Structural Modification of the Antidepressant Mianserin Suggests That Its Anti-inflammatory Activity May Be Independent of 5-Hydroxytryptamine Receptors.

Antidepressants are increasingly recognized to have anti-inflammatory properties in addition to their ability to treat major depressive disorders. To explore if engagement of 5-hydroxytryptamine (5-HT) receptors was required for the anti-inflammatory effect of the tetracyclic antidepressant mianserin, a series of structural derivatives were generated with the aim of reducing 5-HT receptor binding. Primary human peripheral blood mononuclear cells were used to screen for anti-inflammatory activity. The lead compound demonstrated a significant loss in 5-HT receptor binding, as assessed by non-selective 5-HT binding of radiolabelled serotonin in rat cerebral cortex. However, it retained the ability to inhibit endosomal toll-like receptor 8 signaling in primary human macrophages and spontaneous cytokine production from human rheumatoid synovial tissue equivalent to that previously observed for mianserin. These data demonstrate that the anti-inflammatory mechanism of mianserin may be independent of 5-HT receptor activity. This research offers new insights into the mechanism and structural requirements for the anti-inflammatory action of mianserin.

Mirtazapine.

Mirtazapine is one of antidepression which is used mainly in the treatment of depression, moreover, it is sometimes used in the treatment of anxiety disorders, insomnia, nausea, and vomiting, and to produce weight gain when desirable. The action of mirtazapine is an antagonist of certain adrenergic and serotonin receptors, and, furthermore, the drug is used strong as antihistamine, and it is occasionally defined as a noradrenergic and specific serotonergic antidepressant (NaSSA). The comprehensive profile of mirtazapine gives more detailed information about nomenclature, formulae, elemental analysis, and appearance. In addition, the numerous methods of drug synthesis are summarized. Also the profile covers the physicochemical properties as: the value of pKa, drug solubility, melting point, X-ray powder diffraction, and analysis methods for example: (compendial, electrochemical, spectroscopic, and method of chromatographic). Besides that, the profile covered pharmacological profile and clinical pharmacokinetics in subtitle's (absorption, distribution, metabolism, and elimination). About 100 references were given as a proof of the above-mentioned studies.

Development and evaluation of orally disintegrating tablets comprising taste-masked mirtazapine granules.

INTRODUCTION: Orally disintegrating tablets (ODTs) provide an important treatment option for pediatric, geriatric and psychiatric patients. In our previous study, we have performed the initial studies for the formulation development and characterization of new ODT formulations containing a bitter taste drug, mirtazapine, coated with 6% (w/w) Eudragit® E-100 (first group of formulations, FGF) without taste evaluation. In present study, coating ratio of the drug was increased to 8% (w/w) (second group of formulations, SGF) to examine the effect of increased coating ratio of drug on in vitro characterization of the formulations including in vitro taste masking study. MATERIALS AND METHODS: Coacervation technique using Eudragit® E-100 was employed to obtain taste-masked mirtazapine granules. FGF and SGF were compared to original product (Remeron SolTab, an antidepressant drug which produced by pellet technology) in terms of in vitro permeability, in vitro taste masking efficiency which was performed by dissolution studies in salivary medium and dissolution stability. Also, the other tablet characteristics (such as diameter, thickness) of SGF were examined. RESULTS AND DISCUSSION: The disintegration time of the SGF were found as A1 < A2 < A3 < A5 < A4 (8% Eudragit® E-100), but all of the formulations dissolved under 30 seconds and friability values were less than 1%. In vitro taste masking efficiency studies demonstrated that C2 formulation (in FGF) had the most similar dissolution profile to Remeron SolTab. CONCLUSIONS: According to these findings, B2 or C2 (with citric acid or sodium bicarbonate, respectively, with 6% Eudragit® E-100) formulations could be promising alternatives to Remeron SolTab.

Global transcriptomic analysis of zebrafish in response to embryonic exposure to three antidepressants, amitriptyline, fluoxetine and mianserin.

Antidepressants are among the most commonly detected pharmaceuticals in aqueous systems, and, as emerging organic pollutants, may exert negative effects on non-target aquatic organisms. Previously, it has been revealed that antidepressant exposure significantly inhibits the growth and development of fish during their early developmental stages. Thus, in the present study, we aimed to identify and compare the underlying mechanisms of action of different antidepressants at the transcriptional level using zebrafish (Danio rerio) embryos. Through high-throughput RNA sequencing (RNA-Seq) data analysis, 32, 34, and 130 differentially expressed genes (DEGs) were obtained from zebrafish larvae after 120h of embryonic exposure to sublethal concentrations of amitriptyline, fluoxetine, and mianserin, respectively. The expression profiles of the identified DEGs showed similar trends in response to the three antidepressant treatments, suggesting consistent toxic effects of low concentrations of these three drugs on the regulation of gene expression in fish. Several metabolic and signaling pathways, including glycolysis/gluconeogenesis and the insulin pathway, were affected in the exposed fish larvae. The expression profiles of selected DEGs were then verified by the qRT-PCR method, which indicated significant positive correlations with the RNA-Seq results. Next, we determined the concentration-dependent expression patterns of 6 selected DEGs in fish larvae exposed to three antidepressants at a series of environmentally relevant concentrations. The results revealed a significant concentration-dependent reduction in the levels of dual-specificity phosphatase 5 (dusp5) mRNA, as well as a non-concentration-dependent gene expression inhibition of prostaglandin D2 synthase b (ptgdsb); the circadian rhythm-related genes, i.e. those encoding nuclear receptor subfamily 1, group D, member 1 (nr1d1) and period 2 (per2); and genes encoding early growth response factors (egr1 and egr4), in the antidepressant-treated fish larvae. In summary, to our knowledge, our findings demonstrate, for the first time, that the three different categories of antidepressants have common effects on the gene expression involved in multiple biological processes and signaling pathways during the early development of fish and thus provide information for characterizing the adverse outcome pathways and on the ecological risk assessment of these pharmaceutical pollutants in the aquatic environment.

Quantum chemical study and isothermal titration calorimetry of ß-cyclodextrin complexes with mianserin in aqueous solution.

ß-Cyclodextrin (ß-CD) is studied as a carrier of the drug mianserin (MIA). ß-CD with MIA adducts with 1 : 1 and 2 : 1 stoichiometry are investigated in vacuo and in water using quantum chemical methods: PM6 and B3LYP/6-31G(d,p). An effect of the dispersion correction GD2 and the basis set superposition error on the complexation energies is also evaluated. Additionally, the interaction between MIA hydrochloride and ß-CD in aqueous solution at 298.15 K is examined experimentally by isothermal titration calorimetry. Interaction parameters, such as the binding constant, enthalpy, entropy and Gibbs free energy, are presented. Analysis of the obtained data led to the following conclusions: the interaction of MIA with ß-CD is rather strong; there is no significant energetic difference between the 1 : 1 complexes of ß-CD with S-MIA and R-MIA enantiomers; the 2 : 1 (ß-CD : MIA) adduct is energetically more favorable than 1 : 1; the complex formation of MIA + ß-CD is enthalpy and entropy driven.

Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in vivo assays in mice.

Anecdotal reports suggest that abused synthetic cannabinoids produce cannabis-like "highs," but some of their effects may also differ from traditional cannabinoids such as Δ(9)-tetrahydrocannabinol (THC). This study examined the binding affinities of first-generation indole-derived synthetic cannabinoids at cannabinoid and noncannabinoid receptors and their effects in a functional observational battery (FOB) and drug discrimination in mice. All seven compounds, except JWH-391, had favorable affinity (≤159 nM) for both cannabinoid receptors. In contrast, binding at noncannabinoid receptors was absent or weak. In the FOB, THC and the six active compounds disrupted behaviors in CNS activation and muscle tone/equilibrium domains. Unlike THC, however, synthetic cannabinoids impaired behavior across a wider dose and domain range, producing autonomic effects and signs of CNS excitability and sensorimotor reactivity. In addition, mice acquired JWH-018 discrimination, and THC and JWH-073 produced full substitution whereas the 5-HT2B antagonist mianserin did not substitute in mice trained to discriminate JWH-018 or THC. Urinary metabolite analysis showed that the compounds were extensively metabolized, with metabolites that could contribute to their in vivo effects. Together, these results show that, while first-generation synthetic cannabinoids shared some effects that were similar to those of THC, they also possessed effects that differed from traditional cannabinoids. The high nanomolar (or absent) affinities of these compounds at receptors for most major neurotransmitters suggests that these divergent effects may be related to the greater potencies and/or efficacies at CB1 receptors; however, action(s) at noncannabinoid receptors yet to be assessed or via different signaling pathways cannot be ruled out.

