Duloxetine ameliorates lipopolysaccharide-induced microglial activation by suppressing iNOS expression in BV-2 microglial cells.

RATIONALE: It is known that both selective serotonin and serotonin noradrenaline reuptake inhibitors (SSRI, SNRI) are first-line drugs for the treatment of major depressive disorder. It has also been considered that both SSRI and SNRI can improve the symptoms of major depressive disorder by increasing the concentration of monoamine in the synaptic cleft based on the monoamine hypothesis. However, accumulating evidence has indicated that inflammation in the brain may be a key factor in the pathophysiological mechanisms that underlie the development of major depressive disorder. OBJECTIVES: It has been advocated that microglial cells may regulate the inflammatory response under pathological conditions such as major depressive disorder. In this study, we focused on whether duloxetine can ameliorate the inflammatory response induced by lipopolysaccharide (LPS) in BV-2 microglial cells. RESULTS: Our results indicated that duloxetine significantly decreased the NO production induced by LPS. The increase in the protein expression level of iNOS induced by LPS was significantly decreased by treatment with duloxetine. Moreover, the increases in the protein expression levels of phosphorylated-IκBα, phosphorylated-Akt and Akt induced by LPS were also significantly decreased. Unexpectedly, the protein expression levels of other pro-inflammatory factors such as COX-2 and the phosphorylation ratios for various molecules including IκBα and Akt were not changed by treatment with duloxetine. CONCLUSIONS: These findings suggest that duloxetine may have an anti-inflammatory effect, which could contribute to its therapeutic effectiveness for major depressive disorder.

Low plasma serotonin linked to higher nigral iron in Parkinson's disease.

A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson's disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin (p < 0.0001) and higher nigral iron content (SNc: p < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) = - 0.501, p < 0.001). This correlation was significant even in patients newly diagnosed (< 1 year) and stronger in the SNc than any other region examined. This study reveals an early, linear association between low serotonin and higher nigral iron in PD patients, which is absent in controls. This is consistent with a serotonin-iron relationship in the disease process, warranting further studies to determine its cause and directionality.

Cisplatin-induced neurotoxicity involves the disruption of serotonergic neurotransmission.

Neurotoxicity is a frequent side effect of cisplatin (CisPt)-based anticancer therapy whose pathophysiology is largely vague. Here, we exploited C. elegans as a 3R-compliant in vivo model to elucidate molecular mechanisms contributing to CisPt-induced neuronal dysfunction. To this end, we monitored the impact of CisPt on various sensory functions as well as pharyngeal neurotransmission by recording electropharyngeograms (EPGs). CisPt neither affected food and odor sensation nor mechano-sensation, which involve dopaminergic and glutaminergic neurotransmission. However, CisPt reduced serotonin-regulated pharyngeal pumping activity independent of changes in the morphology of related neurons. CisPt-mediated alterations in EPGs were fully rescued by addition of serotonin (5-HT) (≤ 2 mM). Moreover, the CisPt-induced pharyngeal injury was prevented by co-incubation with the clinically approved serotonin re-uptake inhibitory drug duloxetine. A protective effect of 5-HT was also observed with respect to CisPt-mediated impairment of another 5-HT-dependent process, the egg laying activity. Importantly, CisPt-induced apoptosis in the gonad and learning disability were not influenced by 5-HT. Using different C. elegans mutants we found that CisPt-mediated (neuro)toxicity is independent of serotonin biosynthesis and re-uptake and likely involves serotonin-receptor subtype 7 (SER-7)-related functions. In conclusion, by measuring EPGs as a surrogate parameter of neuronal dysfunction, we provide first evidence that CisPt-induced neurotoxicity in C. elegans involves 5-HT-dependent neurotransmission and SER-7-mediated signaling mechanisms and can be prevented by the clinically approved antidepressant duloxetine. The data highlight the particular suitability of C. elegans as a 3R-conform in vivo model in molecular (neuro)toxicology and, moreover, for the pre-clinical identification of neuroprotective candidate drugs.

Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice.

Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 µg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 µg), or MDL-72222 (5-HT3 receptor antagonist, 10 µg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

Dual µ-opioid receptor and norepinephrine reuptake mechanisms contribute to dezocine- and tapentadol-induced mechanical antiallodynia in cancer pain.

Dezocine is an opioid analgesic widely used in China, occupying over 45% of the domestic market of opioid analgesics. We have recently demonstrated that dezocine produced mechanical antiallodynia and thermal antihyperalgesia through spinal µ-opioid receptor activation and norepinephrine reuptake inhibition in neuropathic pain. This study further explored the dual µ-opioid receptor and norepinephrine reuptake mechanisms underlying dezocine-induced mechanical antiallodynia in bone cancer pain, compared with tapentadol, the first recognized analgesic in this class. Dezocine and tapentadol, given subcutaneously, exerted profound mechanical antiallodynia in bone cancer pain rats in a dose-dependent manner, yielding similar maximal effects but different potencies: ED50s of 0.6 mg/kg for dezocine and 7.5 mg/kg for tapentadol, respectively. Furthermore, their mechanical antiallodynia was partially blocked by intrathecal injection of the specific µ-opioid receptor antagonist CTAP, but not κ-opioid receptor antagonists GNTI and nor-BNI or δ-opioid receptor antagonist naltrindole. Intrathecal administrations of the specific norepinephrine depletor 6-OHDA (but not the serotonin depletor PCPA) for three consecutive days and single injection of the α-adrenoceptor antagonist phentolamine/α2-adrenoceptor antagonist yohimbine partially blocked dezocine- and tapentadol-induced mechanical antiallodynia. Strikingly, the combination of CTAP and yohimbine nearly completely blocked dezocine- and tapentadol-induced mechanical antiallodynia. Our results illustrate that both dezocine and tapentadol exert mechanical antiallodynia in bone cancer pain through dual mechanisms of µ-opioid receptor activation and norepinephrine reuptake inhibition, and suggest that the µ-opioid receptor and norepinephrine reuptake dual-targeting opioids are effective analgesics in cancer pain.

Duloxetine Enhances TRAIL-mediated Apoptosis via AMPK-mediated Inhibition of Autophagy Flux in Lung Cancer Cells.

BACKGROUND/AIM: The antidepressant duloxetine is known as a serotonin-norepinephrine reuptake inhibitor, used for treating depression and anxiety. TRAIL selectively induces cell death in a variety of tumor cells by binding to its membrane death receptor (DR). The aim of the study was to examine whether duloxetine affects TRAIL-mediated apoptosis. MATERIALS AND METHODS: Cell viability and apoptosis was measured by morphological image, crystal violet staining, MTT and LDH assay. Immunocytochemistry and western blotting techniques were applied to detect autophagy and apoptosis indicator proteins. TEM assay was used to determine the autophagy. RESULTS: Duloxetine treatment considerably sensitizes human lung adenocarcinoma cells to TRAIL-mediated apoptosis by targeting TRAIL-DR5. Treatment with duloxetine inhibited AMPK phosphorylation and resulted in increased p62 and microtubule-associated protein 1A/1B light chain 3B-II levels, indicating inhibition of autophagy flux. Blockade of DR5 with DR5-specific small-interfering RNA negatively regulated the apoptotic effect. CONCLUSION: Clinical administration of TRAIL in combination with duloxetine may serve as a therapeutic approach for the treatment of TRAIL-resistant lung cancer cells.

Serotonin and Norepinephrine Reuptake Inhibitors.

This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.

Milnacipran: serotonin-noradrenaline reuptake inhibitor approved for fibromyalgia may be a useful antidepressant.

OBJECTIVE: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. CONCLUSION: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50-200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth.

S100B, a member of the multigene family of Ca2+-binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1-5 µM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro. In vivo, however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.

Tumor growth activity of duloxetine in Ehrlich carcinoma in mice.

OBJECTIVE: The objective of this study was to analyze whether duloxetine influences tumor growth in Ehrlich carcinoma. The mice were administered 5 or 30 mg/kg of duloxetine or saline solution. All animals were inoculated with tumor cells. The tumor progression was evaluated by body weight, abdominal circumference, ascites volume and tumor cell count. The effect of duloxetine on immune response was evaluated by lymphoid cells, nitric oxide (NO) production, arginase and superoxide dismutase (SOD) activity and the spleen immunophenotyping. RESULTS: There was no difference between the groups regarding weight, abdominal circumference, ascites volume and number of tumor cells. Duloxetine increased the cells of the inguinal lymph node. There was no difference in the number of cells in the bone marrow and spleen. Ascites SOD activity was greater in Duloxetine groups. There were no differences in the levels of NO, nitrite, and arginase. The number of antibody for CD3 (CD3+), CD4+, CD8+ and CD28+ cells was lower in the duloxetine groups. In conclusion, duloxetine has no direct effect on tumor growth and does not alter immunity. The drug increased the SOD that fights free radicals and led the migration of lymphocytes, suggesting that duloxetine could be used in tumor-bearing individuals.

Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E.

