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P.4.033 The new anxiolytic compound ELB139 does not induce physical dependence or tolerance in rats
P4 Anxiety disorders and anxiolytics Treatment of Anxiety Disorders. Journal of clinical psychopharmacology 19(6) supplement(2), 23S-29S.
~ T i m e course effects of donepezil, ziprasidone or both drugs on motor activity, anxiolytic response, and short and long term memories in mice S. Ortiz 1, J.A. Molina 2, M.D. Julian 1, A. Garcia-Martinez 1, C. Aparicio 1, M.A. Oliveras 3, J. Manzanares 1 *. ]Instituto de
Neurociencias de Alicante, Universidad Miguel Hernandez-CSIC, Sant Joan d'Alacant, Spain; 2Hospital Universitario 12 de Octubre, Department of Neurology, Spain; 3Hospital Universitari de Sant Joan, Unidad de Conductas Adictivas, Spain Donepezil is a selective acetylcholinesterase inhibitor widely used to treat mild or moderate impaired cognition in Alzheimer's disease (AD). Patients with AD often undergo pronounced behavioural alterations including apathy/indifference, depression, agitation, irritability/lability and anxiety that deteriorates severely the quality of life. These symptoms are treated with antidepressants, anxiolytics and antipsychotics or a combination of some of these drugs. Ziprasidone is an atypical antipsychotic that acts as an antagonist of serotonin-5-HT2A and dopamine-D2 receptors, interacts with other serotonin receptors (5-HT1A, 5-HT1D, 5-HT2C), and presents moderate affinity to serotonin and norepinephrine reuptake sites. It has also been reported that ziprasidone reverses the learning deficit induced by the glutamate/Nmethyl-D-aspartate receptor antagonist phencyclidine. Although the combination of donepezil and atypical antipsychotics has been widely used in AD patients, there is a lack of preclinical studies examining behavioural effects of simultaneous administration of these drugs. We have examined the time course effects of donepezil, ziprasidone or a combination of both drugs on motor activity, anxiety-like behaviours and short and long term memories. To this aim, male Swiss mice were divided in 3 experiments (each containing 4 experimental groups, [approximately n 10/group]: at 7, 14, 30 days post-treatment, and vehicle at 30 days): 1) donepezil (0.2mg/kg, p.o.); 2) ziprasidone (0.6mg/kg, p.o.) and 3) donepezil÷ziprasidone (same doses as above). On days 7, 14, and 30 after initiation of treatments motor activity (open field test), anxiety (elevated plus maze test) and short and long term memories (step-down inhibitory avoidance test) were evaluated. The results revealed that repeated treatment with donepezil, ziprasidone or the combination of both do not alter, at any time point examined, the motor activity (speed or distance travelled). In contrast, repeated administration with donepezil (30 days) significantly increased (p < 0.001) time in the open arms. Although ziprasidone alone was without effects, at any time point examined, in the elevated plus maze, the simultaneous administration of both drugs induced a significant (p < 0.001) anxiolytic action on days 7, 14 and 30 after initiation of treatments. The time course effects of repeated administration of donepezil revealed significant (p < 0.014) memory impairment after 14 and 30 days of treatment. The administration of ziprasidone significantly worsened memory (p < 0.007) on day 30. In contrast, simultaneous administration of both drugs produced a transient but significant (p < 0.001) learning deficit at day 14 after the treatments but returned to normal values by day 30. In conclusion, the results suggest that low doses of donepezil induced anxiolytic action after 30 days of treatment and impaired
$541
retention at 14 and 30 days. Low doses of ziprasidone do not present anxiolytic action but produced memory impairment on day 30. Interestingly, combination of both drugs produced a synergistic anxiolytic action at all time points. Furthermore, while administration of both drugs impaired learning deficit on day 14, short and long term memories returned to normal values by day 30 suggesting a reversal of this impairment. Taken together, these results suggest synergistic anxiolytic actions as well as amelioration of memory impairment when donepezil and ziprasidone are given simultaneously.
