Ketamine Treatment Research Articles

A Pilot Study: An Open-Label Biomarker Development of Ketamine for Unipolar Refractory Depression

The primary objective of this study is to evaluate the antidepressant efficacy of an acute intravenous subanesthetic ketamine treatment for patients with unipolar treatment-resistant depression (TRD). The secondary objective of this study is to identify peripheral blood-based biomarkers associated with response to treatment.

Ventral Hippocampal Neural Ensemble Activity Modulates (R,S)-Ketamine’s Prophylactic Fear Buffering Effects

Stress can lead to a wide variety of psychiatric illnesses such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). However, some individuals are more susceptible to developing psychopathology in response to stress, while others exhibit stress resilience; yet, the research into the underlying neurobiology of this phenomenon is still in its infancy. We have previously shown that (R,S)-ketamine can buffer fear expression and that this effect is partially mediated by activity in the ventral CA3 (vCA3) subregion of the hippocampus. However, it is unknown how exactly activity is changed, particularly in vCA3, during prophylactic ketamine treatment, stress, or expression of depressive-like or fear behaviors.

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model.

Background Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

(R,S)-Ketamine Promotes Striatal Neurogenesis and Sensorimotor Recovery Through Improving Poststroke Depression–Mediated Decrease in Atrial Natriuretic Peptide

BackgroundPoststroke social isolation could worsen poststroke depression and dampen neurogenesis. (R,S)-ketamine has antidepressant and neuroprotective effects; however, its roles and mechanisms in social isolation–mediated depressive-like behaviors and sensorimotor recovery remain unclear. MethodsMice were subjected to transient middle cerebral artery occlusion, and then were pair-housed with ovariectomized female mice or were housed isolated (ISO) starting at 3 days postischemia. ISO mice received 2 weeks of (R,S)-ketamine treatment starting at 14 days postischemia. Primary ependymal epithelial cells and choroid plexus epithelial cells were cultured and treated with recombinant human atrial natriuretic peptide (ANP) protein. ResultsThe poststroke social isolation model was successfully established using middle cerebral artery occlusion combined with poststroke isolation, as demonstrated by a more prominent depression-like phenotype in ISO mice compared with pair-housed mice. (R,S)-ketamine reversed ISO-mediated depressive-like behaviors and increased ANP levels in the atrium. The depression-like phenotype was negatively correlated with ANP levels in both the atrium and plasma. Atrial GLP-1 and GLP-1 receptor signaling was essential to the promoting effects of (R,S)-ketamine on the synthesis and secretion of ANP from the atrium in ISO mice. (R,S)-ketamine also increased ANP and TGF-β1 levels in the choroid plexus of ISO mice. Recombinant human ANP increased TGF-β1 levels in both the primarily cultured ependymal epithelial cells and choroid plexus epithelial cells. Furthermore, (R,S)-ketamine increased TGF-β1 levels in the ischemic hemisphere and promoted striatal neurogenesis and sensorimotor recovery via ANP in ISO mice. Conclusions(R,S)-ketamine alleviated poststroke ISO-mediated depressive-like behaviors and thus promoted striatal neurogenesis and sensorimotor recovery via ANP.

Energy metabolism disorder and functional magnetic resonance imaging of the medial prefrontal cortex in mice with chronic unpredictable mild stress

To analyze spontaneous activities and energy metabolism in the medial prefrontal cortex (mPFC) of mice with chronic unpredictable mild stress (CUMS) and explore the correlation of these changes with the mTORC1 signaling pathway. Normal C57Bl/6 mice were randomly divided into control group (n=16) and depression model group (n= 16), and the mice in the latter group were subjected to 8 weeks of modeling with CUMS. Behavioral tests including open field test, sucrose consumption test, tail suspension test and forced swimming test were performed, and the changes in prefrontal gray matter volume and the amplitude of low frequency fluctuation (ALFF) in the mice were detected with functional magnetic resonance imaging. The CUMS mice were then randomized into two groups for treatment with ketamine (n=8) or saline (n=8). The mPFC tissues of the mice were collected for detecting the phosphorylation levels of mTORC1-related proteins with Western blotting and ATP level and NADP +/NADPH ratio with ELISA in the 3 groups. Compared with the control mice, CUMS mice exhibited a distinct depressive phenotype with significantly decreased sucrose preference (P < 0.05) and shortened total distances (P < 0.01) and central exercise distances (P < 0.05) in the open field test without obvious changes of immobile time in tail suspension test and forced swimming test (P>0.05). Prefrontal gray matter volume and mALFF increased (P < 0.01), and the phosphorylation level of mTORC1- related proteins, ATP level and NADP +/NADPH ratio all decreased significantly (P < 0.05) in CUMS mice. After ketamine treatment, the phosphorylation level of mTORC1-related proteins and ATP level increased significantly in CUMS mice (P < 0.05), but the increase of NADP +/NADPH ratio was not statistically significant. The mPFC of CUMS mice shows increased spontaneous activities but lowered productivity efficiency, indicating the presence of energy metabolism disorder in the mPFC, which is related with reduced mTORC1 phosphorylation and can be alleviated by activating the mTORC1 pathway with ketamine.

