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Summary The discovery of rapid eye movement sleep in 1953 led to numerous studies investigating the relationship between rapid eye movement sleep abnormalities and psychiatric disorders. The most salient findings were the association of rapid eye movement sleep alterations—reduced rapid eye movement sleep latency, increased rapid eye movement sleep volume of total sleep, and increased rapid eye movement density—with major depression. This paper briefly reviews the history of rapid eye movement sleep research in psychiatry with a focus on the work related to major depressive disorder and some of the various theories that have been proposed to explain the associated rapid eye movement sleep abnormalities. Given the increasing evidence that rapid eye movement sleep is important for emotional processing, memory and cognition, a better understanding of the underlying mechanisms for the relationship between rapid eye movement sleep and mood disorders could lead to improved treatments for these common and disabling illnesses. [ABSTRACT FROM AUTHOR]

Medicinal chemistry is a science applied to the search and discovery of new therapeutic agents for the treatment of various diseases. Therefore, promising structures have been identified; one of these structures is the piperazine moiety, a cyclic molecule containing two nitrogen atoms in positions 1 and 4 as well as four carbon atoms. Many piperazine derivatives have central pharmacological activity that mainly involves the activation of the monoamine pathway. Thus, piperazine derivatives have been the subject of research for many central therapeutic applications, including antipsychotic, antidepressant and anxiolytic applications. Benzylpiperazine is the prototype of piperazine derivatives; this substance is the main component of recreational drugs, partly due to its stimulant and euphoric effects. This paper describes some piperazine derivatives used therapeutically as antipsychotic (clozapine), antidepressant (vortioxetine) and anxiolytic (buspirone) drugs. [ABSTRACT FROM AUTHOR]

Aim: The aim of this paper is to clarify the inconsistent findings in the association between antidepressant use and the risk of epithelial ovarian cancer (EOC). Methods: This study is a meta‐analysis of observational studies retrieved from the PubMed, EMBASE, and Web of Science databases prior to August 15, 2017. Two researchers independently screened studies and extracted study characteristics and risk estimates. The odds ratios (OR) and 95% confidence intervals (CI) of EOC risk were summarized using an inverse variance weighted random‐effects model. Heterogeneity between studies was assessed with the I2 statistic. Results: Eight case–control studies involving 7878 EOC cases and 73 913 controls were identified. Compared with non‐use, use of antidepressants was not significantly associated with EOC risk (summarized OR = 1.10, 95% CI: 0.91–1.32, I2 = 74.4%). Similar null results were also observed in the use of selective serotonin reuptake inhibitors (OR = 1.04, 95% CI = 0.80–1.35), tricyclic antidepressants (OR = 1.01, 95% CI = 0.79–1.30), and other antidepressant drugs (OR = 0.91, 95% CI = 0.74–1.12). Subgroup analyses of study characteristics, stratified by the type of control subjects, geographic location, exposure assessment, number of cases, and adjustment for potential confounders, showed that the ORs were broadly consistent across strata. The OR per 1 year‐increment of duration was 0.99 (95% CI = 0.94–1.05, I2 = 40.0%, P = 0.154). Additionally, the OR for the greatest intensity of antidepressant use compared with never use was 0.82 (95% CI = 0.70–0.98, I2 = 0%, P = 0.489). Furthermore, no evidence of publication bias was detected through Funnel plots as well as Egger's and Begg's tests. Conclusions: There is no association between antidepressant use and EOC risk. Further prospective studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. Aim: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. Design and Setting: We conducted in‐depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. Method: Semi‐structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio‐recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. Results: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. Conclusion: The lived experience of withdrawal significantly impacts individuals' well‐being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. Patient and Public Involvement (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

This paper presents commentaries on whether Starling's law applies to the esophagus; whether erythromycin affects esophageal motility; the relationship between hypertensive lower esophageal sphincter and vigorous achalasia; whether ethnic- and gender-based norms affect diagnosis and treatment of esophageal motor disorders; health care and epidemiology of chest pain; whether normal pH excludes esophageal pain; the role of high-resolution manometry in noncardiac chest pain; whether pH-impedance should be included in the evaluation of noncardiac chest pain; whether there are there alternative therapeutic options to PPI for treating noncardiac chest pain; and the usefulness of psychological treatment and alternative medicine in noncardiac chest pain. [ABSTRACT FROM AUTHOR]

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β‐arrestin‐2 (β‐Arr2) is required for the antidepressant‐like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult‐born granule cells are absent in the β‐Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)‐expressing cells in the β‐Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX‐expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX‐expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable. [ABSTRACT FROM AUTHOR]

In this paper an attempt is described to measure the cost differential between treating episodes of overdose on older antidepressants (e.g. TCAs) and those involving newer antidepressants (e.g. SSRIs). Data is presented showing that it is possible to demonstrate a marked cost differential between older and newer agents; although there are difficulties in precisely quantifying the difference. The limitations of the data are discussed and recommendations made for the methodology of a larger, more sensitive, study. Copyright © 1999 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this study, the effects of antidepressants on large‐scale brain networks and the neural basis of individual differences in response were explored. A total of 41 patients with major depressive disorder (MDD) and 42 matched healthy controls (HCs) were scanned by resting‐state functional magnetic resonance imaging separately at baseline and after a 12‐week follow‐up. The patients with MDD received escitalopram for 12 weeks. After treatment, patients were classified into those with MDD in remission [MDDr, endpoint 17‐item Hamilton Depression Rating Scale (HAMD) total score ≤7] and those in nonremission (MDDnr). The human Brainnetome Atlas was used to define large‐scale networks and compute within‐ and between‐network resting‐state functional connectivity (rsFC). Results showed the decreased subcortical network (SCN)–ventral attention network (VAN) connectivity at baseline increased in patients with MDD after 12‐week treatment, and it was comparable with that of HCs. This change was only observed in patients with MDDr. However, the decreased within‐network rsFC in SCN and default mode network (DMN) persisted in all patients with MDD, including those with MDDr and MDDnr, after treatment. The strength of SCN–VAN connectivity at baseline was significantly negatively correlated with the reduction rate of HAMD score in all patients with MDD. Thus, SCN–VAN connectivity may be an antidepressant target associated with depressive state changes and a predictor of treatment response to serotonin reuptake inhibitors. The within‐network rsFC in SCN and DMN may reflect a trait‐like abnormality in MDD. These findings provide further insights into the mechanism of antidepressants and their individual differences in response. The trial name is "Appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement" (URL: http://www.chictr.org.cn/showproj.aspx?proj=21377; registration number: ChiCTR‐OOC‐17012566). [ABSTRACT FROM AUTHOR]

