Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 17
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence 1 Introduction There is evidence that the high rates of trauma experienced by those stationed in the Southwest Asia theaters will result in increased demands on the Department of Defense (DoD), the Department of Veterans Affairs (VA), and community health care systems as these service members return, move back to civilian status, and become eligible for VA health benefits. As the number of OIF/OEF veterans grows, their continued care is a national health care concern. —Mapping the Landscape of Deployment Related Adjustment and Mental Disorders, 2006 Mental disorders, including posttraumatic stress disorder (PTSD), constitute an important health care need of veterans, especially those recently separated from service. The Institute of Medicine (IOM) Committee on Treatment of PTSD was charged by the Department of Veterans Affairs (VA) with reviewing and assessing the evidence on PTSD treatment modalities. To prepare this report, the committee undertook a comprehensive, systematic review of the treatment literature dating back to 1980, and included both pharmacologic and psychologic therapies in its review. The committee was given five major tasks: review the scientific evidence and make conclusions regarding efficacy; note restrictions of the conclusions to certain settings and populations; comment on gaps and future research; answer several questions related to the goals, timing, and length 1 OIF/OEF: Operation Iraqi Freedom/Operation Enduring Freedom.
OCR for page 18
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence BOX 1-1 Statement of Task The Department of Veterans Affairs has asked the IOM to convene a new committee to review the literature on various treatment modalities (including pharmacotherapy and psychotherapy) and treatment goals for individuals with PTSD. Specifically, the committee will conduct an evidence-based review on best treatment practices and types and timing of specific interventions, and comment on the prognosis of individuals diagnosed with PTSD (and existing comorbidities). As part of its assessment, the IOM committee shall: Develop descriptive evidence tables including type of study and identify potential bias and generalizations of the study. The committee shall also search for and classify systematic and narrative reviews on the topic of treatment and recovery of individuals with PTSD. The committee shall examine and classify the existing studies on various treatment modalities for PTSD. The committee will report on the highest levels of evidence available. For each study the committee will consider the quality of design and execution, and will be guided by the following classification: I Randomized controlled trial II-1 Controlled trial without randomization II-2 Cohort or case-control study II-3 Time series or uncontrolled experiment III Opinion of respected authority, case report, and expert committee The committee shall consider the following framework to make conclusions about the strength of the available evidence for treatment modalities: Evidence is sufficient to conclude the efficacy of X in the treatment of PTSD. (A qualifier of magnitude may be added if appropriate.) of treatment; and, finally, note areas where the evidence base is limited by insufficient research attention or poorly conducted studies (see Box 1-1 for the complete Statement of Task). In conducting its search of the literature, the committee excluded studies on patient groups that did not fully meet the Diagnostic and Statistical Manual of Mental Disorders definition.2 Box 1-2 below lists other topics that are not included in this report. 2 Two exceptions were studies that included a majority of patients with PTSD and a minority of patients with subsyndromal PTSD.
OCR for page 19
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Evidence is suggestive but not sufficient to conclude the efficacy of X in the treatment of PTSD. (The committee may note inconsistencies in the data.) Evidence is inadequate to determine the efficacy of X in the treatment of PTSD. Evidence is suggestive that X treatment is ineffective in treating PTSD. Evidence is suggestive that X treatment is harmful in the treatment of PTSD. For each of the conclusions above, the restriction of the conclusion regarding the population, provider, setting [of] intervention, or comparator intervention will be noted. As part of its assessment, the IOM committee shall note limitations in the evidence base and make suggestions for further research that could strengthen the evidence or address research gaps in the treatment of PTSD. In conducting its work, the committee shall consider the following questions in relation to treatment modalities (including pharmacotherapy and psychotherapy) and treatment goals for individuals diagnosed with PTSD. What are the goals of PTSD treatment? What is the definition of recovery? For what proportion of patients is recovery possible? Besides recovery, what other outcomes would benefit patients? Does evidence support the value of early intervention? How long should treatment continue? What is the impact of a hiatus in treatment? What is the impact of periodic reexamination for asymptomatic patients? The committee shall note when the evidence base does not allow for responding to these questions due to insufficient research attention or poorly conducted studies. THE STUDY PROCESS The committee held five meetings over a period of approximately nine months. The first meeting on January 16–17, 2007, part of which was an information-gathering session open to the public, included presentations from the sponsor, several subject experts, and veterans organizations (this meeting agenda can be found in Appendix F). The following four meetings were held in closed session (the fifth meeting took place via conference call). Additionally, the committee held weekly conference calls to plan the literature search, discuss findings, and formulate conclusions and recommendations.
OCR for page 20
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence BOX 1-2 Topics Not Addressed in This Report Current clinical practice in the treatment of PTSD, whether in the VA health care system or elsewhere Diagnostic and assessment issues (these were the subject of an earlier IOM report in 2006) PTSD treatment in the context of compensation, a set of issues addressed in the IOM report entitled PTSD Compensation and Military Service (2007b) PTSD in children or adolescents Feasibility, cost, or cost-effectiveness of various treatment modalities The committee also received public submissions of material for its consideration at the meetings and by e-mail throughout the course of the study.3 A Web site (http://www.iom.edu/PTSDtreatment) and e-mail listserv were created to provide information to the public about the committee’s work and to facilitate communication with the committee. Materials from the information-gathering meeting are available in electronic format on the project’s Web site. On the pages that follow in this chapter, the committee provides an overview of PTSD, with a special focus on veterans and treatment. Chapter 2 describes the methods the committee used to search for, organize, and evaluate the literature. In Chapters 3 and 4, respectively, the committee presents its assessment of the pharmacotherapy and psychotherapy modalities by describing key data from the included studies (see evidence tables in Chapters 3 and 4), summarizing the evidence, and making conclusions based on the evidence. Chapter 5 contains a discussion of issues in PTSD research identified by the committee, and responses to other questions posed by the Statement of Task. Additional information is provided in the appendixes referred to in the report (Appendix G provides the committee biographies and Appendix E contains the acronyms used in the report). 3 A list of materials reviewed by the committee (in the form in which they were reviewed), including all submissions of information from the public and many items not cited in this report, can be found in the study’s public access file, obtained from the National Academies Public Access Records Office at (202) 334-3543 or http://www8.nationalacademies.org/cp/ManageRequest.aspx?key=48739.
