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In 1996, when I was prescribed an antidepressant, there was already published research that showed selective serotonin reuptake inhibitors (SSRIs), commonly known as antidepressants, caused withdrawal effects.1 However, at that time, the Defeat Depression campaign had successfully created a narrative adopted by most prescribers, in which anxiety or depression were described to the patient as caused by a ‘chemical imbalance in the brain’ and that SSRIs were safe, effective, and non-addictive. Why would a doctor feel the need to do a full literature review? Today the word is out that my experience of attempting repeatedly to stop taking the drug and experiencing increasingly severe withdrawal effects is by no means uncommon. We now know a drug can cause dependence without causing addiction. Dependence is simply the physiological consequence of taking a drug that causes the body (especially the brain and central nervous system) to change its structure and functioning in response to the ongoing presence of the drug — for example, an antidepressant. The Public Health England (PHE) report Dependence and withdrawal associated with some prescribed medicines. An evidence review , published in 2019,2 established that 25% of adults in England were taking a dependence-forming drug. This led to the Royal College of Psychiatrists publishing a new position statement on antidepressant withdrawal, identifying it as potentially ‘severe and long-lasting’ , and something that patients should be made aware of during informed consent for these medications.3 As a busy GP, should you wish to learn more through reading current research, which papers give you the best insight into …

Agomelatine was a novel and melatonergic antidepressant. The present study was conducted to find out whether age was an important factor for agomelatine in treating depressed type 2 diabetes mellitus (T2DM) patients. In total, 193 depressed T2DM patients were included. There were 84 patients ranged from 27 years old to 49 years old (age phase I) (n = 44 receiving agomelatine, n = 40 receiving paroxetine or fluoxetine), and 109 patients ranged from 50 years old to 70 years old (age phase II) (n = 56 receiving agomelatine, n = 53 receiving paroxetine or fluoxetine). The Hamilton Depression Rating Scale (HDRS) score, Hamilton Anxiety Rating Scale (HARS) score, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) level and body mass index (BMI) were assessed after 12 weeks treatment. After treatment, we found that among patients in age phase I, there were no significant differences in final average HDRS score, HARS score, FPG, HbA1c level, BMI, response rate and remission rate between the two groups. However, among patients in age phase II, compared to patients receiving paroxetine or fluoxetine, patients receiving agomelatine had the significantly lower average HDRS score, HARS score, HbA1c level and BMI, and significantly higher response rate and remission rate. The incidence of treatment-related adverse events was similar between the two groups in both age phases. These results suggested that age was an important factor for agomelatine in treating depressed T2DM patients. Compared to paroxetine/fluoxetine, agomelatine might be more appropriate for elderly depressed T2DM patients.

BackgroundIntravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium.AimsTo explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine.MethodSeven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed.ResultsTreatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission.ConclusionsThese results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

Introduction: The present study aimed to investigate the antidepressant effect of Verbena (V.) officinalis L. aqueous extract in adult female rats. Methods: The present study evaluated the antidepressant effect of V. officinalis L. aqueous (V AE) extract in female rats using the Forced-Swimming Test (FST), Light-Dark Box (LDB) test, and Open Field Test (OFT). The level of glycemia and histological analysis were also studied. The VAE [200 mg/kg Parenterally (PO)] was administered orally for 7 successive days in the separate groups of rats. Results: The oral administration of V. officinalis L. aqueous extract significantly decreased (P< 0.01) the immobility time in the FST, increased the time spent in the light area (LDB), and the number of entry into the central squares (OFT). Thus, the extract at a dose of 200 mg/kg significantly decreased the glycemia level (P

