Norepinephrine Reuptake Inhibitor Venlafaxine Research Articles

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

IntroductionThe selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet.ObjectivesWe performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression.MethodsFour databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal.ResultsHigh-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml.ConclusionVEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Role of vortioxetine in the treatment of neuropathic pain.

Neuropathic pain is an important and disabling clinical problem, its management constitutes a challenge for healthcare professionals. Vortioxetine is a new antidepressant drug with multimodal action, which gives it a unique profile. Tricyclic antidepressants, in particular amitriptyline, and serotonin and norepinephrine reuptake inhibitors venlafaxine and duloxetine are first-line drugs in the treatment of neuropathic pain. The interaction between the pain and depression binomial is very frequent, being the most frequent psychological complication in patients with chronic pain. This comprehensive and descriptive review summarizes the most relevant pharmacological data on vortioxetine, as well as the specific literature on vortioxetine in neuropathic pain and chronic pain.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Post-traumatic Stress Disorder in Middle Age and Beyond.

To review the clinical manifestations and treatment of post-traumatic stress disorder (PTSD) in adults and older people. Articles indexed in PubMed, Embase, psychology databases, and the Cochrane library over the past 10 years using the key words "post-traumatic stress disorder," "stress disorders," and "post-traumatic stress disorder and treatment." Sixty-seven publications were reviewed and criteria supporting the primary objective were used to identify useful resources. The literature included practice guidelines; review articles; original research articles; and product prescribing information for the clinical manifestations, diagnosis, and treatment of PTSD. Psychotherapy is the first-line therapy for PTSD. Pharmacologic therapy is recommended, as second-line therapy, for adults living with PTSD who do not have access to psychotherapy or refuse psychotherapy. Pharmacologic therapy may also be considered in cases of partial, or no, response to psychotherapy. Current guidelines recommend prescribing one of 3 selective serotonin-reuptake inhibitors, either fluoxetine, paroxetine, or sertraline, or prescribing the serotonin norepinephrine reuptake inhibitor venlafaxine, for adult patients who do not have access to psychotherapy or prefer not to use psychotherapy. Unfortunately, these recommended medications have additional cautions for use in older people so may not be appropriate for many older people living with PTSD. Therapy for older people should be tailored to patient-specific symptoms, with careful consideration of the potential benefits and risks of the therapy and coexisting medical conditions of each patient.

Rapid, Precise and Affordable Estimation of Venlafaxine and Its Metabolites in Highly Polluted Effluent Waters: Proof-of-Concept for Methodology.

Widespread presence of pharmaceuticals and their metabolites in the environment of industrialized countries is an emerging global concern. Potential contamination of the soil and water by such pharmacologically active substances poses serious ecotoxicological implications. Several studies assessing the long-term ecological risks of pharmaceutical contaminants mainly focus on the risk assessment of the parent drug, while the potential contributions of their metabolites is often neglected. Presence of selective serotonin and norepinephrine reuptake inhibitor venlafaxine, an antidepressant drug, and its metabolites is a matter of serious concern for aquatic systems, since they are difficult to remove by traditional wastewater treatment processes. The concentration of VEN present in water is reportedly one of the highest among pharmaceuticals; however, the long-term effects of its metabolites have not yet been systematically studied. Given the consideration to complex and time-consuming effluent treatment, and realizing the importance of levels of venlafaxine and its metabolites, a simple and accurate analytical method for quick determination is needed. We designed a selective colorimetric method by using oxidative coupling of drug molecules with 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) reagent, to quantify the presence of venlafaxine and its metabolites in aquatic samples, with special emphasis on effluent. The method was validated for selectivity, specificity and robustness as per the ICH Q2 guidelines to assess its suitability in pharmaceutical samples, as well. Highly sensitive and green economical analytical method was successfully established for estimation of venlafaxine and its metabolites in aquatic samples. The method was quick, as it involved minimum processing steps. The method was accurate and linear in the range of 0.5 to 80 ppm and could successfully detect lowest concentration of 1.3 ppm, thus qualifying its applicability for the desired purpose to check the presence of trace levels of VEN or its metabolites in aquatic samples or in pharmaceutical formulations.

Ancestral Fluoxetine Exposure Sensitizes Zebrafish to Venlafaxine-Induced Reductions in Cortisol and Spawning.

Owing to the prevalence of depression during childbearing, mothers can be prescribed multiple antidepressants; however, little is known about the risk and consequences to the offspring or subsequent generations. Fluoxetine (FLX) is usually the first-line of pharmacological treatment for affective disorders in pregnant women, with venlafaxine (VEN) used as secondary treatment. Given that FLX and VEN readily cross the placenta, a fetus from a treated pregnant woman is potentially at risk of the endocrine disruptive effects of these chemicals. Pharmaceutical agents, including FLX and VEN, reach aquatic ecosystems through sewage release; thus, fish could also be inadvertently affected. We report the results from a 6-day FLX exposure during early zebrafish development to an environmentally relevant level (0.54 µg/L in water) and a concentration detected in the cord blood of FLX-treated pregnant women (54 µg/L in water). The FLX exposure reduced the stress response (arithmetic difference between the stress-induced and unstressed whole-body cortisol levels) in the adult female and male zebrafish, an effect that persisted for four generations. To model the possibility of a second antidepressant exposure, filial generation 4 was exposed to VEN (5 µg/L). We found that FLX exposure sensitized these descendants to VEN. VEN treatment further suppressed cortisol production in females and decreased spawning rates in adult pairs. This is an important demonstration that in an animal model, a brief ancestral exposure of great-great-grandparents to the selective serotonin reuptake inhibitor FLX will shape the physiological responses of future generations to the serotonin and norepinephrine reuptake inhibitor VEN.

Effect of pre-gestational stress and prenatal venlafaxine administration on cardiovascular system of rat offspring

Abstract A number of pregnant women all over the world suffer from depression and are treated during gestation with antidepressants, mostly with selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors. Exposure to prenatal stress is also a great risk factor for a developing fetus and could be responsible for altered fetal development or various neurobehavioral disturbances of a child. Administration of selective serotonin and norepinephrine reuptake inhibitor venlafaxine is associated with various cardiovascular adverse effects, such as tachycardia, increased blood pressure, arrhythmias and hypertensive crisis. The aim of this study was to focus on the effect of pre-gestational chronic mild unpredictable stress and/or administration of antidepressant venlafaxine (10 mg/kg/day, p. o.) on specific parameters, determining the function of the cardiovascular system of male and female rat offspring. Blood pressure and standard ECG were recorded in the offspring. Exposure to pre-gestational stress did not cause significant changes in the systolic, diastolic blood pressure and pulse frequency either in males or in females, compared to the unexposed control animals. Pre-gestational stress caused the shortening of QT interval and prolongation of QRS complex duration in males. On the other hand, in females, the effects of pre-gestational stress were potentiated by the administration of venlafaxine and resulted in elevated systolic and diastolic blood pressure, prolonged QT interval and shortened QRS complex duration, compared to the control. In conclusion, the female rat offspring are more sensitive to exposure to pre-gestational, to chronic mild unpredictable stress and venlafaxine.

Benlafaxinaren eragina ezegonkortasun sozial kronikoa jasandako sagu emeen sistema serotoninergiko zentralean eta jokabidean

Bi bider ohikoagoa da depresioaren diagnosia emakumeengan gizonezkoetan baino, eta, ondorioz, baita farmako antidepresiboen erabilera ere. Hala ere, estresarekin lotutako nahasteen eta haien tratamenduaren inguruko ikerketa gehienak animalia arretan egiten dira, eta ikerketetako emaitzak gizon nahiz emakumeetara orokortzen dira gero. Ildo horretatik, antsietatearen eta depresioaren aurkako tratamenduen eraginkortasuna sexuaren araberakoa da, berezitasun biologikoak izaki. Hori dela-eta, lan honek ezegonkortasun sozial kronikoaren estresa bizi duten sagu emeen jokabidean eta garuneko bide serotoninergikoan benlafaxinak —serotoninaren eta noradrenalinaren birkaptazioaren inhibitzailea— duen eragina du aztergai.

Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.

Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials. The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression. The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes. These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

Rescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3days and further differentiate for 7days in the presence of IL-1β (10ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10µM) or docosahexaenoic acid (DHA, 10µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Three Cases of Major Depression: Different Pharmacological Antidepressant Options

Three cases with different forms of major depression and different pharmacological antidepressant treatments are presented. In the first case report, citalopram, a selective serotonin reuptake inhibitor, improved transient depressive symptoms in a professionally busy man who recovers from the depressive symptoms and solves the social problems in his team. In the second case report showing a severe form of major depression and a suicide attempt, the tricyclic antidepressant drug doxepin failed to improve depressive symptoms. The selective serotonin and noradrenaline reuptake inhibitor venlafaxine partly improved depressive symptoms. Lithium carbonate, a prophylactic drug, which shows antidepressant and antimanic effects, treated depressive symptoms successfully. The cardiac and renal adverse effects were controlled. In the third case report, citalopram was used to treat the chronic form of major depression; however the adverse effects such as sedating and drive-reducing effects and the weight gain were disturbing for the patient. The administration of the selective dopamine and noradrenaline reuptake inhibitor bupropion ameliorated depressive symptoms and sleepiness, however caused hypertension and insomnia. Due to this changed medication, the patient succeeded in coping with a stressful life event, an anti-cancer therapy.

Anxiety and Depression in Parkinson’s Disease

Anxiety and depression, while very common problems in Parkinson's disease (PD), have not been subject to adequate treatment trials. While a handful of double blind placebo-controlled trials of depression have been published, only a small number of subjects have been enrolled in most of these. There have been no adequate treatment trials of anxiety. Thus, most practitioners base their treatments on what has been published in the general population and their own personal experience. The data suggest that depression is probably treatable in some cases, but there are no data to support any drug treatment of anxiety. Much of the rationale for treating these disorders is based primarily on side effect profiles rather than efficacy and is almost entirely based on anecdotal experience. Although we lack convincing data, we do believe in the pharmacologic treatment of depression and anxiety and choose medications based on side effect profiles, some of which may be useful. We favor the selective serotonin reuptake inhibitors (SSRIs) in general for both depression and anxiety because of their relative freedom from side effects but will often choose mirtazapine if insomnia or weight loss is a problem, clonazepam for anxiety without depression if an SSRI is insufficient or if REM sleep behavior disorder is a problem, or a tricyclic antidepressant if drooling is troubling and the patient is not demented. Alternatively, we use the serotonin and noradrenaline reuptake inhibitor venlafaxine in those who do not tolerate an SSRI. SSRIs cannot be used for anxiety on an as needed basis, whereas short-acting benzodiazepines may be useful for this purpose. Psychosocial treatments of both depression and anxiety have also been under-studied, with probable benefits and a benign adverse effect profile.

Antidepressants suppress neuropathic pain by a peripheral β2-adrenoceptor mediated anti-TNFα mechanism

Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through β2-adrenoceptors (β2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor α (TNFα) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on β2-ARs expressed by non-neuronal satellite cells. This stimulation of β2-ARs decreases the neuropathy-induced production of membrane-bound TNFα, resulting in relief of neuropathic allodynia. This indirect anti-TNFα action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the β2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.

In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation

BackgroundAlthough several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis. MethodsThis study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine. ResultsNone of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100μg/l, p<0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram > sertraline > reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen. ConclusionThis study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets.

Evidence-based pharmacotherapy of panic disorder: an update

The evidence-based pharmacotherapy of panic disorder continues to evolve. This paper reviews data on first-line pharmacotherapy, evidence for maintenance treatment, and management options for treatment-refractory patients. A Medline search of research on pharmacotherapy was undertaken, and a previous systematic review on the evidence-based pharmacotherapy of panic disorder was updated. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder, with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option. Temporary co-administration of benzodiazepines can be considered. Maintenance treatment reduces relapse rates, but further research to determine optimal duration is needed. For patients not responding to first-line agents several pharmacotherapy options are available, but there is a notable paucity of data on the optimal choice.

Comparison of Desvenlafaxine and Venlafaxine Ingestions Reported to Texas Poison Centers

Background: Desvenlafaxine is the major active metabolite of the serotonin norepinephrine reuptake inhibitor venlafaxine and is prescribed for the treatment of major depressive disorder. Objective: To compare desvenlafaxine and venlafaxine ingestions reported to a statewide poison center system. Methods: Cases included all desvenlafaxine and venlafaxine ingestions reported to Texas poison centers during 2008–2009. The distribution of all cases by selected demographic factors was identified. After cases that involved coingestants and/or were not followed to a final medical outcome were excluded, the distribution of the remaining cases by clinical and management factors was determined. Results: There were 144 desvenlafaxine and 777 venlafaxine ingestions. The distribution of desvenlafaxine and venlafaxine ingestions was, respectively, female patients 61.8% versus 64.2%, age 0–5 years 31.9% versus 19.3%, unintentional 47.2% versus 39.8%, and involving no coingestants 56.3% versus 46.7%. There were no coingestants and the medical outcome was known for 47 desvenlafaxine and 208 venlafaxine cases. The distribution of this subset of ingestions was, respectively, managed on site 40.4% versus 24.0%, already at or en route to a health-care facility 36.2% versus 52.9%, and referred to a health-care facility 23.4% versus 23.1%. The medical outcome was no effect 72.3% versus 56.3%, minor 14.9% versus 26.4%, moderate 10.6% versus 14.9%, and major 2.1% versus 2.4% for desvenlafaxine and venlafaxine, respectively. Conclusions: The patterns of desvenlafaxine and venlafaxine ingestions were generally similar. However, desvenlafaxine ingestions were more likely to involve young children, be unintentional, not involve coingestants, be managed on site, and involve no effect.

Broken heart syndrome: Tako Tsubo cardiomyopathy associated with an overdose of the serotonin–norepinephrine reuptake inhibitor Venlafaxine

To describe a case of Tako Tsubo cardiomyopathy [TTC] in a patient after an overdose of the serotonin-norepinephrine reuptake inhibitor [SNRI] Venlafaxine. We present a case study including clinical and laboratory data. Current relevant literature is reviewed and summarized in regard to Tako Tsubo syndrome and SNRI. A 43year-old woman was admitted with acute angina pectoris after accidentally taking an overdose on Venlafaxine in order to treat major depression. Because of the ECG-T-wave-inversions in the precordial leads, the slightly increased Troponin/Creatine kinase levels and the apical systolic dysfunction of the left ventricle in echocardiogram a cardiac catheterization was performed. Coronary artery disease could be excluded by coronary angiography. The followed laevocardiography and cardiac MRI scan showed apical akinesis and basal hypercontractibility typical for apical ballooning (Tako Tsubo cardiomyopathy). Urine analysis revealed elevated normetanephrine level potentially caused by Venlafaxine. Six weeks after the first admission the echocardiogram showed a complete recovery to normal left ventricular function. To our knowledge this is the first reported case of an overdose of Venlafaxine (SNRI) associated Tako Tsubo cardiomyopathy.

Co-administered gabapentin and venlafaxine in nerve injured rats: Effect on mechanical hypersensitivity, motor function and pharmacokinetics

A high proportion of patients suffering from neuropathic pain do not receive satisfactory pain relief from their current treatment, due to incomplete efficacy and dose-limiting adverse effects. Hence, one strategy to improve treatment outcome is the use of a combination of analgesic drugs. The potential benefits of such approach include improved and prolonged duration of analgesic effect and fewer or milder adverse effects with lower doses of each drug. Gabapentin is recommended as a first-line drug in the treatment of neuropathic pain, and has recently been demonstrated to act on supraspinal structures to stimulate the descending noradrenergic pain inhibitory system. Hypothetically, the analgesic effect of gabapentin may be potentiated if combined with a drug that prolongs the action of noradrenaline. In this study, gabapentin was co-administered with the serotonin and noradrenaline reuptake inhibitor venlafaxine, and subsequently evaluated for its effect on mechanical hypersensitivity in the rat spared nerve injury model of neuropathic pain. In this model, two branches of the sciatic nerve (the tibial and common peroneal nerves) are ligated and cut, leaving the third branch (the sural nerve) intact to innervate the hind paw of the animal. Treatment-induced ataxia was tested in order to exclude biased effect measurements. Finally, the pharmacokinetics of gabapentin was investigated alone and in combination with venlafaxine to elucidate any alterations which may have consequences for the pharmacological effect and safety. The overall effect on nerve injury-induced hypersensitivity of co-administered gabapentin (60 mg/kg s.c.) and venlafaxine (60 mg/kg s.c.), measured as the area under the effect-time curve during the three hour time course of testing, was similar to the highest dose of gabapentin (200 mg/kg s.c.) tested in the study. However, this dose of gabapentin was associated with ataxia and severe somnolence, while the combination was not. Furthermore, when administered alone, an effect delay of approximately one hour was observed for gabapentin (60 mg/kg s.c.) with maximum effect occurring 1.5 to 2.5 h after dosing, while venlafaxine (60 mg/kg s.c.) was characterised by a rapid onset of action (within 30 min) which declined to baseline levels before the end of the three hour time of testing. The effect of co-administered drugs (both 60 mg/kg s.c.), in the doses used here, can be interpreted as additive with prolonged duration in comparison to each drug administered alone. An isobolographic study design, enable to accurately classify the combination effect into additive, antagonistic or synergistic, was not applied. The pharmacokinetics of gabapentin was not altered by co-administered venlafaxine, implying that a pharmacokinetic interaction does not occur. The effect of gabapentin on the pharmacokinetics of venlafaxine was not studied, since any alterations are unlikely to occur on the basis of the pharmacokinetic properties of gabapentin. In conclusion, the results from this preclinical study support the rationale for improved effect and less adverse effects through combination therapy with gabapentin and venlafaxine in the management of neuropathic pain.

