Quetiapine Improves Sleep Disturbance in Acute Bipolar Disorder: A Case Series

Mania is one of the most severe disorders in psychiatry. Disturbances of the sleep-wake cycle are key features of this disorder [8]. In particular, sleep loss can trigger symptoms of mania or hypomania in certain bipolar patients [10]. Additionally, decreased sleep duration proved to be the best predictor of a manic state the following day in patients afflicted with rapid cycling bipolar disorder [6]. Since mania in turn causes insomnia, the development of mania is potentially self-reinforcing and could become autonomous after being initiated by precipitating factors [11]. Repeatedly, the importance of adequate treatment of sleep disturbance has been underscored over the centuries [4] [8].

However, only few studies have examined objective sleep measures in mania polysomnographically. Compared with age- and sex-matched normal control subjects, manic patients exhibit severely disturbed sleep [7] including significantly decreased total bedtime, decreased total sleep time, increased time awake in the last two hours of recording, shortened rapid eye movement (REM) latency, increased REM activity, and increased REM density [5]. Additionally, an over-activation of the HPA axis (hypothalamus-pituitary-adrenal axis) activity in patients suffering from mania has repeatedly been described and appears to be a relevant factor in the pathophysiology of both depressive and manic episodes.

Therefore, the investigation of HPA axis activity, sleep and treatment of sleep disturbances in mania appears to be very important. The second generation antipsychotic quetiapine has been demonstrated to be an effective treatment of mania [1] as well as bipolar depression [12] and has been demonstrated to have sleep-inducing properties [2]. To the best of our knowledge no data exist on the effect of treatment with quetiapine in mania on polysomnographically registered sleep.

Therefore, we would like to present a case series of four patients suffering from bipolar mania (two male and one female, ages 21, 45, and 48 years ) and bipolar depression (one male, 39 years old) before and under treatment with quetiapine who were studied polysomnographically for a total of seven nights over a three-week period. Additionally, overnight urinary cortisol excretion and psychopathology were determined. Patients were asked to empty their bladder before going to bed and overnight urine was collected including the first morning urine after getting up. The urinary cortisol concentration was determined by ELISA (DRG Instruments GmbH; Marburg, Germany). After written informed consent, one night of adaptation to the sleep laboratory was followed by the baseline night. Immediate treatment effects were determined during the first two nights of titration with quetiapine (100 and 200 mg) while long-term effects were registered after three weeks following one night of adaptation for two consecutive nights. Quetiapine was titrated up to 800 mg in two divided doses as clinically appropriate.

At baseline the average young mania rating scale score of the manic patients was 24.7 (range: 21–28), while it decreased to 12.3 (range: 11–14) after three weeks of treatment. At baseline total sleep time (TST) lasted 322 min (range: 166–424), REM latency was 47.7 min (range: 7–80), and percentage slow wave sleep of sleep period time (SPT) was 10.1% (range: 0.9–22.7%). During the first two treatment nights TST increased by nearly one hour to 377 min (range: 215–520), REM latency increased to 79 min (range: 53–118), and SWS % was 5.1% (range 0–17.7 %). After three weeks of treatment TST increased further to 408 min (range 251–511) and REM latency to 148 min (range 50–277), and SWS was 6.5% (range: 0–19.8%). The depressed patient demonstrated a HAM-D score of 30 points at baseline that decreased to 16 after three weeks. TST increased from 389 min at baseline to 441 min during early titration and 460 min after three weeks of treatment while REM latency increased from 1 min to 55 min and 127 min, respectively. SWS changed only slightly from 26.1% at baseline to 16.9% during early titration and 22.6% after three weeks of treatment.

At baseline cortisol excretion/h of the four patients was 6.8±4.4 μg. With 7.2±4.8 μg/h it was nearly unchanged during early treatment and decreased to 3.9±1.9 μg/h after three weeks of treatment.

In this case series treatment of bipolar disorder with quetiapine demonstrates a clinically significant improvement of the amount and quality of sleep already at the beginning of drug titration that is consolidated during further administration of this medication and paralleled by a down-regulation of the HPA axis after three weeks. Due to the limited number of patients studied, generally valid conclusions about necessary dosages to obtain the clinical effects observed in our case series cannot be drawn. The increase of total sleep time and prolongation of REM latency as well as the decrease of cortisol, however, may be important for the therapeutic effect on the broader spectrum of manic and depressive symptomatology. An up-regulation of dopaminergic activity by sleep deprivation recently described for healthy subjects [9] may also be of relevance for the pathophysiology of bipolar disorder and its down-regulation by the antidopaminergic action of quetiapine may be relevant for the observed effects on sleep, cortisol and psychopathology. Further mechanisms, including the antiserotonergic, antihistaminergic, and antiadrenergic activity of quetiapine, might additionally be involved in its sleep-inducing and cortisol-reducing properties [2] [3] that, in turn, may be relevant for the improvement of affective symptoms ( [Fig. 1]).

Fig. 1 48-year-old manic patient: Polysomnography results displayed as hypnograms from (a) baseline, (b) early treatment with 100–0–0–100 mg quetiapine, and (c) after three weeks of treatment at a dose of 200–200–0–400 mg quetiapine.

Disclosure of Conflicts of Interest: We thank AstraZeneca for funding of the study. Dr. Cohrs: lecture fees from Astra Zeneca, Servier, GSK, Sanofi-Aventis, and Lundbeck; Prof. Falkai: consulting or advisory board fees and lecture fees from AstraZeneca, Janssen, Eli Lilly, Organon, and Pfizer; Prof. Ruether: grants, lecture fees, or advisory board: Eli Lilly, AstraZeneca, Lundbeck, Servier, Wyeth, Janssen, BMS, Boehringer Ingelheim, GSK; Prof. Rodenbeck: grants, advisory board fees or lecture fees from Lundbeck, Boehringer Ingelheim, Cephalon, Takeda, Sanofi-Synthelabo, GSK, Astra Zeneca, Bioprojet.

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