The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder.

The monoamine hypothesis has dominated research on the pathophysiology of mood disorders as well as the development of therapeutic drugs by over half a century. Nowadays a change of perspective is taking place. The glutamate system is increasingly implicated in the pathophysiology of mood disorders. The evidence spans from animal, post-mortem, imaging, pharmacological and genome-wide association studies. Bipolar disorder has been recently re-conceptualized as a synaptic plasticity-related disorder rather than simply as a result of deficits or excesses in individual neurotransmitters. A paradigm shift from a monoamine hypothesis to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the research for new drugs and therapies. In this review we summarize data from clinical and pre-clinical studies that have addressed glutamatergic alterations in bipolar disorder. Along with an in-depth discussion of glutamatergic alterations in bipolar disorder, we also report available data on the neuroprotective and neuroplastic potential of the classic mood stabilizers, ketamine, and psychedelics. The glutamatergic mechanisms underlying the efficacy of these drugs are described and discussed.

Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review.

BACKGROUND: Epigenetics offers one promising method for assessing the psychobiological response to stressful experiences during childhood. In particular, deoxyribonucleic acid (DNA) methylation has been associated with an altered hypothalamus-pituitary-adrenal (HPA) axis and the onset of mental disorders. Equally, there are promising leads regarding the association between the methylation of the glucocorticoid receptor gene (NR3C1-1F) and child maltreatment and its link with HPA axis and psychopathology. OBJECTIVE: The current study aimed to assess the evidence of a link among child maltreatment, NR3C1-1F methylation, HPA axis deregulation, and symptoms of psychopathology. METHODS: We followed the Prisma guidelines and identified 11 articles that met our inclusion criteria. RESULTS: We found that eight studies (72.72%) reported increased NR3C1-1F methylation associated with child maltreatment, specifically physical abuse, emotional abuse, sexual abuse, neglect, and exposure to intimate partner violence, while three studies (27.27%) found no significant association. Furthermore, a minority of studies (36.36%) provided additional measures of symptoms of psychopathology or cortisol in order to examine the link among NR3C1-1F methylation, HPA axis deregulation, and psychopathology in a situation of child maltreatment. These results suggest that NR3C1-1F hypermethylation is positively associated with higher HPA axis activity, i.e. increased production of cortisol, as well as symptoms of psychopathology, including emotional lability-negativity, externalizing behavior symptoms, and depressive symptoms. CONCLUSION: NR3C1-1F methylation could be one mechanism that links altered HPA axis activity with the development of psychopathology.

[Advantages and controversies of depot antipsychotics in the treatment of patients with schizophrenia]. / Chancen und Kontroversen von Depotantipsychotika in der Behandlung von Patienten mit Schizophrenie.

BACKGROUND: The objective of this article is to give an overview of the advantages and disadvantages of the use of depot antipsychotics in the treatment of schizophrenia. The focus is on efficacy, tolerability, relapse prevention, patient compliance and satisfaction compared to oral administration forms. MATERIAL AND METHODS: A literature search was conducted in medical databases. The results of meta-analyses, randomized controlled trials and systematic reviews from the years 1999-2014 were included. RESULTS AND DISCUSSION: Depot antipsychotics ensure maintenance of constant blood levels and a continuous medication delivery. The efficacy and tolerability of depot antipsychotics are comparable to oral administration forms. Due to an improved medication compliance a reduction of relapse and hospitalization rates can be achieved. This is a key focus for improving outcomes and reducing costs in the treatment of schizophrenia.

Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression--A [¹¹C] raclopride PET-study.

Dopamine D2/D3 receptor availability at rest and its association with individual pain perception was investigated using the [(11)C] raclopride PET-method in 24 female Fibromyalgia (FMS) participants with (FMS+, N=11) and without (FMS-, N=13) comorbid depression and in 17 healthy women. Thermal pain thresholds (TPT) and pain responses were assessed outside the scanner. We compared the discriminative capacity, i.e. the individual׳s capacity to discriminate between lower and higher pain intensities and the response criterion, i.e. the subject׳s tendency to report pain during noxious stimulation due to psychological factors. [(11)C] raclopride binding potential (BP), defined as the ratio of specifically bound non-displaceable radioligand at equilibrium (BP(ND)) was used as measure of D2/D3 receptor availability. We found significant group effects of BP(ND) in striatal regions (left ventral striatum, left caudate nucleus and left nucleus accumbens) between FMS+ and FMS- compared to healthy subjects. Correlational analysis showed negative associations between TPT and D2/D3 receptor availability in the left caudate nucleus in FMS-, between TPT and D2/D3 receptor availability in the right caudate nucleus in FMS + and positive associations between TPT and D2/D3 receptor availability in the left putamen and right caudate nucleus in healthy controls. The response criterion was positively associated with D2/D3 receptor availability in the right nucleus accumbens in FMS - and negatively with D2/D3 receptor availability in the left caudate nucleus in healthy controls. Finally, no significant associations between D2/D3 receptor availability and discriminative capacity in any of the groups or regions were determined. These findings provide further support for a disruption of dopaminergic neurotransmission in FMS and implicate DA as important neurochemical moderator of differences in pain perception in FMS patients with and without co-morbid depression.

Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression.

Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [(18)F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression.

Fear-learning deficits in subjects with fibromyalgia syndrome?

BACKGROUND: Fibromyalgia syndrome (FMS) is frequently associated with psychiatric conditions, particularly anxiety. Deficits in contingency learning during fear conditioning have been hypothesized to increase anxiety and, consequently, pain sensation in susceptible individuals. The goal of this study was to examine the relationship between contingency learning and pain experience in subjects with FMS and rheumatoid arthritis (RA). METHODS: Fourteen female FMS subjects, 14 age-matched female RA subjects and 14 age-matched female healthy controls (HCs) were included in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs, the unconditioned stimulus (US) of thermal stimuli. CS- predicted low-temperature exposure (US), while CS+ was followed by low or high temperature. RESULTS: In the FMS group, only 50% of the subjects were aware of the US-CS contingency, whereas 86% of the RA subjects and all of the HCs were aware of the contingency. CS+ induced more anxiety than CS- in RA subjects and HCs. As expected, low-temperature exposure was experienced as less painful after CS- than after CS+ in these subjects. FMS subjects did not show such adaptive conditioning. The effects of the type of CS on heart rate changes were significant in the HCs and the aware FMS subjects, but not in the unaware FMS subjects. CONCLUSIONS: Contingency learning deficits represent a potentially promising and specific, but largely unstudied, psychopathological factor in FMS. Deficits in contingency learning may increase anxiety and, consequently, pain sensation. These findings have the potential to contribute to the development of novel therapeutic approaches for FMS.

Discovering imaging endophenotypes for major depression.

Psychiatry research lacks an in-depth understanding of mood disorders phenotypes, leading to limited success of genetics studies of major depressive disorder (MDD). The dramatic progress in safe and affordable magnetic resonance-based imaging methods has the potential to identify subtle abnormalities of neural structures, connectivity and function in mood disordered subjects. This review paper presents strategies to improve the phenotypic definition of MDD by proposing imaging endophenotypes derived from magnetic resonance spectroscopy measures, such as cortical gamma-amino butyric acid (GABA) and glutamate/glutamine concentrations, and from measures of resting-state activity and functional connectivity. The proposed endophenotypes are discussed regarding specificity, mood state-independence, heritability, familiarity, clinical relevance and possible associations with candidate genes. By improving phenotypic definitions, the discovery of new imaging endophenotypes will increase the power of candidate gene and genome-wide associations studies. It will also help to develop and evaluate novel therapeutic treatments and enable clinicians to apply individually tailored therapeutic approaches. Finally, improvements of the phenotypic definition of MDD based on neuroimaging measures will contribute to a new classification system of mood disorders based on etiology and pathophysiology.

Impact of emotion on cognition in trauma survivors: what is the role of posttraumatic stress disorder?

BACKGROUND: Cognitive theories of anxiety disorders postulate an increased attentional bias to environmental cues associated with threat that underlies the exaggerated fear response. The role of trauma, which may represent strong competitive advantage for attention, remains unclear. We investigated the influence of trauma exposure and the presence of anxiety/stress disorders on the impact of emotional distractors on cognitive performance. METHODS: Fourteen trauma-exposed subjects with PTSD, 12 trauma-exposed subjects with anxiety disorders other than PTSD, 12 trauma-exposed healthy subjects and 19 non-trauma-exposed healthy controls participated in this study. The impact of emotion on cognition was determined by the Affective Stroop task that measures the effect of irrelevant emotional distractors on the speed of operant responding. RESULTS: The speed of cognitive performance was significantly reduced in the presence of negative distractors versus neutral or positive distractors in subjects with PTSD, while there was no significant influence of the distractor type on performance in the other diagnostic groups (diagnosis-by-distractor type interaction, p<0.001). While negative distractors induced the same levels of anxiety and depersonalization in subjects with PTSD and subjects with other anxiety disorders, distractor-induced depersonalization was associated with slowing of cognitive performance in PTSD (p=0.02) but not in other groups. LIMITATIONS: Different types of anxiety disorders in the non-PTSD group might reduce the selectivity of the results; some subjects received medication possibly impacting on their cognitive functioning. CONCLUSIONS: The cognitive impairments in the presence of negative distractors specifically found in PTSD call for research into novel psychotherapeutic approaches, e.g. attentional training, for PTSD.

The neurobiology of affective disorder

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Asthma and body weight change: a 20-year prospective community study of young adults.

OBJECTIVE: There is increasing evidence for an association between asthma and body weight change. The objectives of these analyses were to examine the temporal relationships of this association and to explore the role of childhood depression as an explanatory factor. METHODS: Data were derived from six subsequent semistructured interviews on health habits and health conditions from a single-age community study of 591 young adults followed up between ages 20 and 40 years. RESULTS: Cross-sectionally (over the whole study period), asthma was significantly associated with obesity (odds ratio=3.9 [95% confidence interval 1.2, 12.2]). Multivariate longitudinal analyses revealed that asthma was associated with increased later weight gain and later obesity among women after controlling for potentially confounding variables, whereas weight gain and obesity were not associated with later asthma. A secondary analysis showed that depressive symptoms during childhood were associated with adult obesity and asthma, partially explaining the asthma-obesity comorbidity. CONCLUSION: This study encourages further research on mechanisms underlying the asthma-obesity comorbidity, particularly on shared psychosocial factors operating during critical periods in childhood and adolescence that may influence the development and persistence of both obesity and asthma during adulthood.

Depressive symptoms during childhood and adult obesity: the Zurich Cohort Study.

Depression and obesity have become major health problems with increasing prevalence. Given the limited effectiveness of treatment for weight problems, the identification of novel, potentially modifiable risk factors may provide insights on new preventive approaches to obesity. The purpose of this study was to test the hypothesis that depressive symptoms during childhood are associated with weight gain and obesity during young adulthood. Participants were from a prospective community-based cohort study of young adults (N=591) followed between ages 19 and 40 years. The sample was stratified to increase the probability of somatic and psychological syndromes. Information was derived from six subsequent semistructured diagnostic interviews conducted by professionals over 20 years. The outcome measures were body mass index (BMI) and obesity (BMI>30). Among women, depressive symptoms before age 17 years were associated with increased weight gain (4.8 vs 2.6% BMI increase per 10 years) representing greater risk for adult obesity (hazard ratio=11.52, P<0.05). Among men, only after controlling for confounders, depressive symptoms before age 17 years were associated with increased weight gain (6.6 vs 5.2% BMI increase per 10 years) in adulthood but not with occurrence of obesity. These associations between childhood depressive symptoms and adult body weight were adjusted for baseline body weight, a family history of weight problems, levels of physical activity, consumption of alcohol and nicotine, and demographic variables. As the magnitude of the associations was high, and depression during childhood is a prevalent and treatable condition, this finding may have important clinical implications for the prevention and treatment of obesity. Whether the results of this study are limited to populations with elevated levels of psychopathology remains to be tested.

The associations between psychopathology and being overweight: a 20-year prospective study.

BACKGROUND: Psychiatric disorders and being overweight are major health problems with increasing prevalence. The purpose of this study was to test the hypothesis that being overweight is associated with a range of psychiatric conditions including minor and atypical depressive disorders, binge eating, and aggression. METHOD: Prospective community-based cohort study of young adults (n = 591) followed between ages 19 and 40. Information derived from six subsequent semi-structured diagnostic interviews conducted by professionals over twenty years. Outcomes were being overweight [body-mass index (BMI)> 25] and average yearly weight change between ages 20 and 40 (BMI slope). RESULTS: 18.9 % of the participants were classified as being overweight. Being overweight turned out to be a stable trait: 77.7% of subjects were assigned to the same weight class at each interview. Atypical depression and binge eating were positively associated with both, increased weight gain and being overweight, while psychiatric conditions associated with aggressive behaviors (aggressive personality traits, sociopathy) were positively associated with being overweight, but were not related to the rate of weight change. Generalized anxiety disorder was negatively associated with overweight. These results persisted after controlling for substance use, levels of physical activity, demographic variables and family history of weight problems. CONCLUSIONS: This study shows relatively strong associations between eating-related and aggressive psychopathology and being overweight. Given the high prevalence rates of these conditions, this study encourages further research on the causality of psychopathology-overweight associations that might provide insight on novel preventive approaches for major health problems.

