Treatment-refractory Depression Research Articles

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression

BackgroundDepression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. MethodsSix patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. ResultsDepression and anxiety symptoms improved after 3–6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LimitationsThis study was limited to the small sample size and lack of a healthy control group. ConclusionsChronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Sex Differences in the Antidepressant and Neurocognitive Effects of Nonconvulsive Electrotherapy in Patients with Treatment-Refractory Depression

Sex Differences in the Antidepressant and Neurocognitive Effects of Nonconvulsive Electrotherapy in Patients with Treatment-Refractory Depression

Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study.

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.

Intestinal metabolites predict treatment resistance of patients with depression and anxiety

BackgroundThe impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance.ResultsWe analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69–1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment.ConclusionFecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.

Electroconvulsive therapy enhances degree centrality in the orbitofrontal cortex in depressive rumination

Depressive rumination has been implicated in the onset, duration, and treatment response of refractory depression. Electroconvulsive therapy (ECT) is remarkably effective in treatment of refractory depression by modulating the functional coordination between brain hubs. However, the mechanisms by which ECT regulates depressive rumination remain unsolved. We investigated degree centrality (DC) in 32 pre- and post-ECT depression patients as well as 38 matched healthy controls. An identified brain region was defined as the seed to calculate functional connectivity (FC) in whole brains. Rumination was measured by the Ruminative Response Scale (RRS) and its relationships with identified DC and FC alterations were examined. We found a significant negative correlation between DC of the right orbitofrontal cortex (rOFC) before ECT and brooding level before and after treatment. Moreover, rOFC DC increased after ECT. DC of the left superior temporal gyrus (lSTG) was positively correlated with reflective level before intervention, while lSTG DC decreased after ECT. Patients showed elevated FC in the rOFC with default mode network. No significant association was found between decreased RRS scores and changes in DC and FC. Our findings suggest that functional changes in rOFC and lSTG may be associated with the beneficial effects of ECT on depressive rumination.

The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression

The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression Abstract: Deep Brain Stimulation ("DBS") is a minimally invasive, neurosurgical and hypothesis-driven therapeutic procedure for permanent local regulation of pathological circuits. While depression represents a heterogeneous syndrome with multifactorial etiopathogenesis, neuroscience research is advancing evidence to identify network-level mechanisms that play an important role in the pathophysiology of depression. In the following article, we will review the role of DBS in treatment-resistant or difficult-to-treat depression. The aim is to increase the awareness of DBS and to discuss the challenges of its therapy and implementation.

Predicting Responses to Electroconvulsive Therapy in Adolescents with Treatment-Refractory Depression Based on Resting-State fMRI.

The efficacy of electroconvulsive therapy (ECT) in the treatment of adolescents with treatment-refractory depression is still unsatisfactory, and the individual differences are large. It is not clear which factors are related to the treatment effect. Resting-state fMRI may be a good tool to predict the clinical efficacy of this treatment, and it is helpful to identify the most suitable population for this treatment. Forty treatment-refractory depression adolescents were treated by ECT and evaluated using HAMD and BSSI scores before and after treatment, and were then divided into a treatment response group and a non-treatment group according to the reduction rate of the HAMD scale. We extracted the ALFF, fALFF, ReHo, and functional connectivity of patients as predicted features after a two-sample t-test and LASSO to establish and evaluate a prediction model of ECT in adolescents with treatment-refractory depression. Twenty-seven patients achieved a clinical response; symptoms of depression and suicidal ideation were significantly improved after treatment with ECT, which was reflected in a significant decrease in the scores of HAMD and BSSI (p < 0.001). The efficacy was predicted by ALFF, fALFF, ReHo, and whole-brain-based functional connectivity. We found that models built on a subset of features of ALFF in the left insula, fALFF in the left superior parietal gyrus, right superior parietal gyrus, and right angular, and functional connectivity between the left superior frontal gyrus, dorsolateral-right paracentral lobule, right middle frontal gyrus, orbital part-left cuneus, right olfactory cortex-left hippocampus, left insula-left thalamus, and left anterior cingulate gyrus-right hippocampus to have the best predictive performance (AUC > 0.8). The local brain function in the insula, superior parietal gyrus, and angular gyrus as well as characteristic changes in the functional connectivity of cortical-limbic circuits may serve as potential markers for efficacy judgment of ECT and help to provide optimized individual treatment strategies for adolescents with depression and suicidal ideation in the early stages of treatment.

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

Treatment resistant depression in elderly.

