Nortriptyline blood levels and clinical outcome: …

1 51 Rev Bras Psiquiatr 2000;22(2):51-6 Nortriptyline blood levels and clinical outcome : meta- analysis of published studiesN veis sang neos de nortriptilina e resposta cl nica: metan lise dosestudos publicadosM nica G Ribeiro, Eduardo LA Pereira, Rog rio Santos-Jesus, Eduardo P Sena, K tia Petrib and Irismar R OliveiraDepartamento de Psiquiatria da Universidade Federal da Bahia, BrasilRecebido em 10/4/2000. Aceito em 17/4 de financiamento de interesses : An optimum range has been suggested for Nortriptyline blood levels , above or below whichpatients respond poorly or do not respond at all to : A meta- analysis of published studies was performed to verify the existence of an optimal bloodconcentration range or therapeutic window in Nortriptyline -treated depression patients.

2 A MEDLINE searchthrough the years 1970-1999 was carried out to identify original papers and review articles. Data concerningblood levels and percentage improvement were obtained concerning all included pacients. Univariate andmultivariate analyses were performed for data comparison. Possible confounding variables, such as pre-treatment,setting (in or outpatients), and duration of treatment were also : From the 22 published studies found, only six of them with patients individual data were included. Wefound an optimal range for Nortriptyline concentrations (OR= , 95% CI = to , p= ).

3 Conclusions: There may be a biphasic relationship of efficacy to plasma concentrations of Nortriptyline , with atherapeutic window between 46 to 236 Meta- analysis . blood levels . o: Sugere-se a exist ncia de uma faixa de concentra o tima para os n veis sang neos da nortriptilina,acima e abaixo da qual os pacientes n o respondem ao tratamento ou o fazem todos: Realizamos metan lise dos estudos publicados com o prop sito de verificar a exist ncia de uma faixa deconcentra o sang nea tima (janela terap utica) para os pacientes deprimidos tratados com nortriptilina.

4 Abusca atrav s do MEDLINE envolvendo os anos de 1970 a 1999 foi realizada com o objetivo de identificar artigosoriginais e de revis o. Dados sobre n veis sang neos e percentagem de melhora foram obtidos. Foram realizadasan lises uni e multivariadas para a compara o dos dados. Avaliamos poss veis vari veis de confus o como:per odo de pr -tratamento, ambiente (hospitalar ou ambulatorial) e dura o do : Dos 22 estudos publicados que foram identificados, apenas seis que forneceram os dados individu-ais dos pacientes foram inclu dos. Encontramos uma faixa de concentra o tima para a nortriptilina (OR = 2,25,IC 95% = 1,15 a 4,39, p = 0,02).

5 Conclus es: poss vel que exista uma associa o de tipo bif sico entre as concentra es de nortriptilina e aresposta cl nica, com uma janela terap utica entre 46 e 236 Metan lise. N veis sangu neos. Depress the original report by Asberg et al1 suggesting anoptimum range for Nortriptyline (NT) blood levels , above orbelow which patients responded poorly or did not respond tothe treatment therapeutic window (TW) , manyinvestigators have searched for a direct relation between tricyclicantidepressant (TCA) blood levels and response to , even among authors suggesting a TW fornortriptyline and other TCAs, there is no consensus on theoptimum therapeutic blood levels Bras Psiquiatr 2000.

6 22(2):51-652 Nortriptyline blood levelsRibeiro MG et order to further investigate this problem, we decided toundertake a meta- analysis relating Nortriptyline blood level andclinical outcome studies. Meta- analysis is a review methoddeveloped to quantitatively integrate results of independentresearch. It is useful in increasing statistical power for majorendpoints and subgroup analyses; helps to resolve uncertaintywhen reports disagree; and answers questions not posed atthe start of the individual The aim of this overview wasto investigate the existence of a TW in the blood concentrationsof Nortriptyline -treated depressed reviewWe have adopted the following procedures for review:(i) A MEDLINE search on CD-ROM of studies investigatingnortriptyline blood levels and clinical relationshipthroughout the period 1970-1999.

7 The expressions usedfor the search were Nortriptyline , blood levels , plas-ma levels and serum levels ;(ii) A search of any additional studies indicated in the referencesof the articles found by means of procedure (i). Wheneverthere were two or more publications involving the samepatients, the most recent was retained, unless it failed toprovide individual inclusion criteriaThe studies included in this meta-analyis were thoseproviding patients individual data in tables or graphs and whichaimed to investigate the relationship between bloodconcentrations and clinical outcome in Nortriptyline -treateddepressed patients.

8 The studies were required to utilise a fixed-dose regimen or concentration range and to provide percentageimprovement of depressed symptoms or the possibility ofestimating this. We previously decided that the duration ofactive treatment should be no longer than eight weeks. Sincestudies on blood levels and clinical outcome relationship varywidely in their duration, we decided to deal with this problemby (i) performing a sensitivity analysis by repeating thestatistical calculations after exclusion of studies of shorterduration and (ii) including duration of the treatment as a possibleconfounding variable in the multivariate exclusion criteriaAs it is essential to study a population of patients that can, infact, respond to the drug-treatment, studies including depressedpatients refractory to previous treatments were not accepted inthis meta- analysis .

9 We also excluded studies not providingpatients individual data and those not using a fixed-dose studies were designed to place patients blood levels withina specific range, usually 50-150 ng/ml. Since, in such situations,there are no patients outside the chosen range, the hypothesis ofa TW cannot be tested and these studies were discarded. We alsoexcluded studies of children. Studies not included and the reasonsfor their non-inclusion are presented in Table response evaluationIn each original study, therapeutic response was assessed bymeans of well established depression rating scales (Table 2).

10 1,20-24 Response to treatment was considered to be a 50% improvementor more. As patients individual data were available in the includedpapers, such response criteria were not necessarily the same aswere used by the authors of the original scoringQuality of the studies was assessed by means of a scoremethod especially designed to systematically evaluate thequality of clinical pharmacokinetic studies on the relationshipbetween antipsychotic blood levels and their clinical effects,25 Table 2 - Summary of the six studies included in this authorSample sizeDiagnostic criteriaAssessmentDoseDurationTherapeuti c(year)