Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions

AIMS

The study aimed to investigate the clinical adherence to drug label recommendations on important drug–drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education.

METHODS

This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals ≥15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline.

RESULTS

Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively).

CONCLUSIONS

Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.     

Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers

The selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine have varying degrees of potency in inhibiting the hepatic cytochrome P450 (CYP) 2D6 enzyme. However, the time course for maximum inhibition to occur or for inhibition to dissipate when dosing is discontinued, requires clarification. In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p < 0.01), but the latter were not significantly different from each other (p > 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p < 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine > sertraline >or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. These data define the time course of a persistent effect that fluoxetine, sertraline, and paroxetine have on CYP2D6 following drug discontinuation and should be considered when initiating therapy with a CYP2D6 substrate.     

Reliable HPLC method for therapeutic drug monitoring of frequently prescribed tricyclic and nontricyclic antidepressants

A new high-performance liquid chromatography method is presented for the determination of 10 frequently prescribed tricyclic and nontricyclic antidepressants: imipramine, amitriptyline, clomipramine, fluoxetine, sertraline, paroxetine, citalopram, mirtazapine, moclobemide and duloxetine. The simple and accurate sample preparation step, consisted of liquid:liquid extraction with recoveries ranging between 72% and 86%, except for moclobemide (59%). Separation was obtained using a reverse phase Select B column under isocratic conditions with UV detection (230 nm). The mobile phase consisted of 35% of a mixture of acetonitrile/methanol (92:8, v/v) and 65% of 0.25 mol L(-1) sodium acetate buffer, pH 4.5. The standard curves were linear over a working range of 2.5-1000 ng mL(-1) for moclobemide, 5-2000 ng mL(-1) for citalopram, duloxetine, fluoxetine, 10-2000 ng mL(-1) for sertraline, imipramine, paroxetine, mirtazapine and clomipramine. The intra-assay and inter-assay precision and accuracy were studied at three concentrations (50, 200, and 500 ng mL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 8.8%, and all inter-CVs were less than 10%. Limits of quantification were 2.5 ng mL(-1) for moclobemide, 5 ng mL(-1) for citalopram, duloxetine and amitriptyline, and 10 ng mL(-1) for mirtazapine, paroxetine, imipramine, fluoxetine, sertraline, and clomipramine. No interference of the drugs normally associated with antidepressants was observed. The method has been successfully applied to the analysis of real samples, for the drug monitoring of ten frequently prescribed tricyclic and non-tricyclic antidepressant drugs.     

Genotype‐sensitive reversible and time‐dependent CYP2D6 inhibition in human liver microsomes

Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O‐demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non‐functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of V_max in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters K_i, K_I and k_inact was observed neither with the competitive inhibitor duloxetine nor with the time‐dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype‐sensitive magnitude of drug‐drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles.     

Concurrent Use of Low‐Dose Aspirin and Omega‐3 Fatty Acids and Risk of Upper Gastrointestinal Complications: A Cohort Study with Nested Case–Control Analysis

The risk of upper gastrointestinal complications (UGIC) due to low‐dose aspirin (LDA) can be further increased by the concurrent exposure to other antithrombotic agents. Little is known on the combined therapy with LDA and medications containing omega‐3 (OM3) fatty acids, which also exert antiplatelet activity. The aim of this study was to investigate the risk of UGIC in patients exposed to LDA–OM3 combination. The Italian Health Search IMS Health Longitudinal Patients Database was used to perform a population‐based cohort study. Patients aged ≥18 years with cardio‐ or cerebrovascular ischaemic disease recorded between 2002 and 2012 (cohort entry) were selected. All UGIC cases (index date) observed up to December 2013 were identified. According to a nested case–control analysis, up to 10 controls were matched to each case on age, sex and calendar period. The risk of UGIC was investigated among current (up to 30 days preceding index date), recent (31–60 days) and past users (61–365 days) of the LDA–OM3 combination. Exposure assessment was lagged by 30 days to minimize reverse causation. Additionally, a duration–response analysis was performed. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Non‐users of the LDA–OM3 combination were the reference category. Current (OR = 0.66; 95% CI: 0.44–1.00), recent (OR = 0.83; 95% CI: 0.52–1.33) and past users (OR = 0.81; 95% CI: 0.57–1.15) did not statistically significantly increase the risk of UGIC. No duration–response relationship was found. Our results suggest that LDA–OM3 combination therapy does not affect the UGIC risk in patients with cardio‐ or cerebrovascular ischaemic diseases. Given the novelty of these findings, further studies are needed.     

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram,fluoxetine, fluvoxamine and paroxetine

Objectives: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. Methods: The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg. Results: With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page’s test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page’s test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs. Conclusion: This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account. Received: 11 December 1995/Accepted in revised form: 29 February 1996     

Mirtazapine. A pharmacoeconomic review of its use in depression

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). The antidepressant efficacy of mirtazapine has been established in randomised, double-blind comparative studies. Mirtazapine has generally shown similar efficacy to other antidepressants. There is evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitors (SSRIs) on the basis of mean depression rating scale scores. Data from a long term (mean 240 days) clinical trial that was subsequently used in pharmacoeconomic analyses showed that mirtazapine was associated with significantly higher sustained remission rates and rates of discontinuation because of improvement than amitriptyline and placebo. Although differences were not statistically significant, mirtazapine had higher response rates at 6 weeks than the SSRI fluoxetine in an analysis that was also used as the basis of pharmacoeconomic studies. Mirtazapine improved quality of life to a similar extent to fluoxetine, citalopram and paroxetine in unpublished studies of 6 and 8 weeks' duration. Pooled analyses suggest that mirtazapine may be associated with greater improvement than fluoxetine and citalopram in quality of life after 2 and 4 weeks, although confirmation is required. In a decision analytical model of approximately 6 months' duration, mirtazapine was associated with a higher proportion of successfully treated patients and lower total direct costs than amitriptyline. The direct cost per successfully treated patient with mirtazapine was lower than that with amitriptyline by 33,112 Austrian schillings (S; year of costing not stated), 24,212 French francs (FF; 1995/1996 values), 13,851 Swedish kronor (SEK; 1997 values) and 553 Pounds (1997/1998 values) in Austrian, French, Swedish and UK analyses, respectively. Compared with fluoxetine, mirtazapine was associated with higher per-patient costs in all 4 countries but a higher proportion of successfully treated patients. Mirtazapine was more cost effective than fluoxetine: the direct cost per successfully treated patient was lower by S32,046 in Austria, FF25,914 in France, SEK9796 in Sweden and 327 Pounds in the UK. The additional cost of mirtazapine versus fluoxetine for each additional successfully treated patient at 6 months was S11,732, SEK17,229, 750 Pounds and FF3342 in the Austrian, Swedish, UK and French analyses, respectively. Mirtazapine was generally associated with lower indirect costs (for lost productivity of employed patients) than amitriptyline and similar indirect costs to fluoxetine in the analyses. CONCLUSIONS: Available data suggest that mirtazapine is a cost-effective alternative to amitriptyline and fluoxetine for the treatment of depression. Mirtazapine also has similar effects to SSRIs on quality of life with possibly a shorter time to onset of action, although published trial results are required to confirm these preliminary data.     

<Emphasis Type="BoldItalic">CYP2D6</Emphasis> Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Purpose

This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.

Methods

Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n?=?65) or metoprolol (n?=?33).

Results

CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02–0.75] p?=?0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84–10.30] p?=?0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day).

Conclusion

Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

     

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y₁₂ antagonist) is commonly used to prevent re‐infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y₁₂ antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro‐drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end‐point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on‐treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on‐treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP‐induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss‐of‐function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA‐induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672‐8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1‐year post PCI operations (OR = 2.571; 95% CI: 1.143‐5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.     

The effects of anaesthetics on postoperative physiological reactions: a meta‐analysis

This study aimed to systematically investigate the effects of different anaesthetics on postoperative physiological reactions compared with placebo. The literature search was conducted using three databases: PubMed, EMBASE, and the Cochrane Library. Studies published from January 1990 to January 2015 were screened. The language was restricted to English. Heterogeneity was analyzed by the Q test and I² statistic. A fixed‐effect model was used for homogenous data and a random‐effects model for heterogeneous data. The odds ratio (OR) and 95% confidence interval (CI) were calculated to monitor the incidences of overall adverse events, arterial blood pressure, and cardiac abnormalities. Sensitivity analysis was performed to estimate the strength of the meta‐analysis, and publication bias was analyzed using Egger's test. A total of 24 articles were included in this meta‐analysis. There were 1,810 and 1,806 cases in the anaesthetic group and the placebo group, respectively. The incidence of overall adverse events was significantly lower in the anaesthetic group compared with the placebo group (OR = 0.57; 95% CI, 0.38–0.84). No publication bias was observed, and no inverse estimates were calculated using sensitivity analysis. There was no significant difference for the incidence of arterial blood pressure (OR = 4.62; 95% CI, 0.90–23.70) and cardiac abnormalities (OR = 1.18; 95% CI, 0.53–2.63) between the two groups. Although the incidence of overall adverse events was decreased in the anaesthetic group, it is impossible to determine whether the use of anaesthetics during surgical operation has a protective effect on postoperative physiological reactions.     

Is opioid substitution treatment beneficial if injecting behaviour continues?

Background

Opioid substitution treatment (OST) is recognised as an effective treatment for opioid dependence. Still, a subgroup of OST users continues to inject drugs. This study examines health risks and criminal activity in a population of needle exchange programme (NEP) participants by comparing those identified as current OST users to (i) those identified as former OST users and (ii) those with no OST experience.

Methods

This was a semi-annual cross-sectional study conducted from 2002 to 2011. NEP participants were interviewed in Oslo, Norway (n = 1760); 341 were identified as current OST users, 356 as former OST users and 1063 had no OST experience. The associations between OST status and health risk and criminal activity were assessed through univariate and multiple logistic regression analyses.

Results

Among NEP participants, those currently in OST had fewer non-fatal overdoses (OR = 0.5 [95% CI 0.3, 0.9]) compared to former OST users and those never in OST. Additionally, they were less likely to have injected frequently (OR = 0.4 [95% CI 0.3, 06]), to have used heroin daily or almost daily (OR = 0.3 [95% CI 0.2, 0.4]), and to have committed theft (OR = 0.6 [95% CI 0.4, 1.0]) and engaged in drug dealing (OR = 0.7 [95% CI 0.5, 0.9]) in the past month. Overall, there was a high level of polysubstance use and no group differences on this measure.

Conclusions

NEP participants who are currently in OST have substantially reduced health risks and criminal activity than other NEP participants. The high level of polysubstance use nevertheless poses a public health challenge.     

CYP2D6*4, CYP3A5*3 and ABCB1 3435T polymorphisms and drug-related falls in elderly people

Objective The objective of this study is to investigate the association between CYP2D6*4, CYP3A5*3 and ABCB1 3435T polymorphisms and drug-related falls. Method Multivariate logistic regression was performed in an existing database in order to study the association between falls history and CYP2D6*4, CYP3A5*3, ABCB1 3435T polymorphisms in patients using fall-risk-increasing CYP2D6, CYP3A5 and P-glycoprotein (gene product of ABCB1) substrates. Results No statistically significant increased fall risk was found in ‘poor metabolizers’ compared to ‘extensive’ and ‘intermediate metabolizers’ using fall-risk-increasing CYP2D6 substrates (Odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.2–25.0), CYP3A5 substrates (OR = 0.9; 95% CI 0.2–3.3) and P-glycoprotein substrates (OR = 2.1; 95% CI 0.2–17.2). Conclusion The hypothesis that ‘poor metabolizers’ have an increased fall risk was not confirmed. A larger study population is needed to confirm the potential association that was seen between CYP2D6*4 and ABCB1 3435T polymorphisms and drug-related falls.     

A prediction model‐based algorithm for computer‐assisted database screening of adverse drug reactions in the Netherlands

Purpose

The statistical screening of pharmacovigilance databases containing spontaneously reported adverse drug reactions (ADRs) is mainly based on disproportionality analysis. The aim of this study was to improve the efficiency of full database screening using a prediction model‐based approach.

Methods

A logistic regression‐based prediction model containing 5 candidate predictors was developed and internally validated using the Summary of Product Characteristics as the gold standard for the outcome. All drug‐ADR associations, with the exception of those related to vaccines, with a minimum of 3 reports formed the training data for the model. Performance was based on the area under the receiver operating characteristic curve (AUC). Results were compared with the current method of database screening based on the number of previously analyzed associations.

