Predictors and moderators of time to remission of major depression with interpersonal psychotherapy and SSRI pharmacotherapy.

BACKGROUND: Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy versus depression-specific psychotherapy. METHOD: A total of 318 adult out-patients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy (IPT) at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. Our main focus was on predictors and moderators of time to remission on monotherapy at 12 weeks. RESULTS: Participants with higher scores on the need for medical reassurance factor of the Panic-Agoraphobic Spectrum Self-Report (PAS-SR) had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the Mood Spectrum Self-Report (MOODS-SR) experienced more rapid remission with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. Non-specific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the Social Phobia Spectrum (SHY) total score. Higher baseline scores on the 17- and 25-item Hamilton Depression Rating Scales (HAMD-17 and HAMD-25) and the Work and Social Adjustment Scale (WSAS) also predicted a longer time to remission, whereas being married predicted a shorter time to remission. CONCLUSIONS: This exploratory study identified several non-specific predictors but few moderators of psychotherapy versus pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.

Acceptability, validity and reliability of the Structured Clinical Interview for the Spectrum of Substance Use (SCI-SUBS): a pilot study.

This paper reports on the acceptability, reliability and validity of the Structured Clinical Interview for the Spectrum of Substance Use (SCI-SUBS), a new instrument exploring the interactive pathway between substance abuse and psychiatric disorders. Psychiatric outpatients with (n = 21) and without (n = 32) substance abuse comorbidity according to the DSM-IV, non-psychiatric subjects with opioid dependence (OD, n = 14) and normal controls (n = 33) were assessed with the SCI-SUBS. The presence or absence of psychiatric disorders was determined with the Structured Clinical Interview for DSM IV (SCID). The SCI-SUBS was well accepted by participants. The internal consistency of the domains was satisfactory (between 0.64 and 0.93). Domain scores of OD subjects were significantly higher than those of controls and of psychiatric patients without substance abuse. The cut-off point on the SCI-SUBS total score at which there was optimal discrimination between the presence and the absence of a DSM-IV diagnosis of substance abuse was 45. The pilot version of the SCI-SUBS has satisfactory internal consistency and construct validity.

The development of study exit criteria for evaluating antimanic compounds.

BACKGROUND: There is increasing interest on the part of investigators and the public at large in finding ways to study and improve treatments for the seriously mentally ill without exposing such individuals to unnecessary risks. One group of particular interest in this regard are patients suffering from acute mania. We set out to define "exit" criteria or novel clinical endpoints that might help to assess the efficacy of antimanic compounds. We sought a method that would be safer, more economical, and less sensitive to nonspecific factors in the clinical environment while still allowing unambiguous assessment of efficacy. METHOD: From a pool of subjects being screened for or already participating in intervention studies, we retrospectively identified 76 admissions of patients with a manic or mixed episode according to DSM-IV. We fit a mixed-effects regression model to all available data obtained using the Bech-Rafaelsen Mania Scale from admission to day 28 of treatment. Using the estimated model coefficients, we obtained empirical Bayes (EB) estimates of each subject's trend coefficients based on (1) all available data and (2) data through day 11 of treatment for mania. RESULTS: We found a high correlation (r = .67) between EB estimates of final response at day 28 and actual day 28 scores on the Bech-Rafaelsen scale based on scores through day 11. When subjects were categorized as full, partial, or nonresponders according to their final Bech-Rafaelsen score, we were able to show that only 2 of the 23 predicted nonresponders became full responders, 27 of the 31 predicted full responders became full responders, and 16 of the 22 predicted partial responders became partial or full responders. CONCLUSION: We conclude on the basis of this chart review study that it should be possible to define exit criteria for trials assessing the efficacy of antimanic compounds on the basis of relatively short duration exposure to experimental treatment.

Panic-agoraphobic spectrum: reliability and validity of assessment instruments.

DSM IV is a simple, reliable diagnostic system with many advantages. However, DSM diagnostic criteria may not provide sufficient characterization of clinically significant symptoms. We have undertaken a project to assess an array (spectrum) of clinical features associated with different DSM Disorders. The purpose of this paper is to report on reliability of assessment instruments for Panic-Agoraphobic Spectrum (PAS), to document convergent validity of PAS symptom groupings, and to confirm the relationship between PAS and DSM IV Panic Disorder (PD). We studied 22 normal controls and 95 outpatients who met criteria for Panic Disorder with and without lifetime Major Depression, and Major Depression or Obsessive Compulsive Disorder without lifetime Panic Disorder. Assessment instruments had excellent reliability and there was good concordance between interview and self-report formats. PAS scores were highest in subjects with PD, followed by outpatients without PD, and were lowest in normal controls. PAS scores varied among PD patients, and a subgroup of patients without PD scored high on PAS. We conclude that PAS can be reliably assessed, and that it describes a valid, coherent constellation of features associated with DSM IV Panic Disorder, but providing additional important clinical information.

Citalopram as adjunctive therapy in bipolar depression.

BACKGROUND: The treatment of bipolar depression remains a major clinical challenge. The effectiveness and safety of adjunctive citalopram were evaluated in DSM-IV-diagnosed bipolar depressed patients in a 5-site study. METHOD: The treatment strategy consisted of an open-label add-on design in which patients received 8 weeks of acute treatment with citalopram adjunctive to their ongoing treatment with mood stabilizers. Ongoing treatment with 1 antipsychotic, 1 anxiolytic, and 1 hypnotic agent was permitted. Responders to the 8-week trial then received 16 weeks of additional treatment with citalopram. RESULTS: Forty-five subjects entered the trial; 12 dropped out before the end of the acute treatment phase. Of the 33 patients who completed the acute treatment phase, 64% (N = 21) were responders and 36% (N = 12) were nonresponders. In the continuation phase of the study, 14 patients achieved sustained remission, 3 patients did not achieve remission before completing 16 weeks of continuation treatment, 2 patients experienced a relapse, and 2 patients dropped out of the study and did not have a chance to remit. In spite of the extensive concomitant medication usage allowed in this study, citalopram treatment was well tolerated and the level of reported adverse events (including headache, nausea, diarrhea, and sexual dysfunction) relatively low. CONCLUSION: The high response rate, the high rate of sustained remission, and the low rate of adverse events strongly support the use of citalopram as a treatment for bipolar I or II depression. These findings should stimulate a controlled double-blind trial to demonstrate even more clearly the usefulness of this drug in the therapeutic regimen for bipolar disorder.

Anxiety as a correlate of response to the acute treatment of bipolar I disorder.

OBJECTIVE: Given the adverse impact of anxiety on treatment outcome in unipolar depression and the paucity of data on the role of anxiety in bipolar disorder, the authors sought to determine the effect of anxiety on the acute treatment response of patients with bipolar I disorder. METHOD: The authors examined the correlates of response to the acute treatment of 124 consecutively treated patients with bipolar I disorder. Measures of anxiety included history of panic attacks and a composite variable reflecting current or past anxiety symptoms. RESULTS: History of panic attacks proved to be a significant correlate of nonremission. Anxiety, as assessed with the composite variable, was associated with longer time to remission, as was the treatment of depressive versus manic symptoms and mixed versus manic symptoms. Patients with anxiety as assessed with the composite variable and patients with a history of panic attacks reported more severe medication side effects. They also required a greater number of medications, either sequentially or in combination, in order to achieve remission. CONCLUSIONS: The findings suggest that anxiety is a clinically meaningful correlate of poor outcome in the acute treatment of bipolar I disorder.

Influence of panic-agoraphobic spectrum symptoms on treatment response in patients with recurrent major depression.

