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.

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.

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.

Five-year outcome for maintenance therapies in recurrent depression.

After conducting a randomized, 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy, we asked those individuals who survived the 3-year trial receiving active medication (with or without psychotherapy) to continue in a 2-year additional randomized trial of active medication vs placebo. The question was whether maintaining antidepressant medication at the dosage used to treat the acute episode beyond 3 years would continue to provide a significant prophylactic effect compared with medication discontinuation after the 3 years of effective maintenance treatment. Survival analysis demonstrated a highly significant continued prophylactic effect for active imipramine hydrochloride treatment maintained at an average dose of 200 mg. We conclude that active imipramine treatment is an effective means of preventing recurrence beyond 3 years and that patients with previous episodes less than 2 1/2 years apart, therefore, merit continued prophylaxis for at least 5 years.

Imipramine and weight gain during the long-term treatment of recurrent depression.

The recently completed long-term maintenance trial of full-dose imipramine for recurrent unipolar disorder provided an opportunity to examine the extent to which such doses (200-300 mg daily) are associated with persistent and adverse side effects, particularly weight change. In 115 patients we monitored weight change during the three-year maintenance treatment phase to the point of trial completion, recurrence or termination. No differences were noted between individuals receiving active medication (average gain of 5.8 lbs. during an average treatment period of 725 days) versus those randomized to the 'no-drug' cells (average gain of 2.8 lbs. during an average treatment period of 422 days). Numerous other factors such as body mass index, previous weight gain and gender did not play a differential role in establishing why some individuals gained weight during long-term treatment of depression regardless of specific treatment.

Maintenance treatment and psychobiologic correlates of endogenous subtypes.

Although the endogenous subtype in depression has long been thought to have prognostic significance, to date no long-term maintenance treatment trial has examined the relative risk of recurrence in patients meeting criteria for this subtype. Following our analysis of the primary hypotheses regarding the relationship between treatment assignment and outcome [Frank et al. (1990) Arch. Gen. Psychiatry 47, 1093-1099], we now examine psychobiologic and maintenance treatment correlates for these recurrent unipolar patients grouped according to melancholic, endogenous but not melancholic, and non-endogenous subtype at index presentation. No differences were observed among the three groups in overall survival time; however, in the 52 patients who received psychotherapy without active medication during the maintenance phase, length of survival was inversely related to endogeneity. Interestingly, no differences were found among the three groups in EEG sleep parameters when studied either at baseline or following recovery.

Efficacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression. Contributing factors.

In earlier reports, we demonstrated that in patients with recurrent unipolar depression, survival time without a new episode of major depression following discontinuation of medication was significantly and positively related to continued interpersonal psychotherapy (IPT). To determine whether the prophylactic benefit of monthly sessions of IPT was a function of specific features of the intervention, we examined the contribution of the quality of IPT sessions to the length of the well interval in this 3-year maintenance trial. Therapy sessions were rated on specificity and purity of interpersonal interventions. Analysis of these ratings indicated that psychotherapy that was more specifically interpersonal was associated with significantly increased survival time. Patients whose therapy sessions were rated above the median on specificity of IPT had a median survival time of almost 2 years, while those below the median had a median survival time of less than 5 months. We concluded that when patient and therapist are able to maintain a high level of interpersonal focus, monthly sessions of IPT have substantial prophylactic benefit.

EEG sleep profiles and recurrent depression.

Earlier investigations have suggested that electroencephalographic (EEG) sleep may be altered as a function of the duration of an episode of depression. We compared the EEG sleep profiles in a group of recurrent depressives who had been depressed for less than 6 weeks with their sleep profiles as measured during their previous episode of depression. Findings in this sample of 32 patients point to the presence of specific rapid eye movement (REM) sleep abnormalities as being more pronounced earlier in the course of a depressive episode. Changes in REM latency and REM activity were also reflected in reductions in EEG spectral power in almost all bandwidths during the first REM period of the recurrent episode. These results are not easily explainable on the basis of traditional measures of clinical severity or the number of episodes.

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients.

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.

Fluvoxamine versus desipramine: comparative polysomnographic effects.

Electroencephalogram sleep measures over a 4-week period were obtained on 35 inpatients with major depression (unipolar) who received either fluvoxamine or desipramine in a randomized double-blind trial. Fluvoxamine showed immediate rapid eye movement (REM) sleep suppression and an alerting effect on sleep continuity measures. In contrast, desipramine administration was associated with REM suppression and sleep continuity improvement. The "alerting" quality of fluvoxamine, similar to other serotonergic antidepressants, appears to be unrelated to a lack of clinical efficacy, but may be related to persistent REM sleep suppression. However, it is premature to comment on the serotonin specificity for REM sleep.

Three-year outcomes for maintenance therapies in recurrent depression.

We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Delta sleep ratio. A biological correlate of early recurrence in unipolar affective disorder.

Slow wave sleep abnormalities have long been described in depression but were considered to be nonspecific indicators of psychopathology. Computerized techniques, including amplitude frequency measures and spectral analyses, are permitting new approaches to the examination of delta sleep. Early studies suggested that many depressed patients demonstrate lower delta wave intensity during the first non-rapid eye movement period than the second one. This finding, prominent in middle-aged depressed patients, has led to an examination of the ratio between the first and second non-rapid eye movement periods. This delta sleep measure seems to be a more robust predictor of recurrence than rapid eye movement latency. Analysis of data on 74 patients in a long-term maintenance treatment study for a minimum of 24 months demonstrates that the delta sleep ratio can predict survival time following discontinuation of drug treatment. Individuals with a high delta sleep ratio remain clinically remitted five times longer than those with a low delta sleep ratio.

Electroencephalographic sleep profiles in recurrent depression. A longitudinal investigation.

The electroencephalographic sleep profile of a group of recurrent depressives who had been depressed for less than four weeks was compared with their sleep profile in a prior episode of depression. The findings in these 19 cases indicate that early in the episode, rapid eye movement (REM) sleep findings are more abnormal, including shortened REM latency, REM sleep percent, and REM activity. Other sleep variables, such as sleep continuity measures and decreased delta-wave sleep, are abnormal in a similar fashion in both episodes. The results are not explainable on the basis of clinical severity or number of episodes and call for increased attention to the potential relationships between the psychobiological pattern and duration and course of the depressive episode.

Prediction of pyelocaliectasis in follow-up of patients with spinal cord injury.

Two hundred and fifty spinal cord injury patients were studied on each of two occasions, 12 to 24 months apart, to determine which urological findings could be used to predict the subsequent development of clinically significant pyelocaliectasis. An equation was developed which correctly classified 90% of the patients who remained free of clinically significant pyelocaliectasis and 82% of the patients who subsequently developed clinically significant pyelocaliectasis. The statistically significant risk factors were renal calculi, bladder diverticula and a decrease in effective renal plasma flow. This study suggests that the presence of these risk factors warrants careful monitoring of renal function in these patients and appropriate management of bladder dysfunction.

Relationship of awakening and delta sleep in depression.

It has been demonstrated that deficiencies in slow-wave sleep occur in the sleep profiles of depressed patients. Recent theories of sleep regulation link a deficiency in the so-called "Process S" to these slow-wave sleep alterations. However, the degree of wakening during sleep has been suggested as the explanation for reduced slow-wave sleep. In the present study, the extent of this relationship was examined in both depressed patients and normal subjects. Only a relatively low level of correlation between the degree of wakening and reduction in slow-wave sleep was noted in depressed patients. This finding on 38 unipolar depressed patients is similar to the findings on a smaller sample of depressed individuals.

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients.

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n = 17) and amitriptyline (AT, n = 16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiles for uptake blockade and anticholinergic potency for these two compounds.

REM latency distribution in major depression: clinical characteristics associated with sleep onset REM periods.

In a sample of 92 inpatients with major depression, REM latency showed a unimodal, rather than bimodal, distribution, with peak frequency between 50-59 min (on each of 4 consecutive nights). A total of 20 patients (21.6%) exhibited a sleep onset REM period (SOREMP-10) i.e., REM latency less than or equal to 10 min, during at least 1 of the 4 nights; an additional 11 patients (12%) showed REM latencies of 11-20 min on at least one night. SOREMP-10 positive patients were older both at the time of study (p less than 0.01) and at the age of onset of depressive illness (p less than .01) than the rest of the sample. They also showed greater sleep continuity disturbances, while patients with at least one SOREMP-20, i.e., REM latency less than or equal to 20 min, exhibited higher REM percentage (p less than or equal to 0.05) and a higher first-period density (p less than 0.05) than the remaining patients. No other clinical or polysomnographic correlates of SOREMP positivity were noted with regard to gender, RDC subtypes, severity of illness, or clinical response to tricyclic antidepressants. The unimodal distribution of REM latency, as well as the absence of a relationship between SOREMP positivity and severity of depression or therapeutic outcome, may result from the low representation of psychotic depressives in this sample (n = 6), who might constitute a qualitatively different subgroup.