The eye-catching title of the 2014 Paykel Lecture certainly lived up to its promise of a fascinating talk. Delivered by Dr Oliver Howes of the Institute of Psychiatry, Psychology and Neuroscience (IoPPN – King’s College London), the title made reference to an early paper on the dopamine hypothesis of schizophrenia, where dopamine was referred to as “the wind of the psychotic fire.” An eloquent review of the dopamine hypothesis followed, from the perspective of studies employing positron emission tomography (PET) and magnetic resonance imaging (MRI).
Dopamine is an important neurotransmitter, playing a crucial role in brain processes such as how we predict events and experience rewards. Its over-abundance in the brain has long been posited as a theory for the symptoms of psychosis seen in people with schizophrenia. Brain imaging techniques such as PET, which uses a radioactively labelled tracer, can help us obtain information about all aspects of the dopamine system. We can specifically study dopamine receptors, dopamine synthesis, its transportation or its release from neurons, and these methods have allowed scientists to pinpoint abnormalities in schizophrenia.
Using this technology, Dr. Howes and colleagues studied people with schizophrenia who had received very little treatment, and found that the abnormality of dopamine appears to be at the level of synthesis and release from brain cells, rather than at the receptor as was initially believed.
But this, Dr. Howes went on to explain, does not tell us whether schizophrenia is caused by an abnormality in dopamine regulation, or whether increased dopamine is a result of having schizophrenia. Therefore, his group decided to conduct research studies with a group of people who were at high risk of developing schizophrenia but do not yet show symptoms adequate for a diagnosis. These people are said to be in the prodromal, or sub-clinical, phase of schizophrenia. Whilst many go on to develop further symptoms, some remain stable at the sub-clinical phase and are able to function perfectly well. A prominent historical example of such a person, Dr. Howes explains, was Joan of Arc. Despite hearing voices (which she attributed to angels), she was able to lead the French army to victory over the British.
Thus, using the same PET imaging techniques, Dr Howes and his team found elevated dopamine synthesis in the striatum of people with sub-clinical symptoms, which appeared to be around halfway between controls and people diagnosed with schizophrenia. Further investigation found that this increase in dopamine was in fact specific to those who would go on to develop a full clinical syndrome of schizophrenia, while those with long term sub-clinical symptoms did not demonstrate any increase in dopamine synthesis.
But what is it, Dr. Howes pondered, that the biology of schizophrenia needs to explain? The answer he came up with: Neurodevelopmental and sociodevelopmental risk factors (e.g drugs or stress), and symptoms.
Based on research ongoing in his group, Dr. Howes (alongside Professor Sir Robin Murray) proposed a model to explain how these risk factors and symptoms might fit into the dopamine hypothesis. They proposed that a combination of genes and hazards to the brain disrupt the development of the dopamine system, and cause it become very sensitive. Social stress then acts on this sensitised system, increasing dopamine release, leading to irregular cognitive processing of events. This in turn leads to a paranoid interpretation of events and eventually psychosis, which in itself is a stressful experience, causing a vicious cycle of stress and increased dopamine release.
While this model both supports and is supported by much of the research into the dopamine hypothesis, there are many questions outstanding, and the hypothesis is far from being finally accepted or refuted. Dr Howes identified that further work needs to be done to understand why approximately one third of people with schizophrenia are resistant to treatment with antipsychotic drugs, which act on the dopamine system. The causes of the ‘negative symptoms’ of schizophrenia (e.g. affective flattening, or a reduced display of emotion) and the relationship with substance misuse (such as cannabis, which was not found to increase dopamine in the striatum when cannabis smokers experienced psychotic like symptoms as a result of their drug use).
Dr. Oliver Howes is a group head and reader in imaging of neurochemical processing in psychosis at Kings College London and at the MRC CSC psychiatric imaging group, Hammersmith Hospital, Imperial College. Dr. Howes has been the recipient of many prestigious awards, including most recently the Schizophrenia International Research Society Rising Star Award 2013.