Antidepressants placebo-controlled study

Coincidentally, researchers at a World Health Organization (WHO) centre, the University of Verona in Italy and the Nagoya City University in Japan had already analysed all of the placebo-controlled antidepressant trials on GSK s website, and published their results at just about the same time that we published our analysis of the FDA data. They found 40 placebo-controlled studies of Seroxat for the treatment of major depression, including the 16 that had been sent to the FDA. The results of their analysis... 

A Regulatory Apologia - a Review of Placebo-Controlled Studies in Regulatory Submissions of New-Generation Antidepressants , European Neuropsychopharmacology (2008)... 

Michelson, D., Bancroft, J., Targum, S., Kim, Y., and Tepner, R. (2000) Female sexual dysfunction associated with antidepressant administration a randomized, placebo-controlled study of pharmacologic intervention. Am J Psychiatry 157 239—243. 

As other indications are sought for the SSRls, it is clear that their action extends beyond depression, dysthymia, and the anxiety disorders, and the broad spectrum of therapeutic action of these antidepressants becomes apparent. For example, based on the evidence from placebo-controlled studies [A. Wood 1993], fluoxetine has been licensed in Europe for the treatment of bulimia, and several SSRls are reported to be effective in the treatment of premenstrual syndrome. 

The initial reports from open studies (Artigas et al. 1994 Blier and Bergeron 1995) suggest that the combination is associated with improved efficacy with probable faster onset of action. This rapid response was reported with augmentation of fluoxetine and paroxetine, and more recently with nefazodone (Bakish et al. 1997), but interestingly not with sertraline or low doses of fluvoxamine. These results needed to be confirmed in placebo-controlled studies, and the reports from large studies do indeed find an acceleration of response measured as time to response and possible superiority of action with some antidepressants at the end of treatment (Perez et al. 1997 Tome de la Granja et al. 1997). 

Milnadpran is a rather newer SNRI licensed as an antidepressant in France. It is associated with clear-cut efficacy judged on the placebo-controlled studies [Lecrubier et al. 1996 Macher et al. 1989]. Milnacipran inhibits the reuptake of both noradrenaline and serotonin (Moret et al. 1985]. It has a relatively short half-life and is given optimally in a dose of 50 mg twice daily. The proportion of reuptake inhibition between serotonin and noradrenaline is approximately equal with this antidepressant, and so one would expect that milnacipran would be more effective than SSRIs, assuming the theory is correct that two actions are better than one. 

On the basis of the large placebo-controlled studies, mirtazapine has undoubted antidepressant action and is licensed in both Europe and the United States [Claghorn and Lesem 1995 Sitsen et al. 1995). The evidence for superior efficacy is again limited by the failure to set up studies that were large enough to provide an adequate test of two active antidepressants. Nevertheless, mirtazapine has been shown to be more effective than trazodone in hospitalized patients with major depression (van Moffaert et al. 1995) and in a more recent study, mirtazapine was more effective than fluoxetine given in a dose of 20 mg [S. A. Montgomery 1996). 

Reboxetine is a pure noradrenaline reuptake inhibitor that is licensed as an antidepressant in the United Kingdom. Reboxetine has established efficacy based on placebo-controlled studies both in the short and the long term. Previous noradrenaline reuptake inhibitors, such as desipramine, nortriptyline, and maprotiline, have been relatively selective for noradrenaline compared... 

Georgotas A, Stokes P, McCue RE, et al The usefulness of DST in predicting response to antidepressants a placebo-controlled study. J Affect Disord 11 21-28, 1986... 

Stimulants such as amphetamine and methylphenidate have been used to treat depression for many years. Stimulants should not be used alone, except perhaps in geriatric patients with prominent apathy, medically ill patients with depression, or patients with poststroke depression (Lingam et al. 1988). However, psychostimulants are useful for augmentation of antidepressant therapy in refractory depression, and they are generally safe, even for most patients with cardiac disorders. The nonamphetamine stimulant modafmil was found to be helpful in a recent placebo-controlled study involving 311 patients with partial response to SSRIs (Fava et al. 2005). 

TABLE 7-9. Antidepressant effect (D change in Hamiiton Depression Rating Scaie [HDRS] J as a function of dose in fixed-dose, placebo-controlled studies... 

No studies demonstrate unique efficacy for nefazodone in any subgroup of patients with major depression. There is also no rigorous evidence to support the position that nefazodone is effective in patients who have not benefited from an adequate trial of another antidepressant. However, there is a double-blind, placebo-controlled study showing nefazodone to be superior to placebo in patients hospitalized for major depression. 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

A number of studies have been performed on the efficacy of St. John s Wort as an antidepressant. Several meta-analyses of these studies have also been published. The first such metaanalysis involved 23 randomized trials (15 placebo-controlled and eight active-controlled) involving 1,757 outpatients. It concluded that there was preliminary evidence supporting hypericum extracts as being superior to placebo in patients with mild to moderate clinical depression ( 233). Two more recent reviews of subsequent, placebo-controlled studies also concluded that hypericum is more effective than placebo but possibly less effective than TCAs ( 234, 235). At least two large-scale, multicenter, double-blind, placebo- and active-controlled studies are ongoing in the United States, testing the efficacy of hypericum versus an SSRI in patients with major depression. The results of these studies should further clarify the role of hypericum in the treatment of depressive disorders. 

Onghena, P. and van Houdenhove, B. Antidepressant-induced analgesia in chronic non-malignant pain a meta-analysis of 39 placebo-controlled studies, Pain 1992,49, 205-219. 

In addition to known antidepressants increasing endogenous opioids, opioid ligands have also been administered to depressed patients to determine if opioid compounds have clinical efficacy to treat depression. The opioid ligand cyclazocine improved symptoms in severely depressed, chronically ill mental patients in an open clinical trial and in clinical trials with patients unresponsive to the tricyclic antidepressant imipramine [16]. Intravenous (5-endorphin infusions improved mood in depressed patients in open case studies [17] and in depressed patients in a double-blind placebo-controlled study [18,19]. However, one study found a trend to improve depression scores in patients after acute and chronic (5-endorphin infusions, but it was not significant [20]. 

These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5HT neurotransmission. This notion is supported by the results of a 6-week doubleblind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (4). In a randomized, 8-week, double-blind, placebo-controlled study in 450 patients with major depression, fluoxetine (20 -0 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (5). 

In a double-blind, placebo-controlled study in 90 patients with sexual dysfunction who were taking a variety of 5HT re-uptake inhibitor antidepressants, sildenafil (50-100 mg) produced improvement in all aspects of the sexual response in 54% of antidepressant-treated patients compared with a placebo response rate of 4.4% (NNT = 2) (6). This suggests that sildenafil is an effective treatment for antidepressant-induced sexual dysfunction. 

Treatment guidelines for depression and anxiety increasingly emphasize the value of longer-term maintenance treatment with antidepressants in order to prevent recurrence of illness. It is therefore important to assess the adverse effects burden of longer-term medication. The change in adverse effects profile over 1 year of treatment has been studied in a double-blind, placebo-controlled study of maintenance treatment with imipramine (average daily dose 160 mg) in 53 patients with panic disorder (15). Adverse effects of imipramine, such as sweating, dry mouth, and increased heart rate, persisted over the year... 

Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B. Effect of SSRI antidepressants on ejaculation a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol 1998 18(4) 274-81. 

Cardiotoxic effects are relatively uncommon with mianserin (2). In a placebo-controlled study in 50 patients with a variety of cardiac conditions who were taking anticoagulants, mianserin (up to 30 or 60 mg) had no effects on electrocardiography, blood pressure, or pulse rate after 3 weeks. In a second phase, mianserin (up to 60 mg/day) was compared with amitriptyline (up to 150 mg/day) and placebo in 18 healthy volunteers. Measurements included systolic time intervals, electrocardiography at rest and during exercise, echocardiography, and blood pressure. Amitriptyline had a negative inotropic effect mianserin increased ejection fraction. The results of both these experiments led the authors to conclude that mianserin is an antidepressant with very low cardiac toxicity. 

The addition of lithium in treating major depressive disorder in patients unresponsive to antidepressant drugs has been discussed, and it has been noted that about 50% of patients respond to lithium augmentation in 2 1 weeks (71), while others have pointed to the absence of controlled data for this treatment in bipolar depression, while nevertheless recommending its use (72). In summary, there are data that support the use of lithium augmentation for treatment-resistant unipolar major depression. However, the data are not robust and are based on only a few hundred patients. Placebo-controlled studies of lithium augmentation for treatment-resistant bipolar depression are lacking (73). 

Mirtazapine is a tetracyclic antidepressant, similar to mianserin, and is a potent 5-HT2a/2c receptor antagonist. It has been successfully used to treat akathisia. In a doubleblind, placebo-controlled study in 26 patients with schizophrenia who were receiving neuroleptic drugs, mirtazapine 15 mg/day for 5 days was associated with less akathisia (227). 

Whether elderly patients taking lithium received proper monitoring was questioned in a case note audit of 91 patients, over 40% of whom had deviations from practice standards. These included absence of pretreatment laboratory tests, infrequent monitoring of serum lithium concentrations, lack of adequate adverse effects documentation, and the use of risky concomitant drugs (403). In a placebo-controlled study, there was poor tolerance of hthium augmentation of antidepressants in 76% (13/17) of elderly (mean age 70 years) patients at a mean serum concentration of 0.63 mmol/1, due to tremor and muscle twitches, cognitive disturbance, tiredness and sedation, and gastrointestinal upsets (404). 

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