Suppressive effect of mirtazapine on the HPA system in acutely depressed women seems to be transient and not related to antidepressant action

Impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system is a consistent finding among patients with depression, which can be most sensitively detected with the combined dexamethasone (dex)/corticotrophin releasing hormone (CRH) test. The majority of patients with acute depression shows an exaggerated plasma corticotrophin (ACTH) and cortisol response to this test that normalizes gradually during successful antidepressant therapy. In contrast, persistently high HPA-responses to this challenge are prognostically less favorable. It has been recently questioned, whether this observation applies also to treatment with the atypical antidepressant mirtazapine, as patients treated with this drug showed a distinct attenuation of the endocrine response to the dex/CRH test already after 1 week of treatment. In the present study, we investigated whether the attenuating effect of mirtazapine on the HPA system is an acute pharmacological reaction disappearing after physiological adaptation or whether this effect is related to the antidepressant action of the drug. We examined plasma ACTH and cortisol responses to the dex/CRH test in acutely depressed inpatients treated either with mirtazapine (n=55) or a monoamine reuptake inhibitor (n=105) according to doctor's choice and compared the test results with healthy controls (n=40). Patients treated with monoamine reuptake inhibitors received either selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or the combined serotonin and noradrenalin reuptake inhibitor venlafaxine. We found increased plasma ACTH and cortisol responses to the dex/CRH test in depressed patients compared with healthy controls, but also significantly (p=.017) attenuated plasma cortisol secretion in the mirtazapine group compared to the group of monoamine reuptake inhibitor treated patients. This effect was not significant in male patients. Furthermore this effect was independent of the psychopathological state, but depended on treatment duration. Patient treatment with mirtazapine for up to 7 days resulted in dex/CRH test outcome that was indistinguishable from controls. This effect, however waned as it was not observable in patients treated for a longer period. These results suggest that short-term administration of mirtazapine has immediate but only transient suppressive effects on the HPA system predominantly in women. Our results confirm that dex/CRH tests can be used as predictors of clinical course also under mirtazapine treatment.

Desvenlafaxine succinate for the treatment of major depressive disorder

Major depressive disorder (MDD) remains one of the most common psychiatric disorders with high morbidity and mortality. Effective treatment is limited and response/remission to antidepressant pharmacotherapy remains poor and unpredictable. The development of new antidepressants is thus of great importance to the field. Desvenlafaxine succinate (DVS) is the active metabolite of the serotonin and noradrenaline re-uptake inhibitor venlafaxine and was recently FDA approved for the treatment of MDD. DVS showed efficacy in clinical trials in MDD with doses ranging from 50 – 400 mg. Advantages compared to other antidepressants include once daily dosing at effective doses, no CYP450 metabolism and low drug–drug interactions. Concerns include side effect profile and moderate efficacy. DVS might be a useful addition to the arsenal of antidepressants available to the clinician. Additional studies, in particular head-to-head comparison to other antidepressants and long-term treatment studies, will be necessary to comprehensively evaluate DVS safety and efficacy for clinical practice.