Subanesthetic Ketamine Infusion Research Articles

Examining fMRI time-series entropy as a marker for brain E/I balance with pharmacological neuromodulation in a non-human primate translational model

Recently, there has been a lot of interest in the neuroimaging community in exploring fMRI time-series measures of local neuronal activity and excitation/inhibition (E/I) balance in the brain. In this preliminary study we probed the sensitivity of widely used sample entropy (SE) measure at multiple scales to controlled alteration of the brain’s E/I balance in non-human primates (NHPs) with a well-characterized sub-anesthetic ketamine infusion fMRI model. We found that SE failed to detect the expected changes in E/I balance induced by ketamine. Subsequently, noticing that the complexity in the time series contributing SE could be dominated by non-neuronal noise in this experimental setting, we developed a new time-series measure called restricted sample entropy (RSE) by restricting SE estimations to regular portions of the fMRI time-series. RSE was able to adequately reflect the increased excitatory activity engendered by disinhibition of glutamergic neurons, through sub-anesthetic ketamine infusion. These results show that RSE is potentially a powerful tool for examining local neural activity, E/I balance, and alterations in brain state.

Low Dose Ketamine Infusion for Comorbid Posttraumatic Stress Disorder and Chronic Pain: A Randomized Double-Blind Clinical Trial

Objective To date, treatment options (i.e. psychotherapy, antidepressant medications) for patients with posttraumatic stress disorder (PTSD), are relatively few, and considering their limited efficacy, novel therapies have gained interest among researchers and treatment providers alike. Among patients with chronic pain (CP) about one third experience comorbid PTSD, which further complicates their already challenging pharmacological regimens. Low dose ketamine infusion has shown promise in PTSD, and in treatment of CP, however they have not been studied in comorbid population and under rigorous control conditions. Methods We compared the effects of a single dose of either ketamine (0.5 mg/kg) or ketorolac (15 mg) over a 40-minute of IV infusion in CP patients with and without PTSD, in double blind, randomized study. Measures were collected before, during, one day and seven days after the infusion. A planned sample size of 40 patients randomly assigned to treatment order was estimated to provide 80% power to detect a hypothesized treatment difference after the infusion. Main Outcome and Measures: The primary outcome measures were change in PTSD symptom severity assessed with the Impact of Event Scale–Revised (IES-R) and Visual Analogue Scale (VAS) for pain administered by a study clinician 24 hours post infusion. Secondary outcome measures included Impact of Event Scale–Revised (IES-R), VAS and Brief Pain Inventory (Short Form) for pain 1 week after the infusion. Results Both treatments offered comparable improvement of PTSD and CP symptoms that persisted for 7 days after the infusion. Patients with comorbid PTSD and CP experienced less dissociative side effects compared to the CP group. Surprisingly, ketorolac infusion resulted in dissociative symptoms in CP patients only. Conclusions This first prospective study comparing effects of subanesthetic ketamine versus ketorolac infusions for comorbid PTSD and CP, suggests that both ketamine and ketorolac might offer meaningful and durable response for both PTSD and CP symptoms.

Evaluation of Clinical Factors Associated with Adverse Drug Events in Patients Receiving Sub-Anesthetic Ketamine Infusions.

IntroductionSub-anesthetic ketamine is frequently used as an analgesic to reduce perioperative opioid consumption and has also been shown to have antidepressant effects. Side effects of ketamine include dizziness, diplopia, nystagmus, and psychomimetic effects. It is unclear what clinical factors may be associated with ketamine-related adverse drug events (ADEs).MethodsWe performed a retrospective review of 95 patients who received sub-anesthetic ketamine infusions at our institution. Data examined associations between ketamine-related ADEs and various clinical characteristics including chronic pain, depression, or psychiatric disorder, patient physical characteristics, chronic opioid use, perioperative opioid use, dose and duration of ketamine infusions, pain scores, and perioperative medications such as serotonergic agents, central nervous system (CNS) depressants, and analgesics.ResultsOverall incidence of ketamine-related ADEs was 29.5% and the incidence of psychomimetic effects was 14.8%. We observed that patients with a history of depression have a lower incidence of ketamine-related ADEs compared to patients without a history of depression (10.3% vs 37.3%; p value = 0.007).ConclusionPatients with depression were found to have a statistically significant reduction in the incidence of ketamine-related ADEs. We found no statistically significant positive associations between ketamine-related ADEs and other clinical factors such as a history of chronic pain, psychiatric disease, patient physical characteristics, perioperative opioid use, dose of ketamine infusion, or co-administration of other CNS depressants.

Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex

Objectives Synaptic plasticity and brain-derived neurotrophic factor (BDNF) signalling are proposed to play key roles in antidepressant drug action. Ketamine, an N-methyl-D-aspartate receptor antagonist and putative antidepressant, may increase synaptic plasticity in prefrontal cortex through higher expression of BDNF. Furthermore, ketamine was shown to change resting-state functional connectivity (RSFC) of dorsomedial prefrontal cortex (dmPFC). Methods In a randomised, placebo-controlled study, we investigated acutely (100 min) and at 24 h following subanesthetic ketamine infusion which dmPFC seeded RSFC changes are most strongly associated with plasma BDNF level changes in 53 healthy participants (21 females, age: 24.4 ± 2.9 years) using 7 T-fMRI. Results We observed higher relative levels of BDNF 2 h and 24 h after ketamine compared to placebo. Whole-brain regression revealed that the change in BDNF after 24 h was associated with RSFC decreases from dmPFC to posterior cingulate cortex and ventromedial PFC at 24 h and exploratively also at the 100 min measurement point. Follow-up analyses revealed that RSFC reductions following ketamine were restricted to subjects showing increased BDNF levels at 24 h. Conclusions Our findings indicate BDNF level dynamics following ketamine are related to acute and 24 h RSFC changes. Particularly when BDNF increases are observed after ketamine infusion, a disconnection from dmPFC after 24 h is seen and may reflect synaptic plasticity effects.

Subanesthetic ketamine infusions for the management of pediatric pain in non-critical care settings: An observational analysis.

Guidelines issued by the American Society of Regional Anesthesia and Pain Medicine suggest that ketamine infusions for acute pain management are advantageous as a primary treatment or as an opioid adjunct. Despite significant data regarding its use in adult patients, there remains a paucity of information related to its quality and side effect profile in pediatrics and how it can be effectively used. We aimed to summarize our practice of utilizing ketamine for pediatric pain management in non-critical care settings. Patients aged 0-21 years receiving low-dose ketamine infusions (≤0.3 mg/kg/hour) in inpatient care units over five years were retrospectively analyzed. Demographics, specific quality metrics, and side effects were quantified. About 172 patients received 270 subhypnotic ketamine infusions. The median duration of the infusions was 63.8 hours and 0.2 mg/kg/hour for the highest dose. The primary indication for ketamine was chronic pain exacerbation (83.3%). Despite similar opioid consumption, there was a significant reduction in mean verbal pain scores before (8.9 ± 1.9, P < .001) and after ketamine (6.5 ± 2.7, P < .001) use. Although there were 52 incidences of some side effect (neurologic excitability [10.4%]; over-sedation [7.4%]; rapid response team alerts [1.1%]), none resulted in termination of the infusion or escalations in care. Ketamine can effectively be used as part of a multimodal analgesic regimen in pediatric patients in non-critical care settings. Our five-year experience using low-dose ketamine infusions highlights an acceptable side effect profile, with no attributable escalations in care or serious adverse events.

Augmenting the Treatment of PTSD with Ketamine—a Review

Purpose Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a lifetime prevalence of 6.1% in the general adult population. Clinical guidelines for the treatment of PTSD suggest the use of trauma-focused psychotherapies such as prolonged exposure (PE) and cognitive-behavioral therapy (CBT). As a second-level intervention, these guidelines suggest the use of psychotropic medications, mainly selective serotonin reuptake inhibitors (SSRIs). To date, however, studies have shown that both psychotherapeutic and psychopharmacologic treatments have limited efficacy, with remission rates around 40–70% and dropout rates of up to 50%. This paper reviews a new and emerging treatment approach of medication-augmented psychotherapy for PTSD, with an emphasis on augmenting prolonged exposure therapy (PE) with sub-anesthetic ketamine infusion. Based on animal and human research on fear extinction and memory reconsolidation, neurobiological changes that emerge following a ketamine infusion can enhance learning and thus benefit exposure-based psychotherapies for PTSD.

Use of Ketamine to Treat Depressive Symptoms in Schizoaffective Disorder

The use of subanesthetic ketamine infusions in treatment resistant depression and bipolar depression is becoming more common. Subanesthetic doses of ketamine cause the patient to dissociate, which was initially considered a side effect of this treatment; it is believed to play a role in a patient’s clinical improvement. Researchers attribute this result to an increase in brain-derived neurotrophic factor, a growth factor that stimulates the formation of new synaptic connections. Due to its psychogenic affect, ketamine treatment is less suitable for patients who experience mood disorders with psychotic features. Although symptomatic hallucinations seemingly conflict with the dissociative effects of ketamine, treatment of a patient with depressive type schizoaffective disorder revealed significant improvements in his depressive symptoms, demonstrating ketamine’s potential to be safely administered to patients with a variety of complex disorders.

Default mode network connectivity change corresponds to ketamine's delayed glutamatergic effects.

Ketamine exerts rapid antidepressant effects peaking 24h after a single infusion, which have been suggested to be reflected by both reduced functional connectivity (FC) within default mode network (DMN) and altered glutamatergic levels in the perigenual anterior cingulate cortex (pgACC) at 24h. Understanding the interrelation and time point specificity of ketamine-induced changes of brain circuitry and metabolism is thus key to future therapeutic developments. We investigated the correlation of late glutamatergic changes with FC changes seeded from the posterior cingulate cortex (PCC) and tested the prediction of the latter by acute fractional amplitude of low-frequency fluctuations (fALFF). In a double-blind, randomized, placebo-controlled study of 61 healthy subjects, we compared effects of subanesthetic ketamine infusion (0.5mg/kg over 40min) on resting-state fMRI and MR-Spectroscopy at 7T 1h and 24h post-infusion. FC decrease between PCC and dorsomedial prefrontal cortex (dmPFC) was found at 24h post-infusion (but not 1h) and this FC decrease correlated with glutamatergic changes at 24h in pgACC. Acute increase in fALFF was found in ventral PCC at 1h which was not observed at 24h and inversely correlated with the reduced dPCC FC towards the dmPFC at 24h. The correlation of metabolic and functional markers of delayed ketamine effects and their temporal specificity suggest a potential mechanistic relationship between glutamatergic modulation and reconfiguration of brain regions belonging to the DMN.

A Contemporary Perspective on the Management of Post-Craniotomy Headache and Pain

This article discusses the etiology and management of post-craniotomy headache and pain. A review of available as well as investigatory treatment modalities is offered, followed by suggestions for optimal management of post-craniotomy headache. There is a dearth of evidence-based practice regarding the differential diagnosis, natural history, and management of post-craniotomy headache. The etiology of post-craniotomy headache is typically multifactorial, with patients' medical history, type of craniotomy, and perioperative management all playing a role. Post-craniotomy headaches are often undertreated, yet available evidence supports a multimodal approach for both prophylaxis and management. Many therapeutic techniques that aim to treat or prevent post-craniotomy headache require more robust validation than clinical evidence currently imparts. Pre- and intraoperative locoregional anesthesia should be the mainstay of prophylaxis; the role of opiates co-administered with analgesics, corticosteroids, and antiepileptic therapy in the acute perioperative phase is of paramount importance. Treatment of chronic PCH is less well-defined but should involve trials of analgesic, antineuropathic, and antiepileptic medications before enlisting experimental treatments. Comorbid psychiatric, musculoskeletal, or seizure disorders should be managed distinctly from post-craniotomy headaches. In patients failing all extant therapies, experimental approaches should be considered. These include subanesthetic ketamine infusion or surgical site injection with local anesthetics, corticosteroids, or botulinum toxin. Post-craniotomy headache is a complex phenomenon with many underutilized treatment options available, and many more under investigation. Nonetheless, further research is required to differentiate the efficacy of contemporary treatment strategies and to elucidate the applicability of novel therapies.

Characterizing the course of suicidal ideation response to ketamine

Background: No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine. Methods: Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers. Results: The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders. Limitations: Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used. Conclusion: The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.

Recurrent Subanesthetic Ketamine Infusions for Complex Regional Pain Syndrome Leading to Biliary Dilation, Jaundice, and Cholangitis: A Case Report.

Complex regional pain syndrome is a chronic pain condition that may be resistant to many treatment modalities. Ketamine infusions have demonstrated some promising results, though their use may be associated with a number of adverse effects limiting their widespread applicability. Hepatotoxicity and cholangiopathy have been described in chronic ketamine abuse, though rarely in therapeutic use. We report the impact of recurrent short subanesthetic ketamine infusions for the treatment of complex regional pain syndrome resulting in biliary dilation, jaundice, and cholangitis. We recommend that prescribing physicians consider this and monitor liver function tests throughout the treatment period to minimize morbidity.

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression

BackgroundKetamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. MethodsTreatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response. ResultsFactor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. LimitationsPossible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses. ConclusionsFrom a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study

Efforts to translate sub-anesthetic ketamine infusions into widespread clinical use have centered around developing medications with comparable neurobiological activity, but with attenuated psychoactive effects so as to minimize the risk of behavioral toxicity and abuse liability. Converging lines of research, however, suggest that some of the psychoactive effects of sub-anesthetic ketamine may have therapeutic potential. Here, we assess whether a subset of these effects - the so-called mystical-type experience - mediates the effect of ketamine on craving and cocaine use in cocaine dependent research volunteers. We found that ketamine leads to significantly greater acute mystical-type effects (by Hood Mysticism Scale: HMS), dissociation (by Clinician Administered Dissociative States Scale: CADSS), and near-death experience phenomena (by the Near-Death Experience Scale: NDES), relative to the active control midazolam. HMS score, but not the CADSS or NDES score, was found to mediate the effect of ketamine on global improvement (decreased cocaine use and craving) over the post-infusion period. This is the first controlled study to show that mystical-type phenomena, long considered to have therapeutic potential, may work to impact decision-making and behavior in a sustained manner. These data suggest that an important direction for medication development is the identification of ketamine-like pharmacotherapy that is selectively psychoactive (as opposed to free of experiential effects entirely), so that mystical-type perspectival shifts are more reliably produced and factors lending to abuse or behavioral impairment are minimized. Future research can further clarify the relationship between medication-occasioned mystical-type effects and clinical benefit for different disorders. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

BackgroundRecent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system. MethodsThe effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD). ResultsSubjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion. LimitationsRetrospective nature of this study, lack of control group and use of self-report depression ratings scales. ConclusionsThis is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population

A Case Report

Oncology patients undergoing treatment can experience substantial pain related to their disease or prescribed therapy. Ketamine infusions at subanesthetic doses have been used at our institution to supplement the pain management regimens of 262 patients. We present 2 cases in which young adult patients being treated with subanesthetic ketamine for cancer-related pain experienced urinary urgency and incontinence after initiation or increase of the ketamine infusion. This adverse effect has not been reported previously at this dosing range. These case reports suggest that subanesthetic ketamine infusions may cause side effects that previously have been reported only at anesthetic or abuse doses.

Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study.

BackgroundSubanesthetic doses of ketamine, an N-methyl-d-aspartate receptor antagonist used as an adjuvant to opioid for the treatment of pain in adults with acute and chronic pain, have been shown, in some instances, to improve pain intensity and to decrease opioid intake. However, less is known about the role of ketamine in pain management in children, adolescents, and young adults.PurposeWe examined the effects of subanesthetic ketamine on pain intensity and opioid intake in children, adolescents, and young adults with acute and chronic pain syndromes treated in an inpatient setting.MethodsThis is a longitudinal cohort study of patients treated with subanesthetic ketamine infusions in regular patient care units in a tertiary pediatric hospital. Primary outcomes included changes in pain scores and morphine-equivalent intake.ResultsThe study cohort included 230 different patients who during 360 separate hospital admissions received subanesthetic ketamine infusions for pain management. Overall, ketamine infusions were associated with significant reductions in mean pain scores from baseline (mean pain scores 6.64 [95% CI: 6.38–6.90]) to those recorded on the day after discontinuation of ketamine (mean pain scores 4.38 [95% CI: 4.06–4.69]), p<0.001. Importantly, the effect of ketamine on pain scores varied according to clinical diagnosis (p=0.011), infusion duration (p=0.004), and pain location (p=0.004). Interestingly, greater reductions in pain scores were observed in patients with cancer pain and patients with pain associated with pancreatitis and Crohn’s disease. There were no records of psychotomimetic side effects requiring therapy.ConclusionThese data suggest that administration of subanesthetic ketamine for pain management is feasible and safe in regular inpatient care units and may benefit children, adolescents, and young adults with acute and chronic pain. This study is informative and can be helpful in determining sample and effect sizes when planning clinical trials to determine the role of subanesthetic ketamine infusions for pain management in pediatric patients.

Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study.

BackgroundChronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting.MethodsLongitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake.ResultsOver a 15-month period, 63 children and adolescents (median age 15, interquartile range 12–17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p <0.001) and yielded greater pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (p = 0.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (p = 0.007). In 37 % of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3).ConclusionsThese data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain. Further, patients with CRPS, POTS, and a history of trauma-related chronic pain are more likely to benefit from this therapeutic modality.

Long-term effect of sub-anesthetic ketamine in reducing l-DOPA-induced dyskinesias in a preclinical model

Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson’s disease (PD) and l-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5–20mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.

Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans.

In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.

Multistage drug effects of ketamine in the treatment of major depression.

A substantial number of patients diagnosed with major depression disorder show poor or no response to standard antidepressive drugs. Recent studies showed that ketamine promotes a rapid and sustained antidepressive effect in treatment-resistant depression. Importantly, after a single dose, such antidepressant action appears very fast, reaching maximum efficacy after 1-2 days before it slowly decays after 3-7 days. This temporal pattern is especially interesting since most effects are investigated following single, subanesthetic doses. This means that effects are observed at time points when the blood levels have long fallen below any active threshold. Mechanisms of action thus may be sought either in secondary or compensatory processes, which develop after acute systemic derangement or in molecular downstream mechanisms of action, which after initiation do not require the presence of active drug levels. We here review acute and delayed effects of subanesthetic ketamine infusion and discuss potential origins of antidepressant drug action. We will provide evidences that both acute effects on abnormal network configuration and delayed effects at the level of homeostatic synaptic plasticity may be necessary for antidepressant action. We further argue that such effects should be followed by a temporally well-defined exploitation of these transient changes by therapeutic processes, aiming at sustained changes of network configuration via psychotherapeutic or other methods.