Serotonin has been a centre-stage neurotransmitter in the field of psychiatry for over 6 decades and continues to play a leading role in the theatre of the brain.

Opening a symposium dedicated to new views on serotonin in brain function and psychiatric disorders, Dr Martin Walter of the Department of Psychiatry and Neurology at the Otto-von-Guericke University and Leibniz Institute for Neurobiology in Magedeburg, Germany reflected on the enduring importance of serotonin. He highlighted that research into the importance of serotonin is conducted at a number of levels of observation. These range from studies focusing on genotype, elucidation of molecular pathways, the observation of intermediate phenotypes, behavioural research, right through to study of the role of serotonin in clinical phenotype and in disease states.

Window on the brain

Dr Walter’s own research interests include brain imaging and how influences and factors as diverse as personality, interior intellect, autobiographical memory, stress and emotion, affect not just brain activity but also brain connectivity.

He said that integrating the findings of research that spans from bench to  bedside will help improve understanding of the changes in brain connectivity that might help predict why certain drugs acting on serotonergic systems effect certain changes in psychiatric conditions.

Psychedelic delights

The congress-crowd always turn out in full force to hear from Professor David Nutt of Imperial College London, UK. In an elegant and eloquent overview, he took delegates through scene-setting slides with one clear message. Most antidepressants drugs – historic and contemporary - act on the serotonergic system. Such agents effect their actions through a plethora of different mechanism, but Prof Nutt wanted to take the audience on a psychedellic trip (more on that shortly!) with a focus on the 5HT2a receptor which he is studying as potential new target in depression.

Some things just won’t go away

He started by reminding the audience that many current antidepressants affecting serotonergic systems either have low rates of efficacy (half of patients don’t achieve remission) or have side effects such as weight gain and sexual dysfunction that tarnish any treatment benefits.

Prof Nutt also pointed out that many current antidepressants don’t really target all the signs and symptoms of depression. High in his list was one particular deficiency: current drugs fail to deal with cognitive problems in depression.

Take a trip

Prof Nutt has long been fascinated by the 5HT2a receptor and its pharmacological manipulation. He pointed out that some older antidepressants act as 5HT2a blockers and that some antipsychotics may have 5HT2a blocking activity, explaining reported antidepressant activity in some settings.

He described PET imaging studies which suggest that the more 5HT2a receptors there are in the brain the more depressed and pessimistic the mood. What isn’t known is whether this is fundamental feature of depression or a compensatory response to depression.

To unlock some of the 5HT2a story, Prof Nutt has turned to study of psychedelic agents – long known to induce euphoria, banish pessimism and generally “loosen up” the brain. Some of the effects of these agents can be antagonized by blockade of 5HT2a.

Prof Nutt has studied the 5HT2a receptor and considers it may also play a role in cognition, with animal data suggesting that stimulation of this receptor can enhance learning – possibly allow better brain interconnectivity.

He is currently waiting to conduct tightly controlled studies in patients with depression – in an attempt to determine if a psychedelic agent that acts via 5HT2a – has antidepressant properties. But he said the politics and ethics of such research have proved to be high hurdles – but hurdles that this drug expert is determined to overturn.

Recycling the plastic

The final talk of the morning came from Dr Igor Branchi of the Instituto Superiore di Santia in Rome, Italy. He described genetic studies showing that polymorphisms in the gene coding for serotonin transporters impact on a patient’s mood. Brain plasticity means that while there are subjects genetically predisposed to low mood  (linked with these polymorphisms) – these same patients profit more from interventions and support designed to enhance mood. And vice versa. A predisposition to rigid behaviour defines someone less influenced by environment.

So it seems serotonin matters and remains a good drug target – but we shouldn’t overlook the role of supporting our patients with non-drug therapies.