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What provokes the onset of psychosis?
S. 01. Early intervention and relapse prevention in schizophrenia
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provokes the onset of psychosis?
R. Murray. Institute of Psychiatry, London, United Kingdom Family and twin studies have demonstrated a major genetic component to schizophrenia. However, biometrical and molecular genetic studies demonstrate that no single gene exists which increases the risk of schizophrenia more than threefold - a number of genes must therefore be involved. Among twins with schizophrenia who have presented to the Maudsley Hospital, concordance rates are much higher for those MZ twins who present early and showed premorbid social dysfunction (Cardno et al, 1999). This, and the evidence that the relatives of schizophrenic patients show minor variants of some of the deviations found in their affected kin (e.g. increased lateral ventricular volume), suggests that some of these genes operate via neurodevelopmental impairment. Large, well-designed epidemiological studies have conclusively demonstrated a modest association between schizophrenia and obstetric hazards such as preterm and low birth weight, exposure to prenatal viral infection and perinatal hypoxic-ischaemic damage (Hultman et al, 1999). These obstetric hazards have a more adverse effect on brain structures such as the hippocampus in individuals carrying genetic susceptibility for schizophrenia. Children who later go on to develop schizophrenia tend to have minor developmental delays, a mean IQ about 5 points lower than their peers, as well as social anxiety and interpersonal problems; unfortunately, the predictive power of such characteristics is very low. When do psychotic symptoms begin? In some cases, much earlier than previously anticipated. We (Poulton et al, 2000) have reported on a study in which 789 children aged 11 years were interviewed with the DISC. 96% were re-interviewed at age 26 years using the DIS and 3.7% met DSMIV criteria for schizophreniform disorder. The risk of schizophreniform disorder was increased sixteen-fold in those children who had answered yes to one of 4 questions at age 11 concerning a) their mind being read b) having had a message from the TV/radio c) people following them d) hearing a voice. But what converts an anxious and odd adolescent with some subtle cognitive difficulties and odd ideas into frank psychosis? Recent evidence makes it clear that actively psychotic individuals release more dopamine in response to amphetamine, and the extent of release correlates with degree of psychosis. The excessive dopamine results in excessive salience being attributed to external objects and experiences (producing delusions) and internal thoughts (producing hallucinations). The dysregulation of dopamine is postulated to arise from a process of sensitisation. What causes this? Animal experiments show that such sensitisation can be caused by repeated abuse of dopamine-releasing drugs such as amphetamines, and cocaine. Increasingly, it is clear that the same process can occur in humans, and that some individuals are particularly sensitive to this, either for genetic reasons or through early environmental damage. For example, methamphetamine abusers who develop psychosis are distinguished from those who don't by having relatives with a greater morbid risk of schizophrenia, suggesting that some of the susceptibility genes involve dopamine; this is supported by evidence that in response to a challenge the relatives of schizophrenics produce more HVA than controls. Cannabis appears to have similar risk-increasing effects, as shown by the Swedish Army study, in which those who had taken cannabis more than 50 times at age 18 were 6 times more
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likely to develop psychosis over the next 13 years. We have recently replicated these findings in the Dunedin Follow-up Study (Arseneaux et al, unpublished data). Stress can induce dopamine release in animal studies, and those who have undergone early hippocampal lesions have a particularly strong response. Epidemiological studies have demonstrated the risk-increasing effects of adverse life events for psychosis. There is ample evidence that being a migrant is also a risk factor (Sharpley et al, 2001), and that this is mediated by social isolation. In particular, a recent study shows that the risk in migrants and their children in London is related to the proportion of the population that ethnic minorities comprise in the area in which they live (Boydell et al, 2001). Similar factors may underlie the effect of being raised in cities rather than rural areas. Finally, certain aspects of the schizophrenia syndrome such as schizoaffective symptoms and positive thought disorder have much in common with bipolar disorder, a condition not generally considered to be neurodevelopmental in origin. The most plausible explanation is that some of the genes for schizophrenia appear to be shared with those for schizoaffective disorder and bipolar disorder, and that mood disorder is in itself a risk factor for psychosis, Conclusion: Schizophrenia results from the cumulative operation of a number of risk factors, some but not all of which are neurodevelopmental. Such a view posits that some individuals inherit a number of slightly deviant traits, each of which is not uncommon in the general population but which together render them vulnerable to schizophrenia. This genetic vulnerability may be compounded by early insults to the developing brain. As a result, the child shows slight developmental delays, minor cognitive difficulties and social anxiety. These set the child apart from his/her peers and he/she begins to have quasi-psychotic ideas about them; the reactions of others compound the situation. The child develops on an increasingly deviant social trajectory, becoming increasingly isolated and odd. Finally, stresses in adolescence or early adult life, such as drug abuse, social adversity or, indeed, affective disorder may push the individual over a threshold to the expression of frank psychosis.
References [1] Boydell J, van Os J, McKenzie K, Allardyce J, Goel R, McCreadie R G, Murray R M (2001). Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. British Medical Journal 323, 1336-8. [2] Cardno A, Marshall J, Coid B, Macdonald A, Ribchester T, Davies N, Venturi R Jones L, Lewis S, Sham P, Gottesman I, Farmer A, McGuffin R Reveley A, Murray R (1999). Heritability estimates for psychotic disorders: The Maudsley Twin Psychosis Series. Arch Gen Psychiatry 56, 162-168. [3] Hultman C M, Sparen P, Takei N, Murray R M, Cnattingius S (1999). Prenatal and perinatal risk factors for schizophrenia, affective psychosis and reactive psychosis of early onset: case-control study. British Medical Journal 318, 421-425. [4] Poulton R, Caspi A, Moffitt T E, Cannon M, Murray R, Harrington H (2000). Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Arch Gen Psychiatry 57, 1053-8. [5] Sharpley M S, Hutchinson G, McKenzie K and Murray R M (2001). Understanding the excess of psychosis among the African-Caribbean population in England: review of current hypotheses. British Journal of Psychiatry 178(suppl.40), s60-8.
•
W
h
a
t
provokes the onset of psychosis?
R. Murray. Institute of Psychiatry, London, United Kingdom Family and twin studies have demonstrated a major genetic component to schizophrenia. However, biometrical and molecular genetic studies demonstrate that no single gene exists which increases the risk of schizophrenia more than threefold - a number of genes must therefore be involved. Among twins with schizophrenia who have presented to the Maudsley Hospital, concordance rates are much higher for those MZ twins who present early and showed premorbid social dysfunction (Cardno et al, 1999). This, and the evidence that the relatives of schizophrenic patients show minor variants of some of the deviations found in their affected kin (e.g. increased lateral ventricular volume), suggests that some of these genes operate via neurodevelopmental impairment. Large, well-designed epidemiological studies have conclusively demonstrated a modest association between schizophrenia and obstetric hazards such as preterm and low birth weight, exposure to prenatal viral infection and perinatal hypoxic-ischaemic damage (Hultman et al, 1999). These obstetric hazards have a more adverse effect on brain structures such as the hippocampus in individuals carrying genetic susceptibility for schizophrenia. Children who later go on to develop schizophrenia tend to have minor developmental delays, a mean IQ about 5 points lower than their peers, as well as social anxiety and interpersonal problems; unfortunately, the predictive power of such characteristics is very low. When do psychotic symptoms begin? In some cases, much earlier than previously anticipated. We (Poulton et al, 2000) have reported on a study in which 789 children aged 11 years were interviewed with the DISC. 96% were re-interviewed at age 26 years using the DIS and 3.7% met DSMIV criteria for schizophreniform disorder. The risk of schizophreniform disorder was increased sixteen-fold in those children who had answered yes to one of 4 questions at age 11 concerning a) their mind being read b) having had a message from the TV/radio c) people following them d) hearing a voice. But what converts an anxious and odd adolescent with some subtle cognitive difficulties and odd ideas into frank psychosis? Recent evidence makes it clear that actively psychotic individuals release more dopamine in response to amphetamine, and the extent of release correlates with degree of psychosis. The excessive dopamine results in excessive salience being attributed to external objects and experiences (producing delusions) and internal thoughts (producing hallucinations). The dysregulation of dopamine is postulated to arise from a process of sensitisation. What causes this? Animal experiments show that such sensitisation can be caused by repeated abuse of dopamine-releasing drugs such as amphetamines, and cocaine. Increasingly, it is clear that the same process can occur in humans, and that some individuals are particularly sensitive to this, either for genetic reasons or through early environmental damage. For example, methamphetamine abusers who develop psychosis are distinguished from those who don't by having relatives with a greater morbid risk of schizophrenia, suggesting that some of the susceptibility genes involve dopamine; this is supported by evidence that in response to a challenge the relatives of schizophrenics produce more HVA than controls. Cannabis appears to have similar risk-increasing effects, as shown by the Swedish Army study, in which those who had taken cannabis more than 50 times at age 18 were 6 times more
$83
likely to develop psychosis over the next 13 years. We have recently replicated these findings in the Dunedin Follow-up Study (Arseneaux et al, unpublished data). Stress can induce dopamine release in animal studies, and those who have undergone early hippocampal lesions have a particularly strong response. Epidemiological studies have demonstrated the risk-increasing effects of adverse life events for psychosis. There is ample evidence that being a migrant is also a risk factor (Sharpley et al, 2001), and that this is mediated by social isolation. In particular, a recent study shows that the risk in migrants and their children in London is related to the proportion of the population that ethnic minorities comprise in the area in which they live (Boydell et al, 2001). Similar factors may underlie the effect of being raised in cities rather than rural areas. Finally, certain aspects of the schizophrenia syndrome such as schizoaffective symptoms and positive thought disorder have much in common with bipolar disorder, a condition not generally considered to be neurodevelopmental in origin. The most plausible explanation is that some of the genes for schizophrenia appear to be shared with those for schizoaffective disorder and bipolar disorder, and that mood disorder is in itself a risk factor for psychosis, Conclusion: Schizophrenia results from the cumulative operation of a number of risk factors, some but not all of which are neurodevelopmental. Such a view posits that some individuals inherit a number of slightly deviant traits, each of which is not uncommon in the general population but which together render them vulnerable to schizophrenia. This genetic vulnerability may be compounded by early insults to the developing brain. As a result, the child shows slight developmental delays, minor cognitive difficulties and social anxiety. These set the child apart from his/her peers and he/she begins to have quasi-psychotic ideas about them; the reactions of others compound the situation. The child develops on an increasingly deviant social trajectory, becoming increasingly isolated and odd. Finally, stresses in adolescence or early adult life, such as drug abuse, social adversity or, indeed, affective disorder may push the individual over a threshold to the expression of frank psychosis.
References [1] Boydell J, van Os J, McKenzie K, Allardyce J, Goel R, McCreadie R G, Murray R M (2001). Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. British Medical Journal 323, 1336-8. [2] Cardno A, Marshall J, Coid B, Macdonald A, Ribchester T, Davies N, Venturi R Jones L, Lewis S, Sham P, Gottesman I, Farmer A, McGuffin R Reveley A, Murray R (1999). Heritability estimates for psychotic disorders: The Maudsley Twin Psychosis Series. Arch Gen Psychiatry 56, 162-168. [3] Hultman C M, Sparen P, Takei N, Murray R M, Cnattingius S (1999). Prenatal and perinatal risk factors for schizophrenia, affective psychosis and reactive psychosis of early onset: case-control study. British Medical Journal 318, 421-425. [4] Poulton R, Caspi A, Moffitt T E, Cannon M, Murray R, Harrington H (2000). Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Arch Gen Psychiatry 57, 1053-8. [5] Sharpley M S, Hutchinson G, McKenzie K and Murray R M (2001). Understanding the excess of psychosis among the African-Caribbean population in England: review of current hypotheses. British Journal of Psychiatry 178(suppl.40), s60-8.