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Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.
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The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.
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Transtorno Depressivo Maior , Giro do Cíngulo , Recompensa , Humanos , Giro do Cíngulo/fisiologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Masculino , Adulto , Feminino , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Comportamento de Escolha/fisiologia , Pessoa de Meia-Idade , Ritmo beta/fisiologia , Epilepsia/fisiopatologia , Adulto JovemRESUMO
Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.
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Transtorno Depressivo Resistente a Tratamento , Eletroconvulsoterapia , Ketamina , Humanos , Ketamina/uso terapêutico , Ketamina/administração & dosagem , Eletroconvulsoterapia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Transtorno Depressivo Resistente a Tratamento/terapia , Adulto , Idoso , Resultado do TratamentoRESUMO
In daily life, we must recognize others' emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.
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Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare reimbursement rates and health economics data were used to approximate costs. We performed Monte Carlo (MC) simulations and probabilistic sensitivity analyses to estimate incremental cost-effectiveness ratios (ICER; USD/quality-adjusted life year [QALY]) at a 5-year time horizon. Cost-effectiveness was defined using willingness-to-pay (WTP) thresholds of $100,000/QALY and $50,000/QALY for moderate and definitive cost-effectiveness, respectively. We included 274 patients across 16 studies from 2009-2021 who underwent DBS for TRD and had ≥12 months follow-up in our model inputs. From a healthcare sector perspective, DBS using non-rechargeable devices (DBS-pc) would require 55% and 85% remission, while DBS using rechargeable devices (DBS-rc) would require 11% and 19% remission for moderate and definitive cost-effectiveness, respectively. From a societal perspective, DBS-pc would require 35% and 46% remission, while DBS-rc would require 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. DBS-pc will unlikely be cost-effective at any time horizon without transformative improvements in battery longevity. If remission rates ≥8-19% are achieved, DBS-rc will likely be more cost-effective than TAU for TRD, with further increasing cost-effectiveness beyond 5 years.
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Análise Custo-Benefício , Estimulação Encefálica Profunda , Transtorno Depressivo Resistente a Tratamento , Anos de Vida Ajustados por Qualidade de Vida , Humanos , Estimulação Encefálica Profunda/economia , Transtorno Depressivo Resistente a Tratamento/terapia , Transtorno Depressivo Resistente a Tratamento/economia , Masculino , Feminino , Estados Unidos , Pessoa de Meia-Idade , Qualidade de Vida , Custos de Cuidados de Saúde/estatística & dados numéricos , Método de Monte CarloRESUMO
INTRODUCTION: In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment's effects on implicit self-associations and their relation to symptom improvement. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30-40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial. RESULTS: The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: ß = -0.201; p = 0.049). DISCUSSION: Our findings suggest that changing implicit self-worth during a post-ketamine 'plasticity window' is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention's impact on implicit cognition, as this mechanism appears linked to the intervention's enduring clinical benefits.
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Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.
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Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], -8.9 [0.39] vs -7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030.
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Transtorno Depressivo Maior , Adulto , Feminino , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Quimioterapia Combinada , Método Duplo-Cego , Antidepressivos/efeitos adversos , Resultado do TratamentoRESUMO
The current study evaluated the effectiveness of intravenous ketamine treatment for suicidality in a community-based clinical sample of 295 outpatients (mean age= 40.37; 58.6 % male). We conducted growth mixture modeling to estimate latent classes of changes in symptoms of suicidality measured by the Concise Health Risk Tracking - Self-Report (CHRT-SR) across five infusions in a two-week course of treatment. Best-fit indices indicated three trajectory groups demonstrating non-linear, quadratic changes in CHRT-SR scores during ketamine treatment. The largest group of patients (n= 170, 57.6 %) had moderate CHRT-SR scores at baseline and showed gradual improvement during treatment. The other two groups of patients had severe CHRT-SR scores at baseline and diverged into one group with no improvement throughout treatment (n = 63, 21 %) and one group with rapid improvement (n = 62, 21 %). Of the clinical and demographic variables available and tested, only higher scores pertaining to active thoughts of death and/or plan were found to predict which of the patients with severe CHRT-SR scores at baseline would not benefit from treatment. The present study provides an important contribution to the knowledge of ketamine's effects on symptoms related to suicide over time. providing support for the possible effectiveness of ketamine in a proportion of patients.
