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WHO Bulletin - World Health Organization

The genetics of mental illness: implicationsfor practiceSteven E. Hyman1 Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neuralsubstrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history andtreatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born ofearly pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explainthe pathogenesis of depression or schizophrenia.

only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic ... Bulletin of the World Health Organization, 2000, 78(4) # World Health Organization 2000 455 ...

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Transcription of WHO Bulletin - World Health Organization

1 The genetics of mental illness: implicationsfor practiceSteven E. Hyman1 Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neuralsubstrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history andtreatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born ofearly pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explainthe pathogenesis of depression or schizophrenia.

2 Gone is the notion that there is a single gene that causes any mentaldisorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of geneticcomplexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental in genetics and neuroscience can be expected to lead to better models that provide improvedrepresentation of the complexity of the brain and behaviour and the development of both. There are likely to beprofound implications for clinical practice.

3 The complex genetics of risk should reinvigorate research on theepidemiology and classification of mental disorders and explain the complex patterns of disease transmission withinfamilies. Knowledge of the timing of the expression of risk genes during brain development and of their function shouldnot only contribute to an understanding of gene action and the pathophysiology of disease but should also help todirect the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes canonly become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscienceand the behavioural sciences.

4 Genetics should yield new therapies aimed not just at symptoms but also at pathogenicprocesses, thus permitting the targeting of specific therapies to individual :mental disorders, genetics; neurosciences; mental disorders, drug therapy; genetic predisposition todisease; antipsychotic agents, therapeutic page 460 le re sume en franc ais. En la pa gina 461 figura un resumen en espan is worth considering the complexity of the humanbrain so as to put in perspective what is required ofgenetic tools. The brain is the most complex object ofinvestigation in the history of biological science.

5 Itsdevelopment depends on complex, often non-linear,gene gene and gene-environment interactions, aswell as on stochastic processes associated with theinterconnection of 100 000 million or more we are beginning to understand, the complexity ofthe brain and the combinatorial interactions of manygenes and non-genetic signals involved in building itare consistent with the richness of our mental livesand behaviour. This complexity, however, has madeprogress in the neuroscience and genetics of mentalillness exceedingly difficult. Each neuron in the brainmakes thousands of connections or synapses withneighbouring and distant neurons; there are probablymore than 100 trillion such connections, and acrossthem each neuron may utilize several of more than100 chemical neurotransmitters.

6 Signals encoded byeach neurotransmitter are decoded by the receivingcell, using one or several of the many receptorsubtypes that exist for each neurotransmitter. Forexample, the neurotransmitter serotonin has at least14 different known subtypes of receptors. Neuro-transmitter receptors initiate complex signallingcascades within nerve cells. These cascades processinformation, produce immediate outputs, such as adecision to fire, and, at the same time, initiate long-term, activity-dependent changes in the receivingcells which may eventually lead to synaptic synapse is embedded in one or more neuralcircuits that can be recruited or engaged withexquisite specificity.

7 In the basal ganglia, for example,a given neuron might fire in conjunction with aparticular movement made as part of a specificbehavioural task, but not with the same movementwhen in a different behavioural situation (1).The crowning complexity of the brain, how-ever, is that it is not static. Every time something newis learnt, whether a new name, a new skill or a newemotional reaction, the active neurons alter thesynaptic architecture of the circuit in which thelearning has occurred. This process is termedplasticity; new synapses may be formed and old onesmay be pruned; existing synapses may be strength-ened or weakened.

8 As a result, information isprocessed differently. Ultimately, in ways not yetunderstood, our mental lives and behaviour are1 Director, National Institute of Mental Health , 6001 ExecutiveBoulevard, Room 8235, MSC 9669, Bethesda, MD 20892-9669, of the World Health Organization , 2000,78(4)# World Health Organization 2000emergent properties of the firing patterns of neuronswithin the parallel, distributed and potentially plasticcircuits of our of the brain, whatever their patho-physiological basis, ultimately affect behaviour byaltering the function of brain circuits.

9 For example,stroke is an illness in which neurons die because of alack of oxygen. This event may create gaps in circuitsthat traverse the damaged area or kill cells that giverise to neural projections. The precise functionaldeficit depends on the circuits that have beendisrupted and on the location. In most individuals,for example, information processing and importantoutputs required for the production of fluent speechcome together in Broca s area of the left hemisphereof the cerebral cortex. Stroke in this region oftencauses a motor aphasia, but damage to other regionsof speech circuitry may produce related aphasicsymptoms.

10 Despite the ability of the brain to adapt,brain diseases remind us that natural processes ofplasticity are finite. In adults, only partial recoveryfrom a Broca s aphasia is the rule. In some situations,such as in chronic neuropathic pain resulting fromnerve damage (2), the processes underlying plasticitycan be subverted by illness or injury so as to produceserious symptoms. Indeed, the pathogenesis ofaddictive disorders (3) and post-traumatic stressdisorder (4) may represent the usurpation of normallearning processes in reward and fear as specific neural circuitry underliesprimary sensory processes ( vision or touch) andmotor control, it is now recognized that specificidentifiable circuits underlie different aspects ofcognition (5) and emotion (6,7).


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