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Journal of Affective Disorders Oct 2023MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress, it is known that miRNAs in mitochondria diffuse out of the cytoplasm alongside mtDNA; however, this process has not yet been identified. We hypothesized that miRNAs derived from specific cell nuclei cause mitochondrial damage and mtDNA fragmentation under MDD-associated stress conditions.
METHODS
A comprehensive analysis of the plasma miRNA levels and quantification of the plasma ccf-mtDNA copy number were performed in 69 patients with depression to determine correlations and identify genes and pathways interacting with miRNAs. The patients were randomly assigned to receive either selective serotonin reuptake inhibitors (SSRI) or mirtazapine. Their therapeutic efficacy over four weeks was evaluated in relation to miRNAs correlated with ccf-mtDNA copy number.
RESULTS
The expression levels of the five miRNAs showed a significant positive correlation with the ccf-mtDNA copy number after correcting for multiple testing. These miRNAs are involved in gene expression related to thyroid hormone synthesis, the Hippo signaling pathway, vasopressin-regulated water reabsorption, and lysine degradation. Of these five miRNAs, miR-6068 and miR-4708-3p were significantly associated with the SSRI and mirtazapine treatment outcomes, respectively.
LIMITATIONS
This study did not show comparison with a healthy group.
CONCLUSIONS
The expression levels of specific miRNAs were associated with ccf-mtDNA copy number in untreated depressed patients; moreover, these miRNAs were linked to antidepressant treatment outcomes. These findings are expected to lead to the elucidation of new pathological mechanism of depression.
Topics: Humans; MicroRNAs; DNA, Mitochondrial; Depressive Disorder, Major; Mirtazapine; Depression; Cell-Free Nucleic Acids; Mitochondria; Selective Serotonin Reuptake Inhibitors
PubMed: 37467797
DOI: 10.1016/j.jad.2023.07.073 -
Psychiatria Danubina Oct 2023Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a... (Review)
Review
Bipolar disorder and Parkinson's disease are two distinct neurological conditions that share common features related to dopaminergic dysfunction. This article presents a comprehensive review of the existing literature to investigate the association between bipolar disorder and Parkinson's disease, focusing on the dopaminergic hypothesis and potential therapeutic options. The dopaminergic hypothesis suggests that both bipolar disorder and Parkinson's disease involve impairments in the nigrostriatal or mesolimbic dopaminergic pathways. Studies have demonstrated alterations in dopamine regulation during manic and depressive phases of bipolar disorder. Similarly, Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms. Recent analyses have highlighted a predisposition to Parkinson's disease in individuals with bipolar disorder. Longitudinal studies and meta-analyses have demonstrated an increased risk of developing Parkinson's disease in patients with bipolar disorder. However, differentiating idiopathic Parkinson's disease from parkinsonism induced by medications used in bipolar disorder can be challenging. Dopamine transporter (DAT) scans can aid in making a differential diagnosis. Treatment options for patients with both bipolar disorder and Parkinson's disease are limited. Neuroleptics, commonly used to manage psychotic symptoms in Parkinson's disease, may worsen motor symptoms and have limitations in bipolar disorder patients. Clozapine has shown efficacy in treating psychosis without worsening motor symptoms. Pimavanserin, an inverse agonist of the 5-HT2A receptor can offer new opportunities. However, its efficacy in bipolar disorder patients with Parkinson's disease remains unexplored. In conclusion, the association between bipolar disorder and Parkinson's disease is supported by the involvement of the dopaminergic system in both conditions. The identification of shared mechanisms opens new avenues for potential therapeutic interventions. Further research is needed to investigate the efficacy of pimavanserin and explore other treatment options for individuals with both bipolar disorder and Parkinson's disease.
Topics: Humans; Parkinson Disease; Bipolar Disorder; Drug Inverse Agonism; Piperidines; Dopamine
PubMed: 37800205
DOI: No ID Found -
Journal of Medicinal Chemistry Sep 2023Pharmacological targeting of the dopamine D receptor (DR)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for...
