Assessing the effects of electroconvulsive therapy on cortical excitability by means of transcranial magnetic stimulation and electroencephalography.

Electroconvulsive therapy (ECT) has significant short-term antidepressant effects on drug-resistant patients with severe major depression. Animal studies have demonstrated that electroconvulsive seizures produce potentiation-like synaptic remodeling in both sub-cortical and frontal cortical circuits. However, the electrophysiological effects of ECT in the human brain are not known. In this work, we evaluated whether ECT induces a measurable change in the excitability of frontal cortical circuits in humans. Electroencephalographic (EEG) potentials evoked by transcranial magnetic stimulation (TMS) were collected before and after a course of ECT in eight patients with severe major depression. Cortical excitability was measured from the early and local EEG response to TMS. Clinical assessment confirmed the beneficial effects of ECT on depressive symptoms at the group level. TMS/EEG measurements revealed a clear-cut increase of frontal cortical excitability after ECT as compared to baseline, that was significant in each and every patient. The present findings corroborate in humans the idea that ECT may produce synaptic potentiation, as previously observed in animal studies. Moreover, results suggest that TMS/EEG may be employed in depressed patients to monitor longitudinally the electrophysiological effects of different therapeutic neuromodulators, e.g. ECT, repetitive TMS, and sleep deprivation. To the extent that depression involves an alteration of frontal cortical excitability, these measurements may be used to guide and evaluate treatment progression over time at the single-patient level.

Role of COMT, 5-HT(1A) , and SERT genetic polymorphisms on antidepressant response to Transcranial Magnetic Stimulation.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) is an effective technique in the treatment of depression, specifically in drug-resistant patients. However, there is little data available on the influence of genetic variables on TMS response. METHODS: We analyzed the role of three genetic polymorphisms that affected the antidepressant response: serotonin transporter promoter region (SERTPR) polymorphism, 5-HT(1A) serotonergic receptor promoter region polymorphism (rs6295), and the coding region of COMT gene polymorphism (rs4680). Ninety patients with a major depressive drug-resistant episode due to a Major Depressive Disorder or to a Bipolar Disorder were included in our study. Patients underwent high frequency TMS, focused on the left prefrontal cortex, for 2 weeks. At study completion, the response rate was 45.5%. Effects of gene polymorphisms on clinical improvement were analyzed with an analysis of variance with each gene (SERTPR, 5-HT(1A) , and COMT) as factors and the Hamilton Rating Scale for Depression variation from baseline to the end of the treatment as a dependent variable. RESULTS: We found a significant model in which three factors were not significant (diagnosis, COMT, and SERTPR), whereas factor 5-HT(1A) showed a significant influence on the outcome, with patients with C/C genotype showing a greater improvement than G/G and C/G and no difference between G/G and C/G. CONCLUSION: According to our data, 5-HT(1A) polymorphism may play a role in influencing TMS response. The effect of COMT and SERTPR did not reach statistical significance. The analysis of these and other candidate genes in larger samples could help explain genetic influence on TMS response.

Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression.

Transcranial magnetic stimulation (TMS) has been extensively studied as a treatment for Major Depression. However, no data are available about the role of genetic variables on the response to this treatment. We analysed the role of two polymorphisms that influence the response to antidepressants: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT(1A) serotonergic receptor promoter region (-1019C/G). Ninety-nine patients from two double-blind, randomised, sham-controlled TMS trials were enrolled. There was a significant influence (p=0.016) of the SERTPR polymorphism on treatment outcome, without differences between active and sham stimulation. Conversely, there was a significant (p=0.014) interaction between 5-HT(1A) genotype and type of stimulation: C/C patients showed a higher difference between active and sham stimulation, indicating that these patients benefited more by TMS than C/G and G/G subjects. Our sample has not the power to control for the possible influence of different medications on these results.

Does rTMS hasten the response to escitalopram, sertraline, or venlafaxine in patients with major depressive disorder? A double-blind, randomized, sham-controlled trial.

BACKGROUND/OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been mainly studied as adjunctive treatment for drug-resistant patients. We assessed the effectiveness of rTMS started concomitantly with antidepressant medications in non-drug-resistant major depressive disorder patients. We also evaluated if, among the 3 antidepressants administered, one had a better synergy with rTMS. METHOD: In this 5-week, double-blind, randomized, sham-controlled study, we recruited 99 inpatients suffering from a major depressive episode (DSM-IV criteria). They were randomly assigned to receive venlafaxine, sertraline, or escitalopram in combination with a 2-week period of sham or active 15-Hz rTMS on the left dorso-lateral prefrontal cortex. Data were gathered from February 2004 to June 2005. RESULTS: The active rTMS group showed a significantly faster reduction in Hamilton Rating Scale for Depression (HAM-D) scores compared with the sham group (p = .0029). The response and remission rates were significantly greater in the active rTMS group after the stimulation period (p = .002 and p = .003, respectively), but not at the endpoint. We found no significant difference in HAM-D score reduction among the 3 drugs administered, either in the active or in the sham group. CONCLUSION: These findings support the efficacy of rTMS in hastening the response to antidepressant drugs in patients with major depressive disorder. The effect of rTMS seems to be unaffected by the specific concomitantly administered drug.

Transcranial magnetic stimulation in treatment-resistant depressed patients: a double-blind, placebo-controlled trial.

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance.

Unstimulated production of interleukine-6 (IL-6) is known to be enhanced in patients affected by a major depressive episode. Recent studies supported a role for basal IL-6 levels in predicting response to antidepressant drug treatments. In a sample of 10 consecutively admitted drug-free bipolar depressed inpatients, we investigated the possible correlation between unstimulated pretreatment production of IL-6 and antidepressant response to a night of total sleep deprivation (TSD) followed by a night of sleep phase advance (SPA), a nonpharmacologic treatment which is known to rapidly improve depressive symptomatology. Changes in perceived mood during treatment were recorded with self-administered Visual Analogue Scales (VAS). We observed a significant inverse correlation between IL-6 serum levels and VAS scores after treatment, meaning that higher IL-6 values before treatment were associated with worse response. This finding is in agreement with previous studies about amitriptyline and lithium antidepressant treatments. Our preliminary finding confirms the clinical value of IL-6 baseline concentration as a predictor of response to antidepressant treatment.

Seasonal variations of lithium plasma levels.

The aim of this study was to investigate the seasonal time course of lithium blood levels. We analyzed lithium plasma and red blood cell (RBC) levels in 186 subjects affected by bipolar (n=134) and major depressive (n=52) disorder, with stable oral dosage, followed in our lithium clinic for an average of 36 months. We observed a significant elevation of lithium plasma levels in summer with a more marked variation among early-onset subjects, bipolar subtype, and females. Lithium levels in plasma peaked in summer, and levels in RBC showed a trend in the same direction. Possible stratification factors such as presence of affected relatives or psychotic features did not significantly influence results. In conclusion, we observed a significant variation of lithium plasma levels according to seasons. If confirmed, this finding could have both clinical and research implications.

Effect of reboxetine augmentation in SSRI resistant patients.

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Augmentation effect of repetitive transcranial magnetic stimulation over the orbitofrontal cortex in drug-resistant obsessive-compulsive disorder patients: a controlled investigation.

BACKGROUND: The orbitofrontal cortex (OFC) plays a major role in the pathophysiology of obsessive-compulsive disorder (OCD); functional neuroimaging studies indicate that OCD symptoms are associated with increased activity in the OFC, caudate nucleus, thalamus, and anterior cingulate gyrus. The goal of our single-blind study was to assess whether repetitive transcranial magnetic stimulation (rTMS) over the left OFC would influence OCD symptoms in drug-resistant patients. METHOD: Twenty-three consecutively admitted right-handed inpatients with DSM-IV-TR-diagnosed drug-resistant OCD were given rTMS (80% motor threshold, 1 Hz seconds per minute for 10 minutes every day for 15 days) to the left OFC parallel (active: n = 16) or perpendicular (sham: n = 7) to the scalp. The patients' OCD symptoms, mood, and anxiety were rated at baseline, at the end of treatment, and once every 2 weeks for 3 months after treatment. Data were gathered from June 2006 to November 2007. RESULTS: Considering changes in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores with 2-way analysis of variance for repeated measures for a total of 8 observations (before rTMS, after treatment, and every 2 weeks for 12 weeks' follow-up), we found significant reduction of YBOCS scores comparing active versus sham treatment for 10 weeks after the end of rTMS (P < .02), with loss of significance after 12 weeks (P < .06). We also found a reduction of anxiety and depression symptoms but not a significant difference in the 2 groups. CONCLUSIONS: Low-frequency rTMS of the left OFC produced significant but time-limited improvement in OCD patients compared to sham treatment.