Antidepressant Venlafaxine Research Articles

Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).

Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well-preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980s, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid–liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The response surface methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography–mass spectrometry with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidance (Food and Drug Administration (FDA)). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid and sensitive method. The analytical method was applied to 31 PF samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.

Dose-Corrected Serum Concentrations and Metabolite to Parent Compound Ratios of Venlafaxine and Risperidone from Childhood to Old Age.

Comparative pharmacokinetic data about the antidepressant venlafaxine (VEN) and the antipsychotic drug risperidone (RIS) over the lifespan and especially in children and adolescents is lacking. This is the first cross-sectional study that aimed to investigate differences in dose-corrected serum concentrations (CDs) and metabolite to parent compound ratios (MPRs) of VEN and RIS across the lifespan. Patients treated with VEN and RIS at the University Hospital of Würzburg, Germany were included in the study. Serum level determinations were performed during clinical routine care. Patients with CYP2D6 influencing co-medication were excluded from analyses. In 953 patients (12-93 years) treated with VEN and 552 patients (7-92 years) treated with RIS, children/adolescents (<18 years) showed 11% and 19%, and 44% and 42% lower CDs of the active moieties (CDsAM) of VEN and RIS than adults and elderly (≥60 years) (Kruskal-Wallis tests; p ≤ 0.001). However, when CDs were normalized to body weight, a different pattern emerged. Gender differences, with higher CDsAM in females were present in adults and elderlies but not in children/adolescents. No gender- or age-dependent difference in MPRs was found; however, 80% of MPRs of RIS in children/adolescents were below the range of "normal" CYP2D6 function for adults. We suggest a higher clearance as a reason for lower CDsAM of VEN and RIS in children/adolescents compared to adults/elderlies. Metabolism of VEN or RIS by CYP2D6, characterized by MPRs, was not associated with age. However, MPRs of RIS were lower in children/adolescents, possibly due to a higher renal clearance of 9-OH-risperidone.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio)

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 μg/L, 10 μg/L, 100 μg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 μg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 μg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 μg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 β hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 μg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

Zygotic Venlafaxine Exposure Impacts Behavioral Programming by Disrupting Brain Serotonin in Zebrafish.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is present in surface waters downstream of wastewater treatment plants. We previously showed that zygotic venlafaxine deposition alters larval behavior in zebrafish (Danio rerio), but the mechanisms were unknown. Here we tested the hypothesis that venlafaxine disrupts central serotonergic development, leading to impaired behavioral responses in zebrafish larvae. This was tested by microinjecting embryos with venlafaxine immediately after fertilization and performing spatial distribution of serotonin immunoreactivity, as well as characterizing target genes involved in serotonin turnover in the zebrafish brain. We provide evidence that venlafaxine exposure reduces serotonin immunoreactivity and tyrosine hydroxylase-positive cell populations in specific larval brain regions, and this corresponded with reduced larval activity observed in the drug-exposed group. Lowered serotonin was not due to either reduced synthesis or increased breakdown capacity. However, co-injection of serotonin alongside venlafaxine in embryos recovered brain serotonin immunoreactivity, tyrosine hydroxylase-positive cell populations, and rescued venlafaxine-mediated behavioral changes. Overall, our results demonstrate for the first time that early life exposure to venlafaxine perturbs brain development, which may be due to reduced serotonin, leading to altered larval behavior in zebrafish.

