If low serotonin levels aren’t responsible for depression, what is?
By studying the other effects that antidepressants have in the brain, we may arrive at more effective ways to treat depression
..The final problem is one of evidence. If low serotonin levels were responsible for depressed mood, then we should be able to induce depression in people by decreasing serotonin, and we should find low levels of serotonin in patients with depression. But neither of those things exist. Decreasing serotonin in humans can lower your mood, but it doesn’t always work. And studies looking for low serotonin in depressed patients have been inconclusive. It appears that even though antidepressants increase serotonin, a lack of serotonin doesn’t cause depression (kind of like aspirin treats a headache, but headaches are not caused by a lack of aspirin). Strike three. Serotonin is out…
We’ve all seen the commercials. There’s a sad little white marshmallow, a person in a darkened room unable to attend the party, or unable to enjoy a beautiful day. And then a voice shouts out that here is hope. That depression of yours is a result of imbalances in chemicals in your brain and, if you can correct those chemicals, you will feel better. Easy!
It’s not that these commercials sell you a pack of lies. Most antidepressants do increase the levels of chemical messengers in the brain called neurotransmitters. A specific type of neurotransmitter, the monoamines, appear to be the chemicals of choice for these drugs. Scientists once thought that simply increasing the amount of monoamines in the brain would treat the symptoms of depression. And that meant, of course, that depression itself must be caused by low levels of monoamines, particularly serotonin.
For years, scientists have tried to find drugs that increase these serotonin levels in the brain safely, and tried to find evidence that decreases in monoamines are responsible for depression itself.
Well, after much searching, we did find a lot of very interesting things. But some things just didn’t add up.
The first problem was one of time. If low serotonin levels were really what made you feel depressed, then increasing levels of serotonin should alleviate the symptoms right away. But antidepressants don’t work immediately, and in fact can take more than a month to alleviate symptoms. Strike one.
The second problem was one of whether the drugs actually worked. Serotonin-specific antidepressant drugs don’t work on everyone. In fact, new estimates show that the current antidepressants on the market only work in about 60% of patients. If low serotonin levels were really responsible for depression, then increasing serotonin should have worked on more than 60% of patients. Strike two.
The final problem is one of evidence. If low serotonin levels were responsible for depressed mood, then we should be able to induce depression in people by decreasing serotonin, and we should find low levels of serotonin in patients with depression. But neither of those things exist. Decreasing serotonin in humans can lower your mood, but it doesn’t always work. And studies looking for low serotonin in depressed patients have been inconclusive. It appears that even though antidepressants increase serotonin, a lack of serotonin doesn’t cause depression (kind of like aspirin treats a headache, but headaches are not caused by a lack of aspirin). Strike three. Serotonin is out.
So what’s in? After all, antidepressants do work in some patients. It’s instructive to look at other things these drugs are doing in the brain.
Antidepressants increase levels of neurotransmitters in the brain, but they also increase neurogenesis, the birth of new cells in the brain. Throughout your life, you will grow new neurons in an area of the brain called the hippocampus. And if you take antidepressants for several weeks, you will get increased neurogenesis.
These new neurons correspond to changes in animal behaviours that are associated with long-term antidepressant treatment. The behaviours are novelty-induced hypophagia, which measures how much of a tasty food an animal will eat in a novel environment and reflects aspects of anxiety and anhedonia (the inability to experience pleasure); and the tail suspension test, which measures behavioural despair.
Animals show improvement in both of these tests (eating more, or moving more) after long-term treatment with antidepressants, and these improvements correlate with neurogenesis in the brain.
Not only that, if you make animals display signs of depression, you canreduce this neurogenesis, and you can reverse both the behaviour and the neurogenesis by treating them with antidepressants.
Antidepressants may increase serotonin in your brain, but the alleviation of depression may be due to the long-term effects of the drugs on neurogenesis.
The neurogenesis theory of depression fulfils many of the criteria that the serotonin theory did not. It takes the right amount of time to develop, the three to fours weeks that matches up with long-term treatment with antidepressants. We find reduced neurogenesis in animals and patientsthat display signs of depression.
So far, we’re two-thirds of the way towards an explanation. Many scientists are now examining the role of neurogenesis in depression, and looking for new targets to increase neurogenesis directly, rather than increasing neurotransmitters as the current drugs do.
The role of neurogenesis in the potential treatment of depression is an exciting idea. But it is not flawless. Many studies cannot discern whether there are real changes in neurogenesis in humans with depression.Some studies show changes, but others do not.
While traditional antidepressants do increase neurogenesis and relieve depression symptoms in some animal models, others show thatneurogenesis and antidepressant behaviours are unrelated.
Much of this debate comes down to the fact that we don’t yet have a real understanding of neurogenesis, how it works, and how it is controlled both in normal brains and in the presence of antidepressants. Until we know, finding a truly effective antidepressant may remain out of reach. So while the monoamine/serotonin hypothesis for depression may be out, neurogenesis needs to step it up a little to make it in.
Further notes about neurogenesis
Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.
Centre for Neuroscience, Swammerdam Institute of Life Sciences, University of Amsterdam, P.O. box 94214, 1090 GE Amsterdam, the Netherlands. firstname.lastname@example.org
Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action.
Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment.
Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
The hippocampus is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and atrophy and loss of neurons in the adult hippocampus. One of the cellular mechanisms that could account for alterations of hippocampal structure as well as function is the regulation of adult neurogenesis. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies also demonstrate that neurogenesis is required for the actions of antidepressants in behavioral models of depression. This review discusses the literature that has lead to a neurogenic hypothesis of depression and antidepressant action, as well as the molecular and cellular mechanisms that underlie the regulation of adult neurogenesis by stress and antidepressant treatment.
(c) 2006 Wiley-Liss, Inc.
Hippocampal neurogenesis: regulation by stress and antidepressants.
Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York 10032, USA. email@example.com
Accumulating evidence implicates hippocampal neurogenesis in the pathophysiology of depression. Psychosocial stress reduces neurogenesis in rodents, whereas chronic treatment with antidepressants increases neurogenesis and blocks the effects of stress. The effects of stress and antidepressant treatment on hippocampal neurogenesis parallel behavioral changes in animal models. Moreover, ablating hippocampal neurogenesis renders antidepressants inactive in behavioral paradigms used to model antidepressant response and anxiety-like behavior in mice. In humans, monoamine-modulating antidepressants demonstrate clinical efficacy in treating depression and anxiety, which are often precipitated by psychosocial stress. This review examines the mounting evidence that stress and antidepressant treatment regulate neurogenesis in animals. Special attention is paid to the cellular and molecular mechanisms by which this regulation takes place. An analysis of current animal models used to study response to stress and antidepressants indicates the importance of modeling chronic treatment, which reflects both changes in neurogenesis and clinical response. Exploring responses of hippocampal neurogenesis to experimental challenges in appropriate animal models should delineate the role of adult-born neurons in hippocampal physiology. Focusing on neurogenic response to experimental paradigms of stress and antidepressant treatment is particularly interesting for understanding the pathophysiology of major depressive disorder.