Aim: It has been reported that the expression level of BNIP‐3 mRNA increases by antidepressants and Hochu‐ekki‐To (HET), suggesting that BNIP‐3 may be a candidate depression‐related factor. Therefore, in order to examine the relationship between BNIP‐3 and Qi, the expression levels of BNIP‐3 mRNA were examined using 22 newly extracted crude drugs which were selected from the previous library results on 120 crude drugs in the neuronal cell line N18TG‐2 and in the glial cell line C6Bu‐1. Methods: Based on the results on 120 kinds of crude drugs in a cDNA library, 22 kinds were selected and newly extracted, and then cells were re‐treated with them for a secondary assay by real‐time polymerase chain reaction (PCR) methods. Results: Many of the herbal medicines contained in HET increased BNIP‐3 mRNA expression overall. On the other hand, in the results with especially the neuronal cell line N18TG‐2, the herbal medicines that make up Oren‐gedoku‐To (OGT) and San‐o‐shashin‐To (SOST) strongly showed suppressive effects on the expression. Conclusion: Since HET clinically has the effect of raising mood, while an effect of OGT and SOST is to suppress the rise of mood, the result of this study may be of interest regarding the link between control of the direction of Qi and the expression of BNIP‐3 mRNA. [ABSTRACT FROM AUTHOR]

Background: Generalized anxiety disorder (GAD) is associated with the lowest treatment response rate among all anxiety disorders. Understanding mechanisms of improvement may help to develop more effective and personalized treatments. Aim: The objective of the study was to investigate different improvement mechanisms in the treatment of individuals diagnosed with GAD. Design: We reported data from a randomized controlled trial that evaluated three different GAD treatments (mindfulness‐based intervention, BMT; fluoxetine, FLX; and an active comparison group, QoL) for 8 weeks. Method: Mediation analyses were performed evaluating the association between worry symptoms at baseline and anxiety scoring at the endpoint, considering self‐compassion or mindfulness or its dimensions at mid‐treatment as mediators for the whole sample (assessing GAD improvement mechanism) and the different interventions as moderators. Results: Contrary to mindfulness state scoring (C =.06; 95% CI = −.05 to.20), self‐compassion (C =.11; 95% CI =.01 to.28) and non‐judgement of inner experience (C =.10; 95% CI =.004 to.21) mediated the association between worry symptoms at baseline and anxiety at the endpoint. When comparing BMT to FLX, the intervention modality did not moderate these associations. Conclusion: Self‐compassion and non‐judgement of inner experience seem to be essential targets in GAD treatment, contrary to the mindfulness state itself. Although no difference was found considering the intervention modality, future research may assess how to boost these dimensions in specific treatments for GAD. [ABSTRACT FROM AUTHOR]

The antidepressant medication fluoxetine (FLX) is frequently prescribed for the management of mood‐related illnesses in the adolescent population—yet its long‐term neurobehavioral consequences are not understood. To investigate how juvenile FLX exposure influences feeding behavior in adulthood, we conducted two experiments. In Experiment 1, adolescent male and female Sprague–Dawley rats were administered with 20 mg/kg/day FLX (postnatal day [PND] 35–49) and exposed to a binge access paradigm in adulthood (PND72+) to evaluate potential alterations for sweetened‐fat preference. No long‐term FLX‐induced differences in preference for sweetened fat versus chow, nor total caloric intake, were noted; however, females displayed higher preference for sweetened fat compared to males. In Experiment 2, PND35 male rats received FLX (PND35–49) and were exposed to chronic variable stress (CVS) in adulthood (PND74–88). During treatment, FLX decreased body weight and intake (meal size), but not total meal number. Also, no differences in meal pattern parameters were observed after FLX completion. Likewise, no differences in meal pattern parameters to a palatable diet (45% fat, 17% sucrose) presented from PND74 to PND88, even after CVS, were observed. Our findings indicate that juvenile FLX reduces body weight gain acutely via reduced meal size intake; however, no long‐term changes in ad libitum feeding behavior or binge access to a palatable stimulus are evident. [ABSTRACT FROM AUTHOR]

Background and Aim: Telomere shortening is an accepted indicator of aging. Many studies have investigated an association between leukocyte telomere length (LTL) and psychiatric disorders. Mental or psychological factors could be an important cause of irritable bowel syndrome (IBS). However, there are currently few research evaluating correlations between LTL and IBS. Methods: We examined associations between LTL and IBS using quantitative polymerase chain reaction in independent cohorts, including 205 patients with IBS and 189 healthy controls. Furthermore, we examined whether mental or psychological factors, types of IBS, duration of IBS and antidepressants had an association with LTL in patients with IBS. Results: Among total samples, patients with IBS presented shorter LTL when compared to healthy controls (P < 0.0001). Moreover, in subgroup analyses of patients with IBS, not only the LTL in patients with IBS caused by mental or psychological factors was shorter (P < 0.0001), but also in patients with IBS that were caused by other factors (P = 0.0082). Furthermore, LTL in patients with IBS who had taken antidepressants for more than 1 month was longer than that in patients with IBS who did not take antidepressants or took for less than 1 month (P < 0.0001). Conclusions: This is the first study to describe the relationship between LTL and IBS. This study showed significantly shorter telomeres in patients with IBS. Our findings suggest that LTL may hold the potential to serve as a predictor of IBS diagnosis. [ABSTRACT FROM AUTHOR]

Aim: While evidence‐based antidepressant treatment is available for major depressive disorder, standard approaches for discontinuation of antidepressants after remission have not yet been established. Decision aids are structured clinical tools that facilitate shared decision‐making between patients and healthcare providers. This study aimed to describe the development process and acceptability of decision aids for major depressive disorder following discontinuation of antidepressant treatment after remission. Methods: We systematically developed a decision aids according to the International Patient Decision Aid Standards. First, a decision aids prototype was created using the results of a systematic review and meta‐analysis previously conducted to identify the consequences of continuing and discontinuing antidepressant treatment. Second, a mixed‐methods questionnaire (alpha acceptability testing) was administered to patients and healthcare providers to improve the decision aids prototype and develop it into a final version acceptable for clinical settings. Results: Our decision aids consisted of a description of major depressive disorder, the option to continue or discontinue antidepressant treatment, the advantages and disadvantages of each option, the consequences of each option, and value clarification exercises for each option. The patients (n = 22) reported that the decision aids had acceptable language (91%), adequate information (91%), and a well‐balanced presentation (95%). Healthcare providers (n = 20) provided favorable feedback. The final decision aids fulfilled all six International Patient Decision Aid Standards qualifying criteria. Conclusion: We successfully developed a decision aids for discontinuation of antidepressant treatment after remission, which could be used during the shared decision‐making process. Further studies are needed to verify the effects of using the decision aids during the shared decision‐making process. [ABSTRACT FROM AUTHOR]

