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Keywords:

  • citalopram;
  • major depression;
  • neuropsychology;
  • reboxetine;
  • REM sleep;
  • slow-wave sleep

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

It has been hypothesized that non-rapid eye movement (NREM) sleep facilitates declarative memory consolidation, and rapid eye movement (REM) sleep is particularly important in promoting procedural learning. The aim of this study was to examine the effects of pharmacological REM sleep suppression on performance in different neuropsychological tasks. For our baseline, we chose 41 moderately depressed patients (age range 19–44 years), who were not taking antidepressants. In the morning after polysomnography, we tested memory recall and cognitive flexibility by assessment of verbal and figural fluency, a shift of attention task and the Trail Making Test B. After recording baseline values, patients were assigned randomly to one of three treatment groups: medication with citalopram; medication with reboxetine; or exclusive treatment with psychotherapy. Retesting took place 1 week after onset of treatment. The main results were: (1) an association of slow-wave sleep with verbal memory performance at baseline; (2) a suppression of REM sleep in patients taking citalopram and reboxetine; (3) no differences regarding neuropsychological performance within the treatment groups; and (4) no association of REM sleep diminution with decreases in memory performance or cognitive flexibility in patients treated with citalopram or reboxetine. In line with other studies, our results suggest that there are no negative effects of a decrease in REM sleep on memory performance in patients taking antidepressants.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

Several studies support the role of sleep in consolidation of memory (Diekelmann et al., 2009; Peigneux et al., 2001; Stickgold, 2005). It has been hypothesized that slow-wave sleep (SWS) predominantly facilitates hippocampus-dependent (declarative) memories, whereas procedural or emotional aspects of memory tend to benefit from rapid eye movement (REM) sleep (Diekelmann et al., 2009; Rauchs et al., 2005). But the hypothesis that memories are processed during REM sleep is challenged by the argument that the marked suppression of REM sleep in subjects on antidepressant drugs produces no detrimental effects on cognition (Siegel, 2001). Along the same line, recent studies showed that acute reduction of REM sleep revealed no decreases in procedural or declarative memory performance in healthy subjects (Genzel et al., 2009; Hornung et al., 2007; Rasch et al., 2009; Saxvig et al., 2008).

Other aspects of human cognition involve executive functions, such as planning, problem solving and decision making as well as cognitive flexibility, which includes verbal and figural fluency or flexibility of focussed attention. Studies involving experimental sleep deprivation or clinically related sleep fragmentation reported impaired performance on tasks of executive function, including measures of verbal fluency, creativity and planning skills (Durmer and Dinges, 2005; Horne, 1993). Two recent studies found interesting links between cognitive flexibility or creativity and REM sleep. Healthy subjects performed better in an anagram word puzzle task after being awakened during REM sleep compared with being awakened during non-REM (NREM) sleep (Walker et al., 2002). Cai et al. (2009) have shown that REM sleep – but not NREM sleep – during naps enhanced creative problem solving in the Remote Associates Test. But the effects of the suppression of REM sleep on tasks requiring executive functions such as cognitive flexibility in patients under the influence of antidepressant drugs have not been studied yet.

Furthermore, the link between altered REM sleep characteristics in psychiatric disorders like major depression and performance in cognitive flexibility has also been inadequately studied so far. In this context, it would seem that pathological mental conditions like schizophrenia or major depression with both sleep disturbances and cognitive deficits provide interesting models to analyse the relevance of a link between sleep and cognition. This is supported by studies that found associations of distinct sleep alterations and neuropsychological deficits in these disorders (Göder et al., 2008; Manoach et al., 2010). In major depression many patients show objective findings of sleep continuity disturbances, SWS deficits and REM sleep alterations (Peterson and Benca, 2006), and also deficits in memory performance, executive functions and cognitive flexibility (Clark et al., 2009). In a recent study, sleep-associated off-line motor memory consolidation was impaired in medicated patients with major depression, but objective sleep measurements were not included in this study (Dresler et al., 2010). As mentioned above, antidepressant drugs like selective re-uptake inhibitors of serotonin (SSRI) or norepinephrine (SNRI) suppress undisturbed REM sleep in healthy subjects and also the disinhibited REM sleep in major depression (Kuenzel et al., 2004; Rasch et al., 2009). But there is still a lack of placebo-controlled studies analysing the effects of SSRI or SNRI on memory and cognition in depressed patients. While it is assumed that serotonergic and aminergic pathways play an important role in the modulation of learning and memory, even animal studies are inconsistent as reported results range from negative to positive effects on memory in different animal models, as recently reviewed by Monleon et al. (2008).

