Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.     

Pilot Randomized Clinical Trial of an SSRI vs Bupropion: Effects on Suicidal Behavior,Ideation, and Mood in Major Depression

Randomized controlled trials in depressed patients selected for elevated suicidal risk are rare. The resultant lack of data leaves uncertainty about treatment in this population. This study compared a serotonin reuptake inhibitor with a noradrenergic/dopaminergic antidepressant in major depression with elevated suicidal risk factors. We conducted a double-blind, randomized, clinical pilot trial of paroxetine (N=36) or bupropion (N=38) in DSM IV major depression with a suicide attempt history or current suicidal ideation. The effects during acute (8 weeks) and continuation treatment (up to 16 weeks) were measured. Main outcomes were suicidal behavior and ideation. The secondary outcome was modified 17-item Hamilton Depression Rating Scale score subtracting the suicide item (mHDRS-17). Treatment was not associated with time to a suicidal event and no treatment main effect or treatment × time interaction on suicidal ideation or mHDRS-17 was found. Exploratory model selection showed modest advantages for paroxetine on: (1) mHDRS-17 (p=0.02); and (2) in a separate model adjusted for baseline depression, for suicidal ideation measured with the Beck Scale for Suicidal Ideation (p=0.03), with benefit increasing with baseline severity. Depressed patients with greater baseline suicidal ideation treated with paroxetine compared with bupropion appeared to experience greater acute improvement in suicidal ideation, after adjusting for global depression. Given the lack of evidence-based pharmacotherapy guidelines for suicidal, depressed patients—an important public health population—this preliminary finding merits further study.     

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.     

新型抗抑郁药物的药物相互作用

新型抗抑郁药物的联合治疗及其与其他药物的联合应用可引起经细胞色素P450酶介导的多种药物的药动学改变,药物相互作用研究对临床合理用药具有重要意义。本文综述新型抗抑郁药物的药物相互作用,以期为临床用药提供参考。     

‘They won't do any harm and might do some good’: time to think again on the use of antidepressants?

Despite NICE guidance that should have limited it, antidepressant prescribing continues to increase. Research evidence suggests that much if not all of the observed efficacy should be attributed to complex non-specific effects rather than ‘restoration of disturbed brain chemistry’. According to this view the uncertain benefits of antidepressants are unlikely to outweigh the risks, suggesting the need to explore other approaches to treatment.     

枳术宽中胶囊对抑郁动物模型的抗抑郁作用研究

目的 研究枳术宽中胶囊对动物抑郁模型的抗抑郁作用.方法 采用小鼠强迫游泳试验、悬尾试验、利血平拮抗、5-羟色胺酸(5-HTP)增强,大鼠慢性应激等抑郁模型,观察枳术宽中胶囊的抗抑郁作用.结果 枳术宽中胶囊1.106 g/kg减少了悬尾小鼠和强迫游泳小鼠的不动时间.枳术宽中胶囊各剂量均能拮抗利血平腹腔注射后1h所致的小鼠降温作用.枳术宽中胶囊1.106 g/kg增加了小鼠甩头次数.对慢性应激大鼠,枳术宽中胶囊0.774 g/kg增加了水平运动,0.774g/kg、0.387 g/kg增加了大鼠蔗糖水偏嗜度,降低了血清皮质酮含量.枳术宽中胶囊0.774 g/kg增加了5HT1A受体表达.结论 枳术宽中胶囊可以改善动物抑郁行为,具有抗抑郁作用,其机制可能与改善5-羟色胺(5-HT)能神经元传递、抑制应激引起的皮质激素分泌有关.     

