This case series (n=4) reflects on the use of ketamine (35mg/70kg, up to 8x) as an adjunct treatment for psychotic treatment-resistant depression (TRD). It finds that all participants were in remission after treatment and that suicidal ideation went down.
Psychotic treatment-resistant depression is a complex and challenging manifestation of mood disorders in the clinical setting. Psychotic depression is a subtype of major depressive disorder characterized by mood-consistent hallucinations and/or delusions. Psychotic depression is often underdiagnosed and undertreated. Ketamine appears to have rapid and potent antidepressant effects in clinical studies, and the Federal Drug Agency approved the use of ketamine enantiomer esketamine-nasal spray for treatment-resistant depression pharmacotherapy in 2019. This study aimed to assess the usage of ketamine for major depressive disorder with psychotic features as an add-on treatment to the standard of care. Here we present four inpatients suffering from treatment-resistant depression with psychotic features, including one with severe suicidal crisis, all treated with 0.5 mg/kg intravenous infusion of ketamine. Subsequent monitoring revealed no exacerbation of psychotic symptoms in short and long-term observation, while stable remission was observed in all cases with imminent antisuicidal effect. Results suggest ketamine may benefit individuals with treatment-resistant depression with psychotic features.
Major depressive disorder (MDD) with psychotic features carries a worse prognosis than non-psychotic MDD, with heavier symptom burden, greater relapse risk, and frequent misdiagnosis. Standard treatments endorsed in clinical guidelines prioritise combined antidepressant and antipsychotic therapy or electroconvulsive therapy (ECT), yet a subset of patients remain treatment-resistant. Ketamine and its enantiomers have emerged as rapid-acting antidepressant agents, and esketamine nasal spray has regulatory approval as an add-on in treatment-resistant depression (TRD) and certain acute indications. Nevertheless, most clinical trials exclude patients with psychotic features because of concerns that ketamine could exacerbate psychosis; consequently, evidence on safety and efficacy in psychotic MDD is limited. Siwek and colleagues set out to contribute data on the safety and tolerability of intravenous ketamine as an add-on to standard of care in psychotic TRD. The paper reports four hospitalised patients with MDD and psychotic features drawn from a naturalistic observational registry at a tertiary mood disorders unit (NCT04226963), describing clinical course during a standardised course of ketamine infusions and short- to longer-term follow-up. The authors frame the report as addressing a gap in the literature on whether ketamine precipitates psychotic worsening and on its antidepressant and antisuicidal effects in this subgroup.
Papers cited by this study that are also in Blossom
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Short, B., Fong, J., Galvez, V. et al. · Lancet Psychiatry (2017)
Veraart, J. K. E., Smith-Apeldoorn, S. Y., Spijker, J. et al. · Journal of Clinical Psychiatry (2021)
Murrough, J. W., Burdick, K. E., Levitch, C. F. et al. · Neuropsychopharmacology (2014)
This is a case series drawn from a naturalistic registry of patients treated at a tertiary referral unit. Inclusion criteria for the registry included a DSM-5 diagnosis of major depressive disorder or bipolar disorder and treatment-resistant depression, with TRD defined in this paper as failure to remit after an 8-week therapeutic antidepressant (or combination) trial and/or ECT following at least two trials of first-line evidence-based treatments. Exclusion criteria listed were pregnancy or breastfeeding, ketamine hypersensitivity, uncontrolled hypertension, and other somatic conditions judged by investigators to compromise safety. Psychometric assessment used the Montgomery–Åsberg Depression Rating Scale (MADRS) in a structured interview, with response defined as a 50% reduction from baseline MADRS and remission reported as "MADRS 12 at day 21" in the extracted text (the comparator symbol is not clearly reported in the extraction). Other measures included the Columbia Suicide Severity Rating Scale (C-SSRS), Young Mania Rating Scale (YMRS), Clinician-Administered Dissociative States Scale (CADSS), and Brief Psychiatric Rating Scale (BPRS). Outcome ratings were collected before infusions and on days 1, 8, 14, 21 and at day 35 (one week post-treatment). All four subjects had MDD of duration between one and ten years, were hospitalised for the index psychotic major depressive episode (hospitalisations lasted 2–6 months), and had failed multiple antidepressant treatments; one patient had previously received four ECT sessions that were discontinued because of post-ECT delirium. The ketamine regimen followed the commonly used protocol of 0.5 mg/kg intravenous infusion over 40 minutes, administered twice weekly for four weeks for a total of eight infusions per patient. Dosage reductions for intolerability were noted as an option but were not described as applied in these cases. Concomitant care included ongoing psychotropic medications as clinically indicated and elements of cognitive-behavioural intervention (psychoeducation and behavioural activation) delivered twice weekly during hospitalisation. The extracted text does not clearly report a formal statistical analysis plan or inferential methods, consistent with a descriptive case-series design.