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2-/-), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety- and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons. In Eif4e ki/ki mice, brain IκBα, was decreased, while the NF-κB target, TNFα was elevated. TNFα inhibition in Eif4e ki/ki mice rescued, whereas TNFα administration to wild-type mice mimicked the depression-like behaviors and 5-HT synaptic deficits. We conclude that eIF4E phosphorylation modulates depression-like behavior through regulation of inflammatory responses.

Aprepitant and fosaprepitant drug interactions: a systematic review.

AIMS: Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant. METHODS: We systematically reviewed the literature to September 11, 2016, to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale. RESULTS: A total of 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified, as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin. CONCLUSIONS: The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.

Panicolytic-like effect of tramadol is mediated by opioid receptors in the dorsal periaqueductal grey.

Tramadol is a synthetic opioid prescribed for the treatment of moderate to severe pain, acting as agonist of µ-opioid receptors and serotonin (5-HT) and noradrenaline (NE) reuptake inhibitor. This study evaluated the effects of tramadol in rats submitted to the elevated T-maze (ETM), an animal model that evaluates behavioural parameters such as anxiety and panic. Male Wistar rats were intraperitoneally (i.p.) treated acutely with tramadol (16 and 32mg/kg) and were submitted to the ETM. Tramadol (32mg/kg) promoted a panicolytic-like effect. Considering that dorsal periaqueductal grey (dPAG) is the main brain structure related to the pathophysiology of panic disorder (PD), this study also evaluated the participation of 5-HT and opioid receptors located in the dPAG in the panicolytic-like effect of tramadol. Seven days after stereotaxic surgery for implantation of a cannula in the dPAG, the animals were submitted to the test. To assess the involvement of 5-HT1A receptors on the effect of tramadol, we combined the 5-HT1A receptor antagonist, WAY100635 (0.37nmol), microinjected intra-dPAG, 10min prior to the administration of tramadol (32mg/kg, i.p.). WAY100635 did not block the panicolytic-like effect of tramadol. We also associated the non-selective opioid receptor antagonist, naloxone, systemically (1mg/kg, i.p.) or intra-dPAG (0.5nmol) administered 10min prior to tramadol (32mg/kg, i.p.). Naloxone blocked the panicolytic-like effect of tramadol in both routes of administrations, showing that tramadol modulates acute panic defensive behaviours through its interaction with opioid receptors located in the dPAG.

Current and emerging therapies in premature ejaculation: Where we are coming from, where we are going.

Premature ejaculation is the most common form of sexual dysfunction among men. The pathophysiology of premature ejaculation appears to be multifactorial, implicating the need for multimodal therapeutic regimens to successfully treat premature ejaculation. Multiple treatment regimens have been shown to be effective in extending the time between penetration and ejaculation. These treatment modalities include everything from behavioral modifications and medications to diet alterations and major surgery. The goal of the present article was to review the commonly used treatment regimens used in the treatment of premature ejaculation, as well as to introduce and discuss the newest treatment routines under study for the treatment of premature ejaculation.

Cost-Effective Drug Switch Options After Unsuccessful Treatment With an SSRI for Depression.

OBJECTIVE: Multiple treatment options are available for patients who do not respond to initial treatment for major depressive disorder. Previous results show that bupropion, sertraline, and venlafaxine are comparable in terms of therapeutic effectiveness following unsuccessful treatment with citalopram. In this study, we extended these results by incorporating costs of treatment to determine if one option was more cost-effective relative to others. METHODS: In the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial, 727 patients were randomly assigned to a switch drug treatment during level 2; 239 (33%) were assigned to bupropion, 238 (33%) to sertraline, and 250 (34%) to venlafaxine. For each study medication, the total costs included the costs of the medication, other concomitant medication and antidepressants, and health care facility utilization. Effectiveness was measured as remission and response. Cost-effectiveness was assessed as net health benefits. Stochastic analysis was performed by using the bootstrapping method. RESULTS: During level 2, mean medication costs were significantly higher for venlafaxine than for bupropion and sertraline ($968, $607, and $703, respectively). There were no significant differences among the switch medications in costs for other medications and health care facility utilization. Although the total costs were significantly different for the three medications (p=.025), none of the pairwise differences between medications were significant. Also, after jointly estimating costs and effects, the analyses found that net health benefits were not significantly different among the three drugs. CONCLUSIONS: After unsuccessful treatment with citalopram, the switch options of bupropion, sertraline, and venlafaxine were not significantly different from each other in terms of cost-effectiveness.

[Between depression and fibroniyalgia: the fate of the antidepressant].