Results

A total of 25 026 unique drug‐ADR associations formed the training data for the model. The final model contained all 5 candidate predictors (number of reports, disproportionality, reports from healthcare professionals, reports from marketing authorization holders, Naranjo score). The AUC for the full model was 0.740 (95% CI; 0.734–0.747). The internal validity was good based on the calibration curve and bootstrapping analysis (AUC after bootstrapping = 0.739). Compared with the old method, the AUC increased from 0.649 to 0.740, and the proportion of potential signals increased by approximately 50% (from 12.3% to 19.4%).

Conclusions

A prediction model‐based approach can be a useful tool to create priority‐based listings for signal detection in databases consisting of spontaneous ADRs.     

Direct and metabolism‐dependent cytochrome P450 inhibition assays for evaluating drug–drug interactions

We developed methods for evaluating the ntial inhibition of human cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2 C9, CYP2 C19, CYP2D6, CYP2E1 and CYP3A4, using pooled human liver microsomes (HLMs). The CYP inhibition assay used substrate cocktail sets [set A: phenacetin for CYP1A2, coumarin for CYP2A6, (S)‐(+)‐mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4; set B: bupropion for CYP2B6, tolbutamide for CYP2C9, chlorzoxazone for CYP2E1, and testosterone for CYP3A4] with quantitation by liquid chromatography–tandem mass spectrometry. A direct inhibition assay was performed with the substrate cocktails without β‐nicotinamide adenine dinucleotide phosphate (NADPH) pre‐incubation, and a metabolism‐dependent inhibition (MDI) assay was performed after 30 min of pre‐incubation with NADPH in HLMs. MDI was identified based on the half‐maximal inhibitory concentration (IC₅₀) shifts. The IC₅₀ values of the direct inhibitors determined using the probe substrate cocktails were in good agreement with previously reported values. Eight metabolism‐dependent inhibitors including furafylline, 8‐methoxypsoralen, tienilic acid, ticlopidine, fluoxetine, paroxetine, disulfiram and verapamil against CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, respectively, resulted in significant IC₅₀ shifts (≥2.5‐fold) after pre‐incubation. Thus, these CYP inhibition assays are considered to be useful tools for evaluating both direct inhibition and MDI at an early stage of the drug discovery and development process. Copyright © 2011 John Wiley & Sons, Ltd.     

A review of the pharmacological and clinical profile of mirtazapine

The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.     

Direct and indirect interactions between antidepressant drugs and CYP2C6 in the rat liver during long-term treatment

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg i.p.; desipramine, fluoxetine, sertraline at 5 mg/kg i.p.; mirtazapine at 3 mg/kg i.p.), in the absence of the antidepressants in vitro. Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 7-hydroxylation of warfarin. The obtained K_i values indicated that nefazodone and fluoxetine were the most potent inhibitors of the studied reaction (K_i = 13 and 23 μM, respectively), while tricyclic antidepressants and sertraline were weak in this respect (K_i = 70–127 μM). A one-day (i.e. 24 h) exposure to fluoxetine and mirtazapine resulted in a significant increase in the rate of the 7-hydroxylation of warfarin in rat liver microsomes. The other studied antidepressants did not significantly affect the rate of the CYP2C6-specific reaction. After two-week treatment with the investigated antidepressants, the increase in CYP2C6 activity observed after 24-h exposure to fluoxetine and mirtazapine was more pronounced. Moreover, unlike after one-day exposure, imipramine and sertraline significantly increased the activity of the enzyme. The other tricyclic antidepressants or nefazodone did not produce any significant effect when administered in vivo. The above-described enhancement of CYP2C6 activity correlated positively with the simultaneously observed increases in the enzyme protein level, which indicates the enzyme induction. The studied antidepressants increased the CYP2C6 protein level in the liver microsomes of rats after chronic treatment: imipramine to 174.6 ± 18.3%, fluoxetine to 159.1 ± 13.7%, sertraline to 135.3 ± 11.2% and mirtazapine to 138.4 ± 10.2% of the control. In summary, two different mechanisms of the antidepressant–CYP2C6 interaction have been found to operate in the rat liver: 1) direct inhibition of CYP2C6 shown in vitro mainly for nefazodone and fluoxetine, with their inhibitory effects being somewhat more potent than their action on human CYP2C9; 2) the in vivo induction of CYP2C6 by imipramine, fluoxetine, sertraline and mirtazapine.     

Adverse effects from antidepressant treatment: randomised controlled trial of 601 depressed individuals

Rationale

Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment.

Objectives

To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.

Methods

Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.

Results

Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p?=?0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p?=?0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.

Conclusions

The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.