Norepinephrine-dopamine Reuptake Inhibitor Research Articles

Niosomal Bupropion: Exploring Therapeutic Frontiers through Behavioral Profiling.

Bupropion (Bup) belongs to the norepinephrine-dopamine reuptake inhibitor (NDRI) class and it is the only FDA-approved drug of its class for the treatment of major depressive disorder (MDD), sold under the name of Wellbutrin. Although bupropion is effective in suppressing the symptoms, its regular use and overdose might lead to seizures and liver failure. Thus, we aimed to nanoformulate bupropion onto a niosomal vesicle to improve its efficacy and achieve the same therapeutic effect at lower scheduled doses. A thin film hydration method was adopted to synthesize and optimize Bup entrapped niosomes using three different surfactants of the sorbitan ester series (Span 20, 40, and 60) in combination with cholesterol. The optimization data determined that the niosome formulated with a cholesterol-to-surfactant ratio of 1:1.5 is the most stable system, with the Bup entrapped niosomes containing Span 20 (Bup@N20C) exhibiting minimal in vitro and in vivo toxicity, and demonstrating the sustained release of Bup in artificial cerebrospinal fluid (ACSF). The Bup@N20C formulation showed increased exploration activity and reduced irregular movements in reserpine-induced depression in the adult zebrafish model, suggesting the potential for mood improvement through the suppression of depression-like behavior which was established by statistical analysis and trajectory data. The Bup@N20C-treated group even surpasses the treatment effect of the positive control group and is comparable to the control group. Hence, it can be inferred that niosomal formulations of Bup represent a promising delivery system capable of achieving the brain delivery of the cargo by bypassing the blood-brain barrier facilitated by their small architectural structure.

Chronic Administration of Lisdexamfetamine Induces Apoptosis and Inflammation and Reduces Sperm Quality in Adult Male Rats.

Concerns have been raised about potentially irreversible brain damage and damage to the neuroendocrine system during development when treating attention-deficit/hyperactivity disorder with lisdexamfetamine (LDX), a norepinephrine dopamine reuptake inhibitor. This study aims to elucidate the potential adverse effects of LDX on the male reproductive system due to its widespread use and potential for abuse. In this study, adult male rats were randomized into control and LDX groups. Thirty milligrams per kilogram LDX was administered orally for 3 weeks. After isolation of epididymal spermatozoa, the rats were euthanized and testicular tissues were collected for stereological and molecular analyses. The LDX group showed a decrease in sperm motility and an increase in DNA fragmentation compared to the control group. There was also a dramatic decrease in testosterone in the LDX group. Testicular expression of caspase-3 and TNF-α was significantly increased in the LDX group. According to our findings, prolonged use of LDX leads to reduced sperm quality. It also induces apoptosis, inflammatory response, and pathological changes in the testicular tissue. What we have observed in this study is noteworthy but requires further investigation, particularly in people who use LDX over a longer period of time.

The synthesis of bupropion hydrochloride under greener and safer conditions utilizing flow technologies

Globally, major depressive disorders are a leading cause of disconsolateness affecting more than 300 million individuals.

Bupropion Associated Immunomodulatory Effects on Peripheral Cytokines in Male with Major Depressive Disorder

Background: Experimental and clinical studies have reported increased levels of pro-inflammatory cytokines in patients with major depressive disorder (MDD), suggesting that immune system dysregulation may contribute to MDD pathophysiology. Aim: Due to the lack of knowledge about the immune potential of antidepressants, this study investigated the immunomodulatory effects of bupropion, a norepinephrine–dopamine reuptake inhibitor. Methods: This study involved 18 patients with MDD treated with bupropion (150 mg/d) for 4 weeks and 23 healthy volunteers. All participants underwent multiplex bead-based cytokine assessment before and after bupropion treatment to quantify the following cytokines: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, tumor necrosis factor-α, granulocyte colony-stimulating factor, granulocyte-macrophage CSF, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β. Results: Four-week treatment with bupropion significantly increased the levels of IL-1β (P = 0.011), IL-4 (P = 0.019), IL-5 (P = 0.019), IL-7 (P = 0.021), and IL-8 (P = 0.023) compared to the control group. Furthermore, the percentage change in most cytokines, including anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13, was significantly increased after bupropion treatment. Conclusion: The promoted synthesis of anti-inflammatory cytokines to surpass the pro-inflammatory cytokines may be a crucial step in the treatment of MDD patients with bupropion.

