Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises?

Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises? Prof. Dr. Christoph Hiemke Psychiatrische Klinik und Poliklinik Universität Mainz

Psychopharmacotherapy Psychiatric Patient Diagnosis Symptoms Severity of symptoms Patient s history Selection of medication including dose and/or other treatment options Theory Response Remission

Psychopharmacotherapy Step 1 Step 2 Step 3 Step 4 Step 5 Drug A monotherapy Drug B monotherapy Drug combination Other options: ECT Drugs from other classes Experimental methods Augmentation Augmentation Reality Continuation Continuation Continuation Continuation Continuation

Patient (male, age 29 years) Schizophrenia, psychotic symptoms Case Report First episode Olanzapine, quetiapine, venlafaxine (negative symptoms), insufficient response, relapse Next treatment: Ziprasidone plus quetiapine plus venlafaxine Suicide attempt, intoxication using venlafaxine Intensive care unit, discontinuation of antipsychotic medication Dept of Psychiatry Amisulpride 200 then 600 mg/day motor side effects Amisulpride 400 mg still side effects Clozapine 175 mg Clozapine 300 mg still negative symptoms Reboxetine, 4 mg Citalopram, 40 mg Improvement and stabilization 230 ng/ml 516 ng/ml 310 ng/ml 311 ng/ml 439 ng/ml 159 ng/ml 48 ng/ml

Arzneimittel und Metabolite Genotype Nutrition, smoking, comorbidity, age.. Psychiatric patient Pharmacodynamics Receptor Uptake Enzyme Ion channel e.t.c. Clinical effects Drug and metabolites Drug Arzneimittel- Metabolite und Muttersubstanz Pharmacokinetics Absorption Distribution Metabolism Phenotype Excretion C. Hiemke

Dose and blood level 175 150 Citalopram (ng/ml) 125 100 75 50 25 0 0 10 20 30 40 50 Citalopram Dose (mg/day)

Mean dose Mean plasma concentration (ng/ml) 1800 1600 1400 1200 1000 800 600 400 200 0 Dose and blood level 679 ± 229 mg/d 317 ± 270 ng/ml men women r = 0.32 r s = 0.37 P < 0.0005 (N = 179) 200 400 600 800 10001200140016001800 Amisulpride dose (mg/day)

300 250 Blood and brain concentration r=0.953 P < 0.001 200 150 100 50 0 0 10 20 30 40 Aravagiri et al., 1999

Dose and receptor binding Blood level and receptor binding 100 100 80 80 60 60 40 40 20 20 0 0 250 500 750 1000 1250 0 0 250 500 750 1000

Dose and Uptake-binding Blood level and Uptake-binding Relationship Between Striatal Serotonin Transporter (5- HTT) Occupancy and Dose or Plasma Concentration of Paroxetine in 14 Healthy and Depressed Subjects Meyer et al., 2004

Plasma concentrations are highly variable between patients Plasma concentrations correlate well with brain concentrations Plasma concentrations correlate well with in vivo receptor binding Plasma concentrations reflect brain concentrations

Therapeutic Drug Monitoring Improves therapeutic efficacy Improves drug safety Reduces costs

Nonresponse Intoxication 8 6 4 2 0-2 <50 50-79 80-109 110-139 >140 Åsberg et al. 1971

Promises Therapeutic Drug Monitoring Improves therapeutic efficacy? Improves drug safety? Reduces costs?

Cost effectiveness of TDM in psychiatry

Patients under amitriptyline/ nortriptyline US$ Costs Pharmacokinetic dosing 2100 Benefits Savings from fewer hospital days Savings from an earlier return to work 989 4333 Total savings 5322 Benefit/cost ratio 2,5 Simmons et al., 1985 TDM reduces direct and indirect costs

TDM of tricyclic antidepressants Extra costs per 1000 patients for additional managment Costs for 1000 drug determinations Savings by TDM 199.650 USD 35.000 USD 164.650 USD Preskorn and Fast, 1991 TDM for antidepressants: efficacy, saftey, and cost effectiveness: J Clin Psychiatry 52: 23-33.

TDM of new antidepressants Lundmark et al., (2001) Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr. Scand. 101: 354-359. 127 depressed patients treated with citalopram, paroxetine or sertraline Drug costs before introduction of TDM: USD 71,071 Drug costs after introduction of TDM: USD 60,018 Analytical costs for TDM: USD 5,387 Savings after introduction of TDM: USD 5,666 TDM reduces drug costs

Medical impact of TDM in psychiatry

Therapeutic Drug Monitoring of Antidepressants Depressed patients Treament with a tricylic antidepressant Ther. effects: HAMD and CGI, weekly (day 0-70) Side effects: UKU TDM Blood level measurement Dose recommendation RANDOMIZATION No TDM No dose recommendation

20 15 10 5 0 TDM of tricyclic antidepressants 6 4 2 Change in CGI score TDM no TDM 0 TDM no TDM Müller et al. 2003 Change in HAMD score

20 15 10 5 0 TDM of tricyclic antidepressants plasma concentrations within optimal range plasma concentrations out of optimal range Day 7 Day 14 Day 21 Müller et al. 2003 Change in HAMD score

. The results showed that combining TDM and clinical judgement during the early course of treatment provides a superior outcome in depression. However, the compliance of the psychiatrists in charge to recommendations provided together with serum levels was far from perfect. The results encourage further studies to optimize antidepressant pharmacotherapy when using TDM appropriately. Müller et al. 2003

Therapeutic Drug Monitoring of New Antidepressants Depressed patients Treament with an SSRI or venlafaxine Ther. effects: HAMD and CGI, weekly (day 0-70) Side effects: UKU TDM Blood level measurement Dose recommendation RANDOMIZATION No TDM No dose recommendation

Therapeutic Drug Monitoring of New Antidepressants

Therapeutic Drug Monitoring of New Antidepressants Ocurrence (% of patients)* Discontinuation of drugs with TDM: 9.1 without TDM: 17.9 Change of medication with TDM: 3.2 without TDM: 5.9 *n=219

60 40 20 0 Therapeutic Drug Monitoring of Venlafaxine R 2 = 0.9754 With TDM Without TDM R 2 = 0.9878 9.3 days 0 7 14 21 28 35 42 Days of treatment HAMD % base line score reduction 17.8 days 24.2 days 33.9 days

TDM of antipsychotic drugs

TDM of amisulpride O N H C H 2 N O N H C H 2 N O-CH 3 C 2 H 5 O O-CH 3 C 2 H 5 H 2 NO 2 S C H 3 C H 2 S O NH 2 Sulpiride Amisulpride

Diagnoses TDM of amisulpride 80% SCHIZ (660mg) SAD (590 mg) AFFECT (480mg) ORGAN (500 mg) PERSDIS (800 mg) 6% 3% Müller et al. (2007) J Psychiatr Res 11% N=527

Mean daily dose Mean serum level Serum concentration (ng/ml) 1800 1600 1400 1200 1000 800 600 400 200 0 TDM of Amisulpride 679 ± 229 mg/d 317 ± 270 ng/ml Men Women r = 0.32 r s = 0.37 P < 0.0005 (N = 179) 200 400 600 800 10001200140016001800 Amisulpride dose (mg/day)

TDM of amisulpride Patients with schizophrenia according to DSM IV Antipsychotic monotherapy with amisulpride N=378 Dose 594 ± 262 mg/day Mean trough plasma level 315 ± 277 ng/ml 50% range 120-420 ng/ml Müller et al. (2005) J Psychiatr Res (e-pub ahead)

TDM of amisulpride Response 700 Mean daily dose [mg] 350 Trough plasma level [ng/ml] 600 300 500 250 400 200 300 150 200 100 n.s. 0 Müller et al. (2007) J Psychiatr Res 100 50 P = 0.013 0 Non-Response (9%) At least slight response (91%) Median 248±291 ng/ml 316±253 ng/ml

TDM of amisulpride Side effects 700 600 500 400 300 200 100 0 Mean daily dose [mg] Trough plasma level [ng/ml] 450 400 350 300 250 200 150 n.s. 100 n.s. 50 P = 0.05 0 No EPS (85%) At least mild EPS (15%) Median Müller et al. (2005) J Psychiatr Res

Müller et al. (2005) J Psychiatr Res (e-pub ahead)

Appropriateness of Therapeutic Drug Monitoring in Routine

Appropriateness of Therapeutic Drug Monitoring in Routine Δt BE Δt Lab Δt Reaction Dose Time Dose adaptiation Reporting of results Blood withdrawal Start of dosing Mann, Hiemke, Schmidt, Bates 2006

Appropriateness of Therapeutic Drug Monitoring in Routine ΔtBE 50 40 Antidepressants Frequency 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 >14 Days after change of dose Mann, Hiemke, Schmidt, Bates 2006

Zernig et al. 2004, Therapeutic Drug Monitoring *Retrospective analyses of 2nd requests (antipsychotic drugs) Pharmacokinetic Problems 41%, 0 to 3 days after 1. request 38%, on the day of dose change Clinical Problems 57%, no dose reduction in spite of too high blood levels dose change in spite of optimal level no dose increase in spite of too low blood levels

Lausanne 2004 Pharmacopsychiatry 37 (2004) 243-65 AGNP-Guidelines: Therapeutic Drug Monitoring in Psychiatry

Specific Indications to Use TDM Comorbity Comorbity Renal Renal or or liver liver dysfunction dysfunction Suggested Suggested non-compliance non-compliance Risk Risk of of intoxication intoxication Aged Agedpatients >65 >65 y y Insufficient Insufficient response response Children Children adolescent adolescent TDM Side Side effects effects Distinct Distinct genotype genotype Drug Drug combinations combinations Relapse Relapse Relapse Relapse prevention prevention Suggested Suggested Drug Drug interaction interaction

Indications to use TDM Comorbity Comorbity Renal Renal or or liver liver dysfunction dysfunction Suggested Suggested non-compliance non-compliance Risk Risk of of intoxication intoxication Aged Agedpatients >65 >65 y y Insufficient Insufficient response response Children Children adolescent adolescent TDM Side Side effects effects Distinct Distinct genotype genotype Drug Drug combinations combinations Relapse Relapse Relapse Relapse prevention prevention Suggested Suggested Drug Drug interaction interaction

600 ng/ml Combination Clomipramine-Fluvoxamine-Oxybutynin Clomipramine Patient, female Age: 72 yrs Diagnosis: MDE CYP2D6-Status: EM 400 200 + Fluvoxamine + Oxybutynin 0 25.09./150 + Clomipramine 150 mg 125 mg 75 mg 37,5 mg 25 mg 50 mg 11.10./150 18.10./125 25.10./75 Norclomipramine 07.11./37,5 14.11./25 25.11./25 03.12./25 10.12./50

Haro et al. (2006) J Clin Psychopharmacol 26: 571-578

Cox analysis within the first two years, both groups exhibited identical relapse patterns: then 6fold risk 0.40 0.50 0.60 0.70 0.80 0.90 1.00 > 12% of time on risk < 12% of time on risk 0 2 4 6 8 10 14 18 22 26 30 34 38 42 46 50 54 Solid curve: elevated risk less than 12% of the whole observation period, dashed curve: elevated risk more than 12% of the whole observation period I. Gaertner et al., 2001

TDM and decision making

TDM and Clinical Decision Making TDM REQUEST Change of Medication Blood withdrawal under steady-state Trough levels Drug determination in blood serum or plasma Change of Dose within Serum level therapeutic range not within no Improvement yes Continuation of Drug Treatment

TDM in the future

ANTIPSYCHOTIC DRUG RESPONSE IN SCHIZOPHRENIA

ANTIPSYCHOTIC DRUG RESPONSE IN SCHIZOPHRENIA Improvement* >20% *BPRS total score 54 + fluphenazine 20 mg/day Number of patients 95 19 35 Improvement* >20% Stable reponse Improvement* <20% Improvement* <20% + fluphenazine 20 mg/day 41 Week 1 0 41 Week 4 Improvement* >20% Improvement* <20% Stable nonresponse C.U. Correll et al.: Early prediction of antipsychotic response in schizophrenia Am J Psychiatry 2003; 160:2063 2065

ANTIPSYCHOTIC DRUG RESPONSE IN SCHIZOPHRENIA Improvement* >20% *BPRS total score 56 + fluphenazine 20 mg/day 37 % 63 % Improvement* >20% Stable reponse Improvement* <20% Number of patients 100 Nonresponse predicts nonresponse Improvement* <20% + fluphenazine 20 mg/day P<0.01 44 Week 1 0 % 100 % Week 4 Improvement* >20% Improvement* <20% Stable nonresponse C.U. Correll et al.: Early prediction of antipsychotic response in schizophrenia Am J Psychiatry 2003; 160:2063 2065

ANTIPSYCHOTIC DRUG RESPONSE IN SCHIZOPHRENIA Nonresponse predicts nonresponse Relevant antipsychotic efficacy is unlikely to occur if it does not begin within the first weeks of treatment Objective symptom ratings may be a clinically useful, time-effective, and cost-effective method to guide early antipsychotic treatment decisions Correll et al. (2003) Am J Psychiatry 160:2063 2065

Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises? Pharmacology gives evidence that TDM is helpful for treatment optimization in neuropsychopharmacology since blood levels are highly variable blood levels reflect well brain concentrations blood levels correlate with receptor occupancy There are many distinct indications to use TDM not only suspected non-compliance Evidence is unclear for many antidepressant and antipsychotic drugs that TDM it is cost effective The appropriate use of TDM must be improved in the future considering the TDM guidelines

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