Research reportBrain effects of antidepressants in major depression: A meta-analysis of emotional processing studies
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)
- et al.
Ventromedial prefrontal cortex processing during emotional evaluation in late-life depression: a longitudinal functional magnetic resonance imaging study
Biol. Psychiatry
(2008) - et al.
Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression
J. Affect. Disord.
(2007) - et al.
Localization of cardiac-induced signal change in fMRI
Neuroimage
(1999) - et al.
Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression
J. Affect. Disord.
(2009) - et al.
Neural responses to sad facial expressions in major depression following cognitive behavioral therapy
Biol. Psychiatry
(2008) - et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002) - et al.
Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus
Biol. Psychiatry
(2007) - et al.
Antidepressant drug treatment modifies the neural processing of nonconscious threat cues
Biol. Psychiatry
(2006) - et al.
Cognitive control and brain resources in major depression: an fMRI study using the n-back task
Neuroimage
(2005) - et al.
An optimized individual target brain in the Talairach coordinate system
Neuroimage
(2002)
Self-referential processing and the prefrontal cortex over the course of depression: a pilot study
J. Affect. Disord.
Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response
Biol. Psychiatry
Deep brain stimulation for treatment-resistant depression
Neuron
Psychopathology and pathophysiology of the self in depression — neuropsychiatric hypothesis
J. Affect. Disord.
Limbic over-activity in depression during preserved performance on the n-back task
Neuroimage
Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression
Biol. Psychiatry
Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study
Biol. Psychiatry
Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features
Biol. Psychiatry
Meta-analysis of the functional neuroanatomy of single-word reading: method and validation
Neuroimage
Area-specific modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI: a randomized cross-over study
Neuroimage.
Within-subject variation in BOLD-fMRI signal changes across repeated measurements: quantification and implications for sample size
Neuroimage
Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study
J. Neuropsychiatry. Clin. Neurosci.
Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study
Neuroreport
The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression
Psychol. Med.
Changes in regional cerebral blood flow on recovery from depression
Psychol. Med.
Regional brain metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary findings
Arch. Gen. Psychiatry
Cited by (226)
Amygdala biomarkers of treatment response in major depressive disorder: An fMRI systematic review of SSRI antidepressants
2024, Psychiatry Research - NeuroimagingNetwork-level dynamics underlying a combined rTMS and psychotherapy treatment for major depressive disorder: An exploratory network analysis
2023, International Journal of Clinical and Health PsychologyNeural plasticity and depression treatment
2023, IBRO Neuroscience ReportsAssociations of harsh, unpredictable environment, amygdala connectivity and overeating for children
2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry