Mechanisms of Action

From
Medscape Mental Health

How do Antidepressant or antipsychotic medications work?

Medscape Psychopharmacology Today

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 th e 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 depre ssion, and some da ta 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 eff ect. It is interesti ng 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 t o work on
the transmit ter, 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 fro m 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 mem brane, one
can see how a reu ptake 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 antid epressants on the neuronal lev el 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 instea d seems to be primarily active b y 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. Curr ent thinking in conventional Weste
rn 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 eff ects.
We use the value-laden termino logy 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. S t. 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 uti lizing 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 e xplain why some medications that clearly h ave 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 clo zapine to avoid clozapine's rather unfortuna
te 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 t he 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 cer tainly 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.