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Contains fulltext : 292377.pdf (Publisher’s version ) (Open Access) BACKGROUND: Serotonin-norepinephrine reuptake inhibitors (SNRIs) are among the most frequently prescribed antidepressants (ADs) for major depressive disorder (MDD), with an increasing trend in the last decade. Given the relative dearth of information regarding rationales for their preferred use as first-line ADs in the broad clinical routine, the present study systematically investigated real-world characteristics of MDD patients prescribed either SNRIs or other AD substances across different countries and treatment settings. METHODS: In the present secondary analyses based on a large European, multi-site, naturalistic and cross-sectional investigation with a retrospective assessment of treatment outcome, we firstly defined the proportion of MDD patients receiving SNRIs as first-line AD psychopharmacotherapy and secondly compared their sociodemographic and clinical characteristics to those patients prescribed alternative first-line ADs during their current major depressive episode (MDE). RESULTS: Within the total sample of 1410 MDD patients, 336 (23.8 %) received first-line SNRIs. Compared to other ADs, SNRIs were significantly associated with inpatient care, suicidality and treatment resistance during the current MDE, and a longer lifetime duration of psychiatric hospitalizations. Moreover, greater severity of depressive symptoms at study entry, higher daily doses of the administered ADs, as well as more frequent prescriptions of psychopharmacotherapeutic add-on strategies in general and antipsychotic augmentation in particular, were significantly related to first-line SNRIs. CONCLUSIONS: Considering the limitations of a cross-sectional and retrospective study design, our data point towards a preferred use of first-line SNRIs in a generally more severely ill MDD patients, although they did not lead to superior treatment outcomes compared to alternative ADs.

Background: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. Methods: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. Results: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergicand specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. Conclusions: The identified divergencies may contribute to the concept of maleand female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity.

Background While the association between relationship status and the development of depressive symptoms in the general population were reported previously, its relation to the severity and the course of major depressive disorder (MDD) as well as the treatment patterns and response rates needs to be elucidated. Methods The present international multicenter cross-sectional study performed by the European Group for the Study of Resistant Depression (GSRD) investigated socio-demographic and clinical patterns of relationship status in a real-world sample of 1410 adult in- and outpatients with MDD as primary diagnosis. Results While 49.9% of all MDD patients were partnered, 25.4% were separated, and 24.8% were single. Single relationship status was linked to younger mean age, earlier mean age of onset, and current suicidal risk. Being separated was related to older mean age, unemployment, greater symptom severity, current suicidal risk, and add-on treatment strategies. Partnered relationship status was associated with less frequent current suicidal risk. Limitations The retrospective assessment of treatment response that was exclusively based on psychopharmacotherapeutic strategies should be critically considered and weighed while interpreting the present results providing novel insights into the complex interaction of relationship status with the clinical phenotype of MDD. Conclusions Although MDD patients living in relationships do not seem to be omitted from the evolution of MDD, they may be spared from chronicity and suicidality. Hence, being aware of the current relationship status might support clinicians in the diagnostic and therapeutic process towards optimized management of such challenging clinical phenomena and their negative consequences.

There are pronounced behavioural and neuroimaging parallels between cocaine abuse and narcissism. Although the observed commonalities are not specific to cocaine as opposed to other types of addiction, we argue that the relatively constrained molecular actions of cocaine and, more importantly, the covariance of narcissism-like behaviours with cocaine use build a strong case for taking the known effects of cocaine as a starting point for addressing the hitherto underinvestigated neurophysiology of narcissism. In this review, we discuss the potential relevance of cocaine abuse as a pharmacological model of narcissism. We outline previous research on the role of monoamines across several domains affected in narcissistic personality disorder and subclinical narcissism, namely, selected personality traits, social behaviour, emotional empathy and self-referential processing. We propose that dysregulation in dopamine signalling might underlie addiction-like features of narcissism and that altered serotonergic signalling may account for affective components of narcissism and, in particular, explain the differences between grandiose and vulnerable subtypes. In conclusion, we provide recommendations for future research.

Highlights • Disturbed glycemic control is an intrinsic feature of schizophrenia. • The neurotransmitter dopamine has a key role in regulating glucose homeostasis. • We studied brain dopamine and blood glucose levels in first episode psychosis. • The relationship between glucose and brain dopamine is altered in schizophrenia., An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Introduction: An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behaviour, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signalling in drug-naive patients with first-episode psychosis. Methods: We quantified blood glucose levels and binding of the D 3 preferring dopamine D 2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naive patients and 27 healthy volunteers employing positron emission tomography. Results: Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. One cluster was located in the ventral striatum and pallidum, the other one in the right ventral tegmental area. We observed positive correlations between blood glucose levels and binding-potential values in healthy volunteers but negative correlations in patients with first episode psychosis. Interpretation: Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signalling occurs when goal-directed behaviour is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are low, when blood glucose levels are high and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting a pathogenic alteration underlying two seemingly unrelated aspects of the illness: dysfunctional dopamine signalling and glucose homeostasis. Trial Registration: Clinical Trial Registry:EUDRACT 2010-019586-29 Funding: Vienna Science and Technology Fund; Austrian Science Fund; Medical Scientific Fund of the Mayor of the City of Vienna Declaration of Interests: Without relevance to this work, M. Willeit declares to having received speaker honoraria and consulting fees from Janssen-Cilag Pharma GmbH, Austria. Without relevance to this work, W. Wadsak declares to having received speaker honoraria from GE Healthcare, research grants from Ipsen Pharma, Eckert-Ziegler AG, Scintomics and ITG. WW is a part time eployee ofCBmed Ltd (Center for Biomarker Research in Medicine, Graz, Austria). and is a member of advisory boards of Amgen, Chieri and Sanofi-Aventis. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. S. Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH,KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi,Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. U. Sauerzopf, A. Weidenauer, I. Dajic, M. Bauer, L. Bartova, B. Meyer, L. Nics, C. Philippe, S. Pfaff, V. Pichler, M. Mitterhauser, L. Pezawas and N. Praschak-Rieder have no conflict of interest to declare Ethics Approval Statement: This study was approved by the Ethics-Committee of the Medical University of Vienna and Austrian federal regulatory authorities. All subjects signed an informed consent form.

Summary DiGeorge syndrome or 22q11.2 deletion syndrome is one of the most common genetic microdeletion syndromes in humans. In addition to physical manifestations, DiGeorge syndrome is associated with a high prevalence of psychiatric disorders, such as intellectual disability, schizophrenia and attention-deficit/hyperactivity disorder. Usually, the diagnosis of DiGeorge syndrome is made in early childhood. This article reports on the late diagnosis of a patient with panic disorder and comorbid major depression at the age of 51. Since genetic testing was not available before the 1990s, there might be many over 40-year-old patients, who remained undiagnosed. Psychiatric symptoms exhibit distinctive developmental trajectories and many of these exhibit an increase in incidence during adulthood. Hence, undiagnosed adult DiGeorge patients might present in psychiatric services. As in this case, a correct diagnosis of DiGeorge syndrome in adults may help to improve treatment and outcome.

Background Valproic acid (VPA) has been increasingly shown to trigger hyperammonemic encephalopathies in patients suffering from urea cycle defects and in those receiving polypharmacy. Methods We report on two cases of psychiatric inpatients with regular VPA intake who showed severe cognitive impairment due to non-cirrhotic hyperammonaemia without VPA overdosing. Results In the first case, OTC deficiency appeared to be the underlying cause of a comatose state in a middle-aged bipolar female patient. Besides hyperammonemia, we identified increased plasma levels of glutamine and alanine, decreased plasma levels of arginine and urea, as well as increased urinary levels of orotate. In the second case, we observed severe cognitive impairment in a younger male patient with a current psychotic episode with predominant affective symptoms who we treated with polypharmacy including VPA and topiramate. Limitations As this case series focused on individual patients, the results should be interpreted with caution and cannot be generalized. Conclusions In patients receiving VPA, considering urea cycle deficiencies and potential drug interactions seems crucial for avoiding potential life-threatening symptoms.

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.

(+)-[11C]PHNO, a dopamine D2/3 receptor agonistic radiotracer, is applied for investigating the dopaminergic system via positron emission tomography (PET). An improved understanding of neuropsychiatric disorders associated with dysfunctions in the dopamine system and the underlying mechanism is a necessity in order to promote the development of new potential therapeutic drugs. In contrast to other broadly applied 11C-radiopharmaceuticals, the production of this radiotracer requires a challenging four-step radiosynthesis involving harsh reaction conditions and reactants as well as an inert atmosphere. Consequently, the production is prone to errors and troubleshooting after failed radiosyntheses remains time consuming. Hence, we aimed to optimize the radiosynthesis of (+)-[11C]PHNO for achieving better activity yields without loss of product quality. Therefore, we synthesized (+)-[11C]PHNO and omitted all heating and cooling steps leading to higher activity yields. As a result, radiosynthesis fully conducted at room temperature led to a time-reduced production procedure that saves about 5 min, which is an appreciable decay-prevention of around 15% of the activity yield. Additionally, we established a troubleshooting protocol by investigating reaction intermediates, byproducts, and impurities. Indeed, partial runs enabled the assignment of byproducts to their associated error source. Finally, we were able to generate a decision tree facilitating error detection in (+)-[11C]PHNO radiosynthesis.

(+)-[11C]PHNO, a dopamine D2/3 receptor agonistic radiotracer, is applied for investigating the dopaminergic system via positron emission tomography (PET). An improved understanding of neuropsychiatric disorders associated with dysfunctions in the dopamine system and the underlying mechanism is a necessity in order to promote the development of new potential therapeutic drugs. In contrast to other broadly applied 11C-radiopharmaceuticals, the production of this radiotracer requires a challenging four-step radiosynthesis involving harsh reaction conditions and reactants as well as an inert atmosphere. Consequently, the production is prone to errors and troubleshooting after failed radiosyntheses remains time consuming. Hence, we aimed to optimize the radiosynthesis of (+)-[11C]PHNO for achieving better activity yields without loss of product quality. Therefore, we synthesized (+)-[11C]PHNO and omitted all heating and cooling steps leading to higher activity yields. As a result, radiosynthesis fully conducted at room temperature led to a time-reduced production procedure that saves about 5 min, which is an appreciable decay-prevention of around 15% of the activity yield. Additionally, we established a troubleshooting protocol by investigating reaction intermediates, byproducts, and impurities. Indeed, partial runs enabled the assignment of byproducts to their associated error source. Finally, we were able to generate a decision tree facilitating error detection in (+)-[11C]PHNO radiosynthesis.

Sensitization is defined as a process whereby repeated intermittent exposure to a given stimulus results in an enhanced response at subsequent exposures. Next to robust findings of an increased dopamine synthesis capacity in schizophrenia, empirical data and neuroimaging studies support the notion that the mesolimbic dopamine system of patients with schizophrenia is more reactive compared with healthy controls. These studies led to the conceptualization of schizophrenia as a state of endogenous sensitization, as stronger behavioral response and increased dopamine release after amphetamine administration or exposure to stress have been observed in patients with schizophrenia. These findings have also been integrated into the neurodevelopmental model of the disorder, which assumes that vulnerable neuronal circuits undergo progressive changes during puberty and young adulthood that lead to manifest psychosis. Rodent and human studies have made an attempt to identify the exact mechanisms of sensitization of the dopaminergic system and its association with psychosis. Doing so, several epigenetic and molecular alterations associated with dopamine release, neuroplasticity, and cellular energy metabolism have been discovered. Future research aims at targeting these key proteins associated with sensitization in schizophrenia to enhance the knowledge of the pathophysiology of the illness and pave the way for an improved treatment or even prevention of this severe psychiatric disorder.

