Antidepressant Mirtazapine Research Articles

Mirtazapine in comorbid major depression and an alcohol use disorder: A double-blind placebo-controlled pilot trial

This was a first double-blind, placebo-controlled pilot study to evaluate the efficacy of the novel antidepressant medication mirtazapine for treating both the depressive symptoms and the level of alcohol consumption of subjects with comorbid major depressive disorder and an alcohol use disorder (MDD/AUD). The results of two previous studies of mirtazapine in MDD/AUD subjects had suggested efficacy for mirtazapine for decreasing their level of depressive symptoms, but level of alcohol consumption had not been assessed in those studies. All subjects in this 12-week pilot study were randomized to either mirtazapine or placebo, and also received motivational enhancement therapy. Between-group analyses involving the outcome measures of depressive symptoms, level of alcohol consumption, and level of alcohol craving indicated no significant differences between groups, possibly because of limited sample size. However, within-group t tests in the mirtazapine group showed a significant decrease in depressive symptoms by week 2, also noted at all subsequent assessments (weeks 3, 4, 6, 8, 10, and 12) during the 12-week study. In contrast, no significant decrease in depressive symptoms was noted in the placebo group until week 8. No evidence of efficacy was found for mirtazapine for decreasing level of alcohol consumption in MDD /AUD subjects.

Mirtazapine added to selective serotonin reuptake inhibitors for treatment-resistant depression in primary care (MIR trial): study protocol for a randomised controlled trial.

BackgroundPeople with depression are usually managed in primary care and antidepressants are often the first-line treatment, but only one third of patients respond fully to a single antidepressant. This paper describes the protocol for a randomised controlled trial (MIR) to investigate the extent to which the addition of the antidepressant mirtazapine is effective in reducing the symptoms of depression compared with placebo in patients who are still depressed after they have been treated with a selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 6 weeks in primary care.Methods/DesignMIR is a two-parallel group, multi-centre, pragmatic, placebo controlled, randomised trial with allocation at the level of the individual. Eligible participants are those who: are aged 18 years or older; are currently taking an SSRI/SNRI antidepressant (for at least 6 weeks at an adequate dose); score ≥14 on the Beck Depression Inventory (BDI-II); have adhered to their medication; and meet ICD-10 criteria for depression (assessed using the Clinical Interview Schedule-Revised version).Participants who give written, informed consent, will be randomised to receive either oral mirtazapine or matched placebo, starting at 15 mg daily for 2 weeks and increasing to 30 mg daily thereafter, for up to 12 months (to be taken in addition to their usual antidepressant). Participants, their GPs, and the research team will all be blind to the allocation. The primary outcome will be depression symptoms at 12 weeks post randomisation, measured as a continuous variable using the BDI-II.Secondary outcomes (measured at 12, 24 and 52 weeks) include: response (reduction in depressive symptoms (BDI-II score) of at least 50 % compared to baseline); remission of depression symptoms (BDI-II <10); change in anxiety symptoms; adverse effects; quality of life; adherence to antidepressant medication; health and social care use, time off work and cost-effectiveness. All outcomes will be analysed on an intention-to-treat basis.A qualitative study will explore patients’ views and experiences of either taking two antidepressants, or an antidepressant and a placebo; and GPs’ views on prescribing a second antidepressant in this patient group.DiscussionThe MIR trial will provide evidence on the clinical and cost-effectiveness of mirtazapine as an adjunct to SSRI/SNRI antidepressants for patients in primary care who have not responded to monotherapy.Trial registrationEudraCT Number: 2012-000090-23 (Registered January 2012); ISRCTN06653773 (Registered September 2012)

The theoretical investigation of solvent effects on the relative stability and 15N NMR shielding of antidepressant heterocyclic drug

