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This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers.
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BACKGROUND AND OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD); however, this treatment currently lacks reliable biomarkers of treatment response. TMS-evoked potentials (TEPs), measured using TMS-electroencephalography (TMS-EEG), have been suggested as potential biomarker candidates, with the N100 peak being one of the most promising. This study investigated the association between baseline N100 amplitude and 1 Hz right dorsolateral prefrontal cortex (R-DLPFC) accelerated rTMS (arTMS) treatment in MDD. METHODS: Baseline TMS-EEG sessions were performed for 23 MDD patients. All patients then underwent 40 sessions of 1 Hz R-DLPFC (F4) arTMS over 5 days and a follow-up TMS-EEG session one week after the end of theses arTMS sessions. RESULTS: Baseline N100 amplitude at F4 showed a strong positive association (p < .001) with treatment outcome. The association between the change in N100 amplitude (baseline to follow-up) and treatment outcome did not remain significant after Bonferroni correction (p = .06, corrected; p = .03, uncorrected). Furthermore, treatment responders had a significantly larger mean baseline F4 TEP amplitude during the N100 time frame compared to non-responders (p < .001). Topographically, after Bonferroni correction, F4 is the only electrode at which its baseline N100 amplitude showed a significant positive association (p < .001) with treatment outcome. LIMITATIONS: Lack of control group and auditory masking. CONCLUSION: Baseline N100 amplitude showed a strong association with treatment outcome and thus demonstrated great potential to be utilized as a cost-effective and widely adoptable biomarker of rTMS treatment in MDD.
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Transtorno Depressivo Maior , Córtex Pré-Frontal Dorsolateral , Eletroencefalografia , Potenciais Evocados , Estimulação Magnética Transcraniana , Humanos , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/fisiopatologia , Masculino , Feminino , Estimulação Magnética Transcraniana/métodos , Adulto , Pessoa de Meia-Idade , Potenciais Evocados/fisiologia , Córtex Pré-Frontal Dorsolateral/fisiologia , Resultado do Tratamento , Biomarcadores , Córtex Pré-Frontal/fisiopatologiaRESUMO
Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery-Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood-brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression.
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Transtorno Depressivo Resistente a Tratamento , Estimulação do Nervo Vago , Humanos , Projetos Piloto , Transtorno Depressivo Resistente a Tratamento/psicologia , Depressão , Resultado do Tratamento , InflamaçãoRESUMO
OBJECTIVE: To assess the effectiveness of accelerated transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD) in a tertiary referral center in Quebec, Canada, focusing on a real-world clinical setting. METHODS: We reviewed the data of 247 TRD patients treated between January 2012 and May 2022 who received accelerated TMS. Participants were adults diagnosed with unipolar or bipolar depression, resistant to at least two antidepressant trials, and assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Significant symptom reduction was found in the completer sample (N = 147), with 46.3 % of patients meeting post-treatment response criteria and 36.1 % achieving remission. Baseline severity of depression, age, and the number of antidepressant trials were key predictors of treatment outcomes. Patients who did not complete treatment had generally more severe depressive and anxious symptoms and greater treatment resistance. No significant differences in response rates were observed across different TMS coils. CONCLUSION: The study demonstrated the effectiveness and tolerability of accelerated TMS for TRD in a real-world clinical setting.
