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Objective: Individuals with chronic depression exhibit heterogeneous responses to treatment. Important individual differences may therefore exist within this particularly difficult to treat population that act as moderators of treatment response., Method: The present study examined whether pretreatment levels of dysfunctional attitudes (DA) moderated treatment response in a large sample of chronically depressed individuals. Data were taken from the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) treatment study--a multi-site treatment and augmentation study of 808 chronically depressed individuals. REVAMP comprised two phases: 1) a 12-week open-label antidepressant trial and 2), a subsequent phase, in which phase 1 non-remitters (N = 491) were randomized to either receive an ongoing medication algorithm alone, medication plus cognitive behavioral analysis system of psychotherapy, or medication plus brief supportive psychotherapy., Result: In phase 1, compared to the pharmacotherapy response of patients with lower DA scores, the response for patients with higher DA scores was steeper, but leveled off toward the end of the phase. In phase 2, DA predicted a differential response in the medication only arm, but not in the two psychotherapy + medication conditions. Specifically, in the phase 2 medication only condition, patients with higher DA improved while those with lower DA scores did not., Conclusion: These results indicate that the relation between DA and treatment response in chronic depression is complex, but suggest that greater DA may be associated with a steeper reduction and/or better response to pharmacotherapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In contrast to "remission" from an episode of major depressive disorder (MDD), for which there is general agreement in the literature, the optimal definition of "recovery" from MDD is uncertain. Previous definitions of recovery have used inconsistent thresholds for symptom severity and duration of wellness. To address the effects of duration and degree of recovery from an episode of MDD on recurrence risk, and the impact of maintenance antidepressant treatment on recurrence, we analyzed 258 patients from a randomized, double-blind study of outpatients with recurrent MDD. All patients had responded to 8½ months of venlafaxine extended release and were subsequently randomized to receive venlafaxine ER or placebo during 2 consecutive 12-month maintenance phases. Four definitions of recovery were used to evaluate recovery rates and time to recurrence: (1) 17-item Hamilton Depression Rating Scale (HAM-D(17)) total score ≤3 with duration ≥120 days; (2) HAM-D(17) ≤3 with duration ≥56 days; (3) HAM-D(17) ≤7 with duration ≥120 days; and (4) HAM-D(17) ≤7 with duration ≥56 days. Recovery definitions using lower symptom severity and longer duration thresholds produced lower rates of recurrence. Patients on placebo were more likely to have a recurrence than patients on venlafaxine ER, with hazard ratio (HR) ranging from 2.5 among patients who recovered by the most relaxed criteria (definition 4), to 5.3 among patients who recovered by the most stringent criteria (definition 1). We conclude that protection against recurrence derives from the degree and duration of recovery, particularly for patients maintained on antidepressant medication., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Patients (30-50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication., Method: Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5-3mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of < or =10 on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire., Results: Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR=3.33, p=.011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS< or =10) compared to 24% of the placebo augmentation group (CMH(1)=6.48, p=.011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone., Conclusion: Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.

Depression and sleep researchers typically assess insomnia severity differently. Whereas depression researchers usually assess insomnia with items on depression symptom inventories, sleep researchers usually assess the subjective experience of insomnia with sleep diaries. The present manuscript utilizes baseline data from 397 participants in a large multi-site chronic depression study to assess agreement between these two methodologies. The results indicate that the early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD(24)) and the Inventory of Depression Symptoms - Self Report (IDS-SR(30)) are highly correlated with the weekly mean values of time to sleep onset, time awake after sleep onset, and time awake prior to the planned wake-up obtained from prospective sleep diaries. Results also reveal significant correspondence between the weekly-mean of daily sleep efficiency, an accepted measure of sleep continuity (the ratio between reported time asleep and time in bed), and the insomnia scale scores of the HRSD(24) and the IDS-SR(30) (the mean score on the three insomnia items of each depression measure). Unit increments in HRSD(24) scores for early, middle and late insomnia were associated with significant increases in unwanted minutes awake for corresponding periods on sleep diaries. Similar relationships were found for early insomnia on the IDS-SR(30) but not for middle and late insomnia. Overall, with few exceptions, findings revealed substantial agreement between the HRSD(24), IDS-SR(30) and prospective sleep diary data. The study supports the validity of the sleep items and sleep subscales of the HRSD(24) and the IDS-SR(30) as global measures of insomnia severity in depression. Conventional sleep assessment procedures can complement depression scales by providing additional information about specific aspects of sleep in depression.