Treatment refractory depression (TRD) in the elderly is a common psychiatric disorder with high comorbidity and mortality. Older adults with TRD often have complicated comorbidities and several predisposing risk factors, which may lead to neuropsychiatric dysfunction and poor response to treatment. Several hypotheses suggest the underlying mechanisms, including vascular, immunological, senescence, or abnormal protein deposition. Treatment strategies for TRD include optimization of current medication dose, augmentation, switching to an alternative agent or class, and combination of different antidepressant classes, as well as nonpharmacological adjuvant interventions such as biophysical stimulation and psychotherapy. In summary, treatment recommendations for TRD in the elderly favor a multimodal approach, combining pharmacological and nonpharmacological treatments.

Supplemental Material for Processes of Change in a Randomized Clinical Trial of Radically Open Dialectical Behavior Therapy (RO DBT) for Adults With Treatment-Refractory Depression

Supplemental Material for Processes of Change in a Randomized Clinical Trial of Radically Open Dialectical Behavior Therapy (RO DBT) for Adults With Treatment-Refractory Depression

Therapeutic and Safety Outcomes of Intravenous Ketamine for Treatment-refractory Depression in a Veteran Population: A Case Series.

Major depressive disorder is a serious, recurrent, and disabling psychiatric illness. Despite many proven treatments with multiple medications or therapies, approximately 30% of patients fail to achieve remission and are considered to have treatment-refractory depression (TRD). Recently, there has been a growing interest in the use of intravenous (IV) ketamine for the treatment of TRD. There is limited yet increasing evidence to support the use of ketamine, a glutamate receptor antagonist, in the management of depression; however, the lack of data regarding the safety and tolerability of therapy has limited its clinical use. By analyzing a cohort of veterans with TRD and comorbid psychiatric conditions treated with IV ketamine infusions for a 24-month study period, we aim to provide critical information about ketamine's clinical effectiveness and safety. Based on a retrospective chart review, we identified eight veterans with TRD receiving treatment with repeated-dose IV ketamine from 2018 to 2020. The magnitude of clinical response was based on the Beck Depression Inventory self-report scale and the Patient Health Questionnaire-9, both measured at the initial patient consultation and before the beginning of each ketamine infusion treatment. Safety analysis included changes to pre- and post-ketamine infusion on vital signs, effects on alertness and sedation, and potential psychosis-like effects. For all outcomes, we estimated a linear mixed-effects model that allowed heterogeneous residual variances for each veteran. The effect of continuous predictor variables was estimated using restricted cubic splines with knot points specified at the 5th, 35th, 65th, and 95th percentiles. All the analyses were conducted using SAS v.9.4, with P < .05 indicating the statistical significance. This study had institutional review board approval: 1220. During the study period, the median number of ketamine infusions was 15 across a median of 164 days of treatment follow-up with a median time between ketamine infusions of 4 days. For both Beck Depression Inventory and Patient Health Questionnaire-9 scores, there was a statistically significant reduction across infusions (both P < .001), but the strongest reduction occurred before day 40. The change was statistically significant for decreased heart rate (P = .019) but not for systolic blood pressure (P = .612), diastolic blood pressure (P = .942), respiratory rate (P = .822), oxygen saturation (P = .070), and temperature (P = .943). Side effects were reported in six patients (75%); however, the only side effect reported was excessive sedation or dizziness immediately after infusion. In this study, repeated-dose IV ketamine infusions over a 24-month study period resulted in a significant reduction in depression scores in a group of veterans with TRD. The rapid onset of significant response, absence of psychosis-like effects or dissociative symptoms despite psychiatric comorbidities, and minimal effects on vital signs support the clinical efficacy and safety of this exciting new treatment option for patients with TRD. Limitations include a 2-year study period, lack of information on long-term effects, and the retrospective nature of the study. Prospective studies of longer duration are needed to assess the long-term efficacy and safety of IV ketamine for TRD.

Abstract 13369: Takotsubo Cardiomyopathy Following Electroconvulsive Therapy

Case Presentation: A 71-year-old woman presented to our institution for treatment-refractory depression requiring electroconvulsive therapy (ECT). She underwent a transthoracic echocardiogram (TTE) during a pre-ECT evaluation, which demonstrated no regional wall motion abnormalities and a left ventricular ejection fraction (LVEF) of 60 - 65%. The patient subsequently underwent ECT. During the procedure, sinus tachycardia with associated ST-segment changes were noted on telemetry. Esmolol was administered with subsequent improvement in her tachycardia, however ST-segment changes persisted. A twelve-lead electrocardiogram was obtained and was notable for new T-wave inversions in leads V1-V4 and Q-waves in leads III and aVF. However, STEMI criteria was not met. A TTE obtained shortly after her ECT demonstrated ballooning of the LV apex and an LVEF of 35%, consistent with takotsubo cardiomyopathy. Laboratory evaluation was notable for a high sensitivity troponin peak of 130 ng/L and a brain natriuretic peptide level of 746 pg/mL. Cardiac catheterization was not performed as the patient had a negative stress test prior to admission. The patient’s symptoms improved over the next two days, and she was discharged with close outpatient follow-up. Discussion: Takotsubo cardiomyopathy occurs following physical or psychological stress. Greater than half of patients with takotsubo cardiomyopathy have neurologic or psychiatric disorders. Takotsubo cardiomyopathy is an increasingly recognized serious complication of ECT and can be seen in post-menopausal women with depression. The introduction of beta blocker therapy has been used to prevent recurrent episodes of post-ECT takotsubo cardiomyopathy. Despite this, there are reports of post-ECT takotsubo cardiomyopathy in patients on chronic beta blocker therapy. Thus, the risks and benefits of proceeding with additional ECT treatments must be weighed after an initial episode of takotsubo cardiomyopathy.

Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior.

Refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. Approximately 15% of patients with major depressive disorder are refractory to currently available treatments. We hypothesized metabolic abnormalities contributing to treatment refractory depression are associated with distinct findings identifiable in the cerebrospinal fluid (CSF). Our hypothesis was confirmed by a previous small case-controlled study. Here we present a second, larger replication study. We conducted a case-controlled, targeted, metabolomic evaluation of 141 adolescent and adult patients with well-characterized history of depression refractory to three maximum-dose, adequate-duration medication treatments, and 36 healthy controls. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry, and high-performance liquid chromatography, electrospray ionization, tandem mass spectrometry. Abnormalities were identified in 67 of 141 treatment refractory depression participants. The CSF abnormalities included: low cerebral folate (n = 20), low tetrahydrobiopterin intermediates (n = 11), and borderline low-tetrahydrobiopterin intermediates (n = 20). Serum abnormalities included abnormal acylcarnitine profile (n = 12) and abnormal serum amino acids (n = 20). Eighteen patients presented with two or more abnormal metabolic findings. Sixteen patients with cerebral folate deficiency and seven with low tetrahydrobiopterin intermediates in CSF showed improvement in depression symptom inventories after treatment with folinic acid and sapropterin, respectively. No healthy controls had a metabolite abnormality. Examination of metabolic disorders in treatment refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities and their potential roles in pathogenesis remain to be determined.

Association of anhedonia and suicidal ideation in patients with treatment-refractory depression after intravenous ketamine infusions

Objectives Accumulating evidence suggests that the effects of ketamine administered intravenously at subanaesthetic doses on both anhedonic symptoms and suicidal ideation occur independently of depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD). This study sought to determine the relationship between anhedonia and suicidal ideation after serial ketamine infusions. Methods A total of 79 subjects with either treatment-refractory MDD (n = 60) or BD (n = 19) were included in a clinical ketamine study. The Montgomery–Åsberg Depression Rating Scale (MADRS) anhedonia factor and the first five items of the Scale for Suicidal Ideations (SSI-Part I) were used to assess anhedonia symptoms and suicidal ideation, respectively. Results At baseline, anhedonia, as measured by the MADRS, was not significantly associated with suicidal ideation or specific suicide-related ideation as measured by SSI-Part I (all p’s > 0.05). Only the ‘wish to die’ and ‘desire to make a suicide attempt’ items were positively associated with anhedonia at two weeks after the sixth ketamine infusion, which was independent of the reductions in depressive symptoms (all p’s < 0.05). Conclusion Anhedonia as measured by the MADRS appeared to not be positively related to suicidal ideation after serial ketamine infusions. KEY POINTS Serial ketamine (0.5 mg/kg) infusions have shown quick and dramatic antisuicidal and antianhedonic effects in patients with depression. The association between anhedonia and suicidal ideation after serial ketamine infusions is unclear. Anhedonia appeared to not be positively related to suicidal ideation after serial ketamine infusions.

Stereotactic Radiofrequency Ablation for Treatment-Refractory Depression: A Systematic Review and Meta-Analysis.

(1) Background: Major depressive disorder (MDD) generates a large proportion of global disease burden. Stereotactic radiofrequency ablation (SRA) may be beneficial for selected patients with its most debilitating and refractory forms, but effect size is uncertain. (2) Methods: A systematic literature review and meta-analysis on SRA for MDD was carried out. Patient-level data were extracted from articles reporting validated depression measures (Beck Depression Inventory (BDI), Montgomery–Åsberg Depression Rating Scale (MADRS)), pre- and at least six months post surgery. To accommodate different outcome measures, the standardised mean difference (SMD) between both scores was used as the principal effect size. Data were synthesised using a random-effects model. (3) Results: Five distinct studies were identified, comprising 116 patients (64 included in meta-analysis). Effect size comparing post- vs. pre-operative scores was 1.66 (CI 1.25–2.07). Anterior cingulotomy (two studies, n = 22) and anterior capsulotomy (three studies, n = 42) showed similar effect sizes: 1.51 (CI 0.82–2.20) vs. 1.74 (CI 1.23–2.26). Multiple procedures were performed in 30 of 116 (25.9%) patients. Based on patient-level data, 53% (n = 47) were responders (≥50% improvement), of which 34% reached remission (MADRS ≤ 10 or BDI ≤ 11). BDI mean improvement was 16.7 (44.0%) after a second procedure (n = 19). (4) Conclusions: The results are supportive of the benefit of SRA in selected patients with refractory MDD.

O037 / #247 MULTI TARGETING DEEP BRAIN STIMULATION FOR TREATMENT-RESISTANT DEPRESSION: A 22 MONTH FOLLOW UP CASE REPORT: TRACK 2: BRAIN STIMULATION FOR TREATMENT RESISTANT DEPRESSION, PAIN, AND PARKINSON'S DISEASE

According to WHO, there are more than 300,000,000 people worldwide suffering from depression. It is the world's leading cause of disability and contributes significantly to the overall global burden of disease. 30% of the patients are refractory, being possible candidates for surgical treatment by means of Deep Brain Stimulation (DBS). We present the follow up at 22 months of a patient with Treatment Refractory Depression (TRD) operated on with a new combination of targets.

Low frequency repetitive transcranial magnetic stimulation to the right dorsolateral prefrontal cortex engages thalamus, striatum, and the default mode network.

The positive treatment outcomes of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) when applied over the right dorsolateral prefrontal cortex (DLPFC) in treatment-refractory depression has been verified. However, the mechanism of action behind these results have not been well-explored. In this work we used simultaneous functional magnetic resonance imaging (fMRI) during TMS to explore the effect of LF rTMS on brain activity when applied to the right [RDLPFC1 (MNI: 50, 30, 36)] and left DLPFC sites [LDLPFC1 (MNI: -50, 30, 36), LDLPFC2 (MNI: -41, 16, 54)]. Seventeen healthy adult volunteers participated in this study. To identify brain areas affected by rTMS, an independent component analysis and a general linear model were used. Our results showed an important laterality effect when contrasting rTMS over the left and right sites. Specifically, LF rTMS increased brain activity at the striatum, thalamus, and areas of the default mode network when applied to the right, but not to the contralateral left DLPFC. In contrast, no site differences were observed when evaluating the effect of LF rTMS over the two left sites. These findings demonstrate that LF rTMS to the right DLPFC was able to stimulate the cortico-striato-thalamo-cortical pathway, which is dysregulated in patients with major depressive disorder; therefore, possibly providing some neurobiological justification for the successful outcomes found thus far for LF rTMS in the treatment of depression.

Ablation Surgeries for Treatment-Resistant Depression: A Meta-Analysis and Systematic Review of Reported Case Series

Background and Objectives: Ablative lesion procedures remain as the last option in treatment of refractory depression. Contemporary ablative psychosurgeries involve producing lesions in the anterior limb of the internal capsule (bilateral anterior capsulotomy – BAC), the supragenual anterior cingulate gyrus and cingulum (bilateral anterior cingulotomy – BACING), and subgenual anterior cingulate gyrus and subcortical orbitofrontal white matter (bilateral subcaudate tractotomy – BST). A combination of BACING and BST is known as limbic leukotomy (bilateral limbic leukotomy – BLL). All procedures claim some success, but cohorts are small, depression assessment instruments differ, and inclusion and outcome criteria and follow-up duration vary. In some cohorts, more than one type of surgery was performed in several patients, further confounding interpreting the available data. Current evidence is equivocal on which surgical target works best. Method and Aim: This systematic review and meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standard on published cohorts was conducted to review and identify which is the best standalone ablative procedure for treatment-resistant depression (TRD) based on response rate (event rate) and adverse-effect profile using the Comprehensive Meta-Analysis software. Results and Conclusion: As a standalone neurosurgical procedure, we found that BAC appears to be the most effective and safest of all the ablative targets for TRD. A major limitation of this conclusion is the paucity of published case series where sample sizes are small and all are open label.

From Ketamine to Drugs Targeting Subtype-Selective Benzodiazepine Site-Containing Gamma-Aminobutyric Acid A Receptors as Novel Rapid-Acting Antidepressants

Ketamine is a rapidly acting antidepressant and has shown consistent clinical benefits for about 20 years. In 2019, the U.S. Food and Drug Administration approved its (S)-isomer, (S)-ketamine (intranasal Spravato), for use in patients with treatment-refractory depression. In addition, the fact that ketamine is mechanistically distinct from conventional monoamine-based antidepressants has stimulated research for drugs that would reproduce its rapid therapeutic effects associated with improvement of depressive symptomatology, without the confounds of its psychotomimetic and abuse-related properties.

Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery–Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment‐refractory depression. Ketamine PK/PD data were collected from 21 treatment‐refractory depressed participants who received ketamine (dose titration 0.1–0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two‐compartment models with first‐order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first‐order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration‐response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half‐maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety.