Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation

Background Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques used as therapeutic interventions in major depression.Methods In this study, we report the impact of these stimulation techniques on serum concentrations of brain-derived neurotrophic factor (BDNF) in treatment-resistant patients with a diagnosis of major depression.Results We found no changes of BDNF serum concentrations and no association of neurotrophin concentrations in serum with clinical parameters in our sample.Conclusion Our preliminary results suggest that brain stimulation techniques—in contrast to several antidepressant medications—do not change BDNF serum concentrations.     

探讨重复经颅磁刺激治疗双相抑郁的疗效和安全性

目的探究对双相抑郁(BDD)患者施以重复经颅磁刺激(rTMS)治疗的临床效果及安全性。方法 38例BDD患者,随机分为对照组及观察组,各19例。两组患者均接受拉莫三嗪治疗,在此基础上,对照组患者施以假刺激治疗,观察组患者施以rTMS进行联合治疗。比较两组患者的治疗效果、汉密尔顿抑郁量表(HAMD)和临床疗效总评量表-病情严重程度(CGI-SI)评分以及不良反应发生情况。结果观察组患者的总有效率为73.68%,高于对照组的42.11%,差异有统计学意义(P<0.05)。治疗前,两组患者的HAMD和CGI-SI评分比较,差异均无统计学意义(P>0.05);治疗后,两组患者的HAMD和CGISI评分均较本组治疗前降低,且观察组降低程度优于对照组,差异均具有统计学意义(P<0.05)。观察组患者的不良反应发生率为5.26%,与对照组的10.53%比较,差异无统计学意义(P>0.05)。结论对BDD患者施以rTMS治疗可以早期改善患者的症状,提高治疗效果,安全性好,具有突出的临床应用价值。     

Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode

Repetitive transcranial magnetic stimulation (rTMS) is a new technology which holds promise as a treatment of psychiatric disorders. Most work to date has been on depression. Superiority to placebo has been indicated in three small blind studies. We compared the antidepressant effects of rTMS and ECT in 32 patients suffering major depressive episode (MDE) who had failed to respond to at least one course of medication. There was no limit to the number of treatment sessions which could be given and treatment was continued until remission occurred or response plateaued. A significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on measures of depression overall, however, rTMS produced comparable results on a number of measures. Blind raters using the 17-item Hamilton Depression Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and the percentage improvement over the course of treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not significantly different. Significant differences were shown (p & 0.03) in percentage improvement on Beck Depression Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings of mood (rTMS 42.3%; ECT, 57%). rTMS has antidepressant effects of useful proportions and further studies are indicated.     

精神分裂症幻听和认知功能障碍患者重复经颅磁刺激治疗的进展

精神分裂症是临床上常见的一种重型精神障碍,对患者心身健康和社会功能有很大影响,而幻听则是该症患者常见的知觉障碍,且多数患者的行为和情绪受幻听的影响。认知功能是个体通过思维感知和认识客观事物的水平和能力,表现为多方面,当认知加工中某一或几方面出现问题时,就出现认知功能障碍。对上述患者目前仍以精神病药物治疗为主,但有研究发现高频重复经颅磁刺激(r TMS)可作为无创性治疗。故对r TMS的作用机制、治疗研究及其安全性等做一综述。     

Application of transcranial magnetic stimulation in treatment of drug-resistant major depression—a report of two cases

We report the cases of two drug-resistant major depressed psychotic patients, who were treated with 10 sessions of transcranial magnetic stimulations (TMS) and afterwards with 10 sessions of electroconvulsive therapy (ECT) without changing the concomitant neuroleptic and antidepressive medication. TMS did not exert a therapeutic effect in one patient and only a slight one in the other. However, there was a clear beneficial effect for ECT in the patient not responding to TMS and a slight therapeutic effect in the other. In summary, there was no clear-cut evidence for effectiveness of TMS as a treatment for patients with psychotic, therapy resistant depression. However, since there was a slight therapeutic effect of TMS in one patient it seems worthwhile to explore its therapeutic efficacy in a larger group of depressed patients.     

Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system

Repetitive transcranial magnetic stimulation (rTMS) is suggested to be a potentially useful treatment in major depression. In order to optimize rTMS for therapeutic use, it is necessary to understand the neurobiological mechanisms involved, particularly the nature of the neurochemical changes induced. Using intracerebral microdialysis in urethane-anesthetized and conscious adult male Wistar rats, we monitored the effects of acute rTMS (20 Hz) on the intrahippocampal, intraaccumbal and intrastriatal release patterns of dopamine and its metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid). The stimulation parameters were adjusted according to the results of accurate MRI-based computer-assisted reconstructions of the current density distributions induced by rTMS in the rat brain, ensuring stimulation of frontal brain regions. In the dorsal hippocampus, the shell of the nucleus accumbens and the dorsal striatum the extracellular concentration of dopamine was significantly elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a modulatory effect on both the mesolimbic and the mesostriatal dopaminergic systems. This increase in dopaminergic neurotransmission may contribute to the beneficial effects of rTMS in the treatment of affective disorders and Parkinson's disease.     

