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Neuropsychopharmacology : Official... Apr 2024Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the...
Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.
PubMed: 38609530
DOI: 10.1038/s41386-024-01857-8 -
Mayo Clinic Proceedings Jul 2024The number of midlife women transitioning into menopause is substantial, with more than 1 million women in the United States entering menopause each year. Vasomotor... (Review)
Review
The number of midlife women transitioning into menopause is substantial, with more than 1 million women in the United States entering menopause each year. Vasomotor symptoms (VMS), mood and sleep disturbances, and sexual problems are common during the menopause transition yet often go untreated. Menopausal hormone therapy is the most effective treatment of VMS, and the benefits typically outweigh the risks for women without contraindications who are younger than 60 years or within 10 years from menopause onset. For women who cannot or choose not to use hormone therapy, nonhormone prescription options exist to treat VMS. Many of these therapies have secondary benefits beyond VMS relief. For example, whereas paroxetine is Food and Drug Administration approved to treat VMS, it can also help with depressive and anxiety symptoms. The aim of this paper is to summarize prescription treatments of VMS and their secondary benefits for other common symptoms experienced by midlife women. The tools presented will help clinicians caring for midlife women provide individualized, comprehensive care with the goal of improving their quality of life during the menopause transition and beyond.
Topics: Humans; Female; Menopause; Hot Flashes; Middle Aged; Estrogen Replacement Therapy; Vasomotor System; Quality of Life
PubMed: 38960498
DOI: 10.1016/j.mayocp.2024.03.028 -
Fundamental & Clinical Pharmacology Jun 2024Pharmacologic management of mental health illnesses in patients receiving dialysis is complex and lacking data. (Review)
Review
BACKGROUND
Pharmacologic management of mental health illnesses in patients receiving dialysis is complex and lacking data.
OBJECTIVE
Our objective was to synthesize published data for the treatment of depression, bipolar and related disorders, schizophrenia or psychotic disorders, and anxiety disorders in adults receiving hemodialysis or peritoneal dialysis.
METHODS
We undertook a scoping review, searching the following databases: Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Scopus, and Web of Science. Data on patients who received only short-term dialysis, a kidney transplant, or non-pharmacologic treatments were excluded.
RESULTS
Seventy-three articles were included: 41 focused on depression, 16 on bipolar disorder, 13 on schizophrenia and psychotic disorders, 1 on anxiety disorders, and 2 addressing multiple mental health illnesses. The majority of depression studies reported on selective serotonin reuptake inhibitors (SSRIs) as a treatment. Sertraline had the most supporting data with use of doses from 25 to 200 mg daily. Among the remaining SSRIs, escitalopram, citalopram, and fluoxetine were studied in controlled trials, whereas paroxetine and fluvoxamine were described in smaller reports and observational trials. There are limited published data on other classes of antidepressants and on pharmacological management of anxiety. Data on treatment for patients with bipolar disorder or schizophrenia and related disorders are limited to case reports.
CONCLUSION
Over half of the studies included were case reports, thus limiting conclusions. More robust data are required to establish effect sizes of pharmacological treatments prior to providing specific recommendations for their use in treating mental health illnesses in patients receiving dialysis.
PubMed: 38877814
DOI: 10.1111/fcp.13022 -
Journal of Biomolecular Structure &... 2024Several generations of anti-epileptic drugs (AEDs) are available but have several associated side effects apart from a limited success rate. Drug repositioning...
Several generations of anti-epileptic drugs (AEDs) are available but have several associated side effects apart from a limited success rate. Drug repositioning strategies have gained importance in the last two decades owing to lower failure rates and economic burden. Drugs with similar side effect profiles may share a common mechanism of action and thus can be linked to other disease treatments. The present study was carried out to identify the newly approved drug candidate(s) as AEDs using clinical side-effects drug repositioning strategy. The clinical side effect similarity of drugs available in the SIDER v4.1 database was estimated against common side effects of 5 major marketed AEDs, using the 'dplyr' package library in the R. Further drugs were filtered based on Blood Brain Barrier permeability prediction and FDA-approval status. Molecular docking studies were performed for selected 26 hits (drugs) against previously identified epilepsy target receptors: Voltage-gated sodium channel α2 (Nav1.2), GABA receptor α1-β1 (GABAr α1-β1), and Voltage-gated calcium channel α-1 G (Cav3.1). Only 2 drugs (Ziprasidone and Paroxetine) showed better binding affinities against studied epilepsy receptors Nav1.2, GABAr α1-β1, and Cav3.1, than their corresponding standard AEDs, i.e. Carbamazepine, Clonazepam, and Pregabalin, respectively. Ziprasidone reportedly showed seizure-like symptoms in ∼3% of patients and was hence omitted from further study. The MDS study of docked complexes of Paroxetine with selected epilepsy target receptors showed stable RMSD values and better interaction energies. The study reveals Paroxetine as a potential candidate to be repurposed for 1st line epileptic seizure medication.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Drug Repositioning; Molecular Docking Simulation; Paroxetine; Anticonvulsants; Epilepsy; Piperazines; Thiazoles
PubMed: 37042987
DOI: 10.1080/07391102.2023.2199874 -
Acta Psychiatrica Scandinavica Jan 2024Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment-resistant depression. In this study we examined factors (including severity of...
BACKGROUND
Antipsychotics (AP) have been used to augment antidepressant (AD) medication in treatment-resistant depression. In this study we examined factors (including severity of depression and initial antidepressant) affecting AP augmentation, as well as which APs were initiated as augmentation in young adults.
METHODS
Data were extracted from Finnish nationwide registers. Of persons aged 18-29 years diagnosed with a depression during 2004-2017 we focused on incident AD users (who initiated AD 6 months before and after the diagnosis) whose severity level of depression was recorded (N = 21,966). AP augmentation was studied during 1 year after diagnosis of depression. Persons diagnosed with severe depression with psychotic features (n = 1486) were excluded from main analyses and analyzed separately.
RESULTS
Overall, 8.4% of new antidepressant users initiated AP augmentation. Risk of augmentation increased with severity of depression as 3.9%, 5.8%, and 14.0% of persons with mild, moderate, and severe depression, respectively, initiated augmentation. Male sex, comorbid anxiety and personality disorders, substance abuse and selfharm/suicide attempt were positively associated with augmentation. Compared to citalopram, use of tricyclic antidepressant, paroxetine and venlafaxine were associated with increased risk of augmentation, while use of bupropion was associated with a decreased risk. Quetiapine and risperidone were the most common APs used in augmentation. Among persons with severe depression with psychotic features, use of sertraline was associated with AP augmentation, whereas use of fluoxetine decreased risk of augmentation.
CONCLUSIONS
Use of APs as augmentation of AD therapy was common in severe depression. Comorbidities had only a small effect to augmentation, but selection of initial AD was more closely associated to risk of augmentation. Interestingly, use of bupropion decreased risk of augmentation, which warrants further studies, as well as the decrease in risk of augmentation when fluoxetine in case of psychotic depression was used.
Topics: Male; Young Adult; Humans; Fluoxetine; Depression; Bupropion; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major
PubMed: 37985246
DOI: 10.1111/acps.13633 -
Journal of Affective Disorders Jan 2024Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in... (Randomized Controlled Trial)
Randomized Controlled Trial
Omega-3 supplementation improves depressive symptoms, cognitive function and niacin skin flushing response in adolescent depression: A randomized controlled clinical trial.
BACKGROUND
Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant ω3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of ω3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression.
METHODS
A total of 71 adolescents with depression (aged 13-24; 59.2 % female) were randomly assigned to receive ω3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR.
RESULTS
Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the ω3 + Paxil group compared with Paxil group. Additionally, in the ω3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline.
LIMITATIONS
The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect.
CONCLUSIONS
Our results demonstrate that adjuvant ω3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest ω3 is a promising adjuvant treatment for adolescent depression.
Topics: Adult; Adolescent; Female; Humans; Male; Niacin; Depression; Paroxetine; Cognition; Dietary Supplements
PubMed: 38190276
DOI: 10.1016/j.jad.2023.10.151 -
Neuropharmacology Dec 2023The study aimed to investigate the functional connectivity (FC) between the cerebellum and intrinsic cerebral networks in patients with panic disorder (PD), and to...
