Major Depressive Disorder (MDD), also known simply as 'depression', is a mental disorder characterized by at least two weeks of pervasive low mood.

Current estimates are that severe depression affects around 2% of the global population at any given time, currently more than 150 million. The majority of cases don't appear to have an obvious personal and/or societal cause.

The pathophysiology of depression is not yet understood, but the current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA axis dysfunction and structural or functional abnormalities of emotional circuits.“

Source : Wikipedia

As the quote above explains, the psycho-physical pathways which lead to depression are not yet understood. One leading theory, which was prevalent in the past 40 years or so, was that patients had a imbalance in their levels of the neurotransmitter serotonin. This theory is now under intense scrutiny, and may have no validity (see following section).

Further reading regarding various current theories on the possible cause(s) depression at Wikipedia

The neurotransmitter serotonin was first identified in 1948, Subsequent investigations discovered that it is a wide-ranging and crucial brain chemical involved in cardiovascular regulation, respiration, thermo-regulation, appetite, and a very wide variety of behavioral functions.

In the 1970s, results of a series of macabre experiments with rats suggested that increased levels of serotonin might increase their determination when faced with a 'hopeless' situation - i.e. apparent imminent drowning. (ref.)

Prompting some researchers to speculate that manipulating levels may somehow help with depression in humans.

The first drug specifically designed to increase serotonin levels was fluoxelineplugin-autotooltip__plain plugin-autotooltip_bigFluoxetine

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) used in the treatment of Major Depressive Disorderand Obsessive-Compulsive disorder etc.. It's marketed under the trade names Prozac, Sarafem, Fontex and many others.

SSRIs are believed to act by… - approved in 1987. Since then, the market for fluoxetine and similar drugs (collectively known as Selective Serotonin Re-uptake Inhibitors, or SSRIs) has grown into a multi billion dollar industry - despite the fact that after decades of very widespread use, their efficacy in the treatment of depression has been found to be only marginally better than a placeboplugin-autotooltip__plain plugin-autotooltip_bigPlacebo effect

Placebos are faux medications - typically lactose or microcrystalline cellulose - designed to act as inert, non-functional 'controls' in medical experiments. (There are also faux medical procedures, see section below)

From the beginnings of their use i…

Although SSRIs definitely do increase serotonin levels (by mechanisms which are not yet fully understood) a comprehensive 'umbrella' review study published in 2022 found no evidence that serotonin levels are in fact linked to depression.

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

Source : Molecular Psychiatry, 2022

If generally accepted, that would mean that the (marginal) beneficial effect of the SSRIs must be due to some other as-yet-unknown factor.

Update :

An Oct. 2022 study published in the journal Biological Psychiatry claims to have found, for the first time, a link between natural serotonin levels and depression. biopsych.2022.10.012 ^paywalled

Note: Many of the non-SSRI drugs currently used to treat depression also have as-yet-unexplained mechanisms of action. e.g. ketamineplugin-autotooltip__plain plugin-autotooltip_bigKetamine (treatment for depression)

The use of Ketamine to treat Major Depressive Disorder was formally investigated in a 2006 report for JAMA Psychiatry. A team based at the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, found that :

"Robust…, lithiumplugin-autotooltip__plain plugin-autotooltip_bigLithium (treatment for bipolar disorder)

Lithium, normally in the form of lithium carbonate (Li2CO3) is widely recognised as the 'gold standard' prescribed drug for treating bipolar disorder, depression and mania.

In widespread use since the early 1970s, lithium carbo…, modafinilplugin-autotooltip__plain plugin-autotooltip_bigModafinil

Modafinil (sold under the brand names Alertec, Alertex, Altasomil, Aspendos, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, … etc etc.

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