many researchers have come to view schizophrenia as
a cognitive disorder ...
The prime directive of pharmaceutical research is that
disease is its only legitimate target. Pharma can't set
out to develop drugs to enhance the healthy, only to
treat the unwell. So if new drugs that enhance cognition
in the healthy appear, they are likely to do so as
by-products of research into treatments for illness,
particularly major diseases on which research funding is
Alzheimer's Disease, the epitome of cognitive degradation, is the most obvious example. It's less well appreciated that over the past thirty years, many researchers have come to view schizophrenia as a cognitive disorder too.
The established drug treatments for schizophrenia are directed at its 'positive symptoms', a muted and somewhat incongruous modern term for what used to be called madness. Schizophrenia is marked out by its delusions, paranoia and hallucinations, especially of voices; but these are only the dramatic manifestations of a disorder whose most pervasive impacts arise from its dulling effects upon cognition and mood. Memory, language, attention, processing speed and planning are among the functions it damages.
'The florid problems can be relatively well treated by the drugs that we have now,' says Barbara Sahakian, whose work at the University of Cambridge on cognitive enhancers is geared towards improving cognition in psychiatric disorders. 'Those will treat those hallucinations and delusions, but the patient is still left with a really severe impact on their cognition, and it's that impact that causes them not to be able to go back to university or work.' Thomas Insel, Director of the US National Institute of Mental Health (NIMH), has observed that the disability caused by schizophrenia results more from the 'under-recognized and treatment-refractory' cognitive deficits than from the more obvious 'positive symptoms'.
In this cognition-centred view, schizophrenia is a neurodevelopmental disorder whose cognitive effects appear early in life. Many people with the underlying condition grow up without suffering serious mental disturbance, but as others go through early adulthood, the cognitive impairments provoke the psychotic symptoms that lead to a diagnosis of schizophrenia. Whether they will continue to do so is an open question: Insel suggests that 'what we have labelled schizophrenia for the past century may be many different disorders with different outcomes'.
The cognitive damage will persist, however, until new drugs or other approaches emerge. And so will the consequences. One study, published in 2007, found that only 13% of people with schizophrenia surveyed in Britain were employed: the likelihood of being in work was less than a fifth of that for the population as a whole. A study of death rates in Sweden found that the lives of men with schizophrenia are likely to be fifteen years, and those of women with the condition twelve years, shorter than the national average.
With such a profile, of precarious social position and early death, it's perhaps not surprising to find that people with schizophrenia smoke much more than people in general. The rates are consistently high – often double those of the general population, or more. They have also been found to be higher in schizophrenia patients than among people diagnosed with bipolar disorder or depression, suggesting that they express a neurochemical relationship between nicotine and psychiatric disorder that is peculiar to schizophrenia. Many researchers suspect that people with schizophrenia smoke to try and clear their minds. There is some evidence that this toxic self-medication has the desired effect, offsetting deficits in working memory and attention.
A cognitive enhancer without the tar and the addiction would be far preferable, of course. Amy Arnsten, who views schizophrenia as a disorder of the prefrontal cortex, is optimistic about the prospects. 'What we're really striving for is to understand the molecular influences on prefrontal circuits that are most afflicted in schizophrenia so we can come up with intelligent strategies for treatment,' she says. 'My guess is that work will also yield things that so-called normal individuals might use to optimise their cognition.'
Nicotine acts on the nervous system through receptors, named after it, that control the activity of the neurotransmitter acetylcholine. Arnsten's team at Yale has discovered that a particular type of nicotinic receptor, designated α7, enables prefrontal circuits to communicate. 'Acetylcholine is what normally stimulates these receptors, and it is released when we are awake but not when we are in deep sleep. We think the reason we're unconscious when we're asleep is there's no cholinergic stimulation of these receptors. You add acetylcholine when we wake up, and now the circuits can talk to each other.
Arnsten thinks 'a lot of the cognitive-enhancing effects of cigarette smoking is probably involving this receptor, and we've know for many years that this is a receptor that can be genetically altered in families with schizophrenia. You can imagine if this receptor's not working, you would be less conscious; you would not be able to bring these circuits on line. We think this might help to explain why so many patients with schizophrenia smoke so much.'
The α7 receptor does not appear to be implicated in nicotine addiction, suggesting that α7-stimulating agents might not stimulate the same kind of compulsion in their users. Several companies are trying to develop such drugs, Arnsten says. Even if, as she would expect, the cognitive effects were much greater on people with schizophrenia than those without, the implications are remarkable. A smart successor to nicotine? It could be bigger than caffeine.