Fluvoxamine specificity

In general, the SSRIs have a more tolerable side effect profile than the tricyclic antidepressants with their anticholinergic effects. Review of the rate that subjects in the controlled studies discontinued a SSRI because of adverse effects provides some perspective on how well tolerated the medications are, although the specifics may vary according to dosage and design (e.g., forced titration) and are not directly comparable. The rate of discontinuation was reported to be 12% (4/48) for fluoxetine (Emslie et ah, 1997), 9.7% for paroxetine (Keller et ah, 2001), 13% (12/92) for sertraline (March et ah, 1998), and 33% (19/57) (Riddle et ah, 2001) and 7.9% (5/63) for fluvoxamine (Walkup et ah, 2001). 

Goodman WK, Price LH, Delgado PL, et al Specificity of serotonin reuptake inhibitors in the treatment of obsessive compulsive disorder comparison of fluvoxamine and desipramine. Arch Gen Psychiatry 47 577-585, 1990b Goodman WK, Rasmussen SA, Foa EB, et al Obsessive compulsive disorder, in Clinical Evaluation of Psychotropic Drugs Principles and Guidance. Edited by Prien RF, Robinson DS. New York, Raven, 1994, pp 431-466 Goodnick P Effects of lithium on indices of 5HT and catecholamines in the clinical content a review. Lithium 1 65-73, 1990... 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

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. 

A higher percentage of patients would be expected to relapse in the crossover design for two reasons. First, a significant portion of the patients in the crossover study had, in fact, responded specifically to the drug treatment. After a period of stabilization, these patients were randomly reassigned to placebo and thus would be expected to relapse. Second, a basic problem in the crossover design is that withdrawal symptoms can mimic the recurrence of depressive symptoms. That is true for the SSRIs, particularly fluvoxamine and paroxetine, because of their relatively short half-lives. 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

As mentioned previously, beyond the unusually long half-life of fluoxetine and norfluoxetine, the other clinically meaningful distinction between the SSRIs is whether they produce substantial inhibition of specific CYP enzyme (Table 7-29). Fluvoxamine, fluoxetine, and paroxetine do, whereas citalopram and sertraline do not. As mentioned earlier, it is doubtful that the first three would be developed or approved for today s market because of their effects on CYP enzymes, which can cause serious and even fatal drug-drug interactions. 

Fenfluramine augmentation of SRIs in one open study benefited six of seven patients (233). Many patients have both Tourette s and OCD symptoms, and one case study found that pimozide helped Tourette s symptoms, whereas fluvoxamine helped the OCD symptoms, suggesting some specificity for each symptom (234). In a naturalistic study of Tourette s with associated OCD, adjunctive fluoxetine produced 81% improvement in the complicating OCD symptoms (235). 

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. 

A molecule such as cyclic AMP, cyclic GMP or phosphatidylinositol that regulates intracellular processes in response to an extracellular signal. Uncontrolled or paroxysmal brain activity that is usually expressed through the motor system. Antidepressants such as fluoxetine and fluvoxamine that show specificity in inhibiting the uptake of 5-hydroxytryptamine into platelets or brain tissue in vitro and in vivo. 

Inhibitors obtained from in vitro data include a number of compounds with different selectivities and specificity toward this enzyme. Most of them have not been tested for their in vivo effects and some may also inhibit other enzymes (ticlopidine, fluvoxamine, miconazole, nefazodone, paroxetine, etc.). This query did not yield any additional inhibitors. A summary of substrates (including partial ones) and inhibitors is shown in Table 1 and indicates that clopidogrel and ticlopidine, whose effects have been well documented in vivo and in vitro, are effective inhibitors of CYP2B6 and can be used in an in vivo DI program. 

Fluvoxamine appears to have no specific effects on laboratory tests (4,8,9) although some have reported a significant fall in platelet count and an increase in serum creatinine, most of the values remained well within the reference ranges (10). 

Two young women with metamfetamine abstinence developed mania after taking fluvoxamine, which was prescribed for persistent depressive symptoms (32). Both had abused metamphetamine for several years. Two weeks after starting to take fluvoxamine 100 mg/day and brotizolam 0.5 mg/day they became manic, with elevated mood, talkativeness, and increased activity. When fluvoxamine was withdrawn the manic state gradually abated and they were discharged from hospital 3 months after admission. It is not known whether a manic switch in metamfetamine users with depression is specific to fluvoxamine, or can occur with other SSRIs. 

Fichter, M. M., R. Kruger, W. Rief, R. Holland and J. Dohne (1996). Fluvoxamine in prevention of relapse in bulimia nervosa effects on eating-specific psychopathology. J Clin Psychopharmacol 16(1) 9-18. 

Although favorable reports for other SSRIs have been reported in open-label studies (reviewed by Posey et al., 2006), these are of doubtful value for the reasons discussed above. The fact that the largest, most comprehensive study to date failed to find a benefit of a SSRI for the specific indication for which these agents are most commonly prescribed in ASD casts doubt on the value of this class of medications in ASD. Indeed, aside from one study of fluvoxamine in adults (McDougle et al., 1996) and one of fluoxetine in children (Hollander et al., 2005) (discussed above), there is little to support the use of SSRIs in ASD. Moreover, even in the studies that have reported favorable results, improvement in core symptoms has been found to be variable and generally rather modest, providing little support for the hypothesis that abnormalities in serotonin systems play a central role in autism. 

Fluvoxamine maleate is the most recent of the serotonin-specific antidepressants to reach the muket. fo vitro cuid in vivo animal experiments have shown fluvoxamine to have a marked effect on 5-HT mediated processes and little effect on norepinephrine. Clinical trials suggest similar efficacy to imipramine and clomipramine with a somewhat lower incidence of side effects, especially anticholinergic effects. Fluvoxamine, in contrast to the tricyclic antidepressants, does not appear to produce heMt rate increase, postural hypotension or prolongation of the intraventriculau conduction time auid QT intervcil. 

Several selective serotonin reuptake inhibitors (SSRIs), including escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (Fig. 22.21), are effective as first-line treatment cf seme anxiety disorders, with the purported advantage that they lack the addictive preperties cf benzediazepines (135). Specifically, the SSRIs have been shown to be effective in obsessive-ccmpulsive diserder (139), panic disorder (140), and social phobia (141). The mechanism of action of these agents in anxiety may differ with their role in the treatment of depression however,... 

Although the clinical relevance of this pharmacokinetic interaction has not been assessed, it would seem possible that the effects of ropinirole may be increased. The manufacturers suggest that if therapy with a known potent inhibitor of CYP1A2 is stopped or started during therapy with ropinirole, adjustment ofthe ropinirole dose may be required. The UK manufacturer specifically mentions cimetidine and fluvoxamine in addition to ciprofloxacin. For a full list of CYP1A2 inhibitors, see Table 1.2 , (p.4). 

In view of these effects the US manufacturers suggest halving the dose of cilostazol in the presence ofCYP3A4 inhibitors such as erythromycin, diltiazem, itraconazole, and ketoconazole. However, the UK manufacturers contraindicate CYP3A4 inhibitors, and they specifically name erythromycin, diltiazem, ketoconazole, cimetidine, and the protease inhibitors. Just why these recommendations differ is not clear. The US manufacturers suggest that other CYP3A4 inhibitors, such as azole anti-fungals (fluconazole, miconazole), SSRIs (fluoxetine, fluvoxamine, sertraline) and nefazodone, may also interact. ... 

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