Two anionic β‐cyclodextrins as chiral selectors were successfully applied in the enantioseparation of N‐methyl duloxetine, duloxetine, and fluoxetine by countercurrent chromatography. Sulfobutyl ether‐β‐cyclodextrin and carboxymethyl‐β‐cyclodextrin showed opposite enantioselectivity for both duloxetine and N‐methyl duloxetine enantiomers. Two biphasic solvent systems, n‐hexane: 0.1 mol/L phosphate buffer pH 7.6 with 50 mmol/L of sulfobutyl ether‐β‐cyclodextrin (1:1, v/v) and n‐hexane: 0.1 mol/L phosphate buffer pH 7.2 with 50 mmol/L of carboxymethyl‐β‐cyclodextrin (1:1, v/v), were selected for N‐methyl duloxetine. Enantioseparation of duloxetine was achieved by recycling countercurrent chromatography using a solvent system composed of n‐butyl acetate: 0.1 mol/L phosphate buffer pH 7.2 with 20 mmol/L of sulfobutyl ether‐β‐cyclodextrin or carboxymethyl‐β‐cyclodextrin (1:1, v/v). A solvent system composed of n‐hexane: n‐butyl acetate: 0.1 mol/L phosphate buffer pH 7.6 containing 20 mmol/L of sulfobutyl ether‐β‐cyclodextrin (6:4:10, v/v) was selected for enantioseparation of fluoxetine. [ABSTRACT FROM AUTHOR]

In the postmortem environment, some drugs and metabolites may degrade due to microbial activity, even forming degradation products that are not produced in humans. Consequently, underestimation or overestimation of perimortem drug concentrations or even false negatives are possible when analyzing postmortem specimens. Therefore, understanding whether medications may be susceptible to microbial degradation is critical in order to ensure that reliable detection and quantitation of drugs and their degradation products is achieved in toxicology screening methods. In this study, a "simulated postmortem blood" model constructed of antemortem human whole blood inoculated with a broad population of human fecal microorganisms was used to investigate the stability of 17 antidepressant and antipsychotic drugs. Microbial communities present in the experiments were determined to be relevant to postmortem blood microorganisms by 16S rRNA sequencing analyses. After 7 days of exposure to the community at 37°C, drug stability was evaluated using liquid chromatography coupled with diode array detection (LC‐DAD) and with quadrupole time‐of‐flight mass spectrometry (LC‐QTOF‐MS). Most of the investigated drugs were found to be stable in inoculated samples and noninoculated controls. However, the 1,2‐benzisothiazole antipsychotics, ziprasidone and lurasidone, were found to degrade at a rate comparable with the known labile control, risperidone. In longer experiments (7 to 12 months), where specimens were stored at −20°C, 4°C, and ambient temperature, N‐dealkylation degradation products were detected for many of the drugs, with greater formation in specimens stored at −20°C than at 4°C. [ABSTRACT FROM AUTHOR]

Background Depressive symptoms are common in Huntington's disease (HD), profoundly affect quality of life, and predict suicidal ideation. However, no recent review of antidepressant treatment in HD has been published. Methods We performed a PRISMA systematic review of HD studies, which used a recognized antidepressant and measured change in depressive symptoms using a validated psychiatric scale. Controlled trials, uncontrolled trials, observational studies, and case series were included. Results Eleven studies were included, totalling 190 patients. One study examined venlafaxine, one fluoxetine, one citalopram, one atomoxetine, one modafinil, one lithium, and five antipsychotics. No studies were of adequate duration, size, or outcome, and no controlled trial in a depressed population produced a positive result. Conclusions Inadequate evidence exists to guide antidepressant treatment in HD. Further research is needed to assess antidepressant efficacy and to examine whether treatment of depression represents a modifiable target for the high suicide rate in HD. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

α2‐Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain α2C‐adrenoceptor blockade has also been suggested to be beneficial for antipsychotic action. However, comparing α2‐adrenoceptor subtype affinity is difficult due to significant species and methodology differences in published studies. Here, 3H‐rauwolscine whole cell binding was used to determine the affinity and selectivity of 99 α‐antagonists (including antidepressants and antipsychotics) in CHO cells expressing human α2A, α2B, or α2C‐adrenoceptors, using an identical method to β and α1‐adrenoceptor measurements, thus allowing direct human receptor comparisons. Yohimbine, RX821002, RS79948, and atipamezole are high affinity non‐selective α2‐antagonists. BRL44408 was the most α2A‐selective antagonist, although its α1A‐affinity (81 nM) is only 9‐fold greater than its α2C‐affinity. MK‐912 is the highest‐affinity, most α2C‐selective antagonist (0.15 nM α2C‐affinity) although its α2C‐selectivity is only 13‐fold greater than at α2A. There are no truely α2B‐selective antagonists. A few α‐ligands with significant β‐affinity were detected, for example, naftopidil where its clinical α1A‐affinity is only 3‐fold greater than off‐target β2‐affinity. Antidepressants (except mirtazapine) and first‐generation antipsychotics have higher α1A than α2‐adrenoceptor affinity but poor β‐affinity. Second‐generation antipsychotics varied widely in their α2‐adrenoceptor affinity. Risperidone (9 nM) and paliperidone (14 nM) have the highest α2C‐adrenoceptor affinity however this is only 5‐fold selective over α2A, and both have a higher affinity for α1A (2 nM and 4 nM, respectively). So, despite a century of yohimbine use, and decades of α2‐subtype studies, there remains plenty of scope to develop α2‐subtype selective antagonists. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S‐ketamine, but add‐on therapies with second‐generation antipsychotics, certain nutritive, anti‐inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large‐scale, high‐throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aim: Pharmacotherapy is the primary treatment strategy in major depression. However, two‐thirds of patients remain depressed after the initial antidepressant treatment. Augmented cognitive behavioral therapy (CBT) for pharmacotherapy‐resistant depression in primary mental health care settings proved effective and cost‐effective. Although we reported the clinical effectiveness of augmented CBT in secondary mental health care, its cost‐effectiveness has not been evaluated. Therefore, we aimed to compare the cost‐effectiveness of augmented CBT adjunctive to treatment as usual (TAU) and TAU alone for pharmacotherapy‐resistant depression at secondary mental health care settings. Methods: We performed a cost‐effectiveness analysis at 64 weeks, alongside a randomized controlled trial involving 80 patients who sought depression treatment at a university hospital and psychiatric hospital (one each). The cost‐effectiveness was assessed by the incremental cost‐effectiveness ratio (ICER) that compared the difference in costs and quality‐adjusted life years, and other clinical scales, between the groups. Results: The ICERs were JPY −15 278 322 and 2 026 865 for pharmacotherapy‐resistant depression for all samples and those with moderate/severe symptoms at baseline, respectively. The acceptability curve demonstrates a 0.221 and 0.701 probability of the augmented CBT being cost‐effective for all samples and moderate/severe depression, respectively, at the threshold of JPY 4.57 million (GBP 30 000). The sensitivity analysis supported the robustness of our results restricting for moderate/severe depression. Conclusion: Augmented CBT for pharmacotherapy‐resistant depression is not cost‐effective for all samples including mild depression. In contrast, it appeared to be cost‐effective for the patients currently manifesting moderate/severe symptoms under secondary mental health care. [ABSTRACT FROM AUTHOR]

