Suicidal behavior in patients with current or past panic disorder: five years of prospective data from the Harvard/Brown Anxiety Research Program.

OBJECTIVE: The authors' goals were to examine predictors of suicidal behavior and provide guidelines for assessing suicide risk in patients with panic disorder. METHOD: Four hundred ninety-eight patients with panic disorder were followed for 5 years. Survival analysis was used to examine variables correlated with prospectively observed suicidal behavior. RESULTS: Subjects had a 0.06 probability of suicidal behavior during follow-up. Affective disorders, substance abuse, eating disorders, personality disorders, and being female were risk factors. Two subjects were suicidal in the absence of risk factors; both developed depression during follow-up. CONCLUSIONS: Panic disorder is not associated with suicidal behavior in the absence of other risk factors.

Psychosocial treatment prescriptions for generalized anxiety disorder, panic disorder, and social phobia, 1991-1996.

OBJECTIVE: Pharmacologic prescriptions for anxiety disorders have changed significantly in the last decade. This article investigates whether psychosocial treatments, as reported by 362 subjects in the Harvard/Brown Anxiety Disorders Research Program from 1991 to 1996, changed as well. METHOD: Subjects were interviewed in 1991 and 1995-1996 to determine which psychosocial treatments (behavioral, cognitive, dynamic, or relaxation or meditation) they had received. RESULTS: The percentage of subjects who received each type of psychosocial treatment either declined or remained the same from 1991 to 1995-1996. Dynamic psychotherapy remained the most frequently used method of these four. The percentage of subjects receiving any such method declined. CONCLUSIONS: Behavioral and cognitive treatment, two empirically validated forms of psychotherapy, were less frequently used than dynamic psychotherapy, which lacks such validation. All use of verbal treatment methods declined from 1991 to 1995-1996.

Quality of life and psychiatric morbidity in panic disorder and generalized anxiety disorder.

OBJECTIVE: This report examines the impact of panic disorder and/or generalized anxiety disorder on quality of life and the implications of these findings on nosological categories. METHOD: A total of 357 subjects with a current episode of panic disorder and/or generalized anxiety disorder were diagnosed according to DSM-III-R criteria, using structured clinical interviews, as part of a prospective, naturalistic, longitudinal, multicenter study of a clinical population with anxiety disorders. RESULTS: There was a high degree of coexistence of anxiety disorders and major depressive disorder. Subjects with generalized anxiety disorder almost universally had other disorders, were the most likely to have at least one other anxiety disorder or major depressive disorder at intake, had the earliest age at onset, and had the worst emotional health rating. Subjects with panic disorder without agoraphobia had the most likelihood of a history of alcohol abuse. Nine percent of the subjects had a history of suicide attempts or gestures. CONCLUSIONS: The subjects showed significant impairment in quality of life. The highly frequent coexistence of other anxiety disorders with generalized anxiety disorder and the overall lack of differences on many quality of life measures raise questions of nosology, particularly for generalized anxiety disorder.

Quality of life and dissociation in anxiety disorder patients with histories of trauma or PTSD.

OBJECTIVE: The purpose of this analysis was to examine quality of life and dissociation in anxiety disorder subjects with histories of trauma, some of whom met criteria for posttraumatic stress disorder (PTSD). METHOD: Subjects came from a prospective, longitudinal study of anxiety disorders. Information was gathered on role, social life, suicide attempts, psychiatric hospitalization, alcohol and substance abuse, depression, and dissociation. RESULTS: Subjects with PTSD had the worst functioning on all of the measures examined except social life. Those with histories of trauma but no PTSD differed from subjects who reported no history of trauma, primarily in high rates of alcoholism and minor depression. CONCLUSIONS: PTSD has severe effects on quality of life in virtually all spheres of life. The high levels of depression, suicide attempts or gestures, and alcohol abuse are of particular concern and show that trauma can have long-lasting effects.

Trauma and posttraumatic stress disorder in subjects with anxiety disorders.

