Special Issue "Antidepressants: Mechanistic Insights and Future Directions"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editors

Prof. James W. Murrough
Website
Guest Editor
Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, United States
Interests: depression; mood disorders; anxiety disorders; pharmacotherapy; neuroimaging
Prof. Manish K. Jha
Website
Guest Editor
Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, United States
Interests: inflammation; anhedonia; functional recovery

Special Issue Information

Dear Colleagues,

Major depressive disorder (MDD) is a leading cause of disability worldwide. Depression affects one in five adults during their lifetime and is estimated to cost an estimated 200 billion dollars per year in the United States. Untreated depression is a major contributor to suicide, and rates of suicide have been increasing in recent years. Taken together, there is an urgent public need to address the problem of depression and to identify effective treatments. Current medicines for depression are effective for only a proportion of treated patients, and are based on clinical observations and biological discoveries dating back to the 1950s and 60s.

Advances in basic and translational neuroscience are now elucidating the underlying causes of depression and the mechanisms of action of conventional monoaminergic antidepressants. In particular, the role of different forms of stress and attendant biological sequelae in the pathophysiology of depressive disorders is coming to light. Changes in neuroplasticity pathways, stress hormones, immune signaling, and epigenetic changes are among some of the systems currently being studied.

Recent early phase human trials are showing the promise of mechanistically novel agents that target systems outside of the monoamines. Multiple recent reports show that targeting components of the glutamate system, including the NMDA receptor, has substantial potential to improve treatment outcomes for depression. Recently, studies have also shown that neurosteroids and other novel compounds targeting GABA may have rapid antidepressant effects. Strategies to repurpose compounds approved for other indications and pharmaceutical-grade nutritional supplements (nutraceuticals) are other promising strategies that are being tested for reducing the burden of depression and promoting resilience against stress.

Over the last decade, large-scale neuroimaging studies have been undertaken to parse out the antidepressant-specific response from a placebo as well as the identify predictors of the response to one antidepressant over another. Such an approach to personalizing treatment selection is critically important, as current trial-and-error practices of prescribing medications result in multiple ineffective and burdensome trials before finding an effective treatment. Like pharmacogenomic testing, which is gaining widespread use, blood-based multi-omics approaches promise to usher in an era of precision medicine where treatment selection and optimization is personalized for each individual patient with depression.

The journal Pharmaceuticals invites both reviews and original articles elucidating the pathophysiology of depression, mechanistic insights of antidepressants, promising targets for novel antidepressants, and future directions to personalize treatment selection for patients with depression.

Prof. James W. Murrough
Prof. Manish K. Jha
Guest Editors

Manuscript Submission Information

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Published Papers (8 papers)