Aim: We previously demonstrated that intracerebroventricular injection of resolvin D2 (RvD2), a bioactive lipid mediator derived from docosahexaenoic acid, ameliorated depression‐like behavior in lipopolysaccharide‐induced and chronic mild stress–induced mouse models of depression. In the present study, we examined the antidepressant effect of RvD2 on chronic pain–induced depression‐like behavior. Methods: To prepare the neuropathic pain model, mice were subjected to surgery for unilateral spared nerve injury. Two weeks after surgery, the antidepressant effect of RvD2 was examined using the tail suspension test. Results: Chronic pain significantly increased immobility time, and this depression‐like behavior was attenuated by intracerebroventricular injection of RvD2 (10 ng). No effect of RvD2 on the locomotor activity was observed. Conclusion: RvD2 produces an antidepressant effect in a murine model of chronic pain–induced depression and may be a promising lead for the development of novel antidepressants. [ABSTRACT FROM AUTHOR]

Fluoxetine is an antidepressant medicine causing relaxation and mood improvement in people, with silencing certain personality traits in some cases. The question arise if such phenomena can be observed in nontarget organisms such as fish. Fluoxetine affects fishes behavior; however, it is not known if the medicine affects its "personality." This study aimed to evaluate the reaction of the invasive Neogobius fluviatilis and native Gobio gobio individuals to fluoxetine at environmental concentration of 360 ng/L. We prepared three variants of the experiments: (a) behavioral trials with unexposed fishes, (b) behavioral trials with the same fishes after 21 days of fluoxetine exposure, and (c) behavioral trials with the same fishes after 21-day depuration period, that is, without fluoxetine. The fishes reaction time (RT), that is, difference in time spent on reaching food with and without the necessity of overcoming the obstacle, was analyzed. Additionally, the personality, bold or shy, traits of each fish individual, was assigned. The results indicated that environmental concentrations of the antidepressant influenced RT. The average RT of the fishes cultured with fluoxetine was by 7-min shorter in comparison with the nonexposed control. Share of individuals exposed to fluoxetine assigned as bold raised to 71.4% in comparison with 46.4% in nonexposed control. This sheds new light on wild fishes behavior caught from freshwater. Environmental concentrations of the antidepressant influenced the time of fishes reaction and share individuals assigned as bold. Moreover, 21-day recovery lasting might be not enough to get fluoxetine effect on fishes. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the antidepressant‐like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests. Methods: We investigated the target profile of GW117 using [35S]‐GTPγS and [3H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant‐like and anxiolytic‐like effects of GW117. Results: The current study suggests that GW117 displays serotonin 2C (5‐HT2C) receptor antagonist and melatonin type 1 and 2 (MT1/MT2) receptor agonist properties, as well as evident antidepressant and anxiolytic effects. Conclusion: These data suggest that GW117 is probably a potent antidepressant. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to monitor the trajectories of antidepressant use during pregnancy and the postpartum period among women chronically treated with antidepressants before their pregnancy, and to assess characteristics associated with each trajectory. Methods: This cohort study included all pregnant women whose data were included in the General Sample of Beneficiaries (EGB) database affiliated with the French Health Insurance System, from 2009 to 2014. Women were followed up until 6 months after childbirth. Chronic treatment was defined as exposure over the 6‐month period preceding pregnancy. A group‐based trajectory model (GBMT) was estimated to identify distinctive longitudinal profiles of antidepressant use. Results: Among 760 women chronically treated with antidepressants before their pregnancy, 55.8% stopped their treatment permanently in the first trimester, 20.4% discontinued it for a minimum of 3 months and resumed it postpartum, and 23.8% maintained it throughout pregnancy and postpartum. No sociodemographic or medical characteristics were associated with any trajectory group. Women who maintained treatment presented more frequent obstetric complications and postpartum psychiatric disorders. Among women who interrupted treatment, prescription of benzodiazepines and anxiolytics decreased initially but rose postpartum to a higher level than before pregnancy. Conclusions: Pregnant women treated with antidepressant require a re‐evaluation of psychiatric treatment. It is necessary to pay attention to obstetric complications for severely depressed women. Additionally, as relapse was associated with increased benzodiazepine use, it is important to carefully monitor all women who stop antidepressant treatment during pregnancy. [ABSTRACT FROM AUTHOR]

This article reviewed the results of 21 recent meta‐analyses examining the relationship between maternal use of antidepressants during pregnancy and negative outcomes in newborns and children. PubMed was searched for meta‐analyses published in English between January 1, 2011, and November 30, 2019, by using combinations of the keywords pregnancy, antidepressants, review, meta‐analysis, selective serotonin reuptake inhibitors, selective serotonin‐norepinephrine reuptake inhibitors, tricyclic antidepressants, neonatal outcomes, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), preterm birth, low birth weight, spontaneous abortion, persistent pulmonary hypertension, infant, newborn, children, and offspring. The present review included a total of 21 relevant meta‐analyses that met the inclusion criteria. Most of the meta‐analyses reported that compared to non‐users, the risks of preterm birth, low birth weight, spontaneous abortion, persistent pulmonary hypertension, autism spectrum disorders, and ADHD in offspring of antidepressant users were significantly higher. Some meta‐analyses also noted that the elevated risks were no longer statistically significant when pregnant women with psychiatric diagnoses treated with an antidepressant were compared with control patients who remained untreated. Although this review of current meta‐analyses suggests a moderately increased risk of neonatal and childhood outcomes assessed with maternal use of antidepressants, it is difficult to ascertain whether these outcomes are independent of underlying maternal psychiatric disorders. [ABSTRACT FROM AUTHOR]

