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Shekelle P, Maglione M, Bagley S, et al. Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Jan. (Comparative Effectiveness Reviews, No. 6.)

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Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics [Internet].

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1Introduction

Background

Antipsychotic medications, widely used for the treatment of schizophrenia and other psychotic disorders, are commonly divided into two classes, reflecting two waves of historical development. The conventional antipsychotics--also called typical antipsychotics, conventional neuroleptics, or dopamine antagonists--first appeared in the 1950s and continued to evolve over subsequent decades, starting with chlorpromazine (Thorazine), and were the first successful pharmacologic treatment for primary psychotic disorders, such as schizophrenia. While they provide treatment for psychotic symptoms - for example reducing the intensity and frequency of auditory hallucinations and delusional beliefs - they also commonly produce movement abnormalities, both acutely and during chronic treatment, arising from the drugs’ effects on the neurotransmitter dopamine. These side effects often require additional medications, and in some cases, necessitate antipsychotic dose reduction or discontinuation. Such motor system problems spurred the development of the second generation of antipsychotics, which have come to be known as the “atypical antipsychotics.”

Currently, the U.S. Food and Drug Administration (FDA)-approved atypical antipsychotics are aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Off-label use of the atypical antipsychotics has been reported for the following conditions: dementia and severe geriatric agitation, depression, obsessive-compulsive disorder, posttraumatic stress disorder, and personality disorders. The purpose of this Evidence Report is to review the evidence supporting such off-label uses of these agents. We were also asked to study the use of the atypical antipsychotics for the management of Tourette’s Syndrome and autism in children. The medications considered in this report are those listed above; however, we have excluded clozapine, which has been associated with a potentially fatal disorder of bone-marrow suppression and requires frequent blood tests for safety monitoring. Because of these restrictions, it is rarely used except for schizophrenia that has proven refractive to other treatment.

Dementia and Severe Geriatric Agitation

Dementia is a disorder of acquired deficits in more than one domain of cognitive functioning. These domains are memory, language production and understanding, naming and recognition, skilled motor activity, and planning and executive functioning. The most common dementias – Alzheimer’s and vascular dementia - are distinguished by their cause. Alzheimer’s dementia occurs with an insidious onset and continues on a degenerative course to death after 8 to10 years; the intervening years are marked by significant disturbances of cognitive functioning and behavior, with severe debilitation in the ability to provide self-care. Vascular dementia refers to deficits of cognitive functioning that occur following either a cerebrovascular event – a stroke – leading to a macrovascular dementia, or, alternatively, more diffusely located changes in the smaller blood vessels, leading to a microvascular dementia. These (and other) dementia types commonly co-occur. Psychotic symptoms are frequent among dementia patients and include auditory hallucinations, believing that one’s personal belongings have been stolen, or believing that unknown others are cohabiting with the patient (phantom boarders). Although the cognitive deficits can be severe, it is the behavioral disturbances (such as yelling or combativeness with caregivers) that typically interfere with independent living and necessitate placement in a nursing home.

Management of dementia patients includes both behavioral and psychopharmacologic interventions. Although behavioral interventions are commonly used with dementia patients, they require the presence of trained caregivers. Psychopharmacologic treatments developed specifically for dementia include acetylcholinesterase inhibitors, which attempt to compensate for the loss of neurons that produce the neurotransmitter acetylcholine by inhibiting the enzyme responsible for its degradation. Antipsychotics, including the atypicals, have been used to control both psychotic symptoms and severe behavioral agitation in dementia.

Depression

Depression refers to a potentially severe episodic disturbance of mood, with a constellation of low mood, inability to experience pleasure, sleep and appetite disturbances, loss of energy, difficulty concentrating, thoughts of guilt, worthlessness, and hopelessness, and suicidal ideation. Depression is best thought of as a symptom cluster that can appear in several different psychiatric disorders. These disorders are unipolar depression, bipolar depression, major depression with psychotic features, and depression occurring during psychotic disorders, such as schizophrenia or schizoaffective disorder. (Full descriptions of the diagnostic criteria for these disorders and others discussed in this report can be found in the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, the DSM.)

Unipolar depression refers to the DSM disorder called major depressive disorder and is defined by episodes of at least a majority of the above symptoms lasting at least two weeks. A particularly severe form of major depressive disorder occurs when the depression is accompanied by psychotic symptoms such as auditory hallucinations. Current treatment guidelines for the pharmacologic treatment of major depression are expressed algorithmically as a flowchart, with later steps tried after the failure of the earlier steps.1 Failure may occur for a variety of reasons, including intolerable side effects or lack of improvement after treatment of an appropriate duration. The mainstays of treatment are the antidepressants, including the serotonin reuptake inhibitors (SRIs), including citalopram, escitalopram, fluoxetine, paroxetine, and sertraline; the tricyclic antidepressants, including amitriptyline, imipramine, nortriptyline, and desipramine; and other drugs with dual reuptake inhibition or other mechanisms, including bupropion, duloxetine, mirtazapine, and venlafaxine. Other treatments used include augmenting agents, medications that are not themselves antidepressants, but that speed or improve the antidepressant activity; various psychotherapies; and electroconvulsive therapy. Because of their serotonergic effects, the atypical antipsychotics have been tested as augmenting agents. For depression with psychotic features, the recommended psychopharmacologic treatment consists of the simultaneous use of antidepressants and antipsychotics - most often atypical antipsychotics.1, 2

Bipolar depression refers to the depressed phase of bipolar disorder, a severe mental illness with mood fluctuations both below (depressed) and above (manic) the normal euthymic state. (It is also informally known as manic depression, although that term has been dropped from the official diagnostic terminology.) Treatment of the depressed phase is more complicated than the treatment of unipolar depression because one of the standard treatments for depression, antidepressant medication, has been implicated in a mood destabilization phenomenon known as “switching,” in which the mood of a patient with bipolar depression is not restored to euthymia but moves instead into the elevated mood state of mania. The optimal treatment of bipolar depression is not yet known, but current guidelines suggest that initial treatment with a mood stabilizing agent or contemporaneous use of a mood-stabilizing agent along with an antidepressant may lower the risk of switching. Because the atypical antipsychotics have FDA approval for use as mood stabilizing agents in the treatment of manic or mixed states, they have been used in combination with antidepressants for the treatment of bipolar depression.

Depressive symptoms may also occur during primary psychotic disorders. The DSM-IV-TR discourages the separate diagnosis of major depression during schizophrenia, although it acknowledges that such comorbidity is common. A related disorder, schizoaffective disorder, combines chronic psychotic symptoms similar to schizophrenia with more pronounced episodic mood disturbances, which can resemble either major depression or bipolar disorder. Whether the antipsychotics medications used to treat primary psychotic disorders also effectively treat comorbid depression is not well known.

Obsessive-Compulsive Disorder

The essential features of obsessive-compulsive disorder (OCD) are obsessions (repetitive, intrusive, unwanted thoughts, impulses, or images) and compensatory compulsive behaviors that reduce or remove the distress caused by the obsessions. A common example would involve obsessions about fears of contamination by dirt or germs, which give rise to compulsions to wash one’s hands excessively. The distress caused by the obsessions, and the time devoted to, or the dysfunction caused by, the compulsions can lead to serious psychiatric morbidity. Standard treatments include psychopharmacologic approaches using the serotonin reuptake inhibitors (SRIs), such as fluoxetine, and cognitive-behavioral therapy, which promotes a kind of learning through exposure to the feared or unpleasant stimulus and prevention of the compulsive response. Limited response to both treatments is common, and various psychopharmacologic agents, including the atypical antipsychotics, have been tested for their ability to augment SRIs.

Posttraumatic Stress Disorder

Posttraumatic Stress Disorder (PTSD) describes the development of characteristic disabling symptoms following exposure to trauma such as war or rape. These symptoms are grouped into three clusters: re-experiencing (nightmares, flashbacks), avoidance and numbing (avoidance of reminders of the trauma, inability to recall the trauma, feelings of detachment, restriction of emotion), and increased arousal (anger, problems with concentration, hypervigilance, exaggerated startle response). The symptoms of PTSD span diverse psychiatric categories, and include mood, anxiety, and psychotic symptoms (including auditory hallucinations, suspicion, dissociation, and emotional withdrawal). Treatment of PTSD involves medications that address each of these classes of symptoms (including atypical antipsychotics) and cognitive-behavioral and other psychotherapies.

