Marplan® (isocarboxazid) Clinical Trial Data
Treatment Resistant Depression
Of those patients who, despite antidepressant treatment, continue to suffer from Treatment-Resistant Depression (TRD), a modest 22%-30% will achieve remission. TRD is not consistently defined, and variations in definitions used across treatment centers may complicate discussion of treatments. However, failure to respond to 3 or more adequate trials is frequently used as a standard.
The treatment of depression that has not responded to multiple treatment trials has rarely been systematically studied. ECT has long been considered the primary option for treatment-resistant depression, but high rates of relapse, cognitive side effects, and poor acceptability make this option problematic. Monoamine oxidase inhibitors (MAOIs), such as Marplan, have been used successfully as an alternative to ECT for treatment-resistant depression.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) were first identified as effective antidepressants in the late 1950s. An early report suggested that iproniazid, an antitubercular agent, had mood-elevating properties in patients who had been treated for tuberculosis.
The target function of MAOIs is regulation of the monoamine content within the nervous system. The hydrazine derivatives, including Marplan® (isocaroxazid), are related to iproniazid. The nonhydrazine irreversible MAOI is tranylcypromine, which is chemically similar to amphetamine.
MAOIs are used in a wide range of psychiatric disorders. Early studies suggested that MAOIs are particularly effective in patients who have atypical depression (originally defined as depression with anxiety) or chronic pain, reversed vegetative symptoms, and rejection sensitivity.
Meta-Analyses and Important Individual Clinical Trials
What we know today about the clinical evidence supporting Marplan is detailed in the rigorous meta-analyses performed in the mid-90's which reviewed the data gathered in the early studies conducted during the 60's through the 80's.
Marplan is unique among the irreversible MAOIs in having the largest body of placebo-controlled data supporting the safety and efficacy of its use for the treatment of depression.
We are reporting this range of studies in order to document more fully the clinical basis of the efficacy of Marplan in Treatment-Resistant Depression.
Meta-analyses of Marplan Clinical Trials
- In 1995 Thase, et al1, conducted a meta-analysis of 12 randomized controlled trials in 434 depressed patients, comparing FDA-approved MAO-I drugs.
Using the Intent-To-Treat sample method, the authors concluded that Marplan exhibited a 41.3% average difference vs. placebo in the number of patients randomized to treatment who demonstrated improvement.
Intent-to-treat samples in five of these 12 studies revealed a Marplan efficacy rate of 60.1%.
In eight of the twelve studies, the Adequate Treatment sample method showed a Marplan efficacy rate of 68.2% among outpatients who received at least a minimum number of weeks of treatment.
The 1984 study of Giller, et al2, one of seven placebo-controlled studies in the meta-analysis, out-patients who were crossed over from placebo (due to lack of response) achieved a 69% response rate with Marplan treatment.
Marplan Clinical Trials
Giller, Riddle and Waldo3 conducted a 1988 multiaxial assessment of the effectiveness of Marplan in 43 adult outpatients with major depressive disorder. In addition to depression, patients experienced one or more of the following symptoms: anxiety, somatic complaints, phobia, or panic. Seven patients also were diagnosed with melancholia. The mean duration of the current [sic] episode was 19 [±]16 months.
- The study evaluated 4 outcome areas: symptoms, work, family functioning, and social functioning.
After 6 weeks on Marplan, the 'symptoms' category improved the most. For the 23 patients completing 24 weeks on Marplan ("completers"), all 4 outcome areas were further improved compared with levels at 6 weeks; improvement in work functioning reached statistical significance (p = 0.0006).
The study found, among the completers, further improvement occurred in all 4 outcome areas, and that patients who began to improve at week 6 were the ones who continued to improve at week 24.
The bulk of the improvement in work-related outcomes occurred between weeks 6 and 24, not during the first 6 weeks—in contrast to the early improvement in symptoms, the authors noted, concluding that the importance of continuing Marplan after initial symptomatic improvement "cannot be underestimated."
- In an earlier study (1982), Giller et al4 conducted a 6-week placebo-controlled trial of 30 outpatients diagnosed as having major depressive disorder with melancholia. Dosage of Marplan was titrated to 40mg per day by the end of the first week and increased until 90% of platelet MAO-Inhibition was achieved (or to a maximum of 80mg per day).
The authors observed a significant symptomatic improvement in the Marplan-treated patients compared with patients given placebo. Data for 24 patients who completed at least 6 weeks of the study showed that 92% of patients receiving Marplan improved vs 27% of placebo patients. In the active treatment group, there was a significant improvement in symptoms by week 3.
Anxiety appeared to improve first, with significant improvement from baseline seen in both active and placebo groups at weeks 1 and 2. At week 3 only patients on active medication had sustained the improvement in anxiety. Individual depressive items began to improve at week 2, with the major change occurring at week 3. It was not until week 6 that significant improvement was seen in the cognitive items of helplessness, hopelessness, and worthlessness. At the close of the trial 92% of the Marplan patients had improved vs. 27% of the patients on placebo.
- A 1982 placebo-controlled study by Davidson and Turnbull5 examined results in a predominantly female population of 29 patients exhibiting primary depression or depression secondary to an anxiety disorder. At doses of 30-60mg per day, early superiority for Marplan was noted at week one using the Covi Anxiety scale, and statistically significant superiority in all ratings of clinical findings was seen at week 4.
In their classic 1960 exploratory report on Marplan, Rothman, et al6 studied 25 patients admitted to a psychiatric hospital exhibiting moderate to severe depressive symptoms associated with suicidal preoccupation, psychomotor retardation, self-depreciation, and sleep disturbances. Five of the Marplan patients displayed depressive symptoms concomitant with schizophrenia, one concomitant with schizo-affective reactions, and one with personality disorder.
Patients were started on an initial daily Marplan dosage of 40mg, and titrated down to a 20mg daily maintenance dosage once improvement of symptoms occurred.
Please see Full Prescribing Information including BOXED WARNINGS regarding increased risk of suicidality in children and adolescents. MAO-Inhibitors are contraindicated with certain drugs. Potential hypertensive crises may occur with foods that contain tyramine. As with all antidepressants, patients should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of treatment.
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