Cognitive Behavioral Therapy, Ketamine, and Combination Treatment for Depression: Impressions of Credibility in Participants with Self-Reported Depressive Symptoms

ABSTRACT Ketamine, a novel treatment for depression, has generated considerable interest and research. Few experiments address lay impressions of the credibility of ketamine treatment relative to another popular intervention for depression, CBT. Over 500 participants with depressive symptoms read descriptions of CBT, ketamine, and a treatment that combined the two. Descriptions included pros and cons of each approach. Participants found the combination treatment more credible than ketamine but no better than CBT alone. They rated the credibility of CBT alone significantly higher than ketamine alone. Participants with psychotherapy experience tended to view ketamine as less credible than those who did not report previous psychotherapy. Depression scores did not covary with credibility ratings for any treatment. Despite media coverage and Internet claims, potential clients are cautious about ketamine. These results suggest that providing descriptions of treatments might help reveal important information about their credibility to potential clients. Extended work assessing impressions of many approaches to the treatment of psychopathology and other problems appears justifiable. Given established links between credibility and treatment outcome, additional research on individual differences in perceptions of ketamine and varied treatments for depression seems warranted.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

N-METHYL-D-ASPARTATE RECEPTOR INHIBITION PREVENTS GLUCOMETABOLIC DYSREGULATION AND CARDIAC INJURY IN NICOTINE-EXPOSED MALE RATS

Objective: Since non-smoking nicotine exposure has been associated with cardiometabolic disorders and smoking cessation therapies are of great global and medical significance. N-methyl-D-aspartate receptor (NMDAR) activity has been implicated in diabetes. Although NMDAR is also expressed in cardiomyocytes, there is dearth of information on its activity on cardiometabolic dysfunctions and its associated mechanism yet to be fully elucidated. It is therefore hypothesized that NMDAR inhibition by low-dose ketamine would improve nicotine-induced glucometabolic deregulation and cardiac injury. Design and method: Male Wistar rats (n = 6/group) aged 10 weeks were given (p.o.) vehicle, nicotine (1.0 mg/kg) with or without ketamine (0.2 mg/kg) daily for 28 days. Oral glucose tolerance test was performed 24-hours to the end of the experiment. The insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR). Results: Data showed that nicotine exposure led to insulin resistance, hyperinsulinemia, elevated 1-hour postload glucose, glucose intolerance, triglyceride-glucose index. Likewise, plasma and cardiac uric acid, malondialdehyde, lactate, triglyceride (TG), TG/HDL-C, oxidized glutathione (GSSG) levels, creatinine kinase (CK), lactate dehydrogenase (LDH), adenosine deaminase (ADA), xanthine oxidase (XO) activities were increased in nicotine-exposed rats. On the other hand, plasma and cardiac nitric oxide level was reduced by nicotine exposure. However, ketamine treatment also led to elevated TG, LDH, lactate, CK activity, nitric oxide, and reduced TG/HDL-C, uric acid, MDA, GSSG levels, XO and ADA activities when compared to control. However, these nicotine-induced cardiometabolic disorders were ameliorated in ketamine-treated rats. Conclusions: The results demonstrated that low-dose ketamine prevents glucose dysregulation, plasma and cardiac TG, uric acid, lactate accumulation and suppressed ADA, XO and CK activities. Therefore, these findings imply that inhibition of NMDAR by low dose-ketamine improves glucometabolic regulation and ameliorates cardiac injury through ADA/XO/CK-dependent mechanisms.

A systematic review of ketamine for the management of vaso-occlusive pain in sickle cell disease.

Vaso-occlusive episodes (VOEs) are a common complication of sickle cell disease (SCD) and a significant cause of morbidity. Managing VOE pain can be difficult and complex. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been used to manage VOE pain. This systematic literature review synthesizes research published from 2010 to 2020 on the use of ketamine infusion to decrease VOE pain. The review demonstrates that ketamine, a safe and effective treatment for VOE pain, could be considered more widely. However, the significant variability among published clinical studies with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation highlights the need for standardized ketamine infusion protocols for the management of VOE pain. We conclude with a brief discussion of key components of a potential standardized protocol supported by the literature reviewed as well as areas for future investigation.

Efficacy of ketamine for major depressive episodes at 2, 4, and 6-weeks post-treatment: A meta-analysis.

Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment. Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks. The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment. The present meta-analysis observed large effects at 2 weeks (g = -1.28), 4 weeks, (g = -1.28), and 6 weeks (g = -1.36) post-treatment. The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.

Validation of the McIntyre And Rosenblat Rapid Response Scale (MARRRS) in Adults with Treatment-Resistant Depression Receiving Intravenous Ketamine Treatment

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS).Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours.Results: Sixty-four patients (Mage = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance.Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison.Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants.

Ginkgolide K potentiates the protective effect of ketamine against intestinal ischemia/reperfusion injury by modulating NF-κB/ERK/JNK signaling pathway

Purpose: To investigate the effect of ginkgolide K and ketamine treatments, alone and in combination, on intestinal ischemia/reperfusion injury (I/R)-induced injury in rats, as well as the mechanism involved.&#x0D; Methods: Rats were treated with ginkgolide K (GK, 15 mg/kg i.v) and ketamine (KTM, 100 mg/kg i.p.), either alone or in combination 30 min before the induction of intestinal I/R. The effects of GK and KTM were determined by assessing the levels of cytokines in serum, and parameters of oxidative stress and ROS production in the intestinal tissues of I/R rats. Moreover, intestinal mRNA expressions of JNK, ERK, p38 and NF-kB were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR).&#x0D; Results: GK and KTM treatments, alone and in combination, reduced cytokine levels in serum and oxidative stress parameters in intestinal tissues, when compared to I/R group of rats. Treatments with GK and KTM, alone and in combination, mitigated the altered mRNA expressions of JNK, ERK, p38 and NF-kB in intestinal tissues of I/R-injured rats.&#x0D; Conclusion: These results reveal that GK potentiates the protective effect of KTM100 on I/R-induced intestinal injury in rats by regulating the NF-kB/ERK/JNK signaling pathway. Therefore, GK and KTM may find use in the management of I/R&#x0D; Keywords: Ginkgolide K, Ketamine, Intestinal injury, Ischemia/Reperfusion, Inflammation

A Case of Successful Ketamine Treatment after ECT Failure in a patient with Major Depressive Disorder

