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Controversy Continues Over Cannabis-Psychosis Relationship

26 May 2010. A prospective, 21-year study in the May Archives of General Psychiatry has entered the fray over whether cannabis use causes psychosis. John McGrath, Queensland Brain Institute, Australia, and colleagues uphold prior reports that cannabis exposure predicts the development of psychosis-related outcomes. Most importantly, in a field plagued by concerns over potentially spurious correlations, they found that the relationship between cannabis exposure and the emergence of psychotic-like symptoms persisted in sibling-pair analyses designed to control for extraneous variables.

Observations that cannabis can elicit transient symptoms of psychosis date back at least to 1845 and have since been confirmed using various methods, Deepak D’Souza of Yale University, New Haven, Connecticut, told SRF. However, psychotic symptoms do not necessarily indicate psychotic disorder. Recent literature reviews (e.g., D’Souza et al., 2009; McLaren et al., 2010) have shown some evidence that cannabis contributes causally to psychotic disorders, but methodological and other concerns keep researchers from drawing firm conclusions. In fact, a Lancet meta-analysis noted that adjusting for possible confounding factors often lowers estimated correlations between cannabis exposure and psychosis-related outcomes, although even after adjustment, it found a doubled risk of a psychotic outcome in the most frequent users compared to non-users (see SRF related news story).

A step forward
Yet the notion that cannabis causes psychosis remains controversial, partly due to the inability to rule out other explanations for the correlations between exposures and outcomes. “McGrath and his colleagues have rightfully focused on residual confounding and present a clever way at getting at some of those issues,” said Dana March of Columbia University, New York. Because siblings share many genetic and environmental influences, sibling-pair analyses increase confidence that any observed correlations reflect exposure differences.

McGrath and colleagues used data from a large pregnancy study that gathered 21-year follow-up data on 3,801 offspring, with additional data from 228 siblings of cohort members. Based on subjects’ retrospective reports, they determined time since first use of cannabis. Via e-mail, McGrath told SRF that this measures early exposure, but not duration of use because some subjects may have stopped using cannabis.

Analyses tested for associations between time since first cannabis use and each of three psychosis-related outcomes, controlling for age, sex, hallucinations at age 14, and parental mental illness. Outcomes included non-affective psychosis, based on the Composite International Diagnostic Interview (CIDI), and psychotic-like symptoms, as reflected in scores on the Peters et al. Delusions Inventory (PDI) and reports of experiencing auditory or visual hallucinations on the CIDI.

In the big cohort, subjects with six or more years since first cannabis use were more likely than those who had never used cannabis to show psychosis-related outcomes at age 21. The former were twice as likely to meet criteria for non-affective psychosis, four times as likely to score in the highest quartile on the PDI, and three times more likely to have reported hallucinations. These findings did not seem to result from subjects being intoxicated with cannabis when they completed the PDI, in that analyses performed without those who had used the drug in the prior month produced similar results.

Nor did high rates of substance use associated with psychosis explain the correlations (see Winklbaur et al., 2006), although subjects who reported hallucinations at age 14 tended to start using cannabis particularly early. Yet even after the researchers controlled for reverse causality, the link between exposure and outcomes persisted. In fact, said McGrath, “I was struck by how stubborn the associations were,” not like the “fragile and inconsistent findings” he expects in schizophrenia epidemiology research.

The cohort included only 10 sibling pairs in which one member had psychosis, limiting the power to study exposure-outcome relationships in this group. However, in the 218 pairs in which neither sibling had psychosis, McGrath and colleagues found a positive association between time since first cannabis use and the difference in PDI scores between siblings. Specifically, siblings who started using cannabis earlier had higher PDI scores, which McGrath said reflect “psychotic symptoms, but below the clinical level.”

The researchers have been studying the continuum of psychotic-like experiences, which McGrath likens to thinking about high blood pressure or depression. March sees value in this approach because looking at the population distribution of symptoms may offer clues regarding the transition to full-blown psychotic disorder.

Pitfalls, priorities, and promise
On the other hand, D’Souza, speaking about the field as a whole, said that researchers often fail to clearly define the term “psychosis” when speaking at meetings or writing journal articles. He stressed the need to distinguish psychotic symptoms from psychotic disorders. Furthermore, he added, most epidemiological studies probing the link between cannabis use and psychosis development have looked only at positive symptoms and ignored the harder-to-study negative symptoms and cognitive deficits.

