Thomas AM Kramer, MD^*

The question of putative mechanisms of action continues to haunt psychopharmacology. Put simply, we know these drugs work, but we have very little idea how. We make guesses based on the neurochemical effects of these compounds. We have very little proof, and sometimes very little data, about whether the neurochemical effects that we find have anything to do with the therapeutic effect of the medication.

Recently, I was fortunate enough to attend some professional meetings in Europe. Europeans have a number of psychotropic compounds available to them that, for patent or marketing reasons, we will probably never be able to use in the United States. One of these is called tianeptine, and there are a number of studies in the literature that show its efficacy for the treatment of depression, and some data that show that it may be particularly effective in alcoholic patients. There is nothing particularly extraordinary about the efficacy of tianeptine; the data show that it is pretty much as effective as most antidepressants. What is extraordinary about tianeptine is its putative mechanism of action. It is a selective serotonergic reuptake enhancer. By having the exact opposite neurochemical effect as the most widely used antidepressants, it has exactly the same therapeutic effect. It is interesting that this drug and its putative mechanism of action are relatively unknown to American psychopharmacologists. Am I the only one who finds this paradox mind-boggling?

While trying to think up a pharmacological theory that would explain the efficacy of both tianeptine and selective serotonin reuptake inhibitor (SSRIs), I find myself remembering an old story from the golden days of radio. One day, the main transmitter for CBS went off the air. They called in all their engineers to work on the transmitter, but none of them could figure out what was wrong. Try as they might, they could find nothing wrong with the transmitter, but CBS remained off the air. Finally, they hired an outside expert to come in and look at their transmitter. The expert walked up to the transmitter and stared at it for a few minutes. Then he walked in a large circle around the transmitter. Finally he stopped, picked up his foot, and sharply kicked the transmitter. CBS was back on the air. The next day, CBS got an itemized bill from the outside expert. It said, "One kick, $1. Knowing where to kick, $9999."

One way to understand the effects of psychotropic drugs in general and serotonergic drugs in particular is to see them as well placed kicks to neuronal and neurochemical systems. It is possible that simply jolting the system, either with a serotonergic reuptake inhibitor or serotonergic reuptake enhancer, may provide the therapeutic effect necessary to treat a mood disorder. One of the most effective treatments psychiatry has, electroconvulsive therapy, remains, for the most part, mysterious as to its actual mechanism of action, but could be understood as providing a much more massive jolt of numerous neurotransmitters in order to get the system to reset to a healthier status.

Another way to try to understand both a reuptake enhancer and a reuptake inhibitor having the same effect is to look at neurophysiology. When one looks at the feedback loops created by autoreceptors on the presynaptic membrane, one can see how a reuptake inhibitor and enhancer might have the same effect. Reuptake inhibitors can and do inhibit neuronal firing because the increased amount of neurotransmitter that is made available to receptors on the cell membrane also binds to autoreceptors, which, when activated, decrease the release of neurotransmitter from the presynaptic cell. This might ultimately have the same effect as a reuptake enhancer -- less neurotransmitter released. This implies that the overall goal of antidepressants on the neuronal level is to decrease the firing of that system. There is some data for this, particularly regarding the theory that the time course of recovery corresponds not so much to changes in the firing of neurons, but to downregulation of receptors on the neurons, ostensibly making them less sensitive. This line of thinking quickly runs into problems, however. Mirtazapine has been shown to be an effective antidepressant. As far as we can tell, it has little effect on reuptake, but instead seems to be primarily active by blocking autoreceptors and, as such, increasing both the release of neurotransmitter and neuronal tone. If the overall goal is to decrease firing, mirtazapine should not work.

If jolting the system provides the best explanation for medications with different mechanisms of action having the same effect, this may also provide some potential explanations about how different kinds of pharmacology might work, particularly natural, alternative, and herbal treatments. Current thinking in conventional Western psychopharmacology involves seeing medications as targeting particular receptors and neurotransmitters. We conceptualize our medications as being at their best when they are very specific in their actions. We strive to develop medications that do only 1 or 2 things (ie, blocking serotonin reuptake or blocking D2 and 5HT2a receptors) and do nothing else. We assume that all other mechanisms of action of a medication will not be beneficial and will probably cause side effects. We use the value-laden terminology of "clean" and "dirty" to describe whether a medication has multiple mechanisms of action, making it dirty, or only specific few, making it clean.

Herbal medications with proven effectiveness often have very unclear mechanisms of action. When we do know mechanisms of action for an herbal preparation, it is usually clear that there are many others occurring that we have yet to elucidate. As such, herbal treatments as a group are much dirtier than conventional allopathic pharmacologic treatments. St. John's wort, for example, which has been demonstrated to be an effective antidepressant, has a number of mild neurochemical actions that may contribute to its antidepressant effect, but no clear specific mechanism of action. It appears to be a mild monoamine oxidase inhibitor, a mild serotonin reuptake blocker, and consist of other psychotropic compounds and actions yet to be described and understood. It may be that St. John's wort works as an antidepressant by utilizing a great many mechanisms of action, and, by doing so, changing the balance of neuronal systems to a healthier status by impacting them in multiple simultaneous ways. None of these neurochemical effects might be sufficient to alleviate depression on their own, but all of them together in concert are effective. In other words, herbal medications jolt the system with multiple mechanisms of action, while conventional psychopharmacology tends to focus on intense intervention with 1 or 2.

This may explain why some medications that clearly have multiple mechanisms of action may be more effective, particularly in treatment-resistant patients, than medications that are more "clean." For example, clozapine remains the most effective treatment for treatment-resistant schizophrenia, even though its putative mechanism of action, blockade of 5HT2a and D2 receptors, has been replicated by all of the new generation of antipsychotics. Although all of these medications have been developed to be cleaner than clozapine to avoid clozapine's rather unfortunate side effects, this may have caused them to be somewhat less effective. One might speculate that the dirtier pharmacology makes clozapine a more effective medication. There is also, at least, a mythology that tricyclic antidepressants may be more effective than SSRIs in severe treatment resistant depression. Tricyclics are much dirtier than SSRIs and, because of their multiple side effects from ostensibly unwanted mechanisms of action, they have been, for the most part, abandoned as first-line agents in the treatment of depression. If they are more effective in treatment-resistant patients, it may be that the qualities that make them have more side effects also add to their efficacy.

The crucial point in any discussion of mechanisms of action of psychotropic medication is to maintain a healthy respect for our ignorance. Fundamentally, we have no idea how these medications work. It is the nature of high-quality scientific discourse to postulate plausible theories and try to prove or disprove them. When any currently accepted theory no longer explains all of the data, it must be either modified or discarded. Psychopharmacology has had its share of discarded theories. We once thought that schizophrenia was exclusively a disease of dopamine and that depression was exclusively a disease of deficit of either serotonin or norepinephrine. Lately, we have been focused on the idea that "less is more" as far as the mechanisms of action of our medications. It is certainly true that as we have developed medications with less side effects, patients are more likely to take them regularly and stay on them, and, as such, these newer medications have more effectiveness than older ones. We must always remember, however, that until we figure out exactly what psychiatric illness is on a neurochemical level and what medications that seem to make it better actually do, all mechanisms of action for any effective medication may have potential benefit.