Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3–4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs.

Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT_1A receptor), (2) the effect of dimerization of 5-HT₇ and 5-HT_1A receptors on the internalization and functioning of 5-HT_1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI.

Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.     

Venlafaxine alters microvascular perfusion, [I]-beta-CIT binding and BDI scores in flushing postmenopausal women

Background

Although 70% of postmenopausal women suffer from hot flashes the pathophysiology is poorly understood. The serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine provides relief of flushing although the mechanism is unknown and could involve a central effect and/or a peripheral effect. Using single photon emission computed tomography (SPECT) we studied the central serotonin transporter (SERT) in vivo using [¹²³I]-beta-carbomethoxy-3-β-(4-iodophenyl)tropane (beta-CIT) and, as previous studies have shown that reactivity of the skin blood vessels is enhanced in those who flush, we examined cutaneous microvascular perfusion.

Methods

Cutaneous microvascular perfusion was assessed in 31 postmenopausal women, with flushing, using laser Doppler imaging with iontophoresis (LDI + ION), before and after 8 weeks of treatment with venlafaxine. A sub-group of 14 of these women also had SPECT imaging at both time points to evaluate the availability of SERT in the brain. Flush frequency and score was recorded, and Beck Depression Inventory (BDI) II scores were assessed before and after treatment.

Results

Following treatment with venlafaxine, there was a significant reduction in the [¹²³I]-beta-CIT binding ratio, BDI scores, flushing and endothelial dependent perfusion response. [¹²³I]-Beta-CIT reduction was associated with BDI reduction (r² = 0.54; F = 8.8; p = 0.004), but not flushing reduction or perfusion reduction.

Conclusions

Venlafaxine resulted in a decrease in BDI II scores with an associated reduction in [¹²³I]-beta-CIT binding in a group of non-depressed women. It also improved flush frequency and severity which may be as a result of decreases seen in enhanced cutaneous microvascular perfusion.     

米安色林与SSRI治疗对男性抑郁症引起的性功能障碍影响程度的差异

目的：考察米安色林与SSRI治疗对男性抑郁症引起性功能障碍的差异。方法：选择2010年2月至2013年4月本院精神科门诊治疗的男性抑郁症患者95例,随机分为两个组别,45例米安色林组,50例SSRI治疗组,治疗2个疗程,收集两个组别治疗前后的HAMD和IIEF-5评分。结果：两个组别的疗效无显著差异（P〉0．05）。两个组别治疗前和治疗2w的HAMD与治疗前的IIEF-5评分无显著差异（P〉0．05）。与米安色林组比,SSRI组治疗5～10w的HAMD和治疗2—10w的IIEF-5评分有显著差异（P〈0．05）。结论：米安色林与SSRI类抗抑郁药有着同样肯定的疗效,能够改善性功能障碍。     

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。     

Diuretic-induced hyponatremia and osteoporotic fractures in patients admitted to the emergency department

Objective

Hyponatremia is a complication of diuretic treatment and has been recently identified as a novel factor associated with osteoporosis and fractures. The impact of diuretic-associated electrolyte disorders on osteoporotic fractures (OF) has rarely been studied systematically.

Design and setting

We conducted a study in patients presenting to the emergency department at the University Hospital Bern. In this retrospective case series analysis of prospectively gathered data, over a 2-year period we identified 10,823 adult (≥50 years) outpatients with a measured baseline serum sodium, at admission to the hospital. OF patients were compared to a control group without fractures using standard statistical methods.

Results

Four hundred and eighty (5%) patients had 547 OF. The OF group had a higher mean age (73 vs. 68 years, p < 0.0001), smaller proportion of men (37% vs. 58%, p < 0.0001), higher hospitalisation rate (83% vs. 62%, p < 0.0001) and longer hospital stay (8 vs. 6 days, p < 0.0001). Any diuretic agent (p < 0.0001), loop diurietics (p = 0.02), spironolactone (p = 0.02) and amiloride (p < 0.01) were used significantly more in OF patients, but not thiazides (p = 0.68). The prevalence of hyponatremia increased significantly (p < 0.0001) with the number of diuretics taken. Advanced age (odds ratio [OR] 1.04, p < 0.0001), hyponatremia (OR 1.46, p = 0.011) higher serum creatinine (OR 1.53, p = 0.0001), furosemide use alone (OR 1.40, p = 0.01) and co-treatment with amiloride (OR 2.22, p = 0.02) were associated with a higher risk for OF.

Conclusions

This study highlights the clinical association of hyponatremia during the use of certain diuretics (i.e. furosemide or in combination, i.e. amiloride) with an increased risk of osteoporosis associated fractures. Although evidence-based data is currently lacking a pragmatic approach concerning hyponatremia monitoring and correction appears reasonable in selected groups of patients.     

Gray colored glasses: Is major depression partially a sensory perceptual disorder?

Background

Major depression is a neuropsychiatric disorder that can involve profound dysregulation of mood. While depression is associated with additional abnormalities besides reduced mood, such as cognitive dysfunction, it is not well established that sensory perception is also altered in this disorder (aside from in psychotic depression). Recent studies have shown that visual processing, in as early a stage as the retina, is impaired in depression. This paper examines the hypothesis that major depression can involve alterations in sensory perception.

Methods

A Pubmed literature search investigated several lines of evidence: innervation of sensory cortex by serotonin and norepinephrine; antidepressant drugs and depression itself affecting processing of facial expressions of emotion; electroencephalography (EEG) studies of depressed persons and antidepressant drugs; involvement of the serotonergic 5HT2A receptor in both depression and hallucinogenic drug action; psychotic depression involving sensory distortions; dopamine possibly playing a role in depression; and the antidepressant effect of blocking the NMDA receptor with ketamine.

Results

Data from each of these lines of evidence support the hypothesis that major depression can involve sensory perceptual alterations.

Conclusions

Loss of interest in one's daily activities and inability to experience pleasure, also known as anhedonia, in major depression may in part be mediated by sensory abnormalities, whereby normal sensory perceptions are no longer present to activate reward circuitry.

Limitations

The data supporting the hypothesis tend to be associative, so further confirmation of the hypothesis awaits additional controlled experiments.