BackgroundDuring the first wave of the coronavirus disease 2019 (COVID-19) pandemic, patients with confirmed cases in New York State accounted for roughly 25% of total US cases, with psychiatric hospital in-patients at particularly high risk for COVID-19 infection.AimsThe beneficial effects of mental health medications, such as selective serotonin reuptake inhibitors (SSRIs), on the severity of COVID-19 disease outcomes have been documented. Protective effects against infection have also been suggested for these medications. We therefore tested the hypothesis that medication use modifies the risk of COVID-19 infection in a long-stay, chronic in-patient psychiatry setting, where the potential for exposure was likely uniform across the facility, and where these medications were routinely prescribed.MethodThis was a retrospective cohort study of an adult psychiatric facility operated by the New York State Office of Mental Health. Current medication information and COVID-19 status was collected from electronic medical records for 165 people who were in-patients during the period January to July 2020, and logistic regression was employed to model the main effects of medication use on COVID-19 infection.ResultsA significant protective association was observed between antidepressant use and COVID-19 infection (odds ratio (OR) = 0.33, 95% CI 0.15–0.70, adjusted P < 0.05). Analysis of individual antidepressant classes showed that SSRI, serotonin-norepinephrine reuptake inhibitor and the serotonin-2 antagonist reuptake inhibitor classes of antidepressants, drove this protective effect. Exploratory analyses of individual antidepressants demonstrated an association between lower risk of infection and fluoxetine use (P = 0.023), as well as trazodone use (P = 0.001).ConclusionsThe novel finding of reduced COVID-19 infection risk for psychiatric in-patients taking antidepressants, suggests that antidepressants may be an important weapon in the continued fight against COVID-19 disease. This finding may become particularly salient for in-patient settings if vaccine-resistant strains of the virus appear.

Background: Growing concerns about the impact of coronavirus disease 2019 (COVID-19) will likely lead to increased mental health diagnoses and treatment. To provide a pre-COVID-19 baseline, we have examined antidepressant prescribing trends for 5 years preceding COVID-19. Methods: A retrospective analysis of anonymised data on medicines prescribed by GPs in England from the Open-Prescribing Database (January 2015 to December 2019) identified the 10 most prescribed antidepressant and, for comparison, cardiovascular medicines. Results: Prescription items for the 10 most prescribed antidepressants rose 25% from 58 million (2015) to 72 million (2019). Citalopram was the most prescribed antidepressant; prescriptions for sertraline rose fastest at 2 million items year on year. Over the same period, costs for antidepressant prescribing fell 27.8%. Across all Clinical Commissioning Groups (CCGs) in England, antidepressant prescribing levels, adjusted for population were positively correlated with the index of multiple deprivation (IMD) score. In comparison, prescribing for the top 10 most prescribed cardiovascular medicines increased by 2.75% from 207 million (2015) to 213 million (2019) items. Limitations: Anonymised data in the Open-Prescribing Database means no patient diagnoses or treatment plans are linked to this data. Conclusion: Antidepressant prescribing, particularly sertraline, is increasing. Prescribing is higher in more deprived regions, but costs are falling to

Low dopamine levels may cause depressive symptoms. Dopamine is also involved in sexual behavior. Rotigotine is a nonergolinic dopamine agonist. Fluoxetine, an antidepressant that acts as a selective serotonin (5-HT) reuptake inhibitor, may cause moderate or severe sexual dysfunction. This study aims to investigate the effects of rotigotine-loaded microspheres (RoMS) and rotigotine on fluoxetine-induced impairment of sexual function and their efficacy in depression-model rats. Rats with depressive-like behavior, induced by bilateral olfactory bulbectomy, were treated intragastrically with fluoxetine and co-administered RoMS or rotigotine subcutaneously. Then, copulatory behavior and open field tests were conducted. Serum luteinizing hormone and testosterone levels were assayed with enzyme-linked immunosorbent assay kits. The concentrations of 5-HT, dopamine, and norepinephrine were measured in the raphe nucleus and amygdala. The results showed that sexual function was decreased in olfactory bulbectomy rats and significantly deteriorated by fluoxetine. Co-administration of RoMS partly reversed the fluoxetine-induced impairment of sexual function, but rotigotine administration did not produce any improvement. Hyperactivity in olfactory bulbectomy rats was significantly attenuated by fluoxetine but was not influenced by co-administration of RoMS. Compared with the fluoxetine group, RoMS increased the testosterone, luteinizing hormone, dopamine, and norepinephrine levels. These findings indicated that RoMS improved the fluoxetine-induced impairment of sexual function and did not affect its antidepressant efficacy in depressive rats, which provides a potential treatment for patients with depression that can reduce the possibility of sexual dysfunction. Additionally, co-administration of fluoxetine with RoMS may be beneficial for Parkinson's disease patients with depression.

