Depression Research Most Patients Don't Know

Written by Jessica Walters


A national survey [^] found that 72.8% of respondents endorsed the view that depression was likely to be caused by a “chemical imbalance” (i.e., an imbalance of neurotransmitters in the brain). However, research has never [^] identified a biological cause of, or reliable biological marker for, any mental disorder. This discrepancy – between scientific literature and public perception – has led to heated debate [^] within the academic community. Some researchers [^] have even called for “counter-campaigns” to educate the public about misleading claims promoted by the pharmaceutical industry.

As the founder of Prayers and Apples [^] (a holistic health website dedicated to translating exciting – but complicated! – research via fun, pop-culture-infused posts), I set out to explore 1) what we know, 2) what we don’t know, and, 3) how all of this information directly affects patients. I consolidated my findings into a senior research project [^] at Harvard University, and am thrilled to be joining Depression Army today to share some of the most important facts I found!


In 1987, the Food and Drug Administration (FDA) approved Prozac, the first selective serotonin reuptake inhibitor (SSRI). During the two decades that followed, antidepressant use among American adults increased 400% [^], the United States developed the highest prevalence of depression among 14 countries [^], and disability rates due to mental illness, as measured by Supplemental and Social Security eligibility, more than doubled [^]. While antidepressant use and disability rates increased, use of non-pharmaceutical treatments, such as psychotherapy, decreased considerably during the same time period [^]. Today, in contrast to steadily decreasing mortality rates of cardiovascular disease, stroke, and cancer, there is no evidence for reduced morbidity or mortality from any mental illness [^].

While both events happening close in time does not prove that increased use of pharmaceutical medication is responsible for rising disability rates, researcher B.J. Deacon [^] has suggested that the possibility is “sufficiently plausible” to warrant serious investigation. Likewise, G.A. Miller [^] has criticized biological reductionism – that is, ascribing mental illness to primarily biological causes – as hindering crucial scientific and clinical progress. While further research is needed to determine whether antidepressant use worsens [^] the course of depression, its failure [^] to improve morbidity and mortality is beyond debate.

This conclusion supports the need to explore alternative treatments that might be more effective [^]. As summarized by Thomas Insel [^], former Director of the National Institute of Mental Health, “While psychosocial interventions [e.g., exercise, therarpy] have received much less marketing attention than pharmacological treatments, the results are arguably more encouraging.” Specifically addressing antidepressants, Insel [^] has since added: “The bottom line is that these medications appear to have a relatively small effect in patients broadly classified as having depression.”


Believe it or not, antidepressants were developed and sold before [^] the chemical imbalance theory was introduced. (For a behind the scenes look at how everything fell into place, check out this post [^]!) Encouraged by the discovery of “magic bullet” drugs (e.g., penicillin) which could effectively target specific diseases, the public enthusiastically welcomed antidepressants as a similar cure [^]. However, as drug sales soared, researchers struggled to explain what antidepressants were actually fixing. Working backwards, scientists [^] reasoned that since first-generation antidepressants raised norephinephrine and serotonin levels in the brain, depression might be caused by low levels of norephinephrine and serotonin. Unfortunately, the chemical imbalance theory never panned out [^]. As the American Psychiatric Press Textbook [^ ] concludes, “Additional experience has not confirmed the monoamine depletion hypothesis.”

While no fully developed demonstration of a mechanism by which psychology or biology affects the other has ever been offered [^], a significant body of evidence contradicting [^] the chemical imbalance theory exists. (See, for instance: P.L. Delgado [^] finding that monoamine depletion does not cause depression in healthy volunteers.) However, a summary of the theory’s flaws is perhaps best captured by the “aspirin argument” [^] – that is, the idea that fevers and headaches are helped by aspirin, does not mean that fevers and headaches are caused by low levels of aspirin in the brain.

Writing as recently as 2014, researchers L.M. McMullen and K.J. Sigurdsson [^] concluded that, “how and even whether the regulation of levels of neurotransmitters in the brain works to relieve the symptoms of depression is unknown.”



Believing that depression is caused by a chemical imbalance has been shown [^] to increase patients’ confidence in the effectiveness of antidepressants and decrease confidence in the effectiveness of psychosocial interventions (such as therapy). This is bad for two reasons: 1) As reviewed earlier, antidepressants aren’t doing that great of a job at treating depression, and 2) Research suggests that psychosocial interventions (such as diet, exercise, meditation, therapy, and spiritual/religious practices) can really help!

