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Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

11 January 2012. Elevated dopamine synthesis in the striatum predates the onset of psychosis, according to a study published in December in the American Journal of Psychiatry. Led by Oliver Howes of Kings College London, U.K., the study finds that, among individuals identified as at-risk for a mental disorder, those who later go on to develop psychosis had higher dopamine synthesis capacity in the striatum, as measured by positron emission tomography (PET), compared to those who did not.

The results support the idea that an overactive dopamine system precedes illness, as well as being associated with psychosis itself (see SRF Hypothesis). An inkling of this came from a previous study finding elevated dopamine synthesis in the at-risk group compared to healthy controls (see SRF related news story). The new study looks at these same data again, but with follow-up information in hand about who did and who did not transition to psychosis.

A biomarker that can predict whether someone with "attenuated" psychotic symptoms will develop schizophrenia is much sought after, as only about one-third of individuals with these sub-threshold symptoms develop a psychotic illness within two years (see SRF Live Discussion). One study, published online November 10 in the Schizophrenia Bulletin, proposes a combination of brain measures obtained from structural magnetic resonance imaging (MRI) that may discriminate between at-risk individuals who later go on to develop psychosis and those who do not. The other study, published online December 20 in Molecular Psychiatry, highlights decreased nervonic acid levels from blood samples as a possible predictor of future psychosis.

Dopamine in overdrive
In Howes’ study, the participants were 30 individuals identified as at ultra-high risk of psychosis and 29 matched controls. The researchers used PET scanning with [18F]6-fluoro-L-DOPA as a detectable substrate for the dopamine-making enzyme. This allowed them to measure the dopamine synthesis capacity in the striatum, a recipient of dopaminergic terminals that has shown dopamine dysregulation in psychosis. At least three years later, the researchers found that nine of the ultra-high-risk participants had developed psychosis and 15 had not; the remaining six who had developed schizotypal personality disorder were excluded from the main analysis.

Going back to the pre-psychosis PET scans, the researchers found that the psychosis transition group had a greater dopamine synthesis capacity in the striatum compared to healthy controls. Specifically, the mean uptake value for [18F]DOPA in the striatum was greater in the whole striatum (effect size = 1.18, as measured by Cohen’s d), and in the associative striatum (effect size = 1.24) in the psychosis transition group compared to controls. The associative striatum comprises much of the caudate nucleus and receives inputs from the dorsal lateral prefrontal cortex, a region also implicated in the at-risk state (Fusar-Poli et al., 2010).

The individual PET signals correlated with an individual’s prodromal symptoms in the group developing psychosis later. Greater dopamine synthesis capacity in the whole striatum was associated with more severe symptoms as assessed by the Comprehensive Assessment of At-Risk Mental States (r = 0.67, p = 0.049) and by the Positive and Negative Syndrome Scale (r = 0.71, p = 0.032).

The PET scans also revealed a difference between at-risk individuals, depending on whether they developed psychosis later. Though there was no difference in clinical symptoms at the time of scanning between these two groups, the psychosis transition group had elevated dopamine synthesis capacity in the striatum compared to the ones who did not. Comparison between the non-transition group and the controls did not reveal any differences.

Brain and blood
Could a snapshot of the brain foretell future development of psychosis? Nikolaos Koutsouleris of Ludwig-Maximilian-University in Munich, Germany, and colleagues are trying to do this by analyzing neuroanatomical features seen in structural MRI brain scans with a pattern classifier algorithm. Finding some success in a previous study (Koutsouleris et al., 2009), the researchers tested their classifier out on a second, independent population, drawn from the prospective FePsy study on predicting psychosis in at-risk individuals (Riecher-Rössler et al., 2007). Their algorithm discriminated between MRI scans from those who later developed psychosis and those from healthy controls, correctly identifying 93.8 percent of at-risk individuals who later developed psychosis and 90.9 percent of healthy controls. Among those at risk, the pattern classifier correctly identified 81.0 percent of those who later developed psychosis and 87.5 percent of those who did not.

Others are aiming for the ease of a blood test to predict psychosis. A new study from G. Paul Amminger of the University of Melbourne in Australia and colleagues reports decreased blood levels of nervonic acid in people clinically identified as at-risk for psychosis who subsequently developed psychosis within one year. Nervonic acid is an omega-9 fatty acid important for myelin-making. Abnormal levels of polyunsaturated fatty acids have been implicated in schizophrenia (Assies et al., 2001), and restoring them with dietary supplements may have some benefit (see SRF related news story). The new study examined the fatty acid composition in blood cell membranes—used here as a proxy for the state of neuronal membranes—and found a decreased nervonic acid level in the 11 individuals who converted to psychosis compared to the 30 who didn’t, with an effect size of 0.79 (Cohen’s d).

Whether or not the goal of predicting individual fates is reached, mining the prodromal period for clues may help unravel the processes underlying illness onset and build a more mechanistic understanding of schizophrenia.—Michele Solis.

References:
Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

Comments on News and Primary Papers


Primary Papers: Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 9 January 2012
Posted 9 January 2012

The elegant studies of Oliver Howes and colleagues (Howes et al., 2011; Howes et al., 2009; Howes et al., 2011) have contributed valuable information regarding the high-risk state and dopamine (DA). Because of these studies, it is now clear that striatal dopamine dysregulation precedes onset of psychosis, relates to symptoms, and affects the associative striatum most predominantly, at least initially, extending into the sensorimotor subregion with time (Howes et al., 2011), while the ventral striatum remains relatively spared. These are difficult studies in terms of recruitment, characterization, and retention of subjects for longitudinal follow-up, and represent a great contribution to our field.

The paper discussed here (Howes et al., 2011) expands the initial cohort of 24 subjects at ultra high (Howes et al., 2009) risk by adding six patients to the group. The authors also removed the schizotypal patients (n = 6) from the overall sample on the premise that these patients have elevated dopamine synthesis rates but do not progress to psychosis at the same rate as the remaining subjects do. This highlights the complexity of the clinical assessments in this population. One may argue that if schizotypal patients were included in the initial cohort, they must have displayed signs of “attenuated symptoms” as described, so they fit in the categorization of ultra high-risk group, and there should be little reason to consider them separately at this point. If considered separately and removed from the initial cohort, would that affect the results of the initial study? The authors may want to provide a revised analysis and a revised effect size for the initial sample published in 2009.

The relationship to baseline symptoms is striking, and has not been routinely observed in studies of patients with schizophrenia (Abi-Dargham et al., 1998; Laruelle et al., 1996). The lack of relationship between striatal DA and psychotic symptoms at baseline in schizophrenia, unlike the high-risk state, may be due to the added noise related to effects of duration of illness and treatment on symptoms, which may diminish the strength of this relationship in more chronic and previously treated patients. It also underscores very clearly that dopamine is essential to the emergence of symptoms in a vulnerable brain at the time of “high risk,” and to their mobilization with psychostimulants or stress, but DA may not be as clearly related to symptoms in the chronic phase.

The fact that increased dopamine synthesis affects the associative, and on longitudinal assessment, the sensorimotor striatal subregions is also an interesting observation, not only because of the regions affected, but also because of the regions unaffected. It is surprising that the ventral striatum (VST) does not exhibit the excess dopamine that was historically postulated to be present in limbic dopaminergic pathways and to be associated with psychosis. It has become clear from these findings and from our studies in patients with schizophrenia (Kegeles et al., 2010) that psychotic symptoms are related to excessive dopamine in the head of the caudate, an area of integration between orbitofrontal “limbic” cortex and dorsolateral prefrontal “cognitive” cortex (Haber et al., 2006), and this integration may be at the core of misattributions of meaning or significance that underlie the psychotic thinking. The absence of increase in dopamine in the limbic striatum may be related to the low motivation and anhedonia that is a core feature of the negative symptoms of the illness. In the group, there was no overall abnormality of dopamine synthesis in VST; however, there could be a variable range that may relate to the presence and severity of anhedonia. More specific assessments of functions related to the ventral striatum may be necessary to understand the role of dopamine in the ventral striatum in the pathophysiology of schizophrenia.

Will serial scanning be helpful to identify patients needing treatment? Will it increase our ability to detect patients early on and prevent progression? Identifying high risk before DA dysregulation may be the best therapeutic window for non-dopaminergic drugs that are currently under development. However, the screening itself relies on detecting increased dopamine function, which may already be too late for non-dopaminergic interventions to be effective. In other terms, although very valuable, detecting high-risk subjects by targeting their DA phenotype may be already too late to intervene most optimally. Searching for predecessors to the DA dysregulation may be the best way to optimize prevention.

References:

Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry. 2011;16(9):885-6. Abstract

Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66(1):13-20. Abstract

Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, et al. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011. Abstract

Abi-Dargham A, Gil R, Krystal J, Baldwin R, Seibyl J, Bowers M, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998;155:761-7. Abstract

Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, De Souza CD, Erdos J, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc Natl Acad Sci USA. 1996;93:9235-40. Abstract

Kegeles L, Abi-Dargham A, Frankle W, Gil R, Cooper T, Slifstein M, et al. Increased synaptic dopamine in associative regions of the striatum in schizophrenia. Archives of General Psychiatry. 2010;67((3)):231-9. Abstract

Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J Neurosci. 2006;26(32):8368-76. Abstract

View all comments by Anissa Abi-Dargham

Primary Papers: Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 11 January 2012
Posted 11 January 2012

Howes et al. make an important contribution in reporting increased striatal dopamine synthesis in a patient/subject cohort at ultra high risk for psychosis. Most interesting is the correlation between dopamine synthesis and transition to psychosis. An important milestone in the dopamine hypothesis of schizophrenia came with in-vivo neuroimaging evidence of increased dopamine release in persons with schizophrenia reported by Breier and colleagues (Breier et al., 1997) and by Laruelle and colleagues (Laruelle et al., 1996). This was the first direct evidence for the dopamine hypothesis. Howes et a. cite recent reviews by Abi-Dargham and others, and a meta-analysis is now available with advance access in the Schizophrenia Bulletin (Fusar-Poli and Meyer-Lindenberg, 2011) for the interested reader.

This report is timely for several reasons:

Attenuated psychosis syndrome (APS) may be recommended as a disorder in DSM-5 (see American Psychiatric Association DSM-5 Development). The debate is intense (and has included an SRF online discussion). I have participated in the debate as chair of the psychosis work group for DSM-5 and find the discussion most informed when the following facts are kept in mind:

For more on this issue, Jim van Os and I have discussed the two sides of the DSM-5 debate elsewhere (Carpenter and van Os, 2011).

References:

Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA. 1997 Mar 18;94(6):2569-74. Abstract

Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9235-40. Abstract

Fusar-Poli P and Meyer-Lindenberg A. STRIATAL PRESYNAPTIC DOPAMINE IN SCHIZOPHRENIA, PART II: META-ANALYSIS OF [18F/11C] DOPA PET STUDIES.

Dazzan P, Soulsby B, Mechelle A, Wood SJ, Velakoulis D, Phillips LJ, Yung AR, Chitnis X, Lin A, Murray RM, McGorry PD, McGuire PK, Pantelis C. Volumetric Abnormalities Predating the Onset of Schizophrenia and Affective Psychoses: An MRI Study in Subjects at Ultrahigh Risk of Psychosis Schizophr Bull sbr035 first published online April 25, 2011 doi:10.1093. Abstract

Fusar-Poli P. Voxel-wise meta-analysis of fMRI studies in patients at clinical high risk for psychosis. J Psychiatry Neurosci. 2011 Nov 1, 36(6):110021. Abstract

Ziermans TB, Sschothorst PF, Sprong M, Magnee MJ, van Engeland H, Kemner C. Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence. Schizophr Res. 2012. Jan, 134(1):10-5. Abstract

Cornblatt BA, Carrion RE, Addington J, Seidman L, Walker EF, Cannon TD, Cadenhead KS, McGlashan TH, Perkins DO, Tsuang MT, Woods SW, Heinssen R, Lencz T. Risk factors for psychosis: Impaired social and role functioning. Schizophr Bull. 2011. Nov 10, doi:10.1093. Abstract

Tandon N, Montrose D, Shah J, Rajarethinam RP, Diwadkar VA, Keshavan MS. Early prodromal symptoms can predict future psychosis in familial high-risk youth. J Psychiatr Res, 2012, 46(1):105-110. Abstract

Werbeloff N, Drukker M, Dohrenwend BP, Levav I, Yoffe R, van Os J, Davidson M, Weiser M. Self-reported attenuated psychotic symptoms as forerunners of severe mental disorders later in life. Arch Gen Psychiatry, 2012, Jan 2. Abstract

Fusar-Poli P, Radua J, McGuire P, Borgwardt S. Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies Schizophr Bull sbr134 first published online November 10, 2011 doi:10.1093. Abstract

American Psychiatric Association DSM-5 Development

Carpenter WT and van Os J. Should attenuated psychosis be a DSM-5 diagnosis? Am J Psychiatry. 2011 May;168(5):460-3. Abstract

View all comments by William CarpenterComment by:  Thomas McGlashan
Submitted 21 January 2012
Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified "prodromal" subjects those who are most likely to become psychotic. That such diverse measures proved to be successful in identifying "true positives" can be regarded as a milestone in this line of investigation. It represents a quantitative leap forward in our ability to reduce the uncertainty of predicting psychosis, and hints at the day when tragedies such as the one occurring in Tucson, Arizona, become a thing of the past.

References:

Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

View all comments by Thomas McGlashan

Comments on Related News


Related News: High Dopamine Levels in People With Evidence of Prodromal Schizophrenia

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 28 January 2009
Posted 28 January 2009

This paper introduces new knowledge and at the same time replicates many of the themes that have emerged in the area of dopamine research and schizophrenia. The new knowledge is that DA dysregulation precedes onset, and is present in the same anatomical area and with a similar magnitude to that observed in schizophrenia. It shows once again that the dopamine dysregulation in schizophrenia is one of the most replicated and consistent findings in the field.

The area of pathology within the striatum is, as described in schizophrenia, the associative, rather than the limbic or sensorimotor striatum (Kegeles et al., 2006). This represents the main area of projection of the DLPFC. Furthermore, this part of the striatum receives input from other limbic cortical areas (Haber et al., 2006) and may play a role in integrating emotions and cognition. Alterations in this integrative function could lead to misattributions or mislabelings leading to paranoia or “inappropriate” affect, in addition to the cognitive deficits.

