Thanks for writing this up, it was an interesting read! A couple points:

(a) Are you sure that electroshock therapy could not be described as a "random" perturbation? (with randomness, as I said originally, not meaning statistical white noise, just like untargeted perturbations that don't have anything to do with the etiology)

(b) Are you sure that trepanations were indeed never performed in medieval times, only fantasized about? Here's from Wikipedia (which may be wrong about this, but it seems pretty confident and links sources) https://en.wikipedia.org/wiki/Trepanning

"Hippocrates gave specific directions on the procedure from its evolution through the Greek age, and Galen also elaborates on the procedure. During the Middle Ages and the Renaissance, trepanation was practiced as a cure for various ailments, including seizures and skull fractures. Out of eight skulls with trepanations from the 6th to 8th centuries found in southwestern Germany, seven skulls show clear evidence of healing and survival after trepanation, suggesting that the survival rate of the operations was high and the infection rate was low.[4] . . .

During the 16th and 17th centuries, around 80% of people survived the procedure of trepanation.[8]"

I suppose one could lean on the notion that "various ailments" don't include any mental disorders, but I'd be interested in more about the history of it.

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Thanks for making this critical point, Awais:

"Serotonergic system or even serotonergic alterations may be involved in depression in some complex manner, but depression is a highly heterogenous and multifactorial condition, and involves a range of neurophysiological, psychological, and sociopolitical factors."

The general public's perennial fixation on serotonin--exacerbated by Big Pharma ads and the misleading and muddled "umbrella review" by Moncrieff et al--is partly a consequence of inadequate "messaging" by professional psychiatric organizations and academic psychiatry. All of us (including this writer) could have done a better job in communicating to the public the vast heterogeneity of "depression" and the immense complexity of neurobiological, psychological and sociocultural factors in its genesis. And all of this is aside from the well-established, albeit modest, efficacy of antidepressants in treating at least a significant subgroup of patients with major depression.

Not incidentally, it is worth noting that the whole notion of "serotonergic" antidepressants is misleading to begin with. Sertraline, for example, also affects reuptake of dopamine, while paroxetine has effects on norepinephrine. [see, e.g., Richelson E, J Clin Psychiatry 64 (suppl 13)5-12, 2003). Finally, of course, the antidepressant bupropion [Wellbutrin] has almost no effect on serotonin--it enhances noradrenergic and dopaminergic function--and yet is an effective agent in depression. All this has been known for many years, but was never fully explained to clinicians or the general public.

Most likely--and somewhat ironically--these neurotransmitter effects are largely a "sideshow" vis-a-vis the proximate mechanism of action of most antidepressants, which probably involves enhanced expression of neurotrophic factors like BDNF and enhanced "signalling" among neural networks.

Dr. George Dawson and I explore these issues in detail in Psychiatric Times, and companion pieces by Dr. Alexander Lisinski and me explore the issue of antidepressant efficacy. The links follow, FYI.





Best regards,


Ronald W. Pies, MD

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I really appreciate you bringing up that serotonin isn't necessarily the cause of depression. This is a really important point, especially when you consider that elevated (not normal) levels of serotonin are a major cause of health problems potentially including cancer.


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