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Ketamina , Suicídio , Humanos , Masculino , Adulto , Feminino , Ketamina/farmacologia , Ketamina/uso terapêutico , Psicometria , Ideação Suicida , Fatores de RiscoRESUMO
Developing antidepressants that are not only more effective but are rapidly acting is the Holy Grail for psychiatry. We review multiple issues that arise in determining rapid responses in antidepressant trials. The current status of purportedly rapid acting agents is first reviewed. Then, a number of key questions/issues are addressed: Is there a unifying definition for rapid response across studies? Should rapid response criteria be based on required measurable effects on overall improvement? On specific symptoms such as psychomotor retardation, depressed mood, or anhedonia? In associated symptoms such as anxiety or insomnia? When should onset be considered rapid-by Day 3? Day7? Day 14? If there is a rapid response, for how long should the effects be maintained? Is maintenance of effect dependent on continuing the medication? Is rapid response associated with specific mechanisms of action? Do the mechanisms of action suggest possible risk for drug abuse? How important is rapid response really in an often chronic or recurrent depressive disorder? In which types of patients could rapid response be particularly important? What are the study design issues that need to be considered for assessing rapid response, including: selection of specific types of depressed patients, multiple doses of drug studied, designation of primary and secondary outcome measures, specific time points at which to determine efficacy, requirements for demonstrating durability, etc. A framework for approaching this complex area is developed for both researchers and clinicians.
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Antidepressivos , Depressão , Humanos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , AnsiedadeRESUMO
BACKGROUND: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.
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Estimulação Encefálica Profunda , Transtorno Depressivo Resistente a Tratamento , Epilepsia , Humanos , Epilepsia/terapia , Eletroencefalografia/métodos , Transtorno Depressivo Resistente a Tratamento/terapia , Eletrodos , Estimulação Encefálica Profunda/métodos , Eletrodos ImplantadosRESUMO
This Viewpoint examines key issues stemming from several recent reports of electroconvulsive therapy (ECT) vs ketamine for improving depressive symptoms in treatment-resistant depression (TRD).
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Eletroconvulsoterapia , Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão , Pacientes Ambulatoriais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.
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Anedonia , Recompensa , Humanos , Anedonia/fisiologia , Motivação , Autorrelato , NeuroimagemRESUMO
PURPOSE/BACKGROUND: Once-daily extended-release (ER) lorazepam was developed to reduce fluctuations in plasma levels compared with lorazepam immediate-release (IR) for short-term anxiety relief. Here we report a series of phase 1 randomized, open-label, multiperiod crossover studies characterizing ER lorazepam pharmacokinetics and safety in healthy adults. METHODS/PROCEDURES: These phase 1 studies assessed the pharmacokinetics of ER lorazepam administered: (study 1) 3 mg once daily versus IR lorazepam 1 mg 3 times a day (TID; every 8 hours), (study 2) with or without food, and (study 3) intact versus sprinkled onto food. Study 3 further evaluated the proportionality of 1 × 4- versus 4 × 1-mg doses. Safety was also monitored. FINDINGS/RESULTS: There were 43, 27, and 29 subjects who completed studies 1, 2, and 3, respectively. The 90% confidence intervals for Cmax,SS , Cmin , and AUC TAU,SS of once-daily ER lorazepam compared with IR given TID were within 80% to 125% limits establishing steady-state bioequivalence. Maximum mean lorazepam concentrations were achieved at 11 hours compared with 1 hour after dosing for ER versus IR lorazepam, respectively. Pharmacokinetic parameters ( Cmax , AUC last or AUC 0- t , AUC inf or AUC 0-inf ) of ER lorazepam were bioequivalent whether taken with or without food, administered intact or sprinkled onto food, or administered as intact 1 × 4- versus 4 × 1-mg capsules. No serious safety concerns were found. IMPLICATIONS/CONCLUSIONS: Once-daily ER lorazepam provided a pharmacokinetic profile bioequivalent to IR lorazepam given TID and was well tolerated in healthy adults across all phase 1 studies. These data suggest that ER lorazepam could be an alternative for patients currently treated with IR lorazepam.
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Lorazepam , Adulto , Humanos , Lorazepam/efeitos adversos , Preparações de Ação Retardada , Estudos Cross-Over , Área Sob a CurvaRESUMO
This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.
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Ketamina , Humanos , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Administração IntravenosaRESUMO
Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.
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Depressão , Ketamina , Adulto , Animais , Humanos , Imagem de Tensor de Difusão , Ketamina/farmacologia , Ketamina/uso terapêutico , Córtex Cerebral , Plasticidade NeuronalRESUMO
BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).
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Antidepressivos , Transtorno Depressivo Resistente a Tratamento , Eletroconvulsoterapia , Ketamina , Humanos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/efeitos adversos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/terapia , Administração Intravenosa , Transtornos PsicóticosRESUMO
Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies of real-world practices suggest that antidepressant monotherapy continues to be the most widely used treatment after inadequate response to a first-line treatment. However, rates of remission with antidepressants in TRD are suboptimal. Atypical antipsychotics are the most widely studied augmentation agent and aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are approved for depression. Benefits of using atypical antipsychotics for TRD has to be weighted against their potential adverse events, such as weight gain, akathisia, and tardive dyskinesia.