Rapid Antidepressant Response Research Articles

Ketamine-Induced Glutamatergic Mechanisms of Sleep and Wakefulness: Insights for Developing Novel Treatments for Disturbed Sleep and Mood.

Ketamine, a drug with rapid antidepressant effects and well-described effects on slow wave sleep (SWS), is a useful intervention for investigating sleep-wake mechanisms involved in novel therapeutics. The drug rapidly (within minutes to hours) reduces depressive symptoms in individuals with major depressive disorder (MDD) or bipolar disorder (BD), including those with treatment-resistant depression. Ketamine treatment elevates extracellular glutamate in the prefrontal cortex. Glutamate, in turn, plays a critical role as a proximal element in a ketamine-initiated molecular cascade that increases synaptic strength and plasticity, which ultimately results in rapidly improved mood. In MDD, rapid antidepressant response to ketamine is related to decreased waking as well as increased total sleep, SWS, slow wave activity (SWA), and rapid eye movement (REM) sleep. Ketamine also increases brain-derived neurotrophic factor (BDNF) levels. In individuals with MDD, clinical response to ketamine is predicted by low baseline delta sleep ratio, a measure of deficient early night production of SWS. Notably, there are important differences between MDD and BD that may be related to the effects of diagnosis or of mood stabilizers. Consistent with its effects on clock-associated molecules, ketamine alters the timing and amplitude of circadian activity patterns in rapid responders versus non-responders with MDD, suggesting that it affects mood-dependent central neural circuits. Molecular interactions between sleep homeostasis and clock genes may mediate the rapid and durable elements of clinical response to ketamine and its active metabolite.

A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice.

New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher—and sTNFR1 levels were significantly lower—in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine.

GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT2 receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT2 receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.

Differential regulation of GluA1 expression by ketamine and memantine

Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine’s psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses.

Molecular Mechanism and Clinical Relevance of Ketamine as Rapid-Acting Antidepressant.

Preclinical Research The emergence of rapid-acting antidepressants such as ketamine has motivated studies aiming to reveal the molecular mechanism of the ketamine antidepressant effect and to enable the clinical application of rapid-acting antidepressants. Here, we provide an overview of studies addressing the antidepressant effects of ketamine in depressed patients and animal models of depression and we compare the reduction of depressive symptoms in humans with the reduction in immobility time in the forced swim test in rodents after acute ketamine treatment. We also discuss different theories and potential biochemical pathways involved in the rapid antidepressant response to ketamine including the modulation of glutamatergic neurotransmission and intracellular hub-kinase activation. Finally, we summarize recent brain-region specific studies and we suggest that the activation of the ventral hippocampus-medial prefrontal cortex-dorsal raphae nuclei (vHC-mPFC-DRN) neuronal pathway may mediate the antidepressant effect of ketamine. Although substantial progress has been made, further brain-region specific animal studies and longitudinal clinical trials are necessary for the understanding and successful application of novel rapid-acting antidepressants. Drug Dev Res 77 : 414-422, 2016. © 2016 Wiley Periodicals, Inc.

Deep brain stimulation of the medial forebrain bundle: Distinctive responses in resistant depression

BackgroundTreatment resistant depression (TRD) is a serious, disabling disease. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB), as proposed by Schlaepfer et al. (2013), has led to rapid anti-depressant response but has not been replicated. MethodsIn this interim analysis of an ongoing pilot study of ten subjects, we assessed the efficacy of MFB-DBS in a cohort of four TRD patients over a 52-week period using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary assessment tool. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients. ResultsIntraoperatively, responder patients displayed immediate increased signs of energy and motivation upon stimulation at target. There was no significant mean change in mood during sham stimulation phase. Three of 4 patients had >50% decrease in MADRS scores at 7 days post-stimulation initiation relative to baseline. One patient withdrew from study participation. At 26 weeks, two of 3 remaining patients continue to have >80% decrease in MADRS scores. One patient failed to have response; evaluation of modulated fiber tracts revealed reduced frontal connectivity to the target region. LimitationsThis is an interim report, with limited conclusions. ConclusionThis study of MFB-DBS shows similar rapid anti-depressant effects within the first week of stimulation as initially reported by Schlaepfer et al. (2013). Implementation of anhedonia measurements would greatly augment characterization of the striking motivational effects observed. We urge others to pursue this target to further prove efficacy.ClinicalTrials.gov (identifier: NCT02046330) https://clinicaltrials.gov/ct2/show/NCT02046330

Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice

Current medications for depression typically require weeks of treatment before significant clinical improvement is observed, and are only effective in a relatively small subset of patients. Recent human clinical studies have demonstrated that ketamine, an NMDA receptor antagonist, and scopolamine, a muscarinic acetylcholine receptor antagonist, produce rapid antidepressant responses within hours of administration, and are effective in treatment-resistant patients. We hypothesize that efficacy and tolerability may be improved by combining lower doses of both drugs in the treatment of depression. We therefore conducted a preclinical study in mice to assess whether co-treatment of low doses of scopolamine and ketamine that alone are ineffective has antidepressant-like effects in the forced swim test (FST), an assay with predictive validity for antidepressant drugs. Whereas single administration of ketamine (3mg/kg intraperitoneal [i.p.]) or scopolamine (0.1mg/kg i.p.) did not reduce immobility time in the FST, co-administration of both drugs at these doses significantly reduced immobility time by 45% compared to vehicle treated controls. These results suggest that the combination of subeffective doses of ketamine and scopolamine may prove efficacious for the treatment of depression and should be evaluated in human clinical trials.

Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc

The rapid antidepressant response to the N-methyl-d-aspartate (NMDA) receptor antagonists is mediated by activation of the mammalian target of the rapamycin (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in screening tests and models of depression. We focused these studies in investigating whether activation of the mTOR signaling pathway is also a necessary mechanism of the antidepressant-like activity of Zn. We observed that a single injection of Zn (5 mg/kg) induced an increase in the phosphorylation of mTOR and p70S6K 30 min and 3 h after Zn treatment at time points when Zn produced also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn administered 3 h before the decapitation increased the level of brain derived neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and synapsin I was still observed 24 h after the Zn treatment, although Zn did not produce any effects in the FST at that time point. We also observed that pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling proteins (analyzed 30 min after Zn administration). These studies indicated that the antidepressant-like activity of Zn depends on the activation of mTOR signaling and other signaling pathways related to neuroplasticity, which can indirectly modulate mTOR function.

Serum BDNF as a peripheral biomarker of treatment-resistant depression and the rapid antidepressant response: A comparison of ketamine and ECT

BackgroundKetamine is associated with rapid antidepressant efficacy but the biological mechanisms underpinning this effect are unclear. Serum brain-derived neurotrophic factor (sBDNF) is a potential circulating biomarker of treatment-resistant depression (TRD) and ketamine response but it is unclear if this is a common target of both ketamine and electroconvulsive therapy (ECT), the current gold standard for TRD. Moreover, the impact of multiple ketamine infusions on sBDNF has not yet been established. MethodsThirty five TRD patients with a current DSM-IV diagnosis of recurrent depressive disorder received up to 12 ECT sessions (N=17) or up to three intravenous infusions of low-dose (0.5mg/kg) ketamine (N=18). Blood samples were taken over the course of the study for assessment of sBDNF. Symptom severity and response were monitored using the 17-item Hamilton Depression Rating Scale (HDRS). sBDNF was assessed in 20 healthy controls to allow comparison with TRD patients. ResultsAs expected, sBDNF was lower in TRD patients at baseline compared to healthy controls. Ketamine and ECT treatment were both associated with significant reductions in depressive symptoms. However, sBDNF was significantly elevated only at one week following the first ketamine infusion in those classified as responders one week later. sBDNF was not elevated following subsequent infusions. ECT reduced depressive symptoms, as expected, but was not associated with an enhancement in BDNF. LimitationsPatients continued with their psychotropic medications throughout this trial. ConclusionsSBDNF normalisation does not appear to be a prerequisite for symptomatic improvement in TRD following ketamine or ECT treatment.

Intranasal ketamine shows rapid effects in depression study

A new randomized, double‐blind crossover study has found that a single 50‐mg dose of intranasal ketamine was associated with rapid antidepressant response in patients with treatment‐resistant depression, with a significant effect seen 40 minutes after administration.

Rapid antidepressants stimulate the decoupling of GABA(B) receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η.

A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling.

Ketamine infusion in treatment resistant depression: a case report and brief review of the literature

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may exhibit antidepressant effect. Previous studies of treatment-resistant depression reveal that ketamine infusions may result in a rapid antidepressant response with improvement usually sustained for several days. This case suggests that intravenous administration of ketamine may be effective for immediate relief from symptoms in unipolar depression and may also relieve suicidal ideation. Due to the prolonged period between the initiation of treatment and the onset of action of currently available antidepressants, only a few things can be done for the management of acute and severe suicidal ideation other than close monitoring or hospitalization. Rapid effect of ketamine may be an advantage in the management of suicide risk. Although additional research is needed to ascertain optimal dosing schedules and route of administration of ketamine, NMDA agents warrant further investigation as a treatment option in treatment-resistant depression and as an agent intended to reduce suicides.

Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade.

Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

Disruption of white matter integrity marks poor antidepressant response in bipolar disorder

BackgroundChanges of white matter (WM) microstructure have been proposed as structural biomarkers of bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been proposed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. MethodsWe tested if baseline DTI measures can predict response to treatment in 70 in-patients affected by a major depressive episode in the course of BD, treated with chronotherapeutics for one week. We performed whole-brain tract-based spatial statistics with threshold-free cluster enhancement for the DTI measures of WM microstructure integrity: fractional anisotropy, axial, radial, and mean diffusivity. ResultsIncreased mean and radial water diffusivity correlated with poor antidepressant response to TSD+LT in core WM tracts which are crucial for the functional integrity of the brain, including corpus callosum, corona radiata, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and thalamic radiation. LimitationsLimitations include issues such as generalizability, possible population stratification, medications and their effects on DTI measures, and no placebo control for chronotherapeutics. We could not consider other factors such as gene–environment interactions. ConclusionsThe association of increased radial and mean diffusivity with poor response to chronotherapeutic treatment warrants interest for the study of DTI measures of WM microstructure as markers for treatment response in bipolar depression.

P.2.b.007 Prevalence and psychiatric correlates of suicidal ideation in primary care patients: gender differences

Treatment resistant depression (TRD) is a serious, disabling disease. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB), as proposed by Schlaepfer et al. (2013), has led to rapid anti-depressant response but has not been replicated.In this interim analysis of an ongoing pilot study of ten subjects, we assessed the efficacy of MFB-DBS in a cohort of four TRD patients over a 52-week period using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary assessment tool. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients.Intraoperatively, responder patients displayed immediate increased signs of energy and motivation upon stimulation at target. There was no significant mean change in mood during sham stimulation phase. Three of 4 patients had >50% decrease in MADRS scores at 7 days post-stimulation initiation relative to baseline. One patient withdrew from study participation. At 26 weeks, two of 3 remaining patients continue to have >80% decrease in MADRS scores. One patient failed to have response; evaluation of modulated fiber tracts revealed reduced frontal connectivity to the target region.This is an interim report, with limited conclusions.This study of MFB-DBS shows similar rapid anti-depressant effects within the first week of stimulation as initially reported by Schlaepfer et al. (2013). Implementation of anhedonia measurements would greatly augment characterization of the striking motivational effects observed. We urge others to pursue this target to further prove efficacy.ClinicalTrials.gov (identifier: NCT02046330) https://clinicaltrials.gov/ct2/show/NCT02046330

Novel Therapeutic Strategies in Major Depression: Focus on RNAi and Ketamine

Major depression is a severe psychiatric syndrome with very high prevalence and - socioeconomic impact. Despite extensive research, its pathophysiology is poorly understood, yet several neurotransmitter systems and brain areas have been implicated. The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline (NA) reuptake. These drugs evoke a series of neuronal adaptive mechanisms that limit their full clinical action, making necessary for many patients the use of augmentation strategies. In spite of such strategies, many depressed patients show limited or no improvement, which worsens their quality of life and increases the risk of suicide. Several novel observations in recent years have shaken the antidepressant field, by showing that depressed patients with severe treatment resistance can rapidly experience clinical remission. Hence, deep brain stimulation (DBS) of ventral anterior cingulate cortex (Cg25) evokes rapid mood improvements in treatment-resistant patients. Likewise, single doses of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine evoke rapid and long-lasting (up to 10 days) antidepressant responses in treatment-resistant patients. On the other hand, new molecular strategies aimed at modulating the expression of certain genes show great potential in the antidepressant field. In particular, RNAi strategies have been used to evoke antidepressant-like effects in laboratory animals by knocking-down the expression of genes involved in antidepressant effects, such as the serotonin transporter (SERT) or the 5-HT1A autoreceptor. Here we review these novel strategies due to their potential impact in the identification of new targets and the further development of new antidepressant drugs.

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses.

Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, ketamine can also produce psychotomimetic effects that limit its utility as an antidepressant, raising the question of whether the clinically tolerated NMDAR antagonist memantine possesses antidepressant properties. Despite its similar potency to ketamine as an NMDAR antagonist, clinical data suggest that memantine does not exert rapid antidepressant actions for reasons that are poorly understood. In this study, we recapitulate the ketamine and memantine clinical findings in mice, showing that ketamine, but not memantine, has antidepressant-like effects in behavioral models. Using electrophysiology in cultured hippocampal neurons, we show that ketamine and memantine effectively block NMDAR-mediated miniature excitatory postsynaptic currents in the absence of Mg(2+). However, in physiological levels of extracellular Mg(2+), we identified key functional differences between ketamine and memantine in their ability to block NMDAR function at rest. This differential effect of ketamine and memantine extends to intracellular signaling coupled to NMDAR at rest, in that memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2 or augment subsequent expression of BDNF, which are critical determinants of ketamine-mediated antidepressant efficacy. These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDAR-mediated neurotransmission that have impacts on downstream intracellular signaling, which we hypothesize is the trigger for rapid antidepressant responses. These data provide a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission as a critical determinant necessary to elicit rapid antidepressant responses.

Effet antidépresseur de la kétamine : revue de la littérature sur l’utilisation de la kétamine dans la dépression

Depressive disorders have a major impact on public health. They are prevalent and disabling, with high economic burden for society. Antidepressants have a delayed action and at least one third of patients do not achieve adequate response. The recent discovery of ketamine's unique antidepressant properties, with rapid onset of response and high rate of responders opens new perspectives for treatment-resistant depression (TRD). The aim of this article is to summarize preclinical trials and clinical trials demonstrating ketamine antidepressant properties and to review the different modalities of use. Most clinical studies used ketamine with a single subanesthetic intravenous administration in patients with treatment-resistant depression, demonstrating a rapid but transient antidepressant response with high response rates. To prevent relapse and maintain the initial benefits, few studies have shown the interest of serial infusions of ketamine, while others combined ketamine and electroconvulsive therapy using the former as an anesthetic. So far, relay treatments with glutamatergic agents such as riluzole are disappointing. Although most studies were conducted in patients with TRD in recurrent depression or bipolar disorder, efficacy in acutely suicidal patients is promising. Our review highlights the increasing interest in the use of ketamine in the treatment of treatment-resistant depression. Although a widespread use of ketamine as an antidepressant in routine clinical settings seems limited by psychotomimetic effects and the lack of strategy to maintain initial benefits, ketamine or related drugs might be used to target specific conditions, such as bipolar depression or high suicide risk.

Rapid Treatment Response of Suicidal Symptoms to Lithium, Sleep Deprivation, and Light Therapy (Chronotherapeutics) in Drug-Resistant Bipolar Depression

One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. We studied 143 consecutively admitted inpatients (December 2006-August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder.