Sertraline action

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Since the introduction of the first approved SSRI, fluoxetine (1) in 1987 [9], a number of SSRIs have been developed for the treatment of depression [2], Currently, the five most commonly prescribed SSRIs are fluoxetine, escitalopram (2, S-enantiomer of citalopram), sertraline (3), paroxetine (4) and fluvoxamine (5). Recent effort in the clinical development of new SSRIs has focused on the treatment of premature ejaculation (PE) by taking advantage of the ejaculation-delaying side effects of SSRIs [10]. Although SSRIs have been prescribed off-label to treat this condition, an SSRI with rapid onset of action and rapid clearance could be preferred for on-demand treatment of PE [11,12]. Dapoxetine (LY210448, 6), an... 

A series of DAT selective 3-phenyltropanes have been reported to have potential for treatment of cocaine abuse [33,36,37]. RTI-336,15 (reuptake IC50 — 4.1 nM) was the most potent among these tropane derivatives in locomotor activity and drug discrimination it was less stimulatory than cocaine, and had the slowest onset and longest duration of action. It also reduced self-administration of cocaine in rats and rhesus monkeys. Interestingly, in rhesus monkeys trained to self-administer cocaine, when coadministrated with either citalopram or sertraline, 15 produced significantly more robust reductions in cocaine self-administration compared with 15 alone [38]. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a... 

Sertraline is a recent antidepressant that is called a selective serotonin reuptake inhibitor (SSRI). It is chemically unrelated to the older tricyclic antidepressants (see Section 5.3). It works by preventing the movement of the neurohormone serotonin into nerve endings. It can help to improve mood and mental alertness, increase physical activity, and improve sleep patterns. It is prescribed for obsessive-compulsive disorder and obesity. It may offer some advantage over fluoxetine by exhibiting little central nervous system (CNS) action. It has less sedation and anxiety and is shorter acting. 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

The initial reports from open studies (Artigas et al. 1994 Blier and Bergeron 1995) suggest that the combination is associated with improved efficacy with probable faster onset of action. This rapid response was reported with augmentation of fluoxetine and paroxetine, and more recently with nefazodone (Bakish et al. 1997), but interestingly not with sertraline or low doses of fluvoxamine. These results needed to be confirmed in placebo-controlled studies, and the reports from large studies do indeed find an acceleration of response measured as time to response and possible superiority of action with some antidepressants at the end of treatment (Perez et al. 1997 Tome de la Granja et al. 1997). 

Extensive databases [see Table 24-1) have now shown that paroxetine and sertraline can reduce panic attacks to zero and prevent relapse. Paroxetine studies constitute the largest data set more than 700 patients have been treated for periods ranging from 10 to 36 weeks. In the placebo-controlled comparisons with clomipramine, paroxetine had an earlier onset of action and was better tolerated than clomipramine. Paroxetine was significantly better than placebo from week 4 onward, whereas no separation was seen between clomipramine and placebo until the end of the study. Fewer withdrawals occurred as a result of adverse events with paroxetine (7.3%) than with either clomipramine (14.9%) or placebo (11.4%). The minimum dose shown to be superior to placebo was 40 mg/day. 

With regard to its effects on cognitive performance in the target population, the SSRI sertraline appears to be the most thoroughly studied newer antidepressant. Lane and O Hanlon (1999) listed three controlled clinical studies with fluoxetine and three with sertraline however, all three trials with fluoxetine and one of the trials with sertraline were not sufficiently powered to demonstrate reliable differences between treatments. One of the two adequately powered studies, a comparison between nortriptyline and sertraline in elderly depressed patients (Bondareff et al., 2000 see Box 7.3), supports the notion that antidepressants with anticholinergic action (such as nortriptyline) are similarly... 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

The majority of positive studies have found that later generation antidepressants, especially those with strong serotonergic effects, are effective and may have a more rapid onset of action when used for PMDD (27). Thus, studies with SSRIs (e.g., fluoxetine, sertraline), nefazodone, venlafaxine, and clomipramine have all shown promise. In several studies, luteal phase dosing has been as effective or more effective than continuous dosing in women with PMDD. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

The most widely known SSRIs are fluoxetine hydrochloride (4, Prozac , Lilly), sertraline hydrochloride (5, Zoloft , Pfizer) and paroxetine hydrochloride (6, Paxil , GSK). Fluoxetine (4, Prozac ) was the first SSRl approved and effected a revolutionary change in the treatment of depression. In 2000, it was the most widely prescribed antidepressant drug in the United States with worldwide sales of 2.58B. Sertraline (5, Zoloft ) has been available in the United States since 1992 and had worldwide sales of 2.14B in 2000. Compared to fluoxetine (4), it has a shorter duration of action and fewer CNS activating side-effects such as nervousness and anxiety. Paroxetine (6, Paxil ) generated worldwide sales of 2.35B in 2000 and has a relatively benign side-effect profile, which favors its use with elderly patients. 

FIGURE 6—42. Icon of sertraline with dopamine reuptake inhibition (DRI) and sigma actions, in addition to serotonin reuptake inhibition (SRI). 

Serotonin and dopamine reuptake inhibition. Dual reuptake blockers of both serotonin and dopamine are in clinical testing. Although the SSRI sertraline has some dopamine reuptake inhibition as well as more potent serotonin reuptake inhibition, minaprine and bazinaprine have more potent dopamine actions and are thus dual sero-tonin/dopamine agents. 

It has been known since the mid-1980s that clomipramine, a potent but nonse-lective serotonin reuptake inhibitor, is effective in reducing OCD symptoms. Since then, numerous studies have confirmed the superiority of clomipramine over placebo in OCD patients, whereas other antidepressant medications with less potent inhibitory effects on serotonin reuptake (e.g., nortripytline, desipramine) seem to be ineffective in OCD. Demonstration of the anti-OCD actions of all five SSRIs, namely, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, also supports the hypothesis that the antiobsessional effects of these various pharmacologic agents is due to their potent serotonergic reuptake blocking activity. 

The earliest and unfortunately still one of the commonest treatments of social phobia is self-medication with alcohol. The behaviorally disinhibiting actions of alcohol allow many social phobics to engage in social contacts that would otherwise be impossible. Legitimate therapeutic drugs for social phobia are now being discovered at a fast pace (Fig. 9—7). In fact, one of the SSRIs (paroxetine) already has been formally approved for use in the treatment of social phobia, and several other SSRIs and antidepressants are rapidly accumulating evidence of their efficacies in this condition as well. Specifically, studies of all five SSRIs (paroxetine, fluvoxamine, fluoxetine, sertraline, and citalopram) have indicated their efficacy in social phobia. Currently, SSRIs are considered first-line treatments for social phobia. 

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