The relationship to baseline psychotic symptoms, present for the prodrome but not detected in schizophrenia, as we have previously shown, too (Laruelle et al., 1999), is worth commenting on. It suggests that dopamine may play an essential role in the genesis of psychotic symptoms. This role may be most predominant early on in the disease, rather than later in the course of the illness. Later, symptoms may perpetuate for other reasons. Alternatively, it may be that their partial improvement due to treatment prior to the scan may make the relationship more difficult to detect, and that relationship would be detected if studies included only drug naïve patients. Either way, the relationship to severity of symptoms in the prodromal stage suggests that dopamine dysregulation may be an early part of the pathogenetic pathway, and not a subsequent consequence of other events. This is strengthened by the relationship to deficits on a verbal fluency task, suggesting again a general role for dopamine in the genesis of all symptom domains.

The next questions that emerge from these data are, How early in life is the DA alteration present and what are its effects on the developing brain and the relevant circuitry? As D2 overexpression in the striatum during development resulted in long-lasting alterations in cortical dopamine and cortical function in mice (Kellendonk et al., 2006), it may be that early alterations of D2 signaling within the associative striatum have effects on other targets within the associative striatum and along the whole integrated cortico-striato-thalamocortical circuit that become obvious only at onset. Identifying and halting this process early on are needed in order to prevent long-lasting deficits. In this regard, the paper does not present evidence that increased dopamine predicts conversion, which would be needed if one should propose a test of striatal dopamine for therapeutic intervention. For this to happen, large-scale imaging studies showing sensitivity and specificity of [18F]-DOPA as a biomarker for conversion are needed, similarly to studies conducted now in the field of Alzheimer disease using PET and tracers to label β amyloid.

References:

Kegeles L, Frankle W, Gil R, et al. Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs. J Nucl Med. 2006(47):139P.

Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J Neurosci. Aug 9 2006;26(32):8368-8376. Abstract

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46(1):56-72. Abstract

Kellendonk C, Simpson EH, Polan HJ, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. Feb 16 2006;49(4):603-615. Abstract

View all comments by Anissa Abi-Dargham

Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 16 February 2010
Posted 16 February 2010

The most controversial recommendation being considered by the DSM-V Psychoses Work Group involves creating a risk syndrome section and placing psychosis risk as a class in this new section. The September 2009 issue of Schizophrenia Bulletin carried a concept piece on the risk syndrome by Heckers, a validity report by Woods et al., and an editorial detailing Work Group considerations by me. Reliability has been established among experts, but to eventually make this recommendation for DSM-V, we will have to demonstrate reliability in ordinary clinical settings by ordinary clinicians. Even then, substantial opposition is anticipated, and it seems more likely headed for the appendix (in need of further study) than prime time as a diagnostic class.

Opposition is based primarily on three concerns: 1) high false-positive rates, 2) harm related to stigma and excessive drug prescribing, and 3) lack of an evidence-based therapeutic approach with documented efficacy and effectiveness. The first two can be rebutted to some extent by giving emphasis to the potential advantages for the true positive cases. Regarding the false positive cases, it can be emphasized that distress, disability, and help-seeking are obligatory for the proposed criteria. Therefore, these persons would still be exposed to clinical care that might include excessive medication and stigma. Furthermore, they would still have the risk of an uninformative diagnosis.

On the third point, it is worth noting that the DSM is not a therapeutic manual. Nonetheless, as a practical matter, I have assumed that opposition would melt away if a safe and effective treatment for true positive cases were known, and if the treatment did more good than harm for false positive cases. Amminger et al. move the field a giant step forward in this regard. Omega-3 free fatty acids are thought to be associated with general health benefits without significant adverse effects. I take them daily and hope to live forever. Their report of substantially reduced conversion-to- psychotic-illness rates is reinforced by secondary analyses showing benefits for psychopathology. The number needed to treat is four, a very small number, and I assume the number needed to harm is very high (this could not be determined in the present study since adverse events did not exceed placebo, but infinity is not excluded).

This important report urgently calls for replication or refutation. If confirmed, it provides a basis for hope that therapeutics with a novel compound may substantially improve the fate of persons at risk for psychotic illness. If confirmed, I expect the opposition to formally identifying persons as at risk for psychosis will melt away. We may be closer to issues related to identifying and treating hypercholesterolemia than we are to the supposed harm associated with elevating the risk syndrome to the level of classification in DSM-V.

