New ways of thinking about disease states seldom come from a ‘Eureka moment’ but from the gradual accumulation of knowledge and the piecing together of hard-won evidence.
And this is the case in major depressive disorder (MDD), where decades of therapeutic research, coupled with advances in functional imaging, are helping unveil brain networks and reveal a level of brain plasticity not previously appreciated as key to this disease and approaches to its management.
Meeting of minds
Trevor Robbins, Professor of Cognitive Neuroscience at the University of Cambridge chaired a popular symposium where renowned names in neuroscience came together to focus on neural circuits in the brain and their importance to cognitive function in depression.
As Professor Sharp of the Department of Pharmacology at Oxford University reminded delegates, it has been several decades since thinking moved beyond the simple monoaminergic hypothesis of depression. Scientists accept that increasing serotonin signalling is good for mood. But there is greater appreciation of the importance of brain plasticity in depression.
Plasticity is good
One school of thought is that depression is actually a failure of the brain to show neuroplasticity. Antidepressant agents might help restore things a “normal”, more immature and therefore more plastic and adaptable state.
Preclinical studies show that SSRI antidepressants increase the expression of the protein arc – which is important for synaptic plasticity. And conversely, it is know that stress causes activation of signalling pathways that act to temper plasticity. In short – multiple signalling pathways converge to enhance plasticity in brain circuits and these can be affected by emotional inputs and by therapies.
What’s more, there appear to be powerful interactions between serotonin and the cortex, played out through multiple receptor subtypes that experts believe hold the key to unlocking the mysteries of why many patients with MDD experience cognitive deficits.
Professor Sharp spoke of a future era of ‘pro-cognitive’ antidepressant agents – potentially able to ameliorate not just affective symptoms but also the disabling and often persistent cognitive symptoms that clinicians recognise as an integral feature of MDD.
According to Professor Amit Etkin of Stanford University, neural networks in the prefrontal cortex are altered and abnormal in MDD. He gave a presentation that, as he said, “zoomed out” from the molecular and neuropharmacological research described by Professor Sharp.
In this quest to understand the links between altered mood and impaired executive function, neuroimaging studies are helping shed new light on the circuits and deficits implicated in cognitive control in the MDD brain. Functional MRI has been used in the international iSPOT-D study to map key areas of brain activity during performance of an executive function task. This has allowed researchers to compare findings in healthy controls with those of MDD patients.
The bigger picture
Sophisticated imaging studies have also shown that when a patient with MDD receives repetitive transcranial magnetic stimulation as treatment for depression, circuits involved in cognitive control fire up. These neuroimaging studies lend further support to the idea that cognitive control circuits in the cortex are intimately involved in MDD. And more than that, these neural networks offer themselves as targets for treatment.
How are we doing?
Defining the neurocircuitry, imaging the diseased brain and exploring the pharmacology of MDD in relation to cognition are not purely realms of ivory-tower academic research.
The final speaker at the symposium, Professor Judith Jaeger of Cogstate and The Albert Einstein College of Medicine in New York, assured delegates that clinical research has also been waking up to the importance of cognitive function as an integral feature of MDD.
Clinicians know from experience that disabling cognitive dysfunction often persists despite “successful” antidepressant treatment (i.e. remission of depression).
Small cognitive improvements – massive change for patient function
Professor Jaeger noted however that there are relatively few large clinical studies that were powered to look at cognitive endpoints. She described four studies that have set this as a goal and reported data suggesting that some antidepressants appear to exert beneficial effects on cognition that are independent of their antidepressant effects as measured by HAMD and MADRS. And she warned delegates not to view very small improvements in cognitive function as unimportant to patients or not of clinical relevance.
Disclaimer: “Linking neurocircuitries and imaging to cognitive function in depression” was a CME-accredited symposium supported by an educational grant from Lundbeck. Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented.