Neurotransmitter imbalances are blamed for various psychiatric conditions (depression, ADHD, etc). Clearly plasma levels of neurotransmitters are confirmed to be abnormal in some people with such conditions. BUT, has causality ever been proven? That is; for example, does a serotonin deficiency cause depression or does depression cause a serotonin deficiency?

It is clearly possible to be "situationally depressed" caused, for example, by grief or the loss of a loved one. Do such people also experience a neurotransmitter imbalance?

Is there a definitive study of this?


I have what is mostly a frame-challenge to your question as an answer: the simple "neurotransmitter imbalance" hypothesis is a bit outdated, and it hasn't been strongly influential in a research context for a very long time.

Rather, it is an extremely oversimplified way to try to explain that there are brain differences involved in depression: that it's a real and physical disorder rather than something "made up" or "all in the head". This message might be useful for patients in explaining that their symptoms are not imaginary or something to just "get over", and also for pharmaceutical marketing of those medications. It may also cause harm (see Kemp et al 2014).

The hypothesis is originally based on studies that showed both a) that drugs impairing serotonin signalling could create depressive symptoms in animal models, and b) that drugs like selective serotonin reuptake inhibitors (SSRIs), which (at least initially) increase synaptic availability of serotonin, could treat depressive symptoms. Since then, more work shows that it is very questionable to consider reduced levels of monoamines like serotonin purely causative for depression, because depletion of such monoamines fails to produce depressive symptoms in healthy subjects (France et al 2007 review several such studies).

However, other neurotransmitters are also involved, and serotonin itself acts through numerous receptor subtypes (even completely different families), and many of these influence levels of other neurotransmitters as well. Levels of glutamate, dopamine, and norepinephrine are also both implicated in depression, but like with serotonin there is no clear, simple story.

In the brain, it's not just how much of a substance is present, but where it is released, when it is released, and in what pattern it is released. The same neurotransmitter in different brain areas can have different or even opposite effects. A neurotransmitter released 100 times in 1 second or 100 times in 100 seconds can have different or even opposite effects.

There is also a strong likelihood that depression and related conditions including anxiety disorders are not specific conditions but rather umbrella descriptions for a host of different brain dysfunctions. If there was a simple story, it wouldn't be nearly as complicated to treat.

France, C. M., Lysaker, P. H., & Robinson, R. P. (2007). The" chemical imbalance" explanation for depression: Origins, lay endorsement, and clinical implications. Professional Psychology: Research and Practice, 38(4), 411.

Kemp, J. J., Lickel, J. J., & Deacon, B. J. (2014). Effects of a chemical imbalance causal explanation on individuals' perceptions of their depressive symptoms. Behaviour research and therapy, 56, 47-52.

Lacasse, J. R., & Leo, J. (2005). Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS medicine, 2(12).

Leo, J., & Lacasse, J. R. (2008). The media and the chemical imbalance theory of depression. Society, 45(1), 35-45.

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  • $\begingroup$ Thank you for the very thorough response. The question remains though, whether those "brain differences" which are characteristic of depression are similarly present in persons diagnosed with clinical depression (absent situational causes) and those with situational depression (due to grief, stress, loss, etc)? $\endgroup$ – SchroedingersCat Feb 21 at 21:28
  • $\begingroup$ @SchroedingersCat I think that's a bit too broad of a question. There are dozens upon dozens of differences between depressed and normal brains, covering a variety of measuring modalities. None to my knowledge is diagnostic by itself, rather these are statistical differences in central tendency between groups. Situational depression and major depressive disorder are not the same, so certainly they will have brain differences as well as similarities. $\endgroup$ – Bryan Krause Feb 21 at 21:46
  • $\begingroup$ That gets to the point of the question. You say that Situation Depression and MDD are not the same. In cause they are different, but is there a expressed difference? Is there a physical/biochemical difference between the two? $\endgroup$ – SchroedingersCat Feb 21 at 21:52
  • $\begingroup$ @SchroedingersCat What would be a not "expressed difference"? I think you could ask a separate question about particular differences between situational and non-situational depression, but again, I'm a bit concerned it's too broad. (it wouldn't be nearly as broad if there were, in fact, some simple chemical "cause of depression" which is why I thought it fine to answer with the frame challenge here) It's also likely that situational depression is far less studied from a neuroscientific perspective. $\endgroup$ – Bryan Krause Feb 21 at 23:24
  • $\begingroup$ I am trying to establish causality. If situation depression and MDD both result in the same/similar "brain differences" is leads one to believe that the brain differences don't cause depression, but that situations (even repressed or irrational situations) cause depression and the brain differences are an indicator. Thus the administration of SSRI (and similar drugs) is treating the indicator/symptom rather than the cause. $\endgroup$ – SchroedingersCat Feb 22 at 14:17

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