THE ROLE OF GABA IN THE PATHOGENESIS AND TREATMENT OF ANXIETY: PART 2

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

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Part 2: The Treatment of Alcohol Withdrawal
Introduction

Gamma aminobutyric acid (GABA) is the brain’s major inhibitory neurotransmitter. When GABA binds to a GABA receptor in the brain, it causes a reduction in the ability of that neuron to conduct a neural impulse. Thus, GABA has the ability to “shut down” nerve cells throughout the central nervous system (CNS).

The brain has three types of GABA receptors, GABA_A, GABA_B, and GABA_C. GABA_A receptors mediate fast inhibitory synaptic transmissions. They regulate neuronal excitability, such as the seizure threshhold, and rapid mood changes, such as panic. GABA_A receptors are the targets of sedating drugs, such as benzodiazepines, barbiturates, neurosteroids, and ethanol.^1,2 GABA_B receptors mediate slow inhibitory potentials. They play an important role in memory, depressed moods, and pain.³ Stimulation of GABA_Breceptors can also reduce the release of dopamine, thereby inhibiting the reward/reinforcing response to drug abuse. GABA_C receptors are found in the retina; their physiologic role is poorly understood.

Interest in the behavioral and psychological roles of GABA has focused on the bonding of GABA to the GABA_A receptor, which is widely distributed throughout the brain; 60-75% of all synapses in the CNS are GABAergic.⁴ GABA_A receptors are very heterogeneous, with at least 16 different subunits producing potentially over 150,000 different receptor types. It has recently been discovered that some of these subunits mediate specific behavioral and pharmacological effects. For example, the high-affinity binding of GABA_A receptors to benzodiazepines requires the presence of a γ2 subunit and an adjacent α1, α2, α3, or α5 subunit.⁵

The anxiolytic and sedating effects of the benzodiazepines appear to be governed by different subunits of the GABA_A receptor. Sedation is mediated through interaction with α1-containing GABA_A receptor complexes. Thus, mice that lack the gene for the α1 subunit experience the anxiolytic effects of benzodiazepines, but not the sedative effects. Similarly, drugs that do not evoke potentials in GABA_A receptors containing the α1 subunit may produce the desirable anxiolytic effects of benzodiazepines without the undesirable effects of sedation and ataxia.⁶

GABA and alcohol withdrawal

In addition to anxiolytic and sedative effects, GABA_A receptors are responsible for the intoxicating effects of alcohol and other sedative hypnotics. With chronic use, alcohol, and to a lesser extent, benzodiazepines modify the five protein areas of GABA_A receptors. This down-regulation is responsible for the phenomenon of alcohol withdrawal seen when alcohol is ceased abruptly in individuals who are alcohol-dependent.

The phenomenon of alcohol dependence can be explained on a molecular basis. When GABA binds to the GABA_Areceptor, it opens a chloride channel, which permits extracellular chloride to move into the intracellular compartment. Because the chloride ion is negatively charged, it hyperpolarizes the neuron, which makes it refractory to excitatory postsynaptic potentials. Several compounds, such as neurosteroids, benzodiazepines, ethanol, and barbiturates, potentiate the activity of GABA. When an individual ingests alcohol, it facilitates the ability of GABA to open chloride ion channels, so that greater amounts of chloride ion move from the extracellular to the intracellular space. With chronic use of alcohol, the GABA system is down-regulated and the neuron may eventually become dependent on alcohol to enable GABA to function.

At the same time, the excitatory glutamate system is up-regulated, as well as calcium-channel activity. If alcohol is withdrawn, GABA alone is no longer capable of opening the chloride ion channel, which results in a very excitable cell that is easily stimulated by excitatory postsynaptic potentials. This cellular hyperexcitability is responsible for the irritability, insomnia, hallucinations, tachycardia, hypertension and, in the case of abrupt cessation of long-time alcohol use, seizures. As one faculty member (RM) expressed it, an apt analogy might be an automobile with a stuck accelerator and no brakes.