Perfect example: In 1999, J.A. Blumenthal and colleagues [^] assigned 156 moderately depressed individuals to an exercise, medication, or exercise and medication group. Those in the exercise group walked or jogged on a treadmill for 30 minutes, three times per week for 16 weeks. Those in the medication group received an SSRI (Zoloft). Those in the combination group received both medication and exercise. Results showed that while medication worked to reduce depression symptoms more quickly, there were NO significant differences among treatment groups at 16 weeks. Of even greater interest: a 10-month follow-up revealed that exercise only group members had significantly lower rates of depression than those in the antidepressant or combination groups!




SSRIs – the “treatment of choice” for most indications of depression [^] – selectively inhibit the presynaptic uptake of 5-hydroxytryptamine (5-HT), which leads to an increase of 5-HT (serotonin) concentration at the synaptic cleft [^]. However, the mechanism by which antidepressants “work” does not appear to be related to this function [^]. A serotonin deficiency for depression has not been found [^], which means that instead of correcting low levels of serotonin, SSRI blocking of 5-HT may actually foster a “pathologic” [^] state of synaptic transmission. As a result, researchers have suggested that claimed improvements produced by antidepressants may be best understood as side effects of drug-induced states (or a “partial disabling of the brain” [^]) that are of value to the patient.

For instance, P.R. Breggin [^] has noted that while initial feelings of euphoria are often interpreted as improvement brought on by antidepressants, the experience is actually a “very abnormal state” that precedes mania. In a similar vein, J. Moncrieff and D. Cohen [^] have stressed that psychiatric drugs are, first and foremost, psychoactive drugs. Rather than act against neurochemical substrates of depression, antidepressants appear to produce a drug-induced state of mind that may be viewed by the patient as beneficial. As D.O. Antonuccio and colleagues [^] observed: “One person’s side effect (e.g., sedation, weight gain or loss, ejaculation difficulties) is another person’s positive treatment outcome (e.g., longer sleep, improved appetite or weight control, prolonged sexual pleasure).” Medical spellbinding [^] (that is, the use of a drug preventing the recipient from fully grasping its adverse effects) may further complicate patient perception.



The chemical imbalance theory has provided physicians with a convenient shorthand [^] for communicating with patients. As explained by psychiatrist, David Carlat [^]:

What we don’t know, is we don’t know how the medications actually work in the brain… I’ll often say something like the way Zoloft works, is, it increases the level of serotonin in your brain, in your synapses, the neurons, and, presumably, the reason you’re depressed or anxious is that you have some sort of a deficiency. And I say that not because I really believe it, because I know the evidence really isn’t there for us to understand the mechanism – I think I say that because patients want to know something. And they want to know that we as physicians have some basic understanding of what we’re doing when we’re prescribing medications. They certainly don’t want to know that a psychiatrist essentially has no idea how these medications work.

Selective attention to antidepressant information promoted by the pharmaceutical industry can also make physicians unaware of opposing research that is worthy of clinical interest [^]. Rather than coming as a surprise, J. Avorn and colleagues [^] have suggested that the predominance of non-scientific rather than scientific sources of drug information is consistent with what would be predicted from communications theory and marketing research data:

Drug advertisements are simply more visually arresting and conceptually accessible than are papers in the medical literature, and physicians appear to respond to this difference. When the use of a product promoted in this way is also encouraged by patient demands and the desire of the physician to “do something medical,” counter-arguments from empirical evidence may prove relatively weak and ultimately powerless.

Multiple studies examining the effect of pharmaceutical promotion on physician behavior have since confirmed this prediction. In a population-based survey of 1,050 physicians, E. Murray and colleagues [^] found that of the 222 cases where a patient made a DTCA-prompted medication request, physicians deemed the request inappropriate in 108 cases; however, in 75 of those cases, the physician still did what the patient wanted, either partially or completely. In a randomized controlled trial focused specifically on depression, Kravitz and colleagues [^] trained standardized patients (SPs) to portray symptoms of major depression and request antidepressants. In cases where SPs made general (i.e., not brand specific) requests, the rate of antidepressant prescription was 76%. Brand-specific requests were fulfilled 53% of the time, leading researchers to conclude that patients’ requests have a “profound” [^] effect on prescription practices in major depression.

Schwartz and colleagues [^] found a similar effect, noting that of 110 responses, the most common reason offered by physicians for prescribing inappropriate medication was patient demand. However, the same study also found that over a quarter of the reasons given for non-scientific prescribing stemmed from a belief that clinical expertise, rather than scientific evidence, should govern clinical practice. In the context of depression, this belief may be partially shaped by clinical observation that antidepressants appear to “work” (see earlier discussion of drug-induced side effects). Pharmaceutical promotion, in the form of physician detailing, may also exert significant influence on clinical expertise.

In an analysis of 538 studies between 1994-2000, interaction with pharmaceutical representatives [^] was found to impact the prescribing practice of residents and physicians in terms of non-rational prescribing and preference/rapid prescribing of new drugs. Interestingly, receiving a gift and the number of gifts received correlated with the belief that pharmaceutical representatives have no impact on prescribing behavior. After surveying 74 psychiatry residents, B. Hodges [^] concluded, “The large number of trainees who agreed with the statement that they cannot be influenced by discussions (35%) or the receipt of gifts (57%) suggests some naïveté about the influence of the pharmaceutical industry on prescribing.”

It has been estimated that the pharmaceutical industry spends up to $13,000 per physician per year promoting medications [^]. In the absence of mandatory postgraduate education, J. Avorn [^] have noted that pharmaceutical promotion becomes a major source of continuing education for physicians. The combination of this influence with DTCA-prompted patient demand [^], clinical observation of antidepressant effects [^], and the convenience of biologically based explanations for depression [^] provides a general account for why physicians may prescribe antidepressants, in the absence of convincing evidence to do so.


I developed my research project [^] with the goal of helping patients make informed treatment decisions. As a point of clarity, the value of antidepressant use, in certain cases, has not been disputed. However, this value is argued to be best understood through frameworks presented by P.R. Breggin [^] and J. Moncrieff and D. Cohen [^] – that is, perceived therapeutic benefits are the result of a drug-induced, altered state of mind; antidepressants do not “work” by addressing neurochemical substrates of depression. This distinction highlights an ethical claim propelling the present argument: Patients have a right to base treatment decisions on truly informed consent.

Consumers are empowered to take control of their lives when they are “knowledgeable about what works to solve a problem” [^]. Patients are likely to respond differently to an offer of a drug intended to produce an altered state of mind than a drug said to act on the underlying biological cause of depression [^]. However, most patients are never given this choice. A significant part of recovery involves telling stories about depression and the self that “allow one to go on living” [^] – yet, a majority of today’s stories are based on false truths [^].

If, after developing a more rational understanding of psychopharmaceutical drugs, patients still choose to take antidepressants, then it is my personal belief that they should be free to do so. However, if just one patient – out of the estimated 60 million Americans [^] who take psychotropic medication – would change their mind based on the evidence presented today, then it is firmly argued that organized psychiatry has an ethical obligation to communicate this information. As warned by C. France and colleagues [^]: “Any unitary understanding of human suffering asserted in isolation of its nuances, may mislead those in need of treatment and confound self-understanding.” We do not know how psychology/biology causation works – and there are serious costs to pretending [^] that we do.

Critiquing the chemical imbalance theory – and the biomedical model that it represents – is no more an affront to disorder management than criticizing a campaign that claims headaches are caused by a lack of aspirin in the brain. To the contrary, advocating for an evidence-based understanding of depression supports ethically informed treatment decisions and appropriate use of therapies that might otherwise be avoided. It relaxes blinders placed on research, that may neglect promising but anti-theory evidence, and encourages a rightfully curious approach to scientific inquiry.

It is my hope that my research project [^] will contribute, in some small way, to this literature. There is currently no known biological cause of, or biological marker for, any mental disorder [^] – yet, the majority of Americans [^] believe depression is a confirmed, neurobiological disease. It is the ethical responsibility of the medical community to correct this misconception.

Depression patients deserve to know all the facts – and to be encouraged to consider a wide range of evidence-based treatment options (including diet, exercise, meditation, therapy, and spiritual/religious practices). Antidepressants aren’t the only answer. There are plenty more reasons for hope!

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