Polish standard of treatment with racemic ketamine for patients with depressive disorders developed by a Working Group appointed by the National Consultant in the field of psychiatry. / Polski standard leczenia racemiczna ketamina pacjentów z zaburzeniami depresyjnymi opracowany przez zespól roboczy powolany przez Konsultanta Krajowegow dziedzinie psychiatrii.

The Polish standard of treatment with racemic ketamine for patients with depressive disorders was developed by a Working Group appointed by the National Consultant in the field of psychiatry. Despite the wide range of available medications, as many as one-third of depressed patients do not respond to standard antidepressant treatment, raising the need for an ongoing search for new effective and safe therapies. In recent years, the possible role of overactivity of the glutamatergic system in the etiopathogenesis of depression has again attracted the attention of many experts. The possibility of using substances with a modulating effect on the glutamatergic system in the treatment of depressive disorders has been postulated, among others, the long-known anesthetic ketamine, which is a noncompetitive NMDA receptor antagonist. This paper summarizes the results of studies on the efficacy and safety of racemic ketamine (administered intravenously) in the treatment of patients with depressive symptoms in the course of both unipolar and bipolar affective disorder, and, meeting the expectations of many practicing psychiatrists wishing to broaden the range of therapies offered to their patients, presents recommendations on indications, contraindications, precautions and the treatment regimen itself with intravenous ketamine for patients with mood disorders.

Exploring perinatal ketamine for postpartum depression following cesarean section: A systematic review.

The aim of this study was to explore the use of perinatal ketamine to see if it can be used for the reduction of postpartum depression (PPD) following cesarean section (C-section). PubMed, Cochrane, and Web of Science were the primary databases used for this review. Search terms used on January 5, 2024 incorporated "ketamine," "C-section," "postpartum depression," and related synonyms. The criteria for inclusion centered on studies published between January 1, 2008 and January 5, 2024. The final selection of articles was screened based on extraction criteria leaving eight randomized control trials in the final review. The selected data from the studies incorporated sample characteristics, study and population characteristics, and quantitative analyses covering Edinburgh Postpartum Depression Scale (EPDS) scores and depression rates. The Risk of Bias assessment was utilized to gain a deeper understanding of the quality of methodology used by the research studies. The review showed that ketamine can reduce the symptoms of PPD in mothers who have recently undergone C-sections. Some studies showed decreased EPDS scores following the administration of ketamine while two studies also reported no significant differences in PPD following ketamine administration in C-section patients. For example, Ma et al. found that the EPDS score at postpartum day 4 was significantly lower in the ketamine group compared with the control group (p = 0.007) while Yang et al. found that there were no significant differences between the ketamine and control group at 3 days postpartum (p = 0.553). The research from this review suggests that ketamine administration can prevent or decrease the symptoms of PPD, but more research is needed to establish the causal relationship between ketamine dosage and PPD in C-section patients.

Exploring the Role of Ketamine Sedation in Critically Ill Patients: A Comprehensive Review.

Sedation management in critically ill patients is a critical component of intensive care, aiming to balance the need for comfort and immobilization with preserving vital physiological functions. Ketamine, known for its dissociative anesthetic properties, has emerged as a promising alternative to traditional sedatives due to its unique pharmacological profile. This review explores the pharmacodynamics, clinical applications, benefits, challenges, and current evidence surrounding ketamine as a sedative agent in intensive care settings. Key advantages of ketamine include its ability to maintain respiratory drive and hemodynamic stability, making it particularly suitable for patients requiring continuous monitoring and intervention. The review discusses its role in sedation protocols, compares its effectiveness with other sedatives, and highlights potential areas for further research and optimization. By elucidating the complexities and advancements in ketamine sedation, this review aims to inform clinical practice and contribute to improved outcomes for critically ill patients.

Effects of acute and chronic ketamine administration on spontaneous and evoked brain activity.

