Brain Mechanisms and Targeting Insomnia in Major Depression

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2010 by University of California, Los Angeles.
Recruitment status was  Active, not recruiting
Information provided by:
University of California, Los Angeles Identifier:
First received: February 25, 2008
Last updated: August 19, 2010
Last verified: July 2010
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 Intervention Phase
Major Depressive Disorder
Drug: escitalopram and eszopiclone
Drug: Escitalopram, eszopiclone, and placebo
Drug: Escitalopram
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Brain Mechanisms and Targeting Insomnia in Major Depression

Resource links provided by NLM:

Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:
  • Change in cordance value [ Time Frame: Visits 2-9 ] [ Designated as safety issue: No ]
  • Change in cordance value [ Time Frame: Visit 11 ] [ Designated as safety issue: No ]
  • Change in cordance value [ Time Frame: Visit 13 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Depression symptom severity [ Time Frame: each visit ] [ Designated as safety issue: No ]
  • Serum BDNF [ Time Frame: visits 2-9 ] [ Designated as safety issue: No ]
  • Cognitive testing [ Time Frame: visits 2-7 ] [ Designated as safety issue: No ]
  • Serum BDNF [ Time Frame: Visit 11 ] [ Designated as safety issue: No ]
  • Serum BDNF [ Time Frame: Visit 13 ] [ Designated as safety issue: No ]
  • Cognitive testing [ Time Frame: Visit 9 ] [ Designated as safety issue: No ]
  • Cognitive testing [ Time Frame: Visit 13 ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: May 2008
Estimated Study Completion Date: February 2010
Estimated Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.


Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Both
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.
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Please refer to this study by its identifier: 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
  More Information

Additional Information:
Responsible Party: Ian A. Cook, M.D., University of California Los Angeles Identifier: NCT00628914     History of Changes
Other Study ID Numbers: ESRC973  07-11-013 
Study First Received: February 25, 2008
Last Updated: August 19, 2010
Health Authority: United States: Institutional Review Board

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

Additional relevant MeSH terms:
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mental Disorders
Mood Disorders
Anti-Dyskinesia Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Autonomic Agents
Central Nervous System Agents
Central Nervous System Depressants
Cholinergic Agents
Cholinergic Antagonists
Hypnotics and Sedatives
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Uptake Inhibitors processed this record on April 27, 2016