Fluvoxamine studies/trials

A potential limitation of most of the controlled studies discussed above relates to the numerous exclusion criteria used for patient selection. For example, in order to find homogenous samples, major depression, bipolar disorder, Tourette s disorder, psychosis (clomipramine, fluvoxamine and fluoxetine trials), primary psychiatric disorder other than OCD (clomipramine and sertraline trials), and attention deficit/hyperactivity disorder (ADHD), autism, or other developmental disorders (clomipramine and fluoxetine trials) were excluded. Thus it remains unknown how well these controlled studies will generalize to more naturalistic clinical populations that are highly comorbid and where exclusion criteria are not applied. 

As of the date of this chapter (circa March, 2002), labeling changes regarding pediatric use have resulted from only two programs—the study of buspirone in pediatric GAD and a pharmacokinetic study of fluvoxamine in pediatric OCD (fluvoxamine already had a controlled clinical trial in pediatric patients). Two placebo-controlled trials with buspirone in pediatric GAD did not reveal a treatment effect, and this negative outcome is reflected in Buspar labeling. A pharmacokinetic study of fluvoxamine dosed at 100 mg bid in pediatric... 

Some questions have been raised about the relative efficacy of the SSRls, particularly in severe depression. The pooled analyses of the data from blinded, controlled trials have tended to find similar levels of efficacy between the SSRls and the comparator TCA, imipramine. Paroxetine and fluvoxamine were both found in subanalyses of patients with severe depression included in large placebo- and imipramine-controlled studies to be more effective than imipramine in severe depression (S. A. Montgomery 1992a Ottevanger 1991 Tignol et al. 1992 Wakelin 1988]. However, imipramine may not be the TCA that is most effective in severe depression or may not have been used in the trials at an adequate dose. 

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-... 

Bakish D, Hooper CL, Filteau MJ, et al A double-blind placebo-controlled trial comparing fluvoxamine and imipramine in the treatment of panic disorder with or without agoraphobia. Psychopharmacol Bull 32 135-141, 1996 Bakish D, Hooper CL, Thorton MD, et al Fast onset an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. Int Clin Psychopharmacol 12 91-97, 1997 Baldwin DS Depression and sexual function. J Psychopharmacol 10 (suppl l) 30-34, 1996... 

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. 

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). 

There have been five double-blind studies comparing the antidepressant efficacy of different SSRIs versus different TCAs in patients with HDRS scores of 25 or more (122, 123,124, 125 and 126). Three of these studies permitted inclusion of both inpatients and outpatients ( 122, 123 and 124), whereas the other two were solely done in outpatients (125, 126). Three were placebo-controlled (1.23, 125,126). In these three studies, the SSRI (i.e., fluvoxamine, paroxetine, or sertraline) was either superior to both the f CA and placebo or was comparable with the TCA and superior to placebo. In the other two studies, the SSRI was not different from the TCA and there was no placebo control. There have also been four studies and one metaanalysis of European clinical trials which found no difference in antidepressant efficacy between several different SSRIs and several different tertiary amine TCAs in patients hospitalized for major depression ( 127,128, 129,130 and 131). Finally, there have been two relatively small studies showing that fluoxetine and fluvoxamine both had antidepressant efficacy superior to placebo in patients with melancholia ( 132, 133). Another larger study failed to find a difference between paroxetine and amitriptyline in treating such patients ( 134). 

The meta-analysis of all studies comparing clomipramine or SRIs with placebo for the treatment of OCD found that the active drug produced a better result in every trial. We then calculated the effect size and the statistical significance for clomipramine alone and fluvoxamine alone. Their results showed a highly significant effect for both drugs (Table 13-10 and Table 13-11). There were also several studies with sertraline, fluoxetine, and paroxetine that demonstrated similar results (219, 220, 221, 222. 223,. 224, 225 and 226). 

Both fluvoxamine and sertraline are approved for the treatment of OCD in children and adolescents. Fluvoxamine was proven effective in a 10-week, double-blind, placebo-controlled trial in patients 8 to 17 years of age with OCD ( 149). Dosages in this study were adjusted to a total daily fluvoxamine dose of approximately 100 mg per day over the first 2 weeks using a balanced, twice-daily dosing schedule. After that, the dose was adjusted within a range of 50 to 200 mg per day based on clinical assessment of efficacy and tolerability. Fluvoxamine was superior to placebo on the Children s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) at weeks 1 to 6 and week 10. However, the effect was mainly in the 8- to 11-year-old versus the 12- to 17-year-old age group. The significance of this age difference is not known. 

The ability of SSRIs to cause delayed ejaculation has been used in controlled trials of men with premature ejaculation (61,62). Of the SSRIs, paroxetine and sertraline produced the most benefit in terms of increase in time to ejaculation, but fluvoxamine did not differ from placebo. Clomipramine was more effective than the SSRIs but caused most adverse effects. From a practical point of view many patients might prefer to take medication for sexual dysfunction when needed rather than on a regular daily basis, and it would be of interest to study the beneficial effects of SSRIs on premature ejaculation when used in this way. 

In a systematic review of 32 randomized trials in which 1389 patients took lithium and 2069 took another agent (carbamazepine, divalproex, lamotrigine, or the antidepressants amitriptyline, fluvoxamine, mianserin, and maprotiline), among the seven studies that reported suicides, lithium-treated patients had significantly fewer completed events (242). These included two suicides on lithium (out of 503, 0.4%) and 11 suicides on other agents (two placebo, two amitriptyline, six carbamazepine, and one lamotrigine, out of a total of 601,1.8%) (OR = 0.26 95% Cl = 0.09, 0.77). 

SAD can present in children of preschool to elementary school age. If the disorder is not treated, it can persist into adulthood and increase the risk of depression and substance abuse. CBT and social skills training are effective nonpharmacological therapies in children. Pharmacological evidence is limited to case studies or open-label trials. SSRIs are considered first-line therapy because of tolerability and effectiveness. Fluoxetine, fluvoxamine, sertraline, and paroxetine were effective in children with SAD. Headache, nausea, drowsiness, insomnia, jitteriness, and stomach aches were reported in children receiving SSRIs. 

Compared with other classes of antidepressants, SRIs have a more favorable side-effect profile and better efficacy data. A review of randomized, controlled trials with SRIs for the treatment of PMDD reported that the agents were well tolerated and effective in treating physical as well as behavioral symptoms with either intermittent or continuous dosing. Citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine all have been effective in PMDD placebo-controlled trials (60% to 90% efficacy rates with almost complete relief of symptoms). For fluvoxamine, there are mixed results because one controlled study reported that it had similar efficacy to placebo treatment in PMDD. Although antidepressants usually take... 

The efficacy and tolerability of risperidone, yokukansan and fluvoxamine for the treatment of behavioural and psychological symptoms of dementia was studied in a blinded, randomised trial [239 ]. Compared with the other treatments, risperidone was significantly associated with constipation, muscle rigidity and extrapyramidal symptoms (based on extrapyramidal rating-scale scores) no significant changes in BP or heart rate were observed with any of the treatments. 

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