Schizophrenia is believed to be, at least in part, a dysfunction of the glutamatergic system. In line with anatomical evidence, suppressing N-methyl-D-aspartate (NMDA) neurotransmission leads to symptoms that are characteristic of schizophrenia. Rodent models of schizophrenia often involve the acute application of NMDA antagonists, which produce both behavioural and brain activity changes that closely resemble symptoms observed in schizophrenia. It is, however, important to note that the full spectrum of schizophrenia symptoms may not be manifested following the acute suppression of NMDA receptors. This has led to the proposal of a chronic model where NMDA receptors are suppressed for prolonged periods. Although the chronic model has shown promising results from a behavioural perspective and changes in metabolic processes in the brain, its impact on brain oscillations remains largely unknown. The aim of this study is to examine the impact of acute and chronic NMDA neurotransmission suppression on brains' oscillatory activity. To achieve this, chronic brain activity recordings in mice of both sexes were used to assess both spontaneous and evoked brain oscillations. The study demonstrates that an acute suppression of NMDA receptors alters brain oscillations across a wide frequency spectrum and diminishes the oscillatory potency in evoked responses, paralleling changes observed in schizophrenia. However, the chronic suppression of NMDA receptors did not have the expected cumulative effect on brain activity. This research highlights the robust yet similar impacts of acute and chronic NMDA receptor suppression on brain activity, contributing to the nuanced understanding of rodent models of schizophrenia.

Myelin oligodendrocyte glycoprotein antibody-associated cerebral cortical encephalitis with super-refractory status epilepticus.

BACKGROUND: Seizures are commonly reported in patients with myelin oligodendrocyte glycoprotein antibody-associated cerebral cortical encephalitis (MOG-CCE). However, seizure management during the acute phase has not been established. CASE REPORT: A 9-year-old previously healthy boy presented with fever persisting for approximately 6 days, along with headache and altered consciousness. Plain T2-weighted and fluid-attenuated inversion recovery imaging showed swelling and abnormal hyperintense lesions in the bilateral frontal, parietal, temporal, and insular cortices with left hemisphere predominance. Consciousness disturbance persisted, and focal myoclonic seizures clustered hourly. Seizures were arrested by titrating the thiopental dose but recurred with dose reduction, and the patient exhibited super refractory status epilepticus. Adverse effects due to long-term use of thiopental became apparent. Hence, continuous infusion of ketamine and intrathecal dexamethasone therapy (IT-DEX) was started. After administration of ketamine and IT-DEX, his seizure was arrested promptly. The cerebrospinal fluid and serum at the time of transfer were clear positive for ani-MOG antibody; therefore, the patient was diagnosed with MOG-CCE. The patient received three courses of intravenous methylprednisolone pulse therapy, followed by oral prednisolone gradually tapered over 6 months. He did not experience any relapse for 6 months. CONCLUSION: In MOG-CCE, some cases may present with super-refractory status epilepticus (SRSE) in the acute phase and be refractory to anti-seizure medication, analogous to febrile infection-related epilepsy syndrome. IT-DEX and continuous infusion ketamine are useful for seizure control in MOG-CCE.

Efficacy, Safety, and Tolerability of Psychedelics in Treatment-Resistant Depression (TRD).

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.

KETAMINE: Neural- and network-level changes.

Ketamine is a widely used clinical drug that has several functional and clinical applications, including its use as an anaesthetic, analgesic, anti-depressive, anti-suicidal agent, among others. Among its diverse behavioral effects, it influences short-term memory and induces psychedelic effects. At the neural level across different brain areas, it modulates neural firing rates, neural tuning, brain oscillations, and modularity, while promoting hypersynchrony and random connectivity between neurons. In our recent studies we demonstrated that topical application of ketamine on the visual cortex alters neural tuning and promotes vigorous connectivity between neurons by decreasing their firing variability. Here, we begin with a brief review of the literature, followed by results from our lab, where we synthesize a dendritic model of neural tuning and network changes following ketamine application. This model has potential implications for focused modulation of cortical networks in clinical settings. Finally, we identify current gaps in research and suggest directions for future studies, particularly emphasizing the need for more animal experiments to establish a platform for effective translation and synergistic therapies combining ketamine with other protocols such as training and adaptation. In summary, investigating ketamine's broader systemic effects, not only provides deeper insight into cognitive functions and consciousness but also paves the way to advance therapies for neuropsychiatric disorders.

