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

NCT00070694 | Completed Phase 2

• 2 other identifiers: 03031503-M-0315
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Depressive Disorder

Keywords

Affective Disorders; Refractory; Augmentation; Polysomogram; Combination Therapy; Affective Disorder; Depression; Major Depression

Interventions

MDL100.907 DRUG

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects meeting all of the following criteria will be considered for enrollment into the study:
• Men or women, 18 to 65 years of age.
• A woman of childbearing potential must be using two medically accepted means of contraception. This can include an oral or other hormonal contraceptive started at least 4 weeks prior to randomization plus a barrier method such as condoms or two barrier methods combined. Surgical sterilization of the subject or their partner is also considered acceptable. Hormonal therapies should be in place at least 4 weeks prior to randomization (V8). Women of childbearing potential must agree to a beta test at screening and during Visits 5, 7, 8, 9, 11 and 13 through 16.
• Each subject must have a level of understanding sufficient to agree to all tests and examinations required by the protocol.
• Subjects must be considered reliable (i.e., based on clinical judgment of the investigator the subject is able and willing to cooperate with study procedures (including compliance with medication, use of birth control appropriately, and attend study visits, etc).
• Each subject must understand the nature of the study and must sign an informed consent document.
• Subjects must fulfill the criteria for major depression, without psychotic features as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.
• Subjects must have an initial score at Visit 1 and Visit 2 of at least 20 on the HAM-D (17).
• Subjects must have a total score of HAM-D at the end of the 6th week of escitalopram prospective screening of at least 17 (visit 5).
• Current major depressive episode of at least 4 weeks duration and for the current episode of major depression has a history of failure to respond to at least 4 weeks of any antidepressant medication such as SSRI, Wellbutrin, nefazodone/trazadone, MAOI, or venlafaxine/duloxetine at an adequate or clinically customary dose for antidepressant purposes prior to entering escitalopram screening. Informed consent must be obtained in writing for all subjects at enrollment into the study.

You may not qualify if:

• Subjects presenting with any of the following will not be included in the study:
• No subjects who have previously been treated with the investigational product (M100907) will be enrolled in this study.
• Participation in a clinical trial of another investigational (nonmarketed) drug within 1-month (30 days) prior to study Visit 1.
• Female subjects who are either pregnant or breast-feeding or who do not appear reliable to use adequate contraception.
• Clinically significant cardiovascular, hepatic, endocrinologic (including but not limited to diabetes and uncorrected hypothyroidism or hyperthyroidism), neurological (including but not limited to epilepsy, stroke and sleep apnea), or other major systemic disease making implementation of the protocol or interpretation of the study results difficult
• Subjects with one or more past seizures without a clear and resolved etiology.
• DSM-IV substance abuse (except nicotine and caffeine) within the past 90 days and substance dependence within the past 2 years.
• Treatment with a reversible monoamine oxidase inhibitor, guanethidine, or guanadrel within 1 week prior to Visit 2.
• Treatment with any other concomitant medication with primarily CNS activity, other than specified in Appendix 2 1 day prior to randomization.
• Subjects are excluded if greater than four failed antidepressant trials in the past not including escitalopram (adequate dose and duration) during the index episode of major depression. An adequate trial is defined as 6 weeks of treatment with the antidepressant at a dosage considered therapeutic 159. The doses considered therapeutic are for fluoxetine 20-80 mg/day, paroxetine 20-60 mg/day, sertraline 100-200 mg/day, citalopram 20-40 mg/day, escitalopram 10-20 mg/day, fluvoxamine 100-300 mg/day, bupropion 300-450 mg/day, and venlafaxine 75-375 mg/day.
• Failure to respond to drugs with a 5-HT2 mechanism when added to SSRI including nefazodone, trazodone, mirtazapine/mianserin, SSRI + atypical neuroleptics (clozapine, risperidone, olanzapine, ziprasidone) at therapeutic doses for 4 weeks or longer. (the SSRI must be at clinically appropriate doses and the 5-HT2 antagonist must be at doses that antagonize a significant % of receptors (trazadone greater than 125 mg, nefazodone greater than 300 mg, mirtazapine greater than 30 mg, clozapine greater than 50 mg, risperidone greater than .5 mg, olanzapine greater than 5mg, ziprasidone greater than 20 mg).
• Treatment with electroconvulsive therapy (ECT) within 3 months prior to Visit 2.
• Current diagnosis of schizophrenia or other psychotic or bipolar disorder as defined in the DSM-IV.
• Judged clinically to be at serious risk of suicide based on HAM-D suicide item rating plus direct clinical questioning and assessment.
• History of drug or alcohol dependence criteria in the last 2 years.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institute of Mental Health (NIMH)

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Viguera AC, Baldessarini RJ, Friedberg J. Discontinuing antidepressant treatment in major depression. Harv Rev Psychiatry. 1998 Mar-Apr;5(6):293-306. doi: 10.3109/10673229809003578.

  PMID: 9559348 BACKGROUND

• Solomon DA, Keller MB, Leon AC, Mueller TI, Shea MT, Warshaw M, Maser JD, Coryell W, Endicott J. Recovery from major depression. A 10-year prospective follow-up across multiple episodes. Arch Gen Psychiatry. 1997 Nov;54(11):1001-6. doi: 10.1001/archpsyc.1997.01830230033005.

  PMID: 9366656 BACKGROUND

• Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001 Mar;178:234-41. doi: 10.1192/bjp.178.3.234.

  PMID: 11230034 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder; Mood Disorders; Depression; Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Mental Disorders; Behavioral Symptoms; Behavior

Study Design

• Study Type: interventional
• Phase: phase 2
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: October 6, 2003
• First Posted: October 7, 2003
• Study Start: September 1, 2003
• Study Completion: October 1, 2004
• Last Updated: March 4, 2008

Record last verified: 2004-10

Locations

US (1)