Neuropsychopharmacology (2003) 28, 348–358 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org State Markers of Depression in Sleep EEG: Dependency on Drug and Gender in Patients Treated with Tianeptine or Paroxetine 1,2 1 1 1 1 1 ,1 1 H Murck , T Nickel ,HKu¨nzel , IA Antonijevic , J Schill , A Zobel , A Steiger* , A Sonntag and 1 F Holsboer 1Max Planck Institute of Psychiatry, Munich, Germany; 2Laxdale Ltd., Stirling, UK Tianeptine enhances while paroxetine inhibits serotonin reuptake into neurons; however, both show an antidepressive action. A subgroup of 38 depressed patients from a drug trial comparing the efficacy of tianeptine with that of paroxetine was studied with regard to their effects on sleep regulation, especially in relation to treatment response. We recorded sleep EEGs at day 7 and day 42 after the start of treatment with either compound, which allows measurement of changes due to the antidepressive medication in relation to the duration of treatment. Spectral analysis of the non-REM sleep EEG revealed a strong decline in the higher sigma frequency range (14– 16 Hz) in male treatment responders independent of medication, whereas nonresponders did not show marked changes in this frequency range independent of gender. The patients receiving paroxetine showed less REM sleep and more intermittent wakefulness compared to the patients receiving tianeptine. REM density after 1 week of treatment was a predictor of treatment response in the whole sample. Psychopathological features with regard to the score in single items of the HAMD revealed predictive markers for response, some of which were opposite in the gender groups, especially those related to somatic anxiety. Changes in REM density were inversely correlated to the changes in HAMD in the paroxetine, but not the tianeptine, group. Our data suggest the importance of taking gender into account in the study of the biological effects of drugs. The study further points to the importance of the higher sigma frequency range in the sleep EEG of non-REM sleep and REM density as a marker of treatment response. Neuropsychopharmacology (2003) 28, 348–358. doi:10.1038/sj.npp.1300029 INTRODUCTION cological treatment (Thase et al, 1994; Buysse et al, 1999a) REM density decreases. In drug-free depressed patients, an Most studies that investigated the effect of antidepressants increased REM density is a state marker of depression upon sleep agreed that tricyclic antidepressants and (Lauer et al, 1991). selective serotonin reuptake inhibitors (SSRIs) suppress Concerning changes in non-REM sleep the actions of rapid eye movement (REM) sleep (Sharpley and Cowen, antidepressants are inconsistent. For example, some in- 1995). Some antidepressive substances lack a suppressive crease slow-wave sleep (SWS) as tricyclic antidepressants effect on REM sleep, like trimipramine (Steiger et al, 1989) like amitriptyline and trimipramine, others decrease it, as nefazodone (Vogel et al, 1998) and bupropione (Nofzinger SSRIs like fluoxetine and paroxetine (Sharpley and Cowen, et al, 1995). However, other studies show that early changes of REM sleep parameters, especially REM latency and 1995). Besides these differences related to different drugs, gender also has to be taken into account for the percentage amount of REM during the sleep period time, interpretation of sleep-EEG characteristics. Gender differ- might predict treatment outcome with substances, which ences exist in the sleep EEG of depressed patients under have an accute effect on REM sleep like amitriptyline baseline conditions as a higher incidence of EEG delta (Kupfer et al, 1981; Gillin et al, 1978) and clomipramine activity (Reynolds et al, 1990), more delta and beta EEG (Ho¨chli et al, 1986). Furthermore, changes in REM sleep, activity of a higher amplitude, especially in the right especially REM density, occur in the course of antidepres- hemisphere (Armitage et al, 1995a) or power of the delta- sive treatment with fluoxetine (Buysse et al, 1999a) leading and sigma-frequency range in females (Antonijevic et al, to an increase in REM density, whereas under nonpharma- 2000a). A challenge with growth-hormone-releasing hor- mone (GHRH) led to an increase in sleep efficiency and *Correspondence: Dr A Steiger, Max Planck Institute of Psychia- stage 2 sleep in males, but a decrease in female healthy and try, Kraepelinstrasse 10, D-80804 Munich, Germany, Tel: +49 depressed subjects (Antonijevic et al, 2000a). Recently a 8930622236, Fax: +49 89 30622 548, E-mail: [email protected] differential efficacy for SSRIs compared to tricyclics in men Received 19 December 2001; revised 17 June 2002; accepted 20 June compared to women has been described (Kornstein et al, 2002 2000). With respect to the possible interactions between the Markers of depression in sleep EEG H Murck et al 349 type of drug and gender, we performed a study on the effect treatment without interference with depression was allowed. of two drugs with opposite actions on serotoninergic The patients were not treated with depot neuroleptics, neurotransmission, that is, paroxetine as an SSRI and fluoxetine and irreversible monoanime-oxidase inhibitors tianeptine as a serotonin reuptake enhancer (Mocaer et al, for at least 8 weeks prior to admission, and patients were 1988). This property might correlate with the opposing drug-free for a minimum of 1 week prior to the study. action of tianeptine and the SSRI fluoxetine on hippocampal Patients received either 20 mg paroxetine or 37.5 mg electrical activity (Shakesby et al, 2002). Furthermore, tianeptine beginning at D1. At day 21 (D21), the same dose tianeptine decreases stress-induced HPA-axis activity in a or double the dose, depending on treatment response, was similar way as desipramine, but different from paroxetine administered until day 42 (D42). After D7 and at D42, an (Delbende et al, 1994; Connor et al, 2000). Despite this investigation of the sleep EEG was done. The assessment of diverging effect of the tianeptine and SSRIs, they have some psychopathology was done on D1, D7, D14, D21, D28, D35 properties in common as tianeptine and the SSRI sertraline and D42; we give here only the data of the 38 patients showed similar effects in the Behavioral Despair Test and in included in the sleep-EEG analysis at baseline (D1) and the antagonizing the behavioral effect of olfactory bulbectomy days of the sleep-EEG examinations (D7 and D42). (Kelly and Leonard, 1994). At the cellular level, the effect of After a night of accommodation, the subjects underwent a tianeptine was similar to the tricyclic antidepressants polysomnographic examination. The subjects were allowed imipramine, amitriptyline and desipramine and to the SSRI to sleep between 23:00 and 7:00 h, which was also the time, fluoxetine in inhibiting glucocorticoid-mediated gene tran- when the light was turned off and the sleep recordings were scription (Budziszewska et al, 2000). made. The recordings consisted of two EEGs (C3-A2, C4-A1; We performed the study in a subgroup of patients taking time constant 0.3 s, low-pass filtering 70 Hz), vertical and part in a study comparing clinical and endocrine para- horizontal electro-oculograms (EOG), an electromyogram meters in patients with depression (Nickel et al, in press). (EMG) and an electrocardiogram (ECG). The EEG signals The subjects from this study were examined in the sleep were filtered (EEG: high-pass 0.53 Hz, À3 dB; low-pass laboratory for assessment of the changes in the sleep EEG in 70 Hz, À3 dB; À12 dB octave, band-stop between 42 and the course of the treatment. The aim was to define common 62 Hz, À3 dB) and transmitted by an optical fiber system to changes in the sleep EEG of depressed patients in the course the polygraph (Schwartzer, ED 24). By means of a personal of treatment despite different modes of action of the computer, EEG signals were additionally sampled by an antidepressant drugs, that is, to investigate which changes 8-bit analog-to-digital converter at a sampling rate of in the sleep EEG might be correlated with a treatment 100 Hz and stored on disk for further spectral analysis. response independent of the type of medication. Sleep EEGs were rated visually according to standard criteria (Rechtschaffen and Kales, 1968) by an experienced rater who was blind to the study protocol. The parameters F MATERIALS AND METHODS used were: SOL sleep onset latency (sleep onset defined as the first epoch of 30 s containing stages 2, 3, 4 or REM In a double-blind protocol, we compared the effect of sleep) (min); time spent in each of the following sleep stages tianeptine vs paroxetine in 44 patients with an episode of during time in bed: non-REM stage 2, SWS F slow-wave major depression. This study was approved by the Ethics sleep (non-REM stages 3 and 4), REM; REM latency Committee for Human Experiments of the Bavarian Medical (interval from onset until the first epoch containing stage Council (Bayerische A¨ rztekammer). The patients were REM) (min); REM density (minÀ1) (the average ratio of 3-s hospitalized for evaluation and treatment of depression. mini-epochs of REM sleep including REMs to the total At initial evaluation, all had to meet the criteria for a major number of 3-s mini-epochs of REM sleep per minute); and depressive episode or bipolar I or II disorder (depressed) the duration of intermittent wakefulness (IW) (min). according to DSM-IV (American Psychiatric Association, Spectral analysis was initially performed on the distinct 1994) with a Hamilton depression (HAMD) score on the 21- frequency ranges delta (0.8–4.5 Hz), theta (4.5-8.0 Hz), alpha item HAMD scale 418. To exclude spontaneous remission, (8.0–11.8 Hz), sigma (11.8–15.2 Hz) and beta (15.2–19.0 Hz) the difference of the total HAMD score between selection and thereafter additionally in three smaller ranges covering and inclusion at day 1 (D1) had to be o6 points.