Study of the distribution of antidepressant drugs in vitreous humor using a validated GC/MS method

Vitreous humor has become in recent years an important alternative biological fluid in forensic toxicological analysis especially for the investigation of cases where alcohol and drugs of abuse are involved but there is limited scientific information regarding the distribution of antidepressant drugs in this material. This work aimed to study the distribution of antidepressant drugs in vitreous humor and to estimate the blood/vitreous humor concentration ratios of these drugs. For this purpose, a GC/MS method for the simultaneous determination of 9 antidepressant drugs, namely amitriptyline, nortriptyline, citalopram, clomipramine, fluoxetine, maprotiline, mirtazapine, sertraline and venlafaxine, and 4 of their metabolites, namely desmethylmaprotiline, desmethylmirtazapine, desmethylsertraline, O-desmethylvenlafaxine, was developed and validated. The developed method includes solid-phase extraction followed by derivatization with Heptafluorobutyric Anhydride. For all analytes, LOD and LOQ were 1.50 and 5.00ng/mL, respectively, and the calibration curves were linear within the dynamic range of 5.00–500.0ng/mL (R2≥0.990). The absolute recovery was found to be ≥86.3 % for all analytes. The accuracy (%Er) was found to range between -6.58 and 6.18 %, whereas the precision (%RSD) was less than 10.9 % for all analytes. The developed method was successfully applied to vitreous humor samples from 43 blood positive cases for antidepressant drugs. Whenever antidepressant drugs were detected in blood, they were also detected in the respective vitreous humor samples. The vitreous humor/blood concentration ratios were also calculated and were found to range from 0.04–7.07. Citalopram, mirtazapine, and its metabolite desmethylmirtazapine as well as venlafaxine and its metabolite O-desmethylvenlafaxine were the most identified substances in these samples (n≥4) and their results were better statistically evaluated. Our results suggest that vitreous humor could be an appropriate matrix for the determination of antidepressants in postmortem toxicology.

A combination of six psychoactive pharmaceuticals at environmental concentrations alter the locomotory behavior of clonal marbled crayfish

Pharmaceutically active compounds (PhACs) are ubiquitous in the aquatic environment worldwide and considered emerging contaminants. Their effects on growth, behavior, and physiological processes of aquatic organisms have been identified even at very low concentrations. Ecotoxicological investigations have primarily focused on single compound exposure, generally at a range of concentrations. In the natural environment, pollutants seldom occur in isolation, but little is known about the effects and risks of combinations of chemicals. This study aimed to investigate the effects of concurrent exposure to six psychoactive PhACs on locomotory behavior and life history traits of clonal marbled crayfish Procambarus virginalis. Crayfish were exposed to ~1 μg L−1 of the antidepressants sertraline, citalopram, and venlafaxine; the anxiolytic oxazepam; the opioid tramadol; and the widely abused psychostimulant methamphetamine. In the absence of shelter, exposed crayfish moved significantly shorter distances and at lower velocity and showed significantly less activity than controls. With available shelter, exposed crayfish moved significantly more distance, showed higher activity, and spent a significantly more time outside the shelter than controls. Molting, mortality, and spawning frequency did not vary significantly between the groups. Hemolymph glucose level did not vary among groups and was not correlated with observed behaviors. Results suggest that environmental concentrations of the tested compounds in combination can alter the behavior of non-target aquatic organisms as individual exposure of these compounds, which may lead to disruption of ecosystem processes due to their reduced caution in polluted conditions. Further research is needed using varied chemical mixtures, exposure systems, and habitats, considering molecular and physiological processes connected to behavior alterations.

Antidepressants and movement disorders: a postmarketing study in the world pharmacovigilance database

BackgroundAntidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and antidepressants’ classes. The objective of this study was to assess the putative association of each antidepressant and antidepressants’ classes with movement disorders.MethodsUsing VigiBase®, the WHO Pharmacovigilance database, disproportionality of movement disorders’ reporting was assessed among adverse drug reactions related to any antidepressant, from January 1967 to February 2017, through a case/non-case design. The association between nine subtypes of movement disorders (akathisia, bruxism, dystonia, myoclonus, parkinsonism, restless legs syndrome, tardive dyskinesia, tics, tremor) and antidepressants was estimated through the calculation first of crude Reporting Odds Ratio (ROR), then adjusted ROR on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders.ResultsOut of the 14,270,446 reports included in VigiBase®, 1,027,405 (7.2%) contained at least one antidepressant, among whom 29,253 (2.8%) reported movement disorders. The female/male sex ratio was 2.15 and the mean age 50.9 ± 18.0 years. We found a significant increased ROR for antidepressants in general for all subtypes of movement disorders, with the highest association with bruxism (ROR 10.37, 95% CI 9.62–11.17) and the lowest with tics (ROR 1.49, 95% CI 1.38–1.60). When comparing each of the classes of antidepressants with the others, a significant association was observed for all subtypes of movement disorders except restless legs syndrome with serotonin reuptake inhibitors (SRIs) only. Among antidepressants, mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan and fluvoxamine were associated with the highest level to movement disorders and citalopram, paroxetine, duloxetine and mirtazapine were the most frequently associated with movement disorders. An association was also found with eight other antidepressants.ConclusionsA potential harmful association was found between movement disorders and use of the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine and vilazodone. Clinicians should beware of these adverse effects and monitor early warning signs carefully. However, this observational study must be interpreted as an exploratory analysis, and these results should be refined by future epidemiological studies.

Insights on the metabolization of the antidepressant venlafaxine by meagre (Argyrosomus regius) using a combined target and suspect screening approach

Bioaccumulation of pharmaceuticals in fish exposed to contaminated water can be shaped by their capability to metabolize these xenobiotics, affecting their toxicity and animal welfare. In this study the in vivo metabolization of the antidepressant venlafaxine by the juvenile marine fish meagre (Argyrosomus regius) was evaluated using a combined target and suspect screening analytical approach. Thirteen venlafaxine metabolites were identified, namely N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine, which were unequivocally identified using analytical standards, and 11 more tentatively identified by suspect screening analysis, including two Phase II metabolites formed by amino acid conjugation. All of them were detected in the liver, while in plasma and brain only 9 and 6 metabolites, respectively, were detected. Based on these findings, for the first time, a tentative metabolization pathway of venlafaxine by A. regius is proposed. Contrarily to what happen in humans, N-demethylation was identified as the main route of metabolization of venlafaxine by fish. Our findings highlight species-specificity in the metabolization of venlafaxine and allow a better understanding of venlafaxine's toxicokinetic in fish. These results emphasize the need to investigate the biotransformation of xenobiotics by non-target organisms to have an integrated overview of their environmental exposure and to improve future evaluations of environmental risk assessment.

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model.

Comorbid depressive disorders confound the diagnosis and therapy of schizophrenia. Using a murine model incorporating both MK801 and chronic unpredictable mild stress exposures, we successfully replicated both psychosis and depression. Ex vivo patch clamp recordings and in vivo calcium imaging demonstrated impaired neural activity in the prefrontal cortex (PFC). We then administered triple-drug combinations consisting of two antidepressants (mirtazapine and venlafaxine) plus an antipsychotic (either clozapine or olanzapine), and found improved PFC neuronal activity and performance in behavioral assays. Moreover, the addition of metformin to both psychotropic drug combinations brought further improvements in depressive and schizophrenic-like behaviors and physiological parameters. In summary, our data modeled the neuropathophysiology of schizophrenia with comorbid depression, and may inform drug intervention strategies.

Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects.

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis-ordersin this age group and are used not infrequently off-label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta-review, we systematically searched network meta-analyses and meta-analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications - including antidepressants, antipsychotics, anti-attention-deficit/hyperactivity disorder (ADHD) medications and mood stabilizers - in children and adolescents with mental disorders. We included data from nine network meta-analyses, 39 meta-analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti-ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti-ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti-ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta-review of top-tier evidence regarding the safety of antidepressants, antipsychotics, anti-ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.

Novel Phenethylamines and Their Potential Interactions With Prescription Drugs: A Systematic Critical Review.

The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed. The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals. Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication. A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.

The Influence of Combined CYP2D6 and CYP2C19 Genotypes on Venlafaxine and O-Desmethylvenlafaxine Concentrations in a Large Patient Cohort.

The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population. Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference. The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%. The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.

LC-MS-MS Method for the Determination of Antidepressants and Benzodiazepines in Meconium.

An LC-MS-MS method for the determination of 14 benzodiazepines (BZDs) (alprazolam, α-hydroxyalprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, midazolam and zolpidem) and 15 antidepressants (ADs) (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, norclomipramine, fluoxetine, norfluoxetine, sertraline, norsertraline, paroxetine, venlafaxine, desmethylvenlafaxine, citalopram and desmethylcitalopram) in meconium was developed and validated. Meconium samples (0.25±0.02g) were homogenized in methanol and subjected to mixed-mode cation exchange solid-phase extraction. Chromatographic separation was performed in reversed phase, with a gradient of 0.1% formic acid in 2mM ammonium formate and acetonitrile. Two different chromatographic gradient methods were employed, one for the separation of ADs and another for BZDs. Analytes were monitored by tandem mass spectrometry employing electrospray positive mode in MRM mode (2 transitions per compound). Method validation included: linearity [n=5, limit of quantification (LOQ) to 400ng/g], limits of detection (n=6, 1-20ng/g), LOQ (n=9, 5-20ng/g), selectivity (no endogenous or exogenous interferences), accuracy (n=15, 90.6-111.5%), imprecision (n=15, 0-14.6%), matrix effect (n=10, -73 to 194.9%), extraction efficiency (n=6, 35.9-91.2%), process efficiency (n=6, 20.1-188.2%), stability 72h in the autosampler (n=3, -8.5 to 9%) and freeze/thaw stability (n=3, -1.2 to -47%). The method was applied to four meconium specimens, which were analyzed with and without hydrolysis (enzymatic and alkaline). The authentic meconium samples tested positive for alprazolam, α-hydroxyalprazolam, clonazepam, diazepam, nordiazepam, fluoxetine, norfluoxetine, clomipramine and norclomipramine. Therefore, the present LC-MS-MS method allows a high throughput determination of the most common BZDs and ADs in meconium, which could be useful in clinical and forensic settings.

No association between CYP2C19 genetic polymorphism with treatment remission to antidepressant venlafaxine in Han Chinese population.

Major depressive disorder (MDD) is a global mental health problem. As a serotonin-noradrenaline reuptake inhibitor (SNRI), the antidepressant venlafaxine is used to alleviate MDD clinically. Recent research has shown that Cytochrome P450 (CYP) enzymes affect venlafaxine efficacy by mediating its metabolism. The present study investigates genetic polymorphisms of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) are associated with remission after venlafaxine treatment for MDD. A total of 175 Han Chinese patients with depression were recruited to accept a 6-week treatment with venlafaxine. Three single-nucleotide polymorphisms of CYP2C19 were selected from dbSNP and previous literature to compare the allele and genotype frequencies between patients in remission and nonremission. Seventeen items Hamilton Depression Scale (17-HAMD) was used to access the outcomes of patients' depressive symptoms through the study. Our results denied the role of CYP2C19 polymorphisms for remission after venlafaxine treatment in MDD patients. CYP2C19 genetic polymorphism may not have association with SNRI venlafaxine treatment remission in the Han Chinese population.

Synthetic Cathinones and Their Potential Interactions with Prescription Drugs.

