THE ROLE OF GABA IN THE PATHOGENESIS AND TREATMENT OF ANXIETY AND OTHER NEUROPSYCHIATRIC DISORDERS
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In preclinical studies, gabapentin was shown to have anxiolytic effects
similar to those of diazepam, but did not produce the memory-impairing
effects of the latter drug.21 Gabapentin has also been shown to be beneficial in clinical studies of patients with panic disorder
(PD),20 social phobia (SP),18 obsessive-compulsive disorder(OCD),23 and PTSD.24
In a randomized, double-blind, placebo-controlled, parallel-group study, 69 patients with SP were randomly assigned to gabapentin or placebo for
14 weeks.19 A significant reduction (p < 0.05) in the symptoms of SP were seen in patients on gabapentin compared
with placebo. The adverse events reported were consistent
with the known side-effect profile of gabapentin.
Various case reports have appeared in which gabapentin has
been reportedly useful in PTSD22 and refractory PD, OCD,
and GAD.26 One case report described 18 patients with a
variety of serious psychiatric illnesses and comorbid anxiety
disorders. Gabapentin was administered for up to 38 months.25
Fifteen patients were treated for at least 12 months.
The authors found that the anxiolytic effects of gabapentin
were sustained over several months in most patients, with no
evidence of tolerance or physical dependence after abrupt
discontinuation. In these 18 patients, the most common
adverse effects were drowsiness and dizziness during initiation
of treatment. This is consistent with the literature, which indicates
that gabapentin is generally well tolerated; the most common adverse
effects include somnolence, dizziness, ataxia, fatigue, and weight gain.27
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Tiagabine potentiates CNS GABAergic function through its unique
ability to inhibit GABA reuptake at the GAT-1 GABA transporter.
Tiagabine is the only currently available selective GABA-reuptake
inhibitor (SGRI). Tiagabine increases the amount of available extracellular GABA by up to 200%,28 without perturbing normal physiologic control and without increasing total brain GABA. Some researchers have speculated that this unique mechanism of action may result in fewer adverse effects compared with other GABA-enhancing mechanisms.14,29 Tiagabine has been investigated in open-label clinical studies of a variety of CNS disorders in which GABA may play a role, including migraine,30 sleep disorders,31 postherpetic neuralgia, diabetic neuropathy,32 and tardive dyskinesia.33
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Preclinical studies also suggest potential usefulness in models of anxiety,14,34 spasticity,35 and neuroprotection
against ischemia-induced cell loss.36 Tiagabine is generally well tolerated. Adverse effects include dizziness, fatigue, somnolence, tremor, cognitive slowing, nausea, and abdominal pain.
A conclusive demonstration of the clinical utility of tiagabine and other GAT-1 agents with GABAergic-potentiating properties which provide
anxiolytic efficacy comparable to benzodiazepines but without the liability of physiological dependence or withdrawal would represent a significant advance in treatment of anxiety disorders.
Finally, case reports of patients with severe psychiatric disorders
reported clear benefits from the addition of tiagabine.37
In one patient, with schizoaffective disorder (manic type) tiagabine 8 mg daily was added as an adjunct to paroxetine and olanzapine. The adjunctive tiagabine successfully controlled paranoid features that appeared when the patient stopped taking lamotrigine. Two other patients in this case report and two patients in another report presented with severe, uncontrolled mania (mixed mania, with and without mood-congruent psychosis in the second report) were reported to benefit from the addition of tiagabine to ongoing mood stabilizer and antidepressant
treatment. Tiagabine treatment was followed by complete remission of bipolar symptoms.33,38 One patient began to experience a manic episode at 3 mg/day tiagabine, but these symptoms resolved after the dose was raised to 4 mg/day.