[Establishing and changing therapeutic goals in psychiatric-psychotherapeutic treatment]. / Zur Festlegung und Veränderung von Therapiezielen in psychiatrisch-psychotherapeutischen Behandlungen.

At the onset of psychotherapy, treatment goals are frequently not fully defined. They have to be set during treatment and can be changed in its course. An overview of the current literature on treatment goals from patients' and therapists' perspectives is given. Based on a case report of a patient suffering from panic disorder, the process of setting and changing goals and its influence on therapeutic technique and outcome are described. Finally, a case is made for the importance of "negotiations" between patient and therapist about treatment goals, which helps in building up a constructive therapeutic relationship and a helpful therapeutic process. The point in time of goal-setting, the achievability of treatment goals, and the patient's handling of unattained goals appear to be of particular significance.

Treatment of depressive disorders with and without medication - a naturalistic study.

OBJECTIVE: Although randomized clinical trials are the standard method for comparing the efficacy of various depression treatments, the external validity and generalizability of findings obtained by this approach can be questioned for several reasons. In this naturalistic study, we compared the effectiveness of treatments conducted by psychiatrists and clinical psychologists without prescription of drugs to treatments by psychiatrists and physicians using antidepressant agents in patients with depressive disorders in a representative sample of the normal population. Our assumption was that this sample is more representative for subjects treated for depressive disorders than subjects included in controlled trials. METHODS: In a post hoc analysis, the health status of depressed patients under treatment for major, minor or recurrent brief depression with medication (20 patients) and without medication (30 patients), and untreated depressed subjects were compared over a one-year period using SCL-90-R depression scale scores. RESULTS: At baseline, the two treatment groups were comparable in terms of diagnosis and severity of symptoms. Treatment effects were relatively small; patients treated with antidepressants tended to improve, whereas patients treated without drugs deteriorated slightly over one year. Seven years later, treated and untreated subjects no longer differed. CONCLUSION: The results are consistent with previous studies on usual care of depressed patients showing low response rates for non-standardized treatments outside of research settings. Despite a number of methodological shortcomings (small sample size, heterogeneity of subjects and treatments, unusual rating instruments), the results presented here are unique, and provide relevant insight into usual care of depressed patients. This study underlines the importance of standardized psychotherapy and pharmacotherapy in routine practice, of studies investigating the transferability of results of outcome studies across clinical populations, and of quality assurance in primary care psychiatry.

[Personality of patients with somatoform disorders]. / Zur Persönlichkeit von Patienten mit somatoformen Störungen.

36 patients of a medical outpatient clinic with cardiopulmonary and gastrointestinal somatoform complaints were interviewed two times at an interval of one year about physical symptoms, personal characteristics and need for professional assistance. The investigated patients felt more depressed than a normal cohort of comparable age. In 25% of the tests a disorder of personality according to ICD-10 was diagnosed. Anxious/depressive and obsessive/compulsive personality traits were predominant. Patients with suspected personality disorder felt more disturbed by a somatoform disorder, had more diffuse complaints and suffered more from symptoms of exhaustion. They were less satisfied with the obtained treatment but did on an average not demand more medical help than patients without personality disorders. The results are discussed with regard to the importance to treat patients with somatoform disorders and to the prognosis of the further course of disease.

The failure of aerosolized superoxide dismutase to modify pulmonary oxygen toxicity.

Superoxide (O2-.) is a highly toxic free radical that may be an important component of pulmonary O2 toxicity. The primary defense against this free radical is superoxide dismutase. Rats were exposed to aerosolized superoxide dismutase, and it failed to modify either the time course or the cumulative toxicity of 100 per cent O2. Because the aerosolized enzyme can be expected to be delivered only to the extracellular space of the lung, it is suggested that the primary site of production and of damage due to O2-induced free radicals must be within the intracellular space.

[Erysipelothrix endocarditis (author's transl)]. / Erysipelothrix-Endokarditis

Following erysipeloid a 46-year-old man fell ill with septicaemia and endocarditis. Treatment with high doses of antibiotics could not prevent his death. Infection with Erysipelothrix rhusiopathiae in man occurs through a skin lesion and only rarely leads to spreading of the agent in the body presenting as arthritis, meningitis, or endocarditis. Erysipelothrix endocarditis is a severe disease leading to widespread destruction of the involved cardiac valves. The aortic valve is most commonly involved. 16 out of 28 patients with erysipelothrix endocarditis reported in the literature died, eleven of them despite treatment with antibiotics.