Substance use disorder often coexists with other psychiatric disorders, resulting in the simultaneous use of recreational and prescription drugs. The authors aimed to identify potential pharmacokinetic and pharmacodynamic interactions between new psychoactive substances of the cathinone class and specific prescription drugs. The authors performed a systematic literature review on interactions between synthetic cathinones (mephedrone, methylone, methylenedioxypyrovalerone, and alpha-pyrrolidinopentiophenone) and antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine), attention deficit hyperactivity disorder (ADHD) medications (atomoxetine, dexamphetamine, methylphenidate, modafinil) or HIV medications. Although no pharmacokinetic interactions have been reported in previous literatures, such interactions are likely to occur. Metabolic pathways of cathinones, antidepressants, and ADHD medications have been shown to overlap, including metabolism via cytochrome P450 enzymes and their inhibition. Consistent with this finding, interactions of bupropion (a cathinone) with antidepressants and ADHD medications have been found to increase their serum concentrations and half-lives. Additionally, limited pharmacodynamic interactions have been reported. However, as cathinones, antidepressants, and ADHD medications have been reported to increase the extracellular monoamine concentration by affecting reuptake transporters, interactions among these compounds are likely. Presumably, even higher monoamine concentrations could be observed when cathinones are combined with prescription drugs with a similar mode of action, as has been reported in animals exposed to duloxetine and bupropion. HIV medications have a different mode of action; thus, they have been reported to be less likely to have pharmacodynamic interactions with cathinones. Clinicians should be aware of possible interactions between synthetic cathinones and prescription drugs, which may increase the risk of drug toxicity or reduce the therapeutic efficacy of the drugs. Qualitative drug screening for cathinones using mass spectrometry methods may aid the early detection of these agents.

The omega-3 lipid 17,18-EEQ sensitizes TRPV1 and TRPA1 in sensory neurons through the prostacyclin receptor (IP)

Oxidized lipids play an important role in pain processing by modulation of the activity of sensory neurons. However, the role of many signalling lipids that do not belong to the classical group of eicosanoids, especially of oxidized omega-3 lipids in pain processing is unclear. Here we investigated the role of the endogenously produced omega-3 lipids 17,18-EEQ and 19,20-EDP in modulating the activity of sensory neurons. We found that 17,18-EEQ but not 19,20-EDP can sensitize the transient receptor potential vanilloid 1 and ankyrin 1 ion channels (TRPV1 and TRPA1) in sensory neurons, which depends on activation of a Gs-coupled receptor and PKA activation. Screening of different Gs-coupled lipid receptor-deficient mice, identified the prostacyclin receptor IP as putative receptor for 17,18-EEQ. Since 17,18-EEQ is synthesized by the Cytochrome-P450-Epoxygenase CYP2J2, we established a cellular mass spectrometry-based screening assay to identify substances that can suppress 17,18-EEQ concentrations. Using this assay, we identify the antidepressant venlafaxine and the antihypertensive drug telmisartan as potent inhibitors of CYP2J2-dependent 17,18-EEQ synthesis. These findings identify 17,18-EEQ as first omega-3-derived lipid mediator that acts via the IP receptor and sensitizes the TRPV1 channel in sensory neurons. Moreover, the results give a mechanistic explanation for the antinociceptive effects of venlafaxine, which are still not well understood. Like telmisartan, venlafaxine may reduce neuronal activity by blocking CYP2J2 and 17,18-EEQ synthesis and by inhibiting the IP receptor-PKA-TRPV1 axis in sensory neurons.

Study of mental health outcomes associated with different brands of venlafaxine at the Kumeu medical centre from January 2017 to October 2018.

Background:The antidepressant venlafaxine has been available in New Zealand for two decades and is funded by the New Zealand Drug Purchasing Agency PHARMAC. This audit aimed to determine whether change to a different funded generic formulation of venlafaxine affected patient responses to venlafaxine.Methods:A retrospective review of patient records for all patients at Kumeu Medical Centre, Auckland, New Zealand who received a prescription for venlafaxine since January 2017 was performed. Outcomes for patients who had experienced a stable positive clinical response to either of the two previously funded venlafaxine formulations and who were switched to the newly funded formulation were summarised.Results:Of 49 patients who had been prescribed venlafaxine, 34 patients were excluded; 15 patients had experienced a stable positive clinical response to either of the two previously funded venlafaxine formulations and switched to the newly funded formulation. Of these, 12 (80%) had poor outcomes following the change in venlafaxine formulation. Nine patients switched back to the original brand venlafaxine and showed improvement in clinical symptoms.Conclusion:These cases, reported from a single general practice, should be sufficient to call attention to the possibility of loss of effectiveness for patients treated with a funded generic brand of venlafaxine, and the need for further research.

