Research report
Brain effects of antidepressants in major depression: A meta-analysis of emotional processing studies

https://doi.org/10.1016/j.jad.2010.09.032Get rights and content

Abstract

Background

A consistent brain activity pattern has been identified in major depression across many resting positron emission tomography (PET) studies. This dysfunctional pattern seems to be normalized by antidepressant treatment. The aim of this meta-analysis was to identify more clearly the pattern associated with clinical improvement of depression following an antidepressant drug treatment, in emotional activation studies using functional magnetic resonance imaging (fMRI).

Methods

A quantitative Activation Likelihood Estimation (ALE) meta-analysis was performed across 9 emotional activation fMRI and PET studies (126 patients) using the Activation Likelihood Estimation technique.

Results

Following the antidepressant drug treatment, the activation of dorsolateral, dorsomedial and ventrolateral prefrontal cortices was increased whereas the activation of the amygdala, hippocampus, parahippocampal region, ventral anterior cingulate cortex, orbitofrontal cortex, and insula was decreased. Additionally, there was a decreased activation in the anterior (BA 32) and posterior cingulate cortices, as well as in the precuneus and inferior parietal lobule, which could reflect a restored deactivation of the default mode network.

Limitations

The small number of emotional activation studies, using heterogeneous tasks, included in the ALE analysis.

Conclusions

The activation of several brain regions involved in major depression, in response to emotional stimuli, was normalized after antidepressant treatment. To refine our knowledge of antidepressants' effect on the neural bases of emotional processing in major depression, neuroimaging studies should use consistent emotional tasks related to depressive symptoms and that involve the default mode network, such as self-referential processing tasks.

Introduction

Functional brain imaging investigations in acutely depressed patients revealed a consistent pattern of brain activation, characterized by an abnormal cooperation between cortical, limbic, and subcortical regions. Major Depressive Disorder (MDD) has been associated with a decreased activity in prefrontal areas, including the dorsolateral prefrontal cortex (DLPFC) [i.e. Brodmann Area (BA) 9] and the ventrolateral prefrontal cortex (VLPFC), as well as in other cortical regions, such as the inferior parietal lobule (BA 40) and the dorsal anterior and posterior cingulate cortices. Conversely, increased activity has been demonstrated in limbic and paralimbic regions, such as the ventral part of the anterior cingulate cortex (i.e. subgenual cingulate, BA 25), hippocampus, hypothalamus, amygdala, and insula in MDD. This pattern is frequently observed in studies using positron emission tomography (PET) (Bench et al., 1992, Drevets et al., 1992, Mayberg, 2003) or functional magnetic resonance imaging (fMRI) (Rose et al., 2006, Siegle et al., 2007).

Compared with the results of resting PET studies, those of fMRI and PET studies using activation tasks are easier to interpret, as they are usually based on a controlled design comparing at least two psychological tasks. For instance, fMRI and PET activation studies allow for modelling psychopathological processes such as emotional or cognitive biases associated with MDD. However, as a drawback, the results of fMRI and PET activation studies are also more difficult to generalize due to the different tasks used. For instance, whereas the hypofrontality of depressed patients is well known at rest, fMRI studies yielded mixed results, such as prefrontal hyperactivity during working memory processes when controlling for task performance (Harvey et al., 2005, Fitzgerald et al., 2008a).

Several resting state PET studies highlighted that antidepressant treatments, especially antidepressant drugs, tend to restore a normal brain function (see for review Mayberg, 2003, Mayberg et al., 2000) while improving depressive symptoms. These findings were recently confirmed in a meta-analytic study. Normalization of hypometabolism in neocortical regions (prefrontal and parietal cortex) and of hypermetabolism in limbic and paralimbic areas has been reported (Fitzgerald et al., 2008b). Some fMRI activation studies showed similar effects of antidepressants in acutely depressed patients (e.g. Robertson et al., 2007, Fales et al., 2009). However these findings were more heterogeneous than those of resting state studies. For example, both increased (Davidson et al., 2003) and decreased (Fu et al., 2004) activation in the dorsal anterior cingulate cortex have been reported. These discrepancies may have been caused by differences across activation studies in cognitive and emotional tasks which may have probed different parts of the cortico-limbic network implicated in the pathophysiology of MDD and clinical treatment response.

The main goal of the present study was to identify more clearly the regions targeted by antidepressants in relation to the neural underpinnings of emotional processing as such knowledge may ultimately inform therapeutic strategy. Therefore, we examined the pattern of changes in brain activation during emotional processing associated with a clinical improvement of depression. Note that the fMRI activation studies dealing with the antidepressants effects on cognitive (non-emotional) processing in MDD patients were too few to allow a meta-analysis. We employed a recent quantitative meta-analysis method, using Activation Likelihood Estimation (ALE), which allows the integration of neuroimaging results across studies (Turkeltaub et al., 2002).

Section snippets

Data sources and inclusion criteria

Studies of antidepressant drug effects on brain activation during emotional processing in acute MDD were identified by a systematic literature search in large databases (Medline, Embase, PsychInfo, and Web of sciences) for English-language manuscripts of neuroimaging studies published prior to December 2009. The search keywords were “depressive disorder”, “depression”, “brain imaging”, “fMRI”, “PET”, and “antidepressant”. In addition, we examined the references of the selected papers.

All

Results

Nine studies (8 fMRI studies and 1 PET study) were found (3 of which using an ROI approach), comprising a total of 126 patients [see Table 1 for descriptions of included studies (A) and MDD patients (B)]. Participants from all studies were outpatients with MDD (mean age ± standard deviation = 39.1 ± 9.5 years).

Summary of results and comparison with the literature

In this study we conducted a preliminary meta-analysis of functional brain imaging studies to investigate the effects of antidepressants on brain activation during emotional processing in acutely depressed patients.

Consistent with a recent meta-analysis of resting state PET studies (Fitzgerald et al., 2008b), we found increased neural activity following antidepressant drug treatment not only in several neocortical areas (DLPFC, DMPFC, and VLPFC), but also in subcortical areas such as the

Role of funding source

PD was supported by Institut de Recherches Internationales Servier (IRIS). MJ is an employee of Servier laboratory. Funding of these authors had no further role in the analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

The authors reported no biomedical financial interests or potential conflict of interest.

Acknowledgements

The authors thank Bernard Durning for the correction of English text.

References (52)

  • C. Lemogne et al.

    Self-referential processing and the prefrontal cortex over the course of depression: a pilot study

    J. Affect. Disord.

    (2010)
  • H.S. Mayberg et al.

    Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

    Biol. Psychiatry

    (2000)
  • H.S. Mayberg et al.

    Deep brain stimulation for treatment-resistant depression

    Neuron

    (2005)
  • G. Northoff

    Psychopathology and pathophysiology of the self in depression — neuropsychiatric hypothesis

    J. Affect. Disord.

    (2007)
  • E.J. Rose et al.

    Limbic over-activity in depression during preserved performance on the n-back task

    Neuroimage

    (2006)
  • H.S. Schaefer et al.

    Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression

    Biol. Psychiatry

    (2006)
  • Y.I. Sheline et al.

    Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study

    Biol. Psychiatry

    (2001)
  • G.J. Siegle et al.

    Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features

    Biol. Psychiatry

    (2007)
  • P.E. Turkeltaub et al.

    Meta-analysis of the functional neuroanatomy of single-word reading: method and validation

    Neuroimage

    (2002)
  • C. Windischberger et al.

    Area-specific modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI: a randomized cross-over study

    Neuroimage.

    (2010)
  • B.B. Zandbelt et al.

    Within-subject variation in BOLD-fMRI signal changes across repeated measurements: quantification and implications for sample size

    Neuroimage

    (2008)
  • A. Anand et al.

    Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study

    J. Neuropsychiatry. Clin. Neurosci.

    (2007)
  • I.M. Anderson et al.

    Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study

    Neuroreport

    (2007)
  • C.J. Bench et al.

    The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression

    Psychol. Med.

    (1992)
  • C.J. Bench et al.

    Changes in regional cerebral blood flow on recovery from depression

    Psychol. Med.

    (1995)
  • A.L. Brody et al.

    Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings

    Arch. Gen. Psychiatry

    (2001)
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