~ T h e
new anxiolytic compound ELB139 does not induce physical dependence or tolerance in rats
R. Dost*, B. Langen, C. Rundfeldt. Elbion AG, Pharmacology, Radebeul, Germany Purpose: Modulating GABAA receptor mediated signalling using the benzodiazepine binding site is a well characterised mechanism for anxiolytic and antiepileptic drug therapy. The new concept of developing subtype selective agonists is to get new pharmaceuticals with the effi-cacy of benzodiazepines but lacking their side effects such as development of tolerance and dependence. ELB139 has recently been shown to bind selectively to the alpha3-containing subtype of GABAA receptors. With ELB139, the potential of such alpha-3-subtype selective compounds to induce tolerance and physical dependence after long-term-treatment should be investigated. Methods: We used a modified design of physical dependence which was firstly described by Hosoya (1979). The rats were treated for five days a week followed by two days withdrawal. The test lasted for 6 weeks. The principle criterion in this model is the loss of body weight after withdrawal of a dependence producing drug. In addition the rats are observed regarding side effects of treatment or symptoms of withdrawal. In parallel we tested the anxiolytic properties of the compound after single treatment and after finishing the dependence study using the elevated maze. As, interestingly, the compound revealed anticonvulsant activity, as well, additionally, another test used for investigation of dependence was the MES threshold test before and after multiple administration of the compound (L6scher et al. 1996). Results: The used reference compound in the first test was codeine (100mg/kg), an opioid receptor agonist which is well known to induce physical dependence in animal models. The codeine-treated rats showed a significant loss of body weight (Two Way Repeated Measure Anova) and typical behavioural symptoms after withdrawal as stated in the literature indicating that the used test design opens up the possibility to show liability to physical dependence. For ELB139 (10 and 30mg/kg twice daily) we found no hints of physical dependence or withdrawal symptoms in this test under the chosen test conditions. The anxiolytic activity of the compound was maintained as could be shown using the elevated maze (One Way Anova). Using the MES threshold test in rats, no reduction in seizure threshold (One Way Anova, unpaired Students t-Test) could be observed after termination of a 10 day repeated treatment with 21 mg/kg ELB139 twice daily, giving hints of a lack of development of dependence in rats in this model. Conclusion: In the present studies we could show, that ELB 139 a new anxiolytic compound does not bear the risk of development of tolerance and dependence in rats in a therapeutic dose range. Currently the compound is tested in Phase II clinical studies for
P4 Anxiety disorders and anxiolytics
$542
anxiety. (Supported by the EU fund for reg. dev. (EFRE) and by the Free State of Saxony, SAB 8093)
References [1] Hosoya, E., 1979. Screening of dependence liability of drugs using rats. Pharmac. Ther. 5, 515 517. [2] L6scher, W., Rundfeldt, C., H6nack, D., Ebert, U., 1996. Long term studies on anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. I. Comparison of diazepam, clonazepam, clobazam and abecarnil. J Pharmacol Exp Ther 279:561 572.
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Treatment of panic disorder with and without agoraphobia
D.S. Baldwin*. University of Southampton, Division of Clinical Neurosciences, Southampton, United Kingdom Evidence-based review of treatment of panic disorder with or without agoraphobia, paying particular attention to the recommendations of recent clinical practice guidelines (Baldwin et al; Bandelow et al; National Institute for Clinical Excellence). Acute treatment: Systematic reviews demonstrate that a range of pharmacological, psychological and combination interventions are effective in panic disorder. Randomised double-blind placebocontrolled trials of antidepressants indicate that all SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline); some TCAs (clomipramine, imipramine); and some benzodiazepines (alprazolam, clonazepam, diazepam and lorazepam) are efficacious in acute treatment. Other antidepressants with proven efficacy include the MAOI brofaromine; the SNRI venlafaxine; and the selective noradrenaline reuptake inhibitor reboxetine. Comparator-controlled studies provide some evidence for efficacy of mirtazapine and moclobemide; suggest that escitalopram is superior to citalopram; and indicate some SSRIs (paroxetine, fluvoxamine) are superior to some noradrenaline reuptake inhibitors (reboxetine, maprotiline). Treatments with unproven efficacy in panic disorder include propranolol, buspirone, antihistamines or antipsychotics. Fixed-dose RCTs with SSRIs provide only limited evidence of a dose-response relationship, for fluoxetine and for paroxetine. Longer-term treatment: Doubleblind studies indicate that continuing SSRI treatment from 12 weeks to 52 weeks is associated with an increase in overall treatment response rates. Placebo-controlled and other relapseprevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (fluoxetine, paroxetine, sertraline, imipramine), compared to switching to placebo for up to six months. Comparative efficacy of psychological, pharmacological, and combination treatments: Pooled analyses and randomised controlled trials indicate that drug and psychological treatments, delivered singly, have broadly similar efficacy in acute treatment, but suggest CBT may be superior to TCAs in preventing symptomatic relapse. Overall, it is uncertain whether combining drug and psychological treatments is associated with greater overall efficacy than with either treatment, given alone. However combination treatment with paroxetine was superior to psychological treatment alone, in studies of bibliotherapy, "very brief" CBT and basic CBT; and buspirone may enhance the short term efficacy of CBT. When initial treatments prove unhelpful: There is no clear evidence for the benefit of dose escalation after an initial non-response to low doses. Switching between treatments with proven efficacy may be helpful. Augmentation of CBT with paroxetine may be superior
to continuing with CBT alone, in patients who did not previously respond over 15 sessions; and augmentation of fluoxetine with pindolol was superior to continued monotherapy with fluoxetine. The addition of group CBT may be beneficial in non-responders to pharmacological approaches. There is only limited evidence for augmentation strategies involving benzodiazepines, mood stabilizers or antipsychotic drugs.
References [1] Baldwin DS, Anderson IM, Nutt DJ, et al., Evidence-based guidelines for treating anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. Submitted for publication. [2] Bandelow B, Zohar J, Hollander E, et al (2002). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171 1999.National Institute for Clinical Excellence (2004). The management of panic disorder and generalised anxiety disorder in primary and secondary care. National Collaborating Centre for Mental Health, London. December 2004.
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Repeated administration of topiramate induces pronounced anxiolytic effects without alterations in body weight and fluid or food consumption in rats
O. Olias 1, C. Forner 1, M.D. Julian 1, C. Aparicio 1, G. Rubio 2, M.A. Oliveras 3, J. Manzanares 1 *. JInstituto de Neurociencias
de Alicante, Universidad Miguel Hernandez-CSIC, Sant Joan d'Alacant, Spain; 2Servicio de Salud Mental del Retiro, Departamento de Psiquiatria, Spain; SHospital Universitari de Sant Joan, Unidad de Conductas Adictivas, Spain Topiramate is an atypical anticonvulsant drug that has shown to be particularly useful to treat psychiatric diseases associated with a high level of compulsivity, like occurs in alcohol dependence, binge eating disorders, pathological gambling, obsessivecompulsive disorder and, when used as an adjuvant, to reduce body weight in obese patients. Topiramate acts via multiple mechanisms, including modulation of voltage dependent sodium and calcium channels, potentiation of the GABAA receptor inhibition and antagonization of the AMPA and kainate glutamate receptors. These actions take place within the therapeutic dose range employed to treat seizures. Although topiramate is being considered in psychiatry as an "anti-compulsive drug", there is lack of information regarding its potential anxiolytic action when no compulsion was previously established before treatment. Furthermore there are scarce pre-clinical studies examining the relationship between scalable dosages (similar regimen of administration used in clinical psychiatry) and potential alterations on water and food consumption. The purpose of this study was to examine the effects of repeated and scalable doses of topiramate on anxiety-like behaviours, on food and water consumption, and on body weight. To this aim, male Wistar rats weighing approximately 200 225 g were divided in three groups (n 9/group): 1) Vehicle (2ml/kg/day, p.o; 25 days;), 2) Topiramate, T1 (3 mg/kg/day p.o. for 7 days, followed by 6 mg/kg/day for other 7 days) and 3) Topiramate, T2 (same as T1, followed by 12 mg/kg/day for other 11 days). The influence of topiramate on anxiety behaviour was examined using the elevated plus maze test. Besides, water intake, food consumption and body weight were measured every three days after initiation of treatments with topiramate, or its vehicle.
~ T i m e course effects of donepezil, ziprasidone or both drugs on motor activity, anxiolytic response, and short and long term memories in mice S. Ortiz 1, J.A. Molina 2, M.D. Julian 1, A. Garcia-Martinez 1, C. Aparicio 1, M.A. Oliveras 3, J. Manzanares 1 *. ]Instituto de
Neurociencias de Alicante, Universidad Miguel Hernandez-CSIC, Sant Joan d'Alacant, Spain; 2Hospital Universitario 12 de Octubre, Department of Neurology, Spain; 3Hospital Universitari de Sant Joan, Unidad de Conductas Adictivas, Spain Donepezil is a selective acetylcholinesterase inhibitor widely used to treat mild or moderate impaired cognition in Alzheimer's disease (AD). Patients with AD often undergo pronounced behavioural alterations including apathy/indifference, depression, agitation, irritability/lability and anxiety that deteriorates severely the quality of life. These symptoms are treated with antidepressants, anxiolytics and antipsychotics or a combination of some of these drugs. Ziprasidone is an atypical antipsychotic that acts as an antagonist of serotonin-5-HT2A and dopamine-D2 receptors, interacts with other serotonin receptors (5-HT1A, 5-HT1D, 5-HT2C), and presents moderate affinity to serotonin and norepinephrine reuptake sites. It has also been reported that ziprasidone reverses the learning deficit induced by the glutamate/Nmethyl-D-aspartate receptor antagonist phencyclidine. Although the combination of donepezil and atypical antipsychotics has been widely used in AD patients, there is a lack of preclinical studies examining behavioural effects of simultaneous administration of these drugs. We have examined the time course effects of donepezil, ziprasidone or a combination of both drugs on motor activity, anxiety-like behaviours and short and long term memories. To this aim, male Swiss mice were divided in 3 experiments (each containing 4 experimental groups, [approximately n 10/group]: at 7, 14, 30 days post-treatment, and vehicle at 30 days): 1) donepezil (0.2mg/kg, p.o.); 2) ziprasidone (0.6mg/kg, p.o.) and 3) donepezil÷ziprasidone (same doses as above). On days 7, 14, and 30 after initiation of treatments motor activity (open field test), anxiety (elevated plus maze test) and short and long term memories (step-down inhibitory avoidance test) were evaluated. The results revealed that repeated treatment with donepezil, ziprasidone or the combination of both do not alter, at any time point examined, the motor activity (speed or distance travelled). In contrast, repeated administration with donepezil (30 days) significantly increased (p < 0.001) time in the open arms. Although ziprasidone alone was without effects, at any time point examined, in the elevated plus maze, the simultaneous administration of both drugs induced a significant (p < 0.001) anxiolytic action on days 7, 14 and 30 after initiation of treatments. The time course effects of repeated administration of donepezil revealed significant (p < 0.014) memory impairment after 14 and 30 days of treatment. The administration of ziprasidone significantly worsened memory (p < 0.007) on day 30. In contrast, simultaneous administration of both drugs produced a transient but significant (p < 0.001) learning deficit at day 14 after the treatments but returned to normal values by day 30. In conclusion, the results suggest that low doses of donepezil induced anxiolytic action after 30 days of treatment and impaired
$541
retention at 14 and 30 days. Low doses of ziprasidone do not present anxiolytic action but produced memory impairment on day 30. Interestingly, combination of both drugs produced a synergistic anxiolytic action at all time points. Furthermore, while administration of both drugs impaired learning deficit on day 14, short and long term memories returned to normal values by day 30 suggesting a reversal of this impairment. Taken together, these results suggest synergistic anxiolytic actions as well as amelioration of memory impairment when donepezil and ziprasidone are given simultaneously.
