Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.

Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients.

Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs.

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Non-Q-wave myocardial infarction following thrombolytic therapy: a comparison of outcomes in patients randomized to invasive or conservative post-infarct assessment strategies in the Veterans Affairs non-Q-wave Infarction Strategies In-Hospital (VANQWISH) Trial.

OBJECTIVES: We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non-Q-wave MI (NQMI) following thrombolytic therapy. BACKGROUND: Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome. METHODS: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia. RESULTS: During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality. CONCLUSIONS: Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Excess mortality among 3302 patients with 'pure' anxiety neurosis.

The survival probability and causes of death before the age of 70 years were analyzed among 3302 inpatients with "pure" anxiety neurosis in Stockholm County, Sweden, who were tracked in case registries by means of automated record linkage during a 14-year period. When all patients with other psychiatric diagnoses and substance abuse were excluded, and marital status controlled for, there was a significant excess of deaths due to verified and undetermined suicides, ie, nearly one third of all deaths. These unnatural deaths preempted any excess in natural causes before the age of 70 years, such as cardiovascular disease. Treatment policy with regard to the use of anxiolytic drugs was not found to influence mortality. We concluded that the risk of suicide in inpatients before the age of 70 years with anxiety disorders may be as high as that in persons with depression or other diagnoses who require inpatient care.

Affective syndromes, psychotic features, and prognosis. II. Mania.

Fifty-six patients with mania and psychotic features and 14 with schizoaffective disorder, manic type, were followed up with biannual assessments during a 5-year period. Results were treated as they were in an analogous follow-up of patients with psychotic major depression or schizoaffective disorder, depressed type. Patients with schizoaffective mania experienced more morbidity during follow-up than did patients with psychotic mania. Among patients with schizoaffective mania, those with a chronic subtype did far worse than did the others, while the mainly schizophrenic--mainly affective distinction was not predictive. When depressed and manic groups were combined (n = 173), the following baseline variables were significant independent predictors of a sustained delusional outcome: longer duration of the index episode, temporal dissociation between psychotic features and affective symptoms, and impaired adolescent friendship pattern.

Affective syndromes, psychotic features, and prognosis. I. Depression.

Prognosis is an important issue among patients who have psychotic features and a depressive syndrome; some have outcomes that suggest diagnostic revisions to schizophrenia, and this has far-reaching implications for treatment. To explore this issue, we used biannual evaluations to follow up 103 such individuals for 5 years. Patients with Research Diagnostic Criteria schizoaffective disorder experienced substantially more morbidity of various sorts than did patients with Research Diagnostic Criteria psychotic major depression. Within the group with schizoaffective disorder, patients with the chronic subtype experienced more morbidity than did those with nonchronic schizoaffective disorder; the mainly affective--mainly schizophrenic distinction had less prognostic significance. Factors that predicted sustained delusions at the end of follow-up were exclusively historical and suggested a poor-outcome prototype patient who is single, was socially impaired as an adolescent, and has a history of schizophrenialike psychotic features temporarily dissociated from affective symptoms.

Recovery in major depressive disorder: analysis with the life table and regression models.

Regression models and life tables were used to describe the phenomenon of recovery from major depressive disorder for 101 patients in a naturalistic study in which treatment was not controlled by the investigators. Time to recovery from the onset of the episode was protracted, as only about 50% of patients recovered by one year. Annual rates of recovery then declined steadily to 28% in the second year, 22% in the third year, and 18% in the fourth year. In contrast, speed of recovery from entry into the study was more rapid, and 63% of patients recovered by four months. The recovery rates were about 20% each month for the first four months and then declined sharply for the remaining months of the one-year follow-up. Several clinical variables were statistically significant predictors of recovery when measured from entry into the study: superimposition of the acute episode on a chronic underlying depression, acuteness of onset of he depression, and severity of depression for the subgroup of patients without superimposed illness.

Relapse in major depressive disorder: analysis with the life table.

With the use of life tables to describe time while patients were well and subsequent rates of relapse for 75 patients after their recovery from an episodes of major depressive disorder in naturalistic study, a high risk of relapse was detected shortly after recovery. Twenty-four percent of patients relapsed within 12 weeks at risk, and 12% of patients relapsed with four weeks at risk. The presence of an underlying chronic depression and three or more previous affective episodes predicted a statistically significant increase in the rate of relapse. These data were used to develop an exponential model of relapse probability for a subgroup of the study population.

Outcome in schizoaffective, psychotic, and nonpsychotic depression. Course during a six- to 24-month follow-up.

