The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

/pdf/the-dopamine-hypothesis-of-schizophrenia-version-iii-the-3pqlczm8om.pdf

The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)61162-3.pdf

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

A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was −14.13±23.93 mm Hg in the denervation group as compared with −11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of −2.39 mm Hg (95% confidence interval [CI], −6.89 to 2.12; P = 0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was −6.75±15.11 mm Hg in the denervation group and −4.79±17.25 mm Hg in the sham-procedure group, for a difference of −1.96 mm Hg (95% CI, −4.97 to 1.06; P = 0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. Conclusions This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.)

/pdf/a-controlled-trial-of-renal-denervation-for-resistant-3s96h2f2vp.pdf

A Controlled Trial of Renal Denervation for Resistant Hypertension

https://researchonline.lshtm.ac.uk/1380017/1/1-s2.0-S0895435613003545-main.pdf

Systematic review of the Hawthorne effect: new concepts are needed to study research participation effects.

Papers pp 1195, 1199

The strongest evidence that cannabis use may be a risk factor for later psychosis comes from a Swedish cohort study which found that heavy cannabis use at age 18 increased the risk of later schizophrenia sixfold. 1 2 This study could not establish whether adolescent cannabis use was a consequence of pre-existing psychotic symptoms rather than a cause. We present the first prospective longitudinal study of adolescent cannabis use as a risk factor for adult schizophreniform disorder, taking into account childhood psychotic symptoms3 antedating cannabis use.

View this table:

Association between cannabis use in adolescence and schizophrenia and depressive symptoms and disorders at age 26 (n=759), controlling for childhood psychotic symptoms and use of other drugs in adolescence



The Dunedin multidisciplinary health and development study (a study of a general population birth cohort of 1037 individuals born in Dunedin, New Zealand, in 1972-3)4 has a 96% follow up rate at age 26. It obtained information on psychotic symptoms at age 11 and drug use at ages 15 and 18 from self reports and assessed …

https://www.bmj.com/content/bmj/325/7374/1212.full.pdf

Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study

Background Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses.

Aims To examine critically the evidence that cannabis causes psychosis using established criteria of causality.

Method We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis.

Results On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis.

Conclusions Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.

/pdf/causal-association-between-cannabis-and-psychosis-1jmvzyyxn5.pdf

Causal association between cannabis and psychosis: examination of the evidence

Background and aims
Addictive behaviours are among the greatest scourges on humankind. It is important to estimate the extent of the problem globally and in different geographical regions. Such estimates are available, but there is a need to collate and evaluate these to arrive at the best available synthetic figures. Addiction has commissioned this paper as the first of a series attempting to do this.

Methods
Online sources of global, regional and national information on prevalence and major harms relating to alcohol use, tobacco use, unsanctioned psychoactive drug use and gambling were identified through expert review and assessed. The primary data sources located were the websites of the World Health Organization (WHO), the United Nations Office on Drugs and Crime (UNODC) and the Alberta Gambling Research Institute. Summary statistics were compared with recent publications on the global epidemiology of addictive behaviours.

Results
An estimated 4.9% of the world's adult population (240 million people) suffer from alcohol use disorder (7.8% of men and 1.5% of women), with alcohol causing an estimated 257 disability-adjusted life years lost per 100 000 population. An estimated 22.5% of adults in the world (1 billion people) smoke tobacco products (32.0% of men and 7.0% of women). It is estimated that 11% of deaths in males and 6% of deaths in females each year are due to tobacco. Of ‘unsanctioned psychoactive drugs’, cannabis is the most prevalent at 3.5% globally, with each of the others at < 1%; 0.3% of the world's adult population (15 million people) inject drugs. Use of unsanctioned psychoactive drugs accounts for an estimated 83 disability-adjusted life years lost per 100 000 population. Global estimates of problem gambling are not possible, but in countries where it has been assessed the prevalence is estimated at 1.5%.

Conclusions
Tobacco and alcohol use are by far the most prevalent addictive behaviours and cause the large majority of the harm. However, the quality of data on prevalence and addiction-related harms is mostly low, and comparisons between countries and regions must be viewed with caution. There is an urgent need to review the quality of data on which global estimates are made and coordinate efforts to arrive at a more consistent approach.

/pdf/global-statistics-on-addictive-behaviours-2014-status-report-16s0cwadak.pdf

Global statistics on addictive behaviours: 2014 status report.

Background:Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses. Aims: To examine critically the evidence that cannabis causes psychosis using established criteria of causality. Method: We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis. Results: On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis. Conclusions: Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is...

Causal Association Between Cannabis and Psychosis: Examination of the Evidence

Background: The concept of demand characteristics, which involves research participants being aware of what the researcher is investigating, is well known and widely used within psychology, particularly in laboratory-based studies. Studies of this phenomenon may make a useful contribution to broader consideration of the effects of taking part in research on participant behaviour. This systematic review seeks to summarise data from studies of the effects of demand characteristics on participant behaviours in non-laboratory settings. Methodology/Principal Findings: Electronic databases were searched to identify eligible studies. These had to be purposely designed to evaluate possible effects of demand characteristics on at least one behavioural outcome under the autonomous control of the participants and use longitudinal study designs. Only 7 studies were included, 6 providing observational data and 1 experimental study, with 5 studies involving examination of possible effects on health behaviours. Although studies provided some evidence of effects of demand characteristics on participant behaviour, heterogeneous operationalisation of the construct, the limited number of studies and poor quality of study designs made synthesis and interpretation of study findings challenging. Conclusions/Significance: Although widely accepted as important in psychology, there have been few dedicated studies of the effects of demand characteristics on research participant behaviours outside laboratory settings. This body of literature does not currently contribute to the wider study of research participation effects. A systematic review of data from laboratory-based studies is needed, as are high-quality primary studies in non-laboratory settings. We suggest that unqualified use of the term demand characteristics should be abandoned.

/pdf/the-effects-of-demand-characteristics-on-research-59qcx93n57.pdf

John Witton

Papers

Systematic review of the Hawthorne effect: new concepts are needed to study research participation effects.

Causal association between cannabis and psychosis: examination of the evidence

Global statistics on addictive behaviours: 2014 status report.

Causal Association Between Cannabis and Psychosis: Examination of the Evidence

The effects of demand characteristics on research participant behaviours in non-laboratory settings: a systematic review.