All four patients experienced rapid clinical improvement after initiation of ketamine and achieved remission of psychotic symptoms during the infusion series. No case showed psychotic exacerbation in the short- or longer-term observation reported. Adverse events were mild, transient, and self-limiting: patient 1 reported nausea during the first infusion that resolved within 20 minutes and no further adverse events; patient 2 had mild dizziness during the first three infusions resolving within about 10 minutes; patient 3 reported no adverse effects; and patient 4 experienced mild dizziness after the first and second infusions resolving within 20 minutes. The authors note no relevant cardiovascular or haemodynamic changes across cases as reported in the extracted text. Individual course details are summarised in the extraction. Patient 1 showed rapid mood improvement and full remission of psychotic symptoms after the first infusion; at discharge she was prescribed venlafaxine ER 225 mg, mirtazapine 45 mg and olanzapine 5 mg and sustained full remission at a 1-year follow-up. Patient 2 regained psychomotor function after the fourth infusion, was asymptomatic for psychosis at discharge, and remained so at a 2-year follow-up; discharge medications included sertraline 200 mg and quetiapine 200 mg. Patient 3's nihilistic delusions resolved after the third infusion and the major depressive episode was asymptomatic after the sixth infusion; discharge medications included venlafaxine ER 300 mg, mirtazapine 45 mg and pregabalin 150 mg. Patient 4 improved rapidly after the second infusion with resolution of psychotic symptoms and suicidal thoughts; discharge medications included venlafaxine ER 375 mg, mirtazapine 45 mg and lurasidone 74 mg. The extraction does not present numerical MADRS, CADSS, BPRS or C-SSRS scores for each time point, so effect-size estimates and formal response/remission rates beyond the case descriptions cannot be reported from the provided text.
Siwek and colleagues interpret these four cases as supportive of a favourable safety and tolerability profile for intravenous ketamine used as an add-on in psychotic TRD, including in a patient presenting with suicidality. The clinical observations are presented as consistent with limited prior reports and small studies that have not found ketamine to precipitate or worsen psychosis; in several cited small series and pooled analyses short-term adverse effects tended to be mild, self-limiting dissociative phenomena that resolved within an hour or so post-infusion. The authors note instances from the literature in which ketamine or esketamine was associated with rapid improvement of both depressive and psychotic symptoms in individual cases and small cohorts, and they reference a small meta-analysis and post-hoc analyses suggesting antidepressant effects in patients with a history of psychosis without induction of psychotic symptoms. Beyond clinical outcomes, the discussion broadens to conceptual issues raised by the authors: psychotic features modify the course and treatment response of mood disorders, neurophysiological methods (for example EEG and event-related potentials) may be useful for mechanistic research, and biomarker studies of ketamine's effects remain preliminary. The paper reports that available biomarker, neuroimaging and neurophysiological studies are consistent with ketamine-induced synaptic plasticity and changes in functional connectivity, but notes that no biomarker has been validated for routine clinical use. The authors explicitly acknowledge important limitations. This report comprises only four heterogeneous cases drawn from a naturalistic registry, so selection bias is possible and causality cannot be inferred; generalisation is not supported. Potential confounders such as diet, nicotine use and physical activity can influence pharmacokinetics and pharmacodynamics, although the extracted text states these four patients were nonsmokers without substance-use disorders and had low activity levels. Follow-up duration varied from two months to two years, limiting longitudinal inference. Given these constraints, the authors frame the report as hypothesis-generating and recommend that a history of psychosis should not be an automatic exclusion from therapeutic ketamine exposure, while noting that such patients may experience greater short-term dissociative symptoms. They call for controlled studies to prospectively evaluate ketamine in depressed patients with current psychotic features.