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Transtorno Depressivo Resistente a Tratamento , Estimulação Magnética Transcraniana , Adulto , Humanos , Depressão , Quebeque , Centros de Atenção Terciária , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Resultado do TratamentoAssuntos
Transtorno Depressivo Maior , Dermatite de Contato , Estimulação Transcraniana por Corrente Contínua , Humanos , Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua/efeitos adversos , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Magnética Transcraniana/métodos , Resultado do TratamentoRESUMO
BACKGROUND: For individuals with treatment-resistant depression (TRD), transcranial magnetic stimulation (TMS) has become a well-established approach. In the past decade, intravenous (IV) racemic ketamine has also emerged as a potential treatment for TRD. Currently, little data is available on the clinical effects of IV racemic ketamine in TRD patients who experienced TMS-failure. METHODS: Twenty-one (21) TRD patients who had failed to respond to a standard course of high-frequency left-dorsolateral prefrontal cortex TMS were subsequently scheduled to received IV racemic ketamine infusions. The IV racemic ketamine protocol consisted of 0,5 mg/kg infusions over 60 min, 3 times a week over 2 weeks. RESULTS: Treatment was safe with minimal side-effects. Mean baseline MADRS score was 27.6 ± 6.4 (moderate depression), decreasing down to 18.6 ± 8.9 (mild depression) post-treatment. Mean percent improvement was 34.5 % ± 21.1 from baseline to post-treatment. Paired sample t-test showed significant MADRS score decrease pre- to post-treatment [t(20) = 7.212, p < .001]. Overall, four (4) patients (19.0 %) responded and two (2) of those achieved remission (9.5 %). LIMITATIONS: Limitations of this case series include its retrospective and uncontrolled open-label nature, the lack of self-rating and standardized adverse events questionnaires, as well as follow-ups beyond the immediate treatment period. CONCLUSIONS: Novel ways to increase the clinical effects of ketamine are being explored. We discuss potential combination approaches of ketamine with other modalities to augment its effects. Given the global burden of TRD, novel approaches are needed to curb the current mental health epidemic around the world.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Humanos , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/psicologia , Infusões Intravenosas , Ketamina/efeitos adversos , Estudos Retrospectivos , Estimulação Magnética Transcraniana , Resultado do TratamentoRESUMO
About a third of patients suffering from major depression develop treatment-resistant depression (TRD). Although repetitive transcranial magnetic stimulation (rTMS) and intravenous ketamine have proven effective for the management of TRD, many patients remain refractory to treatment. We present the case of a patient suffering from bipolar TRD. The patient was referred to us after failure to respond to first-and second-line pharmacotherapy and psychotherapy. After minimal response to both rTMS and ketamine alone, we attempted a combination rTMS and ketamine protocol, which led to complete and sustained remission. Various comparable and complimentary mechanisms of antidepressant action of ketamine and rTMS are discussed, which support further study of this combination therapy. Future research should focus on the feasibility, tolerability, and efficacy of this novel approach.
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BACKGROUND: Alcohol use disorder is highly prevalent and has important economical, societal, psychiatric, and medical consequences. All currently approved therapeutic approaches targeting alcohol dependence have relatively modest effects and high relapse rates. Recent evidence suggests that ketamine may be an effective intervention to treat alcohol use disorder and alcoholic withdrawal. This systematic review aimed to assess the current level of evidence for this intervention. METHODS: This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the international database of systematic reviews PROSPERO. Medline(Ovid), CINAHL Complete(EBSCOhost), PsycINFO(Ovid), EBM Reviews(Ovid), EMBASE(Ovid), and Google Scholar were searched for studies using ketamine to treat harmful alcohol use, craving, or withdrawal states in humans. Studies of any methodology that evaluated ketamine in isolation or combination with other interventions were included. The risk of bias was assessed using specific Cochrane critical appraisal tools. RESULTS: Of 1922 abstracts identified, 8 full-text articles were eligible for inclusion, yielding a total sample size of 634 participants. Five studies investigated the impact of ketamine on alcohol use and/or cravings and/or withdrawal in outpatient settings. Three studies looked at the effect of adding ketamine to conventional treatment of withdrawal symptoms in participants admitted to intensive care unit for severe alcohol withdrawal. Results on primary outcomes were mixed within and across trials. CONCLUSIONS: Despite promising results, the current evidence does not permit definitive conclusions about the efficacy of ketamine in alcohol use disorders or withdrawal. Future studies are warranted.
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Alcoolismo , Ketamina , Síndrome de Abstinência a Substâncias , Adulto , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Fissura , Humanos , Ketamina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an effective and safe treatment for major depressive disorder (MDD). rTMS is in need of a reliable biomarker of treatment response. High frequency (HF) dorsolateral prefrontal cortex (DLPFC) rTMS has been reported to induce significant changes in the cardiac activity of MDD patients. Low frequency DLPFC rTMS has many advantages over HF-DLPFC rTMS and thus this study aims to further investigate the effect of low frequency 1 Hz right hemisphere (R)-DLPFC rTMS on the cardiac activity of MDD patients, as well as the potential of using electrocardiogram (ECG) parameters as biomarkers of treatment outcome. METHODS: Baseline ECG sessions were performed for 19 MDD patients. All patients then underwent 40 sessions of accelerated 1 Hz R-DLPFC rTMS one week after the baseline session. RESULTS: Heart rate (HR) significantly decreased from the resting period to the first and third minute of the 1 Hz R-DLPFC rTMS period. Resting HR was found to have a significant negative association with treatment outcome. Prior to Bonferroni correction, HR during stimulation and the degree of rTMS-induced HR reduction were significantly negatively associated with treatment outcome. No significant changes were observed for the heart rate variability (HRV) parameters. LIMITATIONS: Sample size (n = 19); the use of electroencephalography equipment for ECG; lack of respiration monitoring; relatively short recording duration for HRV parameters. CONCLUSION: This novel study provides further preliminary evidence that ECG may be utilized as a biomarker of rTMS treatment response in MDD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04376697.
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Transtorno Depressivo Maior , Estimulação Magnética Transcraniana , Biomarcadores , Depressão , Transtorno Depressivo Maior/terapia , Humanos , Córtex Pré-Frontal , Resultado do TratamentoRESUMO
Intermittent theta burst stimulation (iTBS) using 600 pulses is an effective and FDA-cleared transcranial magnetic stimulation (TMS) protocol for major depressive disorder (MDD). Prolonged iTBS (piTBS) using 1,800 pulses could increase the effectiveness of TMS for MDD, but its real-world effectiveness is still debated. We assessed the safety, tolerability, and preliminary effectiveness of a 3x daily piTBS 1,800 pulses protocol delivered over 2 weeks in 27 participants. Only four participants (18.2%) achieved response, two of them achieving remission (9.1%). Five participants (18.5%) experienced tolerability issues. Future studies should focus on the neurophysiological effects of TBS protocols to determine optimal parameters.
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Transtorno Depressivo Maior , Transtorno Depressivo Maior/terapia , Humanos , Córtex Pré-Frontal/fisiologia , Pesquisa , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Resultado do TratamentoRESUMO
Treatment resistant depression is challenging because patients who fail their initial treatments often do not respond to subsequent trials and their course of illness is frequently marked by chronic depression. Repetitive transcranial magnetic stimulation (rTMS) is a well-established treatment alternative, but there are several limitations that decreases accessibility. Identifying biomarkers that can help clinicians to reliably predict response to rTMS is therefore necessary. Allostatic load (AL), which represents the 'wear and tear' on the body and brain which accumulates as an individual is exposed to chronic stress could be an interesting staging model for TRD and help predict rTMS treatment response. We propose an open study which aims to test whether patients with a lower pre-treatment AL will have a stronger antidepressant response to 4 week-rTMS treatment. We will also assess the relation between healthy lifestyle behaviors, AL, and rTMS treatment response. Blood samples for AL parameters will be collected before the treatment. The AL indices will summarize neuroendocrine (cortisol, Dehydroepiandrosterone), immune (CRP, fibrinogen, ferritin), metabolic (glycosylated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, uric acid, body mass index, waist circumference), and cardiovascular (heart rate, systolic and diastolic blood pressure) functioning. Mood assessment (Montgomery-Åsberg Depression Rating Scale and Inventory of Depressive symptomatology) will be measured before the treatment and at two-week intervals up to 4 weeks. With the help of different lifestyle questionnaires, a healthy lifestyle index (i.e., a single score based on lifestyle factors) will be created. We will use linear and logistic regressions to assess AL in relation to changes in mood score. Hierarchical regression will be done in order to assess the association between AL, healthy lifestyle index and mood score. Long-lasting and unsuccessful antidepressant trials may increase the chance of not responding to future trials of antidepressants and it can therefore increase treatment resistance. It is essential to identify reliable biomarkers that can predict treatment responses.
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Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated intervention for major depressive disorder (MDD). Over 150 randomized controlled trials (RCTs) have been carried out, and its efficacy has been confirmed in dozens of meta-analyses. Real world data has also confirmed the effectiveness of rTMS for MDD in clinical practice, with the most recent literature indicating response rates of 40-50% and remission rates of 25-30%. In this review, we first offer an historical perspective, followed by a review of basic principles, such as putative mechanisms, procedures and protocols, stimulation targets, efficacy and durability of response, side effects, and the placebo controversy. In the second part of this review, we first discuss solutions to increase accessibility to rTMS, such as modifications to treatment equipment, protocols and setting. We continue with possible means to further increase effectiveness, such as treatment personalization and extension. We conclude by addressing the scheduling issue, with accelerated rTMS (arTMS) as a possible solution.
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Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.
