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"/ Y&! R0 @X -` -4 "/ G -5 /- -3 A+(,0 $ bg (KA) R / (AMPA) -! Q BB.(7)- '2 R B 1A/ 7 /- R3+& bg c ] J '! ' Q!( "3 ' R B '! 7M! GK 1A/ 3.1! 7D i 73+&! < ' R B (/, B0/ ' '. ji "/ /! + /! + (/ Z 7 73+&.B' '! "/.-. 5` 'AT.B 50 D2 7 7 G ' 7 73+& 5U R#$- 8$ '( @/ 71 -. Y '(.- (DSM-TV-TR) a!.b' 7@jF "! 45 18 '! ' (8) - 5` G@i 7A Gi-j B0/ ' 1K 7/ 50 100 Gi-j 73+& l..--. 73+&,- ($100mg/day),2 1 K RU#$! < 7/! M0$ -/ 1 @n ' 1K 1 3! 7 - Q!( o 7 0/ p! 7 0/ "#$ - @I.--. q8j 73+&,-. # -J %& '(! "#$ "/ 0/ "(- ' ) +,-. 73+& 8+.1! -2 3! 4# 5.(1) -! 9 7 ;<< B 1 ( @ 1A/ 5-! 4# C3 '! 1! 7. '( 'D2EB 7.-- G $ + B @F "! I,--J HF$ ' 7 K -! ( LM -/ %&, $.(2-3) -! G $ K Q ' 7,R0 @F 7&!,S 0T " /;! /," / /,W0X R3+&.(4) -. " /U ( R0 Y&! L S 5-,L/ Z '! ' "/ 7M S 1 R0 190\ L ](5) 1! -.!( ^M Y D '! ' R0 Y&! L/. 7 ( -! B!L B 1! Q 0 @F 7B '! 72! R0 1 +3 L.(5) _B ' S -. 5` R3+& a! 7 R0 1 ( b '-M c d.(4) 1! -. %& 'J - ' LEB 73+& e2 R B H$ 1M.(6) 1!! ' Rb '/ Q4 @F 7&!
56 28,(\() AT PANSS Q/ 7@jF a! 7/.1 RT ^$,-. @ + 4#.B' 5U B J /- s! --. 4#.1 5` LEB '( Cj 7 7 R- I @J o j.- 1@b 56 28,AT I "/,WBC Z. G. D2( R#I 1 +3 1 /,,-i, 0.- 1@b 56 28,AT 3 -@/ 7/ +j,-! -Z( Q -i ',- LA/ '- Q@! a@+ ' (BMI) - _/-. -.(10) - 7@!K (Kg/m 2 ) -i v ' M 7` SPSS-13 5 R#I F R@b 9 7 1 i ( G 0K 7M t-student 1,7 ;X ' R-, -3, + '!,! Chi-Square 1 c BMI D! qf 1 3 1 J 7M 1.- 5` (\() AT ' -. / 7 @J o 7M 2 (GLM) &$ "- +( c.-. G$ RA L`! ('( J 0/ ) PANSS vim 5 F G. 7!.-. A! ' - -. M R B (Between-Subject) G Q ' 7.-. wk+,/ M 7 ' 7/ 56 28,AT 7@ 7! PANSS ' 7 3 36,LEB 5` j 7 G 5-. 7/ --. q8j A <,73+&.(1G.) @I J R# 2 73+& 1/.,',-i, j 4# G. 7B R#I,Q E,D! qf 1 3 @J o ' 7M!,.B' 7M! A 1@n 4# a M.-. 1@b! 4# R-. (PANSS) 3 30 a M.(9) 1 i A! (( 7) A 4#,(( 7) 1@n 4# L`!.-. ( 3 16) 0/ +B! - 5 Q/,F G. 7 ' Q.--. M -. F D -/ 1 R B B0/ 50 25 -M R B. B0/ 50 25 3-4 -. l. -M.-! 50 300 n/-j 7 1 L @J o 4# GK ' a!, 5U ' - 9, ' ' 7 (5B+) B Hi.-. A! 50 4 n/-j -/ - +) ( 1/. s! RFX2 t ' (R B Hi /! 9.-. 7 0T, 7 ' -/ M D2EB,73+& 7 L!B G 7 2M D2EB ' "u Q.B'.1.- #I ' ' l PANSS -/G (-/). A! ' B.-.- Rb 1A/!.1 RT
!" ().1 P value Clozapin + Placebo N=16 Clozapine+Topiramate N=16 0/742 38/1±4/ 6 37/5±5/ 7 RFX2! ("! {j) 0 /254 11 (6 8) 9 (5 6) _J 0/757 20/72±7/ 68 21/41±4/ 84 0/229 7/14±5/ 31 9/72±5/ 81 +! R3-3 0/855 18/1±5/ 4 17/7±7/ 8 R- 0 /353 10 (6 2) 12(7 5) 0/652 25/21±4/ 42 24/12±3/ 35 D! 1 3 '- 2/ - _/- (Kg/m 2 {j) 7B 3 RA +B!,A 4#,1@n 4#.(2 "-J) -2-2 PANSS G/ S,e.--. L`! (Within-Subject) ' G Q -. 1@b `.- ^X2 7! Y&! 7! t-student '( A! Pair wise +( L`! Mann-Whitney QB \ '(.1 5` v&m 7M,(' 12 20G.) '! 32,l` R- "I "! 37/9±5/1! s! A 16 F G. 7,"! 17/9±6/8.- i ( + B0/ R B + B0/)!,_J,! 9 3 RA -3,.B' + ' D! qf 1 3, R-,.B'.(1 "-J) @ 2 l. BMI P value 0/82 0/087 0/002 0/38 0/018 <0/001 0/52 0/029 $/& 0 56 28 + PANSS $$%& '$()&.2 t Clozapine + Placebo Clozapine + Topiramate 0/22 23/50±7/84 24/06±6/19-1/76-0/75±3/82-3/06±3/56-3/30-0/56±4/41-5/68±4/36-0/88 27/68±10/13 24/75±8/53-2/55-1/00±1/63-3/31±3/23-3/96 0/00±4/60-5/87±3/73-0/65 50/68±10/74 48/06±12/01-2/30 0/18±5/78-4/81±6/49 1@n 4# 7B 28-3 R S 56-3 R S A 4# 7B 28-3 R S 56-3 R S 0/ +B! 7B 28-3 R S 0/009-2/80-0/75±7/49-8/43±7/99 56-3 R S PANSS G/ 0/53-0/62 101/87±23/05 96/87±21/98 7B 0/005-3/03-1/56±9/23-11/18±8/72 28-3 R S <0/001-4/57-1/31±11/13-20/00±11/96 56-3 R S According to Shapiro-wilk test, normality assumptions were violated, but Mann-withney test had same results. 8
.B 7 7J 7/ 1! /} 7 5U M A 1@n 4#,G. \( (' I -j %95) 1@n 4# D 73+& 28,24/06 (20/45-27/67) 73+& 73+& 56 21/00 (17/47-24/56) A 4# D. 18/37 (15/33-21/41) 73+& l. (' I -j %95) (16/77-26/09) 73+& 28,24/75 (19/96-29/53) 1! 7 18/87(14/30-23/44) 73+& 56 21/43.-( 7 BMI,R B ' 1K ' M 56 28,AT { 7/ 23/21±3/54 23/61±3/75,24/12±3/35,D.1.- 3 7J Gi S { 7 56 28,AT { 7 BMI 7@!K 25/42±4/75 25/37±4/68,25/21±4/42. '2 3 S M.-.,/j - -/ G. @J o $ '!B ' Z ;(,' L/ U 56 R B ' 1K 4# 5-/) ' Z ;( J 7.(PF0/05).(2 G.) @ 2 73+& l. 80 75 70 60 50 50 40 34.7 37.5 37.5 topiramate placebo 30 20 10 6.2 6.2 6.2 0! " #$ 7$6 8 9/ 3&.2 '12 (2 ;0 $ </+5 => 6 /& '6? 3& / @) 4 3 { 7 ( B ) / '.-. A! R B A ',(Between-Group) +( 7M B0/ R B ' 1K G / +B!,A 4#, R A. 3 ( 9 7/ -. U 7 @+. @ 3 1@n 4#.(2 "-J) 2 v&m RA (Within Group) ' +( 73+&. 5 3 RA PANSS 0/ (56 28,\() A 4#,(F=18/70 df=2,p<0/001) 1@n 4#,(F=11/42 df=1/58,p<0/001) +B! (F=12/17 df=1/49,p<0/001).-. -2 (F=8/06 df=1/65,p=0/002) 0/ df=2,p<0/001) PANSS 0/ M! (F=10/8 df=2/58,p=0/001) A 4#,(F=14/20 (F=5/82 df=1/65,p=0/008) 0/ +B! (56 28,73+& \()! ' G$- a! 9 (R B )!.1! 3 (,28 (Bivariate) 7I +( 1@n 4#,56 0/ +B! 0/ PANSS +B! A.(1 G.) (PF0/05) 1. 3 RA 28 + & (!" +45) Negative symptom score Positive symptom score General psychopathology symptom score Total PANSS 3 + + PANSS 0 $/& 6+ 56.1 '12 1386 $% /85! /0 1 C
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7/ - '2 $ LEB ' Zhen AMPA - 1 ( Ñ Z '-.( '$ 7 7.(24),!B G. R B @ J o! 7 3+&. ' Z;(! -/ G i L 7 1@!B KO.(25) 1. J 7 -/ - g 73+& É Rb '-! n/-j 7 '! "#$ Q!( 7,R B - R0 1 (.1! "/ A 4# '( bg 7 7J HF$,Q! (. ' L! 4# "/ - A Rb -.-. 7.! $ -i { - 5U '- 5K G -,-K a@ / i( ;J j, 5# (! 7$/ i( c.- 2 '2 0 ZD '2 - T - / '! '!B' '.B'. D!Ö! 2 'AT a- ' S 0-0 / -. 5.(18) 1! -. Z '! 1!! R0 "- -/ - g _@/( 7 0-1@n 4# L { 7 "B _ /.(19-20) -$! A R B ' @J o HF$ L /! -/,!B j 73+& 7 R B ' 1 K ' ' # 7. 2 3 G. 7 /,(Drooling) ' Z ;( - -2 B 0/ - Q!( qf 7 R B ',. 7 R B ' ' KO 73+&.-. 7 1@ 2 ' L/ ' ' 0 200 100 # 7. L -. 2< RA.-. -2 2 ' L/ ' - 7,j 73+& Gi 7< 7/ '2 L/ 7A 8-3 < ' -T "j 7,@ 7J R B ' L/ L/ Ñ i.(2 G.) 1!,1 ^X2 ' G-3 GABA - 1 +3 L 1 +3 AMPA R0 -.(21-23) 9 G-3 Ö + BÖ + 1. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U. How do glial-neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int 2007; 50(2)291-301. "# Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity a hypothesis for the etiology of schizophrenia. Neuroscience 1991; 41(1)1-24. L
3. Atmminga CA, Cascella N, Fakouhi TD, Herting RL. Enhancement of NMDA-mediated transmission in schizophrenia. Effects of milacemide. In Meltzer HY, editor. Novel Antipsychotic Drugs. New York Raven Press Ltd; 1992. p. 177-81. 4. Deutsch SI, Mastropaolo J, Schwartz BL, Rosse RB, Morihisa JM. A "glutamatergic hypothesis" of schizophrenia. Rationale for pharmacotherapy with glycine. Clin Neuropharmacol 1989; 12(1)1-13. 5. Drapalski AL, Rosse RB, Peebles RR, Schwartz BL, Marvel CL, Deutsch SI. Topiramate improves deficit symptoms in a patient with schizophrenia when added to a stable regimen of antipsychotic medication. Clin Neuropharmacol 2001; 24(5)290-4. 6. Arnone D. Review of the use of Topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 2005; 4(1)5. 7. Deutsch SI, Rosse RB, Billingslea EN, Bellack AS, Mastropaolo J. Topiramate antagonizes MK-801 in an animal model of schizophrenia. Eur J Pharmacol 2002; 449(1-2)121-5. 8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, IV text revision. 4 ed. Washington, DC American Psychiatric Association; 2000. 9. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13(2)261-76. 10. Quetelet LA. Physique Social. Brussels C Muquardt; 2007.p.92. 11. Dursun SM, Deakin JF. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia a naturalistic case-series outcome study. J Psychopharmacol 2001; 15(4)297-301. 12. Millson RC, Owen JA, Lorberg GW, Tackaberry L. Topiramate for refractory schizophrenia. Am J Psychiatry 2002; 159(4)675. 13. Tiihonen J, Halonen P, Wahlbeck K, Repo- Tiihonen E, Hyvarinen S, Eronen M et al. Topiramate add-on in treatment-resistant schizophrenia a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66(8)1012-5. 14. Eltayb A, Wadenberg ML, Schilstrom B, Svensson TH. Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride. Naunyn Schmiedebergs Arch Pharmacol 2005; 372(3)195-202. 15. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148(10)1301-8. 16. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51(3)199-214. 17. Harrison PJ, McLaughlin D, Kerwin RW. Decreased hippocampal expression of a glutamate receptor gene in schizophrenia. Lancet 1991; 337(8739)450-2. 18. Ulas J, Cotman CW. Excitatory amino acid receptors in schizophrenia. Schizophr Bull 1993; 19(1)105-17. 19. O'Donnell P, Grace AA. Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull 1998; 24(2)267-83. 20. Csernansky JG, Bardgett ME. Limbic-cortical neuronal damage and the pathophysiology of schizophrenia. Schizophr Bull 1998; 24(2)231-48. 21. White HS, Brown SD, Woodhead JH, Skeen GA, Wolf HH. Topiramate modulates GABAevoked currents in murine cortical neurons by a nonbenzodiazepine mechanism. Epilepsia 2000; 41 Suppl 1S17-S20. 22. Werneke U, Taylor D, Sanders TA. Options for pharmacological management of obesity in patients treated with atypical antipsychotics. Int Clin Psychopharmacol 2002; 17(4)145-60. 23. Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003; 11(6)722-33. 24. Zheng H, Patterson C, Berthoud HR. Behavioral analysis of anorexia produced by hindbrain injections of AMPA receptor antagonist NBQX in rats. Am J Physiol Regul Integr Comp Physiol 2002; 282(1)R147-R155. 25. Ko YH, Joe SH, Jung IK, Kim SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol 2005; 28(4)169-75. V
