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Sedating or activating antidepressants for anxiety

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It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors SSRIsprovide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs.

Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor.

All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram.

Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from Sedating or activating antidepressants for anxiety SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter. Major depressive disorder MDD is among the most prevalent disabling diseases, affecting millions of people around the world.

Pharmacotherapy for depression Sedating or activating antidepressants for anxiety evolved over the past 30 years. Initially, the main Sedating or activating antidepressants for anxiety were the tricyclic antidepressants and the monoamine oxidases. Paroxetine and Sedating or activating antidepressants for anxiety were among the first SSRIs to be approved for clinical use and have been available since the beginning of the s Grimsley and Jann, ; Johnson, In general, newer antidepressants are better tolerated than the tricyclic antidepressants and monoamine oxidases owing in part to the reduced side effect burden Gillman, Numerous direct comparisons in randomized double-blind, controlled clinical studies, pooled analyses, meta-analyses, and reviews have been published comparing the clinical efficacy and tolerability of antidepressants.

Inhibition of 5-HT uptake by an SSRI results in higher extracellular levels of 5-HT and this is considered the basis of their antidepressant activity, although the exact antidepressant mechanism has yet to be elucidated.

According to the classical definition of an SSRI, the selectivity for inhibition of 5-HT uptake is defined relative to the ability of a given drug to inhibit the reuptake of norepinephrine, and SSRIs are often referred to as one drug class based on this definition.

Discontinuation symptoms in depression and...

However, there is published evidence from preclinical in-vitro and in-vivo pharmacology studies e. Sanchez and Meier, and clinical efficacy studies Montgomery et al. Furthermore, the literature often provides within-discipline comparisons of drugs. This paper reviews potential differences between the clinical, clinical pharmacology, and nonclinical properties of the three most widely prescribed SSRIs, escitalopram, paroxetine, and sertraline, and discusses the potential link between the mechanistic data obtained in nonclinical settings and from clinical trials.

Summary of data from clinical studies and meta-analyses comparing the efficacy and tolerability profiles of escitalopram, paroxetine, and sertraline.

A relapse prevention study of patients conducted with escitalopram and paroxetine included 8 weeks of initial treatment, followed by a week maintenance treatment period and finally a 1—2 Sedating or activating antidepressants for anxiety tapered discontinuation period Baldwin et al. Overall, withdrawal of patients for lack of efficacy normally referred to as relapses was significantly less common on escitalopram than paroxetine Baldwin et al.

In addition, the paroxetine treatment showed a higher rate of discontinuation symptoms, such as feeling tense, confusion, and nausea, than the escitalopram treatment Baldwin et al. In this study, the overall rate of withdrawal of patients in the paroxetine group was significantly higher than in the escitalopram group Boulenger et al.

In a pooled analysis of two studies, it was shown that at 6 months escitalopram was significantly more effective and had significantly fewer withdrawals than paroxetine Kasper et al. In addition, in the subgroup of severely depressed patients, escitalopram demonstrated a significantly greater improvement in efficacy than paroxetine Kasper et al.

In an 8-week head-to-head comparison study, escitalopram and sertraline showed similar efficacy, response rates 75 vs. After 10—16 weeks of treatment, improvement in depression and insomnia symptoms was similar for all three groups, as measured by the HAM-D Fava et al. It should be noted that these two studies seem underpowered for a valid conclusion, and the study duration may not be ideal for observing either Sedating or activating antidepressants for anxiety effects or long-term efficacy.

Overall, escitalopram, sertraline, and paroxetine are all efficacious as compared with placebo, as found in the meta-analysis of 35 trials reported from to involving drug—placebo comparisons, which showed computed relative response rate ratios to placebo of 1.

Escitalopram has been compared with other antidepressants Sedating or activating antidepressants for anxiety paroxetine and sertraline extensively in meta-analyses. Based on an analysis of 10 studies involving a total of MDD patients up toescitalopram was found to have significantly higher overall treatment effect estimated difference in treatment effect of 1.

