Oxidative stress in drug-naïve first episode patients with schizophrenia and major depression: effects of disease acuity and potential confounders.

Oxidative stress and immune dysregulation have been linked to schizophrenia and depression. However, it is unknown whether these factors are related to the pathophysiology or whether they are an epiphenomenon. Inconsistent oxidative stress-related findings in previous studies may have resulted from the use of different biomarkers which show disparate aspects of oxidative stress. Additionally, disease severity, medication, smoking, endocrine stress axis activation and obesity are potential confounders. In order to address some of these shortcomings, we have analyzed a broader set of oxidative stress biomarkers in our exploratory study, including urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), 8-OH-2-deoyxguanosine (8-OH-2-dG), and blood levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione S-transferase (GST) in acutely ill drug-naïve first episode patients with schizophrenia (n = 22), major depression (n = 18), and controls (n = 43). Possible confounding factors were considered, and patients were followed-up after 6 weeks of treatment. No differences were observed regarding 8-OH-2-dG, MDA and GST. At baseline, 8-iso-PGF2α levels were higher in patients with schizophrenia (p = 0.004) and major depression (p = 0.037), with a trend toward higher SOD concentrations in schizophrenia (p = 0.053). After treatment, schizophrenia patients showed a further increase in 8-iso-PGF2α (p = 0.016). These results were not related to age, sex, disease severity, medication or adipose tissue mass. However, 8-iso-PGF2α was associated with smoking, endocrine stress axis activation, C-reactive protein levels and low plasma concentrations of brain-derived neurotrophic factor. This study suggests a role of lipid peroxidation particularly in drug-naïve acutely ill schizophrenia patients and highlights the importance of taking into account other confounding factors in biomarker studies.

Sleep changes in smokers before, during and 3 months after nicotine withdrawal.

Nicotine may affect sleep by influencing sleep-regulating neurotransmitters. Sleep disorders can increase the risk for depression and substance dependency. To detect the influence of sleep disturbances on the effect of smoking cessation, we investigated polysomnographically (PSG) the sleep of smoking subjects during a period of smoking, during withdrawal and after a period of abstinence from nicotine. Thirty-three smokers (23 male, 10 female, median age 29 years, Fagerström Test for Nicotine Dependence score 6.3) were examined during smoking, 24-36 hours after smoking and 3 months after cessation. All subjects had an adaptation night followed by the PSG night. Compared with the smoking state, we found increased arousal index and wake time during nicotine withdrawal. Smokers who later relapsed (11) presented a higher degree of nicotine dependence and more withdrawal symptoms than those who abstained (22) and were characterized by less rapid eye movement (REM) sleep, a longer REM latency as well as by more intense sleep impairments in the subjective sleep rating during the withdrawal. Impairments of sleep during the withdrawal phase may reflect more severe nicotine dependence and may contribute to earlier relapse into smoking behaviours.

Impaired sleep quality and sleep duration in smokers-results from the German Multicenter Study on Nicotine Dependence.

Cigarette smoking is a severe health burden being related to a number of chronic diseases. Frequently, smokers report about sleep problems. Sleep disturbance, in turn, has been demonstrated to be involved in the pathophysiology of several disorders related to smoking and may be relevant for the pathophysiology of nicotine dependence. Therefore, determining the frequency of sleep disturbance in otherwise healthy smokers and its association with degree of nicotine dependence is highly relevant. In a population-based case-control study, 1071 smokers and 1243 non-smokers without lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorder were investigated. Sleep quality (SQ) of participants was determined by the Pittsburgh Sleep Quality Index. As possible confounders, age, sex and level of education and income, as well as depressiveness, anxiety, attention deficit hyperactivity, alcohol drinking behaviour and perceived stress, were included into multiple regression analyses. Significantly more smokers than non-smokers (28.1% versus 19.1%; P < 0.0001) demonstrated a disturbed global SQ. After controlling for the confounders, impaired scores in the component scores of sleep latency, sleep duration and global SQ were found significantly more often in smokers than non-smokers. Consistently, higher degrees of nicotine dependence and intensity of smoking were associated with shorter sleep duration. This study demonstrates for the first time an elevated prevalence of sleep disturbance in smokers compared with non-smokers in a population without lifetime history of psychiatric disorders even after controlling for potentially relevant risk factors. It appears likely that smoking is a behaviourally modifiable risk factor for the occurrence of impaired SQ and short sleep duration.

Prostaglandin D synthase (beta-trace) in healthy human sleep.

