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THE ROLE OF GABA IN THE PATHOGENESIS AND TREATMENT OF ANXIETY AND OTHER NEUROPSYCHIATRIC DISORDERS

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This monograph is a companion piece to a 30-minute audio file that contains an edited version of a roundtable discussion that took place in New York City on October 26, 2001. Click on "Round Table Discussion (Real Audio)" link to access online.

Page 2 of 2

Part 2: The Treatment of Alcohol Withdrawal

Anticonvulsants for alcohol withdrawal

There is growing support in the literature for the use of anticonvulsants, both for detoxification and the management of subsequent anxiety symptoms. However, clinical experience has generally been limited to outpatient treatment of mild to moderate alcohol withdrawal. Among the anticonvulsants used to treat alcohol withdrawal are valproate, gabapentin, carbamazepine, and tiagabine. The efficacy of these drugs in the treatment of acute alcohol withdrawal is probably related to their GABAergic effects. To date, most of the studies of these agents have been small and/or open-label, and large-scale controlled studies of anticonvulsants for acute alcohol withdrawal are clearly needed. The current faculty has had some success with carbamazepine, while noting that, because of its numerous interactions with other drugs, it is impractical to use in patients on multiple drug regimens. There have been numerous case reports on the use of valproate for alcohol withdrawal suggesting that the drug is helpful in decreasing seizures and other withdrawal symptoms. Valproate was recently evaluated in three pilot studies of acute alcohol withdrawal.14-16 While the effect on alcohol-related outcomes was modest in these studies, valproate did appear to be useful in decreasing the irritability and mood disturbances associated with alcohol withdrawal. This effect is consistent with the mood-stabilizing benefits of the agent seen in the treatment of bipolar disorder. A major drawback of valproate in long-term therapy is weight gain, an adverse effect that appears to be dose-related.

Gabapentin is an anticonvulsant that has also shown efficacy in the treatment of mood and anxiety disorders.17-20 It appears to act primarily by increasing the release of nonsynaptic GABA from glia.21 In a published case report, three patients with alcohol withdrawal were treated with gabapentin 400 mg tid for three days, 400 mg bid for one day, and 400 mg qd for one day.22 Withdrawal symptoms subsided and no adverse effects were observed.

The anticonvulsant tiagabine also has shown efficacy in a variety of neuropsychiatric disorders, including anxiety.23-28 Tiagabine has a highly specific mode of action: the selective inhibition of GABA reuptake at the GAT-1 GABA transporter (selective GABA-reuptake inhibition, or SGRI). Tiagabine acts at both the GABAA and GABAB receptors, so it is theoretically able to enhance GABA activity while inhibiting the “reward” effect of substance abuse by preventing the release of dopamine. Unlike the benzodiazepines, tiagabine does not interact pharmacokinetically or pharmacodynamically with alcohol.29 And, unlike carbamazepine, tiagabine has virtually no drug interactions. Among the faculty, JG and RM have had extensive experience using tiagabine in patients with substance abuse problems, including patients undergoing withdrawal from benzodiazepines. HM added that tiagabine and other GABAergic medications also have potential in the treatment of cocaine and nicotine dependency.

Patients with anxiety or bipolar disorder who respond to tiagabine generally do so at doses of 4-12 mg day. The same dose range is recommended for the treatment of alcohol withdrawal, although the useful upper limit to this range has not been established. During treatment, response to therapy may be assessed by the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWAAR).30 The latest, simplified version of this scale rates the severity of alcohol withdrawal using 10 clinical parameters, such as anxiety, tremor, and nervousness. Each parameter is scored on a scale of 0 - 7 and patients generally require treatment only if the score is 10 or higher. Hospitalized patients are rated every eight hours by the nursing staff. This scale can be used in a variety of clinical settings, including detoxification units, psychiatric units, and general medical/surgical wards. 30 It provides an objective measurement of the need for medication, of the need to increase the dose, or if inpatient treatment might be required.

It was previously believed that after five to seven days of detoxification, the brain returned to homeostasis. It is now understood, however, that there is a protracted abstinence syndrome, with symptoms of anxiety, irritability, moodiness, and sleep disturbances. Even 12 to 18 months after drinking has ceased, patients may exhibit abnormal sleep patterns, with an absence of deep slow-wave Delta sleep. These patients have frequent awakenings, which may lead some to return to drinking or abuse sedative hypnotics in an effort to sleep. While not a hypnotic, tiagabine appears to normalize sleep architecture by increasing Stage 3 and Stage 4 Delta sleep. Patients report subjectively that the next day they feel more refreshed; they had a “deeper” night’s sleep. The effect of a single oral dose of 5 mg tiagabine on sleep was studied in 10 healthy elderly subjects.31 During the placebo night, the subjects had high amounts of intermittent wakefulness and little slow-wave sleep. During the tiagabine night, the subjects had greatly improved sleep quality, with decreased wakefulness and increases in both slow-wave sleep and low-frequency activity on the EEG within non-REM sleep.

Baclofen, a centrally acting muscle suppressant, is an older drug that, like tiagabine, has activity at the GABAB receptor. One recent study showed it to be effective in rapidly suppressing the alcohol withdrawal syndrome.32 However, the drug must be given three times daily, interacts with CNS depressants, is abusable, and can be fatal in overdose.

Benzodiazepine withdrawal

As noted above, tiagabine may be useful in decreasing the symptoms of benzodiazepine withdrawal. The faculty still see patients who have been on high doses of benozodiazepines for many years. Often, they are obtaining prescriptions from several physicians. The abuse problem may only come to a physician’s attention as the patient ages and experiences greater cognitive and motor impairment from the drug. In some cases, the patient falls or is in an automobile accident. As the benzodiazepine is withdrawn, the patient begins to experience symptoms of agitation and anxiety; if this isn’t treated, the patient is likely to return to benzodiazepine abuse for symptomic relief. JG recommends a cross taper of the benzodiazepine and tiagabine over a period of 4 to 8, or even 12 weeks if the patient has been on chronic benzodiazepines at high doses. As the benzodiazepine is slowly withdrawn, tiagabine is initiated at a dose of 2 mg qd and titrated to 4 mg bid or, in some patients, 8 mg bid. This is approximately the dose range used for tiagabine in the treatment of anxiety and is lower than the doses generally used to treat seizures (32-56 mg/day). This procedure, which is done on an outpatient basis can increase both the comfort of the patient and the likelihood of success. HM employs a slight variant on this procedure, maintaining patients on their current benzodiazepine doses until the dose of tiagabine or other anticonvulsant has reached a steady state. At this point, he initiates a slow taper of the benzodiazepine.

Conclusion

One of the most remarkable developments in psychopharmacology in recent decades has been the targeting of specific neurotransmitters, including serotonin, norepinephrine, dopamine and, recently, GABA and glutamate. For the first time, tools have been developed that enable clinicians to manipulate systems in the brain responsible for widespread neurotransmission. For example, we now have a variety of drugs that increase GABA levels in several different ways, from the highly specific mechanism of tiagabine to the multiple GABAergic mechanisms of valproate. GABAergic drugs have already shown potential in many neuropsychiatric disorders, not the least of which is alcohol withdrawal syndrome. In the treatment of alcohol withdrawal, some of these agents appear to have the potential to be both neuroprotective and to ameliorate the disabling symptoms associated with the syndrome.


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