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Transtorno Depressivo Maior , Depressão , Transtorno Depressivo Maior/terapia , Humanos , Córtex Pré-Frontal , Estudo de Prova de Conceito , Estimulação Magnética Transcraniana , Resultado do TratamentoRESUMO
BACKGROUND: This work describes the clinical symptoms associated with end of service (EOS) of the batteries of vagus nerve stimulation (VNS) generators in treatment-resistant depression (TRD). Because neurostimulator software may not provide reliable information on battery depletion, careful monitoring of clinical symptoms during the EOS period is an important concern in the follow-up of TRD patients treated with VNS therapy. METHODS: Twenty-six (26) patients were implanted and followed at the Centre Hospitalier de l'Université de Montréal. Fourteen (14) patients required battery replacement and we retrieved chart data up to 3 months before generator battery replacement. RESULTS: Our study demonstrated there might be a decrease or increase in VNS associated physical side effects, and possibly an increase in depressive symptoms during EOS. LIMITATIONS: Our observations are limited by the retrospective nature of this small case series, and larger prospective studies evaluating both VNS side effects and depressive symptoms are therefore needed to further validate those findings. CONCLUSION: Our study is the first to examine clinical symptoms associated with EOS of the batteries of VNS in TRD.
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Depressão , Estimulação do Nervo Vago , Depressão/terapia , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento , Nervo VagoRESUMO
INTRODUCTION: Recent studies have revealed a possible link between heart rate variability (HRV) and major depressive disorder (MDD), with decreased HRV in MDD compared with healthy subjects. Corrected Q-T interval (QTc) has been suggested to represent an indirect estimate of HRV, as QTc length is inversely correlated to parasympathetic activity in healthy subjects. This retrospective study assessed the ability of QTc length in predicting response to vagus nerve stimulation (VNS) treatment in refractory depression. METHODS: We measured QTc length in 19 patients suffering from refractory depression, selected to be implanted with VNS. Correlations were calculated between baseline QTc (preimplantation) and long-term mood response. RESULTS: Nineteen patients selected for VNS surgery were included in the study. Baseline 28-item Hamilton Depression Rating Scale scores were 28.5 ± 6.8 and decreased to 15.1 ± 9.5 at 12 months and 12.4 ± 10.4 at 24 months post-VNS. Among the 19 patients, 53% (10) were responders and 26% (5) were in remission at 12 months. Pretreatment QTc averaged 425.5 ± 22.0. Patients with longer baseline QTc displayed larger improvement, with a significant correlation between mood and QTc values after 12 months (r(18) = -0.526, P = 0.02) and also after 24 months of VNS therapy (r(17) = -0.573, P = 0.016). CONCLUSIONS: The presented analysis showed that increased QTc in patients with MDD might be used as a baseline biomarker for depressive episodes that might respond preferentially to VNS. The link between cardiovagal activity in depression and response to VNS treatment requires further investigation in larger cohorts and randomized controlled trials.
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Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/terapia , Eletrocardiografia , Síndrome do QT Longo/diagnóstico , Estimulação do Nervo Vago , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos RetrospectivosAssuntos
Infecções por Coronavirus/epidemiologia , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Pneumonia Viral/epidemiologia , Telemedicina/métodos , Administração Intranasal , Betacoronavirus , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/psicologia , Transtorno Depressivo Resistente a Tratamento/complicações , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/psicologia , SARS-CoV-2 , AutoadministraçãoRESUMO
AIM: No previous study has investigated interventions for homeless youth suffering from first episode psychosis and comorbid substance use disorder (HYPS). An intensive assertive community intervention team (IACIT) offering outreach interventions, housing support as well as integrated care for early psychosis and substance use disorder (SUD) was created in 2012 at the Centre Hospitalier de l'Université de Montréal (CHUM). To explore the impact of the addition of an IACIT to an early intervention for psychosis service (EIS) on housing stability, functional and symptomatic outcomes and mental health service use. METHODS: A two-year longitudinal study comparing the outcome of HYPS receiving combined EIS and IACIT since 2012, to a historical cohort of HYPS receiving EIS only between 2005 and 2011. Socio-demographic data, housing stability, functioning, illness severity, SUD severity, emergency room visits and hospitalizations were assessed at admission, at 1 month, and every 3 months thereafter. RESULTS: HYPS receiving EIS + IACIT achieved housing stability more rapidly and spent less time hospitalized than HYPS getting EIS only (RR 2.38, P = .017). HYPS with cocaine misuse were less likely to attain housing stability (RR 0.25, P = .04). No between-group differences were found for psychiatric symptoms, functioning and SUD outcomes. CONCLUSION: The addition of IACIT-HYPS to EIS was associated with earlier housing stability and reduced total hospitalization days compared to EIS alone.