Article

Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo–control study

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Abstract

Increasing evidence supports a rapid antidepressant and antisuicidal effect of a single subanesthetic dose of ketamine infusion for treatment-resistant depression (TRD). Maintaining the initial clinical response after ketamine infusion in TRD is a crucial next-step challenge. D-cycloserine (DCS), a partial agonist of the glycine co-agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, is potentially effective as a depression augmentation treatment. However, whether DCS maintains the antidepressant and antisuicidal effects of ketamine infusion remains unknown. In all, 32 patients with TRD (17 with major depression and 15 with bipolar depression) who responded to ketamine infusion with an average 17-item Hamilton Depression Rating Scale (HAMD) score of 9.47 ± 4.11 at baseline were randomly divided to 6-week DCS treatment (250 mg for 2 days, 500 mg for 2 days, 750 mg for 3 days, and 1000 mg for 5 weeks) and placebo groups. Depression symptoms were rated at timepoints of dose titration and weekly. During the 6-week treatment, the total scores of HAMD did not differ between the DCS and placebo groups. The results remained consistent when stratified by disorder. A mixed model analysis indicated that the DCS group exhibited lower scores of HAMD item 3 (suicide) compared with the placebo group throughout the follow-up period (p = 0.01). A superior maintenance of the antisuicidal effect of ketamine was observed in the DCS group than in the placebo group. DCS may be therapeutically beneficial for patients with TRD who responded to ketamine infusion but have a residual suicidal risk.

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... Current clinical evidence also supports the rapid antidepressant effect of low-dose ketamine in patients with TRD. More than 60% of Caucasian patients and approximately half of Taiwanese patients respond to a single ketamine infusion, with transient adverse effects of dizziness, hypertension, and dissociation (Chen et al., 2019, Su et al., 2017, Murrough et al., 2013, Zarate et al., 2006. After the rapid antidepressant effect of ketamine infusion was established, researchers attempted to clarify predictive factors for the response to ketamine infusion (Vidal et al., 2018, Pennybaker et al., 2017. ...
... Details for candidates enrolled in the study and experimental procedures have been reported in our two previous clinical trial articles (Chen et al., 2019, Su et al., 2017. In the clinical trial 1 of our previous double-blind, randomized, placebo-control study, patients with TRD were randomized to three treatment groups, namely ketamine 0.5mg/kg (n=24), 0.2mg/kg (n=23), and normal saline placebo (n=24) (Su et al., 2017). ...
... In the clinical trial 1 of our previous double-blind, randomized, placebo-control study, patients with TRD were randomized to three treatment groups, namely ketamine 0.5mg/kg (n=24), 0.2mg/kg (n=23), and normal saline placebo (n=24) (Su et al., 2017). Clinical trial 2 included two phases: phase I study was an open-label trial of two ketamine infusions in TRD and phase II study was a double-blind, randomized, placebo-control trial of D-cycloserine in the maintenance of antidepressant effects after ketamine infusion (Chen et al., 2019). In the phase I study of clinical trial 2, patients with TRD (n=49) received single ketamine infusions of 0.5 mg/kg at Day 1 and Day 4 for the greater response rate (Chen et al., 2019). ...
Article
Background: Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. Methods: The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. Results: The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Discussion: Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. Clinical trial registration: UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).
... This second trial suggested that the antagonistic properties of D-cycloserine begin at a higher dose than expected in the first trial, probably above the level of 500 mg/day. In another trial, 32 patients with TRD (17 with MDD and 15 with bipolar depression) who responded to ketamine infusion with an average 9.47 ± 4.11 HAMD score at baseline were randomly divided into 6-week D-cycloserine treatment versus placebo (Chen et al., 2019). During the 6-week treatment, the total HAMD scores did not differ between the two groups, but a potential effect of D-cycloserine over suicide ideation/behavior was identified by mixed model analysis throughout the follow-up period (Chen et al., 2019). ...
... In another trial, 32 patients with TRD (17 with MDD and 15 with bipolar depression) who responded to ketamine infusion with an average 9.47 ± 4.11 HAMD score at baseline were randomly divided into 6-week D-cycloserine treatment versus placebo (Chen et al., 2019). During the 6-week treatment, the total HAMD scores did not differ between the two groups, but a potential effect of D-cycloserine over suicide ideation/behavior was identified by mixed model analysis throughout the follow-up period (Chen et al., 2019). ...
Article
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Many investigational drugs with antidepressant activity are currently explored in different phases of clinical research, with indications such as major depressive disorder, treatment-resistant major depression, bipolar depression, post-partum depression, and late-life depression. Although the vast majority of the antidepressants in clinical use are based on the monoaminergic hypothesis of depression, recent data supported the launching on the market of two new, non-monoamine-modulating drugs. Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians’ reluctance to prescribe new drugs, and patients’ reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of monoamine-modulating antidepressants, that new pathogenetic pathways should be targeted to increase the response rate in this population.
... Participants and study procedure. Details for candidates enrolled in the study and experimental procedures have been reported in our previous articles (Chen et al., 2019;Su et al., 2017). In Fig. 1, we illustrated the study sample (n = 78) from a randomized, double-blind, placebo-controlled trial (n = 48) and an open-label trial (n = 30) for the current analysis. ...
... In the randomized, double-blind, placebo-controlled trial, patients were only randomized to a single 40-min infusion of 0.5 mg/kg ketamine or normal saline at baseline (day1). In the open-label trial, patients were administrated with two 40-min infusions of 0.5 mg/kg ketamine at day 1 and day 4, respectively (Chen et al., 2019;Su et al., 2017). MRD was defined as failure of treatment response to at least two different antidepressants with adequate dosage and treatment duration (Su et al., 2017). ...
Article
Background Whether a second ketamine infusion in the first week improves the antidepressant, antisuicidal, and anti-inflammatory effects of the first low-dose ketamine infusion remains unclear. Methods A total of 78 patients with medication-resistant depression were allocated to receive two ketamine infusions (n = 30; days 1 and 4), a single ketamine infusion (n = 24; only day 1), or normal saline placebo infusion (n = 24; only day 1). The Montgomery-Asberg Depression Scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HDRS) were administered before and at 40 min, 240 min, day 2, day 4, day 5, and day 7 after infusion. Serum concentrations of interleukin (IL)-2 and tumor necrosis factor (TNF)-α were assessed. Results Two ketamine infusions improved the overall depressive symptoms (p < 0.001) and melancholic symptoms (p < 0.001) than a single ketamine or placebo infusion. The antisuicidal effect did not differ between the ketamine treatment groups. Two ketamine infusions increased TNF-α levels compared with a single ketamine or placebo infusion (p = 0.015). A single ketamine infusion improved the TNF-α-to-IL-2 ratio, an index of average anti-inflammatory effect, than two ketamine infusions or a single placebo infusion (p = 0.027). Discussion Repeated low-dose ketamine infusions improved the antidepressant effect, but not the antisuicidal effect, compared with a single infusion. However, repeated ketamine infusions may exert a lesser anti-inflammatory effect than a single infusion.
... The superior anti-suicidal effect of ketamine in the D-cycloserine group was maintained, which suggests that D-cycloserine may be therapeutically beneficial for patients with TRD who have a good initial response to ketamine infusion. 35 ...
... Considering that all these studies have addressed depression as it is currently classified, clinical trials with more homogenous samples, both in terms of clinical and biological characteristics, with appropriate designs, could optimize intervention efficacy. 64 Box 1 Potential pharmacological and non-pharmacological strategies for treatment-resistant bipolar depression Type of intervention Mechanism of action or regions of stimulation Pharmacological Aripiprazole Partial agonist of D2, D3, D4, 5-HT1A, 5-HT2C, and 5-HT7 receptors 31 D-cycloserine Partial agonist at the glycine recognition of the NMDA receptor 35 Ketamine NMDA receptor antagonist 34 Lurasidone ...
Article
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Treatment-resistant bipolar depression (TRBD) has been reported in about one-quarter of patients with bipolar disorders, and few interventions have shown clear and established effectiveness. We conducted a narrative review of the published medical literature to identify papers discussing treatment-resistant depression concepts and novel interventions for bipolar depression that focus on TRBD. We searched for potentially relevant English-language articles published in the last decade. Selected articles (based on the title and abstract) were retrieved for a more detailed evaluation. A number of promising new interventions, both pharmacological and non-pharmacological, are being investigated for TRBD treatment, including ketamine, lurasidone, D-cycloserine, pioglitazone, N-acetylcysteine, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cyclooxygenase 2 inhibitors, magnetic seizure therapy, intermittent theta-burst stimulation, deep transcranial magnetic stimulation, vagus nerve stimulation therapy, and deep brain stimulation. Although there is no consensus about the concept of TRBD, better clarification of the neurobiology associated with treatment non-response could help identify novel strategies. More research is warranted, mainly focusing on personalizing current treatments to optimize response and remission rates.
... It should be noted that no DCS replication studies have been reported since that initial finding, nor have biomarker/ target engagement studies demonstrated the therapeutic relevance of glycine-site antagonism with regard to the effectiveness of DCS in treating depressive symptoms. However, in a recent 6-week study of TRD participants, Chen and colleagues found that although DCS demonstrated no initial effectiveness as an augmentation agent compared with placebo, it maintained the antidepressant and antisuicidal effects of low-dose ketamine (Chen et al., 2019). ...
Article
Background: Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. 7-chlorokynurenic acid (7-Cl-KYNA) is a potent and specific glycine site N-methyl-d-aspartate (NMDA) receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN) exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression (TRD). Methods: After a two-week drug-free period, 19 participants with TRD were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1,080mg/day for seven days, then 1,440mg/day for seven days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was Hamilton Depression Rating Scale (HAM-D) score, assessed at several time points over a two-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-Cl-KYNA and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy (MRS) brain glutamate levels, resting-state functional magnetic resonance imaging (rsfMRI), and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. Results: Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. Conclusions: In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied.
... Potential antidepressant effects of DCS were first reported in 1959 (16) but not formally studied until recently. Efficacy of DCS in a dose of >500 mg in MDD, including an anti-suicidal effect, is supported by two double-blind studies (15,17). Recently, we reported an open label study of treatment resistant BP-D-a single infusion of ketamine followed by 8 weeks of a combination of DCS + FDA approved medications for BP-D (including lurasidone). ...
Article
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N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy ( ¹ H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D -cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three ¹ H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = −0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.
... 18 to ketamine or other agents. A recent randomized trial of 32 patients with treatment-resistant unipolar or bipolar depression who responded to two open-label ketamine infusions showed that maintenance-phase treatment with adjunctive d-cycloserine (titrated to 1,000 mg daily) over six weeks resulted in lower scores on the 17-item Hamilton Depression Rating Scale (HAMD) (32) suicide item (item 3) than adjunctive placebo (33). However, the D-cycloserine and placebo maintenance groups did not differ significantly with respect to total depression severity scores, both overall and in separate analyses of participants with major depressive disorder and with bipolar disorders. ...
Article
Numerous short-term randomized trials support the acute-phase efficacy of low-dose intravenous (IV) ketamine for patients with treatment-resistant unipolar or bipolar depression. Ketamine's antidepressive effects generally have limited duration, highlighting the need for maintenance treatment after an acute-phase response. It is increasingly likely that psychiatrists will be called upon to manage the care of patients with treatment-resistant unipolar or bipolar depression who have responded acutely to ketamine and to recommend or initiate next-step treatments. However, there is a paucity of controlled evidence to guide best practices for managing treatment of patients with treatment-resistant unipolar or bipolar depression who have had a positive initial response to ketamine. This article reviews the available evidence supporting specific strategies for extending and maintaining acute antidepressive responses to low-dose IV ketamine in patients with treatment-resistant unipolar or bipolar depression and provides some preliminary considerations for clinical practice.
... Because a single intravenous infusion of ketamine as proof-of-concept design was used in most RCTs, the results from the studies could not be directly applied to clinical practice. Protocols for dose-titration, tapering, and maintenance regimens were lacking (Loo, 2018), and until recently, investigators focused on maintenance treatment after intravenous ketamine infusion (Chen et al., 2019a). In addition, most of the earlier RCTs were conducted within a short time period (e.g., several days). ...
Article
Ketamine was initially used as an anesthetic which could induce cognitive impairment and psychomimetic effects. In initial randomized controlled trials (RCTs) that mostly included a small sample size and were investigator-initiated, ketamine reportedly exerted antidepressant effects 1 to 2 h after a single intravenous infusion in patients with major depressive episodes, particularly treatment-resistant depression (TRD). Interest in ketamine was reported in systematic reviews and meta-analyses, however, many were primarily focused on the rapid onset of ketamine effects without equal attention to its safety and tolerability. Furthermore, several meta-analyses were based on many duplicated RCTs. The initial trends emphasized the clinical utility of ketamine as an antidepressant. The development of esketamine nasal spray by a pharmaceutical company led to an RCT with a large sample size and segmented therapeutic strategy, which provided results applicable to patients with TRD in the real-world clinical environment. However, possible effects of ketamine on cognitive function have not yet been investigated in RCTs. In numerous studies, chronic, recreational use of ketamine reportedly substantially impaired cognitive function in most domains. Although results of several human and animal studies indicated the therapeutic use of ketamine for treatment of depression did not induce cognitive impairment, this issue should be further investigated. Based on the current knowledge about ketamine, future antidepressants are expected to be glutamatergic drugs without ketamine-like adverse events (e.g., psychomimetic symptoms and cognitive impairment), but having only ketamine-like therapeutic properties (e.g., rapid antidepressants effects without time lag).
... D-cycloserine is a partial agonist at the glycine site of the NMDAR and has been shown to have pro-plasticity effects in preclinical models and in clinical studies 34,35 . However, d-cycloserine administration following a single ketamine infusion failed to extend antidepressant durability in a recent study (but did extend the durability of anti-suicidal effects) 36 . A similar lack of effect on ketamine' antidepressant durability has also been shown in 2 studies that used NMDAR antagonist riluzole after a ketamine infusion 37,38 . ...
Preprint
Background: Ketamine is a rapid-acting treatment for patients with treatment refractory depression (TRD), however treatment responses are often transient and ketamine's antidepressant action lacks robust clinical durability. Little is known about which patient characteristics are associated with faster or more durable ketamine responses. Ketamine's antidepressant mechanism is proposed to involve modulation of glutamatergic signaling leading to long term potentiation (LTP) and synaptogenesis, and these neuroplasticity pathways have been shown to be attenuated with older age. We therefore investigated the impact of patient age on the speed and durability of ketamine's antidepressant effects in veterans receiving serial intravenous ketamine infusions for TRD. Methods: Beck Depression Inventory (BDI-II) scores from 49 veterans receiving six ketamine infusions (twice weekly) were examined from a retrospective case series. Percent change in BDI-II scores across the infusion series were assessed with respect to patient age using a mixed-linear model. Follow-up analyses examined the age x infusion number interaction effect at each assessment time point. To assess treatment durability, BDI-II change scores three weeks following the sixth infusion were correlated with age. Results: There was a significant age x infusion number interaction (F=3.01, p=.0274) across the six infusions. Beta estimates at each infusion showed a significant effect of age at infusion #4 (B=.88% +/-.29%, t=3.02, p=.004) and a trend towards significance at infusion #5 (B=.62% +/-.31%, t=1.95, p=.057). There was no significant correlation between percent change in BDI-II and age at three-week follow-up. Conclusions: Older age is associated with an altered trajectory of antidepressant response across serial ketamine infusions, with a model-predicted difference of 8.8% less improvement in BDI-II score for each decade in age mid-way through the infusion course. In contrast, antidepressant durability at three-week follow-up was not related to age. These data suggest age is an important moderating factor of patient response to ketamine, and that differing mechanisms may underlie speed and durability of ketamine's antidepressant activity.
