It is not what you have been told.

Low, serotonin levels in the brain are commonly thought to cause depression. But science shows the neurotransmitter has little to do with it. So, what gives?

You’ve probably heard about the chemical imbalance theory of depression. It purports that depression is caused by low levels of the neurotransmitter serotonin in the brain.

The theory originates from the 1960s, when doctors used medications such as Iproniazid mood enhancers, which they believed worked by increasing serotonin concentrations in the brain.

Since then, the idea stuck as an understandable explanation for depression, and one with an attractively simple treatment: taking SSRIs (selective serotonin reuptake inhibitors) such as Prozac and your serotonin levels will be boosted.

Although it has been questioned, especially recently, the serotonin theory of depression remains influential, with most medical textbooks still giving it qualified support, leading researchers endorsing it and much empirical research based on it. Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’. Many general practitioners also subscribe to this view and popular websites commonly cite the theory.

While most doctors will smile while explaining this theory to you as they write out a prescription for your SSRI, possibly as a lifetime medication, those of us closely following developments in neurophysiology and neuropharmacology have known for a long time that this theory is an oversimplification.

Depression has lots of different manifestations and I have yet to meet an imminent neuroscientist or psychiatrist that thinks we can explain all of that by a simple serotonin imbalance.

Now, a systematic umbrella review, published in Molecular Psychiatry, goes even further, concluding that there is “no clear evidence” that low serotonin levels cause depression.

The study, which gathered evidence from 361 peer-reviewed scientific studies, found no link between depression and serotonin levels in the blood. Similarly, the researchers behind it found no differences in serotonin receptors or transporters in the brains of people with depression compared to brains of people without depression.

The study goes on to suggest that SSRI antidepressants such as Prozac, which work by blocking serotonin reuptake in the brain, should not be used to treat depression.

The study points to research that found that antidepressants are not actually very effective at treating depression, particularly in those with moderate or less-severe depression. The authors suggest that belief in the chemical imbalance theory may discourage people from stopping treatment, potentially leading to lifelong dependence on these drugs.

However, David Curtis, honorary professor at UCL Genetics Institute in the UK, challenges this conclusion, “It is very clear that people suffering from depressive illness do have some abnormality of brain function, even if we do not yet know what this is, and that antidepressants are effective treatments for severe depression,” Curtis said.

So, if serotonin isn’t linked with depression, then what causes it? The meta study offers no alternative explanation, but experts say depression is a complex condition with multiple causes.

Unsurprisingly, negative life events, and how we deal with them, have a huge impact on depression. Stress is known to be a major trigger. Life events have a huge impact on depression along with the influence of genetic factors. Genetic predisposition can trigger the onset of depression when distressing life events occur.

Research now has moved away from focussing on a single neurotransmitter and now focus on the physiologic changes that occur in our complex neuronal networks that process emotions and stress when experiencing depression.

Regions of our brain such as the amygdala and prefrontal cortex are being studied for their role in depression. Emotions are processed in the amygdala, which are then assessed for meaning in the prefrontal cortex. People with depression have reduced amygdala volume, and reduced connectivity between the amygdala and the cortex.

Some theories suggest depression is caused by the cortex more negatively appraising emotions, particularly those triggered by events linked with bad memories. Chronic stress can have further impact on these networks, affecting the brain’s ability to adapt to stressful situations. In turn, this causes pre existing vulnerabilities to manifest.

With the realization of the limited ability of the SSRI antidepressants in treating depression, research has been more and more motivated to find new ways to treat depression.

There is increasing evidence for the benefits of mind-altering drugs such as ketamine and psilocybin ‘magic’ mushrooms in treating depression. Brain-imaging studies have found that these drugs help increase connectivity in the brain. The thinking is that the substances help people to reprocess old emotions in a new light, which helps to rewire the brain and reduce depressive tendencies.

According to my former professor, Dr Viktor Frankl, “A man’s concern, even his despair, over the worthwhileness of life is an existential distress but by no means a mental disease.”

While most patients and doctors look for the development of new pharmaceuticals to help treat depression, we must not forget non-pharmacological techniques such as mindfulness, stress reduction and psychotherapy.

Psychotherapy, in particular, over the last few decades, has been pushed aside in favor of medications as pills are less expensive than a qualified psychotherapist. However, psychotherapy helps people handle stress and depression much better. Therapy works with people to find the triggers of their depression. They learn coping mechanisms that empower them to cope with difficult life events rather than falling into a helpless situation.

(News/Medical: What causes depression)