Trauma histories were obtained from 711 subjects in a large study of anxiety disorders, with the intent of determining the prevalence and nature of psychological trauma in this group. Twenty-seven percent of subjects reported significant trauma; 35% of these (10% of all subjects) met DSM-II-R criteria for posttraumatic stress disorder (PTSD). Subjects reporting sexual trauma were significantly more likely to have PTSD. The rate of PTSD was not higher in subjects with panic disorder than in those with other anxiety disorders.

Does major depression result in lasting personality change?

OBJECTIVE: Individuals with a history of depression are characterized by high levels of certain personality traits, particularly neuroticism, introversion, and interpersonal dependency. The authors examined the "scar hypothesis," i.e., the possibility that episodes of major depression result in lasting personality changes that persist beyond recovery from the depression. METHOD: A large sample of first-degree relatives, spouses, and comparison subjects ascertained in connection with the proband sample from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression were assessed at two points in time separated by an interval of 6 years. Subjects with a prospectively observed first episode of major depression during the interval were compared with subjects remaining well in terms of change from time 1 to time 2 in self-reported personality traits. All subjects studied were well (had no mental disorders) at the time of both assessments. RESULTS: There was no evidence of negative change from premorbid to postmorbid assessment in any of the personality traits for subjects with a prospectively observed first episode of major depression during the interval. The results suggested a possible association of number and length of episodes with increased levels of emotional reliance and introversion, respectively. CONCLUSIONS: The findings suggest that self-reported personality traits do not change after a typical episode of major depression. Future studies are needed to determine whether such change occurs following more severe, chronic, or recurrent episodes of depression.

Serum lithium levels and psychosocial function in patients with bipolar I disorder.

OBJECTIVE: This study compared the effect of two different serum lithium levels on the psychosocial functioning of patients with bipolar I disorder. METHOD: Ninety patients with bipolar I disorder were enrolled in a prospective, double-blind, maintenance trial of lithium. The patients were randomly assigned to treatment with doses of lithium adjusted to achieve a serum lithium concentration of either 0.8 to 1.0 mmol/liter (standard) or 0.4 to 0.6 mmol/liter (low). The Longitudinal Interval Follow-Up Evaluation was used to assess psychosocial functioning in the areas of work, interpersonal relationships, and global functioning. All observed values were analyzed with a mixed-effects analysis of covariance. Independent variables included treatment group (low or standard lithium serum level), relapse status, socioeconomic status, time from random treatment assignment to assessment, termination of protocol before or after relapse, length of remission before random treatment assignment, polarity of the last mood episode before random treatment assignment, and number of mood episodes in the 3 years before random treatment assignment. RESULTS: Relapse was associated with large negative effects on psychosocial functioning. Patients in higher socioeconomic brackets had better psychosocial functioning than did those in lower brackets. Patients receiving lithium doses that achieved standard serum levels had better psychosocial functioning than those receiving doses that achieved low serum levels; this effect was partially but not wholly mediated through relapse prevention. CONCLUSIONS: For patients with bipolar I disorder, standard serum lithium levels may enhance psychosocial functioning, above and beyond the effects of relapse prevention.

Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects.

OBJECTIVE: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. METHOD: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. RESULTS: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. CONCLUSIONS: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely ill before treatment with fluoxetine.

DSM-IV and the disappearance of agoraphobia without a history of panic disorder: new data on a controversial diagnosis.

OBJECTIVE: This analysis describes subjects who met rigorous criteria for DSM-III-R agoraphobia without a history of panic disorder and makes inferences from these data regarding relationships among agoraphobia without a history of panic disorder, panic disorder, and panic disorder with agoraphobia. METHOD: Twenty-six subjects (seven men and 19 women) with agoraphobia without a history of panic disorder were identified from among 711 subjects recruited for a multicenter, longitudinal anxiety disorder study. Narrative transcripts prepared by raters from study evaluations were coded for limited symptom attacks, situational panic, catastrophic cognitions, and possible precipitants and stressors, course, and somatic and psychosocial treatments received. RESULTS: Sixty-five percent of the subjects reported experiences consistent with situational panic attacks, and 57% had definite or probable limited symptom attacks; these attacks usually preceded or appeared at the same time as avoidance behavior. Eighty-one percent had catastrophic cognitions associated with agoraphobia. Twenty-six percent reported a likely precipitating factor for symptom onset, and 30% reported a definite or probable major life stressor within 6 months before symptom onset. Cognitive-behavioral treatments were relatively infrequently used. Course was relatively unchanged across the follow-up period. CONCLUSIONS: These data support a view of agoraphobia without a history of panic disorder on a continuum with uncomplicated panic disorder and with panic disorder and agoraphobia, rather than as a separate diagnosis.

