Treatment response to low-dose ketamine infusion for treatment-resistant depression: A gene-based genome-wide association study

BackgroundsEvidence suggested the crucial roles of brain-derived neurotrophic factor (BDNF) and glutamate system functioning in the antidepressant mechanisms of low-dose ketamine infusion in treatment-resistant depression (TRD).Methods65 patients with TRD were genotyped for 684,616 single nucleotide polymorphisms (SNPs). Twelve ketamine-related genes were selected for the gene-based genome-wide association study on the antidepressant effect of ketamine infusion and the resulting serum ketamine and norketamine levels.ResultsSpecific SNPs and whole genes involved in BDNF–TrkB signaling (i.e., rs2049048 in BDNF and rs10217777 in NTRK2) and the glutamatergic and GABAergic systems (i.e., rs16966731 in GRIN2A) were associated with the rapid (within 240 min) and persistent (up to 2 weeks) antidepressant effect of low-dose ketamine infusion and with serum ketamine and norketamine levels.DiscussionOur findings confirmed the predictive roles of BDNF–TrkB signaling and glutamatergic and GABAergic systems in the underlying mechanisms of low-dose ketamine infusion for TRD treatment.     

Efficacy of light therapy for perinatal depression: a review

ABSTRACT: Perinatal depression is an important public health problem affecting 10-20% of childbearing women. Perinatal depression is associated with significant morbidity, and has enormous consequences for the well-being of the mother and child. Treatment of depression during the perinatal period poses a complex problem for both mother and clinician, as antidepressant treatment strategies must consider the welfare of both mother and child during pregnancy and lactation. Bright light therapy may be an attractive treatment for perinatal depression because it is low cost, home-based, and has a much lower side effect profile than pharmacotherapy. The antidepressant effects of bright light are well established, and there are several rationales for expecting that bright light might also be efficacious for perinatal depression. This review describes these rationales, summarizes the available evidence on the efficacy of bright light therapy for perinatal depression, and discusses future directions for investigation of bright light therapy as a treatment for perinatal depression.     

Childhood and adolescent depression: why do children and adults respond differently to antidepressant drugs?

Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group, the differences between adults, children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals, therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.     

综述与专论：甘丙肽对抑郁症状的调控作用及其机制的研究进展

甘丙肽(galanin, GAL)作为治疗抑郁症的可能靶点被关注已久,但目前仍未有广泛应用的GAL类抗抑郁药物。GAL可与3种G蛋白偶联受体(GalR1～3)结合,GalR1和GalR3介导促进抑郁的作用,GalR2介导抗抑郁的作用。GAL的N端有生物活性的片段GAL (1-15),通过其受体GalR1-GalR2异聚体(heteromer),介导比GAL更强的调节抑郁效应。GAL (1-15)还可以通过GalR1-GalR2异聚体与5-羟色胺1A受体(5-HT1AR)相互作用形成GalR1-GalR2-5-HT1AR异聚体的方式,加强5-HT1AR激动剂的抗抑郁效果。此外,GAL及其受体还与去甲肾上腺素、神经肽Y、脑源性神经营养因子、多巴胺等递质或因子交互作用调节抑郁。本文梳理GAL及其受体对抑郁的调节作用及其可能机制,并对以GAL及其受体为靶点开发的药物应用于临床治疗抑郁症的可能性进行探讨。     

甘丙肽对抑郁症状的调控作用及其机制的研究进展

甘丙肽(galanin, GAL)作为治疗抑郁症的可能靶点被关注已久,但目前仍未有广泛应用的GAL类抗抑郁药物。GAL可与3种G蛋白偶联受体(GalR1~3)结合,GalR1和GalR3介导促进抑郁的作用,GalR2介导抗抑郁的作用。GAL的N端有生物活性的片段GAL (1-15),通过其受体GalR1-GalR2异聚体(heteromer),介导比GAL更强的调节抑郁效应。GAL (1-15)还可以通过GalR1-GalR2异聚体与5-羟色胺1A受体(5-HT1AR)相互作用形成GalR1-GalR2-5-HT1AR异聚体的方式,加强5-HT1AR激动剂的抗抑郁效果。此外,GAL及其受体还与去甲肾上腺素、神经肽Y、脑源性神经营养因子、多巴胺等递质或因子交互作用调节抑郁。本文梳理GAL及其受体对抑郁的调节作用及其可能机制,并对以GAL及其受体为靶点开发的药物应用于临床治疗抑郁症的可能性进行探讨。     

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.     

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.     

Abandoning personalization to get to precision in the pharmacotherapy of depression

Effectiveness studies and analyses of naturalistic cohorts demonstrate that many patients with major depressive disorder do not experience symptomatic remission with antidepressant treatments. In an effort to better match patients with effective treatments, numerous investigations of predictors or moderators of treatment response have been reported over the past five decades, including clinical features as well as biological measures. However, none of these have entered routine clinical practice; instead, clinicians typically personalize treatment on the basis of patient preferences as well as their own. Here, we review the reasons why it has been challenging to identify and deploy treatment‐specific predictors of response, and suggest strategies that may be required to achieve true precision in the pharmacotherapy of depression. We emphasize the need for changes in how depression care is delivered, measured, and used to inform future practice.     

Antidepressant drugs: imipramine, mianserin and trazodone

The advent of newer antidepressant drugs (second generation) during the past two decades has provided an alternative to the use of tricyclic antidepressants in the alleviation of depression. These antidepressants have not been proven to be superior in the therapy of depression to the tricyclic antidepressants but they have been reported to cause fewer cardiac effects. Most of the reported adverse cardiac reactions elicited by antidepressant drugs are based on observations from clinical studies. The possible underlying mechanisms by which these adverse reactions arise have for the large part been proposed on the basis of clinical findings which have been extrapolated back to the known pharmacological actions of such drugs. There is a paucity of hard experimental data in this respect.     

A single dose of S‐ketamine induces long‐term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation

Ketamine, an antagonist of N‐methyl‐d ‐aspartate receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and nondeprived Wistar rats were divided into four groups nondeprived + saline; nondeprived + S‐ketamine (15 mg/kg); deprived + saline; deprived + S‐ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase, and 14 days later depressive‐like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated in the rat brain. Maternal deprivation induces a depressive‐like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long‐term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase and catalase were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long‐term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1268–1281, 2015     

A review of clinical and experimental observations about antidepressant actions and side effects produced by Hypericum perforatum extracts

Hypericum perforatum is an herbaceous perennial plant, also known as "St. John's wort", used popularly as a natural antidepressant. Although some clinical and experimental studies suggest it has some properties similar to conventional antidepressants, the proposed mechanism of action seems to be multiple: a non-selective blockade of the reuptake of serotonin, noradrenaline and dopamine; an increase in density of serotonergic and dopaminergic receptors and an increased affinity for GABAergic receptors; moreover, the inhibition of monoaminoxidase enzyme activity has been involved. In any case, the increase of monoamine concentrations in the synaptic cleft resembles several actions exerted by clinically effective antidepressants. In the present article, we review some of the controversial evidence derived from clinical and experimental studies suggesting that H. perforatum exerts antidepressant-like actions, and we also review some of its side effects, such as nausea, rash, fatigue, restlessness, photosensitivity, acute neuropathy, and even episodes of mania and serotonergic syndrome when administered simultaneously with other antidepressant drugs. All of the foregoing suggests that H. perforatum extracts appear to exert potentially significant pharmacological activity involving several neurotransmission systems supposed to be involved in the pathophysiology of depression. However, little information regarding the safety of H. perforatum is available, including potential herb-drug interactions. There is a need for additional research on the pharmacological and biochemical activity of H. perforatum, as well as its side-effects and its several bioactive constituents to further elucidate the mechanisms of antidepressant actions.     

Major Depressive Disorder and Stroke Risks: A 9-Year Follow-Up Population-Based,Matched Cohort Study

Background and Purpose

Major depressive disorder (MDD) is characterized by recurrent depressive episodes and one of the treatment choices is antidepressants. Patients with MDD are at greater risk of developing major metabolic diseases that may in turn lead to stroke. Moreover, both depressive symptoms and taking antidepressant medications are associated with higher risk of stroke. However, whether and how clinical depression increases stroke risk remains an unanswered question. Our aim was to provide answers to this question.

Methods

A matched cohort study of 5015 subjects (1003 MDD patients and 4012 control subjects) was conducted using a nationwide database. Subjects were followed to a maximum of 9 years to determine rates of newly-developed strokes, and controls and MDD groups with different levels of antidepressant refractoriness were compared to determine the temporal relation between stroke and three major metabolic comorbidities (i.e., diabetes mellitus, hypertension and hyperlipidemia). The levels of depressive symptoms and the antidepressant medications before stroke onset were investigated.

Results

Patients with MDD had significantly higher rates of stroke (4.3% vs. 2.8%, p<0.05) during the follow-up. Mediation regression analyses revealed that the occurrence of stroke in the MDD subjects was significantly mediated by the development of major metabolic diseases. Greater severity of depression, but not greater use of antidepressants, preceded the occurrence of stroke.

Conclusions

A clinical diagnosis of major depression leads to stroke indirectly through more intense depressive symptoms and the development of major comorbidities.     

Real-world effectiveness of antidepressants,antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.     

Controlled trial of trimipramine,monoamine oxidase inhibitors,and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks'' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.     

Impaired Prefronto-Thalamic Functional Connectivity as a Key Feature of Treatment-Resistant Depression: A Combined MEG,PET and rTMS Study

Prefrontal left-right functional imbalance and disrupted prefronto-thalamic circuitry are plausible mechanisms for treatment-resistant depression (TRD). Add-on repetitive transcranial magnetic stimulation (rTMS), effective in treating antidepressant-refractory TRD, was administered to verify the core mechanisms underlying the refractoriness to antidepressants. Thirty TRD patients received a 2-week course of 10-Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). Depression scores were evaluated at baseline (W0), and the ends of weeks 1, 2, and 14 (W14). Responders were defined as those who showed an objective improvement in depression scores ≥50% after rTMS. Left-right frontal alpha asymmetry (FAA) was measured by magnetoencephalography at each time point as a proxy for left-right functional imbalance. Prefronto-thalamic connections at W0 and W14 were assessed by studying couplings between prefrontal alpha waves and thalamic glucose metabolism (PWTMC, reflecting intact thalamo-prefrontal connectivity). A group of healthy control subjects received magnetoencephalography at W0 (N = 50) to study whether FAA could have a diagnostic value for TRD, or received both magnetoencephalography and positron-emission-tomography at W0 (N = 10) to confirm the existence of PWTMC in the depression-free state. We found that FAA changes cannot differentiate between TRD and healthy subjects or between responders and non-responders. No PWTMC were found in the TRD group at W0, whereas restitution of the PWTMC was demonstrated only in the sustained responders at W14 and euthymic healthy controls. In conclusion, we affirmed impaired prefronto-thalamic functional connections, but not frontal functional imbalance, as a core deficit in TRD.     

St John's wort for depression--an overview and meta-analysis of randomised clinical trials.

OBJECTIVE--To investigate if extracts of Hypericum perforatum (St John''s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. DESIGN--Systematic review and meta-analysis of trials revealed by searches. TRIALS--23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. MAIN OUTCOME MEASURES--A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. RESULTS--Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. CONCLUSION--There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.     

难治性抑郁症治疗前后血浆单胺类神经递质代谢产物的变化

目的：探讨难治性抑郁症患者抗抑郁剂治疗前后的单胺类神经递质代谢产物的改变。方法：随机入组30例难治性抑郁症患者,进行汉密尔顿抑郁量表（HAMD）的临床评定。用酶联免疫吸附方法对这30例患者进行5-HIAA,MHPG检测,并与随机选取的经汉密尔顿抑郁量表（HAMD）临床评定的30名普通抑郁症患者进行比较。综合治疗8周后对难治性抑郁症患者进行治疗前后对比。结果：难治性抑郁症组治疗前血浆5-HIAA,MHPG浓度低于普通对照组（p〈0.05）,经5-羟色胺重摄取抑制剂治疗的难治性抑郁症患者,5-HIAA和MHPG含量与治疗前比较均有所升高,差异有显著性（p〈0.05）;结论：难治性抑郁症患者存在中枢5-羟色胺和去甲肾上腺素功能低下;个体化合理使用SSRIs类药物辅以心理治疗能有效地提高难治性抑郁症患者的外周单胺类递质水平,减轻患者的抑郁程度。