The origins of the monoamine hypothesis of depression

Depression is a mental disorder characterised by clinical symptoms including low mood, rumination, functional impairment, retardation, and somatic syndromes such as sleep disturbances and loss of appetite (Lorr et al., 1967). Antidepressants were serendipitously discovered in the 1950s, when Iproniazid, a drug originally prescribed as a treatment for tuberculosis, was shown to induce increased vitality and desire for social activity in patients (López-Muñoz & Alamo, 2009).

It had been previously observed that Iproniazid was capable of inhibiting monoamine-oxidase (MAO), a family of enzymes catalysing the oxidation of monoamines such as serotonin and noradrenaline (Zeller et al., 1952). The connexion scientists made between an improved mood in patients with tuberculosis and higher levels of monoamines in their brains led to further research into MAO inhibitors (MAOIs) as a treatment for depression (López-Munoz et al., 2007), and what is now known as the monoamine hypothesis – which poses that depression is caused by a deficiency in serotonin and noradrenaline in the brain (Hirschfeld, 2000).

According to this hypothesis, it is possible to restore normal function in depressed patients by increasing the levels of monoamines at the synaptic level (López-Muñoz & Alamo, 2009). This theory has been ubiquitous for the past fifty years (Van Praag, 2001) and has been said to have inaugurated the modern psychopharmacological era in psychiatry (Healy,1997). Over the course of these years Iproniazid gave way to other agents which are more effectively inhibiting MAO (Jacobsen, 1986). These monoamine reuptake inhibitors (MRI) prevent the removal of monoamines from the synaptic area, thus increasing the overall concentration of monoamines in the brain (Stahl, 1998).

To illustrate the prevalence of MRIs as a therapeutic approach, serotonin reuptake inhibitors are currently recommended by both national and international bodies as first-line treatment for most patients with depression (Cleare et al., 2015) and nowadays, antidepressants are the most widely prescribed drugs (Kirsch, 2002).

But not all researchers are convinced by the efficacy of these commonly prescribed antidepressants which increase the levels of monoamine transmitters in the brain, and some are even investigating their potentially harmful side effects. First, despite the ubiquity of antidepressants, depression remains the most prevalent mental illness (Kessler & Bromet, 2013). Second, there is growing concern that MRI medications may actually increase the odds of suicide (Healy, 2003).

Then, in addition to these mixed outcomes, studies at the biological level show that synaptic concentrations of serotonin and noradrenaline are in fact not lower than normal in all individuals suffering from depression, nor do these individuals have fewer monoamine receptors in their brain, challenging the validity of the monoamine hypothesis (Hinz et al., 2012). The central role of monoamine levels in the onset of depression is further challenged by the delay between increase in monoamine levels in the brain and clinical improvement, which can be often measured in weeks (Vetulani & Sulser, 1975).

The current supremacy of the monoamine theory may have restrained research into other potential process, and slowed down the discovery of safer and more effective antidepressant medications (Hindmarch, 2002). In contrast, an increasingly popular theory states that even if monoamines have a role in some specific forms of depression, they are more often likely to play an indirect role which involves more complex cerebral metabolic mechanisms (Barchas & Altemus, 1999).

Looking beyond the monoamine theory of depression, a multidisciplinary approach embracing the polysyndromic nature of depression, which incorporates metabolic, cellular, genetic and immunological mediators, is allowing researchers to explore novel treatments (Krishnan & Nestler, 2008).

For example, it has been recently observed that sub-anaesthetic doses of intravenously infused ketamine produces rapid antidepressant effects on individuals with treatment-resistant major depression (Zarate et al., 2006). Other researchers are exploring alternative biochemical pathways to treat depression, such as the ones associated with cortisol, the brain’s stress hormone (Keller et al., 2017).

More research is needed and treatments are likely to become increasingly more personalised to each patient, with research currently underway in the areas of pharmacogenetics influencing gene-gene and gene-environment interactions (Gvozdic et al., 2012). In order to uncover novel interventions, these research efforts may need to ignore the pharmacological assumptions characterising the monoamine hypothesis of depression (Mulinari, 2012).

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