Mental health breakthrough: Study links sleep problems to schizophrenia for the first time

Friday, January 20, 2012 by: Elizabeth Walling

Learn more:http://www.naturalnews.com/034699_mental_health_sleep_problems_schizophr enia.html#ixzz1o5qso4JM (NaturalNews) Getting quality sleep could be a vitally important piece for solving the puzzle of mental health. Previous studies have linked poor sleep to depression, bipolar disorder, anxiety and ADHD. Now for the first time, research also shows a strong link between schizophrenia and sleep disturbances. The study followed twenty individuals with schizophrenia, and compared their sleep patterns to those in a control group of 21 healthy individuals. Every single participant with schizophrenia experienced extreme sleep disturbances, independent of medication and social isolation. The study group had trouble falling asleep, spent more time in bed, slept longer and experienced far more variable sleep patterns than those in the control group. Half of the study participants had irregular body clocks, often sleeping in the day while being awake and alert at night. Professor Russell Foster of Oxford University says, "For a long time people have noted that sleep is disrupted in mental health, but it has always been assumed to be associated with medication or the fact that they are socially isolated and, as a result, it has been largely dismissed." The study is unique because researchers examined sleep patterns of patients in a community setting rather than under hospital care. Also important is the length of the study: rather than only studying sleep patterns for a few days, this study attempts to give a fuller, more accurate picture by tracking sleep data over a period of weeks.

Sleep is vital for mental health

We all know that sleep is important, but many of us may underestimate the impact sleep disturbances can have on our health, especially our mental health and moods. Roseanna Sharville, a second year experimental psychology student, says: "Like food and water, sleep is crucial for all living, breathing things. Intuitively, therefore, it certainly seems possible that long-term sleep disturbances could cause severe physical and mental health problems." While some may quibble over cause versus effect, it may be as simple as how sleep impacts our brain chemicals. Foster says, "I think you have to think about it as common neurotransmitter pathways that are being affected." He also adds, "But regardless of whether or not there is a mechanistic link between the body clock and psychiatric conditions, it is clear that treating sleep problems could improve the lives of many patients." Researchers in the study suggest that improving sleep quality should be included in psychiatric care because of the potential benefits it could produce. The study was led by Oxford University and was published online by theBritish Journal of Psychiatry.

Learn more:http://www.naturalnews.com/034699_mental_health_sleep_problems_schizophr enia.html#ixzz1o5qxn9eS

From Current Opinion in Psychiatry

Life Expectancy and Cardiovascular Mortality in Persons With Schizophrenia

Thomas M. Laursen; Trine Munk-Olsen; Mogens Vestergaard Authors and Disclosures Posted: 02/17/2012; Curr Opin Psychiatry. 2012;25(2):83-88. 2012 Lippincott Williams & Wilkins

http://www.medscape.com/viewarticle/758461

Abstract and Introduction

Abstract
Purpose of review To assess the impact of cardiovascular disease on the excess mortality and shortened life expectancy in schizophrenic patients. Recent findings Patients with schizophrenia have two-fold to three-fold higher mortality rates compared with the general population, corresponding to a 1025-year reduction in life expectancy. Although the mortality rate from suicide is high, natural causes of death account for a greater part of the reduction in life expectancy. The reviewed studies suggest four main reasons for the excess mortality and reduced life expectancy. First, persons with schizophrenia tend to have suboptimal lifestyles including unhealthy diets, excessive smoking and alcohol use, and lack of exercise. Second, antipsychotic drugs may have adverse effects. Third, physical illnesses in persons with schizophrenia are common, but diagnosed late and treated insufficiently. Lastly, the risk of suicide and accidents among schizophrenic patients is high. Summary Schizophrenia is associated with a substantially higher mortality and curtailed life expectancy partly caused by modifiable risk factors.

Introduction
Persons with schizophrenia suffer from two-fold to three-fold higher mortality rates compared with the general population.[14] It is well established that suicide plays an important role in the excess mortality; a recent meta-analysis estimated that the risk of suicide was almost 13-fold higher for persons with schizophrenia as compared with the general population.[4] However, mounting evidence suggests that most of the excess mortality is explained by natural causes of death,[5] calling for an increased focus on physical illness to understand and eliminate the excess mortality. As cardiovascular diseases are the most common cause of death in western countries,[6] we aimed at describing the impact of cardiovascular disease on the mortality and life expectancy of persons with schizophrenia. To do so, we reviewed the most recent literature.

Search Strategies
We reviewed articles published in English between January 2010 and September 2011 that fulfilled the following search criterion: schizophrenia, cardiovascular disease, and mortality or schizophrenia and life expectancy. Our search identified 66 studies using PubMed, Medline (National Library of Medicine) and nine additional studies by using Ovid SP search. A total of 50 of the identified studies were excluded because they did not match the aim of the review. The final number of included studies was 25; 12 original studies[5,7,8,9,10-17] and 13 reviews/comments.[18,19,20-22,23,24-26,27,28-30] Note that several original studies appeared in more than one review.

Summary of Reviews and Commentary Studies

Bushe et al. [25] reviewed studies on all-cause mortality in persons with schizophrenia, and found that cardiovascular death was a major contributor to the excess mortality but other causes of death, such as cancer, also played an important role. Mitchell and Lawrence [19] reviewed studies on mortality in psychiatric patients and focused on the impact of invasive cardiac procedures. They found that psychiatric patients in general and schizophrenic patients in particular had fewer invasive procedures after acute coronary syndrome as compared with those without a psychiatric disorder. The proportion was

particularly low for those with schizophrenia, with an incidence that was only half of that in the general population. The authors concluded that the lack of treatment may have an impact on the higher mortality, although no causal link was established. Lawrence et al. [20]reviewed studies on mortality in people with psychiatric disorders, in particular schizophrenia, and concluded that insufficient health service for schizophrenic patients with cardiovascular disease may explain part of the increased mortality caused by natural causes. Mitchell and Lord[23] reviewed studies on invasive cardiac procedures and medication after acute coronary syndrome in patients with schizophrenia compared with those without. The authors concluded that evidence supports that deficits in quality of care contribute to higher than expected mortality in those with schizophrenia. Wildgust et al. [24,26] reviewed studies on risk factors for premature death and found that persons with schizophrenia had elevated rates of the six leading global modifiable mortality risk factors, that is, hypertension, smoking, raised glucose, physical inactivity, obesity, and dyslipidemia. However, the potential impact of these risk factors on mortality among persons with schizophrenia is unknown. Wildgust and Beary[24] reviewed studies on the effect of antipsychotic drugs on excess mortality from cardiovascular disease. They concluded that antipsychotics increased the risk of metabolic syndrome, sudden cardiac death, and myocarditis/cardiomyopathy; but they found no clear evidence to suggest that the risk varied by type of antipsychotic drugs. Bradley and Dinan[22] reviewed studies on the association between chronic stress and excess mortality. They concluded that persons with schizophrenia experience both hyperfunction and hypofunction of the hypothalamicpituitaryadrenal (HPA) axis, and that this may contribute to the poorer physical health and higher mortality rates.

Summary of Original Studies

Two studies from Denmark and Finland[5,8] used registers with national coverage to calculate life expectancy among persons with schizophrenia and identified a reduced life expectancy of up to 20 years compared with the general population. In the Danish study,[5] natural causes of death accounted for the largest part of the excess mortality, especially mortality from diseases of the circulatory system. Another Danish study[10] found that life expectancy was particularly low (49 years) among schizophrenic patients with dual diagnosis (schizophrenia and substance abuse). A study from the UK [9] similarly found that life expectancy was reduced by up to 14.6 years among persons with schizophrenia as compared with the general population. The excess mortality was caused by higher incidences of cardiovascular diseases, cancer, and diabetes among persons with schizophrenia. A study from the USA[11] showed that persons with first episode of psychosis did not have higher cardiovascular risk according to a tool developed by the National Cholesterol Education Program compared with controls matched by age, gender, and race. A casecontrol study from Taiwan showed that persons with schizophrenia had 50% higher risk for acute organ dysfunction and a 56% higher mortality rate when visiting an ICU.[7] Antipsychotic medication may cause adverse effects such as weight gain, dyslipidemia, diabetes mellitus, and arrhythmia that may negatively affect mortality, but it is unclear whether mortality rates vary by different antipsychotic drugs. A randomized trial including 18 154 patients with schizophrenia compared ziprasidone and olanzapine.[12] The study identified no differences in mortality rates betweenthe groups after 1 year, although ziprasidone but not olanzapine may induce heart rate-corrected QT prolongation and sudden cardiac death. The use of the antipsychotic medicine sertindole was suspended for a short period in 1998 because it was associated with higher mortality rates in some studies.[15] A multinational randomized study of 9 858 patients with schizophrenia compared sertindole and risperidone. [15] The study showed no difference in all-cause mortality rates between the two groups, but sertindole users had an increased cardiac mortality. A cohort study including 1686 persons examined two other antipsychotic drugs, risperidone and

clozapine.[17] Despite known differences in risk profile for weight gain and metabolic side effects, the study found no differences in cardiac mortality in the users of the different drugs. The mortality gap of cardiovascular mortality between persons with schizophrenia and the general population has grown deeper during the last decades according to a Danish register-based study;[14] the mortality rate ratio increased from around2.0 in 1994 to 3.5 in 2006 compared with the general population. The study suggests that persons with schizophrenia did not experience the same improvement in cardiovascular mortality as the general population, who experienced an overall improvement in cardiovascular treatment and lifestyle. The same tendency was found in a study from the UK,[16] wherein an excess mortality was also found (mortality rate ratio 23), and they furthermore detected a tendency that cardiac mortality among schizophrenic persons had increased relative to the general population. Contrary to these studies, a study from Finland[8] found that the difference in life expectancy among schizophrenic women compared with the general population diminished during recent years. Only one of the identified studies showed a lower mortality among patients with schizophrenia. In a nationwide study from Taiwan,[13] the authors found that the 90 days mortality after stroke among persons with schizophrenia was much lower than what was observed among persons with no history of schizophrenia. The authors suggested that the surprising results may be due to a positive effect of antipsychotic medication on mortality after stroke.

Overall Summary of the Included Studies in the Present Review

All but one of the reviews/comments and original studies included in the present review concluded that persons with schizophrenia have substantially higher mortality rate in all settings and all age groups compared with the general population. Persons with schizophrenia have a 1025-year shorter life expectancy than persons with no history of schizophrenia. The main reasons for the excess mortality and shortened life expectancy seem to fall into four categories. First, persons with schizophrenia tend to have an unhealthy lifestyle regarding diet, smoking, alcohol, and exercise. Second, antipsychotic medicine may have negative side effects. Third, physical illnesses in persons with schizophrenia are common, diagnosed late, and treated insufficiently. Fourth, the risk of suicide and accidents among schizophrenic patients is high.

Discussion
In the late 19th century, Emil Kraepelin [31] classified patients with psychosis into those with schizophrenia (dementia praecox) and those with bipolar disorder (manic depressive insanity). One of the key elements in this dichotomization was that patients with schizophrenia had higher risk of unfavorable outcomes, including premature death, compared with patients with bipolar disorder. Thus, schizophrenia has been associated with high mortality and shortened life expectancy as long as the diagnosis has existed. Since Kraepelin's definition of schizophrenia,[31] psychiatric classification systems have changed, but the basic features of the schizophrenia diagnoses remain unchanged. Today, mortality rates are still alarmingly high among persons with schizophrenia compared with the general population. A reduction of 1025 years in life expectancy is higher than what is associated with most other risk factors for premature death such as diabetes (2 years), smoking (10 years), and severe obesity (10 years).[9]The question is: what can be done to eliminate the excess mortality?

The Healthcare System

Our review shows that persons with schizophrenia are more vulnerable to chronic physical diseases; the risk of medical disease is higher, and the prognosis poorer. Therefore, diagnosis, treatment, and care management of chronic physical illnesses in persons with schizophrenia need to be optimized. However, it is often complex to provide optimal care for these persons, who need a coordinated and collaborating healthcare system with vertical and especially horizontal care. The challenge is to achieve coordinated care from multiple specialists and ensure that people with schizophrenia experience one integrated healthcare system with one defined entry, shared patient records, well defined responsibilities, and care management programs describing the clinical and organizational guidelines for the care. More research is needed to evaluate which clinical and organizational interventions are effective, and how they are implemented. Care coordinators may help to bridge the gap between mental and physical health teams, and the primary care physicians may be central in defining the needs and coordinating the different initiatives. The primary care physician could provide regular and careful consultations to identify new physical, mental and social needs, and ensure comprehensive follow-up. The healthcare systems should also offer treatments according to evidence-based guidelines to persons with schizophrenia to ensure that they, for example, also receive invasive procedures and drug treatment after myocardial infarction.

Prevention
The decline in cardiovascular mortality in the general population has to some extent been attributed to improvement in potentially modifiable risk factors such as smoking, obesity, and hypertension; however, there have been few attempts to address these factors in people with mental disorders. [20] An optimal starting point for prevention may be when the first signs of the disease occur. [11] At this point of time, persons with schizophrenia tend to have a similar cardiovascular risk profile to age-matched and gendermatched controls. Patients with schizophrenia may need intensive and individual help in changing life style factors. If no actions are made, it is possible and most likely that the disparity in mortality outcomes will persist, as concluded by Lawrence et al.[20]In Denmark, health authorities[32] are currently planning initiatives especially targeted at increasing life expectancy among psychiatric patients, including primary prevention of life style diseases and strengthening the monitoring of the physical health of the psychiatric patients. Furthermore, the plan is to strengthen the cooperation between medical doctors and psychiatrists, thus making it possible to intervene with, for example, lipid-lowering medication, dietary advice, or physical training when necessary.

Side Effects of Antipsychotic Medicine

Antipsychotic drug treatment has had a huge impact on the treatment of schizophrenic patients. However, the antipsychotic drugs may have adverse side effects, and several studies have focused on these possible side effects. We included only a small fraction of studies on antipsychotic medicine, because we restricted the search criteria in the present review to studies with mortality as an outcome. Raedler[27] concluded in his review that it is unclear how antipsychotics influence the excess mortality, but there is no doubt that antipsychotics have adverse effects on cardiovascular risk factors. Some side effects might be counteracted by preventive measures and better treatment of physical illness, as described above. It is of utmost importance to develop antipsychotics with fewer side effects, but it may be possible to expand life expectancy and improve quality of life in schizophrenic patients by increasing the focus on prevention, diagnosis, treatment, and care management of physical illness in the routine treatment of these patients.

Other Causes of Death

In this review, we have focused on natural causes of death, especially cardiac mortality. Excess rates of suicide and accidents have a high impact on the mortality rates among patients with schizophrenia. In a Danish[5] study, the expected age at death was 57.8 years in men with schizophrenia as compared with 76.5 years for men in the general population. If these men with schizophrenia had the same mortality rates forunnatural causes (suicideandaccidents) as menin the general population, the expected age at death would increase to 62.8 years. This large improvement in expected age at death emphasizes that preventive measures against suicide are very important. In several studies, other causes of death play an important role, especially cancer. Many studies may even underestimate the impact of cancer on mortality because their cohort members are young.[25] Thus, future research should also examine the effect of other somatic disorders than cardiovascular diseases on the excess mortality and shortened life expectancy among schizophrenic patients.

Conclusion
More than 100 years ago, Kraepelin defined schizophrenia based on especially poor outcomes in this group of patients, which today worryingly still characterizes people suffering from schizophrenia despite improvements in treatment options during the past decades. Mounting evidence shows that persons with schizophrenia have a reduced life expectancy, and that they have not experienced the same improvement in life expectancy over the past decades as the general population. Persons with schizophrenia constitute a highly vulnerable group of patients who need special attention. At present it is pertinent to evaluate why they are vulnerable to physical diseases and what we can do to improve their life expectancy.

From Schizophrenia Bulletin

Is Traumatic Brain Injury a Risk Factor for Schizophrenia?