(037) Hypersexuality with the Use of Selective Serotonin Receptor Inhibitors

Abstract Introduction We present two cases of hypersexuality in perimenopausal women evaluated, diagnosed, and being managed at this time for what seems to be a sexual dysfunction recently described as a consequence of the use of a combination of 2 kinds of medications: Bupropion, a Norepinephrine Dopamine Reuptake Inhibitor (NDRI), and Sertraline/Fluoxetine, a Selective Serotonin Receptor Inhibitor (SSRI), used as an anti-depressant and anxiolytics for psychiatric conditions. Both cases arrived at our centers referred by their primary care physicians or a psychiatrist for sexual therapy and sexological evaluation. Objective To show a new sexual dysfunction related to the use of SSRI medications. Methods The analysis of 2 cases of a new described sexual dysfunction related with the use of SSRI medications: Bupropion at 150 mg PO bid, and Fluoxetine at 125 mg PO qd. Results The first case, one week after the initiation of Fluoxetine, having been taking Bupropion for months, started to develop uncontrolled need for sex, having sex with multiple men, in addition to her husband. Her husband accepted to have sexual relationships in trios, a situation that lasted for several months. However, after 4-6 weeks, she started to look for additional partners other than her husband. He left. She arrived with extreme anxiety during her first visit. Neither her, nor the psychiatrist understood why this was happening. At that moment, she was having sex with several men on a daily basis. She wanted to preserve her marriage but her sexual compulsion was an impediment. The second patient decided to be unfaithful to her husband of 10 years. In this case, she decided to have hidden sexual relations with several men at the same time with just one. She was also undergoing psychiatric treatment with both medications, Fluoxetine and Bupropion. There was a temporal correlation between the initiation of Fluoxetine and the appearance of the sexual dysfunction. We suspended both medications and around 10 days after this therapeutic step, there was a frank decline in the compulsive sexual behavior. However, due to depression and anxiety symptoms, the psychiatrist decided to restart only Bupropion without the Fluoxetine that was the medication with which the appearance of symptoms have been related. Now, she is okay. Conclusions We describe the possible pharmacological mechanisms involved in the pathophysiology of this disorder and the way in which we have managed the two cases up to now. This condition needs to be differentiated from the hyperactive sexual arousal disorder, previously described in the sexological literature and we need to determine if this is a variant of that kind of syndrome. We have never encountered this kind of reaction before and have only found one publication describing a similar case. Disclosure No

Synthesis of 2-(5-(2-Aminopropyl)-2-hydroxyphenyl)acetic Acid, a Metabolite of the Drug 5-APB

5-(2-Aminopropyl)benzofuran (5-APB), also known as “Benzo Fury,” is a novel psychoactive substance (NPS) belonging to a new class of synthetic phenethylamines. It acts by disrupting serotonergic circuits as a serotonin–norepinephrine–dopamine reuptake inhibitor and is classified as an entactogen, similar to MDMA and MDA. Despite its popularity among users, recent toxicity events have been associated with the consumption of 5-APB and other benzofurans, highlighting the need for a better understanding of their pharmacodynamics and toxicity. One way to achieve this is by developing the synthesis of 5-APB metabolites as biomarkers of exposure. In this study, we present a six-step synthesis for one of the 5-APB metabolites, 2-(5-(2-aminopropyl)-2-hydroxyphenyl)acetic acid (1), involving methylation, formylation, Aldol-type condensation, reduction, and hydrolysis reactions. The compound was obtained in an overall yield of 11%.

Statins and Antidepressants: A Comprehensive Review and Clinical Outlook of the Risks and Benefits of Co-prescription (2022).

Antidepressants are the most prescribed medications in the United States, and the most frequently prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs) followed by serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin antagonist and reuptake inhibitors (SARIs), and norepinephrine-dopamine reuptake inhibitors(NDRI). On the other hand, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are the most prescribed lipid-lowering medications, and because the majority of patients with cardiovascular disease (CVD) have depressive symptoms, it is essential to understand the possible drug-drug interactions these two classes of medications can have, their potential synergistic mechanisms, and possible risks. In our research, we tried to understand the facts and uncover any missing links regarding the potential risks and benefits of statins and antidepressant co-prescription in the current clinical scenario. We reviewed all the relevant information from inception up to October 2022 regarding the antidepressant and statin polypharmacy. The databases we used were PubMed and PubMed Central, and the 11 keywords were "statins," "SSRI," "SNRI," "selective serotonin reuptake inhibitors," "serotonin-norepinephrine reuptake inhibitors," "antidepressants,""HMG-CoA reductase inhibitors," "tricyclic antidepressants," "monoamine oxidase inhibitors," "serotonin antagonist and reuptake inhibitors," and "norepinephrine-dopamine reuptake inhibitors." We carefully screened each of the relevant articles, including animal and human studies. In our study, we concluded that co-prescription of statins and SSRIs/SNRIs was generally safe and should be encouraged due to the potential synergistic nature of their effects in patients with CVD and major depression, and caution is advised with all other classes of antidepressants. We would like to encourage the undertaking of large-scale observational studies and proactive postmarketing surveillance to improve our knowledge regarding this topic considering the immense clinical importance it holds by directly and indirectly affecting half the population worldwide.

MPFC catecholamines modulate attentional capture by appetitive distracters and attention to time in a peak-interval procedure in rats.

The behavioral and neural mechanisms by which distracters delay interval timing behavior are currently unclear. Distracters delay timing in a considerable dynamic range: Some distracters have no effect on timing ("run"), whereas others seem to "stop" timing; some distracters restart ("reset") the entire timing mechanisms at their offset, whereas others seem to capture attentional resources long after their termination ("over-reset"). While the run-reset range of delays is accounted for by the Time-Sharing Hypothesis (Buhusi, 2003, 2012), the behavioral and neural mechanisms of "over-resetting" are currently uncertain. We investigated the role of novelty (novel/familiar) and significance (consequential/inconsequential) in the time-delaying effect of distracters and the role of medial prefrontal cortex (mPFC) catecholamines by local infusion of norepinephrine-dopamine reuptake inhibitor (NDRI) nomifensine in a peak-interval (PI) procedure in rats. Results indicate differences in time delay between groups, suggesting a role for both novelty and significance: inconsequential, familiar distracters "stopped" timing, novel distracters "reset" timing, whereas appetitively conditioned distracters "over-reset" timing. mPFC infusion of nomifensine modulated attentional capture by appetitive distracters in a "U"-shaped fashion, reduced the delay after novel distracters, but had no effects after inconsequential, familiar distracters. These results were not due to nomifensine affecting either timing accuracy, precision, or peak response rate. Results may help elucidate the behavioral and physiological mechanisms underlying interval timing and attention to time and may contribute to developing new treatment strategies for disorders of attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Pathophysiology of Depression: Stingless Bee Honey Promising as an Antidepressant.

Depression is a debilitating psychiatric disorder impacting an individual’s quality of life. It is the most prevalent mental illness across all age categories, incurring huge socio-economic impacts. Most depression treatments currently focus on the elevation of neurotransmitters according to the monoamine hypothesis. Conventional treatments include tricyclic antidepressants (TCAs), norepinephrine–dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SSRIs). Despite numerous pharmacological strategies utilising conventional drugs, the discovery of alternative medicines from natural products is a must for safer and beneficial brain supplement. About 30% of patients have been reported to show resistance to drug treatments coupled with functional impairment, poor quality of life, and suicidal ideation with a high relapse rate. Hence, there is an urgency for novel discoveries of safer and highly effective depression treatments. Stingless bee honey (SBH) has been proven to contain a high level of antioxidants compared to other types of honey. This is a comprehensive review of the potential use of SBH as a new candidate for antidepressants from the perspective of the monoamine, inflammatory and neurotrophin hypotheses.

A Review of Treatments and Clinical Guidelines for Perinatal Depression.

Perinatal depression occurs in approximately 1 in 7 women and is considered the most common complication of pregnancy and childbearing. Management of perinatal depression may include a combination of nonpharmacological and pharmacological therapies depending on the severity of symptoms, the stage of gestation, and maternal preference. Healthcare providers are recommended to review current guidelines and provide information to women during pregnancy and postpartum regarding the risks and benefits of nonpharmacological and pharmacological treatment options for perinatal depression. In addition, healthcare providers should consider common barriers to treatment including inadequate screening and social stigma. This article reviews common treatments of perinatal depression as well as the clinical guidelines provided by the American Association of Obstetricians and Gynecologists (ACOG), the American Psychiatric Association (APA), and the US Preventive Services Task Force (USPSTF). Discussion of nonpharmacological therapies includes cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). Pharmacological treatments are reviewed by drug class and include selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), norepinephrine/dopamine reuptake inhibitors (NDRIs), and tricyclic antidepressants (TCAs). Adjunctive treatments of severe depression, including second-generation antipsychotics (SGAs), are also discussed.

Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study

BackgroundThis study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database.Methods6306 patients identified as having CFS during the 2000–2012 period and 6306 controls (with similar distributions of age and sex) were analyzed.ResultThe patients with CFS were predominantly female and aged 35–64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn’s disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group.ConclusionThis large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.

Physical exercise and catecholamine reuptake inhibitors affect orienting behavior and social interaction in a rat model of attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Effects of stimulant medication on divergent and convergent thinking tasks related to creativity in adults with attention-deficit hyperactivity disorder.

Common pharmacological treatments for attention-deficit hyperactivity disorder (ADHD) are central nervous system stimulants acting as norepinephrine-dopamine reuptake inhibitors. The noradrenergic and dopaminergic systems have been shown to impact performance on tasks assessing creativity. Some previous studies suggest higher performance on creativity tasks in ADHD. Stimulant medication has been shown to differentially impact creativity in those without ADHD. However, the full range of effects of stimulant medication on creativity in those with ADHD is not known. This study examined the effects of stimulants on convergent and divergent tasks associated with creativity in adults with ADHD. Seventeen adults diagnosed with ADHD who were prescribed stimulant medication attended two counterbalanced sessions: one after taking their prescribed stimulant dose and one after the dose was withheld. Participants completed convergent problem-solving (anagrams, Compound Remote Associates) and divergent generative (letter/semantic fluency, Torrance Test for Creative Thinking (TTCT)-Verbal) tasks. There was a significant increase in words generated on the semantic fluency task for the stimulant session. Additionally, significant increases were found in the stimulant session for originality, flexibility, and fluency scores on the TTCT. Stimulant medication did not have an effect on any of the problem-solving tasks. Stimulant medication enhanced verbal fluency in adults with ADHD but had no effect on convergent abilities. Furthermore, stimulants enhanced fluency, flexibility, and originality scores on the TTCT. Therefore, stimulants appear to have positive effects on divergent task performance in adults with ADHD, but not convergent tasks. This finding warrants further studies into the specific roles of norepinephrine and dopamine in this effect.

Betel Quid Addiction: A Review of Its Addiction Mechanisms and Pharmacological Management as an Emerging Modality for Habit Cessation

Background: Areca-nut (AN) and added smokeless-tobacco (SLT) are considered agents that may cause addiction to betel-quid (BQ). However, the primary addictive substance in AN is not clearly understood. Objective: The present review evaluates possible addictive chemicals in AN with their mechanisms of action for progression to BQ dependence, as it is essential to overcome barriers in BQ cessation. It also identifies innovative treatment modalities in BQ cessation including the scope for research on pharmacotherapy using Monoamine-oxidase Inhibitors, Selective Serotonin Re-uptake Inhibitors and Norepinephrine Dopamine Reuptake Inhibitors. Methods: This is a narrative review on addictive properties of BQ and trials undertaken to promote cessation of SLT or AN use. Results: Twenty interventional studies, three by behavioral therapy and seventeen using pharmacotherapy were reviewed. There was heterogeneity in reported follow up times, most studies reporting data at 12 weeks with abstinence rates of 45–55% for SLT cessation and at 8 weeks with abstinence rates around 35% for AN cessation. Conclusion: Even though literature reveals a few cessation programs through behavioral support for BQ addiction, its success has been limited in certain instances mainly due to addictive properties of AN, resulting in withdrawal and relapse. Hence, in line with pharmacotherapy in tobacco smoking cessation, potential pharmacological agents to assist in cessation of SLT and AN require more attention. Several clinical trials for SLT cessation have been carried out with varying levels of success using Nicotine Replacement Therapy and Varenicline while trials on antidepressants for SLT and AN cessation are also emerging.

