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The relationship between clozapine dose and plasma level and side effects
THE RELATIONSHIP BETWEEN CLOZAPINE DOSE AND PLASMA LEVEL AND SIDE EFFECTS KaifU. AH1; ......, R1; Gul...ktr.m, s2; Haye., s2; Jln, y1; Colt!, J2; Oldroyd, J1 ; Cooper, T3; Potkln, SG1. 1Depliltment 01 Psychiatry and Human Behavior, University of California Irvine M.C., Orange, CA • 2Metropolitan State Hospital. Norwalk. CA. 3The NathanS. Kline Institutelor Psychiatric Research. Orangeburg. NY
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Previous WOfk has shown that monitoring Clozapine plasmalevels may help predict clinical response in treatmentresistant schizophrenics. and that a thresholdlevel ellists above whi<:tl clinicalrllSlXl'l88rate increases. However. there have been concerns that increasing the Clozapine dose to achieve a higher p1.sma leVel may lead to higher rates 01 motor symptoms, or other side effects assodated with neurolepticuse. In our study 58 trNtment resistant schizophrenicpatients were entered into. t1xed-dose, double blind trial. At week 4 hall 01 the patients were treated with 400 mg and half with 800 mg. There was no difference in motor or other side effects between the two groups at week 4 and at week 12. Two patients developed seizures during the initial titration at oral doses 01 200 mg a day. Furthermore. there was no relationship betweenside effects and C10zapine plasma concentration.
.:)DU'lC.AtION OP THE !llETHOD 01 AnECTIYX
DISORDER PROPHYLAXIS
~ITH
LlrHIUK SALTS
teoT, '¥'. N•• r.iev Institute for Adva~cad Med. Training, Ukraine Current ~ethod3 cr prophylactio treatment with Lithium salte often lead to their accumulation in the orgro11sm and cause unfavourable side e!t~ctB. In or1~r to d~crea8e 3ire effects of thB therapy with carbonaceous Lithium ;y prevd~tion of its aceumulation in the organism in 60 patients With affective psychosis of endogenic and exogenic-organio genesi~ the ~ntake ot this medicine was cancelled during 4-6 days with '-weeks' interval. In remale patients the intake was cancelled during the period ot ovaeulatlcn (on the 12th-18th day. of tbeir menstrual cicle). Decreased Lithium conCentration in blood did no~ lead to relapses ot psychoses . Positive effect in oomparison with the prototype is explaned by prevdr.tion ot LithiuD accumul~tion in the ~atient8' orga~ nia... In addition, the ;latients have re gu l.ar-« 11 be~n taken ~l oQ d ~ &r.p l e 9 to test Ll~~i~ content in bloo~ which served the psycho traumatte fac ~cr for him/her. [UZll!
ImAVIOUUL UJZCTS 07 110 AHD NX Sal, .llm m :etnUC'UONS WID IlOPAK:OnI1t;1ONIS'l'1 »m ~HUU, IIn1l%l)D AHD IiN%ODI1ZDlnS J:)f MORIn PUVIC118to~
ZlP08iD TO XI11ROtoIP'1'%CI.
..~:1k
Lublin, Xiklcal Mad. . 't. !ol1lieal, %lapartllint P and Iutituta aiological Jsychiatry, nt·fOOO Zoakilde, IaU
:I..
n~rk
01
The glutamatergic Iyltem pa:tic1pate. in important modulatory neural circuitl. Prom tha neocortex ant tl1a thalami neuronal pat=.n.y. run co the .t:riat01:
ware elle glut&llllltergoic and IIxcitatory input intlr· Act. with dopalllinergic input trOlll the lub.tanti& Aigra para compacta and the ventral t'~Atal ar•• upon the activity of GAU.I%g'ic and ac.tylcholinl:g1c ZllNrcnl • III rata it: ha. blln nporud th.t botl glutamatargic: agoni.t. and &nc.goni.t. may 1ucr•••• locomotor ace1viey whln &~1.terld alone . •e ~v. inve.tillltid the behavioural effect I o! the ilutam.tl:gic antagon~.t. PCP and MX 101 inl C.~. apella monkey•. In contra Ie to the .l:fectl in rat. PCP a~ !'IX In inducld. d.yatoo.ia, .ldatio:1 at 10t0 do.e•• bradykinesia and. rlduced arousal. DyltOl1ia wa. p;r:oduc.d in " dOIl-dep.nrant manner. 1(ai~r III nOl: D2 agon1ltl modified thl hlhavi~al rllponl.1 tc NMDA antagoni.ts . Raclopr1~ tended to ~ce the NMDA mtagc::nilt-i.nduced dystonia. BipU'iden bad no 0% only li~tle effece on NMDA antagoaist-Lnducec dYltonia.. werns BZ a.gonists reduced. NN~ antagonist-induced dystonia ~n a dose-dependent manner. The lack of effactl of CA. agonistl 0= biplridan indicaee trAt ~e pathophYliological mechanisml underlying NMOA anl:agon1It-inducllc dy.toni~ arl different f~om tha~ of OA antagonists. The primary effec~s of NMCA antagaciats on dystenia may -oc cur ' l a t e ' in the Itriatal-pallido-nigrothalamic pat:hways \Ithic:b involve G.lUSAergic a8 . .11 as glutamate:gic neuroZ1a. Tht Iffecta of the glutamatlrgic an:agonistl in mo~.YI may .ugg•• t • naurolepeic-li~e profile. Eowevlr, in man both PC~ and. MX aoJ. may produce Ichi;QPl1rani"-lik. plyc:::o.... ~UI. it may be suggested. that t~. plyc~ctom1m.tic and the locomotor effects. respectiVllly, an produce.:! in dillirent brain areas and/or by di!ferlnt TI1!Ichani.ml.
FLASB-VISUAL-EVOKED-RESPONSE DELAYIS ASSOCIATED WITH AGING MooR, NC; Stewart, CA; Eltes, KM; Kbairy, NM; Lindley, PR; VopI, RL; Coburn, KL BrainResearch Center, Macon, GA J 120I, USA.
The ftash-visual-evoked-response (FVER) is the basis of a putative diagnostic; testfor Alzheimer's disease [I}. Wehave shown that the P2 component of tile FVER is delayed in Alzheimer's disease. but not in other dementias or in healthy controls, and that the delayis significantly increased in the same patientsafter six months. If the P2 is to beused u the essential part of a diagnostic test, it is important to determine what other independent variables might affect its latency. Textbooksof evokedpotentials agree that the latency of the pattem-reversal-evoked-response (PVER) increases with advancing age, but contain no such infonnation about the FVER. Becauseage-related changes occur in the rostral visual system(at least in the parts that serve the PVER) we studied normal healthy subjectsto determine whether the P2 mightalso increase with advancing age. The P2 was measured in 42 healthy controls, ranging in age from 21 to 82 years. Thirty were women, and 12 were men. Age was linearly relatedto P2latency (latency = 97.33 + 0.95 age, Pearson r = 0.549, P = 0.00(2), whichshould be considered in futurestudies. [I] Moore NC, Tucker KA, JannMW, Hostetler RM, CoburnKL, Prog. Neuro-Psychopharmacol. & BioI. Psychiat. 19 (1995) 403410.
._...--------_._------_.------_._._.._._-_.----_...---_.....- .. ---
Previous WOfk has shown that monitoring Clozapine plasmalevels may help predict clinical response in treatmentresistant schizophrenics. and that a thresholdlevel ellists above whi<:tl clinicalrllSlXl'l88rate increases. However. there have been concerns that increasing the Clozapine dose to achieve a higher p1.sma leVel may lead to higher rates 01 motor symptoms, or other side effects assodated with neurolepticuse. In our study 58 trNtment resistant schizophrenicpatients were entered into. t1xed-dose, double blind trial. At week 4 hall 01 the patients were treated with 400 mg and half with 800 mg. There was no difference in motor or other side effects between the two groups at week 4 and at week 12. Two patients developed seizures during the initial titration at oral doses 01 200 mg a day. Furthermore. there was no relationship betweenside effects and C10zapine plasma concentration.
.:)DU'lC.AtION OP THE !llETHOD 01 AnECTIYX
DISORDER PROPHYLAXIS
~ITH
LlrHIUK SALTS
teoT, '¥'. N•• r.iev Institute for Adva~cad Med. Training, Ukraine Current ~ethod3 cr prophylactio treatment with Lithium salte often lead to their accumulation in the orgro11sm and cause unfavourable side e!t~ctB. In or1~r to d~crea8e 3ire effects of thB therapy with carbonaceous Lithium ;y prevd~tion of its aceumulation in the organism in 60 patients With affective psychosis of endogenic and exogenic-organio genesi~ the ~ntake ot this medicine was cancelled during 4-6 days with '-weeks' interval. In remale patients the intake was cancelled during the period ot ovaeulatlcn (on the 12th-18th day. of tbeir menstrual cicle). Decreased Lithium conCentration in blood did no~ lead to relapses ot psychoses . Positive effect in oomparison with the prototype is explaned by prevdr.tion ot LithiuD accumul~tion in the ~atient8' orga~ nia... In addition, the ;latients have re gu l.ar-« 11 be~n taken ~l oQ d ~ &r.p l e 9 to test Ll~~i~ content in bloo~ which served the psycho traumatte fac ~cr for him/her. [UZll!
ImAVIOUUL UJZCTS 07 110 AHD NX Sal, .llm m :etnUC'UONS WID IlOPAK:OnI1t;1ONIS'l'1 »m ~HUU, IIn1l%l)D AHD IiN%ODI1ZDlnS J:)f MORIn PUVIC118to~
ZlP08iD TO XI11ROtoIP'1'%CI.
..~:1k
Lublin, Xiklcal Mad. . 't. !ol1lieal, %lapartllint P and Iutituta aiological Jsychiatry, nt·fOOO Zoakilde, IaU
:I..
n~rk
01
The glutamatergic Iyltem pa:tic1pate. in important modulatory neural circuitl. Prom tha neocortex ant tl1a thalami neuronal pat=.n.y. run co the .t:riat01:
ware elle glut&llllltergoic and IIxcitatory input intlr· Act. with dopalllinergic input trOlll the lub.tanti& Aigra para compacta and the ventral t'~Atal ar•• upon the activity of GAU.I%g'ic and ac.tylcholinl:g1c ZllNrcnl • III rata it: ha. blln nporud th.t botl glutamatargic: agoni.t. and &nc.goni.t. may 1ucr•••• locomotor ace1viey whln &~1.terld alone . •e ~v. inve.tillltid the behavioural effect I o! the ilutam.tl:gic antagon~.t. PCP and MX 101 inl C.~. apella monkey•. In contra Ie to the .l:fectl in rat. PCP a~ !'IX In inducld. d.yatoo.ia, .ldatio:1 at 10t0 do.e•• bradykinesia and. rlduced arousal. DyltOl1ia wa. p;r:oduc.d in " dOIl-dep.nrant manner. 1(ai~r III nOl: D2 agon1ltl modified thl hlhavi~al rllponl.1 tc NMDA antagoni.ts . Raclopr1~ tended to ~ce the NMDA mtagc::nilt-i.nduced dystonia. BipU'iden bad no 0% only li~tle effece on NMDA antagoaist-Lnducec dYltonia.. werns BZ a.gonists reduced. NN~ antagonist-induced dystonia ~n a dose-dependent manner. The lack of effactl of CA. agonistl 0= biplridan indicaee trAt ~e pathophYliological mechanisml underlying NMOA anl:agon1It-inducllc dy.toni~ arl different f~om tha~ of OA antagonists. The primary effec~s of NMCA antagaciats on dystenia may -oc cur ' l a t e ' in the Itriatal-pallido-nigrothalamic pat:hways \Ithic:b involve G.lUSAergic a8 . .11 as glutamate:gic neuroZ1a. Tht Iffecta of the glutamatlrgic an:agonistl in mo~.YI may .ugg•• t • naurolepeic-li~e profile. Eowevlr, in man both PC~ and. MX aoJ. may produce Ichi;QPl1rani"-lik. plyc:::o.... ~UI. it may be suggested. that t~. plyc~ctom1m.tic and the locomotor effects. respectiVllly, an produce.:! in dillirent brain areas and/or by di!ferlnt TI1!Ichani.ml.
FLASB-VISUAL-EVOKED-RESPONSE DELAYIS ASSOCIATED WITH AGING MooR, NC; Stewart, CA; Eltes, KM; Kbairy, NM; Lindley, PR; VopI, RL; Coburn, KL BrainResearch Center, Macon, GA J 120I, USA.
The ftash-visual-evoked-response (FVER) is the basis of a putative diagnostic; testfor Alzheimer's disease [I}. Wehave shown that the P2 component of tile FVER is delayed in Alzheimer's disease. but not in other dementias or in healthy controls, and that the delayis significantly increased in the same patientsafter six months. If the P2 is to beused u the essential part of a diagnostic test, it is important to determine what other independent variables might affect its latency. Textbooksof evokedpotentials agree that the latency of the pattem-reversal-evoked-response (PVER) increases with advancing age, but contain no such infonnation about the FVER. Becauseage-related changes occur in the rostral visual system(at least in the parts that serve the PVER) we studied normal healthy subjectsto determine whether the P2 mightalso increase with advancing age. The P2 was measured in 42 healthy controls, ranging in age from 21 to 82 years. Thirty were women, and 12 were men. Age was linearly relatedto P2latency (latency = 97.33 + 0.95 age, Pearson r = 0.549, P = 0.00(2), whichshould be considered in futurestudies. [I] Moore NC, Tucker KA, JannMW, Hostetler RM, CoburnKL, Prog. Neuro-Psychopharmacol. & BioI. Psychiat. 19 (1995) 403410.