A Meta-analysis of Case-controlled Population-based Studies Charlene Molloy; Ronan M. Conroy; David R. Cotter; Mary Cannon Authors and Disclosures Posted: 12/08/2011; Schizophr Bull. 2011;37(6):1104-1110. 2011 Oxford University Press

Abstract and Introduction

Abstract
Traumatic brain injury (TBI) is known to lead to a range of adverse psychiatric sequelae but the question of whether TBI is a risk factor for psychosis and, in particular, schizophrenia remains unclear. Studies examining this issue have yielded conflicting results. We carried out a systematic review of the literature on TBI and psychosis in order to identify all population-based controlled studies which provide estimates of risk for schizophrenia following TBI. Odds ratios (ORs) were combined using random effects metaanalysis. Our literature search yielded 172 studies which were considered to be potentially relevant. From these, we identified 9 studies that could provide estimates of risk in the form of ORs. The pooled analysis revealed a significant association between TBI and schizophrenia (OR = 1.65; 95% CI = 1.172.32), with significant heterogeneity between the studies. Estimates from the family studies (OR = 2.8: 95% CI

=1.764.47) were higher than those from the cohort/nested case-control studies (OR = 1.42: 95% CI = 1.021.97) by a factor of almost 2. There did not appear to be a dose-response relationship between severity of head injury and subsequent risk of schizophrenia. This meta-analysis supports an increased risk of schizophrenia following TBI, with a larger effect in those with a genetic predisposition to psychosis. Further epidemiological and neuroscientific studies to elucidate the mechanisms underlying this association are warranted.

Introduction
Traumatic brain injury (TBI) is associated with significant adverse mental health outcomes in up to onethird of survivors.[1] It is well established that TBI increases the risk for a wide range of neuropsychiatric disturbances such as mood disorders, anxiety disorders, substance use disorders, personality change, and cognitive impairment,[2] but the question of whether TBI is a risk factor for schizophrenia or psychosis remains somewhat controversial. A classic review published in 1969 by Davison and Bagley[3] concluded that among individuals who had experienced TBI, "the observed incidence (of psychosis) over 10- to 20-year periods is 2 to 3 times the expected incidence " Three decades later, David and Prince[4] reexamined this issue in a critical review and came to the conclusion that "the classical casecontrol studies report apparently irreconcilably different estimates for the association between head injury and schizophrenia" and that " given the available published data, one must conclude that it is unlikely that head injury causes schizophrenia." Kim [5] published a narrative review of the literature which concluded that the evidence supported "a risk-modifying effect of TBI in individuals who are genetically at risk of schizophrenia" but did not support TBI as an independent risk factor for schizophrenia. A recent systematic review by Hesdorffer et al[6] has concluded that "there is limited/suggestive evidence of an association between moderate or severe head injury and psychosis." A comprehensive overview in a textbook chapter by Fleminger[2] stated that "it is not possible to come to any definite conclusion about whether head injury can cause a chronic psychotic illness, schizophrenia, or schizophreniform psychosis," although he goes on to say that " a reasonable conclusion to draw is that head injury does increase the risk of psychosis, perhaps doubling it." Therefore, it can be seen that there is little consensus between the previous reviewers of this topic. However, only one of the previous reviews [6] had used systematic review methodology and none had used meta-analytic techniques to give pooled measures of risk. To help clarify this issue and move the debate forward, we conducted a systematic review and meta-analysis of the population-based literature to date on risk of schizophrenia among individuals who have suffered TBI compared with the risk of schizophrenia among a control group. To our knowledge, this is the first metaanalysis on this topic.

Methods
Literature Search
Standard methods for systematic review were used in this article. The following databases were searched from their inception to October 2010: PUBMED, OVID MEDLINE, PsychINFO, and EMBASE. We searched using the format "[psychosis OR schizophrenia OR psychotic disorder OR delusional disorder OR delusions OR nonaffective psychosis OR psychiatric illness OR psychiatric disorder] AND [TBI OR cerebral trauma OR head injury OR craniocerebral injury OR concussion OR open head injuries OR closed head injuries OR skull fractures]" using text words and indexing (MeSH) terms.

Inclusion Criteria
We included published articles that reported on

1. the risk of schizophrenia among individuals who have suffered TBI compared with the risk of schizophrenia in a nonbrain injured population-based control group and 2. allowed calculation of a risk estimate from data provided in the article. TBI was not limited by severity.

Exclusion Criteria
Studies were excluded (1) if they were reviews, case reports, or case series, (2) if they comprised solely a follow-up study of a cohort of brain-injured patients with no comparison group, (3) if there was a nonpopulation-based control group (ie, a patient control group), or (4) if insufficient information was available to allow calculation of risk estimates.

