Low Dose Tiagabine Effectiveness in Anxiety Disorders
Objective: Gamma-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS, is involved in the pathophysiology of a wide variety of disorders including anxiety. Tiagabine hydrochloride acts as a selective GABA reuptake inhibitor (SGRI).
Method: Consecutive patients were offered tiagabine in 1 mg incremental doses for the treatment of anxiety, primarily generalized anxiety disorder. Individuals failing anxiety treatment with benzodiazapines, selective serotonin reuptake inhibitors, buspirone and/or with a strong family or personal history of substance abuse were allowed trials.
Results: The SGRI tiagabine improved anxiety and was well tolerated by adult patients with generalized anxiety and one with anxiety secondary to acute antidepressant withdrawal. One disinhibition treatment failure is also discussed.
Conclusions: In acute anxiety treatment, very low initial dosing with gradual increases may be sufficient for anxiety effects, when compared to the higher doses of tiagabine used in epilepsy treatment. Tiagabine may be useful in the treatment of generalized anxiety.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the CNS. 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 posttraumatic stress disorder,9 panic disorder,10 and as monotherapy or augmentation therapy for patients with anxiety disorders who are partial responders.11,12
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 and consented to treatment with tiagabine.
Case 1. A 32-year old male with a lifetime history of "shyness" and performance anxiety met the Diagnostic Statistical Manual IV-Text Revision (DSM-IV-TR) 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 three 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 "non-addictive" anti-anxiety agent that was not associated with anorgasmia or other sexual side effects. Tiagabine was initiated at 1 mg qhs, which resulted in a 3-point drop in the BAI score to 18 within one day. After 5 days, the tiagabine dose was increased to 1mg AM and 3 mg qhs, resulting in a 14-point drop in BAI score to 4. At tiagabine 2mg AM and 4 mg qhs, 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 five months.
Case 2. A 57-year-old, post-menopausal female with onset of symptoms of GAD and Attention-Deficit/Hyperactivity Disorder (ADHD) occurring in early elementary school years, met the DSM-IV-TR criteria for both disorders. She had a past history of alcoholism in her 30's. A score of 24 on the BAI and 44 on the Utah Wender Rating (UWR) scale14 were suggestive of a diagnosis of GAD and ADHD, respectively. To address the anxiety, tiagabine was initiated at 1 mg AM and at night. After 3 weeks, the dose of tiagabine was increased to 2 mg AM 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 AM and at lunch was added to manage the ADHD, with no complaints of increased anxiety. The patient's UWR 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 male with a lifetime history of "fairly constant anxiety" met 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 positive family history of addiction. While being tapered off clonazepam (at a rate of 0.25 mg every week), the patient reported a relapse in anxiety (chief complaint of 'nerves') at clonazepam 0.5 mg every 8 hours; his BAI score increased to 18. Tiagabine 1 mg AM and 1 mg qhs was initiated. After 4 weeks, the dose of tiagabine was increased to 3 mg AM and 7 mg qhs, 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 female 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 one to two 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 SSRI withdrawal symptoms, tiagabine was initiated at 2 mg nightly with a snack. Over 5 weeks, tiagabine was increased to 2 mg AM and 6 mg qhs. As a result, her BAI decreased from a baseline score 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 male, with a 7-year history of "nervousness and sensitivity," met 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 AM and gabapentin 100 mg every eight hours, reporting less reactivity and some modest improvement in focus and concentration at school. The patient was then prescribed clonazepam 0.25 mg AM and became disinhibited. Buspirone 5 mg AM and qhs for 7 days also resulted in increased anxiety. A tiagabine trial of 1 mg AM and qhs increased anxiety, by self-report and observations by parent and teachers. Tiagabine was discontinued and the dosage of gabapentin was increased to 300 three times daily with further mood stability. Involvement in a highly individualized public school program was also helpful.
The SGRI tiagabine may be an option in the treatment of anxiety. Tiagabine treatment was well tolerated in the adult patients. These positive case reports of low dose tiagabine suggest a need for further study in the treatment of anxiety disorders.
James L. Schaller, MD, MAR
John Thomas MD, MPH