Long-term controlled release of PLGA microparticles containing antidepressant mirtazapine.

The aim of the study was to prepare PLGA microparticles for prolonged release of mirtazapine by o/w solvent evaporation method and to evaluate effects of PVA concentration and organic solvent choice on microparticles characteristics (encapsulation efficiency, drug loading, burst effect, microparticle morphology). Also in vitro drug release tests were performed and the results were correlated with kinetic model equations to approximate drug release mechanism. It was found that dichloromethane provided microparticles with better qualities (encapsulation efficiency 64.2%, yield 79.7%). Interaction between organic solvent effect and effect of PVA concentration was revealed. The prepared samples released the drug for 5 days with kinetics very close to that of zero order (R(2 )= 0.9549 - 0.9816). According to the correlations, the drug was probably released by a combination of diffusion and surface erosion, enhanced by polymer swelling and chain relaxation.

Formulation studies for mirtazapine orally disintegrating tablets.

OBJECTIVE: Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab). MATERIALS AND METHODS: Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900 mL 0.1 N HCl medium, 900 mL pH 6.8 phosphate buffer or 900 mL pH 4.5 acetate buffer at 37 ± 0.2 °C as dissolution medium. RESULTS: Ratio of Eudragit® E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit® E-100) was found closer to the reference product than A2 (4% Eudragit® E-100) and A3 (8% Eudragit® E-100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media. DISCUSSION: Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles. CONCLUSION: Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation.

Molecular salts and co-crystals of mirtazapine with promising physicochemical properties.

Pharmaceutically suitable non-sublimating salts and molecular salts of anti-depressant drug R/S-mirtazapine with one of several dicarboxilic acids were studied. The salts/salt molecules were characterized by powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis and crystal structure of tartarate and oxalate molecular salt were determined by single crystal X-ray diffraction. The salts/salt molecules of mirtazapine do not show any sublimation at elevated temperature whereas sublimation of mirtazapine has been observed at ambient temperature. The aqueous solubility of the mirtazapine molecular salts was significantly improved with a maximum of citrate salt which was about 180 times more than the solubility of the parent mirtazapine at 35 °C.

Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels.

In the present study, we have investigated the antileishmanial potential of mianserin, an antidepressant. Mianserin was found to inhibit both the promastigote and amastigote forms of the parasite in a dose dependant manner. The IC50 values for promastigotes and amastigotes were 21 µM and 46 µM respectively. Interestingly, mianserin failed to inhibit THP-1 differentiated macrophages up to 100 µM concentration thus, exhibiting parasite selectivity. When mianserin was incubated with recombinant Leishmania donovani 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme, it exhibited an IC50 value of 19.8 µM. Inhibition kinetics revealed competitive mode of enzyme inhibition as the Km increased with no change in Vmax. Further structural investigation of enzyme-inhibitor interaction revealed quenching of HMGR tryptophan intrinsic fluorescence with a K(sv) value of 3.025±0.37 M(-1) and an apparent binding constant of 0.0954 mM. We further estimated ergosterol levels which is a major component of Leishmania cell membrane. It is synthesized by HMGR enzyme, the first rate limiting enzyme of the sterol biosynthetic pathway. Analysis of ergosterol levels by HPLC revealed ∼2.5-fold depletion in mianserin treated promastigotes with respect to untreated parasites. This data was further validated by exogenous supplementation of mianserin treated cells with ergosterol and cholesterol. Reversal of growth inhibition was observed only upon ergosterol addition though it was refractory to cholesterol supplementation. Overall, our results demonstrate the possibility of repositioning of an antidepressant for the treatment of Visceral Leishmaniasis.

