Dose Of Tiagabine Research Articles

Imaging the “GABA Shift” in Schizophrenia

A core pathology in schizophrenia is the imbalance in inhibition and excitation in cortical circuits related to alterations in the inhibitory neurotransmitter g-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate, resulting in suboptimal synchronization of neural circuits needed for cognitive function (1). Postmortem studies have provided definitive evidence for abnormal GABA-related parameters in schizophrenia, which are thought to reflect deficits inGABAtransmission,eitherasaprimaryorasecondary adjustment to alterations in glutamate.MRspectroscopy (MRS) measurements have provided discrepant results, indicating the possible effects of antipsychotic medications, as well as age, illness phase, and use of anticonvulsants, on measurements of GABA (2). One limitation of this literature is the absence of in vivo measures of GABA transmission in the vicinity of the synapse, which can only be provided by molecular positron emission tomography (PET) imaging. The ambitious study that Frankle and colleagues report in this issue (3) is an important first step in addressing this deficiency. Frankle et al. combined a few technical maneuvers to obtain their novelmeasureof in vivoperisynapticGABA tone. They used PET radiotracer imaging of the benzodiazepine site on the ionotropic GABAA receptor, with the radiotracer [C]flumazenil, which binds to all alpha subunit-containing GABAAreceptors, thustargetingsynapticaswellasextrasynaptic sites corresponding to the locationof theseGABAAreceptors (4). They combined imagingwith a pharmacological challenge using tiagabine, an inhibitor of the GABA transporter GAT1, to raise GABA levels acutely in the brain in areas where GAT1 is distributed, which include neuronal and glial sites. By imaging the benzodiazepine receptor before and after this intervention, the authorswere able to indirectly assess themagnitudeof change in GABA levels. The change in GABA tone induces a positive allosteric effect on the binding of the radiotracer to the benzodiazepine receptor, called the “GABA shift,” by enhancing the affinity of the receptor, measured here in the postchallenge conditionwithanincreaseinthedistributionvolume(VT)of[ C] flumazenil. Themagnitude of increase inVT (DVT) is an indirect index of the availability of synaptic GABA neurotransmission in the vicinity of the benzodiazepine receptor. This positive modulation suggests that [C]flumazenil may be acting in vivo as a partial agonist in this study. Negative modulation has been reported for inverse agonists. The authors provided validation for this method in earlier work by showing a relationship between GAT1 inhibition, achieved by administering different doses of tiagabine, and increases in GABA levels (5, 6). As opposed toMRSmeasures of GABA, which report on whole-tissue GABA levels, this method is unique in providing measures of GABA in the synaptic space. This is a great advance in the use of PET imaging to probeneurotransmission, and thefirst such report for the GABA-ergic system in schizophrenia. In this study, tiagabine produced a detectable and statistically significant effect in healthy control subjects and in patients with schizophrenia who had past exposure to antipsychotics but were currently antipsychotic free, but not in antipsychotic-naivepatients.Furthermore, antipsychotic-naive patients showed higher baseline VT compared with the other two groups. The authors conclude that low levels of GABA lead to blunting of the effect of tiagabine in antipsychotic-naive patients and to up-regulation of receptors as a potential compensatorymechanism.DVTwas related to gamma power inhealthycontrolsubjects but not in patients. Furthermore, antipsychoticnaive subjects showed a positive relationship between baseline VT and gamma power, indicating that up-regulation of benzodiazepine sites may be compensating to somedegree for the deficits in gammapower but not to the extent of improving cognition in general. The interpretation of the findings offered by the authors may seem, on the surface, to conflict with the concept of GABA shift onwhich this PETmethod is based, inwhich low GABA levels should lower affinity of the receptor for the tracer and result in low baseline VT. However, it is likely that while the affinity may decrease acutely, chronically the receptordensitywould increase, and thecombinationof change in affinity and density could lead to an overall increase in binding of the tracer at baseline. This up-regulation suggests that the GABAA receptor density is also increased, since the benzodiazepine receptor is a site on the GABAA receptor. This first report warrants cautious optimism. Caution is needed because of the relatively small sizes of the patient groups (eight antipsychotic-naive and nine antipsychoticfree patients). Differences between antipsychotic-free and antipsychotic-naive patients here may be a sampling artifact and not necessarily related to priormedication status per se, especially in the absence of a clear relationship between The authors conclude that low levels of GABA lead to blunting of the effect of tiagabine in antipsychoticnaive patients and to upregulation of receptors as a potential compensatory mechanism.

Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus.

Glutamate and γ-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA.

Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.

Tiagabine in clinical practice: effects on seizure control and behavior

ObjectivePreapproval randomized controlled trials of antiepileptic drugs provide data in limited patient groups. We assessed the side effect and seizure reduction profile of tiagabine (TGB) in typical clinical practice. MethodsInvestigators recorded adverse effect (AE), seizure, and assessment-of-benefit data prospectively in sequential patients treated open label with TGB. ResultsTwo hundred ninety-two patients (39 children) were enrolled to be treated long term with TGB. Seizure types were focal-onset (86%), generalized-onset (12%), both focal- and generalized-onset (0.3%), and multiple associated with Lennox–Gastaut Syndrome (2%). Two hundred thirty-one received at least one dose of TGB (median=28mg/day) and had follow-up seizure or AE data reported. Common AEs were fatigue, dizziness, psychomotor slowing, ataxia, gastrointestinal upset, weight change, insomnia, and “others” (mostly behavioral). Serious AEs occurred in 19 patients: behavioral effects (n=12), status epilepticus (n=3), others (n=3), and sudden unexplained death (n=1). No patients experienced suicidal ideation/behavior, rash, nephrolithiasis, or organ failure. Seizure outcomes were seizure freedom (5%), ≥75% reduction (12%), ≥50% reduction (23%), and increased number of seizures (17%), or new seizure type (1%). ConclusionsBehavioral AEs occurred in a larger proportion of patients compared to those reported in TGB preapproval randomized controlled trials. A moderate percentage of patients had a meaningful reduction in seizure frequency. In clinical practice, TGB remains a useful antiepileptic drug.

11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [11C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [11C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [11C]flumazenil VT in Group II in association cortices (6.8±0.8 mL g−1 vs. 7.3±0.4 mL g−1;p = 0.03), sensory cortices (6.7±0.8 mL g−1 vs. 7.3±0.5 mL g−1;p = 0.02) and limbic regions (5.2±0.6 mL g−1 vs. 5.7±0.3 mL g−1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [11C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC

BackgroundThe involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures. MethodsEight cannabis users learned to discriminate 30mg oral Δ9-THC from placebo and then received tiagabine (6 and 12mg), Δ9-THC (5, 15 and 30mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. ResultsΔ9-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on other outcomes. ConclusionsThese results indicate that GABA is involved in the clinical effects of Δ9-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids.

Tiagabine in Adult Patients With Generalized Anxiety Disorder

The objective of these studies was to evaluate the efficacy and tolerability of tiagabine, a selective gamma-aminobutyric acid reuptake inhibitor, in adult patients with generalized anxiety disorder (GAD). Patients with a diagnosis of GAD were enrolled in 1 of 3 randomized, placebo-controlled, 10-week studies. In each study, tiagabine was taken twice daily in divided doses--4, 8, or 12 mg/d in a fixed-dose study and 4-16 mg/d in two flexible-dose trials. The primary efficacy measure was the change from baseline in the 14-item Hamilton Rating Scale for Anxiety (HAM-A) total score at the final visit (last observation carried forward). Additional measures included change from baseline in the anxiety subscale of the Hospital Anxiety and Depression Scale, the Sheehan Disability Scale, and Clinical Global Impressions-Improvement scale. Tolerability was assessed via spontaneous reports as well as rating scales throughout the study period. In all 3 studies, there was no significant differentiation from placebo on the primary measure (change in HAM-A) for any tiagabine dose (P > 0.05). In the 2 flexible-dose studies, the tiagabine group showed improvements over time in the HAM-A that reached significance only in those patients who completed 10 weeks of treatment (study 2, P = 0.018; study 3, P = 0.036). The most common adverse events were dizziness, headache, nausea, fatigue, and somnolence. In conclusion, the results of these studies do not support the efficacy of tiagabine in adult patients with GAD.

Effects of acute tiagabine administration on aggressive responses of adult male parolees

Experimental and clinical studies have supported a relationship between gamma-aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary-reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli.

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions in mice

Numerous studies have implicated prostaglandins as potential modulators in seizure activity. The objective of the present study was to elucidate the effect of rofecoxib (selective COX-2 inhibitor) alone or in combination with newer antiepileptic drug tiagabine (gamma-amino acid reuptake inhibitor) against pentylenetetrazol (PTZ) (80 mg/kg, i.p.)-induced chemoconvulsions in mice. Rofecoxib or tiagabine was administered 45 min prior to the PTZ challenge. In combination study, rofecoxib was administered 10 min before tiagabine and after 35 min the animals were challenged with convulsive dose of PTZ. Mean onset time of jerks, clonus and extensor phases following PTZ challenge was noted. Pretreatment with rofecoxib (1-5.0 mg/kg, i.p.) or tiagabine (1-10 mg/kg, i.p.) dose dependently protected the animals against PTZ-induced convulsions. The mean onset time of jerks, clonus and extensor phase were increased. A subeffective dose of rofecoxib (0.5 mg/kg, i.p.) potentiated the effect of subprotective dose of tiagabine (0.5 mg/kg, i.p.). The results of the present study suggested that the protective effect of rofecoxib, a COX-2 inhibitor against PTZ-induced convulsions may be possibly through the GABAergic modulation. Rofecoxib may have a place as adjuvant therapy with standard antiepileptic drugs such as tiagabine in the treatment of epilepsy.

Tiagabine Increases Slow-Wave Sleep in a Dose-Dependent Fashion Without Affecting Traditional Efficacy Measures in Adults With Primary Insomnia

This study evaluated dose-response effects of tiagabine on sleep in adults with primary insomnia. Men and women with primary insomnia (DSM-IV-TR) were randomly assigned to receive tiagabine 4, 6, 8, 10 mg or placebo in a randomized, double-blind, parallel-group study. Efficacy was assessed using polysomnography and self-report measures. Safety analyses included measures of residual sedation and adverse events. A total of 232 patients (31% men; mean age 44.3 years) received study drug. No significant differences were observed between tiagabine and placebo in wake after sleep onset, latency to persistent sleep, or total sleep time. Significantly greater increases from baseline in slow-wave sleep (stages 3 and 4) were found with the 3 highest doses of tiagabine compared with placebo (p < .01). Stage 1 sleep showed a significantly greater decrease from baseline for all doses of tiagabine than for placebo (p < .01). Self-report measures of sleep and daytime function did not differ from placebo, except for poorer ratings on the 10-mg dose. Similarly, psychomotor performance on the 10-mg dose was worsened compared with placebo. Tiagabine was generally well tolerated; dizziness and nausea were the most common adverse events, particularly at the 2 higher doses. In adults with primary insomnia, tiagabine significantly increased slow-wave sleep in a dose-dependent manner with a corresponding significant decrease in Stage 1 sleep, whereas no significant differences were observed in wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo.