Therefore, the aim of the present study is twofold. As studies on psychiatric patients were criticized because they contained too many confounds (e.g. medication, comorbidities, drug intake), we wanted to perform a study with a homogenous group of well-characterized young patients with major depression without antidepressants at baseline and without comorbidities. It was our intention to analyse associations between distinct sleep parameters and different aspects of cognitive functioning. Because experimental selective sleep deprivation has been criticized for evoking additional unspecific effects such as arousal, emotional irritation and stress, we wanted to further elucidate the relationship between REM sleep and cognition by comparing the effects that pharmacological REM sleep suppression had on our test results after 1 week of treatment with the performance in a patient group treated exclusively with psychotherapy.

We, therefore, carried out sleep recordings, tests for procedural and declarative memory performance and tasks for executive functioning and cognitive flexibility. After a treatment-free night to record baseline values, patients were randomly assigned to a therapy with an antidepressant medication (citalopram or reboxetine) or a treatment exclusively with interpersonal psychotherapy (IPT). Citalopram (half-life 33 h) is a SSRI, and reboxetine (half-life 13 h) is a SNRI. Both antidepressants have no anticholinergic or antihistaminergic side-effects. IPT was developed by Klerman et al. (1984) as time-limited psychotherapy for major depressive disorder. IPT shows no decreasing effects on REM sleep duration, and therefore IPT-treated patients serve as an ideal control group for the REM sleep-related consequences of the above-mentioned antidepressants. Sleep recordings and neuropsychological tasks were repeated after 1 week of treatment. In particular, we hypothesized that correlations existed between SWS duration and declarative memory performance as well as between REM sleep amount and procedural learning. In our hypothesis, pharmacological REM sleep suppression should have resulted in a decrease in procedural memory performance and the performance in cognitive flexibility.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

Subjects

The sample consisted of 41 patients with a non-psychotic major depression diagnosed according to DSM IV based on a SCID 1 interview. Patients ages ranged from 19 to 44 years (mean 31.4 years). The sample included 23 females and 15 inpatients, and there was a mean score of 20.7 on the 21-item Hamilton Rating Scale of Depression (HRSD; Hamilton, 1967). In- and outpatients did not significantly differ regarding age, depression severity (HRSD) or duration of the current depressive episode. Exclusion criteria were: (1) HRSD below 15 pts; (2) primary substance abuse and other primary axis 1 disorders; (3) severe cognitive impairment; (4) borderline personality disorder; (5) acute or unstable medical problems; and (6) acute suicidal tendency. Thirty-nine of the patients were free of psychotropic medication for a minimum of 4 weeks before inclusion in the study. One patient was on opipramol (half-life 6–9 h) and another patient took trimipramine (half-life 20–23 h) until 1 week before baseline. Any relevant medical conditions were assessed by medical history, physical examination and routine laboratory investigation. One patient was medicated with thyroxine because of hypothyroidism. The absence of drug abuse was controlled by urinary drug screenings. All participants gave their written informed consent. The study was approved by the local ethics committee and conformed to the Declaration of Helsinki.

Procedure

The results reported here are part of a study investigating diverse biological markers in the course of different therapies for major depressive disorder. After inclusion in the study, the patients spent 2 nights in our sleep laboratory. The first night was used to adapt the patients to the conditions in the sleep laboratory and to exclude a sleep apnoea syndrome or a periodic limb movement disorder. The second night served as a baseline night (t0). Sleep was recorded between lights off (regulated by the patients themselves between 22:00 h and midnight) and lights on (at 06:45 h). We conducted neuropsychological testing both at 20:00 h prior to the polysomnography during the second night as well as at 07:30 h on the morning thereafter. After baseline values (t0) had been gathered, patients were randomly assigned to one of three treatment groups: (1) medication with the SSRI citalopram; (2) medication with the SNRI reboxetine; or (3) exclusive treatment with IPT (two sessions a week). To do this we first treated the entire sample as one block (restricted randomization). Then, random allocation to each of the three groups was applied by the restricted shuffled approach, which uses a sealed envelope system. The patients in both groups with pharmacotherapy only obtained additional medical care and supportive counselling as required. After 1 week of treatment a polysomnography (over 2 nights: an adaptation night and a study night) and the neuropsychological tests were repeated (t1). The original sample consisted of 45 patients but, before t1, two patients dropped out of the study without explaining motives. Another two patients were excluded because they were under the influence of zolpidem during the study.