The authors present the information about one of the least studied antidepressants- milnacipran. Recommendations of its clinical use have been long based on incorrect conceptions of its pharmacological properties. Currently, milnacipran is considered as ancirepinephrine and serotonin (to a lesser degree) reuptake inhibitor and NMDA receptor blocker. Milnacipran can be successfully used in apatic, asthenic, adynamic and anhedonic depressions as well as in fibromyalgia in patients with marked fatigability and pain. However the recommendations for the latter are not registered in Russia (maybe due to the differences in the diagnosis of fibromyalgia which is traditionally more often diagnosed as neurasthenia).

Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD.

BACKGROUND: The use of psychotropic medications, particularly antidepressants, is common in patients with inflammatory bowel disease (IBD) in spite of a lack of their robust efficacy in this population. This review provides an overview of the use trends of different classes of antidepressant and anti-anxiety medication and their effects on mood, nervous system function, gastrointestinal physiology and immunity drawing from the literature available in the general population, other medical conditions, and when available, patients with IBD. It also covers the evidence base for the actions, efficacy, and potential complications of antidepressants organized by different classes. METHODS: We conducted a PubMed search of articles relating the different drug classes probed to the terms above in different populations of interest. All types of articles were accepted including case reports and series, open and randomized trials, reviews, and expert opinion. We also examined the reference lists of the publications found. RESULTS: Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are the most commonly prescribed agents for anxiety and depression in patients with IBD, though their efficacy for these conditions in the general population are mild to moderate at best. SSRIs are generally well tolerated, though at higher doses, they, like most antidepressant classes, can be associated with activation, serotonergic syndrome, and increased suicidal ideation. TCAs have many more serious side effects but have some shown efficacy for functional GI symptoms. A newer class, the serotonin noradrenergic reuptake inhibitors (SNRIs), can be effective for refractory depression, anxiety and chronic pain syndromes with a side effect profile similar to both SSRIs and more mild manifestations of TCAs. Mirtazapine has moderate efficacy for depression if sedation and weight gain side effects are tolerated and some small support for use in nausea and vomiting. Bupropion targets dopamine and noradrenaline reuptake and has moderate efficacy for depression, and some small support for use in fatigue and smoking cessation. Buspirone has an indication for generalized anxiety disorder though studies show only a minimal benefit. It has some growing evidence for use in functional dyspepsia. Most of these agents have physiological effects on the brain, immune system, and gastrointestinal tract (with the exception of bupropion) hence their therapeutic and side effects manifested in these systems. CONCLUSION: Antidepressant medications are frequently prescribed for depression, anxiety disorders, and chronic pain syndromes, but overall support for their efficacy is modest at best. Psychological interventions have growing support for having much more robust effects without the side effects of antidepressants and should be considered first-line treatment or at least an adjunct to psychotropic medications for these conditions.

Electroacupuncture Enhances the Antiallodynic and Antihyperalgesic Effects of Milnacipran in Neuropathic Rats.

BACKGROUND: Milnacipran, a selective serotonin/norepinephrine-reuptake inhibitor, has been shown to elicit a beneficial effect in various models of neuropathic pain. Previously, we reported that repetitive electroacupuncture (EA) significantly ameliorates neuropathic pain induced by L5 spinal nerve ligation (SNL). In the present study, we sought to determine whether a single treatment with EA produces analgesia and whether EA in combination with a subeffective dosage of milnacipran exhibits an additive effect in SNL rats. METHODS: Mechanical allodynia and thermal hyperalgesia were assessed by measuring paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively, 1 day before and 5 days after neuropathic surgery. In addition, on day 5 post-SNL, time courses of behaviors were assessed at 0, 1, 2, 4, 6, and 8 hours after intrathecal (i.t.) milnacipran (1, 5, and 20 µg) administration. EA (10 Hz/1 mA) was administered at the ST36 and GB34 acupoints for 30 minutes on day 5 and the time courses of behaviors were also assessed at 0, 1, 2, 4, 6, and 8 hours later. Similarly, when treated in combination (milnacipran [5 µg, i.t.] and EA [10 Hz/1 mA]), time courses of behaviors were assessed at the same time points. RESULTS: Intrathecal injection of milnacipran at 5 or 20 µg exerted dose-dependent effects on thermal hyperalgesia but had similar efficacies on mechanical allodynia. Furthermore, EA itself detectably attenuated hyperalgesia at 4 hours after the application, but no statistically significant difference was found in mechanical allodynia. Importantly, cotreatment with EA and milnacipran (5 µL) produced more potent antiallodynic and antihyperalgesic effects than those obtained from EA or milnacipran alone at 1, 2, and 4 hours after treatment, indicating an additive effect. In addition, the analgesic effect of EA plus milnacipran was almost completely abolished by the catecholamine neurotoxin 6-hydroxydopamine hydrobromide (25 µg), which depletes spinal norepinephrine, and by yohimbine (an α2-adrenoceptor antagonist, 30 µg, i.t.). Somewhat surprisingly, the analgesic effect of milnacipran plus EA lasted for 6 hours. CONCLUSIONS: The study shows that, in male rats with SNL, spinal administration of milnacipran effectively alleviates mechanical allodynia and thermal hyperalgesia, and that a single treatment of EA has an antihyperalgesic effect. Furthermore, our findings suggest that coapplication of EA and milnacipran enhanced antiallodynia and antihyperalgesia by activating spinal noradrenergic systems coupled with spinal α2-adrenoceptors and prolongs the duration of analgesia.

