In the presented study, we performed a retrospective analysis of plasma levels of LAI AP. The results of the patients treated at the outpatient psychiatric ward of the University Hospital Ostrava were included. The choice of a specific LAI AP depends on the clinical features of the patient as well as on experiences and preferences of individual physicians at outpatient or inpatient wards, because LAI AP are often administered for the first time during hospitalization.
The obtained results may be found surprising because the plasma levels before a regular administration did not reach the lower borderline of the TRR in more than a half of the patients, even though the recommended dosing was maintained. It is necessary to bear in mind the fact the TRR has been established for oral preparations. In one fifth of the patients, the levels were even undetectable, and so the administration of LAI AP most certainly does not fulfil its basic aim in these cases, i.e. to ensure a permanent presence of the effective agent in the patient´s organism. Similar results have also been recently presented for oral antipsychotics (7), revealing a pseudo-resistance in patients with schizophrenia. However, the main reason of low concentrations of an oral medication, i.e. insufficient treatment adherence, can be excluded in case of LAI AP.
Nevertheless, even subtherapeutic plasma levels might be effective in some patients, what follows from the definition of TRR (1). But the TRRs have been defined for oral preparations with their pharmacokinetic properties, and it is possible that the TRR of LAI AP could be different (8). This is in accordance with the results of Marder et al. (9), who did not observe a connection between the plasma levels of fluphenazine decanoate and its clinical or adverse effects, and the authors assume that even the low (subtherapeutic) plasma levels of LAI fluphenazine may be effective. Also the effect of low doses of flupentixol in the treatment of anxiety and depressive disorders is well known (10).
Especially in cases of monotherapy associated with low levels of LAI AP it is possible to ask a question whether the stabilized clinical condition is a consequence of an effective prophylaxis or whether it is achieved because of the natural course of the disease. The self-evident need of chronic antipsychotic prophylaxis was called into question e.g. in the naturalistic observational study performed by Harrow et al. (11). On the other hand, regular visits to the outpatient department are considered to be one of the favourable factors in patients treated with LAI AP. During these regular visits, the medical staff is also able to recognize the first signs of possible worsening of the clinical condition.
The combined therapy using LAI AP and oral AP is used in a third to a half of the patients in the clinical practice (8, 12) and reached even 87.5% in our cohort. Despite general recommendations where the monotherapy is preferred because of the missing evidence regarding the combined treatment (13), a combination of LAI AP and oral AP does not necessarily have to be associated with more adverse events, and may even lead to a lower number of drop-outs (9). Considering a high rate of patients with combined treatment, we suppose a rather supportive role of LAI AP in a general treatment strategy, the aim of which is to reduce the risk of a complete non-adherence. But the frequent use of a combination with the oral AP might also indicate a therapeutic hesitation regarding determination of a specific dose of LAI AP in a specific patient (if not using TDM), when relying on conversion recommendations only. This is contrary to the case of the short-acting agents, where the connection between the dose changes and the clinical effect is much more evident according to clinical practice. The more frequent use of the TDM in LAI AP treatment might help the physicians to overcome this therapeutic uncertainty in this way.
The deviations in plasma levels can be also associated with drug or food interactions. In our study, we considered the comedication in patients with the undetectable plasma levels only. We did not find the presence of any of the known inhibitors or inducers of the CYP 450 isoenzymes. Smoking as a well-known inducer of CYP1A2 was not relevant to any of the followed antipsychotics.
Interesting results were found in the case of haloperidol. Its plasma levels declined surprisingly in the second blood sample (obtained one week after the initial administration) in 3 of 4 patients; in one patient the plasma level was even on the lower limit of the TRR (1.0 µg/L). An inconstant absorption from the muscle depot can be a possible explanation. In case of fluphenazine, a subtherapeutic plasma level was observed in all patients even in the second blood samples, and so the overall dosing (including the single dose and interval of an application) should be considered insufficient with respect to all the above-mentioned limitations.
The study has several obvious limitations. The first one is the size of the cohort and its diagnostic heterogeneity. The collection of blood samples and their evaluations were performed analogically to the oral medication, and the established regimen of TDM at our department did not respect the pharmacokinetic differences of individual agents but fitted well for everyday clinical use. Also, we did not follow the body weight of the patients and did not analyse all possible interactions in the whole cohort.