Self-reported sleep disturbance as a prodromal symptom in recurrent depression.
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Adult↗
Biomedical subjects
D J Kupfer
Publications and source records attributed to D J Kupfer.
Contributions of risk-factor research to developmental psychopathology.
Risk-factor research refers to the study of antecedent conditions and subsequent outcomes and the ways in which these are interrelated. The research encompasses a broad range of questions and research strategies. The paper discusses the characteristics and contributions of risk-factor research in the context of developmental psychopathology. The ways in which causal paths are conceptualized, the capacity to integrate multiple influences, and applications that can be derived from the findings are discussed. The progression of research is illustrated in relation to key concepts (correlate, risk factor, marker, causal risk factor) that reflect varied levels of understanding antecedent-outcome relations. The identification of causal relations, progressions, and paths over the course of development and the interplay of theory, research, and application are illustrated and discussed.
Adolescent↗
Low rate of membrane lithium transport during treatment correlates with outcome of maintenance pharmacotherapy in bipolar disorder.
Lithium is transported across cell membranes by an exchange diffusion process (Na(+)-Li+ countertransport) that is inhibited during lithium treatment. We hypothesized that low rates of lithium efflux (a potential manifestation of strong transport inhibition) would be associated with better clinical outcome of maintenance pharmacotherapy. We measured the erythrocyte (RBC) apparent rate constant for lithium efflux (kexch) in 22 patients with bipolar disorder who had been euthymic on lithium for 1 month. Subsequently, clinical mood ratings and in vivo RBC: plasma lithium ratios (LiR) were determined monthly. Outcome was categorized according to whether subjects completed 1 year of successful maintenance treatment (n = 10), experienced a recurrent affective episode (n = 8), or dropped out (n = 4). The kexch at the outset of the study was significantly lower (potentially because of greater transport inhibition) in 1-year completers than in patients with recurrences or those who dropped out (median kexch = 0.09, 0.24, and 0.27 h-1, respectively; P < .03). Moreover, 77% of patients with a kexch of 0.11 h-1 or lower were successfully maintained on lithium for 1 year, whereas only 23% of those with a kexch greater than or equal to 0.12 h-1 had a successful treatment outcome. LiR measured during the course of maintenance treatment was significantly higher (suggesting greater transport inhibition) in 1-year completers than in noncompleters (recurrences and dropouts). Measurement of kexch at an early point in treatment may provide a means for prospectively identifying those bipolar patients at greater risk for failure of maintenance lithium therapy.
Adult↗
Power spectral analysis of EEG in a multiple-bedroom, multiple-polygraph sleep laboratory.
OBJECTIVES: We describe the methods for power spectral analysis (PSA) of sleep electroencephalogram (EEG) data at a large clinical and research sleep laboratory. The multiple-bedroom, multiple-polygraph design of the sleep laboratory poses unique challenges for the quantitative analysis of the data. This paper focuses on the steps taken to ensure that our PSA results are not biased by the particular bedroom or polygraph from which the data were acquired. METHODS: After describing the data acquisition system hardware, we present our signal amplitude calibration procedure and our methods for performing PSA. We validate the amplitude calibration procedure in several experiments using PSA to establish tolerances for data acquisition from multiple bedrooms and polygraphs. RESULTS: Since it is not possible to acquire identical digitized versions of an EEG signal using different sets of equipment, the best that can be achieved is data acquisition that is polygraph-independent within a known tolerance. We are able to demonstrate a tolerance in signal amplitude of +/- 0.25% when digitizing data from different bedrooms. When different data acquisition hardware is used, the power tolerance is approximately +/- 3% for frequencies from 1 to 35 Hz. The power tolerance is between +/- 3 and +/- 7% for frequencies below 1 Hz and frequencies between 35 and 50 Hz. Additional data demonstrate that variability due to the hardware system is small relative to the inherent variability of the sleep EEG. CONCLUSION: The PSA results obtained in one location can be replicated elsewhere (subject to known tolerances) only if the data acquisition system and PSA method are adequately specified.
Calibration↗
Circadian rhythms in human performance and mood under constant conditions.
