BDNF Release Is Required for the Behavioral Actions of Ketamine

Background:

Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).

Methods:

Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.

Results:

The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.

Conclusions:

Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.     

The Mood Stabilizer Lithium Potentiates the Antidepressant-Like Effects and Ameliorates Oxidative Stress Induced by Acute Ketamine in a Mouse Model of Stress

Background:

Evidence suggests that mammalian target of rapamycin activation mediates ketamine’s rapid but transient antidepressant effects and that glycogen synthase kinase-3β inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a glycogen synthase kinase-3 inhibitor with strong antisuicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine’s antidepressant-like effects.

Methods:

Mice received chronic restraint stress and long-term pre- or postketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated.

Results:

Subtherapeutic (600mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5mg/kg, intraperitoneally) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex of stressed mice induced by a single ketamine (50mg/kg) injection were sustained by postketamine treatment with 1200mg/L of lithium for at least 2 weeks. These benefits of lithium treatments were associated with activation of the mammalian target of rapamycin/brain-derived neurotrophic factor signaling pathways in the prefrontal cortex. Acute ketamine (50mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200mg/L of lithium.

Conclusions:

Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine.     

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression

BackgroundKetamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor–dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.MethodsResting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.ResultsA reduction in Montgomery–Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.ConclusionsThese preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.     

The Influence of Oxytocin and Prolactin During a First Episode of Psychosis: The Implication of Sex Differences,Clinical Features,and Cognitive Performance

BackgroundApproximately 3% of the population suffers a first episode of psychosis (FEP), and a high percentage of these patients subsequently relapse. Because the clinical course following a FEP is hard to predict, it is of interest to identify cognitive and biological markers that will help improve the diagnosis, treatment, and outcome of such events and to define new therapeutic targets. Here we analyzed the plasma oxytocin and prolactin levels during an FEP, assessing their correlation with clinical and cognitive features.MethodsThe oxytocin and prolactin in plasma was measured in 120 FEP patients and 106 healthy controls, all of whom were subjected to a clinical and neuropsychological assessment. Most patients were under antipsychotics. Statistical analyses aimed to identify factors associated with the FEP and to search for associations between the variables. This study is preliminary and exploratory because the P-values were not corrected for multiple comparisons.ResultsFEP patients had less oxytocin, more prolactin, and a poor premorbid IQ, and they performed worse in sustained attention. Male patients with higher prolactin levels experienced more severe psychotic symptoms and required higher doses of antipsychotics. Low oxytocin was associated with poor sustained attention in women, whereas low oxytocin and high prolactin in men correlated with better performance in sustained attention.ConclusionLow oxytocin, high prolactin, and poor premorbid IQ and sustained attention are factors associated with an FEP, representing potential therapeutic targets in these patients. These biological factors and cognitive domains might play an important role during a FEP, which could help us to develop new strategies that improve the outcomes of this disorder and that should perhaps be gender specific.     

Interaction between Zinc,GPR39, BDNF and Neuropeptides in Depression

As one of the most important elements in our body, zinc plays a part in both the pathophysiology of depression and the antidepressant response. Patients suffering from major depression show significantly reduced zinc levels, which are normalized following successful antidepressant treatment. Recent studies have shown the interaction between zinc, GPR39 and neuropeptides, including galanin and neuropeptide Y (NPY). The zinc-sensing receptor GPR39 forms heterotrimers with 5-HT_1A and the galanin receptor GalR₁ upon their co-expression in mammalian cells. The oligomerization of these heterotrimers is regulated by the zinc concentration, and this may have an influence on depressive-like behavior. The antidepressant-like effect of zinc is linked to elevated levels of brain-derived neurotrophic factor (BDNF) in brain structures associated with emotion, such as the hippocampus and the amygdala. BDNF regulates neuropeptides, including NPY, cholecystokinin (CCK), and substance P or galanin, which are also implicated in mood disorders. This review focuses for the first time on the interaction between zinc, the GPR39 zinc receptor, BDNF and selected neuropeptides in terms of depression in order to determine its possible role in the neuropharmacology of that illness.     

Involvement of Serotonin Receptor Mechanisms in the Discriminative Stimulus Effects of Ketamine in Rats

We have demonstrated previously that the ketamine-induced discriminative stimulus effect is likely to reflect the phencyclidine-like psychotomimetic effects. Therefore, the present study was designed to investigate the effects of the antipsychotics and 5-HT₂ receptor antagonist on the discriminative stimulus effects of ketamine in rats. While sulpiride did not attenuate the discriminative stimulus effects of ketamine, both clozapine and ketanserin attenuated those of ketamine, suggesting that the discriminative stimulus effects of ketamine are mediated by multiple receptors, especially the 5-HT₂ receptor, but not the D₂ receptor. Furthermore, our findings imply that atypical antipsychotics could be useful for the treatment of psychotomimetic effects induced by ketamine.     

Quantifying the Psychological Effects of Ketamine: From Euphoria to the k-Hole

52 ketamine users were “opportunistically” recruited to take part in a survey of the psychological effects of the drug, in Manchester, United Kingdom in 2008. Twenty-seven ketamine-naïve respondents were also recruited for comparison in respect of “other” recreational drug use and level of schizotypy. Ketamine users attributed a wide range of appetitive, aversive, after-effect, and dissociative experiences to the drug. They also reported using a much wider range of other recreational drugs than ketamine non-users. Former users reported significantly fewer positive or dissociative experiences than current users.     

右美托咪定和氯胺酮预防瑞芬太尼麻醉后痛觉过敏效果的比较

目的比较右美托咪定（dexmedetomidine,DEX）和氯胺酮缓解瑞芬太尼麻醉后痛觉过敏的效果。方法择期经腹全子宫切除术患者90例,随机分为对照组、DEX组和氯胺酮组。麻醉维持均采用瑞芬太尼0．4I．tg·kg^-1．min^-1,吸入七氟醚。手术结束前30min3组分别给予生理盐水、DEX1μg·kg^-1。和氯胺酮0．8mg·kg^-1。记录3组患者拔管和苏醒时间,哌替啶使用人数及用量和不良反应的发生情况。分别于苏醒后2h内和苏醒后4,8,12,24,48h进行VAS评分。结果苏醒后2h内对照组VAS评分显著高于DEX组和氯胺酮组（P〈0．05）,苏醒后4～48h差异无统计学意义（P〉0．05）,DEX组和氯胺酮组比较VAS评分差异无统计学意义;对照组要求镇痛人数和哌替啶用量显著大于DEX组和氯胺酮组（P〈0．05）,DEX组和氯胺酮组间比较差异无统计学意义;氯胺酮组有3例出现复视,1例出现幻觉。结论DEX和氯胺酮预防瑞芬太尼麻醉后痛觉过敏的效果确切且差别不明显。     

Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions

BackgroundSubanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment.MethodsThirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report.ResultsTwenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37–0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η _p²=0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36).ConclusionA short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01945047","term_id":"NCT01945047"}}NCT01945047     

Cognitive Mechanisms of Treatment in Depression

Cognitive abnormalities are a core feature of depression, and biases toward negatively toned emotional information are common, but are they a cause or a consequence of depressive symptoms? Here, we propose a ‘cognitive neuropsychological'' model of depression, suggesting that negative information processing biases have a central causal role in the development of symptoms of depression, and that treatments exert their beneficial effects by abolishing these biases. We review the evidence pertaining to this model: briefly with respect to currently depressed patients, and in more detail with respect to individuals at risk for depression and the effects of antidepressant treatments. As well as being present in currently depressed individuals, negative biases are detectable in those vulnerable for depression due to neuroticism, genetic risk, or previous depressive illness. Recent evidence provides strong support for the notion that both antidepressant drugs and psychological therapies modify negative biases, providing a common mechanism for understanding treatments for depression. Intriguingly, it may even be possible to predict which patients will benefit most from which treatments on the basis of neural responses to negative stimuli. However, further research is required to ascertain whether negative processing biases will be useful in predicting, detecting, and treating depression, and hence in preventing a chronic, relapsing course of illness.     

Increased Hippocampal Neurogenesis and p21 Expression in Depression: Dependent on Antidepressants,Sex, Age,and Antipsychotic Exposure

The mammalian hippocampus continues to generate new neurons throughout life. The function of adult-generated neurons remains controversial, but adult neurogenesis in the hippocampus is related to depression. Studies show that neurogenesis in the hippocampus is regulated by antidepressants in both humans and rodents, but no studies have examined the effects of age, sex, or antipsychotic exposure on the relationship between depression, antidepressant exposure, and hippocampal neurogenesis in humans. Hippocampal sections were obtained from the Stanley Medical Research Institute and were immunohistochemically labeled for the immature neuron marker doublecortin and the cell cycle arrest marker p21. We compared the number of cells in the granule cell layer and subgranular zone that expressed these proteins in brains from control subjects (n=12), patients with major depressive disorder (MDD) without psychotic symptoms (n=12), and patients with MDD and psychotic symptoms (n=12). We show here that the density of doublecortin/NeuN expression was increased in MDD patients compared with controls and MDD patients with psychosis, with the effect greater in women. Further, we show that older depressed patients without psychosis had higher levels of p21/NeuN expression and that depressed individuals prescribed antidepressants had higher levels of p21/NeuN expression, but only in older women. We show for the first time that changes in neurogenesis due to prescribed antidepressants or depression are dependent on age, sex, and the presence of antipsychotics or psychotic symptoms.     

