Ketamine In Treatment-resistant Depression Research Articles

Repeated subcutaneous racemic ketamine in treatment-resistant depression: case series.

Interest in the use of parenteral ketamine has been increasing over the last 2 decades for the management of treatment-resistant depression (TRD). While intravenous (IV) ketamine has been the most common parenteral route of administration, subcutaneous (SC) and intramuscular options have been described. We developed a clinical treatment protocol for the use of repeated SC racemic ketamine (maximum six treatments, twice per week) in an inpatient psychiatric care setting with inclusion/exclusion criteria, dosing schedule, and description of treatment, assessment, and monitoring procedures. Results from the first 10 consecutive patients demonstrated the effectiveness of SC racemic ketamine in relieving symptoms of TRD as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR 16 ). Response (≥50% reduction in scores from baseline to endpoint) was achieved in 8/10 cases on the MADRS and 6/10 on the QIDS-SR 16 . Remission was achieved in 8/10 (based on MADRS ≤10) and 5/10 (based on QIDS-SR 16 ≤6). Patients tolerated the treatments well with only transient blood pressure changes and dissociative side effects. Repeated SC ketamine treatments could be a safe, feasible, and effective alternative to IV ketamine infusions for patients with TRD.

Use of ketamine in treatment-resistant depression: a systematic review

RESUMO Objetivo A cetamina apresenta-se como uma alternativa promissora contra a depressão resistente ao tratamento (DRT), no entanto o conhecimento de sua aplicação como antidepressivo ainda é restrito. Diante disso, objetivou-se investigar sua eficácia em pacientes com DRT. Métodos A busca da literatura foi efetuada na base de dados MedLine. Os critérios de inclusão foram: estudos clínicos controlados e randomizados dos últimos cinco anos e em inglês. Excluímos os artigos que não responderam à pergunta PICO e aqueles com tamanho de amostra e metodologia de estudo destoantes, quando comparados aos ensaios que basearam esta revisão. Resultados Considerando uma amostra final de seis artigos, observou-se uma melhor resposta à cetamina (principalmente em ganho de humor), quando comparada ao tratamento convencional contra a DRT. Já com sua primeira infusão, na dose de 0,5 mg/kg, foi possível perceber seus efeitos antidepressivos. A manutenção desses efeitos parece ser obtida com a administração de 0,5 mg/kg do medicamento, três vezes por semana. Por outro lado, a redução de tal dosagem pode diminuir ou anular os efeitos. Conclusões O uso da cetamina apresentou resultados efetivos na melhora do quadro de DRT, com efeitos adversos de pequena gravidade e de fácil controle. Entretanto, outros estudos, com amostras maiores e métodos diferentes, são necessários, para uma conclusão de maior consistência.

Oral prolonged-release ketamine in treatment-resistant depression - a double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation

Oral prolonged-release ketamine in treatment-resistant depression - a double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation

The BEDROC Study; extended release oral ketamine for treatment resistant depression.

The BEDROC Study; extended release oral ketamine for treatment resistant depression.

Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression

BackgroundSub-anesthetic ketamine doses rapidly reduce depressive symptoms, although additional investigations of the underlying neural mechanisms and the prediction of response outcomes are needed. Electroencephalographic (EEG)-derived measures have shown promise in predicting antidepressant response to a variety of treatments, and are sensitive to ketamine administration. This study examined their utility in characterizing changes in depressive symptoms following single and repeated ketamine infusions. MethodsRecordings were obtained from patients with treatment-resistant major depressive disorder (MDD) (N = 24) enrolled in a multi-phase clinical ketamine trial. During the randomized, double-blind, crossover phase (Phase 1), patients received intravenous ketamine (0.5 mg/kg) and midazolam (30 μg/kg), at least 1 week apart. For each medication, three resting, eyes-closed recordings were obtained per session (pre-infusion, immediately post-infusion, 2 h post-infusion), and changes in power (delta, theta1/2/total, alpha1/2/total, beta, gamma), alpha asymmetry, theta cordance, and theta source-localized anterior cingulate cortex activity were quantified. The relationships between ketamine-induced changes with early (Phase 1) and sustained (Phases 2,3: open-label repeated infusions) decreases in depressive symptoms (Montgomery-Åsberg Depression Rating Score, MADRS) and suicidal ideation (MADRS item 10) were examined. ResultsBoth medications decreased alpha and theta immediately post-infusion, however, only midazolam increased delta (post-infusion), and only ketamine increased gamma (immediately post- and 2 h post-infusion). Regional- and frequency-specific ketamine-induced EEG changes were related to and predictive of decreases in depressive symptoms (theta, gamma) and suicidal ideation (alpha). Early and sustained treatment responders differed at baseline in surface-level and source-localized theta. ConclusionsKetamine exerts frequency-specific changes on EEG-derived measures, which are related to depressive symptom decreases in treatment-resistant MDD and provide information regarding early and sustained individual response to ketamine.Clinical Trial Registration: ClinicalTrials.gov: Action of Ketamine in Treatment-Resistant Depression, NCT01945047

Frequency analysis of symptomatic worsening following ketamine infusions for treatment resistant depression in a real-world sample: Results from the canadian rapid treatment center of excellence

Antidepressants are associated with symptomatic worsening in a subgroup of patients. Replicated evidence has demonstrated rapid and robust antidepressant effects with intravenous (IV) ketamine in treatment resistant depression (TRD); however, the risk of ketamine worsening depressive symptoms in a subgroup of patients remains unknown. Herein we report a retrospective analysis on the rates of symptomatic worsening during an acute course of IV ketamine in individuals with unipolar (n = 142) and bipolar (n = 22) TRD. Adults (N = 164; mean age = 45.97) with TRD underwent four sub-anesthetic infusions (0.5–0.75 mg/kg over 40 min) of IV ketamine over two weeks, and were assessed with the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) at baseline and after each infusion. The primary outcome was the proportion of patients experiencing clinically significant worsening of depressive symptoms (≥20% increase on the QIDS-SR16) at each time point relative to baseline. Secondary analyses explored trends in the results. The frequency of clinically significant worsening fluctuated between 1.83% to 5.49%, with no identifiable trend across time. Zero individuals with bipolar TRD reported symptomatic worsening. Limitations include the single-centered, uncontrolled, retrospective nature of this study. Rates of symptomatic worsening associated with IV ketamine therapy for TRD appear to be very low and similar to conventional antidepressants.

Do baseline anxiety symptoms impact response to IV Ketamine in treatment resistant depression?

• We examined if anxious depression impacts Ketamine outcomes. • Forty-three patients received six IV Ketamine infusions over a three-week period. • Patients with anxious depression at baseline had comparable levels of improvement. • Improvement in anxiety was about half the magnitude of improvement in depression. • Depressed patients who present with anxiety may be appropriate for IV Ketamine. In a retrospective study, we analyzed if anxious depression impacts outcomes in patients with treatment resistant depression (TRD) receiving IV Ketamine infusions at an academic center Ketamine clinic. Forty-three patients with TRD received six IV Ketamine infusions over a three-week period. Anxious depression (ANX-TRD) was defined as a Hamilton Depression Rating Scale Anxiety/Somatization factor score of ≥ 7 at the baseline evaluation. Beck Depression Inventory (BDI-II) and Generalized Anxiety Disorder-7 (GAD-7) scales were used through the infusion course to assess symptom change. Twenty-three patients were categorized as ANX-TRD and 20 as non-anxious TRD. Generalized estimating equation (GEE) models revealed BDI-II and GAD-7 scores for ANX-TRD and NANX-TRD groups did not differ significantly during any time point. Symptoms of anxiety and depression improved after treatment in both groups, though the degree of change was significant and greater for depression. This was a naturalistic, retrospective study, without a control group. Symptoms of depression show greater improvement than symptoms of anxiety. IV Ketamine is effective in the treatment of depression, regardless of the baseline anxiety level.

P.0671 The role of intranasal ketamine in treatment-resistant depression

To compare the prevalence of cognitive dysfunction, depression, lower mobility performance, disability and falls in older community-dwelling individuals with type 2 diabetes mellitus (T2DM) and in controls of similar age.We conducted a cross-sectional study in primary health care settings in 3 semi-urban regions in Greece. Were assessed 403 community-dwelling older persons (age ≥65 years, median: 73), 198 with and 205 without diabetes. Common geriatric syndromes were studied using structured individual interviews and widely-used screening scales. An ensuing secondary analysis per age group was performed.After adjusting for several confounding factors, the diabetes group presented a 2-fold greater odds of having abnormal scores in Mini Mental State Examination (95%CI: 1.2–3.4, p = 0.006), a 1.5-fold greater odds of abnormal performance in the Clock Drawing Test (95%CI: 1.0–2.4, p = 0.05) and a 2-fold greater odds of slower performance in Timed-Up-And-Go test (95%CI: 1.1–3.4, p = 0.022). In the analysis per age group, impaired cognitive and mobility performances were observed in individuals with diabetes of the younger subgroup (65–74 years), while in the older subgroup (≥75 years), those differences disappeared.In a community-dwelling population aged ≥65 years, cognitive and physical fragilisation is more frequent and is observed at an earlier age in individuals with T2DM than in those without.

Betaine prevents and reverses the behavioral deficits and synaptic dysfunction induced by repeated ketamine exposure in mice

As an N-methyl-D-aspartate (NMDA) receptor inhibitor, ketamine has become a popular recreational substance and currently is used to address treatment-resistant depression. Since heavy ketamine use is associated with persisting psychosis, cognitive impairments, and neuronal damage, the safety of ketamine treatment for depression should be concerned. The nutrient supplement betaine has been shown to counteract the acute ketamine-induced psychotomimetic effects and cognitive dysfunction through modulating NMDA receptors. This study aimed to determine whether the adjunctive or subsequent betaine treatment would improve the enduring behavioral disturbances and hippocampal synaptic abnormality induced by repeated ketamine exposure. Mice received ketamine twice daily for 14 days, either combined with betaine co-treatment or subsequent betaine post-treatment for 7 days. Thereafter, three-chamber social approach test, reciprocal social interaction, novel location/object recognition test, forced swimming test, and head-twitch response induced by serotonergic hallucinogen were monitored. Data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including disrupted social behaviors, recognition memory impairments, and increased depression-like and hallucinogen-induced head-twitch responses, were remarkably improved by betaine co-treatment or post-treatment. Consistently, betaine protected and reversed the reduced hippocampal synaptic activity, such as decreases in field excitatory post-synaptic potentiation (fEPSP), long-term potentiation (LTP), and PSD-95 levels, after repeated ketamine treatment. These results demonstrated that both co-treatment and post-treatment with betaine could effectively prevent and reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that betaine can be used as a novel adjunct therapy with ketamine for treatment-resistant depression and provide benefits for ketamine use disorders.

420 - Ketamine treatment in geriatric depression

Treatment resistant depression can be very disabling and has a significant negative impact on a patient, their family or caregivers, and the society. There is a growing evidence on the efficacy and safety of ketamine for treatment resistant depression. Ketamine is a racemate consisting of esketamine and arketamine, is an N-methyl D-aspartate receptor antagonist and comes in different formulations and in fact intranasal ketamine is FDA-approved in the US. Despite the existing evidence and FDA approval for treatment resistant depression, data on older individuals remains limited. Late life depression especially those that are treatment resistant can be very disabling, with significant functional and cognitive impairments, increased morbidity and mortality, and the psychosocial burdens.This presentation describes outcomes for 2 cases of older individuals with treatment resistant depression who were treated with intranasal ketamine. One improved, and one did not. The scarce available literature of the use of ketamine in the geriatric population shows ketamine is well tolerated and effective. Remission rates in 3 separate show remission rates of 46.5%, 57% and 69.5% respectively. The discussion will include a review of the mechanism of action of ketamine as a novel antidepressant, the mixed evidence for its role in treatment resistant late life depression, and the practical and operational aspects relevant to running a ketamine clinic.

A positron emission tomography study of the serotonin1B receptor effect of electroconvulsive therapy for severe major depressive episodes

BackgroundElectroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT1B) receptor is a potential target for treatment of depression and low 5-HT1B receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression. MethodsThe objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT1B receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT1B receptor selective radioligand [11C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT1B receptor binding in depression and a dorsal brain stem region were selected. ResultsThirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT1B receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT1B receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions. In an exploratory analysis, strong correlations between changes in 5-HT1B receptor binding and agitation scores on the Hamilton Depression Rating Scale after ECT were observed. LimitationsAlbeit representative of a PET study, the sample size is still small and there are potential confounding effects of medication. ConclusionsIncreased 5-HT1B receptor binding was observed following ECT for depression, corresponding to previous findings of increased 5-HT1B receptor binding in hippocampus after rapid acting ketamine for treatment resistant depression.

Resting-State Functional Magnetic Resonance Imaging Reveals Neuroplasticity After Repeated Treatment With Ketamine in Treatment-Resistant Depression

Resting-State Functional Magnetic Resonance Imaging Reveals Neuroplasticity After Repeated Treatment With Ketamine in Treatment-Resistant Depression

Ketamine for Treatment-Resistant Depression

Major depressive disorder (MDD) is of influence on about 350 million individuals worldwide, which is causing disability consecution and damaging consequences to the affected community and individuals. Treatments as antidepressant are affecting the system of monoamine where symptoms of depressive were relived in about 50% of cases. Such ratio turns into obviously low in depressed persons who failed already to cure following 2 or additional antidepressant drugs at sufficient duration and doses regarding it a treatment-resistant depression (TRD). There is an obvious requisite for quick action and influenced treatments. Ketamine (KMN) is considered an anesthetic old drug that has a promising quick action as an antidepressant in TRD patients with MDD, concentrating on clinical issues, i.e. administration route, dose, and action duration. Other indication proposes that KMN might be influenced in stress disorder as posttraumatic and ideation as acute suicidal.

Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial

Introduction: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. Objective: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). Methods: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. Results: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI –0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI –0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] <1; p ns). Conclusions: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.

A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801

With the increasing use of ketamine as an off-label treatment for depression and the recent FDA approval of (S)-ketamine for treatment-resistant depression, there is an increased need to understand the long-term safety profile of chronic ketamine administration. Of particular concern is the neurotoxicity previously observed in rat models following acute exposure to high doses of ketamine, broadly referred to as ‘Olney's lesions’. This type of toxicity presents as abnormal neuronal cellular vacuolization, followed by neuronal death and has been associated with ketamine's inhibition of the N-methyl-d-aspartate receptor (NMDAR). In this study, a pharmacological and neuropathological analysis of ketamine, the potent NMDAR antagonist MK-801, and the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK)] in rats is described following both single dose and repeat dose drug exposures. Ketamine dosing was studied up to 20 mg/kg intravenously for the single-dose neuropathology study and up to 60 mg/kg intraperitoneally for the multiple-dose neuropathology study. MK-801 dosing was studied up to 0.8 mg/kg subcutaneously for both the single and multiple-dose neuropathology studies, while (2R,6R)-HNK dosing was studied up to 160 mg/kg intravenously in both studies. These studies confirm dose-dependent induction of ‘Olney's lesions’ following both single dose and repeat dosing of MK-801. Ketamine exposure, while showing common behavioral effects, did not induce wide-spread Olney's lesions. Treatment with (2R,6R)-HNK did not produce behavioral effects, toxicity or any evidence of Olney's lesion formation. Based on these results, future NMDAR-antagonist neurotoxicity studies should strongly consider taking pharmacokinetics more thoroughly into account.

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

Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression.

Background:There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine’s safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP).Methods:A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol.Results:No antidepressants were associated with psychomimetic symptomatology except for citalopram (p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed.Conclusions:Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients.ClinicalTrials.gov identifier: NCT04226963

Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: A long-term retrospe

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe, effective and non-invasive treatment for many psychiatric illnesses, including treatment-resistant depression (TRD). Ketamine, an NMDA receptor antagonist, is also an effective antidepressant. This retrospective review examined the clinical benefits of combining these two established treatments for patients suffering from TRD in a novel approach coined combination TMS with ketamine (CTK). Methods: A group of 28 adult patients with a primary diagnosis of unipolar (n=18) or bipolar (n=10) depression received three CTK treatments a week at a private neuropsychiatric practice. Patients were given a concurrent treatment of rTMS (1Hz; 40 minutes; 130% of motor threshold) with bio-marker-determined IV ketamine infusions (0.2-4.7 mg/kg; 30 minutes). The TMS coil was positioned on the mid-prefrontal area. Frequency of treatment was dependent on patient responsiveness (10-30 sessions), which was measured as symptom reduction on the Clinical Global Impression (CGI) scale. CGI data was evaluated pre-treatment, post-treatment and at two-year follow-up. Results: Mean reduction in CGI severity for the patient group following CTK was 4.46 ± 0.54 at a 99% confidence interval and was deemed statistically significant using a paired t-test (α=0.01, t=22.81 p < 0.0001). This significant reduction in CGI severity was sustained for at least 2 years following treatment completion. Conclusions: Despite years of unsuccessful treatments, all 28 patients in this trial obtained substantial and enduring reductions in their depressive symptoms following CTK therapy. Further research into method optimization and randomized controlled trials are warranted.

Copper and anti-anhedonic effect of ketamine in treatment-resistant depression

Treatment-resistant depression (TRD) remains one of the major psychiatric challenges worldwide. Search for non-monoaminergic agents, possibly effective in treatment of TRD is of prime importance. One of those agents is ketamine – a dissociative, anesthetic drug exhibiting a fast antidepressant action in patients with TRD. Concurrently, anhedonia appears to be significant symptom domain with far-reaching impact on course of treatment. There is data demonstrating that abnormal copper levels might be associated with symptoms of depression. As there is common denominator in ketamine and copper role in neurotransmission this paper is to explore the associations of blood copper levels and psychometric measures in patients with TRD in course of major depressive disorder (MDD) and bipolar disorder (BP), focusing on anhedonia measured with Snaith-Hamilton Pleasure Scale (SHAPS) score.

Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

BackgroundKetamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment. MethodsSubjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery–Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment. ResultsBetter complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity. ConclusionThe study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD.