Onset Of Antidepressant Action Research Articles

Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions.

Numerous new agents with rapid onset antidepressant effects are entering clinical trials and clinical practice. Studies focus on either first-line treatment of major depressive disorder or on patients whose major depressive disorder is resistant to prior antidepressant drugs. Novel agents target three very different central nervous system sites: as antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors, as positive allosteric modulators (PAMs) of gamma amino butyric acid (GABA) A neurosteroid and benzodiazepine receptor sites, and as psychedelic agonists of serotonin 2A/2C receptors. Onset of antidepressant action is rapid, sometimes after only one dose whereas traditional agents for depression take several days to weeks to have an antidepressant effect. Although the direct molecular targets of these three classes of agents with rapid antidepressant onset are quite diverse and not clearly related to each other, analysis of the downstream effects of all these agents show that all are "plastogens," namely agents that trigger rapid onset of neuroplasticity that correlates with their rapid onset of antidepressant clinical action. The GABA A PAMs and some of the NMDA antagonists induce neuroplasticity without notable changes in mental status and can be designated "neuroplastogens." Some NMDA antagonists cause mental dissociation, and the psychedelics cause psychotomimetic/hallucinatory experiences and can be designated "psychoplastogens." A great debate exists whether psychoplastogens are effective because of their ability to acutely alter mental state, or whether these acute mental states are unwanted behavioral toxicity. The promise of numerous novel agents with rapid acting antidepressant action and neuroplasticity is set to transform the treatment of major depressive disorder.

Clinical stability after compassionate use of intranasal esketamine in treatment-resistant depression

IntroductionThe compassionate use of intranasal esketamine is approved in Spain for treatment-resistant depression (TRD).ObjectivesThe objective of the study is to assess the clinical stability in the medium-term follow-up of patients with TRD after esketamine use.MethodsDescriptive, retrospective and multicenter study carried out in Spain. Patients with TRD who had received esketamine treatment, and for whom there were clinical data of subsequent evolution, were included. The scores on the MADRS and Hamilton scales were changed into scores on the CGI scale according to the studies by Leucht et al. The Student’s t test was performed to assess differences in the CGI.ResultsEleven patients were included: 72.7% were women and the mean age was 56 (SD: 12.9). The maximum dose of esketamine used was 84mg in 63.7%. The onset of antidepressant action was observed from the 1st dose in 72.6% of the patients. The mean time in treatment was 6.6 months (SD: 2.3) and 90.9% reached remission criteria. After 7.4 months (SD: 3.0) from the end of the treatment, 90.9% remained in remission and without visits to the emergency room or hospitalization for psychiatric reasons. The mean baseline score on the CGI-SI was 5.7 points, at the end of the treatment was 1.2 points and after longitudinal follow-up it was 1. Statistically significant differences were observed (p<0.001) both at the end of the treatment and in the post-esketamine follow-up compared with baseline score.ConclusionsIn our sample, the use of esketamine in TRD shows clinical stability in the medium-term follow-up.DisclosureDaniel Hernández has participated in medical meetings and/or received payment for presentations from Otsuka, Lundbeck, Janssen, Angelini, Casen Recordati, and Ferrer.

Early Prediction of Fluoxetine Response for Han Chinese Inpatients With Major Depressive Disorder

The onset of antidepressant action is vital clinically. This study aimed to testify whether early symptom improvement can predict eventual treatment response at week 6 among depressive hospitalized patients taking fluoxetine. One hundred thirty-one hospitalized patients with major depressive disorder received 20 mg/d of fluoxetine for 6 weeks. Symptom severity was assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17) at weeks 0, 1, 2, 3, 4, and 6. Stable response was defined as a reduction of 50% or more in the HAMD-17 total score at weeks 4 and 6 of treatment. Receiver operating characteristic curve was used to determine the cutoff point of the percentage of HAMD-17 score reduction between stable responders and nonresponders at weeks 1, 2, 3, and 4. At weeks 1, 2, 3, and 4, HAMD-17 score reductions of 25%, 39%, 43%, and 50% seemed to be the optimal cutoff points for predicting eventual response. They provided a sensitivity of 78%, 86%, 91%, and 93% and a specificity of 61%, 74%, 76%, and 92%. The percentage of HAMD-17 reduction at week 4 excellently predicted final response at week 6. Patients with less than a 50% symptom reduction during the first 4 weeks of treatment are unlikely to reach a final stable response. Whether this model can be applied to establish a prediction system for other antidepressants or for outpatients warrants further research.