A small-scale European trial evaluated the use of tiagabine in eight patients with acute mania.39 The patients received higher initial doses (20 mg daily) and a more rapid titration than is typically employed (5 mg per day until limiting side effects occurred or 40 mg daily is reached). Three patients with moderate mania showed
slight improvements, but none of the patients with severe
mania showed a clear benefit. The authors suggested that
tiagabine may not be effective as acute therapy for mania,
but recommended further research on the drug as a mood
stabilizer.
Three major mood stabilizers, lithium, carbamazepine, and valproate,
share GABAergic effects (at GABA-B receptors and/or on GABA
turnover) as one possible common mechanism for mood stabilization.
The GABAergic activity of valproate is believed to be an important
mechanism underlying both its anticonvulsive and mood-stabilizing effects.40 Recent work conducted at Yale University (not yet published) suggests that unipolar patients have mean plasma GABA levels that are only 50% of those of normal volunteers; these rise to 100% with
SSRI treatment. They also reported that depressed bipolar patients, in
contrast to non-bipolar depressives, have near-normal GABA levels,
which become significantly higher than normal as clinical improvement
occurs.
TAK noted that two of the main mood stabilizers, lithium and carbamazepine, are ineffective as anxiolytics, suggesting that therapeutic actions unrelated to GABA are important for these agents. There is a relatively high prevalence of comorbid anxiety disorders in patients with bipolar disorder. Thus, agents that provide a combination of anxiolysis and mood stabilization would be clinically useful. While neither tiagabine nor gabapentin have yet been studied sufficiently to determine if either is effective as monotherapy in bipolar disorder, the faculty have found that they appear to be clinically useful as adjunctive agents, because of their anxiolytic effects (and, in the case of tiagabine, beneficial effects on sleep). Further study is needed to clarify whether these agents may be useful in controlling comorbid anxiety in patients with chronic psychosis. An additional advantage of both gabapentin and tiagabine as adjunctive agents is that they have a low propensity for drug interactions.
EK described his clinical experience using tiagabine to treat severe neuropsychiatric disorders. Based on published case reports, he became interested in using tiagabine to treat patients with bipolar disorder who had failed to respond to lithium, valproate, or carbamazepine, either alone, in combination with each other, or in combination with antipsychotic agents. Some of the patients with the most refractory illness had comorbid anxiety disorders, including some with PTSD resulting from chronic childhood sexual abuse.
In patients with epilepsy, the dose range of tiagabine is 32-56 mg per day, while patients with anxiety or bipolar disorder appear to benefit from doses of 4-12 mg day. Based on clinical reports and personal experience, the faculty recommend initiating tiagabine at a dose of 2-4 mg and increasing the dose by 2-4 mg weekly until efficacy is achieved or limiting side effects occur. Low initial dosing and gradual upward titration may prevent significant adverse effects, such as those observed in the European trial described above.
The accompanying Case Report (Table 2) illustrates one of the more
dramatic successes achieved with tiagabine in a particularly complex
and refractory patient.
Summary and Conclusions
GABA appears to play a role in the pathogenesis of several neuropsychiatric disorders. Many of the traditional agents used to treat psychiatric disorders are known to act, at least in part, by enhancing GABA activity, while some of the newer agents may exert their therapeutic effects exclusively via GABAergic actions. Clinical experience with the newer agents, tiagabine and gabapentin, are preliminary but promising. Controlled studies of these agents are in the planning stages and will be useful in clarifying their potential clinical utility across a range of psychiatric disorders.
The cliché "If you find one thing wrong in the brain, you'll find more
than one" clearly applies to psychiatric disorders. Most individuals with psychiatric disorders suffer from one or more additional disorders at some point, and it is not surprising that many patients require multiple-drug therapy to control their symptoms. Unfortunately, many individuals with comorbid psychiatric disorders fail to respond optimally to treatment. It is likely that specific GABA-enhancing agents will play important roles as treatment for patients with anxiety disorders, with or without comorbidity, and as adjunctive therapy in patients with more complicated neuropsychiatric disorders.
TABLE 2. Click on Case Study to view information in Table 2 of the printed monograph.
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