Therapeutic Drug Monitoring Of Antidepressants Research Articles

TDM of antidepressants shortens length of hospital stay : Reduction in length of stay by routine therapeutic drug monitoring of antidepressants on admission to hospital

TDM of antidepressants shortens length of hospital stay : Reduction in length of stay by routine therapeutic drug monitoring of antidepressants on admission to hospital

Relevance of pharmacogenetic analyses and therapeutic drug monitoring of antidepressants for an individualized treatment of peripartum psychopathology.

Psychiatric disorders burden the peripartum period, often requiring psychopharmacological treatment, including antidepressants. Efficacy and tolerability of antidepressants are influenced by the physiological changes of the peripartum and individual metabolic profiles, which in turn can be modified by pregnancy. The objective of this study is to assess the relationship between antidepressants' pharmacokinetic profiles during pregnancy and individual metabolic profiles, along with the efficacy of the treatment. In total 87 outpatients with diagnoses of bipolar disorder, major depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder who required antidepressant treatment during pregnancy were recruited. Genotyping analysis of hepatic cytochrome P450 (CYPs) individual isoforms was performed. Antidepressants' blood concentrations and psychometric assessments were collected at five time points. Antidepressants' cord blood concentrations were assessed at birth. Sertraline showed greater stability in plasma concentrations and a lower placental penetrance index. Most of the antidepressants' concentrations below the therapeutic range were found in women with an extensive/ultrarapid metabolic profile. Antidepressants mainly metabolized by CYP2C19 were less frequently below the therapeutic range compared with antidepressants metabolized by CYP2D6. Pregnancy modulates cytochrome activity and drugs' pharmacokinetics. Genotyping analysis of CYPs isoforms and therapeutic drug monitoring might be used to guide clinicians in a well-tolerated treatment of psychiatric symptoms in pregnant women.

Therapeutic Drug Monitoring of Antidepressants: An Underused but Potentially Valuable Tool in Primary Care

Depressive disorders are among the most burdensome diseases globally in terms of prevalence, as well as in terms of quality of life, morbidity, and mortality. Hence, it is becoming increasingly common for primary care physicians to administer and monitor the treatment of individuals affected by depressive disorders. In this framework, Therapeutic Drug Monitoring (TDM) comes to the forefront. TDM is the measurement of specific drugs in the blood or plasma/serum, and its usefulness lies in the fact that it allows physicians to assess drug levels to personalize and optimize treatments. TDM has been used for decades to measure several classes of psychotropic drugs, such as antiepileptics and antipsychotics, but the use of this tool is still in its infancy in regard to antidepressants. In the context of primary care, TDM of antidepressant drug treatment shows promise, as it can enable primary care physicians to monitor the safety and efficacy of the treatment, leaving to secondary care, i.e., psychiatrists, the management of the more complex clinical cases.

Determination of 13 antidepressants in blood by UPLC-MS/MS with supported liquid extraction pretreatment

Antidepressants are widely used nowadays. Due to the potential detrimental consequences and involvement in forensic cases, therapeutic drug monitoring of antidepressants is desired. Herein we report a method for sensitive determination of 13 commonly used antidepressants in blood. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method with supported liquid extraction (SLE) was developed for analysis of imipramine, desipramine, fluoxetine, norfluoxetine, paroxetine, maprotiline, sertraline, citalopram, clomipramine, trazodone, doxepin, clozapine and amitriptyline in this study. The limits of detection (LODs) are in the range of 0.0003–0.003 ng/mL, which are lower than other reported methods by several orders of magnitude. The linear ranges are 0.01–200 ng/mL for norfluoxetine, paroxetine and doxepin, while the linear ranges are 0.001–200 ng/mL for the rest antidepressants. The correlation coefficients are over 0.99. Extraction recoveries (ER) ranging in 82.4–101.5% were obtained for the target analytes. The intra-day relative standard deviations (RSDs) range in 4.5–10.3% and inter-day RSDs range in 5.1–12.7%. Reasonable values of matrix effect (ME) ranging in 82.5–110.4% were obtained for quality control samples. The present methodology was used for the analysis of antidepressants in real cases and is expected to have a wide usage for analysis of antidepressants in biomedical area and forensic practice.