In the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression, six-month follow-up evaluations are available for 24 patients with schizoaffective disorder (depressed type), 56 with psychotic depression, and 274 with nonpsychotic major depression. Outcome for patients with schizoaffective depression was significantly worse than for patients with nonpsychotic depression. The psychotic depression group held an intermediate position on most outcome measures and on psychosocial measures had outcomes significantly worse than those of the nonpsychotic group. Recovery rates assumed a very similar pattern in another cohort admitted more than 40 years ago and followed up without somatic treatment. Follow-ups of 12, 18, and 24 months are available for proportions of each diagnostic group. Survival curves suggest similar outcomes in psychotic depression and nonpsychotic depression, whereas outcomes in schizoaffective depression remain disparate. These trends together with family history studies suggest that a small proportion of patients with schizoaffective disorder, depressed type, will have a long-term course consistent with schizophrenia. Moreover, these data show that outcome studies of schizoaffective disorder must control for follow-up length and the effects of psychosis per se.

Premorbid personality assessments of first onset of major depression.

This is a report on personality traits associated with the first onset of major depression in a sample of high-risk subjects. The subjects are the first-degree relatives, spouses, and their controls of patients with affective disorders. None of these subjects had any history of mental disorder as of their initial evaluation. In the subsequent six years, 29 subjects had a first onset of major depression. These first onset subjects were compared with 370 subjects who continued to be free of illness during the six-year follow-up. Personality traits were assessed at the initial evaluation (ie, before the onset of depression in subjects with first onset) by means of scales from five self-report inventories. Lower emotional strength and resiliency significantly differentiated the first onset from the never ill group; overall differences were not found on measures of interpersonal dependency or extraversion. Age was a significant predictor of first onset, both alone (younger age predicted first onsets) and in interaction with personality measures. Among younger subjects (17 to 30 years of age), personality variables did not significantly discriminate between the two comparison groups. Among older subjects (31 to 41 years of age), however, decreased emotional strength, increased interpersonal dependency, and increased thoughtfulness were associated with first onset of depression.

Stability of psychiatric diagnoses. An application to the affective disorders.

In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, data were collected on 2226 first-degree relatives of 612 probands. A second, "blind" reassessment of all relatives was attempted 6 years after the initial evaluation. We report on a final sample of 1629 relatives assessed twice using the Schedule for Affective Disorders and Schizophrenia-Lifetime version. We summarize methods for using stability of diagnosis to model the relationship between clinical covariates and the probability of being a true case. Moreover, we define an index of caseness that can be used to narrow the criteria for who is a case. Of those positive for major depressive disorder at initial evaluation, 74% were positive (on a lifetime basis) at follow-up (ie, were stable). There is a gradient: 48% of those who had three symptoms and no treatment were stable, compared with 96% of those with eight symptoms and treatment. For major depressive disorder, we found the caseness index for those with lifetime mania more severe than that of nonbipolar patients, with those who had hypomania being intermediate. A hierarchical analysis indicated that bipolar I tends to be diagnosed as schizoaffective-manic across occasions, and vice versa. This is consistent with the prior familial analyses that suggest these two diagnoses be combined into a single bipolar phenotype. The analysis for major depressive disorder indicates that caseness appears to represent quantitative, rather than qualitative, differences, with no natural cutoff to identify distinct subgroups. Finally, we discuss implications including utility in genetic analyses, estimation of incidence or prevalence allowing for diagnostic error, and examination of cohort effects.

Impact of severity and chronicity of parental affective illness on adaptive functioning and psychopathology in children.

We report on the impact of specific indexes of the severity and chronicity of parental depression, measures of familial discord, and demographic variables as predictors of impaired adaptive functioning and psychopathology in children. Seventy-two children and their mothers from 37 families were interviewed in person. At least one biological parent in each family had a depressive disorder but neither parent had a history of mania, schizophrenia, or schizoaffective disorder. Almost every measure of severity and chronicity of depression in the biological parents has a statistically significant association with currently impaired adaptation and the presence of a DSM-III-diagnosed disorder in the children, as do the measures of increased discord among married or separated parents. Depression in the mother is more strongly associated with increased psychopathology in the children than is depression in the father.

Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects.

The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospectively observed for 5 years. Twelve percent of the subjects still had not recovered by 5 years. There were decreasing rates of recovery over time. For example, 50% of the subjects recovered within the first 6 months, and then the rate of recovery declined markedly. Instantaneous probabilities of recovery reflect that the longer a patient was ill, the lower his or her chances were of recovering. For patients still depressed, the likelihood of recovery within the next month declined from 15% during the first 3 months of follow-up to 1% to 2% per month during years 3, 4, and 5 of this follow-up. The severity of current psychopathology predicted the probability of subsequent recovery. Subjects with moderately severe depressive symptoms, minor depression, or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder. Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder.

Vitamin E treatment for tardive dyskinesia. Veterans Affairs Cooperative Study #394 Study Group.

