I invite you to imagine a world without ‘dementia’. It is not that I have found a cure for all so-called dementias, or discovered a strategy to prevent them in the future. I am referring to the term ‘dementia’ (from Latin demens, meaning without mind) which has done much disservice to patients and physicians for far too long [1]. Should it not follow ‘neurosis’ into classificatory oblivion?
Most clinicians and researchers accept that neurocognitive disorders lie on a continuum, ranging from very mild impairment almost indistinguishable from normal aging to severe impairment characterized by complete loss of independent function. At what point does one begin to call such impairment ‘dementia’ and why? The general rule followed by clinicians is the presence of ‘significant impairment in social or occupational functioning’ due to decline in cognitive functions such as memory. This is a very subjective determination, especially in the early stages when the decline is very mild. With the same level of cognitive impairment, a 70-year-old man who is still employed but struggling with his job is likely to receive a diagnosis of dementia, whereas his retired friend will often escape the diagnosis. Admittedly, the consequences of the diagnosis are different in the two men, but it does serve to highlight the subjective nature of this diagnosis, an inappropriate situation for a disorder rooted in biology. The ‘impaired functioning’ criterion has also resulted in a threshold effect on the diagnosis, which may be one reason why a high intellectual level is suggested to be protect against dementia, mostly because such an individual has ‘further to fall’ before a dementia diagnosis is appropriate.
There are many different definitions of dementia, and unfortunately the different sets of criteria have poor agreement with each other. Erkinjuntti and his colleagues [1] applied various definitions of dementia to the Canadian Study of Health and Aging, and the proportion of individuals with dementia varied from 3.1% to 29.1% depending upon the definition used.
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, but the term dementia does much disservice to AD itself. As the focus is shifting toward preventing Alzheimer’s, it has become important to recognize the disease early, i.e. at the stage when cognitive impairment is mild and dementia, by its current criteria, cannot be diagnosed. One should therefore not have to wait for dementia before the diagnosis of AD, and for that matter vascular cognitive impairment or fronto-temporal degeneration, but the continuing presence of ‘dementia’ serves to delay the diagnosis unnecessarily.
The definition of dementia has created uncertainty for some other neuropsychiatric disorders. A useful example is alcohol-related brain damage. Most investigators agree that alcohol is an important cause of memory and frontal-executive dysfunction, but considerable debate has raged whether alcohol causes dementia. While some authors have suggested that alcohol-induced dementia is relatively common, others have argued against its acceptance as an entity until a definitive neuropathological basis was established [3]. The debate distracts from the fact that alcohol is responsible for much cognitive dysfunction in society, and has hindered the conduct of treatment studies in this field. Traumatic brain damage is another instance of the difficulties in applying the dementia concept.
Not only is the term dementia limiting in its scope, it has a pejorative connotation in its general usage. The Concise Oxford Dictionary describes the meaning of ‘demented’ as ‘driven mad, crazy’, and the term is commonly used as a form of insult. Its use by the medical profession arouses great anxiety in the patients, evoking images of extreme disability and dependence. The diagnosis has serious consequences in terms of a persons’ competence in employment, legal transactions, driving and even the conduct or ordinary activities of living, far beyond what might be immediately suggested. The diagnosis of dementia may, therefore, become a cross for the patient and the family to bear.
I conclude by suggesting that the limitations and disadvantages of dementia outweigh any usefulness that remains in the term, and it is time that we abandoned it. Admittedly, it has been used for such a long period and has been the subject of vast literature and mythology that it will leave a major void. How will this be filled?
We know from the demise of ‘neurosis’ that terms with a long history can be abandoned, and the field can move on and flourish in the process. Some inheritors of the legacy of dementia are obvious. AD, Huntington’s disease, prion disease, fronto-temporal degeneration and cortical Lewy body disease, all causes of dementia, are established as diseases in their own rights and do not require the appellation of ‘dementia’. Terms such as Neurocognitive Disorder (4) have been suggested to capture the fact that cognitive deficits lie on a spectrum and the clinician should not be constrained by the stigma of diagnosing dementia to be able to diagnose a Neurocognitive Disorder and institute the best available treatment. Stop diagnosing people with dementia, and it will gradually fade away into history.