The study aimed to investigate the functional connectivity (FC) between the cerebellum and intrinsic cerebral networks in patients with panic disorder (PD), and to observe changes in the cerebellar-cerebral FC following pharmacotherapy. Fifty-four patients with PD and 54 healthy controls (HCs) underwent clinical assessments and functional magnetic resonance imaging scans before and after a 5-week paroxetine treatment. Seed-based cerebellar-cerebral FC was compared between the PD and HC groups, as well as between patients with PD before and after treatment. Additionally, the correlations between FC and clinical features of PD were analyzed. Compared to HCs, patients with PD had altered cerebellar-cerebral FC in the default mode, affective-limbic, and sensorimotor networks. Moreover, a negative correlation between cerebellar-insula disconnection and the severity of depressive symptoms in patients with PD (Pearson correlation, r = -0.424, p = 0.001, Bonferroni corrected) was found. After treatment, most of the enhanced FCs observed in patients with PD at baseline returned to levels similar to those observed in HCs. However, the reduced FC at baseline did not significantly change after treatment. The findings suggest that patients with PD have specific deficits in resting-state cerebellar-cerebral FC and that paroxetine may improve PD by restoring the balance of cerebellar-cerebral FC. These findings emphasize the crucial involvement of cerebellar-cerebral FC in the neuropsychological mechanisms underlying PD and in the potential pharmacological mechanisms of paroxetine for treating PD.
PubMed: 37652260
DOI: 10.1016/j.neuropharm.2023.109692 -
Heliyon May 2024To investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the...
AIM
To investigate whether SJF functions in similar manner as the key substance in the inflammatory process, soluble epoxide hydrolase (sEH) inhibitor, to inhibit the arachidonic acid metabolic pathway and nuclear factor kappa-B(NF-κB) signal path in the hippocampi of postpartum depression rats.
METHODS
The rats were subcutaneous injected estradiol benzoate and progesterone to build PPD rat model. SJF, paroxetine hydrochloride and sEH inhibitor (AUDA) were used to treat PPD rats for 3 weeks. Then the morphological changes of hippocampi and various proteins were observed after that behavioral test were conducted in all 36 SD rats in six group: SJF, paroxetine, AUDA, PPD, sham and normal group.
RESULTS
Weight, results of sucrose preference, upright times, total and center squares crossing decreased significantly (P < 0.01), whereas immobility time increased (P < 0.01). Results above were reversed in animals that in the SJF, paroxetine and AUDA groups. Hippocampal neurons in PPD rats partially degenerated with narrowed nuclei, increased autophagy and mitochondria bound to lysosomes were visible while the autophagy of hippocampal neurons in the paroxetine and AUDA group decreased, with a small amount of lysosomes. sEH, COX-2, 5-LOX, TNF-α, IL-1, IL-6, NF-κB p65, and Cor increased in hippocampi of PPD rats while EETs and 5-HT decreased. Protein expressions of Ibal, GFAP, p-IκBα, p65, and p-p65(S536)increased in PPD animals. Those changes were reversed by SJF, paroxetine and AUDA. Gene expressions of TNF-α, IL-1β, IL-6, 5-LOX, COX-2 and p65 increased in PPD rats and the changes of expression in these genes were reversed by paroxetine and AUDA. SJF reversed the gene expression changes of COX-2, TNF-α, and IL-1β.
CONCLUSION
SJF may have an analogous effect as sEH inhibitor to relieve depressive symptoms by suppressing inflammatory signaling pathways in hippocampi of PPD rats, which involves AA metabolic pathway and NF-κB signal pathway.
PubMed: 38726147
DOI: 10.1016/j.heliyon.2024.e29978 -
International Journal of Nanomedicine 2023The tight structure of the blood-brain barrier severely limits the level of drug therapy for central nervous system disorders. In this study, a novel composite delivery...
INTRODUCTION
The tight structure of the blood-brain barrier severely limits the level of drug therapy for central nervous system disorders. In this study, a novel composite delivery system combining nanocarrier and microneedle technology was prepared to explore the possibility of transdermal delivery of drugs to work in the brain.
METHODS
Nanoparticle solutions containing paroxetine and rhodamine-B were prepared using PLGA as a carrier by the emulsification-solvent volatilization method. Then, they were mixed with hyaluronic acid and the PLGA nanoparticulate-based microneedle system (Rh-NPs-DMNs) was prepared by a multi-step decompression-free diffusion method. The particle size, zeta potential, and micromorphology of the nano solution were measured; the appearance, mechanical strength, dissolution properties, and puncture effect of the Rh-NPs-DMNs were evaluated; also, it was evaluated for in vivo live imaging properties and in vitro skin layer transport and distribution properties.
RESULTS
The mean particle size of Rh-NPs was 96.25 ± 2.26 nm; zeta potential of 15.89 ± 1.97 mV; PDI of 0.120 ± 0.079. Rh-NPs-DMNs had a high needle content of 96.11 ± 1.27% and a tip height of 651.23 ± 1.28 μm, with excellent mechanical properties (fracture force of 299.78 ± 1.74 N). H&E skin tissue staining showed that Rh-NPs-DMNs produced micron-sized mechanical pores approximately 550 μm deep immediately after drug administration, allowing for efficient circulation of the drug; and the results of in vivo imaging showed that Rh-B NPs DMNs had a faster transport rate than Rh-B DMNs, with strong fluorescent signals in both brain (<0.01) and hippocampus (<0.05) 48 h after drug administration.
CONCLUSION
Nanoparticles can prolong blood circulation time and intracerebral retention time and have certain brain-targeting properties due to their excellent physical properties. The use of microneedle technology combined with nanocarriers provides new ideas for delivery systems for the treatment of central neurological diseases.
Topics: Skin; Administration, Cutaneous; Skin Absorption; Pharmaceutical Preparations; Brain; Nanoparticles; Drug Carriers; Particle Size
PubMed: 37457799
DOI: 10.2147/IJN.S415728 -
Scientific Reports Oct 2023The aim of this study was to investigate the clinical characteristics, psychological status, sleep quality, and quality of life of patients with functional anorectal...
The aim of this study was to investigate the clinical characteristics, psychological status, sleep quality, and quality of life of patients with functional anorectal pain (FAP). The study also assessed the treatment efficacy of paroxetine in alleviating FAP symptoms. A retrospective comparative study of forty-three patients with FAP who were first treated with an anal plug compound glycolate suppository versus paroxetine combined with anal plug compound glycolate suppository between November 2021 and August 2022. Pain, quality of life, depression, anxiety and sleep quality were assessed before and after treatment by the Chinese version of the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), Health-related quality of life scale (The 12-Item Short-Form Health Survey, SF-12), 17-item Hamilton Depression Rating Scale (HDRS), 14-item Hamilton Anxiety Scale (HAMA), and Pittsburgh Sleep Quality Index (PSQI). A total of 46.5% of patients with FAP were found to have anxiety symptoms (HAMA ≥ 7), 37.2% of patients with FAP were found to have depressive symptoms (HDRS ≥ 8). A total of 32.6% of patients with FAP had sleep disorders (PSQI > 10). Within 1 week after drug withdrawal, the short-term efficacy rate of oral paroxetine was 95.5%. After treatment, the symptom pain score (VAS) and sleep score were lower than those before treatment (P < 0.01). In the areas of vitality (VT), Social Functioning (SF), and Mental Health (MH), the difference between the pre-treatment and 8 weeks posttreatment scores of the study group and the control group was statistically significant (P < 0.05). FAP patients have obvious symptoms of anxiety and depression, and the incidence of sleep disturbance is prevalent. Paroxetine, a typical serotonin reuptake inhibitor (SSRI), was able to alleviate depression, anxiety, and pain symptoms in FAP, which might have clinical application prospects.
Topics: Humans; Paroxetine; Retrospective Studies; Quality of Life; Treatment Outcome; Pelvic Pain; Glycolates
PubMed: 37865675
DOI: 10.1038/s41598-023-45401-y