Sleep was recorded employing standard procedures. Electroencephalographic activity (EEG; C3–A2 and C4–A1), electrooculographic activity and submental electromyographic activity were measured. Recordings were visually scored according to standard criteria (Rechtschaffen and Kales, 1968) by a trained rater under blind conditions. The following parameters were computed: sleep onset latency (time from lights off to the first epoch of stage 2 sleep in minutes); total sleep time (in minutes); sleep efficiency (ratio of total sleep time to time in bed as a percentage); number of awakenings; SWS; stage 1 sleep, stage 2 sleep and REM sleep (all in minutes); REM latency (time from sleep onset to the first epoch of stage REM sleep in minutes); total REM density (ratio of 3-s mini epochs including rapid eye movements to the total number of 3-s mini epochs of REM sleep); total number of stage 2 sleep spindles; and sleep spindle density. For sleep spindle detection we used a band-pass filtered signal of the raw EEG. The band-pass filter only allowed frequencies within the range of 12–16 Hz. Subsequently, all spindles were visually identified in all epochs scored as stage 2 sleep. Spindles exceeded 0.5 s and had a typical waxing and waning spindle morphology. Sleep spindle density was calculated as the ratio of the number of sleep spindles counted in stage 2 sleep to the number of minutes of stage 2 sleep. For a basic spectral analysis (C3–A1 and C4–A2), the Fast Fourier Transform algorithm was used and the truncating error was reduced by applying a Hanning window. Only artefact-free epochs of 30-s duration were analysed. The EEG power values of the delta range (1–4 Hz), the theta range (4–8 Hz) and the alpha range (8–12 Hz) of each sleep stage and of both EEG channels were used for further analysis.

Questionnaires and neuropsychological testing

Severity of depression was estimated by the HRSD at t0 and t1. To rudimentarily estimate the impact of diurnal variations of mood on performance in neuropsychological tasks in different patient groups, we analysed the subscale diurnal variation of the HRSD. To estimate premorbid intelligence, the ‘Mehrfach-Wortschatz-Intelligenz-Test’ (a multiple choice vocabulary test that measures intelligence; MWT-B) was used. The results were converted to the Wechsler Adult Intelligence Scale-Revised Intelligence Quotient (WAIS-R IQ) using standard tables.

The Trail Making Test, part A (TMT-A; Reitan, 1958) was used as a control for measuring attention in the evening and the morning of each session. To test declarative verbal memory, we used a German version of the Rey Auditory-Verbal Learning Test (Helmstaedter et al., 2001). In the evening, before polysomnography on the baseline night (t0), and the study night after 1 week of treatment (t1), a list of 15 words was read to the participants five times. After each of the five presentations and on the next morning, patients were asked to recite as many words as they could remember. We calculated the following parameters: final acquisition (recalled words in trial 5 in the evening); free recall in the morning (number of recalled words in the morning); and retention (number of words in trial 5 in the evening subtracted from the number of recalled words in the morning). We used three different word lists in a randomized order for baseline (t0) and treatment night (t1). To test procedural learning we used a mirror-tracing skill. Patients and controls were asked to carefully trace inside the double lines of a triangle (for warming up, data not evaluated) and a star in the evening and in the morning. The figures had an overall width of 20 cm, and the distance between the two lines was 1 cm. Direct visual access to the platform with the figures on it was prevented by a 22 × 30-cm board. The figures could only be seen via a 18 × 26-cm mirror. We assessed the drawing time and the number of errors (crossing any line with the stylus).

