REM density is associated with treatment response in major depression: Antidepressant pharmacotherapy vs. psychotherapy.

Major depression is one of the most common psychiatric illnesses. Interestingly, a few studies have indicated the existence of depression subgroups, which respond differently to the available treatment options. Previously, sleep abnormalities have been suggested to indicate amenability to different treatment regimens. Thereby, especially REM-sleep parameters seem to play a prominent role, and REM-sleep dysregulation has been repeatedly discussed as a potential endophenotype of depression. With that said, estimating therapy outcome in order to choose the best line of treatment is of utmost importance to patients suffering from depression. The present study looks deeper into these clues by investigating the capability of polysomnographic sleep parameters to predict treatment response in depressed patients to either pharmacotherapy or psychotherapy. Moderately to severely depressed patients (n = 38) were randomly assigned to either psychotherapy (i.e. interpersonal psychotherapy) or pharmacotherapy (i.e., monotherapy with selective serotonin reuptake inhibitors, SSRI, or selective serotonin noradrenalin reuptake inhibitors, SSNRI). Prior to treatment, all patients underwent polysomnography in the sleep laboratory. After treatment, responders and non-responders of both treatment groups were compared regarding their baseline sleep parameters. Higher baseline REM density, i.e. the amount of rapid eye movements during REM sleep, predicted better response to antidepressant pharmacotherapy. In the psychotherapy group, the effect seemed reversed but was not statistically significant. No other sleep parameter predicted treatment response. Our findings support the notion that REM-sleep dysregulation is indeed indicative of a distinct endophenotype of depression and that pharmacotherapy with SSRI/SSNRI might be superior to psychotherapy in these patients.

Sleep recordings in individuals with borderline personality disorder before and after trauma therapy.

Most individuals diagnosed with borderline personality disorder (BPD) have been exposed to severe and traumatic stressors and thus frequently present with symptoms of a posttraumatic stress disorder (PTSD). Severe sleep disturbances often accompany these complex cases, but changes of sleep parameters during therapy and the impact of sleep on treatment response have barely been studied. Narrative Exposure Therapy (NET) is an evidence-based approach for the treatment of trauma-related psychological disorders. To investigate the effect of NET on sleep in patients with BPD and comorbid PTSD, we screened 45 inpatients and outpatients who met the inclusion criteria of both diagnoses according to DSM-IV and who had a minimum of 2 weeks' stable medication. Patients were allocated to NET (N = 13) or treatment as usual (TAU; N = 8) in blocks. Polysomnographies and psychological questionares were performed before, directly and 6 months after the last therapy session. The aim of this pilot study was to investigate the effectiveness of trauma therapy by NET on sleep quantity (total sleep time) and sleep continuity (sleep efficiency and awakenings) in patients with comorbid BPD and PTSD. Participants of the NET group compared with those who received TAU showed an increased reduction in sleep latency from baseline to the end of therapy and a reduction in arousals over time. Patients with longer pre-treatment total sleep time and pre-treatment REM sleep duration showed a better outcome of NET with respect to PTSD symptoms. NET seems not lead to a change in sleep for the worse during therapy and seems to improve sleep as good as treatment as usual. Furthermore, our results provide evidence of an influence of sleep structure at baseline on treatment success later on.

Sleep at baseline and after electroconvulsive therapy in patients with major depression.

Sleep in major depressive disorder is frequently altered and possibly indicative for treatment outcomes. For example, increased rapid eye movement (REM-) sleep density seems to predict worse treatment outcomes of psychotherapy. We therefore investigated pre-treatment sleep and sleep changes after termination of electroconvulsive therapy (ECT). Sleep was polysomnographically recorded. The analysed sample consisted of 15 inpatients with ages ranging from 30 to 80 (mean 59 years). ECT was applied two times a week up to 7 weeks. Stable remission of depressive symptoms was defined by a score in the Hamilton Rating Scale of Depression <8 at six months after ECT. The main results were an increase in sleep efficiency and a decrease in the number of awakenings within the course of ECT in the entire patient group. Significant increases in slow wave sleep and REM sleep duration and a significant decrease in REM density were only seen in stable remitters and not in non-remitters. In pre-treatment baseline sleep a higher REM density of the first REM sleep period was significantly associated with better ECT outcome. In conclusion, REM density of the first REM sleep period seems to be an interesting candidate as putative predictor of stable treatment outcome of ECT.

The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy.