The density functional theory (DFT) and Tomasi’s polarized continuum model (PCM) were used for the investigation of solvent polarity and its dielectric constant effects on the relative stability and NMR shielding tensors of antidepressant mirtazapine (MIR). The obtained results indicated that the relative stability in the polar solvents is higher than that in non-polar solvents and the most stable structure was observed in the water at the B3LYP/6-311++G (d,p) level of theory. Also, natural bond orbital (NBO) interpretation demonstrated that by increase of solvent dielectric constant, negative charge on nitrogen atoms of heterocycles and resonance energy for LP(N10) → σ* and π* delocalization of the structure’s azepine ring increase and the highest values of them were observed in water. On the other hand, NMR calculations showed that with an increase in negative charge of nitrogen atoms, isotropic chemical shielding (σiso) around them increase and nitrogen of piperazine ring (N19) has the highest values of negative charge and σiso among nitrogen atoms. NMR calculations also represented that direct solvent effect on nitrogen of pyridine ring (N15) is more than other nitrogens, while its effect on N19 is less than other ones. Based on NMR data and NBO interpretation, it can be deduced that with a decrease in the negative charge on nitrogen atoms, the intramolecular effects on them decrease, while direct solvent effect increases.

Weight Gain and Metabolic Changes During Treatment with Antipsychotics and Antidepressants.

Weight gain and metabolic disturbances are common side effects during psychopharmacological treatment with specific antipsychotics and antidepressants. The antipsychotics clozapine and olanzapine, and antidepressants tricyclics and mirtazapine have a high risk of inducing weight gain. Recently discovered pathophysiological mechanisms include antihistaminergic effects, activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK), modulation of hormonal signaling of ghrelin and leptin, changes in the production of cytokines such as tumor necrosis factor-alpha (TNF)-alpha and adipokines such as adiponektin, and the impact of genes, in particular the melanocortin 4 receptor (MC4R), serotonin 2C receptor (HTR2C), leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1) genes. Metabolic changes associated with weight gain include disturbances of glucose and lipid metabolism. Clozapine and olanzapine may, in addition to mechanisms resulting from weight gain, impair glucose metabolism by blockade of the muscarinic M3 receptor (M3R). Antidepressants associated with weight gain appear to have fewer unfavourable effects on glucose and lipid metabolism than the second-generation antipsychotics clozapine and olanzapine. To assess the risk of weight gain and its consequences for the patient's health, assessing body weight changes and metabolic monitoring in the first week of treatment as well as in long-term treatment is recommended.

The effect of combined treatment with risperidone and antidepressants on the MK-801-induced deficits in the social interaction test in rats.

Several clinical reports have suggested that augmentation of atypical antipsychotics' activity by antidepressants may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. The aim of the present study was to investigate the effect of antidepressant mirtazapine or escitalopram and risperidone (an atypical antipsychotic), given separately or jointly, on the MK-801-induced deficits in the social interaction test in rats. Antidepressants and risperidone were given 60 and 30 min before the test, respectively. The social interaction of male Wistar rats was measured for 10 min, starting 4 h after MK-801 (0.1 mg/kg) administration. In the social interaction test, MK-801-induced deficits in the parameters studied, i.e. the number of episodes and the time of interactions. Risperidone at a higher dose (0.1 mg/kg) reversed that effect. Co-treatment with an ineffective dose of risperidone (0.01 mg/kg) and mirtazapine (2.5 or 5 mg/kg) or escitalopram only at a dose of 5 mg/kg (but not 2.5 and 10 mg/kg) abolished the deficits evoked by MK-801. The obtained results suggest that especially mirtazapine, and to a smaller degree escitalopram may enhance the antipsychotic-like effect of risperidone in the animal test modeling some negative symptoms of schizophrenia.

Simple and Accurate Quantitative Analysis of 16 Antipsychotics and Antidepressants in Human Plasma by Ultrafast High-Performance Liquid Chromatography/Tandem Mass Spectrometry.

In psychopharmacology, treatment with psychotropic drugs is often suboptimal, mainly because of the high interindividual variability in pharmacokinetic properties. Therapeutic drug monitoring (TDM) can be a valuable tool for monitoring the individual effects of a prescribed dosage in a patient, and it facilitates antipsychotic treatment by increasing the effectiveness and safety of drugs and by reducing treatment costs. The aim of this study was to develop and validate an ultrafast liquid chromatography (UFLC) method with tandem mass spectrometric detection for the measurement of 16 antipsychotics and antidepressants in human plasma samples for TDM or other applications. The method was developed to replace traditional methods using the solid-phase extraction of proteins precipitated with methanol/acetonitrile containing 0.1% formic acid. Quantitative analysis was performed by UFLC combined with a tandem mass spectrometer using a Synergy 3u-Hydro-RP (2.0 × 50 mm, 3 μm) column with a mobile phase consisting of 0.1% formic acid and acetonitrile. A simple, fast, and sensitive UFLC-tandem mass spectrometry method for the simultaneous measurement of commonly used antipsychotics (aripiprazole, chlorpromazine, paliperidone, quetiapine, risperidone, ziprasidone, clozapine, and olanzapine), antidepressants (citalopram, escitalopram, mirtazapine, fluoxetine, paroxetine, sertraline, venlafaxine plus O-desmethylvenlafaxine, and fluvoxamine) and an antidementia drug (donepezil) has been developed. The total run time of the chromatographic separation was 6.0 minutes. The precision and accuracy varied from 0.90% to 14% and from 88.5% to 118%, respectively. A 6-point standard curve covering the clinically relevant ranges with a power function fit was applied for calibration. Ion suppression due to matrix effects and the internal standards were investigated. Their recoveries varied from 89% to 110%. This new validated method fulfills all criteria for TDM and was successfully applied in the routine TDM of antipsychotics and antidepressants at the First Affiliated Hospital of Kunming Medical University.

Clarifying the Mechanisms of Antidepressants.

Commentary on Domschke, et al., Magnetoencephalographic correlates of emotionalprocessing in major depression before and after pharmacological treatment. Understanding the therapeutic effects of psychotropic medication has typically been approached, reasonably enough, with an analysis of the effects on brain chemistry. For example, the effective antidepressant mirtazapine is thought to affect both norepinephrine and serotonin neuromodulators, both of which are important to mood disorders such as major depression. However, understanding the full neuropsychopharmacology of a therapeutic agent requires an analysis of the multiple levels of neural self-regulation that are involved in the disorder and that are affected by the drug. It has long been apparent that if the mechanism of drug action were simply a correction of a biochemical imbalance, then the therapeutic effect would be rapid, limited only by the pharmacokinetics (Cooper et al., 2002). Instead, antidepressants typically require weeks of continued administration before they achieve a therapeutic effect. Although the complexity of drug action is familiar to most psychopathology researchers, clinicians are typically provided with only a superficial training on the neurophysiological and neuropsychological mechanisms for both psychopathology itself and the therapeutic effects of drugs. The result of this limited training is that a patient with depression, for example, is often told by the physician they have a “biochemical imbalance” that will be corrected by drug therapy. Not only is this explanation scientifically incorrect, …

A genome-wide association study of antidepressant response in Koreans.

We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P=3.57 × 10-8). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20–0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.

ChemInform Abstract: Iridium‐Catalyzed Silylation of Aryl C—H Bonds.

AbstractThe catalyst system under conditions A) is found to be optimal for the silylation of arenes, various hetarenes, and a broad spectrum of pharmaceutical agents such as the antidepressants mirtazapine (XX) and bupropion (XXII).

Agomelatine and migraine management: a successfully treated case series.

Headache is the most common reason for consultation in neurology departments in Spain. Despite the greater prevalence of tensional type headache, it is migraine that accounts for most visits to specialists because it is a medical condition causing more disability. The burden caused by headaches is well documented in the literature. It results in days of work or school missed, reduced labour productivity, etc. This field has undergone significant changes in recent years, such as the inclusion of chronic migraine in the new diagnostic classification [Headache Classification Subcommittee of the International Headache Society, 2004], a concept that urgently needed to be revised [Headache Classification Committee et al. 2006] to adapt it to the real situation experienced by patients. New therapeutic approaches include the use of triptans in acute treatment and the use of neuromodulators, particularly topiramate, as preventive therapy [Linde et al. 2013]. Melatonin is physiologically associated with sleep induction and maintenance [enhancing the GABAergic system by modulating γ-aminobutyric acid (GABA) receptor activity], dose-dependent analgesic effects [unknown mechanism related to µ-opioid or GABA(B) receptors], antioxidant effect (prevents free radical induced damage and increases the activity of various antioxidant enzymes such as glutathione S-transferase, glutathione reductase and catalase), chronobiotic properties, a moderate antihypertensive effect and even intraocular pressure-reducing effects [Kurdi and Patel, 2013]. It also acts as a membrane stabilizer, serotonin modulator and GABA potentiator, and protects against glutamate-mediated neurotoxicity [Peres et al. 2006]. Agomelatine is a modern antidepressant with a novel mechanism of action. It is an MT1 and MT2 melatonin receptor agonist and a selective 5-HT2C receptor antagonist. Its efficacy, which is similar to that of standard antidepressants, and low risk of sexual side effects, insomnia and discontinuation syndromes, make it an interesting alternative for the management of depression [Taylor et al. 2014]. Some evidence from pilot and experimental clinical trials [Guglielmo et al. 2013; Tabeeva et al. 2011] suggests that the melatonergic system plays a role in the pathogenesis of migraine and that drugs that act on melatonin receptors may have an effect have on migraine. We present the case of six patients with depression and comorbid migraine who were successfully treated for both conditions with agomelatine. Presentation of cases and discussion A total of 6 patients (measurement data shown in Table 1), all of them women, with a mean age of 38.16 ± 10.45 years, were seen at outpatient mental health clinics for Recurrent Major Depressive Disorder [American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR)]. All presented a moderate depressive episode [mean Montgomery-Asberg Depression Rating Scale (MADRS) score of 26.66 ± 3.72] at the time of assessment. Their personal history included migraine (based on the diagnostic criteria of the International Headache Society, 2004), with a mean age of onset of 20 ± 3.22 years, a mean number of attacks per month of 3.83 ± 1.83 and a pain intensity of 9 ± 0.89 measured on a Visual Analogue Scale (VAS). In all the cases prophylactic treatment for headaches (amitriptyline, beta-blockers and topiramate) had been withdrawn due to lack of response or adverse effects. Table 1. Case series: characteristics of the patients. Treatment with agomelatine at a dose of 25 mg was initiated for the depressive episode. A total of 4 of the 6 patients required an increase in dose to 50 mg/24 hours due to lack of remission after 8 weeks. After 4 months of follow up, the depressive episode was in remission (MADRS 1.16 ± 1.16) and there had been a considerable reduction in the frequency of migraine attacks/month (0.66 ± 1.41) and in the intensity of the attacks (2 ± 1.41). This considerable reduction in frequency of attacks was observed from the first month of treatment. In all these cases, we attribute the improvement to the treatment with agomelatine, since past treatment with other antidepressants (venlafaxine, sertraline, duloxetine and mirtazapine) had had no effect on migraine episodes, despite remission of the depressive symptomatology. Our results are similar to those of two other studies, also case series, previously published on the efficacy of agomelatine in migraine prophylaxis [Guglielmo et al. 2013; Tabeeva et al. 2011], although it must be mentioned that all the patients in our sample had a concomitant depressive disorder, which could introduce bias. The antimigraine effect appears to be related to the synergic action between melatonin agonism and 5-HT2C antagonism, though further studies are needed to clarify the pathophysiological and neurochemical mechanisms involved in the specific antimigraine response.