The order of neuropsychological testing in the evening and the morning was: (1) verbal learning test; (2) mirror tracing; (3) TMT-A. In contrast, all four tests to measure executive functions and especially cognitive flexibility were administered only in the morning after polysomnography at about 08:00 h. The patients carried out a German word fluency task for verbal fluency and the 5-Point Fluency Test (Regard et al., 1982) for figural fluency. Regarding the 5-Point Fluency Test, participants were asked to draw as many different figures as possible in 3 min by connecting two or more dots with straight lines. With the Trail Making Test part B (TMT-B), psychomotor speed, rapid mental sequencing and also cognitive flexibility were measured (Reitan, 1958). From the Test of Attentional Performance (TAP; Zimmermann and Fimm, 1993), the subtest ‘shift of attention’ was used to test flexibility of focused attention. In this test, flexibility is tested by mental alternation between two sets of targets.

Statistics

Associations between sleep measurements and neuropsychological performance were examined by partial correlations controlled for age. Differences among and within the treatment groups with IPT, citalopram or reboxetine were assessed using repeated-measures anova. When the analysis revealed significant main effects, we conducted post hoc t-tests. Distribution of gender and in- or outpatients were tested by Pearson’s Chi-square test. Data analysis was performed with SPSS for Windows, version 17.0 (SPSS Inc., Chicago, IL, USA). The level of significance was set at 5%. No adjustment of the error probabilities for multiple testing was carried out because of the explorative nature of the study. Therefore, the results should be considered with particular caution and for their consistency with other results.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

Associations of sleep and cognition at baseline

There was a significant positive partial correlation (controlled for age) between the duration of SWS at baseline and overnight verbal memory retention (Table 1). In reference to this, patients with a higher amount of SWS forgot fewer of the words they had learned in the evening when asked to recall them the next morning, whereas the number of words learned in the evening was otherwise insignificantly negatively correlated with SWS. Concerning other sleep parameters, such as REM sleep duration, number or density of sleep spindles or delta power, no associations with performance in neuropsychological tasks were found (Table 1).

Table 1.   Partial correlation coefficients (controlled for age) for sleep measurements and neuropsychological performance at baseline (n = 41)
 SWS (amount)Sleep spindles (number) (C4)Delta power (SWS) (C4)REM sleep (amount)
  1. HRSD, Hamilton Rating Scale of Depression; MWT-B, multiple choice word test, Version B; REM, rapid eye movement; SWS, slow-wave sleep; TMT-A, Trail Making Test, part A; TMT-B, Trail Making Test, part B; ev, test in the evening; mo, test in the morning. Positive correlation coefficients = the higher the value of the sleep parameter, the better the performance (speed, number of words or items and accuracy). Final acquisition = correct words in trial 5 of the verbal learning and memory test. Retention = number of words in trial 5 in the evening subtracted from the recalled words in the morning. Significant values in bold.

  2. *P < 0.05.

HRSD0.31−0.160.340.20
Intelligence (MWT-B)0.07−0.14−0.090.03
TMT-A morning−0.21−0.12−0.08−0.24
TMT-A evening−0.01−0.080.02−0.27
Cognitive flexibility
TMT-B morning0.11−0.140.000.10
Shift of attention−0.13−0.09−0.04−0.21
5-Point Fluency Test0.010.210.00−0.13
Verbal fluency−0.200.100.26−0.27
Declarative memory
Final acquisition evening−0.29−0.02−0.10−0.20
Free recall morning0.12−0.09−0.190.05
Retention0.38*0.10−0.150.22
Mirror tracing
Drawing time evening0.150.110.050.0
Drawing time: change mo − ev−0.130.110.090.24
Errors evening0.190.120.170.02
Errors change mo − ev−0.24−0.08−0.11−0.19

Effects of antidepressant medication on sleep and cognition

After baseline measurements, patients were assigned randomly to one of three treatment groups. The three treatment groups (IPT, citalopram, reboxetine) did not significantly differ with respect to age, gender, proportion of in- and outpatients, and severity of depression (Table 2). The means of the administered daily dosages after 1 week of treatment were 18 ± 9 mg for citalopram and 6 ± 2 mg for reboxetine. The mean blood concentration at t1 of citalopram was 86 ± 84 mm and of reboxetin was 350 ± 330 mm. Table 3 shows that after 1 week of therapy both antidepressants effected a suppression of REM sleep with a prolongation of REM latency and a decrease of REM sleep duration (in comparison to baseline and to treatment with IPT, significant values for citalopram and statistical trends for reboxetine). Additionally, reboxetine was associated with an increase in stage 1 sleep and the number of awakenings in comparison to patients treated with IPT and citalopram. There were no differences between the treatment groups concerning SWS, number or density of sleep spindles or spectral power values (Table 3). Regarding the neuropsychological tests, no differences between the treatment groups at baseline and after 1 week of therapy were revealed (Table 4; Fig. 1).

Table 2.   Treatment groups
 IPT (n = 14)SSRI (n = 13)SNRI (n = 14)P-value
  1. HRSD, Hamilton Rating Scale of Depression; IPT, Interpersonal psychotherapy of depression; MWT-B, multiple choice word test, Version B; SNRI, selective noradrenalin re-uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor. *One-way anova.Pearson’s Chi-square test.

Age (years)*31.2 (7.3)31.5 (6.9)31.5 (8.8)0.99
Women/men9/57/67/70.73
In- versus outpatients6/85/84/100.72
HRSD t0*21.0 (3.7)21.2 (4.4)19.9 (2.5)0.63
HRSD t1*18.1 (4.8)16.3 (6.3)16.9 (3.2)0.62
Intelligence* (MWT-B)111 (12)109 (11)114 (10)0.47
Table 3.   Sleep parameters at baseline (t0) and after 1 week of treatment (t1)
 IPT (n = 14) PsychotherapySSRI (n = 13) CitalopramSNRI (n = 14) ReboxetineTimeTime × TreatmentBetween-subject
t0t1t0t1t0t1
  1. IPT, interpersonal psychotherapy of depression; REM, rapid eye movement; REMD, REM sleep density; REML, REM sleep latency; SE, sleep efficiency; SNRI, selective noradrenalin re-uptake inhibitor; SOL, sleep onset latency; SSRI, selective serotonin re-uptake inhibitor; SWS, slow-wave sleep; TIB, time in bed; TST, total sleep time. Means and standard deviations (in brackets). Rightmost columns indicate P-values from anovas. In the case of significant time, treatment or between-subject effects, post hoc pairwise comparisons were conducted using t-tests. (*)P < 0.1; *P < 0.05; **P < 0.01; for t-tests between differences of baseline versus treatment nights of antidepressant-treated patients (SSRI or SNRI) versus IPT-treated patients. P < 0.05; ††P < 0.01 for t-tests between deltas of SSRI- versus SNRI-treated patients. Spectral power values (C4–A2) are based only on 11 patients per group because of technical problems. Significant values in bold italics. [Correction added after online publication 24 February 2011: value of (*) changed from P < 0.01 to P < 0.1 in the table legend.]

