Tag: antidepressants

Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki

To the Editor:

The coronavirus disease 2019 (COVID-19) pandemic causes short-term and long-term health problems in survivors after infection of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2). A recent systematic review using 57 studies with 250,351 survivors of COVID-19 shows that the median proportion of COVID-19 survivors experiencing at least 1 PASC (post-acute sequelae of COVID-19) was 54% at 1 month (short-term), 55% at 2–5 months (intermediate-term), and 54% at 6 or more months (long-term) [1]. The most common sequelae involved neurologic symptoms (i.e., headaches, memory deficits, difficulty concentrating, cognitive impairment), psychiatric symptoms (i.e., depression, anxiety, sleep disorders), pulmonary abnormalities (i.e., dyspnea, cough, increased oxygen requirement, pulmonary diffusion abnormalities, chest imaging abnormalities), and functional mobility impairment (i.e., impairment in general functioning, mobility decline, reduced exercise tolerance). However, there are no therapeutic drugs for long-term symptoms in survivors of COVID-19.

The precise mechanisms underlying SARS-CoV-2 induced long-term detrimental effects remain unclear. Infection of SARS-CoV-2 can damage endothelial cells leading to inflammation, thrombi and brain damage. SARS-CoV-2-associated systemic inflammation leads to decreased monoamines and neurotrophic factors, and microglial activation in the brain, resulting in long-term neurological and psychiatric symptoms in COVID-19 survivors [2]. A retrospective study of Wuhan University (Wuhan, China) reported that patients with Epstein-Barr virus (EBV)/SARS-CoV-2 coinfection have about 3-fold risk of having a fever symptom than patients with SARS-CoV-2 infection alone, and that levels of C-reactive protein and aspartate aminotransferase in patients with EBV/SARS-CoV-2 coinfection were higher than those in patients with SARS-CoV-2 infection alone [3]. This report suggests that EBV reactivation may be associated with the severity of clinical symptoms after SARS-CoV-2 infection.

Interestingly, approximately 67% of patients (20/30) with long-term sequelae of COVID-19 were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse IgG or EBV viral capsid antigen IgM [4]. Thus, EBV reactivation may play a role in long-term symptoms in COVID-19 survivors although further study using a large sample size is needed. The authors suggest that most of long-lasting symptoms in COVID-19 survivors following the recovery from SARS-CoV-2 infection might not be directly affected by the virus but probably result from SARS-CoV-2-associated inflammation and EBV reactivation [4].

In the issue, Khani and Entezari-Maleki proposed that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), may be a new therapeutic drug for long-term consequences of COVID-19 survivors [5]. Fluvoxamine has been demonstrated to prevent clinical deterioration in early-stage subjects with COVID-19 [6]. In addition of serotonin transporter inhibition, sigma-1 receptor chaperone in the endoplasmic reticulum (ER) and acid sphingomyelinase might play a role in the mechanisms of beneficial action of fluvoxamine for patients with SARS-CoV-2 infection [6,7,8]. It is also reported that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory actions by the prevention of inositol requiring enzyme 1α (IRE1) and X-box binding protein-1 (XBP-1) pathway [9]. Collectively, it is likely that sigma-1 receptor agonists such as fluvoxamine could produce potent anti-inflammatory effects through sigma-1 receptor/IRE1/XBP-1 pathway in the ER [6,7,8,9].

Among the SSRIs, fluvoxamine was the most potent at sigma-1 receptor in the brain [6,7,8]. Given the link between EBV reactivation and XBP-1 [10], it is possible that the potent sigma-1 receptor agonist fluvoxamine may have beneficial effects for long-term consequences in COVID-19 survivors through sigma-1 receptor/IRE1/XBP-1 pathway [4]. Therefore, it is of great interest to examine whether fluvoxamine can improve long-term sequelae in COVID-19 survivors.

Source: Hashimoto Y, Suzuki T, Hashimoto K. Comments to “Fluvoxamine and long COVID-19: a new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki. Mol Psychiatry. 2022 Apr 6:1–2. doi: 10.1038/s41380-022-01546-2. Epub ahead of print. PMID: 35388183; PMCID: PMC8985059. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985059/ (Full text)

Selective serotonin reuptake inhibitor combined with dengzhanshengmai capsule improves the fatigue symptoms: a 12-week open-label pilot study

Abstract:

OBJECTIVE: This study was to assess the efficacy and safety of selective serotonin reuptake inhibitor (SSRI) plus Dengzhanshengmai capsule in patients with chronic fatigue syndrome (CFS).

METHODS: SSRI at a moderate dose plus Dengzhanshengmai (n = 134) with SSRI alone (n = 134) were compared for the efficacy and safety in the treatment of CFS. The therapeutic efficacy and safety were evaluated.

RESULTS: As compared to monotherapy group, the efficacy in combined therapy group was better and characterized by the improvement of general fatigue (0.8±0.6 vs. 1.3±0.7), physical fatigue (0.6±0.3 vs. 1.0±0.4) and reduced activity (1.0±0.5 vs. 1.3±0.6) since the 2nd week (P<0.01) and in reduced motivation (2.1±0.8 vs. 2.4±1.0) since the 8th week (P<0.01) and the improvement continued thereafter. The mental fatigue score and HAD score were comparable between two groups (P>0.05). No significant difference was found in the drop-out rate between SSRI group (15.7%) and SSRI plus Dengzhanshengmai group (18.0%). The reasons for drop out were adverse events (7.5% vs. 9.7%), requests of the patients or career requirement (3.7% vs. 4.5%), loss to follow-up and others (2.2% vs. 3.0%) and lack of efficacy (2.2% vs. 0.7%). Although the patients in combined therapy group experienced a higher rate of hypertension than (5.8% vs. 1.5%), no significant difference was observed (P = 0.08).

CONCLUSION: SSRI combined with Dengzhanshengmai capsule may significantly improve the general fatigue, physical fatigue, reduced activity and reduced motivation of CFS patients as compared to monotherapy with SSRI. Furthermore, this combined therapy is safe and tolerable.

 

Source: Li DQ, Li ZC, Dai ZY. Selective serotonin reuptake inhibitor combined with dengzhanshengmai capsule improves the fatigue symptoms: a 12-week open-label pilot study. Int J Clin Exp Med. 2015 Jul 15;8(7):11811-7. eCollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565405/ (Full article)

 

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing.

At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01108731.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

 

Source: Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, Kang G, Coplan JD, Shungu DC. Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 2015 Nov;16(11):1211-9. doi: 10.1016/j.jpain.2015.08.004. Epub 2015 Aug 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630071/ (Full article)

 

A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To assess the efficacy and safety of duloxetine in patients with chronic fatigue syndrome.

METHODS: A 12-week, randomized, double-blind study was designed to compare duloxetine 60-120 mg/d (n = 30) with placebo (n = 30) for efficacy and safety in the treatment of patients with chronic fatigue syndrome. The primary outcome measure was the Multidimensional Fatigue Inventory general fatigue subscale (range: 4-20, with higher scores indicating greater fatigue). Secondary measures were the remaining Multidimensional Fatigue Inventory subscales, Brief Pain Inventory, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression Scale, Centers for Disease Control and Prevention Symptom Inventory, Patient Global Impression of Improvement, and Clinical Global Impression of Severity. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect.

RESULTS: The improvement in the Multidimensional Fatigue Inventory general fatigue scores for the duloxetine group was not significantly greater than for the placebo group (P = 0.23; estimated difference between groups at week 12 = -1.0 [95% CI: -2.8, 0.7]). The duloxetine group was significantly superior to the placebo group on the Multidimensional Fatigue Inventory mental fatigue score, Brief Pain Inventory average pain severity and interference scores, Short Form-36 bodily pain domain, and Clinical Global Impression of Severity score. Duloxetine was generally well tolerated.

CONCLUSION: The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00375973.

Copyright © 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

 

Source: Arnold LM, Blom TJ, Welge JA, Mariutto E, Heller A. A randomized, placebo-controlled, double-blinded trial of duloxetine in the treatment of general fatigue in patients with chronic fatigue syndrome. Psychosomatics. 2015 May-Jun;56(3):242-53. doi: 10.1016/j.psym.2014.12.003. Epub 2014 Dec 16. https://www.ncbi.nlm.nih.gov/pubmed/25660434

 

A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Oxidative stress plays a major role in the pathogenesis of chronic fatigue syndrome (CFS). Keeping in view the proven antioxidant activity of Triticum aestivum L., this study has been undertaken to explore the potential therapeutic benefit of this plant in the treatment of CFS.