Molecular structure, FT-IR, FT-Raman, NMR studies and first order molecular hyperpolarizabilities by the DFT method of mirtazapine and its comparison with mianserin.

Mirtazapine (±)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino(2,1-a)pyrido(2,3-c)(2)benzazepine is a compound with antidepressant therapeutic effects. It is the 6-aza derivative of the tetracyclic antidepressant mianserin (±)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine. The FT-IR and FT-Raman spectra of mirtazapine have been recorded in 4000-400 cm(-1) and 3500-10 cm(-1), respectively. The optimized geometry, energies, nonlinear optical properties, vibrational frequencies, (13)C, (1)H and (15)N NMR chemical shift values of mirtazapine have been determined using the density functional theory (DFT/B3LYP) method. A comparison of the experimental and theoretical results of mirtazapine indicates that the density-functional B3LYP method is able to provide satisfactory results for predicting vibrational and NMR properties. The experimental and calculated results for mirtazapine have also been compared with mianserin.

Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression.

Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.

Bioequivalence study of two mirtazapine oral tablet formulations in healthy Chinese male volunteers.

OBJECTIVE: Mirtazapine is a tetracyclic antidepressant which works relating to noradrenergic and elective serotoninergic receptors. The aim of this study was to assess the pharmacokinetic properties and bioequivalence of a newly developed tablet formulation of mirtazapine with those of an established branded formulation in healthy Chinese male volunteers. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-way crossover study was conducted in healthy Chinese volunteers under fasting conditions with a washout of 14 days between the study periods. A sensitive and credible high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to determine mirtazapine in human plasma. RESULTS: The main PK parameters of the mirtazapine test and reference tables were as follows: mean (SD) C(max), 58.715 (23.89) and 58.255 (22.34) ng/ml; AUC(0-t), 591.406 (186.79) and 596.339 (201.25) ng × h/ml; AUC(0-∞), 627.03 (201.39) and 631.521 (227.32) ng × h/ml; t(1/2), 18.941 (4.79) and 18.285 (3.91) h; t(max) 1.417 (0.61) and 1.424 (0.75) h. The 90% CI for logtransformed ratios of C(max) (88.8 - 112.4%), AUC(0-t) (93.9 - 104.9%) and AUC(0-∞) (94.5 - 105.3%) for the test and reference formulations respectively, meeting the predetermined criteria for bioequivalence. CONCLUSIONS: Both treatments exhibited similar tolerability and safety. The test product is therefore bioequivalent to the reference product with respect to the rate and extent of mirtazapine pharmacokinetics.

A fast, sensitive and simple method for mirtazapine quantification in human plasma by HPLC-ESI-MS/MS. Application to a comparative bioavailability study.

In the present study a simple, fast, sensitive and robust method to quantify mirtazapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by a simple protein precipitation with methanol and were analyzed by high-performance liquid chromatography coupled to an electrospray tandem triple quadrupole mass spectrometer (HPLC-ESI-MS/MS). Chromatography was performed isocratically on a C(18), 5 µm analytical column and the run time was 1.8 min. The lower limit of quantitation was 0.5 ng/mL and a linear calibration curve over the range 0.5-150 ng/mL was obtained, showing acceptable accuracy and precision. This analytical method was applied in a relative bioavailability study in order to compare a test mirtazapine 30 mg single-dose formulation vs a reference formulation in 31 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a 14 day washout period. Since the 90% confidence interval for C(max) , AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration and ANVISA (Brazilian Health Surveillance Agency), it was concluded that mirtazapine 30 mg/dose is bioequivalent to the reference formulation, according to both the rate and extent of absorption.

Evaluation of polysaccharide-based chiral stationary phases in quality control of (S)-mirtazapine.

High-performance liquid chromatographic methods were developed for separation of the enantiomers of mirtazapine and its four process-related substances. The direct separations were achieved on chiral stationary phases containing amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD-H), cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD-H) and cellulose tris(4-methylbenzoate) (Chiralcel OJ-H ). The experimental data were utilized to discuss the effects of the mobile phase composition, the nature of the alcoholic modifier and the specific structural features of the analytes on retention and separation. The elution sequence was determined under the optimized separation conditions.