Narcolepsy with cataplexy is a sleep dysregulation disorder with alterations of REM sleep, i.e., sleep onset REM periods and REM sleep instability. Deficient orexin-A (hypocretin-1) signaling is assumed to be a major cause of narcolepsy with cataplexy. In this study we investigated fourteen subjects with narcolepsy with cataplexy in a within-subject, random-order crossover, placebo-controlled design. Patients received double-blinded intranasal orexin-A (435 nmol) or sterile water (placebo) in the morning. Administration was preceded by an adaptation night and followed by a modified maintenance of wakefulness test, attention testing and a second full night of polysomnographic recording. We found comparable sleep behavior during the adaptation nights between both conditions. After orexin-A administration patients had less wake-REM sleep transitions and a decreased REM sleep duration. In the subsequent night, patients showed an increased N2 duration. In the test of divided attention, patients had fewer false reactions after orexin-A administration. Our results support orexin-A to be a REM sleep stabilizing factor and provide functional signs for effects of orexin-A on sleep alterations and attention in narcolepsy with cataplexy.

Declarative memory performance is associated with the number of sleep spindles in elderly women.

OBJECTIVE: Recent evidence suggests that the sleep-dependent consolidation of declarative memory relies on the nonrapid eye movement rather than the rapid eye movement phase of sleep. In addition, it is known that aging is accompanied by changes in sleep and memory processes. Hence, the purpose of this study was to investigate the overnight consolidation of declarative memory in healthy elderly women. SETTING: Sleep laboratory of University. PARTICIPANTS: Nineteen healthy elderly women (age range: 61-74 years). MEASUREMENTS: We used laboratory-based measures of sleep. To test declarative memory, the Rey-Osterrieth Complex Figure Test was performed. RESULTS: Declarative memory performance in elderly women was associated with Stage 2 sleep spindle density. Women characterized by high memory performance exhibited significantly higher numbers of sleep spindles and higher spindle density compared with women with generally low memory performance. CONCLUSION: The data strongly support theories suggesting a link between sleep spindle activity and declarative memory consolidation.

Reduced sleep-associated consolidation of declarative memory in attention-deficit/hyperactivity disorder.

OBJECTIVE: Sleep supports the consolidation of declarative memory. Patients with attention-deficit/hyperactivity disorder (ADHD) are not only characterized by sleep problems but also by declarative memory deficits. Given that the consolidation of declarative memory during sleep is supported by slow oscillations, which are predominantly generated by the prefrontal cortex, and that ADHD patients display low prefrontal brain activity, we assumed that ADHD patients show reduced sleep-associated consolidation of declarative memory. METHODS: The impact of sleep on the consolidation of declarative memory was examined with a picture recognition task. Twelve ADHD patients (10-16 years) and 12 healthy controls participated in two experimental conditions: in the sleep condition, learning was performed in the evening and picture recognition was tested after nocturnal sleep; in the wake condition, learning was conducted in the morning while retrieval took place after a day of wakefulness. RESULTS: Analyses of recognition accuracy revealed reduced sleep-associated enhancement of recognition accuracy in ADHD. While sleep-associated enhancement of recognition accuracy was correlated with slow oscillation power during non-REM sleep in healthy controls, no such correlations were observed in ADHD. CONCLUSIONS: These data indicate a deficit in sleep-associated consolidation of declarative memory in ADHD. Moreover, our results suggest reduced functionality of slow oscillations in sleep-associated consolidation of declarative memory in ADHD.

Sleep and cognition at baseline and the effects of REM sleep diminution after 1 week of antidepressive treatment in patients with depression.

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.

Effects of daytime naps on procedural and declarative memory in patients with schizophrenia.

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Straight memory deficits and sleep disturbances are well-known in patients with schizophrenia. This study tested the hypothesis that patients with schizophrenia have a deficit in procedural and declarative memory consolidation after a short midday nap when compared to healthy controls and patients with remitted to moderate major depression. Following a normal night's sleep, 22 healthy subjects, 20 patients with major depression and 21 patients with schizophrenia were studied in a napping and wake condition in a random-order cross-over design, early in the afternoon. To test declarative memory, the Rey-Osterrieth Complex Figure Test respectively the Taylor Complex Figure Test and, for procedural learning, a mirror tracing task were performed. The present study is the first to demonstrate significant differences between individuals with schizophrenia, depression and healthy matched controls with regard to measures of sleep and memory performance after a short period of daytime sleep (napping). In particular we found that a daytime nap of only about 40min led to improvement of declarative memory performance in all investigated groups, whereas no beneficial effect was seen on procedural performance in the group of medicated patients with schizophrenia in contrast to healthy controls and patients with remitted to moderate major depression.