According to March, epidemiologists often use crude measures of exposure. “One of the things that I would really like to see come out of this domain of research is a better understanding of the exposure itself,” she said. Emphasizing that not all cannabis exposure is alike, both March and D’Souza want to see more attention paid to such issues as exposure duration, frequency of use, and the cannabis strain used, which may alter the mix of cannabinoids and produce different effects. For instance, D’Souza said that some forms have more cannabidiol, which may actually act as an antipsychotic (see SRF related news story).

Regarding the "big" question, both March and D’Souza harbor reservations about whether cannabis causes psychosis. March said, “For my money, I need to understand more about the association to be convinced that it’s actually causal.”

D’Souza agrees, noting that, “It’s a component cause, if anything,” one among many that may interact with other factors, such as genetic risk, to cause a persistent psychotic disorder. However, in the absence of known causes of schizophrenia, he considers studying component causes very important.

As researchers discuss early interventions to keep high-risk individuals from transitioning to psychosis (see SRF related news story), the question of whether preventing cannabis use might help achieve this goal comes to mind. However, March noted that the evidence supporting a causal role for cannabis pales in comparison to what was known about smoking as a cause of lung cancer before the launch of anti-smoking programs. Still, based on this rather thin evidence, researchers have estimated, on the one hand, that cannabis may cause 14 percent of psychotic outcomes in young adults (Moore et al., 2007) and, on the other, that thousands of heavy cannabis users would need to be kept from using cannabis to prevent just one case of schizophrenia (Hickman et al., 2009).

Instead of merely seeing a research field fraught with uncertainty, however, March looks on the bright side: “This is an area of investigation that’s ripe for a lot of creativity and innovation to try to really understand what’s going on.” Studies like the one by McGrath and colleagues may be a start.—Victoria L. Wilcox.

Reference:
McGrath J, Welham J, Scott J, Varghese D, Degenhardt L, Hayatbakhsh MR, Alati R, Williams GM, Bor W, Najman JM. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. 2010 May;67(5):440-7. Abstract

Comments on Related News


Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Jim van Os
Submitted 8 August 2007
Posted 8 August 2007

This excellent review confirms the previous meta-analysis by Henquet et al. (2005) and as such does not add anything new. The importance lies in the UK context: previously the Lancet has been mostly skeptical with regard to this issue. The fact that the leading UK medical journal now also allows these findings to see daylight is a significant event and helps stimulate further funding for the effort that several groups worldwide have started working on over the last five years: the search for the mechanism explaining the link.

View all comments by Jim van Os

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  John McGrath, SRF Advisor
Submitted 9 August 2007
Posted 10 August 2007
  I recommend the Primary Papers

It is reassuring to see that the results of the latest meta-analysis (Moore et al., 2007) are consistent with previous meta-analyses, and that the various meta-analyses are broadly consistent with the now much-tortured primary data. Despite the meta-analysis fatigue, the results are too important to ignore.

When thinking about the impact of cannabis on schizophrenia frequency measures, it is important to remember that cannabis use may translate to an increase in the prevalence of active psychosis via two mechanisms. The data suggest that as the prevalence of cannabis use increases in a population, the incidence of schizophrenia should also increase (Hickman et al., 2007). Furthermore, in those with established schizophrenia, cannabis use is associated with poorer outcomes (i.e., reduced remission rates). Thus, from a modeling perspective, increased cannabis use could lead to an increase in the prevalence of active psychosis via two mechanisms (i.e., increased “inflow” and decreased “outflow”) (McGrath and Saha, 2007).

The prevalence of active psychosis in the community may be “under the influence” of cannabis from more than one perspective.

References:

Moore THM, Zammit S, Lingford-Hughes A, Barnes TRE, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review. Lancet. 2007 July 28; 370:319-328. Abstract

McGrath J, Saha S. Thought experiments on the incidence and prevalence of schizophrenia “under the influence” of cannabis. Addictions 2007 Apr;102(4):514-5. Abstract

Hickman M, Vickerman P, Macleod J, Kirkbride J, Jones PB. Cannabis and schizophrenia: model projections of the impact of the rise in cannabis use on historical and future trends in schizophrenia in England and Wales. Addiction. 2007 Apr;102(4):597-606. Abstract

View all comments by John McGrath

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Dana MarchEzra Susser (SRF Advisor)
Submitted 20 August 2007
Posted 20 August 2007

The recent meta-analysis in the Lancet (Moore et al., 2007) regarding cannabis use and psychotic or affective mental health outcomes is, indeed, a necessary contribution. It is the first systematic review restricted to longitudinal studies of cannabis use and mental health outcomes. For this addition to the contours of the literature, Zammit and colleagues are to be commended.

