Naturalistic comparison of clomethiazole and Diazepam treatment in alcohol withdrawal: effects on oxidative stress, inflammatory cytokines and hepatic biomarkers.

Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde and induces cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species that cause inflammatory liver damage. Clomethiazole, a drug approved for alcohol withdrawal treatment (AWT) in some European countries, inhibits CYP2E1. We hypothesized that clomethiazole would lead to a faster reduction in oxidative stress, inflammatory cytokines, and liver enzymes compared to diazepam treatment. We analysed respective biomarkers in 50 patients undergoing AWT and 25 healthy individuals but found no statistical difference between the two medication groups over 3-5 days. Hence, our hypothesis was not confirmed during this observation period.

[Dramatic changes in the age structure for medical specialists in the field of mental health]. / Dramatische Veränderungen der Altersstruktur bei Fachärzten im Bereich psychischer Gesundheit.

BACKGROUND: Over the past 20 years the importance of treatment of people with mental and neurological disorders has greatly increased. Parallel to this development it has become more difficult to attract young physicians to this field. The aim of this study was to examine the development of the number of physicians specialized in the care of patients suffering from neurological, mental and psychosomatic disorders with special consideration of the age structure. MATERIAL AND METHODS: The analyses were based on the number of professionally active physicians and specialized physicians published by the German Medical Association for the years 2000-2020. Separate age groups were looked at for psychiatry and psychotherapy (PPT), psychosomatic medicine and psychotherapy (PMPT), Nervenheilkunde (formerly psychiatry and neurology together, NHK) and neurology. RESULTS: In comparison to the year 2000 the number of specialized physicians working in PPT (4736 vs. 12,053), neurology (2226 vs. 8355) and PMPT (3543 vs. 4130) increased in 2020, while the number of specialists actively working in NHK decreased (5184 vs. 2301). Parallel to this the proportion of women increased. Dramatic changes occurred concerning the age structure. Currently, 77.7% of specialists working in NHK and 59.7% working in PMPT are over 60 years old. In 2020 there were 2988 specialists aged over 60 years in the discipline of PPT compared to only 1070 under 40 years, which is dramatically different from 20 years earlier when only 181 were over 60 years but 1491 were under 40 years old. CONCLUSION: The overaging of professional specialists and the shortage of junior physicians jeopardize modern and adequate provision of care for mentally ill patients. Possible solutions include a marked increase in medical school capacities as well as strategies to convince young physicians to work in the disciplines of PPT and PMPT.

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.

Von der Liebe.

The essential philosophical theories about love are contained in a poem and a fable. Although there are many connections between love, psychological experience and psychiatric disorders, love seems to be suspect in psychiatry. Possibly it is a basic complex of psychiatry not only to withdraw from love, but also to exclude the fundamental issues of sexuality and parenting of the mentally ill.

Philosophisch-psychiatrische Reflexionen zur Liebe.

With reference to a poem "Dialogue between two lovers" and a fable "The Last Love", essential aspects of love are described: love as access to the world, as a path to wisdom, self-knowledge and virtue, love as fear of loss and the desire to merge, love as encounter in dialogue, love as care, love as ecstasy, a feeling of pleasure and happiness. These are based on three theories of love from the beginnings of philosophy in ancient Greece by Plato and Aristotle. In the article they are considered from a philosophical-psychiatric perspective and supplemented by newer interpretations. With the help of a brief description of individual psychiatric disorders, a new understanding of love has been formulated. Ethical reflections on love life in psychiatry suggest that love in psychiatry is subject to a taboo, despite the creative possibilities it offers. Possible causes are discussed at the end. The article encourages thinking about love in psychiatry.

Increased S100B+ NK cell counts in acutely ill schizophrenia patients are correlated with the free cortisol index, but not with S100B serum levels.