The authors conclude that these four cases add to literature supporting ketamine's rapid antidepressant and antisuicidal effects in treatment-resistant depression and demonstrate a favourable safety and tolerability profile when administered intravenously as an adjunct to standard of care in psychotic TRD. In the cases described there were no clinically relevant cardiovascular or haemodynamic changes and no psychotomimetic exacerbations during acute treatment or in follow-up, although the authors emphasise the limited and hypothesis-generating nature of the evidence.
Major depressive disorder (MDD) with psychotic features is associated with a less favorable prognosis and outcome as compared to non-psychotic MDD. It is associated with more burdensome symptomatology, course, and a high relapse rate. The exact epidemiology of psychotic depression is unclear as it is frequently misdiagnosed. However, the lifetime prevalence of MDD with psychotic features in the general population is reported from 0.35% to 1%. The psychotic trait may be transmissible irrespective of other characteristics, such as instability of mood or thinking. Consequently, a relationship between a psychosis characteristic and dysregulated mood may result in a psychotic mood disorder profile. As known treatments for MDD with psychotic features are approved, therapies are based upon clinical treatment guidelines supported by registry data and prioritize combined treatments with antidepressants (ADT) and antipsychotics or electroconvulsive therapy ECT. However, a proportion of patients with MDD with psychotic features present psychotic treatment-resistant depression (TRD) and do not respond to recommended therapeutic interventions. The observation that the dissociative anesthetic drug ketamine produces a rapid antidepressant effect in treatment-resistant patients with MDD, along with extensive research with ketamine racemic mixture as well as it is (R)-ketamine (arketamine) and (S)-ketamine (esketamine) enantiomers led to the clinical development and regulatory approval for esketamine-nasal spray (ESK-NS) as an add-on treatment to oral ADT in TRD in acute management and relapse prevention. Consequently, ESK-NS was approved in the acute management of MDD, depressive symptoms in adults with MDD with acute suicidal ideation or behavior (MDSI), and major depressive disorder with a psychiatric emergency (MDD-PE) as an add-on treatment to the standard of care (SOC). With the onset of rapid-acting ADT (RAAD), a high proportion of patients who have been considered treatment-resistant and difficult to treat may benefit from a novel pharmacological approach for mood disorders. Ketamine and its enantiomers exhibit a favorable safety and tolerability profile. The commonly reported adverse drug reactions include psychotomimetic phenomena that are dose-related and self-limiting in time with no sequelae and symptomatology abatement at the time of treatment. Industry clinical trials and the majority of academic research registries exclude patients with psychotic features, as there is a concern about psychosis exacerbation due to ketamine. On the contrary, few data on MDD with psychotic features indicate a good safety and tolerability profile with no psychotic exacerbation. MDD with psychotic features represents an extreme manifestation of a major depression episode (MDE). Major depressive disorder, with the psychotic feature itself or vulnerability to psychosis is a life-threatening condition, but being complicated with treatment resistance to SOC treatment, the options are limited. There is evidence supporting the pro-cognitive effects of ketamine, which imply that ketamine may decrease cognitive performance during infusion or within a few hours following infusion but improve cognition after infusion. Malhotra et al.demonstrated a worsening of cognitive symptoms in patients with schizophrenia following ketamine infusion; the effects were only noticed during the infusion and disappeared 90-120 min later. Therefore, patients with psychotic depression and cognitive symptoms may benefit from exposure to ketamine for a limited period of time. There is significant evidence that an increase in synaptic neuroplasticity is essential for the antidepressant effect of ketamine. In addition to alleviating symptoms and boosting neurobiological learning processes, this approach seems to aid patients by promoting early involvement in cognitive-behavioral therapy (CBT). This therapeutic combination of ketamine and CBT may result in better long-term results while reducing the requirement for continued ketamine exposure. In addition, early data suggests that ketamine might enhance negative self-schemas, which is one of the primary therapy goals of CBT. Both academic research and clinical trials indicate that ketamine, with its enantiomers use, does not precipitate psychotic features; however, there is some limited evidence. There is also limited evidence for efficacy with good safety and tolerability in these patients, with scarce reports available to date. As literature reports on ketamine use in psychotic TRD are scarce, the reports on the intervention outcome with regard to efficacy and, above all, safety and tolerability profile are of vital interest to practitioners. This paper reports on four patients presenting with psychotic TRD demonstrating data on the safety and tolerability of short-term ketamine use as an add-on treatment to SOC. The study was carried out in accordance with the latest version of the Declaration of Helsinki. For each participant, written consent was obtained after the procedures had been fully explained. The study protocol was approved by the Independent Bioethics Committee for Scientific Research at the Medical University of Gda ńsk, Poland. The study population comprises MDD subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963).
The inclusion criteria were a diagnosis of major depressive disorder (MDD) or bipolar disorder (BD) according to DSM-5 criteria; treatment-resistant depression (TRD) was defined as the patient failing to achieve remission within the 8-week trial of an antidepressant or combination at a therapeutic dose after at least two trials of first-line evidence-based treatments and/or electroconvulsive therapy (ECT). The exclusion criteria included pregnancy and breastfeeding, hypersensitivity to ketamine, uncontrolled hypertension, and other uncontrolled somatic conditions that, in the opinion of the investigators, may compromise safety. The structured Montgomery-Asberg depression rating scale interview was used to evaluate the severity of depression symptoms (MADRS-Sigma). Before infusions, on days 1, 8, 14, and 21, as well as one week afterwards, outcome measurements were collected (day 35). Psychometric endpoints included rates of response (50% reduction from baseline MADRS total score) and rates of remission (MADRS 12 at day 21) in addition to the Columbia suicide severity rating scale (C-SSRS), Young mania-rating scale (YMRS), clinician-administered dissociative states scale (CADSS), and brief psychiatric rating scale (BPRS) prior to and during ketamine administration. All patients described in this paper suffered from MDD from one to ten years. They were admitted to the hospital due to the current MDE with psychotic features. As a result of MDE, one of the patients attempted suicide, the other one suffered from substantial psychomotor retardation, the third one presented severe weight loss, and the fourth one had suicidal thoughts. Tablecovers further details about patients. During hospitalizations, which lasted from 2 to 6 months, all of the patients were treated with multiple ADT. None of them showed any results. In addition, patient number 1 had performed four ECT procedures, which resulted in delirium implicating ECT discontinuation. Tablecovers further details about patients' hospitalization. Due to the ineffectiveness of SOC treatment and after considering the risks and benefits, all of the patients were administered intravenous ketamine. It is advised that intravenous ketamine be administered at a rate of 0.5 mg/kg over a period of 40 min; dosages may be reduced in situations of intolerability, although effectiveness at lower doses may be diminished. In individuals with TRD, the optimal frequency of intravenous delivery has not been determined. The acute antidepressant effectiveness on day 15 did not vary between twice weekly and thrice weekly intravenous injections (0.5 mg/kg) in multicenter, double-blind research including individuals (N = 67; ages 18-64) with TRD. Following these results, the dosage was 0.5 mg/kg as an intravenous infusion twice a week over 40 min. The treatment duration was four weeks, making a total of 8 ketamine infusions per patient. All patients received elements of cognitive-behavioral intervention, including psychoeducation and behavioral activation throughout the hospitalization on a twice-weekly regimen.
All of the subjects demonstrated rapid mood improvement with full remission in psychotic symptomatology observed post-ketamine infusion. Patient 1 received eight ketamine intravenous infusions as an add-on treatment with backbone psychotropic treatment, including olanzapine up to 20 mg/day. During the first infusion, the patient felt nauseated-the symptom was remitted within 20 min, and no other adverse events (AE) were observed across infusions and in follow-up. The subject demonstrated rapid mood improvement with full remission in psychotic symptomatology observed post the first ketamine infusion. On discharge, she received: venlafaxine ER 225 mg, mirtazapine 45 mg, and olanzapine 5 mg as prophylactic treatment as a 1-year follow-up. Full remission is sustained as SOC therapy and shows the full recovery, almost to premorbid functional status. Patient 2, after the 4th infusion, regained psychomotor efficiency. The psychotic symptoms were asymptomatic on discharge and at a 2-year-long follow-up. During the first, second, and third ketamine infusions, he reported mild dizziness remitting within 10 min. No other AE appeared. On discharge, his medication was: sertraline 200 mg and quetiapine 200 mg. Patient 3 neglected any adverse effects during eight ketamine intravenous infusions. The subject's state improved after the 3rd infusion, as she no longer demonstrated nihilistic delusions. After the 6th infusion, MDE was asymptomatic. On discharge, she received venlafaxine ER 300 mg, mirtazapine 45 mg, and pregabalin 150 mg. Patient 4 presented rapid improvement after the 2nd infusion-neither psychotic symptomatology nor suicidal thoughts were observed. After the first and second infusions, she reported mild dizziness remitting within 20 min. No other AE was observed. On discharge, she received venlafaxine ER 375 mg, mirtazapine 45 mg, and lurasidone 74 mg. Tablecovers the observed adverse effects of ketamine infusions.
This report supports evidence for good ketamine safety and tolerance in TRD with psychotic symptoms, including one case with suicidality. In line with limited previous reports, no psychotic exacerbation was observed in short and long-term observation. To our best knowledge, this is the second report of MDD with psychotic features and suicidality. Psychotic TRD represents the most severe presentation of MDD, characterized by a high mortality rate and unfavorable prognosis. The report on the multiple intravenous infusions of ketamine for TRD referred to good efficacy and safety profiles in four subjects with TRD with psychotic symptoms as an add-on treatment to SOC, and observations corroborated with safety and tolerability profiles in the domain of dissociation being similar to non-psychotic TRD and characterizing a dose-related self-limiting and transient pattern. Psychotic symptoms were found in a median of 19% of studies that included both inpatients and outpatients or only outpatients, compared to 42% of studies that included only inpatients. Psychotic symptoms are most prevalent in patients with severe depression and are related to poorer treatment results and increased relapse rates. In addition, up to sixty percent of individuals with schizophrenia exhibit negative symptoms that coincide with those of depression. Patients with depression and those with negative symptoms of schizophrenia do not respond favorably to antidepressants and antipsychotics. Antianhedonic effects of subanesthetic dosages of ketamine have been observed without a deleterious impact on the long-term psychotic symptomatology of schizophrenia patients. In a new meta-analysis, the authors synthesize the research on the effects of ketamine for depression in patients with a history of psychosis or current psychotic symptoms, as well as trials evaluating ketamine as a treatment for negative symptoms in schizophrenic patients. Analyzed were nine papers of pilot trials and case reports involving a total of 41 individuals. As side effects were mild and self-limiting, these investigations imply that short-term ketamine treatment for depression and even negative symptoms in patients with a history of psychosis or current psychotic characteristics can be both safe and beneficial. A recent post-hoc analysis investigates whether a lifetime history of psychosis influences patients' response to a single infusion of ketamine in clinical trials for depression. The authors merged the results of three randomized, placebo-controlled crossover trials with depressed patients. Of the 69 patients evaluated, two were diagnosed with MDD with psychotic features and ten with bipolar disorder with psychotic features in the past. This study reveals that a single infusion of ketamine produces antidepressant effects in people with a history of psychosis without generating psychotic symptoms. Two patients were described as the first to use ketamine as an antidepressant for patients with present psychotic symptoms. One was diagnosed with MDD and the other with schizoaffective disorder; both were suffering from MDE with psychotic symptoms. Infusions of ketamine were safe and well tolerated, with rapid cessation of psychotic symptoms. Ajub and Lacerda, described the efficacy of esketamine in four patients with psychotic characteristics and severe depression, following the description of these two individuals. Two patients were diagnosed with major depressive disorder with psychotic symptoms, one with bipolar depressive disorder with mixed features, and one with schizoaffective disorder, depressive type. Three patients exhibited considerable improvement or complete remission of both depressed and psychotic symptoms 24 h after esketamine injection and after two and four weeks of follow-up examination. The administration of esketamine to these four patients did not aggravate their psychotic symptoms. In adolescents with mixed TRD and psychotic traits, repeated infusions of ketamine over 3 and 8 weeks decreased depressive symptoms, suicidal thoughts, and psychotic symptoms. In the majority of investigations, dissociative effects of ketamine were recorded; most were mild and temporary, occurring during the initial dose and diminishing over time, with complete resolution occurring within 60 to 80 min post-infusion. The research suggests that there was no psychotic exacerbation among the participants in the included studies on this topic. In several cases, comorbid psychotic symptoms improved or completely disappeared after the administration of ketamine or esketamine for depression, consistent with the theoretical notions underlying the treatment of TRD with the novel pharmacological approaches. Changes in diagnostic criteria make it challenging to understand psychotic depression studies conducted throughout the years. The clinical and conceptual impacts of a survey are contingent on whether psychosis is characterized by delusions and/or hallucinations, severity, impairment, or melancholia, regardless of whether MDEs were unipolar or bipolar and whether the control subjects comprised of MDD of comparable severity without psychosis, psychosis without depression, or melancholic versus non-melancholic