The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants

 [bib_ref] Augmentation strategies in depression, Nelson [/bib_ref] [bib_ref] Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors, Zullino [/bib_ref] [bib_ref] Randomised controlled trials investigating pharmacological and psychological interventions for treatmentrefractory depression, Stimpson [/bib_ref] [bib_ref] The need for clinically relevant research on treatment-resistant depression, Thase [/bib_ref] [bib_ref] Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder:..., Michelson [/bib_ref] [bib_ref] The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry, Baumann [/bib_ref] [bib_ref] Relationship between plasma level and therapeutic effect of nortriptyline, Asberg [/bib_ref] [bib_ref] Task Force. Tricyclic antidepressants-blood level measurements and clinical outcome: an APA Task..., Bertilsson [/bib_ref] [bib_ref] CYP2D6 and CYP2C19 genotypebased dose recommendations for antidepressants: a first step towards..., Kirchheiner [/bib_ref] [bib_ref] Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing?, Dahl [/bib_ref] 

## Pharmacokinetics, metabolism, and pharmacogenetics of antidepressants
Antidepressants share many common features, such as high lipophilicity, a molecular weight between 200 and 500, and basicity. We therefore present a general summary of their pharmacokinetic properties in , [bib_ref] The relationship between serum concentration and therapeutic effect of haloperidol in patients..., Ulrich [/bib_ref] [bib_ref] Pharmacokinetics of selective serotonin reuptake inhibitors, Hiemke [/bib_ref] [bib_ref] Human cytochromes and some newer antidepressants: kinetics, metabolism, and drug interactions, Greenblatt [/bib_ref] [bib_ref] Newer antidepressants and the cytochrome P450 system, Nemeroff [/bib_ref] [bib_ref] Antidepressants and drug-metabolizing enzymes-expert group report, Meyer [/bib_ref] [bib_ref] Metabolism of tricyclic antidepressants, Rudorfer [/bib_ref] though numerous compounds constitute exceptions: citalopram is known for its high bioavailability (about 90%) and relatively low binding to plasma proteins (80%); venlafaxine, trazodone, tranylcypromine, and moclobemide display a short (about 2-10 h) and fluoxetine a long plasma half-life (3-15 days, taking into account its active metabolite). It should also be considered that many antidepressants, such as venlafaxine, citalopram, *This review takes into consideration antidepressant agents currently available in Switzerland and Germany, and therefore does not claim to be exhaustive. and mirtazapine, are used as racemic compounds, the enantiomers of which differ in their pharmacological, metabolic, and pharmacokinetic properties. [bib_ref] Investigation of xenobiotic metabolism by CYP2D6 and CYP2C19: importance of enantioselective analytical..., Marzo [/bib_ref] [bib_ref] Enantiomers' potential in psychopharmacology-a critical analysis with special emphasis on the antidepressant..., Baumann [/bib_ref] Most antidepressants undergo phase I metabolism by oxidation, such as aromatic ring and aliphatic hydroxylation, N-and O-dealkylation, N-and O-oxidation to N-oxides, carbonyl reduction to secondary alcohols, and S-oxidation to sulfoxides or sulfones, which results in an increase in polarity.The introduction of a functional group (eg, a hydroxy group) or the presence of a tertiary amine group may enable a phase II metabolic step, typically a glucuronidation. [bib_ref] Drug glucuronidation in clinical psychopharmacology, Liston [/bib_ref] [bib_ref] Handbook of Drug Metabolism, Burchell [/bib_ref] [bib_ref] Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers, Penzak [/bib_ref] Metabolism occurs mainly in the liver and in the intestinal mucosa. It may be age-dependent, and vary as a consequence of the influence of environmental factors, such as somatic diseases, comedication, food, and smoking.TDM should include the assay of active metabolites [bib_ref] Formation of active metabolites of psychotropic drugs: an updated review of their..., Caccia [/bib_ref] [bib_ref] Formation of active metabolites of anticonvulsant drugs-a review of their pharmacokinetic and..., Eadie [/bib_ref] [bib_ref] The role of metabolites of antidepressants in the treatment of depression, Rudorfer [/bib_ref] (eg, clomipramine [norclomipramine] and fluoxetine [norfluoxetine]), but the parent compound/inactive metabolite ratio may be helpful to evaluate the metabolic state or compliance of the patient. Considerable