OCR for page 21
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence THE DISORDER PTSD results from exposure to a range of extreme stressors but one of its most common associations has been with war and combat, as described in historic and literary accounts. The name, etiology, cause, diagnosis, and treatment of the disorder all have been subject to considerable debate and controversy over the years (Wilson et al., 2001). PTSD develops in a significant minority (up to a third) of individuals who are exposed to extreme stressors, and symptoms of PTSD almost always emerge within days of the trauma. More information on the prevalence, etiology, and symptomatology of PTSD is provided in an upcoming IOM report, Gulf War and Health: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress (Institute of Medicine, 2007a). The Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association (APA) first formally defined PTSD in 1980 in the DSM-III. The definition was revised in 1987 (DSM-III-R) and 1994 (DSM-IV) (APA, 1987, 1994). There was no change in the 2000 DSM-IV-TR (APA, 2000). The DSM-IV defines PTSD by several criteria: experiencing a traumatic stressor (“experienced or witnessed actual or threatened death, injury, or threat to the physical integrity of self or others”) reacted to with “intense fear, helplessness, or horror” (Criterion A); intrusive recollections of the traumatic event (Criterion B); avoidance and numbing (Criterion C); and hyperarousal in the form of extreme startle reflex, inability to fall or stay asleep, and so on (Criterion D); the symptoms must be experienced for at least 1 month (Criterion E); and the symptoms cause distress or impairment in various areas of functioning (Criterion F) (APA, 2000). According to the DSM-IV, PTSD may be acute (symptom duration under 3 months) or chronic (symptom duration of 3 months or longer), and its onset may be delayed (occurring at least 6 months after exposure). The definition of PTSD does not recognize subtypes classified by type of trauma, such as combat versus civilian or simple exposure versus repeated exposure. PTSD is heterogeneous with respect to symptom expression, severity, and chronicity. This heterogeneity may have important implications for response to specific treatments. Those in whom the predominant disturbance is insomnia might require a different treatment than persons in whom the predominant disturbance is avoidance. The course of PTSD may vary in duration of symptoms and level of disability, with a considerable proportion of persons with the disorder experiencing disabling symptoms for years (Kessler et al., 1995).
OCR for page 22
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Epidemiology of PTSD The most recent estimates of the lifetime prevalence of PTSD in the United States come from the National Comorbidity Survey—Replication (NCS-R), conducted in 2000. The lifetime prevalence of PTSD in the NCS-R is 6.8 percent; 9.7 percent in women and 3.4 percent in men. Current (12 month) prevalence is 3.6 percent, 5.2 percent in women and 1.8 percent in men (Harvard Medical School, 2007). A sex difference in PTSD is a consistent finding in epidemiologic research and is not accounted for by sex differences in overall prevalence of exposure to traumatic events or by sex differences in the prevalence of specific types of traumatic events (e.g., sexual assault). Military personnel are at elevated risk for exposure to trauma. Estimates from the National Vietnam Veterans Readjustment Survey (NVVRS), a congressionally mandated large survey conducted in the late 1980s, reported that 30.9 percent of all men who had served in Vietnam developed PTSD; prevalence in the late 1980s was 15.2 percent. A recent reanalysis of the NVVRS data gave lower estimates: 18.7 percent for lifetime and 9.1 percent for current (at the time the NVVRS was conducted) (Dohrenwend et al., 2006). The reanalysis used military records and data from the clinical examinations conducted on a subsample. The latter enabled the investigators to (1) distinguish between war-related first onset of PTSD and first onsets that occurred before or after service in Vietnam and (2) take into account level of impairment. Surveys of military personnel returning from the wars in Iraq and Afghanistan have yielded a wide range of estimates, for example, 12.6 percent of U.S. men who fought in Iraq and 6.2 percent of U.S. men who fought in Afghanistan. The estimates of PTSD in British combat and noncombat troops that served in Iraq were 6 percent and 3 percent, respectively (Hotopf et al., 2006). Comorbidities and Implications Comorbidity of PTSD with other psychiatric disorders is common in military and civilian epidemiologic samples. In the NVVRS, 98.8 percent of veterans with lifetime PTSD also met criteria for at least one other psychiatric disorder (Kulka et al., 1990). The most common comorbid disorders among male veterans with PTSD were alcohol use disorder and major depression. In civilian samples, comorbidity with other psychiatric disorders occurs in the vast majority of lifetime PTSD cases (>80 percent) (Breslau et al., 1991; Kessler, 1995; Ruzek, 2003). The lifetime prevalence of major depression among men and women with PTSD is nearly 50 percent. Comorbidity is not unique to PTSD; psychiatric disorders are rarely “pure.” There is evidence that people with comorbid disorders have greater impairment than those with a single disorder.