Piper nigrum L. also called black pepper is popular for its numerous uses. The present research is designed to investigate the pharmacological potential of methanol extract of Piper nigrum (MEPN). The antidepressant investigation was performed by using both in vivo forced swimming test (FST) and tail suspension test (TST) methods while the anxiolytic research by hole‐board test (HBT) method. Again, the antipyretic analysis was conducted through yeast‐induced pyrexia method, whereas clot lysis activity was employed by the thrombolytic method. Furthermore, in silico studies followed by molecular docking analysis of several secondary metabolites, pass prediction, and ADME/T were evaluated with AutoDock Vina, Discovery Studio 2020, UCSF Chimera software PASS online, and ADME/T online tools. The plant extract demonstrated dose‐dependent potentiality in antidepressant, anxiolytic, antipyretic, and thrombolytic activities. Induction of MEPN produced a significant (p <.5, p <.001) increase of mobility in FST and TST, and increased the head dipping and decreased the latency of time (p <.01, p <.001) in HBT. MEPN 400 (mg/kg; b.w.; p.o.) lowered the rectal temperature of yeast‐induced pyrexia substantially (p <.001). Besides, MEPN produced promising (p <.001) clot lysis activity. In the computational approach, among all the proteins, a docking score was found ranging from −1.0 to −7.90 kcal/mol. Besides, all the compounds were found safe in ADME/T study. The results of our scientific research validate the suitability of this plant as an alternative source of novel therapeutics. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to estimate the features of suicide rate and its association with antidepressant prescriptions during the past decade in China. Methods: Official data on suicides were obtained and stratified by four age groups, gender, urban/rural areas, and regions (East, Central, and West). The annual antidepressant prescriptions were expressed in pills per 100 persons calculated as the volume of prescriptions divided by the total population. Negative binomial regression was carried out to examine the association between suicide and other variables. Results: Suicide rates in each stratum typically decreased from 2008 to 2015, while annual antidepressant prescriptions were generally increased by the year. The suicide rate increased with age and was greater in adult males than in females; higher in the central area and greater in rural than in urban areas. Suicide rates are negatively associated with antidepressant prescriptions including selective serotonin reuptake inhibitors (Incidence rate ratio [IRR] 0.983, 95% confidence interval [CI] 0.983–0.983), serotonin–norepinephrine reuptake inhibitors (IRR 0.951, 95% CI 0.951–0.951), tricyclic antidepressant (IRR 0.925, 95% CI 0.925–0.925) and total antidepressants (IRR 0.990, 95% CI 0.990–0.990) during 2008–2012. Conclusion: Suicide varied among different studied stratum. Suicide rates are negatively associated with antidepressant prescriptions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies.Experimental Approach: The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4-/- mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays.Key Results: The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4-/- mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways.Conclusions and Implications: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to systematically review published studies, reporting outcomes to offspring following in utero exposure to antidepressant medications, which used an untreated depressed comparison group. Methods: OVID, Scopus, EBSCO Collections, the Cochrane Library and Web of Science databases were searched for relevant publications published between January 1950 and May 2018 and a total of 188 potentially eligible studies were identified. Results: Following review, 16 primary studies were eligible for inclusion. Antidepressant exposure was associated with an increased risk of lower gestational age, preterm birth, but not low birthweight or being small for gestational age compared to untreated depression. There is some evidence that congenital defects are associated with antidepressant use, particularly between cardiac defects and paroxetine use. There is conflicting evidence regarding neurodevelopment in offspring, with some reports of increased incidence of autistic spectrum disorders and depression, but also reports of no problems when measuring emotional symptoms, peer problems, conduct problems and hyperactivity‐inattention scores. Conclusion: When compared with an untreated depressed group, antidepressant exposure was associated with adverse outcomes at birth, while there is insufficient data to determine whether the association between antidepressants and congenital defects or developmental disorders is a true association. However, although we compared treated vs. untreated depression there still may be residual confounding as an untreated depressed group is likely to have less severe depression. [ABSTRACT FROM AUTHOR]

Recent studies suggest that bioactive dietary polyphenol preparation (BDPP) and individual polyphenolic compounds ameliorate stress‐induced depression‐like behaviors, but the underlying molecular mechanisms are incompletely understood. VGF (non‐acronymic) in the dorsal hippocampus (dHc) has been shown to play a role in depression‐like behaviors and antidepressant efficacy, and the VGF‐derived peptide TLQP‐62 (named by the N‐terminal 4 amino acids and length) infused into dHc has been shown to have antidepressant efficacy that is BDNF–TrkB dependent. Here, we investigated whether BDPP influences VGF expression in the dHc, and whether dHc VGF is required for BDPP antidepressant efficacy. We found that BDPP produced antidepressant‐like effects in naive mice and reversed the depression‐like behaviors induced by chronic variable stress. In addition, we found that BDPP had no detectable antidepressant efficacy in floxed mice with prior knockdown in the dHc of either VGF or BDNF, achieved by adeno‐associated virus‐Cre infusion. Our data indicate that dHc VGF and BDNF expression are required for the antidepressant actions of BDPP, and therefore suggest that a VGF(TLQP‐62)–BDNF–TrkB autoregulatory feedback loop could play a role in the regulation of BDPP antidepressant efficacy, much as it has been suggested to function in the antidepressant efficacies of ketamine and TLQP‐62. [ABSTRACT FROM AUTHOR]

Background: Astrocytes have been implicated in the pathophysiology of mood disorders and in the mechanism of the pharmacological effects of antidepressant drugs by the production of neurotrophic/growth factors. Previous studies have identified astrocyte‐expressed Gαi/o‐coupled lysophosphatidic acid receptor 1 (LPAR1), as being involved in antidepressant‐induced production of glial cell line‐derived neurotrophic factor (GDNF) and matrix metalloproteinase‐9 (MMP‐9) activation, an important step in the production of GNDF. However, the precise mechanism of MMP‐9 activation by antidepressants has yet to be identified, in particular the intracellular signaling pathway between LPAR1/Gαi/o and MMP‐9. Methods and Results: Treatment of rat C6 astroglial cells (C6 cells) with amitriptyline increased Src family tyrosine kinase phosphorylation in a time and concentration‐dependent manner. Amitriptyline‐induced GDNF mRNA expression was blocked by Src family tyrosine kinase inhibitors. In addition, inhibiting Src family tyrosine kinase blocked amitriptyline‐induced zymographic MMP‐9 activation in C6 cells. The amitriptyline‐induced zymographic MMP‐9 activity was completely blocked by selective inhibition of Gαi/o protein and LPAR1. Furthermore, the amitriptyline‐induced Src family tyrosine kinase phosphorylation was blocked by LPAR1, but not MMP‐9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of LPAR1. Conclusions: The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the LPAR1/Gαi/o/Src family tyrosine kinase, which leads to MMP‐9 activation and GDNF production. [ABSTRACT FROM AUTHOR]

Electroconvulsive seizure (ECS), a model of electroconvulsive therapy in rodents, strongly increases neurogenesis in the adult hippocampus. Neurogenesis is a multi‐step process that spans proliferation, survival, neuronal differentiation, and functional maturation. Our previous study demonstrated that ECS stimulates the proliferation of neural stem‐like cells. However, the contribution of ECS to survival, neuronal differentiation, and maturation in newborn cells remains unknown. To evaluate the effect of ECS on these processes, we labeled newborn cells with bromodeoxyuridine (BrdU) before ECS treatment to determine the cell age and examined the survival rate and expression of cellular markers in the BrdU‐labeled cells. Our results revealed that exposure to ECS (11 repetitions) during the differentiation phase significantly increased survival and promoted neuronal differentiation of newborn cells in the dentate gyrus. Four of ECS repetitions during the early differentiation phase were sufficient to promote dendritic outgrowth in immature neurons and enhance the expression of the immature neuronal marker, calretinin, in newborn cells. In contrast, exposure to ECS (11 repetitions) during the late maturation phase significantly suppressed the expression of the mature neuronal marker, calbindin, in newborn neurons. These results demonstrate that ECS during the differentiation phase promoted survival and neuronal differentiation and, in contrast, suppressed mature marker expression during the late maturation phase, suggesting that ECS has multiple effects on the different stages of adult neurogenesis. [ABSTRACT FROM AUTHOR]

Aims: Non‐adherence or partial adherence to psychotropic medication is found in 18–70% of patients. Many previously used methods for the assessment of adherence (e.g. questionnaires, pill counts, and electronic systems), however, might underreport actual rates of non‐adherence to medication. The aim of this study was to quantify adherence using plasma level. Methods: We conducted a 6‐week prospective study of all consecutive admitted patients at the Paracelsus Medical University of Salzburg, Clinics of Psychiatry and Psychotherapy, who had been treated with antipsychotics/antidepressants prior to admission (pre‐medication dosage in 161 of 233). Plasma drug levels were determined and compared with expected levels based on known preadmission dosing regimens and average pharmacokinetic data. Results: Seventy‐three percent of the patients had actual plasma levels clearly below or above the intended level. Significantly more patients with schizophrenia (66%) did not take the medication as prescribed, when compared with patients with affective disorders (47%) or those with other psychiatric diagnoses (41%). Only 27% (44 of 161) of the patients had plasma level in the expected range based on the dosage. Conclusion: The risk of partial adherence or non‐adherence is expected in two‐thirds of patients with schizophrenia, half of patients with affective disorders, and approximately 40% of patients with other psychiatric diagnoses. Given that admitting psychiatrists could not provide an accurate assessment of patient adherence, it is strongly suggested that clinical judgment be supplemented with the actual monitoring of adherence – and further optimization of pharmacotherapy – by means of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Objective: We consider how to choose an antidepressant (AD) medication for the treatment of clinical depression. Method: A narrative review was undertaken addressing antidepressant 'choice' considering a range of parameters either weighted by patients and clinicians or suggested in the scientific literature. Findings were synthesised and incorporated with clinical experience into a model to assist AD choice. Results: Efficacy studies comparing ADs offer indicative guidance, while precision psychiatry prediction based on genetics, developmental trauma, neuroimaging, behavioural and cognitive biomarkers, currently has limited clinical utility. Our model offers guidance for AD choice by assessing first for the presence of a depressive subtype or symptom cluster and matching choice of AD class accordingly. Failing this, an AD can be chosen based on depression severity. Within‐class choice can be determined by reference to personality style, patient preference, medical or psychiatric comorbidities and side‐effect profile. Conclusion: Clarification of AD choice would occur if medications are trialled in specific depressive subtypes rather than using the generic diagnosis of major depressive disorder (MDD). Such 'top‐down' methods could be enhanced by 'bottom‐up' studies to classify individuals according to symptom clusters and biomarkers with AD efficacy tested in these categories. Both methods could be utilised for personalised AD choice. [ABSTRACT FROM AUTHOR]

Background: The present study explored the patterns of physical comorbidities and their associated demographic and clinical factors in older psychiatric patients prescribed with antidepressants in Asia. Methods: Demographic and clinical information of 955 older adults were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP‐AD) project. Standardized data collection procedure was used to record demographic and clinical data. Results: Proportion of physical comorbidities in this cohort was 44%. Multiple logistic regression analyses showed that older age (OR = 1.7, P < 0.001), higher number of depressive symptoms (OR = 1.09, P = 0.016), being treated in psychiatric hospital (OR = 0.5, P = 0.002), living in high income countries/territories (OR = 2.4, P = 0.002), use of benzodiazepines (OR = 1.4, P = 0.013) and diagnosis of ‘other psychiatric disorders’ (except mood, anxiety disorders and schizophrenia) (OR = 2.7, P < 0.001) were significantly associated with physical comorbidities. Conclusions: Physical comorbidities in older patients prescribed with antidepressants were common in Asia. Integrating physical care into the treatment of older psychiatric patients should be urgently considered. [ABSTRACT FROM AUTHOR]

Anxiety and depression are prevalent among cancer patients, with significant negative impact. Many patients prefer herbs for symptom relief to conventional medications which have limited efficacy/side effects. We identified single-herb medicines that may warrant further study in cancer patients. Our search included PubMed, Allied and Complementary Medicine, Embase, and Cochrane databases, selecting only single-herb randomized controlled trials between 1996 and 2016 in any population for data extraction, excluding herbs with known potential for interactions with cancer treatments. One hundred articles involving 38 botanicals met our criteria. Among herbs most studied (≥6 randomized controlled trials each), lavender, passionflower, and saffron produced benefits comparable to standard anxiolytics and antidepressants. Black cohosh, chamomile, and chasteberry are also promising. Anxiety or depressive symptoms were measured in all studies, but not always as primary endpoints. Overall, 45% of studies reported positive findings with fewer adverse effects compared with conventional medications. Based on available data, black cohosh, chamomile, chasteberry, lavender, passionflower, and saffron appear useful in mitigating anxiety or depression with favorable risk-benefit profiles compared to standard treatments. These may benefit cancer patients by minimizing medication load and accompanying side effects. However, well-designed larger clinical trials are needed before these herbs can be recommended and to further assess their psycho-oncologic relevance. [ABSTRACT FROM AUTHOR]

Background: Treatment‐emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. Methods: A systematic review and meta‐analysis following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) and Meta‐Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta‐regression and subgroup analysis. Results: Overall, 10 098 depressed patients with bipolar disorder (BD) across 51 studies/arms were included in the quantitative analysis. The cumulative incidence of cases (TEM+) among 4767 patients with BD over 15 retrospective studies was 30.9% (95% confidence interval [CI] 19.6‐45.0%, I2 = 97.9%). The cumulative incidence of TEM+ among 1929 patients with BD over 12 prospective open studies was 14.4% (95% CI 7.4‐26.1%, I2 = 93.7%). The cumulative incidence of TEM+ among 1316 patients with BD over 20 randomized controlled trials (RCTs) was 11.8% (95% CI 8.4‐16.34%, I2 = 73.46%). The pooled prevalence of TEM+ among 2086 patients with BD over four cross‐sectional studies was 30.9% (95% CI 18.1‐47.4%, I2 = 95.6%). Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co‐occurring anxiety, and other clinically relevant moderators precluded further stratification of the results. Conclusions: Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records. Forthcoming RCT studies should adopt consistent operational definitions of TEM and broaden the number of moderators, in order to contribute most effectively to the identification of clear‐cut sub‐phenotypes of BD and patient‐tailored pharmacotherapy. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors ( SSRIs) are the most frequently prescribed antidepressants. However, a major concern is their delayed onset of action, which is hypothesized to be associated with the time required for serotonin (5- HT) autoreceptors to desensitize, which should be reflected by actual neurochemical changes. Numerous in vivo microdialysis studies have been published that report on 5- HT levels in different brain sites following SSRI administration. Here, we performed a meta-analysis on dynamic changes of 5- HT neurotransmission during the course of chronic SSRI treatment. We conducted a meta-analysis on research articles of 5- HT neurotransmission measured by in vivo microdialysis in rat brain after subchronic and chronic SSRI administrations. In total, data from 42 microdialysis studies (798 rats) were analyzed. Within the first week of SSRI treatment, extracellular 5- HT concentrations drop in frontal cortex. Over the next 2 weeks of treatment, a linear increase in extracellular 5- HT levels up to 350% of prior treatment baseline is evident ( n = 269). However, in hippocampus, prefrontal cortex, nucleus accumbens, and ventral tegmental area we found increased 5- HT levels within the first 3 days of SSRI administration. The time course of 5- HT dynamics in frontal cortex is in line with the hypothesis that 5- HT autoreceptors desensitize over 2-3 weeks of SSRI treatment and thereby enhanced extracellular 5- HT levels ensue. Yet, in other regions we did not find evidence supporting the traditional autoreceptor-mediated feedback loops hypothesis and thus other neurobiological adaptation mechanisms may also play a role in the delayed onset of SSRI action. [ABSTRACT FROM AUTHOR]

