Serotonin and depression link not that simple

Research that questions the evidence for a link between low levels of brain serotonin and depression does not address the wider context of the illness and its impact, writes Dr Frederick Sundram.

Depression has complex causes
Depression has complex causes.

A research paper questioning the evidence for a link between the neurotransmitter serotonin and depression has made headlines worldwide. What the researchers did not assess, among other important questions, was the benefits or disadvantages of anti-depressants.

The paper, "The serotonin theory of depression", was published in Molecular Psychiatry, one of the top ten journals globally for psychiatry and concluded there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. This was based on a synthesis of findings called an umbrella review from 17 studies.

The paper has called into question the serotonin hypothesis of depression which has been around since the 1960s and is based on the premise that reduced activity in serotonin pathways causes depression. Serotonin is one of many monoamine neurotransmitters in the brain.

Early research in this area found drugs such as reserpine depleted monoamines in the body and brain and were associated with features of depression while antidepressant agents such as tricyclic antidepressants were found to increase monoamine levels.

While many of these older antidepressants such as tricyclics and monoamine oxidase inhibitors were thought to be effective for depression, they came with considerable side effects. Selective serotonin re-uptake inhibitors were later developed and became the first line go-to antidepressants given their “cleaner” mode of action and side-effect profile.

Thus, the monoamine/serotonergic and chemical imbalance theories of depression became established and have held sway for several decades. From these early experimental studies, causation was assumed but one of the basic pitfalls that scientists warn of is that association may not imply causation.

Antidepressants are often used in situations beyond depression such as in the treatment of anxiety, chronic pain and to aid sleep.

Associate Professor Frederick Sundram University of Auckland

People already on antidepressants for depression who have read the paper or news stories should not abruptly stop their antidepressants. Antidepressants are often used in situations beyond depression such as in the treatment of anxiety, chronic pain and to aid sleep. If people remain hesitant about their antidepressants, they should talk with the person who prescribed them.

We do know that there is a large placebo effect with antidepressants, in the range of 30-40 per cent. They have been around since the 1950s and appear to have a role particularly for moderate to severe depression.

How antidepressants work is not fully known, and there may be other mechanisms at play such as neuroplasticity which is how the brain adapts and changes its structure and function over time.

Depression is a multi-faceted condition which clinicians classify as mild right through to severe based on the number of symptoms: persistently low mood and loss of interests, motivation, sleep, energy, appetite, and many others) over at least a two-week timeframe.

Someone receiving bad news such as not passing an exam or crashing their brand-new BMW may be understandably distressed for a period, but that does not mean they have depression. The sources and contributors to depression are many and broad. They include family history/genetics, life events, ongoing stressors, chronic physical health conditions, personality, addictions impacting on mood and social circumstances among many others.

The brain chemical imbalance theory takes a reductionist approach to a very complex human condition and is not something most psychiatrists in the mental health sector subscribe to. For example, if someone has a history of personal traumas and lives in a setting where there is ongoing social isolation, unemployment, financial stressors, domestic abuse and three young children to support, this contributes to a significant amount of stress that can lead to depression.

Antidepressants are very unlikely to be the fix and it would be unrealistic to expect them to be. As with any prescribed medication, though antidepressants are associated with potential side effects, people and their clinician need to weigh up the benefits versus the cons.

Antidepressants are one of the many possible treatments, but they are not for everyone. Depending on the severity of depression; there are practical measures/green prescriptions, such as establishing a structure and routine to the day alongside improved lifestyle options such as exercise and diet for milder forms of depression.

Psychotherapy which is usually known as talking therapy is also an important treatment option for mild to moderate forms of depression and depending on contributing causes, can be focused on the here and now or possibly historical contributors such as adverse or traumatic experiences.

Psychotherapy can lead to sustained and longer-term improvements in mood and wellbeing in the absence of antidepressants, but unfortunately there are barriers to access such as cost, availability of practitioners and time commitments.

A common psychotherapy option exploring thoughts, emotions and associated behaviours and focusing on the here and now is called cognitive behavioural therapy which usually occurs over 10-12 sessions with a psychotherapist. Furthermore, there is an expanding menu of options involving digital health, computerised psychotherapy and online interactive chatbots.

The focus also needs to be on prevention strategies and early detection/intervention and on a population level and in schools rather than only focusing on treatment once depression has developed. This would allow a holistic and whole of life approach which sadly, doesn’t occur often enough.

Associate Professor Frederick Sundram is the deputy head of the Department of Psychological Medicine at the Faculty of Medical and Health Sciences at the University of Auckland.

This article reflects the opinion of the author and not necessarily the views of the University of Auckland. First published in Newsroom on 2 August.

Media contact: Gilbert Wong,