Paroxetine therapeutic dose

SSRls. SSRI antidepressants have also received considerable scrutiny in the treatment of OCD. Fluoxetine, fluvoxamine, paroxetine, and sertraline are all approved by the FDA for the treatment of OCD. Current studies suggest that each of these medications is more effective for OCD when administered at the higher end of the therapeutic dose range, that is, fluoxetine 60-80 mg/day, fluvoxamine 200-300 mg/ day, paroxetine 40-60 mg/day, and sertraline 150-200 mg/day. No controlled studies are yet available regarding the use of citalopram or escitalopram for OCD. Refer to Chapter 3 for more information regarding SSRl antidepressants. 

All of the SSRIs also show a flat dose-response curve, meaning that there is usually no advantage to increasing the dose above that which is the usually effective minimum dose. Of interest, the four SSRIs marketed as antidepressants in the United States at their usual effective therapeutic dose (i.e., 40 mg per day for citalopram, 20 mg per day for paroxetine and fluoxetine, and 50 mg per day for sertraline) produce comparable effects on either plasma serotonin levels or the serotonin uptake pump in platelets (25). These results are consistent with the conclusion that serotonin uptake inhibition is the mechanism responsible for the antidepressant efficacy of these agents. 

Newer antidepressants (eg, fluoxetine, paroxetine, citalopram, venlafaxine) are mostly SSRIs and are generally safer than the tricyclic antidepressants and monoamine oxidase inhibitors, although they can cause seizures. Bupropion (not an SSRI) has caused seizures even in therapeutic doses. Some antidepressants have been associated with QT prolongation and torsade de pointes arrhythmia. SSRIs may interact with each other or especially with monoamine oxidase inhibitors to cause the serotonin syndrome, characterized by agitation, muscle hyperactivity, and hyperthermia (see Chapter 16). 

Paroxetine is a phenylpiperidine derivative. Its half-life is about 17-22 hours and about 95 % of it is bound to plasma proteins. Its metabolites have no more than 1/50 of the potency of the parent compound in inhibiting serotonin re-uptake. The metabolism of paroxetine is accomplished in part by CYP2D6, saturation of which at therapeutic doses appears to account for the non-linearity of paroxetine kinetics at higher doses and increasing durations of treatment. The adverse effects of paroxetine are those of the SSRIs in general. Commonly observed adverse events... 

In 31 healthy men and women (mean age 28 years) the ability of four SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) to inhibit CYP2D6 activity was assessed in vivo, as judged by the dextromethorphan test (63). All were extensive metabolizers of dextromethorphan. After 8 days treatment at therapeutic doses, four of eight paroxetine-treated and five of eight fluoxetine-treated subjects had become poor metabolizers, presumably because of the inhibitory effect of the two SSRIs... 

B. lit addition, severe rigidity and hyperthermia may occur when patients receiving MAO inhibitors use therapeutic doses of meperidine (Demeroi), dextromethorphan, fluoxetine (Prozac), paroxetine (Paxii), sertraiine (Zoloft), ven-lafaxine (Effexor), or tryptophan the mechanism is unknown but may be related to inhibition of serotonin metabolism in the CNS, resulting in serotonin syndrome (see p 22). 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

Initiate therapy of these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. hydrocodone, oxycodone, desipramine, paroxetine, chlorpheniramine, mesoridazine, alprenolol, amphetamines, atomoxetine)... 

Dosing and Administration. SSRIs should be initiated at doses similar to those used for the treatment of depression and administered as a single daily dose with or without food (except for fluvoxamine). If the patient suffers from comorbid panic disorder, the SSRI dose should be started at one-fourth or one-half of the normal antidepressant dose. Patients should receive the starting dose for 2 to 4 weeks before it is increased slowly (i.e., paroxetine 10 mg/day and sertraline 50 mg/day) in weekly intervals as necessary to obtain a response. Safety for paroxetine in SAD was demonstrated in doses up to 60 mg/day, but additional therapeutic benefits above 20 mg/day were not shown. The maximum dosage of sertraline used in patients with SAD was 200 mg/day. ... 

However, there is one report of a possible decrease in valproate levels in a 30-year-old man after starting lopinavir/ritonavir. This patient, who had been taking valproic acid 375 mg daily as divalproex sodium for 7 months after an episode of mania, had a subtherapeutic valproic acid level of 197 micromol/L, and the dose was increased to 250 mg three times daily. After 25 days his trough valproic acid level was 495 micromol/L, and an antiretroviral regimen of lamivudine, zidovudine, lopinavir/ritonavir was started, and paroxetine for depression. Four days later he was hy-pomanic and the paroxetine was replaced with sertraline, which the patient discontinued. Twenty-one days later he had become increasingly manic, and the valproic acid level was found to be 238 micromol/L, about 50% lower than the previous level. An increase in valproic acid dose to 1.5 g daily was eventually required to achieve a therapeutic level of 392 micromol/L. 

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