Before antidepressants became mainstream, drugs that treated various symptoms of depression were depicted as “tonics which could ease people through the ups and downs of normal, everyday existence,” write Jeffrey Lacasse, a Florida State University professor specializing in psychiatric medications, and Jonathan Leo, a professor of anatomy at Lincoln Memorial University, in a 2007 paper on the history of the chemical imbalance theory.
In the 1950s, Bayer marketed Butisol (a barbiturate) as “the ‘daytime sedative’ for everyday emotional stress”; in the 1970s, Roche advertised Valium (diazepam) as a treatment for the “unremitting buildup of everyday emotional stress resulting in disabling tension.”
Both the narrative and the use of drugs to treat symptoms of depression transformed after Prozac—the brand name for fluoxetine—was released. “Prozac was unique when it came out in terms of side effects compared to the antidepressants available at the time (tricyclic antidepressants and monoamine oxidase inhibitors),” Anthony Rothschild, psychiatry professor at the University of Massachusetts Medical School, writes in an email. “It was the first of the newer antidepressants with less side effects.”
Even the minimum therapeutic dose of commonly prescribed tricyclics like amitriptyline (Elavil) could cause intolerable side effects, says Hyman. “Also these drugs were potentially lethal in overdose, which terrified prescribers.” The market for early antidepressants, as a result, was small.
Prozac changed everything. It was the first major success in the selective serotonin reuptake inhibitor (SSRI) class of drugs, designed to target serotonin, a neurotransmitter. It was followed by many more SSRIs, which came to dominate the antidepressant market. The variety affords choice, which means that anyone who experiences a problematic side effect from one drug can simply opt for another. (Each antidepressant causes variable and unpredictable side effects in some patients. Deciding which antidepressant to prescribe to which patient has been described as a “flip of a coin.”)
Rothschild notes that all existing antidepressant have similar efficacy. “No drug today is more efficacious than the very first antidepressants such as the tricyclic imipramine,” agrees Hyman. Three decades since Prozac arrived, there are many more antidepressant options, but no improvement in efficacy of treatment.
Meanwhile, as Lacasse and Leo note in a 2005 paper, manufacturers typically marketed these drugs with references to chemical imbalances in the brain. For example, a 2001 television ad for sertraline (another SSRI) said, “While the causes are unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.”
Another advertisement, this one in 2005, for the drug paroxetine, said, “With continued treatment, Paxil can help restore the balance of serotonin,” a neurotransmitter.
“[T]he serotonin hypothesis is typically presented as a collective scientific belief,” write Lacasse and Leo, though, as they note: “There is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence.”
Despite the lack of evidence, the theory has saturated society. In their 2007 paper, Lacasse and Leo point to dozens of articles in mainstream publications that refer to chemical imbalances as the unquestioned cause of depression. One New York Times article on Joseph Schildkraut, the psychiatrist who first put forward the theory in 1965, states that his hypothesis “proved to be right.” When Lacasse and Leo asked the reporter for evidence to support this unfounded claim, they did not get a response. A decade on, there are still dozens of articles published every month in which depression is unquestionably described as the result of a chemical imbalance, and many people explain their own symptoms by referring to the myth.
Meanwhile, 30 years after Prozac was released, rates of depression are higher than ever.
There’s not “an iota of direct evidence” for the theory that a chemical imbalance causes depression, Hyman adds. Early papers that put forward the chemical imbalance theory did so only tentatively, but, “the world quickly forgot their cautions,” he says.
“Neuroscientists don’t have a good way of separating when brains are functioning normally or abnormally.” Depression, according to current studies, has an estimated heritability of around 37%, so genetics and biology certainly play a significant role. Brain activity corresponds with experiences of depression, just as it corresponds with all mental experiences. This, says Horwitz, “has been known for thousands of years.” Beyond that, knowledge is precarious. “Neuroscientists don’t have a good way of separating when brains are functioning normally or abnormally,” says Horwitz.
If depression was a simple matter of adjusting serotonin levels, SSRIs should work immediately, rather than taking weeks to have an effect. Reducing serotonin levels in the brain should create a state of depression, when research has found that this isn’t the case. One drug, tianeptine (a non-SSRI sold under the brand names Stablon and Coaxil across Europe, South America, and Asia, though not the UK or US), has the opposite effect of most antidepressants and decreases levels of serotonin.