N-Acetylaspartate Levels in Elderly Patients with Depression during Treatment with Antidepressants and Actovegin

Objectives. To study the N-acetylaspartate (NAA) content in the plasma of elderly patients with depression during treatment with antidepressants combined with Actovegin. Materials and methods. Nineteen patients – seven men, 12 women, age 70.5 ± 5.8 years – were treated in hospital conditions. Patients underwent clinical psychiatric evaluation using a series of psychometric scales, along with computerized tomography (CT) and biochemical assay of NAA. Patients received antidepressants (venlafaxine and fluvoxamine at therapeutic doses) and Actovegin for 28 days and were investigated before and after treatment (day 28). Results and conclusions. Decreases in blood NAA were found in pretreatment patients as compared with healthy subjects, with increases after treatment, which corresponded to a significant improvement in patients’ status both clinically and on psychometric scales. Heterogeneity was found in the cohort of patients in relation to the nature of changes in contents (increases or decreases) of NAA, which was not linked with treatment efficacy but correlated with the burden of comorbid somatic diseases, especially vascular, and some CT features (leukoaraiosis). The authors emphasize the preliminary nature of the results.

Chronic headache treatment: can we always follow international guidelines?

International guidelines on the prevention of migraine recommend the use of five main classes of medications: beta-blockers, antiepileptics, antidepressants (amitriptyline and venlafaxine), angiotensin receptor antagonists and botulinum toxin type A. Chronic tension-type headache (CTTH) guidelines are even more limiting and contain only amitriptyline, venlafaxine and mirtazapine. However, long-term intake of these medications is substantially limited by their tolerability issues. Moreover, most recommended medications cannot control the most frequently observed comorbidities, where depression plays the most important role in treatment selection, efficacy and long-term prognosis. This paper reviews the current migraine and CTTH prevention guidelines and complexities that physicians encounter with their use. The paper also includes a case series of treating chronic headache with a new multimodal antidepressant vortioxetine.

Multiple Stressors in the Environment: The Effects of Exposure to an Antidepressant (Venlafaxine) and Increased Temperature on Zebrafish Metabolism.

Aquatic organisms are continuously exposed to multiple environmental stressors working cumulatively to alter ecosystems. Wastewater-dominated environments are often riddled by a myriad of stressors, such as chemical and thermal stressors. The objective of this study was to examine the effects of an environmentally relevant concentration of a commonly prescribed antidepressant, venlafaxine (VFX) [1.0 μg/L], in addition to a 5°C increase in water temperature on zebrafish metabolism. Fish were chronically exposed (21 days) to one of four conditions: (i) 0 μg/L VFX at 27°C; (ii) 1.0 μg/L VFX at 27°C; (iii) 0 μg/L VFX at 32°C; (iv) 1.0 μg/L VFX at 32°C. Following exposure, whole-body metabolism was assessed by routine metabolic rate (RMR) measurements, whereas tissue-specific metabolism was assessed by measuring the activities of major metabolic enzymes in addition to glucose levels in muscle. RMR was significantly higher in the multi-stressed group relative to Control. The combination of both stressors resulted in elevated pyruvate kinase activity and glucose levels, while lipid metabolism was depressed, as measured by 3-hydroxyacyl CoA dehydrogenase activity. Citrate synthase activity increased with the onset of temperature, but only in the group treatment without VFX. Catalase activity was also elevated with the onset of the temperature stressor, however, that was not the case for the multi-stressed group, potentially indicating a deleterious effect of VFX on the anti-oxidant defense mechanism. The results of this study highlight the importance of multiple-stressor research, as it able to further bridge the gap between field and laboratory studies, as well as have the potential of yielding surprising results that may have not been predicted using a conventional single-stressor approach.