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1.  Schizophrenia and Violence: Systematic Review and Meta-Analysis 
PLoS Medicine  2009;6(8):e1000120.
Seena Fazel and colleagues investigate the association between schizophrenia and other psychoses and violence and violent offending, and show that the increased risk appears to be partly mediated by substance abuse comorbidity.
Background
Although expert opinion has asserted that there is an increased risk of violence in individuals with schizophrenia and other psychoses, there is substantial heterogeneity between studies reporting risk of violence, and uncertainty over the causes of this heterogeneity. We undertook a systematic review of studies that report on associations between violence and schizophrenia and other psychoses. In addition, we conducted a systematic review of investigations that reported on risk of homicide in individuals with schizophrenia and other psychoses.
Methods and Findings
Bibliographic databases and reference lists were searched from 1970 to February 2009 for studies that reported on risks of interpersonal violence and/or violent criminality in individuals with schizophrenia and other psychoses compared with general population samples. These data were meta-analysed and odds ratios (ORs) were pooled using random-effects models. Ten demographic and clinical variables were extracted from each study to test for any observed heterogeneity in the risk estimates. We identified 20 individual studies reporting data from 18,423 individuals with schizophrenia and other psychoses. In men, ORs for the comparison of violence in those with schizophrenia and other psychoses with those without mental disorders varied from 1 to 7 with substantial heterogeneity (I2 = 86%). In women, ORs ranged from 4 to 29 with substantial heterogeneity (I2 = 85%). The effect of comorbid substance abuse was marked with the random-effects ORs of 2.1 (95% confidence interval [CI] 1.7–2.7) without comorbidity, and an OR of 8.9 (95% CI 5.4–14.7) with comorbidity (p<0.001 on metaregression). Risk estimates of violence in individuals with substance abuse (but without psychosis) were similar to those in individuals with psychosis with substance abuse comorbidity, and higher than all studies with psychosis irrespective of comorbidity. Choice of outcome measure, whether the sample was diagnosed with schizophrenia or with nonschizophrenic psychoses, study location, or study period were not significantly associated with risk estimates on subgroup or metaregression analysis. Further research is necessary to establish whether longitudinal designs were associated with lower risk estimates. The risk for homicide was increased in individuals with psychosis (with and without comorbid substance abuse) compared with general population controls (random-effects OR = 19.5, 95% CI 14.7–25.8).
Conclusions
Schizophrenia and other psychoses are associated with violence and violent offending, particularly homicide. However, most of the excess risk appears to be mediated by substance abuse comorbidity. The risk in these patients with comorbidity is similar to that for substance abuse without psychosis. Public health strategies for violence reduction could consider focusing on the primary and secondary prevention of substance abuse.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Schizophrenia is a lifelong, severe psychotic condition. One in 100 people will have at least one episode of schizophrenia during their lifetime. Symptoms include delusions (for example, patients believe that someone is plotting against them) and hallucinations (hearing or seeing things that are not there). In men, schizophrenia usually starts in the late teens or early 20s; women tend to develop schizophrenia a little later. The causes of schizophrenia include genetic predisposition, obstetric complications, illegal drug use (substance abuse), and experiencing traumatic life events. The condition can be treated with a combination of antipsychotic drugs and supportive therapy; hospitalization may be necessary in very serious cases to prevent self harm. Many people with schizophrenia improve sufficiently after treatment to lead satisfying lives although some patients need lifelong support and supervision.
Why Was This Study Done?
Some people believe that schizophrenia and other psychoses are associated with violence, a perception that is often reinforced by news reports and that contributes to the stigma associated with mental illness. However, mental health advocacy groups and many mental health clinicians argue that it is a myth that people with mental health problems are violent. Several large, population-based studies have examined this disputed relationship. But, although some studies found no increased risk of violence among patients with schizophrenia compared with the general population, others found a marked increase in violent offending in patients with schizophrenia. Here, the researchers try to resolve this variation (“heterogeneity”) in the conclusions reached in different studies by doing a systematic review (a study that uses predefined search criteria to identify all the research on a specific topic) and a meta-analysis (a statistical method for combining the results of several studies) of the literature on associations between violence and schizophrenia and other psychoses. They also explored the relationship between substance abuse and violence.
What Did the Researchers Do and Find?
By systematically searching bibliographic databases and reference lists, the researchers identified 20 studies that compared the risk of violence in people with schizophrenia and other psychoses and the risk of violence in the general population. They then used a “random effects model” (a statistical technique that allows for heterogeneity between studies) to investigate the association between schizophrenia and violence. For men with schizophrenia or other psychoses, the pooled odds ratio (OR) from the relevant studies (which showed moderate heterogeneity) was 4.7, which was reduced to 3.8 once adjustment was made for socio-economic factors. That is, a man with schizophrenia was four to five times as likely to commit a violent act as a man in the general population. For women, the equivalent pooled OR was 8.2 but there was a much greater variation between the ORs in the individual studies than in the studies that involved men. The researchers then used “meta-regression” to investigate the heterogeneity between the studies. This analysis suggested that none of the study characteristics examined apart from co-occurring substance abuse could have caused the variation between the studies. Importantly the authors found that risk estimates of violence in people with substance abuse but no psychosis were similar to those in people with substance abuse and psychosis and higher than those in people with psychosis alone. Finally, although people with schizophrenia were nearly 20 times more likely to have committed murder than people in the general population, only one in 300 people with schizophrenia had killed someone, a similar risk to that seen in people with substance abuse.
What Do These Findings Mean?
These findings indicate that schizophrenia and other psychoses are associated with violence but that the association is strongest in people with substance abuse and most of the excess risk of violence associated with schizophrenia and other psychoses is mediated by substance abuse. However, the increased risk in patients with comorbidity was similar to that in substance abuse without psychosis. A potential implication of this finding is that violence reduction strategies that focus on preventing substance abuse among both the general population and among people with psychoses might be more successful than strategies that solely target people with mental illnesses. However, the quality of the individual studies included in this meta-analysis limits the strength of its conclusions and more research into the association between schizophrenia, substance abuse, and violence would assist in clarifying how and if strategies for violence reduction are changed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000120.
The US National Institute of Mental Health provides information about schizophrenia (in English and Spanish)
The UK National Health Service Choices Web site has information for patients and carers about schizophrenia
The MedlinePlus Encyclopedia has a page on schizophrenia; MedlinePlus provides links to other sources of information on schizophrenia and on psychotic disorders (in English and Spanish)
The Schizophrenia and Related Disorders Alliance of America provides information and support for people with schizophrenia and their families
The time to change Web site provides information about an English campaign to reduce the stigma associated with mental illness
The Schizophrenia Research Forum provides updated research news and commentaries for the scientific community
doi:10.1371/journal.pmed.1000120
PMCID: PMC2718581  PMID: 19668362
2.  Psychotic Illness in First-Time Mothers with No Previous Psychiatric Hospitalizations: A Population-Based Study 
PLoS Medicine  2009;6(2):e1000013.
Background
Psychotic illness following childbirth is a relatively rare but severe condition with unexplained etiology. The aim of this study was to investigate the impact of maternal background characteristics and obstetric factors on the risk of postpartum psychosis, specifically among mothers with no previous psychiatric hospitalizations.
Methods and Findings
We investigated incidence rates and potential maternal and obstetric risk factors of psychoses after childbirth in a national cohort of women who were first-time mothers from 1983 through 2000 (n = 745,596). Proportional hazard regression models were used to estimate relative risks of psychoses during and after the first 90 d postpartum, among mothers without any previous psychiatric hospitalization and among all mothers. Within 90 d after delivery, 892 women (1.2 per 1,000 births; 4.84 per 1,000 person-years) were hospitalized due to psychoses and 436 of these (0.6 per 1,000 births; 2.38 per 1,000 person-years) had not previously been hospitalized for any psychiatric disorder. During follow-up after the 90 d postpartum period, the corresponding incidence rates per 1,000 person-years were reduced to 0.65 for all women and 0.49 for women not previously hospitalized. During (but not after) the first 90 d postpartum the risk of psychoses among women without any previous psychiatric hospitalization was independently affected by: maternal age (35 y or older versus 19 y or younger; hazard ratio 2.4, 95% confidence interval [CI] 1.2 to 4.7); high birth weight (≥ 4,500 g; hazard ratio 0.3, 95% CI 0.1 to 1.0); and diabetes (hazard ratio 0).
Conclusions
The incidence of psychotic illness peaks immediately following a first childbirth, and almost 50% of the cases are women without any previous psychiatric hospitalization. High maternal age increases the risk while diabetes and high birth weight are associated with reduced risk of first-onset psychoses, distinctly during the postpartum period.
Unnur Valdimarsdóttir and colleagues studied the risk factors for psychiatric illness following childbirth and found that, for women who had never previously been hospitalized for a psychiatric illness, the risk of mental illness was greatly increased following childbirth.
Editors' Summary
Background.
The first cries of a new life echo around the delivery suite: this is a time of great joy for most women. Yet, in the following days and weeks (the postpartum period), up to 80% of new mothers experience some sort of mental disturbance. Usually, this is the “baby blues,” a normal reaction to childbirth that is characterized by short-lived mood swings or postnatal depression. However, about one in 1,000 women develop postpartum psychosis, a serious mental disorder that needs immediate medical attention. Postpartum psychosis usually develops suddenly in the first 2–3 weeks after delivery and, like other forms of psychosis, is characterized by a loss of contact with reality. Women with postpartum psychosis may have false ideas about current events and about themselves (delusions) and see and hear things that are not there (hallucinations). They sometimes stop eating or sleeping and may become anxious and agitated. In the worst cases, they can have suicidal thoughts or even threaten their baby's life. Treatment for postpartum psychosis includes antipsychotic drugs, counseling, and hospital admission if the woman is a danger to herself or others.
Why Was This Study Done?
Women with a personal or family history of psychosis have an increased risk of developing postpartum psychosis, but what causes this disorder is unknown. The rapid changes in hormone levels that occur after delivery are likely to be involved—but might social circumstances, stress, other illnesses, or the birth itself also affect whether a woman develops postpartum psychosis? If additional risk factors for postpartum psychosis could be identified, it might be possible to prevent some cases of this serious mental disorder. In this study, the researchers investigate the incidence rate (the rate at which new cases occur in a population) and risk factors for psychotic illnesses diagnosed among first-time mothers registered in the Swedish Medical Birth Registry between 1983 and 2000.
What Did the Researchers Do and Find?
The researchers identified three-quarters of a million first-time mothers and, from the Swedish Hospital Discharge Registry, found that 892 of these women (1.2 per 1,000 births) had been admitted to hospital because of psychosis within 90 days of giving birth. Put another way, the incidence rate of psychosis over the first 90 days postpartum in this population was 4.84 per 1,000 person-years. Almost half of the women who developed postpartum psychosis had not been previously admitted to hospital for any psychiatric disorder. Among this subset of women, the incidence rate of postpartum psychosis was highest during the first month after delivery but dropped to less than a tenth of this initial rate after 90 days postpartum. Furthermore, the risk of developing psychosis during the first 90 days postpartum (but not after) increased with age—women older than 35 years were more than twice as likely to develop psychosis than those aged 19 years or less—but was reduced in women who had large babies or who had diabetes. Many other factors (including smoking and not living with the infant's father) did not affect the risk of psychosis during the first 90 days postpartum in these women.
What Do These Findings Mean?
These findings indicate that the occurrence of psychotic illness severe enough to require hospitalization peaks shortly after giving birth for the first time, even in women with no previous psychiatric illness. Indeed, women with no history of mental disorders account for almost half the women admitted to hospital for postpartum psychosis, at least in Sweden. The timing of the peak of postpartum psychosis supports the idea that either giving birth or the hormonal changes that occur shortly after may trigger the development of psychosis, and the findings that maternal diabetes and high infant birth weight reduce the risk of postpartum psychosis whereas increasing maternal age increases the risk provide new clues about the causes of postpartum psychosis. Most importantly, however, these findings highlight the importance of carefully monitoring women for psychosis during the first month after delivery.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000013.
This paper is further discussed in a PLoS Medicine Perspective by Phillipa Hay
The MedlinePlus Encyclopedia contains a page on MedlinePlus encyclopedia psychosis (in English and Spanish); MedlinePlus also provides links to information on psychotic disorders
The UK National Health Service Direct Health encyclopedia has information on psychosis and on postnatal depression
Mental Health America has a fact sheet on postpartum disorders
doi:10.1371/journal.pmed.1000013
PMCID: PMC2637917  PMID: 19209952
3.  The prevalence of psychosis in epilepsy; a systematic review and meta-analysis 
BMC Psychiatry  2014;14:75.
Background
Epilepsy has long been considered to be a risk factor for psychosis. However there is a lack of consistency in findings across studies on the effect size of this risk which reflects methodological differences in studies and changing diagnostic classifications within neurology and psychiatry. The aim of this study was to assess the prevalence of psychosis in epilepsy and to estimate the risk of psychosis among individuals with epilepsy compared with controls.
Methods
A systematic review and meta-analysis was conducted of all published literature pertaining to prevalence rates of psychosis in epilepsy using electronic databases PUBMED, OVIDMEDLINE, PsychINFO and Embase from their inception until September 2010 with the following search terms: prevalence, incidence, rate, rates, psychosis, schizophrenia, schizophreniform illness, epilepsy, seizures, temporal lobe epilepsy.
Results
The literature search and search of reference lists yielded 215 papers. Of these, 58 (27%) had data relevant to the review and 157 were excluded following a more detailed assessment. 10% of the included studies were population based studies. The pooled odds ratio for risk of psychosis among people with epilepsy compared with controls was 7.8. The pooled estimate of prevalence of psychosis in epilepsy was found to be 5.6% (95% CI: 4.8-6.4). There was a high level of heterogeneity. The prevalence of psychosis in temporal lobe epilepsy was 7% (95% CI: 4.9-9.1). The prevalence of interictal psychosis in epilepsy was 5.2% (95% CI: 3.3-7.2). The prevalence of postictal psychosis in epilepsy was 2% (95% CI: 1.2-2.8).
Conclusions
Our systematic review found that up to 6% of individuals with epilepsy have a co-morbid psychotic illness and that patients have an almost eight fold increased risk of psychosis. The prevalence rate of psychosis is higher in temporal lobe epilepsy (7%). We suggest that further investigation of this association could give clues to the aetiology of psychosis.
doi:10.1186/1471-244X-14-75
PMCID: PMC3995617  PMID: 24625201
Psychosis; Epilepsy; Systematic review
4.  Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study 
BMJ : British Medical Journal  1999;318(7181):421-426.
Objective
To examine prenatal and perinatal risk factors for subsequent development of schizophrenia and affective and reactive psychosis.
Design
Three population based, case-control studies conducted within a Sweden-wide cohort of all children born during 1973-9. This was done by linking individual data from the Swedish birth register, which represents 99% of all births in Sweden, to the Swedish inpatient register.
Subjects
Patients listed in inpatient register as having been first admitted to hospital aged 15-21 years with a main diagnosis of schizophrenia (n=167), affective psychosis (n=198), or reactive psychosis (n=292). For each case, five controls were selected.
Main outcome measures
Risks of schizophrenia and affective and reactive psychosis in relation to pregnancy and perinatal characteristics.
Results
Schizophrenia was positively associated with multiparity (odds ratio 2.0), maternal bleeding during pregnancy (odds ratio 3.5), and birth in late winter (odds ratio 1.4). Affective psychosis was associated with uterine atony (odds ratio 2.2) and late winter birth (odds ratio 1.5). Reactive psychosis was related to multiparity (odds ratio 2.1). An increased risk for schizophrenia was found in boys who were small for their gestational age at birth (odds ratio 3.2), who were number four or more in birth order (odds ratio 3.6), and whose mothers had had bleeding during late pregnancy (odds ratio 4.0).
Conclusions
A few specific pregnancy and perinatal factors were associated with the subsequent development of psychotic disorder, particularly schizophrenia, in early adult life. The association of small size for gestational age and bleeding during pregnancy with increased risk of early onset schizophrenia among males could reflect placental insufficiency.
Key messagesThe role of prenatal and perinatal risk factors in the development of schizophrenia and affective and reactive psychosis in early adult life were investigated by linking individual data from the Swedish birth and inpatient registriesAdverse prenatal and perinatal factors were more common in patients with schizophrenia of early onset than in controls and seemed more important in the aetiology of schizophrenia than in that of affective and reactive psychosisMultiparity, bleeding during pregnancy, and small size for gestational age were associated with a threefold to fourfold increased risk for schizophrenia among malesThere was no support for previous claims that head circumference is small in preschizophrenic infantsLate winter birth was associated with increased risk of both schizophrenia and affective psychosis
PMCID: PMC27730  PMID: 9974454
5.  A STUDY OF EPILEPTIC PSYCHOSES - 150 CASES 
Indian Journal of Psychiatry  1986;28(3):231-236.
SUMMARY
One hundred and fifty patients of epileptic psychosis, registered over a period of five years in neuropsychiatry clinics at NIMHANS were studied. Patients with organic causes which may produce both epilepsy and psychosis were excluded. The epileptic psychosis ratio to epilepsy was 1:23 and the epileptic psychosis ratio to psychosis was 1:75. The mean age at the onset of epilepsy was 19.4 years, while the mean age at the onset of psychosis was 29 years and thus the mean duration of epilepsy at the onset of psychosis was 9.4 years. With regard to type of seizures, 93 (62%) had grandmal, 50 (33.3%) had temporal lobe epilepsy and 7 (4.7%) had partial motor or sensory epilepsy with generalization. With regard to type of psychosis, 64 (42.7 %) had post-ictal and/or inter-ictal psychosis, 15(10%) paranoid schizophrenia, 9 (6%) mania, 2 (1.3%) depression and 60 (40%) unspecified psychoses. The mean duration of epilepsy was significantly less (p < 0.05) at the onset of acute psychosis than chronic psychosis. Family history of epilepsy and mental illness, premorbid personality and frequencies of seizures were not significantly associated with pathogenesis of epileptic psychosis.
PMCID: PMC3172536  PMID: 21927181
6.  Epilepsy Care in Ontario: An Economic Analysis of Increasing Access to Epilepsy Surgery 
Background
In August 2011 a proposed epilepsy care model was presented to the Ontario Health Technology Advisory Committee (OHTAC) by an Expert Panel on a Provincial Strategy for Epilepsy Care in Ontario. The Expert Panel recommended leveraging existing infrastructure in the province to provide enhanced capacity for epilepsy care. The point of entry for epilepsy care and the diagnostic evaluation for surgery candidacy and the epilepsy surgery would occur at regional and district epilepsy centres in London, Hamilton, Toronto, and Ottawa and at new centres recommended for northern and eastern Ontario.
This economic analysis report was requested by OHTAC to provide information about the estimated budgetary impact on the Ontario health care system of increasing access to epilepsy surgery and to examine the cost-effectiveness of epilepsy surgery in both children and adults.
Methods
A prevalence-based “top-down” health care system budgetary impact model from the perspective of the Ministry of Health and Long-Term Care was developed to estimate the potential costs associated with expanding health care services to increase access to epilepsy care in general and epilepsy surgery in particular. A 5-year period (i.e., 2012–2016) was used to project annual costs associated with incremental epilepsy care services. Ontario Health Survey estimates of epilepsy prevalence, published epilepsy incidence data, and Canadian Census results for Ontario were used to approximate the number of individuals with epilepsy in the province. Applying these population estimates to data obtained from a recent field evaluation study that examined patterns of care and costs associated with epilepsy surgery in children, a health care system budget impact was calculated and the total costs and incremental costs associated with increasing access to surgery was estimated.
In order to examine the cost-effectiveness of epilepsy surgery in children, a decision analysis compared epilepsy surgery to continued medical management in children with medically intractable epilepsy. Data from the field evaluation were combined with various published data to estimate the costs and outcomes for children with drug-refractory epilepsy over a 20-year period. Outcomes were defined as the number of quality-adjusted life years (QALYs) accumulated over 20 years following epilepsy surgery.
Results
There are about 20,981 individuals with medically intractable epilepsy in Ontario. Of these, 9,619 (1,441 children and 8,178 adults) could potentially be further assessed at regional epilepsy centres for suitability for epilepsy surgery, following initial evaluation at a district epilepsy care centre. The health care system impact analysis related to increasing access to epilepsy surgery in the Ontario through the addition of epilepsy monitoring unit (EMU) beds with video electroencephalography (vEEG) monitoring (total capacity of 15 pediatric EMU beds and 35 adult EMU beds distributed across the province) and the associated clinical resources is estimated to require an incremental $18.1 million (Cdn) annually over the next 5 years from 2012 to 2016. This would allow for about 675 children and 1050 adults to be evaluated each year for suitability for epilepsy surgery representing a 150% increase in pediatric epilepsy surgery evaluation and a 170% increase in adult epilepsy surgery evaluation.
Epilepsy surgery was found to be cost-effective compared to continued medical management in children with drug-refractory epilepsy with the incremental cost-effectiveness ratio of $25,020 (Cdn) to $69,451 (Cdn) per QALY for 2 of the scenarios examined. In the case of choosing epilepsy surgery versus continued medical management in children known to be suitable for surgery, the epilepsy surgery was found to be less costly and provided greater clinical benefit, that is, it was the dominant strategy.
Conclusion
Epilepsy surgery for medically intractable epilepsy in suitable candidates has consistently been found to provide favourable clinical outcomes and has been demonstrated to be cost-effective in both adult and child patient populations. The first step to increasing access to epilepsy surgery is to provide access to evidence-based care for all patients with epilepsy, both adults and children, through the provision of resources to expand EMU bed capacity and associated clinical personnel across the province of Ontario.
Plain Language Summary
Epilepsy, characterized by recurrent, unpredictable, and spontaneous seizures, affects approximately 70,000 people in Ontario. About 30% continue to suffer from seizures despite using 2 or more anti-seizure medications. For these individuals epilepsy surgery is a treatment option to stop the seizures or at least reduce their frequency. Awareness of this treatment option is not widespread and people are not commonly referred to those hospitals in Ontario where this surgery is available. A proposal to increase access to epilepsy care and surgery has been made by an expert committee that provided a report to the Ontario Health Technology Advisory Committee (OHTAC). In order to address the lack of access of patients with medically intractable epilepsy to the possibility of curative surgical treatment, it is necessary to design a system that provides equal availability of evidence-based treatment for all epilepsy patients in Ontario, both adults and children. To this end, the establishment of district epilepsy care centres and the further development of the existing regional epilepsy care centres in the province have been proposed. This report outlines the estimated additional funds that will be required to implement the proposal. It also examines the cost-effectiveness of referral to these centres and epilepsy surgery.
For the 21,000 people in the province with drug-refractory epilepsy, referral to an epilepsy monitoring unit (EMU) located at one of the epilepsy care centres is the first step to determining if epilepsy surgery is an option for them. The expert committee proposal suggests that the number of EMU beds be increased from the current 19 to 50 to allow for the assessment of those individuals with drug-refractory epilepsy. The health care system budget impact model presented in this report estimates that it would cost approximately $18 million (Cdn) each year over the next 5 years to increase the number of EMU beds and expand associated epilepsy care centres to permit the systematic evidence-based care of all Ontarians with epilepsy and evaluate more people for surgery candidacy. This amount would provide appropriate care for patients with epilepsy and ensure that about 675 children and 1050 adults could be assessed each year for suitability for epilepsy surgery. Surgery could then be made available to just over 300 people per year.
Epilepsy surgery over the long term is a less expensive treatment alternative for adults and children with medically refractory epilepsy compared with continued drug treatment. In addition, drug treatment does not always work for some patients; nor does it necessarily provide improved quality of life.
This report includes a cost-effectiveness analysis comparing referral for assessment for epilepsy surgery with continuing medical management in children with drug-refractory epilepsy. In all the cases examined epilepsy surgery provides good value for money over a 20-year period. Similar studies have found that the benefits from epilepsy surgery outweigh those of continuing medical management in adult patients with medically refractory epilepsy.
PMCID: PMC3428718  PMID: 23074428
7.  Risk of Violent Crime in Individuals with Epilepsy and Traumatic Brain Injury: A 35-Year Swedish Population Study 
PLoS Medicine  2011;8(12):e1001150.
Seena Fazel and colleagues report findings from a longitudinal follow-up study in Sweden that evaluated the risks of violent crime subsequent to hospitalization for epilepsy, or traumatic brain injury. The researchers control for familial confounding with sibling controls. The analyses call into question an association between epilepsy and violent crime, although they do suggest that there may be a relationship between traumatic brain injury and violent crime.
Background
Epilepsy and traumatic brain injury are common neurological conditions, with general population prevalence estimates around 0.5% and 0.3%, respectively. Although both illnesses are associated with various adverse outcomes, and expert opinion has suggested increased criminality, links with violent behaviour remain uncertain.
Methods and Findings
We combined Swedish population registers from 1973 to 2009, and examined associations of epilepsy (n = 22,947) and traumatic brain injury (n = 22,914) with subsequent violent crime (defined as convictions for homicide, assault, robbery, arson, any sexual offense, or illegal threats or intimidation). Each case was age and gender matched with ten general population controls, and analysed using conditional logistic regression with adjustment for socio-demographic factors. In addition, we compared cases with unaffected siblings.
