Peter B. Jones

Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review

BACKGROUND Whether cannabis can cause psychotic or affective symptoms that persist beyond transient intoxication is unclear. We systematically reviewed the evidence pertaining to cannabis use and occurrence of psychotic or affective mental health outcomes. METHODS We searched Medline, Embase, CINAHL, PsycINFO, ISI Web of Knowledge, ISI Proceedings, ZETOC, BIOSIS, LILACS, and MEDCARIB from their inception to September, 2006, searched reference lists of studies selected for inclusion, and contacted experts. Studies were included if longitudinal and population based. 35 studies from 4804 references were included. Data extraction and quality assessment were done independently and in duplicate. FINDINGS There was an increased risk of any psychotic outcome in individuals who had ever used cannabis (pooled adjusted odds ratio=1.41, 95% CI 1.20-1.65). Findings were consistent with a dose-response effect, with greater risk in people who used cannabis most frequently (2.09, 1.54-2.84). Results of analyses restricted to studies of more clinically relevant psychotic disorders were similar. Depression, suicidal thoughts, and anxiety outcomes were examined separately. Findings for these outcomes were less consistent, and fewer attempts were made to address non-causal explanations, than for psychosis. A substantial confounding effect was present for both psychotic and affective outcomes. INTERPRETATION The evidence is consistent with the view that cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life.

Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

BACKGROUND Results of array studies have suggested abnormalities in expression of lipid and myelin-related genes in schizophrenia. Here, we investigated oligodendrocyte-specific and myelination-associated gene expression in schizophrenia and bipolar affective disorder. METHODS We used samples from the Stanley brain collection, consisting of 15 schizophrenia, 15 bipolar affective disorder, and 15 control brains. Indexing-based differential display PCR was done to screen for differences in gene expression in schizophrenia patients versus controls. Results were cross-validated with quantitative PCR, which was also used to investigate expression profiles of 16 other oligodendrocyte and myelin genes in schizophrenia and bipolar disorder. These genes were further investigated with an ongoing microarray analysis. FINDINGS Results of differential display and quantitative PCR analysis showed a reduction of key oligodendrocyte-related and myelin-related genes in schizophrenia and bipolar patients; expression changes for both disorders showed a high degree of overlap. Microarray results of the same genes investigated by quantitative PCR correlated well overall. INTERPRETATION Schizophrenia and bipolar brains showed downregulation of key oligodendrocyte and myelination genes, including transcription factors that regulate these genes, compared with control brains. These results lend support to and extend observations from other microarray investigations. Our study also showed similar expression changes to the schizophrenia group in bipolar brains, which thus lends support to the notion that the disorders share common causative and pathophysiological pathways.

Substantia nigra/ventral tegmental reward prediction error disruption in psychosis

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC AESOP study

BACKGROUND The incidence of schizophrenia in the African-Caribbean population in England is reported to be raised. We sought to clarify whether (a) the rates of other psychotic disorders are increased, (b) whether psychosis is increased in other ethnic minority groups, and (c) whether particular age or gender groups are especially at risk. METHOD We identified all people (n=568) aged 16-64 years presenting to secondary services with their first psychotic symptoms in three well-defined English areas (over a 2-year period in Southeast London and Nottingham and a 9-month period in Bristol). Standardized incidence rates and incidence rate ratios (IRR) for all major psychosis syndromes for all main ethnic groups were calculated. RESULTS We found remarkably high IRRs for both schizophrenia and manic psychosis in both African-Caribbeans (schizophrenia 9.1, manic psychosis 8.0) and Black Africans (schizophrenia 5.8, manic psychosis 6.2) in men and women. IRRs in other ethnic minority groups were modestly increased as were rates for depressive psychosis and other psychoses in all minority groups. These raised rates were evident in all age groups in our study. CONCLUSIONS Ethnic minority groups are at increased risk for all psychotic illnesses but African-Caribbeans and Black Africans appear to be at especially high risk for both schizophrenia and mania. These findings suggest that (a) either additional risk factors are operating in African-Caribbeans and Black Africans or that these factors are particularly prevalent in these groups, and that (b) such factors increase risk for schizophrenia and mania in these groups.

The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia.

Objective:  To describe the development and validation of the Clinical Global Impression–Schizophrenia (CGI‐SCH) scale, designed to assess positive, negative, depressive and cognitive symptoms in schizophrenia.

A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort : Clinical and research diagnoses of schizophrenia

As a prerequisite to the use of the Finnish National Hospital Discharge Register in psychiatric epidemiological research, we studied the diagnostic reliability of the register in terms of the psychiatric morbidity experienced by a national birth cohort. We investigated all entries to the register for a sample based upon the Northern Finland 1966 birth cohort at the age of 16 years (n=11017). Until the end of 1993 (age 27 years), a total of 563 subjects had a register diagnosis indicating a psychiatric illness, 37 of them being schizophrenia. When operational criteria (DSM-III-R) were applied to clinical information in the available original hospital records for cases of psychosis, personality disorder and substance abuse (n=249), 71 fulfilled criteria for schizophrenia, including all of the 37 cases in the register and an additional 34 (48% false-negatives), most frequently diagnosed in the register as schizophreniform or other psychosis. Despite the official use of DSM-III-R nomenclature, it appears that the clinical concept of schizophrenia in Finland, manifest within the register, remains very restrictive. The application of operational criteria is a necessary prerequisite for scientific research on schizophrenia.

Vitamin D supplementation during the first year of life and risk of schizophrenia: A Finnish birth-cohort study

OBJECTIVE Based on clues from epidemiology and animal experiments, low vitamin D during early life has been proposed as a risk factor for schizophrenia. The aim of this study was to explore the association between the use of vitamin D supplements during the first year of life and risk of developing schizophrenia. METHOD Subjects were drawn from the Northern Finland 1966 Birth Cohort (n=9,114). During the first year of life, data were collected about the frequency and dose of vitamin D supplementation. Our primary outcome measures were schizophrenia, psychotic disorders other than schizophrenia, and nonpsychotic disorders as diagnosed by age 31 years. Males and females were examined separately. RESULTS In males, the use of either irregular or regular vitamin D supplements was associated with a reduced risk of schizophrenia (Risk ratio (RR)=0.08, 95% CI 0.01-0.95; RR=0.12, 95% CI 0.02-0.90, respectively) compared with no supplementation. In males, the use of at least 2000 IU of vitamin D was associated with a reduced risk of schizophrenia (RR=0.23, 95% CI 0.06-0.95) compared to those on lower doses. There were no significant associations between either the frequency or dose of vitamin D supplements and (a) schizophrenia in females, nor with (b) nonpsychotic disorder or psychotic disorders other than schizophrenia in either males or females. CONCLUSION Vitamin D supplementation during the first year of life is associated with a reduced risk of schizophrenia in males. Preventing hypovitaminosis D during early life may reduce the incidence of schizophrenia.

The functional anatomy of auditory hallucinations in schizophrenia.

We used continuous whole brain functional magnetic resonance imaging (fMRI) with a 3-T magnet to map the cerebral activation associated with auditory hallucinations in four subjects with schizophrenia. The subjects experienced episodes of hallucination whilst in the scanner so that periods of hallucination could be compared with periods of rest in the same individuals. Group analysis demonstrated shared areas of activation in right and left superior temporal gyri, left inferior parietal cortex and left middle frontal gyrus. When the data were examined on an individual basis, the temporal cortex and prefrontal cortex areas were activated during episodes of hallucination in all four subjects. These findings support the theory that auditory hallucination reflects abnormal activation of normal auditory pathways.

Effects of the catechol -O-methyltransferase Val158Met polymorphism on executive function : a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

The catechol-O-methyltransferase (COMT) Val158Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02–0.55; P=0.03), but this was not supported in the patient sample (d=−0.07; 95% CI −0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val158Met genotype and executive function in healthy individuals but not in schizophrenia.

Outcomes of conduct problems in adolescence: 40 year follow-up of national cohort

Objective To describe long term outcomes associated with externalising behaviour in adolescence, defined in this study as conduct problems reported by a teacher, in a population based sample. Design Longitudinal study from age 13-53. Setting The Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). Participants 3652 survey members assessed by their teachers for symptoms of externalising behaviour at age 13 and 15. Main outcome measures Mental disorder, alcohol abuse, relationship difficulties, highest level of education, social class, unemployment, and financial difficulties at ages 36-53. Results 348 adolescents were identified with severe externalising behaviour, 1051 with mild externalising behaviour, and 2253 with no externalising behaviour. All negative outcomes measured in adulthood were more common in those with severe or mild externalising behaviour in adolescence, as rated by teachers, compared with those with no externalising behaviour. Adolescents with severe externalising behaviour were more likely to leave school without any qualifications (65.2%; adjusted odds ratio 4.0, 95% confidence interval 2.9 to 5.5), as were those with mild externalising behaviour (52.2%; 2.3, 1.9 to 2.8), compared with those with no externalising behaviour (30.8%). On a composite measure of global adversity throughout adulthood that included mental health, family life and relationships, and educational and economic problems, those with severe externalising behaviour scored significantly higher (40.1% in top quarter), as did those with mild externalising behaviour (28.3%), compared with those with no externalising behaviour (17.0%). Conclusions Adolescents who exhibit externalising behaviour experience multiple social and health impairments that adversely affect them, their families, and society throughout adult life.