Dose Of Fluvoxamine Research Articles

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Impact of patient-specific factors on clozapine metabolism in individuals with treatment-resistant schizophrenia or schizoaffective disorder.

There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism. To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios. A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios. Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort (n = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine (n = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average. In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Co‑occurring Obsessive‑compulsive Disorder, Autism Spectrum Disorder and Intellectual Disability: A Case Report

Autism spectrum disorders encompass a wide range of clinical presentations, including obsessive‑compulsive symptoms. The comorbidity between these disorders is significant, and it has therapeutic and prognostic implications. While there are a few references on the approach of such comorbid presentations, the literature is even scarcer when this co‑occurrence is superimposed on individuals with intellectual disability. We present the case of a 43‑years‑old male patient with comorbid treatment refractory obsessive‑compulsive disorder, autism spectrum disorder and intellectual disability, exhibiting subacute symptomatic recurrence including hetero‑aggressive outbursts and contamination obsessions. The phenomenological features and therapeutic strategies are discussed, highlighting the centrality of a patient‑centered and methodologically pluralistic approach. Symptomatic remission was achieved employing high end doses of fluvoxamine and haloperidol, alongside daily psychotherapy involving both symptom‑directed behavioral therapy and supportive psychodynamic techniques. An integrative approach may be the best option in the stabilization of complex cases as the one presented.

A Synbiotic Mixture Augmented the Efficacy of Doxepin, Venlafaxine, and Fluvoxamine in a Mouse Model of Depression.

Currently available antidepressant drugs have notable downsides; in addition to their side effects and slow onset of action their moderate efficacy in some individuals may influence compliance. Previous literature has shown that probiotics may have antidepressant effects. Introducing complementary medicine in order to augment the efficacy of therapeutic doses of antidepressant drugs appears to be very important. Therefore, the effect of adding a synbiotic mixture to drinking water was assessed in a mouse model of depression following the administration of three antidepressant drugs belonging to different classes. The marble burying test (MBT) and forced swimming test (FST) were used as animal models of obsessive behavior and despair. The synbiotic mixture was administered to the mice's drinking water (6.25x106 CFU) for 14 days and the tests were performed 30 min after the injection of the lowest dose of doxepin (1 mg/kg), venlafaxine (15 mg/kg), and fluvoxamine (15 mg/kg) on days 7 and 14. After 7 days of ingestion of the synbiotic mixture, immobility time decreased in the FST for doxepin (92±5.5 s) and venlafaxine (17.3±2.5 s) compared to the control group (drinking water), but fluvoxamine decreased immobility time after 14 days of ingestion of the synbiotic mixture (70±7.5 s). Preadministration of the synbiotic mixture improved the MBT test response for venlafaxine, while it did not change the results for the other two drugs. Adding the synbiotic mixture to drinking water improved the efficacy of discrete antidepressant drugs particularly during the FST. Probiotics could be a useful complementary medicine for drug-resistant depressed individuals.

SCL6A4 polymorphisms rs25533 and I425V: Association with obsessive–compulsive disorder and its treatment response in Iranian patients

IntroductionThe influence of the serotonin transporter gene (SLC6A4) in OCD etiology and treatment response has been extensively studied, but there is little data about the role of its two polymorphisms, rs25533 and I425V. This appraisal evaluated the associations between these SNPs and OCD, as well as response to fluvoxamine pharmacotherapy. MethodsA total of 279 OCD patients and 224 controls participated in this study. Demographic and clinical data obtained via structured interview using Y-BOCS. DNAs were extracted from blood samples genotyped for rs25533 and I425V by PCR-RFLP. Patients treated 12 weeks with a 150 mg-300 mg daily dose of fluvoxamine. Based on the reduction in obsessive and compulsive severity scores using Y-BOCS severity scale, patients were classified as responders and non-responders as well as refractory. Association analyses considering clinical characteristics were conducted using chi-square test. Pharmacogenetic association analyses were also performed for the patients who had completed their pharmacotherapy. ResultsThe results revealed an association between rs25533 and OCD (p = 0.008), but I425V did not associate with OCD in Iranian patients. None of these SNPs showed associations with the age of onset, family history of psychiatric disorders or symptoms severities; however, the association of sexual obsessions and rs25533 was detected (p = 0.001). Finally, no association has been found between genotypes and response to fluvoxamine. ConclusionsGenetic and pharmacogenetic association analyses revealed no associations between the studied SLC6A4 variations and OCD and its treatment outcome except an association of rs25533 with OCD which suggests rs25533 as a candidate SNPs in future OCD association studies.

