Major depressive disorder is a mental disorder affecting millions of people worldwide. A considerable proportion of patients demonstrate a lack of response to conventional treatment. With the recent introduction of esketamine, a new treatment option has been approved for treatment-resistant depression. Although the medication is efficacious in a substantial portion of cases, rare, but possibly serious, adverse effects may occur. This case series shows two cases of rhabdomyolysis, a destruction of muscle tissue with elevated creatine kinase levels, after administration of esketamine. The first case presented is about a 33 year old male patient who suffered from a severe episode of a depressive disorder. He got nasal esketamine as an emergency treatment. While there was an initial improvement regarding the depressive symptoms, the patient developed muscle pain and fatigue after the administration of the fourth dose, with creatine kinase (CK) levels above 22,000 U/L, indicating rhabdomyolysis. Following the discontinuation of esketamine and the implementation of supportive care, the CK levels returned to normal and the depressive symptoms abated. The second case is about a 22-year-old male patient who also suffered from a severe depressive episode and got eketamine as an emergency treatment. Following the tenth dose, the patient exhibited muscle weakness and elevated CK levels (8,032 U/L), which persisted even after dose reduction. Esketamine administration was stopped, and the following monitoring demonstrated a slow return to normal levels of CK and liver enzymes. In both cases, there was no known medical history and both patients developed rhabdomyolysis after administration of esketamine. The temporal connection suggests a possible causal relationship. We found no literature on esketamine-induced rhabdomyolysis following the administration of nasal esketamine. However, these two cases emphasize the need of monitoring for laboratory changes like elevated CK-levels in patients receiving esketamine, especially considering its growing use in treatment-resistant depression.

Treatment-resistant depression (TRD) is defined as patients diagnosed with depression having a history of failure with different antidepressants with an adequate dosage and treatment duration. The NMDA receptor antagonist ketamine rapidly reduces depressive symptoms in TRD. We examined neural correlates of treatment response to ketamine in TRD through a systematic review of brain magnetic resonance imaging (MRI) studies. A comprehensive search in PubMed was performed using \"ketamine AND depression AND magnetic resonance.\" The time span for the database queries was \"Start date: 2018/01/01; End date: 2024/05/31.\" Total 41 original articles comprising 1,396 TRD and 587 healthy controls (HC) were included. Diagnosis of depression was made using the Structured Clinical Interview for DSM Disorders (SCID), the Mini-International Neuropsychiatric Interview (MINI), and/or the clinical assessment by psychiatrists. Patients with affective psychotic disorders were excluded. Most studies applied ketamine [0.5mg/kg racemic ketamine and/or 0.25mg/kg S-ketamine] diluted in 60cc of normal saline via intravenous infusion over 40 min one time, four times, or six times spaced 2-3 days apart over 2 weeks. Clinical outcome was defined as either remission, response, and/or percentage changes of depressive symptoms. Brain MRI of the T2*-weighted imaging (resting-state or task performance), arterial spin labeling, diffusion weighted imaging, and T1-weighted imaging were acquired at baseline and mainly 1-3days after the ketamine administration. Only the study results replicated by ≥ 2 studies and were included in the default-mode, salience, fronto-parietal, subcortical, and limbic networks were regarded as meaningful. Putative brain-based markers of treatment response to ketamine in TRD were found in the structural/functional features of limbic (subgenual ACC, hippocampus, cingulum bundle-hippocampal portion; anhedonia/suicidal ideation), salience (dorsal ACC, insula, cingulum bundle-cingulate gyrus portion; thought rumination/suicidal ideation), fronto-parietal (dorsolateral prefrontal cortex, superior longitudinal fasciculus; anhedonia/suicidal ideation), default-mode (posterior cingulate cortex; thought rumination), and subcortical (striatum; anhedonia/thought rumination) networks. Brain features of limbic, salience, and fronto-parietal networks could be useful in predicting the TRD with better response to ketamine in relief of anhedonia, thought rumination, and suicidal ideation.

UNASSIGNED: Treatment-resistant depression (TRD) is defined as the failure of at least two antidepressants in adequate doses and timing during a major depressive episode. Esketamine intranasal (ESK-IN) has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of TRD in combination with other antidepressants.
UNASSIGNED: To assess the effectiveness and tolerability of a sample of TRD patients who received treatment with ESK-IN as part of the compassionate use program.
UNASSIGNED: A retrospective, observational study was carried out on patients with a diagnosis of TRD enrolled in the early access program of ESK-IN in nine centers. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS) at four time points: baseline, 28, 90, and 180 days of treatment.
UNASSIGNED: The sample included 71 patients (70% women) with a mean baseline MADRS score of 38.27 ± 5.9 and total or partial work disability rates of 85%. ESK-IN treatment was associated with a statistically and clinically significant reduction in the severity of depressive symptoms at all time points assessed. The presence of side effects was common but the majority were mild in severity and resolved after the observation period. Those patients who received psychotherapy in combination with ESK-IN showed a significantly lower MADRS score at 90 and 180 days than those patients who did not undergo psychotherapy.
UNASSIGNED: ESK-IN has proven to be effective and safe in a clinical sample of patients with severe TRD. To optimize clinical outcomes, the pharmacological treatment for TRD should always be integrated into a comprehensive therapeutic plan that encompasses strategies such as psychotherapy, social support, and family interventions.

Background: The psychiatric needs of those with cancer and other advanced illnesses are becoming increasingly recognized. Ketamine is emerging as a promising treatment option for depressive disorders in psychiatric and palliative care. In the palliative care setting, its study has been hindered by lack of consistent administration routes and dosing. Intranasal (IN) esketamine (Spravato®) has recently received U.S. Food and Drug Administration (FDA) approval as an adjunctive agent for treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal ideation (SI). Objective: We sought to offer IN esketamine to patients suffering from TRD and SI at a comprehensive cancer center. Methods: We designed and implemented a protocol to administer IN esketamine and describe three cases in which it was provided to patients with TRD and SI at a palliative care clinic in the United States. Results: Following treatment, all three patients had substantial reduction in depression severity and no further suicidalideation. These improvements were maintained for up to a year. No serious adverse events occurred. Conclusions: These cases illustrate the potential utility of IN esketamine in the palliative care setting.

BACKGROUND: For depression, ketamine is more conveniently administered by oral than by intravenous (iv) routes. The relative antidepressant efficacy of oral vs iv ketamine is unknown.
OBJECTIVE: To assess the acute efficacy and the persistence of improvement with open-label oral versus iv ketamine in outpatients with treatment-resistant depression (TRD).
METHODS: Adults with TRD were randomized to oral (N=30) or IV (N=31) ketamine. Oral ketamine was dosed at 150 mg in 50 mL of water, sipped across 15 min. IV ketamine was dosed at 0.5 mg/kg, infused across 40 min. Ketamine sessions (total, 7) were administered on alternate days for 2 weeks. Ongoing antidepressant drugs were continued unchanged. Patients were assessed at baseline, day 14, and day 30. The primary outcome was the endpoint Hamilton Rating Scale for Depression score on day 14. Secondary outcomes were endpoint scores on the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, and Clinical Global Impression-Severity of Illness and Improvement.
RESULTS: Overall dropout was lower with oral than with iv ketamine (26.7 % vs 54.8 %; P=0.03). The 2 groups did not differ in depression ratings and in response and remission rates on all instruments on both days 14 and 30. Adverse events such as headache (56.7 % vs 74.2 %) and drowsiness (0.0 % vs 22.6 %) were less common with oral ketamine.
CONCLUSIONS: In TRD outpatients treated in general hospitals, oral ketamine maybe better accepted and tolerated than iv ketamine. Conclusions about relative efficacy cannot be drawn because of the high dropout rate with iv ketamine.

Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents\' quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.

Major depressive disorder (MDD) represents a major health issue in adolescents and young adults, leading to high levels of disability and profoundly impacting overall functioning. The clinical presentation of MDD in this vulnerable age group may slightly differ from what can be observed in adult populations, and psychopharmacological strategies do not always lead to optimal response. Resistance to antidepressant treatment has a prevalence estimated around 40% in youths suffering from MDD and is associated with higher comorbidity rates and suicidality. Several factors, encompassing biological, environmental, and clinical features, may contribute to the emergence of treatment-resistant depression (TRD) in adolescents and young adults. Furthermore, TRD may underpin the presence of an unrecognized bipolar diathesis, increasing the overall complexity of the clinical picture and posing major differential diagnosis challenges in the clinical practice. After summarizing current evidence on epidemiological and clinical correlates of TRD in adolescents and young adults, the present review also provides an overview of possible treatment strategies, including novel fast-acting antidepressants. Despite these pharmacological agents are promising in this population, their usage is expected to rely on risk-benefit ratio and to be considered in the context of integrated models of care.

BACKGROUND: Late-life depression (LLD) is associated with cognitive impairment, yet substantial heterogeneity exists among patients. Data on the extent of cognitive impairments is inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant vs. nonresistant LLD and aimed to identify distinct cognitive subgroups. Additionally, we examined whether cognitive subgroups differentially responded to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS).
METHODS: 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared to healthy controls (HC) on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups.
RESULTS: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than HC. A three-cluster solution was found, including \"Cognitively Intact\" (n = 89), \"Cognitively Diminished\" (n = 29), and \"Impaired Memory\" (n = 47) subgroups. Both the \"Cognitively Diminished\" and \"Impaired Memory\" subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the \"Cognitively Intact\" group, though the latter did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment.
CONCLUSIONS: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three identified cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationship among cognitive subgroups, cognitive decline, and neurodegeneration.

UNASSIGNED: Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients.
UNASSIGNED: 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments.
UNASSIGNED: 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all.
UNASSIGNED: Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

UNASSIGNED: In the United States (US), prescription drug coverage is subject to prior authorization (PA) criteria, which may vary between health plans and may exceed drug label requirements. This study aimed to characterize profiles and treatment history of patients with treatment-resistant depression (TRD) who initiated esketamine nasal spray, by stringency of their health plans\' PA criteria relative to the esketamine label.
UNASSIGNED: Adults with evidence of TRD (≥2 antidepressant courses of adequate dose and duration) prior to initiating esketamine were identified using US insurance claims data (03/2016-02/2022). Based on health plan PA criteria for esketamine obtained from Managed Markets Insight & Technology data (05/2020-02/2022), patients were grouped into stringent (PA criteria exceeds label) and non-stringent (PA criteria less stringent or equal to label) cohorts. Patient treatment history before esketamine initiation was compared using Wilcoxon rank sum and Fisher\'s exact tests.
UNASSIGNED: The stringent cohort included 168 patients (mean age: 45 years, 63% female) and the non-stringent cohort included 400 patients (mean age: 45 years, 70% female). During the ongoing major depressive episode before esketamine initiation, the stringent versus non-stringent cohort completed 3.9 versus 3.8 antidepressant treatment courses, on average (p = 0.217); 94.6% versus 96.8% used augmentation therapy (p = 0.240), including 59.3% versus 58.1% with an antipsychotic (p = 0.844), respectively.
UNASSIGNED: Regardless of health plan stringency, on average, patients exceeded US label-mandated number of antidepressant trials before esketamine initiation, which questions the need for health insurance plans PA criteria above label.