Sertraline other SSRIs

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

Sertraline (Zoloft). Sertraline was the second SSRI released in the United States and is approved for the treatment of major depression and many anxiety disorders. It should be started at 25-50 mg/day and increased to lOOmg/day over the first 10-14 days. Many patients require doses nearing 150 mg/day for full benefit. The side effects of sertraline are comparable to other SSRIs. 

Other SSRIs may be selected as an alternative to fluvoxamine in the event that fluvoxamine cannot be used. Sertraline is the first option because of efficacy for pediatric GAD (Rynn et ah, 2001) paroxetine is an option because of controlled treatment data for adolescent depression (Keller et ah, 2000) and OCD (see Chapter 39) and fluoxetine is an option because of controlled treatment data for pediatric depression (Em-slie et ah, 1997). Eorazepam is included as a short acting alternative to clonazepam. Nortriptyline, which is less anticholinergic and thus may be better tolerated, is included as an alternative to IMF... 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

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. 

It is believed that SSRIs produce movement disorders by facilitating inhibitory serotonin interactions with dopamine pathways. While all SSRIs are potent inhibitors of serotonin re-uptake, they have other pharmacological actions that might contribute to their clinical profile. Sertraline has an appreciable affinity for the dopamine re-uptake site, and for this reason might be presumed less likely to cause movement disorders than other SSRIs. However, there is little clinical evidence to support this suggestion and a case of sertraline-induced parkinsonism has been reported (13). 

Of 93 cases of neonatal symptoms associated with the use of SSRIs in mothers around the time of delivery 64 were associated with paroxetine but reactions were also reported in infants whose mothers had taken citalopram, fluoxetine, and sertraline (87). It is unclear from these data whether paroxetine is actually most likely to provoke the neonatal syndrome, but in adults its use is associated with more severe withdrawal reactions than other SSRIs. It should also be noted that it is not clear whether the syndrome described in neonates is due to SSRI withdrawal or a form of serotonin toxicity. 

Patients who are sensitive to the prolactin-elevating properties of other SSRis (sertraline is the one SSRI that generally does not elevate prolactin)... 

Like other SSRIs, sertraline should not be used within 2 weeks of discontinuing monoamine oxidase inhibitors (MAOIs) and MAOIs should not be started for at least 2 weeks after stopping sertraline. 

Sertraline and fluoxetine undergo metabolic demethylation. Unlike the metabolites of most other SSRIs, the desmethyl metabolite of fluoxetine, norfluoxetine(34), retains the ability to inhibit serotonin reuptake (205). Hence, fluoxetine takes longer to achieve steady-state levels, and it retains activity after metabolism. The half-life of fluoxetine is approximately 1 day, but elimination of norfluoxetine is prolonged (7-15 days) (205). In addition to its actions as an SSRI, norfluoxetine also binds at 5-HT, receptors (127). 

SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, nefazodone, trazodone, atomoxetine... 

Figure 3.4 Prozac (fluoxetine) was the first SSRI to be patented and widely sold to the public. It was created specifically to alter serotonin levels in the brain. The green and white pills, shown here, have become synonymous with depression treatment. Since Prozac s creation in the 1980s, many other SSRIs have been synthesized. These include Paxil (paroxetine), Luvox (fluvoamine), Zoloft (sertraline), and Celexa (citalopram).

DA agonists levodopa, bromocriptine, ropinirole, pramipexole, selegiline AAAD inhibitor carbidopa M-blockers benztropine, trihexiphenidyl MAOIs phenelzine, tranylcypromine TCAs amitriptyline, imipramine, clomipramine SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, nefazodone, trazodone... 

Few data are available about sertraline interactions with MAOIs, even though they are expected to be similar to those of the other SSRIs. However, serotonin syndrome has been reported with the combined tranylcypromine-sertraline (and clonazepam also) regimen. At present, only this specific combination should be avoided. 

ANS adverse effects and cardiotoxic potential than tricyclics. Tox CNS stimulation, sexual dysfunction, seizures in overdose, serotonin syndrome. Other SSRIs citalopram, paroxetine, sertraline. 

Although sertraline appears to differ structurally from the other SSRIs, it is a phenylaminotetralin, in which the diphenylpropylamine nucleus is constrained into a rigid bicyclic ring system (Fig. 21.13). In the early work with the discovery of SSRIs at Pfizer, tametraline was initially synthesized in 1978. Animal studies showed it to be a stimulant and to block NE and DA uptake, a use that Pfizer was not interested in pursuing. Subsequently, one or two chlorine atoms were introduced into tametraline to produce new molecules that were potent inhibitors of 5-HT reuptake in the brain. One of the dichloro compounds was to become known as sertraline. 

Sertraline contains two chiral centers, and only the S,S-(+)-diastereomer is marketed. The R,R-, R,S-, and S,R-diastereomers are significantly weaker as inhibitors of 5-HT reuptake. Sertraline was marketed in the United States in 1992, emphasizing its pharmacokinetic differences from the other SSRIs. 

Sertraline is a potent and selective inhibitor of the neuronai reuptake 5-HT transporter, in vitro binding studies suggest that sertraiine has a substantiaiiy higher seiectivity for inhibiting 5-HT reuptake than other SSRis or TCAs, inciuding ciomipramine (Fig. 21.6). it has oniy weak effects on neuronai uptake of NE and dopamine, its mechanism of action is common to the SSRis. Sertraiine is very seiective, iacking affinity for other neuroreceptors at therapeutic concentrations. 

Fluvoxamine is a highly selective inhibitor of 5-HT reuptake at the presynaptic membrane. Potency data from in vitro affinity studies suggest that fluvoxamine is less potent than the other SSRIs (e.g., paroxetine, sertraline, and citalopram). Its mechanism of action is similar to that of the other SSRIs. Fluvoxamine appears to have little or no effect on the reuptake of NE or dopamine. In vitro studies have demonstrated that fluvoxamine possesses virtually no affinity for other neuroreceptors. Its onset of action is similar to the other SSRIs (2-4 weeks). 

None of the other SSRIs studied (citalopram, fluoxetine, paroxetine) have been shown to alter the pharmacokinetics of warfarin, and neither fluoxetine nor paroxetine increased the prothrombin time. However, citalopram and sertraline caused a less than 10% increase in prothrombin time, and a few patients taking paroxetine with warfarin had bleeds. However, in general, these effects would generally not be expected to be clinically relevant. Nevertheless, because SSRIs alone can rarely cause bleeding, some predict that this may result in additive effects with cou-marins and indanediones, and recommend caution with all SSRIs. Note that there are case reports of interactions with warfarin for many of the SSRIs (citalopram, fluoxetine, paroxetine, sertraline). 

Fluvoxamine is an inhibitor of CYP3A4 and so theoretically could affect the metabolism of tacrolimus. Close monitoring of tacrolimus levels is therefore advised. Paroxetine and sertraline and possibly other SSRIs may be suitable alternative antidepressants, but the evidence is slim, so additional monitoring may still be warranted. Further study on the use of antidepressants with tacrolimus is needed. 

Zussman BD, Davie CC, Fowles SE, Kumar R, Lang U, Wargenau M Sourgens H. Sertraline, like other SSRIs, is a significant inhibitor of desipramine metabolism in vivo. BrJ Clin Pharmacol 99S) 39, 550P-551P. 

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