The serotonin theory of depression: a systematic umbrella review of the evidence.

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Peer-supported Open Dialogue: a thematic analysis of trainee perspectives on the approach and training.

BACKGROUND: Open Dialogue (OD) is a Finnish social network based model of care, with practice and organisational aspects. Peer-supported Open Dialogue (POD) is a UK version involving peer workers, whose contributions include building on fragmented social networks. Fifty-four NHS staff undertook the first training in POD between 2014 and 2015. The training course was organised as four separate residential weeks, together with reflective sharing on an online platform. AIMS: This study aimed to explore the perspectives of the POD trainees on the training and the POD approach. METHODS: At the end of the training year, four focus groups were conducted using a semi-structured interview measure examining trainees' perspectives on the training and POD approach. A thematic analysis was performed on the transcripts to analyse data. RESULTS: Four superordinate themes emerged: personal experience, practice development, principles of POD, and pedagogical issues, each with a variety of subordinate themes. CONCLUSIONS: The course was widely reported as a positive experience, with substantial changes in attitudes and approaches to clinical work arising thus. Across the four superordinate themes, participant responses described a highly experiential course, experienced as an emotional journey which enabled them to embody the principles of POD, as well as use them at work.

Correlation of stoichiometries for Rb+ extraction determined by mass spectrometry and electrochemistry at liquid|liquid interfaces.

The electrochemical extraction of rubidium at micro water|1,2-dichloroethane (w|DCE) and water|room-temperature ionic liquid (w|RTIL) interfaces housed at the tip of a 25-µm capillary using octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO) in the TRans Uranic EXtraction (TRUEX) process, was examined. Rubidium is of great interest in a modern spent nuclear fuel cycle as well as toward myocardial perfusion imaging utilizing (82)Sr/(82)Rb isotopic generators. The ligand-to-metal stoichiometry (n:1) and overall complexation constant (ß) for interfacial complexation reactions induced by an applied potential were determined by the interfacial electrochemistry. One stoichiometry, n = 2, was observed at the w|DCE interface with ß = 3.3 × 10(4). In the w|RTIL system, two rubidium salt solutions were employed: RbNO(3) and RbNO(3) plus Rb(2)SO(4). The former demonstrated a stoichiometry of n = 2 and ß = 2.4 × 10(6), while the latter showed n = 4 and ß = 3.3 × 10(12). These stoichiometries of the reaction were confirmed by electrospray ionization mass spectrometry, using an emulsion generated by shaking water and DCE phases containing the dissolved metal and ligand, respectively. Both RbCMPO(+) and RbCMPO(2)(+) complexes were observed. The influence of ion pair interactions in this system will be discussed.

Facile determination of formal transfer potentials for hydrophilic alkali metal ions at water|ionic liquid microinterfaces.

The formal transfer potentials of hydrophilic alkali metal ions Li(+), Na(+), K(+), Rb(+), and Cs(+) were determined at water|room temperature ionic liquid (w|RTIL) interfaces. A working curve for an interface held at the tip of a micropipette (25 µm in diameter) was developed through simulated cyclic voltammograms (CVs) via finite element analysis with Comsol Multiphysics software. This methodology takes advantage of the symmetric diffusion regime experienced at the w|RTIL micropipette interface between two immiscible electrolytic solutions (micro-ITIES) which generates peak-shaped waves in the forward and reverse scans similar to those in CVs obtained at large (centimeter scale) ITIES. Through the simulation a profile of IT was generated in order to construct the working curve from which, in conjunction with experimentally obtained CVs, the formal transfer potentials were extrapolated. The unique characteristics of diffusion at an interface utilizing a pulled capillary make this approach possible. Additionally, within the simulation the geometry can be tailored to approximate closely the actual physical and experimental conditions. In this way the formal transfer potentials of Li(+), Na(+), K(+), Rb(+), and Cs(+) were found to be 0.565, 0.548, 0.521, 0.531, and 518 V, respectively, at the interface between water and our extremely hydrophobic ionic liquid, trihexyltetradecylphosphonium tetrakis(pentafluorophenyl)borate. The implications of these constants towards the evaluation of metal ion extractions will also be discussed.

Uranyl ion extraction with conventional PUREX/TRUEX ligands assessed by electroanalytical chemistry at micro liquid/liquid interfaces.

The facilitated ion transfer (FIT) of uranyl or dioxouranium (UO(2)(2+)) was studied electrochemically using a micro interface between two immiscible electrolytic solutions (micro-ITIES) in order to evaluate the complexation stoichiometry and complexation constants (ß) of two widely used ligands in spent fuel reprocessing: tributylphosphate (TBP) and octyl(phenyl)-N,N-diisobutylcarbamoylmethyl-phosphine oxide (CMPO). For the first time, discrete interfacial complexation reaction steps of varying uranyl to the two ligands ratios were resolved using the micro-ITIES hosted at the tip of a 25 µm diameter glass capillary. Two stoichiometries for UO(2)NO(3)TBP(n)(+) were determined including n = 3 and 4 with ß values of 3.2 × 10(11) and 3.9 × 10(13), respectively. Subsequently, three distinct complexation reactions of CMPO with UO(2)(2+) were discovered corresponding to UO(2)NO(3)CMPO(2)(+), UO(2)NO(3)CMPO(3)(+), and UO(2)CMPO(5)(2+) whose respective complexation constants were determined to be 8.0 × 10(11), 8.8 × 10(14), and 6.5 × 10(32). The participation of nitrate anions in these complexation reactions is also discussed.

