Chronic Treatment-resistant Depression Research Articles

Ketamine and chronic treatment-resistant depression: real-world practice and after relapse

BackgroundChronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients.MethodsIn this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months.Results23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts.ConclusionsIntroducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.

Buprenorphine for the Treatment of Military-related PTSD With Treatment-resistant Depression and Unexpected Benefit for Chronic Pain: Case Report.

The prevalence of treatment-resistant depression within global and military populations highlights the need for novel treatment approaches beyond monoamine neurotransmitter modulators. Buprenorphine (BUP), a semi-synthetic partial opioid agonist, is approved for the treatment of opioid use disorder and has shown promise in treating both depression and chronic pain. This case report discusses the use of transdermal BUP in treating a 36 year-old man with treatment-resistant depression with prominent anhedonia, military-related posttraumatic stress disorder, and chronic pain because of barosinusitis. Significant reductions in anxious and depressive symptoms, including in anhedonia, were observed with lasting effects. An unexpected finding was the discontinuation of prescribed hydromorphone for pain, suggesting the potential unique benefit of BUP in treating chronic pain and treatment resistant depression comorbidities. These findings implicate the diverse beneficial potential of BUP in psychiatric treatments for military populations.

Predictive modeling of response to repetitive transcranial magnetic stimulation in treatment-resistant depression.

Identifying predictors of treatment response to repetitive transcranial magnetic stimulation (rTMS) remain elusive in treatment-resistant depression (TRD). Leveraging electronic medical records (EMR), this retrospective cohort study applied supervised machine learning (ML) to sociodemographic, clinical, and treatment-related data to predict depressive symptom response (>50% reduction on PHQ-9) and remission (PHQ-9 < 5) following rTMS in 232 patients with TRD (mean age: 54.5, 63.4% women) treated at the University of California, San Diego Interventional Psychiatry Program between 2017 and 2023. ML models were internally validated using nested cross-validation and Shapley values were calculated to quantify contributions of each feature to response prediction. The best-fit models proved reasonably accurate at discriminating treatment responders (Area under the curve (AUC): 0.689 [0.638, 0.740], p < 0.01) and remitters (AUC 0.745 [0.692, 0.797], p < 0.01), though only the response model was well-calibrated. Both models were associated with significant net benefits, indicating their potential utility for clinical decision-making. Shapley values revealed that patients with comorbid anxiety, obesity, concurrent psychiatric medication use, and more chronic TRD were less likely to respond or remit following rTMS. Patients with trauma and former tobacco users were more likely to respond. Furthermore, delivery of intermittent theta burst stimulation and more rTMS sessions were associated with superior outcomes. These findings highlight the potential of ML-guided techniques to guide clinical decision-making for rTMS treatment in patients with TRD to optimize therapeutic outcomes.

Reduction in Cognitive Symptoms Following Intranasal Esketamine Administration in Patients With Chronic Treatment-resistant Depression: A 12-Week Case Series.

Cognitive symptoms are a core feature of depressive disorders, interfere with full functional recovery and are prominent in patients with treatment-resistant depression (TRD), particularly in severe chronic cases. Intranasal (IN) esketamine was recently approved for the treatment of TRD; however, its effects on cognitive symptoms are unclear. In this article, we describe cognitive changes in 8 patients with chronic TRD who were treated with IN administration of esketamine. Eight outpatients with chronic TRD received IN esketamine over 3 months and were assessed at baseline and after 4, 8, and 12 weeks of treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Digit Symbol Substitution Test (DSST), the Trail Making Test-B (TMT-B), the Patient Deficits Questionnaire for Depression 5-item (PDQ-D5), the Hamilton Anxiety Rating Scale (HARS), and the Clinical Global Impressions Scale (CGI). We observed reductions in cognitive symptoms according to DSST, TMT-B, and PDQ-D5 scores within the first 2 months of treatment with IN esketamine. These improvements were observed before patients achieved clinical response (≥50% decrease in baseline MADRS scores), and they also occurred earlier than reductions in HARS scores. A clinical response to IN esketamine was detected in severely ill patients with chronic TRD after 3 months of treatment. Interestingly, improvements on measures of cognitive symptoms were observed before patients achieved antidepressant response. These preliminary observations suggest an additional value to the antidepressant properties of IN esketamine. Clinical studies specifically investigating cognition as a primary outcome measure of IN esketamine in TRD are warranted.

ID:16557 Longitudinal Changes in Default Mode Network With Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

Subcallosal cingulate deep brain stimulation (SCC DBS) has been investigated as a novel treatment option for severe and chronic treatment-resistant depression (TRD) [1-2]. The aim of this study is to characterize the longitudinal brain changes in default mode network (DMN) with SCC DBS using 15O-water PET and test in a new cohort of subjects in18F-FDG PET.

Treatment-Resistant Depression in Portugal: Perspective From Psychiatry Experts.

Guidance about treatment-resistant depression (TRD) in Portugal is very limited, even though depression prevalence is among the highest in European countries. A questionnaire was conducted, followed by two advisory boards with seven Portuguese psychiatry experts, to characterize and discuss MDD and TRD epidemiology, diagnosis, patient journey, treatment options, and unmet clinical needs. Consensus was reached on the main issues. In daily practice, TRD can be defined as moderate to severe MDD episodes with insufficient clinical improvement after two antidepressant treatments, taken in adequate doses and duration. TRD diagnosis and treatment are mostly decided by psychiatrists at public hospitals. Treatment type and duration must be adjusted to characteristics of the patient and the depressive episode, including symptoms, number of previous episodes, comorbidities, and previous treatment response and side effects. The most relevant objectives of TRD treatment are reaching response and remission, prevention of suicide, and improvement of quality of life, functionality, and wellbeing. Regarding pharmacotherapy, antidepressant switch occurs more frequently with non-response, while optimization, combination, and augmentation are considered for patients with partial response. Psychotherapy should be considered in parallel to pharmacological treatment. Brain stimulation techniques are underused. Lifelong treatment is required for recurrent or more chronic TRD episodes, but patient adherence is also poorer in these cases. In Portugal, TRD management is limited by lack of access to specialist care and to many treatment options. These aspects highlight that conventional pharmacotherapy does not lead to remission in many patients and that optimization strategies are frequently necessary to achieve satisfactory treatment outcomes.

The Impact of the COVID-19 Pandemic on the Health and Coping Behaviors of Patients With Treatment-Resistant Depression

The COVID-19 pandemic has had a disastrous impact globally. For the general public and for people with mental illnesses, this pandemic may cause mental/physical stress and major life impacts. This study was designed to explore the related changes in daily life and impacts on the well-being of a group of patients with chronic treatment-resistant depression (TRD) during the COVID-19 pandemic. This study was a part of a long-term, follow-up study of a cohort of patients with TRD collected in 2018. All of the subjects who were diagnosed with major depression and fit the inclusion criteria were referred by the psychiatrists from two teaching hospitals. Structured interviews were used to collect data on physical and psychological changes during the pandemic period between January and May 2020. The researchers organized the key points by recording or note taking. Thematic analysis was used to summarize and classify themes and units. The 116 respondents revealed that the COVID-19 pandemic affected their health in the biological, psychological, and social dimensions. The three emerging themes included: The threatening of homogeneity in the whole person's health, the interaction between bio-psycho-social aspects, and positive growth of individuals with TRD. Although the participants had confidence in the prevention strategies of the government related to COVID-19, they expressed feelings of distress and restlessness with regard to COVID-19-related news reports. The COVID-19 pandemic has affected the health of patients with TRD in both positive and negative ways. As the goal of government preventive strategies is to protect and promote public health, regular attention should be paid to the negative effects of long-term exposure to pandemic-related news on this vulnerable population.

Longitudinal effects of rTMS on neuroplasticity in chronic treatment-resistant depression

Major depressive disorder (MDD) is amongst the most prevalent of psychiatric disorders. Unfortunately, a third of patients will not respond to conventional treatments and suffer from treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) has been proven effective in treating TRD. The research suggests that rTMS acts via neuroplastic effects on the brain, which can be measured by changes in hippocampal and amygdala volume as well as cortical thickness. This sham-controlled study investigates longitudinal effects of rTMS on the volumes of the hippocampus and amygdala and cortical thickness in patients with chronic TRD. 31 patients received 20 sessions of high-frequency rTMS (N = 15) or sham treatment (N = 16) over the left dorsolateral prefrontal cortex during 4 consecutive weeks. Using structural magnetic resonance imaging, we investigated longitudinal treatment effects on hippocampus and amygdala volume as well as thickness of the paralimbic cortex. We found no clinical differences between the active and sham rTMS group. Longitudinal changes in hippocampal and amygdala volume did not differ significantly, although males showed a significant decrease in left amygdala volume, irrespective of treatment group. Changes in cortical thickness of the paralimbic cortex differed significantly between the active and sham groups. Most notably, the increase in cortical thickness of the isthmus of the left cingulate gyrus was greater in the active as compared to the sham rTMS group. Our data suggest that rTMS can induce neuroplastic changes, particularly in cortical thickness, independent of treatment response. We also found longitudinal changes in amygdala volume in males. For clinical effects to follow these neuroplastic effects, more intensive rTMS treatment might be needed in chronically depressed patients.Trial registration number: ISRCTN 15535800, registered on 29-06-2017.

Experts Debate What's Next for DBS for Depression

Experts Debate What's Next for DBS for Depression

Does DBS Have a Future in Depression Treatment?

Does DBS Have a Future in Depression Treatment?

Alternate day dTMS combined with SSRIs for chronic treatment resistant depression: A prospective multicenter study

IntroductionChronic treatment resistant depression takes a substantial toll on patients' quality of life and alternative treatment options are limited. This prospective multicenter study evaluated the safety, tolerability and efficacy of four weeks of thrice-a-week deep transcranial magnetic stimulation (dTMS) in combination with selective serotonin reuptake inhibitors (SSRIs). MethodsForty patients who failed to respond during a 16-week double-blind placebo controlled (DBPC) trial of dTMS or sham dTMS as monotherapy were screened and started a treatment of previously tolerable but ineffective SSRI. After ten days of medication, high frequency dTMS was added three times a week for four weeks. ResultsdTMS combined with SSRIs was well tolerated, with only headaches as a related adverse event (n = 4), which did not cause drop outs. Six patients were excluded from analysis: 1 was missing screening data and 5 received less than 10 sessions. Out of 34 patients included in this study, 12 (35.3%) patients remitted (HDRS-21 < 10). No significant differences were found between patients who had received sham or active dTMS in the earlier DBPC multicenter trial. LimitationsThis was a small scale open study of dTMS with SSRIs in patients that failed to respond during a DBPC dTMS trial, although a carryover effect cannot be excluded. Comparative efficacy of dTMS with and without SSRIs and specific dosing and protocol parameters warrant specifically-designed large-scale controlled studies. ConclusionsThrice weekly dTMS at 120% motor threshold(MT), 10 HZ, 3‑s trains, 20‑s intervals, 2400 daily pulses, can augment formerly ineffective SSRI treatment.

Higher Risk for Obstructive Sleep Apnea in Chronic Treatment-Resistant Depression

Higher Risk for Obstructive Sleep Apnea in Chronic Treatment-Resistant Depression

Domiciliary transcranial direct current stimulation over a two year period for treatment-refractory psychiatric and neurological conditions. A three case report