Income and attrition in the treatment of depression: a STAR*D report

Background: Attrition, or dropping out of treatment, remains a major issue in the care of depressed outpatients. Whether different factors are associated with attrition for different socioeconomic groups is not known. This report assessed whether attrition rates and predictors of attrition differed among depressed outpatients with different income levels. Methods: Outpatients with nonpsychotic major depressive disorder treated for up to 14 weeks with citalopram in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were divided by household incomes of <$20,000, $20,000–<$40,000, and ≥$40,000. Attrition rates and sociodemographic and clinical correlates of attrition were identified for each group. Results: Regardless of income level, remission rates were lower for participants who dropped out of treatment. Attrition rates increased as income decreased. For all income levels, younger age was independently associated with attrition. For the lowest income level, less education, better mental health functioning, being on public insurance, and having more concurrent Axis I conditions were associated with a greater likelihood of attrition. For the middle income group, less education, better mental health functioning, being Black or of another non‐White race, and treatment in a psychiatric versus primary‐care setting predicted greater attrition. For the highest income group, being Hispanic, having a family history of drug abuse, and melancholic features predicted attrition. Atypical symptom features (middle income group) and recurrent depression (highest income group) were associated with retention. Conclusions: Efforts to retain patients in antidepressant treatment should focus especially on less educated patients with lower household incomes and younger patients. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc.     

Total antioxidant capacity and total oxidant status in patients with major depression: Impact of antidepressant treatment

Aim:  The purpose of the present study was to investigate whether total antioxidant capacity (TAC) and total oxidant status (TOS) are associated with major depressive disorder (MDD) and to evaluate the impact of antidepressant treatment on TAC and TOS in MDD.
Methods:  Fifty-seven MDD patients and 40 healthy controls participated in the study. Serum TAC and TOS were measured both in patients and controls using Erel's methods. Patients were treated with antidepressant drugs for 12 weeks. The treatment course was evaluated using the Montgomery–Asberg Depression Rating Scale (MADRS) in all patients.
Results:  TOS and oxidative stress index (OSI) were higher ( P  = 0.0001 for both) and TAC was lower ( P  = 0.0001) in the MDD group compared with those of the controls. After 3 months of antidepressant treatment, TOS and OSI were decreased and TAC was increased compared with the pretreatment values ( P  = 0.0001, for all). Furthermore, there were significant positive correlations between the severity of the disease and serum TOS and OSI (r = 0.584, P  = 0.0001; r = 0.636, P  = 0.0001, respectively). A negative correlation was found between the severity of the disease and serum TAC (r = −0.553, P  = 0.0001) at the pre-treatment stage.
Conclusion:  Treatment administered for 3 months to MDD patients increases TAC while decreasing TOS and OSI.     

Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress

In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis. Rats received mifepristone on the last 4 days of a 21-day chronic unpredictable and inescapable stress regimen. Neurogenesis was analysed by stereological quantification of adult-generated cell survival (bromodeoxyuridine), young neuronal survival (doublecortin) and cell proliferation (Ki-67). The results show that only 4 days of mifepristone treatment normalized the stress-induced reductions in neurogenesis. Importantly, mifepristone by itself had no effect on neurogenesis. We conclude that, contrary to other compounds interfering with the effects of chronic stress on neurogenesis, like antidepressants, the normalizing effects of mifepristone on neurogenesis are rapid and particularly potent in a high stress environment. This neurogenic action of mifepristone could potentially contribute to its clinical mechanism of action.     

Eosinophilic pneumonia due to duloxetine

A 32-year-old man presented with a 2-month history of worsening fever, chills, and cough despite therapy with oral antibiotics. Chest radiographs demonstrated migrating, peripheral upper lobe infiltrates. A CBC count demonstrated significant eosinophilia. At bronchoscopy, eosinophil-rich mucus was seen impacted throughout his bronchi. A transbronchial biopsy confirmed the diagnosis of eosinophilic pneumonia. Symptoms, eosinophilia, and radiographic abnormalities were reversed with cessation of duloxetine. This case report briefly reviews the diagnosis of drug-induced pulmonary infiltrates with eosinophilia (PIEs) and eosinophilic pneumonia. To our knowledge, this is the first reported case of PIEs due to duloxetine.