Quetiapine XR efficacy and tolerability as monotherapy and as adjunctive treatment to conventional antidepressants in the acute and maintenance treatment of major depressive disorder: a review of registration trials

Results from pivotal registration trials in major depressive disorder cohere with outcomes from effectiveness studies indicating that the majority of individuals receiving single-agent pharmacotherapy fail to achieve and sustain symptomatic remission. Several factors provided the impetus for this review: suboptimal efficacy with existing pharmacotherapy for major depressive disorder, quetiapine XR efficacy in the acute and maintenance treatment of bipolar depression, emerging pharmacodynamic evidence that quetiapine XR (and/or its metabolites) uniquely engages monoaminergic systems salient to symptom relief in depressive syndromes, the increasing use of second-generation antipsychotics in the treatment of major depressive disorder and the recent FDA review of quetiapine XR in major depressive disorder. Studies reviewed herein are pivotal registration trials that evaluated the acute and maintenance efficacy and tolerability of quetiapine XR (as monotherapy and as adjunctive treatment) in major depressive disorder. In addition, we also review recent investigations characterizing the pharmacodynamic effect of quetiapine's principal active metabolite, norquetiapine. All studies were obtained from AstraZeneca (Wilmington, DE, USA) and have been presented at national/international scientific meetings. Taken together, extant studies demonstrated that quetiapine XR (50 – 300 mg) provides rapid and sustained symptomatic improvement in the acute and maintenance treatment of major depressive disorder. Quetiapine XR may also offer advantages relative to duloxetine in time to onset of antidepressant action. The major limitations of quetiapine XR use in major depressive disorder relate to weight gain and disrupted glucose/lipid homeostasis as well as sedation/somnolence. Quetiapine XR has tolerability advantages compared with duloxetine on measures of sexual dysfunction. The data from the studies reviewed herein also indicate that quetiapine XR poses a low risk for extrapyramidal side effects in middle-aged and elderly individuals with major depressive disorder.

The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder

Objective: Debate continues regarding whether onset of analgesia is faster than antidepressant effect in antidepressants with both properties. Duloxetine hydrochloride (from here on referred to as duloxetine) is effective in both major depressive disorder and diabetic peripheral neuropathic pain. This post-hoc analysis of six placebo-controlled duloxetine trials in patients with major depressive disorder was designed to compare onset of antidepressant activity to pain relief.Research design and methods: Duloxetine was administered at 40–120 mg/day versus placebo for up to 9 weeks in outpatient clinic settings. The primary depression measure was the HAMD17 and pain severity was measured using visual analog scale (VAS) measuring overall pain, headache, back and shoulder pain, and pain while awake. The time course of improvement was profiled using repeated measures modeling and Kaplan–Meier product limit estimation.Results: In all but one case, significant reductions in HAMD17 and VAS scores were seen within 2 weeks of treatment. Median time to VAS response was consistently shorter across all VAS measures than that to HAMD17 response in both placebo- and duloxetine-treated patients with at least modest levels of pain at study entry. Regression analyses consistently demonstrated little association between analgesic and antidepressant responses. Limitations of these findings include that the studies used in these analyses did not require the patients to enroll with any specific level of pain. Moreover, the type of pain exhibiting at presentation was not routinely identified; therefore, the impact of different pain types on these findings is unknown.Conclusions: Duloxetine's analgesic effect is independent of the drug's antidepressant effect. Additionally, faster onset of the analgesic effect appears to be a population-specific phenomenon that is unmodified in the presence of active agents.

Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder

ABSTRACTBackground: Duloxetine and escitalopram were compared in an 8-month, randomized, double-blind, placebo-controlled trial in adult outpatients meeting DSM‑IV criteria for major depressive disorder (MDD). The results regarding the primary objective of the study (onset of antidepressant action) have been previously published. The current paper focuses on the longer-term (8-month) comparisons of efficacy and safety between duloxetine and escitalopram.Research design and methods: Upon completion of the 8-week, fixed-dose, placebo-controlled, acute-treatment phase (duloxetine 60 mg/day (n = 273), escitalopram 10 mg/day (n = 274), placebo (n = 137)), patients remaining in the duloxetine (n = 188) and escitalopram (n = 208) groups were eligible for double-blind dose increases (duloxetine to 120 mg/day, escitalopram to 20 mg/day), and placebo non-responders were eligible for double-blind rescue to active drug.Main outcome measures: Efficacy was primarily assessed using the HAMD17. Safety/tolerability assess­ments included spontaneously reported adverse events (AEs), overall rates and reasons for discontinuation, laboratory analyses, and vital signs.Results: Both drugs demonstrated similar remission rates over the course of the study, with the probability of remission reaching 70% (duloxetine) and 75% (escitalo­pram) at 8 months ( p = 0.44). Similar improvement was observed for both duloxetine and escitalopram on efficacy measures with the exception of the sleep subscale of the HAMD17, wherein escitalopram had a statistically signif­icant advantage over duloxetine in improving sleep. Over the entire 8-month study, discontinuation rates differed significantly for duloxetine (62%) compared with escitalo­pram (55%; p = 0.02). Rates of discontinuation due to AEs did not differ significantly between duloxetine (12.8%), escitalopram (12.0%), and placebo (10.2%) ( p > 0.05 all pairwise comparisons). AEs associated with duloxetine tended to emerge early in treatment (e.g., nausea, dry mouth), whereas AEs associated with escitalopram tended to emerge later in treatment (e.g., diarrhea, weight increase). The incidence of sustained hypertension was similar between drugs (1.5 vs. 1.1% patients for dulox­etine and escitalopram, respectively). Statistically signif­icant drug differences were identified in the mean changes from baseline to study endpoint for pulse (+3.05 beats per minute (bpm), duloxetine; –0.89 bpm, escitalopram; p < 0.001) and systolic blood pressure (+3.73 mmHg, duloxetine; +0.31 mmHg, escitalopram; p < 0.05), but not diastolic blood pressure (+0.81 mmHg, duloxetine; –0.24 mmHg, escitalopram; p = 0.27). At 8 months, mean change in weight was significantly higher for escitalopram compared with duloxetine (+0.61 kg, duloxetine; +1.83 kg, escitalopram; p < 0.05), however, the incidence of treatment-emergent abnormal weight gain (≥ 7% increase in weight from baseline) was similar between drugs and was significantly greater for both duloxetine and escitalopram compared with placebo.Limitations: Because so few patients on placebo (n = 15), in comparison to duloxetine (n = 104) or escitalopram (n = 123), completed the entire 8-month study, the power to detect a difference between the active treatments and placebo after 8 weeks was significantly decreased and very likely insufficient.Conclusion: Throughout the 8-month study, similar improvement was observed for both duloxetine and escitalopram on most efficacy measures with the exception of the sleep subscale of the HAMD17. Drug differences were identified in safety/tolerability measures.

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study

ABSTRACTObjective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment1. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor).Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM‑IV criteria for Major Depressive Disorder (MDD) received duloxetine 60 mg once daily (QD; N = 273), escitalopram 10 mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group.Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17‑item Hamilton Rating Scale for Depression (HAMD17) Maier subscale that was maintained or exceeded at all subsequent visits.Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo ( p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups.Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo.Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8‑week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10 mg QD was better tolerated than duloxetine at a starting dose of 60 mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram.Trial registration: ClinicalTrials.gov identifier: NCT00073411.

Mirtazapine monotherapy versus combination therapy with mirtazapine and aripiprazole in depressed patients without psychotic features: A 4-week open-label parallel-group study

Background: There is preliminary evidence that the atypical antipsychotic aripiprazole, which is a partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptors, may be useful as an augmentation strategy in treatment-resistant depression.Method: In this 4-week open-label non-randomized parallel-group study, the safety and efficacy of aripiprazole as add-on treatment strategy in patients suffering from non-delusional depression was investigated. Forty drug-free depressed inpatients without psychotic symptoms (13 men, 27 women), suffering from a major depressive episode or bipolar disorder, depressive state (DSM-IV criteria), were included in the study. The patients were treated either with mirtazapine monotherapy (45 mg/day) or combination therapy (mirtazapine 45 mg/day plus aripiprazole 15 mg/day) for 4 weeks. Safety and efficacy were assessed weekly using the Hamilton Depression Rating Scale, the Simpson–Angus Scale and the Barnes Akathisia Scale.Results: Mirtazapine monotherapy and combined treatment with mirtazapine and aripiprazole showed comparable antidepressant effects as assessed at the endpoint of the study period. However, additional administration of aripiprazole accelerated the onset of antidepressant action in patients suffering from treatment-resistant depression. Additive use of aripiprazole reduced the mirtazapine-induced increase in the body mass index. Moreover, mirtazapine had favourable effects on aripiprazole-induced akathisia. No other extrapyramidal side effects were seen in the combination therapy group.Conclusion: Combined therapy with mirtazapine and aripiprazole is a safe and well-tolerated treatment option which may be useful especially in treatment-resistant depression. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole in depressed patients.

Spotlight on Escitalopram in the Management of Major Depressive Disorder1

Escitalopram (Cipralex), Lexapro), the active S-enantiomer of the racemic SSRI citalopram (RS-citalopram), is a highly selective inhibitor of the serotonin transporter protein. It possesses a rapid onset of antidepressant activity, and is an effective and generally well tolerated treatment for moderate-to-severe major depressive disorder (MDD). Pooled analyses from an extensive clinical trial database suggest that escitalopram is consistently more effective than citalopram in moderate-to-severe MDD. Preliminary studies suggest that escitalopram is as effective as other SSRIs and the extended-release (XR) formulation of the serotonin/noradrenaline (norepinephrine) reuptake inhibitor venlafaxine, and may have cost-effectiveness and cost-utility advantages. However, additional longer-term, comparative studies evaluating specific efficacy, tolerability, health-related quality of life and economic indices would be helpful in definitively positioning escitalopram relative to these other agents in the treatment of MDD. Nevertheless, available clinical and pharmacoeconomic data indicate that escitalopram is an effective first-line option in the management of patients with MDD.

Onset of antidepressant action: a pharmacological question?

This study was conducted to analyse the onset of action of antidepressants in naturalistic conditions. Multicenter, prospective, open-label, non-comparative naturalistic study among 582 depressed outpatients treated with mirtazapine. The patients were assessed at screening, and after 1, 2 and 4 weeks by the 17-item Hamilton depression rating scale (17-HAM-D) and clinical global impression (CGI). Onset of action was measured by traditional analyses based on the time to a persistent reduction of more than 50% from baseline on the 17-HAM-D. Patients were grouped into four groups: very fast responders, fast responders, traditional responders and partial or non-responders. The non-parametric Kruskall-Wallis test was used to assess differences between the groups and logistic regression to predict response after 1 week of treatment. 16% of patients had a very fast response, 42.1% a fast response, 26.5% a traditional response and 15.5% a partial or non-response. There were no significant differences between these groups with regard to dose of mirtazapine or sociodemographic characteristics. The baseline total 17-HAM-D was lower in the faster groups than in the slower groups. The evolution of 17-HAM-D items was similar in each responder group. Time to response varied from early faster response to late slower response. The evolution of 17-HAM-D for each type of response was similar, but occurred at a different time in each group.

P.1.032 Mirtazapine vs SSRls: A meta-analysis on onset of antidepressant activity in more than 2500 patients with major depression

P.1.032 Mirtazapine vs SSRls: A meta-analysis on onset of antidepressant activity in more than 2500 patients with major depression

Partial 5-HT1A receptor agonist properties of (-)pindolol in combination with citalopram on serotonergic dorsal raphe cell firing in vivo.