STUDY OBJECTIVES: The prostaglandin D system plays an important role in animal sleep. In humans, alterations in the prostaglandin D system have been found in diseases exhibiting sleep disturbances as a prominent symptom, such as trypanosoma infection, systemic mastocytosis, bacterial meningitis, major depression, or obstructive sleep apnea. Assessment of this system's activity in relation to human physiologic sleep was the target of the present study. DESIGN: Serum concentrations of lipocalin-type prostaglandin D synthase (L-PGDS, former beta-trace), and plasma levels of the pineal hormone melatonin were measured in 20 healthy humans (10 women, 10 men; aged: 23.3 +/- 2.39 years) at 4-hour intervals over a period of 5 days and nights, which included physiologic sleep, rapid eye movement sleep deprivation, and total sleep deprivation. In addition, the serum L-PGDS and plasma melatonin levels of 6 subjects were determined under conditions of bright white (10,000 lux) or dark red light (< 50 lux) in a crossover design during total sleep deprivation. Nocturnal blood sampling was performed by a through-the-wall tube system. L-PGDS was measured by an automated immunonephelometric assay, and melatonin was analyzed by direct radioimmunoassay. RESULTS: Serum L-PGDS concentrations showed marked time-dependent changes with evening increases and the highest values at night (P < .0005). This nocturnal increase was suppressed during total sleep deprivation (P < .05), independent of external light conditions and melatonin secretion. Rapid eye movement sleep deprivation had no impact on circulating L-PGDS levels. CONCLUSIONS: The circadian L-PGDS pattern and its suppression by total sleep deprivation indicate an interaction of the prostaglandin D system and human sleep regulation. L-PGDS measurements may well provide new insights into physiologic and pathologic sleep regulation in humans.

Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects.

RATIONALE: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a frequent finding in psychiatric disorders, including psychotic depression and schizophrenia. Conflicting results exist concerning the influence of antipsychotics on the HPA-axis. OBJECTIVE: Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the effect of quetiapine on nocturnal urinary cortisol and melatonin excretion in 13 healthy male subjects under conditions of undisturbed and experimentally disturbed sleep. METHODS: Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Placebo, quetiapine 25 mg or quetiapine 100 mg was administered orally 1 h before bedtime on nights 1 and 2. Urine produced during the 8-h bedtime period was collected for later determination of cortisol and melatonin concentrations by standard radioimmunoassays. RESULTS: MANOVA showed a significant effect for N1 vs. N2 with elevated total amount of cortisol ( p<0.005) and melatonin ( p<0.05) excretion after acoustic stress. Both quetiapine 25 mg and 100 mg significantly ( p<0.0005) reduced the total amount of cortisol excretion in comparison to placebo. No interaction effect of stress condition was observed. There was no effect of quetiapine on melatonin levels. CONCLUSION: The significant reduction of nocturnal cortisol excretion following quetiapine reflects a decreased activity of the HPA-axis in healthy subjects. This finding may be an important aspect in quetiapine's mode of action in different patient populations.

Polysomnographic findings in five adult patients with pituitary insufficiency before and after cessation of human growth hormone replacement therapy.

OBJECTIVE: We observed the new onset of severe obstructive sleep apnoea syndrome (OSAS) in an adult male patient during human growth hormone (hGH) replacement therapy. This prompted us to evaluate the potential influence of hGH substitution therapy on sleep in middle-aged men. DESIGN: A longitudinal study. SUBJECTS: Five male patients (aged 44-56 years, median age 54 years) with postoperative pituitary insufficiency given hGH replacement therapy for 1-2 years (median dose 2.0 U/day; median IGF-I serum concentration 351 microg/l) and 6 months after cessation of hGH treatment (median IGF-I level 77 microg/l - 1 microg/l = 0.131 nmol/l). MEASUREMENTS: Polysomnographic studies were performed, and the following parameters were determined: time in bed (TIB), sleep period time (SPT), total sleep time (TST), sleep efficiency (SE = TST/TIB), sleep stage 1 onset latency (SL), different sleep stages [W (wake), S1, S2, SWS (slow wave sleep = S3 + S4) and REM; % of SPT], stage shifts per hour of SPT (SS/h), stage shifts to W/h of SPT [A/h (awakening)], index of apnoea and hypopnoea events per hour of TST (AH/h), arousals from apnoea and hypopnoea per hour of TST (Ar/h), index of obstructive (OAH/h), central (CAH/h) and mixed (MAH/h) events of apnoea and hypopnoea per hour of TST and minimal desaturation (MD). RESULTS: Median baseline results were: TIB, 479 min; SPT, 465 min; TST, 405 min; SE, 77%; SL, 8.5 min; W, 18.9%; S1, 8.2%; S2, 52.7%; REM, 13.5%; SS/h, 17.7; A/h, 2.8; AH/h, 11.9; Ar/h, 4.4; MD, 80%. These parameters did not change significantly after cessation of hGH treatment. In contrast, median SWS decreased significantly from 33 min (7.1%) to 7.5 min (1.8%; P = 0.03). Median OAH/h decreased significantly from 4.4 to 0.1 (P = 0.03) whereas CAH/h increased from 6.3 to 14.6 (P = 0.03) after cessation of hGH. Correspondingly, one patient with OSAS improved markedly whereas another patient developed new and asymptomatic central SAS after cessation of hGH. CONCLUSION: This study showed that hGH replacement therapy influenced sleep reaction in a complex way in middle-aged men; cessation of treatment was associated with a significant decrease in slow wave sleep and a shift from obstructive to central apnoea and hypopnoea.