BACKGROUND: Several short-term, controlled trials have documented the efficacy of vitamin E in treating tardive dyskinesia. However, the persistent nature of the disease prompted us to perform a multicenter, longer-term trial of vitamin E. METHODS: The study was a prospective, randomized, 9-site trial of up to 2 years of treatment with d-vitamin E (1600 IU/d) vs matching placebo. One hundred fifty-eight subjects with tardive dyskinesia who were receiving neuroleptic medications were enrolled. The blinded assessments performed were clinical (Abnormal Involuntary Movements Scale, Barnes Akathisia Scale, and Modified Simpson-Angus [for Extrapyramidal Symptoms] Scale) and electromechanical assessments of movement disorders, psychiatric status (Brief Psychiatric Rating Scale), and functioning (Global Assessment of Functioning). There were no significant differences in baseline demographic characteristics or in study assessments between the group that received vitamin E and the group that received placebo. RESULTS: Vitamin E was well tolerated and subject compliance with medication was good and similar between treatment groups. One hundred seven subjects (70% of those receiving vitamin E and 66% of subjects receiving placebo) completed at least 1 year of treatment. There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, electromechanical measures of dyskinesia, or scores from the other 4 scales. CONCLUSION: This long-term, randomized trial of vitamin E vs placebo found no evidence for efficacy of vitamin E in the treatment of tardive dyskinesia.

Birth-cohort trends in rates of major depressive disorder among relatives of patients with affective disorder.

As part of the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression Clinical Study, 2,289 relatives of 523 probands with affective disorder were interviewed with the Schedule for Affective Disorders and Schizophrenia and diagnosed for major depressive disorder by the Research Diagnostic Criteria. Data were analyzed using life-table and survival methods. The findings suggest a progressive increase in rates of depression in successive birth cohorts through the 20th century and an earlier age at onset of depression in each birth cohort. A predominance of female depressives was found in all birth cohorts but the magnitude of female-male differences fluctuated over the decades. The existence of these trends is reported to stimulate further research. These findings are discussed in terms of possible gene-environment interactions. However, no conclusive causal inferences can be drawn pending further investigation.

Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence.

In 1988, the MacArthur Foundation Research Network on the Psychobiology of Depression convened a task force to examine the ways in which change points in the course of depressive illness had been described and the extent to which inconsistency in these descriptions might be impeding research on this disorder. We found considerable inconsistency across and even within research reports and concluded that research on depressive illness would be well served by greater consistency in the definition change points in the course of illness. We propose an internally consistent, empirically defined conceptual scheme for the terms remission, recovery, relapse, and recurrence. In addition, we propose tentative operational criteria for each term. Finally, we discuss ways to assess the usefulness of such operational criteria through reanalysis of existing data and the design and conduct of new experiments.

Subsyndromal symptoms in bipolar disorder. A comparison of standard and low serum levels of lithium.

Ninety-four patients with bipolar disorder participating in a random-assignment, double-blind, prospective maintenance trial of standard- (0.8 to 1.0 mmol/L) vs low-range (0.4 to 0.6 mmol/L) serum lithium levels were assessed to determine the presence and significance of subsyndromal symptoms during periods of remission and recovery. A significant relationship was found between prescribed serum lithium level and the probability of major affective relapse and the occurrence of subsyndromal symptoms. Patients given lithium carbonate to achieve low-range levels had 2.6 times the risk of major affective relapse as those given lithium for standard-range levels and nearly twice the risk of developing subsyndromal symptoms. Patients given the low-range therapy showed a greater variance in weekly Psychiatric Status Rating measures, and their symptoms were more likely to worsen at any time than were symptoms in their standard-level group counterparts. The first occurrence of subsyndromal symptoms increased the risk of major affective relapse fourfold. Following the onset of subsyndromal symptoms, the patients originally randomized to receive standard-range lithium therapy were still better protected from relapse than were patients randomized to receive low-range lithium treatment. Patients were two times more likely to develop depressive than hypomanic symptoms between acute episodes of illness. However, onset of hypomanic symptoms predicted subsequent major affective relapse twice as strongly as did depressive symptoms. Seventy-six percent of patients who became hypomanic had a major affective relapse, compared with 39% of patients who were subclinically depressed.

Low levels and lack of predictors of somatotherapy and psychotherapy received by depressed patients.

We examined the treatment of 338 patients with nonbipolar major depressive disorders during the first eight weeks after entry into the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression: Clinical Study. Of the 250 entered as inpatients, 31% received either no antidepressant somatotherapy or very low or unsustained levels, and only 49% received at least 200 mg of imipramine hydrochloride (or its equivalent) for four consecutive weeks. Of these patients, 19% received less than 30 minutes of psychotherapy per week. Among the 88 who entered as outpatients, 29% received no antidepressant somatotherapy; another 24% received very low or unsustained levels; only 19% received at least 200 mg of imipramine hydrochloride or its equivalent for four consecutive weeks. Of these patients, 52% received less than 30 minutes of psychotherapy per week. Only a few clinical factors were found to be predictive of treatment intensity. Very large differences in the amount and type of treatment across the five collaborating university centers do not appear to be related to differences in patient characteristics.