New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move ...beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Here, we integrate this perspective within a broader framework-in other words, a dual pathology model of ( a) stress-related synaptic loss arising from amino acid-based pathology and ( b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy.
It is well known that neuroinflammation is closely related to the pathophysiology of depression. Due to individual differences in clinical research, the reduction of hippocampal volume in patients ...with depression is still controversial. In this experiment, we studied a typical kind of tricyclic antidepressant, clomipramine. We designed a series of experiments to find its role in depressive-like behavior, hippocampal neuroinflammation as well as hippocampal volume changes induced by chronic unpredictable mild stress (CMS). Rats exhibited defective behavior and hippocampal neuroinflammation after 12 weeks of CMS, which included elevated expression of cleaved interleukin-1β (IL-1β) and NLRP3 inflammasome together with the activation of microglia. Rats exposed to CMS showed weakened behavioral defects, reduced expression of IL-18, IL-6, and IL-1β along with reversed activation of microglia after clomipramine treatment. This indicates that the antidepressant effect of clomipramine may be related to the reduced expression of NLRP3 inflammasome and cleaved IL-1β. Moreover, we found an increased hippocampal volume in rats exposed to CMS after clomipramine treatment while CMS failed to affect hippocampal volume. All these results indicate that the NLRP3 inflammasome of microglia in the hippocampus is related to the antidepressant effects of clomipramine and CMS-induced depressive-like behavior in rats.
Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N -methyl-D-aspartate glutamate ...receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research.
Serotonin Syndrome Park, Susie H.; Wackernah, Robin C.; Stimmel, Glen L.
Journal of pharmacy practice,
02/2014, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Background:There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug–drug interaction resulting in serotonin syndrome ...(SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome.
Objectives:There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS.
Methods:Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded.
Results:Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug–drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors.
Conclusions:Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.
Background: Weight gain is a concern among patients taking antidepressants and a frequently cited reason for medication nonadherence. However, few real-world studies have compared long-term ...medication-induced weight change across the most common antidepressant treatments. Methods: We obtained electronic health record data in a cohort of 234,618 U.S. patients aged 20-65 years across eight health systems who were newly prescribed 1 of 6 antidepressant treatments from 2010 to 2019: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), serotonin modulators, bupropion, or mirtazapine. We used inverse probability weighting under a marginal structural model to estimate the average population weight change (kg) at 6, 12, and 24 months had everyone initiated and subsequently adhered to each treatment, adjusting for demographic characteristics and time-varying health and prescription drug information. We estimated the difference in mean weight change under each medication compared to SSRIs. We examined associations overall and stratified by sex. Results: We estimated an average 24-month weight change of 2.38 kg (95% Cl: 1.84, 2.99), 2.01 kg (95% Cl: 0.64, 3.61), and 3.91 kg (95% Cl: 1.03, 6.93) had everyone initiated and adhered to SSRIs, SNRIs, and mirtazapine, respectively. We did not observe weight change for initiation and adherence to TCAs (mean = 0.15 kg, 95% Cl: -1.32, 1.43), serotonin modulators (mean = -0.44 kg, 95% Cl: -2.02, 0.95), or bupropion (mean = -0.52 kg, 95% Cl: -2.09, 0.85). Compared to the mean weight change under SSRIs, we estimated similar weight gain under SNRIs and mirtazapine, but less weight gain under TCAs (mean difference = -2.23 kg, 95% Cl: -3.87, -0.86), serotonin modulators (mean difference = -2.82 kg, 95% Cl: -4.50, -1.34), and bupropion (mean difference = -2.90 kg, 95% Cl: -4.65, -1.49). Patterns were similar for 6- and 12-month weight change and between males and females. Conclusions: Initiation and continued use of SSRIs, SNRIs, and mirtazapine may cause more weight gain over 24 months than TCAs, serotonin modulators, and bupropion. These results may help clinicians make decisions that prevent weight gain and improve medication adherence among patients taking antidepressants.
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