Most currently used psychotropic medications, including benzodiazepines, antipsychotics, SSRI’s, and anticonvulsants seem to enhance GABA neurotransmission, albeit thorough different mechanisms. A few studies show a direct role of GABA in ECT. In another study, cortical glutamate / glutamine levels in the left anterior cingulate of depressed patients normalized after ECT, but only in responders. In non-responders, levels remained low. Limitations in this study’s MRI methodology did not allow obtaining separate measurements for GABA because of overlapping resonances of glutamate, glutamine, and GABA. In a study of plasma GABA in depressed patients treated with ECT, plasma GABA levels tended to decrease for about one hour after ECT.

 

 

Two of the major types of drugs used to treat anxiety are benzodiazepines and SSRIs. Both may achieve anxiety relief, at least in part, through a common mechanism in the amygdala – enhancement of the inhibitory effects of GABA. Benzodiazepines directly enhance the inhibitory effects of GABA. By increasing inhibition, benzodiazepines weaken the ability of external or internal stimuli to activate the amygdala and produce fear and anxiety. SSRIs may also increase inhibition in the amygdala, though indirectly. It is known that increasing serotonin levels in the amygdala leads to an inhibition of amygdala activity, but this is achieved by exciting GABA cells, which then do the inhibiting. Since SSRIs make more serotonin available at the synapse preventing uptake and thus breakdown, they would presumably also lead to GABA excitation and thus inhibition.

 

The classic anti-anxiety drugs work primarily by facilitating GABA inhibitory transmission in the brain, making it harder for glutamate to elicit excitation at the postsynaptic synapse. This is true for alcohol, barbiturates, and benzodiazepines. However, each achieves its effect differently. When a neurotransmitter binds to its receptors, the receptor opens, allowing electrically charged chemical ions to flow from the extracellular space into the cell. In the case of GABA receptors, the flow of chloride ions makes the inside of the cell more negative , which means that more positively charged ions have to flow into the cell through glutamate receptors to initiate an action potential. Barbiturates enhance inhibition by acting directly on GABA receptors, keeping the chloride channel open longer, allowing more negative ions to enter the cell. Alcohol has a similar effect, but at a different GABA receptor. Benzodiazepines, however, work differently, as they have their own receptors, which are linked to GABA receptors. So when benzodiazepine receptors are occupied, linked GABA receptors bind GABA more easily. As a result, the same amount of GABA released from a GABA terminal will have a greater inhibitory effect on the postsynaptic cell.

 

 

Benzodiazepines work by enhancing the effect of the inhibitory neurotransmitter GABA) at GABA_A receptors, resulting in a depressant effect on the central nervous system. Common medications are lorazepam (Ativan), clonazepam (Klonopin), alprazolam (Xanax), and diazepam (Valium). They are used to treat a wide variety of conditions and symptoms and are usually a first choice when short-term CNS sedation is needed.

 

            Non-Benzodiazepines

 

The nonbenzodiazepines are positive allosteric modulators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex.

 

 

Barbiturates are rarely prescribed these days. I am relying on LeDoux’s statement above related to their effects on GABA inhibition.

 

            5-HT_1A agonists - Buspirone

 

Buspirone is a serotonin 1A agonist. It lacks the sedation and the dependence associated with benzodiazepines and causes much less cognitive impairment. It may be less effective than benzodiazepines in patients who have been previously treated with benzodiazepines as the medication does not provide the euphoria and sedation that these patients may expect or equate with anxiety relief. If it effects GABA, it would presumably be through the same pathways LeDoux described above related to SSRIs.

 

            Gabapentin

 

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter GABA, but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. In preclinical studies, gabapentin was shown to have anxiolytic effects similar to those of diazepam (valium), but did not produce the memory-impairing effects of the latter drug. Gabapentin has also been shown to be beneficial in clinical studies of patients with panic disorder (PD), social phobia (SP), obsessive-compulsive disorder (OCD), and PTSD.

 

            Beta-Receptor Blockers

 

Though not anxiolytics, beta-receptor blockers such as propranolol and oxprenolol can be used to combat the somatic symptoms of anxiety. Beta blockers block the actions of noradrenaline, an excitatory neurotransmitter. With beta blockers, the physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

 

 

There are various anti-depressants that have been used in the past but that are rarely prescribed today due to side effects including the MAOI’s and the tricyclics. The two most commonly prescribed anti-depressants today are the SSRI’s, by far the most used, and the SNRIs (serotonin and noradrenaline reuptake inhibitors).

 

 

SSRIs are the most commonly prescribed anti-depressant. The link to GABA is set forth by LeDoux above.

 

            SNRI’s

 

SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine. If there is a link to GABA, it would likely be through the mechanism LeDoux suggested above.

 

Depressants produce a wide variety of different kinds of effects by inhibiting the activity of the central and peripheral nervous systems

 

 

From one site: The input of alcohol into the brain on three neurotransmitters (GABA, serotonin, and dopamine) produces much interference that result in certain output behavior. These interferences can involve either the individual neurotransmitter or the interactions of the neurotransmitters working together. One form of interference that alcohol causes on 5HT is by increasing its serotonin release in the nervous system. Studies have shown that after a single drink, there has been increase in concentrations of serotonin in the individual urine and blood. This 5HT increase indicates that more 5HT's were released at the serotonergic synapses, thus increasing 5HT's influence on the output behavior such as emotion, mood and thinking.

 

In the similar way, alcohol also works to increase the activity and effectiveness of GABA. Since GABA is an inhibitory neurotransmitter, alcohol increases its ability to inhibit. When alcohol is introduced into this system, its immediate (i.e. acute) effect is to add to (i.e. potentiate) the inhibition caused by the GABA consequently, neurons receiving messages through GABA are even more inhibited by this transmitter than usual when alcohol is present in the brain. And because GABA neurons are located not in one specific part of the brain, the presence of alcohol inhibits many activities within the brain, influencing behavioral output.

 

 

            These drugs also act as depressants.

 

 

Most agents described as "mood stabilizers" are also categorized as anti-convulsants. Although this group is also defined by effect rather than mechanism, there is at least a preliminary understanding of the mechanism of most of the anticonvulsants used in the treatment of mood disorders.

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.  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.

 

Lithium ions interfere with chemical reactions (sodium pump) that relay and amplify messages carried to the cells of the brain

 

Valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. In addition to blocking transamination of GABA, Valproate is believed to reverse the transamination process to form more GABA. Hence, Valproate indirectly acts as a GABA agonist. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years. Valproic acid also blocks the voltage-gated sodium channels and T-type Calcium channels. These mechanisms make Valproic Acid a Broad Spectrum Anticonvulsant drug.

 

Lamotrigine is also an anti-convulsant that has shown promise in treating autism. Lamotrigine was found to improve autistic symptoms in 8/13 ASD children separate of whether there was an improvement in their epilepsy or not. It works in part by blocking the action of glutamate in the brain. One proposed mechanism of action for lamotrigine involves an effect on sodium channels, although this remains to be established in humans. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (for example glutamate and aspartate.

 

In addition to the quote by Dhossche et al above, I have seen various studies that show that anti-psychotics activate GABA secreting neurons.