References:

Heckers S. Who is at risk for a psychotic disorder? Schizophr Bull. 2009 Sep;35(5):847-50. Epub 2009 Jul 24. Abstract

Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, McGlashan TH. Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull. 2009 Sep;35(5):894-908. Abstract

Carpenter WT. Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull. 2009 Sep;35(5):841-3. Abstract

View all comments by William Carpenter

Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Stuart Maudsley
Submitted 19 February 2010
Posted 19 February 2010

The recent work of Pajonk and colleagues is one of the most recent demonstrations of the beneficial neurological actions of physical exercise. Physical activity not only can improve cardiovascular health directly, but also appears to engender a strong neurotrophic effect that can be isolated somewhat from the cardiovascular actions. Recreational physical activity has been demonstrated to improve learning and memory functions in healthy adults (Winter et al., 2007), reduce the risk of dementia in elderly patients (Karp et al., 2006; Vaynman and Gomez-Pinilla, 2006), attenuate progression and development of Alzheimer’s disease (AD) (Wilson et al., 2002), and productively increase brain volume in areas concerned with spatial memory and executive function (Colcombe et al., 2006; Erickson et al., 2009). This final aspect of physical exercise, i.e., actual increased central nervous system development, is the subject of the Pajonk et al. study. Rather than the neurological developmental effects of exercise upon healthy, aged, or AD patients, Pajonk and colleagues have studied the actions of exercise upon the hippocampal regions of schizophrenic patients.

Hippocampal function and structure are sensitive to the environment
The hippocampus, primarily concerned with the acquisition and transfer of short-term memories, has been demonstrated to be exceptionally sensitive to volume alteration with cognitive or physical exercise paradigms (Boyke et al., 2008; Erickson et al., 2009; Pereira et al., 2007). Although pathology of the hippocampus is primarily linked to AD (Maudsley et al., 2007), abnormalities in the structure of this brain region have been reported in schizophrenia (Reif et al., 2006) and may contribute to defects in neural plasticity in this area.

Pajonk et al. have attempted to apply the well-known effects of exercise upon hippocampal structure and volume to patients presenting with schizophrenia. This group recruited patients with schizophrenia along with a healthy control group. Half of the schizophrenic group was exposed to a coordinated and supervised physical exercise regimen (cycling), while the rest of the schizophrenic patients were occupied for a similar period of time with a hand-eye coordination skill that did not induce significant physical exertion (table football). The control individuals were also placed on an exercise regimen (cycling), but oddly, none was subjected to the table football task, a potential flaw in the study’s experimental design.

Physical exercise increases hippocampal volume in schizophrenic patients
Crucial neurophysiological measurements were made in all the experimental subjects at the beginning of the study and after three months of the protocols. One of the primary indices measured, using magnetic resonance imaging, was the change in relative hippocampal volume. As one would expect, the control patients experiencing the exercise paradigm demonstrated a significant increase in hippocampal volume. In the patients with schizophrenia, this was mirrored only in the exercise group; those who played table football failed to show any increase in hippocampal volume.

Here it would have been interesting to have investigated the table football-playing actions in the control patients, as learning coordinated motor skills (without significant physical strain), such as juggling, can increase hippocampal volume in healthy adults (Draganski et al., 2004). Nevertheless, the exercise-induced increase in relative hippocampal volume was clearly apparent in the exercising patients who had schizophrenia. Therefore, it seems likely that the complex physiological response mechanisms required for the translation of physical activity to neuromodulatory effects are still intact even in patients with schizophrenia. At a certain level, the brains of these patients could be considered still relatively healthy and normal.

Schizophrenic patients respond in a unique manner to exercise
To assess the functional integrity of the newly created neurons in the hippocampus, Pajonk et al. studied the ratio of N-acetylaspartate (NAA) to the metabolite creatine (Cr). High N-acetylaspartate levels are often associated with healthy functional neurons and were consistently increased in the exercising patients with schizophrenia. In exercising control patients, the NAA:Cr ratio was relatively unchanged, and some subjects showed a marked reduction. This difference could point to a potentially different mechanism by which patients with schizophrenia increase hippocampal volume compared to control patients who demonstrate the same physiological response to exercise.

Reinforcing the ultrastructural and biochemical effect of exercise upon the schizophrenic hippocampus improved its functional integrity as well. The group with schizophrenia demonstrated a profound increase in short-term memory, while the non-exercising patients with schizophrenia demonstrated a reduction. In addition to proving beneficial for memory function, the exercise paradigm improved schizophrenic symptomology. The non-exercising patients with schizophrenia experienced a worsening of their symptomology.

Physical exercise regimens may improve neurological health in schizophrenic patients
Taken together, these interesting findings indicate that, as with healthy control individuals, the incredibly complex endogenous response mechanism to the strains of exercise is intact and functional in patients with schizophrenia. This excellent news will potentially allow the use of this simple therapeutic paradigm to treat patients with schizophrenia and those with other neurological disorders.

There are likely to be multiple mechanisms by which physical exercise can be translated into improved neurological health. These may include enhanced stress responses, elevation of neurotrophic agents such as brain-derived neurotrophic factor or insulin-like growth factor-1, improvement of cellular metabolism, and angiogenesis. Considerable research has demonstrated that many of these factors are implicated, but in truth the effects of exercise are likely due to a complex interaction of all these factors. It is excellent news that patients with schizophrenia still possess this ability to benefit from the effects of exercise upon the central nervous system.

Potential of pharmacotherapeutics that can mimic exercise
One caveat in this story is familiar to everyone: exercise is a “medicine” that not everyone wants to take. If physical activity were considered a pharmacotherapeutic, it would possess one of the worst compliance rates of any drug. If we could start to understand the endogenous exercise translating mechanisms, we may be able to shortcut the need for many hours at the gym and tap into these mechanisms to enhance the actions of a short jog to those only previously generated by weeks of training (Stranahan et al., 2009).

Even with the potential ability to mimic the effects of exercise, we must remember that these effects do not happen in a simple linear manner. The effects of training are generated by the complex interaction of tens or hundreds of individual factors; if we can start to understand such an intricate interplay between our physiology at rest and during exercise, we may eventually be able to therapeutically exploit this evolutionarily conserved benefit of exercise.

References:

Boyke J, Driemeyer J, Gaser C, Büchel C, May A. Training-induced brain structure changes in the elderly. J Neurosci. 2008 Jul 9;28(28):7031-5. Abstract

Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wójcicki TR, McAuley E, Kramer AF. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009 Oct;19(10):1030-9. Abstract

Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5638-43. Epub 2007 Mar 20. Abstract

Colcombe SJ, Erickson KI, Scalf, PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61:1166-70. Abstract

Vaynman S, Gomez-Pinilla F. Revenge of the "sit": how lifestyle impacts neuronal and cognitive health though molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res. 2006;84:699–715. Abstract

Karp A, Paillard-Borg S, Wang HX, Silverstein M, Winblad B, Fratiglioni L. Mental, physical, and social components in leisure activities equally contribute to decrease dementia risk. Dement Geriat Cogn Disord. 2006;21:65–73. Abstract

Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287:742–8. Abstract

Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A, Krueger K, Fromme A, Korsukewitz C, Floel A, Knecht S. High impact running improves learning. Neurobiol Learn Mem. 2007;87:597-609. Abstract

Maudsley S, Martin B, Luttrell LM. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Curr Alzheimer Res. 2007 Feb;4(1):3-19. Abstract

Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006 May;11(5):514-22. Abstract

Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: changes in grey matter induced by training. Nature. 2004 Jan 22;427(6972):311-2. Abstract

Stranahan AM, Zhou Y, Martin B, Maudsley S. Pharmacomimetics of exercise: novel approaches for hippocampally-targeted neuroprotective agents. Curr Med Chem. 2009;16(35):4668-78. Abstract

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Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Anthony Hannan
Submitted 19 February 2010
Posted 19 February 2010
  I recommend the Primary Papers

These important new papers (Amminger et al., 2010; Pajonk et al., 2010) suggest interesting approaches for delaying/preventing onset of, and treating, schizophrenia. As the interventions, and cohorts, are very different, it is likely the therapeutic mechanisms are distinct; however, in both cases neurobiological insights may be provided by animal models.

The exercise study (Pajonk et al., 2010) is supported by experimental studies involving environmental manipulations of animal models, which may provide some insight into underlying mechanisms. There is prior evidence, in a knockout mouse model of schizophrenia exhibiting predictive validity, that environmental enrichment (which enhances mental/physical activity levels) from adolescence onwards can ameliorate schizophrenia-like endophenotypes (McOmish et al., 2008). While this model does exhibit hippocampal dysfunction, these mutant mice are also known to have abnormal activity-dependent synapse formation and/or elimination in the postnatal neocortex (Spires et al., 2005), and, therefore, the enhanced mental and physical activity may be inducing its beneficial effects via additional areas outside the hippocampus. In another mouse model of schizophrenia, with a mutation in the neuregulin-1 gene, a minimal form of environmental enrichment provided throughout development can also modulate specific behavioral endophenotypes (Karl et al., 2007).

Environmental enrichment provides opportunities for enhanced sensory, cognitive, and motor activity (exercise), and has been shown to induce beneficial effects in various animal models of neurological and psychiatric disorders (reviewed by Laviola et al., 2008; Sale et al., 2009). Increased physical activity alone has a range of effects, at molecular, cellular, and systems levels, on brain function and cognition (reviewed by Cotman et al., 2007; Hillman et al., 2008). While Pajonk et al. (2010) have identified the hippocampus as a region of interest, enhanced exercise clearly has the potential to induce beneficial effects via additional systems outside the hippocampus. One key aspect of applying these environmental interventions in valid animal models is that we might identify the molecular/cellular mechanisms mediating the beneficial effects, and thus pave the way for the development and optimization of new therapeutic approaches.

