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Low-Dose Tiagabine Effectiveness in Anxiety Disorders

James L. Schaller, MD, MAR; John Thomas, MD, MPH; David Rawlings, PhD

Medscape General Medicine. 2004;6(3):8.
2004 Medscape
Posted 09/17/2004

Abstract and Introduction

Abstract

Background: Gamma-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter of the central nervous system, is involved in the pathophysiology of a wide variety of disorders, including anxiety. Tiagabine hydrochloride acts as a selective GABA reuptake inhibitor (SGRI). Methods and Results: Consecutive patients were offered tiagabine in 1-mg incremental doses for the treatment of anxiety, primarily generalized anxiety disorder. Individuals failing anxiety treatment with benzodiazepines, selective serotonin reuptake inhibitors, and buspirone, and/or with a strong family or personal history of substance abuse were allowed trials. The SGRI tiagabine improved anxiety and was well tolerated by adult patients with generalized anxiety disorder as well as one patient with anxiety secondary to acute antidepressant withdrawal. One disinhibition treatment failure is also discussed.

Conclusion: In acute anxiety treatment, very low initial dosing with gradual increases may be sufficient for anxiety effects, when compared with the higher doses of tiagabine used in epilepsy treatment. Tiagabine may be useful in the treatment of generalized anxiety disorder.

Introduction

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. Alterations in the GABA system are known to be involved in the pathophysiology of a wide variety of disorders, including anxiety.[1-4] Agents that enhance GABA neurotransmission have been used in the treatment of anxiety.[5-7] Tiagabine hydrochloride increases synaptic GABA availability by blocking the reuptake of GABA via transporter inhibition, thus acting as a selective GABA reuptake inhibitor (SGRI). Tiagabine has shown promise in the treatment of generalized anxiety disorder (GAD),[8] post-traumatic stress disorder,[9] and panic disorder,[10] and as monotherapy or augmentation therapy for patients with anxiety disorders who are partial responders.[11,12]

Case Reports

Of the 5 patients, 4 had GAD and 1 had significant anxiety comorbid with major depressive disorder (MDD). All patients were referrals from primary care physicians and consented to treatment with tiagabine.

Case 1

A 32-year-old man with a lifetime history of "shyness" and performance anxiety met the Diagnostic Statistical Manual of Mental Disorders DSM-IV-TR (Text Revision) criteria for GAD and had a Beck Anxiety Inventory (BAI) score of 21, indicating mild-to-moderate anxiety.[13] The patient was initially treated with buspirone 10 mg 3 times daily for approximately 1 month and experienced increased anxiety, insomnia, restlessness, and mild shortness of breath. When considering optional therapies, he specifically requested a "nonaddictive" antianxiety agent that was not associated with anorgasmia or other sexual side effects. Tiagabine was initiated at 1 mg at bedtime, which resulted in a 3-point drop in the BAI score to 18 within 1 day. After 5 days, the tiagabine dose was increased to 1 mg in the morning and 3 mg at bedtime, resulting in a 14-point drop in his BAI score to 4. At tiagabine 2 mg in the morning and 4 mg at bedtime, the patient reported no symptoms of anxiety and had a normal BAI score of 5. The anxiolytic effect of tiagabine 6 mg/day has been sustained for over 5 months.

Case 2

A 57-year-old, postmenopausal woman with the onset of symptoms of GAD and attention-deficit/hyperactivity disorder (ADHD), occurring in her early elementary school years, met the DSM-IV-TR criteria for both disorders. She had a history of alcoholism in her 30's. A score of 24 on the BAI and 44 on the Wender Utah Rating (WUR) scale[14] were suggestive of a diagnosis of GAD and ADHD, respectively. To address the anxiety, tiagabine was initiated at 1 mg in the morning and at night. After 3 weeks, the dose of tiagabine was increased to 2 mg in the morning and 6 mg at night, and the patient's BAI score decreased to 3. With the anxiety effectively controlled with tiagabine, methylphenidate 7.5 mg in the morning and at lunch was added to manage the ADHD, with no complaints of increased anxiety. The patient's WUR score decreased to 19. At a 3-month follow-up, the patient had not experienced any anxiety symptoms while continuing treatment with tiagabine 8 mg/day.

Case 3

A 46-year-old man with a lifetime history of "fairly constant anxiety" met the DSM-IV-TR criteria for GAD. The patient had been previously treated with paroxetine (maximum dose, 20 mg/day), which caused sedation and moderate anorgasmia. Clonazepam was initiated at 1 mg every 8 hours. The patient reported an improvement in anxiety and had a BAI score of 2. However, the patient wanted to discontinue clonazepam treatment due to a positive family history of addiction. Although he was tapered off clonazepam (at a rate of .25 mg every week), the patient reported a relapse in anxiety (chief complaint of "nerves") at clonazepam .5 mg every 8 hours; his BAI score increased to 18. Tiagabine 1 mg in the morning and 1 mg at bedtime was initiated. After 4 weeks, the dose of tiagabine was increased to 3 mg in the morning and 7 mg at bedtime; the patient no longer complained of anxiety at this dose, and his BAI score had decreased to 4. Currently, the patient has been in remission for 14 weeks while receiving tiagabine monotherapy at 10 mg/day and reports feelings of being rested and calm, similar to those experienced with clonazepam.

Case 4

A 58-year-old woman who met the criteria for ADHD and had a 15-year history of MDD achieved full remission of depressive symptoms with paroxetine 40 mg/day. However, the patient would regularly miss 1 to 2 doses per week (due to unfocused nature and ADHD symptoms) and experience intermittent mild anxiety, myalgia, nausea, headache, crying, and diarrhea. To improve the daily anxiety associated with selective serotonin reuptake inhibitor (SSRI) withdrawal symptoms, tiagabine was initiated at 2 mg nightly with a snack. Over 5 weeks, tiagabine was increased to 2 mg in the morning and 6 mg at bedtime. As a result, her BAI score decreased from a baseline of 13 to 1. Curiously, the patient reported 85% improvement of SSRI withdrawal symptoms with treatment of tiagabine 8 mg/day. No explanation can be offered for this observation. Tiagabine may reduce antidepressant withdrawal.

Case 5

A 15-year-old boy, with a 7-year history of "nervousness and sensitivity," met the criteria for GAD and ADHD. He also has significant central auditory processing deficits and a reading disability, as determined by auditory, psychological, and neuropsychological testing. He worried a great deal about his single mother and was socially reactive if "overwhelmed." The patient was initially treated with methylphenidate 5 mg twice daily; however, he became more anxious. A similar reaction developed with sertraline 12.5 mg for 4 days, and thus treatment was discontinued. He was partially responsive to selegiline 5 mg in the morning and gabapentin 100 mg every 8 hours, reporting less reactivity and some modest improvement in focus and concentration at school. The patient was then prescribed clonazepam .25 mg in the morning and became disinhibited. Buspirone 5 mg in the morning and at bedtime for 7 days also resulted in increased anxiety.A tiagabine trial of 1 mg in the morning and at bedtime increased anxiety, by self-report and observations by parent and teachers. Tiagabine was discontinued, and the dosage of gabapentin was increased to 300 mg 3 times daily with further mood stability. Involvement in a highly individualized public school program was also helpful.

Follow-up Evaluation

Since the initial draft of these cases, a number of findings have occurred of clinical utility. We have treated over 150 patients with tiagabine for anxiety disorders. In contrast to the short-term cases discussed above, rarely do the clinically effective doses remain in the 2-12-mg range after 6 months. Our common treatment range is 20-46 per day in those treated for various anxiety disorders over 6 months. Typically, one fourth of the daily dose is given in the morning with food and three fourths at night.The most common side effects are related to 2 factors. First, patients complain of nausea, rapid sedation, and occasionally headaches if medicated with empty stomachs. Dosing with food typically removes these complaints. Further, dose increases over 1-2 mg per 3-5 days are occasionally associated with nausea, sedation, and headaches. Slow-dose increases reduce these complaints. However, in those receiving over 16 mg/day, most individuals are able to tolerate 4-mg increases per week.

Finally, we explored the issue of contraindications and toxicity with tiagabine. In a PubMed review searching "tiagabine" with "contraindication" and "contraindications," no applicable articles are found. Nevertheless, tiagabine is contraindicated if patients have hypersensitivity reactions. An additional search under "tiagabine" and "toxicity" suggested that tiagabine may be less pathologic to astrocytes and neuronal tissue than some other neuropsychiatric medications. Specifically, at higher concentrations tiagabine, along with gabapentin and lamotrigine, seem to be better tolerated than carbamazepine, topiramate, and oxcarbazepine in rat astrocytes.[15] Further, tiagabine does not precipitate any significant neurotoxicity and does not appear to accumulate in the retina, in contrast to long-term vigabatrin treatment.[16] Also, tiagabine, at the usual recommended doses, does not induce rat DNA fragmentation unless raised to very high concentrations.[17]

Conclusion

The SGRI tiagabine may be an option in the treatment of anxiety. Tiagabine treatment was well tolerated in the adult patients. Conclusions from these positive case reports should be guarded due to the limited patient number and the use of only low-dose tiagabine. Larger studies tailored to specific subtypes of anxiety with a double-blind placebo control, extended over 6 months, would advance understanding of tiagabine's clinical utility. We would consider the use of a benzodiazepine arm in these studies as critical in determining tiagabine's relevance in clinical treatment decisions for anxiety disorders.

References

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James L. Schaller, MD, MAR, Director, Professional Medical Services of Naples, Naples, Florida

John Thomas, MD, MPH, Medical Director, Life Counseling Services, Paoli, Pennsylvania; Affiliate, Horsham Clinic, Ambler, Pennsylvania

David Rawlings, PhD, Neuropsychology Consultants, Naples, Florida; Staff Psychologist, Naples Community Hospital, Naples, Florida

Disclosure: James L. Schaller, MD, MAR, has disclosed that he has received an unrestricted educational grant from Cephalon. He has also received past grants from Zeneca, AstraZeneca, Forrest, and Nutraceutical Sciences Institute.

Disclosure: John Thomas, MD, MPH, has disclosed that he is a speaker for Eli Lily, GlaxoSmithKline, McNeil, and Forrest.

Disclosure: David Rawlings, PhD, has no significant financial interests or relationships to disclose.


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