Paroxetine studies/trials

A prospective, randomized, placebo-controlled trial of paroxetine in adults with chronic post-traumatic stress disorder (PTSD) was recently conducted (Marshall etal., 2007). The subjects were New Yorkers, predominantly female (67%) and Hispanic (65.4%). Seventy subjects entered the study and after a one week placebo lead-in, 52 subjects were randomized to placebo or paroxetine for ten weeks. The subjects were treated with a flexible dosage design (mean dosage, 40.4 mg/day). Dropout rates were 32% for paroxetine and 51.9% for placebo. There were no differences in rates of adverse effects between treatment arms. Paroxetine was superior to placebo in ameliorating the primary symptoms of PTSD (56% vs. 22.2%). 

Pemoline (Cylert), (112.5 to 185.5 mg) was assessed in a 3-week open trial in 15 adolescents with CD, ADHD, and SUD (Riggs et ah, 1996). Three of the subjects were receiving other psychotropic medications (clonidine (Catapres) and paroxetine [Paxil]). All subjects had a significant improvement in ADHD symptoms (p <0.002) while 10/13 reported that the pemoline (Cylert) assisted in their substance rehabilitation. No subjects developed a significant elevation in their liver function tests, nor did any subjects test positive for substances of abuse for the duration of the study. No interactions between pemoline (Cylert) and any substances of abuse were reported. 

Of the SSRIs, fluoxetine has been studied most extensively. Birmaher et al. (1994) and Fairbanks et al. (1997) both found significant improvement in various anxiety disorder symptoms in typically developing children. Fluoxetine was also found to be effective in the treatment of selective mutism (Black and Udhe, 1994 Dummit et ah, 1996). Fluoxetine has also been studied in individuals with MR and autistic disorder. In an open trial. Cook et al (1992) found that fluoxetine was associated with significant improvement in the Clinical Global Impression (CGI) severity ratings in 15 of 23 individuals (65%) with autistic disorder and in 10 of 16 individuals (62%) with MR. All of the SSRIs appear to have similar properties and have been approved for panic disorder, phobias, OCD, and anxiety disorder. Sertraline has been approved for treatment of PTSD, and paroxetine, for social phobia. 

Results from two large multicenter trials evaluating SRIs for the treatment of dysthymia were similar to those found above (M. Steiner, personal communication, December 1995 Halbreich et ah, in press). In a study evaluating the efficacy of sertraline versus that of IMl and placebo for the treatment of dysthymia, women were again found more likely to respond to sertraline than to either IMI or placebo. Similarly, dysthymic women treated with paroxetine were more likely to respond using a definition of 50% decrease in the HRS-D. In this latter case, 54% of women treated with paroxetine responded compared with 21% of women treated with placebo, whereas 30% of men in either treatment cell responded (M. Steiner, personal communication, December 1995). 

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. 

Ballenger JG, McDonald S, Noyes R, et al The first double bhnd, placebo controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112-119) in generalized anxiety disorder. Psychopharmacol Bull 27 171-179, 1991 Ballenger JG, Wheadon DE, Steiner M, et al Double-blind, fixed-dose, placebo-con-trolled study of paroxetin in the treatment of panic disorder. Am J Psychiatry 155 36-42, 1998... 

Lecrubier Y, Judge R Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Acta Psychiatr Scand 95 153-160, 1997 Lecrubier Y, Puech AJ, Azcona A, et al A randomized double-blind placebo-con-trolled study of tropisetron in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology 112 129, 1993 Lecrubier Y, Pletan Y, Selles A, et al Clinical efficacy of milnacipran placebo-con-trolled trials. Int Chn Psychopharmacol 11 (suppl 4 29-34, 1996 Lecrubier Y, Bakker A, Dunbar G, et al A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Acta Psychiatr Scand 95 145-152, 1997... 

A number of SSRIs and SNRIs were tested for their effects on cognitive function in repeated-dose studies in healthy, non-depressed volunteers. Studies with SSRIs before 1999 have been reviewed by Lane and O Hanlon (1999) and some more recent reports deal with nefazodone. paroxetine and sertraline (Furlan et al., 2001 Schmitt et al., 2001 van Laar et al.. 2002). However, considering the populations studied in these trials (non-depressed subjects), the duration of drug administration (1 2 weeks) and the mostly low drug doses used, the relevance of these studies for a clinical situation may be questioned. 

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). 

Since the study by Emsiie and colleagues, there has also been a positive, double-blind, placebo-controlled study with paroxetine (120), and sertraline has also shown promise in an open-label trial in adolescents with major depression (121). 

Several placebo-controlled studies have demonstrated the effectiveness of SSRIs in the treatment of social phobia, particularly paroxetine [147-150], However, due to its adverse impact on sleep, the SSRIs may not be the first choice for social phobia with sleep complaints. Serotonin/norepinephrine re-uptake inhibitors (SNRI), such as venlafaxine [151], have also been reported to be effective for social phobia in several open label studies. However, no placebo-controlled trial has been conducted... 

Even worse, GSK made sure that Study 329 was eventually published in a whitewashed form in the prestigious Journal of the American Academy of Child and Adolescent Psychiatry (Keller et ah, 2001). The title left no doubt about the scientific nature of the study Efficacy of Paroxetine in the Treatment of Adolescent Major Depression A Randomized, Controlled Trial. The conclusion to the lengthy analysis, a mere one sentence long, left no doubt about what the reader was supposed to learn Paroxetine is generally well tolerated and effective for major depression in adolescents. That one sentence, so prominently displayed as the last line of the abstract, was a drug company public relations triumph, one bound to vastly increase the off-label prescription to children of their ineffective, dangerous drug. 

The suit provided an analysis of efficacy in GSK s trials, indicating that the drug was often no better than placebo. In an analysis of safety, it found that several combined studies showed that possibly suicide-related behaviors were approximately two times more likely in the paroxetine group than the placebo group. It disclosed that in five studies, GSK coded suicidal thinking and acts, as well as mood swings, crying and similar behaviors, as emotional lability. ... 

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. 

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