Pindolol has been reported to shorten the onset of antidepressant action of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) as well as to increase their efficacy. It has been postulated that pindolol enhances the antidepressant effect of SSRIs by blocking somatodendritic 5-HT1A autoreceptors, thus antagonizing the SSRI-induced feedback inhibition of midbrain 5-HT cell firing. A recent study, however, found that pindolol suppresses the firing rate of central 5-HT cells, suggesting that the compound possesses agonistic activity at 5-HT1A autoreceptors. The purpose of the present study was to investigate if acute administration of (-)pindolol antagonizes the decrease in firing rate of dorsal raphe 5-HT cells produced by acute treatment with the SSRI citalopram. Extracellular recordings of single 5-HT neurons in the dorsal raphe nucleus in anaesthetized rats. Administration of 0.25 or 3.0 mg/kg (IV) (-)pindolol alone decreased the firing rate of a majority of the 5-HT cells studied, an effect that was reversed by the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, IV). Neither 0.25 nor 3.0 mg/kg (-)pindolol reversed the citalopram (0.1-0.2 mg/kg. IV)-induced suppression of 5-HT cell activity, but produced a further decrease in firing rate. In contrast, WAY100635 (0.1 mg/kg) completely reversed this effect of citalopram. Yet, pretreatment with 3.0, but not 0.25 mg/kg (-)pindolol significantly attenuated the acute inhibitory effect of citalopram on serotonergic cell firing. The present findings support the previous notion that (-)pindolol possesses prominent agonistic activity at somatodendritic 5-HT1A autoreceptors, but also indicate that it may possess a weak antagonistic action at these receptors.

Psychopharmacology of 5-HT 1A receptors

Serotonin 1A (5-HT 1A) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT 1A receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT 1A receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT 1A receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT 1A receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT 1A receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT 1A autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT 1A receptor antagonists.

The selective noradrenaline re-uptake inhibitor reboxetine has an early onset of antidepressant action

INTRODUCTION: Most antidepressants take several weeks to demonstrate a therapeutic effect. We examined the time to onset of action of reboxetine, a unique selective noradrenaline re-uptake inhibitor (selective NRI). METHODS: In a multinational, multicentre, double-blind, parallel-group study, 56 inpatients with major depression were randomized to receive placebo or reboxetine titrated to 10 mg/day for 6 weeks. Efficacy was principally assessed by the Hamilton Depression Rating Scale. RESULTS: Reboxetine was associated with a significantly greater reduction in mean HAM-D total score from baseline to last assessment when compared with placebo. The effect of reboxetine separated from placebo at day 10 (P=0.006), indicated an early onset. In accordance with this observation, individual HAM-D item scores early showed significant improvements among patients treated with reboxetine when compared with those who received placebo: mood improved by day 10 (P=0.004), insomnia and interest in work and daily activities by day 14 (P=0.006 and 0.003, respectively) and somatic symptoms and anxiety by day 21 (P<0.001 in both cases). CONCLUSION: Reboxetine is an effective antidepressant with an early onset of action. Depressed mood is relieved first, followed by an improvement in interest in daily activities.

Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo

Venlafaxine is a dual serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake inhibitor which has been claimed to have an onset of antidepressant action which is faster than for other comparable drugs. The effects of venlafaxine on brain 5-HT levels in vivo have not yet been examined. Acute administration of venlafaxine to rats by i.p. injection resulted in dose-dependent increases in cortical and hippocampal 5-HT levels, as measured by in vivo microdialysis, over the range 5–20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.) for 4 weeks did not change basal 5-HT levels in either brain area. The effect of 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg s.c.) to reduce 5-HT levels was unaffected by chronic venlafaxine at this dose, indicating that there was no change in sensitivity of presynaptic 5-HT 1A autoreceptors.

Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain

5-HT1A receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5-HT1A receptor agonism. Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT2A receptors. This reduction in the effect of locally-applied DOI was no longer present following 7-day flibanserin administration. Two-day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administration, 5-HT neuronal firing activity had returned to normal and the somatodendritic 5-HT1A autoreceptors were desensitized. The responsiveness of postsynaptic 5-HT1A receptors located on CA3 hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically-applied 5-HT and gepirone, was unchanged following a 7-day flibanserin treatment. As demonstrated by the ability of the 5-HT1A receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2- and 7-day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5-HT1A receptors in this brain region. The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action.

