systematic reviews. If no direct head-to-head evidence exists, placebo and active controlled (conventional antipsychotics) trials were included.
  • Major adverse events: For life-threatening adverse events or those that are important and occur only with longer-term treatment, head-to-head randomized controlled trials, good-quality systematic reviews and meta-analyses, and comparative observational studies (cohort studies, including database studies, and case-control studies) will be included. Before-after studies or single-arm extension studies were included only if follow up was longer than 2 years.
  • Adherence and persistence: Randomized controlled trials and comparative observational studies (cohort studies including database studies) examining the relationship between improved adherence or persistence and improved outcomes were analyzed.
Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10391

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