Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Study protocol: combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms [FAB-study].

BACKGROUND: Antidepressant discontinuation is associated with a broad range of adverse effects. Debilitating discontinuation symptoms can impede the discontinuation process and contribute to unnecessary long-term use of antidepressants. Antidepressant trials reveal large placebo effects, indicating a potential use of open-label placebo (OLP) treatment to facilitate the discontinuation process. We aim to determine the effect of OLP treatment in reducing antidepressant discontinuation symptoms using a series of N-of-1 trials. METHODS: A series of randomized, single-blinded N-of-1 trials will be conducted in 20 patients with fully remitted DSM-V major depressive disorder, experiencing moderate to severe discontinuation symptoms following antidepressant discontinuation. Each N-of-1 trial consists of two cycles, each comprising two-week alternating periods of OLP treatment and of no treatment in a random order, for a total of eight weeks. Our primary outcome will be self-reported discontinuation symptoms rated twice daily via the smartphone application 'StudyU'. Secondary outcomes include expectations about discontinuation symptoms and (depressed) mood. Statistical analyses will be based on a Bayesian multi-level random effects model, reporting posterior estimates of the overall and individual treatment effects. DISCUSSION: Results of this trial will provide insight into the clinical application of OLP in treating antidepressant discontinuation symptoms, potentially offering a new cost-effective therapeutic tool. This trial will also determine the feasibility and applicability of a series of N-of-1 trials in a clinical discontinuation trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05051995, first registered September 20, 2021.

Peripheral edema associated with antidepressant use: Systematic review of case reports.

BACKGROUND: Oedema associated with psychotropics can impose a considerable burden, leading to increased morbidity and cost. Peripheral oedema is sometimes related to the use of antidepressants, which are among the most prescribed psychotropic medications. We reviewed the reported cases of antidepressant-associated oedema to understand the risk factors, aetiology and outcome. METHODS: We searched the Medline, Web of Science and Embase databases to identify reported cases of peripheral oedema associated with antidepressant use. We included studies published in English and those with full-text availability. A systematic review of the reports was done to identify the antidepressants associated with oedema, explore possible risk factors, investigate potential mechanisms, and assess the outcome. RESULTS: We identified a total of 45 cases (27 case reports and five case series) that reported oedema associated with antidepressant use. Almost all major classes of antidepressants were found to be associated with oedema. Among these drugs, trazodone, mirtazapine, and escitalopram were the most implicated. Older age and female gender were more commonly associated with oedema. Etiologically, antagonism of α1 adrenergic receptors and 5HT2A receptors, leading to vasodilation and oedema, emerged as the most prevalent mechanisms. In most cases, the oedema subsided following the discontinuation of the antidepressants. CONCLUSIONS: Peripheral oedema associated with antidepressant use can represent a significant adverse drug reaction involving various classes of antidepressants. To ensure timely identification and proper management of oedema, regular monitoring is crucial.

Discontinuation of antidepressant treatment: a retrospective cohort study on more than 20,000 participants.

BACKGROUND: Factors influencing antidepressant treatment discontinuation are poorly understood. In the present study, we aimed to estimate the prevalence of antidepressant treatment discontinuation and identify demographic characteristics, psychiatric comorbidities, and specific side effects associated with treatment discontinuation. METHODS: We leveraged data from the Australian Genetics of Depression Study (AGDS; N = 20,941) to perform a retrospective cohort study on antidepressant treatment discontinuation. Participants were eligible if they were over 18 years of age, had taken antidepressants in the past 4 years, and provided informed consent. RESULTS: Among the ten antidepressants studied, the highest discontinuation rates were observed for Mirtazapine (57.3%) and Amitriptyline (51.6%). Discontinuation rates were comparable across sexes except for Mirtazapine, for which women were more likely to discontinue. The two most common side effects, reduced sexual function and weight gain, were not associated with increased odds of treatment discontinuation. Anxiety, agitation, suicidal thoughts, vomiting, and rashes were associated with higher odds for treatment discontinuation, as were lifetime diagnoses of PTSD, ADHD, and a higher neuroticism score. Educational attainment showed a negative (protective) association with discontinuation across medications. CONCLUSIONS: Our study suggests that not all side effects contribute equally to discontinuation. Common side effects such as reduced sexual function and weight gain may not necessarily increase the risk of treatment discontinuation. Side effects linked to discontinuation can be divided into two groups, psychopathology related and allergy/intolerance.