The domiciliary use of transcranial direct current stimulation (tDCS) for treatment-resistant neurological and psychiatric disorders in three adult patients for a two year period is described. The first patient was diagnosed with chronic treatment-resistant depression, the second with fibromyalgia and the third with borderline personality disorder, bipolar disorder, self-harm, drug addiction and she was also pregnant. The three patients sought treatment for their conditions utilizing tDCS. Initial evaluation confirmed previous diagnoses, treatments, motivation and competency. Individual training to self-administer tDCS was provided at the clinic, with subsequent training, supervision, evaluation and consultation sessions accomplished via Skype. Protocols were individualized and subsequently modified as a result of the patient response and need for additional treatment as the therapeutic benefits waned with time. All three patients improved with the tDCS treatment. The most important indicators of improvement, as evaluated by the patients themselves, were the ability to function at work, social interaction and quality of life. Proficiency to self-administer was accomplished within the first week. Protocols were accurately followed and modifications were made as a result of doctor-patient collaboration. Side effects were minor, rapidly identified and treated. Domiciliary treatment can be a viable option for those conditions which respond to tDCS. Specific advantages include increased availability, convenience and lower cost.

Vagus nerve stimulator-related speech/exercise induced cough

Vagal nerve stimulation (VNS) therapy is an effective adjunctive treatment for chronic or recurrent treatment resistant depression. Although considered a safe procedure, increasing output current can be associated with stimulation induced side effects. We report the first case of dry cough induced by speech and mild exercise, occurring in the off mode following implantation of a vagal nerve stimulator (VNSor). We discuss the possible pathophysiology and the potential treatment options of this rare complication.

ID 8 – Repetitive transcranial magnetic stimulation in chronic anxiety and depression

Objective Presenting the case of a gentleman with chronic treatment resistant depression (TRD) and social anxiety disorder, who first failed ECT and left sided high frequency repetitive transcranial magnetic stimulation (rTMS) but then responded to right sided low frequency rTMS in order to highlight the therapeutic potential of right sided rTMS for the treatment of TRD with co-morbid anxiety. Methods 44 year old married mixed race male with primary symptoms of chronic sadness, deep sense of worthlessness and hopelessness, irritability, anergia, poor concentration, intermittent suicidal ideation and anxiety. Since the mid 1990s, he’s had adequate trials of multiple psychotropic medications and psychotherapy. Twenty sessions of bilateral ECT offered no therapeutic benefit. He thus began left unilateral, high frequency (10 Hz) rTMS. Results Using the Montgomery–Asberg Depression Rating Scale (MADRS), his initial score was 28. He received 32 left sided treatments, but failed to respond. He was switched to right sided rTMS and after 20 sessions his MADRS score decreased to 9. He has been continued on maintenance rTMS therapy monthly and remains in remission. Conclusion This case illustrates that if left sided high frequency rTMS proves ineffective, then right sided, low frequency treatment should be considered in patients suffering with chronic depression and anxiety.

A negative randomised sham-controlled trial of ventral capsule/ventral striatum stimulation in treatment-resistant depression: an unsuccessful trial or treatment?

ABSTRACT FROM: Dougherty DD, Rezai AR, Carpenter LL, et al . A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry...

Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation.

The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown. To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression. Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015. Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes. Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch." This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

A Case of Major Depressive Disorder With Mixed Features: Diagnostic and Treatment Issues.

A Case of Major Depressive Disorder With Mixed Features: Diagnostic and Treatment Issues.

A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention

To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. The small sample size limited the statistical power and external validity. These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. NCT01268137 (ClinicalTrials.gov).

Vagus nerve stimulation for treatment-resistant mood disorders: a long-term naturalistic study.

BackgroundLimited therapeutic options are available for patients with treatment-refractory major depression who do not respond to routinely available therapies. Vagus nerve stimulation showed adjunctive antidepressant effect in chronic treatment resistant depression, even though available studies rarely exceed 2-year follow up.We report a naturalistic 5-year follow up of five patients who received VNS implant for resistant depression (3 patients with major depressive disorder and 2 with bipolar disorder).MethodsResponse was defined as a reduction of the 17-item HDRS total score ≥50% with respect to baseline, remission as a score ≤7.ResultsResponse and remission rates were both 40% (2/5) after 1 year, and 60% (3/5) at 5 years. Two patients withdrew from the study because of side effects or inefficacy of stimulation.ConclusionsOur case series showed that long-term VNS may be effective in reducing severity of depression in a small but significant minority of patients, although two patients had stimulation terminated because of adverse effects and/or refusal to continue the study.