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 systematic review of all reported incidence and prevalence studies of population rates of subclinical psychotic experiences reveals a median prevalence rate of around 5% and a median incidence rate of around 3%. A meta-analysis of risk factors reveals associations with developmental stage, child and adult social adversity, psychoactive drug use, and also male sex and migrant status. The small difference between prevalence and incidence rates, together with data from follow-up studies, indicates that approximately 75-90% of developmental psychotic experiences are transitory and disappear over time. There is evidence, however, that transitory developmental expression of psychosis (psychosis proneness) may become abnormally persistent (persistence) and subsequently clinically relevant (impairment), depending on the degree of environmental risk the person is additionally exposed to. The psychosis proneness-persistence-impairment model considers genetic background factors impacting on a broadly distributed and transitory population expression of psychosis during development, poor prognosis of which, in terms of persistence and clinical need, is predicted by environmental exposure interacting with genetic risk.

/pdf/a-systematic-review-and-meta-analysis-of-the-psychosis-468eokeeyn.pdf

A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder

https://www.ukcia.org/research/COMTgene.pdf

Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction.

Psychotic syndromes can be understood as disorders of adaptation to social context. Although heritability is often emphasized, onset is associated with environmental factors such as early life adversity, growing up in an urban environment, minority group position and cannabis use, suggesting that exposure may have an impact on the developing 'social' brain during sensitive periods. Therefore heritability, as an index of genetic influence, may be of limited explanatory power unless viewed in the context of interaction with social effects. Longitudinal research is needed to uncover gene-environment interplay that determines how expression of vulnerability in the general population may give rise to more severe psychopathology.

https://sites.oxy.edu/clint/physio/article/theenvironmentandschizophrenia.pdf

The environment and schizophrenia

Cannabis use may increase the risk of psychotic disorders and result in a poor prognosis for those with an established vulnerability to psychosis. A 3-year follow-up (1997-1999) is reported of a general population of 4,045 psychosis-free persons and of 59 subjects in the Netherlands with a baseline diagnosis of psychotic disorder. Substance use was assessed at baseline, 1-year follow-up, and 3-year follow-up. Baseline cannabis use predicted the presence at follow-up of any level of psychotic symptoms (adjusted odds ratio (OR) = 2.76, 95% confidence interval (CI): 1.18, 6.47), as well as a severe level of psychotic symptoms (OR = 24.17, 95% CI: 5.44, 107.46), and clinician assessment of the need for care for psychotic symptoms (OR = 12.01, 95% CI: 2.24, 64.34). The effect of baseline cannabis use was stronger than the effect at 1-year and 3-year follow-up, and more than 50% of the psychosis diagnoses could be attributed to cannabis use. On the additive scale, the effect of cannabis use was much stronger in those with a baseline diagnosis of psychotic disorder (risk difference, 54.7%) than in those without (risk difference, 2.2%; p for interaction = 0.001). Results confirm previous suggestions that cannabis use increases the risk of both the incidence of psychosis in psychosis-free persons and a poor prognosis for those with an established vulnerability to psychotic disorder.

/pdf/cannabis-use-and-psychosis-a-longitudinal-population-based-3too0qdfxr.pdf

Cannabis Use and Psychosis: A Longitudinal Population-based Study

Objective: Remission criteria for schizophrenia have been proposed, consisting of a time criterion and a symptomatic remission criterion. With longitudinal data of a representative patient group (N=317; median follow-up: 1,132 days), validity of the symptomatic remission criterion was investigated. Method: In a group of 145 patients meeting the symptomatic remission criterion at baseline and a group of 172 patients not meeting it at baseline, change over time in remission status was examined in relation to change in various functional outcomes. Results: In both groups, change over time with the symptomatic remission criterion was associated with substantial changes in unmet needs, Global Assessment of Functioning scale scores, satisfaction with services and, to a lesser extent, quality of life. Changing the symptomatic remission criterion to include depression and suicidality did not affect the results. Conclusions: The proposed symptomatic remission criterion has clinical validity and represents the righ...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.2006.163.11.2000

Validation of remission criteria for schizophrenia.

Toxic rise of clozapine plasma concentrations in relation to inflammation.

Objective: To examine the reliability of a brief instrument to assess coping with symptoms by patients with psychotic illness.

Method: A semi-structured interview (MACS) was developed to assess the amounts of distress, control and coping in relation to psychotic symptoms. Two raters interviewed 23 symptomatic but stable patients with a diagnosis of chronic schizophrenia on two separate occasions. Case managers were also interviewed.

Results: Both the number of coping strategies used for different groups of symptoms, and the amount of coping used in different domains of coping strategies could be assessed reliably between interviewers (intraclass correlation coefficients range: 0.90–0.97) and between interview sessions (ICCs range: 0.75–0.80). Reliability with case managers, however, was low.

Conclusion: The MACS may be a reliable and useful instrument to assess coping in relation to subjective experience of distress by and control over psychotic symptoms.

/pdf/maastricht-assessment-of-coping-strategies-macs-i-a-brief-2h4847jvdi.pdf

Maastricht Assessment of Coping Strategies (MACS-I): a brief instrument to assess coping with psychotic symptoms.

Objective: Associations between subjective experience of control and the use of self-initiated coping strategies were examined in patients with psychotic symptoms.



Method: Twenty-three patients were interviewed to assess (i) the subjective experience of distress with and control over symptoms and (ii) the coping strategies used.



Results: There was a positive association between coping type and control (OR=1.07, 95% CI: 1.03–1.12). Active coping strategies had the strongest association with experience of control (active problem-solving: OR=1.41 95% CI: 1.18–1.68; active problem-avoiding: OR=1.45 95% CI: 1.18–1.68). Symptomatic coping was negatively associated with control (OR=0.40, 95% CI: 0.30–0.55), but was the most frequently used strategy. Depressive symptoms were associated with the highest number of coping strategies.



Conclusion: Coping strategies differ in the degree and direction of associated subjective control, and symptoms differ in the degree with which coping is mobilized. Assessment of coping strategies may be useful as a prelude to psychological therapy.

M.L.F.J. Bak

Papers

Cannabis Use and Psychosis: A Longitudinal Population-based Study

Validation of remission criteria for schizophrenia.

Toxic rise of clozapine plasma concentrations in relation to inflammation.

Maastricht Assessment of Coping Strategies (MACS-I): a brief instrument to assess coping with psychotic symptoms.

MACS-II: does coping enhance subjective control over psychotic symptoms?