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Schizophrenia and psychotic disorders

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A decade for psychiatric disorders

There are many ways in which the understanding and treatment of conditions such as schizophrenia are ripe for a revolution. A media circus surrounded President Bill Clinton’s visit to a New York medical centre in 2004 for a quadruple heart bypass.

Yet barely a whisper was heard about other high-profile individuals’visits there for the treatment of psychiatric disorders. In Britain, the public donates £500 million (US$800 million) each year to charities for cancer research. For mental-health research, the figure is a few million, and most of that is for work on neurodegenerative diseases such as Alzheimer’s, rather than for earlieronset conditions that can undermine people’s entire lives, such as depressive disorders. It is time for such disparities to be addressed in a more coherent and aggressive way than in the past. The stigma of psychiatric disorders is misplaced, their burdens on society are significantly greater than more publicized diseases in developed and developing nations alike, and biomedical science is poised to make significant strides. The timescales are daunting and the challenges great — human neurons are less accessible than tumour cells, separating genetic and environmental influences is tough, and the diagnosis of the conditions is highly problematic. There is much to be done, and a decade is the timescale over which enhanced commitment is required. The problem of stigma persists. In some countries, progress in this regard has been made with depression: a few high-profile and brave sufferers in some Western countries have stood up and identified themselves. By contrast, schizophrenia, when covered by the media at all, is mostly associated with murders carried out by a tiny minority of sufferers who have an acute form of the condition.

Research challenges

Schizophrenia — a combination of delusions, reduced motivation and diminished cognitive functions — exemplifies many of the research challenges posed by psychiatric disorders as a whole. The extreme behaviours covered by the media are far from typical. Population studies indicate that the lifetime prevalence of all psychotic disorders (whose sufferers experience some sort of misperception of reality) is as much as 3%. Schizophrenia is controllable by medication and cognitive therapy, with a significant chance (a few tens of per cent) of beneficial positive outcomes. Frustratingly, the effectiveness of medications has stalled. Nobody understands the links between the symptoms of schizophrenia and the crude physiological pathologies that have so far been documented: a decrease in white brain matter, for example, and altered function of the neurotransmitter dopamine. The medications, which are often aimed at the dopamine systems associated with delusions, have advanced over the decades not in their efficacy but in a reduction of their debilitating side effects. Both diagnosis and drugs primarily address a late stage in the development of schizophrenia — the presentation of delusions. The earlier stages are much less well defined and are ambiguous in that, as currently characterized, they could lead to a number of alternative conditions. Here, above all, is where progress is needed in the form of reliable biomarkers to identify those at risk and to allow biomedical or cognitive interventions to prevent or mitigate the development of the disorders. Early intervention would lead to better outcomes. A deeper understanding of the underlying biology is essential to improve diagnoses and therapies. New techniques — genome-wide association studies, imaging and the optical manipulation of neural circuits — are ushering in an era in which the neural circuitry underlying cognitive dysfunctions, for example, will be delineated. Tantalizingly, work in genetics is indicating how non-specific some genes are for schizophrenia, having associations in common with bipolar disorder and with autism. This suggests that the earlier stages of psychiatric disorders are multi valent, reinforcing the hope that early detection, coupled with a clearer understanding of the environmental factors, may allow prevention.

Environmental influence

Too little fundamental research is devoted to environmental factors. About 80% of the pattern of schizophrenia in populations seems to be determined by genetics, but part of that genetic influence lies in susceptibility to environmental influences. The remaining 20% of direct environmental influence is also ripe for more extensive investigation — epidemiological studies point to social stress (associated, for example, with migration or urbanization) as a significant influence, albeit in a minority of schizophrenia sufferers. As stated in a recent review of schizophrenia, a “worldwide challenge is to bring together the various disciplines that are needed to examine models of disease causation based on various aspects of gene–environment interplay” (J. van Os and S. Kapur Lancet 374, 635–645; 2009). Of course it won’t be just the basic biology of molecules and their circuits that will be essential in understanding the mechanisms of schizophrenia. There is a higher level of explanation required to understand, for example, delusions and their persistence. Whether for schizophrenia, depression, autism or any other psychiatric disorders, it is clear, as Tom Insel, head of the US National Institute of Mental Health has emphasized (T. R. Insel J. Clin. Invest. 119, 700–705; 2009), that understanding of these conditions is entering a scientific phase more penetratingly insightful than has hitherto been possible. But Insel also highlights the disruptive impact of the science on the practices of clinical psychiatrists — as biological insights develop, the crudity of current psychiatric diagnoses will become all too clear. Yet the exposure of many psychiatrists to contemporary biology is shallow at best. That, too, will need to change over the next decade. Nat Rev Neurosci. 2009 Jan;10(1):48-58. Epub 2008 Dec 3. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia.

Fletcher PC, Frith CD.

University of Cambridge, Department of Psychiatry, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ , UK.

Advances in cognitive neuroscience offer us new ways to understand the symptoms of mental illness by uniting basic neurochemical and neurophysiological observations with the conscious experiences that characterize these symptoms. Cognitive theories about the positive symptoms of schizophrenia—hallucinations and delusions—have tended to treat perception and belief formation as distinct processes. However, recent advances in computational neuroscience have led us to consider the unusual perceptual experiences of patients and their sometimes bizarre beliefs as part of the same core abnormality—a disturbance in error-dependent updating of inferences and beliefs about the world. We suggest that it is possible to understand these symptoms in terms of a disturbed hierarchical Bayesian framework, without recourse to separate considerations of experience and belief.

Br J Psychiatry. 2009 Nov;195(5):382-90. Harmonisation of ICD -11 and DSM -V: opportunities and challenges.

First MB.

New York State Psychiatric Institute, Columbia University Department of Psychiatry, 1051 Riverside Drive – Unit 60, New York, NY 10032 , USA. mbf2@columbia.edu

Comment in:

  • Br J Psychiatry. 2009 Nov;195(5):379-81.

BACKGROUND : Differences in the ICD -10 and DSM -IV definitions for the same disorder impede international communication and research efforts. The forthcoming parallel development of DSM -V and ICD -11 offers an opportunity to harmonise the two classifications. AIMS : This paper aims to facilitate the harmonisation process by identifying diagnostic differences between the two systems. METHOD : DSM-IV-TR criteria sets and the ICD -10 Diagnostic Criteria for Research were compared and categorised into those with identical definitions, those with conceptually based differences and those in which differences are not conceptually based and appear to be unintentional. RESULTS : Of the 176 criteria sets in both systems, only one, transient tic disorder, is identical. Twenty-one per cent had conceptually based differences and 78% had non-conceptually based differences. CONCLUSIONS : Harmonisation of criteria sets, especially those with non-conceptually based differences, should be prioritised in the DSM -V and ICD -11 development process. Prior experience with the DSM -IV and ICD -10 harmonisation effort suggests that for the process to be successful steps should be taken as early as possible.

Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G.

Lancet. 2007 Jul 28;370(9584):319-28. Review.PMID: 17662880 [PubMed – indexed for MEDLINE ]Related articles

Hum Genet. 2009 Jul;126(1):3-12. Epub 2009 Jun 12. Genetics of psychosis; insights from views across the genome.

O’Donovan MC, Craddock NJ, Owen MJ.

Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Heath Park, Cardiff CF23 6BQ , UK. odonovanmc@cf.ac.uk

The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

Harrison PJ, Weinberger DR.

Mol Psychiatry. 2005 Jan;10(1):40-68; image 5. Review. Erratum in: Mol Psychiatry. 2005 Apr;10(4):420. Mol Psychiatry. 2005 Aug;10(8):804. PMID : 15263907 [PubMed – indexed for MEDLINE ]Related articl es

Kirkbride JB & Jones PB, 2008, The Mental Ill-Health of People Who Migrate and Their Descendants: Risk Factors, Associated Disability and Wider Consequences. Mental Capital and Wellbeing Foresight State of Science Review SR-B13. Accessible from

http://www.foresight.gov.uk/OurWork/ActiveProjects/Mental%20Capital/ProjectOutputs.asp

This talk is part of the Graduate Programme in Cognitive and Brain Sciences series.

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