Selective Serotonin-norepinephrine Re-uptake Inhibition Limits Renovas-cular-hypertension Induced Cognitive Impairment, Endothelial Dysfunction, and Oxidative Stress Injury.

Hypertension has been reported to induce cognitive decline and dementia of vascular origin. Serotonin- norepinephrine reuptake transporters take part in the control of inflammation, cognitive functions, motivational acts and deterioration of neurons. This study was carried out to examine the effect of venlafaxine; a specific serotonin-norepinephrine reuptake inhibitor (SNRI), in two-kidney-one-clip-2K1C (renovascular hypertension) provoked vascular dementia (VaD) in albino rats. 2K1C technique was performed to provoke renovascular-hypertension in adult male albino Wistar rats. Learning and memory were assessed by using the elevated plus maze and Morris water maze. Mean arterial blood pressure- MABP, as well as endothelial function, were assessed by means of BIOPAC system. Serum nitrosative stress (nitrite/ nitrate), aortic superoxide anion, brain oxidative stress, inflammation, cholinergic dysfunction and brain damage (2,3,5-triphenylterazolium chloride staining) were also assessed. 2K1C has increased MABP, endothelial dysfunction as well as learning and memory impairments. 2K1C method has increased serum nitrosative stress (reduced nitrite/nitrate level), oxidative stress (increased brain thiobarbituric acid reactive species and aortic superoxide anion content along with decreased levels of brain superoxide dismutase, glutathione, and catalase), brain inflammation (increased myeloperoxidase), cholinergic dysfunction (increased acetylcholinesterase activity) and brain damage. Treatment with venlafaxine considerably attenuated renovascular-hypertension induced cognition impairment, endothelial dysfunction, serum nitrosative stress, brain and aortic oxidative stress, cholinergic function, inflammation as well as cerebral damage. The finding of this study indicates that specific modulation of the serotonin-norepinephrine transporter perhaps regarded as potential interventions for the management of renovascular hypertension provoked VaD.

The effect of serotonin-noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats.

INTRODUCTION: Neuropathic pain, commonly related to intervertebral disk (IVD) degeneration, responds poorly to standard pain treatments. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce neuropathic pain; however their effect on radiculopathy induced by lumbar disk herniation remains unclear. The aim of this study was to investigate the effect of SNRI duloxetine in rat model of IVD-related neuropathic pain. MATERIALS AND METHODS: Effects of SNRI duloxetine were tested in Sprague-Dawley rats (n = 135). Neuropathic pain was induced by applying autologous nucleus pulposus (NP) on the left L5 dorsal root ganglion (DRG). Duloxetine in concentrations 0.4 mg/kg (low dose) and 1.2 mg/kg (high dose) or saline were administered orally for 10 days. Von Frey test was carried out on post-operative days 2, 7, 14, 21, and 28 to test pain sensitivity. Immunohistochemistry of L5 DRG and L5 segment of spinal cord (SC) was performed on days 7 and 21 to examine expressions of tumor necrosis factor alpha (TNF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ionized calcium-binding adapter molecule 1 (Iba1). On days 14, 21, and 28, expressions of TNF in DRG as well as NGF and BDNF in SC were tested by immunoblotting. Sham-operated rats and naive rats were used as controls. RESULTS: Duloxetine in both concentrations significantly improved pain threshold from postoperative day 21 onward, compared to the NP + saline group (p < 0.05). High-dose duloxetine significantly inhibited the expression of TNF in DRG (day 28, p < 0.05). Both duloxetine concentrations reduced the expression of NGF in SC (day 21, p < 0.05), but the expression of BDNF remained unchanged. CONCLUSION: SNRI duloxetine inhibited neuropathic pain in rats possibly via down-regulating TNF, NGF, and microglia activation. We conclude that duloxetine, and most likely other SNRIs, may be used for the management of lumbar neuropathic pain.