New generation antidepressants for depression in children and adolescents: a network meta-analysis.

New generation antidepressants for depression in children and adolescents: a network meta-analysis.

Randomized Controlled Trial of Solriamfetol for Excessive Daytime Sleepiness in OSA: An Analysis of Subgroups Adherent or Nonadherent to OSA Treatment

BackgroundSolriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d).Research QuestionDoes solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?Study Design and MethodsParticipants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated.ResultsAt baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, –2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were –2.4 (95% CI, –4.2 to –0.5), –1.3 (95% CI, –3.1 to 0.5), –4.2 (95% CI, –5.7 to –2.7), and –4.7 (95% CI, –6.1 to –3.2) and among nonadherent participants were –0.7 (95% CI, –3.5 to 2.1), –2.6 (95% CI, –5.4 to 0.1), –5.0 (95% CI, –7.2 to –2.9), and –4.6 (95% CI, –7.0 to –2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol.InterpretationSolriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.Trial RegistryClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu

Individual Differences in Response to Antidepressants

Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02). Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

Reduced Motivation in Perinatal Fluoxetine-Treated Mice: A Hypodopaminergic Phenotype.

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.SIGNIFICANCE STATEMENT The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

Why the Maternal Medication List Matters: Neonatal Toxicity From Combined Serotonergic Exposures

Serotonergic medications are used for the prevention and treatment of depression during pregnancy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause poor neonatal adaptation, which has been attributed to withdrawal versus toxicity. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is often used as an adjunctive agent to selective serotonin reuptake inhibitors or SNRIs for refractory depression. Quetiapine, an atypical antipsychotic, may also be used in more complex cases. When combined with serotonergic drugs, bupropion and quetiapine are associated with increased risk of serotonin syndrome in adults. We describe a neonate exposed to venlafaxine (an SNRI), bupropion, and quetiapine in utero who presented nearly immediately after birth with encephalopathy and abnormal movements. The severity and rapidity of symptoms may be attributable to potentiation of venlafaxine's serotonergic effects by bupropion and quetiapine. Neonatal providers should be aware of maternal medications and prepare for possible adverse effects, particularly from common psychotropic exposures.

Selective serotonin reuptake inhibitor use is associated with worse sleep-related breathing disturbances in individuals with depressive disorders and sleep complaints: a retrospective study.

The effects of serotonergic agents on respiration neuromodulation may vary according to differences in the serotonin system, such as those linked to depression. This study investigated how sleep-related respiratory disturbances relate to depression and the use of medications commonly prescribed for depression. Retrospective polysomnography was collated for all 363 individuals who met selection criteria out of 2,528 consecutive individuals referred to a specialized sleep clinic (Ottawa, Canada) between 2006 and 2016. The apnea-hypopnea index (AHI), oxygen saturation nadir, and oxygen desaturation index during REM and NREM sleep were analyzed using mixed analyses of covariance comparing 3 main groups: (1) medicated individuals with depressive disorders (antidepressant group; subdivided into the selective serotonin reuptake inhibitor and norepinephrine-dopamine reuptake inhibitor subgroups), (2) non-medicated individuals with depressive disorders (non-medicated group), and (3) mentally healthy control patients (control group). Individuals with depressive disorders (on antidepressants or not) had significantly higher AHIs compared to control patients (both P ≤ .007). The antidepressant group had a lower NREM sleep oxygen saturation nadir and a higher NREM sleep oxygen desaturation index than the control and non-medicated groups (all P ≤ .009). Within individuals with depressive disorders, independent of depression severity, the selective serotonin reuptake inhibitor group had a lower oxygen saturation nadir and a higher oxygen desaturation index during NREM sleep than the norepinephrine-dopamine reuptake inhibitor (both P ≤ .045) and non-medicated groups (both P < .001) and a higher NREM sleep AHI than the non-medicated group (P = .014). These findings suggest that the use of selective serotonin reuptake inhibitors may be associated with impaired breathing and worse nocturnal oxygen saturation in individuals with depressive disorders and sleep complaints, but this needs to be confirmed by prospective studies.