An Investigation of the Antidepressant Efficacy of the 5-HT2A Antagonist, M100907, in Combination With Citalopram in Treatment Resistant Depression

Depressive Disorder Clinical Trial

Official title: An Investigation of the Antidepressant Efficacy of the 5-HT2A Antagonist, M100907 in Combination With Escitalopram in Treatment Resistant Depression

Status Completed

Clinical Trial Summary

This study will examine whether a highly specific and powerful 5-hydroxytryptamine 2A (5-HT2A) antagonist, M100907, combined with escitalopram, is responsible for an antidepressant effect. Major affective disorders are common and can be chronic and life threatening. Yet as many as 50 to 75 percent of patients get only a partial response to the use of antidepressants. Some do not respond to medications in the category of serotonin reuptake inhibitors (SSRIs)-or they experience side effects that sharply interfere with daily life. This study will determine the extent to which M100907 improves sleep and improves fatigue in people who are treated, and how it reduces cognitive impairment, that is, limitations to awareness, in the depressive syndrome. It will also look at allele frequencies as being covariates in the analysis and to collect data.

Patients 18 to 65 years of age who meet the criteria for major depression, without psychotic features, may be eligible for this study. Women of childbearing potential must be using two medically accepted contraception methods and must agree to a (Beta)-HCG (human chorionic gonadotropin, a polypeptide hormone produced by the human placenta) test at the screening and at several intervals.

In random groups, participants will receive treatment with escitalopram and either M100907 or a placebo. The timing of escitalopram can be adjusted to manage side effects. If already taking any other medications for psychiatric purposes, participants will be tapered from those medications and monitored.

Participants will also undergo the following tests and procedures:

• Test of vital signs, lying and standing

• Physical exam

• 12-lead electrocardiogram (SCG)

• Psychiatric examination for screening

• Thyroid screening

• Collection of blood for chemistry and hematology

• Hepatitis B and C/HIV screening

• Beta-HCG pregnancy test, if applicable

• Urine drug screening

• Urinalysis

• Tests using the Hamilton Depression Rating Scale and the Montgomery-Asburg Depression Rating Scale

• Use of the Antidepressant Treatment History

A sleep study will be conducted during the steady state period and again toward the end of the double blind treatment period. Each study will involve 2 consecutive nights of polysomnographic recording done by an EEG technologist experienced in using the technique.

Clinical Trial Description

Major Affective Disorders are common and often chronic life threatening illnesses. Furthermore a significant fraction of patients do not respond to treatment with serotonin reuptake inhibitors (SSRI's), have only a partial response with continued significant morbidity and functional impairment, or suffer from drug induced side effects that decrease the individuals' quality of life. Side effects from SSRI's include gastrointestinal symptoms, anxiety, sleep disturbance, and sexual dysfunction. Evidence from recent clinical trials and preclinical studies suggests that blockade of 5-HT2 receptors may have antidepressant effects when combined with reuptake blockade of serotonin at serotonin transporters. In order to better determine whether 5-HT2A receptors are responsible for this effect we propose to study the highly specific and potent 5-HT2A antagonist, M100907, in combination with escitalopram in SSRI resistant major depression.

Subjects aged 18-65 will be studied who prospectively are shown to be treatment resistant to the SSRI escitalopram. Subjects will be randomized in a double-blind fashion to receive continued open treatment with escitalopram+M100907 or continued escitalopram+placebo. Subjects will have weekly mood and safety ratings during this randomized period for four weeks. At that time subjects who were initially randomized to placebo (and are non-responders) will be switched to active drug for four weeks of randomized treatment while the active group continues an additional four weeks of combination therapy. Those meeting remission criteria will be eligible to extend therapy in open treatment with the combination therapy for an additional period of up to 6 months.

Due to the potential for M100907 to improve sleep architecture in general and slow wave sleep in particular, sleep will be studied using polysomnographic methods before and after randomization. Sleep disturbance is also a well-known side effect of SSRI's, and the addition of M100907 may improve sleep disturbance related to the affective disorder itself or to iatrogenic SSRI effects on sleep. Examination of improvement in sexual side effects, gastrointestinal side effects, headache frequency, and anxiety will also be investigated in the comparison of addition of M100907 versus placebo in escitalopram treated subjects. DNA samples will be collected for neurotransmitter-related genetic polymorphisms for covariance.

Finally, 5-HT2A receptors on cortical apical dendrites sit in a crucial location to influence cognitive processing and excitatory transmission. Since some 5-HT2A antagonists can lead to a down-regulation of 5-HT2A receptors and their altered distribution, as well as increased prefrontal cortical monoamine levels, neuropsychological testing to compare between and within subjects treated with M100907 and placebo may increase our understanding of the importance of serotonin receptors in cognition and depression. Subjects will be studied neuropsychologically before and twice following randomization. If M100907 enhances cognition in depression this would be an important advance given the high rates of impairment in functioning and residual cognitive difficulties observed in patients with depression. ;

Study Design

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Treatment-Resistant

• NCT number: NCT00070694
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 2
• Start date: September 2003
• Completion date: October 2004