Effects Of Ketamine Research Articles

Ketamine alleviates fear memory and spatial cognition deficits in a PTSD rat model via the BDNF signaling pathway of the hippocampus and amygdala

BackgroundPost-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits. Studies have demonstrated that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nonetheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear. MethodsIn this study, different concentrations of ketamine (5, 10, 15, and 20 mg/kg, i.p.) were evaluated in rat models of single prolonged stress and electrophonic shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis and immunohistochemistry. ResultsThe data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment. The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10–15 mg/kg resulted in significant changes in behavioral outcomes. These manifestations of improvement in cognitive function and molecular changes were reversed at high doses (15–20 mg/kg). ConclusionOverall, ketamine reversed SPS&S-induced fear and spatial memory impairment and the down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. A dose equal to 15 mg/kg rapidly reversed the behavioral and molecular changes and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 effects could be involved in the therapeutic efficiency of ketamine for PTSD.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults.

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.

Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals

Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine’s effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine’s antidepressant and anti-anhedonic action.

A clinical, comparative, prospective, and observational study of two different ratios of ketamine and propofol in short surgical procedures at a tertiary care hospital

Background: Ketamine and propofol are two medications commonly used for procedural sedation because they possess many of the desired characteristics including rapid induction and recovery. The opposing physiologic effects of ketamine and propofol suggest the potential for synergy, and this has led to an interest in their combined use, commonly termed “Ketofol.” The purpose of this study is to compare two different proportions of ketamine and propofol, 1:2 and 1:3 in short surgical procedures. Aims and Objectives: The aim of the study was to compare the quality of analgesia, level of sedation, and respiratory and hemodynamic parameters of two different proportions of ketamine and propofol in the ratio of 1:2 and 1:3 in short surgical procedures. Materials and Methods: After obtaining approval from the institutional ethics and scientific committee, with IEC no.MIMS/IEC/2021/474 dated February 23, 2021, 86 consenting patients of 18–60 years categorized under American Society of Anesthesiologists Category I and II undergoing elective short surgical procedures lasting for about 20 min were selected. The study patients were divided into two groups of 43 each by convenient sampling method. In Group A, 43 patients received 1 mL of ketamine (50 mg/mL) mixed with 10 mL of 100 mg propofol (10 mg/mL). In Group B, 43 patients received 30 mg of ketamine mixed with 9 mL of 90 mg propofol (10 mg/mL). Non-invasive blood pressure, heart rate, oxygen saturation, Ramsay Sedation Score, Modified Aldrete Score, and any incidence of side effects were recorded. Results: The quality of analgesia and level of sedation was achieved better in Group A compared to Group B. No significant difference was observed between the two groups with respect to hemodynamic and respiratory parameters. Conclusion: The combination of propofol and ketamine has several benefits such as hemodynamic stability, lack of respiratory depression, good recovery, and potent procedural analgesia. Ketofol 1:2 proportion is comparatively better and can be used safely in short surgical procedures.

The effect of low dose nalbuphine or ketamine in the prevention of emergence agitation after sevoflurane anesthesia in children undergoing tonsillectomy with or without adenoidectomy

ABSTRACT Background Children’s agitation increases following sevoflurane anaesthesia. With indefinite results, nalbuphine and midazolam have been used as preventative treatments. Patients and Methods This study involved 90 children with American Society of Anesthesiologists score I-II and aged 4–10 who had sevoflurane-based adenotonsillectomy. Each child was randomly assigned to one of three groups; group N, group K, and group S. Nalbuphine was given to Group N at 0.1 mg/kg, ketamine was given to Group K at 0.25 mg/kg, and saline was given to Group S at equivalent volume. Sevoflurane was discontinued after the procedure, and the study drugs were given. The emergence agitation (EA) scale was used in the post-anesthesia care unit (PACU) to measure agitation upon admission (T0), after 5 min (T5), 10 min (T10), 15 min (T15), 20 min (T20), 25 min (T25), and 30 min (T30). Clinical trials. gov ID: NCT05176119. Results In the PACU, the incidence of EA was significantly lowered in N (6.6%) and K Group (16.6%) compared to S group (33%) with (p = 0.044), the duration in PACU was significantly prolonged in S in comparison to K and N groups (p-value = 0.011), more patients experienced postoperative pain in S group compared to N group and K group (p-value < 0.001). Conclusion Children who had sevoflurane-induced adenotonsillectomy can avoid emergence agitation with ketamine 0.25 mg/kg or nalbuphine 0.1 mg/kg.

Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN)

BackgroundPrehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury.MethodsA two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes.DiscussionThe PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia.Trial registration: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474

Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain

IntroductionChronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic.MethodsThis study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale.Results73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p &amp;lt; 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p &amp;lt; 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine.DiscussionThis work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key messageThis real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions.

Ketamine - A New Antidepressant Drug with Anti-Inflammatory Properties.