OBJECTIVE: To study the protective effect of the ethanolic extract of the leaves of Triticum aestivum (EETA) in an experimental mice model of CFS.

MATERIALS AND METHODS: Five groups of albino mice (20-25 g) were selected for the study, with five animals in each group. Group A served as the naïve control and Group B served as the stressed control. Groups C and D received EETA (100 mg/kg and 200 mg/kg b.w.). Group E received imipramine (20 mg/kg b.w.). Except for Group A, mice in each group were forced to swim 6 min each for 7 days to induce a state of chronic fatigue. Duration of immobility was measured on every alternate day. After 7 days, various behavioral tests (mirror chamber and elevated plus maize test for anxiety, open field test for locomotor activity) and biochemical estimations (malondialdehyde [MDA] and catalase activity) in mice brain were performed.

RESULTS: Forced swimming in the stressed group resulted in a significant increase in immobility period, decrease in locomotor activity and elevated anxiety level. The brain homogenate showed significantly increased MDA and decreased catalase levels. The extract-treated groups showed significantly (P < 0.05) improved locomotor activity, decreased anxiety level, elevated catalase levels and reduction of MDA.

CONCLUSION: The study confirms the protective effects of EETA in CFS.

 

Source: Borah M, Sarma P, Das S. A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome. Pharmacognosy Res. 2014 Oct;6(4):285-91. Doi: 10.4103/0974-8490.138251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166815/ (Full article)

 

Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study

Abstract:

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep-wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition.

Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50mg u.i.d. with sustained release melatonin 10mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study.

Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.

Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

 

Source: Pardini M, Cordano C, Benassi F, Mattei C, Sassos D, Guida S, Serrati C, Primavera A, Amore M, Cocito L, Emberti Gialloreti L. Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study. Eur Neuropsychopharmacol. 2014 Jun;24(6):939-44. doi: 10.1016/j.euroneuro.2014.02.010. Epub 2014 Feb 25. https://www.ncbi.nlm.nih.gov/pubmed/24636462

 

Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial

Abstract:

AIM: We examined whether activation of serotonergic descending pathways improves pain inhibition during exercise in patients with chronic fatigue syndrome (CFS) and comorbid fibromyalgia (FM) in comparison with rheumatoid arthritis (RA) and sedentary, healthy controls in a double-blind randomized controlled trial with cross-over design.

PATIENTS AND METHODS: Three female CFS/FM patients, one female RA patient and two healthy women were randomly allocated to the experimental group (2 ml of citalopram intravenously) or the placebo group (2 ml of 0.9% NaCl intravenously). Participants performed a submaximal exercise protocol, preceded and followed by an assessment of endogenous pain inhibition. Seven days later, groups were crossed over.

RESULTS: Significant side-effects were observed in all, but one participant immediately after intravenous administration of citalopram. One CFS/FM patient withdrew because of severe post-exertional malaise.

CONCLUSION: It was decided that proceeding with the study would be unethical. No conclusion could be made regarding pain inhibition during exercise in CFS/FM compared to RA and controls.

 

Source: Meeus M, Ickmans K, De Clerck LS, Moorkens G, Hans G, Grosemans S, Nijs J. Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial. In Vivo. 2011 Nov-Dec;25(6):1019-25. https://www.ncbi.nlm.nih.gov/pubmed/22021700

 

Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice

Abstract:

BACKGROUND AND OBJECTIVE: The present study was designed to elucidate the possible nitric oxide (NO) mechanism in the protective effect of antidepressants using mice model of chronic fatigue syndrome (CFS).

MATERIALS AND METHODS: Male albino laca mice were forced to swim for each 6 min session for 7 days and immobility period was measured on every alternate day (1(st), 3(rd), 5(th), 7(th)). After 7 days various behavioral tests (locomotor, mirror chamber, and plus maze tests for anxiety) were performed and biochemical estimations (lipid peroxidation, nitrite levels, GSH (reduced glutathione), and catalase activity) in mice brain were performed. Animals were pretreated with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) daily for 7 days.

RESULTS: The present study showed that continued forced swimming for 7 days caused chronic fatigue-induced anxiety-like behavior as assessed in mirror chamber, plus maze tests, and impairment in locomotor activity followed by oxidative damage (as evidenced by increased lipid peroxidation, nitrite levels, depleted reduced glutathione, and catalase activity) in animals. Seven days pretreatment with citalopram (5 and 10 mg/kg) and imipramine (10 and 20 mg/kg) significantly improved behavioral and biochemical alterations. Further, L-nitro-arginine methyl ester (L-NAME,5 mg/kg) and methylene blue (MB, 10 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) potentiated their protective effect. However, l-arginine (100 mg/kg) pretreatment with citalopram (5 mg/kg) or imipramine (10 mg/kg) reversed their protective effect as compared with their effect per se (P < 0.05).

CONCLUSION: The present study suggests that protective effect of citalopram and imipramine might be due to its NO modulation against chronic fatigue induced behavioral and biochemical alterations.

 

Source: Kumar A, Garg R, Gaur V, Kumar P. Nitric oxide modulation in protective role of antidepressants against chronic fatigue syndrome in mice. Indian J Pharmacol. 2011 May;43(3):324-9. Doi: 10.4103/0253-7613.81506. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113388/ (Full article)

 

Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome

CFS a complex disorder characterized by unexplained severe fatigue for over 6 months with a broad range of additional symptoms involving the nervous, endocrine and immune systems, and an estimated prevalence of 1%1. Tricyclic antidepressants (TCAs) are prescribed off label for a number of painful diseases that are often comorbid, such as chronic fatigue syndrome (CFS), fibromyalgia, interstitial cystitis, and irritable bowel syndrome, the symptoms of which are worsened by stress2. However, there is no known mechanism to explain the apparent beneficial action of TCAs3.

Mast cells and their mediators have been implicated in inflammatory diseases4, including CFS5. Mast cells are located perivascularly in close proximity to neurons in the thalamus and hypothalamus, especially the median eminence6, where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive nerve processes7. CRH activates mast cells to release vascular endothelial growth factor (VEGF)8, which could participate in neurogenic inflammation and contribute to the pathogenesis of CFS. Such mediators may be released locally in the brain or may cross the blood-brain-barrier (BBB), which can be disrupted by stress, subsequent to mast cell activation9. Given the above, we hypothesized that TCAs may be helpful through inhibition of mast cell release of pro-inflammatory mediators.

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/

 

Source: Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. J Clin Psychopharmacol. 2011 Jun;31(3):385-7. doi: 10.1097/JCP.0b013e3182196e50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/ (Full article)

 

Classifying medication use in clinical research

Abstract:

BACKGROUND: Medication use data are usually collected in clinical research. Yet no standardized method for categorizing these exists, either for sample description or for the study of medication use as a variable.

OBJECTIVE: The present investigation was designed to develop a simple, empirically based classification scheme for medication use categorization.

METHOD: The authors used factor analysis to reduce the number of possible medication groupings. This permitted a pattern of medication usage to emerge that appeared to characterize specific clinical constellations. To illustrate the technique’s potential, the authors applied this classification system to samples where sleep disorders are prominent: chronic fatigue syndrome and sleep apnea.

RESULTS: The authors’ classification approach resulted in 5 factors that appear to cohere in a logical fashion. These were labeled Cardiovascular or Metabolic Syndrome Medication, Symptom Relief Medication, Psychotropic Medication, Preventative Medication, and Hormonal Medication.

CONCLUSIONS: The findings show that medication profile varies according to clinical sample. The medication profile for participants with sleep apnea reflects known comorbid conditions; the medication profile associated with chronic fatigue syndrome appears to reflect the common perception of this condition as a psychogenic disorder.

 

Source: Rizzo D, Creti L, Bailes S, Baltzan M, Grad R, Amsel R, Fichten CS, Libman E. Classifying medication use in clinical research. J Prim Care Community Health. 2011 Jan 1;2(1):26-32. doi: 10.1177/2150131910385843. Epub 2010 Oct 27. https://www.ncbi.nlm.nih.gov/pubmed/23804659