Early onset of antidepressant activity of venlafaxine compared with placebo and fluoxetine in outpatients in a double-blind study

Early onset of antidepressant activity of venlafaxine compared with placebo and fluoxetine in outpatients in a double-blind study

Responsiveness of observer rating scales by analysis of number of days until improvement in patients with major depression

Several well-known observer scales, including the Hamilton Depression Scale (HAM-D), Montgomery-Asberg Scale (MADRS), Major Depression Rating Scale (MDS), Melancholia Scale (MES), and Inventory for Depressive Symptomatology (IDS) used for measuring severity of depressive states have been compared by their responsiveness in an open trial including patients treated with a combination of citalopram and mianserin. The patients fulfilled the Diagnostic and Statistical Manual (DSM)-IV criteria for major depressive episode, and all scored 18 or more on the HAM-D before treatment. Onset of antidepressant action was defined as an improvement of rating scale scores of 25% or more of pre-treatment scores. A response to treatment was defined as a reduction of 50% or more on the pre-treatment scores. The results showed that the number of treatment days until improvement was 11 to 13 with no difference between the scales. The days until response were between 18 and 21 with no difference between the scales. In conclusion, the depression scales were found to be equal in their ability to detect changes in depressive symptoms during treatment. The mean of days to response was 19 for the combination of citalopram and mianserin. This is similar to the response for the combination of fluoxetine and pinolol.

A review of the efficacy and tolerability of venlafaxine

Venlafaxine is a selective serotonin norepinephrine reuptake inhibitor with no activity at muscarinic, histaminergic or adrenergic receptors. The antidepressant activity of venlafaxine has been demonstrated in placebo-controlled and active comparator-controlled clinical trials. Venlafaxine was effective in outpatients and hospitalized patients with major depression and in those with melancholia, agitated or retarded symptoms, and refractory or treatment-resistant depression. Venlafaxine was at least as effective as comparative antidepressants and was more effective than fluoxetine or imipramine in some trials. A positive dose-response relationship has been shown with venlafaxine. When doses of venlafaxine are titrated rapidly upward, an onset of antidepressant action has been detected within one week in some studies. Venlafaxine is well tolerated during short- and long-term treatment. The most common adverse effects are nausea, somnolence and dry mouth. The overall tolerability of venlafaxine appears to exceed that of tricyclic antidepressants and compares favorably with that of selective serotonin reuptake inhibitors. Venlafaxine is a novel antidepressant that is appropriate for first-line therapy in patients with major depression.

Pharmacotherapeutic profile of venlafaxine

When selecting an antidepressant, a number of factors must be considered. These considerations are summarized under the mnemonic STEPS: Safety, Tolerability, Efficacy, Payment (eg, cost-effectiveness), and Simplicity of use. Venlafaxine is the first of a new class of antidepressants that selectively blocks the serotonin and noradrenaline uptake pumps without blocking muscarinic, histaminergic and adrenergic receptors or inhibiting sodium fast channels. Because venlafaxine avoids these mechanisms of action, it has a wide therapeutic index, an improved tolerability profile and a reduced risk of causing pharmacodynamically mediated drug-drug interactions when compared to tricyclic antidepressants (TCAs). In contrast to some other new antidepressants, venlafaxine also avoids effects on cytochrome P450 which are likely to cause clinically meaningful, pharmacokinetically mediated drug-drug interactions. The effects on the uptake pumps of both serotonin and noradrenaline appear to be responsible for some of venlafaxine's unique features in terms of antidepressant efficacy, including its ascending antidepressant dose-response curve and its apparent rapid onset of antidepressant action at the upper end of its clinically relevant dosing range. Venlafaxine is effective in a broad spectrum of patients, including outpatients and inpatients, those with and without melancholia, patients with symptoms of anxiety or agitation or retardation and patients with first time or recurrent episodes of major depression. An important factor when selecting an antidepressant is the simplicity of the dosing regimen and the ability to rapidly and confidently achieve the optimal dose for the patient. In this regard, venlafaxine can be initiated at a clinically effective dose from the beginning. If the patient fails to respond to this dose, there is evidence that increased antidepressant efficacy can be achieved by increasing the dose rather than having to resort to an augmentation strategy or switch to another class of antidepressants. In the immediate release form, venlafaxine has proven antidepressant efficacy when using a twice-or three-times-a-day schedule. A sustained release formulation is expected to be marketed soon and will permit once-a-day-dosing.