Attenuation of compulsive-like behavior by fluvoxamine in a non-induced mouse model of obsessive-compulsive disorder.

The current study evaluated the role of strain and compulsive trait differences in response to fluvoxamine, a common obsessive-compulsive disorder (OCD) drug, in two different mouse strains (BIG1 and BIG2) with a spontaneous compulsive-like phenotype. For compulsive-like nest-building behavior, dose-dependent attenuation of nesting by fluvoxamine was observed for the BIG1 compulsive-like strain during the first hour after administration. No significant differences were found for the BIG2 strain during the first hour, although a dose-dependent trend similar to that in the BIG1 strain was observed. Fluvoxamine dose dependently decreased the number of marbles buried in both strains 1 h after administration. For anxiety-like behaviors in the open field, no significant drug effects were found for the latency to leave the center and the number of line crossings. Significant strain differences were observed, with the BIG2 strain showing higher anxiety-like behaviors and reduced locomotor activity compared with the BIG1 strain. Consequently, this study adds predictive validity to our mouse model of OCD, whereas the anxiety-like differences between the strains add heterogeneity to our mouse model, similar to the heterogeneity observed in OCD.

Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice

Ethnopharmacological relevanceYokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. Aim of the studyTo evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. Materials and methodsThe anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT1A and 5-HT2A receptor in the mouse brain regions were quantified by western blot analysis. ResultsA single administration of fluvoxamine (5–20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5-HT2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. ConclusionThe present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of anxiety disorders.

Influence of fluvoxamine on plasma interleukin-6 or clinical improvement in patients with major depressive disorder.

ObjectivesThe etiology of depression remains unknown. There is, however, a growing body of evidence that cytokines are involved in the pathophysiology of depression. The aim of this study is to investigate the effects of fluvoxamine on plasma interleukin-6 (IL-6) levels and on clinical improvement of the depressive state.Subjects and methodsThirty patients who met the DSM-IV criteria for major depressive disorder (MDD) were enrolled in the study. Thirteen were male and 17 were female, and their ages ranged from 26 to 70 years (mean ± standard deviation 45.0±14.2). The patients were treated with fluvoxamine for 8 weeks. The dosages of fluvoxamine varied among the patients and, based on ethical considerations, were not fixed.ResultsThe fluvoxamine doses were positively related to plasma fluvoxamine levels (r =0.8798, P<0.001). A significant correlation was observed between the patients’ plasma IL-6 levels and their 17-item Hamilton Rating Scale for Depression (HAMD17) scores (r =0.4555, P=0.0010). A positive correlation was found between the delta plasma IL-6 (week 0–week 8) and the delta HAMD17 (week 0–week 8) (r =0.5226, P=0.002).ConclusionEffect of fluvoxamine on IL-6 is partially associated with its clinical efficacy for MDD.

The Effects of Fluvoxamine on the Steady-State Plasma Concentrations of Escitalopram and Desmethylescitalopram in Depressed Japanese Patients

The aim of this study was to determine the impact of fluvoxamine, an inhibitor of Cytochrome P450 (CYP) 2C19 (CYP2C19), on the pharmacokinetics of escitalopram, a substrate of CYP2C19. Thirteen depressed patients initially received a 20-mg/d dose of escitalopram alone. Subsequently, a 50-mg/d dose of fluvoxamine was administered because of the insufficient efficacy of escitalopram. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using high-performance liquid chromatography before and after fluvoxamine coadministration. The QT and corrected QT (QTc) intervals were measured before and after fluvoxamine coadministration. Fluvoxamine significantly increased the plasma concentrations of escitalopram (72.3 ± 36.9 ng/mL versus 135.2 ± 79.7 ng/mL, P < 0.01) but not those of desmethylescitalopram (21.5 ± 7.0 ng/mL versus 24.9 ± 12.0 ng/mL, no significance [ns]). The ratios of desmethylescitalopram to escitalopram were significantly decreased during fluvoxamine coadministration (0.37 ± 0.21 versus 0.21 ± 0.10, P < 0.01). The CYP2C19 genotype did not fully explain the degree of the change. Fluvoxamine coadministration did not change the QT or QTc intervals. The results of this study suggest that adjunctive treatment with fluvoxamine increases the concentration of escitalopram. The QTc interval did not change in this condition.

The role of sigma-1 receptor and brain-derived neurotrophic factor in the development of diabetes and comorbid depression in streptozotocin-induced diabetic rats.

Depression is highly prevalent in diabetes (DM). Brain-derived neurotrophic factor (BDNF) which is mainly regulated by the endoplasmic reticulum chaperon sigma-1 receptor (S1R) plays a relevant role in the development of depression. We studied the dose-dependent efficacy of S1R agonist fluvoxamine (FLU) in the prevention of DM-induced depression and investigated the significance of the S1R-BDNF pathway. We used streptozotocin to induce DM in adult male rats that were treated for 2weeks p.o. with either different doses of FLU (2 or 20mg/bwkg) or FLU + S1R antagonist NE100 (1mg/bwkg) or vehicle. Healthy controls were also enrolled. Metabolic, behaviour, and neuroendocrine changes were determined, and S1R and BDNF levels were measured in the different brain regions. In DM rats, immobility time was increased, adrenal glands were enlarged, and thymuses were involuted. FLU in 20mg/bwkg, but not in 2mg/bwkg dosage, ameliorated depression-like behaviour. S1R and BDNF protein levels were decreased in DM, while FLU induced SIR-BDNF production. NE100 suspended all effects of FLU. We suggest that disturbed S1R-BDNF signaling in the brain plays a relevant role in DM-induced depression. The activation of this cascade serves as an additional target in the prevention of DM-associated depression.

Coadministration of Fluvoxamine and Tolperisone in relation to CYP2D6 genotype

Tolperisone, a piperidine derivate, is used to relieve spasticity of neurological origin and muscle spasm. CYP2D6 was identified as the key enzyme in the metabolism of tolperisone and CYP1A2 and CYP2C19 were also involved in the metabolism of tolperisone. Fluvoxamine is an antidepressants and known as one of CYP2C19 inhibitors. As CYP2D6 is very high polymorphic and causes large interindividual differences in drug response, we investigated the effects fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetic parameters of tolperisone. Thirty healthy Korean subjects were volunteered and divided into three different groups according to CYP2D6 genotype: CYP2D6*wt/*wt (*wt = *1 or *2, n = 10), CYP2D6*wt/*10 (n = 10), and CYP2D6*10/*10 (n = 10). All subjects received a single oral dose of 150 mg tolperisone in the control phase after overnight fasting. Before study day (day 6), a 50 mg oral dose of fluvoxamine was administered once a day for five days. On day 6, subjects received a single oral dose of tolperisone one hour after the administration of fluvoxamine. Blood samples were collected up to 12 hours after drug administration, and plasma concentrations of tolperisone were determined by using liquid chromatography-tandem mass spectrometry system. Cmax and AUCinf of tolperisone was significantly different in each group between control phase and study day (P < 0.01). On study day, Cmax increased by 3.6-fold, 2.0-fold, and 5.0-fold, respectively in the CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase. Also, apparent oral clearance (CL/F) of tolperisone on study day decreased by 74.2%, 72.0%, and 86.2%, respectively in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 group, compared to control phase Significant differences in the pharmacokinetics of tolperisone were observed after coadministration of fluvoxamine in relation to CYP2D6 genotype.

Effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of clopidogrel in rats

1. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is often coprescribed with clopidogrel for the treatment of ischemic vascular diseases. The aim of this study was to explore the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of clopidogrel.2. Twelve male rats were employed to investigate the effect of fluvoxamine on the pharmacokinetics of clopidogrel in vivo. Clopidogrel carboxylic acid was used for the pharmacokinetic study of clopidogrel.3. After pretreatment with high dose of fluvoxamine (27 mg/kg), there were significant increases in the AUC0 − t (from 9850 ± 4060 to 27 300 ± 6910 µg/l h; p < 0.05), AUC0 − ∞ (from 9850 ± 4060 to 27 600 ± 6800 µg/l h; p < 0.05) and t1/2 (from 2.07 ± 0.0942 to 7.49 ± 1.22 h; p < 0.05) of clopidogrel carboxylic acid. The pharmacokinetic data for clopidogrel carboxylic acid showed significant decreases in VLz/F (from 0.765 ± 0.299 to 0.256 ± 0.0594 l/kg; p < 0.05) after pretreatment with high dose of fluvoxamine. Pharmacodynamic studies that measure platelet aggregation percentage (from 21.63 ± 6.05% to 45.98 ± 5.11%; p < 0.01) show that high doses of fluvoxamine significantly inhibit the effect of clopidogrel.4. In conclusion, the pharmacokinetics and pharmacodynamics of clopidogrel were significantly affected by high doses of fluvoxamine. This study indicated that potential drug–drug interaction between fluvoxamine and clopidogrel should be taken into consideration in clinical use.

Effects of calcium channel blocker, nifedipine, on antidepressant activity of fluvoxamine, venlafaxine and tianeptine in mice

Background: Cardiovascular diseases are commonly associated with depression. Calcium channel blockers (CCBs) form commonly used group of drugs for the treatment of a number of cardiovascular diseases. Nifedipine, a CCB, has been shown to possess antidepressant activity and potentiate antidepressant activity of imipramine and sertraline, however, literature on its interaction with newer antidepressant drugs such as fluvoxamine, venlafaxine and tianeptine is limited. Hence, the present study was undertaken. Methods: The study was carried out in albino mice in two phases. In Phase I, antidepressant activity of nifedipine, fluvoxamine, venlafaxine and tianeptine were confirmed after their single dose administration using forced swim test (FST) and tail suspension test (TST) and their minimum antidepressant doses were determined. In Phase II, the effect of nifedipine on antidepressant activity of fluvoxamine, venlafaxine and tianeptine was studied by orally administering sub-antidepressant doses of these drugs for 28 days. FST and TST were carried out on 1 st , 14 th and 28 th day of the study and change in immobility period was observed. Results: In Phase I, all the studied drugs exhibited dose dependent antidepressant activity in both FST and TST. Minimal antidepressant dose of nifedipine, fluvoxamine, venlafaxine and tianeptine was observed as 10, 25, 25 and 10 mg/kg respectively. In Phase II, combinations of sub-antidepressant dose of nifedipine (5 mg/kg) with sub-antidepressant doses of fluvoxamine (12.5 mg/kg), venlafaxine (12.5 mg/kg) and tianeptine (5 mg/kg) exhibited enhanced antidepressant activity when compared to the control group and individual drug groups after same duration of treatment. Conclusions: Nifedipine, fluvoxamine, venlafaxine and tianeptine possess antidepressant activity and nifedipine exhibits synergistic antidepressant activity with fluvoxamine, venlafaxine and tianeptine.