~ T h e
new anxiolytic compound ELB139 does not induce physical dependence or tolerance in rats
R. Dost*, B. Langen, C. Rundfeldt. Elbion AG, Pharmacology, Radebeul, Germany Purpose: Modulating GABAA receptor mediated signalling using the benzodiazepine binding site is a well characterised mechanism for anxiolytic and antiepileptic drug therapy. The new concept of developing subtype selective agonists is to get new pharmaceuticals with the effi-cacy of benzodiazepines but lacking their side effects such as development of tolerance and dependence. ELB139 has recently been shown to bind selectively to the alpha3-containing subtype of GABAA receptors. With ELB139, the potential of such alpha-3-subtype selective compounds to induce tolerance and physical dependence after long-term-treatment should be investigated. Methods: We used a modified design of physical dependence which was firstly described by Hosoya (1979). The rats were treated for five days a week followed by two days withdrawal. The test lasted for 6 weeks. The principle criterion in this model is the loss of body weight after withdrawal of a dependence producing drug. In addition the rats are observed regarding side effects of treatment or symptoms of withdrawal. In parallel we tested the anxiolytic properties of the compound after single treatment and after finishing the dependence study using the elevated maze. As, interestingly, the compound revealed anticonvulsant activity, as well, additionally, another test used for investigation of dependence was the MES threshold test before and after multiple administration of the compound (L6scher et al. 1996). Results: The used reference compound in the first test was codeine (100mg/kg), an opioid receptor agonist which is well known to induce physical dependence in animal models. The codeine-treated rats showed a significant loss of body weight (Two Way Repeated Measure Anova) and typical behavioural symptoms after withdrawal as stated in the literature indicating that the used test design opens up the possibility to show liability to physical dependence. For ELB139 (10 and 30mg/kg twice daily) we found no hints of physical dependence or withdrawal symptoms in this test under the chosen test conditions. The anxiolytic activity of the compound was maintained as could be shown using the elevated maze (One Way Anova). Using the MES threshold test in rats, no reduction in seizure threshold (One Way Anova, unpaired Students t-Test) could be observed after termination of a 10 day repeated treatment with 21 mg/kg ELB139 twice daily, giving hints of a lack of development of dependence in rats in this model. Conclusion: In the present studies we could show, that ELB 139 a new anxiolytic compound does not bear the risk of development of tolerance and dependence in rats in a therapeutic dose range. Currently the compound is tested in Phase II clinical studies for
P4 Anxiety disorders and anxiolytics
$542
anxiety. (Supported by the EU fund for reg. dev. (EFRE) and by the Free State of Saxony, SAB 8093)
References [1] Hosoya, E., 1979. Screening of dependence liability of drugs using rats. Pharmac. Ther. 5, 515 517. [2] L6scher, W., Rundfeldt, C., H6nack, D., Ebert, U., 1996. Long term studies on anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. I. Comparison of diazepam, clonazepam, clobazam and abecarnil. J Pharmacol Exp Ther 279:561 572.
•
Treatment of panic disorder with and without agoraphobia
D.S. Baldwin*. University of Southampton, Division of Clinical Neurosciences, Southampton, United Kingdom Evidence-based review of treatment of panic disorder with or without agoraphobia, paying particular attention to the recommendations of recent clinical practice guidelines (Baldwin et al; Bandelow et al; National Institute for Clinical Excellence). Acute treatment: Systematic reviews demonstrate that a range of pharmacological, psychological and combination interventions are effective in panic disorder. Randomised double-blind placebocontrolled trials of antidepressants indicate that all SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline); some TCAs (clomipramine, imipramine); and some benzodiazepines (alprazolam, clonazepam, diazepam and lorazepam) are efficacious in acute treatment. Other antidepressants with proven efficacy include the MAOI brofaromine; the SNRI venlafaxine; and the selective noradrenaline reuptake inhibitor reboxetine. Comparator-controlled studies provide some evidence for efficacy of mirtazapine and moclobemide; suggest that escitalopram is superior to citalopram; and indicate some SSRIs (paroxetine, fluvoxamine) are superior to some noradrenaline reuptake inhibitors (reboxetine, maprotiline). Treatments with unproven efficacy in panic disorder include propranolol, buspirone, antihistamines or