ABSTRACT [ABSTRACT FROM AUTHOR]

Objectives We examined differences in treatment outcome between Diagnostic and Statistical Manual Fourth Edition (DSM-IV)-defined rapid cycling and average lifetime-defined rapid cycling in subjects with bipolar II disorder. We hypothesized that, compared with the DSM-IV definition, the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment. Methods Subjects ≥18 years old with a bipolar II major depressive episode (n=129) were categorized into DSM-IV- and average lifetime-defined rapid cycling and prospectively treated with either venlafaxine or lithium monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. Results These exploratory analyses found moderate agreement between the two rapid-cycling definitions (κ=0.56). The lifetime definition captured subjects with more chronic courses of bipolar II depression, whereas the DSM-IV definition captured subjects with more acute symptoms of hypomania. There was no difference between rapid-cycling definitions with respect to the response to acute venlafaxine or lithium monotherapy. However, the lifetime definition was slightly superior to the DSM-IV definition in identifying subjects who went on to experience hypomanic symptoms during continuation therapy. Conclusions Although sample sizes were limited, the findings suggest that the lifetime definition of rapid cycling may identify individuals with a chronic rapid-cycling course and may also be slightly superior to the DSM-IV definition in identifying individuals with hypomania during relapse-prevention therapy. These findings are preliminary in nature and need replication in larger, prospective, bipolar II studies. [ABSTRACT FROM AUTHOR]

Nociceptin/Orphanin FQ (N/ OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor ( NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP−/− mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies ( NOP and serotonin reuptake transporter [ SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere. [ABSTRACT FROM AUTHOR]

Background Health insurance claims are a rich data source to examine medication use in pregnancy. Our objective was to identify pregnant women, their pregnancy outcomes, and date of their last menstrual period (LMP), and to estimate antidepressant dispensations in pregnancy. Methods From a literature search, we identified diagnosis and procedure codes indicating the end of a pregnancy. Using Truven Health MarketScan® Commercial Claims and Encounters Databases, we identified all inpatient admissions and outpatient service claims with these codes. We developed an algorithm to assign: (1) pregnancy outcome (ectopic pregnancy, induced or spontaneous abortion, live birth, or stillbirth), and (2) estimated gestational age, to each inpatient or outpatient visit. For each pregnancy outcome, we estimated the LMP as the admission (for inpatient visits) or service (for outpatient visits) date minus the gestational age. To differentiate visits associated with separate pregnancies, we required ≥ 2 months between one pregnancy outcomes and the LMP of the next pregnancy. We used this algorithm to identify pregnancies in 2013 and to estimate the proportion of women who filled a prescription for an antidepressant from an outpatient pharmacy at various time points in pregnancy. Results We identified 488,887 pregnancies in 2013; 79% resulted in a live birth. A prescription for an antidepressant was filled in 6.2% of pregnancies. Dispensations varied throughout pregnancy and were lowest (3.1%) during the second trimester. Conclusion This work will inform future efforts to estimate medication dispensations during critical periods of preconception, interconception, and pregnancy using health insurance claims data. Birth Defects Research (Part A) 106:927-934, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims Urinary retention (UR) occurs in patients on antipsychotic and antidepressant medication despite no apparent underlying urological cause. This review was undertaken to ascertain which of these medications are associated with UR and how often. Methods A systematic literature search for evidence on antipsychotic and antidepressant medications and UR was completed in June 2015 using Scopus, Pubmed, Web of Science, and the Cochrane library. Search terms included urinary retention, antidepressants and antipsychotics as well as individual drug names. Filters used were: humans and English language. PRISMA guidelines were employed. Results Out of 614 articles initially identified, one meta-analysis, five RCT's, five cohort studies and 27 case reports were finally included. There was a wide range of definitions of UR. Studies which appropriately defined UR revealed it occurred in 1/21 patients on ziprasidone (an atypical antipsychotic), 17.6% of those on imipramine but only 0.1% of those on all tricyclic antidepressants analysed together. It was not reported in any of the 1,139 patients given duloxetine (a combined serotonin and noradrenaline reuptake inhibitor). It was reported in 0.025% of patients on selective serotonin reuptake inhibitors. UR was also reported in patients on typical antispychotics, selective noradrenaline reuptake inhibitors but the studies did not define UR. The majority of case reports reported an improvement in UR on discontinuation or dose reduction. Conclusion Antipsychotics and antidepressants interact with the urinary system in many ways. Clinicians treating acute UR need to keep in mind the role of antipsychotic and antidepressants as a precipitating cause. Neurourol. Urodynam. 35:866-874, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Glutamatergic system and the structural plasticity hypothesis are principal components for rapid and sustained antidepressant effects of novel antidepressant therapeutics. This study represents the first investigation of the structural plasticity of the hippocampus as one of the main contributed mechanisms to the sustained anti-depressive effect of ketamine. Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline 7 days before perfusion-fixed. The optical fractionator method was used to estimate the total number of neurons in the granular cell layer. Microvessel length in the molecular layer of DG was evaluated with global spatial sampling method. By use of the physical disector method, the number of synapses was estimated. The volume of the hippocampus was larger in the FRL-vehicle rats compared with FSL-vehicle group and in FSL-ketamine versus FSL-vehicle rats ( P < 0.05). The number of non-perforated synapses was significantly higher in the FSL-ketamine versus FSL-vehicle group, ( P = 0.01). A significant effect of ketamine on enhancement of the number of neurons in DG in FSL rats was observed ( P = 0.01). The total length of the microvessels 1 week after ketamine treatment in the FSL rats significantly increased ( P < 0.05). Our results indicate that neurovascular changes of hippocampus could be one of the possible mechanisms underlying the sustained antidepressant effect of ketamine by reversing alteration of the number of the excitatory synapses, neuronal number and length of the microvessels in the hippocampus. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In the present work, novel salts of the multimodal antidepressant drug vortioxetine (VT) were crystallized with pharmaceutically acceptable acids, aiming to improve the solubility of VT. The acids for VT were selected based on ΔpKa being greater than 2 or 3. Salts of hydrobromic acid (HBr), hydrochloric acid (HCl), p-hydroxybenzoic acid (PHBA), saccharin (SAC) and l-aspartic acid (ASP) were reported. All salts were characterized by single-crystal X-ray diffraction, FT-IR, powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The acidic proton is transferred to the secondary N atom on the piperazine ring of VT, forming the charge-assisted hydrogen bond N+—H· · ·X· (X = Cl, Br, O). Solubility and intrinsic dissolution rate (IDR) experiments were carried out in distilled water (pH = 7.0) to compare the solubilities of the salts with that of VT. The VT–ASP–H2O (1:1:2) salt showed 414 times higher solubility and 1722 times faster IDR compared with VT. VT–ASP–H2O (1:1:2) is a high solubility salt that is stable in a slurry experiment at 298 K in 95% ethanol. The experimental data for the VT–ASP–H2O (1:1:2) salt identify it as a promising drug candidate. [ABSTRACT FROM AUTHOR]

