Absence of neuropsychologic deficits in patients receiving long-term treatment with alprazolam-XR for panic disorder.

Studies to date on the effects of benzodiazepines on neuropsychologic function have yielded conflicting data with respect to the type, severity, and duration of deficits that may be induced by these agents. As part of a placebo-controlled trial of alprazolam-XR (extended release) administered in combination with cognitive-behavioral therapy in patients with panic disorder, a battery of tests was used to measure neuropsychologic function. Thirty-eight outpatients were randomly assigned to receive either alprazolam-XR or placebo. Dosages were titrated up so that the alprazolam group (N = 18) received a mean dose of 4 mg/day (reduced in two patients because of sedative side effects). Neuropsychologic function after 6 weeks of therapy at the target dosage was compared with baseline assessments in each group. Both groups showed a statistically significant improvement from baseline to repeated assessments on measures of attention, executive functioning, psychomotor speed, and visual memory (p < 0.001); these gains were attributed to a practice effect. No significant changes were noted in measures of learning, verbal memory, or reaction time, and neither group showed any deterioration from baseline to retesting in any aspect of neuropsychologic function. These findings call into question the assumption that long-term benzodiazepine therapy produces significant neuropsychologic deficit in patients with diagnosed anxiety disorders.

Changes in psychiatric diagnoses from admission to discharge: review of the charts of 159 patients consecutively admitted to a geriatric psychiatry inpatient unit.

The diagnosis of psychopathology among geriatric acute inpatients requires comprehensive evaluation. To our knowledge, no recently published papers in the geriatric psychiatry literature have systematically examined diagnostic changes during single admissions. We reviewed the charts of 159 patients consecutively admitted to an acute geriatric psychiatry unit over 18 months. We recorded admission diagnoses from initial treatment plans, and discharge diagnoses from discharge summaries. Mean patient age was 80 years and average length of stay was 17 days. The most common primary diagnoses were psychotic and depressive disorders. The most common secondary diagnoses were dementias and depressive disorders. Primary diagnoses changed from admission to discharge in 31 patients (20%), and secondary diagnoses changed in 76 patients (48%). There was a significant change involving the diagnosis of dementia, but not that of depressive or psychotic disorders. A large proportion of inpatients had their diagnoses altered, especially those involving dementias, during hospitalization. Inpatient admission may be valuable for clarifying the diagnoses of elderly psychiatric patients.

Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness?

OBJECTIVE: This study investigated the influence of incomplete recovery from first lifetime major depressive episodes on long-term outcome. METHOD: After their first lifetime major depressive episode, patients were divided into asymptomatic (N=70) and residual subthreshold depressive symptom (N=26) recovery groups and compared on longitudinal course during up to 12 years of prospective naturalistic follow-up. RESULTS: Patients with residual subthreshold depressive symptoms during recovery had significantly more severe and chronic future courses. Those with residual symptoms relapsed to major and minor depressive episodes faster and had more recurrences, shorter well intervals, and fewer symptom-free weeks during follow-up than asymptomatic patients. CONCLUSIONS: Resolution of major depressive episodes with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course. When ongoing subthreshold symptoms continue after major depressive episodes, the illness is still active, and continued treatment is strongly recommended.

Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Quality of well being in panic disorder: the assessment of psychiatric and general disability.