Association between selective serotonin and serotonin-noradrenaline reuptake inhibitor therapy and hematuria.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are used as first-line treatment for many psychiatric diseases, especially major depressive disorder. However, an important side effect of these drugs is the risk of bleeding due to platelet dysfunction. The aim of this study was to determine the frequency of hematuria in patients using SSRI/SNRIs and to compare with a control group. METHODS: This study included patients who were followed up and treated with SSRI/SNRI in the psychiatric outpatient clinic of the Antalya Medical Park Hospital between 1 January 2021 and 31 March 2021 and a control group comprising patients who presented to the medical check-up outpatient clinic between the same dates. Complete urinalysis was performed for all patients and the results were compared between the groups. RESULTS: Each group included 100 patients with a female/male ratio of 1. The mean age was 41.45 ± 13.47 (16-74) years in the study group and 40.51 ± 13.75 (20-70) years in the control group (p = 0.519). Mean duration of SSRI/SNRI use in the study group was 13.35 ± 1.32 (1-64) months. The prevalence of hematuria was 17% in the SSRI/SNRI group and 6% in the control group (p = 0.015). All cases of hematuria were microscopic hematuria. CONCLUSION: Hematuria is significantly more common in patients receiving SSRI/SNRI treatment. The use of SSRI/SNRI should also be taken into account when investigating the etiology of hematuria.

Efficacy and safety of serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRI) for children and adolescents with anxiety disorders: a systematic review and meta-analysis.

PURPOSE: To assess the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs) in comparison with various control contingencies (e.g. pill placebo and cognitive behavioral treatment) for pediatric anxiety disorders. Additionally, we wanted to investigate whether serious adverse events or adverse events are more common with medication treatment compared with pill placebo. MATERIALS AND METHODS: Studies were selected if they were randomized controlled trials evaluating SSRIs or SNRIs. Eligible studies included participants aged 17 years or younger. Eleven studies were included, with 2122 participants. Primary outcomes were (1) remission, (2) a continuous scale such as the Social Phobia and Anxiety Inventory for Children and (3) serious adverse events. We also calculated number needed to treat and number needed to harm. RESULTS: SSRIs and SNRIs are an effective treatment of childhood anxiety disorders and are superior to pill placebo. While the risk of serious adverse events was low with SSRI/SNRI treatment, there was an increased risk of experiencing behavioral activation with SSRI/SNRI treatment. CONCLUSION: SSRI and SNRI treatment is effective for childhood anxiety disorders, with positive effect of treatment outweighing the negative effects.

SSRI/SNRI -induced Hyponatremia: A Case Series of 26 Patients in a Single Institution from 2018 to 2020.