We may be more optimistic than the authors, however, about the potential for future longitudinal studies to shed further light on the question of causality, and perhaps more cautious about the present state of the evidence. Given the public health and policy implications, we propose a concerted effort to complete observational studies that are designed to rule out the main alternative explanations for the association (e.g., genetic or social factors that independently influence both cannabis use and psychosis). The Swedish conscript study (Zammit et al., 2002) is a fine example of one such study. We should also be considering natural experiments and designs based on instrumental variables enabled by in order to complement this work. For instance, we might capitalize on situations created by policy changes that affect the availability—and therefore use—of cannabis in order to examine the impact on the development of psychosis. Whether at the individual or the population level, both creativity and rigor are required.

References:

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007 Jul 28;370(9584): 319-28. Abstract

Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002 Nov 23;325 (7374):1199. Abstract

View all comments by Dana March
View all comments by Ezra Susser

Related News: Meta-analysis Supports Case for Cannabis in Etiology of Psychosis

Comment by:  Amresh Shrivastava
Submitted 20 October 2007
Posted 24 October 2007

Current interest in cannabis and the onset of psychosis is laudable. The Lancet paper no doubt establishes a causal link based upon what has been known in the literature (Raphael et al., 2005; Roberts et al., 2007; Rey et al., 2004; Wittchen et al., 2007). The authors need to be congratulated for taking extreme care to incorporate most of the studies and also for making conclusions with a sense of skepticism. That is where further questions arise.

1. Cannabis is used only in certain cultures and known to be involved in a maximum 50 percent of cases of psychosis, schizophrenia, and schizophreniform psychosis (Gregg et al., 2007). In that sense, are there two different phenotypes of schizophrenia, a) where exposure to cannabis is necessarily a factor and b) where a different set of potentiating or precipitating factors work, not cannabis?

2. Even if we focus only on the first possibility, there are few unanswered questions such as, what are the concurrent clinical conditions along with cannabis abuse? Do these patients have cognitive dysfunction? Is that reflective of broader brain mechanism changes?

3. There seems to be no reliable biological explanation as to why exposure to cannabis should precipitate psychosis. Cannabis is one of the most commonly used illicit drugs. Its active compound “cannabidols” has 64 active isomers, each having differing effects on health and behavior. There is strong support for a link between cannabis and development—exacerbation of psychosis as well as other mental health conditions (e.g., anxiety, depression). Further research is needed to determine the underlying neurochemical processes and their possible contributions to etiology, as well as the social factors that contribute to the increasing use of cannabis by young people.

4. There is a theory that preexisting cognitive dysfunction is a core feature of schizophrenia. Accepting this, there are no studies to show “causal relationship” between cannabis and cognitive dysfunction.

The current levels of information and understanding, though collected over last 25-30 years of research, are far from adequate to establish any direct relationship except “mere association.” It is hoped that more precise biological, imaging, and neuropsychological studies would be able to throw fresh light on this important area of research.

Acute cannabis administration can induce memory impairments, sometimes persisting months following abstinence. There is no evidence that residual effects on cognition remain after years of abstinence. The scarce literature on neuroimaging, mainly done in non-psychotic populations, shows little evidence that cannabis has effects on brain anatomy. Acute effects of cannabis include increases of cerebral blood flow, whereas long-term effects of cannabis include attenuation of cerebral blood flow. In animals Δ9-tetrahydrocannabinol enhances dopaminergic neurotransmission in brain regions known to be implicated in psychosis. Studies in humans show that genetic vulnerability may add to increased risk of developing psychosis and cognitive impairments following cannabis consumption. Δ9-tetrahydrocannabinol induces psychotic-like states and memory impairments in healthy volunteers (Linszen et al., 2007).

On the basis of six studies, it is concluded that there was insufficient evidence to prove conclusively that long-term cannabis use causes or does not cause residual abnormalities. The results of several reviews were also inconclusive as to whether cannabis use during adolescence may have a lasting effect on cognitive functioning and brain structure. However, it could not rule out that a) certain cognitive and cerebral abnormalities existed in patients before cannabis use began and b) that patients were suffering from subacute effects of cannabis (Weeda et al., 2006).

Continued cannabis use by persons with schizophrenia predicts a small increase in psychotic symptom severity but not vice versa (Degenhardt et al., 2007). Currently, there is a lot of interest in cannabis use as a risk factor for the development of schizophrenia. Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. In this situation, we need to examine the similarities between these in the context of the neurobiology underlying cognitive dysfunction, particularly implicating the endogenous cannabinoid system, which plays a significant role in attention, learning, and memory, and in general, inhibitory regulatory mechanisms in the brain. Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. The theoretical and clinical significance of further research in this field is enhancing our understanding of underlying pathophysiology and improving the provision of treatments for substance use and mental illness (Solowij et al., 2007). Many studies now show a robust and consistent association between cannabis consumption and the ulterior development of psychosis. Furthermore, our better understanding of cannabis biology allows the proposal of a plausible hypothetical model, based notably on possible interactions between cannabis and dopaminergic neurotransmission (Jockers-Scherubl, 2006). Do they suffer from other disorders, which are underlying or may be causal or comorbid, and do these comorbid conditions also have neurocognitive changes, e.g., psychosis, ADHD, LD, Tourette disorder, and other movement disorders, or depression? Is there an interrelationship among these factors to cause abuse and degree of cannabis consumption?

References:

Raphael B, Wooding S, Stevens G, Connor J. Comorbidity: cannabis and complexity. J Psychiatr Pract. 2005 May; 11(3): 161-7.

Roberts RE, Roberts CR, Xing Y. Comorbidity of substance use disorders and other psychiatric disorders among adolescents: Evidence from an epidemiologic survey. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S4-13. Epub 2007 Feb 1. Abstract

Rey JM, Martin A, Krabman P. Is the party over? Cannabis and juvenile psychiatric disorder: the past 10 years. J Am Acad Child Adolesc Psychiatry. 2004 Oct; 43(10): 1194-205. Abstract

Wittchen HU, Frohlich C, Behrendt S. Cannabis use and cannabis use disorders and their relationship to mental disorders: A 10-year prospective-longitudinal community study in adolescents. Drug Alcohol Depend. 2007 Apr;88 Suppl 1:S60-70. Epub 2007 Jan 25. Abstract

Gregg L, Barrowclough C, Haddock G. Reasons for increased substance use in psychosis. Clin Psychol Rev. 2007 May;27(4):494-510. Epub 2007 Jan 19. Abstract

Linszen D, van Amelsvoort T. Cannabis and psychosis: an update on course and biological plausible mechanisms. Curr Opin Psychiatry. 2007 Mar; 20(2): 116-20. Abstract

Weeda MR, Peters BD, De Haan L, Linszen DH. Residual neuropsychological, structural and functional brain abnormalities after long-term cannabis use] Tijdschr Psychiatr. 2006; 48(3): 185-93. Abstract

Degenhardt L, Tennant C, Gilmour S, Schofield D, Nash L, Hall W,McKay D. The temporal dynamics of relationships between cannabis, psychosis and depression among young adults with psychotic disorders: findings from a 10-month prospective study. Psychol Med. 2007 Feb 9; 1-8.

Solowij N, Michie PT. Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci. 2007 Jan; 32(1): 30-52. Abstract

Jockers-Scherubl MC. [Schizophrenia and cannabis consumption: epidemiology and clinical symptoms] Prax Kinderpsychol Kinderpsychiatr. 2006; 55(7): 533-43. Abstract

Curtis L, Rey-Bellet P, Merlo MC. [Cannabis and psychosis] Rev Med Suisse. 2006 Sep 20; 2(79): 2099-100, 2102-3.

Costentin J. [Neurobiology of cannabis--recent data enlightening driving disturbances] Ann Pharm Fr. 2006 May; 64(3): 148-59. Abstract

View all comments by Amresh Shrivastava

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Comment by:  Kathryn Abel
Submitted 22 April 2009
Posted 5 May 2009

It is impossible to understand the meaning of cortisol correlations in the summary from the final presentation without knowing more about those data. It looks as though they were cross-sectional measures in women and men at high risk, but the summary does not comment on their ages or menstrual phases or other data on socioeconomic status, smoking, drug, alcohol use or time of day of measures (although I'm sure the investigators know all this information).

Place in social hierarchy is an interesting confound of HPA responses, as well as baseline measures, in human and other animal populations and possibly important/relevant to schizophrenia.

View all comments by Kathryn Abel

Related News: ICOSR 2009—Cur(e)ious Cannabinoids: Implications for Psychosis and Its Treatment

Comment by:  Suzanne King
Submitted 25 May 2009
Posted 27 May 2009

Great summary!

