Seminarium 1

Halina Matsumoto

Medical University of Warsaw

Chair and Department of Psychiatry

Laboratory of Psychopharmacology

Granada, LLP ERASMUS, June 5, 2013

Deante Toscano

Possible consequences of CYP2D6

genotype on treatment effect

Dose adjustment depending on

CYP2D6 genotype

Different drugs require different level of

dose adjustment (depending on

genotype).

CYP2D6 and Clinical Outcome

Targeted interventions – clozapine

response

• Clozapine: approximately 60% efficacy for

schizophrenia

• Works through dopaminergic and

serotonergic mechanisms

• In some studies:

– Response predicted by polymorphisms at 5HT2A

and 5HT2C receptors, 5-HTT

– Predict response in 78% of patients (female)

Clozapine in treatment resistant

schizophrenia• Approximately one third of patients fail to antipsychotic medication and are said to suffer from

treatment resistant schizophrenia (TRS)

• The only drug with proven efficacy in this group of patients is clozapine and NICE (The National

Institute for Health and Clinical Excellence) has recommended that: „In individuals with evidence of

TRS, clozapine should be introduced at the earliest opportunity”.

• However, clozapine has potentially serious side effects and its use is often accompanied by

apprehension from clinicians, patients and carers.

• In addition, only approximately half of clozapine treated patients will show meaningful

symptomatic improvement.

• The genetic test provides clinicians with an indication of a patient’s probability of response to

clozapine. Reassuring the clinician and the patient that exposure to clozapine is merited, based on

the likelihood of response, can stop clozapine being used only as a last resort, thus allowing

patients to benefit from the proven efficacy of the drug at the earliest possible opportunity. For

patients on longterm clozapine treatment who are ahowing equivocal response, the test may

guide the clinician as to the merit of continuing treatment.

Clozapine response – side effects

• Risk of agranulocytosis is a prominent reason for not prescribing clozapine

• Clozapine can be associated with a drop in white blood cell count even with blood monitoring

• Incidence of clozapine-induced leukopenia is 2.95%

• Incidence of clozapine-induced agranulocytosis (CIA) is 0.38%

• The risk of CIA rises steeply the first 2 months of therapy and peaks during month 3-4

• Prescribing clozapine requires mandatory blood monitoring to help reduce the incience of CIA

TDM STANDARDS IN PSYCHIATRY ACCORDING TO AN INTERNATIONAL GROUP OF

EXPERTS FROM GERMAN SPEAKING COUNTRIES ( AGNP= ger. Arbeitsgeeinschaft für

Neuropsychopharmakologie und Pharmakopsychiatrie) Baumann et al., 2004

• GENERAL INDICATIONS FOR TDM METHOD DURING PHARMACOTHERAPY OF PSYCHIATRIC DISEASES:

• Noncompliance

• Therapy with drugs that routinely require TDM (lithium salts)

• No clinical improvement of insufficient efficacy of treatment, despite using adequate doses of medicaments

• Adverse side effects during treatment with therapeutic doses

• Suspicion of drug interactions

• Pharmacovigilance

• Combined pharmacotherapy with a drug with hight interaction potential, while treating „comorbidities”, „potentialisation” of pharmacotherapy

• Prophylaxis of psychiatric disease reccurences in longterm treatment

• Reccurence of disease despite compliance and using adequate doses of drugs

• Genetic polymorphism in drug metabolism, genetic deficiency or amplification of genes involved in the drug metabolism

• Population of children (up to 12 years) and adolescents (12-18 years)

• Elderly patients

• Patietns with renal/liver failure, cardiovascular diseases

• Forensic psychiatry

• Changing original drug to a generic

LEVELS OF RECOMMENDATIONS FOR TDM METHOD IN THE

TREATMENT OF PSYCHIATRIC DISORDERS FOR DIFFERENT

PSYCHOTROPIC DRUGS

Level 1 Evidence Based Medicine

(EBM)

Drugs

Level 1: Strongly

recommended

Evidence: Reported drug

concentrations are established

and evaluated therapeutic

reference ranges. Controlled

clinical trials have shown benefi

cial eff ects of TDM, reports on

decreased tolerability or

intoxications.

Lithium

Antidepressant drugs

TCAs

-Amitriptyline+nortriptyline

- Imipramine+desipramine

- Clomipramine+desmethylo-

clomipramine

Antipsychotic drugs

- Clozapine

- Haloperidol

- Fluphenazine

- Olanzapine

Level 2: Recommended Evidence: Reported drug

concentrations were

obtained from

plasma concentrations at

therapeutically eff ective

doses and

related to clinical eff ects;

reports on decreased

tolerability or

intoxications at

“supratherapeutic” plasma

concentrations.

Recommendation: TDM is

recommended for dose

titration

and for special indications

or problem solving.

Antidepressant drugs:

- Desipramine

- Venlafaxine +

Desmethylvenlafaxine

Antipsychotic drugs

- Chlorpromazine

- Flupentixol

- Perazine

- Risperidone + 9-

hydroxyrisperidone

Other

- Carbamazepine

- Valproic acid

- Donepezil

- Taurine

- Methadone

Level 3: Useful Evidence: Reported drug

concentrations were calculated

from plasma concentrations at eff

ective doses obtained from

pharmacokinetic studies. Plasma

concentrations related to

pharmacodynamic eff ects are

either not yet available or

based on retrospective analysis of

TDM data, single case

reports or non-systematic clinical

experience.

Recommendation: TDM is useful for

special indications or

problem solving.

Antidepressant drugs:

- Citalopram

- Dexepine + Nordoxepine

- Fluoxetine +

Norfluoxetine

- Mianserin

- Mirtazapine

- Paroxetine

- Sertraline

- Trazodone

- Trimipramine

- Viloxazine

Antipsychotic drugs:

- Amisulprid

- Chlorprothixen

- Levomepromazine

- Quetiapine

Benzodiazepines

- Alprazolam

Other

- Galantamine

- Acamprosate

Level 4:

Potentially useful

Evidence: Plasma concentrations do

not correlate with clinical

eff ects due to unique

pharmacology of the drug, e. g.,

irreversible

blockade of an enzyme, or dosing

can be easily

guided by clinical symptoms, e. g.,

sleep induction by a hypnotic

drug.

Antidepressant drugs:

- Escitalopram

- Moclobemide

- Reboxetine

Antipsychotic drugs:

- Melperone

- Pimozide

- Ziprasidone

Anxiolytic drugs

- Buspiron

- Lorazepam

- Midazolam

Other

- Bupropion

- Memantine

- Naltrexone

Level 4: Not

recommended

TDM is not recommended in cases

of unique pharmacology of a drug.

i.e. irreversible enzyme inhibition or

diversed drug dosing depending on

diagnosis and clinical symptoms

Tranylcypromine

Zolpidem

Zopiclone

Clomethiazole

Disulphiram

ANTIDEPRESSANT TREATMENT

RESPONSE ENDOPHENOTYPESLeuchter i wsp.:A new paradigm for the prediction of antidepressant

treatment response. Dial Clin Neurosci, 2009,11,435-446

1. RE – response endophenotypes – a class of predictors consisting of clinical symptoms or neurobiological reaction present at the beginning of the treatment with high predictive value for response of individual treatment

2. Implementation of response endophenotype strategy in pharmacological treatment consists a new paradigm in clinical trials. A drug that will probably be inefficient could be stopped after 1-2 weeks and replaced with a new, more efficient drug (based on specific markers)

3. Potential predictors of response to treatment”– Early changes is symptoms severity

– Results of QEEG

– Gene expression examiantions.