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The plasma level of methylphenidate in the single-dose oral methylphenidate test
638
BIOL PSYCHIAT"~I" i~}0;2~.638-640
BRIEF REPORTS
The Plasma Lew l of Methylphen date in the Single-Dose Oral Me,hylphenldate Test G.M.J. Van Kempen, J.G. Geekoop, H.B. zong, P.M. Edelbroek, and F.A. de Wolff
Introduction Pharmacological challenge tests are thought to be of value in pr:dicting response to a specific treatment in depression. Sabelli et al. (1983) suggested that the methylphenidate te ~t (MPT) may be useful for making a rational choice among, tricyclic antidepressants. In their study, v. mood elevation frc,m methylphcnidate (MP) p-edictec' a therapeutic response to infipramine or desipramine, while ~ r~gative response favored nortriptyline, a mort: serot:>nergic-acting antidepressant. Recently. Spar and LaRue (1985~ advocated a single-dose oral MPT whic~ because of its relative simplicity and easier execution, would be preferable (in a clinical setting) to the more sophisticated procedure of Fawcetx et at. (1984), who titrated the dose of MP until a response was reached. Evaiuation of a challenge test is complicamd L.. uy pharmacokinetic factors vou~, "~'¢*" !986). Because this may be the case especially for the single-dose oral MPT, in contrast to ~,4PTs using multiple doses or MP given intl'avenously, we investigated the relation between the acute response to a 20 mg ~ral dose of MP (Spar and LaRue i985) raid plasma levels oftne drug. This
was made feasible because of the recent availability of an ass,~y fi~:,t is sufficiently sensitive for measming M ) in human plasma after a single low dose (Lala,:de et al. 1987). The different findings on the relation between the subjective response to MP and an increase of co~isol (Brown and Williams 1976; Joyce et al. 1986) prompted us to ,,mdy the cortisol levels .,,t baseline ,rod after I ~ ;,ntake. Methods EigLt inpatients, 1 mien, 7 women, participated in this study, which was approved by the Ethics Committee of the Medical Faculty and Universit)" Hospital of the University of Leiden. Inclusion criteria were major affective disorder, dysthymic disorder, or atypical depression aco~rding to the criteria of DSM-HI. Exclusion criteria were pregnancy, lactation, and heart, kidney, or liver pathology. The mean age of the patients was 43 _+ 14 (SD) years, ra,'ige 2,%-59 years. Bloc,t was collected by venipu~cture and the plasma, amlcoagulateO with hepazin, was frozen immediately. In 2 patients, the M F i was repeated after recovery. The results of these tests are inci,aded in Table 1, but for hhe :-':- ' analysis., only the first values obtain sd from these patients were used. At 9 AM, just before, and 1.5 ~ ,.after oral intake of 20 mg MP, tile Kusta-score (Binz mad Wendt 1983) was determined in order to rate the change in emotional state. Blood for analysis . . . .
From the Psychiatric Hospital Endegeest, O'gstgeest a~d the Department of Psychiatry, Univet.~i~ of Leiden (G.M.J.V.K., J.G.G.); and ~he Laboratory of To,dc{,logy, University Hospital of Lei~aen (F.A.deW., P.M.E., H.B.J ), The Netherlands. Address reprint request~ to Dr G.M.J. Van Kempen, Psychi.~,~c Hospital Endegeest, POB 1230, 2340 BG Oegstg~st, The N,etherlands. Received December 27, 198~; ~evised March 29, 1700.
© 1990 Society of Biological Psychiatry
0006-3223190/$03.50
Brie~ Repcrts
BIOL PSYCPdATRY 1990;28:638-640
639
Table 1. P l a s m a L e v e l s o f M P a n d Increases in K u s t a Scores and Cortisol
Patient no. la lb 2 3 4 5 6 7a *i 7b Mean SD
MP plasma level (ng/ml)
Kasta-score increase (total)
0 0 1.6 3.6 3.8 5.0 6.3 8.6 10.5 11.1 5.1 4.0
0 10 - 2 6 3 8 !5 0 34 21
of MP and cortisol was taken immediately before intake of MP and 1.5 ha" later. The Kustascale is a self-rating scale developed for studying intraindividual changes of emotional state at short ir,tervals. We used the sum of the scores on the three subscales~mood, alertness, and relaxation. The maximum score l~:~rsubscale is 17, making a maximum total of 5 ~,. The effect o? MP was rated as ~ e increase in tb,:~total score af~er MP. Plasma MP was essentially determined by the me~od of Lalande et al. (1987) with som~: modifications. The imernal s~mdard, e~hylpi~c.':~qdate, was synthesized from a-phenyi-2-piper~ dine acetic acid by the method of Gal et al. (ii977). Extraction of MP from 1 ml plasma containing the internal standard and 0.5 trd borate buffer pH 9 wa~ pe~,~rmed with 5 ml cyclohexane. After addition of 6.05 ml ~ N HCI, the extract was evaporated under nitrogen at 55°C. The residue was dk,~solved i~: the mobile phase, 25% acetonimle in 0.07% triethylamine in H20 broagh~ to pH 3.4 with phosphoric acid. gei~ration was peffo .rm_ed with a Phenyl Hypetsii (7 ,~m0 column from Shandon, Cheshire, England, and was followed by UV detection at 192 nmo Standards were prepared by addition of l~nown amounts of I',~ to pooled normal serum. The hmit cf ,~.,,,,,,,,.,,.a"'°"';"".o:~ 1 r~g/m!. ,'P.-e samples take I~fore administration of MP were used as
Cortiso2 Before (~mol/2iter)
After (gmol/liter)
Increase (%)
9.25 0.52 . 0.~9 0.49 0.63 0.53 0.38 0.27 0.43 0.42 0.15
0.62 0.24
148 -53
.
.
. 0.21 0.29 0.84 0.#3 0.24 0.22 0.51 0.39 0.23
!0 - 61 25 - 19 - 37 - 29 19
individual blanks. (Methylphenidate and aphenyl-2-piperidine a,: etic acid vJ~re ~ s from Ciba-Geigy Corp., A r ~ e m , the Netherlands.) Plasma levels & COl~isoi were determined by a high-performance liqmd chromatographic procedure. Association between vati~les was studied by the Spea~-~:aanrank corr~htioa coefficient.
Results The results for plasma levels and the changes in Kusta-seores are presented in "able 1. After administration of MP, no significant changes in cortisol were observed nor was there any correlation between c o , sol levels before or after MP, or between cortisol and the Kusta-scores. There was a significant (p < n.05) association between the increase ir, Kusta-scores and the plasma level of MP (Tab]~ i). This was also the case for Lhe subscale relaxation.
Discossion Our findings on cortisol are in agreement with the results of Brown ea-idWilliams (1976) who, after a 20-rag oral dose of MP, found that coitisol concentrations a:e not affected. This is in contrast to a report by Joyce et al. ~1986) who measured a plasma co~isol increase following
640
Brief Reports
BIOL PSYCHIATRY 1990;28:638-640
ina'avenou~ MP in all their 20 s~jects. An expiration for these discrepancies ~,ay be fouad in the route (oral producing subst~t~ally lower MP ~vels than intravenous), but aL~oin ~he time of a6ninistration of MP. Brown ~ d Williams (1976) and our group chose *.he morning and Joyce et al. (1986) administered the drug later in the day. On the ba,:~:is of only two obse;vat~ons in 1 volunteer, Lal::~de et aL (1987) reported a plasma ~evel of about 4.8 ng/ml 1.5 hr after a single oral dose of 10 mg .MP. This is approximately the same as the mean value obse:wed in our patients afte~ the double dose of 20 mg orally. After oral administration of 0.25 mg/kg (which !s about the same dose we used) to 1 volunteer, N,~kajima et al. (1986) found a maximal plasma concentration of 6.4 ng/ml after 1 hr, with a rapid decline thereafter. This means that the. measure(: plasma levels in our study are in good agreement with the few data from the literature f~r ~ P b~od levee ~.a ad~.i;.~. In respo~se to a stimulant chat'~nge, change over time within a given individual may occur, as suggested by Fawcett et al. (1914). This is supported by our findings in patients 1 and 7 who evidently had a different mood ~sponse before and after resolution of their depressive episode. This suggests that the affecfive state itself may be an important variable. The conclusion from this first application of MP plasma level measurements in interpreting the ,oral MPT in adults is that pharmacokinetie factors are a big influence, as predicted by Goff (1986). To elimiaa:e these confoundin:.g factors, a l.~radua!!y increasing dose schedule seems a belter strategy.
References Binz U, Wendt G (1983): Kusta Manual. Frankfurt, FRG: Ciba-Geigy. Brown WA, Williams BW (1976): Methylphenidate increases seran,, ~ov~h bornaone concentrations. J Clin Endocrinol l~$etab 43:937-939. Fawcett J, Kravitz HN~, Sabelli HC (i984): Stimulant challenge tests. In: Hall RCE, Beresford TP (eds), Handbook of P~chia~::.c Diagnostic Procedures, Vol. 1. Lancaster, England: MTP Press Ltd, p? 223-251. Gal J, Hodshon BJ, Pintauro C, Flanml BL, Cho AK (1977): Phannacokinetics of methylphenidate in the rat using single ion monitoring GLC-mass spec~ometry. J Pharm Sci 66:866-869. Goff DC (1986): The stimulant challenge test in depression. J Clin Psychiatry 47:538-543. Joyce PR, Donald RA, Niche!Is MG, Livesey JH, Abbott RM (1986): End~rine and behavioral responses to methylphen~date in normal subjects. Biol Psychiatry 21.1015-1023. Lalanoe M, Wilson DL, McGilveray 1! (1987): HPLC determination of methylphenid~e in human plasma. 3 Liq Ci~,~matogr 10:2257~-2264. Hakajima K. K¢ ~akiH, Saitoh Y, Nakagawa F (1986): l.~tern~ ~t~.~ of methy~phenidate and its ~.aain metabolize in plasma by gas-chromatographychemical ionizatiea mass spectrometry. Chem Pharm Bull 34:1701-1708. Sabelii HC , Fawcett J, Javaid JI, Bagri S (i983): The methylphenidate test for differenr;ating desipramine-responsive from nortriptyline-responsire depression. Am J Psychiatry 140:212-214. Spar JA~ LaRue A (i985): Acute response to methylphenidate as a predictor of outcome of treatment with TCAs in the elderly. J Clin Psychiatry 46:466469.
BIOL PSYCHIAT"~I" i~}0;2~.638-640
BRIEF REPORTS
The Plasma Lew l of Methylphen date in the Single-Dose Oral Me,hylphenldate Test G.M.J. Van Kempen, J.G. Geekoop, H.B. zong, P.M. Edelbroek, and F.A. de Wolff
Introduction Pharmacological challenge tests are thought to be of value in pr:dicting response to a specific treatment in depression. Sabelli et al. (1983) suggested that the methylphenidate te ~t (MPT) may be useful for making a rational choice among, tricyclic antidepressants. In their study, v. mood elevation frc,m methylphcnidate (MP) p-edictec' a therapeutic response to infipramine or desipramine, while ~ r~gative response favored nortriptyline, a mort: serot:>nergic-acting antidepressant. Recently. Spar and LaRue (1985~ advocated a single-dose oral MPT whic~ because of its relative simplicity and easier execution, would be preferable (in a clinical setting) to the more sophisticated procedure of Fawcetx et at. (1984), who titrated the dose of MP until a response was reached. Evaiuation of a challenge test is complicamd L.. uy pharmacokinetic factors vou~, "~'¢*" !986). Because this may be the case especially for the single-dose oral MPT, in contrast to ~,4PTs using multiple doses or MP given intl'avenously, we investigated the relation between the acute response to a 20 mg ~ral dose of MP (Spar and LaRue i985) raid plasma levels oftne drug. This
was made feasible because of the recent availability of an ass,~y fi~:,t is sufficiently sensitive for measming M ) in human plasma after a single low dose (Lala,:de et al. 1987). The different findings on the relation between the subjective response to MP and an increase of co~isol (Brown and Williams 1976; Joyce et al. 1986) prompted us to ,,mdy the cortisol levels .,,t baseline ,rod after I ~ ;,ntake. Methods EigLt inpatients, 1 mien, 7 women, participated in this study, which was approved by the Ethics Committee of the Medical Faculty and Universit)" Hospital of the University of Leiden. Inclusion criteria were major affective disorder, dysthymic disorder, or atypical depression aco~rding to the criteria of DSM-HI. Exclusion criteria were pregnancy, lactation, and heart, kidney, or liver pathology. The mean age of the patients was 43 _+ 14 (SD) years, ra,'ige 2,%-59 years. Bloc,t was collected by venipu~cture and the plasma, amlcoagulateO with hepazin, was frozen immediately. In 2 patients, the M F i was repeated after recovery. The results of these tests are inci,aded in Table 1, but for hhe :-':- ' analysis., only the first values obtain sd from these patients were used. At 9 AM, just before, and 1.5 ~ ,.after oral intake of 20 mg MP, tile Kusta-score (Binz mad Wendt 1983) was determined in order to rate the change in emotional state. Blood for analysis . . . .