Antidepressant medications are widely used by patients with depression or a depressive disorder. In spite of a generally favorable safety profile of selective serotonin reuptake inhibitors or serotonin - norepinephrine reuptake inhibitors (SSRI/SNRI), several cases of a possible connection between SSRI/SNRI and hyponatremia have been reported. To describe the clinical characteristics of patients with hyponatremia after SSRI/SNRI exposure, and to examine the association between SSRI/SNRI exposure and the presence of hyponatremia in a Chinese population. A retrospective single-center case series study. We performed a retrospective evaluation of inpatients with SSRI/SNRI-induced hyponatremia from a single institution in China between 2018 and 2020. Clinical data were obtained through review of medical records. Patients who met the initial inclusion criteria but did not develop hyponatremia acted as controls. The study was approved by the Clinical Research Ethics Board of Beijing Hospital (Beijing, P.R. China). We identified 26 patients with SSRI/SNRI-induced hyponatremia. The incidence rate of hyponatremia was 1.34% (26/1937) in the study population. The mean age at diagnosis was 72.58 (±12.84) years, with a male: female ratio of 1:1.42. The duration between SSRI/SNRI exposure and the onset of hyponatremia was 7.65 (±4.88) days. The minimum serum sodium level was 2328.23 (±107.25) mg/dL in the study group. Seventeen patients (65.38%) received sodium supplements. Four patients (15.38%) switched to another antidepressant. Fifteen patients (57.69%) recovered by the time of discharge. There were significant differences in serum potassium, serum magnesium and serum creatinine level between the two groups (p < 0.05). The rate of use of sertraline was significantly higher in the study group compared with the control group (p < 0.05). This pattern was not found in other SSRI/SNRI (p > 0.05). The results of our study show that SSRI/SNRI exposure, in addition to hyponatremia, may also affect the level of serum potassium, serum magnesium and serum creatinine. A history of hyponatremia and exposure to SSRI/SNRI may be potential risk factors for the development of hyponatremia. Future prospective studies are needed to validate these findings.

Impact of Venlafaxine on Platelet Count and Activity-Case Report and Narrative Review.

Venlafaxine (VEN) is considered to be one of the most effective antidepressants. It belongs to the group of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs). NA and 5-HT have receptors on the surface of platelets and are involved in platelet aggregation. In this case study, we present the case of a patient treated for one of the types of myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), in whom VEN was added to pharmacotherapy during the treatment of a severe episode of depression with psychotic symptoms. We observed a gradual reduction in platelet count when increasing the dose of VEN. We also present a narrative review of literature about the effect of VEN on platelet counts and activity. We conclude that, in the group of patients taking VEN, attention should be paid to the rare adverse effect of a decrease in the number of platelets.

Antidepressant-induced serotonin syndrome in older patients: a cross-sectional study.

BACKGROUND: Widespread prescription of antidepressants and their resulting role in serotonin syndrome (SS) are of great importance for clinical practice in the elderly. This study aims to investigate possible associations of antidepressant drug-induced SS with related variables in these patients. METHODS: A total of 238 older adults using antidepressants were included. Patients who fulfilled the Hunter Serotonin Toxicity Criteria (HSTC) for SS were considered as the clinical groups (mild, moderate, or severe), and those who did not as the control group. We recorded all patients' demographic and clinical characteristics, including age, gender, comorbidity index, number of medications, daily equivalent dose of the relevant antidepressant according to fluoxetine per day, electrocardiogram test results, laboratory results, and management. RESULTS: The mean age of all patients was 75.4 ± 7.6 years and 63.4% were female. Sixty patients had SS, while 178 patients did not. There was a significant difference between those with and without SS in terms of gender, frequency of combination antidepressant therapy, and daily equivalent antidepressant dose (P < 0.05). The most common diagnostic findings in SS patients were tremor and hyperreflexia and 31.7% was mild, and moderate in 68.3% with higher median age and number of medications (P < 0.041). Antidepressants were discontinued in all patients regardless of severity, of whom 71.7% were treated with benzodiazepines and 36.7% with cyproheptadine. After adjusting for age and sex, association with use of SSRI + SNRI, use of any combination therapy, and daily equivalent dose remained significant. CONCLUSIONS: The widespread single or combined use of antidepressants in older adults represents an increased clinical concern for SS and physicians should be aware of this drug-related complication in older patients.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

M1/M2 polarization in major depressive disorder: Disentangling state from trait effects in an individualized cell-culture-based approach.