Optimization of the Fluvoxamine dose for a poor metabolizer child using TDM: case study

Therapeutic drug monitoring is a good tool for dose optimization and therapy improvement. TDM is needed when problems arise as uncertain drug adherence, intolerability, non-response at therapeutic doses, or drug-drug interactions. It is mainly helpful for children, elderly patients, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities. Our work represents the case of a twelve year old girl that has been treated at the in-patient clinic due to severe obsessive-compulsive disorder. She was treated with fluvoxamine in combination with behavioral therapy und has had a suspected problem with her metabolism state. Method: Fluvoxamine concentration was measured using HPLC method. The obtained values were then evaluated by using the program CONBEST. Results: The dose of fluvoxamine was increased slowly within a month to 200 mg/d. The measured concentration was between 1400 and 1600 ng/ml, which exceeding the therapeutic range (60 – 230 ng/ml). After dose reduction we found that elimination of the drug took place very slowly. Following three-day pausing, the reduction of the dose to 50 mg every second day gave an insignificant decrease in drug concentration. Conclusion: The steady state concentration reached slowly because of the poor metabolism, so the assessment of the current dosage is possible after about two weeks. TDM was helpful for dose optimization and therapy improvement in combination with a behavioral therapy.

Behavioural effects of monoamine reuptake inhibitors on symptomatic domains in an animal model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioural disorder. Several lines of evidence have implicated monoamine signalling systems, including transporters and receptors, in the pathogenesis of ADHD. We explored the heterogeneity of neural mechanisms that may possibly underlie symptomatic abnormalities in ADHD, by investigating the effects of monoamine reuptake inhibitors with differential spectrums for each monoamine transporter on ADHD-like behaviours in an animal model of ADHD, i.e. juvenile (6-week-old) male stroke-prone spontaneously hypertensive rats (SHRSP/Ezo). The impaired spontaneous alternation performance in a Y-maze task, demonstrated the inattentive features of SHRSP/Ezo, was improved by a selective DA reuptake inhibitor GBR-12909 (1 and 3mg/kg, i.p.). Desipramine (1, 3 and 10mg/kg, i.p.) and milnacipran (30mg/kg, i.p.), which possess a noradrenaline (NA) reuptake inhibitory activity, also ameliorated inattentive behaviour. Increased locomotor activity in open-field apparatus and total arm entries in a Y-maze task, which demonstrate the hyperactive features of SHRSP/Ezo, were improved by desipramine and milnacipran, but impaired by a high dose of GBR-12909 (10mg/kg, i.p.). A selective serotonin (5-HT) reuptake inhibitor fluvoxamine (10 and 30mg/kg, i.p.), did not affect inattention but significantly suppressed hyperactivity at a high dose (30mg/kg, i.p.). Moreover, a low dose of fluvoxamine (3mg/kg, i.p.) ameliorated the increased open arm spent time in an elevated plus-maze without affecting total arm entries, indicating an effect on impulsive features based on the anxiolytic characteristics of SHRSP/Ezo.These behavioural effects of monoamine reuptake inhibitors support the heterogeneity of monoaminergic systems, which are responsible for ADHD-like behaviours in SHRSP/Ezo. These findings may provide pharmacological evidence for the development of ADHD treatments that target more appropriate monoamine transporters.

Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing

The aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions. A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a microdose (25 μg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit P-glycoprotein and metabolism by cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2C9. When administered alone, pharmacokinetics for all four microdosed compounds scaled well with those reported for therapeutic doses and with previously performed microdose studies. The pharmacokinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole and fluvoxamine, showing statistically significant (p < 0.01) 12.8-, 8.1- and 3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC(∞) was observed for tolbutamide. The changes in pharmacokinetics mediated by ketoconazole and fluvoxamine were quantitatively consistent with previously reported, non-microdose, drug-drug interaction data from studies including the same compounds. The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions.

P-1109 - Synergistic effect of some psychopharmacs may lead to an side effect

To show that a combination of psychopharmacotherapy can result in unwanted side effect. We are presenting a 31-year-old patient addmitted to the hospital with diagnosis of a Acute stress reaction due to divorce. Before hospitalization, the patient was in occesional psychiatric treatment because of Anorexia Nervosa on Axis I, and with Borderline personality disorder on Axis II. The pre-hospital pharmacological treatment were consisted of olanzapine, diazepam and fluvoxamine.Upon addmitence the patient was restless and in persistent moving and diagnosis of akathisia was established. In the mental status dominated depressive ideas, listless. After addmission to the hospital, to the pharmacotherapy mentioned earlier were added lamotrigine as a mood stabilizer,and propranolol for akathisia, and the dose of fluvoxamine was reduced. After four days of hospitalization (the patient insists on a discharge from the hospital) was succeeded partially to regulate sleep, but there were still present early-morning awakening, appetite was slightly better, there was no loss of weight. Patient was less intrapsychic tense. Depressive ideas were paler but present. Symptoms of akathisia were reduced. Considering that the patient was treated with fluvoxamine and olanzapine, we believe that their synergistic effect was responsible for the occurrence of akathisia. Although the antipsychotic alone can have this side effect,in combination with fluvoxamine these side effect may intensify. Specifically fluvoxamine is an inhibitor CY P1A2. This cytochrome is responsible for the metabolic pathway of olanzapine,so when using fluvoxamine may increase serum concentrations of olanzapine, which may result in the appearance of akathisia.

P-1089 - With psychopharmacs titration to the therapeutic effectiveness and reduction of side effect

Aim Describe the possibility that medications without anticipated anticholinergic effects can have that type of side effect. Method We would like to present a 57-year-old patient, admitted to hospital because symptoms of major depressive episode with psychotic features. The main symptoms were auditory delusions with imperative character, base diminished mood and unregulated restless sleep. Psychological testing is obtained and showed the difficulty in sustaining attention, confused thinking, a strong depressive shift, a drop of vital energy, hypersensitivity, which turned into projections. Results At the beginning of hospitalization were corrected prescribed drugs before admission and transferred to fluvoxamine and at sixth day of hospitalization, quetiapine was added, with a gradual reduction until the termination of risperidon and promasinum. Within a week after taking fluvoxamine in dose of 200 mg per day patient allege the occurrence of dry mouth. Regard that the quetiapine and fluvoxamine usually have tha side effect of dry mouth, We have decided to reduce the dose of fluvoxamine on the usual daily-defined dose of 100 mg and the dose of quetiapine keep the same, because at lower doses at patient were still present auditory hallucinations. Conclusion Regard that the reduction of dose of fluvoxamine showed also reduction of side effect, we believe that in the presented case fluvoxamine was drug responsible for the appearance of aforementioned side effect, although we do not exclude a synergistic effect.

The effect of different antidepressant drugs on oxidative stress after lipopolysaccharide administration in mice.

This study investigated the effect of the serotonin selective reuptake inhibitors (SSRIs) fluoxetine, sertraline, fluvoxamine and the tricyclic antidepressant (TCA) impiramine on oxidative stress in brain and liver induced by lipopolysaccharide administration in mice. Each drug was administered subcutaneously at doses of 10 or 20 mg/kg, for two days prior to intraperitoneal (i.p.) administration of lipopolysaccharide E (LPS: 200 µg/kg). Mice were euthanized 4 h after administration of the lipopolysaccharide. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) concentrations were measured in brain and liver. Results: The administration of lipopolysaccharide increased oxidative stress in brain and liver; it increased brain MDA by 36.1 and liver MDA by 159.8 %. GSH decreased by 34.1 % and 64.8 % and nitric oxide increased by 78.7 % and 103.8 % in brain and liver, respectively. In brain, MDA decreased after the administration of sertraline and by the lower dose of fluoxetine or fluvoxamine, but increased after the higher dose of imipramine. Reduced glutathione increased after sertraline, fluvoxamine and the lower dose of fluoxetine or imipramine. Nitric oxide decreased by sertraline, fluoxetine, fluvoxamine and by the lower dose of imipramine. In the liver, all drugs decreased MDA and increased GSH level. Nitric oxide is decreased by sertraline, fluvoxamine and by the lower dose of fluoxetine or imipramine. It is concluded that, during mild systemic inflammatory illness induced by peripheral bacterial endotoxin injection, the SSRIs fluoxetine, sertraline and fluvoxamine reduced, while the TCA impiramine increased oxidative stress induced in the brain. The SSRIs as well as imipramine reduced oxidative stress due to lipopolysaccharide in liver tissue.