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D2 and D3 dopamine receptor distribution by applying the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and human gene expression data. Since [11C]-(+)-PHNO has a higher affinity for D2 compared to D2 receptors, we hypothesized that there is a stronger relationship between D2/3 non-displaceable binding potentials (BPND) and D3 mRNA expression. To investigate the relationship between D2/3 BPND and mRNA expression of DRD2 and DRD3 we performed [11C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D2/D3 mRNA expression ratios to imitate the mixed D 2/3 signal of [11C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [11C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D2/D3 mRNA expression ratios also showed a positive correlation with [11C]-(+)-PHNO binding, reflecting the mixed D2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.

Background Cardio-pulmonary-resuscitation (CPR) training starting at the age of 12 years is recommended internationally. Training younger children is not recommended because young children lack the physical ability to perform adequate CPR and discouragement to perform CPR later is apprehended. The aim of this study was to answer the following questions: Are younger children discouraged after CPR training? Is discouragement caused by their lack in physical ability to perform adequate chest compressions on a standard manikin and would the use of manikins with a reduced resistance affect their motivation or performance? Methods We investigated the motivation and CPR performance of children aged 8–13 years after CPR training on manikins of different chest stiffness in a prospective, randomized, single-blind, controlled trial. 322 children underwent randomization and received 30 minutes CPR training in small groups at school. We used two optically identical resuscitation manikins with different compression resistances of 45kg and 30kg. Motivation was assessed with a self-administered questionnaire. Performance was measured with the Resusci®Anne SkillReporter™. Findings Motivation after the training was generally high and there was no difference between the two groups in any of the questionnaire items on motivation: Children had fun (98 vs. 99%; P = 0.32), were interested in the training (99 vs. 98%; P = 0.65), and were glad to train resuscitation again in the future (89 vs. 91%; P = 0.89). CPR performance was generally poor (median compression score (8, IQR 1–45 and 29, IQR 11–54; P

IntroductionTreatment resistant depression (TRD) affecting approximately 10–30% of all depressed patients often remains misdiagnosed and undertreated, leading to a higher risk of relapse and suicide. Electroconvulsive therapy (ECT) and sub-anesthetic ketamine have repeatedly shown to be effective in the TRD population. Administering ketamine as an anesthetic component to augment antidepressant efficacy of ECT has been proven inconclusive, while a combination of alternating ECT and ketamine has not been investigated yet.Case reportWe present a severely depressed and chronically suicidal female inpatient who failed multiple antidepressant treatment attempts, requiring frequent psychiatric admissions. Since available conventional as well as non-conventional antidepressant treatment strategies were nearly exhausted, we employed a combination of ECT (bilateral stimulation up to 150%) 2–3 times/week, while intravenous racemic ketamine (up to 75 mg per infusion) was administered on ECT free days 2–3 times/week. Consequently, robust anti-suicidal and antidepressant effects could be observed already during the first treatment week. The temporarily occurring subjective forgetfulness disappeared after the last ECT. Summarizing, we employed 9 ECT treatments and 7 ketamine infusions leading to a stable psychopathological state even after discharge from psychiatric inpatient care. In order to prevent relapse a maintenance-therapy comprising ECT once monthly and 2 ketamine infusions (up to 100 mg per infusion) administered on the day before and after ECT was established.ConclusionsIn our patient alternating ECT and intravenous racemic ketamine were proven safe and long-term effective after numerous failed antidepressant trials including ECT and ketamine alone. We may hence encourage clinicians to widen their therapeutic armamentarium in severe TRD.Disclosure of interestThe authors have not supplied their declaration of competing interest.