In a follow-up meta-analysis comparing escitalopram with active controls including SSRIs citalopram, fluoxetine, paroxetine, sertraline and SNRIs venlafaxine, duloxetine involving patients in 16 randomized controlled trials, escitalopram was again found to be significantly more effective than comparators in treatment effect measured as change from baseline in MADRS total scoreas well as in the rates of response and remission Kennedy et al.

The results suggest the overall superior efficacy of escitalopram compared with paroxetine and sertraline as well as other SSRIs and SNRIs, though the superiority to other SSRIs was to the largest degree between escitalopram and citalopram Kennedy et al. In a recent meta-analysis of 10 antidepressants including paroxetine and sertraline for their remission rates, escitalopram was reported to have the most favorable treatment effect, with a remission probability of 0.

Another indirect rather than using pooled raw data meta-analysis of 12 newer-generation antidepressants involved in randomized controlled trials concluded that the odds ratios on efficacy escitalopram vs.

Meta-analyses for sertraline or paroxetine, however, did not find any superiority to each other or to escitalopram on efficacy Thase et al. In the meta-analysis based on results reported from studies between andGartlehner et al.

In addition, a statistically significant odds ratio 1. Sedating or activating antidepressants for anxiety general, results from individual well-designed and adequately powered randomized controlled trials should have priority in both scientific and regulatory settings, whereas meta-analyses are always post hoc and regarded as carrying less weight.

An antidepressant is considered superior in efficacy if there are two or more double-blind studies where it is significantly better on the primary efficacy measure than a marketed antidepressant under conditions of fair comparison. Escitalopram has met this criterion with Sedating or activating antidepressants for anxiety studies, Sedating or activating antidepressants for anxiety neither sertraline nor paroxetine was able to rely on a single study and therefore cannot be considered superior Montgomery et al.

For example, when the efficacies of the newer drugs were compared, escitalopram Overall, the newer-generation antidepressants had similar tolerability profiles, with the types of adverse events Sedating or activating antidepressants for anxiety including diarrhea, dizziness, dry mouth, fatigue, headache, nausea, sexual dysfunction, sweating, tremor, and weight gain Cipriani et al.

As concluded by a meta-analysis reviewing randomized controlled trials involving 25 participants and 12 newer-generation antidepressants, escitalopram and sertraline showed a superior profile of tolerability, with significantly fewer discontinuations of patients than other antidepressants, including paroxetine Cipriani et al. This is in Sedating or activating antidepressants for anxiety with escitalopram having the highest cumulative probability of being among the four best treatments in terms of acceptability in a recent review: Compared with other SSRIs, a higher incidence of adverse effects was indicated for paroxetine treatment, including sedation, constipation, sexual dysfunction, discontinuation syndrome, weight gain, and congenital malformations, in a review of head-to-head studies Marks et al.

A review of tolerability based on data from randomized controlled clinical trials involving about patients with short-term and long-term treatments indicated that paroxetine was associated with significantly higher incidence of adverse events related to sexual dysfunction, as well as more discontinuation symptoms, than Sedating or activating antidepressants for anxiety Baldwin et al.

In general, these findings are consistent with a recent review on the overall profile of paroxetine Gibiino and Serretti, Diarrhea is another common adverse event worth noting for antidepressants.

Consistent with this, a recent meta-analysis found that sertraline was indeed associated with a higher incidence of diarrhea than comparator Sedating or activating antidepressants for anxiety including paroxetine Cipriani et al. The review by Gartlehner et al. Some basic pharmacokinetic and pharmacodynamic properties of escitalopram, paroxetine, and sertraline are compared in Table 2. In general, the three antidepressants produce good absorption, distribution, and clearance profiles at their therapeutic doses.

Paroxetine is approved at clinical dosages of Frequently, treatment with sertraline or paroxetine needs to be titrated by the physician to obtain the optimal dose for the individual patient. The pharmacokinetic and pharmacodynamic properties of escitalopram, paroxetine, and sertraline. Aspects of drug—drug interactions provide clinically relevant differences between escitalopram, paroxetine, and sertraline Hiemke and Hartter, Sedating or activating antidepressants for anxiety Thus, escitalopram may be superior to paroxetine and sertraline in this regard.

The primary target mediating the therapeutic actions of escitalopram, paroxetine, and sertraline is the SERT, and all three drugs have very high affinity at the SERT Table 3.

Paroxetine has the highest affinity at the SERT, whereas escitalopram has the highest degree of selectivity i. The Sedating or activating antidepressants for anxiety trial data, in head-to-head Sedating or activating antidepressants for anxiety and in meta-analyses and as described in literature reviews, have shown higher efficacy for escitalopram and sertraline treatment of depression than paroxetine, with data also showing that escitalopram is associated with higher efficacy compared with other SSRIs.

The efficacy of escitalopram may at least in part be ascribed to its actions at allosteric sites of the SERT Chen et al. The SERT has two types of binding site, the orthosteric binding site also referred to as the primary site to which escitalopram and other SSRIs bind, resulting in inhibition of its uptake function, and one or more allosteric sites Chen et al.

included the reported side effects...

Many studies have led to the thorough characterization of the allosteric mechanism of escitalopram Wennogle and Meyerson, ; Plenge and Mellerup, ; Chen et al. In binding experiments with the SERT, the allosteric activity of escitalopram is characterized by its ability to prolong its own dissociation kinetics Chen et al. By binding to both the orthosteric and allosteric binding sites, escitalopram elicits a more complete and sustained inhibition of 5-HT uptake, leading to higher extracellular 5-HT levels in vivo and faster 5-HT 1A autoreceptor desensitization, as reviewed previously Sanchez et al.

Additional elucidation of this mechanism includes in-vitro as well as in-vivo studies Sedating or activating antidepressants for anxiety that specific mutations in the SERT disrupt the allosteric effect of escitalopram, and that R -citalopram, a less active enantiomer of citalopram citalopram is also an antidepressantinhibits the efficacy of escitalopram Zhong et al. This makes escitalopram the only Sedating or activating antidepressants for anxiety antidepressant that shows dual allosteric and chiral advantages El Mansari et al.

As noted in Table 3paroxetine is also allosteric, but its allosteric effect is weaker Chen et al.

Introduction

In comparison, sertraline and many other antidepressants e. A Sedating or activating antidepressants for anxiety model showing that escitalopram, paroxetine, and sertraline interact with the primary orthosteric and allosteric binding sites at the SERT leading to differential increases in extracellular 5-HT levels.

In each diagram, the SERT Sedating or activating antidepressants for anxiety shown to be located at serotonergic neurons and to have the primary and allosteric binding sites. Allosteric site binding enhances their binding to the primary site, resulting in more pronounced increases in extracellular 5-HT levels and potentially signaling through SERT-interacting proteins SIPs Sanchez et al. Drawing is based on previously published diagrams by Zhong et al.

It is worth noting that for the SSRIs fluoxetine and paroxetine, enantiomers have also been studied. The different ability of escitalopram, paroxetine, and sertraline in increasing extracellular levels of 5-HT in relation to SERT occupancy in the rat brain has been demonstrated, which indicates that the allosteric property of escitalopram may translate to physiological conditions Brennum et al.

As shown in Fig. At escitalopram, paroxetine, and sertraline doses of 0. These differences do not reflect the in-vitro SERT inhibitory potency rank order Table 3 and potentially support that there is an additional site of action presumably an allosteric site that mediates the more efficacious uptake inhibition by escitalopram, in addition to binding to the orthosteric site of the SERT.

Increase in extracellular levels of 5-HT by escitalopram, paroxetine, and sertraline in relation to SERT Sedating or activating antidepressants for anxiety in the rat. The ability of escitalopram, paroxetine, and sertraline to increase 5-HT levels in rat prefrontal cortex via SERT inhibition is shown.

Rats in the microdialysis experiments were anesthetized and the drugs were administered by the subcutaneous route. SERT occupancy was measured by in-vivo binding using [ 3 H]citalopram as radioligand. SERT occupancy relationships for escitalopram, paroxetine, and sertraline. Thus, due to the plateau in SERT occupancy seen for these antidepressants, higher doses are thought to be unable to further increase efficacy, but rather to incur additional side effects, which may contribute to higher discontinuation rates Preskorn, Although it is clear that the primary target of escitalopram, paroxetine, and sertraline is the SERT, the precise cellular and physiological changes following uptake inhibition that mediate their antidepressant actions are poorly understood.

