Medication-resistant Major Depression Research Articles

Hostility in medication-resistant major depression and comorbid generalized anxiety disorder is related to increased hippocampal\u2013amygdala 5-HT2A receptor density

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are severe and difficult-to-treat psychiatric illnesses with high rates of comorbidity. Although both disorders are treated with serotonergic based psychotropic agents, little is known on the influence of the serotonergic neurotransmitter system on the occurrence of comorbid GAD when clinically depressed. To investigate this poorly understood clinical question, we examined the involvement of frontolimbic post-synaptic 5-HT2A receptors in 20 medication-resistant depressed (MRD) patients with half of them diagnosed with comorbid GAD with 123I-5-I-R91150 SPECT. To explore whether 5-HT2A receptor-binding indices (BI) associated with comorbid GAD could be related to distinct psychopathological symptoms, all were assessed with the symptom Checklist-90-Revised (SCL-90-R). MRD patients with comorbid GAD displayed significantly higher 5-HT2A receptor BI in the hippocampal–amygdala complex, compared to MRD patients without GAD. Correlation analyses revealed that the 5-HT2A receptor BI in these areas were significantly related to the SCL-90-R subscale hostility (HOS), especially for those MRD patients with comorbid GAD. Comorbid MRD-GAD may be characterized with increased hippocampal–amygdala 5-HT2A receptor BI which could represent enhanced levels in hostility in such kinds of patients. Adapted psychotherapeutic interventions may be warranted.

Influence of an adjuvant antidepressant on the efficacy of electroconvulsive therapy: A systematic review and meta-analysis.

Objective:The primary indication for electroconvulsive therapy is medication-resistant major depression. There is some evidence that combining electroconvulsive therapy with an antidepressant, instead of electroconvulsive therapy monotherapy, might improve remission rates. However, data on this topic have not been systematically studied. We undertook a systematic review and meta-analysis to determine the effectiveness of an adjuvant antidepressant during electroconvulsive therapy for major depression.Methods:Embase, Medline Ovid, Web of Science, Cochrane Central, PsychINFO Ovid and Google Scholar were searched up to January 2019. Randomized controlled trials and cohort studies reporting on the influence of an adjuvant antidepressant on the efficacy of electroconvulsive therapy for major depression were included. Authors independently screened records, extracted data and assessed study quality. We reported this systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Results:Nine studies were included in the meta-analysis. The meta-analysis revealed a significant advantage of adjuvant antidepressants versus placebo. The overall effect size per category of antidepressant was as follows: tricyclic antidepressants: Hedges’ g 0.32 (95% confidence interval: [0.14, 0.51]) (k = 6) with low heterogeneity (I2: 4%, p = 0.39); selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitors: Hedges’ g 0.27 (95% confidence interval: [0.03, 0.52]) (k = 2) with a lack of heterogeneity (I2: 0%, p = 0.89); and monoamine oxidase inhibitors: Hedges’ g 0.35 (95% confidence interval: [−0.07, 0.77]) with moderate heterogeneity (I2: 43%, p = 0.17) (k = 3).Conclusion:An adjuvant antidepressant enhances the efficacy of electroconvulsive therapy for major depression. Tricyclic antidepressants, selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitors and monoamine oxidase inhibitors showed the same effect size. However, the effect sizes of tricyclic antidepressants and monoamine oxidase inhibitors are most likely underestimated, due to insufficient doses in most of the included studies. We recommend the routine use of an adequately dosed antidepressant during electroconvulsive therapy for major depression.

Three Weeks of rTMS Treatment Maintains Clinical Improvement But Not Electrophysiological Changes in Patients With Depression: A 6-Week Follow-Up Pilot Study.