TIB (min)455 (20)483 (41)450 (63)463 (36)436 (48)455 (46)0.010.720.26
TST (min)400 (39)404 (64)398 (65)383 (55)359 (64)382 (64)0.680.270.26
SOL (min)24.6 (25.1)38.0 (45.6)29.6 (16.2)43.9 (28.5)26.8 (15.5)19.5 (13.5)0.190.160.24
SE (%)87.9 (7.5)84.2 (14.4)88.5 (6.6)81.6 (10.2)82.4 (13.4)84.0 (11.7)0.190.320.66
Awakenings (N)9.3 (4.8)9.1 (3.7)9.5 (7.1)10.8 (5.7)10.6 (4.9)20.5** (9.0)0.0050.0030.02
Stage 1 (min)35.2 (17.8)38.1 (18.7)42.9 (22.1)46.6 (18.9)50.1 (40.6)79.9** (45.6)††0.0010.0010.03
Stage 2 (min)220 (28)229 (63)225 (42)242 (47)197 (46)219 (71)0.070.820.31
SWS (min)60.4 (37.8)50.5 (33.6)49.0 (29.0)38.9 (28.0)42.8 (36.1)32.5 (34.8)0.0060.990.33
REM sleep (min)84.9 (19.9)86.3 (25.1)81.2 (32.4)55.5** (29.3)68.6 (30.7)50.5(*) (22.0)0.0010.0280.019
REML (min)86.1 (38.1)113.6 (93.8)57.7 (20.5)194.2** (57.5)91.3 (37.0)182.1(*) (90.1)0.0010.0090.1
REMD (%)4.3 (3.4)3.7 (4.1)3.9 (2.7)3.1 (2.1)4.1 (4.0)3.1 (3.6)0.080.960.90
Spindles (C4) (N)342 (280)480 (465)422 (427)422 (422)314 (239)375 (302)0.150.470.81
SWS Delta power (μV2)78.1 (4.6)76.3 (5.8)75.7 (6.7)75.9 (6.9)77.8 (5.9)76.0 (7.4)0.110.440.84
Theta power (μV2)66.4 (5.0)64.3 (6.5)63.9 (6.5)63.9 (6.9)66.0 (6.0)64.2 (7.9)0.090.460.84
Alpha power (μV2)61.2 (5.2)59.1 (6.8)58.7 (7.1)58.8 (7.6)61.2 (6.1)59.3 (8.2)0.10.420.84
REM sleep Delta power (μV2)68.6 (4.7)66.8 (6.2)65.8 (6.2)64.7 (6.1)66.1 (8.0)63.9 (8.6)0.090.330.54
Theta power (μV2)63.4 (4.3)61.5 (5.9)60.5 (6.4)59.7 (6.3)60.3 (8.4)58.1 (8.5)0.10.340.42
Alpha power (μV2)58.7 (4.5)56.8 (6.2)55.7 (6.9)55.2 (6.8)56.4 (8.0)54.7 (8.0)0.230.300.65
Table 4.   Neuropsychological tests at baseline (t0) and after 1 week of treatment (t1)
 IPT (n = 14) PsychotherapySSRI (n = 13) CitalopramSNRI (n = 14) ReboxetineTimeTime × TreatmentBetween-subject
t0t1t0t1t0t1
  1. IPT, interpersonal psychotherapy of depression; SNRI, selective noradrenalin re-uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor; TMT-A, Trail Making Test, part A; TMT-B, Trail Making Test, part B; ev, evening; mo, morning. Means and standard deviations (in brackets). Rightmost columns indicate P-values from anovas. Retention, number of words in trial 5 in the evening (final acquisition) subtracted from the recalled words in the morning. Significant values in bold italics.

TMT-A evening (s)28.6 (8.8)22.2 (4.9)33.1 (14.6)25.1 (8.0)28.1 (7.2)21.9 (6.0)0.0010.810.35
TMT-A morning (s)24.9 (4.6)20.6 (3.3)30.2 (11.4)25.8 (8.8)26.7 (10.0)22.4 (7.8)0.0010.990.20
Cognitive flexibility
TMT-B morning (s)58.0 (17.2)43.9 (12.4)63.3 (15.1)56.8 (21.0)56.5 (19.4)45.1 (15.1)0.0010.410.22
Shift of attention (ms)711 (112)600 (154)817 (189)752 (204)776 (284)620 (127)0.0010.360.14
5-Point Fluency Test (items)40.1 (6.9)46.5 (8.4)35.1 (8.6)41.0 (10.3)34.5 (8.5)41.0 (8.2)0.0010.980.12
Verbal fluency (words)61.4 (9.1)62.0 (11.3)54.8 (10.9)57.7 (8.6)62.0 (15.8)63.9 (17.2)0.210.800.31
Declarative memory
Final acquisition ev (words)14.8 (0.8)15.0 (0.1)14.6 (1.0)14.8 (0.6)14.4 (1.6)14.6 (0.9)0.170.990.50
Recall mo (words)13.0 (1.7)12.5 (2.1)13.2 (2.1)12.2 (2.4)12.4 (1.9)12.6 (2.0)0.270.430.88
Retention (words)−1.8 (1.5)−2.5 (2.1)−1.4 (1.5)−2.7 (2.5)−2.1 (1.7)−2.1 (2.1)0.130.470.98
Mirror tracing
Drawing time evening (s)109 (63)45 (10)139 (71)47 (19)127 (58)55 (25)0.0010.460.48
Drawing time change mo − ev (s)−53 (56)−9 (7)−70 (49)−11 (9)−51 (47)−10 (9)0.0010.630.55
Errors evening (N)5.7 (6.2)3.6 (6.4)9.1 (12.1)1.2 (2.1)12.6 (11.8)2.6 (2.6)0.0010.160.41
Errors change mo − ev (N)−2.8 (5.6)−2.1 (5.6)−5.7 (9.9)+0.5 (3.8)−9.8 (11.8)−1.8 (2.4)0.0030.150.20
image

Figure 1.  REM sleep and memory performance at re-test after 1 week of antidepressant treatment. (a) REM sleep duration was significantly lower in the SNRI group (n = 14) and in the SSRI group (n = 13) in comparison to the IPT group (n = 14). (b) There were no differences between the treatment groups with regard to declarative memory performance (free recall in the morning after polysomnography). (c) There were no differences between the treatment groups with regard to procedural memory performance (overnight improvement of drawing time). Means and standard deviations are shown, **P < 0.01. IPT, interpersonal psychotherapy of depression; SNRI, selective noradrenalin re-uptake inhibitor; SSRI, selective serotonin re-uptake inhibitor.

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We additionally performed partial correlational analyses (controlled for age) of changes in REM sleep and changes in neuropsychological performance from baseline to re-test after 1 week for the patients treated with antidepressants (pooled together; n = 27). We found no significant associations between REM sleep suppression and worse performance in any of the neuropsychological tasks (declarative or procedural memory or cognitive flexibility). To analyse whether the effects of REM sleep suppression on cognition could be masked by depressed mood or acute drug effects, we also performed correlational analyses (controlled for age) of changes between neuropsychological performance and changes in the HRSD score as well as with blood levels of citalopram or reboxetine at t1. There were no significant correlations of cognitive performance with changes in depression severity. We found a statistical trend (P < 0.1) regarding the association of reboxetine blood levels with increases in REM latency from baseline to follow up, but not for the amount of REM sleep and not for citalopram blood concentrations. Concerning citalopram, there were significant correlations between blood levels and decreases in performance in the TMT-A and TMT-B and with increases in the final acquisition of the word list in the evening, but not with overnight performance in any memory parameter (Table 5).

Table 5.   Partial correlation coefficients (controlled for age) for changes in neuropsychological performance from baseline to re-test after 1 week with changes in REM sleep and changes in depression severity (HRSD) and blood levels of reboxetine or citalopram (only patients treated with antidepressants)
Changes (t1 − t0) inREM sleep change (n = 27)HRSD change (n = 27)Reboxetine blood level t1 (n = 14)Citalopram blood level t1 (n = 13)
  1. HRSD, Hamilton Rating Scale of Depression; REM, rapid eye movement; TMT-A, Trail Making Test, part A; TMT-B, Trail Making Test, part B; ev, test in the evening; mo, test in the morning. Positive correlation coefficients = a decrease of neuropsychological performance (speed, number of words, items or accuracy) is associated with a decrease in REM sleep, a decrease in HRSD or a low serum level of citalopram or reboxetine. Final acquisition = correct words in trial 5 of the verbal learning and memory test. Retention = number of words in trial 5 in the evening subtracted from the recalled words in the morning.

  2. (*)P < 0.1; *P < 0.05.

REM sleep amount−0.02−0.40−0.06
REM sleep latency−0.010.61(*)−0.03
HRSD−0.010.09−0.09
TMT-A morning−0.10−0.180.03−0.72*
TMT-A evening −0.120.15−0.05
Cognitive flexibility performance
TMT-B morning0.02−0.100.11−0.68*
Shift of attention−0.190.24−0.13−0.18
5-Point Fluency Test−0.06−0.070.16−0.25
Verbal fluency0.19−0.13−0.190.06
Declarative memory
Final acquisition evening0.030.01−0.510.75*
Free recall morning0.12−0.200.350.31
Retention0.11−0.190.50−0.05
Mirror tracing performance
Drawing time evening0.07−0.180.31−0.21
Drawing time: change mo − ev−0.04−0.04−0.380.25
Errors evening0.07−0.170.48−0.08
Errors change mo − ev0.05−0.23−0.400.15

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

The main results of the present study in patients with moderate major depression were: (1) an association of SWS with verbal memory performance at baseline; (2) a suppression of REM sleep duration in patients taking citalopram and reboxetine after 1 week of treatment; (3) no differences regarding neuropsychological performance within the treatment groups (citalopram or reboxetine versus psychotherapy); and (4) no associations of REM sleep diminution with decreases in memory performance in patients treated with antidepressants.