antipsychotics. Fixed-dose RCTs with SSRIs provide only limited evidence of a dose-response relationship, for fluoxetine and for paroxetine. Longer-term treatment: Doubleblind studies indicate that continuing SSRI treatment from 12 weeks to 52 weeks is associated with an increase in overall treatment response rates. Placebo-controlled and other relapseprevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (fluoxetine, paroxetine, sertraline, imipramine), compared to switching to placebo for up to six months. Comparative efficacy of psychological, pharmacological, and combination treatments: Pooled analyses and randomised controlled trials indicate that drug and psychological treatments, delivered singly, have broadly similar efficacy in acute treatment, but suggest CBT may be superior to TCAs in preventing symptomatic relapse. Overall, it is uncertain whether combining drug and psychological treatments is associated with greater overall efficacy than with either treatment, given alone. However combination treatment with paroxetine was superior to psychological treatment alone, in studies of bibliotherapy, "very brief" CBT and basic CBT; and buspirone may enhance the short term efficacy of CBT. When initial treatments prove unhelpful: There is no clear evidence for the benefit of dose escalation after an initial non-response to low doses. Switching between treatments with proven efficacy may be helpful. Augmentation of CBT with paroxetine may be superior
to continuing with CBT alone, in patients who did not previously respond over 15 sessions; and augmentation of fluoxetine with pindolol was superior to continued monotherapy with fluoxetine. The addition of group CBT may be beneficial in non-responders to pharmacological approaches. There is only limited evidence for augmentation strategies involving benzodiazepines, mood stabilizers or antipsychotic drugs.
References [1] Baldwin DS, Anderson IM, Nutt DJ, et al., Evidence-based guidelines for treating anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. Submitted for publication. [2] Bandelow B, Zohar J, Hollander E, et al (2002). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders. World J Biol Psychiatry 3:171 1999.National Institute for Clinical Excellence (2004). The management of panic disorder and generalised anxiety disorder in primary and secondary care. National Collaborating Centre for Mental Health, London. December 2004.
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Repeated administration of topiramate induces pronounced anxiolytic effects without alterations in body weight and fluid or food consumption in rats
O. Olias 1, C. Forner 1, M.D. Julian 1, C. Aparicio 1, G. Rubio 2, M.A. Oliveras 3, J. Manzanares 1 *. JInstituto de Neurociencias
de Alicante, Universidad Miguel Hernandez-CSIC, Sant Joan d'Alacant, Spain; 2Servicio de Salud Mental del Retiro, Departamento de Psiquiatria, Spain; SHospital Universitari de Sant Joan, Unidad de Conductas Adictivas, Spain Topiramate is an atypical anticonvulsant drug that has shown to be particularly useful to treat psychiatric diseases associated with a high level of compulsivity, like occurs in alcohol dependence, binge eating disorders, pathological gambling, obsessivecompulsive disorder and, when used as an adjuvant, to reduce body weight in obese patients. Topiramate acts via multiple mechanisms, including modulation of voltage dependent sodium and calcium channels, potentiation of the GABAA receptor inhibition and antagonization of the AMPA and kainate glutamate receptors. These actions take place within the therapeutic dose range employed to treat seizures. Although topiramate is being considered in psychiatry as an "anti-compulsive drug", there is lack of information regarding its potential anxiolytic action when no compulsion was previously established before treatment. Furthermore there are scarce pre-clinical studies examining the relationship between scalable dosages (similar regimen of administration used in clinical psychiatry) and potential alterations on water and food consumption. The purpose of this study was to examine the effects of repeated and scalable doses of topiramate on anxiety-like behaviours, on food and water consumption, and on body weight. To this aim, male Wistar rats weighing approximately 200 225 g were divided in three groups (n 9/group): 1) Vehicle (2ml/kg/day, p.o; 25 days;), 2) Topiramate, T1 (3 mg/kg/day p.o. for 7 days, followed by 6 mg/kg/day for other 7 days) and 3) Topiramate, T2 (same as T1, followed by 12 mg/kg/day for other 11 days). The influence of topiramate on anxiety behaviour was examined using the elevated plus maze test. Besides, water intake, food consumption and body weight were measured every three days after initiation of treatments with topiramate, or its vehicle.