This doesn’t mean that antidepressants that affect levels of serotonin definitively don’t work—it simply means that we don’t know if they’re affecting the root cause of depression. A drug’s effect on serotonin could be a relatively inconsequential side effect, rather than the crucial treatment.
[ed. See also: Sometimes Depression Means Not Feeling Anything At All]
In the 1950s, Bayer marketed Butisol (a barbiturate) as “the ‘daytime sedative’ for everyday emotional stress”; in the 1970s, Roche advertised Valium (diazepam) as a treatment for the “unremitting buildup of everyday emotional stress resulting in disabling tension.”
Both the narrative and the use of drugs to treat symptoms of depression transformed after Prozac—the brand name for fluoxetine—was released. “Prozac was unique when it came out in terms of side effects compared to the antidepressants available at the time (tricyclic antidepressants and monoamine oxidase inhibitors),” Anthony Rothschild, psychiatry professor at the University of Massachusetts Medical School, writes in an email. “It was the first of the newer antidepressants with less side effects.”
Even the minimum therapeutic dose of commonly prescribed tricyclics like amitriptyline (Elavil) could cause intolerable side effects, says Hyman. “Also these drugs were potentially lethal in overdose, which terrified prescribers.” The market for early antidepressants, as a result, was small.Rothschild notes that all existing antidepressant have similar efficacy. “No drug today is more efficacious than the very first antidepressants such as the tricyclic imipramine,” agrees Hyman. Three decades since Prozac arrived, there are many more antidepressant options, but no improvement in efficacy of treatment.
Meanwhile, as Lacasse and Leo note in a 2005 paper, manufacturers typically marketed these drugs with references to chemical imbalances in the brain. For example, a 2001 television ad for sertraline (another SSRI) said, “While the causes are unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.”
Another advertisement, this one in 2005, for the drug paroxetine, said, “With continued treatment, Paxil can help restore the balance of serotonin,” a neurotransmitter.
“[T]he serotonin hypothesis is typically presented as a collective scientific belief,” write Lacasse and Leo, though, as they note: “There is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence.”
Despite the lack of evidence, the theory has saturated society. In their 2007 paper, Lacasse and Leo point to dozens of articles in mainstream publications that refer to chemical imbalances as the unquestioned cause of depression. One New York Times article on Joseph Schildkraut, the psychiatrist who first put forward the theory in 1965, states that his hypothesis “proved to be right.” When Lacasse and Leo asked the reporter for evidence to support this unfounded claim, they did not get a response. A decade on, there are still dozens of articles published every month in which depression is unquestionably described as the result of a chemical imbalance, and many people explain their own symptoms by referring to the myth.
Meanwhile, 30 years after Prozac was released, rates of depression are higher than ever.
* * *
Hyman responds succinctly when I ask him to discuss the causes of depression: “No one has a clue,” he says.There’s not “an iota of direct evidence” for the theory that a chemical imbalance causes depression, Hyman adds. Early papers that put forward the chemical imbalance theory did so only tentatively, but, “the world quickly forgot their cautions,” he says.
“Neuroscientists don’t have a good way of separating when brains are functioning normally or abnormally.” Depression, according to current studies, has an estimated heritability of around 37%, so genetics and biology certainly play a significant role. Brain activity corresponds with experiences of depression, just as it corresponds with all mental experiences. This, says Horwitz, “has been known for thousands of years.” Beyond that, knowledge is precarious. “Neuroscientists don’t have a good way of separating when brains are functioning normally or abnormally,” says Horwitz.
If depression was a simple matter of adjusting serotonin levels, SSRIs should work immediately, rather than taking weeks to have an effect. Reducing serotonin levels in the brain should create a state of depression, when research has found that this isn’t the case. One drug, tianeptine (a non-SSRI sold under the brand names Stablon and Coaxil across Europe, South America, and Asia, though not the UK or US), has the opposite effect of most antidepressants and decreases levels of serotonin.
This doesn’t mean that antidepressants that affect levels of serotonin definitively don’t work—it simply means that we don’t know if they’re affecting the root cause of depression. A drug’s effect on serotonin could be a relatively inconsequential side effect, rather than the crucial treatment.
by Olivia Goldhill, Quartz | Read more:
Image: Reuters/Lucy Nicholson[ed. See also: Sometimes Depression Means Not Feeling Anything At All]
