Strategies for treatment-resistant depression

Approximately 30% of patients with major depression respond poorly to treatment with any given antidepressant regimen, and as many as 60% to 75% experience residual or recurrent symptoms. Strategies for improving response include extending the duration of each treatment beyond the usual 2-4 weeks, increasing the antidepressant dose, switching to another antidepressant, using two or more antidepressants together, and using adjunctive medications or other treatment modalities. Some of these strategies have strong support from clinical investigations while others are based more on clinical experience. This article reviews the risk factors for treatment resistance and provides strategies for improving treatment outcomes.     

Anthelmintics for drug repurposing: Opportunities and challenges

Drug repositioning is defined as a process to identify a new application for drugs. This approach is critical as it takes advantage of well-known pharmacokinetics, pharmacodynamics, and toxicity profiles of the drugs; thus, the chance of their future failure decreases, and the cost of their development and the required time for their approval are reduced. Anthelmintics, which are antiparasitic drugs, have recently demonstrated promising anticancer effects in vitro and in vivo. This literature review focuses on the potential of anthelmintics for repositioning in the treatment of cancers. It also discusses their pharmacokinetics and pharmacodynamics as antiparasitic drugs, proposed anticancer mechanisms, present development conditions, challenges in cancer therapy, and strategies to overcome these challenges.     

难治性抑郁症药物治疗的研究进展

抑郁症是常见的精神障碍性疾病,多呈慢性、复发件病程,对患者的社会功能有较大影响.大多数抑郁症患者可用药物和心理疗法治愈,但有20%～30%的病例对各种治疗没有反应,即通常所称的难治性抑郁症(TRD).本文就近年针对TRD的药物治疗研究进展进行综述.     

Quetiapine augmentation in treatment-resistant depression: a naturalistic study

Rationale Treatment-resistant depression (TRD) is a common clinical problem, often complicated with suicidal ideations and greater lifetime functional impairment, and represents a considerable challenge to management and treatment.Objective The aim of a prospective, open-label, noncomparative, flexible-dosed 20-week study was to evaluate the effects of quetiapine, as an add-on therapy, in patients with TRD who were refractory to previous treatments.Method Eighteen patients with major depressive disorder (DSM-IV criteria) were treated for 20 weeks with quetiapine (mean dose 315±109 mg/day). Patients were evaluated at baseline, weekly from 1 to 9 weeks, and then after 12, 16, and 20 weeks of treatment, using Hamilton rating scale for depression–17 items (HAMD) scale.Results Fourteen patients with TRD completed the 20-week open trial with quetiapine. The augmentation with quetiapine significantly reduced total scores and scores listed in the anxiety subscale on the HAMD, and these effects were observed after the fourth week of treatment, while the depressed mood scores were significantly reduced after the fifth week of treatment. Quetiapine add-on treatment significantly decreased the scores listed in the insomnia subscale on the HAMD subscale after the second week of treatment.Conclusion Our preliminary data indicate that quetiapine add-on therapy appears to have beneficial effects in the treatment of patients with TRD.     

Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response

Rationale

The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain.

Objectives

Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocognitive effects of ketamine in depressed patients. Therefore, the aims of the current study were to characterize the relationship between baseline neurocognition and antidepressant response to ketamine, measure the acute impact of ketamine on neurocognition, and investigate the relationship between acute neurocognitive effects of ketamine and antidepressant response.

Methods

Neurocognitive functioning was assessed in 25 patients with TRD using a comprehensive battery: estimated premorbid intelligence quotient (IQ), current IQ, and tests from the MATRICS Consensus Cognitive Battery (MCCB). A subset of the MCCB was repeated immediately following a 40-min intravenous infusion of ketamine (0.5 mg/kg).

Results

Patients who responded to ketamine 24 h following treatment had poorer baseline neurocognitive performance relative to nonresponders and, in particular, slower processing speed (F?=?8.42; df?=?23; p?=?0.008). Ketamine was associated with selective impairments in memory recall, and the degree of cognitive change carried negative prognostic significance (e.g., negative cognitive effects immediately after ketamine predicted lower response rate at 24 h; Fisher's exact test two-sided p?=?0.027).

Conclusions

Taken together, our findings suggest a potential baseline neurocognitive predictor of ketamine response and an inverse relationship between the cognitive effects of ketamine and antidepressant efficacy.     

难治性抑郁症的临床特征

目的:探讨难治性抑郁症病人的临床特点。方法:采用汉密尔顿抑郁量表17项(HAMD17),汉密尔顿焦虑量表(HAMA)对87例难治性抑郁症病人与78例非难治性抑郁症病人进行评定。结果:难治性抑郁症病人与非难治性抑郁症病人相比,文化程度偏低,病程较长,HAMD行为阻滞因子分(9.3±s5.2vs8.0±2.5)存在极显著差异(P<0.01)。Logistic回归发现,行为阻滞症状对难治性抑郁症具有一定的判别意义(P<0.01)。结论:行为阻滞症状可能是难治性抑郁症病人的特征性症状。     

Ketamine for treatment-resistant unipolar depression: current evidence

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5?mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.     

A novel cognitive-behavioral approach for treatment-resistant drug dependence

Despite the application of treatments that combine methadone administration, weekly counseling, and contingency reinforcement strategies, many opiate-dependent patients continue illicit drug use. In this controlled study we piloted a novel cognitive-behavioral treatment (CBT) designed to reduce illicit drug use among patients receiving methadone treatment. The treatment targeted the reduction of sensitivity to interoceptive cues associated with drug craving, and trained alternative responses to these cues. Patients (N = 23) were randomly assigned to either this novel CBT program or a program of increased counseling, such that the two programs of treatment were equated for therapist contact, assessment time, and contingency-reinforcement strategies. We found that, compared to a doubling of contact with their outpatient counselor, the new program was associated with significantly greater reductions in illicit drug use for women, but not for men. Reasons for differential performance by women and men and future directions for this new treatment are discussed.     

Interaction of 5-HT and HPA axis in depression and treatment-resistant depression

Psychoendocrinology studies of depressed patients focus on the disregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Abnormalities in the HPA axis have been noted in depressed patients. Numerous data have demonstrated the existence of reciprocal interactions between the central serotonin (5-HT) system and HPA axis. These interactions are of particular relevance when considering pathological conditions, such as depression, in which modifications of both the 5-HT system and HPA axis have been evidenced. In our laboratory, we examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test and on the wet-dog shakes induced by the DOI, 5-HT2 receptor agonist with the administration of imipramine and lithium. The reduction of immobility, induced by the chronic administration of imipramine for 15 days, was blocked by treatment with ACTH for 14 days. And, chronic ACTH treatment for 14 days increased the wet-dog shake response. This effect of ACTH was not inhibited by a 14-day administration of imipramine. Accordingly, the chronic treatment of rats with ACTH may prove to be an effective model for antidepressant-treatment-resistant depression. We believe that behavioral pharmacological and molecular biological research into the interaction between the 5-HT and HPA axis will elucidate the pathogenesis of depression or antidepressant-treatment-resistant depression and the mechanism of antidepressants action.     

DrugRep: an automatic virtual screening server for drug repurposing

Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/.     

Economic implications of treatment-resistant depression among employees

BACKGROUND: Conservative estimates indicate between 10% and 20% of all individuals with major depressive disorders (MDDs) fail to respond to conventional antidepressant therapies. Amongst those with MDD, individuals with treatment-resistant depression (TRD) have been found to be frequent users of healthcare services and to incur significantly greater costs than those without TRD. Given the prevalence of the disorder, it is understandable that MDDs are responsible for a significant amount of both direct and indirect healthcare costs. OBJECTIVE: To provide empirical findings for employees likely to have TRD based on analysis of employer claims data, in the context of previous research.METHODS: We conducted a claims data analysis of employees of a large national (US) employer. The data source consisted of medical, pharmaceutical and disability claims from a Fortune 100 manufacturer for the years 1996-1998 (total beneficiaries >100000). The employee sample included individuals with medical or disability claims for MDDs (n = 1692). A treatment pattern algorithm was applied to classify MDD patients into TRD-likely (n = 180) and TRD-unlikely groups. Treated prevalence of select comorbid conditions and the patient costs (direct and indirect) from the employer perspective by condition were compared among TRD-likely and TRD-unlikely employees, and with a 10% random sample of the overall employee population for 1998. RESULTS: The average annual cost of employees considered TRD-likely was dollars US 14490 per employee, while the cost for depressed but TRD-unlikely employees was dollars US 6665 per employee, and dollars US 4043 for the employee from the random sample. TRD beneficiaries used more than twice as many medical services compared with TRD-unlikely patients, and incurred significantly greater work loss costs.CONCLUSION: TRD has gained increasing recognition due to both the clinical challenges and economic burdens associated with the condition. TRD imposes a significant economic burden on an employer. TRD-likely employees are more likely to be treated for selected comorbid conditions and have higher medical and work loss costs across all conditions.