Brain Mechanisms and Targeting Insomnia in Major Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00628914
Recruitment Status : Unknown
Verified July 2010 by University of California, Los Angeles.
Recruitment status was:  Active, not recruiting
First Posted : March 5, 2008
Last Update Posted : August 20, 2010
Information provided by:
University of California, Los Angeles

Brief Summary:
Preliminary studies suggest that the response to antidepressant medication can be accelerated by targeting insomnia with adjunctive use of eszopiclone. It is not yet known what mechanism(s) support this acceleration in response, though preliminary findings support the hypothesis that early restoration of sleep may facilitate BDNF-based effects of antidepressant medications. The optimal duration of co-treatment is also unknown. This study will test specific hypotheses about brain mechanisms and evaluate the effects of continued eszopiclone beyond the time window when response acceleration should be observed.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Insomnia Drug: escitalopram and eszopiclone Drug: Escitalopram, eszopiclone, and placebo Drug: Escitalopram Phase 4

Detailed Description:

A critical challenge in the management of major depressive disorder (MDD) is the delay between initiating treatment with an antidepressant medication and clinical improvement. Preliminary studies (Fava et al., 2006; Krystal et al., 2007) suggest that targeting insomnia with eszopiclone (ESZ) in patients receiving fluoxetine may lead to more rapid resolution of symptoms. Studies have not yet been able to differentiate between competing explanations of this phenomenon: whether co-treatment with ESZ actually accelerates changes in the brain associated with antidepressant treatment response, or if its effects on the insomnia component are confined to the symptomatic level ("masking"). As a non-benzodiazepine GABA-receptor agonist with FDA approval for long-term use in the treatment of sleep disturbances, ESZ is an appropriate agent for targeting insomnia in MDD without major concerns around the development of tolerance. Further research in co-treatment would be advanced by understanding the mechanism(s) underlying accelerated improvement.

Our prior work (Cook et al., 2001, 2002, 2005; Leuchter et al. 2002) has studied a new physiologic biomarker of response to SSRI and mixed-action antidepressants. The EEG-based cordance biomarker can detect the physiologic effects of successful antidepressant treatment at 48 hours, 1 week, and 2 weeks of treatment; in contrast, symptom differences between responders and non-responders did not separate until 4 weeks of treatment in our placebo-controlled trials. Additionally, the magnitude of early physiologic change was associated with the completeness of clinical response. Our biomarker has been independently studied and our findings replicated (Bareš et al., 2007). The cordance biomarker can be considered as a leading indicator or predictor of treatment outcome. As a non-invasive probe of brain physiology, it may detect early neurophysiologic changes associated with accelerated clinical response from eszopiclone.

Other research has reported that brain derived neurotrophic factor (BDNF) is reduced in many patients with MDD (Karege et al., 2002, 2005, Shimizu et al., 2003) and may rise during the course of treatment with antidepressant medication (e.g., Gonul et al., 2005; Yoshimura et al., 2007; Huang et al., 2007). BDNF-related neuroplasticity has been suggested as a mechanism by which medications can lead to mood improvement (Duman 2002; Manji et al., 2003). Sleep patterns have also been shown to have an impact on neuroplasticity (Taishi et al., 2001; cf. Benington & Frank, 2003). A simple acute phase-shift in sleep can impact BDNF levels (Sei 2003), suggesting that a link between sleep and symptomatic recovery from depression might operate via a BDNF mechanism and reflect changes in brain physiology.

While Krystal and colleagues (2007) previously reported that the beneficial clinical effects of 8 weeks of co-treatment did not diminish significantly in the two weeks following ESZ discontinuation, controlled studies have not examined outcomes in clinically-likely scenarios employing shorter co-treatment periods (e.g., 4 weeks, during which much of the acceleration occurs).

