Before we try to answer this question, it is important to concede up front that researchers do not know for sure how any antidepressants work. But we have a strong suspicion that most anti-depressants work by affecting the way nerve signals are conducted from one nerve cell (neurone) to another. The brain consists of millions of neurones, which communicate with one another at synapses, points at which they are in close proximity but do not actually touch. Neural signals pass along the transmitting neurone in the form of electrical impulses until they reach the synapse, where they are converted to chemical signals that stimulate the receiving neurone, where they are once again converted into electrical signals. Normal transmission of electrical signals along neuronal pathways is necessary for the proper maintenance of all brain-regulated functions, including the control of mood, sleep, eating, thinking and other basic processes that are disrupted in depression.
The chemical transmission of the signal at the synapse involves the release of specific nerve chemical messengers or neurotransmitters, which are housed in little pockets or vesicles in the transmitting neurone, into the synaptic cleft, where they act on specific receptors on the surface of the receiving neurone. After they have communicated their chemical messages, the neurotransmitters are taken back up into the transmitting neurone again, where they are broken down by an enzyme called monoamine oxidase or MAO. This reuptake of released neurotransmitters is handled by special transporter proteins attached to the surface of the transmitting neurone. The transporter proteins for the neurotransmitters involved in synaptic transmission have been the focus of considerable attention, because most commonly used anti-depressants inhibit the reuptake of neurotransmitters by these proteins, a step that is thought to be the initial action that sets in motion a cascade of effects ultimately responsible for reversing the symptoms of depression.
Different neurones use different types of neurotransmitters to conduct their messages. Those neurotransmitters that have been most intensively studied are serotonin, norepinephrine and dopamine. One of the major ways in which anti-depressants differ from one another stems from the relative potency with which they inhibit the reuptake of these different neurotransmitters. These differences affect their side-effect profiles and, probably, their therapeutic effects as well. Older anti-depressants were rather unselective in their effects, affecting many different types of receptors. For this reason they caused several undesirable side-effects. When the newer family of anti-depressants including the enormously popular Prozac” and Lustrar’ were introduced, their major attraction was that they selectively affected serotonin reuptake without affecting other neurotransmitters to anywhere near the same degree: hence their generic name, selective serotonin reuptake inhibitors (SSRIs). Another anti-depressant commonly used in the US, bupropion or Wellbutrin, is thought to act more selectively on dopamine and norepinephrine. Most of these studies, incidentally, have been conducted on ground-up extracts of rat brains, though the results are believed to be applicable to the intact human brain as well.
Given the central role that inhibition of the reuptake of neurotransmitters appears to play in the action of other anti-depressants, it was logical to study whether St John’s Wort might have such effects as well, and that is precisely what Walter E Miiller and colleagues in Frankfurt, Germany set out to study. What they found is that an extract of St John’s Wort is capable of inhibiting the reuptake of all three neurotransmitters mentioned above: serotonin, norepinephrine and dopamine. Curiously, St John’s Wort appears to inhibit the reuptake of these neurotransmitters in a manner different from that encountered with other antidepressants. These are exciting findings to a psycho-pharmacologist such as myself because they have implications both in terms of the type of anti-depressant response and the profile of side-effects one might expect to encounter when using St John’s Wort.
I have often treated depressed patients with a selective serotonin reuptake inhibitor such as Prozac or Lustral and have observed only a partial response or an initial response that later fades. In such situations I have found that the addition of an antidepressant which acts primarily on norepinephrine transmission, such as bupropion or desipramine, will nicely complement the serotonergic drug and take care of the remaining depressive symptoms. I have treated some patients with such medication combinations for years without observing any loss of effectiveness.
As far as side-effects are concerned, the newer SSRIs appear to cause the most bothersome sexual side-effects in some people, whereas the older anti-depressants, which affected both serotonin and norepinephrine systems, appear to cause fewer problems in this regard. The balanced profile of neurotransmitter reuptake inhibition observed by Miiller and colleagues may explain why many people appear to experience fewer sexual side-effects on St John’s Wort than they do on the SSRIs.
Another important question that Miiller and his colleagues tackled was whether St John’s Wort has any significant effects on inhibiting the enzyme monoamine oxidase (MAO). An earlier report had suggested that it did have such activity, though this was not corroborated in a subsequent study As I mentioned above, MAO is responsible for breaking down neurotransmitters after they have been taken back up into the transmitting neurone at the synapse. If this enzyme is inhibited, the concentrations of these neurotransmitters would increase in the synapse, which is believed to be the way in which a group of anti-depressants, the MAO-inhibitors (or MAOIs), exert their anti-depressant effects. A major problem with these drugs, however, is that they inhibit MAO elsewhere in the body, most importantly in the bowel where the enzyme is normally responsible for detoxifying chemicals contained in ordinary foods such as yellow cheese and red wine. As a consequence, if someone on an MAO-inhibitor should eat one of these prohibited foods, a serious toxic reaction can result, with marked and sometimes dangerous elevation of blood pressure. In addition, there is a potential for dangerous interactions between MAO-inhibitors and other drugs, such as the SSRIs. If St John’s Wort were indeed an MAO-inhibitor of any potency, this would seriously limit its usefulness. The good news is that Miiller and colleagues found that St John’s Wort is not an MAO-inhibitor to any significant degree, which means that there are no food restrictions for anyone on the herbal anti-depressant and no concern on this basis about combining it with most other anti-depressants, such as the SSRIs. Just as with other anti-depressants, however, you should not take St John’s Wort if you are also taking an MAO-inhibitor.
One aspect of the mode of action of anti-depressants that needs to be explained is why it generally takes anti-depressants, including St John’s Wort, several weeks to have their effects. The effects on reuptake of neurotransmitters seen following administration of most anti-depressants are immediate and are therefore unlikely to be a complete explanation of clinical effects that take weeks to unfold. Current thinking is that the effects of antidepressants on the reuptake of neurotransmitters may be just the first in a cascade of biochemical steps necessary for reversing the symptoms of depression. Certain brain changes following the administration of anti-depressants have been found to occur a few weeks after treatment is started, after a time lag very similar to that required for the anti-depressants’ clinical effects to kick in. Researchers have suggested that these other brain changes may play a role in the mode of action of anti-depressants. Interestingly, Miiller and colleagues have found that delayed brain changes similar to those seen with other anti-depressant treatments also occur in rats a few weeks after they have been given St John’s Wort. This is another piece of biochemical evidence linking the effects of the herbal anti-depressant to those of conventional synthetic ones. It is not only in ground-up extracts of rat brains that St John’s Wort has been found to resemble other anti-depressants, but also in live rat models of depression, where the herbal anti-depressant increases an animal’s resistance to a variety of stresses just as is seen with its synthetic counterparts.