Our results showing a significant association between the amount of SWS and verbal memory retention at baseline are in line with current concepts of consolidation of declarative memories, preferentially during SWS (Diekelmann et al., 2009). We found similar results of an association of SWS and declarative memory performance in our recent studies in patients with schizophrenia (Göder et al., 2008), suggesting that the decrease of SWS in different psychiatric disorders has an impact on the diminished declarative memory performance of these patients. However, in our first pilot study with major depression patients we found an association between performance in a visuospatial memory task with the duration of REM sleep but not with the amount of SWS (Göder et al., 2007). But there are notable differences between the two studies. The patients in the present study showed a markedly lower severity of depression and a considerably lower age range. This latter factor might partially explain the discrepancy, as there are several indications that the mechanisms of sleep-related memory consolidation change within the life span (Diekelmann et al., 2009; Hornung et al., 2007).

There are indications that REM sleep plays an important role in processing procedural learning and emotional memory. But the general role of REM sleep in memory consolidation is challenged by recent REM sleep deprivation studies in young healthy humans. Acute decreases of REM sleep, up to 15% of baseline, induced by awakenings or through antidepressant medication showed no decrements in verbal learning, mirror-tracing learning or simple motor tasks (Genzel et al., 2009; Rasch et al., 2009; Saxvig et al., 2008). As REM sleep deprivation by repeated awakenings has been criticized because of the induction of stress, we studied the application of antidepressants, which have been shown to reduce REM sleep in healthy subjects and patients with major depression. As expected, citalopram and reboxetine reduced REM sleep after 1 week of treatment in comparison to baseline and in contrast to a group of patients treated with psychotherapy. In accordance with a study by Kuenzel et al. (2004), reboxetine also significantly increased the number of awakenings. As shown in other studies, SSRI or SNRI within 1 week of treatment had no major effects on delta, theta or alpha power values (Feige et al., 2002; Kuenzel et al., 2004; Schlösser et al., 1998). As in the study by Rasch et al. (2009), the SSRI had no effect on the number or density of sleep spindles, but Rasch and his colleagues found a significantly higher number of fast spindles after intake of reboxetine, whereas in our study there was only an insignificant increase in sleep spindles in the reboxetine group. Like the results in the study of Feige et al. (2002), we found no correlation between blood levels of citalopram or reboxetine and REM sleep duration either with the change from baseline to follow up or with the amount at t1.

Similar to the acute effects in healthy subjects found in the study by Rasch et al. (2009), performance in verbal memory or procedural learning after 1 week of treatment was not decreased either. This is also in line with long-term studies analysing the effects of antidepressants on memory performance in depressed patients (Siegel, 2001). It might be argued that we did not find an effect of REM sleep suppression on memory or cognitive flexibility because of enhancing effects of the antidepressants on cognition by serotonergic or aminergic mechanisms. There are human and animal studies indicating that these mechanisms play an important role in memory processes, but the precise nature of this regulation is unclear (Monleon et al., 2008). We found an association between higher blood levels of citalopram and an increase in words learned in the evening, but not with overnight memory performance, thus indicating that acute drug effects did not counteract possible effects of REM suppression on memory performance.

There are limitations as to whether our study can be generalized. For one thing, there is the small sample size after randomization and, for another, we studied patients with moderate major depression without a control group of healthy subjects. Due to the small sample size, further studies are needed to validate our results. The advantages of our design are that we avoided stress by nocturnal awakenings to suppress REM sleep and that we avoided giving antidepressants with all their adverse side-effects to healthy subjects. In future studies, the effects of antidepressive REM sleep diminution on emotional memory performance and executive functions should be explored.

In conclusion, our study supports earlier findings of different roles of SWS and REM sleep in promoting diverse cognitive functions. Our results suggest that, in line with other studies, there are no negative effects of a REM sleep decrease by antidepressants on declarative or procedural memory performance.

Disclosure Statement

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

This was not an industry-supported study. The authors have confirmed that there are no financial conflicts of interest.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References

This study was supported by the Deutsche Forschungsgemeinschaft (DFG): KO 2067/1-2 to J.K., R.G. and J.A., and SFB 654 A9 to R.G. and J.A. We thank Nicola Wendisch for technical assistance and Birgit Gottwald for support in choosing the neuropsychological tasks.

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  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure Statement
  8. Acknowledgements
  9. References
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