BACKGROUND: Panic disorder is a common and debilitating anxiety disorder which significantly disrupts the lives of patients and their family members. Recent epidemiological studies and analyses of data from clinical trials suggest that patients with panic disorder suffer significant work and social dysfunction. The authors hypothesized that this dysfunction could be characterized using both a well-validated, generalized scale of functioning and a specifically designed scale for assessing function in psychiatric patients and that these findings would correlate with symptomatology. METHOD: Fifty-six patients with panic disorder were characterized using the Sheehan Disability Scale, the Anxiety Sensitivity Index, and the Spielberger State Trait Anxiety Scale. Measures of health related quality of life from the Quality of Well Being Scale were compared with ratings for matched, historical, and population controls. RESULTS: Patients with panic disorder lost 39 quality-adjusted days for each year that they lived with the disorder. This decrease in quality of life is similar to what is observed in patients with non-insulin dependent diabetes. Diminished quality of life is correlated with the number of panic attacks, state anxiety, and depressive symptoms. These patients also demonstrated significant dysfunction in Sheehan total disability and subscale scores, including work-related functioning. CONCLUSIONS: This study demonstrates that the specific disabilities inherent in panic disorder can be linked to declines in quality of life as measured by the Quality of Well Being Scale and by measures of work-related dysfunction. Such an association between disease specific measures and a generalized measure of health related quality of life may offer clinicians a new tool to understand panic disorder and to conceptualize it within the broader context of disease and disability.

Delineating the longitudinal structure of depressive illness: beyond clinical subtypes and duration thresholds.

Through the use of polysomnographic, epidemiologic, and prospective clinical follow-up studies, the authors document that the course of major depressive disorder (MDD) is expressed by fluctuating symptoms in which depressive subtypes included in official diagnostic systems do not represent discrete disorders, but are stages along a dimensional continuum of symptomatic severity. Depressive symptoms at the major, minor, dysthymic or otherwise sub-threshold levels are all integral components of the longitudinal clinical structure of MDD with each symptom level representing a different phase of illness intensity, activity and severity. Detailed analyses indicate that patients are symptomatic 60 % of the time, much of it at the minor, dysthymic or subthreshold level. The symptomatic phases of illness activity are interspersed sporadically with inactive phases, when patients are asymptomatic. These findings are pertinent to both clinical cohorts and community-based epidemiologic samples. Each level of depressive symptom severity is associated with significant psychosocial impairment; such impairment increases progressively with each stepwise increment in symptom severity. When patients are asymptomatic their psychosocial functioning returns to good or very good levels. Residual subthreshold symptoms in the course of MDD are associated with high risk for early episode relapse and a significantly more chronic course of illness. Asymptomatic recovery from MDD is associated with significant delays in episode relapse and recurrence and a more benign course of illness. We submit that, as in the case of chronic medical conditions, the goal of treating unipolar depressive illness should optimally be to return the patient to as asymptomatic a level as is feasible by all available therapeutic means.

A brief assessment of psychosocial functioning of subjects with bipolar I disorder: the LIFE-RIFT. Longitudinal Interval Follow-up Evaluation-Range Impaired Functioning Tool.

Those afflicted with bipolar disorder often suffer from substantial functional impairment both when in episode and when in remission. This study examined the psychometric properties of a brief assessment of psychosocial functioning, the Range of Impaired Functioning Tool (LIFE-RIFT), among subjects with bipolar I disorder. The study sample consisted of 163 subjects who presented with bipolar I disorder at intake into the NIMH Collaborative Depression Study (CDS). All LIFE-RIFT items come from the Longitudinal Interval Follow-up Evaluation (LIFE). Follow-up data that were used to examine the reliability and validity of the scale come from assessments of psychosocial functioning that were conducted 6, 12, 18, and 24 months after intake into the CDS. The results of factor analyses indicate that the scale items are measures of one construct, psychosocial functioning. The interrater agreement on the scale score was very good with an intraclass correlation coefficient was 0.94. The internal consistency reliability among the scale items was uniformly satisfactory over the four assessment periods, with coefficient alpha ranging from 0.78 to 0.84. Mixed-effect regression analyses showed that during mood episodes subjects were significantly more impaired than those in recovery. In conclusion, the psychometric properties of the LIFE-RIFT were examined in subjects with bipolar I disorder. The analyses from this longitudinal, observational study provide empirical support for the reliability and validity of the scale. The LIFE-RIFT provides a brief, inexpensive alternative to scales currently used to assess psychosocial functioning and can be easily added to semistructured assessments that are used in clinical and treatment outcome studies.

