Sleep and treatment response in depression: new findings using power spectral analysis
Introduction
Findings from several independent samples have indicated a relationship between abnormal sleep at baseline and poor treatment outcome in depression both with pharmacologic treatment (e.g. Kupfer et al., 1981, Rush et al., 1989) and with psychotherapy (Buysse et al., 1992a, Buysse et al., 1992b, Thase et al., 1996, Thase et al., 1997a, Thase et al., 1997b, Dew et al., 1997, Buysse et al., 1999a). In recent studies, poor treatment outcomes have been observed among patients who report subjectively poor sleep; who have increased amounts of REM sleep; who have increased numbers of eye movements during REM sleep; or who have an abnormal sleep ‘profile’ comprising poor sleep efficiency, short REM sleep latency and increased numbers of rapid eye movements. Poor response, defined as failure to remit or longer time to remission, has been observed using interpersonal psychotherapy for depression (IPT), cognitive-behavior therapy (CBT) and combined IPT plus nortriptyline. The relationship between poor sleep and poor outcome has been seen in single-episode and recurrent depression, men and women, and ages from young adulthood to late life. Thus, the relationship between sleep and treatment outcome appears to be a robust one.
One of the remaining questions regards the significance of this finding: why should disturbed sleep — and REM sleep in particular — be related to poor outcome in depression? One possibility is that sleep disturbance is simply a proxy for greater depression severity. However, the studies cited above have not shown a consistent relationship between degree of sleep disturbance and global severity of depression, as rated by the Hamilton Rating Scale for Depression (HRSD). Other possibilities are suggested by considering the mechanisms involved in the regulation of sleep-wake states, and REM sleep in particular. The appearance of REM sleep is regulated by reciprocal interactions between cholinergic nuclei of the laterodorsal and peduculopontine tegmentum (which show increased firing rates during REM sleep) and noradrenergic and serotonergic nuclei of the locus coeruleus and raphe nuclei (whose firing is virtually absent during REM). Transection experiments demonstrate that these nuclei in the upper pons are necessary and sufficient for the generation of REM sleep. Furthermore, the occurrence of eye movements during REM sleep is controlled almost exclusively by brainstem mechanisms (Siegel, 2000). Although brainstem mechanisms are clearly responsible for the REM sleep state and the appearance of eye movements during REM, functional imaging experiments have consistently shown that widespread areas of the cortex and limbic system are also activated during REM sleep (Maquet et al., 1996, Braun et al., 1997, Nofzinger et al., 1997). Furthermore, the pattern of cortical and limbic activation during REM sleep differs among depressed patients and healthy control subjects (Nofzinger et al., 1999). The core symptoms of depression (e.g. low mood, anhedonia, poor concentration) also demonstrate the importance of cortical and limbic dysregulation in depression. Thus, the above observations suggest two additional potential explanations for the relationship between REM sleep disturbances and treatment outcome in depression: namely, that alterations in REM sleep and phasic REM activity are an index of primarily brainstem dysregulation; or of primarily cortical dysregulation.
One way to address these competing hypotheses is to compare treatment responders and non-responders on measures that primarily reflect brainstem activity during REM sleep and on measures that primarily reflect cortical activity. The number of eye movements during REM is an example of the first type of measure. We have previously reported that phasic REM activity was higher among patients who failed to remit with psychotherapy (Buysse et al., 1999a). Power spectral analysis (PSA) of the sleep EEG is an example of the second type of measure. PSA is a quantitative method that describes the distribution of EEG power in the frequency domain. It conveys characteristics of the EEG during sleep more fully than traditional visual sleep stage scoring, which assigns a single stage score to REM and four stages to NREM sleep. Previous studies have examined PSA and pharmacologic treatment outcome in depression, but have generally found no differences between treatment responders and non-responders (Luthringer et al., 1995, van Bemmel et al., 1993, van Bemmel et al., 1995).
In addition to identifying correlates of acute treatment response, EEG sleep studies may also be useful for examining treatment-related changes in neurobiology. Previous studies have indicated that REM sleep and sleep continuity measures, generally show some degree of ‘normalization’ during sustained remission of the acute depressive episode following psychotherapy or pharmacotherapy followed by drug discontinuation (e.g. Thase et al., 1998, Rush et al., 1986, Sitaram et al., 1980, Buysse et al., 1992a, Buysse et al., 1992b, Thase et al., 1994). Furthermore, acute and chronic antidepressant treatment are associated with significant modifications of PSA (Luthringer et al., 1996, Hoffmann et al., 1999, Neckelmann et al., 1996, van Bemmel et al., 1995). However, no studies have reported on changes in PSA of the sleep EEG as a function of psychotherapy treatment.
The aims of the current study were: (1) To compare phasic REMS and PSA of the EEG during REM and NREM sleep among patients who remitted and who did not remit with psychotherapy treatment. This aim addresses PSA correlates of remission following acute treatment; (2) To compare phasic REMS and PSA of the EEG during REM and NREM in a matched subgroup of patients who responded to either psychotherapy alone or combined medication/psychotherapy treatment. This aim addresses the sleep correlates of recovery with different types of treatment. Because these types of analyses have not been reported, they are primarily descriptive rather than hypothesis-testing.
Section snippets
Methods
The results reported here are one component of a study investigating the efficacy of three ‘doses’ of interpersonal psychotherapy (IPT) as a maintenance treatment for recurrent major depressive disorder (MDD) in women (MH 49115, E. Frank, Principal Investigator). The study design involves acute open treatment with IPT until patients recover from the index episode. Patients who fail to remit with IPT as a sole treatment (see criteria below) are treated openly with fluoxetine in addition to IPT.
Demographic and clinical findings
Baseline demographic and clinical variables for the IPT remitters vs. IPT non-remitters, and for the IPT recoverers vs. IPT+fluoxetine recoverers, are shown in Table 1. As previously reported in a smaller sample (Buysse et al., 1998, Buysse et al., 1999a), IPT non-remitters had significantly worse subjective sleep quality, measured by the PSQI; worse social functioning, measured by the GAS; and a non-significant trend toward higher severity, measured by the HRSD-17. As previously reported,
Discussion
Results from the current analyses confirm and extend our previous observations regarding EEG sleep correlates of remission and recovery with psychotherapy and combined psychotherapy–antidepressant treatment. Prior to treatment, IPT non-remitters had increased phasic REM sleep compared with remitters. However, EEG power spectral profiles during REM sleep and NREM sleep did not significantly differ among these groups. Patients who recovered with IPT+fluoxetine had an increase in REM sleep
Acknowledgments
The research reported was supported by MH49115, MH24652, MH30915 and AG00972.
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