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Special Issue "Antidepressants and Mood Stabilizers: Novel Research Avenues and Recent Evidence-Based Clinical Insights"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2018).

Special Issue Editors

Guest Editor
Prof. Dr. Domenico De Berardis

1. National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital "G. Mazzini", ASL 4, Teramo, Italy
2. Chair of Psychiatry, University “G. d’Annunzio” of Chieti-Pescara, Italy
3. Polyedra Research Group, Italy
Website | E-Mail
Interests: clinical psychiatry; clinical psychopharmacology; clozapine; newer antidepressants; long-acting antipsychotics; alexithymia; emotions; functional somatic symptoms; anxiety disorders; mood disorders; schizophrenia; functional magnetic resonance; obsessive-compulsive disorder
Guest Editor
Prof. Dr. Michele Fornaro

Federico II University of Naples, Department of Psychiatry, Naples, Italy
Website 1 | Website 2 | E-Mail
Interests: bipolar disorder; major depressive disorder; anxiety disorders; clinical psychopharmacology; clinical epidemiology of mood disorders

Special Issue Information

Dear Colleagues,

Within the past few decades, the release of novel compounds occurred for the sole antidepressant class, rather than lithium or traditional anticonvulsant mood-stabilizers. Shifting of the boundary (and largely flawed) “class-effect” and the monoamine-modulation approach may have played a role on the latter scenario, especially in view of concurrent preliminary evidence suggesting a potential trans-nosological effect of selected second-generation antipsychotics, beyond only schizophrenia-spectrum disorders.

The present Special Issue aims at providing an overview on both the current and most promising novel avenues, of both standard antidepressant and “mood-stabilizer” agents in a broader sense, thus encompassing both boundary diagnostic systems, as well as alternative, evidence- and spectrum-based approaches, ideally driving a conscious prescription of pharmacological agents that are effective both in the treatment of major depressive episodes and the ideal longitudinal stabilization of bipolar disorder.

Prof. Dr. Domenico De Berardis
Dr. Michele Fornaro
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • antidepressant
  • depression
  • mania
  • mixed features/states
  • mood-stabilizer
  • lithium
  • second-generation antipsychotics
  • monoamines
  • experimental drugs

Published Papers (11 papers)

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Research

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Open AccessArticle
Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats
Int. J. Mol. Sci. 2018, 19(1), 162; https://doi.org/10.3390/ijms19010162
Received: 1 November 2017 / Revised: 27 December 2017 / Accepted: 2 January 2018 / Published: 5 January 2018
Cited by 9 | PDF Full-text (8222 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal [...] Read more.
A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2′-deoxyuridine was injected at days 8–10 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect. Full article
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Open AccessArticle
Aqueous Extract of Pomegranate Alone or in Combination with Citalopram Produces Antidepressant-Like Effects in an Animal Model of Menopause: Participation of Estrogen Receptors
Int. J. Mol. Sci. 2017, 18(12), 2643; https://doi.org/10.3390/ijms18122643
Received: 3 November 2017 / Revised: 24 November 2017 / Accepted: 30 November 2017 / Published: 19 December 2017
Cited by 1 | PDF Full-text (1667 KB) | HTML Full-text | XML Full-text
Abstract
It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of [...] Read more.
It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of estrogen receptors (ER). AE-PG (0.1, 1.0, 10, or 100 mg/kg) was evaluated in ovariectomized female Wistar rats subjected to the forced swimming test. The effects induced by AE-PG were compared with those of citalopram (2.5, 5.0, 10, and 20.0 mg/kg) and 17β-estradiol (E2; 2.5 5.0, and 10 μg/rat). Likewise, the combination of suboptimal doses of AE-PG (0.1 mg/kg) plus citalopram (2.5 mg/kg) was evaluated. To determine if ER participates in the antidepressant-like action of pomegranate, the estrogen antagonist tamoxifen (15 mg/kg) was administered with AE-PG (1 mg/kg). AE-PG produced antidepressant-like actions with a similar behavioral profile induced by citalopram and E2. Suboptimal doses of citalopram plus AE-PG produced antidepressant-like effects. Tamoxifen was able to block AE-PG’s antidepressant-like actions. These results confirm the participation of ER in AE-PG’s antidepressant-like effects. Furthermore, the additive effects observed with the combined treatment of AE-PG plus citalopram could be advantageous in the treatment of depressive disorders, such as menopause. Full article
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Open AccessArticle
Activation of TREK-1, but Not TREK-2, Channel by Mood Stabilizers
Int. J. Mol. Sci. 2017, 18(11), 2460; https://doi.org/10.3390/ijms18112460
Received: 13 October 2017 / Revised: 14 November 2017 / Accepted: 16 November 2017 / Published: 19 November 2017
Cited by 5 | PDF Full-text (1107 KB) | HTML Full-text | XML Full-text
Abstract
Earlier studies have demonstrated that the tandem pore domain weak inward rectifying K+ channel (TWIK)-related K+ (TREK)-1 channel is inhibited by antidepressants and is associated with major depression. However, little is known about the effect of mood stabilizers that are commonly [...] Read more.
Earlier studies have demonstrated that the tandem pore domain weak inward rectifying K+ channel (TWIK)-related K+ (TREK)-1 channel is inhibited by antidepressants and is associated with major depression. However, little is known about the effect of mood stabilizers that are commonly used for treatment of bipolar disorder on TREK channels, members of the two-pore domain K+ (K2P) channel family. This study sought to investigate the effect of mood stabilizers on TREK-1 and TREK-2 channels. HEK-293A cells were transfected with human TREK-1 or TREK-2 DNA. The effect of mood stabilizers on TREK-1 and TREK-2 was studied using the patch clamp technique. Changes in TREK protein expression by mood stabilizers were studied in the HT-22 mouse hippocampal neuronal cells using western blot analysis. Lithium chloride (LiCl, 1 mM), gabapentin (100 μM), valproate (100 μM), and carbamazepine (100 μM) increased TREK-1 currents by 31 ± 14%, 25 ± 11%, 28 ± 12%, and 72 ± 12%, respectively, whereas they had no effect on TREK-2 channel activity. In addition, western blot analysis showed LiCl and carbamazepine slightly upregulated TREK-1 expression, but not TREK-2 in the HT-22 cells. These results suggest that TREK-1 could be a potential therapeutic target for treatment of bipolar disorders as well as depression, while TREK-2 is a target well suited for treatment of major depression. Full article
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Review