The relationship between fluoxetine use and suicidal behavior in 654 subjects with anxiety disorders.

BACKGROUND: In the past few years, there has been controversy over the relationship between suicidal behavior and fluoxetine use. This report examines the relationship between fluoxetine use and suicidal behavior in the Harvard/Brown Anxiety Disorders Research Program (HARP). METHOD: HARP is a naturalistic, prospective, longitudinal anxiety disorders study. Probabilities of suicidal behavior for 654 subjects were examined using life table analysis for the study group as a whole and stratified by depression status at intake. RESULTS: Subjects not using fluoxetine during follow-up had almost twice the probability of making a suicide attempt or gesture during the follow-up than subjects who were using fluoxetine, although this difference was not statistically significant. Subjects having episodes of major depressive disorder (MDD) at intake were more likely than those not having an episode to receive fluoxetine during follow-up (74/166 [45%] vs. 118/488 [24%], chi squared= 24.85, df= 1, p < .0001). Among those subjects having episodes of MDD at intake, there was a statistically significantly lower probability of suicide attempts/gestures for those taking fluoxetine than for those not using fluoxetine during follow-up (log-rank chi squared= 5.10, df= 1, p= .02). CONCLUSION: We found no evidence that fluoxetine use is associated with increased risk of suicide attempts or gestures. However, we did find that subjects with more suicide risk factors at intake were more likely to use fluoxetine than those without these risk factors.

Benzodiazepine use in anxiety disordered patients with and without a history of alcoholism.

BACKGROUND: People with a history of alcohol use disorders are thought to be at risk for misusing prescribed benzodiazepines. We examine the use of prescribed benzodiazepines in anxiety disordered subjects with and without a history of alcohol dependence or abuse. METHOD: A group of 343 subjects in the Harvard/Brown Anxiety Disorders Research Program (HARP) who were taking benzodiazepines at the time of entry into a prospective study of anxiety disorders serve as the study group. Subjects with (N=99) and without (N=244) a history of alcohol use or dependence (DSM- III-R) are examined for their reported total daily dose, p.r.n. use, or continued use of benzodiazepines. RESULTS: There is no significant difference in maximum daily dose or continued use of benzodiazepines over 12 months of follow- up. There is a clinically small but statistically significant difference in median daily dose during the second but not the first 6 months of follow-up for the alcohol history positive versus alcohol history negative groups. Additionally, there was significantly less reported use of p.r.n. benzodiazepines in the alcohol history positive versus alcohol history negative subjects during the second 6 months, but not the first 6 months, of follow-up. CONCLUSION: The presence or absence of a history of alcohol use disorders is not a strong predictor of the use of benzodiazepines in subjects with anxiety disorders over 12 months of prospective follow-up.

Utilization of behavioral methods in a multicenter anxiety disorders study.

BACKGROUND: There are abundant data to justify the use of behavioral methods in treating patients with anxiety disorders. Yet there also is evidence that these methods have been underutilized in treating these patients. In this study we examined a large sample of patients with anxiety disorders to determine the extent to which behavior therapy methods were used in their treatment. METHOD: As part of a multicenter longitudinal study of patients with anxiety disorders in New England, we analyzed data pertinent to the type of treatment received by 231 patients at nine study sites. Study subjects received a battery of interview and self-report instruments administered by trained study interviewers at intake and at 6-month follow-up. A Psychosocial Treatments Interview designed by study personnel and administered by study interviewers at 6 months after intake provided data as to types of psychosocial treatment received by study subjects. RESULTS: Behavioral methods were used less frequently than supportive psychotherapy. medication, or psychodynamic psychotherapy. Among behavioral treatments, relaxation and imaginal exposure were used more frequently than in vivo exposure. Obsessive compulsive disorder and agoraphobia without panic were the diagnoses most likely to be treated behaviorally. Behavioral methods were used more frequently in combination with other modalities than they were alone. CONCLUSION: When compared with previous studies, the frequency of utilization of behavioral methods appears to have increased moderately. But our data are still consistent with a pattern of inappropriately low utilization of these effective treatment methods.