Response to Letter to the Editor Navigating the challenge of patient selection and scales to measure outcomes in ketamine trials for treatment-resistant depression.

The letter about the article "Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study" that discusses some points about methodology, outcome measures, and results.

Navigating the challenge of patient selection and scales to measure outcomes in ketamine trials for treatment-resistant depression.

The letter about the article "Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study" that discusses some points about methodology, outcome measures, and results.

Different development patterns of reward behaviors induced by ketamine and JWH-018 in striatal GAD67 knockdown mice.

IMPORTANCE: Glutamic acid decarboxylase 67 (GAD67) is a gamma-aminobutyric acid (GABA) synthesis enzyme associated with the function of other neurotransmitter receptors, such as the N-methyl-D-aspartate (NMDA) receptor and cannabinoid receptor 1. However, the role of GAD67 in the development of different abused drug-induced reward behaviors remains unknown. In order to elucidate the mechanisms of substance use disorder, it is crucial to study changes in biomarkers within the brain's reward circuit induced by drug use. OBJECTIVE: The study was designed to examine the effects of the downregulation of GAD67 expression in the dorsal striatum on reward behavior development. METHODS: We evaluated the effects of GAD67 knockdown on depression-like behavior and anxiety using the forced swim test and elevated plus maze test in a mouse model. We further determined the effects of GAD67 knockdown on ketamine- and JWH-018-induced conditioned place preference (CPP). RESULTS: Knockdown of GAD67 in the dorsal striatum of mice increased depression-like behavior, but it decreased anxiety. Moreover, the CPP score on the NMDA receptor antagonist ketamine was increased by GAD67 knockdown, whereas the administration of JWH-018, a cannabinoid receptor agonist, did not affect the CPP score in the GAD67 knockdown mice group compared with the control group. CONCLUSIONS AND RELEVANCE: These results suggest that striatal GAD67 reduces GABAergic neuronal activity and may cause ketamine-induced NMDA receptor inhibition. Consequently, GAD67 downregulation induces vulnerability to the drug reward behavior of ketamine.

Structural Insight on Interaction of NMDA receptor with fentanyl, ketamine and Isoflurane: A Computational Study to Unravel Mode of Binding.

NMDA receptors are considered targets for many anesthetics if they are modulated by the drugs at clinically relevant concentrations. Volatile anesthetics like isoflurane and ketamine interact with NMDA receptors, inhibiting channel activation and thus blocking NMDA neurotransmission at clinically relevant concentrations. The mode of binding of commonly used drugs like ketamine, isoflurane, and fentanyl is poorly understood. We used molecular docking, molecular dynamics simulations, and DFT calculation of these drugs against the NMDA receptor. Using well-defined computational methods, we identified that these drugs have high docking scores and significant interaction with receptors. These drugs bind to the substrate-binding pocket and form a remarkable number of interactions. We have found that these interactions are stable and have low HOMO-LUMO energy gaps. This study provides enough evidences of strong and stable interaction between drugs and NMDA receptor.

Lidocaine and Dexamethasone, Ketamine and Dexamethasone, and Dexamethasone Alone in Tonsillectomy Complications.

Background: Common complications including stridor, laryngospasm, and bronchospasm are important in patients undergoing general anesthesia. Dexamethasone, lidocaine, and ketamine could have significant roles in reducing these complications. Here we aimed to compare the use of these drugs during tonsillectomy. Materials and Methods: This study was performed on 100 children that were candidates of tonsillectomy. Patients were divided into 4 groups receiving dexamethasone 0.1 mg/kg and lidocaine 1 mg/kg, ketamine 0.5 mg/kg and dexamethasone 0.1 mg/kg, dexamethasone 0.1 mg/kg, and normal saline after surgical procedures. We evaluated and compared data regarding the duration of anesthesia, oxygenation saturation, blood pressure (systolic and diastolic (SBP and DBP)), re-intubation, laryngospasm, bronchospasm, requiring analgesics after surgeries, recovery stay duration, and nausea and vomiting. Results: Administration of ketamine and dexamethasone was associated with the lowest pain and lowest need for postoperative analgesic administrations in patients (P = 0.02). Patients that received lidocaine and dexamethasone had the lowest frequencies of airway stimulations (P < 0.001). Evaluations of complications in patients revealed that stridor was significantly lower in patients that received ketamine and dexamethasone (P = 0.01). Conclusion: Usage of ketamine and dexamethasone was associated with the lowest pain severities and lowest complications. On the other hand, patients that received lidocaine and dexamethasone had the least airway stimulations.

Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine.

BACKGROUND AND PURPOSE: The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. EXPERIMENTAL APPROACH: The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain. KEY RESULTS: 60 min after injection, ketamine (10 mg·kg-1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg-1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice. CONCLUSION AND IMPLICATIONS: This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.

Intravenous Sedation and Analgesia in a Pediatric Emergency Department: A Retrospective Descriptive Study.

Background Painful procedures in the pediatric emergency department often require the use of sedation and analgesia to ensure adequate pain control, a right of children and adolescents. This study aims to describe the procedural sedation and analgesia with intravenous medications performed in a pediatric emergency department. Methods This is a retrospective descriptive study of intravenous sedoanalgesia used in a pediatric emergency department of a level II district hospital in the Lisbon metropolitan area from October 2018 to December 2023. The type of intervention, drugs used, and adverse events were analyzed. Results A total of 615 patients were included in the study; 65.7% (n=404) were male with a median age of 6 years. The most frequently performed procedures were wound suturing (50.9%, n=313) and fracture reduction (36.3%, n=223). The drugs used for sedation and analgesia were ketamine (99.2%, n=610), midazolam (95.8%, n=589), propofol (1.6%, n=10), and morphine (0.5%, n=3). The majority of patients received midazolam and ketamine in association (93.8%, n=577). A total of 50 adverse events (8.1%) were recorded in 42 patients. The most frequent side effects were transient oxygen desaturation (2%, n=12), vomiting (1.5%, n=9), apnea/bradypnea (1%, n=6), and hallucinations (0.8%, n=5). The occurrence of adverse events was not dose-dependent (p >0.05). Respiratory complications resolved without requiring invasive interventions. Children were sedated by a pediatric intensivist in 68.1% (n=419), by a general pediatrician in 26.7% (n=164), and by a pediatric resident in 2% (n=12). Conclusions The results of this study demonstrate that intravenous sedoanalgesia, particularly the combination of ketamine and midazolam, is a safe method for sedation in pediatric patients, with a low rate of adverse events.

Lumbar Sympathetic Block to Treat CRPS in an 18-Month-Old Girl: A Breaking Barriers Case Report and Review of Literature.

BACKGROUND: Children under the age of 3 years have been diagnosed with complex regional pain syndrome (CRPS). They were found to be functionally disadvantaged and psychologically distressed in relation to children with other painful conditions. CASE PRESENTATION: An 18-month-old baby girl was referred to the pain clinic with a history of severe right lower limb pain that had begun 2 months earlier. The parents were unable to recall any trauma before the painful situation. Pain and allodynia were severe and extended from the toes to the gluteus area. She was low weight for her age (6700 g). The patient was on the maximum doses of gabapentin and amitriptyline accepted for her body weight and did not have the possibility to start rehabilitation due to severe pain and allodynia. After discussing the risks and potential benefits of a planned lumbar sympathetic block (LSB), the parents approved the interventional procedure. This is the first case report describing the LSB technique at such a young age. METHOD: A lumbar sympathetic block was carried on at the third lumbar vertebral level, fluoroscopy-guided, and under general anesthesia (GA) initiated with ketamine iv. A 4-cm needle was introduced using a tunneled vision approach in an oblique view at the L3 level until adequate depth was confirmed in the lateral position. Safety considerations were taken in relation to the radiation dose and all drugs injected with dose adjustment to her body weight. The block was successful (the skin temperature increased by 2.8 °C) and was uneventful. Pain and allodynia were completely alleviated in the recovery room. At the follow-up after 3 and 8 weeks, the parents reported an 80% improvement in pain and allodynia, a 70% improvement in sleep, a weight gain of 900 g, and that she had started rehabilitation. CONCLUSIONS: Lumbar sympathetic blocks can be considered at a very young age to treat CRPS if other non-invasive measures fail.