Jump to: Research

Open AccessReview
Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors
Int. J. Mol. Sci. 2018, 19(10), 2888; https://doi.org/10.3390/ijms19102888
Received: 7 September 2018 / Accepted: 19 September 2018 / Published: 23 September 2018
Cited by 5 | PDF Full-text (1042 KB) | HTML Full-text | XML Full-text
Abstract
Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate [...] Read more.
Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person’s suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl-d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics. Full article
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Open AccessReview
The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review
Int. J. Mol. Sci. 2018, 19(8), 2410; https://doi.org/10.3390/ijms19082410
Received: 2 July 2018 / Revised: 31 July 2018 / Accepted: 8 August 2018 / Published: 15 August 2018
Cited by 6 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
Abstract
Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission. Thus, novel strategies are needed to successfully address those who did not respond, or partially [...] Read more.
Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission. Thus, novel strategies are needed to successfully address those who did not respond, or partially respond, to available antidepressant pharmacotherapy. Research findings revealed that the opioid system is significantly involved in the regulation of mood and incentives salience and may be an appropriate target for novel therapeutic agents. The present study aimed to systematically review the current literature about the use of buprenorphine (BUP) for major depression, treatment-resistant depression (TRD), non-suicidal self-injury (NSSI) behavior, and suicidal behavior. We investigated Pubmed and Scopus databases using the following keywords: “buprenorphine AND depression”, “buprenorphine AND treatment resistant depression”, “buprenorphine AND suicid*”, “buprenorphine AND refractory depression”. Several evidence demonstrate that, at low doses, BUP is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and NSSI, even in patients with TRD. However, more studies are needed to evaluate the long-term effects, and relative efficacy of specific combinations (e.g., BUP + samidorphan (BUP/SAM), BUP + naloxone (BUP/NAL), BUP + naltrexone) over BUP monotherapy or adjunctive BUP treatment with standard antidepressants, as well as to obtain more uniform guidance about the optimal BUP dosing interval. Full article
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Open AccessReview
A History of the Pharmacological Treatment of Bipolar Disorder
Int. J. Mol. Sci. 2018, 19(7), 2143; https://doi.org/10.3390/ijms19072143
Received: 4 June 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 23 July 2018
Cited by 4 | PDF Full-text (7731 KB) | HTML Full-text | XML Full-text
Abstract
In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and [...] Read more.
In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and the beginning of the so-called “Psychopharmacological Revolution” in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed. Full article
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Open AccessReview
Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation
Int. J. Mol. Sci. 2018, 19(1), 233; https://doi.org/10.3390/ijms19010233
Received: 1 November 2017 / Revised: 27 December 2017 / Accepted: 10 January 2018 / Published: 12 January 2018
Cited by 6 | PDF Full-text (1057 KB) | HTML Full-text | XML Full-text
Abstract
Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to [...] Read more.
Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments. Full article
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Open AccessReview
l-Acetylcarnitine: A Mechanistically Distinctive and Potentially Rapid-Acting Antidepressant Drug
Int. J. Mol. Sci. 2018, 19(1), 11; https://doi.org/10.3390/ijms19010011
Received: 30 October 2017 / Revised: 9 December 2017 / Accepted: 18 December 2017 / Published: 21 December 2017
Cited by 4 | PDF Full-text (634 KB) | HTML Full-text | XML Full-text
Abstract
Current therapy of mood disorders has several limitations. Although a high number of drugs are clinically available, as of today, nearly two-thirds of individuals do not achieve full symptomatic remission after treatment with conventional antidepressants. Moreover, several weeks of drug treatment are usually [...] Read more.
Current therapy of mood disorders has several limitations. Although a high number of drugs are clinically available, as of today, nearly two-thirds of individuals do not achieve full symptomatic remission after treatment with conventional antidepressants. Moreover, several weeks of drug treatment are usually required to obtain clinical effects, a limitation that has considerable clinical implications, ranging from high suicide risk to reduced compliance. The characteristic lag time in classical antidepressant effectiveness has given great impulse to the search for novel therapeutics with more rapid effects. l-acetylcarnitine (LAC), a small molecule of growing interest for its pharmacological properties, is currently marketed for treatment of neuropathic pain. Recent preclinical and clinical data suggested that LAC may exert antidepressant effects with a more rapid onset than conventional drugs. Herein, we review data supporting LAC antidepressant activity and its distinctive mechanisms of action compared with monoaminergic antidepressants. Furthermore, we discuss the unique pharmacological properties of LAC that allow us to look at this molecule as representative of next generation antidepressants with a safe profile. Full article
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Open AccessReview
An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms
Int. J. Mol. Sci. 2017, 18(12), 2679; https://doi.org/10.3390/ijms18122679
Received: 28 October 2017 / Revised: 4 December 2017 / Accepted: 7 December 2017 / Published: 11 December 2017
Cited by 6 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text
Abstract
Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive [...] Read more.
Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium’s specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3β, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium. Full article
Open AccessReview
Analgesic Mechanisms of Antidepressants for Neuropathic Pain
Int. J. Mol. Sci. 2017, 18(11), 2483; https://doi.org/10.3390/ijms18112483
Received: 22 October 2017 / Revised: 17 November 2017 / Accepted: 19 November 2017 / Published: 21 November 2017
Cited by 14 | PDF Full-text (7599 KB) | HTML Full-text | XML Full-text
Abstract
Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear. The inhibitory effects of these antidepressants for [...] Read more.
Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear. The inhibitory effects of these antidepressants for neuropathic pain manifest more quickly than their antidepressive effects, suggesting different modes of action. Recent studies of animal models of neuropathic pain revealed that noradrenaline is extremely important for the inhibition of neuropathic pain. First, increasing noradrenaline in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through α2-adrenergic receptors. Second, increasing noradrenaline acts on the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain. The mechanisms of neuropathic pain inhibition by antidepressants based mainly on experimental findings from animal models of neuropathic pain are discussed in this review. Full article
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Open AccessReview
Antidepressants and Mood Stabilizers: Novel Research Avenues and Clinical Insights for Bipolar Depression
Int. J. Mol. Sci. 2017, 18(11), 2406; https://doi.org/10.3390/ijms18112406
Received: 29 September 2017 / Revised: 6 November 2017 / Accepted: 9 November 2017 / Published: 13 November 2017
Cited by 2 | PDF Full-text (375 KB) | HTML Full-text | XML Full-text
Abstract
The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the [...] Read more.
The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the treatment of major depressive episodes (MDEs) and to obtain long-term stability in BDs. Before treating MDEs, screening tools, specific symptom evaluation and medical history should be used to distinguish between bipolarity and mixed features in patients for whom AD monotherapy may present a risk. In these patients, a combination of ADs plus MSs or atypical antipsychotics is recommended, rather than AD monotherapy. Studies evaluating MSs for bipolar depression suggest that lamotrigine is the most reliable treatment and lithium has modest effects; there is a lack of clear evidence regarding the efficacy of valproate and carbamazepine. Recently, significant progress has been made with respect to the pathophysiology of mood disorders and the application of potential biomarkers. There is an opportunity to study novel drug mechanisms through the rediscovery of fast-acting drugs such as ketamine. It is anticipated that future research developments will involve the discovery of potential targets for new drugs and their application to personalized treatments. Full article
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