References:

Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain Ω-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54. Abstract

Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007 Sep;30(9):464-72. Abstract

Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008 Jan;9(1):58-65. Abstract

Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav. 2007 Oct;6(7):677-87. Abstract

Laviola G, Hannan AJ, Macrì S, Solinas M, Jaber M. Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis. 2008 Aug;31(2):159-68. Abstract

McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Phospholipase C-beta1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol Psychiatry. 2008 Jul;13(7):661-72. Abstract

Pajonk F-G, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Müller S, Oest M, Meyer T, Backens M, Schneider-Axmann T, Thornton AE, Honer WG, Falkai P. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010 Feb;67(2):133-43. Abstract

Sale A, Berardi N, Maffei L. Enrich the environment to empower the brain. Trends Neurosci. 2009 Apr;32(4):233-9. Abstract

Spires TL, Molnár Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ. Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb Cortex. 2005 Apr;15(4):385-93. Abstract

View all comments by Anthony Hannan

Related News: Attenuated Psychotic Symptoms: Risky, But Not Predictive of Psychosis

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 8 March 2012
Posted 8 March 2012

Werbeloff et al. make a valuable contribution with an epidemiological cohort that permits estimates of self-reported attenuated psychosis-like experiences as a risk factor for a future psychotic disorder in the non-ill population. The possibility that attenuated psychosis syndrome would be included in DSM-5 has created an intense and interesting debate. Jim van Os and I, both members of the responsible DSM-5 Work Group, provided an update on the controversy last year (Carpenter and van Os, 2011), and I have offered a rebuttal to some of the objections elsewhere (Carpenter, 2011). As this is a work in progress, I will briefly state where we are, at the moment, in the DSM-5 process.



References:

Carpenter WT and van Os J. Should Attenuated Psychosis Syndrome Be a DSM-5 Diagnosis? Am J Psychiatry 2011 168: 460-463. Abstract

Carpenter Jr. WT. Criticism of the DSM-V risk syndrome: A rebuttal. Cognitive Neuropsychiatry, 16(2):101-106, 2011. Abstract

Fusar-Poli P, Bonoldi I, Yung AR, Borgwardt S, Kempton MJ, Valmaggia L, Barale F, Caverzasi E, McGuire P. Predicting Psychosis: Meta-analysis of Transition Outcomes in Individuals at High Clinical Risk. Arch Gen Psychiatry. 2012; 69(3);220-229. Abstract

View all comments by William Carpenter

Related News: Attenuated Psychotic Symptoms: Risky, But Not Predictive of Psychosis

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 9 March 2012
Posted 9 March 2012

Editor's note: This is an addendum to Will Carpenter's previous comment above.

Jim van Os and colleagues now report on transition to psychosis from a non-clinical population sample. Transition rates are elevated for those with psychotic-like experiences, and persistence of these experiences increases risk for transition. Rates are substantially higher than the representative population without psychotic experiences, but much lower than clinical referral populations reported in studies to date.

References:

Kaymaz N, Drukker M, Lieb R, Wittchen HU, Werbeloff N, Weiser M, Lataster T, van Os J. Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results. Psychol Med. 2012 Jan 20;1-15. Abstract

View all comments by William Carpenter

Related News: What Can Hearing Loss Tell Us About Social Defeat, Dopamine Sensitization, and Schizophrenia?

Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 13 October 2014
Posted 13 October 2014

This is a study in a cohort of hearing impaired subjects thought to be at risk for psychosis, compared to healthy volunteers. There are two findings of interest: 1) increased amphetamine-induced dopamine (DA) release, and 2) lack of a relationship between DA release and the reported increase in psychotic-like symptoms after amphetamine, although the nature of these symptoms and their magnitude are not clear, and whether they qualify as psychotic is also unclear.

Nevertheless, if we assume that patients indeed exhibited psychosis after amphetamine, the paradox of measuring increased DA, psychosis, and yet no relationship between these two measures is worth discussing. The authors suggest factors that may have prevented detection of this relationship, including a selection bias resulting in a cohort with minor impairment, limited sensitivity of the scale used, or lack of power.

We (Abi-Dargham et al., 2003) and others (Volkow et al., 1999) have previously shown that higher levels of DA release in healthy volunteers who do not exhibit psychosis correlate strongly with the subjective effects of stimulants. In these subjects, larger DA release does not translate into psychosis. We also have shown that lower DA release per se does not protect against psychosis, as patients who are comorbid for schizophrenia and addiction showed a psychotic response associated with the magnitude of amphetamine-induced DA release despite lower levels of DA release than those measured in controls (Thompson et al., 2013). These data suggest a complicated picture that goes beyond DA levels, where absolute levels of DA per se are not psychotogenic; rather, the interaction between D2 and DA is psychotogenic, and raises the possibility that a state of "supersensitivity" or "altered sensitivity" of D2 receptors to DA is a necessary requirement for psychosis, and this sensitivity relates to the emergence or exacerbation of psychosis.