Changes in CREB phosphorylation and BDNF plasma levels during psychotherapy of depression.

BACKGROUND: The cyclic adenosine monophosphate response element-binding proteins (CREB) and their interaction with brain-derived neurotrophic factor (BDNF) are essential elements in signal transduction pathways important for cellular resilience and neuroplasticity. They play a decisive role in the concept of altered neuroplasticity in major depression. We have previously demonstrated that the increase in phosphorylated CREB (pCREB) in T lymphocytes is significantly associated with clinical improvement in patients treated with antidepressants. In the present study, we focused on patients treated only with psychotherapy to exclude direct pharmacological actions. In addition to pCREB, we also measured the BDNF plasma levels. METHODS: pCREB in T lymphocytes was determined by Western blot; the BDNF plasma levels with solid-phase ELISA. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Thirty patients meeting DSM-IV criteria for major depressive episodes (MDE) were recruited into this 6-week study. They received interpersonal psychotherapy (IPT) twice weekly. RESULTS: After 6 weeks of IPT, 17 patients responded (reduction of > or =50% of baseline HAMD); after 1 week of treatment pCREB increased significantly compared to the nonresponder group. Measurement of the BDNF plasma levels revealed no differences between the responder and nonresponder groups. Furthermore, the correlations between BDNF plasma levels and pCREB were not significant. CONCLUSIONS: The early increase in pCREB is related to treatment response and does not depend on pharmacological interventions or BDNF plasma levels. For the first time, cellular biological markers could be associated with response to psychotherapy.

A flow-cytometric method to investigate glutamate-receptor-sensitivity in whole blood platelets - results from healthy controls and patients with schizophrenia.

Hypofunction of glutamate receptors may contribute to the symptoms of schizophrenia. Human platelets express glutamate receptors and can serve as peripheral surrogate model for neuronal cells. Aim of this study was to establish a fast and sensitive flow-cytometric method to determine the glutamate-dependent kinetics of intracellular calcium ([Ca++]i) mobilization in platelets of schizophrenic patients. Glutamate stimulated [Ca++]i response was measured with a flow-cytometer in anti-CD-41a-labelled whole blood platelets of treated schizophrenic patients (n=18) and controls (n=18). In two control experiments the NMDA-receptor antagonist MK-801 and the dopamine antagonist amisulpride, respectively, were added to probes from healthy subjects. Stimulation with glutamate led dose-dependently to a mobilization of [Ca++]i in both healthy controls and patients. This effect was significantly reduced in patients. In vitro NMDA-antagonism inhibited the glutamate response, whereas dopamine-antagonism had no effect. Our flow-cytometric method allows to measure glutamate-receptor mediated [Ca++]i response in whole blood platelets, without requiring platelet rich preparations. The reduced glutamate-response in the patients was not explained by a direct inhibitory treatment effect. However, further studies with drug naive patients will be necessary to find out whether or not the observed hypoglutamergic function of platelets is endogenous to the disorder.

Sleep in major depression: relation to memory performance and outcome after interpersonal psychotherapy.

BACKGROUND: Earlier findings suggest both a link between sleep and memory consolidation and a relationship between abnormal sleep at baseline and poor treatment outcome in major depression after interpersonal psychotherapy (IPT). METHODS: Pre-treatment polysomnography was examined in 32 patients with a major depressive episode (mean age = 39.5 years, 20 women). Declarative memory was tested by the Rey-Osterrieth Complex Figure Test and a paired associative word list and procedural learning was assessed by a mirror tracing skill. All patients were treated with IPT according to the manual and did not receive any antidepressant medication. Twenty-three patients took part in a minimum of 12 sessions of IPT. Remission was defined as 2 consecutive weeks with a score <8 on the Hamilton Rating Scale of Depression. RESULTS: Declarative visual memory performance was associated with total sleep time and total amount of rapid eye movement sleep. In IPT remitters (n = 14), there was a trend towards a decrease in rapid eye movement density (first period) and a significant decrease in delta power in pre-treatment sleep in comparison to non-remitters (n = 9). Treatment outcome after IPT was also associated with declarative memory performance at baseline (as a trend). CONCLUSIONS: Further indications of a role of sleep in memory processes and of the importance of specific sleep parameters as markers for a positive treatment response to psychotherapy were found.