Accumulating evidence indicates the specific involvement of inflammatory processes in major depressive disorder (MDD), particularly affecting innate immunity. Most immune alterations have so far been determined based on plasma or cerebrospinal fluid cytokine levels. To precisely characterize putative innate immune-mediated mechanisms in MDD pathogenesis, we sought to disentangle "state" from "trait" effects in a patient-specific cell model by quantifying the impact of patient-derived autologous sera (AS) on patient-specific monocyte-derived macrophages (Mo-MФs) polarization in vitro. Mo-MФs were generated from 28 patients with moderate to severe MDD and 28 age-, sex-, smoking status- and BMI-matched healthy controls (HC). Cells were treated either with AS or fetal calf serum (FCS) and polarized into M1 (LPS), M2 (IL-10, IL-4, TGF-ß) or M0 (unstimulated) macrophages. Polarization capacity was quantified by means of specific M1 (CCR7, CD86, CXCL10, IL-12p70, TNF-α, IL-6, IL-1ß, IL-12p40, IL-23, IP-10) and M2 (CD206, IL-10, TARC, IL-1RA) markers. Compared to HC, significantly increased M1-polarization was observed for MDD patients in the presence of FCS, however, polarization in AS enriched media determined an increased M2-polarization in patients. Moreover, female MDD patients exhibited increased M1- and decreased M2-polarization in both conditions compared to male MDD patients. Our data suggests that Mo-MФs derived from patients with MDD exhibit facilitated M1-polarization under traditional cell culture conditions and an increased potential for M2-polarization when cultured in AS. Striking inter-individual variation and pronounced gender effects highlight the potential utility of our personalized cell model-based approach to aid diagnostic and therapeutic decisions.

The potential for adverse effects in fish exposed to antidepressants in the aquatic environment.

Antidepressants are one of the most commonly prescribed pharmaceutical classes for the treatment of psychiatric conditions. They act via modulation of brain monoaminergic signaling systems (predominantly serotonergic, adrenergic, dopaminergic) that show a high degree of structural conservation across diverse animal phyla. A reasonable assumption, therefore, is that exposed fish and other aquatic wildlife may be affected by antidepressants released into the natural environment. Indeed, there are substantial data reported for exposure effects in fish, albeit most are reported for exposure concentrations exceeding those occurring in natural environments. From a critical analysis of the available evidence for effects in fish, risk quotients (RQs) were derived from laboratory-based studies for a selection of antidepressants most commonly detected in the aquatic environment. We conclude that the likelihood for effects in fish on standard measured end points used in risk assessment (i.e., excluding effects on behavior) is low for levels of exposure occurring in the natural environment. Nevertheless, some effects on behavior have been reported for environmentally relevant exposures, and antidepressants can bioaccumulate in fish tissues. Limitations in the datasets used to calculate RQs revealed important gaps in which future research should be directed to more accurately assess the risks posed by antidepressants to fish. Developing greater certainty surrounding risk of antidepressants to fish requires more attention directed toward effects on behaviors relating to individual fitness, the employment of environmentally realistic exposure levels, on chronic exposure scenarios, and on mixtures analyses, especially given the wide range of similarly acting compounds released into the environment.

Adiponectin predicts poor response to antidepressant drugs in major depressive disorder.

OBJECTIVE: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. METHODS: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. RESULTS: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. CONCLUSIONS: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.

The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies.

RATIONALE: Depression has the topmost prevalence of all psychiatric diseases. It is characterized by a high recurrence rate, disability, and numerous and mostly unclear pathogenic mechanisms. Besides the monoamine or the neurotrophic hypothesis of depression, the inflammatory mechanism has begun to be supported by more and more evidence. At the same time, the current knowledge about the standard treatment of choice, the selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs), is expanding rapidly, adding more features to the initial ones. OBJECTIVES: This review summarizes the in vivo anti-inflammatory effects of SSRIs and SNRIs in the treatment of depression and outlines the particular mechanisms of these effects for each drug separately. In addition, we provide an overview of the inflammation-related theory of depression and the underlying mechanisms. RESULTS: SSRIs and SNRIs decrease the neuroinflammation through multiple mechanisms including the reduction of blood or tissue cytokines or regulating complex inflammatory pathways: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inflammasomes, Toll-like receptor 4 (TLR4), peroxisome proliferator-activated receptor gamma (PPARγ). Also, SSRIs and SNRIs show these effects in association with an antidepressant action. CONCLUSIONS: SSRIs and SNRIs have an anti-neuroinflammatory role which might contribute the antidepressant effect.

