Medial prefrontal cortex activity during memory encoding of pictures and its relation to symptomatic improvement after citalopram treatment in patients with major depression.

BACKGROUND: Brain imaging studies of major depressive disorder have shown alterations in the brain regions typically involved in episodic memory, including the prefrontal cortex and medial temporal areas. Some studies of major depressive disorder have linked episodic memory performance to treatment response. In this study, we sought to identify brain regions whose activity, measured during the encoding of pictures, predicted symptomatic improvement after 8 weeks of citalopram treatment. METHODS: We included 20 unmedicated depressed patients. These patients performed an episodic recognition memory task during functional magnetic resonance imaging. During the encoding phase, 150 pictures depicting emotionally positive, negative or neutral content were presented, and the participants were required to classify each picture according to its emotional valence. The same 150 pictures were presented, along with 150 new ones, for a recognition task. We asked participants to distinguish the old pictures from the new ones. We assessed symptom severity by use of the 21-item Hamilton Rating Scale for Depression (HAM-D) at baseline and after 8 weeks of citalopram treatment. We performed subsequent memory effect analyses using SPM2 software. We explored the relation between brain activation during successful encoding of pictures and symptomatic improvement. RESULTS: Patients showed a mean symptomatic improvement of 54.5% on the HAM-D after 8 weeks. Symptomatic improvement was significantly and positively correlated with picture recognition memory accuracy. We also found that the activity of the ventromedial prefrontal cortex and anterior cingulate cortex during successful encoding was significantly correlated with symptomatic improvement. Finally, we found greater activation in the ventromedial prefrontal cortex during the successful encoding of positive pictures in comparison with neutral pictures. LIMITATIONS: During the recognition memory task, 5 participants (among the best responders to treatment) were not included in the valence-specific analyses because they had very few errors. A more challenging task would have allowed the inclusion of most patients. CONCLUSION: Different types of functional imaging paradigms have been used to explore whether the activity of specific brain regions measured at baseline is predictive of a better response to treatment in major depressive disorder. Among these regions, the medial prefrontal cortex and anterior cingulate cortex usually show the strongest predictive value. According to our results, the medial prefrontal cortex and anterior cingulate cortex could have an effect on treatment response in major depressive disorder by contributing to the successful encoding of positively valenced information.

Pharmacogenomic predictors of citalopram treatment outcome in major depressive disorder.

OBJECTIVES: A significant proportion of patients with major depressive disorder (MDD) do not improve following treatment with first-line antidepressants and, currently, there are no objective indicators of predictors of antidepressant response. The aim of this study was to investigate pre-treatment peripheral gene expression differences between future remitters and non-responders to citalopram treatment and identify potential pharmacogenomic predictors of response. METHODS: We conducted a gene expression study using Affymetrix HG-U133 Plus2 microarrays in peripheral blood samples from untreated individuals with MDD (N = 77), ascertained at a community outpatient clinic, prior to an 8-week treatment with citalopram. Gene expression differences were assessed between remitters and non-responders to treatment. Technical validation of significant probesets was carried out by qRT-PCR. RESULTS: A total of 434 probesets displayed significant correlation to change in score and 33 probesests were differentially expressed between eventual remitters and non-responders. Probesets for SMAD 7 (SMA- and MAD-related protein 7) and SIGLECP3 (sialic acid-binding immunoglobulin-like lectin, pseudogene 3) were the most significant differentially expressed genes following FDR correction, and both were down-regulated in individuals who responded to treatment. CONCLUSIONS: These findings point to SMAD7 and SIGLECP3 as candidate predictive biomarkers of antidepressant response.

Are neuroticism and extraversion associated with the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS)? An exploratory 4-week trial.

Several randomized, controlled trials have found high frequency repetitive transcranial magnetic stimulation (HF-rTMS) to be effective for treating major depressive disorder (MDD), but its antidepressant mechanisms have yet to be firmly understood. In this context, pre-treatment personality traits and subsequent changes in personality concomitant to treatment may be relevant for our understanding of these mechanisms. To investigate this issue we conducted a naturalistic trial in which 14 subjects with moderate to severe depression were treated with daily HF-rTMS over the left dorsolateral prefrontal cortex for 4 weeks. Objective depressive symptoms (as assessed by the HAM-D(21)) and the major personality dimensions of neuroticism and extraversion were measured pre-post HF-rTMS. Pre-rTMS levels of extraversion predicted subsequent decrease in depressive symptoms. Also, HF-rTMS treatment resulted in a decrease in neuroticism scores, and this relative decrease was associated with the relative decrease in depression. Our results suggest that HF-rTMS may positively affect the personality dimension of neuroticism. Also, pre-treatment levels of extraversion may predict the subsequent antidepressant response to HF-rTMS. However, further studies with larger samples and controlled designs are needed to better clarify these preliminary findings.

Theory of mind in subjects with major depressive disorder: is it influenced by repetitive transcranial magnetic stimulation?

OBJECTIVES: To assess, in a sample of subjects with current major depressive disorder, whether high frequency repetitive transcranial magnetic stimulation (HF-rTMS) is able to influence affective "theory of mind" (ToM). METHODS: We conducted a pilot naturalistic trial in which 14 subjects with MDD were treated with daily HF-rTMS over their left dorsolateral prefrontal cortex for 4 weeks. Objective depressive symptoms and affective ToM (as assessed, respectively, by the 21-item Hamilton Depression Rating Scale and the Reading the Mind in the Eyes Test [RMET]) were measured pre-post HF-rTMS treatment. RESULTS: Our findings indicated the absence of a significant main effect for pre-post RMET scores, yet a significant interaction between pre-post RMET performance and change in depressive symptoms. Therefore, depressed subjects in our sample exhibited ToM improvements in proportion to their antidepressant response. CONCLUSIONS: We have shown that HF-rTMS is able to influence ToM in subjects with MDD. We hypothesize that this effect could be associated, at least in part, with clinical improvement over time. However, further studies with larger samples and controlled designs are needed to better clarify our preliminary findings.

High frequency repetitive transcranial magnetic stimulation as an augmenting strategy in severe treatment-resistant major depression: a prospective 4-week naturalistic trial.

BACKGROUND: Randomized, controlled trials (RCTs) have found repetitive transcranial magnetic stimulation (rTMS) to be effective for major depression, but its usefulness as an augmenting strategy for severe treatment-resistant depression (TRD) has yet to be firmly established. METHODS: In a naturalistic trial, 15 chronically depressed, severely treatment-resistant patients were treated with daily high frequency (HF) rTMS over the left dorsolateral prefrontal cortex (DLPFC) for 4 weeks as an augmenting strategy. Depressive and anxious symptoms (both subjective and objective), as well as quality of life (QOL) domains were measured pre-post rTMS treatment. RESULTS: Pre-post rTMS comparisons revealed significant reductions of both clinician-rated and selfreport depression and anxiety measures and increases in three (out of five) domains of subjective QOL (i.e., global, physical, and psychological). LIMITATIONS: Small sample size and non-controlled design. CONCLUSIONS: Our results suggest that HF rTMS, when used as an augmenting strategy, positively affects depressive and anxious symptoms as well as QOL in patients with severe TRD. However, further studies with larger samples and controlled designs are needed to better clarify our preliminary findings.