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Research

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Open AccessArticle
Safety of Repeated Administration of Parenteral Ketamine for Depression
Pharmaceuticals 2020, 13(7), 151; https://doi.org/10.3390/ph13070151 - 13 Jul 2020
Abstract
The objective of this study was to investigate the safety of repeated parenteral ketamine for depression. An electronic survey inquiring about the frequency of adverse events was distributed to providers of parenteral ketamine for depression. In addition, the investigators conducted a search of [...] Read more.
The objective of this study was to investigate the safety of repeated parenteral ketamine for depression. An electronic survey inquiring about the frequency of adverse events was distributed to providers of parenteral ketamine for depression. In addition, the investigators conducted a search of published studies describing six or more repeated parenteral ketamine treatments administered to individuals for depression, and extracted reported adverse events. The survey was sent to 69 providers, of which 36 responded (52% response rate); after eliminating those that were incomplete, 27 were included in the analysis. The providers in the analysis collectively reported treating 6630 patients with parenteral ketamine for depression, one-third of whom received more than 10 treatments. Only 0.7% of patients experienced an adverse effect that required discontinuation of ketamine. Psychological distress during the treatment was the most frequent cause. Other adverse events were extremely rare (such as bladder dysfunction (0.1%), cognitive decline (0.03%) and psychotic symptoms (0.03%)). Among the 20 published reports of repeated parenteral ketamine treatments, rates of significant adverse events resulting in discontinuation were low (1.2%). The rate of adverse effects reported in the survey and the published literature is low, and suggests that long-term treatment of depression with ketamine is reasonably safe. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessArticle
Higher S100B Levels Predict Persistently Elevated Anhedonia with Escitalopram Monotherapy Versus Antidepressant Combinations: Findings from CO-MED Trial
Pharmaceuticals 2019, 12(4), 184; https://doi.org/10.3390/ph12040184 - 17 Dec 2019
Abstract
Background: Elevated S100 calcium binding protein B (S100B) levels in systemic circulation may induce neuroinflammation and reflect greater blood–brain barrier (BBB) dysfunction. Neuroinflammation in patients with major depressive disorder (MDD), in turn, may reduce likelihood of improvement with serotonergic antidepressants. Methods: Levels of [...] Read more.
Background: Elevated S100 calcium binding protein B (S100B) levels in systemic circulation may induce neuroinflammation and reflect greater blood–brain barrier (BBB) dysfunction. Neuroinflammation in patients with major depressive disorder (MDD), in turn, may reduce likelihood of improvement with serotonergic antidepressants. Methods: Levels of S100B were measured in plasma samples obtained prior to initiation of treatment with bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine in participants of Combining Medications to Enhance Depression Outcomes trial (n = 153). Depression severity was measured with 16-item Quick Inventory of Depressive Symptomatology Self-Report and anhedonia was measured with 3 items of 30-item Inventory of Depressive Symptomatology. Differential changes in depression severity and anhedonia over acute-phase (baseline, weeks 1, 2, 4, 6, 8, 10, and 12) in the three treatment arms were tested with logS100B-by-treatment-arm interaction in mixed model analyses after controlling for age, gender, and body mass index. Results: There was a significant logS100B-by-treatment-arm interaction for anhedonia (F = 3.21; df = 2, 142; p = 0.04) but not for overall depression severity (F = 1.99; df = 2, 142; p = 0.14). Higher logS100B levels were associated with smaller reductions in anhedonia (effect size = 0.67, p = 0.047) in escitalopram monotherapy but not in the other two arms. Correlation coefficients of anhedonia severity averaged over acute-phase (including baseline) with baseline S100B levels were 0.57, −0.19, and 0.22 for escitalopram monotherapy, bupropion-plus-escitalopram and venlafaxine-plus-mirtazapine arms respectively. Conclusion: Higher baseline S100B levels in depressed patients resulted in poorer response to escitalopram monotherapy. Addition of bupropion, a dopaminergic antidepressant, partially mitigated this effect. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessArticle
Lurasidone Sub-Chronically Activates Serotonergic Transmission via Desensitization of 5-HT1A and 5-HT7 Receptors in Dorsal Raphe Nucleus
Pharmaceuticals 2019, 12(4), 149; https://doi.org/10.3390/ph12040149 - 06 Oct 2019
Cited by 5
Abstract
Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptor-binding profile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on transmitter systems of schizophrenia and mood disorders, however, have not been well clarified. Thus, this study examined the mechanisms underlying the clinical [...] Read more.
Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptor-binding profile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on transmitter systems of schizophrenia and mood disorders, however, have not been well clarified. Thus, this study examined the mechanisms underlying the clinical effects of lurasidone by measuring mesocortical serotonergic transmission. Following systemic and local administrations of lurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe nucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and γ-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance liquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are predominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R, respectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but concomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R inhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently increased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasidone chronically enhanced serotonergic transmission and GABAergic disinhibition in the DRN by desensitizing both 5-HT1AR and 5-HT7R. These effects of lurasidone acutely prevented MK801-evoked 5-HT release by GABAergic disinhibition via N-methyl-D-aspartate (NMDA)/glutamate receptor (NMDA-R)-mediated inhibition of 5-HT1AR function, but enhanced MK801-induced 5-HT release by desensitizing 5-HT1AR and 5-HT7R. These results indicate that acutely lurasidone fails to affect 5-HT release, but chronically enhances serotonergic transmission by desensitizing both 5-HT1AR and 5-HT7R. These unique properties of lurasidone ameliorate the dysfunctions of NMDA-R and augment antidepressive effects. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessFeature PaperArticle
The Impact of Childhood Maltreatment on Intravenous Ketamine Outcomes for Adult Patients with Treatment-Resistant Depression
Pharmaceuticals 2019, 12(3), 133; https://doi.org/10.3390/ph12030133 - 11 Sep 2019
Cited by 3
Abstract
Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood [...] Read more.
Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood maltreatment could influence ketamine’s treatment response. We examined the relationship between childhood maltreatment using the Childhood Trauma Questionnaire (CTQ) and treatment response using the Quick Inventory of Depressive Symptoms–Self Report (QIDS-SR) in TRD patients receiving intravenous ketamine at a community outpatient clinic. We evaluated treatment response after a single infusion (n = 115) and a course of repeated infusions (n = 63). Repeated measures general linear models and Bayes factor (BF) showed significant decreases in QIDS-SR after the first and second infusions, which plateaued after the third infusion. Clinically significant childhood sexual abuse, physical abuse, and cumulative clinically significant maltreatment on multiple domains (maltreatment load) were associated with better treatment response to a single and repeated infusions. After repeated infusions, higher load was also associated with a higher remission rate. In contrast to conventional antidepressants, ketamine could be more effective in TRD patients with more childhood trauma burden, perhaps due to ketamine’s proposed ability to block trauma-associated behavioral sensitization. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessArticle
VitalSign6: A Primary Care First (PCP-First) Model for Universal Screening and Measurement-Based Care for Depression
Pharmaceuticals 2019, 12(2), 71; https://doi.org/10.3390/ph12020071 - 14 May 2019
Cited by 4
Abstract
Major depressive disorder affects one in five adults in the United States. While practice guidelines recommend universal screening for depression in primary care settings, clinical outcomes suffer in the absence of optimal models to manage those who screen positive for depression. The current [...] Read more.
Major depressive disorder affects one in five adults in the United States. While practice guidelines recommend universal screening for depression in primary care settings, clinical outcomes suffer in the absence of optimal models to manage those who screen positive for depression. The current practice of employing additional mental health professionals perpetuates the assumption that primary care providers (PCP) cannot effectively manage depression, which is not feasible, due to the added costs and shortage of mental health professionals. We have extended our previous work, which demonstrated similar treatment outcomes for depression in primary care and psychiatric settings, using measurement-based care (MBC) by developing a model, called Primary Care First (PCP-First), that empowers PCPs to effectively manage depression in their patients. This model incorporates health information technology tools, through an electronic health records (EHR) integrated web-application and facilitates the following five components: (1) Screening (2) diagnosis (3) treatment selection (4) treatment implementation and (5) treatment revision. We have implemented this model as part of a quality improvement project, called VitalSign6, and will measure its success using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework. In this report, we provide the background and rationale of the PCP-First model and the operationalization of VitalSign6 project. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Review