The infrequency of "pure culture" diagnoses among the anxiety disorders.

BACKGROUND: Anxiety disorders are known to commonly coexist in individuals, both with other anxiety disorders and with mental disorders from other groupings, such as affective disorders. We questioned how frequently anxiety disorders actually occur in isolation, as "pure cultures." METHOD: We examined diagnostic patterns among the 711 subjects entered into a large, multicenter study of anxiety disorders, the Harvard/ Brown Anxiety Disorders Research Program (HARP), which focused on panic, agoraphobia, generalized anxiety disorder, and social phobias as "index disorders" required for intake. RESULTS: We used various definitions for "pure culture." By all definitions, subjects with "pure culture" represented a minority, especially in cases of generalized anxiety disorder and social phobia, where comorbidity was virtually ubiquitous. "Pure culture" status was associated with later onset of illness and less chronicity. CONCLUSION: Future studies of anxiety disorder should aim to document the extensive comorbidity, rather than eliminate it by restrictive diagnostic exclusion criteria, lest they yield atypical or even misrepresented groups of patients. Clinicians should not stop at identifying only the "main" diagnosis but look for other, comorbid diagnoses that are often present.

Patterns of remission and relapse in obsessive-compulsive disorder: a 2-year prospective study.

OBJECTIVE: This study examined the course of illness in patients with obsessive-compulsive disorder (OCD) over a 2-year period. METHOD: Sixty-six patients with a primary diagnosis of DSM-III-R OCD were followed prospectively for 2 years. Baseline information was collected on demographic characteristics, Axis I and II diagnoses, and severity of OCD symptoms. Follow-up measures obtained at 3, 6, 12, and 24 months after baseline assessment included information on symptomatic and diagnostic status as well as behavioral and somatic treatments received. RESULTS: The probability of full remission from OCD over the 2-year period was 12%. The probability of partial remission was 47%. After achieving remission from OCD, the probability of relapse was 48%. No factors were identified that significantly predicted full or partial remission. Seventy-seven percent (N = 51) of the subjects received a serotonin reuptake inhibitor (SRI) for > or =12 weeks, and 68% (N = 45) received medium-to-high doses of SRIs for > or =12 weeks. Only 18% received a full trial of behavior therapy. CONCLUSION: Despite exposure to at least 1 adequate trial of an SRI, the likelihood of full remission of OCD in this study was low. Results of this study also suggest that behavior therapy may be under-utilized.

Reliability and validity of the longitudinal interval follow-up evaluation for assessing outcome of anxiety disorders.

The LIFE-UP, an instrument for prospectively following course for psychiatric disorders, has been extended to include Psychiatric Status Ratings (PSRs) for the DSM-III-R anxiety disorders panic (with and without agoraphobia), agoraphobia without panic, generalized anxiety disorder, social phobia, and simple phobia. This paper reports data on the reliability and validity of the LIFE-UP as used in the Harvard/Brown Anxiety Disorders Research Program. We found generally good reliability for the PSRs, both inter-rater and long-term test-retest. The reliability coefficients for the rater-administered instruments were very similar to those for the self-reports, suggesting that a large proportion of the variance was due to subject variability rather than rater variability. Reliability for the beginning of the year of follow-up was very similar to that for the time just before the interview. In addition, correlations with other measures of psychosocial function or anxiety symptomatology provided evidence for the external validity of the PSRs as measures of psychiatric morbidity.

Are secular trends in major depression an artifact of recall?

