Reexamining the Monoamine Hypothesis of Depression – What “Chemical Imbalance” Theories Miss
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The monoamine hypothesis, stating that depression is linked with low levels of monoamine activity, and serotonin activity in particular, has dominated research into depression since the 1950s. This hypothesis has also driven the development and marketing of antidepressant medications for decades. Where did this idea originate?
An early contributor to the monoamine hypothesis of depression involved the plant Rauvolfia serpentina (Indian snakeroot), which had been used in India for centuries to treat various medical and psychological conditions. Mahatma Gandhi was said to have used the plant as a tranquilizer. The main ingredient, reserpine, was extracted in the 1950s and approved for use in treating high blood pressure and as an antipsychotic.
However, some patients treated with reserpine appeared to experience depression. Reserpine’s mode of action was straightforward and well-understood. It interferes with the storage of monoamines, including serotonin, in synaptic vesicles. As a result of having less available neurochemicals to release, the affected synapse would be less active. Logically, if a drug that depletes monoamines results in depression, perhaps low monoamine levels produce a depressed mood.
A second piece of evidence, also emerging during the 1950s, was the observation that certain drugs used to treat tuberculosis produced elevated mood in patients. One such drug, iproniazid, was found to inhibit the enzyme monoamine oxidase, which typically breaks down any monoamines that are not contained in vesicles within a cell. This time, we see that enhancing monoamine levels by blocking an enzyme that normally breaks them down produces a positive mood.
Combining these two lines of thinking, researchers postulated that depleting monoamines correlates with depressed mood and increasing monoamine levels correlates with positive mood. These connections were synthesized in a 1967 paper by Joseph Shildkraut in the American Journal of Psychiatry, which became the most frequently cited paper ever published in that prestigious publication.
The monoamine hypothesis experienced a brief setback when the antidepressant imipramine was found to not affect monoamine oxidase. How did it work?
Researchers discovered that imipramine blocked the reuptake of norepinephrine into presynaptic axon terminals. Note that researchers were still operating on the notion that catecholamines, like norepinephrine, were more critical to mood. The focus on serotonin, an indoleamine rather than a catecholamine, came later.
Hints of a role for serotonin in depression occurred along the way in the form of experiments with tryptophan, a precursor in the synthesis pathway for serotonin. Extra tryptophan resulted in euphoria in a group of volunteers. This led to the proposal of a serotonin version of the monoamine hypothesis by Coppen in 1967. Coppen’s position was strengthened by the development of selective serotonin reuptake inhibitors (SSRIs).
Whether norepinephrine or serotonin was most important to the monoamine hypothesis remained an active area of debate, and reuptake inhibitors affecting norepinephrine (SNRIs) provide an alternate approach to treatment to the SSRIs.
Does Reserpine Really Cause Depression?
The first of the two pillars supporting the monoamine hypothesis is controversial at best and most likely wrong.
Baumeister et al. (2003) carefully reviewed existing reports of a correlation between reserpine and depression. Their analysis identified about 10 percent of the cases that could be classified as having depression, which is not statistically distinct from the rate of depression in the general population, especially considering that patients receiving reserpine were struggling with chronic illness. It is possible that reserpine’s tendency to slow movement had been mistaken as depression.
The study presented conclusions that suggest that reserpine is more likely to act as an antidepressant than as a depressogenic substance. The authors concluded that “there has never been a good reason to believe that reserpine is depressogenic” (p. 216).
If that’s indeed the case, why has this belief persisted? I’m embarrassed to say that I have repeated this “settled science” in my own textbooks and was shocked to learn that it was inaccurate.
Baumeister et al. (2003) suggest several reasons for the persistence of misinformation about reserpine and the continued acceptance of the monoamine hypothesis in the face of conflicting evidence.
First, no alternate or competing theory has emerged. Even inaccurate theories can guide research. Good science demands that a theory shown to be inaccurate must be revised or discarded, and the monoamine hypothesis has not been subjected to this much-needed correction.
Second, as Baumeister et al. (2003) pointed out, the monoamine hypothesis has been an enormous financial boon to the pharmaceutical industry. Roughly one in eight American adults takes an antidepressant medication. The monoamine hypothesis provides a quick, simple story for physicians and patients: “You have a chemical imbalance, and this drug will fix it.”
Serotonin and Depression
Another assumption emerged from the monoamine hypothesis: low serotonin levels are associated with depression. This is another “fact” I’m embarrassed to have included in my textbooks, with the exception of my most recent edition, fortunately.
Moncrieff et al. (2022) concluded as follows: “Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity” (p. 11).
I needed to read this paper several times before their conclusions fully sunk in—and I am not alone in having bought into this hypothesis! Moncrieff et al. (2022) reported that 80 percent of the public believes that depression is a result of chemical imbalances. Popular medical websites present this as fact, and most practicing physicians and leading researchers still ascribe to this approach. Yes, doubts in the research community about the serotonin hypothesis emerged now and then, but it still enjoys overwhelming popular and even expert support.
Moncrieff et al. (2022) were extremely thorough:
- People with depression do not show reduced levels of serotonin activity compared to people who do not have depression.
- Tryptophan depletion does not cause depression.
- Genetic studies do not find links between genes involved with serotonin and the likelihood of depression.
When data do not support a hypothesis, it is essential for good science to either discard or revise it.
What are the Implications?
Your initial reaction to reading that the monoamine and serotonin hypotheses are flawed might be a sense of despair. How can something so familiar be wrong?
In another light, however, not only is it important to develop the most accurate hypotheses possible but there are negative outcomes to viewing depression as a “chemical imbalance.” Rejecting this view opens our minds to other possibilities that are more positive.
First, the chemical imbalance explanation is remarkably deterministic. If my mood is indeed the result of biochemical reactions outside my conscious control, I am helpless in the face of this problem. In contrast, if we give more weight to other factors known to relate to depressed mood—e.g., stress levels, cortisol action, and inflammation—not only will we be doing better science, but we are able to help people cope more effectively. I don’t know how to “fix” my serotonin levels, but I definitely know how to cope with stress.
Second, the debunking of the serotonin hypothesis should prompt the pharmaceutical companies to revisit their procedures and messaging. Physicians should no longer rely on the chemical imbalance message to explain a medication to patients. If they can’t tell you how it works, or even if it does work, perhaps it shouldn’t be prescribed.
In the US, approval for new drugs does not require “registered” studies, which include the publication of methods, hypotheses, and positive and negative results. A significant “file drawer” problem persists, in which only studies showing benefits over placebo appear in journals. Often, full disclosure of clinical trial data only results from lawsuits, which compel the release of all data collected about the efficacy and risks of a drug.
A case in point is Study 329, which claimed that an SSRI, paroxetine, was both safe and effective for adolescents with major depressive disorder (Keller et al., 2001). This study was selected by a group of European investigators as part of the Restoring Invisible and Abandoned Trials (RIAT) initiative.
The funder of the Keller et al. study, pharmaceutical giant SmithKline Beecham (SKB; now GlaxoSmithKline or GSK) continued to support the results of Keller et al., but turned over their data to the RIAT group (Le Noury et al., 2015). The RIAT analysis produced very different conclusions than the original Keller et al. study.
Paroxetine showed no benefits over a placebo whatsoever, and there was evidence that more harm occurred in the clinical trials than were reported, particularly those involving suicidal ideation and attempts.
The Keller et al. study has not been retracted, but GSK was fined $3 billion in 2012 for withholding data. Sales of paroxetine have reached nearly $12 billion.
Irving Kirsch (2014) is a vocal critic of antidepressants. He argues that a true double-blind study of antidepressants is not possible due to the side effects caused by these drugs. In a double-blind study, the participants do not know if they’re receiving a placebo or an active drug. However, if you feel side effects, this can unblind you to your condition. Then it is likely that you will conform to the expectations of the study (i.e., feeling less depressed).
In addition, despite their various methods of action (reuptake inhibitors, monoamine oxidase inhibitors, and so on), antidepressants all seem to produce the same types and magnitudes of effects. This leads Kirsch to believe that antidepressants are truly active placebos, but far from benign ones. Antidepressants notoriously lead to sexual dysfunction and sleep disruption—side effects often not discussed with patients before prescription.
Moncrieff et al. (2022) have been roundly criticized for extending their results to a call for revisiting antidepressant efficacy, which their study did not directly address. Nonetheless, the pharmaceutical companies owe the public a better explanation.
Fortunately, effective alternatives exist for the treatment of depression. Psychotherapy and even aerobic exercise are at least as effective as antidepressants, placebo or not, and carry no side effects.
Conclusion – The Future of Treating Depression
Nobel laureate Konrad Lorenz famously said, “It is a good morning exercise for a research scientist to discard a pet hypothesis every day before breakfast. It keeps him young.” We should embrace data that allow us to reject an inaccurate hypothesis, as this paves the way to better solutions.
Unfortunately, for various human reasons, people often have difficulty letting go of an idea. Change can be tough with professional identities and billions of dollars at stake.
Nonetheless, it looks like it is time to reject the monoamine hypothesis of depression and the chemical imbalance rationale for medication once and for all. Alternate hypotheses focusing on stress, the gut-brain axis, inflammation, and cortisol activity might bring us closer to the truth and set the stage for more effective treatments for depression.