UNLABELLED: This study explored the relationship between circadian performance rhythms and rhythms in rectal temperature, plasma cortisol, plasma melatonin, subjective alertness and well-being. Seventeen healthy young adults were studied under 36 h of 'unmasking' conditions (constant wakeful bedrest, temporal isolation, homogenized 'meals') during which rectal temperatures were measured every minute, and plasma cortisol and plasma melatonin measured every 20 min. Hourly subjective ratings of global vigour (alertness) and affect (well-being) were obtained followed by one of two performance batteries. On odd-numbered hours performance (speed and accuracy) of serial search, verbal reasoning and manual dexterity tasks was assessed. On even-numbered hours, performance (% hits, response speed) was measured at a 25-30 min visual vigilance task. Performance of all tasks (except search accuracy) showed a significant time of day variation usually with a nocturnal trough close to the trough in rectal temperature. Performance rhythms appeared not to reliably differ with working memory load. Within subjects, predominantly positive correlations emerged between good performance and higher temperatures and better subjective alertness; predominantly negative correlations between good performance and higher plasma levels of cortisol and melatonin. Temperature and cortisol rhythms correlated with slightly more performance measures (5/7) than did melatonin rhythms (4/7). Global vigour correlated about as well with performance (5/7) as did temperature, and considerably better than global affect (1/7). IN CONCLUSION: (1) between-task heterogeneity in circadian performance rhythms appeared to be absent when the sleep/wake cycle was suspended; (2) temperature (positively), cortisol and melatonin (negatively) appeared equally good as circadian correlates of performance, and (3) subjective alertness correlated with performance rhythms as well as (but not better than) body temperature, suggesting that performance rhythms were not directly mediated by rhythms in subjective alertness.
Adult↗
Slow-wave sleep: do young adult men and women age differently?
The differential effects of ageing on polysomnographic and EEG spectral characteristics of sleep were explored in men and women between the ages of 20 and 40. Men and women in their twenties were found to have similar percentages of slow-wave sleep (SWS) (% Stage 3 and 4) and mean EEG slow wave activity (quantified by spectral analysis). Significant reductions in the percentage of SWS and mean slow wave activity over the night occurred in men during their thirties but not in the women. This suggests that gender difference in SWS may emerge between age 30 and 40 in young adults. Men in this sample were also found to have significant increases in Stage 2 sleep, and decreases in REM sleep time, REM activity, REM density and REM intensity. No significant effects of age were found for women in any visually scored sleep variables. Both men and women had age related reductions in spectral power in the spindle frequencies. Taken together, these findings suggest that the sleep of men and women over age 20-40 may age differently.
Adult↗
Genetic segregation analysis of early-onset recurrent unipolar depression.
Major depression is a relatively common psychiatric disorder that can be quite debilitating. Family, twin, and adoption studies indicate that unipolar depression has both genetic and environmental components. Early age at onset and recurrent episodes in the proband each increase the familiarity of the illness. To investigate the potential genetic underpinnings of the disease, we have performed a complex segregation analysis on 832 individuals from 50 multigenerational families ascertained through a proband with early-onset recurrent unipolar major depression. The analysis was conducted by use of regressive models, to test a variety of hypotheses to explain the familial aggregation of recurrent unipolar depression. Analyses were conducted under two alternative definitions of affection status for the relatives of probands: (1) "narrow," in which relatives were assumed to be affected only if they were diagnosed with recurrent unipolar depression; and (2) "broad," in which relatives were assumed to be affected if diagnosed with any major affective illness. Under the narrow-definition assumption, the model that best explains these family data is a transmitted (although non-Mendelian) recessive major effect with significant residual parental effects on affection status. Under the broad-definition assumption, the best-fitting model is a Mendelian codominant major locus with significant residual parental and spousal effects.
Adolescent↗
The effects on human sleep and circadian rhythms of 17 days of continuous bedrest in the absence of daylight.
As part of a larger bedrest study involving various life science experiments, a study was conducted on the effects of 17 days of continuous bedrest and elimination of daylight on circadian rectal temperature rhythms, mood, alertness, and sleep (objective and diary) in eight healthy middle-aged men. Sleep was timed from 2300 to 0700 hours throughout. Three 72-hour measurement blocks were compared: ambulatory prebedrest, early bedrest (days 5-7), and late bedrest (days 15-17). Temperature rhythms showed reduced amplitude and later phases resulting from the bedrest conditions. This was associated with longer nocturnal sleep onset latencies and poorer subjectively rated sleep but with no reliable changes in any of the other sleep parameters. Daily changes in posture and/or exposure to daylight appear to be important determinants of a properly entrained circadian system.
Adult↗
Longitudinal changes in diary- and laboratory-based sleep measures in healthy "old old" and "young old" subjects: a three-year follow-up.