<h3>Introduction</h3> Electroconvulsive therapy (ECT) has long been a treatment modality of choice for treatment resistant depression. It remains one of the most effective treatments in psychiatry for a multitude of diseases. However, if patients fail ECT there is a lack of robust options for alternative treatments. This case describes a patient who was initially treated with ECT with no response after several treatments and subsequently transitioned to IV ketamine. Once started on ketamine patient showed a significnat improvement in his depressive symptoms and was able to be discharged from an inpatient psychiatric unit. Mr. X is a 70 year old male with a history of major depressive disorder and three prior suicide attempts. He had multiple recent life stressors, including a spouse diagnosed with cancer and being unable to work after back surgery which significantly contributed to his depression. He was admitted to the psychiatric hospital after an attempted overdose. He was started on escitalopram and buproprion XL, which were titrated to max doses throughout his hospitalization. Given his history of incomplete response with medication, his severe depression, and his high suicide risk, aggressive treatment was warranted. ECT was initiated and he underwent 5 treatments of right unilateral, 2 treatments of bifrontal, and 1 treatment of bitemporal. Throughout the course of ECT he had a lack of seizures despite flumazenil, hyperventilation, various induction agents (including ketamine) and pharmacology. During that time he was not getting out of bed, reporting consistently depressed mood, amotivated, and apathetic. He also began noticing some increased cognitive difficulties with the bifrontal and bitemporal ECT treatments. He ultimately was deemed an ECT failure after 8 treatments with no response. Given his continued depression and failure of ECT, it was decided to attempt IV ketamine infusions as the next intervention for his depression. <h3>Methods</h3> A literature review was conducted searching for Ketamine vs ECT treatment for depression and suicidality using MESH terms of "(Depression) AND (Suicidal behavior) AND (Electroconvulsive therapy OR Electroshock therapy OR Shock therapy OR Electroshock OR Shock treatment OR Convulsive therapy OR Electric shock therapy OR Electric Convulsive therapy OR ECT) AND Ketamine" and "(Depression) AND (Suicidality) AND (Electroconvulsive therapy OR Electroshock therapy OR Shock therapy OR Electroshock OR Shock treatment OR Convulsive therapy OR Electric shock therapy OR Electric Convulsive therapy OR ECT) AND Ketamine." Additional literature regarding Ketamine for treatment resistant depression was searched for using MESH terms of "(Ketamine OR CI-581 OR CI 581 OR CI581 OR Ketalar OR Ketaset OR Ketanest OR Calipsol OR Kalipsol OR Calypsol) AND (therapy OR medical plan OR treatment OR regimen) AND (treatment resistant depression OR therapy resistant depression OR TRD OR refractory depression)." <h3>Results</h3> After initiation of ketamine Mr. X noticed an immediate improvement. He was given 3 total treatments while inpatient with significant clinical improvment noted after each treatment. He was noted to be more engaged, had improved eye contact, and was reporting improvment in his mood. He was also more active, and was noted to be consistently out of bed ambulating with his walker. After the 3 treatments inpatient he was deemed psychiatrically stable for discharge with the plan to continue an acute course of treatment post discharge. He received 2 more treatments after discharge as an outpatient before ultimately being lost to follow up. Electroconvulsive Therapy continues to show a robust response rate of approximately 80%, with remission in about 75% of cases. Even with these response rates, there is a significant patient population that will not respond to ECT. Research has shown that ketamine can have an immediate response of up to or greater than 70% of patietns within the 24 hours post-infusion. Duration of response is varied, though has been found to be present in about 50–70% of patients. However, there has not been significant published research looking into response to ketamine post ECT failure. <h3>Conclusions</h3> Mr. X is a prime example of the ongoing difficulties in treating patients with treatment resistant depression who do not respond to ECT. This case shows that after ECT failure it is appropriate to attempt treatment with ketamine barring the patient having any contraindications for treatment. Given that there is little published data regarding the response of patients who have failed ECT but subsequently respond to ketamine infusions, this case is an attempt to add to the literature in that regard. <h3>Funding</h3> None

Metaplastic Effects of Ketamine and MK-801 on Glutamate Receptors Expression in Rat Medial Prefrontal Cortex and Hippocampus

Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients’ refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on relevant brain areas for mood disorders. The aim of the present study was to investigate the molecular changes occurring at glutamatergic synapses 24 h after ketamine or MK-801 treatment in the rat medial prefrontal cortex (mPFC) and hippocampus (Hipp). In particular, we analyzed the levels of the glutamate transporter-1 (GLT-1), NMDA receptors, AMPA receptors subunits, and related scaffolding proteins. In the homogenate, we found a general decrease of protein levels, whereas their changes in the post-synaptic density were more complex. In fact, ketamine in the mPFC decreased the level of GLT-1 and increased the level of GluN2B, GluA1, GluA2, and scaffolding proteins, likely indicating a pattern of enhanced excitability. On the other hand, MK-801 only induced sparse changes with apparently no correlation to functional modification. Differently from mPFC, in Hipp, both substances reduced or caused no changes of glutamate receptors and scaffolding proteins expression. Ketamine decreased NMDA receptors while increased AMPA receptors subunit ratios, an effect indicative of permissive metaplastic modulation; conversely, MK-801 only decreased the latter, possibly representing a blockade of further synaptic plasticity. Taken together, these findings indicate a fine tuning of glutamatergic synapses by ketamine compared to MK-801 both in the mPFC and Hipp.

Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials

ObjectiveKetamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD. MethodsIn 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery–Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis. ResultsKetamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen’s d = 0.47–0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not. ConclusionThe findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD. SignificanceThe predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.

Spectral signatures of L-DOPA-induced dyskinesia depend on L-DOPA dose and are suppressed by ketamine

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

Molecular mechanisms involved in the prevention and reversal of ketamine-induced schizophrenia-like behavior by rutin: the role of glutamic acid decarboxylase isoform-67, cholinergic, Nox-2-oxidative stress pathways in mice

Mounting evidences have shown that nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox-2) pathway modifies glutamic-acid decarboxylase-67 (GAD67) (GABAergic enzyme) and cholinergic systems via oxidative-nitrergic mechanisms in schizophrenia pathology. Rutin, a neuroactive antioxidant compound, with proven neuroprotective property has been shown to reduce schizophrenic-like behavior in mice. This study sought to investigate the mechanisms of action of the psychopharmacological activity of rutin in the preventive and reversal effects of ketamine-induced schizophrenic-like behavior, oxidative-nitrergic stress, cholinergic and GABAergic derangements in mice. In the preventive treatment, male mice were given rutin (0.1, 0.2 and 0.4mg/kg) or risperidone (0.5mg/kg) orally for 14days prior to ketamine (20mg/kg, i.p.) treatment from the 8 to 14th day. However, in the reversal treatment, ketamine was given for 14days prior to rutin and risperidone. Behavioral (open-field, social-interaction and Y-maze tests), biochemical (oxidative/nitrergic stress markers, acetylcholinesterase activity), immunohistochemical (GAD67, Nox-2) and neuronal cell deaths in the striatum, prefrontalcortex, and hippocampus were evaluated. Ketamine-induced behavioral impairments were prevented and reversed by rutin. Exposure of mice to ketamine increased malondialdehyde, nitrite contents, acetylcholinesterase activity, neuronal cell death and Nox-2 expressions in the striatum, prefrontalcortex and hippocampus. Conversely, these derangements were prevented and reversed by rutin. The decreased glutathione levels due to ketamine were marked increased by rutin. Rutin only prevented ketamine-induced decrease in GAD67 expression in the striatal-hippocampal region. Altogether, the study showed that the prevention and reversaltreatments of mice with rutin attenuated ketamine-induced schizophrenic-like behaviors via reduction of Nox-2 expression, oxidative/nitrergic stresses, acetylcholinesterase activity, and increased GAD67 enzyme.

Effect Neonatal Ketamine Treatment on Exploratory and Anxiety-like Behaviours in Adulthood.

ObjectiveIn this study, we evaluated the effect of neonatal ketamine exposure on anxiety-like and exploratory behaviours in adult the Balb/c and C57BL/6 strains of mice which anxiety responses are different.MethodsKetamine was administered at two different doses single dose (10, 20 mg/kg, 0.1 ml/10 g body weight, intraperitoneally) and repeated doses (10, 20 mg/kg every 240 minutes; thrice times) on the 7th postnatal day to male Balb/c and C57BL/6 mice. In adulthood, open-field (OF) and elevated plus maze (EPM) apparatuses were used to evaluate exploratory and anxiety-like behaviour.ResultsIn the C57BL/6 mice, the 20 mg/kg single dose decreased open-arm time and total-arm entries in EPM and increased time of central latency and decreased distance travelled in OF. Both the 10 and 20 mg/kg repetitive doses increased time of central latency and decreased time spent in the centre, frequency of rearing and centre crossing in OF and decreased open-arm time, total-arm entries, number of open-arm entries in EPM. The 20 mg/kg repetitive dose decreased number of head dipping behaviours in EPM. In the Balb/c mice, both the single and repetitive 10−20 mg/kg doses had no significant effect on anxiety-like and exploratory behaviours.ConclusionThere were no significant differences in anxiety-like and exploratory behaviour in different strains by the single 10 mg/kg dose. However, in the C57BL/6 mice, both the single and repetitive 20 mg/kg doses and the 10 mg/kg repetitive dose increased anxiety-like behaviour and decreased exploratory behaviour in EPM and OF. In conclusion, hereditary factors may be effective on the effect of neonatal ketamine treatment on anxiety-like and exploratory behaviour.

Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine

Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine’s chemical half-life of ~2 h. Ketamine’s sustained antidepressant action may be due to modulation of cortical plasticity. We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout. Thus, we conceptualize that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine’s acute and long-lasting antidepressant effects.

Hypomania associated with high dose ketamine treatment.

For more than 50 years, pharmacotherapy for major depressive disorder (MDD) has narrowly focused on enhancing monoaminergic neurotransmission resulting in more than 30 FDA- approved treatments. In contrast, the glutamatergic, non-competitive N-methyl D-aspartate (NMDA) receptor antagonist ketamine has been "repurposed" as a rapid acting antidepressant1 ; the enantiomer S-ketamine, or esketamine, is now FDA-approved for treatment resistant unipolar depression (TRD).