Ketamine is a new, potent and rapid-acting antidepressant approved for therapy of treatment-resistant depression, which has a different mechanism of action than currently-available antidepressant therapies. It owes its uniquely potent antidepressant properties to a complex mechanism of action, which currently remains unclear. However, it is thought that it acts by modulating the functioning of the glutamatergic system, which plays an important role in the process of neuroplasticity associated with depression. However, preclinical and clinical studies have also found ketamine to reduce inflammation, either directly or indirectly (by activating neuroprotective branches of the kynurenine pathway), among patients exhibiting higher levels of inflammation. Inflammation and immune system activation are believed to play key roles in the development and course of depression. Therefore, the present work examines the role of the antidepressant effect of ketamine and its anti-inflammatory properties in the treatment of depression. SIGNIFICANCE STATEMENT: The present work examines the relationship between the antidepressant effect of ketamine and its anti-inflammatory properties, and the resulting benefits in treatment-resistant depression (TRD). The antidepressant mechanism of ketamine remains unclear, and there is an urgent need to develop new therapeutic strategies for treatment of depression, particularly TRD.

Comparison of the effects of ketamine via nebulization versus different pharmacological approaches in pediatric sedation: a systematic review and meta-analysis of randomized controlled trials

BackgroundNebulized drug delivery is commonly used in pediatric clinical practice. The growing number of literatures have reported the application of nebulized ketamine in pediatric sedation in recent years. This meta-analysis of randomized controlled trials comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches was conducted to estimate the effects of this technique in pediatric sedation.MethodsWe searched PubMed, Embase, and Cochrane Library from inception to Feb 2023. All randomized controlled trials used nebulized ketamine as presurgical and pre-procedural sedatives in children were included. Sedative effects and various adverse events were considered as the outcomes.ResultsTen studies with 727 pediatric patients were enrolled. Compared to nebulized dexmedetomidine, using of ketamine via nebulization showed similar sedation satisfaction (54.79% vs. 60.69%, RR = 0.88, with 95%CI [0.61, 1.27]), success rate of parental separation (57.27% vs. 73.64%, RR = 0.81, with 95%CI [0.61, 1.08]), and mask acceptability (37.27% vs. 52.73%, RR = 0.71, with 95%CI [0.45, 1.10]). However, the using of combination of two medications (nebulized ketamine plus nebulized dexmedetomidine) was associated with better sedative satisfaction (33.82% vs. 68.11%, RR = 0.50, with 95%CI [0.27, 0.92]) and more satisfactory mask acceptance (45.59% vs. 71.01%, RR = 0.69, with 95%CI [0.56, 0.86]). Compared with nebulized ketamine, using of nebulized dexmedetomidine was associated with less incidence of emergence agitation (18.18% vs. 3.33%, RR = 4.98, with 95%CI [1.88, 13.16]).ConclusionsBased on current evidences, compared to nebulized dexmedetomidine, nebulized ketamine provides inconspicuous advantages in pediatric sedation, and it has a relatively high incidence of emergence agitation. Combination of nebulized ketamine and dexmedetomidine might be considered as one preferred option in pediatric sedation as it can provide more satisfactory sedative effects. However, there is insufficient evidence regarding nebulized ketamine versus ketamine administered through other routes and nebulized ketamine versus other sedatives. The overall low or moderate quality of evidence evaluated by the GRADE system also calls for more high-quality studies with larger sample sizes in future.Research registrationThe protocol of present study was registered with PROSPERO (CRD42023403226).

Antinociceptive and adverse effects of morphine:ketamine mixtures in rats.

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

Anti-suicidal effects of IV ketamine in a real-world setting

The current study evaluated the effectiveness of intravenous ketamine treatment for suicidality in a community-based clinical sample of 295 outpatients (mean age= 40.37; 58.6 % male). We conducted growth mixture modeling to estimate latent classes of changes in symptoms of suicidality measured by the Concise Health Risk Tracking – Self-Report (CHRT-SR) across five infusions in a two-week course of treatment. Best-fit indices indicated three trajectory groups demonstrating non-linear, quadratic changes in CHRT-SR scores during ketamine treatment. The largest group of patients (n= 170, 57.6 %) had moderate CHRT-SR scores at baseline and showed gradual improvement during treatment. The other two groups of patients had severe CHRT-SR scores at baseline and diverged into one group with no improvement throughout treatment (n = 63, 21 %) and one group with rapid improvement (n = 62, 21 %). Of the clinical and demographic variables available and tested, only higher scores pertaining to active thoughts of death and/or plan were found to predict which of the patients with severe CHRT-SR scores at baseline would not benefit from treatment. The present study provides an important contribution to the knowledge of ketamine's effects on symptoms related to suicide over time. providing support for the possible effectiveness of ketamine in a proportion of patients.

Evaluation of toxicological effects of ketamine and ethanol on the kidney of albino rats. Biochemical and Histopathological study

Evaluation of toxicological effects of ketamine and ethanol on the kidney of albino rats. Biochemical and Histopathological study

Ketamine-Propofol Coadministration for Induction and Infusion Maintenance in Anesthetized Dogs: Effects on Electroencephalography and Antinociception.

The effects of concurrent ketamine and propofol (ketofol) constant rate infusion (CRI) were examined in six dogs. The K:P ratio was 1:2, with an initial CRI of 0.25/0.5 mg/kg/min over ten minutes, followed by a 0.5 mg/kg ketamine bolus for induction. During induction, a comprehensive EEG frequency spectrum from delta to gamma was observed, accompanied by subanesthetic-dose ketofol-induced behavioral excitation, including nystagmus, tongue flicking, salivation and active muscle activity. The dogs were maintained on three 15 min decremental doses of ketofol CRI (0.8/1.6, 0.4/0.8 and 0.2/0.4 mg/kg/min). This phase featured a significant decrease in the Patient State Index, electromyographic activity and a shift to low beta waves (SEF95: 13-18 Hz). Additionally, profound antinociception to electric stimulation and a stable heart rate and blood pressure (MBP 81.5-110 mmHg) were observed, as well as a merging of ketamine and propofol EEG characteristics during maintenance. In the recovery phase, a return to beta and gamma EEG patterns and excitement behavior occurred, accompanied by a significant reduction in antinociception, highlighting features of low doses of ketofol. This study reveals biphasic EEG dynamic changes, associated behaviors and robust antinociception and cardiovascular function, suggesting the utility of ketofol as a total intravenous anesthetic combination in dogs.

A systematic review and meta-analysis comparing the efficacy and safety of ketamine versus morphine for the treatment of acute pain.

Ketamine is reported as a potent opioid alternative that provides significant reduction in pain with no severe adverse events. However, some studies didn't find its use satisfactory and reported less reduction in pain score with ketamine. The purpose of this study is to compare the efficacy and safety of ketamine versus morphine for the treatment of acute pain in emergency situations. The PubMed, MEDLINE, PsycINFO EMBASE, Cochrane Library, PROSPERO registry platform, and ClinicalTrials.gov websites were queried in accordance with the PRISMA guidelines in order to locate relevant studies. According to the predefined PICOS criteria, articles were included and event data pertaining to changes in Visual Analog Scale or Numeric Rating Scale pain scales were extracted. Using RevMan and MedCalc, a meta-analysis was conducted to compare the effects of ketamine and morphine for the treatment of acute pain. Twelve studies met the criteria for inclusion in this meta-analysis. Ketamine was found to be more effective than morphine at reducing pain scores, with an odds ratio of 0.60 (95% CI 0.48 to 0.76). Similarly, no severe adverse events related to ketamine were reported in any study, and it has a low-risk ratio of 0.78 (95% CI 0.70 to 0.87). Egger's Test P values (0.3052) and Begg's Test P values (0.3869) indicate a low risk of bias, and the Bland-Altman plot demonstrates a high degree of concordance. Ketamine is a potent and effective alternative to morphine for the management of acute pain, and it reduces pain score significantly with minimal side effects.

MO28-5 Effectiveness of ketamine for depression among advanced cancer patients in palliative care: A systematic review

MO28-5 Effectiveness of ketamine for depression among advanced cancer patients in palliative care: A systematic review

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats.

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

Ketamine retards recovery from reward downshift and supports conditioned taste aversion

Ketamine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist with antidepressant, anxiolytic, and memory effects in clinical and preclinical studies. The present studies investigated the behavioral effects of ketamine in animals exposed to a consummatory successive negative contrast (cSNC) task involving unexpected reward downshift, negative emotion (frustration), and aversive memory. Food-restricted male rats had 5-min access to 32 % sucrose in each of 10 preshift sessions followed by 4 % sucrose in 4 postshift sessions. Unshifted controls had access to 4 % sucrose during all 14 sessions. Ketamine (10 mg/kg, ip) was injected 30 min before sessions 11 and 12 (Experiment 1) or immediately after session 11 (Experiment 3). The results showed that both pre- and postdownshift session injection of ketamine increased consummatory suppression, as Group 32-4/Ket exhibited lower sucrose intake than Groups 32-4/Sal, 4-4/Ket, and 4-4/Sal. These effects extended beyond the day(s) of injection. Experiments 2 and 4 showed that the same dose, route of administration, and time of injection induced significant conditioned taste aversion to 4 % sucrose, in the absence of reward downshift. These data suggest that ketamine induces an aversive state that may summate with frustration induced by reward downshift in the cSNC task and also support a conditioned taste aversion to 4 % sucrose in the absence of reward downshift. Implications for these and other experiments involving pre- and postsession administration of ketamine are discussed.

Aromatase inhibition and ketamine in rats: sex-differences in antidepressant-like efficacy

BackgroundKetamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response.MethodsWe performed several consecutive studies in adult Sprague–Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference).ResultsThe main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs.ConclusionsThe present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.

The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder

BackgroundExisting treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD).MethodsSKY-D is a double-masked, randomised controlled trial funded by the Australian Government’s National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes.DiscussionResults from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people.Trial registrationAustralian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513.