Concentration-effect relationships with carbamazepine

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1 Journl of Neurology, Neurosurgery, nd PsychitrY 1988;51: Concentrtion-effect reltionships with crbmzepine nd its epoxide on psychomotor nd cognitive function in epileptic ptients R A GILLHAM,* N WILLIAMS,* K WIEDMANN,* E BTLER,t J G LARKIN,t M J BRODIEt From the Deprtment of Clinicl Psychology,* Institute of Neurologicl Sciences, Southern Generl Hospitl, nd Clinicl Phrmcology nit,t niversity Deprtment of Medicine, Western Infirmry, Glsgow, Scotlnd SMMARY A bttery of psychometric tests ws dministered to 85 ptients with epilepsy, of whom 26 were untreted, 4 received crbmzepine monotherpy nd 19 took crbmzepine with nother nticonvulsnt. Crbmzepine lone hd little effect on performnce, but crbmzepine polyphrmcy produced significnt impirment. Incresing concentrtions of crbmzepine (four tests) nd its ctive metbolite, crbmzepine 1,1 1 epoxide (seven tests), correlted with decresing performnce in the monotherpy ptients. Since the epidemiologicl studies of the 195s, n ssocition hs been estblished between seizure disorders nd neuropsychologicl deficit.' 2 The complex reltionship between fits, cognitive impirment, psychosocil difficulties nd underlying cerebrl pthology hs been the subject of severl recent investigtions.3 The tngle of cuslity between these four fctors hs not been fully unrvelled. Since the first controlled study of Reynolds nd Trvers,6 there hs been growing body of evidence tht fifth fctor, the presence of ntiepileptic drugs in the brin, contributes independently to disruption of intellectul functioning. Thompson nd Trimble7 nd Ludgte nd his collegues8 hve shown tht ptients receiving multiple nticonvulsnts function less well on cognitive testing thn those treted with monotherpy nd tht reducing the number of circulting drugs cn led to improvement in performnce without producing deteriortion in seizure control. Ptients tking crbmzepine pper to show less evidence of cerebrl impirment thn those treted with older gents such s phenytoin or phenobrbitone.9y'1 However, Mcphee nd co-workers, in recent series of studies using bttery of simple psychomotor tests, hve demonstrted tht subtle derngement cn be produced in nive subjects Address for reprint requests: Dr Mrtin J Brodie, Clinicl Phrmcology nit, niversity Deprtment of Medicine, Western Infirmry, Glsgow GIl 6NT, Scotlnd, K. Received 22 Jnury Accepted 15 Mrch 1988 following single dose of crbmzepine, 12 in ptients with epilepsy given single supplementry dose,'3 nd in ptients on chronic crbmzepine monotherpy.'4 The purpose of the present investigtion ws to exmine more closely the reltionship between crbmzepine, its ctive metbolite crbmzepine 1,11 epoxide (CBZ-E) nd psychomotor nd cognitive functioning in ptients with epilepsy. Mterils nd methods Ptients Eighty-five ptients ttending the epilepsy clinic t the Western Infirmry were studied (tble 1). Forty were tking crbmzepine lone nd 19 received crbmzepine with one other nticonvulsnt (8 sodium vlprote, 6 phenytoin, 3 primidone, 2 phenobrbitone). Dosges hd not been ltered over the previous 3 months nd ll ptients were complint with their nticonvulsnt mediction s judged by consistent concentrtions t out-ptient ttendnces. No other drugs were being prescribed nd no ptient ws known to buse lcohol. Twenty-six untreted ptients were included s controls. They were studied following n isolted seizure, during investigtion of likely seizure disorder or t lest 6 months fter tril of drug withdrwl. The protocol hd the pprovl of the Western Ethics Committee nd ll ptients gve informed consent. Anlyses Blood smples were tken from the treted ptients t the time of testing nd stored t - 2C for btch nlysis. Crbmzepine nd CBZ-E concentrtions were obtined using high performnce liquid chromtogrphy by modifiction of the method outlined by Meijer.'5 Lower 929 J Neurol Neurosurg Psychitry: first published s /jnnp on 1 July Downloded from on 2 Jnury 219 by guest.

2 93 Tble 1 Clinicl fetures in ll ptient groups ntreted Crbmzepine Crbmzepine controls monotherpy polyphrmcy Age (yr) 27-1 (1-9) 28-3 (8 9) 3 (7 6) Sex 12m 14f 18m 22f 5m 14f Secondry Eduction (yr) 41 (1-7) 47 (19) 41 (7) Type of epilepsy Centren- Centren- Centrencephlic 15 cephlic 5 cephlic 12 CPE + CPE + CPE + SG 25 SG 14 SG 14 Durtion (yr) 6-4 (7-6) 9-5 (8-9) 14 8 (1-1) Vlues re men (SD). CPE + SG = Complex prtil epilepsy ± secondry generlistion. limit of detection for the CBZ-E ssy ws -2 mg/l which hd coefficient of vrition of < 5%. Test Bttery The test bttery ws dministered immeditely fter blood smpling in ll ptients. The verge time for completion ws 45 minutes. The following tests were performed: (1) Performnce IQ: Clculted from score on Rvens Stndrd Progressive Mtrices. (2) Decision Time: Time (ms) to respond to light coming on by removing finger from bse button in choice rection time tsk. A men of 3 tests ws recorded. (3) Choice Rection Time: Time (ms) to move finger from bse button to extinguish light. A men of 3 tests ws recorded. (4) Finger Tpping: Number of tps (per minute) of dominnt index finger on clcultor button in constnt ddition mode. (5) Threshold Detection: An rry of smll rectngles is displyed on VD. After very brief period of time n extr rectngle is dded to the rry. The subject is required to indicte which is the extr rectngle. The "threshold" is the minimum time gp in Frme nits between the presenttion of the rry nd the dditionl stimulus which the subject requires to perceive tht n extr rectngle hs been dded. (6) Movement Detection: An rry of smll rectngles is displyed on VD. One moves out of position nd bck once. The subject is required to indicte which rectngle moved. Score is number of correct responses out of 32. (7) ForwrdDigit Spn: Mximum number of digits subject cn recll immeditely following orl presenttion. The subject is llowed two trils t ech level nd the tsk is discontinued when he fils both. (8) Bckwrd Digit Spn: Mximum number of digits the subject cn recll in reverse order immeditely following orl presenttion. The subject is llowed two trils t ech level nd the tsk is discontinued when he fils both. (9) Pired Assocition Lerning: Number of trils to rech criterion of three correct in lerning unrelted word pirs. (1) Visul Spn: An rry of boxes is displyed on VD. Some re unshded nd some shded. The first rry is replced by second fter 1 ms. In the second disply one box which ws previously shded is now unshded. The Gillhm, Willims, Wiedmnn, Butler, Lrkin, Brodie subject is required to indicte which box hs chnged. In the first exmple there re only two boxes. The tsk mkes incresing demnds on the subject's visul memory s more boxes re dded. The visul spn is the highest number of boxes in the disply before the subject is unble to identify the chnge. (11) Sedtion Score: Subjects rting of level of lertness using 1 cm line where is "nerly sleep" nd 1 "wide wke". (12) Side effect Score: The subject is presented with stndrdised list of 15 side-effects ssocited with crbmzepine therpy (for exmple dizziness, diplopi, nuse, hedche). Ech one is rted on four point scle s follows: = not present, 1 = mild, 2 = moderte, 3 = severe. The individul rtings re summted to produce side effect score. Tests 2 nd 3 were crried out using the choice rection time fcility of the Leeds Psychomotor Tester. Tests 5, 6 nd 1 were developed in the Psychology Deprtment t Stirling niversity nd hve been stndrdised using norml controls nd lcoholic ptients. They were dministered using n Apple Ile microcomputer. Tests 7 nd 8 re the Digit Spn sub-test of Wechsler Memory Scle. Test 9 ws the Inglis Pired Associte Lerning test. Results There were no significnt differences in ge, in yers of secondry eduction or in durtion or type of epilepsy between the three groups (tble 1, ANOVA). Ptients tking more thn one nticonvulsnt drug hd higher circulting levels of CBZ-E (t test, p <.1) but men crbmzepine concentrtions in these two groups were lmost identicl (tble 2). Monthly seizure frequency nd scores for ech test re shown in tble 3. ANOVA reveled significnt differences between the groups on three tests: forwrd digit spn (p < 5), sedtion (p < -5) nd side effect scores (p < -1). Multivrite nlysis gve n F vlue (Pillis) of2-1 (df 2,26; p <.2) showing the discrimintive vlue of the test bttery tken s whole. When seizure frequency ws tken out of this nlysis s covrite, the F vlue remined significnt t the 2% level (F vlue 1 87, df 2,26; p < 2). There ws no difference in performnce between ptients on crbmzepine monotherpy nd untreted ptients, except with the movement detection tsk (p < 5). Ptients treted with Tble 2 Concentrtions (men, SD) of crbmzepine nd crbmzepine 1,11 epoxide (CBZ-E) in monotherpy nd polyphrmcy ptients Crbmzepine (mg/l) CBZ-E (mg/l) Monotherpy (n = 4) 1-4 (4 5) 1-3 (9)* Polyphrmcy (n = 19) 11 1 (39) 25 (1l5) Sttistics obtined by t test. * p < 5. J Neurol Neurosurg Psychitry: first published s /jnnp on 1 July Downloded from on 2 Jnury 219 by guest.

3 Concentrtion-effect reltionships with crbmzepine nd its epoxide on epileptic ptients Tble 3 group Men (SD) seizurefrequency nd test scores in ech Epileptic Crbmzepine Crbmzepine Test controls monotherpy polyphrmcy Seizures* t 16t (per month) (4-3) (2-) (8-5) Performnce IQ (17.7) (17.2) (13 2) Decision Time* (ms) ( I 1) (.23) (-59) Choice Rection Time* (ms) (-21) ( 27) (-57) Finger Tpping (per min) (91-4) (679) (73-) Threshold Detection* (Frme units) (4 5) (5 ) (5 2) Movement *8t 14-6 Detection (9.2) (1.2) (9 1) Forwrd Digit Spn (1 3) (1-2) (1 3) Bckwrd $ Digit Spn (1-3) (16) (1 1) Pired Assocition Lerning* (3-1) (4.4) (46) Visul Spn (4 1) (4-5) (4-6) Sedtion Score (cm) (2) (29) (3 1) Side Effect $ Score* (3-4) (46) (5 5) * Denotes test where low score is better thn high score. t t test shows control group better thn Crbmzepine monotherpy group p < -5. $ t test shows control group better thn Crbmzepine polyphrmcy group p < 5. t test shows CBZ monotherpy group better thn Crbmzepine polyphrmcy group p < -5. crbmzepine nd one other nticonvulsnt did less well in choice rection time, bck digit spn, pired ssocition lerning (ll p < -5) thn the epileptic control group nd in performnce IQ nd forwrd nd bck digit spn (ll p < -5) thn the monotherpy ptients. The polyphrmcy group lso reported greter sedtion nd side effects thn the other ptients (ll p < 5). Spermn correltions between crbmzepine nd CBZ-E concentrtions nd test scores re outlined in tble 4. There were significnt negtive correltions for four tests with crbmzepine nd for seven tests with CBZ-E. The reltionships between crbmzepine nd CBZ-E nd choice rection time nd threshold detection re illustrted in figs 1 nd 2 respectively. The poorer correltion between CBZ-E s percentge of crbmzepine (two tests only) suggests tht crbmzepine nd CBZ-E exert independent effect on psychomotor function. Circulting levels of CBZ-E (r = -35, p = -14) but not crbmzepine correlted positively with seizure frequency. To compre directly performnces of ptients with 931 high nd low concentrtions, the smple ws divided into two groups; those with crbmzepine levels < 1 mg/l (n = 18) nd those > I- mg/l (n = 2). The high concentrtion ptients scored significntly worse (Mnn-Whitney test) on threshold detection (p < -1), finger tpping (p < 5), decision time (p < 5) nd choice rection time (p < 2). There ws no significnt difference between these two groups in terms of seizure frequency or durtion of the disorder. The smple ws divided into two further groups; those with CBZ-E concentrtion < 1-15 mg/l (n = 19) nd those > 115 mg/l (n = 19). The high concentrtion ptients scored significntly worse on threshold detection (p < -1), decision time (p < -5), nd choice rection time (p < -2). Once gin, there ws no significnt difference in seizure frequency or durtion of epilepsy. Discussion The three groups of ptients in this study were not bsolutely mtched for seizure frequency or durtion of epilepsy. Not surprisingly lso, both the crbmzepine groups reported higher seizure frequency nd longer durtion of epilepsy thn the controls. Previous reserch hs provided evidence to suggest tht these fctors re ssocited with poorer cognitive performnce.4 16 Thus, ny superiority shown by n untreted control group my be due to combintion of three fctors: low seizure frequency, short durtion of epilepsy nd no nticonvulsnt mediction. Multivrite nlysis demonstrted, however, tht the test bttery s whole still discriminted between the groups when fit frequency ws tken out s covrite. Thus it my be concluded tht the vrince Tble 4 Significnt correltion coefficients between tests scores nd crbmzepine nd crbmzepine 1,11 epoxide (CBZ-E) concentrtions Crbmzepine CBZ-E CBZ-E % Test (mg/l) (mg/l) Crbmzepine Performnce IQ - 28t --29t Decision Time* t Choice Rection Time* -3t Finger Tpping - 28t Threshold Detection* Digits Bck --31t Visul Spn Pired Assocition Lerning* 31t * Denotes tests where low score is better thn high score. tp < 5. ++p < 2. < 1. J Neurol Neurosurg Psychitry: first published s /jnnp on 1 July Downloded from on 2 Jnury 219 by guest.

4 932 1X2 * L IO.8 d -. 1 :3 X6*n C.bomorepm co.cetrot.o.n Img/ll Crbmwozepr.e co.chtrolio' (mg/ll Fig 1 Correltions between choice rection time nd threshold detection with circulting crbmzepine concentrtion in 3 epileptic ptients receiving the drug s monotherpy. between the groups is not ttributble to the effect of seizures per se. (1) Comprison between monotherpy ptients nd untreted controls The point of interest here is tht the control group showed superiority on only one test: movement detection. The similrity between epileptic controls nd crbmzepine monotherpy ptients despite their higher seizure frequency llows the inference to be drwn tht crbmzepine produced negligible cognitive impirment. This is in ccordnce with previous findings by other workers.9 11,17 Nevertheless, ptients who develop severe psychomotor impirment with crbmzepine reunlikelyoto tolerte the drug long-term nd so will exclude themselves from study. (2) Comprison between monotherpy nd polyphrmcy ptients Crbmzepine monotherpy nd polyphrmcy ptients were well mtched for seizure frequency nd durtion of epilepsy. The monotherpy group ws found to be superior in performnce IQ, forwrd nd bckwrd digit spn nd both sedtion nd side effect scores. Ptients were not rndomly llocted to the ) 9 E u L-,.5 ) ! *.m * nf 39 r=.43 p< Corbmczzepine 1,11 epokide (mg/l) Gillhm, Willims, Wiedmnn, Butler, Lrkin, Brodie tretment conditions nd so it cnnot be concluded tht the cuse of these differences lies purely in their tretment; some unmesured fctor cnnot be excluded. However, the results do confirm tht in clinicl popultion where therpies hve not been determined by experimentl design, there re rel differences between ptients tking crbmzepine lone nd those tking it in combintion with nother drug. This finding supports deleterious effect of polyphrmcy on overll cerebrl function.8 '9 18 The ctive metbolite, CBZ-E, hs nticonvulsnt efficcy similr to the prent compound in niml epilepsy models19 nd is more potent thn crbmzepine in the tretment of trigeminl neurlgi.2 CBZ-E is lso known to contribute to crbmzepine neurotoxicity.21 In this study, CBZ-E levels in the polyphrmcy group were lmost double those of the monotherpy ptients with equivlent crbmzepine concentrtions. This ssocition is well known22-23 nd is relted to induction of crbmzepine epoxidtion by phenytoin nd phenobrbitone22 nd inhibition of CBZ-E brekdown by sodium vlprote.24 Thus, CBZ-E my hve contributed substntilly to the psychomotor impirment experienced by the polyphrmcy ptients in this study. (3) Concentrtion-effect reltionships Performnce on four nd seven tests deteriorted with incresing crbmzepine nd CBZ-E concentrtions respectively. Andrews et l1' found reltionship between circulting crbmzepine levels nd performnce on trcking tsk. In view of the inter-individul vrition in response to these tests, lrge groups of ptients require to be studied over wide rnge of crbmzepine concentrtions which my explin the inbility of others to document such cler-cut concentrtion-effect reltionship It is worth noting tht more tests showed LL. ' I * 1 2 3e 5 Crbmzepine 1,11 epoxide (mg/li) Fig 2 Correltions between choice rection time nd threshold detection with circulting crbmzepine 1,11 epoxide concentrtion in 4 epileptic ptients receiving crbmzepine monotherpy. :.. n= 39 r:.61 p<.1 J Neurol Neurosurg Psychitry: first published s /jnnp on 1 July Downloded from on 2 Jnury 219 by guest.