Conditions of application of repeated transcranial magnetic stimulation to rats may mask the effects of the treatment

Rats of sham repeated transcranial magnetic stimulation (rTMS) group, kept in noisy room and transiently immobilized (5 min) for 12 consecutive days, showed similar inhibition of body weight gain, increase in exploratory locomotor activity, and elevation of motor response to apomorphine as rats undergoing magnetic stimulation of the brain, and had only slightly lower response in apomorphine stereotypy. Some of the responses ascribed to antidepressant action of rTMS in animal experiment may be due to environmental conditions, and not alternating magnetic field passing the brain.     

Escitalopram for the treatment of major depressive disorder in youth

Genomic variations influencing response to pharmacotherapy of pain are under investigation. Candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy are discussed. Drug metabolising enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some NSAIDs are dependent on CYP2C9 activity, whereas opioid-receptor polymorphisms are discussed for differences in opioid mediated analgesia and side effects. Pharmacogenetics as a diagnostic tool has the potential to improve patient therapy and care, and it is hoped that pharmacogenetics will individualise drug treatment to a greater extent in the near future.     

The hypodopaminergic state ten years after: transcranial magnetic stimulation as a tool to test the dopamine hypothesis of drug addiction

An altered dopamine transmission has been described for different types of addiction for a long time. Preclinical and clinical evidence support the hypodopaminergic hypothesis and underpin the need to increase dopamine transmission to obtain therapeutic benefit. Repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex shows efficacy in treating some forms of addiction. Recent imaging studies confirmed that the therapeutic effect of rTMS is correlated with an enhancement of dopamine transmission. Novel targets for rTMS are under evaluation to increase its effectiveness in treating addiction, and research is ongoing to find the optimal protocol to boost dopaminergic transmission in the addicted brain. TMS can thus be considered a useful tool to test the dopamine hypothesis of drug addiction and instrumental in the search for addiction therapeutics.     

Priming stimulation enhances the effectiveness of low-frequency right prefrontal cortex transcranial magnetic stimulation in major depression

OBJECTIVES: Low-frequency, right-sided repetitive transcranial magnetic stimulation (rTMS) to the prefrontal cortex has been shown to have antidepressant effects. Recent research has suggested that preceding low-frequency rTMS with a period of low-intensity, 6-Hz stimulation ("priming") enhances the physiological effects of low-frequency stimulation. The aim of this study was to investigate whether priming stimulation would enhance therapeutic response to low-frequency rTMS in patients with depression. METHOD: The study consisted of a 2-arm, double-blind, randomized, controlled trial in 60 patients with treatment-resistant depression. Right 1-Hz rTMS was provided in one continuous, 15-minute train to all subjects. The priming stimulation (twenty 5-second, 6-Hz trains) or an equivalent, sham preceded 1-Hz stimulation. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: There was a significant overall reduction in MADRS scores across the 4 weeks of the study and a significantly greater reduction in MADRS scores in the active-priming group compared with the sham-priming group. CONCLUSIONS: Low-intensity, high-frequency priming stimulation appears to enhance the response to low-frequency, right-sided rTMS treatment in patients with treatment-resistant depression.     

A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression

Repetitive transcranial magnetic stimulation (rTMS) is an emerging potential treatment for depression, but the data supporting its efficacy have not been systematically reviewed. The purpose of this study was to conduct a meta-analysis of rTMS trials in the treatment of depression. A search for all published and unpublished sham-controlled studies of left or right prefrontal cortical rTMS in the treatment of depression evaluated by the Hamilton Depression Rating Scale (HDRS) was conducted using no language restrictions. Fixed- and random-effects meta-analyses were performed on 12 studies comparing the decrease in HDRS scores achieved with rTMS and sham stimulation. Initial results with a fixed-effects analysis failed homogeneity testing; thus, a random-effects analysis was used to calculate all results. In 12 studies (16 individual effect sizes), the weighted mean effect size was 0.81 (95% CI: 0.42-1.20, P < .001). For studies using left dorsolateral pre-frontal cortex (DLPFC) stimulation (11 studies, 14 effect sizes), the weighted mean effect size was 0.89 (95% CI: 0.44-1.35, P < .001). For studies using left DLPFC stimulation in a parallel-groups design (seven studies, nine effect sizes), the weighted mean effect size was 0.88 (95% CI: 0.22-1.54, P < .01). No study showed a mean decrease in HDRS scores of > 50%, and the number of responders to rTMS (defined as a > 50% decrease in HDRS scores) across studies was relatively small (13.7% with rTMS versus 7.9% with sham stimulation). rTMS is statistically superior to sham stimulation in the treatment of depression, showing a moderate to large effect size. However, the clinical significance of these results is modest. The differences in response to rTMS across studies are not clearly explained, and, therefore, more research is needed.     

Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS)

There is evidence that motor and premotor cortex are hyperexcitable in obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). We tested whether low-frequency repetitive transcranial magnetic stimulation (rTMS) could normalize overactive motor cortical regions and thereby improve symptoms. Subjects with OCD or TS were treated with active rTMS to the supplementary motor area (SMA) for 10 daily sessions at 1 Hz, 100% of motor threshold, 1200 stimuli/day. Suggestions of clinical improvement were apparent as early as the first week of rTMS. At the second week of treatment, statistically significant reductions were seen in the YBOCS, YGTSS, CGI, HARS, HDRS, SAD, BDI, SCL-90, and SASS. Symptoms improvement was correlated with a significant increase of the right resting motor threshold and was stable at 3 months follow-up. Slow rTMS to SMA resulted in a significant clinical improvement and a normalization of the right hemisphere hyperexcitability, thereby restoring hemispheric symmetry in motor threshold.     

Prediction of treatment outcomes in major depressive disorder

Improving the treatment of major depressive disorder will require identification of moderators that predict differential outcomes across treatments at the level of the individual patient, referred to as precision medicine. Currently, there are no biological measures demonstrated to enhance treatment selection accuracy although there are some clinical variables that have prognostic value. Several recent studies comparing treatments with differing mechanisms of action have identified potential moderators that may eventually be used in precision medicine approaches. Genetic combination tests, systemic inflammation, electroencephalography and neuroimaging, in particular, show significant potential for near-term development as clinically meaningful moderators for use in treatment selection. Ultimately, combinations of moderators may provide the greatest level of precision in selecting optimal treatment approaches for individual depressed patients.     

Desvenlafaxine for the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.

Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.

Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.     

Adjunctive brexpiprazole for the treatment of major depressive disorder

Introduction: The lifetime prevalence of major depressive episodes in the United States is nearly 17%. Clinical trials and clinical effectiveness studies have demonstrated that many patients will fail to achieve remission using traditional monotherapy, contributing to significant morbidity and suffering. Because of this, augmentation strategies have been proposed to improve both treatment response and remission.

Areas covered: Brexpiprazole is a second generation antipsychotic (SGA) approved by the US FDA in 2015 as an add-on treatment to an antidepressant medication for the treatment of adults with MDD, based on the results of two large-scale, randomized, placebo-controlled trials. It is thought to exert its antidepressant effect by a partial agonism of both the dopamine D2 and serotonin 5HT1A receptors. In addition, it also has potent antagonistic activity at 5HT2A, α1B and α2 C receptors, which may also contribute to monoamine transmission regulation.

Expert Opinion: Overall, the tolerability of brexpiprazole is promising with relatively low rates of side effects and discontinuation rates, thus establishing it as a new option for the treatment of depression.     

Repetitive transcranial magnetic stimulation causes significant changes of chemical substances in the brain of rabbits with experimental intracerebral hemorrhage

More and more studies have reported the usefulness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of stroke patients. This article is to explore if rTMS can cause changes of such chemical substances as N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) in the surrounding area of experimental intracerebral hematoma of rabbits. A total of 36 rabbits were randomly divided into 3 groups: a control group (group A), a sham rTMS group (group B) and an rTMS group (group C). The experimental intracerebral hemorrhage (ICH) was induced by intracerebral injection of selfbody blood of the animals in groups B and C, while those of the group A serving as controls were injected with normal saline. The rabbits of groups B and C were treated with sham and real rTMS, respectively, but those of group A were not. The contents of chemical substances including NAA, Cho and Cr in the perihematomal brain tissues were measured by using ¹H-magnetic resonance spectroscopy (¹H-MRS) 12 hours, 72 hours, 1 week and 2 weeks after the experimental ICH was induced. The results show that the contents of NAA, Cr and NAA/Cr ratio were decreased significantly, but Cho, Cho/Cr increased significantly in groups B and C (P < 0.01) as compared against those in group A. A comparison between the groups B and C revealed that the contents of NAA, Cr, NAA/Cr were higher, but Cho and Cho/Cr were significantly lower in group C than those in group B (P < 0.01). It is concluded that rTMS could result in changes of the chemical substance contents in perihematomal brain tissues, which leads to neuroprotective effects in the brain.     

重复经颅磁刺激治疗脑卒中后失语症的研究进展

失语症是脑卒中病常见的功能障碍和后遗症之一,脑卒中伴失语的发病率为21%~38%.失语症严重妨碍了患者的正常交流,影响患者的生活质量,给家庭和社会带来了沉重的负担.目前国内外仍以传统的言语语言训练为主要治疗手段,但起效缓慢,难以达到满意效果.近年来有报道经颅磁刺激对失语症有一定效果,本文将对重复经颅磁刺激治疗脑卒中后失语症的应用进行综述.     

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial

Background: Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. Method: In this randomized, double-blind, placebo-controlled trial, adult outpatients (age ≥18 years) meeting DSM-IV criteria for MDD received placebo (n=93), duloxetine 80 mg/day (40 mg BID; n=95), duloxetine 120 mg/day (60 mg BID; n=93), or paroxetine (20 mg QD; n=86) for 8 weeks. Patients who had a ≥30% reduction from baseline in HAMD₁₇ total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score, HAMD₁₇ subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). Results: During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD₁₇ total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD₁₇ total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). Conclusion: These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.