Fluvoxamine indications

The prototypical serotonin reuptake inhibitor (SRI) medication is the non-selective agent clomipramine, a tricyclic antidepressant (TCA). The Selective SRIs (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalo-pram (Celexa). The Food and Drug Administration (FDA) approved clinical indications for these medications are described in Table 22.1. 

Clomipramine, fluvoxamine, and sertraline labeling all describe positive results of trials of these drugs in pediatric patients with OCD, in effect, granting an indication for these drugs in pediatric OCD. 

Some evidence indicates that social phobia responds to SSRls, and case reports and studies with fluoxetine [B. Black et al. 1992 Van Ameringen et al. 1993), fluvoxamine [Mendels et al. 1995), paroxetine [Pitts et al. 1996 Ringold 1994), and sertraline [Katzelnick et al. 1995) have reported positive results. Although the full details of these studies have not been published, it seems that SSRls might well prove, in due course, to be effective treatments for social phobia. At the moment, the only treatment licensed for social phobia is moclobemide, which is a reversible inhibitor of monoamine oxidase-A [Nutt and Montgomery 1996 Versiani et al. 1992), and it is possible that it... 

Basic pharmacology. Fluvoxamine is an effective serotonin reuptake inhibitor with an ICjg value of 0.3 pmol/L comparable ICjg values for desipramine and fluoxetine are 0.8 jmol/L and 1.3 omol/L, respectively [Bradford 1984]. The ICjo values for NA and dopamine were 100 times higher than those for serotonin [Bradford 1984]. In vitro data indicate that fluvoxamine has little or no affinity for Oj, a, Pi, P2, Dj, S-HTj, muscarinic, or histaminergic receptors [Benfield and Ward 1986]. Fluvoxamine has a total of 11 metabolites, and the 2 principal ones have little or no pharmacological activity [Claassen 1983]. 

Efficacy. To date, more than 15 clinical trials have been conducted comparing fluvoxamine with other active agents and placebo. Imipramine was the most common comparator drug used, and studies have indicated that fluvoxamine was effective as the reference drug, although significantly supe-... 

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... 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

Zimelidine was the first serotonin reuptake inhibitor available for clinical use, but in 1982 was withdrawn worldwide because of its toxicity ( 110). Despite this initial setback, five members of this class have been marketed in the United States and various countries around the world citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). All except fluvoxamine have marketed indications in the United States for the treatment of major depression. Fluvoxamine is marketed in the United States for the treatment of obsessive-compulsive disorder rather than major depression, although it is marketed in a number of other countries for major depression. 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

MAOIs, TCAs, lithium, clomipramine (alone or with topical steroids), fluoxetine, and fluvoxamine may reduce the frequency and intensity of this disorder ( 210, 226, 255, 256, 257, 258, 259, 260 and 261) however, controlled trials are needed to conclusively establish efficacy. Relapse after initial improvement has also been reported, however. Data also indicate that both trichotillomania and OCD may respond to venlafaxine ( 262, 263). For children, such treatments should be reserved for only those with the more severe, refractory forms. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

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. 

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. 

Carbamazepine Some, but not all, reports indicate that carbamazepine serum levels can be increased by fluoxetine and fluvoxamine. Toxicity may develop. Sertraline normally appears not to affect carbamazepine, but sertraline levels may be reduced by carbamazepine. Isolated cases of Par-kinson-like and serotonin syndrome have occurred with fluoxetine and carbamazepine, while an isolated case of pancytopenia has been reported with sertraline and carbamazepine. The metabolism of citalopram may be increased. 

Trade names Apo-Fluvoxamine Dumirox Dumyrox Faverin Favoxil Fevarin Luvox (Solvay) Maveral Indications Obsessive-compulsive disorder, depression Category Antidepressant Selective serotonin reuptake inhibitor Half-life 15 hours... 

Some selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, fluvoxamine, and paroxetine, are potent inhibitors of CYP2D6 activity. Therefore, multiple dosing causes autoinhibition of CYP2D6 and conversion from extensive to slow metabolizer phenotype and from ultrafast to extensive metabolism [16,17]. In the case of fluvoxamine, diflerences in areas under the curve (AUCs) were described after single doses [18,19], whereas multiple doses result in similar AUCs in PMs and EMs, indicating a strong inhibitory effect on CYP2D6 in EMs [20]. 

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. 

Three additional agents in this group were introduced in 1993-1994 paroxetine, ven-lafloxine, and fluvoxamin. They differ from the earlier agents in duration of action, dosages, and metabolism rather than in mechanism or clinical indications. 

The SSRIs are highly protein bound and may affect the pharmacodynamic effect of other protein-bound drugs with narrow therapeutic indices (e.g., warfarin). The changes appear to be clinically significant, however, only for fluoxetine, fluvoxamine, and paroxetine (50). Close monitoring of prothrombin time and international normalized ratio is necessary if these drugs are used together. 

---