... The mechanism of action is based on binding with high affinity to the glycine site of the NMDA receptor; therefore, the drug has characteristics of a selective partial NMDA agonist [142]. The potential antidepressant properties of D-cycloserine were evaluated in a number of neuropsychiatric studies [143][144][145][146]. In a crossover RCT in patients with treatmentresistant MDD, symptom reduction was observed after administration of D-cycloserine (add-on therapy to various stable psychotropic medications) at a dose of 250 mg/day, but there were no significant differences between D-cycloserine and placebo [143]. ...
Article
Introduction Recently, a considerable attention has been paid to glutamatergic conception of mood disorders. The development of new treatment strategies targeted at glutamate provides new opportunities for the treatment of mood disorders. It is expected that these novel therapeutic options will provide a fast and sustained antidepressant effect and will be better tolerated by patients than the currently available antidepressants. Areas covered This paper discusses glutamatergic abnormalities in mood disorders and reviews novel glutamate-based drugs developed for the treatment of these disorders. We have searched the PubMed and EMBASE databases, presented the results of relevant clinical studies and also describe novel glutamate-based agents that are under investigation. Expert opinion The glutamatergic system plays many important roles in energy metabolism of the brain and neurotransmission; therefore, any attempt to identify novel therapeutic targets within this system seems justified. The effective development of new glutamate-based drugs requires, among others, a more in-depth exploration and understanding of the anatomy, function, and localization of different glutamatergic receptors in the brain. In our opinion, novel glutamate-based antidepressants will find application in the treatment of mood disorders and present an option will be widely used in clinical practice in the future.
... Racemic ketamine can also rapidly reduce suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation (Reinstatler and Youssef, 2015;López-Díaz et al., 2017;Grunebaum et al., 2018;Wilkinson et al., 2018;Williams et al., 2019;Witt et al., 2020). While these findings are mostly limited to unipolar depression, some emerging studies point to the efficacy of ketamine for bipolar significant depression Grunebaum et al., 2017;Chen et al., 2019). Racemic ketamine has also led to many preclinical and biomarker discoveries (Zanos et al., 2016;Zanos and Gould, 2018), leading to new possibilities in safer alternatives to mitigate dissociation and reduce the propensity for misuse and diversion of ketamine (Newport et al., 2015;Burger et al., 2016;Lener et al., 2017). ...
Article
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Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, the efficacy in bipolar depression is less clear. Objectives: This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression. Methods: We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since database inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies. Findings: We identified six studies, with 135 participants (53% female, 44.7 years, SD 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from one to six; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well-tolerated; however, two participants (one receiving ketamine and one receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in two trials. Conclusions: There is some preliminary evidence for intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.
... Its antidepressant properties have been demonstrated in a clinical trial setting among 26 TRD adults (298), although no replication or biomarker studies have been published since then. Recently, however, DCS has been tested as an augmentation treatment and has been shown to maintain antidepressant and antisuicidal effects of ketamine in TRD patients, although with no efficacy as a monotherapy (299). A new line of neurophysiological research is under development, where DCS administration is paired with neurostimulation techniques, such as rTMS, to investigate its effects on synaptic plasticity in the nodes of the SMN among depressed patients (168,300,301). ...
Article
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Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of non-response. To address these challenges, preclinical and clinical studies have sought to characterize antidepressant response through monoamine-independent mechanisms. One striking example is glutamate, the brain's foremost excitatory neurotransmitter: since the 1990s, studies have consistently reported altered levels of glutamate in MDD, as well as antidepressant effects following molecular targeting of glutamatergic receptors. Therapeutically, this has led to advances in the discovery, testing, and clinical application of a wide array of glutamatergic agents, particularly ketamine. Notably, ketamine has been demonstrated to rapidly improve mood symptoms, unlike monoamine-based interventions, and the neurobiological basis behind this rapid antidepressant response is under active investigation. Advances in brain imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, enable the identification of the brain network-based characteristics distinguishing rapid glutamatergic modulation from the effect of slow-acting conventional monoamine-based pharmacology. Here, we review brain imaging studies that examine brain connectivity features associated with rapid antidepressant response in MDD patients treated with glutamatergic pharmacotherapies in contrast with patients treated with slow-acting monoamine-based treatments. Trends in recent brain imaging literature suggest that the activity of brain regions is organized into coherent functionally distinct networks, termed intrinsic connectivity networks (ICNs). We provide an overview of major ICNs implicated in depression and explore how treatment response following glutamatergic modulation alters functional connectivity of limbic, cognitive, and executive nodes within ICNs, with well-characterized anti-anhedonic effects and the enhancement of “top-down” executive control. Alterations within and between the core ICNs could potentially exert downstream effects on the nodes within other brain networks of relevance to MDD that are structurally and functionally interconnected through glutamatergic synapses. Understanding similarities and differences in brain ICNs features underlying treatment response will positively impact the trajectory and outcomes for adults suffering from MDD and will facilitate the development of biomarkers to enable glutamate-based precision therapeutics.
... A total of ten RCTs and eight open-label trials ( Table 1) were identified that assessed the extension of racemic IV ketamine's antidepressant effect using a pharmacological intervention (i.e., clonidine, D-cycloserine, lamotrigine, lithium, rapamycin, riluzole; k = 5), psychotherapy (i.e., cognitive behavioral therapy [CBT]; k = 1), electroconvulsive therapy (ECT) (k = 1), or IV ketamine monotherapy (k = 9). The majority of prospective studies (12/18) included repeat ketamine infusions [12,13,[22][23][24][25][27][28][29][30][31][32]. ...
Article
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Introduction: Ketamine treatment is capable of significant and rapid symptom improvement in adults with treatment-resistant depression (TRD). A limitation of ketamine treatment in TRD is the relatively short duration of time to relapse (e.g., median 2-4 weeks). The objective of the systematic review herein is to identify strategies capable of prolonging the acute efficacy of ketamine in adults with TRD. Methods: PubMed/MEDLINE databases were searched from inception to December 2020 for clinical studies written in English using the following key terms: ketamine, prolong, and depression. A total of 454 articles were identified from the literature search which included all clinical studies regarding prolonging the antidepressant effects of ketamine. Twenty-two articles were included: ten randomized controlled trials (RCTs), eight prospective open-label trials, one retrospective chart review, and three case reports. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data extraction. The primary outcome was prolonged effect, defined as statistically significant antidepressant effects following acute ketamine treatment. Results: A total of 454 articles were identified, and 22 articles were included. Different treatment modalites including pharmacological interventions, manualized-based psychotherapies, electroconvulsive therapy, transcranial magnetic stimulation, and intravenous monotherapy were examined to determine their impact on the prolongation of antidepressant effects following acute ketamine treatment. No treatment modality, other than repeat-dose IV ketamine, has demonstrated ability to significantly prolong the acute efficacy of IV ketamine in TRD. Conclusion: Hitherto, available open-label data and controlled trial data support repeat administration of IV ketamine as an effective strategy to prolong the efficacy of ketamine's antidepressant effects (although not the focus of the study herein, maintenance repeat-dose esketamine treatment is proven effective in esketamine responders). There is a need to identify multimodality strategies that are safe and capable of prolonging the efficacy of ketamine in adults with TRD.
... These findings suggest a hypothetical model of mood disorders whereby deficient GABAergic inhibition of the cortical glutamatergic system results in its overactivity. This model is supported by treatment studies showing that NMDAR antagonists, such as ketamine and D-cycloserine (DCS), have antidepressant benefit in both MDD [9][10][11] and BPD [12,13]. Moreover, some GABA agonists show promise as antidepressants [14]. ...
Article
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Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy ( ¹ H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using ¹ H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.
Article
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RationaleKetamine is a novel, rapid-acting antidepressant for treatment refractory depression (TRD); however, clinical durability is poor and treatment response trajectories vary. Little is known about which patient characteristics predict faster or more durable ketamine responses. Ketamine’s antidepressant mechanism may involve modulation of glutamatergic signaling and long-term potentiation (LTP); these neuroplasticity pathways are also attenuated with older age.ObjectiveA retrospective analysis examining the impact of patient age on the speed and durability of ketamine’s antidepressant effects in 49 veterans receiving serial intravenous ketamine infusions for TRD.Method The relationship between age and percent change in Beck Depression Inventory (BDI-II) scores was compared across six serial ketamine infusions (twice-weekly for 3 weeks) using a linear-mixed model.ResultsA significant Age-X-Infusion number interaction (F = 3.01, p = .0274) indicated that the relationship between age and treatment response depended on infusion number. Follow-up tests showed that younger age significantly predicted greater clinical improvement at infusion #4 (t = 3.02, p = .004); this relationship was attenuated at infusion #5 (t = 1.95, p = .057) and was absent at infusion #6. Age was not a significant predictor of treatment durability, defined as percent change in BDI-II 3 weeks following infusion #6.Conclusions These data preliminarily suggest that younger age is associated with a faster response over six serial ketamine infusions; by infusion #6 and subsequent weeks of clinical follow-up, age no longer predicts ketamine’s antidepressant activity. Age may mediate the speed but not the durability or total efficacy of ketamine treatment, suggesting that dissociable mechanisms may underlie differing aspects of ketamine’s antidepressant activity.
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In many countries suicide rates have been trending upwards for close to twenty years-presenting a public health crisis. Most suicide attempts and deaths are associated with psychiatric illness, usually a depressive disorder. Subanesthetic ketamine is the only FDA-approved antidepressant that works in hours not weeks-thus potentially transforming treatment of suicidal patients. We reviewed all randomized controlled trials of the effect of ketamine on suicidal ideation to determine if ketamine rapidly reduces suicidal ideation [SI] in depressed patients and how long the benefit persists after one dose and if the route of administration or dose affects the outcome. A systematic review was conducted as per PRISMA [preferred reporting items for systematic reviews and meta-analyses] criteria. PubMed search inclusive of "ketamine" and "suicide" yielded 358 results. Papers (N = 354) were then read by at least two authors, identifying 12 meeting eligibility requirements and eleven RCTs examining whether ketamine treatment ameliorated SI. Four of five RCTs examined racemic ketamine (0.5 mg/kg) given intravenously and found an advantage for ketamine over control for rapid reduction in SI in acutely depressed patients. Two studies examined intranasal esketamine in depressed suicidal patients and found no advantage over saline. One study examined outcome six weeks after a single intravenous dose of ketamine and found benefit for SI sustained relative to 24 h post-dose. Further research is warranted into: optimal dosing strategy, including number and frequency; and long-term efficacy and safety. Ultimately, it remains to be shown that ketamine's benefit for SI translates into prevention of suicidal behavior.
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Increasing evidence indicate that dysfunction of glutamate receptors is involved in the pathophysiology of major depressive disorder (MDD). Although accumulating evidence focus on the applications and mechanisms underlying antidepressant-like effects of ketamine, a non-selective antagonist of N-methyl-d-aspartate receptor (NMDAR), the role of specific glutamate receptor subunit in regulating depression is not completely clear. The current review aims to discuss the relationships between glutamate receptor subunits and depressive-like behaviors. Research literatures were searched from inception to July 2020. We summarized the alterations of glutamate receptor subunits in patients with MDD and animal models of depression. Animal behaviors in response to dysfunction of glutamate receptor subunits were also surveyed. To fully understand mechanisms underlying antidepressant-like effects of modulators targeting glutamate receptors, we discussed effects of each glutamate receptor subunit on serotonin system, synaptic plasticity, neurogenesis and neuroinflammation. Finally, we collected most recent clinical applications of glutamate receptor modulators and pointed out the limitations of these candidates in the treatment of MDD.
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Deep brain stimulation (DBS) is a very well-established and effective treatment for patients with extrapyramidal diseases. Despite its generally favorable clinical efficacy, some undesirable outcomes associated with DBS have been reported. Among such complications are incidences of suicidal ideation (SI) and behavior (SB) in patients undergoing this neurosurgical procedure. However, causal associations between DBS and increased suicide risk are not demonstrated and they constitute a debated issue. In light of these observations, the main objective of this work is to provide a comprehensive and unbiased overview of the literature on suicide risk in patients who received subthalamic nucleus (STN) and internal part of globus pallidum (GPi) DBS treatment. Additionally, putative mechanisms that might be involved in the development of SI and SB in these patients as well as caveats associated with these hypotheses are introduced. Finally, we briefly propose some clinical implications, including therapeutic strategies addressing these potential disease mechanisms. While a mechanistic connection between DBS and suicidality remains a controversial topic that requires further investigation, it is of critical importance to consider suicide risk as an integral component of candidate selection and post-operative care in DBS.
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Rationale Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment. Objectives Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks. Methods The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment. Results The present meta-analysis observed large effects at 2 weeks (g = −1.28), 4 weeks, (g = −1.28), and 6 weeks (g = −1.36) post-treatment. Conclusions The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.
Article
INTRODUCTION : Research into the pharmacologic management of bipolar type I illness continues to progress. AREAS COVERED Randomized clinical trials performed with type I bipolar disorder in the years 2015 – August 2020 are reviewed. There are new indications for the use of cariprazine, for bipolar mania and depression, and a long-acting injectable formulation of aripiprazole has also been approved for relapse prevention in bipolar illness. Most of the randomized clinical trials are effectiveness studies. EXPERT OPINION Over the 20 years from 1997 through 2016, the use of lithium and other mood stabilizers has declined by 50%, while the use of both second-generation antipsychotics (SGAs) and antidepressants has increased considerably. Over the same time period (1990 – 2017), disability-adjusted life years (DALYs) increased by 54.4%, from 6.02 million in 1990 to 9.29 million in 2017 which is greater than the 47.74% increase in incidence of the disease, suggesting that the changes in prescribing patterns have not been helpful for our patients. Furthermore, recent effectiveness studies continue to confirm the superiority of lithium and other mood stabilizers in the management of bipolar illness for both psychiatric and medical outcomes, reaffirming their role as foundational treatments in the management of type I bipolar disorder.
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Bipolar affective disorder is a relatively common psychiatric disorder that affects millions of people worldwide. Existing antidepressants and mood stabilizers used to treat it are not always sufficient for all patients and typically depression in patients with bipolar disorder (BD) is not well responding to antidepressants. Glutamate is the major excitatory neurotransmitter of the CNS and is present in more than 50% of nerve tissue. The relationship between glutamatergic dysfunction and the pathophysiology of depression either unipolar or bipolar has been documented over the past 20 years. Although the first clinical trial investigating ketamine’s potential antidepressant effect was conducted approximately 25 years ago, and the relevant literature is relatively limited, new pharmaceutical agents targeting the glutamatergic system are under investigation. The glutamate hypothesis of etiology of mood disorders is expected to complement and improve the prevailing monoamine hypothesis and may indicate novel therapeutic targets. There are currently few pharmacological agents that act on the glutamatergic system and have been approved for the treatment of bipolar disorder. In fact, only S-Ketamine has been recently approved (2019) in the United States FDA from March 2019. Current research is Focused on: a) broad glutamatergic modulators such as ketamine, S-ketamine, dextromethorphan, AVP-786, nitric oxide (N2O), AZD6765, b) N-methyl-d-aspartate (NMDA) specific subunit receptor antagonists (NR2B) such as CP-101,606, MK-0657 (CERC-301), c) some NMDA receptor glycine site agonists such as d-cycloserine (Chen et al. 2019), GLYX-13, sarcosine, AV-101,d) d) metabotropic glutamate receptors (mGluRs) modulators such as AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819). There are even other potentially interesting targets of the glutamate receptor with preclinical antidepressant-like efficacy, including AMPA agonists (for example, CX-691/ORG 2448 and ORG-26576) as well as mGluR agonists (Fountoulakis et al. 2012a, b). Τhe range of spectrum of the above recent findings dictates most intensive and targeted study based on both preclinical and clinical studies of agents that influence the glutamatergic system with the aim of developing new effective therapies for bipolar disorder.
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Despite the important advances in the understanding of the pathophysiology of MDD, a large proportion of depressed patients do not respond well to currently available pharmacological agents. The present review focuses on new targets and future directions in the pharmacological treatment of MDD. Novel agents and their efficacy in the treatment of depression are discussed, with a focus on the respectively target pathophysiological pathways and the level of available evidence. Although it is expected that classic antidepressants will remain the cornerstone of MDD treatment, at least for the near future, a large number of novel compounds is currently under investigation as for their efficacy in the treatment of MDD, many of which with promising results.
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Background Whether a single low-dose ketamine infusion may have rapid antidepressant and antisuicidal effects in patients with treatment-resistant double depression remains unclear. Methods This study enrolled 35 patients with treatment-resistant double depression, 12 of whom received 0.5 mg/kg ketamine, 11 received 0.2 mg/kg ketamine, and 12 received normal saline as a placebo. The patients were assessed using the 17-item Hamilton Rating Scale for Depression (HDRS) prior to the initiation of infusions, at 40 and 240 min post-infusion, and sequentially on Days 2–7 and on Day 14 after ketamine or placebo infusions. Results A single 0.5 mg/kg ketamine infusion had rapid antidepressant (p = 0.031, measured by the HDRS) and antisuicidal (p = 0.033, measured by the HDRS item 3 scores) effects in patients with treatment-resistant double depression. However, 0.2 mg/kg ketamine was insufficient to exert rapid antidepressant and antisuicidal effects in this patient population with severe and chronic illness. Discussion In this patient population, the commonly used dose of 0.5 mg/kg was sufficient. Additional studies are required to investigate whether repeated infusions of low-dose ketamine may also maintain antidepressant and antisuicidal effects in patients with treatment-resistant double depression.
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Severe psychiatric condition, including major unipolar depression (MDD) and post-traumatic stress disorders (PTSD), are characterized by a strong comorbidity with suicide ideations and attempts. Predictors of suicide risk in humans include impulsivity and aggressiveness, which can be reproduced in rodents by aggressive behavior using the resident-intruder test and other behavioral tests that measure the impulsivity, irritability, and hopelessness of rodents. Animal models of behavioral traits of suicide in humans provide means to better understand the neurobiology of suicidal behavior, as well as they help to understand neural mechanisms and circuits underlying suicide. The search for biomarker-tailored therapies against suicide is urgently needed. Neurosteroid biosynthesis modulates emotional state and stress response and evidence shows that its downregulation during pathophysiological conditions underlays rapid changes in mood and may result in affective disorders. Similarly, several lines of preclinical and clinical evidence suggest that these neuromodulators may underlay suicidal risk and thereby may offer valuable biomarkers. Hereinafter, we analyze animal model approaches that reproduce suicidal-like behaviors in rodents and we highlight findings on the role of neurosteroid biosynthesis in suicidal behavior observed in stress-models of PTSD/suicide in humans.
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Bipolar spectrum disorders carry a significant public health burden. Disproportionately high rates of suicide, incarceration, and comorbid medical conditions necessitate an extraordinary focus on understanding the intricacies of this disease. Elucidating granular, intracellular details seems to be a necessary preamble to advancing promising therapeutic opportunities. In this chapter, we review a wide range of intracellular mechanisms including mitochondrial energetics, calcium signaling, neuroinflammation, the microbiome, neurotransmitter metabolism, glycogen synthase kinase 3-beta (GSK3β), protein kinase C (PKC) and diacylglycerol (DAG), and neurotrophins (especially BDNF), as well as the glutamatergic, dopaminergic, purinergic, and neurohormonal systems. Owing to the relative lack of understanding and effective therapeutic options compared to the rest of the spectrum, special attention is paid in the chapter to the latest developments in bipolar depression. Likewise, from a therapeutic standpoint, special attention should be paid to the pervasive mechanistic actions of lithium as a means of amalgamating numerous, disparate cascades into a digestible cognitive topology.
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Ethnopharmacological relevance Baihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years. Aim of the study LBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron. Materials and methods In this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization. Results In the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144–3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144–3p expression. Conclusions These findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144–3p mediated GABA synthesis and release.
Article
What is known and objective Esketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist, which has stronger sedative and analgesic effects and fewer adverse events than ketamine. The effects of low-dose esketamine on haemodynamics and postoperative quality of recovery in elderly patients have not been evaluated. To evaluate whether low-dose esketamine can be safely used for anaesthesia induction in the elderly. Methods Eighty elderly patients were selected for unilateral total knee replacement under general anaesthesia from February 2021 to August 2021. Patients were randomly divided into two groups (n = 40): control group (C group) and esketamine group (K group). During induction of anaesthesia, the control group was intravenously injected with normal saline of equal volume, and the esketamine group was intravenously injected with 0.2-mg/kg esketamine. Both groups were induced by etomidate, sufentanil and rocuronium and maintained by combined intravenous and inhaled anaesthesia during operation. Main outcome measures HR, SBP, DBP, MAP and BIS values were recorded before induction of anaesthesia (T0), immediately before endotracheal intubation (T1), 1min(T2) and 5min(T3) after endotracheal intubation, surgical skin incision (T4), 1min(T5) and 5min(T6) after surgical skin incision. Results Compared with the C group, SBP, DBP, MAP, HR and BIS of the K group were significantly higher at T1-T3 (p < 0.05). There were no significant differences in SBP, DBP, MAP, HR and BIS between the two groups at T4-T6 (p > 0.05). Compared with T0, SBP, MAP and BIS values of the two groups at T1-T6 were decreased (p < 0.05). DBP of the K group at T2 was not significantly different from DBP at T0 (p < 0.05), but DBP of the C group decreased from T1 to T6 (p < 0.05). Compared with T0, HR in both groups decreased at T1, T3, T4, T5 and T6 (p < 0.05). Compared with the C group, the incidence of cough in the K group was significantly lower (p < 0.05); There was no significant difference in the number of myoclonus during induction between the two groups (p > 0.05). Compared with the C group, the number of hypotension episodes in the K group during induction was much smaller (p < 0.05). There were no significant differences in the incidence of hypertension, bradycardia and tachycardia (p > 0.05). There were no significant differences in postoperative recovery quality and incidence of adverse events between the two groups (p > 0.05). What is new and conclusion Low-dose esketamine for anaesthesia induction in the elderly undergoing knee arthroplasty may better maintain the stability of haemodynamics and has no adverse effect on the quality of early recovery after operation.
Article
Background: Racemic ketamine and esketamine have demonstrated rapid antidepressant effects. We aimed to review the efficacy and safety of racemic and esketamine for depression. Research design and methods: We conducted a PRISMA-guided review for relevant randomized controlled trials of racemic or esketamine for unipolar or bipolar major depression from database inception through 2021. We conducted random-effects meta-analyses using pooled rate ratios (RRs) and Cohen's standardized mean differences (d) with their 95% confidence intervals (CI). Results: We found 36 studies (2903 participants, 57% female, 45.1 +/- 7.0 years). Nine trials used esketamine, while the rest used racemic ketamine. The overall study quality was high. Treatment with any form of ketamine was associated with improved response (RR=2.14; 95% CI, 1.72-2.66; I2=65%), remission (RR=1.64; 95% CI, 1.33-2.02; I2=39%), and depression severity (d=-0.63; 95% CI, -0.80 to -0.45; I2=78%) against placebo. Overall, there was no association between treatment with any form of ketamine and retention in treatment (RR=1.00; 95% CI, 0.99-1.01; I2<1%), dropouts due to adverse events (RR=1.56; 95% CI, 1.00-2.45; I2<1%), or the overall number of adverse events reported per participant (OR=2.14; 95% CI, 0.82-5.60; I2=62%) against placebo. Conclusions: Ketamine and esketamine are effective, safe, and acceptable treatments for individuals living with depression.
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Objective: Subanesthetic ketamine doses have been shown to have rapid yet transient antidepressant effects in patients with treatment-resistant depression, which may be prolonged by repeated administration. The purpose of this study was to evaluate the antidepressant effects of a single ketamine infusion, a series of repeated ketamine infusions, and prolongation of response with maintenance infusions. Methods: Forty-one participants with treatment-resistant depression completed a single-site randomized double-blind crossover comparison of single infusions of ketamine and midazolam (an active placebo control). After relapse of depressive symptoms, participants received a course of six open-label ketamine infusions administered thrice weekly over 2 weeks. Responders, classified as those participants who had a ≥50% decrease in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), received four additional infusions administered once weekly (maintenance phase). Results: Compared with midazolam, a single ketamine infusion elicited a significantly greater reduction in depressive symptoms at the primary efficacy endpoint (24 hours postinfusion). Linear mixed models revealed cumulative antidepressant effects with repeated infusions and doubling of the antidepressant response rate. Fifty-nine percent of participants met response criteria after repeated infusions, with a median of three infusions required before achieving response. Participants had no further change in MADRS scores during weekly maintenance infusions. Conclusions: Repeated ketamine infusions have cumulative and sustained antidepressant effects. Reductions in depressive symptoms were maintained among responders through once-weekly infusions. These findings provide novel data on efficacious administration strategies for ketamine in patients with treatment-resistant depression. Future studies should further expand on optimizing administration to better translate the use of ketamine into clinical settings.
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Learning objective: After participating in this activity, learners should be better able to evaluate the evidence supporting the antidepressant effects of glutamatergic modulators.Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).
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Objective: We investigated if the degree of treatment resistance of depression, as measured by the Maudsley Staging Method (MSM), is predictive of a worse depression outcome by using a large naturalistic cohort of depressed patients. Methods: 643 subjects from the general population, primary care, and secondary care who suffered from current depressive disorder were included from the Netherlands Study of Depression and Anxiety baseline assessment. The diagnostic criterion was major depressive disorder (MDD) in the last month, based on the Composite Interview Diagnostic Instrument (CIDI), or a CIDI diagnosis of MDD in the past 6 months with an Inventory of Depressive Symptomatology Self-Report score > 24 at baseline. In these subjects, composite scores of the MSM, based on duration, severity, and treatment history of current episode, were determined retrospectively. We then determined if the MSM score prospectively predicted the 2-year course of depression after baseline. The primary outcomes were percentage of follow-up time spent in a depressive episode and being "mostly depressed" (≥ 50% of the follow-up) between baseline and 2-year follow-up. Results: The MSM predicted "percentage of follow-up time with depression" (P < .001) and was associated with being "mostly depressed" (OR = 1.40; 95% CI, 1.23-1.60; P < .001). These effects were not modified by having received treatment. Conclusions: The current study shows that the MSM is a promising tool to predict worse depression outcomes in depressed patients. In this study that adds to previous work, we show the applicability of MSM in a wider range of primary and secondary care patients with depression.
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Objective: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation. Method: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration. Results: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms. Conclusions: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.
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Background: Ketamine, administered in subanesthetic doses, is an effective off-label treatment for severe and even treatment-refractory depression; however, despite dozens of studies across nearly 2 decades of research, there is no definitive guidance on matters related to core practice issues. Methods: This article presents a qualitative review and summary about what is known about ketamine dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions. Results: Ketamine is most commonly administered in the dose of 0.5 mg/kg, but some patients may respond to doses as low as 0.1 mg/kg, and others may require up to 0.75 mg/kg. The ketamine dose is conventionally administered across 40 minutes; however, safety and efficacy have been demonstrated in sessions ranging between 2 and 100 minutes in duration. Bolus administration is safe and effective when the drug is administered intramuscularly or subcutaneously. Whereas the intravenous route is the most commonly employed, safety and efficacy have been described with other routes of administration, as well; these include oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous routes. Patients may receive a single session of treatment or a course of treatment during the acute phase, and treatment may rarely be continued for weeks to years to extend and maintain treatment gains in refractory cases. When so extended, the ideal frequency is perhaps best individualized wherein ketamine is dosed a little before the effect of the previous session is expected to wear off. Conclusions: There is likely to be a complex interaction between ketamine dose, session duration, route of administration, frequency of administration, and related practice. Until definitive studies comparing different doses, rates of administration, routes of administration, and other considerations are conducted, firm recommendations are not possible. From the point of view of clinical practicability, subcutaneous, intranasal, and oral ketamine warrant further study. If domiciliary treatment is considered, the risk of abuse must be kept in mind.
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The antidepressant effects of ketamine are thought to depend on BDNF genotype and dose. The purpose of this study was to characterize the dose-related antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind randomized parallel group placebo controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%) and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least two days between days 2 and 5) also revealed a significant dose-related effect (saline:12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.Neuropsychopharmacology accepted article preview online, 11 May 2017. doi:10.1038/npp.2017.94.
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Rationale: There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning. Methods: Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task. Results: D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses). Conclusion: The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms.
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Background: Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear. Method: We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects. Results: A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant. Conclusions: A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
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Objective: Electroconvulsive therapy (ECT) is regarded by many clinicians as the most effective treatment for treatment-resistant bipolar depression, but no randomized controlled trials have been conducted, to the authors' knowledge. They compared efficacy measures of ECT and algorithm-based pharmacological treatment in treatment-resistant bipolar depression. Method: This multicenter, randomized controlled trial was carried out at seven acute-care psychiatric inpatient clinics throughout Norway and included 73 bipolar disorder patients with treatment-resistant depression. The patients were randomly assigned to receive either ECT or algorithm-based pharmacological treatment. ECT included three sessions per week for up to 6 weeks, right unilateral placement of stimulus electrodes, and brief pulse stimulation. Results: Linear mixed-effects modeling analysis revealed that ECT was significantly more effective than algorithm-based pharmacological treatment. The mean scores at the end of the 6-week treatment period were lower for the ECT group than for the pharmacological treatment group: by 6.6 points on the Montgomery-Åsberg Depression Rating Scale (SE=2.05, 95% CI=2.5-10.6), by 9.4 points on the 30-item version of the Inventory of Depressive Symptomatology-Clinician-Rated (SE=2.49, 95% CI=4.6-14.3), and by 0.7 points on the Clinical Global Impression for Bipolar Disorder (SE=0.31, 95% CI=0.13-1.36). The response rate was significantly higher in the ECT group than in the group that received algorithm-based pharmacological treatment (73.9% versus 35.0%), but the remission rate did not differ between the groups (34.8% versus 30.0%). Conclusion: Remission rates remained modest regardless of treatment choice for this challenging clinical condition.
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Objective: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. Method: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. Conclusions: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
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Patients with major depression respond to antidepressant treatment, but 10%-30% of them do not improve or show a partial response coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. The aim of this paper is to review the therapeutic options for treating resistant major depressive disorder, as well as evaluating further therapeutic options. In addition to Google Scholar and Quertle searches, a PubMed search using key words was conducted, and relevant articles published in English peer-reviewed journals (1990-2011) were retrieved. Only those papers that directly addressed treatment options for treatment-resistant depression were retained for extensive review. Treatment-resistant depression, a complex clinical problem caused by multiple risk factors, is targeted by integrated therapeutic strategies, which include optimization of medications, a combination of antidepressants, switching of antidepressants, and augmentation with non-antidepressants, psychosocial and cultural therapies, and somatic therapies including electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As a corollary, more than a third of patients with treatment-resistant depression tend to achieve remission and the rest continue to suffer from residual symptoms. The latter group of patients needs further study to identify the most effective therapeutic modalities. Newer biomarker-based antidepressants and other drugs, together with non-drug strategies, are on the horizon to address further the multiple complex issues of treatment-resistant depression. Treatment-resistant depression continues to challenge mental health care providers, and further relevant research involving newer drugs is warranted to improve the quality of life of patients with the disorder.
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The patients described in this report used medications that could cause cognitive impairment. Memantine could have antagonized these effects, through unclear mechanisms. To our knowledge, this is the first report on the usefulness of memantine in the treatment of cognitive impairment in bipolar disorder patients. Randomized double-blind controlled studies are needed to validate these preliminary observations.
Article
Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist d-cycloserine (DCS) improves extinction retention in adolescent rats. We investigated whether DCS affected recruitment of the PFC and amygdala during extinction by measuring pMAPK-immunoreactive (IR) neurons. Adolescent rats were trained to fear a conditioned stimulus in one context followed by extinction in a second context or equivalent context exposure only (i.e., no extinction). DCS (15 mg/kg, s.c.) or saline was administered systemically immediately after extinction training or context exposure. DCS enhanced extinction learning and this was associated with increased activation of the MAPK signaling pathway in the OFC after extinction training and increased activation in the medial PFC and amygdala at extinction retention. These findings suggest that DCS improves extinction learning in adolescents because it augments OFC contributions to extinction learning, enabling better medial prefrontal contributions to extinction retention.
Article
Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.
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In the treatment of bipolar disorder, the manic phase has received the most attention from the pharmaceutical industry. However, it is actually the bipolar depressed phase that has the largest impact on public health due to the proportion of time spent depressed and the associated disability. The bipolar depressive episodes are also the most lethal phase of the disorder, associated with the majority of lifetime suicide attempts, which occur in 25%-56% of patients, and deaths by suicide, which occur in 10%-19%. © Copyright 2015 Physicians Postgraduate Press, Inc.
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To the Editor: Bipolar depression is a leading cause of disability in the United States. Recently, N-methyl-D-asparate glutamate-receptor (NMDAR) antagonists, such as ketamine, have been shown to induce remission in bipolar depression. Nevertheless, ketamine use is limited by transient effects and psychogenic potential during repeated administration. © Copyright 2015 Physicians Postgraduate Press, Inc.
Article
Neurological rehabilitation involving motor training results in clinically meaningful improvements in function, but is unable to eliminate many of the impairments associated with neurological injury. There is a growing need for interventions which facilitate motor learning during rehabilitation therapy, to optimize recovery. D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist which enhances neurotransmission throughout the central nervous system, (Ressler et al., 2004) has been shown to facilitate declarative and emotional learning. We therefore tested whether combining DCS with motor training facilitates motor learning after stroke in a series of two experiments. Forty-one healthy adults participated in Experiment I and twenty adults with stroke participated in Experiment II of this two-session, double-blind study. Session one consisted of baseline assessment, subject randomization, and oral administration of DCS or placebo (250 mg). Subjects then participated in training on a balancing task, a simulated feeding task, and a cognitive task. Subjects returned 1-3 days later for posttest assessment. We found that all subjects had improved performance from pretest to posttest on the balancing task, the simulated feeding task, and the cognitive task. Subjects who were given DCS prior to motor training, however, did not show enhanced learning on the balancing task, the simulated feeding task, or the associative recognition task compared to subjects given placebo. Moreover, training on the balancing task did not generalize to a similar, untrained balance task. Our findings suggest that DCS does not enhance motor learning or motor skill generalization in neurologically intact adults or in adults with stroke.
Article
Unlabelled: Abstract Objective: Research on D-cycloserine (DCS), a partial N-methyl-d-aspartic acid (NMDA) agonist, has suggested that it may enhance exposure-based therapies for anxiety disorders. RESULTS with DCS in adult posttraumatic stress disorder (PTSD) have been conflicting; however, no data have been reported on children with PTSD. Although many individuals with PTSD respond to exposure-based cognitive behavioral therapy (CBT), there are subgroups of individuals who are nonresponders, and many responders still have substantial residual symptoms. This randomized, triple-blind, placebo-controlled study tested DCS as an adjunct to CBT to improve and speed treatment response for PTSD in youth. Methods: Seven to 18 year-old youth with exposure to trauma and PTSD were offered a 12 session, manualized CBT treatment. Those who remained in treatment at the fifth session were randomly allocated (n=57) to either CBT and DCS or CBT and placebo. Results: Youth in the CBT and DCS group had significant reductions in symptoms, but these reductions were not greater than those in the CBT and placebo group. There was a trend toward DCS speeding PTSD symptom recovery during the exposure-based sessions, and evidence that the CBT and DCS group better maintained stability of gains on inattention ratings from posttreatment to the 3 month follow-up. Conclusions: This initial study of CBT and DCS to treat pediatric PTSD provided suggestive and preliminary evidence for more rapid symptom recovery and beneficial effects on attention, but did not show an overall greater effect for reducing PTSD symptoms. It appears that augmentation with DCS represents unique challenges in PTSD. Because PTSD involves complex, life-threatening trauma memories, as opposed to the imagined dreadful outcomes of other anxiety disorders, the use of DCS may require greater attention to how its use is coupled with exposure-based techniques. DCS may have inadvertently enhanced reconsolidation of trauma memories rather than more positive and adaptive memories. In addition, the results suggest that future research could focus on the longer-term benefits of DCS on attention and ways to capitalize on attention-enhancing therapies. ClinicalTrials.gov registry: Effect of D-cycloserine on Treatment of Posttraumatic Stress Disorder (PTSD) in Youth, #NCT01157416, http://clinicaltrials.gov/ct2/results?term=NCT01157416&Search=Search , and D-cycloserine Adjunctive Treatment for Posttraumatic Stress Disorder (PTSD) in Adolescents, #NCT01157429, http://clinicaltrials.gov/ct2/results?term=NCT01157429&Search=Search .
Article
This article describes the design of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The main study objective was to compare the efficacy and tolerability of various antidepressant therapies through four sequential treatment levels. To maximize the generalizability of the results, broad inclusion and minimal exclusion criteria were used to recruit patients with major depression from a large number of real-world settings. The goal of treatment was to achieve full remission. A measurement-based care system was used to guide and optimize treatment at each level. Patients were treated for up to 12 weeks at each level (with an optional week 14 visit, if needed). All patients started with citalopram at Level 1. The three subsequent levels of treatment options were randomized and open label, and patients could accept or decline treatments as long as sufficient options were left that allowed randomization between at least two different options. For any treatment level, patients who reached full remission, and those with satisfactory response, could continue the same treatment during 1-year naturalistic follow up. Patients who did not reach full remission were encouraged to enter subsequent levels.
Article
Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research.
Article
OBJECTIVE: Executive deficits may play an important role in late-life suicide. Yet, current evidence in this area is inconclusive and does not indicate whether these deficits are broadly associated with suicidal ideation or are specific to suicidal behavior. This study examined global cognition and specifically executive function impairments as correlates of suicidal ideation and suicidal behavior in depressed older adults, with the goal of extending an earlier preliminary study. DESIGN: Case-control study. SETTING: University-affiliated psychiatric hospital. PARTICIPANTS: All participants were age 60+: 83 depressed suicide attempters, 43 depressed individuals having suicidal ideation with a specific plan, 54 nonsuicidal depressed participants, and 48 older adults with no history of psychiatric disorders. MEASUREMENTS: Global cognitive function was assessed with Dementia Rating Scale (DRS) and executive function with Executive Interview (EXIT). RESULTS: Both suicide attempters and suicide ideators performed worse than the two comparison groups on the EXIT, with no difference between suicide attempters and suicide ideators. On the DRS total score, as well as on Memory and Attention subscales, suicide attempters and ideators and nonsuicidal depressed subjects performed similarly and were impaired relative to nonpsychiatric control subjects. Controlling for education, substance use disorders, and medication exposure did not affect group differences in performance on either the EXIT or the DRS. CONCLUSIONS: Executive deficits, captured with a brief instrument, are associated broadly with suicidal ideation in older depressed adults but do not appear to directly facilitate suicidal behavior. Our data are consistent with the idea that different vulnerabilities may operate at different stages in the suicidal process.
Article
D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei.
Article
Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy. Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions. Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period. Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.
Article
Antagonism of N-methyl-d-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. d-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ⩾50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.
Article
Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. We performed a literature review of the research findings related to treatment-resistant BD reported through February 2012. Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive-dysthymic-dysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic trials for treatment-resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N-methyl-D-aspartate (NMDA)] antagonists, dopamine agonists, calcium-channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation-all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up.
Article
Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
Article
This article describes the design of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The main study objective was to compare the efficacy and tolerability of various antidepressant therapies through four sequential treatment levels. To maximize the generalizability of the results, broad inclusion and minimal exclusion criteria were used to recruit patients with major depression from a large number of real-world settings. The goal of treatment was to achieve full remission. A measurement-based care system was used to guide and optimize treatment at each level. Patients were treated for up to 12 weeks at each level (with an optional week 14 visit, if needed). All patients started with citalopram at Level 1. The three subsequent levels of treatment options were randomized and open label, and patients could accept or decline treatments as long as sufficient options were left that allowed randomization between at least two different options. For any treatment level, patients who reached full remission, and those with satisfactory response, could continue the same treatment during 1-year naturalistic follow up. Patients who did not reach full remission were encouraged to enter subsequent levels.
Article
The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.
Article
Recently, we have shown that 1-aminocyclopropanecarboxylic acid (ACPC) acts simultaneously as a high affinity full glycine agonist and a low affinity glutamate site competitive antagonist for NMDA receptor channels. In this paper, we have attempted to determine the subunit specificity and mechanism of action of a different putative cyclic partial agonist, D-cycloserine (DCS). NMDA receptor currents were measured utilizing the two-electrode voltage clamp technique on Xenopus oocytes injected with NR1-1a cRNA and either NR2A, NR2B or NR2C cRNA. Efficacies of DCS were 35-68% of glycine controls for channels containing NR1-1a and NR2A or NR2B subunits, but channels containing NR2C subunits had efficacies greater than glycine controls (192%). Unlike ACPC, DCS efficacy does not increase with increasing NMDA concentration; however, the lowered efficacy elicited by DCS results solely through its interaction with the glycine binding site. The efficacy of DCS was pH sensitive for NR2A or NR2B-containing channels, but not for channels containing NR2C. From this, we suggest that the protonated and deprotonated forms of DCS when bound, probably open NMDA channels with different efficiency. Two models compatible with these results are presented.
Article
The glycine-binding site of the glutamatergic N-methyl-D-aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist D-cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials. We showed that DCS facilitated NMDAr-mediated synaptic potentials. In addition, we found that the magnitude of NMDAr-dependent long-term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered. We found that DCS decreased neurotransmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the γ-aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine. These results, therefore, show opposite effects of DCS on NMDA and non-NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long-term synaptic plasticity that may support the DCS-induced enhanced cognitive performances. British Journal of Pharmacology (2003) 140, 1051–1056. doi:10.1038/sj.bjp.0705541
Article
Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.
Article
Compounds that reduce N-methyl-d-aspartate receptor (NMDAR) function, including NMDAR antagonists and partial agonists at the NMDAR-associated glycine (GLY) site, may act as antidepressants. The antibiotic drug d-cycloserine (DCS) acts as a partial agonist at the NMDAR-GLY site. Preclinical and clinical data suggest that at dosages >or=100 mg/day DCS acts as a functional NMDAR antagonist and may have antidepressant effects. Twenty-two treatment resistant major depression patients participated in a double-blind, placebo-controlled 6-week crossover trial with 250 mg/day DCS added to their ongoing antidepressant medications. DCS treatment was well tolerated and resulted in symptom reductions. However, biweekly-performed clinical assessments, including the Hamilton Depression Rating Scale, Hamilton Rating Scale for Anxiety and Zung Self-Rating Depression Scale did not reveal statistically significant therapeutic advantages of DCS vs. placebo adjuvant treatment. Small sample, uneven treatment resistance criteria across subjects. The exposure to DCS (dose/length of treatment) may not have been sufficient. This exploratory study represents the first attempt to assess the effects of a NMDAR-GLY site partial agonist in depression treatment. The findings and limitations of this study should be taken into account in the planning of future clinical trials with NMDAR modulators in depression.
Article
Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.
Article
Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.
The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis
  • S T Wilkinson
  • E D Ballard
  • M H Bloch
  • S J Mathew
  • J W Murrough
  • A Feder
  • ST Wilkinson
Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression
  • P R Shiroma
  • B Johns
  • M Kuskowski
  • J Wels
  • P Thuras
  • C S Albott
  • PR Shiroma
Treatment-resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm-based pharmacological treatment
  • H K Schoeyen
  • U Kessler
  • O A Andreassen
  • B H Auestad
  • P Bergsholm
  • U F Malt
  • HK Schoeyen
Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression
  • J W Murrough
  • A M Perez
  • S Pillemer
  • J Stern
  • M K Parides
  • M Het Rot
  • JW Murrough