Pharmacological targeting of the dopamine D receptor (DR)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target DR. We identified several compounds with high DR binding affinity ( ≤ 6.9 nM) and >91-fold selectivity over other D-like receptors (DR, DR) with diverse partial agonist and antagonist profiles. Novel analogue is a potent low-efficacy DR partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC > 3). (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by DR-selective antagonists. Off-target antagonism of 5-HT or 5-HT may also contribute to these effects. Results with support further efforts to target DR in SUD treatment.
Topics: Humans; Animals; Rats; Serotonin; Benzothiazoles; Substance-Related Disorders; Brain; Cocaine
PubMed: 37646374
DOI: 10.1021/acs.jmedchem.3c00734 -
Annals of General Psychiatry Sep 2023Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist... (Review)
Review
Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist and reuptake inhibitor (SARI) antidepressant approved for major depressive disorder (MDD) in adults, has established efficacy that is comparable to other available antidepressants, and is effective for a range of depression symptoms, including insomnia, which is one of the most common and bothersome symptoms of depression. Also, trazodone's pharmacodynamic properties allow it to avoid the side effects of insomnia, anxiety and sexual dysfunction often associated with selective serotonin reuptake inhibitor antidepressants. In this narrative review, we have summarized recent clinical trials and real-world data on trazodone, including the recently introduced once-daily formulation, which has single dose pharmacokinetic properties that maintain effective blood trazodone levels for 24 h, while avoiding concentration peaks associated with side effects. This, combined with a low incidence of weight gain, and sexual dysfunction, may improve adherence to treatment. The most common adverse effects of trazodone are somnolence, headache, dizziness and xerostomia. It has minimal anticholinergic activity but may be associated infrequently with orthostatic hypotension (especially in patients with cardiovascular disease or older adults), QT interval prolongation, cardiac arrhythmias, and rare episodes of priapism. The low liability for activating side effects, the efficacy on symptoms such as insomnia and psychomotor agitation and the rapid onset of action make it useful for many depressed patients, both in monotherapy at nominal dosages of 150-300 mg/day, and in combination with other antidepressants at lower dosages.
PubMed: 37660092
DOI: 10.1186/s12991-023-00465-y -
Naunyn-Schmiedeberg's Archives of... May 2024Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review... (Review)
Review
Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review provides a pharmacological update on MTZ and summarizes the research findings of MTZ's effects on different diseases. MTZ is hypothesized to have antidepressant effects because of the synergy between noradrenergic and serotonergic actions and is effective in treating major depressive disorder and depression associated with epilepsy, Alzheimer's disease, stroke, cardiovascular disease, and respiratory disease. In cancer patients, MTZ significantly reduced sadness, nausea, sleep disruption, and pain and improved quality of life. Also, it has promising effects on Parkinson's disease, schizophrenia, dysthymia, social anxiety disorder, alcohol dependency, posttraumatic stress disorder, panic disorder, pain syndromes, obsessive-compulsive disorder, and sleep disorders. Additionally, MTZ is potentially therapeutic in different situations associated with depression, such as liver, kidney, cardiovascular, respiratory, infertility, heavy metal-induced neurotoxicity, and pruritus. Potent antioxidative, anti-inflammatory, and anti-apoptotic bioactivities mediate these promising effects. These positive outcomes of the scientific investigations motivate more and more clinical trials for a golden exceptional antidepressant in different conditions.
Topics: Humans; Mirtazapine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic
PubMed: 37943296
DOI: 10.1007/s00210-023-02818-6 -
Psychopharmacology Oct 2023Clozapine is a unique medication with a potential role in the treatment of severe borderline personality disorder (BPD). (Review)
Review
RATIONALE
Clozapine is a unique medication with a potential role in the treatment of severe borderline personality disorder (BPD).
OBJECTIVES
The review examines the effectiveness of clozapine as a medication for management for severe BPD with high risk of suicide, violence or imprisonment, and aims to help guide clinical practice in managing severe BPD.
METHODS
A database search of the terms "Clozapine" AND "BPD"; "Antipsychotics" AND "BPD"; "Clozapine" AND "Borderline Personality Disorder"; and "Antipsychotics" AND "Borderline Personality Disorder" were performed in CINAHL, Cochrane Library, Embase, Medline, PsychINFO, PubMed, and Web of Science. Full-text articles of clinical clozapine use for BPD were included for review.
RESULTS
A total of 24 articles consisting of 1 randomised control trial, 10 non-controlled trials, and 13 case reports were identified. Most of the studies reported benefits from clozapine when used for severe BPD. Many of the studies focused on clozapine use in BPD patients at high risk of suicide. Results from these non-controlled and case reports support the use of clozapine in patients with severe BPD at high risk of suicide.
CONCLUSION
There may be a role for clozapine in treating severe treatment refractory BPD, especially for those patients at high risk of suicide and frequent hospitalisations.
Topics: Humans; Clozapine; Antipsychotic Agents; Suicide; Borderline Personality Disorder; Randomized Controlled Trials as Topic
PubMed: 37572113
DOI: 10.1007/s00213-023-06431-6 -
Journal of Psychopharmacology (Oxford,... Jul 2023The classical psychedelics, psilocybin, peyote, ayahuasca/-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric... (Review)
Review
BACKGROUND
The classical psychedelics, psilocybin, peyote, ayahuasca/-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials.
METHODS
We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance.
RESULTS
We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias.
CONCLUSION
Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity.
Topics: Humans; Hallucinogens; Randomized Controlled Trials as Topic; Lysergic Acid Diethylamide; Psilocybin; Anxiety Disorders
PubMed: 37403379
DOI: 10.1177/02698811231180276 -
Drug Design, Development and Therapy 2023This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of... (Review)
Review
This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D, 5-hydroxytryptamine (5-HT), and 5-HT receptors and a partial agonistic effect on the 5-HT receptor with low affinities for muscarinic M, histamine H, and a adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT and 5-HT receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.
Topics: Humans; Lurasidone Hydrochloride; Schizophrenia; Serotonin; Isoindoles; Thiazoles; Antipsychotic Agents; Weight Gain
PubMed: 37789971
DOI: 10.2147/DDDT.S366769 -
International Journal of Molecular... Aug 2023Alzheimer's disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few... (Review)
Review
Alzheimer's disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into AD is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Using microdosing, psychedelic drugs may prove to help combat this devastating disease by eliciting psychiatric benefits via acting through various mechanisms of action such as serotonin and dopamine pathways. Herein, we review the studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its related depressive symptoms. We used the listed keywords to search through PubMed for relevant preclinical, clinical research, and review articles. The putative mechanism of action (MOA) for psychedelics is that they act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression.
Topics: Humans; Hallucinogens; Alzheimer Disease; Depression; Serotonin; Lysergic Acid Diethylamide
PubMed: 37569888
DOI: 10.3390/ijms241512513 -
Journal of Medicinal Chemistry Aug 2023The cardiotoxicity associated with -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT) has solidified the receptor's place as an... (Review)
Review
The cardiotoxicity associated with -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT) has solidified the receptor's place as an "antitarget" in drug discovery. Conversely, a growing body of evidence has highlighted the utility of 5-HT antagonists for the treatment of pulmonary arterial hypertension (PAH), valvular heart disease (VHD), and related cardiopathies. In this Perspective, we summarize the link between the clinical failure of fenfluramine-phentermine (fen-phen) and the subsequent research on the role of 5-HT in disease progression, as well as the development of drug-like and receptor subtype-selective 5-HT antagonists. Such agents represent a promising class for the treatment of PAH and VHD, but their utility has been historically understudied due to the clinical disasters associated with 5-HT. Herein, it is our aim to examine the current state of 5-HT drug discovery, with an emphasis on the receptor's role in the central nervous system (CNS) versus the periphery.
Topics: Humans; Receptor, Serotonin, 5-HT2B; Serotonin; Fenfluramine; Heart Valve Diseases; Drug Discovery
PubMed: 37584406
DOI: 10.1021/acs.jmedchem.3c01178