Hybrid silica monolith for microextraction by packed sorbent to determine drugs from plasma samples by liquid chromatography–tandem mass spectrometry

The present study (1) reports on the synthesis of two hybrid silica monoliths functionalized with aminopropyl or cyanopropyl groups by the sol–gel process; (2) evaluates these monoliths as selective stationary phase for microextraction by packed sorbent (MEPS) to determine drugs in plasma samples via liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the multiple reactions monitoring (MRM) mode; and (3) discusses important factors related to the optimization of MEPS efficiency as well as the carryover effect. The prepared hybrid silica monoliths consisted of a uniform, porous, and continuous silica monolithic network. The structure of the aminopropyl hybrid silica monolith was more compact than the structure of the cyanopropyl hybrid silica monolith. The Fourier-transform infrared spectroscopy (FTIR) spectra of the hybrid silica monoliths displayed readily identifiable peaks, characteristic of the cyanopropyl and aminopropyl groups. Compared with the aminopropyl hybrid silica phase, the cyanopropyl hybrid silica phase exhibited higher binding capacity for most of the target drugs. The developed method afforded adequate linearity at concentrations ranging from the lower limit of quantification (0.05–1.00ngmL−1) to the upper limit of quantification (40–10,500ngmL−1); the coefficients of determination (r2) were higher than 0.9955. The precision of the method presented coefficients of variation (CV) lower than 14%; the relative standard error (RSE) of the accuracy ranged from −12% to 14%. The developed method allowed for simultaneous analysis of five antipsychotics (olanzapine, quetiapine, clozapine, haloperidol, and chlorpromazine) in combination with seven antidepressants (mirtazapine, paroxetine, citalopram, sertraline, imipramine, clomipramine, fluoxetine), two anticonvulsants (carbamazepine and lamotrigine), and two anxiolytics (diazepam and clonazepam) in plasma samples from schizophrenic patients, which should be valuable for therapeutic drug monitoring purposes.

A case report of hyponatremia associated with maprotiline treatment

Background: Maprotiline is a tricyclic antidepressant (sometimes classifi ed as a tetracyclic antidepressant), which is predominantly a norepinephrine/noradrenaline reuptake inhibitor, commonly prescribed for depression. Aim: To present a female patient with depressive episode and occurrence of hyponatremia during the maprotiline treatment. Case Report: A 62-year-old female was diagnosed with depressive episode four years ago. She was treated ambulatory with maprotiline 50mg/day and bromazepam 6mg/ day, from local psychiatrist. The patients also used enalapril 2x10 mg/day, metoprolol 2x50 mg/day, nifedipine 5 mg/day and simvastatin 20 mg/day for treating hypertension and dyslipidemia. After about 12 months of maprotiline use she was hospitalized at the Endocrinology unit of a local hospital due to appearance of confusion, unstable walking, cramps, as well as an increase in blood pressure. Then diagnosed hyponatremia (serum sodium level-112 mmol/L), corrected (137 mmol/L) by using parenteral therapy. The patient continued to use maprotiline without consultation with her psychiatrist. After one year, the patient was hospitalized at the Endocrinology unit of tertiary level due to detailed re-examination because of recurrent hyponatramia (117 mmol/L), corrected (136 mmol/L) by ambulatory use of parenteral therapy at a local hospital. Water test load was used and the Syndrome of inappropriate antidiuretic hormone secretion was diagnosed. Insulin Tolerance Test showed preserved the integrity of the hypothalamic-pituitary-adrenal axis. Antidepressant mirtazapine (15 mg/ day) was introduced due to recurrence of depression. Gradual reduction of depressive symptoms was observed to mirtazapine. Antihypertensive therapy, restriction of fl uid intake and dietary regimen were still applied. Serum sodium concentrations were in the normal ranges over the past 18 months. Conclusion: Serum sodium level should be measured before and during the therapy with any class of antidepressants, especially in those patients with increased risk of the hyponatremia occurrence.

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 (R2 = 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.

Effects of cytochrome P450 2D6 and 3A5 genotypes and possible coadministered medicines on the metabolic clearance of antidepressant mirtazapine in Japanese patients

A personalized treatment approach should be considered with the second-generation psychiatric drug mirtazapine because of high frequencies of side effects, including characteristic drowsiness. Plasma concentrations of mirtazapine in patients are influenced by many factors, including polymorphic cytochrome P450 enzymes contributing to its transformation to 8-hydroxymirtazapine and N-demethylmirtazapine. The aim of this study was to investigate the determinant factors for individual variations of metabolic clearance of mirtazapine using in vitro and in vivo methods. In vitro analyses using liver microsomes from individual humans in correlation assays and recombinantly expressed P450 enzymes revealed that CYP2D6 was the major contributor to mirtazapine 8-hydroxylation with high affinity, and that CYP3A5 catalyzed N-demethylation in a similar high-capacity manner to that of CYP3A4. CYP1A2 was a minor contributor to mirtazapine 8-hydroxylation. Metabolic clearance of mirtazapine determined in substrate depletion assays and mirtazapine 8-hydroxylation activities in individual liver microsomes were significantly lower in CYP2D6 intermediate metabolizers (IM) and poor metabolizers (PM) than in extensive metabolizers (EM) (p<0.05). Trough plasma concentration/dose ratios of mirtazapine from 14 patients were significantly higher in the CYP2D6 IM/PM group than in the EM group and were also higher in the CYP3A5 poor-expressors group than in the expressors group (p<0.05). Mirtazapine clearance in pooled human liver microsomes was inhibited by quinidine (a CYP2D6 inhibitor), ketoconazole (a CYP3A inhibitor), and in combination with risperidone and duloxetine, possible coadministered medicines. These results suggested that mirtazapine metabolic clearance could be variously influenced by the CYP2D6 and CYP3A5 genotypes and coadministered drugs in clinical patients.

Impact of lithium alone and in combination with antidepressants on cytokine production in vitro.

Lithium is an important psychopharmacological agent for the treatment of unipolar as well as bipolar affective disorders. Lithium has a number of side effects such as hypothyroidism and aggravation of psoriasis. On the other hand, lithium has pro-inflammatory effects, which appear beneficial in some disorders associated with immunological deficits, such as human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE). Therefore, immunological characteristics of lithium may be an important consideration in individualized therapeutic decisions. We measured the levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-22, IL-17 and tumour necrosis factor (TNF)-α in the stimulated blood of thirty healthy subjects supplemented with lithium alone, the antidepressants citalopram, escitalopram or mirtazapine alone, the combination of each antidepressant with lithium, and a no drug control. These drugs were tested under three blood stimulant conditions: murine anti-human CD3 monoclonal antibody OKT3 and the 5C3 monoclonal antibody (OKT3/5C3), phytohemagglutinin (PHA), and unstimulated blood. Lithium, alone and in combination with any of the tested antidepressants, led to a consistent increase of IL-1ß, IL-6 and TNF-α levels in the unstimulated as well as the stimulated blood. In the OKT3/5C3- and PHA-stimulated blood, IL-17 production was significantly enhanced by lithium. Lithium additionally increased IL-2 concentrations significantly in PHA-stimulated blood. The data support the view that lithium has pro-inflammatory properties. These immunological characteristics may contribute to side effects of lithium, but may also explain its beneficial effects in patients suffering from HIV infection or SLE.

Pharmacological Profile of Brain-derived Neurotrophic Factor (BDNF) Splice Variant Translation Using a Novel Drug Screening Assay: A “Quantitative Code”

The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests.

Therapeutic Interventions for Itch in AD

Atopic dermatitis (AD) is characterized by severe pruritus, which has a negative impact on the quality of life of patients. AD pruritus is usually of high intensity, occurs predominantly during the night and leads to severe scratching. Thus, the therapy has to focus not only on the suppression of the symptom but also on improvement of sleep and therapy of scratch lesions. Today, the therapy of AD pruritus is mainly based on conventional topical and systemic anti-inflammatory drugs and off-label application of mu-opioid receptor antagonists, the antidepressant mirtazapine, and – without evidence from controlled studies – the neurokinin-1 receptor antagonist aprepitant. The pathophysiology of AD-associated pruritus is still not fully understood; however, recent identification of several key mediators and mechanisms might enable development of novel therapies such as receptor antagonists for neurokinin 1, histamine 4, interleukin 31, thymic stromal lymphopoietin (TSLP), and nerve growth factor (NGF). Controlled studies that are currently being carried out can be expected to pave the way for improved treatment options in AD pruritus.

