Antidepressant trials

Moncrieff J. (2001). Are antidepressants overrated A review of methodological problems in antidepressant trials. /. Nerv. Ment. Dis., 189(5), 288-95. 

This is not just speculation. It is backed by evidence. Some antidepressant trials are conducted without placebo groups. 

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... 

Turner, Erick H., Annette M. Matthews, Eftihia Linardatos, Robert A. Tell and Robert Rosenthal, Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy , New England Journal of Medicine 358 (2008) 252-60... 

A 6-week antidepressant trial at a maximum dosage is considered an adequate trial. Patients must be told about the expected lag time of 2 to 4 weeks before the onset of antidepressant effect. 

As with any decision to initiate an antidepressant trial, it should be based on the potential risks and benefits. The limited evidence that exists indicates that both drugs and ECT can be used safely and effectively in such patients when appropriate allowances are made for health status. Empirical trials are wanting but clearly warranted. 

Severe depression is another term that is frequently seen in the literature discussing clinical depression and antidepressant trials. There is no uniform definition of this term. One or more of the following criteria may be used to differentiate patients with nonsevere versus severe depression ... 

These issues must be kept in mind when interpreting claims made on the basis of clinical trial results. The variability in scales and definition of terms used in antidepressant trials also confounds attempts to make comparisons across studies and to do meta-analyses. With these caveats in mind, the next several sections review the acute and maintenance efficacy of the available antidepressant options, as well as some currently investigational antidepressants. 

However, the patient s subjective sense of depression, anhedonia, and hopelessness may not improve until the fourth to sixth week of treatment, often prompting them to pressure the physician to prematurely abandon a potentially successful antidepressant trial. 

Perhaps the greatest research need in antidepressant pharmacotherapy is what to do when the first antidepressant trial fails to produce response. Indeed, in clinical trials, 35% to 40% of patients do not achieve a 50% reduction in their symptoms on any single antidepressant and the majority do not have a full remission. Thus, this discussion is relevant to the majority of patients with major depression. 

The recovering patient who remains depressed after appropriate treatment of the abstinence syndrome should be given an antidepressant trial. Treatment planning should take into account the patient s physical status, especially because it may affect the pharmacokinetics and pharmacodynamics of the agent selected (see Chapter 3). 

It is also prudent to explain other options, especially if the first medication trial is unsuccessful. Thus, it is crucial to reassure the patient before the first antidepressant trial that if unsuccessful, there is a good chance of responding to an alternative therapy. Patients understand and accept the concept of empirical trials. Educating and involving them in the decision-making process is not only politically correct, but also therapeutic because this approach... 

The combination was reported to be superior to either agent alone in reducing parent ratings of conduct problems. However, the combination has never been tested in children with ADHD alone for the core symptoms of hyperactivity, inattention, and impulsivity. There is also concern about the safety of this combination because there have been four deaths in children (105). However, there were enough complicating factors present in each of these cases that no conclusions could be drawn about the role of methylphenidate and clonidine in these deaths. For these reasons, the use of clonidine for the treatment of ADHD should be tried only after trials of more than one psychostimulant and after an antidepressant trial. 

Moncrieff, J. 2003a, A comparison of antidepressant trials using active and inert placebos, Int.J.Methods Psychiatr.Res., vol. 12, no. 3, pp. 117-127. 

In a re-analysis of antidepressant trial data there was an odds ratio for a suicidal act while taking SSRIs relative to placebo of 2.0 (Cl = 1.2, 3.3), while the risk for completed suicide on SSRIs, although raised, had wide confidence intervals (RR = 3.1 Cl = 0.4, 23.1) (23). One of the author s arguments was that in previous analyses suicidal behaviors occurring during placebo wash-out have been misclassified as happening during placebo treatment. Separation of these two classes of event allows a pro-suicidal effect of SSRIs to be revealed. 

The FDA has mandated a label warning that antidepressant use can increase suicidal ideation in adolescents and young adults receiving these agents [46]. This was based on a review of 4582 pediatric participants in 24 antidepressant trials. There were no completed suicides in any of these patients, but suicidal ideation and suicidal behaviors were nearly twice as common among recipients of antidepressants as those receiving placebo... 

Consider longer-acting stimulant trial or antidepressant trial... 

Even C, Siobud-Dorocant E, Dardeimes RM. Critical approach to antidepressant trials. Blindness protection is necessary, feasible and measurable. Br J Psychiatry 2000 177 47-51... 

Treatment-resistant depression typically refers to an inadequate response to at least one antidepressant trial of adequate dose (superior to placebo in controlled clinical trials) and duration (e.g. 6-12 weeks). Treatment-resistant depression is a relatively common occurrence in clinical practice, with up to 50-60% of patients not achieving an adequate response following antidepressant treatment. Although the more traditional view of treatment resistance has focused on non-response, from the perspective of clinicians and patients, not achieving remission despite adequate treatment represents a significant challenge. In addition, response without remission has a potentially poor outcome, as residual symptoms are associated with poorer outcome and increased relapse risk. With this treatment approach in mind, inadequate response implies that the treatment has failed to achieve remission from the clinician s and patient s perspective, remission typically implies achieving a relatively asymptomatic state. ... 

---