OCR for page 23
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Theoretically, comorbidity in PTSD can occur through several alternative (but not mutually exclusive) pathways. Preexisting disorders might increase the risk for exposure to traumatic events or to PTSD following exposure. PTSD might increase the risk for subsequent onset of other disorders (e.g., drug use disorder in persons who use drugs to relieve painful symptoms). PTSD and comorbid disorders might share common vulnerabilities or result from the traumatic experience that precipitated PTSD (Wilson et al., 2001; Yehuda, 1998). The limited empirical evidence from prospective studies suggests different pathways across the comorbid disorders. The possibility that the trauma that precipitated PTSD is the cause of the comorbid disorders is not supported. The incidence of other disorders in victims of trauma is primarily concentrated in the small subset who have developed PTSD. Comorbidity with other diagnoses may create greater complexity in treating PTSD, although there is little research in this area. Many of the PTSD treatment studies reviewed by the committee excluded cases with comorbid diagnoses, such as depression, other anxiety disorders, and alcohol and substance use disorders. The fact that people with comorbidities are often excluded from treatment efficacy trials necessarily raises questions about the generalizability of study results. Exclusion of Subjects with Co-Occurring Disorders Psychotherapy studies, specifically prolonged exposure, which is the most extensively researched psychotherapy, have few exclusion criteria. Exposure therapy studies allow certain drugs (such as selective serotonin reuptake inhibitors [SSRIs]) and several comorbid mental disorders (such as major depression and other anxiety disorders). In general, they exclude organic brain syndrome, current (or lifetime) psychoses, high suicide risk, and active substance abuse or dependence. (Some also exclude “severe” major depression.) Psychopharmacology studies, specifically those of SSRIs, which are the most extensively researched in this category, often have more exclusions. In addition to the exclusions applied in psychotherapy studies, SSRI studies often exclude primary or principal4 (though not comorbid) major depression and various anxiety disorders to avoid their potentially confounding role, especially when a study is conducted as part of an expected application for a PTSD indication to the Food and Drug Administration (FDA). Some exclude all or primary Axis I disorders, and they also exclude patients on other psychoactive medications. In some, concomitant psychotherapy is an 4 “Primary” or “principal,” referring to depression or other co-occurring disorder, means that onset of the condition preceded or is currently of greater severity or clinical importance than the PTSD.
OCR for page 24
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence exclusion criterion (Marshall et al., 2001; Martenyi et al., 2002). An additional reason to exclude subjects with comorbid disorders is to decrease heterogeneity and increase statistical power. Inclusion of subjects with comorbid disorders that also are strong prognostic indicators usually must be managed with a more complex research design, such as prerandomization stratification and recruiting larger samples. The first goal is to show that an experimental treatment has efficacy. Once efficacy is established, effectiveness in populations actually seen (such as those with comorbid conditions) can be addressed, but little treatment research in PTSD has been extended to this question of effectiveness. A few published studies focus on treatment of patients with dual diagnoses, such as PTSD comorbid with substance use disorders (Brady et al., 2005). These studies do not address the broader question of generalizability of findings in the general population or to the veteran population. PTSD IN THE VETERAN POPULATION VA provides health care services to approximately 7 million veterans (Department of Veterans Affairs, 2004). According to recent data, PTSD constitutes a substantial proportion of the burden of illness among veterans. In a study of 103,788 Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF) veterans seen at VA health care facilities between September 2001 and December 2005, PTSD was the most commonly diagnosed military service-related mental health diagnosis (13,205 cases), accounting for more than half of the veterans receiving a mental health diagnosis and 13 percent of all OIF/OEF veterans in the study (Seal et al., 2007). In their presentation to this committee, VA officials stated that during Fiscal Year (FY) 2006, VA medical center programs served over 346,000 veterans diagnosed with PTSD in specialized outpatient programs and general mental health clinics (Batres and Zeiss, 2007). It is important to note, however, that not all veterans receive care from VA facilities, so the committee was careful to make reference both to the VA and veteran populations in its research and in this report. The committee’s review of the evidence was not restricted to veterans, but included all relevant studies of PTSD treatment in a variety of populations, including veterans. Since such a broad examination of the literature is necessary, it presents an important challenge in the question of applicability of nonveteran research findings to veteran populations. This challenge and how the committee sought to address it is discussed in Chapter 5. The U.S. veteran population is not homogeneous; there is great variation among veterans, and not only in terms of sex, ethnicity, and socioeconomic and educational status. Veterans of World War II, the Vietnam and Korean conflicts, the Gulf War, and the current OIF/OEF have been
OCR for page 25
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence exposed to different types of stressors in considerably different social contexts. This heterogeneity constitutes yet another challenge for evaluation discussed in more detail in Chapter 5. Special Issues Related to PTSD in the Military Military sexual assault (sexual assault experienced while in military service5) is an additional traumatic stressor that affects military personnel, and subsequently, is identified as an exposure leading to PTSD in some, generally female, veterans. There is evidence that military sexual assault makes PTSD more likely than sexual assault occurring before or after military service (Himmelfarb et al., 2006; Yaeger et al., 2006), and potentiates the risk of developing PTSD from combat exposure (Himmelfarb et al., 2006; Kang et al., 2005).. One of the major challenges of diagnosing and treating PTSD is the stigma associated with it and mental illness in general. Stigma may have a profoundly negative effect on individual self-esteem, care-seeking behaviors, and social interaction (Department of Health and Human Services, 1999; Sartorius, 2002). In the military context, where self-reliance and inner strength are highly valued, mental illness may be considered a sign of weakness or a reason for shame, leading people to deny their illnesses or, once diagnosed, to avoid seeking care. Data on this issue in the veteran population are limited, but a 2003 study of several thousand current members of the Army and Marine Corps before and after deployment explored mental health status, interest in receiving care, and health care service utilization (Hoge et al., 2004). The study’s findings were striking, highlighting several common themes, including the role of perceived stigma as a barrier to accessing services, perception of stigma and damage to one’s military career, and other negative views of what suffering from a mental health condition and seeking care for it would mean for one’s future in the military (Hoge et al., 2004). As a result of stigma, only 23–40 percent of those in need of mental health services actually seek care (Hoge et al., 2004). TREATMENT OF PATIENTS WITH PTSD Treatments available for PTSD include a variety of pharmacologic and psychotherapeutic modalities, and they are provided in diverse settings. For veterans, a considerable proportion receive services at both inpatient and outpatient VA facilities. The general population receives services in community clinics (some may specialize in specific types of trauma), from 5 The IOM report PTSD Compensation and Military Service notes that a majority of perpetrators in military sexual assault cases were military peers or supervisors (IOM, 2007b).
OCR for page 26
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence private professionals, and in the hospital setting. Providers range from clinicians such as psychiatrists to psychologists, social workers, and other therapists, as well as support and self-help groups. In many areas, including rural and underserved settings, primary clinicians also play a major role in PTSD treatment. There are two main categories of PTSD treatment examined by the committee, pharmacotherapy and psychotherapy, described below. Description of the Pharmacotherapies In its review of the literature the committee found seven main categories (and a miscellaneous category) of pharmacotherapy used to treat PTSD for which there are randomized controlled clinical trials (RCTs). These treatments are listed and briefly described below. The specific studies included in the evidence review by the committee are listed in Chapter 3. The committee also came across several drug therapies for PTSD for which there were either no RCTs (open label, case series, etc.), the population studied did not have diagnosed PTSD, or the main study outcome was not PTSD, so did not meet inclusion criteria (these drug therapies are listed below and inclusion criteria is discussed in Chapter 2). Alpha-Adrenergic Blockers Prazosin is an alpha-adrenergic blocker that has been proposed for reducing nightmares and improving sleep in patients with PTSD. Prazosin is currently approved by FDA to treat hypertension. It is hypothesized to work by blocking noradrenergic arousal during sleep. Known potential common side effects of prazosin include dizziness, drowsiness, headache, weakness, nausea, and syncope with sudden loss of consciousness after the first use of the drug. Anticonvulsants Anticonvulsants used in treating patients with PTSD include lamotrigine and topiramate. Drugs in this class work in different ways and are used to control epileptic seizures, prevent migraines, and treat other brain disorders. More recently they have also been used as mood stabilizers to treat mania and bipolar disorder. Lamotrigine is a glutamate-inhibiting anticonvulsant with antidepressant properties (Hertzberg et al., 1999) and topiramate enhances GABA6-activated chloride channels (Tucker et al., 2007). Lamotrigine is FDA approved to treat seizures and bipolar disorder; 6 GABA refers to gamma-aminobutyric acid.
OCR for page 27
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence topiramate is approved to treat seizures and migraines. Known potential common side effects for anticonvulsants include dizziness, drowsiness, fatigue, nausea, tremor, rash, and weight gain. Novel Antipsychotic Medications Novel atypical antipsychotics such as olanzapine and risperidone are known to be used in the treatment of PTSD. Both drugs are hypothesized to work by controlling psychotic symptoms through antagonism (opposing) of selected dopamine and serotonin receptors. Olanzapine is FDA approved to treat the mixed or manic episodes of bipolar I disorder; risperidone is FDA approved to treat schizophrenia, symptoms of bipolar disorder, and in autistic children to treat symptoms of irritability. Known potential common side effects of olanzapine include agitation, behavior problems, difficulty in speaking or swallowing, restlessness, stiffness of arms or legs, and trembling or shaking of hands and fingers. For risperidone, common side effects include extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes), dizziness, hyperactivity, tiredness, and nausea. Benzodiazepines Benzodiazepines, such as alprazolam, are sometimes used in treating patients with PTSD (APA, 2004; Friedman, 1998; VA/DOD, 2002). Benzodiazepines treat anxiety, insomnia, and irritability. Alprazolam specifically is an antianxiety agent and central nervous system depressant and works by decreasing abnormal excitement in the brain. Benzodiazepines have a known risk of dependency and of withdrawal after abrupt discontinuation; if there is current or past drug abuse or dependence, dependence on this class of drugs is more likely to develop. Other known potential side effects include drowsiness, light-headedness, tiredness, dizziness, irritability, talkativeness, dry mouth, increased salivation, changes in sex drive or ability, changes in appetite, weight changes, and difficulty urinating. Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs), such as brofaromine and phenelzine, are another class of drugs used to treat patients with PTSD. MAOIs irreversibly inhibit monoamine oxidase, the enzyme responsible for the degradation of serotonin and related molecules in the central nervous system. Brofaromine is a reversible and selective type-A MAOI that also has serotonin reuptake inhibitory properties. It currently is not available in the United States. Phenelzine is used to treat symptoms of depression includ-
OCR for page 28
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence ing feelings of sadness, fear, anxiety, or worry about physical health. It is usually utilized after other antidepressants have been unsuccessful for the patient. Potential common side effects of MAOIs include dizziness, feeling weak or drowsy, sleep problems (insomnia), constipation, upset stomach, dry mouth, decreased urination, and impotence or difficulty achieving an orgasm. Drinking alcohol while taking an MAO inhibitor may also cause serious side effects. Selective Serotonin Reuptake Inhibitors SSRIs, such as paroxetine, sertraline, fluoxetine, and citalopram, are a class of antidepressants also used to treat anxiety disorders. SSRIs are hypothesized to relieve symptoms of depression by blocking the reuptake of the neurotransmitter serotonin in certain synapses in the brain. Fluoxetine,7 paroxetine,8 and sertraline9 are all FDA approved to treat depression. Sertraline and paroxetine are the only pharmacotherapies approved by FDA to treat PTSD. The four studies submitted to the FDA to gain approval were included in the literature reviewed by the committee: Brady et al., 2000, and Davidson et al., 2001, for sertraline; and Marshall et al., 2001, and Tucker et al., 2001, for paroxetine. Common side effects of SSRIs include nausea, sexual dysfunction, headache, diarrhea, nervousness, rash, agitation, restlessness, increased sweating, drowsiness, insomnia, and weight gain. Stopping treatment abruptly or missing several doses can cause withdrawal-like symptoms. It should be noted that FDA requires that SSRIs carry a boxed warning on their label about increased risk of suicidality. Other Antidepressants Tricyclic Antidepressants Tricyclic antidepressants (TCAs) also may be used in treating patients with PTSD. TCAs include amitriptyline, imipramine, and desipramine. The pathway through which they improve depression symptoms is not fully understood although it is hypothesized that they increase the activity of norepinephrine or serotonin in the brain. 7 Also FDA approved to treat depression, obsessive-compulsive disorder, bulimia nervosa, premenstrual dysphoric disorder, and panic disorder. 8 Also FDA approved to treat social anxiety disorder. 9 Also FDA approved to treat social anxiety disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder.
OCR for page 29
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Mirtazapine Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) tetracyclic, FDA approved to treat major depression. How mirtazapine improves depression symptoms is not fully understood although it is hypothesized that it increases the activity of norepinephrine or serotonin in the brain, which helps improve mood. Common known side effects are abnormal dreams and thinking, constipation, dizziness, drowsiness, dry mouth, flu symptoms, increased appetite, weakness, and weight gain. Venlafaxine Venlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) that is FDA approved to treat depression and generalized as well as social anxiety disorders, but it is also one of the drugs used in the treatment of patients with PTSD. Potential side effects include anxiety, blurred vision, changes in taste, constipation, sexual dysfunction, dizziness, drowsiness, dry mouth, flushing, headache, increased sweating, loss of appetite, nausea, nervousness, stomach upset, trouble sleeping, vomiting, weakness, and weight loss. Nefazodone Nefazodone is another drug used in PTSD treatment that is FDA approved to treat depression. Its mechanism of action, as with other antidepressants, is unknown but clinical trials have shown that it inhibits neuronal uptake of serotonin and norepinephrine. Nefazodone has a boxed warning stating that cases of life-threatening hepatic failure (hepatotoxicity) have been reported in patients treated with nefazodone hydrochloride tablets. Common side effects include abnormal dreams, abnormal skin sensations, changes in taste, chills, confusion, constipation, decreased concentration, decreased sex drive, diarrhea, dizziness, drowsiness, dry mouth, fever, frequent urination, headache, incoordination, increased appetite, and others. Other Drugs D-cycloserine and inositol each have been studied to treat PTSD in one randomized controlled trial. D-cycloserine is an antibiotic used in the treatment of tuberculosis. It is also a partial N-methyl-D-aspartic acid (NMDA) agonist that boosts the activity of NMDA in the brain, which is needed for fear extinction. Inositol, specifically myo-inositol, is a second-messenger system constituent that has been investigated in the treatment of anxiety disorders, including PTSD (Freeman et al., 2002).
OCR for page 30
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Other drugs researched in the treatment of PTSD for which there are no published RCTs at the time of this writing include the following: Naltrexone and disulfiram (Lubin et al., 2002; Petrakis et al., 2006) Tianeptine (Onder et al., 2006) Baclofen (Drake et al., 2003) Propranolol (alpha-adrenergic blocker) (Pitman et al., 2002) Carbamazepine, divalproex, valproate (anticonvulsants) (Berlant and van Kammen, 2002; Clark et al., 1999) Quetiapine and levomepromazine (antipsychotics) (Ahearn et al., 2006; Aukst-Margeti et al., 2004) Clonazepam (benzodiazipine) (Cates et al., 2004) Fluvoxamine (SSRI) (Escalona et al., 2002; Spivak et al., 2006; Tucker et al., 2000) Description of the Psychotherapies As with most of the pharmacotherapies, psychotherapies are used to treat a variety of mental health conditions. Several psychotherapeutic interventions are used in the treatment of PTSD, sometimes in combination with medication. These interventions include cognitive behavioral therapies (CBTs). Components of psychotherapy used to treat PTSD include: (1) exposure to trauma-related memories or stimuli used in exposure therapies, such as eye movement desensitization and reprocessing (EMDR); (2) cognitive restructuring used in cognitive therapy and cognitive processing therapy; (3) coping skills training used in stress inoculation training, relaxation, and in social, family, and vocational interventions; (4) hypnosis; and (5) psychodynamic interpretation. Psychotherapy is designed to reduce the intrusion, avoidance, and hyperarousal symptoms of PTSD by some combination of reexperiencing and working through trauma-related memories and associated emotions, and teaching better means of managing trauma-related stressors. Psychotherapy approaches are designed to help patients control and reduce symptoms through either inducing them under controlled circumstances and then modulating them, or by focusing on stress management and nontrauma-related aspects of the person’s life. Behavioral therapy includes approaches such as systematic desensitization, biofeedback, and relaxation. The cognitive and behavioral approaches in CBT may be separated, but “aspects of both are frequently combined, and studies that identify the effective components of these therapies or that distinguish one from another are not available” (APA, 2004). For example, Harvey et al. (2003) described four basic components of CBT: psychoeducation, exposure, cognitive restructuring, and anxiety management
OCR for page 31
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence training. The theoretical literature also acknowledges the overlap among these approaches (as well as incomplete understanding of the mechanisms at work when these interventions are used) (APA, 2004; Harvey et al., 2003). Further explanation of the various psychotherapies can be found in Appendix A. SUMMARY OF THE MAJOR CLINICAL PRACTICE GUIDELINES To be sure that the committee was aware of all pharmacotherapies and psychotherapies in general clinical use, a search was conducted for clinical practice guidelines developed by major professional organizations. The committee reviewed clinical practice guidelines developed by the Management of Post-traumatic Stress Working Group of VA and the Department of Defense (DoD), the American Psychiatric Association (APA), the British National Institute for Clinical Excellence (NICE), the International Society for Traumatic Stress Studies (ISTSS), and the Australian Centre for Posttraumatic Mental Health of the Australian National Health and Medical Research Council. The committee made no judgments about the quality of these guidelines in the processes used or conclusions reached, but found them useful in defining the domain of clinical PTSD interventions. The VA/DoD Clinical Practice Guideline (2004) classifies four psychotherapy treatments as being of significant benefit: cognitive therapy, exposure therapy, stress inoculation therapy, and EMDR. Treatment modalities considered to offer some benefit include imagery rehearsal therapy, psychodynamic therapy, and PTSD patient education. The guidelines also identified two adjunctive treatments: dialectical behavioral therapy and hypnosis. Among the pharmacotherapy interventions, only one group, the SSRIs, was classified as being of significant benefit. Medications identified as having some benefit include TCAs, MAOIs, sympatholytics, and novel antidepressants. Anticonvulsants, atypical antipsychotics, nonbenzodiazepine hypnotics, and the antianxiety drug buspirone were identified as having unknown benefit. Finally, drugs with no benefit or possible harm include benzodiazepines and typical antipsychotics. The APA (2004) practice guidelines grouped its recommendations into categories: (I) recommended with substantial clinical confidence; (II) recommended with moderate clinical confidence; and (III) may be recommended on the basis of individual circumstances. SSRIs were the only pharmacotherapy rated as category I, while TCAs and MAOIs were rated category II, and benzodiazepines, anticonvulsants, antipsychotics and adrenergic inhibitors were rated category III. The guidelines found clinical effects in studies with women with chronic PTSD related to rape or assault are particularly noteworthy in the SSRI class. The evidence for MAOIs was limited to male combat veterans. For benzodiazepines, the evidence identified by