depression. Although psychosis may not always precede every future depressive episode, it operates as an autonomous component of depression that fundamentally modifies mood disorders, distinguishing it from other kinds of depression. Inasmuch as psychosis, rather than the degree of depression, tends to modify the course and treatment response of mood disorders, identifying psychosis in depressed patients, especially those who do not react as predicted to antidepressant medication, is a critical therapeutic endeavor. Psychosis may be less evident in clinical practice than in research studies. This paper supports evidence for the distinct phenomenology of psychosis and dissociation that pose separate diagnostic entities. The idea of downstaging, which influences the course and prognosis of mood disorders, is consistent with psychotic TRD as determined by the disease's development stage and the ketamine effect found in the studied instances. Since psychosis is characterized by perceptual and cognitive abnormalities that often emerge prior to the beginning of the illness, biomarkers of brain functions in connection to information processing are especially intriguing for elucidating its origin. Due to their remarkable temporal resolution, neurophysiological methods, particularly electroencephalography (EEG) and event-related potentials (also known as evoked potentials), which are changes in the EEG induced by stimuli, are promising for the study of perception and cognition in vivo. In addition to abnormalities found in patients, neurophysiological indicators of genetic and clinical risk for psychosis might enhance our mechanistic knowledge and perhaps improve therapeutic management. However, imaging methods, such as neurophysiological indicators of genetic risk (endophenotypes), are also essential for elucidating disease causes. In case-control studies, it is important to include possible confounders, notably antipsychotic drugs. The great majority of neurophysiological investigations included antipsychotic-treated subjects. Although medication-free first-episode psychosis patients demonstrate comparable neurophysiological abnormalities to chronic patients, these deficits are often considered to be less severe. The combined use of neurophysiological indicators and genetics has the potential to shed light on the genesis of psychosis and assist the development of novel medications, whilst research on high-risk individuals might expedite psychosis patients' access to psychological and medical therapy. There are relatively little biomarker data for TRD patients exposed to ketamine and its enantiomers. Review findings show that ketamine may provide an anti-inflammatory impact and reduce at least one inflammatory marker when administered. Neuroimaging studies have indicated that the cingulate cortex is the primary site of ketamine's effect. The bulk of blood-based, neuroimaging, and neurophysiological studies reviewed demonstrate that ketamine induces normalization of major depressive disorder aetiology through synaptic plasticity and functional connectivity. Currently, no biomarker/biosignature has been well validated for clinical use, although some seem intriguing. This report has several limitations. Firstly, it refers to four cases, presenting substantial variability regarding the severity stage and symptomatology of the disease. Moreover, the data reported come out of the naturalistic registry, and the risk of selection bias in post hoc registry data exploration exists. Thus, no causative effect must be drawn as the conclusion, the generalization of the observation is not possible and the tendency for overinterpretation must be strongly restricted. In the case of certain food patterns, drug use disorders (such as nicotine dependence), and physical activity levels, it is recognized that they may create both pharmacokinetic and pharmacodynamic consequences that confuse our results. All patients reported above having a healthy diet were nonsmokers and lacked a drug use issue. Their degree of activity was minimal. Due to the variability of cases presented it can not be replicated. Besides, the follow-up ranges from 2 months to 2 years, with an extensive longitudinal observation missing. Thus, this report is hypothesis generating in value. Our results support the notion that a history of psychosis should not exclude people from receiving ketamine in a therapeutic context. However, such patients may be at risk of experiencing more significant short-term dissociative symptoms. Future studies should investigate how ketamine treatment affects depressed patients with current psychotic features, given these patients may benefit from a trial of ketamine.
This paper contributes to the literature supporting the rapid antidepressant effect in TRD and demonstrates the good safety and tolerability profile of intravenous ketamine use as the add-on SOC in psychotic TRD. All cases described correspond with previous literature reports on safety and tolerability, with neither relevant cardiovascular and hemodynamic changes nor psychomimetic exacerbations in the acute treatment phase as well as in the follow-up.
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