Study Selection and Data Extraction

We examined all titles and abstracts and obtained full texts of potentially relevant studies. We read each article to determine whether it met inclusion criteria for the review. We searched reference lists of included studies. We extracted data relating to risk for schizophrenia following TBI from each article or calculated risk estimates from data available in the article. In extraction of data from the articles, we took a conservative approach and used the risk estimates pertaining to narrow definition of schizophrenia and the longest follow-rate reported in the articles for the main analysis. We contacted authors where necessary to obtain extra information to calculate risk estimates. We extracted information on source of information about TBI, severity of head injury, age at onset of head injury, and source of information on psychotic outcomes.

Data Analysis
Estimates of risk of schizophrenia associated with TBI from different studies were combined using random-effects meta-analysis, with heterogeneity among studies estimated using Cochran Q and the I 2 statistic.[7] The I 2statistic describes the percentage of variation among studies that is due to heterogeneity rather than chance, andI 2 values of 25%, 50%, and 75% can be taken to indicate low, moderate, and high levels of heterogeneity, respectively. We carried out subgroup analyses on mild vs severe TBI, childhood TBI and on broadly defined psychosis because there was felt to be sufficient numbers of studies in each group to allow these analyses. Meta-regression was undertaken to examine the influence of study design (family vs nested case-control/cohort). All of the analyses were undertaken with Stata statistical software package,[8] using the "metan" package.[9]

Results
Our literature search and search of reference lists yielded 9131 references and, after perusing the titles, 172 were considered to be potentially relevant. From examination of the abstracts and, where indicated, full texts of the articles, we identified 9 studies (see Table 1) which met our inclusion criteria, of which 2 were nested case-control studies,[12,17] 5 were cohort studies,[10,13,15,16,18] and 2 were family studies.[11,14] Two studies[15,16] reported from the same dataset but for different age groups and therefore, both were included in this analysis. A summary of the 9 studies included in the analysis is presented inTable 1. The overall pooled analysis revealed significant heterogeneity (in the high range) between studies (I 2 = 83.2%, P< .001). Accordingly, a random effects model was used. There was an overall association between TBI and subsequent schizophrenia (pooled OR = 1.65, 95% CI = 1.172.32) (see figure 1).

When studies were subdivided by study design, the 2 family studies[11,14] yielded a pooled OR of 2.8 (95% CI = 1.74.5) with no heterogeneity (I2 = 0.0%, P = .43) and the 7 cohort/nested case-control studies yielded a pooled OR of 1.42 (95% CI = 1.01.9) with a high degree of heterogeneity (I 2 = 79%, P < .002). Family studies found larger effect than cohort/case-control studies, by a factor of almost 2, with trendlevel significance on meta-regression (OR = 1.94 [95% CI = 0.94.3]; P = .08). When subdivided by severity of TBI, the pooled ORs were similar with studies providing rates for mild TBI specifically,[12,13,15] yielding a pooled OR of 1.17 (95% CI = 0.72.1) with low heterogeneity (I 2 = 44%, P < .17), (see figure 2) and the studies giving estimates for severe TBI specifically, [10,12,13,16] yielding a pooled OR of 1.18 (95% CI = 0.91.6) with moderate heterogeneity (I 2 = 61%, P < .04) (see figure 3). Subgroup analysis of the risk of TBI associated with a broadly defined psychosis [14,17] yielded a pooled OR of 1.3 (95% CI = 1.11.48) with no heterogeneity. Subgroup analysis of the risk associated with Childhood TBI (less than 15 y)[1315] yielded a pooled OR of 1.6 (95% CI = 0.62.6) with no heterogeneity.

Figure 1. Overall pooled risk estimate for risk of psychosis following traumatic brain injury.

(Enlarge Image)

Figure 2. Pooled risk estimate for psychosis following mild traumatic brain injury.

(Enlarge Image)

Figure 3. Pooled risk estimate for psychosis following severe traumatic br

(Enlarge Image)

Discussion
This article adds to the literature on the association between TBI and subsequent schizophrenia. Following a systematic review and meta-analysis, we report an increased risk of schizophrenia following TBI of about 60%. However, finding an association does not mean that causality is definitively established. As discussed in detail by David and Prince,[4] it is difficult to tease apart whether the TBI caused the psychosis or whether a particular individual was already on the trajectory toward psychosis before the injury occurred. The association could also be due to confounds such as substance abuse [19] or the existence of premorbid factors including motor and attentional problems, which are known to be associated with later schizophrenia.[20] The contribution of TBI seems to be greater among those with an inherited vulnerablity to schizophrenia.[11,14]Malaspina[11] found that TBI doubled the risk for schizophrenia in family members of probands with schizophrenia but also noted that TBI was more frequent among relatives of schizophrenia probands than among relatives of control probands suggesting that genes for schizophrenia may influence the exposure to TBI, as well as the consequences. Fann and colleagues [16] also found an increased rate of preexisting psychosis among individuals with head injury and speculated that psychosis increases the risk for TBI. The apparent complexity of the causal pathway between TBI and schizophrenia adds to the difficulty in investigating this relationship. The apparent lack of a dose-response relationship between severity of head injury and risk for psychosis is intriguing, particularly in view of the recent interest in outcomes of mild head injury among athletes and soldiers.[1]This lack of effect of severity of TBI has been noted previously in studies comparing characteristics of cases with head injury and psychosis with matched head injury controls with no psychosis.[21,22] On the one hand, a strong dose-response relationship between exposure and outcome would provide some reassurance that an association may be causal. On the other hand, it is possible that some other aspect of the head injury, such as location of trauma, or psychosocial stress associated with the trauma, may be more relevant than the clinical measure of severity in increasing risk of psychosis. Our analysis did not support the hypothesis that childhood or adolescent head injury is more likely to be associated with later schizophrenia.[23,24] However, this subgroup analysis was based on just 3 studies.[13 15] Two of these studies[14,15] did find significant associations between childhood or adolescent onset TBI and later schizophrenia but the largest study did not find an association. [13] Previously, Wilcox and Nasrallah[24] reported a highly significant 10-fold increase in risk for schizophrenia following head injury before the age of 10 years, but this study was not included in the meta-analysis because it used surgical controls.

Limitations
1. Methodological heterogeneity: As discussed in previous reviews of this topic, [47] there are many methodological differences between the studies examining TBI and psychosis such as: (1) different sources of information about the head injuryself-report[10,11,14] vs hospital admission data; (2) different degrees of severity of head injury studied; (3) different definitions of psychotic illnessnarrow schizophrenia outcomes,[1013] vs broader definitions,[14,17] and (4) variations in length of follow-up post TBI ranging from 3 years[1316] to 35 years.[14] Nevertheless, we felt that there was sufficient similarity between the exposure and outcome variables in these casecontrolled population-based studies to allow us to proceed to meta-analysis. Although there was a high degree of statistical heterogeneity in the data for the cohort and nested case-control

studies, there was no heterogeneity for the family studies. We used a random effects metaanalysis and meta-regression to take account of heterogeneity. 2. Location of TBI: We were not able to examine the effect of location of the TBI in this analysis. One of the limitations of the use of hospital discharge registers as a source of exposure information is that exact location of the brain injury cannot be determined. It has been proposed by some investigators that temporal and frontal lobe lesions are more likely to be associated with an increased risk of later psychosis compared with lesions in other brain regions. [3,21,22] However, the classic 22-year follow-up study of 3532 Finnish soldiers by Achte and colleagues [25] found no association between location of head injury and the subsequent development of psychosis 3. Another limitation is that none of the studies included in this review provided information on epilepsy. This could be a potential confounder of the association as head injury can cause epilepsy[2] and epilepsy is associated with an increased risk of psychosis.[26,27] In conclusion, our systematic review and meta-analysis has found that there is an increased risk of schizophrenia following TBI. The increase in risk associated with TBI is not large, in the order of about 60%, but this is not unusual for environmental risk factors for schizophrenia. [28] In particular, the risk appears higher in those who have a family history of schizophrenia suggesting a gene-environment interaction[29] or an epigenetic mechanism.[30]Investigation of the molecular or epigenetic consequences of TBI in relation to psychosis risk, or genetic investigation of families in which TBI and psychosis cluster, may be fruitful lines of enquiry.

http://www.medscape.com/viewarticle/752208_4