Controlled release chitosan microspheres of mirtazapine: in vitro and in vivo evaluation.

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 µm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 µg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.

Enantiomeric separation of mirtazapine and its metabolite in rat plasma by reverse polar ionic liquid chromatography using fluorescence and polarimetric detectors connected in series.

A simple and rapid reverse polar ionic LC method was developed and validated for simultaneous separation and determination of mirtazapine, an antidepressant drug, and its main metabolite N-desmethyl mirtazapine using fluorescence and polarimetric detectors connected in series. The chromatographic separation was achieved on Chirobiotic V column packed with vancomycin as a stationary phase in an isocratic mode of elution of methanol:glacial acetic acid:anhydrous triethyl amine (100:0.2:0.1, v/v/v) as a mobile phase. The compounds were detected by their excitation at 290nm and emission at 370nm using fluorescence detector while the optical rotation (+/-) of the enantiomers was identified by polarimetric detector. The analytes were extracted from rat plasma by precipitation of proteins and the average yield was 88-111% for mirtazapine and 85-123% for N-desmethyl mirtazapine. The method was linear over the concentration range of 20-5000ng/mL. The method was successfully applied on rat plasma spiked with the enantiomers of mirtazapine and N-desmethyl mirtazapine.

Therapeutic potential of new second generation antipsychotics for major depressive disorder.

IMPORTANCE OF THE FIELD: Although a range of antidepressant medications are available, a substantial number of patients either do not respond adequately to these or are unable to tolerate their adverse effects. A treatment strategy that has gathered substantial empirical support is the use of second generation antipsychotic agents (SGAs) in combination with antidepressants for treatment-resistant nonpsychotic depression (TRD) or major depressive disorder (MDD) inadequately responsive to antidepressants. Aripiprazole, olanzapine and quetiapine each have indications that involve MDD. Growing evidence indicates that quetiapine, evaluated as the extended release formulation, is efficacious as monotherapy for nonpsychotic MDD. AREAS COVERED IN THIS REVIEW: The pharmacological rationale for using SGAs in MDD, randomized, placebo-controlled data on individual SGAs in treatment of MDD and the emerging role of SGAs in the management of MDD. WHAT THE READER WILL GAIN: A balanced overview of the evidence supporting the use of newer SGAs in MDD. TAKE HOME MESSAGE: SGAs will have an increasingly important role in treatment of MDD, especially as augmentation agents. Further research is needed to clarify their efficacy and safety profiles, especially compared with other strategies for TRD.

Racemic intrathecal mirtazapine but not its enantiomers acts anti-neuropathic after chronic constriction injury in rats.

The unique noradrenergic and specific serotonergic antidepressant mirtazapine acts antinociceptive. It is optically active and currently marketed as racemate. In an animal model of acute pain it has been shown that the enantiomers exhibit differential effects: the R(-)-enantiomer showed anti-, the S(+)-enantiomer pronociceptive properties while the racemate acted antinociceptive at low doses and profoundly pronociceptive after high-dose application. Aim of the present study was to evaluate potential enantioselective effects of mirtazapine in neuropathic pain. In a chronic constriction injury model of neuropathic pain, Wistar rats were injected (+/-)-mirtazapine and the enantiomers intrathecally. All substances were dosed between 0.001 and 1mg/kg and compared to vehicle in a randomized and blinded approach. Thermal hyperalgesia and mechanical allodynia were assessed. In contrast to the acute pain results, only racemic mirtazapine exerted significant sustained analgesic effects up to 48 h. Antinociception was observed at all dosages with a maximum in the range of 0.01 mg/kg. Surprisingly, neither enantiomer was pro- nor antinociceptive at any dose or time. Our findings suggest that the synergism of both enantiomers is required to evoke a significant analgesic effect for the treatment of neuropathic pain. Our study gained no evidence for the use of either R(-) nor S(+)-mirtazapine alone. Due to the unique characteristics of (+/-)-mirtazapine and its proven efficacy in acute pain our results suggest that racemic mirtazapine may be a particularly useful antidepressant in the adjunctive treatment of chronic neuropathic pain states and could provide additional benefit to current therapeutic options.