Background Individuals with treatment-resistant depression (TRD) experience a high burden of illness. Current guidelines recommend a stepped care approach for treating depression, but the extent to which best-practice care pathways are adhered to is unclear. Aims To explore the extent and nature of ‘treatment gaps’ (non-adherence to stepped care pathways) experienced by a sample of patients with established TRD (non-response to two or more adequate treatments in the current depressive episode) across three cities in the UK. Method Five treatment gaps were considered and compared with guidelines, in a cross-sectional retrospective analysis: delay to receiving treatment, lack of access to psychological therapies, delays to medication changes, delays to adjunctive (pharmacological augmentation) treatment and lack of access to secondary care. We additionally explored participant characteristics associated with the extent of treatment gaps experienced. Results Of 178 patients with TRD, 47% had been in the current depressive episode for >1 year before initiating antidepressants; 53% had received adequate psychological therapy. A total of 47 and 51% had remained on an unsuccessful first and second antidepressant trial respectively for >16 weeks, and 24 and 27% for >1 year before medication switch, respectively. Further, 54% had tried three or more antidepressant medications within their episode, and only 11% had received adjunctive treatment. Conclusions There appears to be a considerable difference between treatment guidelines for depression and the reality of care received by people with TRD. Future research examining representative samples of patients could determine recommendations for optimising care pathways, and ultimately outcomes, for individuals with this illness.

BackgroundImprovement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not.AimsWe aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission.MethodWe obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms.ResultsFor week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance.ConclusionsExamining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.Declaration of interestNone.

The gut microbiota is increasingly recognized to influence brain function through the gut-brain axis. Albiflorin, an antidepressant natural drug in China with a good safety profile, is difficult to absorb and cannot be detected in the brain after oral administration. Accordingly, the antidepressant mechanism of albiflorin in vivo has not been elucidated clearly. Methods: We identified benzoic acid as the characteristic metabolite of albiflorin in vivo and in vitro, then discovered the roles of gut microbiota in the conversion of albiflorin by carboxylesterase. Pharmacodynamic and pharmacokinetic studies were performed for the antidepressant activities of albiflorin in animals, and the efficacy of benzoic acid in inhibiting D-amino acid oxidase (DAAO) in brain was further investigated. Results: We validated that gut microbiota transformed albiflorin to benzoic acid, a key metabolite in the intestine that could cross the blood-brain barrier and, as an inhibitor of DAAO in the brain, improved brain function and exerted antidepressant activity in vivo. Intestinal carboxylesterase was the crucial enzyme that generated benzoic acid from albiflorin. Additionally, the regulatory effect of albiflorin on the gut microbiota composition was beneficial to alleviate depression. Conclusion: Our findings suggest a novel gut-brain dialogue through intestinal benzoic acid for the treatment of depression and reveal that the gut microbiota may play a causal role in the pathogenesis and treatment of the central nervous system disease.

Purpose The objective of this study was to compare the initiation and type of antidepressant use between refugees and matched Swedish-born youth after a diagnosis of a common mental disorder (CMD) and assess sociodemographic and clinical factors associated with the initiation. Methods The study cohort included youth aged 16–25 years, with an incident diagnosis of CMD based on specialized health care registers in Sweden 2006–2016, without prior antidepressant use during 1 year. One Swedish-born person was matched for each identified refugee youth (N = 3936 in both groups). Initiation of antidepressant use and factors associated with the initiation, were investigated with logistic regression yielding Odds ratios, OR, and 95% Confidence Intervals, CI. Results Refugees were less likely to initiate antidepressant use compared with Swedish-born (40.5% vs. 59.6%, adjusted OR 0.43, 95% CI 0.39–0.48). Selective serotonin reuptake inhibitors (SSRIs) were less frequently initiated for refugees than Swedish-born (71.2% vs. 81.3% of initiations, p Conclusion Young refugees with a CMD seem to initiate antidepressants in general and those most effective considerably less often than their Swedish-born counterparts.