Depressive symptoms in schizophrenia.

OBJECTIVE: The authors assessed the presence and severity of depressive symptoms, as well as their associations with other clinical measures, in a group of mid- to late-life patients with schizophrenia who were not in a major depressive episode or diagnosed with schizoaffective disorder. METHOD: Sixty outpatients with schizophrenia between the ages of 45 and 79 years and 60 normal comparison subjects without major neuropsychiatric disorders, proportionally matched for age and gender, were studied. Depressive symptoms were rated primarily with the Hamilton Depression Rating Scale. Standardized instruments were also used to measure global psychopathology, positive and negative symptoms, abnormalities of movement, and global cognitive status. RESULTS: Depressive symptoms were more frequent and more severe in schizophrenic patients than in normal comparison subjects; 20% of the women with schizophrenia had a Hamilton depression scale score of 17 or more. Severity of depressive symptoms correlated with that of positive symptoms but not with age, gender, negative symptoms, extrapyramidal symptoms, or neuroleptic dose. CONCLUSIONS: Depressive symptoms are common in older patients with schizophrenia. They may be an independent, core component of the disorder or, alternatively, may be a by-product of severe psychotic symptoms.

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND: The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS: MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS: Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS: Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS: MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.

A comparison of descriptive characteristics of male outpatients and inpatients with affective disorders.

Recent studies of patients with affective disorders have found that there are biological differences between inpatients and outpatients. Concerned by these findings, we compared individuals admitted to our inpatient and outpatient affective disorders clinical research center who met criteria for major depression. We hypothesized that inpatients would be more severely ill, more suicidal, more functionally impaired, and have more co-morbid disorders and higher ratings of depression and mood state dysfunction. The demographic profiles, lifetime co-morbid Axis I diagnoses, consumption histories, symptom profiles, global assessment of functioning, and severity of current stressors (Axis IV) were compared and contrasted for the two groups. Inpatients had more severe current psychosocial stressors, lower current levels of functioning, increased lifetime co-morbid Axis I diagnoses, and increased rates of psychiatric hospitalizations, however, they did not have higher depression symptom ratings. In conclusion, inpatients and outpatients differed significantly in the severity of their stressors, coping abilities and history of previous hospitalizations, but not in most demographic variables or their current symptoms of depression.

Comorbidity as a fundamental feature of generalized anxiety disorders: results from the National Comorbidity Study (NCS).

Generalized anxiety disorder (GAD) is a relatively common mental disorder in the general population, afflicting approximately 3% of community residents during their lifetime. It is not a benign condition, since significantly increased disability and dysfunction are found in GAD subjects compared to non-GAD subjects. For decades GAD has frequently been observed in the context of other mental and substance abuse disorders. Initially the weight of clinical opinion indicated that GAD was a residual disease which should only be diagnosed when other mental disorders are not present. More recently there has been a growing recognition that comorbidity is a fundamental characteristic of the course and nature of GAD. In a series of secondary analyses conducted in subjects in the National Comorbidity Study database, we found that 8 out of 10 subjects with lifetime GAD also had a comorbid mood disorder during their lifetime. We found unipolar disorders to be four times more common in GAD than bipolar disorders (67% vs. 17%), providing indirect support for the previously reported observation that GAD and major depression may share a common genetic diathesis. In addition, our analyses support the conclusion that when comorbid mood disorders are present in GAD, a significant increase in associated disability and dysfunction is also found. Thus this comorbid relationship has important implications for clinical course and outcome.

Historical highlights of the National Institute of Mental Health from 1946 to the present.

This introduction briefly highlights NIMH's history from its inception until today. It is not meant as, nor could it be, a detailed history of NIMH but is offered primarily as a perspective by which to read the articles in this supplement. Obviously, the history of any institution is the personal history of its leadership, and contained in this special issue are the personal reminiscences of six of the eight Directors of NIMH, who review their tenures at the Institute from the perspective of the central contributions and advances made by NIMH during the time they served as Director. As such, it is an interesting and informative personalized history of one of the world's great institutions and one that has played and continues to play a central and vital role in this nation's response to its mentally ill citizens.

NIMH during the tenure of Director Lewis L. Judd, M.D. (1987-1990): the decade of the brain and the four national research plans.

My tenure at NIMH was an exhilarating, heady time of great satisfaction and achievement for all of us at the Institute. I have great affection and loyalty for NIMH, but my fondest memories are of the individuals who led and staffed the Institute's programs while I was there. One of the most gratifying aspects of my tenure was the opportunity to recruit and appoint people to new responsibilities and to interact with and support them as they grew into and beyond their positions of leadership within NIMH. When I left NIMH, I felt that the Institute's managers and staff were unparalleled in their creativity, competence, commitment, loyalty, and sheer hard work on behalf of the Institute and our field. My thanks and deep gratitude genuinely go out to the entire staff at NIMH during my tenure. However, a special debt of gratitude is owed to a group of colleagues and friends who, at my request, carried very heavy responsibilities and excelled in meeting them: Dr. Alan Leshner (Deputy Director of NIMH, now Director of NIDA); Dr. Stephen Koslow, Dr. Stephen Paul, Dr. Jack "Jay" Burke, Dr. David Segal, Dr. Ira Glick, Dr. Ellen Stover, Dr. Irene Levine, Dr. Daryl Kirsch, Dr. Rex Cowdry, Dr. Sam Keith, Dr. Delores Paron, Leroy Goldman, Richard Pine, William Fitzsimmons, Gordon Seidenberg, Lewis Steinberg, Gemma Weiblinger, George Halter, and my invaluable assistant, Margaret Shanley.

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Minor depressive disorder and subsyndromal depressive symptoms: functional impairment and response to treatment.

BACKGROUND: This study quantifies functional impairment and depressive symptomatology in patients with minor depressive disorder (MinD) and subsyndromal depressive symptomatology (SSD) before and after 8 weeks of treatment with fluvoxamine. Study patients were compared and contrasted with archival data from a sample of the general population measured by the Medical Outcome Survey Short Form 36. METHOD: Fifteen patients with MinD and 15 patients with SSD were identified from primary care clinics, referrals and newspaper advertisements. Patients signed informed consent and were offered open label treatment with fluvoxamine 25-100 mg/day. Patients were seen biweekly and measures of functional impairment and depressive symptomatology were gathered systematically. RESULTS: MinD and SSD were associated with dysfunction and disability when compared to archival normative data from the general population. Eight week treatment with fluvoxamine was associated with a substantial decrease in depressive symptomatology and a normalization of psychosocial functioning. CONCLUSION: This is the first study to quantify functional impairment and the severity of depressive symptomatology in a clinical sample of patients with MinD and SSD, and to demonstrate that treatment with a selective serotonin reuptake inhibitor decreases depressive symptomatology and improves psychosocial functioning. Placebo-controlled double-blind confirmation of these preliminary observations seems warranted.

A neuropsychological study of panic disorder: negative findings.

BACKGROUND: Gray (1982) proposed that the septo-hippocampal system, which plays an important role in learning and memory, may partially mediate anxiety. Thus, patients with anxiety disorders may manifest neurocognitive performance deficits. We hypothesized that patients with panic disorder would demonstrate learning and memory deficits relative to normal comparison subjects. METHOD: Comprehensive neuropsychological batteries were administered to 69 panic disorder subjects and 19 normal volunteers. RESULTS: There were no significant group differences in any neuropsychological performance domain including learning, memory, attention, visuospatial functioning, and psychomotor speed. Multiple regression conducted to evaluate the contribution of clinical symptoms to neuropsychological impairment within the panic disorder sample revealed that anxiety severity did not affect neuropsychological test performance. LIMITATIONS: Most patients had mild or moderate, rather than severe, panic disorder. CONCLUSION: Neuropsychological dysfunction was not associated with panic disorder.