Paroxetine 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. 

Therapy with phentolamine may result in reflex tachycardia, arrhythmias, and hypotension the latter effect can be exacerbated by other vasodilatory drugs and by the simultaneous ingestion of ethanol. The pharmacological actions of trazodone can be reduced by paroxetine and possibly 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... 

Citalopram and paroxetine have the largest age-related change in plasma drug levels in comparison with other SSRIs. Their levels can be up to 100% greater in physically healthy individuals older than 65 years of age versus younger individuals. For this reason, the recommendation is to start these two SSRIs at half the usual dose and adjust upward more slowly in elderly patients. Age-related changes in SSRI plasma levels are important because elderly patients are likely to be on concomitant medications and effects on specific CYP enzymes are concentration dependent. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

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. 

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. 

Of the SSRIs, paroxetine is the agent most likely to cause weight gain however, in this study the authors reported no change in body mass index during the 3 months of treatment, suggesting a more direct effect of paroxetine on metabolism. Further work will be needed to see if similar metabolic effects are associated with other SSRIs and in patients with other treatment indications. 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

PAROXETINE PARASYMPATHOMIMETICS -GALANT AMINE T galantamine levels Inhibition of CYP2D6-mediated metabolism of galantamine Monitor PR and BP closely, watching for bradycardia and hypotension. Be aware that there is a theoretical risk with other SSRIs... 

Unlike other SSRIs and antidepressants where dosage increments can be double and triple the starting dose, paroxetine s dosing increments are in 50% increments (i.e., 20, 30, 40 or 25, 37.5, 50 CR)... 

Withdrawal effects can be more common or more severe with paroxetine than with some other SSRIs... 

Tramadol Five reports describe the development of the serotonin syndrome in patients on fluoxetine, paroxetine, or sertraline when tramadol was added. Another patient developed hallucinations with tramadol and paroxetine. Other reports suggest that the SSRI/tramadol combination is therapeutically valuable and normally safe. Also, carefully monitor concomitant use with fluvoxamine. 

Oxidative metabolism of clozapine was found to correlate with caffeine metabolism (462)and is thus largely carried out by cytochrome P4501A2 (CYP1A2). No correlation with CYP2D6 polymorphism was found (461, 462). Several interaction studies of clozapine with SSRI antidepressants have been reported (465-469). Fluvoxamine increased plasma concentrations of clozapine in schizophrenic patients (463,464), presumably through inhibition of CYP1A2 catalyzed N-demethylation (465). Fluoxetine was found to increase the plasma concentrations of clozapine and its major metabolites, suggesting that this SSRI must interfere with pathways other than N-demethylation and N-dealkylation (466). Two other SSRIs, paroxetine (463) and citalopram (467), had no apparent effects on clozapine levels. 

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).

The involvement of central serotonergic neurotransmission in human ejaculation has been investigated mainly in animal studies. To date, it seems that the beneficial effect of SSRI treatment in premature ejaculation results from 5-HT2C receptor stimulation. Among the SSRIs, paroxetine has been demonstrated to be more effective than clomipramine and the other SSRIs. Moreover, it has been suggested that long-term SSRI administration is much more efficient than short-term treatment. - ... 

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

Other SSRIs developed during this period that have become household words include paroxetine (patented 1975 by Ferrosan to SmithKIineBeecham to GlaxoKline), citalopram (patented 1979 Lindberg, licensed to... 

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). 

The psychological effects of ecstasy (MDMA, methylenedi-oxymethamfetamine) may be reduced if citalopram has previously been given. It seems likely that other SSRIs will also reduce or block some of the effects of ecstasy, but increased serotonin effects may, in theory, also be possible. An isolated report describes a neurotoxic reaction in a man taking citalopram when he took unknown amounts of ecstasy. Fluoxetine and paroxetine may decrease the metabolism of ecstasy. 

The study of ecstasy with citalopram was primarily undertaken to find out how eestasy works, but on the basis of these results and animal studies it seems likely that patients already taking citalopram may not be able to get as high on usual doses of ecstasy, and some adverse effects may also be redueed. Furthermore, if the proposed mechanism of interaction is correct, the same is also likely to be true if they are taking any other SSRI and some cases have been reported. However, be aware of possible pharmaeokinetie interaetions with some SSRIs that are potent CYP2D6 inhibitors (e.g. fluoxetine, paroxetine), which may increase ecstasy levels. There is also a risk of increased serotonergic activity and there have been a few reports of interaetions involving other sympathomimetics and SSRIs or related drugs, see Phentermine + Fluoxetine , p.205. 

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). 

There is some evidence to suggest that the metabolism of some benzodiazepines (such as alprazolam, bromazepam, diazepam, and also possibly midazolam, nitrazepam and triazolam) may be reduced by some SSRIs (such as fluoxetine and fluvoxamine). On the whole, no clinically significant interaction appears to occur between other SSRIs and the benzodiazepines or related dri s such as cloral hydrate or zaleplon. There is some evidence to support the su estion that sedation is likely to be increased by the concurrent use of SSRIs and benzodiazepines. Rare cases of hallucinations have been seen with zolpidem and some SSRb. Symptoms of the serotonin syndrome have been reported in two patients taking paroxetine and a benzodiazepine. 

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