西酞普兰合并低剂量阿米替林与帕罗西汀治疗抑郁症的疗效观察

目的探讨西酞普兰合并低剂量阿米替林与帕罗西汀治疗抑郁症的疗效价值和安全性。方法对2009年1月-2009年10月我院门诊及住院抑郁症患者112例,随机分为西酞普兰合并低剂量阿米替林组和帕罗西汀组各56例,疗程6周,采用汉密顿抑郁量表（HAMD）和不良反应量表（TESS）在治疗前、后1、2、4、6周末评定药物疗效和不良反应。结果西酞普兰合并低剂量阿米替林和帕罗西汀两组治疗1～2周前后HAMD评分差异有显著性（P〈0．05）,治疗4—6周,两组差异无显著性（P〉0．05）,西酞普兰合并低剂量阿米替林组不良反应总发生率为26．79％,帕罗西汀则为46．43％,两组差异有显著性（P〈0．05）。结论西酞普兰合并低剂量阿米替林与帕罗西汀治疗抑郁症均有效,不良反应较轻,但西酞普兰合并低剂量阿米替林更安全,服用方便,不良反应更小,可作为治疗抑郁症的首选联合药物。     

Brain Structural Effects of Antidepressant Treatment in Major Depression

Depressive disorder is a very frequent and heterogeneous syndrome. Structural imagingtechniques offer a useful tool in the comprehension of neurobiological alterations that concerndepressive disorder. Altered brain structures in depressive disorder have been particularly located inthe prefrontal cortex (medial prefrontal cortex and orbitofrontal cortex, OFC) and medial temporal cortex areas(hippocampus). These brain areas belong to a structural and functional network related to cognitive and emotionalprocesses putatively implicated in depressive symptoms. These volumetric alterations may also represent biologicalpredictors of response to pharmacological treatment. In this context, major findings of magnetic resonance (MR) imaging,in relation to treatment response in depressive disorder, will here be presented and discussed.     

Sex Differences in Animal Models of Depression and Antidepressant Response

Abstract: Many stress‐related mental disorders, including depression and post‐traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiological sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clinical research documents sex differences in brain anatomy, chemistry and function, as well as in stress and drug responses. For example, some clinical studies have reported that women may have a better outcome when treated with selective serotonin re‐uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioural aspects, as well as neurochemical, neurobiological and pharmacological findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide‐induced sickness behaviour, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochemical responses were differently affected in males and females, ultimately producing sex‐dependent behavioural effects. In addition, Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex‐differentiated neurochemical and behavioural alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.     

HPLC测定盐酸氯胺酮原料药中的有关物质

目的 建立HPLC检测盐酸氯胺酮原料药中有关物质的方法。方法 采用Waters Xbridge C18色谱柱,以0.005 mol·L-1己烷磺酸钠水溶液-乙腈-磷酸(90︰10︰0.1)为流动相A,乙腈为流动相B,梯度洗脱,流速1.0 mL·min–1,检测波长215 nm,柱温30℃。结果 主成分与各杂质间最小分离度>1.5;主成分以及其6个杂质在各自的浓度范围内呈良好的线性关系(r>0.999);平均回收率为97.6%～103.0%,RSD为0.8%～2.8%。结论 本方法准确、灵敏、可靠,适用于盐酸氯胺酮有关物质的测定。     

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.     

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, -serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.     

Beagle犬静脉注射S（＋）盐酸氯胺酮和盐酸氯胺酮急性毒性及毒代动力学比较研究

目的比较Beagle犬静脉注射S（＋）盐酸氯胺酮和盐酸氯胺酮的急性毒性反应,同时进行毒代动力学研究,为S（＋）盐酸氯胺酮的安全性评价提供依据。方法采用近似致死剂量法（ALD）,给药剂量分别为3．5、8、18、40．5、91．2、136．8mg／kg。同时进行毒代动力学采血,采血时间为药后0min、10min、20min、30min、1h、2h、4h、6h。采用LC／MS方法测定血药浓度,使用DAS软件进行数据处理。结果给药剂量为136．8mg／kg时,S（＋）盐酸氯胺酮和盐酸氯胺酮组动物死亡。各剂量组药后分别可见流涎、流泪、颤抖、肌张力增加或下降等反应。3．5、8、18、40．5、91．2剂量下S（＋）盐酸氯胺酮的AUC0-4分别为60870、81801、556309、1608988、3969715μg／L（min,Cmax分别为9870,6824,81430、218966、523788μg／L,t1／2z分别为16．6、14．2、35．1、68．2、73．2min;盐酸氯胺酮组AUC0-1分别为17738、115982、831504、2105286、4924419μg／L（min,Cmax分别为1515、10655、112319、295016、669319μg／L,t1／2z分别为16．7、32．6、34．4、38．6、74．8min。结论Beagle犬静脉注射S（＋）盐酸氯胺酮、盐酸氯胺酮等剂量下的毒性反应基本相同,近似致死剂量范围均为136．8～91．2mg／kg。两者的主要药动学参数也随着剂量的增加规律性的相应增加,变化趋势基本一致。