There is evidence that rates of major depression have increased over this century, with successive birth cohorts showing increased lifetime risks and earlier ages of onset. Two memory effects have been considered possible artifactual causes of these trends: age-related forgetting and postdating early episodes. In this study, relatives were reinterviewed six years after study entry using interviewers blind to initial reports. We examined the stability of lifetime diagnoses of MDD and ages of first onset. Older relatives were no more likely than younger ones to lose diagnoses nor to postdate their ages of first MDD onset. This is evidence that memory artifacts are not solely responsible for the observed secular trends.

Maintaining reliability in a long-term psychiatric study: an ongoing inter-rater reliability monitoring program using the longitudinal interval follow-up evaluation.

The Longitudinal Interval Follow-up Evaluation (LIFE), has been shown to be a valid and reliable instrument for characterizing the week-by-week course of anxiety disorders examined retrospectively over the period of 1 year. Due to the chronic nature of these disorders, there is a need for reliable, valid instruments for measuring course over periods of several years if we are to learn more about the natural history of these disorders. This paper describes a rater-monitoring program designed to ensure long-term inter-rater reliability and prevent "rater drift". In this program, clinical interviewers score taped interviews and are required to maintain a median intra-class correlation coefficient (ICC) of at least 0.80 with the other raters. Raters also assess tapes from previous years, to ensure that they are using the same diagnostic criteria as earlier generations of interviewers. A reliability study was conducted to compare psychiatric status ratings (PSRs) collected using biweekly telephone interviews with the semi-annual interviews. The ICCs for panic, agoraphobia, social phobia, and generalized anxiety disorder were very good to excellent. Another reliability study examined the PSRs of subjects who had been previously lost to follow-up. ICCs for panic, agoraphobia, generalized anxiety disorder and depression were good to excellent. These results show that the LIFE, when used in conjunction with an intensive training and rater monitoring system, is a reliable instrument for use in longitudinal studies of the course of anxiety disorders.

The use of conditional probabilities to examine age-period-cohort data: further evidence for a period effect in major depressive disorder.

There is growing evidence that rates of major depression have been increasing over this century, with successive birth cohorts showing increased lifetime risks and earlier ages of onset. In this paper, we describe and compare onset rates in six birth cohorts of first degree relatives of probands with affective disorders from the NIMH Collaborative Study, using graphs of conditional probabilities of first onset. There is evidence of a period effect and age-period interaction for both men and women.

Suicidal behavior in patients with panic disorder: retrospective and prospective data.

This paper examines factors associated with suicidal behavior in patients with anxiety disorders. HARP is a naturalistic, prospective, longitudinal follow-up study. This paper examines 527 subjects with panic disorder (with or without agoraphobia). 9% of the subjects reported past suicidal behavior. Factors associated with suicidal behavior were depressive disorders, substance abuse, eating disorders, PTSD and personality disorders as well as having early onset of the first anxiety or depressive disorder. Subjects had a 4.5% P of suicidal behavior during the first 30 months of follow-up. All prospectively recorded suicidal behavior occurred in subjects with depressive disorders. In these panic disorder patients, suicidal behavior rarely occurred in the absence of affective disorders. Certain nondepressive disorders also substantially increased the risks of suicide attempts/gestures.

Patterns of personality pathology in patients with generalized anxiety disorder, panic disorder with and without agoraphobia, and social phobia.

The relationship between co-occurring personality disorders and anxiety disorders (panic disorder with or without agoraphobia, social phobia, and generalized anxiety disorder) was examined, taking into account the effect of major depression. This article describes findings for 622 participants in the Harvard/Brown Anxiety Research Project, a longitudinal follow-up study of DSM-III-R-defined anxiety disorders. A total of 24% of participants had at least one personality disorder, with avoidant, obsessive compulsive, dependent, and borderline most common. Generalized anxiety disorder, social phobia, and major depression were positively associated with the occurrence of one or more personality disorders, whereas panic disorder with agoraphobia was not associated. Major depression was associated in particular with dependent, borderline, histrionic, and obsessive compulsive personality disorders and social phobia was associated with avoidant personality disorder. Whereas some of our findings confirm results from earlier studies, others are somewhat inconsistent with previous results and indicate the need for further investigation.