TOPIC Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that requires a multidisciplinary approach to treatment. Psychopharmacology can play an important role within an array of services to help children and adolescents with ASD. PURPOSE This article reviews the current evidence supporting the use of various psychiatric medications to treat common symptoms that often compromise functioning: severe irritability, interfering repetitive behaviors, ADHD, anxiety, depression, and sleep dysregulation. Based on the accumulating research, the article also offers practice recommendations. SOURCES The article primarily draws on the science generated by investigators from the Research Units on Pediatric Psychopharmacology Autism Network. This body of work consists of randomized controlled trials, meta-analyses, open trials, and review articles. CONCLUSIONS There are currently no FDA-approved medications to treat the core symptoms of ASD. Consequently, all medications, besides risperidone and aripiprazole for severe irritability, are considered off-label. Additionally, due to reduced levels of effectiveness and higher rates of side effects, more typical medications such as antidepressants and stimulants should be used with caution. However, the evidence indicates that the thoughtful use of psychiatric medication in conjunction with other interventions may be beneficial in helping children and adolescents with ASD thrive at school and home. [ABSTRACT FROM AUTHOR]

Objective Our goal was to model the temporal dynamics of sleep-wake transitions, represented by transitions between rest and activity obtained from actigraphic data, in patients with bipolar disorder using a probabilistic state transition approach. Methods We collected actigraphic data for 14 days from 20 euthymic patients with bipolar disorder, who had been characterized clinically, demographically, and with respect to their circadian preferences ( chronotype). We processed each activity record to generate a series of transitions in both directions between the states of rest (R) and activity (A) and plotted the estimated transition probabilities (pRA and pAR). Each 24-hour period was also divided into a rest phase consisting of the eight consecutive least active hours in each day and an active phase consisting of the 16 consecutive most active hours in each day. We then calculated separate transition probabilities for each of these phases for each participant. We subsequently modeled the rest phase data to find the best fit for rest-activity transitions using maximum likelihood estimation. We also examined the association of transition probabilities with clinical and demographic variables. Results The best-fit model for rest-activity transitions during the rest phase was a mixture (bimodal) of exponential functions. Of those patients with rapid cycling, 75% had an evening-type chronotype. Patients with bipolar II disorder taking antidepressants had a lower probability of transitioning back to rest than those not on antidepressants [mean ± SD = 0.050 ± 0.006 versus 0.141 ± 0.058, F(1,15) = 3.40, p < 0.05]. Conclusions The dynamics of transitions between rest and activity in bipolar disorder can be accounted for by a mixture (bimodal) of exponential functions. Patients taking antidepressants had a reduced probability of sustaining and returning to sleep. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. Methods Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at −91, −182, −273 and −365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. Results Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. Conclusion Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Several practice guidelines were published by French regulatory agencies between 2006 and 2009 to improve psychotropic drug use in older patients. The objectives of the study were to assess compliance with these guidelines in older patients hospitalized in psychiatric units and to identify characteristics associated with compliance. A cross-sectional study was conducted in 117 patients aged 65 years and older hospitalized in two psychiatric departments of a public hospital, at three dates randomly chosen between January and May 2014. Medical and sociodemographic characteristics were collected from electronic medical records. In all, 8% of psychotropic prescriptions were compliant with guidelines. A total of 98% of antidepressant prescriptions complied with guidelines for product selection (no tricyclics) and 72% for initial dosage (half of that recommended for younger adults). Regarding benzodiazepines, short half-life drugs were chosen in 73% of treatments, low maintenance dosage was found in 64% of treatments, and a discontinuous administration rhythm was noted in 33% of treatments. Regarding antipsychotics, initial dosage was a quarter of the allowed initial dosage for younger adults in 39% of prescriptions and metabolic blood testing was performed in 17% of prescriptions. Neurological and cognitive tolerance was monitored in 41% and 61% of prescriptions, respectively. Few clinical factors were found to be associated with compliance or noncompliance with guidelines in older psychiatric inpatients. Practice guidelines on psychotropic drug prescription were partially respected in older inpatients. Practitioners should take into account the risks associated with non-recommended patterns of psychotropic drug use in this vulnerable population. [ABSTRACT FROM AUTHOR]

Objective Paroxetine titration may be difficult in older individuals as they are more sensitive to side effects. The current study extends to 6 months our previously published report in which paroxetine was started at 2.5 mg/day and slowly increased by 2.5 mg on alternate days (slow titration) or rapidly titrated to target dose from 10 mg/day (standard titration) in a naturalistic setting. Methods Here, the follow-up period was extended to 26 weeks. We performed an intent-to-treat analysis of 47 subjects from the original sample (major depressive disorder and/or generalized anxiety disorder (GAD); >60 years of age). Missing evaluations were replaced by last observations carried forward. GAD was included as a stratification factor. Results Patients in whom paroxetine was slowly up-titrated were more likely to remit (84.0% vs 54.5%; p = 0.028) and had lower core depression ( p = 0.0015) and psychic anxiety levels ( p = 0.006) after 26 weeks. Dropout rate was 20% in the slow titration group compared with 77.3% in the standard titration arm ( p < 0.001). Patients with GAD accounted for all significant associations. No substantial differences were reported between slow and standard titration groups in the subsample without GAD. Conclusions Despite some limitations, these findings suggest that paroxetine treatment should be started at lower doses in older depressed patients and slowly up-titrated. This strategy would allow to increase antidepressant response and the likelihood of completing treatment cycle in patients with high anxiety levels and GAD comorbidity. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]