Special Populations: Treatment-Resistant Depression in Children and Adolescents.

Major depressive disorder is a substantial public health challenge impacting at least 3 million adolescents annually in the United States. Depressive symptoms do not improve in approximately 30% of adolescents who receive evidence-based treatments. Treatment-resistant depression in adolescents is broadly defined as a depressive disorder that does not respond to a 2-month course of an antidepressant medication at a dose equivalent of 40 mg of fluoxetine daily or 8 to 16 sessions of a cognitive behavioral or interpersonal therapy. This article reviews historical work, recent literature on classification, current evidence-based approaches, and emerging interventional research.

Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.

BACKGROUND: Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. OBJECTIVE: The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). METHODS: A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. RESULTS: Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. CONCLUSION: Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. CLINICAL TRIAL REGISTRATION: TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro.

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1­adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D­ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D­AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.

Association of Antidepressant Continuation in Pregnancy and Infant Birth Weight.

PURPOSE: The aim of the study was to evaluate the association of antidepressant continuation in pregnancy with infant birth weight among women using antidepressants before pregnancy. METHODS: This retrospective cohort study used electronic health data linked with state birth records. We identified singleton live births (2001-2014) to enrolled women with 1 or more antidepressant prescriptions filled 6 months or less before pregnancy, including "continuers" (≥1 antidepressant fills during pregnancy, n = 1775) and "discontinuers" (no fill during pregnancy, n = 1249). We compared birth weight, small or large for gestational age (SGA or LGA), low birth weight (LBW; <2500 g), and macrosomia (>4500 g) between the 2 groups, using inverse probability of treatment weighting to account for pre-pregnancy characteristics, including mental health conditions. RESULTS: After weighting, infants born to antidepressant continuers weighed 71.9 g less than discontinuers' infants (95% confidence interval [CI], -115.5 to -28.3 g), with a larger difference for female infants (-106.4 g; 95% CI, -164.6 to -48.1) than male infants (-48.5 g; 95% CI, -107.2 to 10.3). For female infants, SGA risk was greater in continuers than discontinuers (relative risk [RR],1.54; 95% CI, 1.02 to 2.32). Low birth weight risk was greater in continuers with 50% or more of days covered (RR, 1.69; 95% CI, 1.11 to 2.58) and exposure in the second trimester (RR, 1.53; 95% CI, 1.02 to 2.29), as compared with discontinuers. CONCLUSIONS: Depending on infant sex, as well as duration and timing of use, continuation of antidepressant use during pregnancy may be associated with lower infant birth weight, with corresponding increases in LBW and SGA.

Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.

Special Report from the CDC Antidepressant subclass use and fall risk in community-dwelling older Americans.

INTRODUCTION: Falls among older adults are a significant health concern affecting more than a quarter of older adults (age 65+). Certain fall risk factors, such as medication use, increase fall risk among older adults (age 65+). AIM: The aim of this study is to examine the association between antidepressant-medication subclass use and self-reported falls in community-dwelling older adults. METHODS: This analysis used the 2009-2013 Medicare Current Beneficiary Survey, a nationally representative panel survey. A total of 8,742 community-dwelling older adults, representing 40,639,884 older Medicare beneficiaries, were included. We compared self-reported falls and psychoactive medication use, including antidepressant subclasses. These data are controlled for demographic, functional, and health characteristics associated with increased fall risk. Descriptive analyses and multivariate logistic regression analyses were conducted using SAS 9.4 and Stata 15 software. RESULTS: The most commonly used antidepressant subclass were selective serotonin reuptake inhibitors (SSRI) antidepressants (13.1%). After controlling for characteristics associated with increased fall risk (including depression and concurrent psychoactive medication use), the risk of falling among older adults increased by approximately 30% among those who used a SSRI or a serotonin-norepinephrine reuptake inhibitors (SNRI) compared to non-users. The adjusted risk ratio (aRR) for SSRI was 1.29 (95% CI = 1.13, 1.47) and for SNRI was 1.32 (95% CI = 1.07, 1.62). CONCLUSION: SSRI and SNRI are associated with increased risk of falling after adjusting for important confounders. Medication use is a modifiable fall risk factor in older adults and can be targeted to reduce risk of falls. Practical Applications: Use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors increased the risk of falling in older adults by approximately 30%, even after controlling for demographic, functional, and health characteristics, including depression. Health care providers can work towards reducing fall risk among their older patients by minimizing the use of certain medications when potential risks outweigh the benefits.

Efficacy and safety of antidepressants for the treatment of back pain and osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To investigate the efficacy and safety of antidepressants for back and osteoarthritis pain compared with placebo. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to 15 November and updated on 12 May 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials comparing the efficacy or safety, or both of any antidepressant drug with placebo (active or inert) in participants with low back or neck pain, sciatica, or hip or knee osteoarthritis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data. Pain and disability were primary outcomes. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst pain or disability). A random effects model was used to calculate weighted mean differences and 95% confidence intervals. Safety (any adverse event, serious adverse events, and proportion of participants who withdrew from trials owing to adverse events) was a secondary outcome. Risk of bias was assessed with the Cochrane Collaboration's tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework. RESULTS: 33 trials (5318 participants) were included. Moderate certainty evidence showed that serotonin-noradrenaline reuptake inhibitors (SNRIs) reduced back pain (mean difference -5.30, 95% confidence interval -7.31 to -3.30) at 3-13 weeks and low certainty evidence that SNRIs reduced osteoarthritis pain (-9.72, -12.75 to -6.69) at 3-13 weeks. Very low certainty evidence showed that SNRIs reduced sciatica at two weeks or less (-18.60, -31.87 to -5.33) but not at 3-13 weeks (-17.50, -42.90 to 7.89). Low to very low certainty evidence showed that tricyclic antidepressants (TCAs) did not reduce sciatica at two weeks or less (-7.55, -18.25 to 3.15) but did at 3-13 weeks (-15.95, -31.52 to -0.39) and 3-12 months (-27.0, -36.11 to -17.89). Moderate certainty evidence showed that SNRIs reduced disability from back pain at 3-13 weeks (-3.55, -5.22 to -1.88) and disability due to osteoarthritis at two weeks or less (-5.10, -7.31 to -2.89), with low certainty evidence at 3-13 weeks (-6.07, -8.13 to -4.02). TCAs and other antidepressants did not reduce pain or disability from back pain. CONCLUSION: Moderate certainty evidence shows that the effect of SNRIs on pain and disability scores is small and not clinically important for back pain, but a clinically important effect cannot be excluded for osteoarthritis. TCAs and SNRIs might be effective for sciatica, but the certainty of evidence ranged from low to very low. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020158521.

Natural volatile oils derived from herbal medicines: A promising therapy way for treating depressive disorder.

Depression is a common global mental disorder that seriously harms human physical and mental health. With the development of society, the increase of pressure and the role of various other factors make the incidence of depression increase year by year. However, there is a lack of drugs that have a fast onset, significant effects, and few side effects. Some volatile oils from traditional natural herbal medicines are usually used to relieve depression and calm emotions, such as Lavender essential oil and Acorus tatarinowii essential oil. It was reported that these volatile oils, are easy to enter the brain through the blood-brain barrier and have good antidepressant effects with little toxicity and side effects. In this review, we summarized the classification of depression, and listed the history of using volatile oils to fight depression in some countries. Importantly, we summarized the anti-depressant natural volatile oils and their monomers from herbal medicine, discussed the anti-depressive mechanisms of the volatile oils from natural medicine. The volatile oils of natural medicine and antidepressant drugs were compared and analyzed, and the application of volatile oils was explained from the clinical use and administration routes. This review would be helpful for the development of potential anti-depressant medicine and provide new alternative treatments for depressive disorders.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.

Depression, antidepressants and low hemoglobin level in the Paris Prospective Study III: A cross-sectional analysis.

Anemia is known to be associated with depression both in community and clinical populations. However, it is still unknown if this association depends or not on antidepressant intake. We investigated the respective association of depression and antidepressant intake with low hemoglobin level in a large community-based cohort. In 8640 volunteers aged 50 to 75 recruited between June 2008 and June 2012 in Paris (France), we assessed hemoglobin levels (g/dl), depressive symptoms and antidepressant intake. We examined the association of both depression and antidepressant intake with hemoglobin level, adjusting for numerous socio-demographic and health variables. We also assessed the association with specific antidepressant classes. Depression and antidepressant intake were independently associated with lower hemoglobin level (ß = -0.074; p = .05 and ß = -0.100; p = .02 respectively in the fully-adjusted model). Regarding antidepressant classes, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) intake were associated with lower hemoglobin level (ß = -0.11; p = .01). To conclude, both depression and antidepressant intake were associated with lower hemoglobin level. In particular, as SSRI or SNRIs intake was also related to lower hemoglobin level, these classes should be used with caution in depressed individuals at risk for anemia.

Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 9: Interactions Mediated by Drug-metabolizing Cytochrome P450 Enzymes.

This column is the ninth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmaco-dynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. The seventh and eighth columns presented the concept of relative receptor binding and included tables summarizing the relative receptor binding affinity of currently available antipsychotics and antidepressants, respectively. This ninth and final column in this series discusses pharmacokinetic DDIs with a focus on psychiatric medications and contains 3 tables. The first table is an abbreviated version of a table available online showing which drugs are substrates for which cytochrome P450 (CYP) enzymes and which drugs are inhibitors or inducers of specific CYP enzymes. The abbreviated version of the table presented in this column focuses on psychiatric medications. This table and the larger website version can allow prescribers to anticipate which drug combinations may pose the risk of a CYP enzyme-mediated DDI. The second table summarizes which antidepressants inhibit specific CYP enzymes and which antidepressants do not or are unlikely to inhibit specific CYP enzymes. The third table presents psychiatric medications whose clearance is not principally dependent on CYP enzyme-mediated oxidative metabolism as a necessary step in their clearance from the body. The latter 2 tables inform prescribers as to which drugs they may prefer to use to avoid CYP enzyme-mediated DDIs. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 8: Relative Receptor Binding Affinity as a Way of Understanding the Differential Pharmacology of Currently Available Antidepressants.

This column is the eighth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. The sixth column discussed key pharmacodynamic interactions involving ethanol, opioids, and monoamine oxidase inhibitors. That column focused particularly on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors and also DDIs involving psychiatric medications with adverse effects on the cardiovascular system and on the central nervous system. The seventh column presented the concept of relative receptor binding and included a table summarizing the relative receptor binding affinity of antipsychotics including all of the newer agents as well as some of the older agents such as haloperidol. This eighth column in this series presents a parallel table to the one in the seventh column summarizing the relative receptor binding affinity of currently available antidepressants. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use ≥2 drugs in combination to optimally treat a patient.

Tianeptina, un abordaje farmacológico atípico de la depresión / Tianeptine, an atypical pharmacological approach to depression

La introducción de los primeros antidepresivos en la década de los cincuenta del sigloxx modificó de forma radical el tratamiento de la depresión, a la vez que aportó información sobre aspectos fisiopatológicos de esta enfermedad. Los nuevos fármacos antidepresivos (agomelatina, tianeptina, vortioxetina) están aportando datos que dan lugar a hipótesis fisiopatológicas de la depresión que difieren de la clásica teoría monoaminérgica. En este sentido, la tianeptina, un fármaco atípico por su mecanismo de acción diferencial, contribuye a clarificar que en la fisiopatología de la depresión hay algo más que monoaminas. Así, la tianeptina no modifica la tasa de serotonina extracelular, por lo que no aumenta ni disminuye la recaptación de serotonina. La administración crónica de tianeptina no altera la densidad ni la afinidad de más de un centenar de receptores clásicos relacionados con la depresión. Recientemente se ha descrito una acción débil de la tianeptina sobre receptores opioidesMu que podría explicar la liberación de dopamina en el sistema límbico y su participación en la modulación de mecanismos glutamatérgicos. Estos mecanismos sustentan la hipótesis del posible mecanismo de acción de este antidepresivo. La tianeptina es un antidepresivo con propiedades ansiolíticas que puede mejorar síntomas somáticos. La tianeptina como modulador glutamatérgico, entre otros mecanismos, permite abordar la depresión desde un punto de vista diferente al del resto de antidepresivos

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants

Indices of Change, Expectations, and Popularity of Biological Treatments for Major Depressive Disorder between 1988 and 2017: A Scientometric Analysis.