Therapeutic Drug Monitoring of Antidepressants for the Treatment of Chronic Musculoskeletal Pain With and Without Depression.

Antidepressants are recommended for the treatment of chronic musculoskeletal pain; however, target serum concentrations based on therapeutic drug monitoring (TDM) have not been established. Therefore, the authors analyzed routine care TDM data of antidepressants in patients with chronic pain with and without depression in terms of treatment outcomes in an interdisciplinary multimodal pain treatment (IMPT) program. Patients with chronic musculoskeletal pain and TDM for amitriptyline (n = 45) or duloxetine (n = 30) were retrospectively included. The German pain questionnaire for pain intensity and the Depression Anxiety Stress scale were applied at T0 and at the end of the IMPT program (T1). A relief of pain intensity score ≥2 was considered as a positive outcome. Comorbid depression was diagnosed based on ICD-10 criteria. Serum concentrations of antidepressants were measured for routine clinical care TDM. After IMPT, stress improved in all subgroups, and depressive symptoms improved only in the duloxetine group. Overall, 40% and 27% of patients in the amitriptyline and duloxetine subgroup, respectively, were responders in terms of maximum pain score relief. Responders with comorbid depression were treated with a dose that led to a 1.7-fold higher serum concentration of the active moiety of amitriptyline (amitriptyline + nortriptyline) compared with nonresponders. Similarly, a 2.3-fold higher serum concentration was observed in depressed responders than in nondepressed responders (at minimum 131.5 ng/mL). Dosing of antidepressants for chronic pain relief should specifically take comorbid depression into account. TDM may provide better outcomes of pain relief in an IMPT setting in patients with comorbid depression.

A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants

BackgroundTherapeutic drug monitoring (TDM) of antidepressants is important to ensure compliance and to rule out pharmacokinetic abnormalities. Therefore, reliable methods for quantification are important for clinical laboratories. Most of the currently used mass spectrometry methods use triple quadrupoles as mass analyzers. We aimed to develop a method using high-resolution mass spectrometry (HRMS) and wanted to test the suitability of this analyzer for quantitative TDM assays. This would be beneficial since HRMS instruments can also be used for metabolomics and protein analysis and, thus, many different analyses could be run on one instrument. MethodsAfter manual protein precipitation of serum samples, further sample clean-up was achieved using a Turbo Flow column preconnected to the analytical LC column. Stable isotope-labelled counterparts of the target analytes were used as internal standards. For detection, we used a Q Exactive Focus Orbitrap mass spectrometer operating in full-scan mode. Ionization was performed in positive ESI. ResultsAccuracy, recovery, and matrix effect were acceptable for all analytes. The method demonstrated outstanding precision (within-run imprecision <4.5%, between-run imprecision <7.5%). The selectivity of the method was ensured by chromatographic separation of all isobaric compounds. Close agreement between Orbitrap and triple stage based quantification was observed in a comparison measurement of leftover patient samples. ConclusionsWe have established a selective method for the quantification of antidepressants with outstanding precision using a high-resolution Orbitrap mass spectrometer. The applicability of HRMS instruments to TDM was demonstrated.

A clinical validation study for application of DBS in therapeutic drug monitoring of antidepressants.

A bridging study of plasma and DBS concentrations for therapeutic drug monitoring of antidepressants was performed. RESULTS & METHODOLOGY: Potassium-based hematocrit analysis was included. In addition, we defined acceptance criteria based on the differences between individual data points of plasma and DBS concentrations. These criteria were applied to test acceptability of error found in predicted nortriptyline plasma concentrations. Potassium-based hematocrit predicted a negative bias for DBS concentrations of amitriptyline, but not for the other compounds. To predict plasma concentrations of antidepressants based on DBS concentrations, a factor of 0.8, 0.65, 0.84 and 0.78 was found for nortriptyline, desmethylclomipramine, venlafaxine and desmethylvenlafaxine, respectively. Application of the factor and newly formulated acceptance criteria demonstrated prediction of nortriptyline plasma concentrations based on DBS concentrations.

Prevalence of Therapeutic Drug Monitoring for Antidepressants and Antipsychotics in Stockholm, Sweden: A Longitudinal Analysis.

Background:Although therapeutic drug monitoring (TDM) is considered an underused tool in psychiatric care, the prevalence of TDM is largely unknown. The aim of this study was to analyze the prevalence of TDM for antidepressants and antipsychotics during 2006–2013.Methods:The study population consisted of individuals ≥5 years of age residing in Stockholm County. The prevalence of TDM for each study year was calculated with the number of individuals in whom TDM had been performed as nominator (extracted from the TDM database at Karolinska University Laboratory) and the number of treated individuals as denominator (extracted from the Swedish Prescribed Drug Register). All data were obtained at the third and the fifth level of the anatomical therapeutic chemical classification system (pharmacological subgroup and chemical substance, respectively). The prevalence of TDM was compared between substances according to the level of TDM recommendation by guidelines.Results:For antidepressants, the prevalence of TDM decreased from 0.48% (95% confidence interval, 0.45%–0.52%) in 2006 to 0.36% (0.33%–0.39%) in 2013 (among 133,275 and 162,998 treated individuals, respectively). For antipsychotics, the prevalence of TDM increased from 2.3% (2.2%–2.5%) to 4.1% (3.9%–4.3%) (31,463 and 32,534 treated individuals). For both drug groups, TDM was more common in men than in women. The most frequently analyzed drugs were clozapine, perphenazine, zuclopenthixol, nortriptyline, and flupentixol. Although not reaching statistical significance, the TDM prevalence was greater for substances strongly recommended for TDM than for substances with a lower level of recommendation, median (interquartile range): 5.6% (2.8%–22%) versus 1.1% (0.2%–2.2%), P = 0.063.Conclusions:The prevalence of TDM is generally low, more frequent, and increasing for antipsychotics, and more frequent for men and substances where TDM is strongly recommended.

Modern chromatographic and electrophoretic measurements of antidepressants and their metabolites in biofluids

Depression is one of the most frequently occurring psychiatric conditions affecting the economic and social functioning of people all over the world. There are a few classes of drugs commonly used to treat patients with depression disorders. Therapeutic drug monitoring of antidepressants provides the possibility to reduce side effects and optimize the treatment of patients with depression. Hence, there is a need to develop reliable analytical methods for the determination of these agents in biological fluids. Moreover, an important part of understanding the mechanisms of action of these medicines is also associated with the recognition of the metabolites' function because of their potential influence on therapeutic benefits and/or adverse effects. Some of them possess the same primary activity as their parent compounds and may contribute to the therapeutic efficacy whereas the biochemical actions of other metabolites may be different from that of the parent drug. In this review, several validated high-performance liquid chromatographic, gas chromatographic and capillary electrophoretic methods for quantification of antidepressants and their metabolites in biofluids are compared. In addition, the review covers areas such as mechanism of actions, structure-activity relationships and metabolism of the cited antidepressants.

Is there a therapeutic window with some antidepressants for analgesic response?

Most antidepressants and anticonvulsants used in chronic pain syndromes have dose- and concentration-response curves developed for their application to treat psychiatric disorders. Because these are important clinical tools in medication management of psychiatric syndromes, it is reasonable to expect that utilizing concentration-effect relationships and known sources of pharmacokinetic variability for determining doses for analgesia may also improve treatment tolerability and outcomes. Efforts to identify dosing "therapeutic windows" or minimum "thresholds" for analgesic efficacy have provided useful guidance for initiating treatment, reducing toxicity, and assisting with decision making in the face of limited therapeutic response. This article reviews the strengths, limitations, and potential of therapeutic drug monitoring of antidepressants and anticonvulsants as analgesics for selected chronic pain syndromes.