5 Concentrtion-effect reltionships with crbmzepine nd its epoxide on epileptic ptients significnt correltion with CBZ-E thn with totl crbmzepine. This suggests tht CBZ-E my be more importnt in producing performnce decrement. If cognitive impirment were solely ttributble to the effects of CBZ-E on cerebrl function, the rtio of CBZ-E to totl crbmzepine would be expected to be more sensitive predictor of dysfunction thn totl crbmzepine. Tht it ws not supports n independent effect of both crbmzepine nd its metbolite in producing psychomotor impirment. The term "impirment" in this context is reltive; the crbmzepine group performed significntly worse thn n pproprite control group on only one tsk. Nevertheless, the generl trend ws towrds poorer performnce with incresing crbmzepine nd CBZ-E concentrtions. Cre must be tken in inferring cuse nd effect between significnt correltions; the reltionship between ny given pir of vribles my be indirect, with third fctor "cusing" both. Severity of epilepsy my led to incresed prescribing of crbmzepine nd to incresed cognitive impirment. Fit frequency, resonble mesure of severity, did not correlte with totl crbmzepine concentrtion. It did however pper to relte to CBZ-E level nd it is possible tht ptients with higher CBZ-E levels hd more severe seizure disorder. The division of the smple into high nd low concentrtion groups served to identify the most discrimintive tsks; for crbmzepine: threshold detection, finger tpping, decision nd choice rection times; for CBZ-E: threshold detection, decision nd choice rection times. It is cler tht these tsks require reltively little informtion processing nd hve strong visuo-motor component. It ppers tht the more primitive spects of neuropsychologicl function re most ffected by crbmzepine nd its metbolite. These tsks my be of vlue in clinicl prctice to identify erly those ptients who re likely to become intolernt to high crbmzepine dosge. We re grteful to Mrs Ky Cockburn for expert secretril ssistnce nd the Epilepsy Assocition of Scotlnd for finncil support. References 1 Lennox WG, Lennox MA. Epilepsy nd Relted Disorders. 196; Boston: Little, Brown. 2 Pond DA, Bidwell BH. A survey of epilepsy in fourteen generl prctices. II Socil nd psychologicl spects Epilepsi 1: Smith DB, Crft BR, Collins J, Mttson RH, Crmer JA. The VA Coopertive Study Group 118. Behviourl chrcteristics of epilepsy ptients compred with norml controls. Epilepsi 1986;27: Dodrill CE. Correltes of generlised tonic-clonic seizures with intellectul, neuropsychologicl, emotionl nd socil function in ptients with epilepsy. Epilepsi 1968;27: Bern RG, Flngn PJ. Psychologicl sequele of epilepsy. The role of ssocited cerebrl pthology. Epilepsi 1987;28: Reynolds EH, Trvers RD. Serum nticonvulsnt concentrtions in epileptic ptients with mentl symptoms. Br J Psychitry 1974;124: Thompson PJ, Trimble MR. Anticonvulsnt drugs nd cognitive functions. 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