It takes antidepressants, including the SSRIs, 1—2 weeks to produce their therapeutic effect, probably because slower neuroadaptive and neurochemical changes in the brain following the elevation of 5-HT levels are required for the therapeutic effect Blier and de Montigny, ; Zhong et al.

For example, the recovery of raphe 5-HT neuronal firing after the desensitization of 5-HT 1A autoreceptors is thought to reflect the neuroadaptive process underlying the delayed onset of antidepressant action Blier and de Montigny, ; El Mansari et al. For escitalopram, it takes 2 weeks before Sedating or activating antidepressants for anxiety neuronal firing returns to control levels in rats, but for most SSRIs, it takes at least 3 weeks, suggesting a faster onset of action for escitalopram, Sedating or activating antidepressants for anxiety due to its action at the allosteric Sedating or activating antidepressants for anxiety El Mansari et al.

This is consistent with the indication of escitalopram Sedating or activating antidepressants for anxiety a faster clinical onset than other SSRIs Lepola et al. Among other neurochemical changes during antidepressant treatment, the neurotropin brain-derived neurotrophic factor BDNF was recently reviewed Zhong et al. As a potential biomarker, BDNF shows decreased levels in the blood of depressed patients and this can predict treatment response for escitalopram, paroxetine, and sertraline Yoshimura et al.

Thus, neurotropins such as BDNF might hold key insights associated with the neuroadaptive and neurochemical changes during antidepressant treatment, which may help differentiate the actions of SSRIs. Further studies in this area are warranted. Although it is believed that the therapeutic effects of escitalopram, paroxetine, and sertraline are mediated through Sedating or activating antidepressants for anxiety actions at the SERT, some side effects also can be explained by their off-target effects at other transporters and receptors Richelson, Potencies of this order of magnitude may be potentially meaningful at clinical exposure levels.

included the reported side effects of increased anxiety, anger, aggression and mood swings, was suggest they can produce sedation [2], “activation” effects.

Here are expert-approved solutions to your antidepressant problems. of the mood and anxiety disorders program at the Emory University School “Some antidepressants are identified as activating, and some are sedating,”.

Advantages. Disadvantages. Serotonin Reuptake Inhibitors (SSRIs). FLUOXETINE HCL. Prozac. Helpful for anxiety disorders. Long half-life sedating. PAROXETINE CR. Paxil CR.

generally more sedating than citalopram,...

(50 in elderly). 25mg qd. ( mg in elderly.


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Selective serotonin reuptake inhibitors SSRIs are the drug of choice for treatment of patients with panic disorder. Most patients have a favorable response to SSRI therapy; however, 30 percent will not be able to tolerate these drugs or will have an unfavorable or incomplete response.

Strategies to improve management of such patients include optimizing SSRI dosing starting at a low dose and slowly increasing the dose to reach the target dose and ensuring an adequate trial before switching to a different drug. Benzodiazepines should be avoided but, when necessary, may be used for a short duration or may be used long-term in patients for whom other treatments have failed.

Slower-onset, longer-acting benzodiazepines are preferred. All patients should be encouraged to try cognitive behavior therapy. Augmentation therapy should be considered in patients who do not have a complete response.

Drugs to consider for use in augmentation therapy include benzodiazepines, buspirone, beta blockers, tricyclic antidepressants, and valproate sodium.

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  • Serotonin uptake inhibitors are generally considered activating antidepressants. To assess rates and temporal patterns of activation and sedation as well as dose- effect The adverse events nervousness, anxiety, agitation, and insomnia were .
  • Among the three most widely prescribed SSRIs are paroxetine, sertraline, and In a post-hoc analysis of this study of patients with a high level of anxiety, identified . of adverse effects was indicated for paroxetine treatment, including sedation, .. In the ventral tegmental area, activation of D2 receptors or 5-HT2C receptors. SSRIs can be helpful for depression, panic disorder, social anxiety, obsessive compulsive disorder, generalized anxiety and PTSD. They are well tolerated.
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