Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism

Paulzen, Michael; Haen, Ekkehard; Hiemke, Christoph; Fay, Bianca; Unholzer, Sandra; Gründer, Gerhard; Schoretsanitis, Georgios

doi:10.1016/j.jad.2017.11.046

Cited by 16 publications

(7 citation statements)

References 38 publications

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“…The impact of comedications needs to be verified in a larger population. In addition, comedication like doxepin ( Paulzen et al, 2018a ) was identified to increase concentrations of VEN and VEN + ODV in patients in other research, but this concomitant medication was rare and therefore not discussed in our study. Fourth, the underlying mechanisms of morbidity state and the concomitant use of amisulpride on clearance are unknown and need to be further explored.…”

Section: Discussionmentioning

confidence: 72%

“…A number of studies have indicated significant intra-and inter-individual pharmacokinetic variability for VEN and ODV. The influences of sex, age, gene polymorphism (CYP2D6, CYP2C19) and comedications (e.g., valproic acid, doxepin, trimipramine, quetiapine) have been previously reported (Klamerus et al, 1996;McAlpine et al, 2011;Paulzen et al, 2018a;Paulzen et al, 2018b;Lin et al, 2018;Kowalewski et al, 2019;Wang et al, 2020). However, studies exploring these effects on dose and concentration have shown inconsistent results and mixed effects.…”

Section: Introductionmentioning

confidence: 99%

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Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication

Wang

Huang

et al. 2022

Front. Pharmacol.

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Introduction: Venlafaxine (VEN) is a widely used dual selective serotonin/noradrenaline reuptake inhibitor indicated for depression and anxiety. It undergoes first-pass metabolism to its active metabolite, O-desmethyl venlafaxine (ODV). The aim of the present study was to develop a joint population pharmacokinetic (PPK) model to characterize their pharmacokinetic characters simultaneously.Methods: Plasma concentrations with demographic and clinical data were derived from a bioequivalence study in 24 healthy subjects and a naturalistic TDM setting containing 127 psychiatric patients. A parent-metabolite PPK modeling was performed with NONMEM software using a non-linear mixed effect modeling approach. Goodness of fit plots and normalized prediction distribution error method were used for model validation.Results and conclusion: Concentrations of VEN and ODV were well described with a one-compartment model incorporating first-pass metabolism. The first-pass metabolism was modeled as a first-order conversion. The morbid state and concomitant amisulpride were identified as two significant covariates affecting the clearance of VEN and ODV, which may account for some of the variations in exposure. This model may contribute to the precision medication in clinical practice and may inspire other drugs with pre-system metabolism.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication

Wang

Huang

et al. 2022

Front. Pharmacol.

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“…The use of multiple medications can in certain cases be the appropriate and necessary therapeutic option [21][22][23][24]. For F3 patients, however, there are no reliable data in the literature comparing monotherapy with polypharmacy in terms of efficacy and adverse side effects [25,26]. As to the treatment of F2 patients, several authors pointed out that "antipsychotic polypharmacy can work for some clinically difficult conditions but should be the exception rather than the rule and may be avoidable in many patients" [27], this in accordance with the guidelines [28].…”

Section: Discussionmentioning

confidence: 99%

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia

Stassen¹,

Bachmann²,

Bridler

et al. 2021

Eur Arch Psychiatry Clin Neurosci

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Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today’s acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: “F2x.x”; n = 94; “F2 patients”) or depressive disorders (ICD-10: “F3x.x”; n = 226; “F3 patients”). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history» and «severity at baseline» played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2–3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the “natural” time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.

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“…With regard to limitations of this analysis, the retrospective, naturalistic, and explorative nature of the investigation must be considered. For example, comedication, which was not controlled for, is known to potentially affect the pharmacokinetics of drugs, especially by inductors or inhibitors of CYP450 enzymes [30,[43][44][45][46][47]. Possibly patients with increased CRP values suffer from any physical disease that will probably be pharmacologically treated.…”

Section: Discussionmentioning

confidence: 99%

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting

et al. 2019

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Introduction Infections can alter drug clearance, but the impact of inflammation-induced changes is still not well known. The aim of the investigation was to examine the effect of pathological C-reactive protein (CRP) values (≥0.5 mg/dL) and leukocyte count on the metabolism of 4 different atypical antipsychotics. Methods Steady-state serum concentrations of individual patients under therapy with risperidone (n=45), aripiprazole (n=30), olanzapine (n=24), and quetiapine (n=166) were retrospectively analyzed during a period of inflammation by Spearman’s Rho correlation analysis. Mann-Whitney U test was applied for comparison of patients with serum concentrations above and below the upper limit of the therapeutic reference range of each target drug with regard to CRP concentration and leukocyte count. Linear regression analysis was applied to correct for confounding parameters age and sex. Results Pathological concentrations of CRP were significantly associated with elevated values of C/D of quetiapine (n=166, Spearman’s Rho: r=0.269, p<0.001; linear regression: p<0.001). Among patients with quetiapine serum concentrations below 500 ng/mL, CRP concentrations were significantly (p=0.006) lower compared to patients with quetiapine concentrations above 500 ng/mL. A trend for a positive correlation between CRP and serum concentration was found for olanzapine (n=24, Spearman’s Rho: r=0.385, p=0.063; linear regression: p=0.086). Conclusion During a period of inflammation in patients taking quetiapine, according to our results, attention in dosing strategies is required to prevent toxic plasma concentrations.

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Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism

Cited by 16 publications

References 38 publications

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting

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