Alcohol withdrawal is also associated with neurotoxicity. Chronic ethanol ingestion results in an up-regulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, a phenomenon associated with withdrawal seizures.⁷ Together, alcohol and glutamate cause increases in the number of neuronal calcium receptors. When chronic alcohol use suddenly ceases, calcium floods into the cell, a phenomenon associated with cell death. The neurotoxicity tends to worsen with each successive withdrawal, a “kindling” process similar to that seen in epilepsy. The symptoms are more severe and seizures are likely to worsen. Yet, even mild withdrawal can be associated with neuronal damage. People undergoing mild alcohol withdrawal who were not treated with any agent have been found to have increased levels of oxidative radicals and glutamate metabolites in the cerebrospinal fluid. These are suggestive of oxidative damage to cells, damaging calcium influx into cells, and damaging intracellular proteins. This suggests that even mild withdrawal may lead to CNS damage, particularly if it is repeated several times over the course of alcohol dependency, and therefore needs to be treated.

Preventing neurotoxicity and controlling symptoms during alcohol withdrawal

One approach to mitigating the damage of alcohol withdrawal is to downregulate the glutamate system with acamprosate. Acamprosate has been approved for use in over 70 countries, and Phase III trials have been completed in the U.S. While trials of acamprosate have generally had positive

outcomes, the current faculty emphasized that it must be combined with established psychosocial therapies to be of real benefit. These may include cognitive behavioral therapy, motivational therapies, or 12-step programs.

In a 2001 study of animals undergoing ethanol withdrawal, acamprosate was shown to reduce increases in glutamate-induced calcium entry into cells and prevent glutamate-induced neurotoxicity.⁸ A 2001 Montreal symposium provided additional support for the neuroprotective effects of acamprosate.⁹ A meta-analysis of controlled trials of naltrexone and acamprosate showed both drugs to have significant but modest benefits on treatment retention and/or drinking outcomes.¹⁰ Similarly, a clinical review of published double-blind, placebo-controlled trials of acamprosate showed a greater rate of treatment completion, time to first drink, and abstinence rate and/or duration compared with placebo.¹¹

In a recent study of 627 people (almost all men) with severe alcohol dependence, naltrexone was not shown to be effective.¹² However, the current faculty noted that their experience with naltrexone has often been positive. They emphasized the need for concomitant psychosocial support; in fact, none of the pharmacologic therapies for alcoholic withdrawal, opiate addiction, or smoking cessation are effective as stand-alone therapies. One faculty member (RM) had a remarkable response from naltrexone from a patient in his 70s who had been alcohol-dependent for 50 years and had refused most forms of psychosocial treatment. Naltrexone, he said, removed his desire to drink; it was “like turning off a switch.” As an opiate-receptor antagonist, naltrexone shuts down the “reward” response to drinking. Unlike the patient described above, the faculty felt that patients most likely to respond to naltrexone are young and in the early stages of alcohol dependence.

Despite their drawbacks, benzodiazepines are still commonly used to treat alcohol withdrawal. The present faculty try to avoid using benzodiazepines in substance abusers, especially severe alcoholics. In addition to the dangers of combining the drugs with alcohol, RM and HM have noted that patients on benzodiazepines often don’t recognize drug-induced ataxia when it occurs. Nevertheless, it may be necessary to use this class of drugs for brief periods in some patients. For example, in patients with a history of delerium tremens or withdrawal seizures, HM uses a combination of a benzodiazepine and an anticonvulsant; these patients generally receive inpatient treatment.

Another danger is that benzodiazepines may actually “prime” alcoholics to start drinking again. A recent randomized trial by RM and HM compared carbamazepine and lorazepam in 136 patients undergoing single and multiple previous alcohol withdrawals.¹³ The two drugs were found to be equally effective in decreasing withdrawal symptoms, while carbamazepine was superior to lorazepam in reducing anxiety and improving sleep. Furthermore, lorazepam-treated patients had a significantly higher risk of rebound of alcohol-withdrawal symptoms post-treatment (p=0.007), and the risk of having a first drink was three times greater with the lorazepam-treated patients than with the carbamazepine-treated patients (p=0.04).

Benzodiazepines are themselves abusable drugs and, if a patient decides to drink while taking them, the interaction can lead to increased sedation, motor incoordination, and ataxia. Furthermore, when the benzodiazepine is withdrawn after five to seven days, the patient is often left with symptoms of generalized anxiety disorder and may even experience panic attacks. The question then becomes how to manage the anxiety symptoms. Chronic benzodiazepines are inappropriate in such individuals. JG noted that, while selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) can be helpful, people with substance abuse problems generally do not like these drugs; they tend to experience more side effects from antidepressants than people without abuse problems. In his practice, JG has had more success treating anxiety symptoms with atypical antipsychotic agents, such as quetiapine.

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