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.

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one month's duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

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.

1. Panic disorder (PD) is an illness that can be acute or chronic and is often complicated by depression, phobias and obsessions. This illness affects at least 10% of the population. 2. Panic disorder has been recognized as a psychopathologic condition for at least 100 years. Over the last several decades, health professionals have changed their view of PD, and in 1987 the DSM-III included PD as a distinctive syndrome. 3. Several studies have shown PD to be a chronic illness with only little to no improvement in 36-40% of the subjects after 1 to 20 years of treatment. Studies also suggest that duration of illness affects the degree of impairment: subjects who had PD for more than 6 months showed more impairment that subjects who had PD for less than 6 months. 4. Several studies show that 50-75% of patients with PD have had at least one episode of major depression. Findings also indicate that subjects with both PD and secondary depression are a more severely ill group. 5. The HARP study is an ongoing 12-site naturalistic, longitudinal examination of patients with current or past PD. One of the major goals of this study is to describe the patterns of the clinical course of PD related disorders. 6. Clinical experience indicates that an estimated 40% of PD patients may need treatment for one year and between 20-40% will require continued maintenance treatment. Long-term treatment may include behavioral therapy and/or medication. 7. Anxiety disorders are common and familial and are consistently higher among women. Panic Disorder is a chronic condition frequently complicated by Axis I and II disorders. Continued long-term maintenance studies of medications and psychotherapy for anxiety disorders is critical in the treatment of this chronic illness.

Seven percent (19 of 275) of children and adolescents not ascertained for seeking treatment received a DSM-III diagnosis of alcohol or drug use disorder. Their entire families were recruited into a research program designed to study the risk to offspring of parental psychopathology. The ages of those diagnosed were between 12 and 18 years. The drug and alcohol use disorders had a mean duration of 2 years, and the adolescents who remitted had a high likelihood of developing subsequent psychopathology. These adolescents also showed high rates of other psychiatric disorders. A high rate of alcoholism was found among their parents.

Expressed emotion (EE) refers to a set of emotional aspects of speech for which ratings have been derived. Seven independent studies have established that higher EE ratings in the relatives of patients with schizophrenia predict higher rates of relapse in these patients and two studies have established an association of higher EE in spouses with relapse of depression in their mate. There are no previous studies of parental EE as a predictor of childhood affective disorder or other disorders not in the schizophrenia spectrum. In this study we investigated the relationship between the level of maternal EE and the incidence of DSM-III affective disorder (major depression or mania or dysthymia), substance abuse, or conduct disorder in 273 children. We found that a higher degree of maternal expressed emotion was associated with a three-fold increase in a child's risk (odds multiplier) for having at least one of the following diagnoses: depressive disorder (major depression or dysthymia), substance abuse, or conduct disorder. This increased risk acts in addition to the increased risk of child diagnosis associated with parental affective illness. Research and clinical implications are discussed.

In this study we assess the reliability of rating past psychiatric symptoms and lifetime diagnoses in a currently ill population using the SADS and RDC. Five raters from different centers interviewed 25 subjects in a short-interval test-retest design. Subjects had a wide diversity of affective and non-affective diagnoses and high levels of manifest psychopathology. Our results demonstrate that it is possible for raters from different research centers to reliably rate lifetime diagnoses and previous symptoms. Two important exceptions to the high reliability are the lifetime diagnoses of hypomania and the recurrent unipolar subtype of major depressive disorder, and we alert clinicians and researchers to be cautious when diagnosing these conditions. We conclude that the next step in measuring reliability should be a long-interval test-retest design with separate interviews conducted at the later assessment, one by the original rater and the other by a blind rater.

Analyses of data from the NIMH-CRB Collaborative Depression Study on age at onset of Major Depressive Disorder (MDD) in 1144 directly interviewed siblings of patients with major affective disorder show a strong secular trend toward increased lifetime risk and earlier onset in successive cohorts of birth since 1930. The proportionate increases in the instantaneous probabilities (hazard) of onset of MDD for each one year difference in year of birth were 5% for brothers and 7% for sisters. Age-period-cohort analysis suggests a powerful period effect may be responsible for this secular trend in rates of MDD, with rates of onset for siblings between 15 and 50 years of age doubling between the 1960s and 1970s. Possible artifacts are investigated.

No statistically significant associations were found between ABO blood group distributions and RDC subtype diagnoses in 79 subjects with unipolar (single episode and recurrent) and bipolar major depressive disorder using data from our sample. We discuss methodological issues related to the control samples and choice of statistical methods in the reported studies which have looked for associations between ABO blood types and patients diagnosed as having an affective disorder. After presenting our rationale for employing the logarithm of the cross product ratio (lambda) in place of the more traditionally utilized chi-squared, we used lambda to reanalyze the original data from nine studies in the literature. The individual studies are equivocal on the basic issue of an association between type O blood and bipolar I illness, either compared to controls or to recurrent unipolar patients. The combined (weighted average) measure of association indicates a small but definite association, but statistical analysis of the dispersion of the individual estimates around this combined estimate reveals that the studies have a higher degree of heterogeneity in results than expected by chance. The consequences of this finding are discussed, and possible explanations are offered.

Using survival methods the authors review and reanalyze nine published reports on relapse after recovery from depression. Despite wide disagreement over cross-sectional rates of relapse, the reanalysis reveals a common finding that the hazard of relapse declines steadily for the first three years after recovery. Methodological and design issues are discussed and summarized for the 40 naturalistic studies that report on longitudinal outcome after recovery from depression. The principles and techniques of survival methods are briefly introduced in an Appendix.

In a test-retest reliability study involving 25 psychiatric patients and 5 professional raters we demonstrate that research clinicians from collaborating institutions are able to achieve good reliability for most areas of the SADS and RDC when assessing psychiatrically ill patients under interview conditions that provide even less data than ideally obtained in the practice of clinical research. We expect greater reliability in the actual use of the SADS/RDC on most items and diagnoses since the SADS is intended to be used in conjunction with information obtained from relatives, friends, and treatment staff to confirm and clarify the judgements made by the raters on the patient interviews. Moreover, we are reassured that the diagnosis of schizo-affective disorders and schizophrenia is protected from the item unreliability found with specific delusions and hallucinations. Similarly, the difficulties in determining the episodic and chronic nature of the present episode does not substantially interfere with making an RDC diagnosis of the current condition. A complex diagnostic interview system such as the SADS and RDC requires multiple complementary techniques to determine reliability. We find that establishing explicit procedures for raters to discuss and categorize the reasons for their disagreements on individual items and diagnoses provides valuable data for understanding reliability problems. This has helped us to identify specific areas of the interview and criteria that require further clarification and more intensive rater training to improve ratings made by interviewers.

Analysis of family history and family study diagnoses of major affective disorder in 4806 relatives of affectively ill probands from the NIMH Collaborative Study of the Psychobiology of Depression (Clinical) suggests that rates of disorder in uninterviewed relatives are greatly underestimated by family history. The implications of these underestimates for family and genetics analyses using the family history method are discussed, and other estimates are developed that have better statistical properties. Using the Model Based Direct Adjustment method, the rate of major affective disorder in all relatives (interviewed and uninterviewed) is estimated to be 32%, compared to 25% by the consensus (standard) method, which uses the Family History-RDC interview with one or more family members to make diagnoses on all uninterviewed relatives. This difference (over ten standard errors) is due to the much higher rate of illness estimated for the uninterviewed relatives (28% compared to 14%). Analysis of the sources of insensitivity of the FH-RDC is used to explain the difference between observed and imputed diagnosis rates.