OBJECTIVE: The authors tested the hypothesis that a lifetime history of panic-agoraphobic spectrum symptoms predicts a poorer response to depression treatment. METHOD: A threshold for clinically meaningful panic-agoraphobic spectrum symptoms was defined by means of receiver operating characteristic curve analysis of total scores on the Structured Clinical Interview for Panic-Agoraphobic Spectrum in a group of 88 outpatients with and without panic disorder. This threshold was then applied to a group of 61 women with recurrent major depression, who completed a self-report version of the same instrument, in order to compare treatment outcomes for patients above and below this clinical threshold. RESULTS: Women with high scores (> or =35) on the Panic-Agoraphobic Spectrum Self-Report were less likely than women with low scores (<35) to respond to interpersonal psychotherapy alone (43.5% versus 68.4%, respectively). Women with high scores also took longer (18.1 versus 10.3 weeks) to respond to a sequential treatment paradigm (adding a selective serotonin reuptake inhibitor when depression did not remit with interpersonal psychotherapy alone). This effect was only partially accounted for by the higher likelihood that patients with high scores required the addition of antidepressants. Although four domains from the Panic-Agoraphobic Spectrum Self-Report were individually associated with a longer time to remission, only stress sensitivity emerged as significant in multivariate regression analyses. CONCLUSIONS: A lifetime burden of panic-agoraphobic spectrum symptoms predicted a poorer response to interpersonal psychotherapy and an 8-week delay in sequential treatment response among women with recurrent depression. These results lend clinical validity to the spectrum construct and highlight the need for alternate psychotherapeutic and pharmacologic strategies to treat depressed patients with panic spectrum features.

Interpersonal psychotherapy and antidepressant medication: evaluation of a sequential treatment strategy in women with recurrent major depression.

BACKGROUND: Few data are available to guide treatment selection in major depression. With increasing pressure to maximize the efficiency and minimize the costs of treatment, it is important to have information that could guide treatment selection or point to treatment strategies that have a high probability of success. METHOD: We used a successive cohort approach to compare 2 highly similar groups of women with recurrent unipolar disorder (DSM-III-R or DSM-IV): one in which the combination of interpersonal psychotherapy (IPT) and pharmacotherapy was initiated at the outset of treatment and a second in which IPT alone was provided first and only those who did not remit with IPT alone were offered the combination treatment. RESULTS: In the group in which the combination was initiated at the outset of treatment (N = 180), the remission rate was 66%, comparable to the remission rate observed in most outpatient treatment studies of major depression. In contrast, among the women in the second cohort who were first treated with IPT alone and only those who did not remit were given combination therapy (N = 159), the remission rate was 79%, significantly greater than that observed in the group that received combination treatment from the outset (chi2 = 6.55, p = .02). CONCLUSION: These results suggest that the strategy of offering IPT to women with recurrent unipolar disorder and, in the absence of remission, adding antidepressant pharmacotherapy can be a highly effective treatment, one that may be particularly attractive to women in the childbearing years. Although slower in its onset of action, this sequential strategy is likely to enable the clear majority of such women to achieve a full remission of depressive symptoms.

Stabilization in the treatment of mania, depression and mixed states.

While one major need for improved therapeutic approaches in bipolar disease is the development of long-term treatment strategies, a systematic approach during the acute phase of bipolar disorder is also required. In our own studies we have arbitrarily divided the initial treatment of subjects by the predominant polarity for which they are treated acutely: manic, depressed, or mixed/cycling.1 In this larger investigation of over 150 patients with bipolar disorder, we now demonstrated again that the time to initial stabilization is generally the shortest with a manic episode and the longest with a mixed/cycling episode with the depressed episode in the middle (although almost as long as the mixed/cycling episode). These findings indicate the difficulty of treating both the depressed phase and mixed/cycling episodes in bipolar disorder. It is also noteworthy that gender does not have a significant effect on time to stabilization. Such findings in the acute phase have profound implications in designing and carrying out long-term therapeutic strategies for this disorder.

Insulin-like growth factor 1 and growth hormone binding protein in depression: a preliminary communication.

This study was undertaken in order to advance our understanding of the distal growth hormone axis in depression. Insulin-like growth factor 1 (IGF-1) and growth hormone binding protein (GHBP) were measured in a group of 19 depressed women and a group of 16 healthy women. Using a generalized linear model, IGF-1 levels were negatively correlated with age (p = 0.0001), influenced by menstrual phase (p = 0.016), and significantly increased in the depressed group (p = 0.02). Using the same type of analysis, GHBP was significantly related to menstrual phase (p = 0.0001) and body mass index (p = 0.0001), but was not significantly different in patients and controls. IGF-1 and GHBP were positively correlated among healthy subjects (r = 0.46, p = 0.08), but not among depressed patients (r = -0.16, p = 0.51), although these correlation coefficients were not statistically significantly different from each other. These findings confirm the importance of several physiological factors in the regulation of IGF-1 and GHBP, and suggest that depression further influences this regulation.

The Pittsburgh study of normal sleep in young adults: focus on the relationship between waking and sleeping EEG spectral patterns.

The effects of age and gender on spectral characteristics of the waking EEG were investigated in a large sample of young adult men and women. In addition, relationships between spectral characteristics of the waking and sleeping EEG within an individual were explored. The sample included 28 females and 33 males in two age groups: 20-29 years (n = 32), and 30-40 years (n = 29). Spectral analysis was used to quantify EEG frequency characteristics for waking EEG just prior to sleep onset, as well as for the entire sleep recording. Significant effects of age were seen in the waking EEG but only in the delta frequency range (0.5-4.5 Hz) with lower delta activity in the older group (F = 11.6, P = 0.001). No significant gender effects were found in the waking EEG. Independent of age and gender, spectral profiles in the delta, theta, alpha and beta frequency bands of a subject's waking EEG were found to be highly correlated with their sleep EEG. In addition, subjects with high voltage alpha profiles during waking were found to sleep significantly longer and deeper than those with low voltage records. Significant correlations between waking and sleep EEG suggest that the spectral signature of an individual's EEG may be found across sleep/wake states.

The prophylaxis of depressive episodes in recurrent depression following discontinuation of drug therapy: integrating psychological and biological factors.

Models of long-term treatment in recurrent unipolar illness ideally should integrate both psychological and biological factors. In earlier reports we noted that high treatment specificity (i.e. good-quality maintenance interpersonal psychotherapy) and high delta sleep ratio were each associated with significantly increased wellness intervals in the absence of pharmacotherapy among patients with recurrent unipolar depression. To determine how these specific factors when taken together are related to length of survival time, we examined the concurrent effects of treatment specificity and delta sleep ratio on wellness intervals using survival analysis. We found significant effects of both treatment specificity and delta ratio on survival time. Seventy-three per cent of the patients in the high treatment specificity/high delta ratio group survived the 3-year trial, while 44% of the patients in the low delta ratio but high treatment specificity group survived. None of those rated low on both variables survived. We also found an effect for individual clinicians on treatment specificity and survival time and noted that the prophylactic effect of treatment specificity was maintained even within subsets of therapists grouped by their patients' survival times. Secondary analyses revealed an effect of patient attitudes on treatment specificity and survival time, although, when taken together, treatment specificity was the only variable remaining significantly associated with outcome. We conclude that patients remain well the longest when pre-treatment delta sleep parameters more closely approximate those of non-depressed individuals and when monthly psychotherapy is of higher quality. The key finding is that high specificity is of significant prophylactic benefit even for patients with a biological vulnerability for recurrence. We also conclude that in addition to therapists, patient expectancies contribute to treatment specificity, and high treatment specificity is, in turn, reflected in longer times to recurrence.

Growth hormone secretion timing in depression: clinical outcome comparisons.

