Escitalopram but not placebo modulates brain rhythmic oscillatory activity in the first week of treatment of Major Depressive Disorder

Abstract

Serotonin modulates brain oscillatory activity, and serotonergic projections to the thalamus and cortex modulate the frequency of prefrontal rhythmic oscillations. Changes in serotonergic tone have been reported to shift oscillations between the combined delta-theta (2.5–8 Hz) and the alpha (8–12 Hz) frequency ranges. Such frequency shifts may constitute a useful biomarker for the effects of selective serotonin reuptake inhibitor (SSRI) medications in Major Depressive Disorder (MDD). We utilized quantitative electroencephalography (qEEG) to measure shifts in prefrontal rhythmic oscillations early in treatment with either the SSRI escitalopram or placebo, and examined the relationship between these changes and remission of depressive symptoms. Prefrontal delta-theta and alpha power were calculated for 194 subjects with moderate MDD prior to and one week after start of treatment. Changes at one week in delta-theta and alpha power, as well as the delta-theta/alpha ratio, were examined in three cohorts: initial (N = 70) and replication (N = 76) cohorts treated with escitalopram, and a cohort treated with placebo (N = 48). Mean delta-theta power significantly increased and alpha power decreased after one week of escitalopram treatment, but did not significantly change with placebo treatment. The delta-theta/alpha ratio change was a specific predictor of the likelihood of remission after seven weeks of medication treatment: a large increase in this ratio was associated with non-remission in escitalopram-treated subjects, but not placebo-treated subjects. Escitalopram and placebo treatment have differential effects on delta-theta and alpha frequency oscillations. Early increase in delta-theta/alpha may constitute a replicable biomarker for non-remission during SSRI treatment of MDD.

Introduction

Medications that inhibit serotonin reuptake (selective serotonin reuptake inhibitors, or SSRIs) are effective for the treatment of Major Depressive Disorder (MDD), leading to substantial reduction in symptoms in as many as 50% of patients (Krishnan and Nestler, 2010). Conversely, experimental interventions that deplete serotonin stores commonly are associated with transient exacerbation of depressive symptoms (Castrén, 2005). These observations, along with the behavioral effects of drugs that alter serotonergic neurotransmission in animal models of depression (Carr and Lucki, 2010), indicate that serotonin is a potent modulator of mood.

In addition to its demonstrated effects on mood, serotonin modulates a broad range of physiologic processes including functional connectivity (Salomon et al., 2011, Schaefer et al., 2014), circadian and ultradian rhythms (Salomon and Cowan, 2013, Westrich et al., 2015), plasticity and learning (Barre et al., 2016), and memory and cognition (Zhang and Stackman, 2015). The ubiquity of brain processes affected by serotonergic tone may reflect the fact that serotonin modulates brain network function through its effects on rhythmic oscillations in the brain (Puig and Gener, 2015). Serotonin regulates the firing rate of pacemaker neurons in multiple brain structures, thereby driving changes in oscillatory frequency and brain network formation (Hughes and Crunelli, 2005, Ramirez et al., 2004). Serotonergic effects on rhythmic oscillations may be most pronounced in prefrontal cortical networks. Prefrontal oscillatory synchrony is regulated by pacemakers in the dorsomedial nucleus (DM) of the thalamus, which has rich reciprocal connections with prefrontal cortex (Staudigl et al., 2012). The DM receives extensive serotonergic projections from the raphe nuclei (Geday et al., 2005, Vertes et al., 2010) and has among the highest concentrations of serotonin transporter (SERT) binding sites in the brain (Takano et al., 2011).

While serotonergic tone affects oscillations across a wide frequency spectrum (Celada et al., 2013), rhythmic oscillations in the 2.5–12 Hz frequency range are of particular interest. Frontal oscillations in this frequency range are regulated in part by a distinct population of thalamic pacemaker cells (Hughes and Crunelli, 2005). When hyperpolarized, these cells drive cortical rhythms in the lower frequency delta (2.5–4 Hz) and theta (4–8 Hz) range through thalamocortical projections; conversely, when depolarized, they shift cortex towards production of alpha (8–12 Hz) range oscillations (Celada et al., 2013, Crooks et al., 2012, Feige et al., 2005, Hughes and Crunelli, 2005, Kudina et al., 2004). Hyperpolarization of thalamic nuclei has been hypothesized to lead to MDD by causing thalamocortical dysrhythmia (TCD), a state of persistent highly resonant oscillatory activity in thalamocortical loops within the high delta and theta frequency bands (Llinás et al., 1999, Llinás et al., 2001, Llinás et al., 2005, Schulman et al., 2011). TCD causes brain network dysfunction (Leuchter et al., 2014a, Leuchter et al., 2015), consistent with the highly synchronous brain oscillatory activity seen in the prefrontal region in patients with MDD (Cook et al., 2014, Leuchter et al., 2012). With depolarization of thalamic nuclei, pacemaker cells burst at faster frequencies generating alpha rhythms (8–12 Hz), which is hypothesized to lead to resolution of TCD (Crunelli et al., 2006, Hughes and Crunelli, 2005, Hughes et al., 2004).

Previous studies have found that SSRI treatment is associated with changes in prefrontal oscillatory activity in the delta, theta, or alpha frequency bands (Bares et al., 2008, Bares et al., 2010, Cook et al., 2002, Knott et al., 1996, Leuchter et al., 2009a, Leuchter et al., 2009b). These studies have not, however, examined the balance of oscillatory activity between the slow wave (delta and theta) and alpha bands. Based upon the role of serotonin in regulating oscillations across this portion of the frequency spectrum, a shift in oscillatory energy between lower and higher segments of the 2.5–12 Hz band may be a biomarker for a true physiologic response to medication, as well as a predictor of treatment outcome (Leuchter et al., 2010, Leuchter et al., 2014a). In this study, we examined shifts in prefrontal oscillatory activity over the first week of treatment with the SSRI escitalopram using quantitative electroencephalography (qEEG). In order to examine the reproducibility of our findings, we examined shifts in qEEG relative power in both an initial and a replication cohort of escitalopram-treated subjects (70 and 76 subjects, respectively). In order to examine the specificity of the findings, we compared the results from escitalopram-treated subjects to a group of 48 subjects treated with placebo. We aimed to test two hypotheses: first, that treatment with escitalopram but not placebo would be associated with a shift in prefrontal relative power between the delta-theta and alpha frequency bands; and second, that a combined measure of the degree of shift between the slow wave (delta and theta) and alpha bands -- a delta-theta/alpha ratio -- would reliably predict remission of depressive symptoms in each cohort of subjects treated with escitalopram, but not subjects treated with placebo.