The Science Behind Anti-Depressants May Be Completely 'Backwards' Anti-depressants are the most commonly-prescribed medication in the U.S., with one in 10 Americans currently taking pills like Zoloft and Lexapro to treat depression. But these pharmaceuticals are only effective less than 30 percent of the time, and often come with troublesome side effects.
In a controversial new paper published in the journal Neuroscience & Biobehavioral Reviews, psychologist Paul Andrews of McMaster University in Ontario argues that this failure of medication may be based in a misunderstanding of the underlying chemistry related to depression.
Andrews surveyed 50 years' worth of research supporting the serotonin theory of depression, which suggests that the disease is caused by low levels of the "happiness" neurotransmitter, serotonin.
But Andrews argues that depression may actually be caused by elevated levels of serotonin. And this fundamental misunderstanding may be responsible for inappropriate treatment: The most common form of antidepressants are selective serotonin re-uptake inhibitors (SSRIs), which operate by targeting serotonin receptors in the brain in an effort to amplify serotonin production.
Currently, scientists are unable to measure precisely how the brain releases and uses serotonin, because it can't be safely observed in a human brain. But Andrews points to research on animals which suggests that serotonin might work just the opposite from what we've assumed.
In this scenario, elevated serotonin levels that are released and used by the brain during depressive episodes trigger processes that promote rumination -- the obsessive negative thinking that is the hallmark of depression. Then, because they facilitate the production of serotonin, SSRI treatments exacerbate rumination and actually worsen symptoms of depression, especially at first, Andrews explained. Over time, in come cases, the SSRIs can reverse ruminative processes and reduce symptoms -- but this is in spite of the medication, not because of it.
HuffPost Science spoke to Andrews about why we've gotten anti-depressants "backwards" -- and what the future of depression treatment might hold.
HuffPost: Where did the low-serotonin hypothesis originate?
Andrews: The hypothesis didn't originate because anybody measured serotonin in depression or in any depressed-like state in an animal. It's really based on circumstantial evidence. Researchers back in the '40s and '50s happened to find that certain drugs that were trying to treat tuberculosis and schizophrenia had depression-relieving properties, and they wondered, why were they relieving depressive symptoms? They eventually figured out that the drugs increased serotonin in rodent models.... They reasoned that if these drugs relieved depressive symptoms in humans -- and, as best as we can tell, they increased serotonin -- then depression must be a state of low or reduced serotonin transmission.
There have been problems with the low-serotonin hypothesis for a while. If you look to any serious neuroscientist, they'll all acknowledge that there are serious problems with it. It still is, nevertheless, the backbone of research on depression in neuroscience.
What evidence is there to suggest that the low-serotonin hypothesis of depression may not be accurate?
There is no way to be absolutely certain for two reasons. First, we cannot directly measure how fast serotonin is released, or transmitted. You can't do that even in a rat. You can measure the concentration of serotonin in a particular brain region, but you can't measure the transmission of it. The transmission would be to measure the release of the serotonin into the synapse.
The only thing we can measure is a marker of transmission, which reflects what happens to serotonin after it is released into the synapse and metabolized. Second, it is currently impossible to study this issue in humans without cutting holes in their skulls. But these studies can be done in animals. In these studies, there is abundant evidence that this marker of transmission is elevated.
We reviewed 15 different models of depression that are used in neuroscience research that had measured this particular marker that we're concerned with. Of those 15 studies, 13 were consistent with the high-serotonin hypothesis, and the other two were not inconsistent with it. If you extrapolate to humans... that would strongly suggest that the evidence is in favor of the high-serotonin hypothesis of depression.
OK, so how do anti-depressants work then?
Another problem with the low serotonin hypothesis is that these drugs increase serotonin pretty rapidly, within minutes to hours. You'd think that if the low serotonin hypothesis was true, the anti-depressant drugs would work rapidly too. But they don't -- it takes three to four weeks for their symptom-reducing effects to kick on. So there's always been this disconnect between the onset of the pharmacological effects of the anti-depressants and their therapeutic effects.
So what's actually happening to depressive symptoms when you first start taking these drugs? Well, it's extremely common for people to start saying "I feel worse" rather than getting better. That's theoretically important because these drugs are working very quickly in terms of increasing serotonin. So what's happening to serotonin in the brain as those three or four weeks pass? It's falling.... As time goes on [after the initial peak], serotonin dips below the baseline and that's when you actually start feeling better.
But things will eventually smooth out again and the brain will return to its steady state. That's what happens over prolonged anti-depressant use. Even when taking the drugs, people experience relapses. They might have that initial worsening of symptoms, then they'll feel better, and over prolonged period of use, they'll tell the doctor that the drugs aren't working anymore... And commonly the doctor will increase the dose or add on another drug.
But the brain is always fighting these drugs and trying to bring itself back to its homeostatic equilibrium.
Antidepressants are known to cause many side effects. What are some of the most common?
Limited efficacy at reducing depressive symptoms, sexual difficulties, difficulty concentrating, and problems with the digestive system are the most common. But many other types of problems can occur, including increased risk of relapse, a decrease in bone mineral density, abnormal bleeding, stroke, suicidal behaviour. Some of these problems can cause death -- several studies have shown that anti-depressants, especially in older people, are associated with an increased risk of death.
You all them all up, and they all can be potentially serious things.
What do you think is the future of depression treatment?
As people and physicians become more aware that antidepressants only work for a limited period of time, and are less safe than they have been supposed, the use of antidepressant medications will decline and the use of psychotherapies will increase.
I would suggest that the attempt to pharmacologically reduce depressive symptoms is not likely to produce lasting effects. You can get these temporary effects, but they're not likely to be lasting effects, and they can cause a whole lot of problems.
Psychotherapy is more likely to produce lasting effects, and can help people cope with the things that actually triggered their depressive episodes, and that's why these therapies are more productive in the long run.
This interview has been edited for clarity and length.
In a controversial new paper published in the journal Neuroscience & Biobehavioral Reviews, psychologist Paul Andrews of McMaster University in Ontario argues that this failure of medication may be based in a misunderstanding of the underlying chemistry related to depression.
Andrews surveyed 50 years' worth of research supporting the serotonin theory of depression, which suggests that the disease is caused by low levels of the "happiness" neurotransmitter, serotonin.
But Andrews argues that depression may actually be caused by elevated levels of serotonin. And this fundamental misunderstanding may be responsible for inappropriate treatment: The most common form of antidepressants are selective serotonin re-uptake inhibitors (SSRIs), which operate by targeting serotonin receptors in the brain in an effort to amplify serotonin production.
Currently, scientists are unable to measure precisely how the brain releases and uses serotonin, because it can't be safely observed in a human brain. But Andrews points to research on animals which suggests that serotonin might work just the opposite from what we've assumed.
In this scenario, elevated serotonin levels that are released and used by the brain during depressive episodes trigger processes that promote rumination -- the obsessive negative thinking that is the hallmark of depression. Then, because they facilitate the production of serotonin, SSRI treatments exacerbate rumination and actually worsen symptoms of depression, especially at first, Andrews explained. Over time, in come cases, the SSRIs can reverse ruminative processes and reduce symptoms -- but this is in spite of the medication, not because of it.
HuffPost Science spoke to Andrews about why we've gotten anti-depressants "backwards" -- and what the future of depression treatment might hold.
HuffPost: Where did the low-serotonin hypothesis originate?
Andrews: The hypothesis didn't originate because anybody measured serotonin in depression or in any depressed-like state in an animal. It's really based on circumstantial evidence. Researchers back in the '40s and '50s happened to find that certain drugs that were trying to treat tuberculosis and schizophrenia had depression-relieving properties, and they wondered, why were they relieving depressive symptoms? They eventually figured out that the drugs increased serotonin in rodent models.... They reasoned that if these drugs relieved depressive symptoms in humans -- and, as best as we can tell, they increased serotonin -- then depression must be a state of low or reduced serotonin transmission.
There have been problems with the low-serotonin hypothesis for a while. If you look to any serious neuroscientist, they'll all acknowledge that there are serious problems with it. It still is, nevertheless, the backbone of research on depression in neuroscience.
What evidence is there to suggest that the low-serotonin hypothesis of depression may not be accurate?
There is no way to be absolutely certain for two reasons. First, we cannot directly measure how fast serotonin is released, or transmitted. You can't do that even in a rat. You can measure the concentration of serotonin in a particular brain region, but you can't measure the transmission of it. The transmission would be to measure the release of the serotonin into the synapse.
The only thing we can measure is a marker of transmission, which reflects what happens to serotonin after it is released into the synapse and metabolized. Second, it is currently impossible to study this issue in humans without cutting holes in their skulls. But these studies can be done in animals. In these studies, there is abundant evidence that this marker of transmission is elevated.
We reviewed 15 different models of depression that are used in neuroscience research that had measured this particular marker that we're concerned with. Of those 15 studies, 13 were consistent with the high-serotonin hypothesis, and the other two were not inconsistent with it. If you extrapolate to humans... that would strongly suggest that the evidence is in favor of the high-serotonin hypothesis of depression.
OK, so how do anti-depressants work then?
Another problem with the low serotonin hypothesis is that these drugs increase serotonin pretty rapidly, within minutes to hours. You'd think that if the low serotonin hypothesis was true, the anti-depressant drugs would work rapidly too. But they don't -- it takes three to four weeks for their symptom-reducing effects to kick on. So there's always been this disconnect between the onset of the pharmacological effects of the anti-depressants and their therapeutic effects.
So what's actually happening to depressive symptoms when you first start taking these drugs? Well, it's extremely common for people to start saying "I feel worse" rather than getting better. That's theoretically important because these drugs are working very quickly in terms of increasing serotonin. So what's happening to serotonin in the brain as those three or four weeks pass? It's falling.... As time goes on [after the initial peak], serotonin dips below the baseline and that's when you actually start feeling better.
But things will eventually smooth out again and the brain will return to its steady state. That's what happens over prolonged anti-depressant use. Even when taking the drugs, people experience relapses. They might have that initial worsening of symptoms, then they'll feel better, and over prolonged period of use, they'll tell the doctor that the drugs aren't working anymore... And commonly the doctor will increase the dose or add on another drug.
But the brain is always fighting these drugs and trying to bring itself back to its homeostatic equilibrium.
Antidepressants are known to cause many side effects. What are some of the most common?
Limited efficacy at reducing depressive symptoms, sexual difficulties, difficulty concentrating, and problems with the digestive system are the most common. But many other types of problems can occur, including increased risk of relapse, a decrease in bone mineral density, abnormal bleeding, stroke, suicidal behaviour. Some of these problems can cause death -- several studies have shown that anti-depressants, especially in older people, are associated with an increased risk of death.
You all them all up, and they all can be potentially serious things.
What do you think is the future of depression treatment?
As people and physicians become more aware that antidepressants only work for a limited period of time, and are less safe than they have been supposed, the use of antidepressant medications will decline and the use of psychotherapies will increase.
I would suggest that the attempt to pharmacologically reduce depressive symptoms is not likely to produce lasting effects. You can get these temporary effects, but they're not likely to be lasting effects, and they can cause a whole lot of problems.
Psychotherapy is more likely to produce lasting effects, and can help people cope with the things that actually triggered their depressive episodes, and that's why these therapies are more productive in the long run.
This interview has been edited for clarity and length.
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