Several studies have provided evidence for increased S100B serum concentrations in schizophrenia. The pathophysiological significance of this finding is still uncertain because S100B is involved in many cellular mechanisms and is not astrocyte-specific as was previously assumed. S100B is also expressed by subsets of CD3+ CD8+ T cells and natural killer (NK) cells and may therefore be linked to the immune hypothesis of schizophrenia. We have quantified S100B+ CD3+ CD8+ T cells and NK cells by flow cytometry in the peripheral blood of 26 acutely ill schizophrenia cases and 32 matched controls. In parallel, S100B concentrations and the free cortisol index (FCI), a surrogate marker for stress axis activity, were determined in serum samples from the same blood draw. Psychopathology was monitored using the Positive and Negative Syndrome Scale (PANSS). The patient group had increased S100B+ NK cell counts (P=0.045), which correlated with the FCI (r=0.299, P=0.026) but not with the PANSS or the elevated (P=0.021) S100B serum concentrations. S100B+ CD3+ CD8+ T cell counts were not significantly changed in the patient group and did neither correlate with the FCI and PANSS, nor with S100B serum concentrations. In conclusion, despite the observation of an increase in S100B+ NK cells in schizophrenia patients, the lack of a correlation with serum S100B concentrations suggests that these cells are probably not a major source of S100B in the blood of schizophrenia patients. Notably, elevated S100B+ NK cell counts may be linked with stress axis activation.

Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations?

Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.

"Evolution oder Wie der Mensch das Bewusstsein erlangte".

The satirical story describes how the first person became "conscious".

[Comments on Relationships with Artificial Emotional Intelligence - from "Here and Now" to "There and Then"]. / Zur Beziehungsgestaltung mit Künstlicher emotionaler Intelligenz ­ vom "Hier und Jetzt" zum "Dort und Dann".

The structure of relationships in the past, the present and the future is shaped by the idea of humanism. Based on this construct, the article illuminates various aspects and configurations of humanism on a timeline from "here and now" to "there and then". The current reality of care goes hand in hand with an emotional alienation of relationships. Advances in technology and reductionist neurobiological ideas can make it difficult to look at a person's mental illness as a whole. Any (communication) technology that has been developed in the past or will be developed in the future will sooner or later find its way into psychiatry and psychotherapy and change relationships. Transhumanism runs the risk that people will become alienated from each other and their species. Neural networks are algorithms that work regardless of the hardware used, be it based on organic carbon units such as humans or non-organic silicon units such as the computer/cyborg. There will be different ways to achieve super intelligence. Intelligence is a "must" and consciousness is a "can". If there is a change from a homocentric to a data-centered world view and the power of humans is transferred to the algorithms, humans could lose their economic value and the humanistic goals of health and happiness would be lost.

[Perspectives and Opportunities for Psychotherapeutic Interventions in Inpatient Psychiatric Treatment Delivered by Nurses]. / Perspektiven und Chancen für pflegerisch-psychotherapeutische Interventionen in der stationären psychiatrischen Behandlung.

BACKGROUND: Psychotherapy is an essential part of treating people with mental illness. However, the implementation of psychotherapeutic interventions in the field of inpatient psychiatric treatment remains well behind demand. At the same time, the use of psychotherapeutic interventions by other professional groups - such as social workers and nursing - is not a common practice in Germany. OBJECTIVE: What can we learn from the international research with regard to nursing for Germany in view of the insufficient supply of psychotherapeutic care. METHOD: Based on a literature analysis, the German situation of care is related to international developments and a German training curriculum is presented. RESULT: A look at the international literature shows that in other countries especially trained nurses perform psychotherapeutic Interventions. In addition, there are effective training curricula whose transferability to Germany appears to be possible after appropriate adjustments.An 18 months lasting training program for nurses is presented. In addition to disorder-specific competences, this curriculum also provides psychotherapeutic interventions with a general approach. CONCLUSION: Collaborative care in the collaboration of different health professionals has been repeatedly and stably proven to be effective and helpful in treating people with various mental disorders. In order to better meet the growing need for psychotherapeutic interventions in the population in the sense of a stepped care model, trained nurses need to be more involved in the provision of psychotherapeutic services.

[Be Searching for Happiness - An Excursus to Some Scientific Basics]. / Auf der Suche nach dem Glück ­ ein Exkurs zu einigen wissenschaftlichen Grundlagen.

Starting with the fairy-tale "Hans in luck" some scientific basics of social economy, neurobiology, psychology, psychiatry, and philosophy in the context of happiness are elucidated and from a personal point of view assigned to a moral, an aesthetic, an intellectual, and a spiritual dimension as fundamental principles of the human living together.

[Ethical Reflections on Parenthood of Mentally Ill Patients]. / Ethische Betrachtungen zur Elternschaft psychisch Erkrankter.

Ethical aspects towards the parenthood of mentally ill patients will be discussed in the German health care system. The "concept of an ethical therapist" offers new perspectives for solutions concerning the individual level. Structural and systemic problems require institutional and political configurations. The "ethical compass of psychiatric parenthood" points the dimensions of autonomy, heteronomy, egoism, and public spirit. Reductions of psycho-social burden, an age-dependent differentiated prevention und early external assessment contribute to successful parenthood of mentally ill patients.

The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects.

RATIONALE: Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis is an important aspect of the pathophysiology of major depression and schizophrenia. Despite the usefulness of atypical antipsychotics in the treatment of depression and their positive influence on cognitive functioning possibly related to their impact on cortisol, little is known about their effect on HPA axis function. OBJECTIVE: Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the influence of the atypical antipsychotics quetiapine and olanzapine in comparison with haloperidol and placebo on plasma adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. Eleven healthy male volunteers were studied during four sessions one week apart, orally receiving placebo, quetiapine (50 mg), olanzapine (5 mg), or haloperidol (3 mg). Blood samples were taken at hourly intervals from 0900 until 1700 hours. For ACTH, cortisol, and prolactin a significant effect of treatment condition (p < or = 0.005; p < or = 0.035; p < or = 0.0001, respectively) for area under the curve (AUC) was found. In comparison to placebo, quetiapine and olanzapine significantly reduced ACTH (p < or = 0.002; p < or = 0.05, respectively) and cortisol (p < or = 0.005; p < or = 0.03, respectively). No effect of haloperidol on AUC of ACTH or cortisol levels was observed. In comparison with placebo, haloperidol (p < or = 0.0001) and olanzapine (p < or = 0.0001) elevated AUC of prolactin plasma levels, whereas no significant effect was observed for quetiapine as a main effect of treatment condition. The atypical antipsychotics' strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals' blockade of serotonergic receptors, but blockade of adrenergic or histaminergic receptors may play a role as well. The observed HPA-axis down-regulation may be clinically important for the atypicals' effects on depressive symptomatology and cognitive functioning.

Improved sleep continuity and increased slow wave sleep and REM latency during ziprasidone treatment: a randomized, controlled, crossover trial of 12 healthy male subjects.

OBJECTIVE: Ziprasidone, an atypical antipsychotic, is a potent dopamine (D(2)) and serotonin (5-HT(2A/C)) receptor blocker, has agonistic properties at the 5-HT(1A) receptor, and blocks serotonin and norepinephrine reuptake. These transmitter systems are closely related to the regulation of sleep. METHOD: The aim of this double-blind, placebo-controlled, randomized, crossover study was to investigate the effects of ziprasidone on polysomnographic sleep structure and subjective sleep quality. Twelve healthy male subjects were randomly assigned to receive ziprasidone 40 mg or placebo for 2 sessions each composed of 2 consecutive nights (night 1, standard sleep conditions; night 2, acoustic stress) 5 days apart. Treatment was administered orally 2 hours before bedtime. The study was conducted from April 2004 to July 2004. RESULTS: Ziprasidone significantly increased total sleep time, sleep efficiency, percentage of sleep stage 2, and slow wave sleep; decreased the number of awakenings; and significantly affected tonic and phasic REM sleep parameters, i.e., it decreased percentage of REM and REM density and profoundly increased REM latency. CONCLUSION: Ziprasidone's effects on the sleep profile are somehow opposite to what is known about sleep of depressed patients (e.g., disturbances of sleep continuity, a reduciton of slow wave sleep, and a disinhibition of REM sleep). Its REM sleep-suppressing properties resemble those of most, although not all, antidepressants and may be clinically relevant. The drug also demonstrates sleep-consolidating properties under both standard routine and acoustic stress conditions. These effects are most likely related to ziprasidone's 5-HT(2C) antagonism, 5-HT(1A) agonism, and serotonin and norepinephrine reuptake inhibition.

Obstructive sleep apnea: Plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure.

Assessment of plasma endothelin-1 (ET-1) reveals conflicting results in cerebral and noncerebral conditions. Obstructive sleep apnea (OSA) syndrome has been used as a definite challenge for the investigation of endothelin measurements. Despite marked sleep-related breathing disturbances in untreated patients peripherally measurable ET-1 concentrations remained within the normal range and did not change after an appropriate therapy with continuous positive airway pressure (CPAP). In contrast, its precursor, big ET-1, was considerably elevated in untreated patients and dropped to normal values after long-term CPAP depending on compliance. Relatively stable big ET-1 elevations in untreated patients, during sleep and wakefulness, suggest that a general endothelial alteration beyond that explained by a direct impact of nocturnal breathing disturbances on the vascular system occurs. CPAP-therapy effectively lowered plasma big ET-1 in compliant patients and thus possibly their related risk for vascular diseases. Big ET-1 has been demonstrated to be a more appropriate marker of endothelial alteration than ET-1 because of its longer half-life. Simultaneous measurements are to be recommended.

Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington's disease.

A significant atrophy and loss of hypocretin neurons in the brains of human patients with Huntington's disease (HD) and in R6/2 mice have been reported. We included 10 patients with HD and 12 patients with chorea-like hyperkinetic movement disorders (non-HD). All patients of the HD group and eleven patients of the non-HD group showed normal hypocretin-1 levels. Thus, hypocretin-1 may not serve as an additional diagnostic marker for HD.

Narcolepsy increased L-PGDS (beta-trace) levels correlate with excessive daytime sleepiness but not with cataplexy.

OBJECTIVES: Alterations in the prostaglandin-D-system have been found in animal sleep experiments and disorders that present with hypersomnia or sleep disturbances. The recently demonstrated involvement of the leptomeningeal lipocalin-type prostaglandin-Dsynthase (L-PGDS) (beta-trace) in human physiological sleep encouraged us to investigate its role in the pathophysiology of narcolepsy. METHODS: In a pilot study, serum LPGDS and melatonin concentrations were assessed in 14 narcoleptic patients during undisturbed sleep and total sleep deprivation, compared with those from 14 healthy controls during undisturbed sleep. Excessive daytime sleepiness was measured by a standardized questionnaire (Epworth sleepiness scale, ESS). RESULTS: In narcoleptic patients, markedly increased baseline L-PGDS levels were significantly correlated with the ESS score, but not with the degree of cataplexy. Serum L-PGDS concentrations in patients as well as in controls followed a time-dependent fluctuation with evening increases, highest values during the night and in the morning. Compared with controls, patients exhibited significant/increased amplitude of circulating L-PGDS without any suppression by total sleep deprivation. CONCLUSION: These findings indicate that the prostaglandin-D-system contributes to the pathophysiology of narcolepsy, e. g. the regulation of excessive daytime sleepiness. Since it has been suggested that L-PGDS is also involved in neurodegenerative disorders, there may be a more specific role of the prostaglandin- D-system in narcoleptic aetiogenesis. Moreover, its linkage with the immune system as well as with human sleep regulation offers a direct access for investigating both systems.

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.

Sleep-promoting properties of quetiapine in healthy subjects.

The aim of this study was to investigate the effects of quetiapine, an atypical antipsychotic, on polysomnographic sleep structure and subjective sleep quality. This double-blind, placebo-controlled, randomized cross-over study investigated the polysomnographic sleep structure and subjective sleep quality of 14 healthy male subjects given placebo, quetiapine 25 mg or quetiapine 100 mg. Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Treatment was administered orally 1 h before bedtime on nights 1 and 2. Quetiapine 25 mg and 100 mg significantly improved sleep induction and continuity under standard and acoustic stress conditions. Increases in total sleep time, sleep efficiency, percentage sleep stage 2 and subjective sleep quality were seen. A significant increase in periodic leg movements during sleep was observed with quetiapine 100 mg. The sleep-improving properties of quetiapine may be important in counteracting different aspects of psychopathology in schizophrenia and other disorders. These sleep-inducing and sleep-modifying properties are probably related to quetiapine's receptor-binding profile, including its antihistaminergic, antidopaminergic and antiadrenergic properties. Other mechanisms might be relevant as well and further investigation is required.

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.