Drug-resistant Depressed Patients Research Articles

Dorsolateral prefrontal transcranial magnetic stimulation in patients with major depression locally affects alpha power of REM sleep.

Sleep alterations are among the most important disabling manifestation symptoms of Major Depression Disorder (MDD). A critical role of sleep importance is also underlined by the fact that its adjustment has been proposed as an objective marker of clinical remission in MDD. Repetitive transcranial magnetic stimulation (rTMS) represents a relatively novel therapeutic tool for the treatment of drug-resistant depression. Nevertheless, besides clinical evaluation of the mood improvement after rTMS, we have no clear understanding of what are the neurophysiological correlates of such treatment. One possible marker underlying the clinical outcome of rTMS in MDD could be cortical changes on wakefulness and sleep activity. The aim of this open-label study was to evaluate the efficacy of a sequential bilateral rTMS treatment over the dorsolateral prefrontal cortex (DLPFC) to improve the mood in MDD patients, and to determine if rTMS can induce changes on the sleep structure, and if those changes can be used as a surrogate marker of the clinical state of the patient. Ten drug-resistant depressed patients participated to ten daily sessions of sequential bilateral rTMS with a low-frequency TMS (1 Hz) over right-DLPFC and a subsequent high-frequency (10 Hz) TMS over left-DLPFC. The clinical and neurophysiological effects induced by rTMS were evaluated, respectively by means of the Hamilton Depression Rating Scale (HDRS), and by comparing the sleep pattern modulations and the spatial changes of EEG frequency bands during both NREM and REM sleep, before and after the real rTMS treatment. The sequential bilateral rTMS treatment over the DLPFC induced topographical-specific decrease of the alpha activity during REM sleep over left-DLPFC, which is significantly associated to the clinical outcome. In line with the notion of a left frontal hypoactivation in MDD patients, the observed local decrease of alpha activity after rTMS treatment during the REM sleep suggests that alpha frequency reduction could be considered as a marker of up-regulation of cortical activity induced by rTMS, as well as a surrogate neurophysiological correlate of the clinical outcome.

Deep brain stimulation in treatment-resistant depression in mice: Comparison with the CRF1 antagonist, SSR125543

Deep brain stimulation (DBS) has been demonstrated to represent a targeted therapeutic alternative for treatment-resistant depression. In this study, we used the unpredictable chronic mild stress (UCMS) test to validate high-frequency electrical stimulation of the cingulate cortex (CC) as a possible treatment to improve behavioral symptoms associated with a depressive-like state in treatment-resistant mice. The effects of DBS were compared with those of the CRF(1) antagonist, SSR125543. Mice were subjected to UCMS, which consisted of the sequential and unpredictable application of mild stressors for a total of 8 weeks. From week 4 until the end of week 6, mice received either a saline injection or were treated with the antidepressant, fluoxetine (10 mg/kg, i.p.). At the end of week 6, fluoxetine-treated mice were subdivided into two populations, that is one responding to fluoxetine, and one not responding, based on their fur coat state, an index of depressive-like state in this test. Non-responders were subsequently subjected to bilateral DBS (at 80 or 120 Hz, 1-h/day) or were treated with SSR125543 (20 mg/kg, i.p.) for two weeks. Stimulation of the CC at 120 Hz in treatment-resistant mice resulted in a normalization of motivated-like responses, anxiety-related behaviors, hyperactivity and aggressiveness. SSR125543 improved motivated-like and aggressive behaviors. These findings demonstrate that bilateral DBS of the CC and, to a lesser extent, pharmacological blockade of the CRF(1) receptor in treatment-resistant mice can attenuate several aspects of depressive-like behaviors, suggesting further that these approaches may represent valid alternatives for the treatment of drug-resistant depressed and/or anxious patients.

P-935 - Augmentation of antidepressants with bright light therapyin patients with comorbid depression and borderline personality disorder

Borderline personality disorder (BPD) is typically characterized by instability and impairmed behaviour, affectivity, interpersonal relations and lifestyle. The most common condition comorbid with BPD is a depressive episode. Depression is associated with severe disturbance of the circadian rhythms. This is apparent in depressive patients with BPD. Bright light may be an effective in treatment of seasonal affective disorder. Several studies have suggested antidepressant effects of phototherapy in non-seasonal depressive episodes. The treatment of comorbid depressive disorder and borderline personality disorder (BPD) is usually reported to be less successful than the treatment of patients without personality disorder. Studies describing the use of bright light in depressed patients with comorbid BPD have not been published so far. The aim of this open study was to assess the effectiveness of a 6-week combined therapy with the application of bright light (10,000 lux, 6:30 to 7:30 a.m. for 6 weeks) added to SSRIs in drug-resistant depressed patients with comorbid BPD who did not respond with improvement to 6-week administration of antidepressants. The study comprised 13 female patients who met the ICD-10 diagnostic criteria for research and the DSM-IV-TR diagnostic criteria for major depression. The participants were regularly evaluated using the CGI, HAMD and MADRS scales and the BDI and BDI self-report inventories. According to all the assessment instruments, the application of bright white light leads to a significant improvement. However, the results must be interpreted with caution due to the open nature of the study. By IGA MZ CR NT 11047-4/2010

Aripiprazole augmentation strategy in clomipramine-resistant depressive patients: An open preliminary study

Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 ± 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5 mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow-up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine-related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved.

Vascular Endothelial Growth Factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which induces vasopermeability and facilitates neurogenesis and synaptic plasticity in the adult brain. Expression studies in animal models have reported that brain VEGF is regulated by electroconvulsive seizures (ECS), which are used in an experimental paradigm similar to clinical electroconvulsive therapy (ECT) a treatment for drug resistant depressed (TRD) patients. The aim of this study was to investigate putative modulations of ECT on VEGF serum levels in TRD patients. Nineteen patients were enrolled in the study; illness severity and VEGF serum contents were assessed before the treatment (T0), the day after the end of ECT (T1) and one month later the end of ECT (T2). ECT treatment improved depression symptomatology as measured by MADRS scores (p<0.0001). No changes occurred in serum VEGF between T0 and T1, whereas a significant increase was observed between T0 and T2 (p=0.042). Moreover a significant correlation was observed between the VEGF increase at T2 and the reduction in MADRS scores (p=0.049). This study is the first to evaluate putative modulations of serum VEGF induced by ECT in TRD patients.

AUGMENTATION OF ANTIDEPRESSANTS WITH BRIGHT LIGHT THERAPY IN PATIENTS WITH COMORBID DEPRESSION AND BORDERLINE PERSONALITY DISORDER

Borderline personality disorder (BPD) is typically characterized by instability and impaired behaviour, affectivity, interpersonal relations and lifestyle. The most common condition comorbid with BPD is a depressive episode. Depression is associated with severe disturbance of the circadian rhythms. This is apparent in depressive patients with BPD. Both sleep and diurnal rhythms are disturbed and the symptoms fluctuate. Bright light may be an effective in treatment of seasonal affective disorder, circadian sleep disorder and jet lag. It also improves sleep-wake patterns and behavioural disorders in hospitalized patients with Alzheimer's disease. Several studies have suggested antidepressant effects of phototherapy in non-seasonal depressive episodes. The treatment of comorbid depressive disorder and borderline personality disorder (BPD) is usually reported to be less successful than the treatment of patients without personality disorder. Studies describing the use of bright light in depressed patients with comorbid BPD have not been published so far. The aim of this open study was to assess the effectiveness of a 6-week combined therapy with the application of bright light (10,000 lux, 6:30 to 7:30 a.m. for 6 weeks) added to SSRIs in drug-resistant depressed patients with comorbid BPD who did not respond with improvement to 6-week administration of antidepressants. The study comprised 13 female patients who met the ICD-10 diagnostic criteria for research and the DSM-IV-TR diagnostic criteria for major depression. The participants were regularly evaluated using the CGI, HAMD and MADRS scales and the BDI and BDI self-report inventories. According to all the assessment instruments, the application of bright white light leads to a significant improvement. However, the results must be interpreted with caution due to the open nature of the study.

P.2.d.020 Serum VEGF during electroconvulsive therapy (ECT) in drug resistant depressed patients

P.2.d.020 Serum VEGF during electroconvulsive therapy (ECT) in drug resistant depressed patients

Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): A pilot study in drug resistant depressed patients

Refractory depression is a highly debilitating mental condition that originates major social and economic burden. About 50% of the patients experience a chronic course of illness and up to 20% show an insufficient response to drug treatments. Electroconvulsive therapy (ECT) is the most effective treatment method in refractory depression, although its mechanism of action is still unknown. Brain-derived neurotrophic factor (BDNF) is decreased in depressive episodes, and increases with antidepressant treatment, being suggested as a biomarker of response to ECT. We report the findings of a study on the effects of ECT on BDNF and clinical outcomes in a group of drug resistant depressive patients before and after ECT. The patients post-ECTs have shown an important improvement of depressive symptomatology on the HDRS (p=0.001), of psychotic features on the BPRS (p=0.001) and of the severity of illness on the CGI (p=0.001). There were no changes in the serum BDNF before and after the ECT treatment (p=0.89). These results do not support the hypothesis that the clinical improvement following ECT is due to changes in the BDNF.

Transcranial direct current stimulation for the treatment of drug-resistant depression

transcranial direct current stimulation (tDCS) is recently receiving a renewed interest as a tool for the treatment of major depressive episodes. The aim of this study is to test the potential of tDCS as add-on therapy in drug-resistant depressed patients.

Electroconvulsive Therapy (ECT) increases serum Brain Derived Neurotrophic Factor (BDNF) in drug resistant depressed patients

Several findings have suggested that the neurotrophin BDNF could contribute to clinical efficacy of antidepressant treatments. The purpose of this study was to analyse if ECT operates a modulation of serum BDNF levels in a sample of drug resistant depressed patients. The results obtained show significantly higher serum levels of BDNF following ECT. More specifically, while no change occurred in the whole sample between T0 (baseline) and T1 (after ECT) (p=0.543) a significant increase has been identified at T2, one month after the end of ECT (p=0.002). However, the BDNF augmentation was evident even between T0 and T1 in a subgroup of patients who has low baseline BDNF levels. Although future researches are needed, the results herein presented show for the first time that ECT is associated with changes in serum BDNF and further support the possible involvement of BDNF in antidepressant therapies

Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients

Background Depression has been associated with low brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs appear to mend this alteration. The purpose of this study was to assess BDNF serum levels in drug resistant depressed patients before and after repetitive Transcranial Magnetic Stimulation (rTMS) antidepressant treatment. Methods BDNF levels were measured in serum of 16 resistant depressed patients using the ELISA technique. Results BDNF baseline levels showed a negative correlation with illness severity measured by HDRS scores ( R = − 0.517, p = 0.04) and a significant increase of serum BDNF was found after rTMS treatment ( t = − 2.549, df = 15, p = 0.022). Conclusions Our findings support the relationship between decreased serum BDNF and depression symptomatology and suggest a normalizing effect of rTMS antidepressant treatment. Further replications in larger samples will help to clarify the relevance of this preliminary data in the rTMS mechanism of action.

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 χ 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.

Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression?

Objective Repetitive transcranial magnetic stimulation (rTMS) is proposed for the treatment of drug-resistant depression. Studies performed in accordance with evidence-based medicine (EBM) are scarce, particularly in seeking optimal treatment and evaluation parameters. We aimed to test various types of rTMS in a large sample of depressed patients following EBM rules and to investigate treatment-related changes in plasma levels of neurotransmitters involved in depression. Methods Seventy-one drug-resistant depressed patients were randomly assigned to low (1 Hz) or high (17 Hz) rate TMS, applied for 5 days over the left dorsolateral prefrontal cortex (L-DLPFC). Patients were separated into two study designs. One group (20 patients) received only active treatment, while the other entered a double-blind, placebo-controlled, crossover design. Pre- and post-treatment blood samples were taken for evaluation of plasma levels of dopamine and serotonin. Results After a week of treatment patients had a measurable benefit. However, overall the placebo stimulation did not differ significantly from real stimulation, nor were differences observed between the two rates of rTMS. The only difference emerged when the real stimulation was applied at 17 Hz following placebo treatment. Plasma levels of neurotransmitters between active and placebo rTMS were similar. Conclusions Using the treatment schedule of 1 week, although a clinical improvement after active treatment was indeed observed, this was both clinically and biochemically indistinguishable from that seen in the placebo arm. Significance This suggests that most of the previous emphasis, for short period of treatment, should be tempered down and that further work is required in order to verify whether optimal stimulation and evaluation parameters for TMS-treatment of depression beyond the placebo effect may be found following EBM rules.

Effect of Chronic Repetitive Transcranial Magnetic Stimulation on Regional Cerebral Blood Flow and Regional Cerebral Glucose Uptake in Drug Treatment-Resistant Depressives

Brain imaging studies have shown that repetitive transcranial magnetic stimulation (rTMS) is biologically active. The aim of the present study was to investigate the patterns of the regional cerebral glucose uptake rate (rCMRGlu) and regional ^99mTc HMPAO uptake rate (regional cerebral blood flow; rCBF) during a series of therapeutic rTMS sessions at low frequency. Four drug-resistant depressed patients underwent 10 rTMS sessions as an add-on measure over 14 days. One day before and 1 day after the TMS series, 511-keV SPECT with simultaneous ¹⁸F-fluorodeoxyglucose and ^99mTc HMPAO measurements were carried out. All patients showed a good clinical outcome. Statistically significant common changes in rCBF and rCMRGlu patterns were found in the upper frontal regions bilaterally in terms of increased uptake rates and in the left orbitofrontal cortex in terms of decreased uptake rates of both isotopes compared to controls. However, the lateralization patterns of rCBF and rCMRGlu after rTMS treatment revealed marked differences. Thus, although no relevant changes in lateralization of the glucose uptake were observed, a clear right-sided preponderance of rCBF also in areas remote from the stimulation site was described. Therapeutic rTMS seems to influence distinct cortical regions, affecting rCBF and rCMRGlu in a homogeneous manner as well as in different ways, which are probably region dependent and illness related. The role of the stimulation coil placement site should be taken into account.

Low frequency rTMS as an add-on antidepressive strategy: heterogeneous impact on 99mTc-HMPAO and 18 F-FDG uptake as measured simultaneously with the double isotope SPECT technique. Pilot study.

Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are examination procedures that have shown that repetitive transcranial magnetic stimulation (rTMS) is biologically active. The aim of the present study was to investigate the patterns of regional cerebral 18F-fluorodeoxyglucose (18F-FDG) uptake and regional 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) uptake simultaneously during a series of therapeutic rTMS at low frequency. Four drug-resistant depressed patients underwent 10 rTMS as an add-on measure over 14 days. One day before and one day after TMS, simultaneous measurements of 18F-FDG, representing regional cerebral metabolic rate (rCMR), and 99mTc-HMPAO, representing regional cerebral blood flow (rCBF), were carried out. A conventional double head SPECT camera with 511 keV collimators was used. Statistically significant simultaneous overall changes of rCBF and rCMR were found in the upper prefrontal regions bilaterally in terms of increased uptake rates and in the left gyrus frontalis inferior in terms of decreased uptake rates of both isotopes compared to controls. Although this method improves our understanding of rTMS mechanism, there are limitations due to the lower resolution provided. Therapeutic rTMS seems to influence distinct, cortical regions affecting rCBF and rCMR.

Regional cerebral blood flow changes in drug-resistant depressed patients following treatment with transcranial magnetic stimulation: a statistical parametric mapping analysis

Changes of regional cerebral blood flow (rCBF) in five drug-resistant depressed patients were examined by single photon emission computed tomography (SPECT) with 99mTc-hexamethylpropyleneamine oxime ( 99mTc-HMPAO) before and after treatment with transcranial magnetic stimulation (TMS). The SPECT images were analysed with the Statistical Parametric Mapping (SPM) package. TMS administered in the region of the left dorsolateral prefrontal cortex (DLPFC) of the depressed patients was associated with an increase of rCBF at a focal region some distance from the stimulation site. No change was observed at any other remote region.

Cognitive/Behavioural Therapy and Pharmacotherapy with Chronic, Drug-Refractory Depressed Inpatients: A Note of Optimism

Several previous studies have reported that cognitive/behavioural treatments have been relatively ineffective for chronic, drug-resistant depressed patients. In the present report, six chronic, drug-resistant depressed patients were treated with an integrated program consisting of cognitive/behavioural treatment, pharmacotherapy, and short term hospitalization. The obtained improvement rates were substantially better than previous studies. Potential explanations for these findings are discussed.