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.
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
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.
- 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.
- 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
- 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
- Any history of seizures, brain surgery, skull fracture, significant head trauma, or
previous abnormal EEG.