Current investigational drugs for major depression

Background: The World Health Organization (WHO) report has predicted that major depression will become a key cause of illness-induced disability by the year 2020, second only to ischemic heart diseases. Objectives/methods: Although a large number of antidepressant drugs (from monoamine oxidase inhibitors and tricyclic antidepressants to dual reuptake inhibitors) are available for treatment of the disease, approximately 30% of patients failed to respond to this therapy. Therefore, the search for newer or novel drug targets for the treatment of major depression continues. Some of these targets include dopamine, triple reuptake inhibition, L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, sigma-1 receptors, neurosteroids, melatonin, glutamate, 5HT₆, 5HT₇ serotonin receptor antagonists, β-3 adrenoceptor antagonist, vasopressin V(Ib) receptor antagonists, NK2 tachykinin receptor antagonists, glucocorticoid receptor antagonists and corticotropin-releasing factor-1 receptor antagonists, as well as herbal antidepressant drugs. The present review attempts to discuss the status of some of these novel approaches and the drugs that are under investigation for the treatment of major depression. An attempt is also made to review the status of three indigenous plant-derived drugs, berberine, curcumin and rutin, as novel and safe future herbal antidepressants. Results/conclusion: There is an exciting future in the discovery of novel targets and target-specific agents for the management of major depression.     

IL-6 levels decrease with SSRI treatment in patients with major depression

OBJECTIVE: Some evidence indicates that an immune response with an increased production of proinflammatory cytokines often accompanies major depression. The objective of this study was to examine the serum levels of IL-6 in patients with major depression and the changes occurring in IL-6 levels during treatment with selective serotonin reuptake inhibitors (SSRI). METHOD: Twenty-three patients with a DSM-IV diagnosis of major depressive disorder and 23 healthy matched controls were included in the study. The severity of depression was measured with the Hamilton rating scale for depression. Blood samples for IL-6 levels were obtained at baseline and at week 6 of treatment and IL-6 concentrations were evaluated using a solid phase sandwich enzyme immunoassay. All patients were treated with an SSRI. RESULTS: The IL-6 levels showed no statistically significant difference between the patients and the controls at baseline. However, IL-6 levels after treatment with SSRIs were significantly lower compared with the baseline IL-6 levels of both the patients and the controls. CONCLUSION: The results of this study suggest that proinflammatory cytokines show some changes during the course of treatment of major depression. These findings might also be considered as supporting the hypothesis of a modulatory role of antidepressants on the immune system.     

Targeting IL-1 in depression

Introduction: Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodegeneration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels.

Areas covered: This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA).

Expert opinion: Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL-1. In some, but not all studies, antidepressant treatment decreased IL-1β levels. In translational models, IL-1β administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL-1/IL-1RA ratio.     

Neuroendocrine and anthropometric measures in major depression: the effect of antidepressant treatment

It has been suggested that weight change might be associated with certain neuroendocrine abnormalities often observed in patients suffering from a depressive illness. This preliminary study examined whether objective measures of weight change were associated with dexamethasone suppression test (DST) results or plasma levels of thyroid hormones, and whether they correlated with clinical improvement. Specific measures included plasma cortisol following dexamethasone, plasma free thyroxine (T4) and triiodothyronine (T3), as well as anthropometric measures (skinfolds, percentage body fat, body density). The majority of patients (75 per cent) showed some weight gain after treatment. A strong positive correlation was observed between weight gain and plasma tricyclic levels (P<0·005) but only a weak correlation was found between plasma tricyclic levels and therapeutic response (r=0·14). A gender difference was seen in the relationship between weight gain and therapeutic response, with weight gain being associated with less improvement in men and more improvement in women. Therefore, weight gain during treatment may not necessarily indicate clinical improvement for all patients. The only variable that reliably predicted treatment response was free T4. High levels of free T4 prior to treatment were highly correlated with better clinical status as indicated by HAMD scores (r=0·87, P<0·005). Following treatment with imipramine, plasma cortisol levels after dexamethasone administration were reduced in treatment responders but not in nonresponders. Overall, patients that showed the largest decreases in post-dexamethasone cortisol levels from before to after treatment also showed the largest decreases in HAMD total scores (r=0·37) and, especially, somatic anxiety scores (r=0·58, p<0·05). These effects were stronger in women than men. © 1997 John Wiley & Sons, Ltd.     

糖皮质激素受体与重型精神病性抑郁症的治疗

1IntroductionPsychotic major depression ( PMD ), whichresponds poorly to tricyclic anti-depressants, is adistinct syndrome of depression. Hypercortisolemia(cortisone hypersecretion), a biological abnormalityexisting in many patients with PMD, has led to v…     

Serum cortisol concentration in patients with major depression after treatment with clomipramine

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol (CORT) levels are characteristics of the pathophysiology of major depressive disorder.The aim of this study was to determine whether increased plasma CORT levels appear in patients with major depression and if effective antidepressant treatment by clomipramine (CLO) leads to regulation of CORT level. Plasma CORT levels were measured using high performance liquid chromatography (HPLC) methods in patients with major depression at time zero (before therapy) and after 3 h, 24 h, 4, 6 and 8 weeks of CLO administration. The study included 17 patients (12 women, 5 men; mean age 54.5 years, SD = 12.3) and 21 healthy comparison subjects. The patients had a mean score on the 21-item Hamilton Depression Rating Scale (HDRS) of 26.8 (range 22–35). Eight of the patients with major depression recruited for the study showed a 46% increase in CORT concentration compared to the established standard. In 13 patients treated with CLO, serum CLO levels reached a therapeutic range. In recovered depressed patients, antidepressant treatment significantly reduced HDRS scores from the 6th week of treatment. Adrop in plasma CORT levels in recovered depressed subjects occurred 0 to 6 weeks after CLO treatment (n = 5, p < 0.046). However, neither subject group exhibited any definitive markers of CORT secretion. In the population studied, patients had distinct profiles of HPA axis dysregulation. Finding a linear correlation between lower CORT secretion and therapeutic plasma CLO levels is the first aim of monitored therapy and may be important for understanding the pathophysiology of major depressive disorder.     

Cilobamine in the treatment of atypical depression

Sixteen patients meeting our criteria for atypical depression were treated in a 7-week single-blind pilot study with cilobamine mesylate, an investigational antidepressant structurally distinct from tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). Nine patients (56 per cent) responded to cilobamine. Cilobamine patients were compared with a group of similar patients receiving placebo for 6 weeks in a separate double-blind study. The response rate to cilobamine was superior to that of placebo. Cilobamine patients also showed significantly greater improvement in Hamilton Depression Scale scores than did placebo patients. Previous studies have demonstrated the efficacy of MAOIs in atypical depression. This study suggests that certain antidepressants which are not MAOIs, and are free of dietary restrictions and the risk of hypertensive crises, may also be effective in atypical depression.     

Differences in FKBP51 Regulation Following Chronic Social Defeat Stress Correlate with Individual Stress Sensitivity: Influence of Paroxetine Treatment

Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.     

抑郁症致病机制及中药治疗抑郁症的机制研究

抑郁症严重危害人类身心健康,世界卫生组织预测：2020年抑郁症将成为非正常死亡和残疾的第二大原因。目前临床上大多使用三环类抗抑郁药（TCA）、四环类抗抑郁药、选择性5-HT再摄取抑制药等来治疗抑郁症,但长期应用这类药物易产生耐药性,不良反应明显,且这种通过单一成分阻断特定单一靶点的药物,对于涉及体内多个系统的生物学异常往往难以达到治疗效果。中药组方通过其所包含的多组分能同时调节多靶点、调节疾病网络的多个环节,在获得较高疗效的同时可降低化学药单靶点引起的毒副作用,且目前国内外对一些传统中药抗抑郁作用机制的研究报道也日渐增多,主要集中在神经递质水平释放、海马脑源性神经营养因子（BDNF）表达及细胞因子等方面。此外,最新的研究认为肠道菌群可能参与了从情感性疾病到神经系统疾病的发生发展。综述近年来中药抗抑郁神经保护作用的机制研究进展,以期为抑郁症发病机制探讨及抗抑郁药物研究提供借鉴和指导。     

Reduced number of red blood cells,lowered hematocrit and hemoglobin,and increased number of reticulocytes in major depression as indicators of activation of the inflammatory response system: effects of antidepressant drugs

There is some evidence that major depression is characterized by an activation of the inflammatory response system (IRS). Activation of the IRS and major depression are accompanied by changes in the erythron, such as a lowered number of red blood cells (RBC), lowered hematocrit (Hct), and hemoglobin (Hb). The purpose of this study was to examine hematological variables in 32 healthy volunteers and in 47 major depressed patients, both before and after treatment with serotonergic antidepressants. Major depressed subjects had a significantly lower number of RBC, lower Hct and Hb than normal volunteers. Mean corpuscular volume (MCV) and MC Hb (MCHb) were not significantly different between major depressed subjects and normal controls. Major depressed patients had a significantly greater RBC distribution width (RDW), and a significantly increased number of reticulocytes than healthy volunteers. The number of neutrophils and, consequently the number of leukocytes, was significantly higher in major depressed subjects than in normal controls. There were significant and positive correlations between the number of reticulocytes and number of leukocytes and neutrophils. There was no significant effect of a 5‐week treatment with serotonergic antidepressive drugs on the above haematological variables. Copyright © 1999 John Wiley & Sons, Ltd.     

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES-D score (p = .001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.     

Cytokines for the treatment of gastrointestinal cancers: clinical experience and new perspectives

Introduction: Cytokines are key mediators of the immune system and have been proposed as therapeutic agents against cancer, either as recombinant proteins, or as transgenes in gene therapy approaches. Stimulation of immune responses against cancer cells is an appealing method to treat tumors with high risk of relapse and systemic dissemination.

Areas covered: We provide a critical overview of clinical trials involving the use of cytokines for the treatment of liver, colon and pancreatic cancers. Special attention has been paid to advances in the field of gene therapy and oncolytic viruses. The potential of new developments still in a pre-clinical stage is also discussed. We have revised public sources of information (PubMed, US National Institutes of Health clinical trials database) up to January 2013.

Expert opinion: The complexity of the immune system and the unfavorable pharmacokinetic properties of cytokines limit the efficacy of these molecules as single agents for the treatment of cancer. Expression from gene therapy vectors, together with new methods of targeting and stabilization, may overcome these hurdles. We believe cytokines will play a crucial role as part of combined approaches, enhancing the action of adoptive cell immunotherapy, oncolytic viruses or biological therapies.     

应激在抑郁症失眠中的作用和常用应激动物模型的睡眠特点

抑郁症导致的失眠常表现为睡眠中断和早醒, 慢波睡眠 (slow wave sleep, SWS) 减少或消失以及快速动眼 (rapid eye movement, REM) 睡眠潜伏期缩短。这些异常特征与应激引起的下丘脑-垂体-肾上腺 (hypothalamic-pituitary-adrenal, HPA) 轴去抑制亢进导致的睡眠异常极为相似, 提示两者之间可能有密切的联系。因此由应激引起的动物模型, 如创伤后应激障碍和慢性温和不可预知应激等模型, 可用来评价抗抑郁和改善睡眠的药物, 并为深入研究抑郁及伴发的失眠机制提供比较可靠的平台。本文重点阐述抑郁症失眠的特点、可能的病理生理机制、常用应激动物模型的建立方法并分析其睡眠结构。     

A preliminary study of dexamethasone treatment on pituitary–adrenal responsivity in major depression

Major depression is characterized by overactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Dexamethasone (DEX), the glucocorticoid agonist, has been shown to be effective in the treatment of depression. We chose to examine the impact of a short course of DEX treatment on depressive symptomatology, and on the pituitary‐adrenal response to CRH administration. In this preliminary study, five subjects with major depression were treated for 4 days with 3 mg DEX; a CRH test was performed before and after treatment. Four subjects showed a reduction in ACTH (p=0·01) and cortisol output (p<0·01) following DEX treatment. All subjects showed a drop in depression scores after treatment; the Hamilton Depression score fell by 11·4±1·7 (mean±SEM) from baseline (p=0·01) and the Beck Depression score by 9·2±2·5 (mean±SEM) from baseline (p=0·01); this represented a reduction by almost 50 per cent from baseline levels on both depression indices. We suggest that the impact of DEX treatment on depressive symptoms may reflect a restraining influence on an overactive HPA, with a normalization of pituitary–adrenal response to CRH drive. Larger studies are required to investigate this further and to ascertain whether the mood and neuroendocrine changes induced by dexamethasone are sustained. Copyright © 1999 John Wiley & Sons, Ltd.     

Antidepressant agents for the treatment of chronic pain and depression

Depression and painful somatic symptoms commonly occur together. Depression and chronic pain can have devastating effects on a patient's health, productivity, and overall quality of life. When moderate-to-severe pain exists, it can impair patient function while making treatment more difficult or resistant, with increased severity in depressive symptoms and worse outcomes. A variety of chronic pain syndromes exist, including diabetic neuropathy. A high prevalence of patients with chronic pain display depressive symptoms. Treatment for these conditions relies on pharmacologic therapy coupled with diligent, periodic assessments of changes in symptom severity. The link between pain and depression lies in the central and peripheral nervous systems. The brain stem serves as an important connection between the higher brain centers and the spinal cord. In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.