Among the traumatic brain injury cases, 2,011 individuals (8.8%) committed violent crime after diagnosis, which, compared with population controls (n = 229,118), corresponded to a substantially increased risk (adjusted odds ratio [aOR] = 3.3, 95% CI: 3.1–3.5); this risk was attenuated when cases were compared with unaffected siblings (aOR = 2.0, 1.8–2.3). Among individuals with epilepsy, 973 (4.2%) committed a violent offense after diagnosis, corresponding to a significantly increased odds of violent crime compared with 224,006 population controls (aOR = 1.5, 1.4–1.7). However, this association disappeared when individuals with epilepsy were compared with their unaffected siblings (aOR = 1.1, 0.9–1.2). We found heterogeneity in violence risk by age of disease onset, severity, comorbidity with substance abuse, and clinical subgroups. Case ascertainment was restricted to patient registers.
Conclusions
In this longitudinal population-based study, we found that, after adjustment for familial confounding, epilepsy was not associated with increased risk of violent crime, questioning expert opinion that has suggested a causal relationship. In contrast, although there was some attenuation in risk estimates after adjustment for familial factors and substance abuse in individuals with traumatic brain injury, we found a significantly increased risk of violent crime. The implications of these findings will vary for clinical services, the criminal justice system, and patient charities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
News stories linking mental illness (diseases that appear primarily as abnormalities of thought, feeling or behavior) with violence frequently hit the headlines. But what about neurological conditions—disorders of the brain, spinal cord, and nerves? People with these disorders, which include dementia, Parkinson's disease, and brain tumors, often experience stigmatization and discrimination, a situation that is made worse by the media and by some experts suggesting that some neurological conditions increase the risk of violence. For example, many modern textbooks assert that epilepsy—a neurological condition that causes repeated seizures or fits—is associated with increased criminality and violence. Similarly, various case studies have linked traumatic brain injury—damage to the brain caused by a sudden blow to the head—with an increased risk of violence.
Why Was This Study Done?
Despite public and expert perceptions, very little is actually known about the relationship between epilepsy and traumatic brain injury and violence. In particular, few if any population-based, longitudinal studies have investigated whether there is an association between the onset of either of these two neurological conditions and violence at a later date. This information might make it easier to address the stigma that is associated with these conditions. Moreover, it might help scientists understand the neurobiological basis of violence, and it could help health professionals appropriately manage individuals with these two disorders. In this longitudinal study, the researchers begin to remedy the lack of hard information about links between neurological conditions and violence by investigating the risk of violent crime associated with epilepsy and with traumatic brain injury in the Swedish population.
What Did the Researchers Do and Find?
The researchers used the National Patient Register to identify all the cases of epilepsy and traumatic brain injury that occurred in Sweden between 1973 and 2009. They matched each case (nearly 23,000 for each condition) with ten members of the general population and retrieved data on all convictions for violent crime over the same period from the Crime Register. They then linked these data together using the personal identification numbers that identify Swedish residents in national registries. 4.2% of individuals with epilepsy had at least one conviction for violence after their diagnosis, but only 2.5% of the general population controls did. That is, epilepsy increased the absolute risk of a conviction for violence by 1.7%. Using a regression analysis that adjusted for age, gender, and various socio-demographic factors, the researchers calculated that the odds of individuals with epilepsy committing a violent crime were 1.5 times higher than for general population controls (an adjusted odds ratio [aOR] of 1.5). The strength of this association was reduced when further adjustment was made for substance abuse, and disappeared when individuals with epilepsy were compared with their unaffected siblings (a sibling control study). Similarly, 8.8% of individuals with traumatic brain injury were convicted of a violent crime after their diagnosis compared to only 3% of controls, giving an aOR of 3.3. Again, the strength of this association was reduced when affected individuals were compared to their unaffected siblings (aOR = 2.0) and when adjustment was made for substance abuse (aOR = 2.3).
What Do These Findings Mean?
Although some aspects of this study may have affected the accuracy of its findings, these results nevertheless challenge the idea that there are strong direct links between epilepsy and violent crime. The low absolute rate of violent crime and the lack of any association between epilepsy and violent crime in the sibling control study argue against a strong link, a potentially important finding given the stigmatization of epilepsy. For traumatic brain injury, the reduced association with violent crime in the sibling control study compared with the general population control study suggests that shared familial features may be responsible for some of the association between brain injury and violence. As with epilepsy, this finding should help patient charities who are trying to reduce the stigma associated with traumatic brain injury. Importantly, however, these findings also suggest that some groups of patients with these conditions (for example, patients with head injuries who abuse illegal drugs and alcohol) would benefit from being assessed for their risk of behaving violently and from appropriate management.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001150.
This study is further discussed in a PLoS Medicine Perspective by Jan Volavka
The US National Institute of Neurological Disorders and Stroke provides detailed information about traumatic brain injury and about epilepsy (in English and Spanish)
The UK National Health Service Choices website provides information about severe head injury, including a personal story about a head injury sustained in a motor vehicle accident, and information about epilepsy, including personal stories about living with epilepsy
Healthtalkonline has information on epilepsy, including patient perspectives
MedlinePlus provide links to further resources on traumatic brain injury and on epilepsy (available in English and Spanish)
doi:10.1371/journal.pmed.1001150
PMCID: PMC3246446  PMID: 22215988
8.  Early intervention for psychosis 
Background
Proponents of early intervention have argued that outcomes might be improved if more therapeutic efforts were focused on the early stages of schizophrenia or on people with prodromal symptoms. Early intervention in schizophrenia has two elements that are distinct from standard care: early detection, and phase-specific treatment (phase-specific treatment is a psychological, social or physical treatment developed, or modified, specifically for use with people at an early stage of the illness).
Early detection and phase-specific treatment may both be offered as supplements to standard care, or may be provided through a specialised early intervention team. Early intervention is now well established as a therapeutic approach in America, Europe and Australasia.
Objectives
To evaluate the effects of: (a) early detection; (b) phase-specific treatments; and (c) specialised early intervention teams in the treatment of people with prodromal symptoms or first-episode psychosis.
Search methods
We searched the Cochrane Schizophrenia Group Trials Register (March 2009), inspected reference lists of all identified trials and reviews and contacted experts in the field.
Selection criteria
We included all randomised controlled trials (RCTs) designed to prevent progression to psychosis in people showing prodromal symptoms, or to improve outcome for people with first-episode psychosis. Eligible interventions, alone and in combination, included: early detection, phase-specific treatments, and care from specialised early intervention teams. We accepted cluster-randomised trials but excluded non-randomised trials.
Data collection and analysis
We reliably selected studies, quality rated them and extracted data. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis (ITT).
Main results
Studies were diverse, mostly small, undertaken by pioneering researchers and with many methodological limitations (18 RCTs, total n=1808). Mostly, meta-analyses were inappropriate. For the six studies addressing prevention of psychosis for people with prodromal symptoms, olanzapine seemed of little benefit (n=60, 1 RCT, RR conversion to psychosis 0.58 CI 0.3 to 1.2), and cognitive behavioural therapy (CBT) equally so (n=60, 1 RCT, RR conversion to psychosis 0.50 CI 0.2 to 1.7). A risperidone plus CBT plus specialised team did have benefit over specialist team alone at six months (n=59, 1 RCT, RR conversion to psychosis 0.27 CI 0.1 to 0.9, NNT 4 CI 2 to 20), but this was not seen by 12 months (n=59, 1 RCT, RR 0.54 CI 0.2 to 1.3). Omega 3 fatty acids (EPA) had advantage over placebo (n=76, 1 RCT, RR transition to psychosis 0.13 CI 0.02 to 1.0, NNT 6 CI 5 to 96). We know of no replications of this finding.
The remaining trials aimed to improve outcome in first-episode psychosis. Phase-specific CBT for suicidality seemed to have little effect, but the single study was small (n=56, 1 RCT, RR suicide 0.81 CI 0.05 to 12.26). Family therapy plus a specialised team in the Netherlands did not clearly affect relapse (n=76, RR 1.05 CI 0.4 to 3.0), but without the specialised team in China it may (n=83, 1 RCT, RR admitted to hospital 0.28 CI 0.1 to 0.6, NNT 3 CI 2 to 6). The largest and highest quality study compared specialised team with standard care. Leaving the study early was reduced (n=547, 1 RCT, RR 0.59 CI 0.4 to 0.8, NNT 9 CI 6 to 18) and compliance with treatment improved (n=507, RR stopped treatment 0.20 CI 0.1 to 0.4, NNT 9 CI 8 to 12). The mean number of days spent in hospital at one year were not significantly different (n=507, WMD, −1.39 CI −2.8 to 0.1), neither were data for ‘Not hospitalised’ by five years (n=547, RR 1.05 CI 0.90 to 1.2). There were no significant differences in numbers ‘not living independently’ by one year (n=507, RR 0.55 CI 0.3 to 1.2). At five years significantly fewer participants in the treatment group were ‘not living independently’ (n=547, RR 0.42 CI 0.21 to 0.8, NNT 19 CI 14 to 62). When phase-specific treatment (CBT) was compared with befriending no significant differences emerged in the number of participants being hospitalised over the 12 months (n=62, 1 RCT, RR 1.08 CI 0.59 to 1.99).
Phase-specific treatment E-EPA oils suggested no benefit (n=80, 1 RCT, RR no response 0.90 CI 0.6 to 1.4) as did phase-specific treatment brief intervention (n=106, 1 RCT, RR admission 0.86 CI 0.4 to 1.7). Phase-specific ACE found no benefit but participants given vocational intervention were more likely to be employed (n=41, 1 RCT, RR 0.39 CI 0.21 to 0.7, NNT 2 CI 2 to 4). Phase-specific cannabis and psychosis therapy did not show benefit (n=47, RR cannabis use 1.30 CI 0.8 to 2.2) and crisis assessment did not reduce hospitalisation (n=98, RR 0.85 CI 0.6 to 1.3). Weight was unaffected by early behavioural intervention.
Authors’ conclusions
There is emerging, but as yet inconclusive evidence, to suggest that people in the prodrome of psychosis can be helped by some interventions. There is some support for specialised early intervention services, but further trials would be desirable, and there is a question of whether gains are maintained. There is some support for phase-specific treatment focused on employment and family therapy, but again, this needs replicating with larger and longer trials.
doi:10.1002/14651858.CD004718.pub3
PMCID: PMC4163966  PMID: 21678345
*Psychotic Disorders [diagnosis; therapy]; *Schizophrenia [diagnosis; therapy]; Cognitive Therapy; Early Diagnosis; Randomized Controlled Trials as Topic; Suicidal Ideation; Time Factors; Humans
9.  Autoimmune diseases, bipolar disorder, and non-affective psychosis 
Bipolar disorders  2010;12(6):638-646.
Objective
Clinic-based studies of immune function, as well as comorbidity of autoimmune diseases, bipolar disorder, and schizophrenia, suggest a possible autoimmune etiology. Studies of non-affective psychosis and schizophrenia suggest common etiologies. The objective was to determine the degree to which 30 different autoimmune diseases are antecedent risk factors for bipolar disorder, schizophrenia, and non-affective psychosis.
Methods
A cohort of 3.57 million births in Denmark was linked to the Psychiatric Case Register and the National Hospital Register. There were 20,317 cases of schizophrenia, 39,076 cases of non-affective psychosis, and 9,920 cases of bipolar disorder.
Results
As in prior studies, there were a range of autoimmune diseases which predicted raised risk of schizophrenia in individuals who had a history of autoimmune diseases, and also raised risk in persons whose first-degree relatives had an onset of autoimmune disease prior to onset of schizophrenia in the case. These relationships also existed for the broader category of non-affective psychosis. Only pernicious anemia in the family was associated with raised risk for bipolar disorder (relative risk: 1.7), suggesting a small role for genetic linkage. A history of Guillain-Barré syndrome, Crohn’s disease, and autoimmune hepatitis in the individual was associated with raised risk of bipolar disorder.
Conclusions
The familial relationship of schizophrenia to a range of autoimmune diseases extends to non-affective psychosis, but not to bipolar disorder. The data suggest that autoimmune processes precede onset of schizophrenia, but also non-affective psychosis and bipolar disorder.
doi:10.1111/j.1399-5618.2010.00853.x
PMCID: PMC2950824  PMID: 20868462
autoimmune disease; bipolar disorder; epidemiology; non-affective psychosis; register; schizophrenia
10.  Paternal age and schizophrenia: a population based cohort study 
BMJ : British Medical Journal  2004;329(7474):1070.
Objective To investigate the association of paternal age at conception with the risk of offspring developing schizophrenia.
Design A population based cohort study.
Setting Sweden.
Subjects 754 330 people born in Sweden between 1973 and 1980 and still alive and resident in Sweden at age 16 years.
Main outcome measures Hospital admission with schizophrenia or non-schizophrenic, non-affective psychosis.
Results After adjustment for birth related exposures, socioeconomic factors, family history of psychosis, and early parental death the overall hazard ratio for each 10 year increase in paternal age was 1.47 (95% confidence interval 1.23 to 1.76) for schizophrenia and 1.12 (0.98 to 1.29) for non-schizophrenic non-affective psychosis. This association between paternal age and schizophrenia was present in those with no family history of the disorder (hazard ratio for each 10 year increase in paternal age 1.60, 1.32 to 1.92), but not in those with a family history (0.91, 0.44 to 1.89) (P = 0.04 for interaction).
Conclusions Advancing paternal age is an important independent risk factor for schizophrenia. The stronger association between paternal age and schizophrenia in people without a family history provides further evidence that accumulation of de novo mutations in paternal sperm contributes to the overall risk of schizophrenia.
doi:10.1136/bmj.38243.672396.55
PMCID: PMC526116  PMID: 15501901
11.  SCHIZOPHRENIA AND EPILEPSY: IS THERE A SHARED SUSCEPTIBILITY? 
Neuroscience research  2009;63(4):227-235.
Individuals with epilepsy are at increased risk of having psychotic symptoms that resemble those of schizophrenia. More controversial and less searched is if schizophrenia is a risk factor for epilepsy. Here we review overlapping epidemiological, clinical, neuropathological and neuroimaging features of these two diseases. We discuss the role of temporal and other brain areas in the development of schizophrenia-like psychosis of epilepsy. We underline the importance of ventricular enlargement in both conditions as a phenotypic manifestation of a shared biologic liability that might relate to abnormalities in neurodevelopment. We suggest that genes implicated in neurodevelopment may play a common role in both conditions and speculate that recently identified causative genes for partial complex seizures with auditory features might help explain the pathophysiology of schizophrenia. These particularly include the leucine-rich glioma inactivated (LGI) family gene loci overlap with genes of interest for psychiatric diseases like schizophrenia. Finally, we conclude that LGI genes associated with partial epilepsy with auditory features might also represent genes of interest for schizophrenia, especially among patients with prominent auditory hallucinations and formal thought disorder.
doi:10.1016/j.neures.2009.01.002
PMCID: PMC2768382  PMID: 19367784
schizophrenia; epilepsy; temporal lobe; susceptibility; neurodevelopment; LGI genes
12.  Research in People with the Psychosis Risk Syndrome: A Review of the Current Evidence and Future Directions 
After decades of research, schizophrenia and related psychotic disorders are still among the most debilitating disorders in medicine. The chronic illness course in most individuals, greater treatment responsiveness during the first episode, progressive grey matter decline during early disease stages, and retrospective accounts of “prodromal” or early illness signs and symptoms formed the basis for research on the psychosis risk syndrome,, known variably as “clinical high risk”(CHR), or “ultra-high risk“ (UHR), or “prodromal”. The pioneering era of research on the psychosis risk syndrome focused on the development and validation of specific assessment tools and the delineation of high risk criteria. This was followed by the examination of conversion rates in psychosis risk cohorts followed naturalistically, identification of predictors of conversion to psychosis, and investigation of interventions able to abort or delay the development of full psychosis. Despite initially encouraging results concerning the predictive validity of the psychosis risk syndrome criteria, recent findings of declining conversion rates demonstrate the need for further investigations. Results from intervention studies, mostly involving second-generation antipsychotics and cognitive behavioral therapy, are encouraging, but are currently still insufficient to make treatment recommendations for this early, relatively non-specific illness phase. The next phase of research on the psychosis risk syndrome just now beginning, has moved to larger, “multi-site” projects to increase generalizability and to ensure that sufficiently large samples at true risk for psychosis are included. Emphasis in these emerging studies is on: 1) identification of biomarkers for conversion to psychosis; 2) examination of non-antipsychotic, neuroprotective and low-risk pharmacologic and non-pharmacologic interventions; 3) testing of potentially phase-specific interventions; 4) examination of the relationship between treatment response during yhre of psychosis risk syundrome and prognosis for the course of illness; 5) follow-up of patients who developed schizophrenia despite early interventions and comparison of illness trajectories with patients who did not receive early interventions; 6) characterization of individuals with outcomes other than schizophrenia spectrum disorders, including bipolar disorder and remission from the psychosis risk syndrome, including false positive cases; 7) assessment of meaningful social and role functioning outcomes. While the research conducted to date has already yielded crucial information, the translation of the concept of a clinically identifiable psychosis risk syndrome into clinical practice does not seem justified at this point.
doi:10.1111/j.1469-7610.2010.02235.x
PMCID: PMC3085111  PMID: 20214698
Schizophrenia; Psychosis; Risk Syndrome; Prodrome; Early Recognition; Early Intervention; Biomarker; DSM-V
13.  Are women with psychosis receiving adequate cervical cancer screening? 
Canadian Family Physician  2010;56(4):358-363.
ABSTRACT
OBJECTIVE
To investigate the rates of cervical cancer screening among female patients with psychosis compared with similar patients without psychosis, as an indicator of the quality of primary preventive health care.
DESIGN
A retrospective cohort study using medical records between November 1, 2004, and November 1, 2007.
SETTING
Two urban family medicine clinics associated with an academic hospital in Toronto, Ont.
PARTICIPANTS
A random sample of female patients with and without psychosis between the ages of 20 and 69 years.
MAIN OUTCOME MEASURES
Number of Papanicolaou tests in a 3-year period.
RESULTS
Charts for 51 female patients with psychosis and 118 female patients without psychosis were reviewed. Of those women with psychosis, 62.7% were diagnosed with schizophrenia, 19.6% with bipolar disorder, 17.6% with schizoaffective disorder, and 29.4% with other psychotic disorders. Women in both groups were similar in age, rate of comorbidities, and number of full physical examinations. Women with psychosis were significantly more likely to smoke (P < .0001), to have more primary care appointments (P = .035), and to miss appointments (P = .0002) than women without psychosis. After adjustment for age, other psychiatric illnesses, number of physical examinations, number of missed appointments, and having a gynecologist, women with psychosis were significantly less likely to have had a Pap test in the previous 3 years compared with women without psychosis (47.1% vs 73.7%, respectively; odds ratio 0.19, 95% confidence interval 0.06 to 0.58).
CONCLUSION
Women with psychosis are more than 5 times less likely to receive adequate Pap screening compared with the general population despite their increased rates of smoking and increased number of primary care visits.
PMCID: PMC2860833  PMID: 20393098
14.  Schizophrenia in Croatia: interregional differences in prevalence and a comment on constant incidence. 
STUDY OBJECTIVE--The aim was to examine why differences exist in schizophrenia prevalence and risk in some areas of Croatia, when schizophrenia incidence rates do not appear to vary. DESIGN--Areas differing by schizophrenia admission rates in patients born in 1953 and admitted by the age of 31 years are compared using a number of indicators relating both to general population characteristics and to those of schizophrenic cases in these populations. SETTING--The study covers the whole of Croatia (4,601,469 inhabitants, 1981 census). SUBJECTS--By the age of 31 years, out of 80,445 individuals born in Croatia in 1953, 464 were admitted for and diagnosed as having schizophrenia. MAIN RESULTS--Admission risk rates are higher in those parts of Croatia where emigration rates are high and lower where immigration rates are high. There is also a positive correlation with schizophrenia prevalence and manic depressive psychosis rates. There is a negative correlation with age of onset of schizophrenia and with schizophrenic reproduction rates. In the study areas, hospital incidence rates are not significantly different. CONCLUSIONS--Economic migration and negative selection in the domestic population are likely to be the most significant factors leading to differences in schizophrenia prevalence. The approximately equal incidence rates in the population, with different prevalence and admission risks, are linked to differences in the disease onset among schizophrenics with a positive family history for this condition. In other words, these patients, when part of the population with a greater prevalence and a greater hereditary loading, experience the onset more often at an earlier age. Thus they have a lower reproduction rate than in a population with a lower prevalence and a lower hereditary loading. Thus incidence rates in populations with different prevalences and different hereditary loads are maintained roughly equal over generations.
Images
PMCID: PMC1059562  PMID: 1645081
15.  Psychiatric Disorders after Epilepsy Diagnosis: A Population-Based Retrospective Cohort Study 
PLoS ONE  2013;8(4):e59999.
Background
Psychiatric manifestations after occurrence of epilepsy have often been noted. However, the association between newly diagnosed epilepsy and psychiatric disorders afterward is not completely understood. We conducted two longitudinal cohorts for patients with and without epilepsy to investigate the risk factors and hazard ratios of developing psychiatric disorders after patients were newly diagnosed with epilepsy.
Methods
We identified 938 patients with a new diagnosis of epilepsy and 518,748 participants without epilepsy from the National Health Insurance Research Database in 2000–2002 and tracked them until 2008. We compared the incidence of developing psychiatric disorders between the two cohorts, evaluated risk factors and measured the associated hazard ratios (HRs) and 95% confidence intervals (CIs) of developing psychiatric disorders.
Findings
The incidences of psychiatric disorders for people with and without epilepsy were 94.1 and 22.6 per 1000 person-years, respectively. After adjusting the covariates, the epilepsy cohort showed the highest risks in mental retardation (HR 31.5, 95% CI 18.9 to 52.4), bipolar disorder (HR 23.5, 95% CI 11.4 to 48.3) and alcohol or drug psychosis (HR 18.8, 95% CI 11.1 to 31.8) among psychiatric complications developed after newly diagnosed epilepsy. The risk increased with epileptic general seizure and frequency of outpatient visits for epilepsy, as well as with emergency room visits and hospitalizations for epilepsy, and with older age. Chronologically, the highest risk occurred in the first year after epilepsy diagnosis (HR 11.4, 95% CI 9.88 to 13.2).
Conclusion
Various psychiatric disorders were demonstrated after newly diagnosed epilepsy and closely related to general seizure and use of medical services for epilepsy. This shows a need for integrated psychiatric care for patients newly diagnosed with epilepsy, especially in the first year.
doi:10.1371/journal.pone.0059999
PMCID: PMC3618118  PMID: 23577079
16.  Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker 
Psychiatry research  2012;199(1):8-11.
Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S were hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype.
doi:10.1016/j.psychres.2012.03.010
PMCID: PMC3470780  PMID: 22503356
TASTE; ENDOPHENOTYPE; PREDICTION; MENTAL ILLNESS; PSYCHOSIS; RISK
17.  Epilepsy (partial) 
Clinical Evidence  2011;2011:1214.
Introduction
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy).
Key Points
During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission.
After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects, and their long-term benefit is unknown. Antiepileptic drug treatment after a single seizure does not reduce the risk of drug refractory epilepsy in the long term.
Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed partial epilepsy, but we found no RCTs comparing them with placebo, and a placebo-controlled trial would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs. Adding second-line drugs to usual treatment reduces seizure frequency in people with drug-resistant partial epilepsy, but it increases adverse effects such as dizziness and somnolence. We don't know if any one antiepileptic drug is more likely to reduce seizures compared with the others.
CAUTION: Vigabatrin, which may be used as second-line treatment, causes concentric visual-field abnormalities in about 40% of people, which are probably irreversible.
In people who have been seizure free for at least 2 years on treatment, almost 60% of those with partial or generalised epilepsy who withdraw from antiepileptic treatment will remain seizure free, compared with almost 80% of people who continue treatment.
Educational programmes may reduce seizure frequency and improve psychosocial functioning in people with partial or generalised epilepsy, but we don't know whether relaxation, yoga, biofeedback, CBT, relaxation plus behavioural modification, or family counselling are beneficial.
There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in people with drug-resistant temporal lobe epilepsy, but they can cause neurological adverse effects.
High-level vagus nerve stimulation may reduce seizure frequency in people with drug-resistant partial seizures, but it may cause hoarseness and dyspnoea, and long-term effects are unknown. We don't know whether different stimulation cycles are more effective at reducing seizure frequency or at increasing the proportion of responders.
We don't know whether lesionectomy improves seizure control in people with drug-resistant temporal lobe epilepsy.
PMCID: PMC3217777  PMID: 21549021
18.  Injuries in epilepsy: a review of its prevalence, risk factors, type of injuries and prevention 
Neurology International  2009;1(1):e20.
