Historical perspectives on tardive dyskinesia.

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with dopamine receptor blocking agents including antipsychotic medications. Although uncertainty and concern about this drug side effect have vacillated since its initial recognition 60 years ago, recent commercial interest in developing effective treatments has rekindled scientific and clinical interest after a protracted period of neglect. Although substantial research has advanced knowledge of the clinical features and epidemiology of TD, many fundamental questions raised by early investigators remain unresolved. In this paper, we review the early clinical reports that led to the acceptance of TD as an iatrogenic disorder and the lingering controversies that emerged thereafter. Continued research on TD as a serious adverse reaction to treatment may not only enhance patient outcomes and recovery efforts but may also provide insights into both the mechanism of action of antipsychotic drugs and the nosology and pathophysiology of idiopathic psychomotor disorders.

The development of antipsychotic drugs.

Antipsychotic drugs revolutionised psychiatric practice and provided a range of tools for exploring brain function in health and disease. Their development and introduction were largely empirical but based on long and honourable scientific credentials and remarkable powers of clinical observation. The class shares a common core action of attenuating central dopamine transmission, which underlies the major limitation to their use - high liability to disrupt extrapyramidal function - and also the most durable hypothesis of the basis of psychotic disorders, especially schizophrenia. However, the Dopamine Hypothesis, which has driven drug development for almost half a century, has become a straight-jacket, stifling innovation, resulting in a class of compounds that are largely derivative. Recent efforts only cemented this tendency as no clinical evidence supports the notion that newer compounds, modelled on clozapine, share that drug's unique neurological tolerability and can be considered 'atypical'. Patients and doctors alike must await a more profound understanding of central dopamine homeostasis and novel methods of maintaining it before they can again experience the intoxicating promise antipsychotics once held.

Longitudinal gray matter change in young people who are at enhanced risk of schizophrenia due to intellectual impairment.

BACKGROUND: Existing studies of brain structural changes before the onset of schizophrenia have considered individuals with either familial risk factors or prodromal symptomatology. We aimed to determine whether findings from these studies are also applicable to those at enhanced risk of developing schizophrenia for another reason-intellectual impairment. METHODS: Participants with intellectual impairment (mean IQ: 78.2) received magnetic resonance imaging of the brain at baseline (mean age: 16 years old) and again 6 years later. The Positive and Negative Syndrome Scale was used to assess psychotic symptoms. Participants were dichotomized using their Positive and Negative Syndrome Scale scores at follow-up and gray matter changes were compared between the groups using tensor based morphometry and semiautomated region of interest analysis. RESULTS: Forty-six individuals had scans of sufficient quality to be included in the study. The tensor based morphometry analyses revealed that those with psychotic symptoms at follow-up showed significantly greater gray matter reductions over 6 years in the medial temporal lobes bilaterally. Region of interest analyses revealed that those individuals with psychotic symptoms at follow-up showed a reduced right hippocampal volume at age 16 and reduced bilateral hippocampal volumes at follow-up. CONCLUSIONS: This unique study of individuals vulnerable to schizophrenia due to intellectual impairment highlights aberrant development in the medial temporal lobe associated with the occurrence of psychotic symptoms. These developmental changes are also evident in populations at enhanced risk of schizophrenia for familial and symptomatic reasons, suggesting they are central to the development of the disorder regardless of the nature of the vulnerability state.

Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia.

A single nucleotide polymorphism (val66met) in the brain derived neurotrophic factor (BDNF) gene has been shown to be a risk factor for a number of psychiatric disorders, including schizophrenia. This polymorphism has also been shown to have effects on prefrontal brain morphology and function. This study aims to clarify the effects of the val66met polymorphism on prefrontal brain function in a population at high genetic risk for schizophrenia. The Edinburgh High Risk Study has followed young individuals who had one first- or second-degree relative with schizophrenia and a minimum of one further genetic relative with the illness. A sample of 62 individuals provided both genetic and functional imaging data using the Hayling sentence completion task. Individuals with the BDNF ValVal (presumed risk) genotype (n = 41) showed relatively increased activation of the anterior cingulate cortex in relation to Met carrier individuals (n = 21) during sentence completion conditions versus baseline, against a background of similar levels of task performance. It appeared from further investigation that this relatively increased activation was attributable to a failure to disengage or suppress activation in the high risk ValVal group during the task condition, suggesting that BDNF may contribute to the abnormal default network reported in schizophrenia. These results suggest that this gene affects prefrontal brain function in those at high genetic risk for the disorder, unconfounded by medication effects. BDNF may therefore be one of the heritable factors involved in the development of abnormal prefrontal function in schizophrenia. © 2010 Wiley-Liss, Inc.

