The Effect of Serotonin-Norepinephrine Reuptake Inhibitor Milnacipran on Anxiety-like Behaviors in Diabetic Mice

Background: Diabetes mellitus is a chronic disease that causes neuronal plasticity and increased hypothalamic pituitary adrenal (HPA) axis of stress disorders. The change in metabolism is reportedly associated with inadequate response to antianxiety and antidepressant agents. Objective: This study aimed to determine the effect of milnacipran antidepressants on anxiety-like behavior in mice with diabetes mellitus. Methods: Male ICR mice were divided into naive, stress, diabetes mellitus (DM), DM + stress groups to measure anxiety-like behavior. Diabetes mellitus was induced using alloxan, and electric footshock stress was used as a stressor for 14 consecutive days. Anxiety-like behavior was measured using the light-dark box (LDB) and elevated plus maze (EPM) test at days 0, 7 and 14. The antidepressant milnacipran (MIL) was given for 7 days, on days 8 to 14. On day 14, evaluation of anxiety-like behavior after administration of MIL was carried out in all groups using LDB and EPM tests. Results: The results showed that administration of milnacipran effectively ameliorated anxiety-like behavior in the non-DM, but not in the DM group, using the LDB test. A similar result was demonstrated in the EPM test showing the non-DM group's attenuation after milnacipran administration. Conclusion: The present results indicate that there is an inadequate attenuation of the anxiety-like behavior after treatment with milnacipran in diabetes conditions.

Design strategies, chemistry and therapeutic insights of multi-target directed ligands as antidepressant agents

: Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to its multifactorial complexity, single-target drugs did not always produce satisfactory results and lacks the desired level of therapeutic efficacy. Recent literature reports revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents for the design of multi-target ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies were also described. This article will be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.

An audit on prescribing practice and risk of serotonin syndrome among patients with chronic pain

AimsTo determine the incidence of prescribing practice with associated risk of serotonin toxicity among patients with chronic pain conditions.BackgroundSerotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity, usually from drug interactions. Concurrent use of antidepressants is strongly linked to serotonin syndrome, with recent data revealing record numbers of NHS prescribed antidepressants in 2019. Antidepressant medications are also used in chronic pain management for their anti-neuropathic pain properties. However, it is well-recognised that a significant number of chronic pain patients suffer from anxiety and depression. This cohort of patients is therefore vulnerable to being exposed to multiple concurrent antidepressant agents, and thus at relatively higher risk of serotonin syndrome compared to other patient groups. Additionally, these patients are likely to be exposed to the concurrent use of antidepressants and certain analgesic agents particularly phenylpiperidine derivatives which increases serotonin toxicity risk.MethodMedications of patients presenting to a secondary care pain clinic within the last year were looked into. Patients were selected at random by pain management secretaries. Concurrent use of multiple antidepressant agents including Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Noradrenaline Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs) or Tetracyclic Antidepressant (TeCA) was noted. Additionally, concurrent use of any of these antidepressant agents and phenylpiperidine derivatives such as Fentanyl and Tramadol was noted.ResultData on medications of 97 patients were collected. A total of 28 patients (28.8%) were observed to have at-risk medication combinations. Out of these, five patients were on both SSRI and TCA. Two patients were on both TCA and TeCA. Four other patients were on either a combination of SSRI and SNRI, SNRI and TCA, SSRI and TeCA, or TCA and TCA. Three patients were on both Fentanyl patches and an antidepressant. Fourteen patients were on both an antidepressant and Tramadol. None of these patients were diagnosed with serotonin syndrome; however, it is unclear as to whether these patients experienced milder symptoms of the syndrome.ConclusionA considerable number of patients in this group were on medication combinations putting them at risk of serotonin syndrome. Despite no documented patient harm, there is an urgent need for an increased awareness among prescribers on drug interactions which may lead to this syndrome and a subsequent change in prescribing practice.

Synthesis, Molecular Docking, Druglikeness Analysis, and ADMET Prediction of the Chlorinated Ethanoanthracene Derivatives as Possible Antidepressant Agents

Ethanoanthracene cycloadducts (5–7) anti, (5–7) syn, and (5–7) dec have been synthesized from the Diels–Alder (DA) reaction of diene 1,8-dichloroanthracene 2, with the dienophiles; acrylonitrile 3, 1-cynavinyl acetate 4, and phenyl vinyl sulfone 5, individually. The steric effect of dienophile substituents were more favorable toward the anti-isomer formation as deduced from 1H-NMR spectrum. The cheminformatics prediction for (5–7) anti and (5–7) syn was investigated. The in silico anticipated anti-depression activity of the (5–7) anti and (5–7) syn compounds were investigated and compared to maprotiline 9 as reference anti-depressant drug. The study showed that steric interactions play a crucial role in the binding affinity of these compounds to the representative models; 4xnx, 2QJU, and 3GWU. The pharmacokinetic and drug-like properties of (5–7) anti and (5–7) syn exhibited that these compounds could be represented as potential candidates for further development into antidepressant-like agents.