Currently, there is intense clinical research into various aspects of the medical risks relating to epilepsy, including total and cause-specific mortality, accidents and injuries in patients with epilepsy and mortality related with seizures. Seizures occurring in precarious situations and resulting in injuries are still an important concern for patients with epilepsy, their employers and their care-givers. Submersion injuries, motor vehicle accidents, burns, and head injuries are among the most feared epilepsy-related injuries. These concerns seem valid because the hallmark of epilepsy, episodic impairment of consciousness and motor control, may occur during interictal EEG epileptiform discharges, even in the absence of a clinical seizure. In addition, psychomotor comorbidity and side effects of antiepileptic drugs may contribute to the risk of injuries in patients with epilepsy. Published risk factors for injuries include the number of antiepileptic drugs, history of generalized seizures, and seizure frequency. In general, epidemiological information about incidence of injuries has been conflicting and sparse. In general, studies focusing on populations with more severe forms of epilepsy tend to report substantially higher risks of injuries than those involving less selected populations. On the other hand, studies based on non-selected populations of people with epilepsy have not shown an increased frequency of injuries in people with epilepsy compared with the general population. Some studies have shown that patients with epilepsy are more frequently admitted to the hospital following an injury. Possible explanations include: more cautious attitude of clinicians toward injuries occurring in the setting of seizures; hospitalization required because of seizures and not to the injuries themselves; and hospitalization driven by other issues, such as comorbidities, which are highly prevalent in patients with epilepsy. Potentially the high rate of hospitalizations could be related with the severity of the injury. This article reviews the best available epidemiological information about injuries, including incidence and risk factors. Also this article reviews information about specific types of injuries such as fractures, burns, concussions, dislocations, etc. Information about accidents in people with epilepsy is also discussed.
doi:10.4081/ni.2009.e20
PMCID: PMC3093233  PMID: 21577358
injuries; epilepsy.
19.  Suicidal Behavior in Adolescents with First-Episode Psychosis 
Background
Studies have reported an increased risk for suicide in adults with schizophrenia, but limited data on younger populations are available.
Aims
We hypothesize that first-episode psychosis is associated with an increased risk of suicidal behavior in adolescents.
Method
A retrospective study was conducted with patients (n=102) diagnosed with psychosis not otherwised specified (NOS), schizophreniform disorder, schizoaffective disorder or schizophrenia within six months prior to admission. A control group consisting of ninety-eight patients with other (nonpsychosis) psychiatric diagnoses admitted to the same unit was matched by age, gender and ethnicity. All patients and controls were administered the Brief Psychiatric Rating Scale-Children version to assess severity of psychiatric symptoms and suicidality, and medical records were used to assess suicidal behavior and possible risk factors.
Results
When compared to controls, patients with psychosis had over twice as many suicide attempts overall (p<0.01). The 32% incidence of suicide attempts reported in this cohort is nearly double what is reported in adults with psychosis. Depressive symptoms were significantly correlated with increased suicide attempts (p<0.05).
Conclusions
There was no significant difference between the number of pediatric psychosis inpatients versus nonpsychotic psychiatric inpatients who attempted suicide. There was, however, a significant difference between the total number of attempts between groups, illustrating that children and adolescents with psychosis are more likely than nonpsychotic psychiatric inpatients to have repeat, or multiple, suicide attempts. Longer duration of untreated psychosis, ADHD and depressive symptoms were found to be the strongest risk factors for patients with psychosis.
doi:10.3371/CSRP.4.1.2
PMCID: PMC4001852  PMID: 20643627
Adolescents; First-Episode Psychosis; Suicidality; Suicidal Behavior
20.  Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable? 
BMC Psychiatry  2012;12:221.
Use of amphetamine and methamphetamine is widespread in the general population and common among patients with psychiatric disorders. Amphetamines may induce symptoms of psychosis very similar to those of acute schizophrenia spectrum psychosis. This has been an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders. To distinguish the two types of psychosis on the basis of acute symptoms is difficult. However, acute psychosis induced by amphetamines seems to have a faster recovery and appears to resolve more completely compared to schizophrenic psychosis. The increased vulnerability for acute amphetamine induced psychosis seen among those with schizophrenia, schizotypal personality and, to a certain degree other psychiatric disorders, is also shared by non-psychiatric individuals who previously have experienced amphetamine-induced psychosis. Schizophrenia spectrum disorder and amphetamine-induced psychosis are further linked together by the finding of several susceptibility genes common to both conditions. These genes probably lower the threshold for becoming psychotic and increase the risk for a poorer clinical course of the disease.
The complex relationship between amphetamine use and psychosis has received much attention but is still not adequately explored. Our paper reviews the literature in this field and proposes a stress-vulnerability model for understanding the relationship between amphetamine use and psychosis.
doi:10.1186/1471-244X-12-221
PMCID: PMC3554477  PMID: 23216941
Drug induced psychosis; Amphetamine; Methamphetamine; Primary psychotic disorder; Schizophrenia
21.  Schizophrenia-like psychosis arising de novo following a temporal lobectomy: timing and risk factors 
Objectives: To clarify risk factors for the development of schizophrenia-like psychotic disorders following temporal lobectomy, and to explore the possibility that the early postoperative period is a time of high risk for the onset of such chronic psychotic disorders.
Methods: Patients who developed schizophrenia-like psychosis were identified from a series of 320 patients who had a temporal lobectomy for medically intractable epilepsy. The relationship of their disorders to both the operation and subsequent seizure activity was examined. Using a retrospective case–control design, risk factors for the development of schizophrenia-like psychosis were established.
Results: Eleven patients who developed schizophrenia-like psychosis postoperatively were identified and compared with 33 control subjects who remained free of psychosis postoperatively. The onset of de novo psychotic symptoms was typically in the first year following the operation. No clear relationship between postoperative seizure activity and fluctuations in psychotic symptoms emerged. Compared with the controls, patients who become psychotic had more preoperative bilateral electroencephalogram (EEG) abnormalities, pathologies other than mesial temporal sclerosis in the excised lobe and a smaller amygdala on the unoperated side.
Conclusions: Temporal lobectomy for medically intractable epilepsy may precipitate a schizophrenia-like psychosis. Patients with bilateral functional and structural abnormalities, particularly of the amygdala, may be at particular risk for the development of such psychoses.
doi:10.1136/jnnp.2003.022392
PMCID: PMC1739094  PMID: 15201360
22.  Mismatch negativity (MMN) and sensory auditory processing in children aged 9–12 years presenting with putative antecedents of schizophrenia☆ 
Identification of markers of abnormal brain function in children at-risk of schizophrenia may inform early intervention and prevention programs. Individuals with schizophrenia are characterised by attenuation of MMN amplitude, which indexes automatic auditory sensory processing. The current aim was to examine whether children who may be at increased risk of schizophrenia due to their presenting multiple putative antecedents of schizophrenia (ASz) are similarly characterised by MMN amplitude reductions, relative to typically developing (TD) children. EEG was recorded from 22 ASz and 24 TD children aged 9 to 12 years (matched on age, sex, and IQ) during a passive auditory oddball task (15% duration deviant). ASz children were those presenting: (1) speech and/or motor development lags/problems; (2) social, emotional, or behavioural problems in the clinical range; and (3) psychotic-like experiences. TD children presented no antecedents, and had no family history of a schizophrenia spectrum disorder. MMN amplitude, but not latency, was significantly greater at frontal sites in the ASz group than in the TD group. Although the MMN exhibited by the children at risk of schizophrenia was unlike that of their typically developing peers, it also differed from the reduced MMN amplitude observed in adults with schizophrenia. This may reflect developmental and disease effects in a pre-prodromal phase of psychosis onset. Longitudinal follow-up is necessary to establish the developmental trajectory of MMN in at-risk children.
Highlights
•Examined MMN (duration deviant) in children purportedly at risk of schizophrenia•Greater frontal MMN amplitude for children at risk than typically developing peers•Increased MMN contrasts with MMN amplitude reduction in adults with schizophrenia•Possible basis in maturational and disease processes in frontal and temporal lobes•May index pre-prodromal phase of psychosis onset in children at risk
doi:10.1016/j.ijpsycho.2013.05.008
PMCID: PMC3807658  PMID: 23707338
Event-related potentials; High-risk; Psychopathology; Development; Cognition; Biomarker
23.  Prevalence and characteristics of epilepsy in the Belgian shepherd variants Groenendael and Tervueren born in Denmark 1995–2004 
Background
The Belgian shepherd Groenendael and Tervueren is believed to be at higher risk of developing epilepsy than dogs of the common population. This epidemiological study was designed to estimate the prevalence of epilepsy in the Danish population of Groenendael and Tervueren born between 1995 and 2004. Furthermore, it was the intention to describe the clinical manifestation (seizure types and phenomenology) of epilepsy and to identify risk factors for euthanasia once the dog was diagnosed as having epilepsy.
Methods
All owners of Groenendael and Tervueren dogs born between January 1995 and December 2004 and registered in the Danish Kennel Club (1,248 dogs) were contacted and asked to answer a mailed questionnaire concerning epilepsy. Positive responders were subsequently validated in a follow-up interview conducted by telephone using a standardized questionnaire. Owners were questioned about age at first seizure, seizure frequency, seizure duration, a detailed description of seizure phenomenology, post-ictal signs and if a veterinarian had diagnosed the dog with epilepsy.
Results
Prevalence of epilepsy was estimated at 9.5%. Mean age of epilepsy debut was 3.3 years (range 0.5–8.0 years). There was an almost equal number of Groenendael (25) and Tervueren (24). The distribution of females and males was 31 and 18 respectively. Twenty-five per cent experienced focal seizures, 53% experienced focal seizures with secondary generalization and 18% experienced primary generalized seizures. In four percent seizures were unclassifiable. The most commonly reported focal seizure phenomenology included ataxia, crawling, swaying, fearful behavior, salivation, excessive attention seeking and disorientation. In 16% of the cases, epilepsy led to euthanasia. Intact dogs with epilepsy had a significantly increased risk of being euthanized because of epilepsy compared to neutered dogs with epilepsy. In 22% of the cases the owners reported that anxiety/hyperactivity/stress could act as a seizure provoking factor.
Conclusion
A high prevalence of epilepsy appears to be present in the Danish Groenendael and Tervueren population. The relatively late debut age of epilepsy in this breed contributes greatly to the increased prevalence of epileptic individuals, because dogs developing epilepsy late in life are used for breeding unintended.
doi:10.1186/1751-0147-50-51
PMCID: PMC2633289  PMID: 19102738
24.  Research implications of the Institute of Medicine Report, Epilepsy Across the Spectrum: Promoting Health and Understanding 
Epilepsia  2013;54(2):207-216.
In March 2012 the Institute of Medicine (IOM) released the report, Epilepsy Across The Spectrum: Promoting Health And Understanding. This report examined the public health dimensions of the epilepsies with a focus on four areas: public health surveillance and data collection and integration; population and public health research; health policy, health care, and human services; and education for providers, people with epilepsy and their families, and the public.
The report provided recommendations and research priorities for future work in the field of epilepsy that relate to: increasing the power of data on epilepsy; prevention of epilepsy; improving health care for people with epilepsy; improving health professional education about epilepsy; improving quality of life for people with epilepsy; improving education about epilepsy for people with epilepsy and families; and raising public awareness about epilepsy.
For this article, the authors selected one research priority from each of the major chapter themes in the IOM report: expanding and improving the quality of epidemiological surveillance in epilepsy; developing improved interventions for people with epilepsy and depression; expanding early identification/screening for learning impairments in children with epilepsy; evaluating and promoting effective innovative teaching strategies; accelerating research on the identification of risk factors and interventions that increase employment and improve quality of life for people with epilepsy and their families; assessing the information needs of people with epilepsy and their families associated with epilepsy-related risks, specifically sudden unexpected death in epilepsy; and developing and conducting surveys to capture trends in knowledge, awareness, attitudes, and beliefs about epilepsy over time and in specific population subgroups.
For each research priority selected, examples of research are provided that will advance the field of epilepsy and improve the lives of people with epilepsy. The IOM report has many other research priorities for researchers to consider developing to advance the field of epilepsy and better the lives of people with epilepsy.
doi:10.1111/epi.12056
PMCID: PMC3566357  PMID: 23294462
25.  A review of MRI findings in schizophrenia 
Schizophrenia research  2001;49(1-2):1-52.
After more than 100 years of research, the neuropathology of schizophrenia remains unknown and this is despite the fact that both Kraepelin (1919/1971: Kraepelin,E., 1919/1971. Dementia praecox. Churchill Livingston Inc., New York) and Bleuler (1911/1950: Bleuler, E., 1911/1950. Dementia praecox or the group of schizophrenias. International Universities Press, New York), who first described ‘dementia praecox’ and the ‘ schizophrenias’, were convinced that schizophrenia would ultimately be linked to an organic brain disorder. Alzheimer (1897: Alzheimer, A., 1897. Beitrage zur pathologischen anatomie der hirnrinde und zur anatomischen grundlage einiger psychosen. Monatsschrift fur Psychiarie und Neurologie. 2, 82–120) was the first to investigate the neuropathology of schizophrenia, though he went on to study more tractable brain diseases. The results of subsequent neuropathological studies were disappointing because of conflicting findings. Research interest thus waned and did not flourish again until 1976, following the pivotal computer assisted tomography (CT) finding of lateral ventricular enlargement in schizophrenia by Johnstone and colleagues. Since that time significant progress has been made in brain imaging, particularly with the advent of magnetic resonance imaging (MRI), beginning with the first MRI study of schizophrenia by Smith and coworkers in 1984 (Smith, R.C., Calderon, M., Ravichandran, G.K., et al. (1984). Nuclear magnetic resonance in schizophrenia: A preliminary study. Psychiatry Res. 12, 137–147). MR in vivo imaging of the brain now confirms brain abnormalities in schizophrenia.
The 193 peer reviewed MRI studies reported in the current review span the period from 1988 to August, 2000. This 12 year period has witnessed a burgeoning of MRI studies and has led to more definitive findings of brain abnormalities in schizophrenia than any other time period in the history of schizophrenia research. Such progress in defining the neuropathology of schizophrenia is largely due to advances in in vivo MRI techniques. These advances have now led to the identification of a number of brain abnormalities in schizophrenia. Some of these abnormalities confirm earlier post-mortem findings, and most are small and subtle, rather than large, thus necessitating more advanced and accurate measurement tools. These findings include ventricular enlargement (80% of studies reviewed) and third ventricle enlargement (73% of studies reviewed). There is also preferential involvement of medial temporal lobe structures (74% of studies reviewed), which include the amygdala, hippocampus, and parahippocampal gyrus, and neocortical temporal lobe regions (superior temporal gyrus) (100% of studies reviewed). When gray and white matter of superior temporal gyrus was combined, 67% of studies reported abnormalities. There was also moderate evidence for frontal lobe abnormalities (59% of studies reviewed), particularly prefrontal gray matter and orbitofrontal regions. Similarly, there was moderate evidence for parietal lobe abnormalities (60% of studies reviewed), particularly of the inferior parietal lobule which includes both supramarginal and angular gyri. Additionally, there was strong to moderate evidence for subcortical abnormalities (i.e. cavum septi pellucidi—92% of studies reviewed, basal ganglia—68% of studies reviewed, corpus callosum—63% of studies reviewed, and thalamus—42% of studies reviewed), but more equivocal evidence for cerebellar abnormalities (31% of studies reviewed).
The timing of such abnormalities has not yet been determined, although many are evident when a patient first becomes symptomatic. There is, however, also evidence that a subset of brain abnormalities may change over the course of the illness. The most parsimonious explanation is that some brain abnormalities are neurodevelopmental in origin but unfold later in development, thus setting the stage for the development of the symptoms of schizophrenia. Or there may be additional factors, such as stress or neurotoxicity, that occur during adolescence or early adulthood and are necessary for the development of schizophrenia, and may be associated with neurodegenerative changes. Importantly, as several different brain regions are involved in the neuropathology of schizophrenia, new models need to be developed and tested that explain neural circuitry abnormalities effecting brain regions not necessarily structurally proximal to each other but nonetheless functionally interrelated.
Future studies will likely benefit from: (1) studying more homogeneous patient groups so that the relationship between MRI findings and clinical symptoms become more meaningful; (2) studying at risk populations such as family members of patients diagnosed with schizophrenia and subjects diagnosed with schizotypal personality disorder in order to define which abnormalities are specific to schizophrenia spectrum disorders, which are the result of epiphenomena such as medication effects and chronic institutionalization, and which are needed for the development of frank psychosis; (3) examining shape differences not detectable from measuring volume alone; (4) applying newer methods such as diffusion tensor imaging to investigate abnormalities in brain connectivity and white matter fiber tracts; and, (5) using methods that analyze brain function (fMRI) and structure simultaneously.
PMCID: PMC2812015  PMID: 11343862
Schizophrenia; Magnetic resonance imaging; MRI; Psychosis; First episode schizophrenia

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