References:
1. Sachdev P. Is it time to retire the term ‘dementia’? J Neuropsychiatry & Clin Neurosci 2000; 12:276-279.
2. Erkinjuntti T, Ostybe T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. N Engl J Med 1997; 337:1667-74.
3. Lishman WA Alcohol and the brain. Br J Psychiatry 1990; 156:635-644.
4. Sachdev P. Vascular cognitive disorder. Intern J Geriatric Psychiatry 1999; 14: 402-403.
Thursday, January 28, 2010
Wednesday, August 12, 2009
The Yipping Tiger
My new book "The Yipping Tiger and Other Tales from the Neuropsychiatric Clinic"
(By Perminder Sachdev, UNSW Press, ISBN 1742230849) has just been published. It comprises ten case studies selected to reveal the workings of the brain. The case studies are gems from the rich pickings in the clinic I have run at the NPI for 20 years. The clinical descriptions are interspersed with commentary and dialogue, and peppered with other examples. The final presentation may therefore not simulate what exactly transpired in the clinical encounters. At times some literary concessions have been taken but without compromising scientific accuracy or clinical authenticity. I could be accused of some embellishment, but the stories are based on real patients whose identities have been completely camouflaged to protect their privacy. I justify the literary touch-up for the simple reason that these stories are addressed to a lay audience and not a scientific journal.
If the reader, after having read this book, walks away with wonderment about the brain, my objective would be fulfilled. If he or she is also amazed and enthralled by the human condition that these cases present, my joy would be boundless. In their brain–mind foibles, I hope to have captured some of their humanity in all its frailty and emotion-laden sanity. We are not human if we are perfect. We may strive to be, but it is my belief – should I even say ‘hope’ – that we will never attain that goal.
The titles of the chapters may seem enigmatic, but each has a reference to a neuropsychiatric syndrome. They can be decoded as follows:
The Yipping Tiger (Golfer’s cramps)
Shaking hands with Dr Strangelove (The alien hand syndrome)
Swearing like a Spanish sailor (Coprolalia in Tourette’s syndrome)
The Mozart Complex (Brain enhancement)
The mirror always lies (Anorexia nervosa)
The dead homunculus (Frontal lobe dysfunction)
Serotonin’s seductive song (Major depression)
A chesty problem (Obsessive-compulsive disorder)
Lord Nelson’s ghost (Phantom limb)
Freudian slips and semantic slides (Mild cognitive impairment)
The book has only been released in Australia, and the international edition will be released in Spring 2010.
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Sunday, May 31, 2009
What are the big questions in Psychiatry?
Confronted with the challenge to do a Thought Leader presentation on 10th July, I have been thinking about the Big Questions in Psychiatry, and would welcome your input.
Some thoughts that come to mind:
Perminder
Some thoughts that come to mind:
- Is the current classification of psychiatric disorders useful in psychiatric practice? What might be a more useful classification system?
- In our enthusiasm for newer drugs, have been abandoned the more effective antidepressants?
- Are the second generation antipsychotics really an advance, or are they merely draining our mental health budget?
- Can we prevent or reduce the burden of mental illness in future generations by massively intervening in our schools?
- Is therapy through the internet the wave of the future?
Perminder
Does head injury cause schizophrenia?
Dear colleagues,
Welcome to my first blog on neuropsychiatry. For this, I have chosen a topic which I have had to confront recently from a medico-legal viewpoint. There have been a number of competent reviews of this topic, but somehow clarity has not been achieved. while not attempting to review the topic once again, I present some reasons why a causal relationship between schizophrenia and traumatic brain injury is difficult to establish. While this does not pose a major problem for Psychiatry, it makes lawyers trying to argue for their clients quite nervous.
I think this is an extremely difficult question to answer as it is bedevilled by numerous methodological issues. It is important to understand the methodological issues in order to fully appreciate the reasons for the differing opinions between experts:
1. Schizophrenia is a very heterogeneous disorder, and may in fact be a group of disorders. The question then arises: are we looking for an association with a particular subtype of schizophrenia, or schizophrenia in general, or indeed any psychosis that resembles schizophrenia?
2. Head injury is also extremely varied, and may vary from a whiplash injury with no loss of consciousness to extensive brain damage and bleeding. The brain regions affected can vary considerably depending upon whether it is a closed or open injury, caused by deceleration or a missile, etc, and a number of other factors, including associated injuries and the psychological aspects of the injury. Not all head injuries come to medical attention.
3. In the face of this heterogeneity, establishing cause is daunting at the very outset. However, one can try to narrow this task down by clearly defining both schizophrenia and head injury, and this is the first place where studies differ and therefore produce differing results.
4. The process of establishing a cause of a disorder in medicine is complex. The first step is an epidemiological one, in which investigators establish an association (in this case, for argument, that schizophrenia and head injury have more than a chance association). Much of the debate in the literature is focused on this (I will come to this later). Of course, it is implicitly acknowledged that head injury would occur first and schizophrenia later for head injury to be causative. However, the reverse association is also possible – individuals with schizophrenia might be more vulnerable to head injury because of their proneness to accidents or violence or due to postural or gait problems due to the drugs. This is usually not an issue if schizophrenia has been diagnosed prior to the head injury (although the issue of worsening of psychosis can then be raised). It is more problematic if an individual who suffers a head injury is in the prodromal or prepsychotic phase of schizophrenia, which is possible since schizophrenia may develop very slowly over months and sometimes years. There is also a suggestion that individuals prone to schizophrenia may have some abnormalities much before they become unwell, and these could be present from birth. These abnormalities could also make them vulnerable to accidents and head injury.
5. Even if an association is established, it does not mean that a cause had been found. Epidemiological studies have reported an association between head injury and a number of neuropsychiatric disorders, which include dementia, Parkinson’s disease, schizophrenia and bipolar disorder, among others. There are many reasons why spurious associations can be thrown up by epidemiological studies (ascertainment bias, recall bias, etc.). An association must be followed by biological plausibility of the cause, and an understanding of the mechanism by which the putative cause produces the result. This is where the major difficulty with head injury and schizophrenia lies. Since we do not know the cause of schizophrenia, no association can be dismissed outright as being implausible if the brain has been affected in some way, however minor. For this reason, no head injury can be dismissed as being irrelevant if it is thought that brain trauma has occurred.
6. Furthermore, there are different types of causes. Of course, head injury cannot be a necessary cause of schizophrenia. Is it however a sufficient cause, or should it occur on a substrate of vulnerability for schizophrenia to occur? Since head injury is very common, and schizophrenia is an uncommon disorder, most models propose that it is unlikely to be a sufficient cause. It therefore is a contributory cause, if at all. It is proposed as one of multiple possible factors that increase the risk of developing schizophrenia, of which genetic factors are the strongest. This topic has been extensively reviewed in many places, and the Tandon et al (2008) article is a good recent summary. This paper does show that of the many factors, head injury does not feature high on the list.
7. But what about the epidemiological evidence? That experts have reached differing conclusions suggests that the message is not clear-cut. This is partly because medical research has a different objective from a legal discourse. In the case of schizophrenia, the objective of pursuing this association, minor as it might be, is to develop some insights into the mechanisms by which schizophrenia develops; it is not intended to apportion blame. Every study has its limitations. The ideal study would be one in which a very large cohort of individuals who sustain a head injury, and a comparable control group without a head injury, are followed up over many years to determine whether the rates of schizophrenia are different. Even such a massive study cannot be fool-proof as many other factors will need to be considered, and totally unbiased populations do not exist in reality. The question, whether head injury causes schizophrenia can therefore, in my opinion, cannot be answered until we understand the pathological mechanisms of schizophrenia itself. There are many such debates in the medical literature involving complex disorders, the mechanisms of which are not known.
9. What is the consensus? I would agree with the recent review of Dr Edward Kim in the journal Current Opinion in Psychiatry in 2008 (I invited Dr Kim to do this review as editor of the Neuropsychiatry section of the journal). The consensus, in my opinion, is that we do not know for sure whether head injury does increase the risk of schizophrenia. If it does, the relative risk is most likely to be in the order of 1.5 to 2.0. I agree that the recent Scandinavian studies (Nielsen et al, 2002 and Harrison et al, 2006) are the most systematic epidemiological studies, but they are not without their limitations. We should place this relative risk in context. The risk of an individual developing schizophrenia in their lifetime is about 0.7% (figures between 0.5% and 1.0% are cited). Having received a head injury possibly increases this risk to 1.0 – 1.4%, according to these estimates. How this risk estimate translates into the occurrence of schizophrenia in one individual is, however, not known, but the conclusion would be that head injury would be a minor factor, if at all. There is no consensus on the type of injury and this risk, although some evidence suggests that more severe injury may be worse. It is also not established whether injury to any particular brain region is worse for this risk, although temporal lobe injury has been suggested by some studies.
How can one reach a decision about causal association in an individual case?
From a medical perspective, this is impossible. It is therefore more of a legal issue, and stems from the fact that the law is unable to deal with probabilities and possibilities in the same manner as medical science can. The difference between the two perspectives could be narrowed if legal argument was able to apportion part-causation (or a contribution from a risk) and judge responsibility or blame accordingly.
Having said this, clinicians do sometimes encounter individuals who never recover following brain trauma and go on to develop what appears to be schizophrenia. It is quite reasonable for the clinician to then ask the question whether the trauma did in fact cause the disorder. Family members are also impressed by the fact that the individual was well prior to the head injury, and they therefore blame the head injury for the problem. In fact, their retrospective recall of the individual’s functional status is often biased by this knowledge, and they usually paint a positive picture of the pre-injury individual. We know from many other examples in medicine that these inferences can be erroneous, and that is why systematic evidence is collected before an association can become an established fact. In the case of head injury and schizophrenia, the association cannot be said to be established fact, although it cannot be dismissed outright either.
What is then a reasonable way forward? For medical science, it is more research on many fronts, including better epidemiological studies. I am not an expert on legal matters and my opinion is not well-informed from a legal perspective. However, my opinion is that if most (if not all) of the following can be established in a particular case, then some contribution of the head injury should be acknowledged:
1. The individual was well functioning prior to the head injury, from an occupational and social perspective, i.e. related well with others and functioned well in age-appropriate roles.
2. The head injury produced significant brain trauma, as evidenced by loss of consciousness and/or a period of amnesia and/or cognitive deficits (attributable to the head injury).
3. The first signs of schizophrenia, including social withdrawal and odd behaviours, emerged after the head injury.
4. There is no period of complete normalcy (absence of all psychiatric or neurological symptoms and no cognitive dysfunction) between the head injury and the onset of schizophrenia. (It is possible that there is a return to normalcy in some cases, but the association become more difficult to establish, especially if there is a long interval).
These may be strict criteria, but in the face of controversy, it is better to have strict criteria. They do not deal with the situation in which head injury has arguably worsened psychosis in someone who already has schizophrenia, but this is not the topic of discussion at present. If the above criteria are met, then one should not dismiss the possibility that head injury has made a contribution to the development of schizophrenia, although it should still be considered to be a minor contribution, and so compensated in law.
References:
1. Nielsen AS, Mortensen PB, O’Callagahn E, et al. Is head injury a risk factor for schizophrenia? Schizophrenia Research 2002 55:93-98.
2. Harrison G, Whitley E, Rasmussen F, Lewis G, Dalman C, Gunnell D. Risk of schizophrenia and other non-affective psychosis among individuals exposed to head injury: Case control study. Schizophrenia Research 2006; 88:119-126.
3. Zhang QC, Sahdev PS. Psychotic disorder and traumatic brain injury. Curr Psychiatry Rep 2003;5(3):197-201.
4. Kim E. Does traumatic brain injury predispose individuals to develop schizophrenia? Curr Opin Psychiatry. 2008 May;21(3):286-9.
5. van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial Stress and Psychosis. A Review of the Neurobiological Mechanisms and the Evidence for Gene-Stress Interaction. Schizophrenia Bulletin 2008; 34 (6): 1095–1105.
6. Howes OD, McDonald C, Cannon M, Arseneault L, Boydell J, Murray RM. Pathways to schizophrenia: the impact of environmental factors. International Journal of Neuropsychopharmacology 2004; 7 (Supplement 1), S7–S13.
7. Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, "Just the Facts": what we know in 2008 part 1: overview. Schizophr Res. 2008 Mar;100(1-3):4-19. Review.
Welcome to my first blog on neuropsychiatry. For this, I have chosen a topic which I have had to confront recently from a medico-legal viewpoint. There have been a number of competent reviews of this topic, but somehow clarity has not been achieved. while not attempting to review the topic once again, I present some reasons why a causal relationship between schizophrenia and traumatic brain injury is difficult to establish. While this does not pose a major problem for Psychiatry, it makes lawyers trying to argue for their clients quite nervous.
I think this is an extremely difficult question to answer as it is bedevilled by numerous methodological issues. It is important to understand the methodological issues in order to fully appreciate the reasons for the differing opinions between experts:
1. Schizophrenia is a very heterogeneous disorder, and may in fact be a group of disorders. The question then arises: are we looking for an association with a particular subtype of schizophrenia, or schizophrenia in general, or indeed any psychosis that resembles schizophrenia?
2. Head injury is also extremely varied, and may vary from a whiplash injury with no loss of consciousness to extensive brain damage and bleeding. The brain regions affected can vary considerably depending upon whether it is a closed or open injury, caused by deceleration or a missile, etc, and a number of other factors, including associated injuries and the psychological aspects of the injury. Not all head injuries come to medical attention.
3. In the face of this heterogeneity, establishing cause is daunting at the very outset. However, one can try to narrow this task down by clearly defining both schizophrenia and head injury, and this is the first place where studies differ and therefore produce differing results.
4. The process of establishing a cause of a disorder in medicine is complex. The first step is an epidemiological one, in which investigators establish an association (in this case, for argument, that schizophrenia and head injury have more than a chance association). Much of the debate in the literature is focused on this (I will come to this later). Of course, it is implicitly acknowledged that head injury would occur first and schizophrenia later for head injury to be causative. However, the reverse association is also possible – individuals with schizophrenia might be more vulnerable to head injury because of their proneness to accidents or violence or due to postural or gait problems due to the drugs. This is usually not an issue if schizophrenia has been diagnosed prior to the head injury (although the issue of worsening of psychosis can then be raised). It is more problematic if an individual who suffers a head injury is in the prodromal or prepsychotic phase of schizophrenia, which is possible since schizophrenia may develop very slowly over months and sometimes years. There is also a suggestion that individuals prone to schizophrenia may have some abnormalities much before they become unwell, and these could be present from birth. These abnormalities could also make them vulnerable to accidents and head injury.
5. Even if an association is established, it does not mean that a cause had been found. Epidemiological studies have reported an association between head injury and a number of neuropsychiatric disorders, which include dementia, Parkinson’s disease, schizophrenia and bipolar disorder, among others. There are many reasons why spurious associations can be thrown up by epidemiological studies (ascertainment bias, recall bias, etc.). An association must be followed by biological plausibility of the cause, and an understanding of the mechanism by which the putative cause produces the result. This is where the major difficulty with head injury and schizophrenia lies. Since we do not know the cause of schizophrenia, no association can be dismissed outright as being implausible if the brain has been affected in some way, however minor. For this reason, no head injury can be dismissed as being irrelevant if it is thought that brain trauma has occurred.
6. Furthermore, there are different types of causes. Of course, head injury cannot be a necessary cause of schizophrenia. Is it however a sufficient cause, or should it occur on a substrate of vulnerability for schizophrenia to occur? Since head injury is very common, and schizophrenia is an uncommon disorder, most models propose that it is unlikely to be a sufficient cause. It therefore is a contributory cause, if at all. It is proposed as one of multiple possible factors that increase the risk of developing schizophrenia, of which genetic factors are the strongest. This topic has been extensively reviewed in many places, and the Tandon et al (2008) article is a good recent summary. This paper does show that of the many factors, head injury does not feature high on the list.
7. But what about the epidemiological evidence? That experts have reached differing conclusions suggests that the message is not clear-cut. This is partly because medical research has a different objective from a legal discourse. In the case of schizophrenia, the objective of pursuing this association, minor as it might be, is to develop some insights into the mechanisms by which schizophrenia develops; it is not intended to apportion blame. Every study has its limitations. The ideal study would be one in which a very large cohort of individuals who sustain a head injury, and a comparable control group without a head injury, are followed up over many years to determine whether the rates of schizophrenia are different. Even such a massive study cannot be fool-proof as many other factors will need to be considered, and totally unbiased populations do not exist in reality. The question, whether head injury causes schizophrenia can therefore, in my opinion, cannot be answered until we understand the pathological mechanisms of schizophrenia itself. There are many such debates in the medical literature involving complex disorders, the mechanisms of which are not known.
9. What is the consensus? I would agree with the recent review of Dr Edward Kim in the journal Current Opinion in Psychiatry in 2008 (I invited Dr Kim to do this review as editor of the Neuropsychiatry section of the journal). The consensus, in my opinion, is that we do not know for sure whether head injury does increase the risk of schizophrenia. If it does, the relative risk is most likely to be in the order of 1.5 to 2.0. I agree that the recent Scandinavian studies (Nielsen et al, 2002 and Harrison et al, 2006) are the most systematic epidemiological studies, but they are not without their limitations. We should place this relative risk in context. The risk of an individual developing schizophrenia in their lifetime is about 0.7% (figures between 0.5% and 1.0% are cited). Having received a head injury possibly increases this risk to 1.0 – 1.4%, according to these estimates. How this risk estimate translates into the occurrence of schizophrenia in one individual is, however, not known, but the conclusion would be that head injury would be a minor factor, if at all. There is no consensus on the type of injury and this risk, although some evidence suggests that more severe injury may be worse. It is also not established whether injury to any particular brain region is worse for this risk, although temporal lobe injury has been suggested by some studies.
How can one reach a decision about causal association in an individual case?
From a medical perspective, this is impossible. It is therefore more of a legal issue, and stems from the fact that the law is unable to deal with probabilities and possibilities in the same manner as medical science can. The difference between the two perspectives could be narrowed if legal argument was able to apportion part-causation (or a contribution from a risk) and judge responsibility or blame accordingly.
Having said this, clinicians do sometimes encounter individuals who never recover following brain trauma and go on to develop what appears to be schizophrenia. It is quite reasonable for the clinician to then ask the question whether the trauma did in fact cause the disorder. Family members are also impressed by the fact that the individual was well prior to the head injury, and they therefore blame the head injury for the problem. In fact, their retrospective recall of the individual’s functional status is often biased by this knowledge, and they usually paint a positive picture of the pre-injury individual. We know from many other examples in medicine that these inferences can be erroneous, and that is why systematic evidence is collected before an association can become an established fact. In the case of head injury and schizophrenia, the association cannot be said to be established fact, although it cannot be dismissed outright either.
What is then a reasonable way forward? For medical science, it is more research on many fronts, including better epidemiological studies. I am not an expert on legal matters and my opinion is not well-informed from a legal perspective. However, my opinion is that if most (if not all) of the following can be established in a particular case, then some contribution of the head injury should be acknowledged:
1. The individual was well functioning prior to the head injury, from an occupational and social perspective, i.e. related well with others and functioned well in age-appropriate roles.
2. The head injury produced significant brain trauma, as evidenced by loss of consciousness and/or a period of amnesia and/or cognitive deficits (attributable to the head injury).
3. The first signs of schizophrenia, including social withdrawal and odd behaviours, emerged after the head injury.
4. There is no period of complete normalcy (absence of all psychiatric or neurological symptoms and no cognitive dysfunction) between the head injury and the onset of schizophrenia. (It is possible that there is a return to normalcy in some cases, but the association become more difficult to establish, especially if there is a long interval).
These may be strict criteria, but in the face of controversy, it is better to have strict criteria. They do not deal with the situation in which head injury has arguably worsened psychosis in someone who already has schizophrenia, but this is not the topic of discussion at present. If the above criteria are met, then one should not dismiss the possibility that head injury has made a contribution to the development of schizophrenia, although it should still be considered to be a minor contribution, and so compensated in law.
References:
1. Nielsen AS, Mortensen PB, O’Callagahn E, et al. Is head injury a risk factor for schizophrenia? Schizophrenia Research 2002 55:93-98.
2. Harrison G, Whitley E, Rasmussen F, Lewis G, Dalman C, Gunnell D. Risk of schizophrenia and other non-affective psychosis among individuals exposed to head injury: Case control study. Schizophrenia Research 2006; 88:119-126.
3. Zhang QC, Sahdev PS. Psychotic disorder and traumatic brain injury. Curr Psychiatry Rep 2003;5(3):197-201.
4. Kim E. Does traumatic brain injury predispose individuals to develop schizophrenia? Curr Opin Psychiatry. 2008 May;21(3):286-9.
5. van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial Stress and Psychosis. A Review of the Neurobiological Mechanisms and the Evidence for Gene-Stress Interaction. Schizophrenia Bulletin 2008; 34 (6): 1095–1105.
6. Howes OD, McDonald C, Cannon M, Arseneault L, Boydell J, Murray RM. Pathways to schizophrenia: the impact of environmental factors. International Journal of Neuropsychopharmacology 2004; 7 (Supplement 1), S7–S13.
7. Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, "Just the Facts": what we know in 2008 part 1: overview. Schizophr Res. 2008 Mar;100(1-3):4-19. Review.
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