Dissecting psychosis

People often think of psychosis as being a frightening - and extreme - condition, yet it is more common than diabetes in young adults: around three out of every 100 young people will experience a psychotic episode. Symptoms vary from being afraid to leave the house, withdrawing from friends or family, and having confused, slowed or racing thoughts, through to delusions and hallucinations, and hearing voices that no one else can hear.

Moreover, since the illness takes many different forms and can change markedly over time, it can be hard to predict how a psychotic patient will fare in the long term. Some people respond well to medication, recover and are never ill again - while others suffer repeated episodes and deteriorate.

"This heterogeneity of symptoms and outcomes makes it difficult to make an accurate diagnosis, and therefore deliver effective, targeted treatments," explains Professor Eileen Joyce at Imperial College London. The problem is compounded by the fact that similar psychotic symptoms are seen in both schizophrenia and bipolar disorder (manic depression), yet these are currently classified as separate conditions. Furthermore, the diagnosis is based purely on observation of symptoms: "There are no biological markers indicating whether a patient with psychotic symptoms has schizophrenia or bipolar disorder, and as a result some patients are misdiagnosed in the early stages of illness," says Professor Joyce.

Professor Joyce and Professor Thomas Barnes at Imperial, and Professor Maria Ron and Dr Gareth Barker at the Institute of Neurology, are seeking to understand more about the biological basis of psychosis. In 1995, they began a five-year study into ‘first-episode’ schizophrenia (i.e. working with patients after their first psychotic attack), which enabled them to describe motor (movement), oculomotor (eye movement), cognitive and brain abnormalities associated with the disease. Supported by a new Wellcome Trust programme grant they are now extending the study to embrace all forms of psychosis, including bipolar disorder. "In this new five-year longitudinal study, we want to characterise further cognitive impairments and structural brain abnormalities, and to establish relationships between these and clinical symptoms," says Professor Joyce.

Brain structure and function

The team will be looking at first-episode psychosis patients in a geographically defined catchment area covering a population of a million inner and outer London residents. "This will ensure that we get a representative sample and capture the entire range of psychotic phenotypes," explains Professor Joyce. "We want to focus on first-episode patients, partly because diagnostic boundaries are imprecise at onset, and partly because some of our measures may be contaminated by long-term medication, inactivity and withdrawal from society. We want to pick up abnormalities related solely to the illness."

Professor Ron and Dr Barker are testing the usefulness of new, highly sensitive magnetic resonance imaging (MRI) techniques to detect structural changes in the brain. "Conventional MRI techniques can only detect brain abnormalities when they are severe enough to cause loss of brain volume, and they don’t tell us enough about the pathological processes going on," says Professor Ron. The new approaches, magnetisation transfer imaging and diffusion tensor imaging, have the potential to provide more specific neuropathological information and to detect abnormalities invisible on conventional MRI.

To look at how structural brain abnormalities relate to cognitive abnormalities, Dr Joyce and Professor Barnes will apply the widely used Cambridge Automated Neuropsychological Tests Battery (CANTAB) - a series of tasks, which probe cognitive flexibility, decision making and planning. "These tests have been used in other neurological disorders, where the pathology is well defined, like Alzheimer’s disease and Parkinson’s disease, or where the brain damage is localised to particular areas of the cerebral cortex. So we can use the results in those patients to compare the results in our patients," explains Professor Joyce.

The cognitive tests will be complemented by oculomotor tests. "The brain systems that control eye movement are very well understood and we can get an exact measure of how well they’re functioning," explains Professor Joyce. "We ask patients to do very precise tasks with their eyes and analyse their errors. Comparing and contrasting eye movement deficits in patients helps us understand more about their cognitive function."

Symptoms

Over the past ten or so years two main types of cognitive deficit have been identified in patients with schizophrenia: memory and executive function. "The memory impairment means you may have trouble in remembering things you have done or need to do. Executive function involves things like decision making, planning and forming strategies. It helps you to use your store of knowledge to confront new situations in an appropriate way. If that’s impaired, you may find it hard to respond to new challenges in day-to-day life." Some executive functions seem to improve with treatment, whereas others may even deteriorate. "We need to determine which impairments are progressive to help guide the timing and targeting of treatment."

An important recent discovery has been that of all the symptoms of psychosis, cognitive function is one of the main indicators of how a patient will function socially and occupationally in the long term. "People seem to be able to function if they have hallucinations or delusions, but not if they have memory or executive impairment. We’re trying to find out more about whether cognitive function can be used as an accurate predictive measure. That’s the importance of doing a longitudinal study, with repeated measures, over a period of five years."

Another important aim of the study is to clarify the differences and increasingly acknowledged similarities between bipolar disorder and schizophrenia. Recent evidence suggests that both cognitive and brain abnormalities found in bipolar disorder overlap with those found in schizophrenia, suggesting they could be facets of the same illness, psychosis.

"We want to answer the scientific question: are we dealing with one type of illness that differs across a single dimension, or two separate illnesses?" says Professor Joyce. "There may be subgroups of patients with different clusters of symptoms and cognitive profiles, and different trajectories, that cut across diagnostic boundaries. If so, we want to identify them, and find out what areas of the brain are involved so that we can establish better biologically-based phenotypes."

The research team also want to establish whether psychosis is a progressive rather than a static disease, at least in some patients. "We want to look at changes over time, to see whether there is deterioration in our three biological measures - brain abnormalities, oculomotor function and cognitive function. We will track patients over the five-year period of the study and compare changes with a group of healthy controls."

The team also hope to look at the effects of different types of medication on the course of the illness - and whether early intervention can make a difference to the outcome of the illness by preventing deterioration. Currently, some drugs seem to improve some aspects of the illness; others seem to make it worse.

By collecting information from such a large population - the west London study is probably the largest of its type in the world - the team should be able to tease apart various subtypes of schizophrenia psychosis. A key goal is to move from a subjective description of psychosis towards biological features that can be measured and assessed over time. Most immediately that could lead to more accurate diagnosis and better targeted drug treatments, while in the longer term it should contribute to a better understanding of this mysterious and distressing condition.

See also

• Escaping the rollercoaster: Article on borderline personality disorder.
• Mad, bad or ill?: Article on new insights into antisocial behaviour
• Listening more closely to Prozac: Article on the growth of biomedical models of brain function
• Getting back on an even keel: Article on comparing people-based treatments for psychosis

Further reading

Foong J, Symms M R, Barker G J, Maier M, Woermann F G, Miller D H, Ron M A (2001). Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging. Brain, 124: 882-92.

Sigmundsson T, Suckling J, Maier M, Williams S C R, Bullmore E T, Greenwood K E, Fukuda R, Ron M A, Toone B K (2001). Structural abnormalities in frontal, temporal and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. American Journal of Psychiatry, 158: 234-43.

Foong J, Symms M R, Barker G J, Maier M, Miller D H, Ron M A (2002). Investigating regional white matter in schizophrenia using diffusion tensor imaging. Neuro Report, 13: 333-336.