Our previous study demonstrated that 3 weeks of repetitive transcranial magnetic stimulation (rTMS) increases P200 amplitudes and improves the symptoms of depression and anxiety in depression patients. In the present study, we investigated whether 3 weeks of rTMS treatment maintained the P200 amplitude in patients with depression at 6 weeks of follow-up. We measured the 6-week maintenance effects of rTMS using clinical questionnaires and an auditory oddball paradigm. Twenty-one patients with medication-resistant major depression participated in this pilot study. All patients underwent rTMS treatment for 3 weeks; they completed clinical ratings and performed the auditory oddball task at the pre-treatment, post-treatment, and 6-week follow-up visit (3 weeks after finishing rTMS treatment). The results revealed an increase in P200 amplitudes as well as improvements in the symptoms of depression and anxiety by 3 weeks of rTMS treatment. Furthermore, the results demonstrated maintenance effects on clinical ratings at 6-week follow-up. Depression and anxiety scales showed improvements in post-treatment and maintenance effects at the 6-week follow-up. Although P200 amplitude showed a significant main effect for 3 time points (baseline, post-treatment, and 6-week follow-up visit), at 2 time point comparisons, P200 amplitudes significantly increased in post-treatment compared to those of the baseline condition but did not show the maintenance effects of long-term rTMS at the 6-week follow-up compared to those of the baseline condition ( p = .173, Bonferroni correction). Standardized low-resolution brain electromagnetic tomography (sLORETA) for P200 showed significant activation in the left middle frontal gyrus in post-treatment but no significant activation at the 6-week follow-up. Moreover, the amplitudes of overall topographic distribution were reduced at 6 weeks of follow-up. The 3 weeks of rTMS treatment induced the maintenance of the improvements in the symptoms of depression and anxiety. However, considering the results of the event-related potential (ERP) and sLORETA, 3 weeks of rTMS treatment may not be sufficient to maintain this improvement, implying that a treatment period of more than 3 weeks may be required to reveal the electrophysiological maintenance effect of rTMS.

The Impact of Repetitive Transcranial Magnetic Stimulation on Oxidative Stress in Subjects With Medication-Resistant Depression.

Recent studies have shown that oxidative stress is involved in the neurobiology of depression. We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on a novel oxidative stress marker, thiol-disulfide homeostasis, in subjects with medication-resistant major depression (MRD). Twenty-six subjects with MRD underwent 15 rTMS sessions. Sociodemographic and baseline and post-rTMS Montgomery-Asberg Depression Rating Scale (MADRS) data were collected. Serum levels of native thiol, total thiol, and disulfide and their pairwise ratios were measured in baseline and post-rTMS blood samples. Serum levels of native and total thiol were significantly decreased after rTMS treatment (P < 0.05). Serum levels of thiol-disulfide and their ratios did not significantly differ (P > 0.05) between rTMS treatment responders (>50% reduction in MADRS score, n = 11) and rTMS treatment nonresponders (n = 15). The percentage MADRS score changes did not correlate with the changes in the levels of serum thiol-disulfide from baseline to post-rTMS treatment in any subject (P > 0.05). Our results showed that rTMS treatment was effective in subjects with MRD and was associated with changes in serum thiol levels regardless of improvement in depression severity. Thus, the results did not support a possible therapeutic relationship between rTMS and thiol-disulfide homeostasis in subjects with MRD.

Subgenual Anterior Cingulate–Medial Orbitofrontal Functional Connectivity in Medication-Resistant Major Depression: A Neurobiological Marker for Accelerated Intermittent Theta Burst Stimulation Treatment?

BackgroundAccelerated repetitive transcranial magnetic stimulation paradigms have been shown to result in fast decreases in depressive symptoms and suicidal ideation. Although the subgenual anterior cingulate cortex (sgACC) region has been put forward as a possible biological marker, so far, no studies evaluated the clinical effects of accelerated intermittent theta burst stimulation (aiTBS) on sgACC functional connectivity (FC). MethodsFifty patients with treatment-resistant depression were enrolled in this registered randomized double-blind sham-controlled crossover aiTBS treatment study. All received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (5 daily sessions spread over 4 days). Forty-four complete resting-state functional magnetic resonance imaging scans were collected. Baseline resting-state functional magnetic resonance imaging scans were compared with a matched healthy control group. Besides depression severity, all patients were also assessed with the Scale for Suicide Ideation and the Beck Hopelessness Scale. ResultsOur main resting-state functional magnetic resonance imaging findings indicate that a positive sgACC FC correlation with the medial orbitofrontal cortex could distinguish aiTBS responders from nonresponders at baseline. Beneficial aiTBS treatment strengthened sgACC–medial orbitofrontal cortex FC patterns. Moreover, this increased FC pattern was associated with a decrease in feelings of hopelessness. ConclusionsClinical response to aiTBS treatment is not only characterized by stronger FC patterns between the sgACC and the medial orbitofrontal cortex, but it is also associated with decreases in hopelessness. Our observations provide a possible neurobiological explanation why accelerated repetitive transcranial magnetic stimulation paradigms may result in prompt attenuation of negative thinking in depressed patients.

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission?

Although accelerated repetitive Transcranial Magnetic Stimulation (rTMS) paradigms and intermittent Theta-burst Stimulation (iTBS) may have the potency to result in superior clinical outcomes in Treatment Resistant Depression (TRD), accelerated iTBS treatment has not yet been studied. In this registered randomized double-blind sham-controlled crossover study, spread over four successive days, 50 TRD patients received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). The accelerated iTBS treatment procedure was found to be safe and resulted in immediate statistically significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham). While only 28% of the patients showed a 50% reduction of their initial Hamilton Depression Rating Scale score at the end of the two-week procedure, this response rate increased to 38% when assessed two weeks after the end of the sham-controlled iTBS protocol, indicating delayed clinical effects. Importantly, 30% of the responders were considered in clinical remission. We found no demographic predictors for response. Our findings indicate that only four days of accelerated iTBS treatment applied to the left DLPFC in TRD may lead to meaningful clinical responses within two weeks post stimulation.

The effects of 3 weeks of rTMS treatment on P200 amplitude in patients with depression

Previous studies have reported that repetitive transcranial magnetic stimulation (rTMS) induces neuronal plasticity in the brain. Although event-related potential (ERP) is an exploration tool, the rTMS effects on ERPs in patients with major depression have not been fully explored. We demonstrated that rTMS treatment induces changes in brain function in patients with medication-resistant major depression using the ERP. Eighteen patients with medication-resistant major depression (five males and 13 females) participated in this study. The patients received rTMS treatment for 3 weeks. All patients completed clinical scales, including the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (SAI, TAI), Ruminative Response Scale, Emotion Regulation Questionnaire, and Cognitive Emotion Regulation Questionnaire (CERQ), as well as the ERP auditory oddball task, at their first visit (baseline) and at the 3-week visit (3-weeks). The HAM-D, HAM-A, BDI, SAI, and “blaming others” scale of the CERQ decreased significantly after rTMS treatment. In ERP auditory oddball task, when FP1, FP2, FZ, FCZ, CZ, and PZ channels were analyzed, P200 amplitudes showed a main effect for time of measurement and increased after 3 weeks of rTMS treatment. Standardized low-resolution brain electromagnetic tomography showed significant activation in the left middle frontal gyrus by 3 weeks of rTMS treatment. The results suggest that relatively longer rTMS treatment induces changes in brain function in patients with medication-resistant major depression, which can be identified using ERP.

The Impact of High-Frequency Repetitive Transcranial Magnetic Stimulation on Fine Motor Functions in Medication-Resistant Major Depression

Objectives: Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the left dorsolateral prefrontal cortex (DLPFC) has been reported to improve mood symptoms in major depressive disorder (MDD), research on its impact on psychomotor symptoms is scarce. This study assessed the psychomotor effects of 1 and 10 sessions, respectively, of HF-rTMS over the left DLPFC. Methods: Ten HF-rTMS sessions were applied in 21 medication-free MDD patients over a 2-week period. At the beginning, one placebo (sham)-controlled rTMS session was also applied in a cross-over, single-blind design. Psychomotor variables were digitally recorded during completion of a Fitts’ task, at baseline, after the first and second real/sham session and at the end point. Results: The total 10-session treatment period resulted in a decrease of depression severity. One HF-rTMS session resulted in improvements on the Fitts’ task, without a difference between active and sham stimulation, however. No further improvements occurred from session 2 to session 10. Conclusions: No evidence was provided to link the observed psychomotor improvements to HF-rTMS stimulation, as a practice effect could have impacted the significant psychomotor outcomes.

Episode length and mixed features as predictors of ECT nonresponse in patients with medication-resistant major depression

This study aimed to ascertain predictors of nonresponse to electroconvulsive therapy (ECT) in a large sample of major depressive patients resistant to pharmacologic treatment. A total of 208 depressive patients (31 with major depression [UP], 101 with bipolar disorder II [BP II], and 76 with bipolar disorder I [BP I] according to DSM-IV criteria) were included in the study and treated with bilateral ECT on a twice-a-week schedule. The patients were assessed before (baseline) and a week after the ECT course (final score) using the Hamilton Rating Scale for Depression-17 items (HAM-D-17), the Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Improvement (CGI). Responders were defined as those patients with a reduction of at least 50% in HAM-D-17 score and a rating of 2 ("much improved") or 1 ("very much improved") in the CGI-Improvement subscale. At the end of the ECT course, 152 patients (64%) were classified as responders and 56 patients (36%) were classified as nonresponders. On backward stepwise logistic regression, bipolar subtype (odds ratio [OR]=17.85; 95% confidence level [CL]=1.786-178.407), higher mean baseline YMRS scores (OR=1.094; 95% CL=1.025-1.166), lower mean baseline HAM-D-17 scores (OR=0.928; 95% CL=0.860-1.002), and length of current episode (OR=1.047; 95% CL=1.009-1.086) were identified as statistically significant predictors of nonresponse. ECT was an effective treatment for approximately two-thirds of the patients with medication-resistant depression who were included in this study. ECT nonresponse was associated with bipolar subtype, presence of manic symptoms during depression, slightly less severe depressive symptomatology, and protracted duration of the episode.

Influence of prefrontal target region on the efficacy of repetitive transcranial magnetic stimulation in patients with medication-resistant depression: a [18F]-fluorodeoxyglucose PET and MRI study

It is currently unknown whether the antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) depends on specific characteristics of the stimulated frontal area, such as metabolic changes. We investigated the effect of high-frequency rTMS, administered over the most hypometabolic prefrontal area in depressed patients in a two-site, double-blind, randomized placebo-controlled add-on study. Forty-eight patients with medication-resistant major depression underwent magnetic resonance imaging and [(18)F]-fluorodeoxyglucose positron emission tomography (PET) in order to determine a target area for rTMS. After randomization to PET-guided (n = 16), standard (n = 18), or sham rTMS (n = 14) conditions, the patients received 10 sessions of 10-Hz rTMS (1600 pulses/session) at 90% motor threshold. Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores did not differ between PET-guided, standard and sham groups at 2-wk end-point. Exploratory comparison of left PET-guided (n = 9), right PET-guided, standard, and sham rTMS revealed significant effects. The highest improvement in MADRS scores was observed with left PET-guided (60 + or - 31%), significantly superior to sham (30 + or - 37%, p = 0.01) and right-guided (31 + or - 33%, p = 0.02) stimulation. Comparison between left PET-guided and standard rTMS (49 + or - 28%) was not significant (p = 0.12). Comparison between stimulation over dorsolateral prefrontal cortex (BA 9-46), stimulation of other areas, and sham rTMS was statistically significant. Stimulation over BA 9-46 region (n = 15) was superior to sham rTMS (p = 0.02). The results do not support the general hypothesis of increased antidepressant effects of high-frequency rTMS with prefrontal hypometabolism-related PET guidance. Nonetheless, whether metabolism and anatomy characteristics of left frontal area underneath the coil might account for an increase or speeding up of rTMS effects needs further investigation.

Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression

Changes in Regional Cerebral Blood Flow After Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Treatment-Resistant Depression

Within-Session Mood Changes From TMS in Depressed Patients

Within-Session Mood Changes From TMS in Depressed Patients

Transcranial Magnetic Stimulation Reduces Pain in Patients With Major Depression

This study evaluated the change in reported pain in patients with medication-resistant major depression receiving transcranial magnetic stimulation (TMS) compared with sham stimulation. In this study, 68 subjects with major depression were randomized to either TMS or sham stimulation. Repetitive TMS was delivered to the left dorsolateral prefrontal cortex at a frequency of 10 Hz in 5-second trains at 110% of the estimated prefrontal cortex threshold. The level of pain was assessed before, during, and after treatment using the Systematic Assessment for Treatment Emergent Effects (SAFTEE) item for pain in the muscles, bones, and joints. Compared with sham, TMS was associated with a significant (p < 0.05) reduction in the SAFTEE pain item during the study. The reduction in pain could not be explained by the antidepressant effects.

A Case Study of a Patient With a Medication-resistant Major Depression Treated With Ketamine Infusion Followed by Pharmacotherapy Alone vs. Combined ECT and Pharmacotherapy

Caric, Damira MD, PhD; Kaithackachalil, Shirley J. MD; Kim, Joseph U. MD*; Nickell, Patton V. MD; Nathan, Swami MD Author Information

Combined Use of ECT with Duloxetine and Olanzapine

A 38-year-old woman with medication-resistant major depression and posttraumatic stress disorder was treated with electroconvulsive therapy (ECT) concurrent with a duloxetine-olanzapine combination. The treatment resulted in complete resolution of major depression without any complications. This case report suggests that treatment with the combination of duloxetine and olanzapine concurrently with ECT was found safe and uncomplicated. The literature on the combined use of antidepressants and ECT is briefly reviewed.

A Controlled Study of Repetitive Transcranial Magnetic Stimulation in Medication-Resistant Major Depression

Repetitive transcranial magnetic stimulation (TMS) as a treatment for depression has shown statistically significant effects, but the clinical significance of these effects has been questioned. Patients with medication-resistant depression were randomized to receive 15 sessions of active or sham repetitive TMS delivered to the left dorsolateral prefrontal cortex at 110% the estimated prefrontal cortex threshold. Each session consisted of 32 trains of 10 Hz repetitive TMS delivered in 5-second trains. The primary end point was treatment response defined as a >or=50% decrease in Hamilton Depression Rating Scale (HDRS) score at both 1 and 2 weeks following the final repetitive TMS treatment. Remission was defined as a HDRS score < 8. The response rate for the TMS group was 30.6% (11/35), significantly (p = .008) greater than the 6.1% (2/33) rate in the sham group. The remission rate for the TMS group was 20% (7/35), significantly (p = .033) greater than the 3% (1/33) rate in the sham group. The HDRS scores showed a significantly (p < .002) greater decrease over time in the TMS group compared with the sham group. Transcranial magnetic stimulation can produce statistically and clinically significant antidepressant effects in patients with medication-resistant major depression.

Severe Depression Responds To Low-Frequency Stimulation

Severe Depression Responds To Low-Frequency Stimulation

Transcranial Magnetic Stimulation in the Treatment of Depression&lt;subtitle&gt;A Double-blind, Placebo-Controlled Trial&lt;/subtitle&gt;

<h3>Background</h3> High-frequency left-sided repetitive transcranial magnetic stimulation (HFL-TMS) has been shown to have antidepressant effects in double-blind trials. Low-frequency stimulation to the right prefrontal cortex (LFR-TMS) has also shown promise, although it has not been assessed in treatment-resistant depression and its effects have not been compared with those of HFL-TMS. <h3>Objective</h3> To prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group. <h3>Design</h3> A double-blind, randomized, sham-controlled trial. <h3>Setting</h3> Two general psychiatric services. <h3>Participants</h3> Sixty patients with treatment-resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex, or any clinical variables. All patients completed the double-blind phase of the study. <h3>Interventions</h3> Twenty 5-second HFL-TMS trains at 10 Hz and five 60-second LFR-TMS trains at 1 Hz were applied daily. Sham stimulation was applied with the coil angled at 45° from the scalp, resting on the side of one wing of the coil. <h3>Main Outcome Measure</h3> Score on the Montgomery-Åsberg Depression Rating Scale. <h3>Results</h3> There was a significant difference in response among the 3 groups (F_56,2= 6.2), with a significant difference between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (<i>P</i>&lt;.005 for all) but not between the 2 treatment groups. Baseline psychomotor agitation predicted successful response to treatment. <h3>Conclusions</h3> Both HFL-TMS and LFR-TMS have treatment efficacy in patients with medication-resistant major depression. Treatment for at least 4 weeks is necessary for clinically meaningful benefits to be achieved. Treatment with LFR-TMS may prove to be an appropriate initial repetitive TMS strategy in depression taking into account safety, tolerability, and efficacy considerations.

Electroconvulsive therapy in the era of modern psychopharmacology.

Fifty years of advances in the pharmacotherapy of major depression (MDE), mania, schizophrenia, and other severe and persistent psychiatric disorders have neither made ECT obsolete nor unnecessary. However, advances in pharmacotherapy have radically changed the practice of ECT. ECT is rarely a first-line treatment of mental disorder, unless the clinical situation is desperate. Otherwise, ECT is most often offered to persons who have failed to respond to pharmacotherapy, thus defining a relatively treatment-refractory population for ECT. The physician who refers patients for ECT, as well as the ECT provider, must be able to judge at what point a patient is deemed "medication resistant", implying expertise in pharmacotherapy for both the referring physician and the ECT provider. Authoritative sources from 20 years ago quoted antidepressant response rates > or = 90% for ECT, but the antidepressant response rate in medication-resistant MDE may be only 60%. Improvements in the safety of ECT have resulted in the referral of large numbers of older persons for ECT. High relapse rates after ECT are perhaps the biggest problem presently facing patients and providers. High relapse rates are not surprising given that (i) most patients are medication resistant, and (ii) ECT is usually withdrawn at the moment it becomes effective. Although continuation/maintenance ECT is an option in preventing relapse, it may not be a practical solution for persons still in their productive years, and it is resource-intensive. Still, continuation/maintenance ECT is the only method to prevent relapse and recurrence of severe psychiatric disorder for some persons.

Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold

Background: The pathophysiology of depression may include synaptic hypoactivity of left prefrontal cortex. Several groups of investigators have described improved mood associated with rapid transcranial magnetic stimulation (rTMS) but have not looked for possible cognitive side effects associated with left prefrontal magnetic stimulation. Methods: We measured the effects of left prefrontal rTMS on mood, cognition, and motor evoked potential threshold in 10 patients with medication-resistant major depression. Results: In a 2-week open trial of left prefrontal rTMS off antidepressant medications, scores on the Hamilton Rating Scale for Depression and the Beck Depression Inventory decreased by 41% and 40%, respectively. After resuming pre-rTMS antidepressant medication, improvement in mood was still significant at 1 and 3 months later. rTMS had no adverse effects on neuropsychological performance. rTMS treatments were associated with significant decreases in motor evoked potential threshold in the 9 of 10 patients who remained off psychotropic medications during the 2-week treatment period. Conclusions: These preliminary data suggest that left prefrontal rTMS is safe and improves mood in patients with medication-resistant major depression. Changes in motor evoked potential threshold suggest that prefrontal rTMS may alter brain activity at sites remote from the stimulation. Double-blind, sham-controlled studies are needed.