An Open-label Study of Tiagabine as Augmentation Therapy for Anxiety

At least 50% of patients with anxiety disorders experience only partial response to pharmacotherapy and require augmentation therapy. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, and agents that modulate GABA neurotransmission have shown promise in the treatment of anxiety disorders and are often used as augmentation agents. This study evaluated tiagabine, a selective GABA reuptake inhibitor (SGRI), as augmentation therapy. This 8-week, open-label study enrolled patients who remained symptomatic despite adequate drug trials for treatment of anxiety symptoms. Tiagabine augmentation therapy was initiated at 4 mg/d (taken in 2 doses; one in the morning with breakfast and one in the evening with a snack) for 2 days and increased to 8 mg/d for 10 days. Dose was then adjusted according to efficacy/tolerability in increments of 2 mg every 3 days up to a maximum of 20 mg/d. Effect was assessed using the Hamilton Rating Scale for Anxiety (HAM-A), Beck Anxiety Inventory (BAI), Clinical Global Impression (CGI) scale, Pittsburgh Sleep Quality Index (PSQI), and 36-item Short-Form Health Survey (SF-36). Of the 18 patients enrolled, 17 were included in the efficacy analysis; one withdrew due to an adverse event prior to post-baseline assessment. Mean final dose of tiagabine was 13 mg/d. Tiagabine as augmentation therapy further reduced anxiety symptoms, as shown by significant decreases in mean HAM-A total and BAI scores at Week 8 (P<0.001). Thirteen patients (76%) responded (> or =50% reduction in HAM-A total score), and 10 patients (59%) achieved remission (HAM-A total score < or =7) at Week 8. Tiagabine improved sleep quality, with a significant reduction seen in PSQI global score at Week 8 (P=.001). Augmentation therapy with tiagabine was generally well tolerated. These preliminary findings suggest that the SGRI tiagabine may be an effective and generally well tolerated augmentation therapy in patients with anxiety who remain symptomatic despite adequate drug trials for treatment of anxiety symptoms.

Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers

Preclinical studies suggest that medications enhancing the brain gamma amino butyric acid (GABA) system attenuate the rewarding effects of stimulants including nicotine. These preclinical studies have not been followed up in systematic human studies. This study was conducted to examine the effects of a GABAergic medication, tiagabine, on acute physiological and subjective effects of intravenous (i.v.) nicotine and on tobacco withdrawal symptoms in overnight abstinent smokers. The proposed mechanism of action for tiagabine is selective inhibition of GABA transporter type I, which leads to increases in synaptic GABA levels. Eight male and four female smokers participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, participants were treated orally with a single 4- or 8-mg dose of tiagabine or placebo. Two hours following the medication treatment, participants received i.v. saline, followed 30 min later by 1.5 mg/70 kg i.v. nicotine. Tiagabine treatment did not affect the heart rate or blood pressure changes induced by nicotine. There was a significant treatment effect for the subjective responses to nicotine, such that tiagabine, compared to placebo, attenuated the ratings of "good effects" and "drug liking." Tiagabine treatment at 8 mg attenuated the craving for cigarettes and enhanced the cognitive performance in the Classical Stoop Tests, compared to placebo or 4 mg tiagabine condition. These results suggest that GABA enhancing medication tiagabine may reduce the rewarding effects of nicotine and improve cognitive performance in abstinent smokers. The utility of GABA medications for smoking cessation needs to be examined further in controlled clinical trials.

Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans

Drugs affecting central γ-aminobutyric acid (GABA) systems may have promise as treatments for cocaine addiction. In the present study, tiagabine (Gabatril ®), a GABA reuptake inhibitor, was investigated for its ability to modify the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of cocaine–tiagabine combinations. A higher dose of tiagabine (8 mg) was then tested in a larger group ( n = 6). Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0–150 mg, p.o.) administered alone and in combination with tiagabine were then determined. Subject-rated, performance and cardiovascular measures were obtained at regular intervals. The reinforcing effects of cocaine, tiagabine and cocaine–tiagabine combinations were assessed using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate). In general, acute administration of tiagabine did not alter the effects of oral cocaine. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects.

Novel therapeutic agents: A study to assess the maximum tolerated dose of tiagabine in patients with painful diabetic polyneuropathy

Novel therapeutic agents: A study to assess the maximum tolerated dose of tiagabine in patients with painful diabetic polyneuropathy

P.1.005 The serum cytokines and nutritional status after antidepressant treatment in hemodialysis patients

Background: Tiagabine (Gabitril) is a GABA uptake inhibitor recently introduced in the United States as an adjunctive treatment for partial complex seizures. Three published studies have addressed the use of tiagabine for bipolar disorder (BPD); two described positive results and one negative results. We assessed the efficacy of add-on tiagabine in a larger sample of adult BPD outpatients. Methods: Twenty-two adult outpatients with DSM-IV diagnosed BPD of some type who were considered unsatisfactory responders to standard medications for BPD were treated in an open fashion with adjunctive tiagabine in a low-dose range. After baseline demographic data and mood state at the time of entry were documented, each patient was monitored clinically for at least 6 months while the dose of tiagabine was adjusted according to the patient’s clinical status. The subjects were rated using the clinical global impression-bipolar version scale (CGI-BP). Results: After 6 months, eight (36%) of the patients were responders to tiagabine by CGI-BP rating. The dose range of tiagabine for responders was 1–8 mg per day. All 14 nonresponders had to discontinue tiagabine because of unacceptable but reversible side effects; one nonresponder experienced breakthrough absence seizures. Limitations: This study was performed in a nonrandom, open naturalistic clinical setting. The sample size was small. Conclusions: Low-dose tiagabine appears to have mood-stabilizing and antimanic properties as an add-on medication for some adult outpatients who have BPD refractory to standard medications. Tiagabine appears to be safe for most adult BPD outpatients. The results of this preliminary open study await confirmation by double-blind controlled studies.

Poster 103: Small case series of gabitril (tiagabine) for prophylaxis of chronic daily headache with migrainous features.

Objective: To investigate whether gabitril (Tiagabine) is effective in the prophylaxis of chronic daily headaches and migraine headaches. Design: Retrospective chart review analyzing the reports of headache before and after the administration of Tiagabine. Setting: Outpatient pain clinic. Participants: 5 patients with chronic daily headache with migrainous features. Intervention: Patients were treated with an initial dose of Tiagabine at 2mg/d for the first week and their dosages were increased by up to 14mg/d. Main Outcome Measures: A visual analog scale (VAS) was used to measure the intensity of the headaches before and after treatment with Tiagabine. The number of days with headaches before and after treatment with Tiagabine were reported. Also, the number of hours with headache before and after treatment were noted. Adverse side effects were also included. Results: Using a paired t test, the pretest VAS mean was 7.7 and the posttest mean was 4.4 on a scale from 0 to 10 ( t 4=2.703, P=.054), with 10 representing the most severe pain. The mean dose of Tiagabine for all patients was 5.1mg/d. The mean number of headache days per month decreased from 21.6/28 days to 11.2/28 days. The mean duration of the headache attack decreased in 2 of the 5 patients. Adverse events were reported by 2 of the 5 patients, which included dizziness during titration, abdominal pain, and easy bruising. Conclusions: Tiagabine may be useful to treat chronic daily headaches with migrainous features. Because of the small number of patients and wide variation in ratings, statistical significance was not obtained. With a larger sample, statistical significance would have been more likely. Further studies are needed with larger sample sizes to clarify the significance of using Tiagabine for the prophylactic treatment of chronic daily headaches.

Clinical and EEG findings in six patients with altered mental status receiving tiagabine therapy

Tiagabine (TGB), a novel GABA reuptake inhibitor antiepileptic drug, has been reported to induce nonconvulsive status epilepticus (NCSE) in patients with generalized or partial onset seizures. We describe six patients with refractory partial epilepsy treated with add-on TGB. They developed acute intermittent or progressive chronic confusion associated with diffuse slowing of the electroencephalogram (EEG), shortly after an increase in dose of TGB. This remitted in each situation after reduction of the daily dose. The possibility of nonconvulsive status epilepticus or toxic encephalopathy is discussed.

Tolerability of tiagabine: a prospective open‐label study

ABSTRACT Tiagabine was used as add‐on therapy in the treatment of epilepsy with partial and/or secondarily generalised seizures to evaluate tolerability and efficacy. Five hundred and seventy‐four patients (299 men and 275 women, mean age 38.1 years), with refractory partial seizures, were enrolled in this prospective, open‐label study. Tiagabine was added to one (44.1%) or more (up to nine) antiepileptic drugs. The median daily dose of tiagabine was 30 mg (mean 29.1, SD 12.0). The mean duration of follow‐up was 94.9 ± 42.7 days. 12.3% of patients were completely seizure‐free at the end of the observation period. Median total seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. Adverse events occurred in 78 patients (13.6%). Tiagabine proved to be a well‐tolerated AED.

An open case series on the utility of tiagabine as an augmentation in refractory bipolar outpatients

Background: Tiagabine (Gabitril) is a GABA uptake inhibitor recently introduced in the United States as an adjunctive treatment for partial complex seizures. Three published studies have addressed the use of tiagabine for bipolar disorder (BPD); two described positive results and one negative results. We assessed the efficacy of add-on tiagabine in a larger sample of adult BPD outpatients. Methods: Twenty-two adult outpatients with DSM-IV diagnosed BPD of some type who were considered unsatisfactory responders to standard medications for BPD were treated in an open fashion with adjunctive tiagabine in a low-dose range. After baseline demographic data and mood state at the time of entry were documented, each patient was monitored clinically for at least 6 months while the dose of tiagabine was adjusted according to the patient’s clinical status. The subjects were rated using the clinical global impression-bipolar version scale (CGI-BP). Results: After 6 months, eight (36%) of the patients were responders to tiagabine by CGI-BP rating. The dose range of tiagabine for responders was 1–8 mg per day. All 14 nonresponders had to discontinue tiagabine because of unacceptable but reversible side effects; one nonresponder experienced breakthrough absence seizures. Limitations: This study was performed in a nonrandom, open naturalistic clinical setting. The sample size was small. Conclusions: Low-dose tiagabine appears to have mood-stabilizing and antimanic properties as an add-on medication for some adult outpatients who have BPD refractory to standard medications. Tiagabine appears to be safe for most adult BPD outpatients. The results of this preliminary open study await confirmation by double-blind controlled studies.

Neuroprotective effect of tiagabine in transient forebrain global ischemia: an in vivo microdialysis, behavioral, and histological study

The neuroprotective effect of tiagabine was investigated in global ischemia in gerbils. Two groups of the animals received 15 mg/kg of tiagabine 30 min before ischemia. In the first group, the temperature was controlled at 37 °C from time of injection to 1 h after ischemia. In the second group, the temperature was left uncontrolled to see the hypothermic effect of tiagabine. Microdialysis was performed in CA1 region of hippocampus in half of the animals in each group to assess the levels of glutamate and γ-amino-butyric acid (GABA). Animal behavior was also tested in 28-day groups in a radial-arm maze. Histology was done 7 and 28 days after ischemia in CA1 region of hippocampus to assess early and delayed effect of drug. A significant suppression of glutamate was noted in both groups ( P<0.01). Behavioral results showed that in the temperature-uncontrolled treatment group, animals significantly reduced their working memory errors as compared to the temperature-controlled treatment group. Histology revealed a significant neuroprotection ( P<0.001) in the temperature-uncontrolled treatment group. In the temperature-controlled treatment group, however, neuroprotection was insignificant ( P>0.05). A third group of animals received the same dose of tiagabine 3 h after ischemia. Temperature was not controlled in this group. The animals were sacrificed after 7 days so no behavior testing was carried out. Histology showed no neuroprotection in this group ( P>0.05). These results show that tiagabine offers a significant neuroprotection in global ischemia in gerbils when given 30 min before ischemia but not when given 3 h after ischemia.