Supplemental Digital Content is Available in the Text. Mefloquine/amitriptyline THN101 combination reduces cuff-induced neuropathic hypersensitivity by recruiting noradrenergic descending pathways and α2 adrenoceptors and by blocking connexin in mice., Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms, and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and importantly, connexins—transmembrane proteins involved in cell–cell communication—contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the antihyperalgesic effect of amitriptyline, a widely used antidepressant. In this study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. In addition, we showed that this potentiation was not due to pharmacokinetic interactions between the 2 drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenoceptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain.

Background: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. Method: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). Results: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC–mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC–mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. Conclusions: The synergism between VEN and vHPC–mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC–mPFC pathway.

Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear. We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively. Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides. Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.

Background There has been a recent rise in antidepressant prescriptions. After the episode for which it was prescribed, the patient should ideally be supported in withdrawing the medication. There is increasing evidence for withdrawal symptoms (sometimes called discontinuation symptoms) occurring on ceasing treatment, sometimes having severe or prolonged effects. Aims To identify and compare current knowledge, attitudes and practices of general practitioners (GPs) and psychiatrists in Cornwall, UK, concerning antidepressant withdrawal symptoms. Method Questions about withdrawal symptoms and management were asked of GPs and psychiatrists in a multiple-choice cross-sectional study co-designed with a lived experience expert. Results Psychiatrists thought that withdrawal symptoms were more severe than GPs did (P = 0.003); 53% (22/42) of GPs and 69% (18/26) of psychiatrists thought that withdrawal symptoms typically last between 1 and 4 weeks, although there was a wide range of answers given; 35% (9/26) of psychiatrists but no GPs identified a pharmacist as someone they may use to help manage antidepressant withdrawal. About three-quarters of respondents claimed they usually or always informed patients of potential withdrawal symptoms when they started a patient on antidepressants, but patient surveys say only 1% are warned. Conclusions Psychiatrists and GPs need to effectively warn patients of potential withdrawal effects. Community pharmacists might be useful in supporting GP-managed antidepressant withdrawal. The wide variation in responses to most questions posed to participants reflects the variation in results of research on the topic. This highlights a need for more reproducible studies to be carried out on antidepressant withdrawal, which could inform future guidelines.

Background: Treatment-resistant bipolar depression can be treated effectively using electroconvulsive therapy, but its use is limited because of stigma and cognitive adverse effects. Magnetic seizure therapy is a new convulsive therapy with promising early evidence of antidepressant effects and minimal cognitive adverse effects. However, there are no clinical trials of the efficacy and safety of magnetic seizure therapy for treatment-resistant bipolar depression. Methods: Participants with treatment-resistant bipolar depression were treated with magnetic seizure therapy for up to 24 sessions or until remission. Magnetic seizure therapy was applied over the prefrontal cortex at high (100 Hz; n = 8), medium (50 or 60 Hz; n = 9) or low (25 Hz; n = 3) frequency, or over the vertex at high frequency (n = 6). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression. Participants completed a comprehensive battery of neurocognitive tests. Results: Twenty-six participants completed a minimally adequate trial of magnetic seizure therapy (i.e., ≥ 8 sessions), and 20 completed full treatment per protocol. Participants showed a significant reduction in scores on the Hamilton Rating Scale for Depression. Adequate trial completers had a remission rate of 23.1% and a response rate of 38.5%. Per-protocol completers had a remission rate of 30% and a response rate of 50%. Almost all cognitive measures remained stable, except for significantly worsened recall consistency on the autobiographical memory inventory. Limitations: The open-label study design and modest sample size did not allow for comparisons between stimulation parameters. Conclusion: In treatment-resistant bipolar depression, magnetic seizure therapy produced significant improvements in depression symptoms with minimal effects on cognitive performance. These promising results warrant further investigation with larger randomized clinical trials comparing magnetic seizure therapy to electroconvulsive therapy. Clinical trial registration NCT01596608; clinicaltrials.gov