We report a longitudinal study of diary- and laboratory-based sleep measures in 50 healthy elderly subjects followed prospectively over a 3-year interval. Our hypothesis was that "old old" subjects (aged 75 to 87; n = 27) would show decline over time in measures of sleep quality, continuity, and depth, whereas "young old" subjects (aged 61 to 74; n = 23) were expected to show stability of outcome measures. Using analysis of variance-based planned contrast procedures, we found that this hypothesis was strongly supported for subjective sleep quality and laboratory measures of sleep latency, sleep efficiency, wakefulness after sleep onset, and slow-wave sleep percent. These changes were accompanied by increased napping in the old old. However, there was no change of habitual time in bed (total time or temporal placement of nighttime sleep), daily social rhythms, or sleep apnea. Change in medical burden scores did not correlate significantly with change in sleep efficiency or other outcome variables in the old old. Intervention designed to slow age-dependent decreases in sleep quality, continuity, and depth is discussed. The current results are representative of healthy elderly; sleep would probably deteriorate earlier and more quickly in elderly with more serious health problems and heavier medication use.
Aged↗
Effects of diagnosis on treatment recommendations in chronic insomnia--a report from the APA/NIMH DSM-IV field trial.
The objective of this study was to determine whether sleep specialists and nonspecialists recommend different treatments for different insomnia diagnoses according to two different diagnostic classifications. Two hundred sixteen patients with chronic insomnia at five sites were each interviewed by two clinicians: one sleep specialist and one nonsleep specialist. All interviewers indicated diagnoses using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV); sleep specialists also indicated diagnoses according to the International Classification for Sleep Disorders (ICSD). Interviewers then indicated how strongly they would recommend each item in a standard list of treatment and diagnostic interventions for each patient. We examined differences in treatment recommendations among the six most common DSM-IV diagnoses assigned by sleep specialists at different sites (n = 192), among the six most common ICSD diagnoses assigned by sleep specialists at different sites (n = 153), and among the six most common DSM-IV diagnoses assigned by nonspecialists at different sites (n = 186). In each analysis, specific treatment and polysomnography recommendations differed significantly for different diagnoses, using either DSM-IV or ICSD criteria. Conversely, different diagnoses were associated with different rank orderings of specific treatment and diagnostic recommendations. Sleep specialist and nonspecialist interviewers each distinguished treatment recommendations among different diagnoses, but in general, nonspecialists more strongly recommended medications and relaxation treatments. Significant site-related differences in treatment recommendations also emerged. Differences in treatment recommendations support the distinction between different DSM-IV and ICSD diagnoses, although they do not provide formal validation. Site-related differences suggest a lack of consensus in how these disorders are conceptualized and treated.
Adolescent↗
Sleep and morningness-eveningness in the 'middle' years of life (20-59 y).
The following four issues were assessed in a group of 110 adults between the age of 20 and 59y: (1) the effect of age (regarded as a continuous variable) on polysomnographic sleep characteristics, habitual sleep-diary patterns, and subjective sleep quality; (2) the effects of age on morningness-eveningness; (3) the effects of morningness-eveningness on sleep, after controlling for the effects of age; and (4) the role of morningness-eveningness as a mediator of the age and sleep relationship. Increasing age was related to earlier habitual waketime, earlier bedtime, less time in bed and better mood and alertness at waketime. In the laboratory, increasing age was associated with less time asleep, increased number of awakenings, decreased sleep efficiency, lower percentages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, higher percentages of Stage 1 and 2, shorter REM latency and reduced REM activity and density. Increasing age was also associated with higher morningness scores. After controlling for the effects of age, morningness was associated with earlier waketime, earlier bedtime, less time in bed, better alertness at waketime, less time spent asleep, more wake in the last 2 h of sleep, decreased REM activity, less stage REM (min and percentage), more Stage 1 (min and percentage) and fewer minutes of Stage 2. For one set of variables (night time in bed, waketime, total sleep time, wake in the last 2 h of sleep and minutes of REM and REM activity), morningness-eveningness accounted for about half of the relationship between age and sleep. For another set of variables (bedtime, alertness at waketime, percentages of REM and Stage 1), morningness-eveningness accounted for the entire relationship between age and sleep. In conclusion, age and morningness were both important predictors of the habitual sleep patterns and polysomnographic sleep characteristics of people in the middle years of life (20-59 y).
Adult↗
Clinical factors contributing to the differential diagnosis of primary insomnia and insomnia related to mental disorders.
OBJECTIVE: Primary insomnia and insomnia related to mental disorders are the two most common DSM-IV insomnia diagnoses, but distinguishing between them is difficult in clinical practice. This analysis was performed to identify clinical factors used by sleep specialists to distinguish primary insomnia from insomnia related to mental disorders. METHOD: Clinicians evaluated 216 patients referred for insomnia at five clinical sites, rated a list of clinical factors judged to contribute to each patient's presentation, and assigned diagnoses. Analysis of variance was performed, with contributing factors as the dependent variable and diagnostic group and clinic location as independent variables. RESULTS: Sleep specialists rated a psychiatric disorder as a stronger factor for insomnia related to mental disorders and rated negative conditioning and sleep hygiene as stronger factors for primary insomnia. However, a psychiatric disorder was rated as a contributing factor for 77% of patients who received a first diagnosis of primary insomnia. CONCLUSIONS: While neither sleep hygiene nor negative conditioning is a diagnostic criterion in DSM-IV, these results support the face validity of these clinical factors distinguishing between primary insomnia and insomnia related to mental disorders. The use of a psychiatric disorder as an inclusion criterion for insomnia related to mental disorders and an exclusion criterion for primary insomnia reinforces a categorical distinction between the two diagnoses, but the contribution of psychiatric symptoms in primary insomnia appears to be a clinically relevant one. These findings suggest the need for studies on the validity of negative conditioning and sleep hygiene in the etiology of primary insomnia, as well as on the significance of psychiatric disorders, especially depression, in primary insomnia.
Adolescent↗
Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles.
OBJECTIVE: The authors tested the hypothesis that patients whose episodes of major depression evidenced more neurobiological disturbance would be less responsive to psychotherapy. METHOD: The study subjects were outpatients who were given a diagnosis of recurrent major depressive disorder (unipolar or bipolar II), according to the Research Diagnostic Criteria, following an interview with the Schedule for Affective Disorders and Schizophrenia. They were classified into a group with normal sleep profiles (N = 50) and a group with abnormal sleep profiles (N = 41) on the basis of a validated index score derived from three EEG sleep variables monitored for 2 nights: sleep efficiency, REM latency, and REM density. The groups' responses to short-term interpersonal psychotherapy were compared by means of chi-square tests and life table and random effects model analyses. Responses to the addition of pharmacotherapy for subjects who did not respond to interpersonal psychotherapy were also compared. RESULTS: The patients with abnormal sleep profiles had significantly poorer clinical outcomes with respect to symptom ratings, attrition rates, and remission rates than the patients with more normal sleep profiles. Seventy-five percent of the patients who did not respond to interpersonal psychotherapy had remissions during subsequent pharmacotherapy. CONCLUSIONS: These findings help to define further a neurobiological "boundary" that may limit response to psychotherapy in depression. An abnormal sleep profile may reflect a more marked disturbance of CNS arousal that warrants pharmacotherapy.
Adult↗
Which elderly patients with remitted depression remain well with continued interpersonal psychotherapy after discontinuation of antidepressant medication?
OBJECTIVE: This study was conducted to identify which elderly patients with remitted recurrent major depression remain well with maintenance interpersonal psychotherapy after discontinuation of active antidepressant medication (nortriptyline). METHOD: The authors examined outcomes of maintenance therapy over 1 year for 47 elderly patients who were randomly assigned to monthly maintenance interpersonal psychotherapy with placebo (N = 19) or to placebo and a supportive medication clinic without interpersonal psychotherapy (N = 28). A Kaplan-Meier survival analysis was performed on the basis of treatment assignment and subjective sleep quality assessed by the Pittsburgh Sleep Quality Index, on which good subjective sleep quality is indicated by a score of 5 or lower. RESULTS: Nine (90%) of 10 patients reporting good subjective sleep quality (by 1 month into continuation treatment) remained well for at least 1 year when treated with monthly maintenance interpersonal psychotherapy, versus five (31%) of 16 patients with good sleep quality assigned to a medication clinic, three (33%) of nine patients with impaired sleep quality treated with maintenance interpersonal psychotherapy, and two (17%) of 12 patients with impaired sleep quality assigned to a medication clinic. CONCLUSIONS: Recovery of good subjective sleep quality by early continuation treatment is useful in identifying which remitted elderly depressed patients will remain well with monthly maintenance interpersonal psychotherapy, following discontinuation of antidepressant medication, and which patients may be more vulnerable to recurrence of major depressive episodes in the absence of antidepressant medication.
Amitriptyline↗
Differences over the life span in daily life-style regularity.