Depressive Symptomatology and Response to Treatment With Antidepressants in Patients With a Dual Diagnosis

Objectives: The objective of the study was to compare the response to treatment with 3 types of antidepressants (duloxetine, mirtazapine, or venlafaxine) in patients with a dual diagnosis, in terms of: (1) changes in depressive symptomatology 1 and 3 months after starting the treatment; and (2) adherence to treatment through a year of follow-up. Methods: We carried out a naturalistic, open-label (nonblinded) study in which participants were randomly allocated to 1 of the 3 treatments (n=45, 44, and 45, respectively). Results: In all cases, we observed a significant reduction in clinical signs and symptoms after 3 months, with the best results being observed in the duloxetine group. Furthermore, adherence to the treatment program after 1 year was higher in all the groups treated with antidepressants than in those not receiving this type of drugs. Conclusions: The results suggest that the use of antidepressants in people with a dual diagnosis is effective in terms of improving the affective symptomatology and adherence to treatment programs.

Can Mirtazapine Counteract the Weight Loss Associated With Alzheimer Disease? A Retrospective Open-label Study

Weight loss is a frequent complication of Alzheimer disease (AD), associated with increased morbidity and mortality. Increased appetite and weight gain are known side effects of the antidepressant mirtazapine. This analysis was undertaken to assess the safety and potential utility of mirtazapine to counteract weight loss in patients with AD or mixed AD (AD with cerebrovascular lesions). We performed a retrospective analysis of the clinical records of all outpatients attending our memory clinic for AD or mixed AD, who had received mirtazapine (30 mg daily) with the specific purpose of inducing weight or appetite gain. Data were available for a total of 22 patients (mean age, 80.9 y, 86.4% female). The mean weight at baseline was 52.4 kg and the mean BMI was 20.5 kg/m. 77.3% of the patients had gained weight after 3 months (mean gain, 1.93 kg or 3.9% of initial body weight) and 82.3% after 6 months (2.11 kg or 4.6%). One patient had to discontinue mirtazapine because of daytime sleepiness. Mirtazapine seems to be a safe and useful approach to counteract weight loss in AD, if possible in combination with nonpharmacological interventions. Body weight should be monitored during treatment to avoid excessive weight gain.

The effect of risperidone on the mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex

BackgroundThe aim of our study was to understand the mechanism of clinical efficacy of the combination of an antidepressant and risperidone in drug-resistant depression. MethodsWe studied the effect of an antidepressant (mirtazapine) and risperidone (atypical antipsychotic), given separately or jointly on extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. The animals were given a single intraperitoneal injection of risperidone (1mg/kg) and mirtazapine (10 and 20mg/kg). The release of monoamines in the rat frontal cortex was investigated using a microdialysis in freely moving animals, and monoamine levels were assayed by HPLC with coulochemical detection. ResultsRisperidone increased the cortical extracellular levels of DA, 5-HT and NA. Similarly, mirtazapine dose-dependently increased the cortical extracellular levels of the monoamines studied. A combination of mirtazapine either at the higher dose (20mg/kg) or at both doses (10 and 20mg/kg) with risperidone produced a significant effect on DA and NA release, respectively compared to the effect of any drug given alone. The increase in the DA (but not NA) release induced by mirtazapine plus risperidone was partly blocked by the selective 5-HT1A antagonist WAY 100635 (0.2mg/kg). ConclusionsOur data indicate that the increase of cortical extracellular levels of DA and NA by combined administration of mirtazapine and risperidone may be of crucial importance to the pharmacotherapy of drug resistant depression, and that, among other mechanisms, 5-HT1A, 5-HT2A, α2-adrenergic and histamine H1 receptors may play some role in this effect.