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Open AccessReview
Pharmacological Treatments for Patients with Treatment-Resistant Depression
Pharmaceuticals 2020, 13(6), 116; https://doi.org/10.3390/ph13060116 - 04 Jun 2020
Abstract
Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk [...] Read more.
Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk of suicide. Next step treatment options for patients with TRD, include switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another (non-antidepressant) medication. It is unclear which of these treatment approaches should be applied to a given patient, and in what order. Due to this ambiguity, comparing antidepressants and augmentation agents on the basis of their efficacy, tolerability, and speed of symptom relief would be beneficial for clinicians. To accomplish this, a systematic search was conducted following PRISMA guidelines. Only randomized controlled trials were included in this qualitative synthesis, resulting in 66 articles. This review identified several effective pharmaco-therapeutic strategies that are currently available for patients with TRD. Ketamine and esketamine appear to be effective for the treatment of TRD. Augmentation with certain second generation antipsychotics, such as quetiapine or aripiprazole is likewise effective, and may be preferred over switching to antidepressant monotherapy. While the combination of olanzapine and fluoxetine was one of the first pharmacotherapy approved for TRD, and its use may be limited by metabolic side-effects. Other effective strategies include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants including bupropion, tricyclics, or mirtazapine. There is insufficient research to demonstrate the efficacy of ziprasidone or levothyroxine (T4). A shared decision-making approach is recommended to guide treatment selection to address each patient’s individual needs. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessReview
Neural Predictors of the Antidepressant Placebo Response
Pharmaceuticals 2019, 12(4), 158; https://doi.org/10.3390/ph12040158 - 19 Oct 2019
Abstract
The antidepressant placebo response remains a barrier to the development of novel therapies for depression, despite decades of efforts to identify and methodologically address its clinical correlates. This manuscript reviews recent neuroimaging studies that aim to identify the neural signature of antidepressant placebo [...] Read more.
The antidepressant placebo response remains a barrier to the development of novel therapies for depression, despite decades of efforts to identify and methodologically address its clinical correlates. This manuscript reviews recent neuroimaging studies that aim to identify the neural signature of antidepressant placebo response. Data captured in clinical trials have primarily focused on antidepressant efficacy or predicting antidepressant response and have reliably implicated the rostral anterior cingulate cortex (rACC) in antidepressant placebo response, but also in medication response. Imaging and electroencephalography (EEG) experiments specifically interrogating the mechanism of antidepressant placebo response, while few, suggest the reward network, including opiate neurotransmission, is also involved. Therefore, while the rACC is likely involved in the antidepressant placebo response, its observation in isolation is unlikely to prospectively distinguish antidepressant placebo from medication responders. Instead, future studies of antidepressant placebo response should probe the reward network as a whole and incorporate sophisticated computational analytical approaches. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessReview
Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP
Pharmaceuticals 2019, 12(3), 113; https://doi.org/10.3390/ph12030113 - 29 Jul 2019
Cited by 3
Abstract
Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and [...] Read more.
Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke interleukin-6 (IL-6) trans-signaling. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychological symptoms, and a decline in cognitive functions. Recognition of the sequence of pathological events allows the prediction of novel targets for therapeutic intervention. Amongst others, these include blockade of the big-K potassium channel, blockade of the P2X4 channel, TYK2-kinase inhibition, noradrenaline α2B-receptor antagonism, nicotinic α7-receptor stimulation, and the Sgp130Fc antibody. A better understanding of downstream processes evoked by inflammation and stress also allows suggestions for tentatively better biomarkers (e.g., SERPINA3N, MARCKS, or 13C-tryptophan metabolism). Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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