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61st Annual Meeting of the Society of Biological Psychiatry

Toronto, Ontario / May 18-20, 2006

The notion that it takes weeks for an antidepressant to be effective emerged from several influential analyses in which the largest gap in response between active treatment and placebo was seen quite late in the course of treatment. This notion was also compounded by the need for patients to meet fairly demanding criteria for improvement as judged by scales such as the Clinical Global Impression Scale and the Hamilton Depression Scale (HAM-D). Large decrements in depression scores from baseline would usually take three to four weeks to occur.

Analyzing Trial Results

The “delayed onset of action” hypothesis was reassessed here during a dedicated symposium. As Dr. Armin Szegedi, Roseland, New Jersey, noted in an interview, following initiation of antidepressant therapy, “What you see is more or less continuous improvement on a scale such as the HAM-D scale and this improvement can be reliably measured after only one to two weeks of treatment.” Indeed, at two weeks, the majority of patients already have a 20% decrease in their HAM-D scores from baseline.

To analyze this phenomenon more closely, Dr. Szegedi and colleagues observed individual treatment responses in a database made up of approximately 6500 patients who had participated in 41 different randomized clinical trials involving mirtazapine, venlafaxine, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. Their intent was to assess not only whether early changes in response to antidepressant therapy were present but, if present, whether these early changes identified patients who would respond over the longer term. “Improvement was defined as a HAM-D-17 score reduction ³20%,” investigators noted, “and stable response or remission was defined as being present both at week 4 and week 6.”

Results of this extensive analysis showed that approximately 60% to 70% of patients who improve with antidepressant treatment after two weeks of therapy would become responders—defined as a 50% reduction in the HAM-D score from baseline—at six weeks. Conversely, only about 10% of patients who finally become responders or remitters have no sign of early improvement at two weeks. “With mirtazapine, if titrated quickly to an effective dose of 35 to 40 mg/day, you can lower this percentage even further,” Dr. Szegedi added. For example, when investigators analyzed results in trials between mirtazapine and venlafaxine, fewer than 2% of patients who responded to or who remitted with mirtazapine did not have this early response to treatment, compared with 4.2% of patients treated with venlafaxine. “This is very useful to know,” Dr. Szegedi observed, “because it enables you to make a very early decision as to whether or not you are on the right track with your patient. It is also good for the patient because it means they do not have to wait another two to four weeks for no good reason.”

Dr. Szegedi also noted that as far as their analysis showed, there is no specific domain that has to be addressed in order to induce the early recovery process. “What we have seen with mirtazapine is that it is not only the sleep domain which is positively affected, but the anxiety somatization factor as well and, contrary to what you might expect with a drug that has some sedating component, retardation is not worsened but rather improved,” Dr. Szegedi observed.

Nor does it appear to matter which depression assessment scale is used to measure early response, as they all appear to support the importance of an early response as a predictor of later response. In their analysis, for example, response to antidepressant therapy was assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) in some 4000 patients. When investigators limited their analysis to only this subgroup of patients, “results were very comparable, so it does not appear to depend on the rating scale used, it is much more important to capture this by clinician assessment,” Dr. Szegedi stated. There was also no difference in treatment response in patients who were taking concomitant sleep medications, “so this again strengthens the idea that we are measuring a real phenomenon that we can pick up quite early,” he added.

Prospective Study

Another recently published prospective study in which Dr. Szegedi was involved compared the onset of antidepressant action between orally disintegrating tablets of mirtazapine RD with that of the venlafaxine extended-release (XR) formulation in patients with major depression (Benkert et al. J Clin Psychopharmacol 2006;26(1):75-8). “These two compounds are believed to be particularly effective in the early course of treatment,” Dr. Szegedi indicated, “and both drugs were aggressively titrated within six days to a very effective dose, the intention being to allow both compounds to show their full potential as quickly as possible.” The primary efficacy outcome was the average change in HAM-D-17 total score on days 5, 8, 11 and 15.

Results showed that the orally disintegrating tablet was significantly more efficacious than the XR agent (P=0.008). “In addition, calculating the HAM-D score without the sleep items resulted in significant reductions in favour of mirtazapine RD on days 8 [P=0.002], 11 [P=0.004] and 22 [P=0.037],” investigators stated in a published abstract of the study. The proportion of responders, defined as a reduction in the HAM-D score of 50% or greater from baseline, was also higher in the mirtazapine RD group on all assessment days, and more patients achieved remission (defined as a HAM-D total score of 7 or less up to day 29) than those treated with the XR formulation.

Indeed, not a single patient treated with mirtazapine RD in this comparative study became a responder or remitter who had not reacted to the antidepressant by the second week, “so this is obviously a drug which very nicely allows you to make an accurate assessment after two weeks of treatment as to whether you should continue patients on the drug or whether you should consider adding something else or change the regimen altogether,” Dr. Szegedi commented. He also noted that he personally would always choose a therapy such as mirtazapine RD or venlafaxine that addresses more than one neurotransmitter system if patients do not achieve an early response to an SSRI. “There are sets of data showing that the percentage of patients who react to antidepressants that affect more than one neurotransmitter system is significantly higher in the early course of treatment compared with an SSRI, so the likelihood that you can induce this recovery process is higher with the dual monoamine oxidase inhibitor drugs than with the SSRIs,” he said. Interestingly, the incidence of side effects has been shown to be actually lower when the combination of mirtazapine RD and venlafaxine is used than when either agent is given alone, he added.

Dr. Alan Frazer, Professor and Chair, Department of Pharmacology, Professor of Pharmacology and Psychiatry, University of Texas Health Science Center, San Antonio, and colleagues reported that their randomized, double-blind trial comparing onset of action with desipramine, paroxetine or placebo in hospitalized depressed patients again showed that active treatment regimens produced distinct patterns of behavioural improvement within the first two weeks of treatment in those patients who responded to therapy after six weeks of treatment. “This was not seen in patients treated with placebo or in non-responders,” Dr. Frazer noted, who also concluded, “Early drug-specific effects are highly predictive of ultimate clinical response to the different antidepressants.”