Opioid Exposure Negatively Affects Antidepressant Response to Venlafaxine in Older Adults with Chronic Low Back Pain and Depression.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) are commonly co-prescribed with opioids for chronic pain. The purpose of this study was to describe pain and mood response to venlafaxine among older adults with chronic low back pain (CLBP) and depression relative to opioid exposure. DESIGN: Secondary analyses were collected from a randomized clinical trial testing a stepped-care approach to comorbid pain and depression in older patients: the Addressing Depression and Pain Together study (ADAPT: 2010-2016). SETTING: University-based late-life mental health research clinic. SUBJECTS: Two hundred twenty-seven adults aged 65+ years with CLBP and depression. METHODS: Participants received six weeks of lower-dose venlafaxine (≤150 mg/d). Pain and depression were measured each week. Response for both pain and depression at the end of six weeks was defined by a ≥30% improvement on a 0-20 numeric rating scale for low back pain and a Patient Health Questionnaire-9 score ≤5. Opioid exposure was analyzed as prescribed (yes or no) and by morphine equivalent dosing (MED). RESULTS: Patients co-prescribed an opioid were less likely to report a pain response to venlafaxine. MED was negatively correlated with pain response. Depression response was not impacted. CONCLUSIONS: Opioids are negatively associated with older adults' early analgesic response to lower-dose venlafaxine. These findings suggest that clinicians may wish to consider either nonopioid or alternative antidepressant approaches to pain management in these complex patients. It is reassuring that opioids do not prevent depression response. Future research should examine both longer duration of treatment and a wider range of doses.

Recent advances in liquid chromatographic methods for the determination of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.

Depression is now the second largest public health burden throughout the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have replaced older antidepressants to become first-line medications to treat this disease with increased remission rates and markedly decreased incidence of severe adverse events. Traditional and modern bioanalytical strategies for SSRI and SNRI determination are being continuously improved. There has also been a recent increase in the use of unconventional sample preparation methods. This review critically evaluates the development of SSRI and SNRI liquid chromatographic analytical methods published between 2014 and mid-2019, with special attention to novel sample preparation methods.

SSRI/SNRI Therapy is Associated With a Higher Risk of Gastrointestinal Bleeding in LVAD Patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is common in left ventricular assist device (LVAD) patients. Serotonin release from platelets promotes platelet aggregation, and selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy inhibits the transporter responsible for re-uptake. METHODS: We reviewed the records of LVAD (HeartMateII™, Abbott Medical, Lake Bluff, IL, USA and Heartware™, Medtronic, Minneapolis, MN, USA) patients at the Medical University of South Carolina and Johns Hopkins Hospital between January 2009 and January 2016. After exclusions, 248 patients were included for analysis. After univariate analysis, logistic regression multivariate analysis was performed to adjust for any demographic, cardiovascular, and laboratory data variables found to be associated with GI bleeding post-LVAD. RESULTS: Gastrointestinal bleeding occurred in 85 patients (35%) with 55% of GIBs due to arteriovenous malformations (AVMs). Of the total cohort, 105 patients received an SSRI or SNRI during LVAD support. Forty-four (44) SSRI/SNRI (41.9%) and 41 non-SSRI/SNRI (28.7%) patients had a GIB (RR 1.46, p = 0.03). Twenty-six (26) (24.8%) of the SSRI/SNRI patients had a GIB due to AVMs versus 21 (14.7%) of the non-SSRI/SNRI patients (RR 1.69, p = 0.05). In fully-adjusted multivariate regression analysis, SSRI/SNRI therapy was independently associated with GIB (OR 1.78, p = 0.045). For GIB, the number needed to harm (NNH) was 7.6. CONCLUSION: In conclusion, SSRI/SNRI therapy is independently associated with an increased risk of GIB in LVAD patients.

In vivo electrophysiological recordings of the effects of antidepressant drugs.

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.

Hidden in the sand: Alteration of burying behaviour in shore crabs and cuttlefish by antidepressant exposure.

Pharmaceuticals such as antidepressants are constantly released into the aquatic environment. Consequently, fluoxetine (FLX) and venlafaxine (VEN), the active molecules of Prozac© and Effexor©, are detected up to several µg.L-1 in freshwater and marine coastal waters. Both compounds act on the serotoninergic system, which may result in behavioural impairment, especially in juvenile animals presumed to be more susceptible to low concentrations than adults. The objective of this study was to determine whether environmental concentrations of FLX alone or combined with VEN modulate innate burying behaviour in two juvenile marine invertebrates, i.e. Sepia officinalis and Carcinus maenas. Juvenile cuttlefish were exposed from hatching to 30 days post-hatching to either FLX alone (i.e. 5 ng.L-1) or in mixture with VEN (i.e. either 2.5 ng.L-1 or 5 ng.L-1 of each antidepressant). Juvenile crabs (<2 cm carapace width) were exposed for a period of 22 days to 5 ng.L-1 of FLX and a mixture of 5 ng.L-1 of FLX and VEN each. Several parameters of sand-digging behaviour were analysed weekly in both species. The occurrence of sand-digging behaviour decreased in cuttlefish exposed to a mixture of FLX and VEN at the lowest concentration (2.5 ng.L-1 each). Because sand-digging behaviour improved in controls, this decrease was likely to be related to a modification of maturation and/or learning processes. At the mixture of 5 ng.L-1 VEN and FLX each, a better body covering was observed in juvenile crabs. In both species, innate behaviour was modified under exposure to mixtures of FLX and VEN at environmentally realistic concentrations. These alterations were observed at an early developmental stage, when animals are particularly prone to predation. Hence, modified maturation of behavioural traits and, putatively, learning processes by exposure to pseudo-persistent antidepressants may affect the survival of these two species in the long term.

Characterization of intentional-abuse venlafaxine exposures reported to poison control centers in the United States.

Background: Venlafaxine use to achieve an amphetamine-like high has been described but data regarding the epidemiology and clinical effects are sparse. Objectives: Describe the prevalence and toxicity of venlafaxine abuse reported to US poison control centers. Methods: This was a retrospective review of venlafaxine exposures reported to the National Poison Data System (NPDS) from 2000 to 2016. Inclusion criteria were: age 12 years and older, reason for exposure intentional-abuse, and either single-substance exposure or venlafaxine was the first substance. The primary outcome was prevalence of intentional-abuse of venlafaxine. Secondary outcomes characterized demographics, geographic distribution, toxicity, and outcomes. Results: Intentional-abuse accounted for 752 of 85,621 venlafaxine exposures. Overall prevalence was 87.8 intentional-abuse exposures/10,000 venlafaxine exposures reported to NPDS (range, 59.3-117.6/10,000). Prevalence decreased from 107/10,000 in 2000 to 59.3/10,000 in 2016. Median age was 23 years and 50% were female. Primary route was ingestion (90.8%) with 4.7% using venlafaxine via inhalation/intranasal insufflation, and 3.7% both routes. There were 227 venlafaxine-only exposures; 54.0% were treated/released from the emergency department, 20% were admitted for medical management, 9.0% to a psychiatric facility, and 17.0% managed at home. Known medical outcomes for single-substance exposures were: no effect (24.0%), minor (39.0%), moderate (33.0%), and major (4.0%); no deaths occurred. Most frequent clinical effects were tachycardia (33.9%), drowsiness (20.7%), and agitation (11.5%). Conclusion: The prevalence of venlafaxine abuse reported to poison control centers has decreased. Medical outcomes are usually not serious. Clinicians should be aware that non-medical use is possible but infrequently reported to poison control centers.