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A friend of mine showed me a paper (Kirsch, 2014) where the author claims that antidepressants work mostly through a placebo effect (backed up with relevant citations). Antidepressants are generally serotonin enhancers and their mechanism of action hinges on the premise that there is a chemical imbalance of serotonin in the brain. But not only do they not work significantly better than placebos, but also there are antidepressants that do not enhance serotonin but suppress it. There are some that do nothing to serotonin at all, but their therapeutic effects are all the same, according to Hirsch. So the effect is independent of the chemical composition. That means the chemical imbalance theory is wrong. Is my understanding, as a layperson, correct?

If all of this is legitimate, does that makes any sense to take medicines for an ADHD patient as well? I mean, does the placebo effect, if true, affect ADHD patients, too?

I fear that if people get to see this paper, they may misinterpret the results and may refuse to go to a psychiatrist and get treated even if they have legitimate issues. This is alarming, IMO.

Reference
- Kirsch, Antidepressants and the Placebo Effect, Zeitschrift für Psychologie (2014); 222(3): 128–134

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Short answer
Don't believe everything you read.

Background

  • The article cited (Kirsch, 2014) appears in a German journal with a mediocre impact factor. Not the most convincing platform.
  • I'll cite parts of the abstract, starting with

But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect.

His reference list includes some 40+ references; if I type in "antidepressant AND serotonin" in Scopus (an established academic search engine I often use) I get 23k+ hits. With a bald statement like Hirsch makes, he might be skipping the literature proving him wrong.

Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit.

The new generation of antidepressants, the SNRIs, also have action on nor-epinephrine and may be more effective than the regular SSRIs. Serotonin may and likely is not the whole story. Depression is a complex disease with variable etiologies. Thinking it's all about serotonin is a bit short-sighted.

Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind.

Oh come on - when you put forth such a line in the abstract that other researchers can't successfully perform a proper masked clinical trial, only testifies of a lack of proper data to back his [flawed] claims up.

The serotonin theory is as close as any theory in the history of science to having been proved wrong.

This is a totally subjective thing to say. I don't care where it ranks in a ladder. Especially not in an abstract. Saying stuff like this only testifies he has nothing better to say in the abstract.

Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.

This would need carefully planned prospective clinical studies to prove. Until this is addressed, he shouldn't be going down this path.

Lastly - Hirsch has been criticized proclaiming the same stuff since the 1990's, without changing the contents of his message. Perhaps he should stop theorizing and start experimenting to put his conspiracy theories to the test.

According to Klein (1998), Kirsch bases his claims on a flawed study (Kirsch & Sapirstein, 1998), where Kirsch claims that the substantial majority of drug effect is due to placebo effect and the rest is either measurement error or active placebo effect. Klein criticizes the article, because it was derived from a relative small group of unrepresentative, inconsistently and erroneously selected articles arbitrarily analyzed by an obscure, misleading effect size. Further, he identifies problems with the meta-analytic approach in general, such as the lack of attempts to further segment the placebo response. Lastly, he points to the lack of peer review and the opportunity provided by an electronic journal for rapid publication.

References
- Kirsch, Zeitschrift für Psychologie (2014); 222(3): 128–34
- Kirsch & Sapirstein, Prevention & Treatment (1998); 1: 0002a
- Klein, Prevention & Treatment (1998); 1: 0006c

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Let me supplement Alice's nice answer with a few more points. Regarding

there are antidepressants that do not enhance serotonin but suppress it.

That seems to be tianeptine; it is often brought up such discussions as the counterexample to SSRIs being "real" anti-depressants. More recent research on tianeptine suggests it acts on the opioid receptors... and that's not a new line of antidepressant treatment, but rather an old one, potentially sharing the same addiction risks as other opioid-acting medications (e.g. painkillers).

Which brings us to the next point

There are some that do nothing to serotonin at all, but their therapeutic effects are all the same, according to Hirsch.

Surely there are; bupropion is a more widely used (at the least in the US) anti-depressant that is not an obvious SSRI.

So the effect is independent of the chemical composition. That means the chemical imbalance theory is wrong.

That's basically jumping to conclusions (and more than once). The effect is not totally independent of the chemical composition of the medication. An alternative conclusion is that depression, which is diagnosed based on a checklist of symptoms, is a heterogeneous disease with multiple causes producing somewhat similar symptoms (which, by the way, don't all have to be present to get a diagnostic).

Actually almost every individual neurotransmitter that is suspect to be involved in depression, including serotonin, but also catecholamines (norepinephrine and dopamine) have been subjected to experimental manipulation typically via dietary changes (in live humans). You can read more details in my answer on skeptics, but the main pattern seems to be that while we can't cause healthy individuals to get (majorly) depressed by lowering the aforementioned neurotransmitters, in previously depressed individuals (and to a lesser extent in their relatives) such interventions that lower these neurotransmitters do produce more significant mood changes; the most significant changes are seen in patients who are taking exactly the medication that the diet intervention counteracts. (see e.g. Kumar et al.).

Also current anti-depressants are only 30% to 60% effective (depending who reviews the evidence and more importantly whether substituting medications [several times] counts etc.)

So what to conclude from this? The most sensible conclusion to me is that not everything is understood about the neurochemistry of depression, but surely concluding that neurotransmitters are not involved is rubbish.

Almost every researcher who works in this field has some favorite hypothesis that explains better the current non-quite-satisfactory simple explanations based on one neutrotrasmitter or antoher, e.g. a 2008 review in Nature by Krishnan and Nestler said:

It is now thought that acute increases in the amount of synaptic monoamines induced by antidepressants produce secondary neuroplastic changes that are on a longer timescale and involve transcriptional and translational changes that mediate molecular and cellular plasticity.

I doubt that's the ultimate word on the topic (all such narrative reviews have their biases when it comes to the less investigated aspects, no matter how prestigious the venue or the author), but it's clear that the "brighter bulbs" keep looking for more satisfying answers than the monoamine hypothesis (this what's called in the mass media "chemical imbalance"). I think any ultimately useful answer has to account for how the current antidepressants work... which is by acting on neurotransmitters, which in turn does alleviate depression (better than placebo) in some people but alas does not in quite a few others.

What Krishnan and Nestler favor is another fairly circulated notion (but not so much in the mass media!) that a final common pathway for depression exists. But alas, the case is far from being closed on that. Here are a few textbook paragraphs that contrast diabetes (another heterogeneous disease) with depression, which also gets to this final-common-pathway issue, as well as the difficulty in distinguishing cause from effect with individual neurotransmitter systems:

Researchers have compared MDD [major depressive disorder] to other chronic, heterogeneous diseases such as diabetes mellitus (Krishnan & Nestler, 2008), which, like MDD, is projected to increase in prevalence in the coming decades. [...] Like depression, diabetes can present with a variety of symptoms, such as polyuria, polydipsia, polyphagia, as well as with cardiovascular, digestive, and nervous system dysfunction. Unlike MDD, however, these symptoms are a product of a known molecular basis of the disease: a deficit in the production or utilization of insulin. The involvement of insulin—due to the lack of the hormone or to failure of its intended signaling—represents a final common molecular pathway (FCMP) in diabetes that unites the involvement of disparate physiological systems. This FCMP has allowed researchers to begin to use powerful animal models to understand the symptoms, risk factors, and complications of this disorder. In addition, the identification of insulin and the pancreatic ß-cells involved in insulin production have led to dramatic improvements in the prevention and treatment of diabetes. At this point, however, an FCMP is absent in the study of MDD; presently, there is no neurobiological equivalent in depression of insulin from ß-cells.

Over the past few decades, many molecular systems have been implicated in depression. [...] Because of the wide array of molecular systems that are disrupted in MDD, or in which disruption leads to depression, it has been difficult for researchers and clinicians to cleanly link molecular and behavioral systems. Investigators have noted limitations with all these single-system theories of MDD; indeed, to date, there is no known single molecule that is both necessary and sufficient to explain all the varied combinations of symptoms that can be present in individuals diagnosed with MDD. Genetic studies of MDD, too, have not been definitive in determining consistent risk loci, due to heterogeneity, environmental factors, and nosological limitations (Shyn & Hamilton, 2010). Even evidence of successful antidepressant action is not sufficient to demonstrate the primacy of the targetted molecular system in the pathophysiology of MDD. In fact, some researchers have argued that anomalies in traditional molecules implicated in the pathophysiology of MDD, like monoamines or glutamate, are unlikely to be at the etiological core of depression (Krishnan & Nestler, 2010). This difficulty disentangling the causal links between symptoms profiles and molecular systems has historically led to simplifications and misconceptions of the neurobiology of depression (Lacasse & Leo, 2005).

A primary challenge for investigators is differentiating between molecules that are disrupted as a consequence of depression and molecules that, when disrupted, are involved in the etiology of MDD. Demonstrating that a particular molecule—for example, a metabolite of a neurotransmitter— is up- or down-regulated in MDD is not sufficient to claim that disruption in this molecule causes MDD. Even when molecules can be causally linked to depression, the heterogeneity of this disorder prevents researchers from linking that molecule to all forms of MDD. For example, showing that interferon alpha (IFN-) can cause MDD is not equivalent to proving that IFN- underlies all cases of the disorder. Indeed, whereas some molecular systems may be strongly associated with one particular domain of impairment (e.g., dopamine and deficits in motivation and behavior), the effects of other molecular systems, like norepinephrine, may be less specific. Adding to this complexity is the fact that MDD is a moderately heritable disorder (Levinson, 2009) in which preexisting vulnerabilities interact with stressful life events to increase risk for initial and recurrent depressive episodes in a manner similar to the kindling model of epileptogenesis (Kendler, Thornton, & Gardner, 2000). Moreover, different symptoms and symptom clusters in MDD are inherited at different rates. For example, sleep and appetite disruption have higher heritability estimates than does psychomotor retardation (Jang, Livesley, Taylor, Stein, & Moon, 2004).

Reproduced from Chen and Gotlib "Molecular Foundations of the Symptoms of Major Depressive Disorder" in The Oxford Handbook of Molecular Psychology, OUP 2015

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