and clinically relevant knowledge has been acquired during the past 30 years on the important role of cytochrome P-450 (CYP) isozymes, CYP 1A2, CYP 2D6, CYP 2C9, CYP 2C19, and CYP 3A4/5, in the biotransformation of antidepressants. [bib_ref] Molecular genetics of CYP 2D6: clinical relevance with focus on psychotropic drugs, Bertilsson [/bib_ref] [bib_ref] Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication, Cascorbi [/bib_ref] [bib_ref] Inhibition mechanisms, genetic regulation and effects of liver disease, Murray [/bib_ref] [bib_ref] Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics, Dahl [/bib_ref] [bib_ref] Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the..., Kirchheiner [/bib_ref] [bib_ref] Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism, Vasiliou [/bib_ref] [bib_ref] Polymorphic cytochromes P450 and drugs used in psychiatry, Coutts [/bib_ref] The genetically determined polymorphism of CYP 2D6 is of high clinical relevance for antidepressants, which are substrates of this isozyme, including tricyclic antidepressants, some selective serotonin reuptake inhibitors (SSRIs) (eg, paroxetine and fluoxetine), and "third-generation" antidepressants (eg, venlafaxine and mirtazapine). About 5% to 8% and 1% to 7% of the Caucasian population are considered as poor metabolizers (PMs) or ultrarapid metabolizers (UMs), respectively . [bib_ref] Human cytochromes and some newer antidepressants: kinetics, metabolism, and drug interactions, Greenblatt [/bib_ref] [bib_ref] Cytochrome P450 polymorphisms and response to antipsychotic therapy, Scordo [/bib_ref] In Caucasians, there is a lower proportion (3%-5%) of PMs of CYP 2C19, which is frequently involved in N-demethylation of tertiary amines (amitriptyline and citalopram). CYP 3A4/5 shows wide interindividual variability in its activity. CYP 3A5 is expressed in only one-third of the Caucasian population. [bib_ref] Sequence diversity in CYP3A promoters and characterization of the genetic basis of..., Kuehl [/bib_ref] As regards CYP 1A2, only its inducibility (eg, by tobacco smoke) is genetically polymorphic. [bib_ref] Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on..., Nakajima [/bib_ref] [bib_ref] Functional significance of a C_A polymorphism in intron I of the cytochrome..., Sachse [/bib_ref] Clinically, a PM status may represent a higher risk for adverse effects in patients treated with antidepressants known to be substrates of the deficient enzyme, while UMs undergo a higher risk for nonresponse, due to subtherapeutic plasma concentrations. [bib_ref] Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics, Dahl [/bib_ref] [bib_ref] Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry, Brsen [/bib_ref] [bib_ref] Pharmacogenetics and drug metabolism of newer antidepressant agents, Devane [/bib_ref] [bib_ref] Pharmacogenetics of classical and new antipsychotic drugs, Otani [/bib_ref] [bib_ref] Pharmacogenetic screening and therapeutic drugs, Steimer [/bib_ref] [bib_ref] Individualized medicine-implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive..., Kirchheiner [/bib_ref] [bib_ref] Therapeutic monitoring of antidepressants in era of pharmacogenetics studies, Eap [/bib_ref] The clinical relevance of the genetic polymorphisms of UDP-glucuronosyltransferases in pharmacopsychiatry is not clear. [bib_ref] Drug glucuronidation in clinical psychopharmacology, Liston [/bib_ref] [bib_ref] Glucuronidation enzymes, genes and psychiatry, De Leon [/bib_ref] Genotyping, which represents a "trait marker," is readily available and clinically recommended for CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, and CYP 3A4/5; phenotyping, used as a "state-marker," may be performed for the same enzymes. The result of genotyping is not influenced by environmental factors and has life-long validity. Phenotyping requires the administration of drugs and is therefore a more invasive procedure. Therefore, indications for phenotyping and genotyping may differ. As mentioned in , transport proteins such as P-glycoprotein in the intestinal mucosa and in the blood-brain barrier may be implicated in the regulation of the availability of antidepressants for the brain, but there is still a lack of clinical data. [bib_ref] Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance, Marzolini [/bib_ref] [bib_ref] abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into..., Uhr [/bib_ref] [bib_ref] Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in..., Uhr [/bib_ref] 

## Relationships between drug doses, plasma concentrations, and clinical variables
TDM is based on the hypothesis assumption that there is a well-defined relationship between the drug plasma concentration and its clinical effects (therapeutic effect, adverse effects, and toxicity). However, while such a relationship is generally well admitted for lithium and for the tricyclic antidepressants nortriptyline, amitriptyline, desipramine, and imipramine, inconsistent results were obtained in studies on other tricyclic or similarly structured antidepressants, SSRIs, and other recently introduced antidepressants. 20,58-62 Interestingly, systematic reviews and meta-analyses 14,59 that were based on adequately designed studies yielded evidence of a relationship between clinical variables and plasma concentration for some tricyclic drugs. This suggests that numerous studies were poorly designed methodologically in order to demonstrate an evident relationship between concentration and effects or side effects. Recently, Ulrich and Lauter 60 defined criteria for quality assessment of TDM studies, which include the use of valid chemical and analytical methods, adequate psychopathology rating scales, appropriate selection criteria for patients (eg, exclusion of known nonresponders), and reporting of comedication.

## Analytical procedures
Plasma or serum samples are generally used for TDM. Concentrations of antidepressants are low, most often in the nmol/L (ng/mL) range. Therefore, highly sensitive and selective analytical methods are needed for accurate and precise quantification. [bib_ref] A practical guide to analytical method validation, Green [/bib_ref] [bib_ref] Method validation in the bioanalytical laboratory, Buick [/bib_ref] [bib_ref] Analytical methods validationbioavailability, bioequivalence and pharmacokinetic studies, Shah [/bib_ref] [bib_ref] Validation of chromatographic methods in biomedical analysis viewpoint and discussion, Causon [/bib_ref] Most laboratories use now gas chromatography (GC) or high-performance liquid chromatography (HPLC) for the assay of antidepressants for TDM purposes. For GC, the most recommended detection systems are mass spectrometry (GC-MS) or nitrogen phosphor detectors (GC-NPD). Ultraviolet (UV) detectors, fluorescence detectors, and mass spectrometry (LC-MS), in increasing order, are useful for a selective and sensitive drug assay. Clearly, the need for sample preparation before chromatographic separation represents a time-consuming step, and this procedure also implies a limited sample throughput, despite the availability of automated sample preparation prior to GC or HPLC. [bib_ref] Quantitative determination of tricyclic antidepressants and their metabolites in plasma by solid-phase..., De La [/bib_ref] Direct injection ("column switching HPLC") of plasma or serum into the HPLC system is now available for a number of antidepressants. [bib_ref] Monitoring serum concentrations of clomipramine and metabolites: fluorescence polarization immunoassay versus high..., Banger [/bib_ref] [bib_ref] Simultaneous determination of seven tricyclic antidepressant drugs in human plasma by direct-injection..., Kollroser [/bib_ref] [bib_ref] Column-switching procedures for the analysis of drugs in biologic samples, Veuthey [/bib_ref] LC-MS and LC-MS-MS (tandem mass spectrometry) will increasingly be the method of choice, as it may be applied to almost any psychotropic drug including metabolites, while GC-MS is applicable only for volatile compounds.

## Economic aspects of tdm in psychiatry
TDM for a single psychoactive drug, including a metabolite, costs between 20 and 80 , which includes costs for staff, instrumentation, chemicals, and other materials. In some countries, analyses may be billed according to the analytical technique used (higher rates for mass spectrometric quantification). A proof of cost-effectiveness has been provided for only a few antidepressants. [bib_ref] Cost-benefit analysis of prospective pharmocokinetic dosing of nortriptyline in depressed inpatients, Simmons [/bib_ref] [bib_ref] Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies..., Lundmark [/bib_ref] However, additional studies are required. They should be designed to take account of the complexity of the TDM process . For example, a recent prospective study carried out under naturalistic conditions showed that dose adjustment by the treating physician was frequently inappropriate, in that he or she neglected the results of the laboratory assays. [bib_ref] Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical..., Muller [/bib_ref] Preliminary data suggest that phenotyping or genotyping of patients may help decrease the cost of their treatment with substrates of CYP 2D6. [bib_ref] The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on..., Chen [/bib_ref] The costs of treating patients who are either UMs or PMs (CYP 2D6) are seemingly thousands of US dollars per year higher than those for extensive metabolizers (EMs). [bib_ref] Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism..., Chou [/bib_ref] However, the tools to assess the cost-effectiveness of pharmacogenetic tests are still insufficiently developed. [bib_ref] Assessing the cost-effectiveness of pharmacogenomics, Veenstra [/bib_ref] P h a r m a c o l o g i c a l a s p e c t s Consensus TDM should be limited to situations where it may be expected that the result will help to solve a therapeutic problem. There are many indications for using TDM [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] in antidepressant pharmacotherapy, such as suspicion of noncompliance or intoxication. In pharmacovigilance programs, TDM may be considered as a valid indication for all drugs and groups of patients. To recommend TDM as routine monitoring, it must be proven that TDM is of value. Five levels of recommendation for TDM were defined, which range from "strongly recommended" to "not recommended." In a second step, a recommendation tailored to the individual drug was defined.

## Levels of recommendations to use tdm as routine monitoring
The therapeutic strategy will only be improved by the use of TDM, if the already mentioned criteria are fulfilled. [bib_ref] Comprehensive survey of the relationship between serum concentration and therapeutic effect of..., Ulrich [/bib_ref] There is sufficient evidence that TDM can be useful for patients treated with antidepressants, as concluded by the authors of this consensus guideline, after a careful examination of the literature: (i) guidelines; (ii) meta-analyses; (iii) prospective studies on the clinical effectiveness of drugs in which drug plasma concentrations were reported; and (iv) pharmacokinetic studies. However, the latter often do not allow definition of a therapeutic plasma concentration range, in the absence of clinical data. Five levels of recommendation to use . Specific requests may be useful for any psychoactive drug and many indications Lack of response, insufficient response, side effects at therapeutic doses, potential drug interaction or other specific indications TDM as routine monitoring were defined as follows, as reported earlier. [bib_ref] Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder:..., Michelson [/bib_ref] 

## Strongly recommended
- Established therapeutic range - Level of evidence: Controlled clinical trials have shown benefit of TDM; reports on toxic effects at "supratherapeutic" plasma concentrations. - Clinical consequences: At therapeutic plasma concentrations highest probability of response; at "subtherapeutic" plasma concentrations response rate similar to placebo; at plasma concentrations higher than therapeutic concentrations increasing risk of adverse effects.

## Recommended
- Suggested therapeutic ranges obtained from plasma concentrations at therapeutically effective doses (fixed dose studies). - Level of evidence:At least one well-designed prospective study with well-defined outcome criteria reports intoxications at "supratherapeutic" plasma concentrations. - Clinical consequences:TDM most probably will optimize response in nonresponders: at "subtherapeutic" plasma concentrations risk of poor response; at "supratherapeutic" plasma concentrations risk of adverse effects and/or decreased response.

## Useful
- Suggested therapeutic ranges are plasma concentrations at effective doses obtained from steady-state pharmacokinetic studies. - Level of evidence: Clinical data from retrospective analysis of TDM data; single case reports; or nonsystematic clinical experience. - Clinical consequences: TDM useful to control whether plasma concentrations are plausible for a given dose; optimizing of clinical response in nonresponders who display low concentrations is possible.

## Probably useful
- Suggested therapeutic ranges from steady-state pharmacokinetic studies at therapeutically effective doses. - Level of evidence: Valid clinical data so far lacking or inconsistent results.
- Clinical consequences: TDM useful to control whether plasma concentrations are plausible for a given dose.

## Not recommended
- Unique pharmacology of the drug, eg, irreversible blockade of an enzyme or flexible dosing according to clinical symptoms. - Level of evidence: Textbook knowledge, basic pharmacology.
- Clinical consequences: TDM should not be used.

## Drug-specific tdm recommendations
The knowledge of plasma concentrations ranges observed after treatment of subjects at well-defined doses of the antidepressant [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] may efficiently help the clinician in some of the situations listed in [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] : suspicion of noncompliance, drug interactions, problems occurring after switching from an original preparation to a generic form (and vice versa), or presence of a pharmacogenetic PM or UM status. The information available in [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] is also helpful in situations where the levels of recommendations 3 and 4 apply (ie, TDM useful or probably useful). However, the data presented in [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] are insufficient to allow levels of recommendations 1 or 2, as it does not include studies on the plasma concentration-clinical effectiveness relationship. Therefore, the literature had to be reexamined to define which antidepressants may get a level 3 or 4 of recommendation for their monitoring. By consensus, a therapeutic range was then also defined for their "main" (= depression) indication , as data for other indications (eg, anxiety disorders) are most often lacking, and some studies suggest that optimal ranges may differ, depending on the pathology. [bib_ref] Therapeutic effects of imipramine are counteracted by its metabolite, desipramine, in patients..., Mcleod [/bib_ref] Antidepressants differ widely in their chemical structure and their pharmacological activity, even though most are serotonergic and/or noradrenergic. "Therapeutic windows" have been defined for most tricyclic antidepressants, and TDM is recommended to avoid intoxications, which may be lethal . As regards more recently introduced antidepressants, a clearcut plasma level-clinical effectiveness relationship was not demonstrated for tetracyclic antidepressants (maprotiline, mianserin, or mirtazapine), trazodone, reboxetine, the monoamine oxidase inhibitors moclobemide and tranylcypromine, [bib_ref] Pharmacokinetic optimisation of therapy with newer antidepressants, Goodnick [/bib_ref] and SSRIs. [bib_ref] Pharmacokinetics of selective serotonin reuptake inhibitors, Hiemke [/bib_ref] [bib_ref] Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors, Baumann [/bib_ref] [bib_ref] Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding..., Rasmussen [/bib_ref] However, TDM of SSRIs was shown to be cost-effective, as it helps to use minimum effective doses. [bib_ref] Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical..., Lundmark [/bib_ref] Therefore, data on the plasma concentrations at therapeutic doses may be clinically useful for these drugs [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] , in situations of noncompliance, nonresponse, adverse effects, or intoxication.

## P h a r m a c o l o g i c a l a s p e c t s

## Specific indications for tdm in psychiatry
Therapeutic windows should be interpreted in the context of the clinical situation, before the decision to change treatment strategy is taken. As an example, low levels may be sufficient for the antidepressant doxepin, if it is used to obtain sedation. [bib_ref] Doxepin plasma concentrations: is there really a therapeutic range?, Leucht [/bib_ref] Interestingly, despite the increasing use of generics, there are few data available that demonstrate unambiguously the occurrence of pharmacokinetic problems after switching from an original preparation to a generic form (and vice versa). 157-160 TDM is a general indication for the administration of psychotropic drugs in children and adolescents because psychopharmacotherapy of children and adolescents differs from that of adults (Gerlach et al, in press): (i) There are differences in the pharmacokinetic behavior of drugs used in dependence on the stage of development; it is therefore not appropriate to use dosages recommended for adults. (ii) Many drugs are not approved for use in children and adolescents; the consequence is that the criteria for efficacy and safety, guaranteed for the use in adults, are not given for administration in children and adolescents. There is, however, a need to carry out standardized studies to find therapeutic ranges of plasma concentrations for children and adolescents. In these patients, but also in elderly subjects, TDM may help distinguish between pharmacokinetic and pharmacodynamic factors in the occurrence of adverse effects. Consequently, TDM also represents a useful tool in situations of pharmacovigilance programs. Antidepressants should be monitored in the blood of pregnant or lactating women in order to minimize drug exposure of the fetus or newborn infant. [bib_ref] The use of psychotropic medications during breast-feeding, Burt [/bib_ref] [bib_ref] Mood stabilizers during breastfeeding. A review, Chaudron [/bib_ref] [bib_ref] Psychotropic medications in lactation, Llewellyn [/bib_ref] [bib_ref] The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics, Ernst [/bib_ref] Investigations on the "therapeutic window" of patients should not only be included in phase IV studies. If possible, they should also be carried out in phase III studies, in relationship with clinical ratings, in order to propose TDM with the introduction of the new drug.As stated in the document published by the European Agency for the Evaluation of Medicinal Products,an established concentration-response relationship is the basis to forecast the chance of toxicity due to pharmacokinetic differences, drug-disease, or drug-drug interactions.

## Pharmacogenetic tests in addition to tdm
There is increasing evidence for an advantage to combine pharmacogenetic tests with TDM. [bib_ref] CYP2D6 and CYP2C19 genotypebased dose recommendations for antidepressants: a first step towards..., Kirchheiner [/bib_ref] [bib_ref] Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics, Dahl [/bib_ref] [bib_ref] Cytochrome P450 polymorphisms and response to antipsychotic therapy, Scordo [/bib_ref] [bib_ref] Polymorphic drug oxidation-relevance to the treatment of psychiatric disorders, Bertilsson [/bib_ref] However, pharmacogenetic tests alone have limited value, as environmental factors also regulate drug metabolism. [bib_ref] Pharmacogenetics-the therapeutic drug monitoring of the future?, Ensom [/bib_ref] Some of the most important indications for phenotyping and/or genotyping (in combination with TDM) are the following. [bib_ref] Pharmacogenetic screening and therapeutic drugs, Steimer [/bib_ref] [bib_ref] Pharmacogenetics-the therapeutic drug monitoring of the future?, Ensom [/bib_ref] - The metabolism of the medication (or its active metabolite) is governed to a significant extent by the enzyme, which is considered to be phenotyped or genotyped. - The patient is treated with a substrate whose metabolism shows a wide interindividual variability, as demonstrated by TDM. - A drug is characterized by a low therapeutic index, ie, risk of toxicity in the case of a genetically impaired metabolism or, on the other hand, risk of nonresponse due to an ultrarapid metabolism and the inability to reach therapeutic drug levels. - The patient presents unusual plasma concentrations of the drug or its metabolite(s), and genetic factors are suspected to be responsible.

## P h a r m a c o l o g i c a l a s p e c t s
- The patient suffers from a chronic illness, which requires life-long treatment. As outlined above, both phenotyping and genotyping are recommended in some circumstances, as a "traitmarker" and a "state-marker." Currently, data obtained by TDM represent a "state-marker."

## Practical aspects of tdm
Previous studies suggest that the "compliance" of the treating physician needs to be improved, as many requests or indications for TDM were inappropriate. [bib_ref] Use of plasma level monitoring of antidepressants in clinical practice-towards an analysis..., Vuille [/bib_ref] Moreover, clinicians frequently do not follow the recommendations given by the laboratory to adjust the treatment. [bib_ref] Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical..., Muller [/bib_ref] Therefore, some practical recommendations are summarized (see reference 11 for a comprehensive presentation) for the optimal use of TDM, as illustrated in .

## Recommendations for the treating physician
Preparation of TDM Some patients may particularly benefit from TDM: an antidepressant drug should then be recommended for which TDM is available, either to minimize adverse effects or optimize its clinical efficacy. A well-defined "therapeutic window" for this drug or at least known plasma concentration ranges for clinical doses [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] should be available. Blood should be collected for TDM in steady-state conditions, ie, at least 5 drug half-lives after changes in dose and during the terminal -elimination phase. Generally, the appropriate sampling time for most antidepressants (except for fluoxetine) is 1 week after stable daily dosing and immediately before ingestion of the morning dose, ie, about 12 to 16 h (or 24 h if the drug is given once daily) after the last medication. It should be considered that both after a modification of the dose and after prescription of a comedication, which may inhibit or enhance the metabolism of the drug to be measured, steady-state conditions are reached again only after a few days. TDM should then be delayed, in case unexpected side effects are observed. Most antidepressants are stable in serum or plasma for at least 24 h 170 and can therefore be sent to the laboratory at room temperature. It is mandatory to consider technical recommendations given by the laboratory: choice of anti-coagulant (plasma, serum), sample volume and its labeling, conditions for mailing, influence of light, and temperature. Information on comedication may help the laboratory to avoid analytical problems (interferences with other drugs). It is strongly recommended to fill out the request forms adequately and completely (diagnosis, comorbidities, comedications, treatment duration, doses, sex and age of the patient, and reasons for the request), in order to allow interpretation of the result by clinical pharmacologists. Some of these data may also represent important information for the laboratory to judge plausibility of the result.

## Critical appreciation of the results
A pharmacological treatment should be guided by sound clinical judgment. TDM has to be considered as an additional and useful tool for optimizing therapy. Analytical methods used in the laboratories may differ in their quality. The physician should be aware that some drug levels are not accurately measured, even though most laboratories have introduced a program to measure quality. Indeed, worldwide external quality-control programs show considerable variability between laboratories in the results of analysis of control samples. The physician may obtain discrepant results when a drug was monitored several times in a patient, but analyzed in different laboratories. When comparisons of TDM values obtained from different laboratories are carried out, the clinician should take into account the units (ng/mL, g/L, mol/L, nmol/L) in which the results of the analysis are expressed. Low plasma drug concentrations suggest either irregular intake of the drug or ultrarapid metabolism, and in this situation, a pharmacogenetic test may be indicated. In the first case, TDM should be repeated in order to verify compliance. These examples show that it may be advantageous for the clinician to collaborate with a TDM laboratory that offers pharmacological consultation.

## Tdm interpretation and treatment of patients
A TDM result represents a guide to adjust the treatment of the individual patient, but expert interpretation and adequate use of this pharmacokinetic data are mandatory for an optimal clinical benefit. Reporting of results and inclusion of dose recommendations and other com-

## The agnp-tdm expert group consensus guidelines -baumann et al
Dialogues in Clinical Neuroscience - ments by the laboratory must be guided by the best available evidence. However, the laboratory has only limited knowledge of the clinical context. The physician should also take into consideration whether the "reference plasma concentrations range" reflects only "drug plasma concentrations at clinically relevant doses" [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] or whether they are "therapeutic ranges" . Information on the level of recommendation for TDM of the particular drug may also help evaluate the clinical significance of the result . If the plasma concentration of the drug is within the therapeutic range, an adaptation of the dose is, of course, only recommended when clinical reasons, such as adverse effects or nonresponse, clearly justify such a decision. When the advice given on the TDM report is not followed, the reason for such a decision should be carefully documented.

## Recommendations for the laboratory

## Analytical procedures
The concentrations of antidepressants are generally low, in the ng/mL range, and many patients are comedicated with various, potentially interfering drugs. The methods should be adapted to this situation by precision (coefficient of variation <15%), accurateness (deviation from nominal value <15%), and robustness. [bib_ref] Third-generation antidepressantsdo they offer advantages over the SSRIs?, Olver [/bib_ref] Each assay needs to be validated, documented, and regularly assessed for linearity, selectivity, accuracy, precision, recovery, and sensitivity (limits of detection and quantification . Internal and external quality control procedures are mandatory to ensure maximal quality of TDM. If quality controls are outside the expected range, the reason underlying the outlier needs to be clarified and documented. [bib_ref] Method validation in the bioanalytical laboratory, Buick [/bib_ref] [bib_ref] Analytical methods validationbioavailability, bioequivalence and pharmacokinetic studies, Shah [/bib_ref] [bib_ref] Validation of chromatographic methods in biomedical analysis viewpoint and discussion, Causon [/bib_ref] Where indicated the laboratory should analyze both the drug and its active metabolite(s) [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref]. Moreover, the analysis of (active and inactive) metabolites represents an additional tool to verify compliance of patients.

# Reporting of results
In addition to the result, the appropriate target range should be communicated to the physician [fig_ref] Table II: General indications for therapeutic drug monitoring [/fig_ref] , using, of course, the same units (either mass or molar units). The LOD, or preferentially the LOQ, should be indicated in situations when plasma drug concentrations are below these values. The results should be available for clinical interpretation within a clinically meaningful time, especially in case of suspected intoxications. An interpretation and clinical and pharmacological advice should be provided with every report. Therefore, it is advantageous for the clinician to choose a laboratory that offers this service. Plasma concentrations must be interpreted in the light of sound clinical judgment. Most frequently, recommendations on dose changes are given, and in a situation of drug concentrations above the recommended range, rapidity of communication may enhance successful intervention in patients at risk of toxicity. The physician will also appreciate comments related to genetic polymorphisms, risk for pharmacokinetic interactions in situations, and pharmacokinetic properties of the drug when given to elderly patients or patients with hepatic or renal insufficiency. In situations where drug concentrations are particularly low, it is often not clear whether the patient is an UM or whether he or she is noncompliant in that the drug intake is irregular. The analysis of a second plasma sample may help verify compliance but, depending on the result, a pharmacogenetic test should be carried out. Clearly a PM (CYP 2D6) status should not automatically result in interruption of a treatment, [bib_ref] CYP2D6 and CYP2C19 genotypebased dose recommendations for antidepressants: a first step towards..., Kirchheiner [/bib_ref] [bib_ref] The impact of the CYP 2D6 polymorphism on haloperidol pharmacokinetics and on..., Brockmoller [/bib_ref] but the dose should be adapted using clinical judgment and TDM.

# Conclusion
TDM is a valuable approach to optimize both shortterm and lifelong treatment of psychiatric patients with antidepressants, [bib_ref] Therapeutic drug monitoring of psychotropic drugs TDM "nouveau, Bengtsson [/bib_ref] and a combination of TDM with pharmacogenetic tests will be increasingly useful, particularly because in near future, pharmacogenetic tests regarding pharmacodynamic parameters will also be clinically relevant. [bib_ref] Psychopharmacogenetics-a challenge for pharmacotherapy in psychiatry, Bondy [/bib_ref] Many data on plasma concentrations of psychotropic drugs and the plasma concentration-clinical effectiveness relationship have accumulated over the past few years, and encouraged this interdisciplinary collaboration of specialists who brought about this consensus on TDM. [bib_ref] The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry, Baumann [/bib_ref] Hopefully, it will help to use TDM optimally from a scientific, clinical, and economic point of view.  P h a r m a c o l o g i c a l a s p e c t s
[fig] 2005, Figure 1: The AGNP-TDM Expert Group Consensus Guidelines -Baumann et alDialogues in Clinical Neuroscience -Vol 7 . No. 3 . Summary of the therapeutic drug monitoring (TDM) process for optimization of the pharmacotherpy of psychiatric patients. Routine monitoring should be restricted to psychoactive drugs with established therapeutic ranges and who levels of recommendation to use TDM are at least 2 [/fig]