TCR: Dr. Goddard, you’ve done a lot of neurobiological research in anxiety disorders. It’s a very complex area, but basically what goes on in patients’ brains when they have a panic attack?
Dr. Goddard: It is complex, and initially researchers focused on the actions of monoamines in both depression and anxiety.
TCR: Remind us what the monoamines are.
Dr. Goddard: They are perhaps the most well known neurotransmitters: serotonin, norepinephrine, and dopamine. They have been at the center of thinking about depression and anxiety for a long time. The “monoamine theory” of depression holds that depression is caused by a depletion of norepinephrine and serotonin.
TCR: Is anxiety thought to result from the same thing?
Dr. Goddard: One theory is that panic results from spontaneous overactivity in the locus coeruleus (LC), which is the part of the brain where most of the noradrenergic neurons are located. One idea is that when somebody has a panic attack they have this sort of storm or surge of noradrenaline neurotransmission in the LC. An important inhibitory input to this structure is from serotonergic neurons. The serotonin system comes on line to modulate the LC overactivity that leads to the panic. So essentially, what SSRIs do is to increase that normal compensatory mechanism, enhancing that inhibition.
TCR: So that’s a nice, neat theory: SSRIs increase serotonin input into the locus coeruleus, which dampens norepinephrine, easing anxiety.
Dr. Goddard: It’s a nice theory, but we think it really doesn’t explain the underlying pathology of panic. To understand this, researchers are delving into the GABA and glutamate systems.
TCR: What is GABA anyway?
Dr. Goddard: GABA (gamma aminobutyric acid) is a small amino acid neuro- transmitter. It is basically a byproduct of glucose metabolism, and it is a byprod- uct of glutamate.
TCR: We’ve certainly been hearing a lot about glutamate lately in psychiatry.
Dr. Goddard: Yes, that’s because glutamate is one of the main excitatory neurotransmitters in the brain, so it is one of the main “on buttons,” if you will, to neural activity. And GABA is the flip side of that: it inhibits neural activity.
TCR: And a lot of us have heard about GABA in terms of the actions of both benzodiazepines and alcohol. Can you give us a brief review of what those two agents do to GABA?
Dr. Goddard: Sure. Native GABA (the GABA that we produce ourselves) acts in various brain regions by attaching to postsynaptic GABA-A receptors and open- ing ionic/chloride ion channels. Right next to the GABA-A receptors there is a specific benzodiazepine modulatory site. Benzodiazepines attach to this site on the receptor, and they enhance the opening of the ion channel. I think of it as turbocharging the efficacy of native GABA at the postsynaptic GABA-A receptor.
TCR: But that’s strange: Why do we have a specific benzodiazepine receptor in our brain? Do we have endogenous benzodiazepines?
Dr. Goddard: That’s something of a mystery. Back in the 1970s, researchers discovered the opiate receptors in brain regions, which led to an intensive search for endogenous opiates. People eventually identified endorphins and enkephalins. And there was a similar search for endogenous benzodiazepines in the ‘80s and ‘90s. One molecule that has been identified in this searchis a neuropeptide called diazepam binding inhibitor (DBI), which is an inverse agonist at the benzo receptor. However CSF levels of DBI are normal in panic disorder which is a bit puzzling.
TCR: What about alcohol? How does that affect the GABA complex?
Dr. Goddard: Alcohol affects GABA in a very different way. There is no “alcohol receptor” in the GABA complex. Instead, alcohol seems to cause some stabilizing effect on the membrane of the GABA neurons and may cause extra GABA release by that mechanism. But it’s not a simple “lock and key” story like the benzos.
TCR: All right, so we’ve covered how benzos and alcohol work on GABA. But how might GABA be involved in panic disorder?
Dr. Goddard: The short answer is that we don’t know. It may be that subpopulations of the GABA-A receptors are deficient in some panic patients or that there are deficits in the production and release of GABA presynaptically. But many of us believe that the monoamines (serotonin and norepinephrine) are not the main players in anxiety, and that they basically serve to modulate or tweak the major systems, which are glutamate and GABA. Some interesting information relating to this story has come about through studying the actions of some of the newer anticonvulsants.
TCR: Can you give us a rundown of these medications, some of which are under investigation for the treatment of anxiety?
Dr. Goddard: Sure. There are five of them: tiagabine (Gabitril), pregabalin (Lyrica), gabapentin (Neurontin), lamotrigine (Lamictal), and D-cycloserine. Tiagabine is essentially a GABA reuptake inhibitor, in the same way that SSRIs are serotonin reuptake inhibitors. Part of the way in which the GABA chemical signal is ended is by reuptake into the presynaptic neuron. Tiagabine blocks the GABA reuptake transporter protein and so disrupts that process and makes GABA more likely to linger in the synapse.
TCR: And more GABA in the synapse may lead to an anti-anxiety effect?
Dr. Goddard: Yes, especially since tiagabine blocks GABA reuptake most strongly in areas of the brain that have a lot to do with anxiety, namely the amygdala and hippocampus, which are part of the limbic system.
TCR: What about pregabalin (Lyrica) and gabapentin (Neurontin)?
Dr. Goddard: Pregabalin and gabapentin are pretty closely related chemically, sort of chemical cousins, if you will, and pregabalin is more potent and more bioavailable to the central nervous system than gabapentin. We really don’t know how they might work in anxiolysis, but one theory is that they enhance presynaptic release of GABA through alterations in calcium metabo- lism.
TCR: How does Lamictal affect GABA?
Dr. Goddard: Lamictal may affect GABA indirectly. It seems to inhibit release of glutamate, thereby altering the excitatory/inhibito- ry balance between glutamatergic and GABAergic neurons.
TCR: That’s interesting. So either inhibiting glutamate or increasing the action of GABA lead to anti-anxiety effects.
Dr. Goddard: Right, but the story is a bit more complicated than that. Surprisingly, it may be that some medicines that briefly increase glutamate activity could be useful therapeutically for some types of anxiety. For example, we know that glutamate is involved in laying down new memories. And memories--learning--is involved in anxiety. For instance, a patient develops a simple phobia by learning to associate, say, a snake with fear. We believe that this process is mediated by a brief increase in glutamate activity within the brain.
TCR: But if that’s true, how would a medication that enhances glutamate be helpful?
Dr. Goddard: Because in order to extinguish a phobia, the brain has to lay down new memories to replace the old ones. Thus, one research group has shown that if you give phobia patients a hefty dose of D-cycloserine (a glutamate enhancer) before behav- ior therapy, you can significantly amplify the response to treatment.
TCR: Meaning that glutamate can work both both ways--allowing phobias to be learned in the first place, but aiding in their extinction if you bump up levels just before therapy?
Dr. Goddard: Exactly. And this is fascinating, because it suggests an entirely new model of therapeutics and how to best combine psychotherapy and pharmacotherapy. Our usual clinical practice is to give standing doses of medications for anxiety and depression and maintain our patients on those. But it may be that there is a role for intermittent pharmacotherapy in anxiety disorders that really hasn’t been explored fully.
TCR: Is D-cycloserine available to prescribe?
Dr. Goddard: Yes, it is an old tuberculosis drug so it has been around since the ‘50s, and it is marketed under the trade name of Seromycin. I think the neuroscience group at Eli Lilly is interested in looking at the molecule more closely and possibly developing medications based on its structure.
TCR: Thank you, Dr. Goddard, for sharing these fascinating insights.
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