// Fei Liu 1, 2, * , You-ping Liu 1, 3, * , Gang Lei 1 , Peng Liu 1 , Zheng Chu 1 , Cheng-ge Gao 4 , Yong-hui Dang 1, 5, 6 1 College of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, PR China 2 Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, PR China 3 Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China 4 Department of Psychiatry, First Affiliated Hospital of Xi’an Jiaotong University Health Science Center, Xi’an, 710061, Shaanxi, PR China 5 Key Laboratory of the Health Ministry for Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi’an 710061, Shaanxi, PR China 6 Key Laboratory of Forensic Medicine of Shaanxi Province, Xi’an Jiaotong University Health Science Center, Xi’an 710061, Shaanxi, PR China * These authors have contributed equally to this work Correspondence to: Yong-hui Dang, email: psydyh@mail.xjtu.edu.cn Keywords: social isolation, depression, NT4-NAP/AAV, intranasal administration, antidepressant Received: October 09, 2016 Accepted: December 13, 2016 Published: December 29, 2016 ABSTRACT The purpose of the present study was to observe the depression-like behavior induced by social isolation; detect the antidepressant effect of a recombinant adeno-associated virus (AAV) expressing NAP on social isolation mice by intranasal delivery. After construction of NT4-NAP/AAV, expression of NAP was confirmed in vitro . 3-week-old C57/BL mice were bred individually in cages as social isolation-rearing. Six weeks later, the first subset of mice underwent behavioral tests and western blot; the second was for enzyme-linked immunosorbent assay. NT4-NAP/AAV was delivered quaque die by nasal administration for consecutive 10 days before behavioral test. Several depression-like behaviors were observed in social isolation mice, including decreased relative sucrose preference, longer immobility time in forced swimming test, lower plasma corticosterone and decreased brain-derived neurotrophic factor in hippocampus. Thus, social isolation procedure appears to be an animal model of depression with good face and construct validity. What’s more, the antidepressant effect in social isolation-rearing mice was observed after intranasal administration of NT4-NAP/AAV, suggesting that this might be a promising therapeutic strategy for depressive disorder.

Aims and methodTo discern changes in body mass index (BMI) in patients on long-term antidepressant treatment in a general practice population and establish BMI changes in patients with and without a diagnosis of diabetes. We used a retrospective observational method and identified patients on four antidepressants of interest. We excluded those who did not have start and current BMI readings within the past 3 years and noted whether or not patients had a diagnosis of diabetes.ResultsLong-term treatment with citalopram, fluoxetine, mirtazapine and sertraline was associated with increased BMI in two-thirds of patients. There was reduction in BMI in patients with diabetes and an increase in BMI for patients who did not have diabetes.Clinical implicationsAwareness of environmental factors and their impact on individuals is important. Medication is not the only cause of abnormal metabolic effects. Overall monitoring of physical health is important in all groups of patients.

Estrogen therapy (ET), an effective treatment for perimenopausal depression, often fails to ameliorate symptoms when initiated late after the onset of menopause. Our previous work has suggested that alternative splicing of RNA might mediate these differential effects of ET.Female Sprague–Dawley rats were treated with estradiol (E2) or vehicle 6 days (early ET) or 180 days (late ET) after ovariectomy (OVX). We investigated the differential expression of RNA splicing factors and tryptophan hydroxylase 2 (TPH2) protein using a customized RT2 Profiler PCR Array, reverse-transcription polymerase chain reaction, immunoprecipitation and behaviour changes in clinically relevant early and late ET.Early ET, but not late ET, prolonged swimming time in the forced swim test and reduced anxiety-like behaviours in the elevated plus maze. It reversed OVX-increased (SFRS7 and SFRS16) or OVX-decreased (ZRSR2 and CTNNB1) mRNA levels of splicing factors and ERβ splicing changes in the brains of OVX rats. Early ET, but not late ET, also increased the expression of TPH2 and decreased monoamine oxidase A levels in the dorsal raphe in the brains of OVX rats. In late ET, only diarylpropionitrile (an ERβ-specific agonist) achieved similar results — not E2 (an ERα and ERβ agonist) or propylpyrazoletriol (an ERα-specific agonist).Our experimental paradigm mimicked early and late ET in the clinical setting, but the contribution of age and OVX might be difficult to distinguish.These findings suggest that ERβ alternative splicing and altered responses in the regulatory system for serotonin may mediate the antidepressant efficacy of ET associated with the timing of therapy initiation. It is likely that ERβ-specific ligands would be effective estrogen-based antidepressants late after the onset of menopause.

Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg −1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg −1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg −1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg −1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

We investigated roles of plasma homocysteine and MTHFR gene in relation to risks and treatment responses of depression in ACS. A sample of 969 patients with recent ACS were recruited and 711 followed 1 year later. In addition, of 378 baseline participants with depressive disorder, 255 were randomized to a 24-week double blind trial of escitalopram (N = 127) or placebo (N = 128). A higher homocysteine concentration was independently associated with prevalent depressive disorder at baseline irrespective of MTHFR genotype; and with both incident and persistent depressive disorder at follow-up only in the presence of TT genotype. MTHFR genotype was not itself associated with depressive disorder after ACS. No associations were found with 24-week antidepressant treatment responses. Plasma homocysteine could be a biomarker for depressive disorder particularly in the acute phase of ACS. Focused interventions for those with higher homocysteine level and MTHFR TT genotype might reduce the risk of later depressive disorder.

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5–20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5–20mg/day) was 4.5–7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5–20mg/day) were nausea (20.9–31.2%) and vomiting (2.9–6.5%). For vortioxetine (5–20mg/day), the incidence of TEAEs associated with insomnia was 2.0–5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6–1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7–0.8kg. Thus, vortioxetine (5–20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder.

Objective: To study the anti-inflammatory activity of fluoxetine and escitalopram in newly diagnosed patients of depression and also to evaluate the association between depression and inflammation. Materials and Methods: Ninety-eight newly diagnosed patients of depression were recruited as cases. From these, 48 had started treatment with fluoxetine (20 mg/day) and 50 had started treatment with escitalopram (20 mg/day). After 2 months of treatment of these patients, Hamilton rating scale for depression (HRSD scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count were measured and compared to their respective baseline values before starting treatment. One hundred healthy volunteers were recruited as controls and their baseline of CRP, ESR and WBC count were measured and compared with their respective baseline values of cases. Severity of depression was measured by HRSD scale and anti-inflammatory activity was measured by reduction CRP, ESR and WBC count. Results: On baseline comparison between cases and controls, there were significant increases in the levels of CRP (P = 0.014), ESR (P = 0.023) and WBC count (P = 0.020) in cases. In fluoxetine (20 mg/day) treatment group, there was a significant reduction in the levels of CRP (P = 0.046), ESR (P = 0.043) and WBC count (P = 0.021) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.190). Similarly, in escitalopram treatment group, there was a significant reduction in CRP (P = 0.041), ESR (P = 0.030) and WBC count (P = 0.017) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.169). Conclusion: In newly diagnosed patients of depression, inflammatory markers such as CRP, ESR and WBC count were significantly raised and Selective serotonin reuptake inhibitors SSRIs such as fluoxetine and escitalopram reduced them independent of their antidepressant effect. So, SSRIs have some anti-inflammatory activity independent of their antidepressant action.

Commentary on Domschke, et al., Magnetoencephalographic correlates of emotionalprocessing in major depression before and after pharmacological treatment. Understanding the therapeutic effects of psychotropic medication has typically been approached, reasonably enough, with an analysis of the effects on brain chemistry. For example, the effective antidepressant mirtazapine is thought to affect both norepinephrine and serotonin neuromodulators, both of which are important to mood disorders such as major depression. However, understanding the full neuropsychopharmacology of a therapeutic agent requires an analysis of the multiple levels of neural self-regulation that are involved in the disorder and that are affected by the drug. It has long been apparent that if the mechanism of drug action were simply a correction of a biochemical imbalance, then the therapeutic effect would be rapid, limited only by the pharmacokinetics (Cooper et al., 2002). Instead, antidepressants typically require weeks of continued administration before they achieve a therapeutic effect. Although the complexity of drug action is familiar to most psychopathology researchers, clinicians are typically provided with only a superficial training on the neurophysiological and neuropsychological mechanisms for both psychopathology itself and the therapeutic effects of drugs. The result of this limited training is that a patient with depression, for example, is often told by the physician they have a “biochemical imbalance” that will be corrected by drug therapy. Not only is this explanation scientifically incorrect, …

Background: Moclobemide, a benzamide, is one of the new-generation monoamine oxidase-A inhibitors (MAO-AIs) which belongs to the class of reversible inhibitors of monoamine oxidase (RIMA). Numerous studies have shown that moclobemide is well-tolerated and as effective as other antidepressants. So far, there is no evidence available regarding its efficacy and tolerability in India. Aim: To compare the efficacy and safety of moclobemide with that of imipramine, a tricyclic antidepressant, in the treatment of major depressive disorder. Methods: In this prospective study, patients (n=60) were randomly assigned to treatment with moclobemide or imipramine for 6 weeks. Efficacy of the drugs was assessed by observing the mean change in scores on the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Scale (MADRS). Results: Both the groups showed significant decrease in scores at the end of 6 weeks. Patients who received moclobemide had a better side-effect profile. Conclusion: Moclobemide is an effective antidepressant and is better tolerated than imipramine.

Personalized medicine - the adaptation of therapies based on an individual's genetic and molecular profile - is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults.This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings.The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (-3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction.Limitations to our study included short treatment duration and lack of an active control arm.Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population.NCT01377194.

International audience; BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT-/-) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT-/- mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).

Background: Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits, the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown. Methods: The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≧40 years. Participants were randomly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks. An ANCOVA compared improvement in the cognitive composite scores, and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups. Results: There were no differences between the citalopram and placebo groups in changes in cognition. Baseline cognitive status did not moderate antidepressant treatment response. Conclusions: Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention, treatment does not substantially affect the level of cognitive functioning. Given the effects of cognitive deficits associated with schizophrenia on functional disability, there remains an ongoing need to identify effective means of directly ameliorating them.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Depression is one of the leading causes of disability worldwide. The majority of patients suffering from depressive disorder are diagnosed and managed in primary care. Optimal management reduces the risk of relapse and improves the quality of life. The main treatment modalities are antidepressants and psychological therapies. Lifestyle changes, exercise and psychoeducation also play an important role in management.

Five percent of menstruating women have severe premenstrual symptoms and impairment of functioning defined as premenstrual dysphoric disorder (PMDD). Clinically significant premenstrual symptoms occur in at least an additional 20% of menstruating women. The diagnosis of PMDD should be confirmed by prospective symptom charting over 2 menstrual cycles to confirm the timing of the symptoms and to rule out other diagnoses. The burden of illness of PMDD includes disruption of parenting and partner relationships and decreased productivity in work roles. In addition, women with PMDD have increased use of health care services such as clinician visits and increased use of prescription medications and over-the-counter preparations. The etiology of PMDD is multifactorial. In particular, dysregulation of the serotonin and allopregnanolone systems is implicated. Several effective treatment options exist, including serotonergic antidepressant medications and an oral contraceptive that contains ethinyl estradiol and drosperinone. In addition, other hormones that suppress ovulation, anxiolytics, cognitive therapy, chasteberry and calcium may be helpful.

The role of hippocampal atrophy in the pathogenesis of major depression remains under investigation. Here, we show, within a neural network model, that the incorporation of atrophy reproduces the changes observed in cognitive impairment in depression and could also contribute to the maintenance of the depressed mood. Some other clinical observations, such as treatment resistance and frequent relapses of illness, could also be explained within the framework of the model. We also simulate the action of cognitive therapy and a combined treatment of cognitive therapy and antidepressant drugs. Our findings suggest that, in the presence of hippocampal atrophy, the incorporation of antidepressant drugs would be necessary for the reversal of symptomatology.

Flavoprotein monoamine oxidase is located on the outer membrane ofmitochondria. It catalyzes oxidative deamination of monoamine neurotransmitters such asserotonin, norepinephrine and dopamine and hence is a target enzyme for antidepressantdrugs. MAO (mono amine oxidase) has two isoforms, namely MAO-A and MAO-B.MAO-A isoform has higher affinity for serotonin and norepinephrine, while, MAO-Bpreferentially deaminates phenylethylamine and benzylamine. These important propertiesdetermine the clinical importance of MAO inhibitors. Selective MAO-A inhibitors are usedin the treatment of neurological disorders such as depression. In this article we havedeveloped a Hypogen pharmacophore for a set of 64 coumarin analogs and tried to analyzethe intermolecular H-bonds with receptor structure.

Objective To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. Design Nested case-control study. Setting Primary care in the United Kingdom. Participants 146 095 individuals with a first prescription of an antidepressant for depression. Main outcome measures Suicide and non-fatal self harm. Results 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. Conclusion We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.