Ketamine - An Imperfect Wonder Drug?

Ketamine is a potent sedative and dissociative anesthetic agent that has been used clinically for over 50 years since it was first developed in the 1960 s as an alternative to phencyclidine (PCP). When compared to PCP, ketamine exhibited a much lower incidence of severe side effects, including hallucinations, leading to its increased popularity in clinical practice. Ketamine was initially used as an anesthetic agent, especially in emergency medicine and in surgical procedures where rapid induction and recovery was necessary. However, over the last few decades, ketamine was found to have additional clinically useful properties making it effective in the treatment of a variety of other conditions. Presently, ketamine has a wide range of clinical uses beyond anesthesia including management of acute and chronic pain, as well as treatment of psychiatric disorders such as major depression. In addition to various clinical uses, ketamine is also recognized as a common drug of abuse sought for its hallucinogenic and sedative effects. This review focuses on exploring the different clinical and non-clinical uses of ketamine and its overall impact on patient care.

Psychoactive substances for the treatment of neuropsychiatric disorders.

In the contemporary landscape of psychiatric medicine, critical advancements have been noted in the utilization of psychoactive substances such as hallucinogens, 3,4-methylenedioxymethamphetamine (MDMA), and ketamine for the treatment of severe mental health disorders. This review provides a detailed evaluation of these substances, focusing on their mechanisms of action and the profound clinical outcomes observed in controlled environments. Hallucinogens like lysergic acid diethylamide and psilocybin primarily target the 5-HT2A receptor agonist-2 (5-HT2AR), inducing substantial perceptual and cognitive shifts that facilitate deep psychological introspection and significant therapeutic advances, particularly in patients suffering from depression and anxiety disorders. MDMA, influencing multiple neurotransmitter systems including 5-Hydroxytryptamine (5-HT), dopamine, and norepinephrine, has been demonstrated to effectively alleviate symptoms of post-traumatic stress disorder, enhancing patients' emotional engagement and resilience during psychotherapy. Meanwhile, ketamine, a glutamate receptor antagonist, rapidly alleviates depressive symptoms, offering a lifeline for individuals with treatment-resistant depression through its fast-acting antidepressant properties. The integration of these substances into psychiatric practice has shown promising results, fundamentally changing the therapeutic landscape for patients unresponsive to traditional treatment modalities. However, the potent effects of these agents also necessitate a cautious approach in clinical application, ensuring careful dosage control, monitoring, and risk management to prevent potential abuse and mitigate adverse effects.

The quest for optimal ketamine dosing formula in treatment-resistant major depressive disorder.

BACKGROUND: Emerging evidence indicates that intravenous ketamine is effective in managing treatment-resistant unipolar and bipolar depression. Clinical studies highlight its favorable efficacy, safety, and tolerability profile within a dosage range of 0.5-1.0 mg/kg based on actual body weight. However, data on alternative dosage calculation methods, particularly in relation to body mass index (BMI) and therapeutic outcomes, remain limited. METHODS: This retrospective analysis of an open-label study aims to evaluate dose calculation strategies and their impact on treatment response among inpatients with treatment-resistant major depressive disorder (MDD) (n = 28). The study employed the Boer and Devine formulas to determine lean body mass (LBM) and ideal body weight (IBW), and the Mosteller formula to estimate body surface area (BSA). The calculated doses were then compared with the actual doses administered or converted to a dosage per square meter for both responders and non-responders. RESULTS: Regardless of treatment response, defined as a reduction of 50% in the Montgomery-Åsberg Depression Rating Scale, the use of alternative ketamine dosing formulas resulted in underdosing compared to the standardized dose of 0.5 mg/kg. Only two participants received higher doses (102.7% and 113.0%) when the Devine formula was applied. CONCLUSIONS: This study suggests that ketamine dosing formulas, alternative to the standardized 0.5 mg/kg based on body weight, may lead to underdosing and potentially impact outcome interpretation. To enhance dosing accuracy, future studies should consider incorporating body impedance analysis and waist-to-hip ratio measurements, as this study did not account for body composition.