It was styled as a gladiatorial debate, but there was far more agreement than blood in the sand when Professor David Nutt, of Imperial College, London, clashed with Professor Thomas Schlaepfer, of the University of Bonn.
The question at issue? Is cognitive dysfunction a primary event in MDD, and perhaps even a contributory cause? (Professor Schlaepfer.) Or is impaired cognition a phenomenon secondary to depression? (Professor Nutt.) At the end of a lively session, the audience gave the thumbs-up to both contestants by splitting roughly 50:50. Despite its lack of clear conclusion, this was a fitting start to the 27th ECNP Congress and a standing room-only event.
Both sides agreed that depression and cognitive dysfunction are intimately linked. (And this message was reinforced by the Symposium’s other speakers.) DSM-5 itself includes poor thinking and concentration, indecisiveness and psychomotor retardation among the criteria for MDD. During a depressive episode, patients report having cognitive symptoms 94% of the time. Even between episodes, they spend almost half of their time with cognitive problems. The more depressed patients are, the more cognitive symptoms they have. MAOs are involved in both depression and cognition – so there is a common neurobiological basis. This is also reflected in overlapping circuitry in the hippocampus and prefrontal cortex.
The difference arose when it came to comparing the time course of depression with that of cognitive impairment. Professor Schlaeper argued that there is evidence cognitive deficits may precede a depressive episode – both as an index event and as relapse. And he pointed to the fact that treatments effective in restoring normal mood leave significant residual cognitive impairment in many patients. To which Professor Nutt replied that such patients may not be in genuine remission from depression.
But the two combatants agreed again that impaired neurocognitive function, whether causing depression or caused by it, is profoundly bad for quality of life, work opportunities and personal relationships. Cognitive impairment may contribute to the impaired function often seen in patients with episodic and relapsing depression, Professor Bernhard Baune from the University of Adelaide, told the meeting. And this phenomenon is present in patients independent of age.
Even so, cognition problems in depression have tended to take a back seat in comparison with low mood and suicidal ideation. It is time they received greater attention as a target of therapy.
Given this consensus, an obvious question is whether modern anti-depressants, which are perceived as equally good at raising mood, are also equally good at relieving cognitive dysfunction. The answer, according to Professor Philippe Fossati, of the Pitié Salpêtrière Hospital in Paris, is that they may not be. Although this conclusion was qualified by saying that most studies on which we might base such a judgement have major limitations.
Professor Fossati went on to remind us that MDD is heterogeneous and suggested that a distinction might be made between patients with excessive emotional reactivity (perhaps better suited to serotonergic drugs) and those with psychomotor retardation (perhaps better suited to dopaminergic or noradrenergic drugs). This suggestion – admittedly speculative – led neatly onto the presentation by Professor Dan Stein, of the University of Cape Town, who considered the possibility of personalized medicine.
So, should different patients get different drugs? Unfortunately, the situation is not so simple, Professor Stein said. A recent authoritative report had concluded that the data supporting MDD subtypes were thin. On the other hand, much progress has been made. We have moved from a period in which the psychoactive effect of drugs was discovered almost by accident to one in which drugs are consciously designed to have specific effects through known mechanisms of action.
A wealth of information is being gathered from trials that focus on particular symptoms associated with depression. Cognition is increasingly viewed as an integral part of the disease. These insights will inform future drug development, along with the explosion of knowledge about biomarkers and genomics.
There is far to go before these insights can reliably be translated into the clinic. But, to those with neural circuitry of an optimistic persuasion, the glass is already half full.