Functional magnetic resonance imaging of BDNF val66met polymorphism in unmedicated subjects at high genetic risk of schizophrenia performing a verbal memory task.

Multiple strands of evidence suggest a role for Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology of schizophrenia. It is not yet clear, however, how BDNF may contribute to altered brain function seen in the disorder, or in those at high genetic risk. The current study examines functional imaging correlates of the BDNF val66met polymorphism in a population at high genetic risk of schizophrenia. Subjects at high genetic risk for the disorder (n=58) provided both BDNF genotyping and fMRI data while performing a verbal memory task. During encoding, participants were presented with a word and asked to make a 'living'/'non-living' classification. During retrieval, individuals were requested to make an 'old'/'new' word classification. For encoding, we report decreased activation of the inferior occipital cortex and a trend in the cingulate cortex in Val homozygote individuals relative to Met carriers. For retrieval, we report decreases in activation in the prefrontal, cingulate cortex and bilateral posterior parietal regions in Val homozygote individuals versus Met carriers. These findings add to previous evidence suggesting that genetic variation in the BDNF gene modulates prefrontal and limbic functioning and suggests that it may contribute to differences in brain function seen in those at high risk of the disorder.

A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms.

NRG1, encoding neuregulin 1, is a susceptibility gene for schizophrenia, but no functional mutation causally related to the disorder has yet been identified. Here we investigate the effects of a variant in the human NRG1 promoter region in subjects at high risk of schizophrenia. We show that this variant is associated with (i) decreased activation of frontal and temporal lobe regions, (ii) increased development of psychotic symptoms and (iii) decreased premorbid IQ.

A neuropsychological investigation into 'Theory of Mind' and enhanced risk of schizophrenia.

Theory of Mind (ToM) is the ability to correctly determine the intentions and behaviours of others. It is known that this capability is compromised in individuals with schizophrenia. It is has not been fully elucidated whether this observed phenomenon is of a state or trait nature. This study investigated whether ToM impairments could be linked to schizophrenia liability. A battery of ToM tests (the Hinting Task, a Self-Monitoring drawing task and cartoon picture stories) were used to compare healthy controls (n=13) with relatives of individuals with schizophrenia who had experienced psychotic symptoms (HR+, n=12) and those relatives who had not (HR-, n=13). All participants belonged to the Edinburgh High Risk Study. Significant group differences were seen on the Self-Monitoring and cartoon tasks for the HR+ group, particularly those who had experienced symptoms at or around the time of testing. The observed ToM deficits measured by this battery of ToM tasks appeared to be related to state effects rather than enhanced risk of schizophrenia.

A visual joke fMRI investigation into Theory of Mind and enhanced risk of schizophrenia.

Theory of Mind (ToM) or mentalizing is the ability of individuals to determine the intentions and behavior of others. This ability is known to be compromised in schizophrenia and has been shown to fluctuate with symptom severity. Neuropsychological investigations into relatives of individuals with schizophrenia have shown that some relatives also show a deficit in this area of social cognition. In order to address this state and trait issue, we investigated the performance of high-risk relatives of individuals with schizophrenia to those of a matched control group (n = 13) on a blocked design visual joke fMRI paradigm. The task involved looking at two sets of cartoon jokes, one set which required mentalizing abilities to understand the jokes and another set that did not require such abilities. Relatives were divided into two groups based on the presence (HR+, n = 12) or absence (HR-, n = 12) of positive symptoms. The task provided robust activations across the groups in areas previously associated with mentalizing abilities, such as the PFC, precuneus, and temporal lobes. Significant between-group activations were observed in the PFC (primarily BA6, 8, and 9) with the HR- activating significantly greater than the HR+ in these regions. Both a secondary state-specific analysis and a third post hoc analysis further investigating state effects showed significant PFC between-group differences. This study is the first time relatives of individuals with schizophrenia have been imaged using a ToM paradigm, and the results provide evidence of both a state and state-mediated trait effect.