Therapeutic Drug Monitoring of Antidepressants and Cytochrome P450 Genotyping in General Practice

In the psychiatric setting, therapeutic drug monitoring and genotyping for cytochrome P450 (CYP) polymorphisms help to ensure and maintain therapeutic drug levels. In this study, the authors extended the therapeutic drug monitoring and genotyping protocol routinely used in their psychiatric clinic to primary care patients treated with antidepressants. They examined the variation in serum concentrations and assessed the role of CYP polymorphisms, wrong dosing, and noncompliance in deviating serum concentrations. Of 227 serum concentrations obtained, 127 (56%) were more than 20% outside therapeutic ranges. Of these 127 cases, 64 (50%) were congruous with aberrant CYP2D6 or CYP2C19 genotypes, incorrect dosing, or a pharmacy record suggesting noncompliance. Prevalence of aberrant CYP2D6 and CYP2C19 genotypes did not differ significantly between the investigated primary care patients and 751 secondary care users of antidepressants. The therapeutic drug monitoring and the genotyping findings resulted in recommendations to physicians to alter the medication strategy of 146 (64%) patients. These results strongly suggest that the rationale for therapeutic drug monitoring and CYP genotyping when prescribing antidepressants in secondary care also applies to the primary care setting.

Appropriateness of Therapeutic Drug Monitoring for Antidepressants in Routine Psychiatric Inpatient Care

Although there is sufficient evidence of the benefits of therapeutic drug monitoring (TDM) for optimizing antidepressant therapy, its current use in routine care is far from optimal. As a prerequisite for developing improvement strategies, the appropriateness of TDM use was investigated in a psychiatric hospital in which TDM is applied routinely to a large extent. A retrospective analysis of all patients admitted in 2003 with a unipolar depressive disorder was performed. Based on detailed chart review, for all TDM tests, the time of blood sample taking in relation to the medication process and the consequences of the TDM results for clinical decision making were analyzed. Altogether, 748 plasma levels were measured for antidepressants. The evaluation identified considerable inappropriate use of TDM. After a preceding change of dose, only the minority of TDM tests was performed within an optimum time interval. Overall, 30% of blood samples were taken too early, before steady state had been reached. The high number of repeat tests without preceding change of drug dose points to potentially redundant use. There also was evidence of underuse of TDM, as in many cases additional plasma level determinations might have been useful to speed up optimal dosing. Frequent discrepancies were found between the laboratory's recommendations and actual clinical decision making. Suggested dose changes were followed in only 30%. The findings clearly indicate the need for measures to improve the implementation of TDM in routine care. Based on the identified pattern of current TDM utilization and experiences from other fields of medicine, a combination of strategies, including both educational and electronic interventions, may have the greatest potential for improvement.

Therapeutic Drug Monitoring of Antidepressants and Length of Stay of Psychiatric Inpatients

Therapeutic Drug Monitoring of Antidepressants and Length of Stay of Psychiatric Inpatients

Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Pharmacokinetics of amoxapine and its active metabolites in healthy subjects

Therapeutic drug monitoring for antidepressants is problematic because the blood concentration is usually poorly correlated with the dose. We have developed a simple method to simultaneously determine the pharmacokinetics of amoxapine (AMX) and its active metabolites 7-hydroxyamoxapine (7-OHAMX) and 8-hydroxyamoxapine (8-OHAMX). Using this method, we studied the pharmacokinetics of AMX and its metabolites in six male and six female healthy volunteers. The subjects received 25-mg and 50-mg single doses of AMX. After each dose, the pharmacokinetic parameters were determined according to their serum concentration-time curves. The area-under-the-curve value for 8-OHAMX was three to five times greater than that for AMX. Serum concentrations of AMX and 8-OHAMX 12 hours after administration were closely associated with the doses of AMX per body weight. This association was even more apparent when AMX and 8-OHAMX were combined. Consequently, AMX may be a useful marker for therapeutic drug monitoring, although the pharmacologic action attributable to its active metabolites should be taken into account.

A definite place for therapeutic drug monitoring of antidepressants

A definite place for therapeutic drug monitoring of antidepressants

Monitoring Cyclic Antidepressants

Therapeutic drug monitoring of antidepressants can ensure that a reasonable amount of drug reached the circulation, can aid in dosage adjustments for treating endogenous depression, can avoid toxicity, and aid in the diagnosis of drug-induced delirium. This article reviews the justification for antidepressant monitoring, discusses sample collection procedures, and presents guidelines for the interpretation of data.