Growth hormone (GH) secretion in the 100 minutes preceding sleep onset (preSO), as well as in the first half of the night (1st HN), was examined for a group of 13 healthy women and 43 women with recurrent depression who participated in a 3-year maintenance therapy study. GH studies were obtained at several points during treatment and every 3 months during maintenance, during which patients were randomly assigned to active drug or drug-free maintenance treatment cells for 3 years, or until recurrence of depression. Depressed patients were divided into subgroups according to their maintenance treatment assignment (active drug or drug free) and treatment outcome (completing in remission or having a recurrence). Imipramine caused an increase in the GH ratio in all subgroups. Protocol completers had a significantly larger imipramine-induced increase in the GH ratio than did recurrers. The difference in time of GH secretion relative to sleep onset was found to correlate with treatment outcome and was independent of medication status during maintenance.

Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: I. Comparison during acute depressive states.

The current study was conducted to examine if recurrent depression is associated with more severe disturbances of all-night EEG sleep profiles than single-episode depressions. Unmedicated sex- and age-matched groups of 22 single-episode (SE) and 44 recurrent unipolar (RU) outpatients with DSM-III-R/SADS/RDC major depression underwent 2 consecutive nights of EEG sleep recording. Multivariate analyses of covariance (MANCOVAs) and/or analyses of covariance (ANCOVAs) were performed on six sets of sleep measures. Recurrent unipolar depression was associated with significantly increased phasic REM sleep, as well as increased REM counts on the second night of study. Recurrent depression also was associated with significantly poorer sleep efficiency, although the groups did not show consistent differences in sleep architecture or slow-wave sleep. Our findings generally support the hypothesis that recurrent depression is associated with a more severe neurophysiologic substrate than phenotypically similar SE cases. Results are, for the most part, compatible with Post's (1992) model of illness progression, particularly with respect to greater disturbances of state-dependent sleep abnormalities in the RU cases. Longitudinal studies are needed to confirm the evolution of such changes prospectively.

Effect of pulse loading with clomipramine on EEG sleep.

Two different initial dosing regimens with clomipramine (CMI) were used to compare early response indicators and dose strategies. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading group received 150 and 200 mg of CMI on 2 consecutive evenings and then received a placebo for 8 days. The traditional dosing group began at 50 mg of CMI followed by gradual increases every second day until 200 mg was reached. After 10 days, both groups were placed on an adjustable dosing schedule of CMI, initially set at 200 mg, for an additional 2 weeks. Significant drug effects were noted on several sleep parameters demonstrating suppression of rapid eye movement (REM) sleep. In the pulse-loading group, drug responders were found to have a significantly faster and more robust rebound in REM sleep than nonresponders. Both measures of REM activity and REM sleep time showed a significant difference between the groups. In addition, a significant correlation was found between falling levels of the desmethylclomipramine metabolite of CMI and REM sleep activity during the rebound phase. The clinical and theoretical implications of these findings are discussed.

Sleep-related growth hormone secretion is persistently suppressed in women with recurrent depression: a preliminary longitudinal analysis.

Growth hormone secretion was monitored during sleep in a group of 43 women with recurrent major depression who were participating in a 3-year maintenance therapy program. Patients were studied before acute treatment, after complete remission, and at 3-month intervals during maintenance treatment and the data generated were compared to those obtained in a control group of 14 age-matched healthy women studied once under identical conditions. When compared to the control group, the depressed patients secreted significantly less growth hormone before treatment. This reduction in growth hormone secretion, which was confined to the first half of the sleep period, persisted across the length of the maintenance study regardless of whether the subjects completed three years of therapy or experienced a recurrence.

Persistent effects of antidepressants: EEG sleep studies in depressed patients during maintenance treatment.

Electroencephalographic (EEG) sleep studies represent a research tool that can be used to examine depressed patients over different phases of their illness. We examined the long-term effects of imipramine on EEG sleep in 27 subjects who completed 3 years of maintenance treatment on imipramine without experiencing a recurrence. The analyses were performed on EEG sleep data collected prior to acute treatment, after 3 months in maintenance, and every 3 months thereafter. The major aim was to examine specific changes in rapid eye movement (REM) and slow-wave sleep (SWS) as they unfolded over the course of illness and recovery during long-term drug maintenance. The acute changes in the sleep profile produced by antidepressants remained essentially the same throughout the entire period of drug administration. The REM sleep parameters, which were affected immediately, remained essentially unchanged thereafter, even as long as 3 years into maintenance treatment. A rapid redistribution of slow-wave sleep in the first part of the night was also observed without an increase in the total amount of slow-wave sleep throughout the night. The application of spectral analysis confirmed that the sleep changes following drug administration remained stable throughout all phases of drug treatment. Thus, it appears that sustained clinical improvement is accompanied by persistent sleep alterations on tricyclic antidepressant medication.

Electroencephalographic sleep studies in depressed patients during long-term recovery.

Analytic electroencephalographic (EEG) sleep procedures were used to examine specific changes in rapid eye movement (REM) and slow wave sleep (SWS) as they unfolded during depressive illness and recovery. The subjects were 15 patients with recurrent depression who remained well during 3 years of nonpharmacologic maintenance treatment without a recurrent episode of major depression. The analyses were performed on EEG sleep studies conducted before acute treatment, after 3 months in maintenance treatment, and every 3 months thereafter for 3 full years of maintenance treatment. There was no change between the index sleep and sleep during the first year of maintenance treatment as determined by period analysis or visual inspection of REM sleep parameters, except that average REM counts decreased over time. Thus, it is possible that REM parameters may represent one indicator of long-term recovery from depression. Finally, a significantly higher amount of 12-20 Hz spectral power density was found during the index episode than during the period of remission.

Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression.

Recent evidence points to the prophylactic efficacy of maintaining recurrent unipolar patients on the same dose of antidepressant medication that was used to treat the acute episode (Frank et al., 1990; Kupfer et al., 1992). Therefore, the question of whether such patients should be tapered to a lower maintenance dose after successful resolution of an acute episode is clearly important. In this report we describe a small randomized clinical trial in which patients were assigned to either full-dose or half-dose maintenance treatment for a period of 3 years. Survival analysis suggests that superior prophylaxis can be achieved with a full-dose as compared to a half-dose maintenance treatment strategy (p < 0.07). Mean survival time for the full-dose subjects was 135.17 (SE 19.75) weeks as compared to 74.94 (SE 19.78) weeks (median of 43.1 weeks) for the half-dose subjects. We conclude that for patients who have suffered several recurrences, full-dose maintenance treatment is the more effective prophylactic strategy.

Concordance between habitual sleep times and laboratory recording schedules.

The validity of laboratory-based studies of sleep depends, in part, upon good concordance between habitual sleep schedule and laboratory recording schedule. Without good concordance, error variance due to the circadian misplacement of sleep and to different amounts of time in bed is probable. In an assessment of scheduling concordance in 1,762 research patient nights over two time intervals, we observed good concordance (< 30-minute discrepancy) in 71.2-77.3% of bedtimes and waketimes, discrepancy (difference of > or = 30 minutes) in 14.9-24.2% of bedtimes and waketimes, and missing data in 4.6-7.5% of times. Waketime differences were consistently in the direction of earlier laboratory than habitual waketimes, whereas differences in bedtime were about equally divided between earlier and later (laboratory vs. habitual). Subjects with schedule discordance averaged 19.5 minutes less time in bed during laboratory sessions as compared with their habitual sleep schedule, whereas subjects with schedule concordance averaged only 3.6 minutes less (p < 0.001). Our experience suggests that it may be more difficult to achieve higher rates of concordance among young adult and middle-aged subjects than among elders and that patient requests related to external constraints on scheduling were a frequent reason for discrepancy. We strongly recommend a policy of routinely including data on laboratory versus habitual sleep times in peer-reviewed publications.