Based on these previous studies, this study will assess patients with MDD during treatment with an SSRI antidepressant, escitalopram (ESC), administered along with either ESZ or placebo (PBO), using (a) clinical symptom ratings, (b) serum levels of BDNF, (c) cognitive function, and (d) brain physiology with EEG.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Brain Mechanisms and Targeting Insomnia in Major Depression
Study Start Date : May 2008
Estimated Primary Completion Date : November 2009
Estimated Study Completion Date : February 2010

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: 1
Open label escitalopram plus eszopiclone for 8 weeks
Drug: escitalopram and eszopiclone
escitalopram 10mg tabs QD and eszopiclone 3 mg tabs QD for 8 weeks
Other Names:
  • Lexapro
  • Lunesta
Escitalopram and eszopiclone for initial 4 weeks, then switch to escitalopram and placebo for final 4 weeks.
Drug: Escitalopram, eszopiclone, and placebo
Escitalopram 10mg tabs QD for 8 weeks; Eszopiclone 3mg tabs QD for initial 4 weeks then placebo tabs QD for final 4 weeks
Other Names:
  • Lexapro
  • Lunesta
Placebo Comparator: 3
Escitalopram plus placebo for 8 weeks
Drug: Escitalopram
Escitalopram 10mg tabs QD and placebo tabs QD for 8 weeks
Other Name: Lexapro

Primary Outcome Measures :
  1. Change in cordance value [ Time Frame: Visits 2-9 ]
  2. Change in cordance value [ Time Frame: Visit 11 ]
  3. Change in cordance value [ Time Frame: Visit 13 ]

Secondary Outcome Measures :
  1. Depression symptom severity [ Time Frame: each visit ]
  2. Serum BDNF [ Time Frame: visits 2-9 ]
  3. Cognitive testing [ Time Frame: visits 2-7 ]
  4. Serum BDNF [ Time Frame: Visit 11 ]
  5. Serum BDNF [ Time Frame: Visit 13 ]
  6. Cognitive testing [ Time Frame: Visit 9 ]
  7. Cognitive testing [ Time Frame: Visit 13 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Outpatients with non-psychotic, unipolar Major Depressive Disorder (MDD).
  • A score of >14 on the HAM-D17.
  • Presence of insomnia, manifest by a total score of ≥ 4 combining all three sleep disturbance items on the HAM-D17 scale.
  • Age range: 18-64.
  • Patients with suicidal ideation are eligible only if the thoughts of death or of life not being worth living are not accompanied by a plan or intention for self-harm.

Exclusion Criteria:

  • Patient is mentally or legally incapacitated, unable to give informed consent.
  • Patients who have a lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, MDD with psychotic features, or dementia (any etiology).
  • Patients with diagnostic uncertainty or ambiguity (e.g. rule-out pseudodementia of depression) will be excluded.
  • Patients with a current diagnosis of anorexia nervosa, bulimia nervosa, or obsessive compulsive disorder.
  • Patients who have met diagnostic criteria for any current substance abuse disorder at any time in the 6 months prior to enrollment.
  • Insomnia symptoms that have not responded to a previous trial of a sedativehypnotic prescription medication.
  • Any history of seizures, brain surgery, skull fracture, significant head trauma, or previous abnormal EEG.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00628914

United States, California
Semel Institute for Neuroscience and Human Behavior at UCLA
Los Angeles, California, United States, 90024
Sponsors and Collaborators
University of California, Los Angeles
Principal Investigator: Ian A Cook, MD Semel Institute for Neuroscience and Human Behavior at UCLA

Additional Information:
Responsible Party: Ian A. Cook, M.D., University of California Los Angeles Identifier: NCT00628914     History of Changes
Other Study ID Numbers: ESRC973
First Posted: March 5, 2008    Key Record Dates
Last Update Posted: August 20, 2010
Last Verified: July 2010

Keywords provided by University of California, Los Angeles:
Major Depressive Disorder

Additional relevant MeSH terms:
Depressive Disorder
Depressive Disorder, Major
Sleep Initiation and Maintenance Disorders
Behavioral Symptoms
Mood Disorders
Mental Disorders
Sleep Disorders, Intrinsic
Sleep Wake Disorders
Nervous System Diseases
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists