Usually the antipsychotics are titrated very fast in first 1-3 weeks. However there are several reasons for non-response and one of them is also 'pharmacokinetic failure', when usually even higher doses are used as recommended. Often, because of non-optimal titration (too fast) patients are treated with high doses to fast and serious adverse event (e.g. EPS) are often occured. Although is known from EBM trials that for optimal effect prescriber should wait smth until 8-12 weeks of monotherapy within the maximal recommended dose, usually in clinical practice doses are too fast titrated and consequences are often seen in antipsychotic polypharmacy, which has not many support in EBM and clinical guidelines for management of schizophrenia. Easy question, however very hard to answer ...
I assume you have access to a TDM service? Such should definitely be performed to substantiate suspicion of "PK failure" prior to dose-increase above recommended levels. Refer to to the AGNP Consensus Guideline.
Per
Denmark
http://www.ncbi.nlm.nih.gov/pubmed/22053351
I also would recommend TDM in the first place, potentially followed by CYP-genotyping which is pretty robust for CYP 2D6, 2C9 and 2C19, which could explain variances in levels especially of AD's. For AP however, genotyping is partly useless, as for clozapine and CYP 3A4..
Many thanks for this link Per, i know this nice article from Germany, which was presented at EPA also this year, however usually in many countries worldwide this measure (TDM) is not possible (except antiepileptics) or it is possible with a big delay (e.g. 2 weeks or even more). Genotyping is even more expensive and is rarely seen in countries worldwide, except some countries (e.g. Germany). What to do without this two important measurements.
Because in many situations inappropriate prescribing in term of drug administration is seen (e.g. haloperidol and food, ziprasidone without food, Seroquel SR and food, clozapine and ciprofloxacin together etc ... ) and consequently higher doses are used. Another important thing is to wait enough time, because corelation between max plasma drug levels and maximal effect should be established.
In my opinion the basic knowledge about pharmacokinetics is essential for appropriate drug management and consequently appropriate treatment. For 'pharmacokinetic failure' cooperation between prescriber and clinical pharmacist/pharmacologist is also important to avoid possible several harms for patients treated with higher doses.
Considering TDM the only antipsychotic I would strongly vote for would be clozapine. But at least in Poland access to that service is very much limited.
Dear Tomasz,
thanks for this answer, I agree with You. However, TDM would be applicable in every case almost If there are financial resources available. Clozapine TDM is very useful and especially also risperidone (fast versus slow metabolizers).
Another chapter are DDIs with another antipsychotic or another drug, for example ciprofloxacin and clozapine. However in these chapters We can also use the basic knowledge of clinical psychopharmacology and to reduce dose of clozapine for at least 50 % at the beggining of the treatment with ciprofloxacin. Especially important issue is in primary psychiatry, where there are no so many possibilities for TDM and cooperation between GPs and clinical pharmacist is very advisable in these cases. To avoid for example ciprofloxacin and prescribe nitrofurantoin for the treatment of lower urinary tract infections in patients younger than 65 years and penicilines for upper urinary infections. Because pharmacotherapy with clozapine is usually permanent. In these cases TDM is very important, however the extended knowledge about clinical pharmacology can help.
It would be a good idea to establish if the patient was actually metabolising the drug before titration. 'Pharmacokinetic failure' is frequently associated with the inability of the patient to metabolise the drug and also in an alarming number of cases where the wrong drug is being administered.
The often cited and utterly unscientific nonesense of 'treatment resistant schizophrenia' is nothing of the sort. The reason the patient 'resists' the medication is because it is the wrong medication. Psychiatrists and psychiatric nurses should be required to complete a full course in pharmacology before being allowed to prescribe. the fact remains that many prescribers have little more than a rudimentary understanding of pharmacokinetics and pharmacodynamics and simply follow the pack when it comes to treatment.
The death rate from faulty prescribing is an alarming testimony to the pharmacological ignorance of many practitioners.
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