Original Article Journal of Isfahan Medical School Vol 25, No 85, Summer 2007 Received 23.4.2007 Accepted 5.7.2007 Background Methods Findings Conclusion Key words Page count Tables Figures References Address of Correspondence Add-On Topiramate In Treatment of Schizophrenia Mousavi SG MD, Golchin SH MD, Afshar H MD, Rooh Afza HR MD Associate Professor, Psychiatry Department, Isfahan Medical School, Isfahan University of Medical Sciences Assistant of Psychiatry, Psychiatry department, Isfahan Medical School, Isfahan University of Medical Sciences AssistantPprofessor, Psychiatry Department, Medical School, Isfahan University of medical sciences Psychiatrist, Isfahan Cardiovascular research center, Isfahan University of Medical Sciences Abstract Using Glutamate antagonists such as topiramate has been suggested on the basis of glutamate hypothesis for schizophrenia; as its properties encourage its exploration and possible development as a medication for the treatment of schizophrenia. A randomized, double-blind, placebo controlled clinical trial was performed on 18-45 years old schizophrenic patients. Baseline information including vital signs, height, weight, smoking status, demographic characteristics, (past) psychiatric history, medication history and medication-related adverse effects was collected. Patients were randomly assigned to topiramate or placebo group. Efficacy was assessed by administering positive and negative syndrome scale (PANSS), and tolerability was recorded in both groups on days 0 (baseline), 28, and 56. Total PANSS score in topiramate group was 96.87 (85.37-108.37), 85.68 (74.67-96.70) and 76.87 (66.06-87.69) compared with 101.87 (90.37-113.37), 100.31 (89.29-111.32) and 100.56 (89.74-111.37) in placebo group in baseline, 28th and 56th days, respectively (95% confidence interval). General linear Model for repeated measure analysis showed that topiramate has lowered PANSS score significantly (p<0.05). Significant decline pattern was also found in all three PANSS components (negative, positive and psychopathology symptoms) (p<0.05). Topiramate can be an effective medication in controlling schizophrenic symptoms, because of its effect on decreasing negative symptoms and controlling antipsychotic-associated weight gain. Topiramate, schizophrenia, positive and negative syndrome scale, clinical trial 9 2 2 25 Seyed Ghafour Mousavi MD, Psychiatry Department, Isfahan University of Medical Sciences E-mail mousavi@med.mui.ac.ir 1386 $% /85! /0 1 ^