Milnacipran: a unique antidepressant?

Tricyclic antidepressants (TCAs) are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and norepinephrine reuptake inhibitors (SNRIs). Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine), and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1). Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug–drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability

Endothelial dysfunction in adipose triglyceride lipase deficiency

AbstractSystemic knockout of adipose triglyceride lipase (ATGL), the pivotal enzyme of triglyceride lipolysis, results in a murine phenotype that is characterized by progredient cardiac steatosis and severe heart failure. Since cardiac and vascular dysfunction have been closely related in numerous studies we investigated endothelium-dependent and -independent vessel function of ATGL knockout mice. Aortic relaxation studies and Langendorff perfusion experiments of isolated hearts showed that ATGL knockout mice suffer from pronounced micro- and macrovascular endothelial dysfunction. Experiments with agonists directly targeting vascular smooth muscle cells revealed the functional integrity of the smooth muscle cell layer. Loss of vascular reactivity was restored ~50% upon treatment of ATGL knockout mice with the PPARα agonist Wy14,643, indicating that this phenomenon is partly a consequence of impaired cardiac contractility. Biochemical analysis revealed that aortic endothelial NO synthase expression and activity were significantly reduced in ATGL deficiency. Enzyme activity was fully restored in ATGL mice treated with the PPARα agonist. Biochemical analysis of perivascular adipose tissue demonstrated that ATGL knockout mice suffer from perivascular inflammatory oxidative stress which occurs independent of cardiac dysfunction and might contribute to vascular defects. Our results reveal a hitherto unrecognized link between disturbed lipid metabolism, obesity and cardiovascular disease

Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

<div><p>Background</p><p>The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene <i>SLC6A4</i> and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence.</p><p>Methods</p><p>A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (V_max) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet V_max.</p><p>Results</p><p>The present study demonstrates that increases in platelet V_max significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within <i>SLC6A4</i>. Furthermore, functional connectivity analyses indicate that platelet V_max is related to global DMN activation and not intrinsic DMN connectivity.</p><p>Conclusion</p><p>This study provides evidence that platelet V_max predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal V_max coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.</p></div

Functional brain correlates of platelet 5-HT uptake velocity.

<p>(<b>A–B</b>) Figures display right-hemispheric surface mappings of a whole-brain correlation analysis between platelet V_max and BOLD activity (n = 48). Significant brain areas showed positive and negative correlations. Negatively correlated clusters comprised areas of the DMN such as regions within the mPFC/ACC as well as the PCC, MTG, and ITG. Positive correlations were found in the fronto-parietal control system encompassing the CEN and SN with a significant cluster located in the right MOC and PMC. The corresponding left-hemispheric mapping is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092543#pone.0092543.s002" target="_blank">Figure S2</a>. Colorbar represents t-values. (<b>C</b>) Scatter plot shows the negative relationship between platelet V_max and BOLD activity averaged across the mPFC cluster (peak at [−7.7, 44.1, 27.5]). (<b>D</b>) Scatter plot shows the positive relationship between platelet V_max and BOLD activity averaged across the MOC cluster (peak at [20.8, −21.6, 69.1]). All analyses are controlled for age, gender and 5-HTTLPR. Serotonin, 5-HT; maximal 5-HT uptake velocity, V_max; default mode network, DMN; medial prefrontal cortex, mPFC; anterior cingulate cortex, ACC; posterior cingulate cortex, PCC; middle temporal gyrus, MTG; inferior temporal gyrus, ITG; central executive network, CEN; salience network, SN; motor cortex, MOC; premotor cortex, PMC; blood-oxygen-level dependent, BOLD; a.u., arbitrary units.</p

Correlation analysis between maximal platelet 5-HT uptake velocity (V_max) and neuronal activation (n = 48).

<p>Medial prefrontal cortex, mPFC; anterior cingulate cortex, ACC; motor cortex, MOC; premotor cortex, PMC; posterior cingulate cortex, PCC; precuneus, PRE; middle temporal gyrus, MTG; inferior temporal gyrus, ITG; p, uncorrected p value; significance level after correction for multiple comparisons based on recent recommendations <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092543#pone.0092543-Johnson1" target="_blank">[63]</a>: ***p<0.001; **p<0.005; *p<0.05; x, y, z are coordinates in Talairach space; L, left hemisphere; R, right hemisphere; cluster size expressed as number of voxels.</p