OCR for page 32
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence the guideline authors was unclear, and the class was recommended only for anxiety and improving sleep, not as monotherapy. Among the antipsychotics, studies of olanzapine and risperidone found some suggestive evidence from preliminary studies in patients with psychotic symptoms. The guideline authors found no controlled studies in alpha 2-adrenergic agonists but found preliminary evidence of possible benefit for prazosin. The psychotherapies reviewed by the APA include CBT and other exposure-based therapies, which demonstrated the strongest evidence, category I (but several studies showed increase in symptoms in some individuals). Stress inoculation, imagery rehearsal and prolonged exposure (which, in this report and elsewhere have been categorized under the CBT heading), psychodynamic therapy, hypnosis (little empirical support, few RCTs for psychodynamic therapy and hypnosis, but usefulness supported by clinical consensus), and EMDR were rated as category II. Finally, the guideline assigned a category III rating to case management, psychoeducation, other supportive interventions, and to group present-centered and trauma-focused therapy. The NICE guidelines rated interventions on an A through C scale. An A rating means that the evidence comes from “at least one RCT as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence level I10) without extrapolation.” A B rating means that evidence comes from “well-conducted clinical studies but no randomised clinical trials on the topic of recommendation” (evidence levels II or III11) or that evidence was extrapolated from level-I evidence. A C rating means evidence came from “expert committee reports or opinions and/or clinical experiences of respected authorities (evidence level IV12) or extrapolated from level I or II evidence. This grading indicates that directly applicable clinical studies of good quality are absent or not readily available. Of the psychotherapies, trauma-focused CBT and EMDR were rated A, and relaxation was rated B. The guidelines identified only a short list of pharmacotherapies, including the SSRI paroxetine and the NaSSA mirtazapine for general use, and the TCA amitriptyline and the MAOI phenelzine for use by mental health specialists, both categories to be used in patients unwilling or unable to receive psychotherapy. Hypnotic medication was rated C to be used on a temporary basis, and olanzapine was rated C to be used as an adjunctive. The NICE guidelines also recommended that 10 (I) Evidence obtained from a single randomised controlled trial or a meta-analysis of randomised controlled trials. 11 (IIa) Evidence obtained from at least one well-designed controlled study without randomization; or (IIb) evidence obtained from at least one other well-designed quasi-experimental study; or (III) evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies, and case studies. 12 (IV) Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.
OCR for page 33
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence medication be offered if psychological treatments are not effective, but they noted that the former are not as helpful as trauma-focused psychological treatments. Medication is recommended as first line of treatment when the patient prefers not to have psychological treatment, it would be difficult to start psychological treatment because of a threat of further trauma, or if psychological treatment was not helpful. Pharmacotherapy is also recommended as adjunct to psychotherapy in cases with comorbid depression or severe hyperarousal that interferes with psychotherapy. ISTSS reviewed the evidence base for treatment of PTSD and made recommendations on six “categories of endorsement” in its 2000 Practice Guidelines (Foa et al., 2000). ISTSS found that CBT and SSRIs are shown to be effective, with some evidence of effectiveness for several additional psychotherapies, including psychodynamic therapy, hypnotherapy, and EMDR. The guideline discusses the evolution of CBT approaches, from the older therapies (systematic desensitization, relaxation training, bio-feedback) that are based on learning theory, to the more recent techniques, based on emotional and information processing theories, and which include exposure, cognitive therapy, and cognitive processing therapy. The guideline reviewed eight CBT techniques, three of which are combinations of other techniques: exposure, systematic desensitization, stress inoculation therapy, cognitive processing therapy, cognitive therapy, assertiveness training and biofeedback (both are anxiety management approaches), relaxation training, stress inoculation therapy plus exposure, exposure plus relaxation plus cognitive therapy, and cognitive therapy plus exposure. At the time of this writing, the Australian government’s Centre for Posttraumatic Mental Health had just published its Australian Guidelines for the Treatment of Adults with Acute Stress Disorder and Posttraumatic Stress Disorder. The guidelines drew on the British NICE guidelines and U.S. VA/DoD guidelines, and the authors reviewed studies published after the NICE review. The guidelines recommended the use of trauma-focused interventions (namely, trauma-focused CBT or EMDR, in addition to in vivo exposure) first, with SSRIs as the first choice in pharmacologic treatment. In regard to the scientific evidence on SSRIs, however, the guidelines found that the four SSRI studies conducted after the publication of the NICE “failed to provide evidence that these drugs were superior to placebo either in the treatment of PTSD symptoms or in the treatment of depression in the context of PTSD.” The guidelines also recommended that group CBT therapy “may be provided as adjunctive to” but not as an alternative to individual therapy (Australia Centre for Posttraumatic Mental Health, 2007: xviii).
OCR for page 34
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence SUMMATION In this chapter we reviewed the charge to the committee from VA, the DSM definition of PTSD and epidemiologic information about its prevalence, provided an overview of treatment research for PTSD that has appeared in peer-reviewed journals over the past 30 years, and summarized several major clinical practice guidelines. The following chapter addresses the methods that were developed and used to evaluate the quality of published PTSD treatment research for this report. REFERENCES Ahearn, E. P., M. Mussey, C. Johnson, A. Krohn, and D. Krahn. 2006. Quetiapine as an adjunctive treatment for post-traumatic stress disorder: An 8-week open-label study. International Clinical Psychopharmacology 21(1):29-33. APA (American Psychiatric Association). 1987. DSM-III-R, section 309.89: Post-traumatic stress disorder. In Diagnostic and statistical manual of mental disorders. 3rd ed. Rev. Washington, DC: APA. APA. 1994. DSM-IV, section 309.81: Posttraumatic stress disorder. In Diagnostic and statistical manual of mental disorders. 4th ed. Rev. Washington, DC: APA. APA. 2000. DSM-IV-TR, section 309.81: Posttraumatic stress disorder. In Diagnostic and statistical manual of mental disorders. 4th ed. Rev. Washington, DC: APA. APA. 2004. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Washington, DC: APA. Aukst-Margeti, B., B. Margeti, G. Tosi, and A. Bili-Prci. 2004. Levomepromazine helps to reduce sleep problems in patients with PTSD. European Psychiatry: The Journal of the Association of European Psychiatrists 19(4):235-236. Australia Centre for Posttraumatic Mental Health. 2007. Australian guidelines for the treatment of adults with acute stress disorder and posttraumatic stress disorder. Melbourne, Victoria: ACPMH. Batres, A., and A. Zeiss. 2007 (January 16). Presentation to the Institute of Medicine Committee on the Treatment of Posttraumatic Stress Disorder, Meeting One: Treatment of PTSD in VA facilities and programs. Washington, DC: IOM. Berlant, J., and D. P. van Kammen. 2002. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: A preliminary report. Journal of Clinical Psychiatry 63(1):15-20. Brady, K., T. Pearlstein, G. M. Asnis, D. Baker, B. Rothbaum, C. R. Sikes, and G. M. Farfel. 2000. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: A randomized controlled trial. Journal of the American Medical Association 283(14):1837-1844. Brady, K. T., S. Sonne, R. F. Anton, C. L. Randall, S. E. Back, and K. Simpson. 2005. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcoholism: Clinical and Experimental Research 29(3):395-401. Breslau, N., G. C. Davis, P. Andreski, and E. Peterson. 1991. Traumatic events and posttraumatic stress disorder in an urban population of young adults. Archives of General Psychiatry 48(3):216-222. Cates, M. E., M. H. Bishop, L. L. Davis, J. S. Lowe, and T. W. Woolley. 2004. Clonazepam for treatment of sleep disturbances associated with combat-related posttraumatic stress disorder. Annals of Pharmacotherapy 38(9):1395-1399.
OCR for page 35
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Clark, R. D., J. M. Canive, L. A. Calais, C. R. Qualls, and V. B. Tuason. 1999. Divalproex in posttraumatic stress disorder: An open-label clinical trial. Journal of Traumatic Stress 12(2):395-401. Davidson, J. R., B. O. Rothbaum, B. A. van der Kolk, C. R. Sikes, and G. M. Farfel. 2001. Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Archives of General Psychiatry 58(5):485-492. Department of Health and Human Services. 1999. Mental health: A report of the Surgeon General. Rockville, MD: National Institute of Mental Health. Department of Veterans Affairs. 2004. 2003 survey of veteran enrollees’ health and reliance upon VA: With selected comparisons to the 1999 and 2002 surveys. Washington, DC: Veterans Health Administration. Department of Veterans Affairs Office of Research and Development, National Institute of Mental Health, and United States Army Medical Research and Materiel Command. 2006. Mapping the landscape of deployment related adjustment and mental disorders: A meeting summary of a working group to inform research. Rockville, MD: Department of Veterans Affairs. Dohrenwend, B. P., J. B. Turner, N. A. Turse, B. G. Adams, K. C. Koenen, and R. Marshall. 2006. The psychological risks of Vietnam for U.S. veterans: A revisit with new data and methods. Science 313(5789):979-982. Drake, R. G., L. L. Davis, M. E. Cates, M. E. Jewell, S. M. Ambrose, and J. S. Lowe. 2003. Baclofen treatment for chronic posttraumatic stress disorder. Annals of Pharmacotherapy 37(9):1177-1181. Escalona, R., J. M. Canive, L. A. Calais, and J. R. T. Davidson. 2002. Fluvoxamine treatment in veterans with combat-related post-traumatic stress disorder. Depression and Anxiety 15(1):29-33. Foa, E., T. Keane, and M. Friedman. 2000. Effective treatments for PTSD: Practice guidelines from the International Society for Traumatic Stress Studies. New York: The Guilford Press. Freeman, M. P., S. A. Freeman, and S. L. McElroy. 2002. The comorbidity of bipolar and anxiety disorders: Prevalence, psychobiology, and treatment issues. Journal of Affective Disorders 68(1):1-23. Friedman, M. J. 1998. Current and future drug treatment for posttraumatic stress disorder patients. Psychiatric Annals 28(397):461-468. Harvard Medical School. 2007. Lifetime prevalence of DSM-IV/WMH-CIDI disorders by sex and cohort 1 (n=9282). http://www.hcp.med.harvard.edu/ncs/ftpdir/table_ncsr_LTprevgenderxage.pdf (accessed August 20, 2007). Harvey, A. G., R. A. Bryant, and N. Tarrier. 2003. Cognitive behaviour therapy for posttraumatic stress disorder. Clinical Psychology Review 23(3):501-522. Hertzberg, M. A., M. I. Butterfield, M. E. Feldman, J. C. Beckham, S. M. Sutherland, K. M. Connor, and J. R. Davidson. 1999. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biological Psychiatry 45(9):1226-1229. Himmelfarb, N., D. Yaeger, and J. Mintz. 2006. Posttraumatic stress disorder in female veterans with military and civilian sexual trauma. Journal of Traumatic Stress 19(6):837-846. Hoge, C. W., C. A. Castro, S. C. Messer, D. McGurk, D. I. Cotting, and R. L. Koffman. 2004. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. New England Journal of Medicine 351(1):13-22. Hotopf, M., L. Hull, N. T. Fear, T. Browne, O. Horn, A. Iversen, M. Jones, D. Murphy, D. Bland, M. Earnshaw, N. Greenberg, J. H. Hughes, A. R. Tate, C. Dandeker, R. Rona, and S. Wessely. 2006. The health of UK military personnel who deployed to the 2003 Iraq war: A cohort study. Lancet 367(9524):1731-1741.
OCR for page 36
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence IOM (Institute of Medicine). 2006. Posttraumatic stress disorder: Diagnosis and assessment. Washington, DC: National Academies Press. IOM. 2007a (in press). Gulf war and health: Physiologic, psychologic, and psychosocial effects of deployment-related stress. Washington, DC: The National Academies Press. IOM. 2007b. PTSD compensation and military service. Washington, DC: The National Academies Press. Kang, H., N. Dalager, C. Mahan, and E. Ishii. 2005. The role of sexual assault on the risk of PTSD among Gulf War veterans. Annals of Epidemiology 15(3):191-195. Kessler, R. C. 1995. Epidemiology of psychiatric comorbidity. In Textbook in psychiatric epidemiology. Edited by M. T. Tsuang, M. Tohan, and G. E. P. Zahner. New York: John Wiley and Sons. Kessler, R. C., A. Sonnega, E. Bromet, M. Hughes, and C. B. Nelson. 1995. Posttraumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry 52(12):1048-1060. Kulka, R., J. Fairbank, K. B. Jordan, and D. Weiss. 1990. Trauma and the Vietnam War generation: Report of findings from the national Vietnam veterans readjustment study. New York: Routledge. Lubin, G., A. Weizman, M. Shmushkevitz, and A. Valevski. 2002. Short-term treatment of post-traumatic stress disorder with naltrexone: An open-label preliminary study. Human Psychopharmacology 17(4):181-185. Marshall, R. D., K. L. Beebe, M. Oldham, and R. Zaninelli. 2001. Efficacy and safety of paroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study. American Journal of Psychiatry 158(12):1982-1988. Martenyi, F., E. B. Brown, H. Zhang, S. C. Koke, and A. Prakash. 2002. Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. British Journal of Psychiatry 181:315-320. Onder, E., U. Tural, and T. Aker. 2006. A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake. European Psychiatry: The Journal of the Association of European Psychiatrists 21(3):174-179. Petrakis, I. L., J. Poling, C. Levinson, C. Nich, K. Carroll, E. Ralevski, and B. Rounsaville. 2006. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biological Psychiatry 60(7):777-783. Pitman, R. K., K. M. Sanders, R. M. Zusman, A. R. Healy, F. Cheema, N. B. Lasko, L. Cahill, and S. P. Orr. 2002. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biological Psychiatry 51(2):189-192. Sartorius, N. 2002. Iatrogenic stigma of mental illness (editorial). British Medical Journal 324(June 22):1470-1471. Seal, K. H., D. Bertenthal, C. R. Miner, S. Sen, and C. Marmar. 2007. Bringing the war back home: Mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities. Archives of Internal Medicine 167(5):476-482. Spivak, B., R. D. Strous, G. Shaked, E. Shabash, M. Kotler, and A. Weizman. 2006. Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: A double-blind, fixed-dosage, controlled trial. Journal of Clinical Psychopharmacology 26(2):152-156. Tucker, P., K. L. Smith, B. Marx, D. Jones, R. Miranda, Jr., and J. Lensgraf. 2000. Fluvoxamine reduces physiologic reactivity to trauma scripts in posttraumatic stress disorder. Journal of Clinical Psychopharmacology 20(3):367-372.
OCR for page 37
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence Tucker, P., R. Zaninelli, R. Yehuda, L. Ruggiero, K. Dillingham, and C. D. Pitts. 2001. Paroxetine in the treatment of chronic posttraumatic stress disorder: Results of a placebo-controlled, flexible-dosage trial. Journal of Clinical Psychiatry 62(11):860-868. Tucker, P., R. P. Trautman, D. B. Wyatt, J. Thompson, S. C. Wu, J. A. Capece, and N. R. Rosenthal. 2007. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: A randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 68(2):201-206. VA (Veterans Affairs), DoD (Department of Defense), Management of Post-Traumatic Stress Working Group. 2004. VA/DoD clinical practice guideline for the management of posttraumatic stress, version 1.0. Washington, DC: Department of Veterans Affairs and Department of Defense. Wilson, J. P., M. Friedman, and J. Lindy, eds. 2001. Treating psychological trauma and PTSD. New York: The Guilford Press. Yaeger, D., N. Himmelfarb, A. Cammack, and J. Mintz. 2006. DSM-IV diagnosed posttraumatic stress disorder in women veterans with and without military sexual trauma. Journal of General and Internal Medicine (Suppl 3):S65-S69. Yehuda, R., ed. 1998. Psychological trauma. In Review of psychiatry series. Edited by J. M. Oldham and M. B. Riba. Washington, DC: American Psychiatric Press.
OCR for page 38
Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence This page intentionally left blank.