Fluoxetine therapeutic dose

It is perhaps not surprising that, even after taking into account pharmacokinetic differences between these drugs, the therapeutic doses of the SSRIs do not parallel their Ki for inhibition of 5-HT reuptake. For instance, citalopram is about a thousand times more selective than fluoxetine for inhibition of 5-HT uptake, and yet their clinically effective doses are similar. In short, not only is their selectivity for the 5-HT transporter in vitro a poor predictor of their efficacy in vivo but it has to be questioned whether any of these compounds actually work by blocking 5-HT uptake alone. 

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). 

Adverse affects Commonly observed adverse effects of fluoxetine are summarized in Figure 12.7. Loss of libido, delayed ejaculation and anorgasmia are probably under-reported side effects often noted by clinicians but are not prominently featured in the list of standard side effects. Overdoses of fluoxetine do not cause cardiac arrhythmias but can cause seizures. For example, in a report of patients who took an overdose of fluoxetine (up to 1200 mg compared with 20 mg/day as a therapeutic dose) about half of the patients had no symptoms. 

Fluoxetine has been associated with seizures, both in therapeutic doses (3,13) and in overdose (3,14). It has also been shown to lengthen seizure duration during electroconvulsive therapy (SEDA-17, 20). Four patients had suspected seizures during studies (3) and one who took a 3000 mg overdose (3) had unequivocal convulsions but recovered. 

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. 

If, following absorption, medications were undisturbed by the body, we would need to take only one dose for an eternal effect. Of course, this is not the case. As soon as drugs enter the bloodstream, the process of metabolism ensues. The body recognizes the drug as a foreign substance and eliminates it outright (say, via the kidneys, as in the case of lithium) or transforms it chemically, using a complex enzyme mechanism located in the liver. This chemical transformation enables the medication to be eliminated from the body. In some cases, the chemical transformation produces a new compound that may also have therapeutic effects (or, in some rare instances, a toxic effect). For example, fluoxetine (trade name Prozac) is transformed into norfluoxetine, which is also an antidepressant. A similar situation occurs with the old tricyclic antidepressants (amitriptyline—trade name Elavil—to nortriptyline the latter, in fact, is... 

SSRIs NNRTIs - EFAVIRENZ 1. Possible efficacy and adverse effects, including serotonin syndrome, with fluoxetine 2. Possible 1 efficacy with sertraline 1. Uncertain mechanism possibly bioavailability 2. CYP2B6 contributed most to the demethyla-tion of sertraline, with lesser contributions from CYP2C19, CYP2C9, CYP3A4 and CYP2D6 1. Use with caution consider l dose of fluoxetine 2. Watch for therapeutic failure, and advise patients to report persistence or lack of improvement of symptoms of depression. dose of sertraline as required titrate to clinical response... 

Nortriptyline appears to be the one antidepressant that has a bell-shaped response curve (or therapeutic window) both doses too low and too high are less effective. Thus blood levels can be very helpful when using nortriptyline. For other antidepressants, blood levels may be helpful to see if the dose needs to be increased. Usually antidepressants are started at a low dose, for example, fluoxetine at 10-20 mg or desipramine at 10-25 mg, and titrated upward. This is because of the wide variability (greater than terifold) in absorption of these medicaitons. 

Proof-of-concept studies have demonstrated that lOOx Cmax is a reasonable scaling factor to differentiate hepatotoxic (or positive) versus nontoxic (or negative) drugs.108 For example, in a family of antidepressant drugs, nefazodone was consistently positive, whereas buspirone and fluoxetine remained negative, but all tested at 100x of their respective single-dose therapeutic Cmax.108... 

A double-blind crossover trial of low-dose fluoxetine vs. placebo in 45 children and adolescents with ASD yielded more encouraging results. Fluoxetine treatment was initiated with a relatively low dose of 2.5 mg/day, which was then titrated over 4 weeks based on therapeutic response and side effects up to a maximum dose of 0.8 mg/kg, with treatment maintained for an additional 4 weeks. This was followed by a 4-week washout period and an 8-week double-blind crossover trial. Thirty-four subjects completed both phases of the trial. Significant improvement was found in repetitive behaviors as scored on the Children s Y-BOCS. There was no significant increase in adverse events as compared to placebo (Hollander et al., 2005). 

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