Interfacial complexation reactions of Sr2+ with octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide for understanding its extraction in reprocessing spent nuclear fuels.

The complexation reactions between strontium (Sr(2+)) and octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO) were studied at the aqueous|1,2-dichloroethane (w|DCE) and aqueous|room-temperature ionic liquid (w|RTIL) microinterfaces, in order to understand its extraction in reprocessing spent nuclear fuels, remediation of environmental contamination, and potential radiological isotope feed stock for (90)Y from its isotope (90)Sr in fission byproducts. The stoichiometry (or metal to ligand ratios) and overall complexation constant (ß) for these reactions at these two interfaces are described herein. Two stoichiometries at the w|DCE interface were discovered, that is, [Sr(CMPO)(2)](2+) and [Sr(CMPO)(3)](2+) with ß values of 4.5×10(19) and 5.5×10(25), respectively. Only one stoichiometry was observed at the w|RTIL interface: [Sr(CMPO)(3)](2+) with ß equal to 1.5×10(34). The larger complexation constant for [Sr(CMPO)(3)](2+) at the w|RTIL interface than those found at the w|DCE interface supported the previous observation of a greater distribution ratio in the aqueous-RTIL metal extraction than that in the aqueous-alkane processing. The kinetics of the reactions at the w|RTIL interface was slow. The stoichiometries at the w|DCE interface were confirmed using biphasic electrospray ionization mass spectrometry (BESI-MS) as well as direct injection of Sr(2+) and CMPO mixture by means of a "shaking flask" experiment to conventional ESI-MS.

Definitions of relapse in trials comparing antipsychotic maintenance with discontinuation or reduction for schizophrenia spectrum disorders: A systematic review.

INTRODUCTION: Avoidance of relapse is the main aim of long-term antipsychotic treatment in schizophrenia, yet how 'relapse' is defined in trials is not well-known. METHODS: We conducted a systematic review of definitions of relapse in trials of continuous antipsychotic treatment compared with discontinuation, intermittent treatment or dose reduction for people with schizophrenia spectrum disorders. Trials were identified from previous Cochrane reviews and a new search. The quality of relapse definitions was rated in terms of reliability and clinical relevance and associations between quality of definitions and trial characteristics and outcome were explored. RESULTS: We identified 82 reports of 81 trials which employed 54 different definitions of relapse. There were 33 definitions in the 35 trials published since 1990, with recent trials employing complex definitions often involving alternative criteria. Only ten primary definitions of relapse required the presence of psychotic symptoms in all cases, and only three specified this in combination with a measure of overall severity or functional decline. Only two definitions specified a duration longer than two days. Relapse definitions were rated as showing good reliability in 37 trials, but only seven showed good clinical relevance. Six trials with definitions that were both reliable and clinically relevant were slightly longer, but did not differ from remaining trials in other characteristics or overall or relative risk of relapse. CONCLUSIONS: Antipsychotic trials define relapse in numerous different ways, and few definitions consistently reflect suggested indications of a clinically significant relapse.

SSRI and SNRI withdrawal symptoms reported on an internet forum.

BACKGROUND: Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. OBJECTIVE: We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. METHODS: We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. RESULTS: 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). LIMITATIONS: The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). CONCLUSIONS: People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.

Tetraoctylphosphonium tetrakis(pentafluorophenyl)borate room temperature ionic liquid toward enhanced physicochemical properties for electrochemistry.

Presented herein is the facile preparation of a new room temperature ionic liquid (RTIL), tetraoctylphosphonium tetrakis(pentafluorophenyl)borate (P(8888)TB). Subsequently, its physicochemical properties such as density, viscosity, and conductivity were characterized relative to temperature, demonstrating values of 1.22 g·cm(-3), 727 mPa·s, and 180 µS·cm(-1), respectively, at 60 °C. The electrochemistry of P(8888)TB was also investigated using cyclic voltammetry at a Pt-disk ultramicroelectrode and at a microinterface between water and the RTIL; this analysis revealed a wide metal-electrolyte potential window, ∼3.5 V, and a large liquid|liquid polarizable potential window, ∼0.9 V, at a temperature of 60 °C. Additionally, electron transfer (ET) reactions at a metal electrode|RTIL interface along with ion transfer (IT) reactions at the water|P(8888)TB interface were examined; the kinetics of these reactions were explored using finite element analysis. Increased ET and IT kinetics combined with enhancements of physicochemical properties versus RTILs we made previously seemingly suggest modest improvements. However, taken as a whole, they demonstrate significant progress toward a hydrophobic RTIL that can be used in conventional electrochemistry and biphasic metal ion extractions.