Personality Disorders

A Personality Disorder is “an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is stable over time, and leads to distress or impairment.”3 The current edition of the DSM defines 10 such disorders. Optimal treatment of such disorders is not well understood, although some of the disorders are the focus of active research. Because of the long-term nature of the disorders, they are often treated through psychotherapy in an attempt to facilitate long-term personality change, while psychiatric medications are thought to play a role in moderating some of the symptomatic manifestations. Only two personality disorders have been treated in clinical trials with atypical antipsychotics: schizotypal personality disorder (SPD) and borderline personality disorder (BPD).

SPD is defined by pervasive deficits in interpersonal relationships, cognitive and perceptual disturbances, and eccentric behavior. The perceptual and behavioral changes often appear similar to a mild form of schizophrenia, and there is some evidence of familial aggregation of SPD in relatives of those with schizophrenia. Because of this connection, treatment with atypical antipsychotics has been tried.

BPD’s essential characteristic is instability in interpersonal relationships, self-image, and mood, along with impulsive behavior, intense anger, and recurrent suicidal gestures or attempts. There are often severe dissociative symptoms and paranoid ideation, which may occur or worsen with stress. BPD is a significant cause of psychiatric morbidity, and, because of the increased risk for suicide, mortality. Effective treatment of BPD is an area of active research. The cornerstone of treatment is psychotherapy of various kinds, with dialectical behavior therapy and mentalization-based therapy, among others, having shown some efficacy in clinical trials.4 Psychiatric medications are also commonly used, to treat both comorbid conditions, such as mood disorders, and the symptoms of BPD, although the evidence supporting such use is not strong. Because of the occurrence of psychotic symptoms, and because atypical antipsychotics have mood stabilizing properties, they are commonly tried in the treatment of BPD.

Tourette’s Syndrome

Tourette’s Syndrome refers to the condition of multiple motor and vocal tics, which are rapid, recurrent, stereotyped movements. Tics of Tourette’s include eye blinking, facial grimacing, throat clearing, grunting, and, uncommonly, although most notably, coprolalia, the uttering of obscenities. The tics typically start around age six (the diagnosis requires that tics must appear by age 18). Pharmacologic treatments that have been tried include antipsychotic medications and medications from other classes, including clonidine, some of the tricyclic antidepressants, and benzodiazepines.

Autism

Autism is characterized by abnormal development of social interaction and communication skills and significant restriction of activities, interests, and behaviors, with symptoms developing by age three. It is categorized as one of the pervasive developmental disorders, which also include Asperger’s disorder, and the catchall category of Pervasive Developmental Disorder Not Otherwise Specified (PDD NOS). Depending on the severity of symptoms, differentiating autism, Asperger’s disorder, and PDD NOS can be difficult, and they are occasionally grouped together for study. The primary treatment for autism is therapy for behavior modification, special education, and family counseling. Psychiatric medications are often used for symptom control; commonly used medications include antidepressants, mood stabilizers, and antipsychotics, including the atypicals.

Both Tourette’s Syndrome and autism can persist into adulthood, but the evidence reviewed in this report applies only to children and adolescents.

Scope and Key Questions

The EPC was originally asked to investigate the following questions:

Key Question 1. What are the leading off-label uses of antipsychotics in the literature?

Key Question 2. What does the evidence show regarding the effectiveness of antipsychotics for off-label indications, such as depression? How do antipsychotic medications compare to other drugs for treating off-label indications?

Key Question 3. What subset of the population would potentially benefit from off-label uses?

Key Question 4. What are the potential adverse effects and/or complications involved with off-label antipsychotic prescribing?

Key Question 5. What is the appropriate dose and time limits for off-label indications?

Representatives of the topic nominator, the state of Washington, narrowed the scope of the project to the atypical class of antipsychotics (excluding clozapine, because of its limited use in resistant schizophrenia) in December, 2004. This nominator also narrowed the psychiatric conditions to dementia/geriatric agitation, depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and personality disorders among adults and autism and Tourette’s syndrome among children/adolescents.

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