BACKGROUND: Major Depressive Disorder (MDD) is the most common psychiatric disorder with high prevalence and disease burden. Biological treatments of MDD over the last several decades include a wide range of antidepressants and neurostimulation therapies. While recent meta-analyses have explored the efficacy and tolerability of antidepressants, the changing trends of biological treatments have not been evaluated. Our study measured the indices of change, expectations, and popularity of biological treatments of MDD between 1988 and 2017. METHODS: We performed a scientometric analysis to identify all relevant publications related to biological treatments of MDD from 1988 to 2017. We searched the Web of Science websites for publications from 1 January 1988 to 31 December 2017. We included publications of fluoxetine, paroxetine, citalopram, sertraline, amitriptyline, fluvoxamine, escitalopram, venlafaxine, duloxetine, milnacipran, desvenlafaxine, levomilnacipran, clomipramine, nortriptyline, bupropion, trazodone, nefazodone, mirtazapine, agomelatine, vortioxetine, vilazodone, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and transcranial direct current stimulation (tDCS). We excluded grey literature, conference proceedings, books/book chapters, and publications with low quality as well as publications not related to medicine or human health. The primary outcomes assessed were indices of change, expectations, and popularity. RESULTS: Of 489,496 publications identified, we included 355,116 publications in this scientometric analysis. For the index of change, fluoxetine, sertraline and ECT demonstrated a positive index of change in 6 consecutive periods. Other neurostimulation therapies including rTMS, VNS, DBS and tDCS had shown a positive index of change since 1998. We calculated the index of change of popularity index (PI), which indicates that from 2013 to 2017, the number of publications on tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were reduced by 85.0% and 81.3% respectively, as compared with the period 2008-2012. For the index of expectation, fluoxetine and ECT showed the highest index of expectations in six consecutive periods and remained the highest in 2013-2017. For popularity, the three antidepressants with highest PI were fluoxetine (4.01), paroxetine (2.09), and sertraline (1.66); the three antidepressants with lowest PI were desvenlafaxine (0.08), vilazodone (0.04) and levomilnacipran (0.03). Among neurostimulation therapies, ECT has the highest PI (2.55), and tDCS the lowest PI (0.14). The PI of SSRI remained the highest among all biological treatments of MDD in 2013-2017. In contrast, the PI of ECT was reduced by approximately 50% during the period 2008 to2012 than that in the period 2013 to 2017. CONCLUSIONS: This scientometric analysis represents comprehensive evidence on the popularity and change in prospects of biological treatments for MDD from 1988 to 2017. The popularity of SSRI peaked between 1998 and 2002, when their efficacy, tolerability and safety profile allowed them to replace the TCAs and MAOIs. While the newer neurostimulation therapies are gaining momentum, the popularity of ECT has sustained.

Staging Treatment Intensity and Defining Resistant Depression: Historical Overview and Future Directions.

OBJECTIVE: To review existing staging models and definitions of treatment-resistant depression (TRD) and offer future directions within the context of up-to-date evidence. DATA SOURCES: A PubMed search was conducted on February 25, 2018, for articles in English on TRD staging or definition using the following keywords: depressive disorder, treatment-resistant OR treatment resistant depression cross-referenced with staging OR degree OR level OR definition. Relevant cross-references from identified articles were also included. STUDY SELECTION: A total of 18 articles were identified that included a proposed TRD staging model, a proposed TRD definition, empirical work to support a model or definition, or any combination thereof. DATA EXTRACTION: Included articles were summarized in chronological order in terms of the date the TRD staging model (and accompanying TRD definition if applicable) was first proposed. Findings from validation studies pertaining to staging or definition were then synthesized. RESULTS: Five staging models were identified. Strengths identified across staging models include rigorous assessment of adequacy of treatment, differentiation of resistance versus symptom return, assignment of equal weights to different pharmacotherapies, and accounting for augmentation. Future considerations should include differential weighting to specific augmentation agents based on available evidence, added weight to electroconvulsive therapy and ketamine treatments, and the addition of evidence-based psychotherapies. Dichotomous versus continuous approaches to TRD diagnosis were considered, with the latter (beginning with 1 failed trial) best explaining available data from large trials. CONCLUSIONS: The most up-to-date evidence in the literature should guide future research in the definition and staging of TRD.

Association of Antidepressant Medication Type With the Incidence of Cardiovascular Disease in the ARIC Study.

Background The association of antidepressant medication type with the risk of cardiovascular disease ( CVD ) is unclear. We hypothesized that selective serotonin reuptake inhibitors ( SSRI s) are associated with lower risks of CVD events relative to tricyclics and other non- SSRI antidepressants. Methods and Results We studied 2027 participants from the ARIC (Atherosclerosis Risk in Communities) study (mean age 63±10 years; 29% men; 78% white) treated with antidepressants at some time between 1987 and 2013. Antidepressant usage was confirmed by participants bringing pill bottles to study visits. CVD events in the study sample were identified, including atrial fibrillation, heart failure, myocardial infarction, and ischemic stroke. Hazard ratios were used to compare CVD events adjusted for sociodemographic and clinical risk factors in SSRI s users (47%) versus non- SSRI users. Participants were followed from antidepressant initiation up to 2016 for a median of 13.5 years. We identified 332 atrial fibrillation, 365 heart failure, 174 myocardial infarction and 119 ischemic stroke events. CVD risk was similar for SSRI s and non- SSRI antidepressant users (hazard ratio, 1.10; 95% CI , 0.86-1.41 for atrial fibrillation; hazard ratio, 0.98; 95% CI, 0.77-1.25 for heart failure; hazard ratio, 0.91; 95% CI , 0.64-1.29 for myocardial infarction; and hazard ratio, 1.07; 95% CI , 0.70-1.63 for ischemic stroke). Conclusions SSRI use was not associated with reduced risk of incident CVD compared with non- SSRI antidepressant use. These results do not provide evidence supporting the use of SSRI s compared with tricyclics and other non- SSRI antidepressants in relation to CVD risk.

Evaluation of Antidepressant Effects on Recovery of Electrical Field Stimulation-Induced Contractions that have been Suppressed by Clonidine in Isolated Rat Vas Deferens.

BACKGROUND: A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α2-adrenoceptor (α2-AR) is lacking. OBJECTIVES: The present study was performed to evaluate the potential of clinically available antidepressants to reverse α2-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment. METHOD: The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10-8 mol/L clonidine (a selective α2-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations. RESULTS: The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT2A receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D2-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist). CONCLUSIONS: These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α2-AR antagonism.

Adherence to and Persistence with Antidepressant Medication during Pregnancy: Does It Differ by the Class of Antidepressant Medication Prescribed?

OBJECTIVE: Pregnant women are often concerned about the impact of medication use on their pregnancy, such as congenital abnormalities. This study examined the rate of adherence to and persistence with antidepressant medications during pregnancy based on the class of antidepressants prescribed. METHODS: Women who gave birth between 2012 and 2015 in Alberta, Canada; had ≥1 diagnosis of depression within 1 year of preconception in outpatient physician claims, emergency department, or hospitalization administrative data; and were adherent (medication possession ratio ≥80%) to ≥2 consecutive antidepressant prescriptions during the preconception year ( n = 1865) were included in this retrospective cohort study. The rates of adherence and persistence (prescription refill gap ≤30 days) were calculated by antidepressant class and were compared using chi-square tests. RESULTS: During pregnancy, 834 (44.7%; 95% CI, 42.4% to 47.0%) women discontinued antidepressants. Among those continuing antidepressants, the overall rate of adherence was 62.6% (95% CI, 59.4% to 65.7%). The rate differed significantly by medication class ( P < 0.0001), with a rate of 75.1% (95% CI, 68.3% to 80.9%) for serotonin-norepinephrine inhibitors, 60.9% (95% CI, 57.2% to 64.5%) for selective serotonin reuptake inhibitors, 42.8% (95% CI, 19.9% to 69.3%) for nonselective monoamine reuptake inhibitors, and 37.5% (95% CI, 22.5% to 55.4%) for atypical antidepressants. Only, 40.7% (95% CI, 37.5 to 44.1) of women were persistent with antidepressants for the full pregnancy period-the rate differed significantly by medication class ( P < 0.0001). CONCLUSIONS: Adherence to and persistence with antidepressants is low during pregnancy and varies by medication class. Low adherence and persistence can interfere with a therapeutic effect of antidepressants, which may contribute to the worsening of depression symptoms.