The effects of cannabis on psychotic symptoms may be especially great in COMT Val allele carriers. Caspi's data (Caspi et al., 2005) suggested this in his birth cohort study which found that cannabis use predicted schizophreniform disorder (n = 28) but only in subjects with the Val allele.

We reported similar findings at ICOSR (Massé et al., 2009): we found a significant interaction between the estimated amount of premorbid cannabis use and COMT in discriminating between 72 schizophrenia patients and 63 community controls. We also found that, only in Val allele carriers, greater cannabis use explained significant variance in the severity of psychotic (or psychotic-like) symptoms in both patients and controls.

We welcome continued research into Gene-by-Cannabis interactions or correlations, as well as other GxG or ExE associations in psychosis.

References:

Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. 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. Biol Psychiatry . 2005 May 15 ; 57(10):1117-27. Abstract

Massé, M., Liu, A., Joober, R. & King, S. (2009) More Premorbid Cannabis Use with the Val Allele of the Catechol-O-Methyltransferase Gene Associated with Increased Risk for Schizophrenia. International Congress on Schizophrenia Research, San Diego, March 28 – April 1, 2009. Published in Schizophrenia Research, 35: Supplement 1, page 78.

View all comments by Suzanne King

Related News: ICOSR 2009—Social Outcome and Schizophrenia: Back to the Future

Comment by:  Amresh Shrivastava
Submitted 16 July 2009
Posted 16 July 2009

Perspectives in social outcome of schizophrenia
The ongoing discussion about social outcome is exciting and timely. Repeatedly it has been demonstrated that only clinical remission does not reflect “real-life” situation (Eberhard et al., 2009; Cassidy et al., 2009). The decline in social functions not only forms a pathognomonic symptom of schizophrenia but also serves as a marker and predictor for outcome status. Further, social outcome in early psychosis also serves as an indicator, which helps differentiate various syndromes amongst the broad classification of “non-affective psychosis” or “schizophrenia spectrum disorder” (Horan et al., 2009). The early intervention research for at-risk individuals is faced with three main difficult objectives:

1. To identify whether the individual will transition to florid psychotic state, no matter of what diagnostic category.

2. To find measures which can contain the transition and restore the psychosocial functions.

3. To develop clinical markers which can predict with high reliability and specificity chances of developing hardcore schizophrenia.

The appropriateness of multidimensional measurement of outcome needs to be investigated. We suggest that it needs to measure at least on two different parameters: clinical and social.

Research in the early phase of psychosis has developed evidence for early intervention, particularly “critical period” (Birchwood et al., 1998; Cassidy et al., 2009). It provides scientific and biological arguments for early identification and treatment. Furthermore, it has been suggested that the critical period should be extended to include prodromal as well as early phase of psychosis. There is more to “early intervention” in psychosis than merely intervening early.

The long-term outcome of schizophrenia should answer these two questions:

1. What do we do to maximize outcome and achieve complete social integration, and when?

2. How can we identify subjects who may not respond favorably to treatments and facilitate planning for impending disability right from the beginning?

Social outcome
In the literature, social recovery (overall good outcome) is measured by different social and occupational parameters and is found to be around 40-60 percent (Priebe, 2007). One of our long-term follow-up studies (Srivastava, A, Thakar, M, unpublished) attempted to identify the effects of multiple outcome criteria in 10 years’ long-term follow-up of first-episode hospitalized patients. The social parameters included quality of life, level of functioning, independent living, interpersonal social functioning, work and employment, presence of family burden, and social burden (Meltzer et al., 1997). We observed that outcome status declines if both clinical and social parameters are included: 61 percent of patients showed clinical remission, 32 percent showed good social remission, and only 25 percent improved on both clinical and social parameters. Just 10 percent of the patients fulfilled a maximum of four parameters. The largest group of patients (25.7 percent) recovered on only two parameters. Social parameters appear to be inter-dependent, yet recovery on any one parameter is not associated with recovery on any other parameter. Therefore, some patients are employed but unable to live independently and others show good quality of life but are still unable to be gainfully employed. In this study it is observed that only 23-25 percent of patients show social recovery on two to three different parameters.

Conceptual framework
The outcome criteria have been ill defined for long-term studies. Commonly used outcome terminology has been “poor outcome," "good outcome," "favorable outcome," "unfavorable outcome," "hospitalization," "repeated relapse rate," "living with family," "return to education," "employment," and "marital status." It is difficult to arrive at a conclusion for minimum criteria for defining “good outcome” in the long term. Recently there have been a few attempts to look at this aspect scientifically (Addington et al., 2004; Crumlish et al., 2009), particularly from the working group of the American Psychiatric Association on defining criteria for remission, which has developed a consensus statement about “remission” in schizophrenia. (Andreasen and Olsen, 1982) Based on an examination of popular rating scales (SAPS and SANS, PANSS, and BPRS), the working group identified appropriate criteria to serve as the basis for defining “symptomatic remission” in schizophrenia. In addition, the working group proposed that remission criteria might be described separately for positive and negative symptoms, to allow primary consideration of these symptom groups independently in the assessment of symptomatic remission. Specific items selected for consideration as criteria for remission in schizophrenia were chosen to map the three dimensions of psychopathology identified by factor analyses: 1) psychoticism; 2) disorganization; and 3) negative symptoms. This represents the conceptualization and quantification of remission. It is noteworthy that remission as an outcome measure is far less than what is required to capture real-life outcome. There are expectations from the families and the public at large to define the outcome in a real-life situation.

We therefore propose that outcome needs to be measured on a minimum of two groups of parameters, each having three or more parameters in the least: 1) clinical outcome that measures psychopathology, side effects, and hospitalization. The psychopathology includes aggression, suicidality, and depression besides parameters of “psychoticism”; 2) social outcome, which measures quality of life, global assessment of functioning, and social cognition. The parameter of social cognition includes ability to learn and reproduce, coping, independent living, and interpersonal skills.

We need to investigate dimensions of social decline and social improvements that are objective, definable, and quantifiable. Thus, the ongoing work of social outcome is very significant.

References:

Addington J, Van Mastrigt S, Addington D. Duration of untreated psychosis: impact on 2-year outcome. Psychol Med. 2004 Feb 1;34(2):277-84. Abstract

Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry. 1982 Jul 1;39(7):789-94. Abstract

Birchwood M, Todd P, Jackson C. Early intervention in psychosis. The critical period hypothesis. Br J Psychiatry Suppl. 1998 Jan 1;172(33):53-9. Abstract

Cassidy CM, Norman R, Manchanda R, Schmitz N, Malla A. Testing Definitions of Symptom Remission in First-Episode Psychosis for Prediction of Functional Outcome at 2 Years. Schizophr Bull. 2009 Mar 25; Abstract

Crumlish N, Whitty P, Clarke M, Browne S, Kamali M, Gervin M, McTigue O, Kinsella A, Waddington JL, Larkin C, O”Callaghan E. Beyond the critical period: longitudinal study of 8-year outcome in first-episode non-affective psychosis. Br J Psychiatry. 2009 Jan 1;194(1):18-24. Abstract

Eberhard J, Levander S, Lindström E. Remission in schizophrenia: analysis in a naturalistic setting. Compr Psychiatry. 2009 May-Jun ;50(3):200-8. Abstract

Horan WP, Kern RS, Shokat-Fadai K, Sergi MJ, Wynn JK, Green MF. Social cognitive skills training in schizophrenia: an initial efficacy study of stabilized outpatients. Schizophr Res. 2009 Jan 1;107(1):47-54. Abstract

Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL, Thompson PA. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry. 1997 Apr 1;154(4):475-82. Abstract

Priebe S. Social outcomes in schizophrenia. Br J Psychiatry Suppl. 2007 Aug 1;50():s15-20. Abstract

Srivastava, Amresh and Thakar, Meghan, Outcome in Schizophrenia: The Long-Term Good Outcome in Schizophrenia Is Not Yet Good Enough (2008). Psychiatry Presentations. Paper 7.

View all comments by Amresh Shrivastava

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Comment by:  John McGrath, SRF Advisor
Submitted 5 November 2010
Posted 5 November 2010

The large study from Nuevo and colleagues is very thought provoking. There was substantial between-site variation in response to various psychosis-screening items. Assuming that endorsement of these items is a mix of: 1) "true" psychotic-like experiences, 2) "true" responses that are understandable from the perspective of local cultures and beliefs, and 3) innocent misinterpretations of the questions, why is there such marked variation? For example, why do 46 percent of respondents from Nepal endorse at least one psychotic-like experience and a third report auditory hallucinations?

It seems self-evident that populations with strong religious and/or cultural beliefs related to psychotic-like experiences might endorse psychosis-screening items more readily (type 2 in the above list). But could it be feasible that these same populations might also “kindle” psychotic experiences in vulnerable people? This notion is pure speculation, but we should remain mindful that dopaminergic pathways related to psychosis are vulnerable to the process of endogenous sensitization (Laruelle, 2000).

What does it mean to be a member of a cultural group that is more “prone” to psychotic-like experiences? Tanya Luhrmann, an anthropologist based at Stanford University, has examined individuals attending evangelical churches who “hear” the voice of God during prayer (Luhrmann et al., 2010). The vignettes suggest that some individuals reported more “hearing the voice of God” after improving their prayer skills. Practice makes perfect, but could it also kindle pathways related to schizophrenia?

Regardless of the underlying mechanisms, understanding variations in these symptoms is a fascinating topic worthy of more multidisciplinary research.

References:

Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev. 2000;31(2-3):371-84. Abstract

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

View all comments by John McGrath

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Tanya Luhrmann
Submitted 12 November 2010
Posted 12 November 2010

It seems to me that there may be two different patterns that show up in these large epidemiological studies: the psychotic continuum and phenomena associated with absorption. Absorption is basically a capacity for/interest in being caught up in your imagination. It is associated with hypnotizability and dissociation, but not identical to them (Tellegen and Atkinson, 1974).

In my own work on evangelical Christianity, I identify a pattern in which people report hallucination-like phenomena that are rare, brief, and not distressing (as opposed to the pattern associated with psychotic disorder, in which the hallucinations are often frequent, extended, and distressing). Those who report hearing God’s voice audibly or seeing the wing of an angel are also more likely to score highly on the Tellegen absorption scale (Luhrmann et al., 2010). This relationship between unusual experiences and absorption also shows up in a significant relationship between absorption and the Posey-Loesch hearing voices scale when these scales are given to undergraduates. Among undergraduates, the rates for hallucination-like phenomena are also consistently far higher than the Nuevo paper reports, perhaps because neither the absorption scale nor the Posey-Loesch scale seems to probe for pathology (Luhrmann, forthcoming).

I am not the only one to have found a significant association between unusual sensory experiences and absorption. Aleman and Laroi (2008) report that a handful of other researchers have also found significant correlations between hallucination scales and the absorption scale. As a result of this work, I think that there may be different pathways to hallucination-like phenomena—some pathological, others less so.

Yet, I also wonder whether there is indeed something like “priming” psychosis, as John suggested. This would arise if there were some looseness in the relationship between psychosis and dissociation, which there appears to be. At least that's the way I interpret some of the phenomena that Romme and Escher (1993) report. If there is some kind of loose relationship, it would suggest that someone could have an absorption/dissociation response to trauma that would look psychotic; it might also suggest that an intensely absorbing negative imaginative experience (being pursued by demons, e.g.) might contribute to a vulnerable person exhibiting more psychotic-like symptoms.

How would we begin to pull this apart?

References:

Aleman A, Laroi F. Hallucinations: The science of idiosyncratic perception. Washington, DC: American Psychological Association, 2008.

Luhrmann TM. When God speaks back. New York: Knopf, forthcoming.

Luhrmann TM, Nusbaum H, Thisted R. The absorption hypothesis: learning to hear God in evangelical Christianity. American Anthropologist. 2010;112 (1):66-78.

Romme M, Escher S. Accepting voices. London: Mind, 1993.

Tellegen A, Atkinson G. Openness to absorbing and self-altering experiences (“absorption”): a trait related to hypnotic susceptibility. J Abnorm Psychol. 1974;83(3):268-77. Abstract

View all comments by Tanya Luhrmann

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Mary Cannon
Submitted 15 November 2010
Posted 15 November 2010

This beautifully written piece serves to excite interest in the fascinating epidemiology of schizophrenia. In our search for the “missing heritability” of schizophrenia, we don’t have to look too far for clues. There are many contained in this piece. It just requires some Sherlock Holmes-type deductive reasoning to put them all together now!

The realization that psychotic symptoms (or psychotic-like experiences) can be used as a proxy for schizophrenia risk has opened up new vistas for exploration (Kelleher and Cannon, 2010). For instance, the paper by Nuevo and colleagues will provide a fertile ground for testing ecological hypotheses on the etiology of schizophrenia—such as examining cross-national vitamin D levels (McGrath et al.) or fish oil consumption. Geneticists have yet to appreciate the potential value of studying such symptoms. Ian Kelleher, Jack Jenner, and I have argued in a recent editorial that the non-clinical psychosis phenotype provides us with a population in which to test hypotheses about the evolutionary benefit of psychosis genes (Kelleher et al., 2010; see also Nesse, 2004). This non-clinical psychosis phenotype gives rise to the possibility of moving beyond just-so stories into the realm of testable hypotheses.

References:

Kelleher I, Cannon M. Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis. Psychol Med. 2010 May 19:1-6. Abstract

Kelleher I, Jenner JA, Cannon M. Psychotic symptoms in the general population - an evolutionary perspective. Br J Psychiatry. 2010 Sep;197(3):167-9.

Nesse RM. Cliff-edged fitness functions and the persistence of schizophrenia. Behav Brain Sci. 2004;27:862-3.

View all comments by Mary Cannon

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Jean-Paul Selten
Submitted 17 November 2010
Posted 17 November 2010
  I recommend the Primary Papers

With interest, I read Victoria Wilcox's summary of some thought-provoking papers published this year. It seems that schizophrenia, like cancer, has many different causes. I would like to point out that three of the studies (Zammit et al., 2010; Wicks et al., 2010; Schofield et al., 2010) support the idea that social defeat and/or social exclusion increase risk. The paper by Zammit et al. showed this in an elegant way: being different from the mainstream, no matter on what account, increased the subject's risk. The next step is to show that social exclusion has an impact on an individual's dopamine function. My group is examining this in young adults with an acquired hearing impairment, using SPECT.

References:

Zammit S, Lewis G, Rasbash J, Dalman C, Gustafsson J-E, Allebeck P. Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders. Arch Gen Psychiatry. 2010 Sep;67(9):914-22. Abstract

Wicks S, Hjern A, Dalman C. Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry. 2010 Oct;167(10):1240-6. Epub 2010 Aug 4. Abstract

Schofield P, Ashworth M, Jones R. Ethnic isolation and psychosis: re-examining the ethnic density effect. Psychol Med. 2010 Sep 22:1-7. Abstract

View all comments by Jean-Paul Selten

Related News: Research Roundup —The Tapestry of Environmental Influences in Psychosis

Comment by:  Chris Carter
Submitted 26 November 2010
Posted 26 November 2010
  I recommend the Primary Papers

I have been collecting diverse references for environmental risk factors in schizophrenia at Schizophrenia Risk Factors. These include many prenatal influences due to maternal infection, usually with some sort of virus, or immune activation with fever. Several animal studies have shown that infection or immune activation in mice can produce schizophrenia-like symptoms in the offspring. Toxoplasmosis has often been cited as a risk factor in adulthood.

Many of the genes implicated in schizophrenia are also involved in the life cycles of these pathogens, and interactions between genes and risk factors can together contribute to endophenotypes; for example, MICB and Herpes simplex infection have single and combined effects on grey matter volume in the prefrontal cortex.

Over 600 genes have been associated with schizophrenia. When these were pumped through a Kegg pathway analysis, the usual suspects (neuregulin, dopamine, and glutamate pathways, among others) figure highly in the list of pathways. Immune-related pathways are also highly represented, as are many pathogen entry pathways, including that for toxoplasmosis, which heads the list. Some of the more exotic pathways, for example, Chaga’s disease, should be considered as generic, as well as specific.

These Kegg-generated data suggest that there are strong relationships between genes and risk factors. Perhaps stratification of GWAS data in relation to infection could take this into account.

References:

Bortolato M, Godar SC. Animal models of virus-induced neurobehavioral sequelae: recent advances, methodological issues, and future prospects. Interdiscip Perspect Infect Dis . 2010 Jan 1 ; 2010():380456. Abstract

Carter CJ. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. Schizophr Bull . 2009 Nov 1 ; 35(6):1163-82. Abstract

Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry . 1999 Mar 1 ; 4(2):145-54. Abstract

Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse . 2005 Aug 1 ; 57(2):91-9. Abstractx

Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry . 2006 Mar 15 ; 59(6):546-54. Abstract

Prasad KM, Bamne MN, Shirts BH, Goradia D, Mannali V, Pancholi KM, Xue B, McClain L, Yolken RH, Keshavan MS, Nimgaonkar VL. Grey matter changes associated with host genetic variation and exposure to Herpes Simplex Virus 1 (HSV1) in first episode schizophrenia. Schizophr Res . 2010 May 1 ; 118(1-3):232-9. Abstract

Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry . 2008 May 1 ; 13(5):470-9. Abstract

Zuckerman L, Weiner I. Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res . 2005 May 1 ; 39(3):311-23. Abstract

View all comments by Chris Carter