A diary-based instrument-the Social Rhythm Metric (SRM)-was used to assess the level of stability of daily social and behavioral rhythms in a group of 239 healthy subjects (112 male, 127 female) ranging in age from 20 to 89 years. Each subject completed the instrument for two consecutive weeks, which were averaged to yield one measure (SRM score) of life-style regularity [range 0 (least regular) to 7 (most regular)] and another of activity level index (ALI), corresponding to the number of (diary listed) activities done per week (max. = 119). SRM score increased reliably with age group at an average rate of 0.018 units per year. ALI showed an "inverted U"-shaped function with a maximum at about 50 years. SRM changes appeared not to be related to demographic differences between the age groups, although ALI differences may have been so related. No main effects or interactions were found with gender. Life-style regularity appears to increase over the life span in response to both biological and psychosocial changes and may represent an adaptation to age-related changes in the circadian system's sensitivity to entraining agents. Regular behavioral rhythms may be conducive to continued good health and well-being.
Activities of Daily Living↗
Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy?
BACKGROUND: This analysis sought to determine whether lorazepam influences time to response or rate of response in elderly depressed patients receiving nortriptyline and psychotherapy and to examine clinical and polysomnographic correlates of lorazepam treatment. METHOD: Patients with recurrent major depressive disorder (N = 119; mean +/- SD age = 68.0 +/- 6.1 years; diagnosis defined by Research Diagnostic Criteria) received acute treatment with nortriptyline and interpersonal psychotherapy. Thirty-five patients received open-label adjunctive lorazepam for anxiety or insomnia symptoms (LZ+) and 84 did not. Statistical analyses were conducted between the LZ+ group and a group of 35 patients who received no lorazepam (LZ-) and were matched for anxiety level. Patients had polysomnographic studies prior to treatment and after remission of depressive symptoms. RESULTS: The LZ+ group reported more anxiety on the Brief Symptom Inventory (p = .04) compared with the remaining 84 patients. The LZ+ group had a greater proportion of endogenous depression subtype than the anxiety-matched LZ- group, in addition to more abnormal EEG sleep (higher percentage of REM sleep, shorter REM latency, lower delta sleep ratio). Mean time to initial antidepressant response was no different between groups. However, a significantly greater proportion of LZ+ than LZ- patients responded to acute treatment (91.4% vs. 71.4%; p < .03). CONCLUSION: Adjunctive lorazepam does not slow the antidepressant response to combined antidepressant/psychotherapy treatment in elderly depressed patients, and it is associated with a greater likelihood of antidepressant response. A greater percentage of patients treated with lorazepam have endogenous depression subtype and abnormal sleep findings (EEG) than those who are not treated with lorazepam. Adjunctive lorazepam is useful for treating anxiety in elderly depressed patients.
Age Factors↗
Bipolar depression: an underestimated treatment challenge.
We sought to determine whether depressive and mixed/cycling episodes were as responsive to standardized pharmacotherapeutic interventions as were manic episodes in bipolar 1 patients. As part of the Maintenance Therapies in Bipolar Disorder (MH29618, E. Frank, PI) study, forty-two acutely ill bipolar 1 patients who had been randomly assigned to one of two preliminary phase non-pharmacologic treatment strategies (interpersonal and social rhythm therapy [IPSRT] or a standard medication clinic approach) were treated according to a standardized pharmacotherapeutic protocol. Symptom severity was measured weekly with the Hamilton Depression Rating Scale and the Bech-Rafaelsen Mania Scale in order to assess symptomatic remission. Survival analysis with the proportional hazards model was performed on time to remission. Manic patients were significantly more likely to achieve clinical remission than the depressed patients (100 vs. 59%) and did so significantly more rapidly. The difference in proportion remitting and time to remission between the depressed and mixed/cycling groups was not statistically significant. No significant effect for non-pharmacologic treatment assignment was found. These results point to the need to develop more effective treatments for bipolar depression. They also suggest that psychotherapy has a limited impact in the acute phase treatment of bipolar episodes.
Adult↗
Generalized covariance-adjusted discriminants: perspective and application.
When discriminant analysis is used in practice for assessing the usefulness of diagnostic markers, the lack of control over covariates motivates the need for their adjustment in the analysis. This necessity for adjustment arises especially when the researcher's aim is classification based on a set of diagnostic markers and is not based on a set of covariates for which there exists known heterogeneity among the subjects with respect to the groups under consideration. The traditional covariance-adjusted approach is restrictive for such applications in that they assume linear covariates and a normal distribution for the the feature vector. Further, there is no available method for variable selection in using such covariance-adjusted models. In this paper, we generalize the traditional covariance-adjusted model to a general normal and logistic model, where these generalized models not only relax the distributional assumptions on the feature vector but also allow for nonlinear covariates. Exact and asymptotic tests are also derived for the problem of variable selection for these new models. The methodology is illustrated with both simulated data and an actual data set from a psychiatric study on using the Social Rhythm Metric for patients with anxiety disorders.
Activities of Daily Living↗