From the Psychiatric Hospital Endegeest, O'gstgeest a~d the Department of Psychiatry, Univet.~i~ of Leiden (G.M.J.V.K., J.G.G.); and ~he Laboratory of To,dc{,logy, University Hospital of Lei~aen (F.A.deW., P.M.E., H.B.J ), The Netherlands. Address reprint request~ to Dr G.M.J. Van Kempen, Psychi.~,~c Hospital Endegeest, POB 1230, 2340 BG Oegstg~st, The N,etherlands. Received December 27, 198~; ~evised March 29, 1700.
© 1990 Society of Biological Psychiatry
0006-3223190/$03.50
Brie~ Repcrts
BIOL PSYCPdATRY 1990;28:638-640
639
Table 1. P l a s m a L e v e l s o f M P a n d Increases in K u s t a Scores and Cortisol
Patient no. la lb 2 3 4 5 6 7a *i 7b Mean SD
MP plasma level (ng/ml)
Kasta-score increase (total)
0 0 1.6 3.6 3.8 5.0 6.3 8.6 10.5 11.1 5.1 4.0
0 10 - 2 6 3 8 !5 0 34 21
of MP and cortisol was taken immediately before intake of MP and 1.5 ha" later. The Kustascale is a self-rating scale developed for studying intraindividual changes of emotional state at short ir,tervals. We used the sum of the scores on the three subscales~mood, alertness, and relaxation. The maximum score l~:~rsubscale is 17, making a maximum total of 5 ~,. The effect o? MP was rated as ~ e increase in tb,:~total score af~er MP. Plasma MP was essentially determined by the me~od of Lalande et al. (1987) with som~: modifications. The imernal s~mdard, e~hylpi~c.':~qdate, was synthesized from a-phenyi-2-piper~ dine acetic acid by the method of Gal et al. (ii977). Extraction of MP from 1 ml plasma containing the internal standard and 0.5 trd borate buffer pH 9 wa~ pe~,~rmed with 5 ml cyclohexane. After addition of 6.05 ml ~ N HCI, the extract was evaporated under nitrogen at 55°C. The residue was dk,~solved i~: the mobile phase, 25% acetonimle in 0.07% triethylamine in H20 broagh~ to pH 3.4 with phosphoric acid. gei~ration was peffo .rm_ed with a Phenyl Hypetsii (7 ,~m0 column from Shandon, Cheshire, England, and was followed by UV detection at 192 nmo Standards were prepared by addition of l~nown amounts of I',~ to pooled normal serum. The hmit cf ,~.,,,,,,,,.,,.a"'°"';"".o:~ 1 r~g/m!. ,'P.-e samples take I~fore administration of MP were used as
Cortiso2 Before (~mol/2iter)
After (gmol/liter)
Increase (%)
9.25 0.52 . 0.~9 0.49 0.63 0.53 0.38 0.27 0.43 0.42 0.15
0.62 0.24
148 -53
.
.
. 0.21 0.29 0.84 0.#3 0.24 0.22 0.51 0.39 0.23
!0 - 61 25 - 19 - 37 - 29 19
individual blanks. (Methylphenidate and aphenyl-2-piperidine a,: etic acid vJ~re ~ s from Ciba-Geigy Corp., A r ~ e m , the Netherlands.) Plasma levels & COl~isoi were determined by a high-performance liqmd chromatographic procedure. Association between vati~les was studied by the Spea~-~:aanrank corr~htioa coefficient.
Results The results for plasma levels and the changes in Kusta-seores are presented in "able 1. After administration of MP, no significant changes in cortisol were observed nor was there any correlation between c o , sol levels before or after MP, or between cortisol and the Kusta-scores. There was a significant (p < n.05) association between the increase ir, Kusta-scores and the plasma level of MP (Tab]~ i). This was also the case for Lhe subscale relaxation.
Discossion Our findings on cortisol are in agreement with the results of Brown ea-idWilliams (1976) who, after a 20-rag oral dose of MP, found that coitisol concentrations a:e not affected. This is in contrast to a report by Joyce et al. ~1986) who measured a plasma co~isol increase following
640
Brief Reports
BIOL PSYCHIATRY 1990;28:638-640
ina'avenou~ MP in all their 20 s~jects. An expiration for these discrepancies ~,ay be fouad in the route (oral producing subst~t~ally lower MP ~vels than intravenous), but aL~oin ~he time of a6ninistration of MP. Brown ~ d Williams (1976) and our group chose *.he morning and Joyce et al. (1986) administered the drug later in the day. On the ba,:~:is of only two obse;vat~ons in 1 volunteer, Lal::~de et aL (1987) reported a plasma ~evel of about 4.8 ng/ml 1.5 hr after a single oral dose of 10 mg .MP. This is approximately the same as the mean value obse:wed in our patients afte~ the double dose of 20 mg orally. After oral administration of 0.25 mg/kg (which !s about the same dose we used) to 1 volunteer, N,~kajima et al. (1986) found a maximal plasma concentration of 6.4 ng/ml after 1 hr, with a rapid decline thereafter. This means that the. measure(: plasma levels in our study are in good agreement with the few data from the literature f~r ~ P b~od levee ~.a ad~.i;.~. In respo~se to a stimulant chat'~nge, change over time within a given individual may occur, as suggested by Fawcett et al. (1914). This is supported by our findings in patients 1 and 7 who evidently had a different mood ~sponse before and after resolution of their depressive episode. This suggests that the affecfive state itself may be an important variable. The conclusion from this first application of MP plasma level measurements in interpreting the ,oral MPT in adults is that pharmacokinetie factors are a big influence, as predicted by Goff (1986). To elimiaa:e these confoundin:.g factors, a l.~radua!!y increasing dose schedule seems a belter strategy.
References Binz U, Wendt G (1983): Kusta Manual. Frankfurt, FRG: Ciba-Geigy. Brown WA, Williams BW (1976): Methylphenidate increases seran,, ~ov~h bornaone concentrations. J Clin Endocrinol l~$etab 43:937-939. Fawcett J, Kravitz HN~, Sabelli HC (i984): Stimulant challenge tests. In: Hall RCE, Beresford TP (eds), Handbook of P~chia~::.c Diagnostic Procedures, Vol. 1. Lancaster, England: MTP Press Ltd, p? 223-251. Gal J, Hodshon BJ, Pintauro C, Flanml BL, Cho AK (1977): Phannacokinetics of methylphenidate in the rat using single ion monitoring GLC-mass spec~ometry. J Pharm Sci 66:866-869. Goff DC (1986): The stimulant challenge test in depression. J Clin Psychiatry 47:538-543. Joyce PR, Donald RA, Niche!Is MG, Livesey JH, Abbott RM (1986): End~rine and behavioral responses to methylphen~date in normal subjects. Biol Psychiatry 21.1015-1023. Lalanoe M, Wilson DL, McGilveray 1! (1987): HPLC determination of methylphenid~e in human plasma. 3 Liq Ci~,~matogr 10:2257~-2264. Hakajima K. K¢ ~akiH, Saitoh Y, Nakagawa F (1986): l.~tern~ ~t~.~ of methy~phenidate and its ~.aain metabolize in plasma by gas-chromatographychemical ionizatiea mass spectrometry. Chem Pharm Bull 34:1701-1708. Sabelii HC , Fawcett J, Javaid JI, Bagri S (i983): The methylphenidate test for differenr;ating desipramine-responsive from nortriptyline-responsire depression. Am J Psychiatry 140:212-214. Spar JA~ LaRue A (i985): Acute response to methylphenidate as a predictor of outcome of treatment with TCAs in the elderly. J Clin Psychiatry 46:466469.