Efficacy In Severe Depression Research Articles

Ketamine for the treatment of major depression: a systematic review and meta-analysis

Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response. In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157). The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High:-0.73,-0.91 to-0.56; Esket-High:-0.48,-0.75 to-0.20; Rac-Low:-0.33,-0.54 to-0.12; Esket-Low:-0.55,-0.87 to-0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (-0.61;-1.02 to-0.20) and Rac-Low (-0.55,-1.09 to-0.00), but not Esket-Low (-0.15,-0.49 to 0.19) or Esket-High (-0.22,-0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (-0.65;-1.23 to-0.07) but not esketamine (-0.33;-0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio=1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6. Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose. None.

Antidepressants Are Effective for Mild Depressions: The Last Word?

Some studies, not uniformly replicated, have showed greater antidepressant efficacy in severe depression than in milder depression, and some major

P.1.h.006 Anti-allodynic effects of agomelatine combined with gabapentin in neuropathic rats with infraorbital nerve constriction

Agomelatine is a new antidepressant with an innovative pharmacological profile. It is a potent melatonergic agonist (MT1 and MT2) and also has 5-HT2c antagonist properties. Agometatine's efficacy in treating major depressive disorder (MDD) was first described in a placebo-controlled, dose-ranging study with paroxetine as a validator. In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03). Robust evidence of agomelatine's efficacy in severe depression comes from analysis of a patient subgroup with baseline HAM-D scores >25. Analysis of pooled data from three different trials confirmed this observation and suggested that the agomelatine-placebo difference tends to increase with the severity of depression. Results suggest favorable tolerabitity of agomelatine compared with a serotonin and noradrenaline reuptake inhibitor, and agomelatine is associated with less sexual side effects that are troublesome with some antidepressants. As predicted from its pharmacological profile, agomelatine improves sleep quality without associated daytime drowsiness. Agomelatine was also shown not to induce a discontinuation syndrome. Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.

Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist

Summary Agomelatine is a new antidepressant with an innovative pharmacological profile. It is a potent melatonergic agonist (MT 1 and MT 2 ) and also has 5-HT 2c antagonist properties. Agometatine's efficacy in treating major depressive disorder (MDD) was first described in a placebo-controlled, dose-ranging study with paroxetine as a validator. In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) ( P = 0.026) and the Clinical Global Impression Severity ( P = 0.017), with an improved response rate ( P = 0.03). Robust evidence of agomelatine's efficacy in severe depression comes from analysis of a patient subgroup with baseline HAM-D scores >25. Analysis of pooled data from three different trials confirmed this observation and suggested that the agomelatine-placebo difference tends to increase with the severity of depression. Results suggest favorable tolerabitity of agomelatine compared with a serotonin and noradrenaline reuptake inhibitor, and agomelatine is associated with less sexual side effects that are troublesome with some antidepressants. As predicted from its pharmacological profile, agomelatine improves sleep quality without associated daytime drowsiness. Agomelatine was also shown not to induce a discontinuation syndrome. Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.

Why do we need new and better antidepressants?

The range of available antidepressants is reviewed in relation to mechanisms of action and the evidence of efficacy in general and efficacy in severe depression in particular. In studies investigating efficacy in major depressive disorder, not all antidepressants have been shown to have clear-cut efficacy in severe depression. Here, the minimum standards for the necessary methodology to investigate efficacy in severe depression are reviewed and the methods that are needed to establish efficacy as a superior antidepressant or as an antidepressant with a faster than expected response are suggested. A review of the mechanisms of action of different antidepressants is accompanied by a critical review of the properties of an antidepressant likely to achieve either efficacy in severe depression or the status of a superior antidepressant.

C.09.01 Pharmacology of a new antidepressant: benefit of the implication of the melatonergic system

Agomelatine is a new antidepressant with an innovative pharmacological profile. It is a potent melatonergic agonist (MT1 and MT2) and also has 5-HT2c antagonist properties. Agometatine's efficacy in treating major depressive disorder (MDD) was first described in a placebo-controlled, dose-ranging study with paroxetine as a validator. In a recent placebo-controlled study, 212 MDD patients were randomly assigned double-blind to receive placebo or agomelatine 25 and 50 mg/day. There was a significant advantage for agomelatine after 6 weeks according to scores on the Hamilton Depression Rating Scale (HAM-D) (P = 0.026) and the Clinical Global Impression Severity (P = 0.017), with an improved response rate (P = 0.03). Robust evidence of agomelatine's efficacy in severe depression comes from analysis of a patient subgroup with baseline HAM-D scores >25. Analysis of pooled data from three different trials confirmed this observation and suggested that the agomelatine-placebo difference tends to increase with the severity of depression. Results suggest favorable tolerabitity of agomelatine compared with a serotonin and noradrenaline reuptake inhibitor, and agomelatine is associated with less sexual side effects that are troublesome with some antidepressants. As predicted from its pharmacological profile, agomelatine improves sleep quality without associated daytime drowsiness. Agomelatine was also shown not to induce a discontinuation syndrome. Agomelatine may fill the gap in the current therapeutic armamentarium by combining efficacy with a favorable tolerability profile and additional clinical benefits.

Ethyl-eicosapentaenoate and dexamethasone resistance in therapy-refractory depression

Preliminary evidence shows that ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used as an adjunct in therapy-refractory depression. EPA belongs to the class of polyunsaturated omega-3 fatty acids. The mechanism of its action in depression is not fully understood. There are two related fields where the pathophysiology of refractory depression meets the effect of EPA. First, a general immunosuppressive effect of EPA meets a general immunoactivation in severe depression, especially an increase in CD4/CD8 ratio, neutrophilia, and an increase in interleukins (IL)-6 and IL-12 and of prostaglandin E2 (PGE2). Secondly, a resistance to dexamethasone (Dex) suppression of the HPA axis meets the effects of EPA on multidrug resistance reversing and HPA axis suppression. The effects of EPA on the immune system, the HPA axis, and multidrug resistance are connected through the action of a transport protein called p-glycoprotein (p-gp). Physiological and synthetic steroids such as cortisol and Dex are substrates of p-gp, and so Dex resistance in depression may be related to dysfunction of this protein. In addition, expression of p-gp is induced by PGE2, and EPA inhibits the synthesis of PGE2. The reversal of drug resistance by EPA may be mediated via this immunological mechanism and lead to its antidepressive efficacy. In addition, antidepressants such as amitriptyline, which have special efficacy in severe depression, decrease p-gp function. EPA may, furthermore, enhance the action of antidepressants, like many SSRIs that are p-gp substrates, which are actively transported out of the intracerebral space at the level of the blood-brain barrier.

Magnetic Seizure Therapy Improves Mood in Refractory Major Depression

This report describes the successful treatment of a patient suffering from an episode of drug-resistant major depression using magnetic seizure therapy (MST). The patient suffered from recurrent major depression since adolescence. MST is a novel brain stimulation method using transcranial magnetic stimulation at convulsive parameters in order to induce therapeutic seizures under general anesthesia in the same setting used for electroconvulsive therapy (ECT). The first use of therapeutic magnetic seizure induction in a psychiatric patient took place at the University Hospital in Bern, Switzerland, in May 2000. Results of a recent randomized, within-subject, double-masked trial comparing ECT and MST in 10 patients indicate that MST appears to have less subjective and objective side effects, is associated with faster recovery of orientation, and is superior to ECT on measures of attention, retrograde amnesia, and category fluency. ECT has an unparalleled and well-documented efficacy in severe depression but is associated with cognitive side effects. MST is currently under study in several centers with respect to its antidepressant efficacy. We report here on the treatment of a patient with refractory major depression (DSM IV-R), who underwent a series of 12 sessions of MST in an inpatient setting. Baseline Hamilton Depression Rating Scale (HRSD-21) of 33 and Beck Depression Inventory (BDI) of 40 decreased to 6 and 11 respectively, 1 week after completion of the MST trial. Measures of cognitive functions support the hypothesis that MST is associated with a less severe profile of cognitive side effects. [(99m)Tc]-HMPAO SPECT studies (baseline and 4 days after the completion of the MST trial) point to a raise of blood flow at baseline in the left fronto-parietal region and the brainstem. Our preliminary data support the prospect of antidepressant efficacy of MST and point to a benign cognitive side-effect profile in a patient suffering from severe treatment-resistant major depression.

Predicting response: serotonin reuptake inhibition.

The introduction of selective serotonin reuptake inhibitors (SSRIs) has helped clarify our understanding of the actions of serotonin in depression. The serotonergic network of the central and peripheral nervous systems comprises many different pathways and at least 14 distinct serotonin receptors. By using our knowledge of neuroanatomy and the pharmacology of SSRIs, it is possible to predict many of the therapeutic and non-therapeutic effects of modulating serotonin levels. The efficacy of SSRIs in mild to moderate depression is well established but their efficacy in severe depression varies, compared with tricyclic antidepressants. The SSRIs also have predictable effects in a range of other affective disorders including obsessive-compulsive disorder, anxiety and bulimia, the efficacy varying between the different SSRIs. The adverse event profile is different from that of the tricyclic antidepressants and again is predictable through an understanding of the different serotonergic pathways.

Selective serotonin reuptake inhibitors have broadened the utilisation of antidepressant treatment in accordance with recommendations: Findings from a Swedish prescription database

Background: With the advent of the selective serotonin reuptake inhibitors (SSRIs), the use of antidepressants has increased drastically in Sweden. The use of tricyclic antidepressants (TCAs) has, however, decreased. Methods: We surveyed a prescription database in the Swedish county of Jämtland and compared prescription patterns for patients prescribed SSRIs with those prescribed TCAs. Results: The incidence of treatments of antidepressants increased from 0.76% to 1.33% during the period 1991–1996. There were no significant differences between SSRIs and TCAs with regard to patients having only one prescription dispensed within three months from the index prescription, or patients who switched class of antidepressant. Only a minority of the treatments were continued for at least six months, but significantly more SSRI than TCA treatments (42% and 27%). A second treatment period suggesting recurrence was three-times more common in the TCA group than in the SSRI group. Conclusion: Provided that the increased use of SSRIs is mainly for depression, these drugs appear, despite a lower efficacy in severe depression, to have enabled a broader utilisation of antidepressants with regard to incidence, dosage and duration, in accordance with recommendations. Further analyses of this phenomenon relative to diagnostic criteria and outcome measures are required.

Is severe depression a separate indication?

There is not an accepted definition of severe depression, but using cut-off scores on rating scales severe depression is considered to lie at one extreme of a continuum of severity. The evidence from epidemiological, biological, and clinical efficacy studies does not support severe depression as a separate illness category. A good response to antidepressants is seen in both moderate and severe depression. The available evidence supports the view that in most cases an effective antidepressant in moderate depression is likely to have efficacy in severe depression. Few studies have found differences between antidepressants in their efficacy in treating severe depression. Most evidence of differential efficacy derives from studies of clomipramine, which is perceived as a particularly potent antidepressant by many clinicians. Other tricyclic antidepressants do not appear to have an advantage in severe depression. Separate studies to demonstrate efficacy in severe depression are not necessary for the registration of a new antidepressant. However if efficacy in severe depression is demonstrated in separate studies this information could be included in the summary of product characteristics to provide guidance to clinicians.

Safety and antidepressant efficacy of selective serotonin re‐uptake inhibitors

AbstractThis review deals with the safety and antidepressant efficacy of selective serotonin re‐uptake inhibitors (SSRIs). At present, five SSRIs are used therapeutically in European countries (fluvoxamine, fluoxetine, paroxetine, sertraline and citalopram). The antidepressant efficacy of these drugs has been tested both versus placebo and versus reference antidepressants (amitriptyline, imipramine) revealing comparable antidepressant efficacy to the active compounds and a significant superiority compared with placebo. Furthermore, the available studies provide initial evidence that SSRIs have good antidepressant efficacy in severe depression and suggest that they might lead to a faster decline of suicidal tendencies within major depression. Since they have a favourable side‐effects profile in sum, compared with tri‐ and tetracyclic antidepressants, they can be recommended from the aspect of a ‘side‐effects‐derived indication’.