We do not fully understand the cellular or circuit level effects of D2 stimulation that lead to psychosis, although it is clear now that excess striatal D2 stimulation during development can alter connectivity (Cazorla et al., 2014) as well as reward and cognitive functions (Simpson et al., 2010), and that D2 signaling plays a major role in long-term potentiation and synaptic plasticity in the frontal cortex (Xu and Yao, 2010). Recent genomewide association studies (GWAS) analyses have confirmed the relevance of the D2 receptor (Schizophrenia Working Group of the Psychiatric Genomics, 2014). It is important that we elucidate the intermediate steps leading from altered D2 function to the final phenotype of psychosis or schizophrenia, and its association with dysregulated dopamine.

References:

Abi-Dargham A, Kegeles LS, Martinez D, Innis RB, Laruelle M. Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naïve healthy volunteers: results from a large cohort. Eur Neuropsychopharmacol . 2003 Dec ; 13(6):459-68. Abstract

Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, Ahmari SE, Moore H, Kellendonk C. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron . 2014 Jan 8 ; 81(1):153-64. Abstract

Schizophrenia Working Group of the Psychiatric Genomics. Biological insights from 108 schizophrenia-associated genetic loci. Nature . 2014 Jul 24 ; 511(7510):421-7. Abstract

Simpson EH, Kellendonk C, Kandel E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron . 2010 Mar 11 ; 65(5):585-96. Abstract

Thompson JL, Urban N, Slifstein M, Xu X, Kegeles LS, Girgis RR, Beckerman Y, Harkavy-Friedman JM, Gil R, Abi-Dargham A. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry . 2013 Aug ; 18(8):909-15. Abstract

Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Wong C, Hitzemann R, Pappas NR. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther . 1999 Oct ; 291(1):409-15. Abstract

Xu TX, Yao WD. D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex. Proc Natl Acad Sci U S A . 2010 Sep 14 ; 107(37):16366-71. Abstract

View all comments by Anissa Abi-Dargham

Related News: What Can Hearing Loss Tell Us About Social Defeat, Dopamine Sensitization, and Schizophrenia?

Comment by:  Ceren AkdenizAndreas Meyer-Lindenberg
Submitted 15 October 2014
Posted 15 October 2014
  I recommend the Primary Papers

Social defeat is defined as an "outsider status" (Selten and Cantor-Graae, 2005), or the experience of being excluded which is characterized by a subordinate position, stress, and isolation (Selten et al., 2013). Selten and coworkers have proposed that social defeat underlies several environmental risk factors for psychosis such as urbanicity and migration, and contributes to the impact of drug abuse and low intelligence (Selten et al., 2013). Even though the individual risk and resilience equation is complex and involves multiple levels on both the biological (such as genetics and epigenetics) and social environmental aspects (such as family and social network characteristics) (van Os et al., 2008; Akdeniz et al., 2014), perceived social threat, perceived discrimination, and low social status may plausibly result in a status of social defeat. This may lead to psychosis through dopaminergic hyperactivity in the corticolimbic system, which was previously shown in animal models of schizophrenia (Selten and Cantor-Graae, 2005; Selten et al., 2013; Tidey and Miczek, 1996). Yet before this paper, experimental evidence of dopamine sensitization in a socially excluded group of people was scarce.

The study by Martin Gevonden and colleagues addresses this by investigating the relationship between endogenous dopamine release after exposure to dexamphetamine sulfate and social exclusion in minorities (Gevonden et al., 2014). In their study, they selected a group of participants with severe hearing impairment (SHI) as "socially excluded minorities." Hearing impairment is a risk factor for psychotic experiences (Stefanis et al., 2006; van der Werf et al., 2010; Fors et al., 2013), which could be explained due to feelings of social exclusion and social defeat (Selten et al., 2013; Gevonden et al., 2014). They used single-photon emission computed tomography (SPECT) to examine the link between the dopaminergic activity, social exclusion, and amphetamine-induced psychotic symptoms. As they hypothesized, the participants with severe hearing impairment reported higher levels of loneliness and social defeat, and showed higher amphetamine-induced striatal dopamine release, along with stronger emotional responses to amphetamine. Even though the researchers did not find a relationship among social exclusion scores, changes in psychotic symptoms, and dopamine release per se, their findings offer a substantial step forward in being one of the first experimental studies showing a sensitized dopamine system in a population with increased risk for psychosis.

This observation fits well with experimental data on the neural processing of social stress in at-risk populations (Lederbogen et al., 2011; Akdeniz et al., 2014). These studies indicate that healthy individuals living in urban environments, as well as ethnic minorities with no history of psychiatric disorders, exhibit an alteration in neural functioning of the anterior cingulate cortex (ACC) during social stress (Lederbogen et al., 2011; Akdeniz et al., 2014). Taken together, these studies begin to establish a framework for a final common pathway for the development of psychosis related to environmental risk (Akdeniz et al., 2014). In this theoretical framework, schizophrenia risk resulting from an interaction of early stress and genetic risk factors may ultimately yield sensitization in the dopaminergic system and increased subcortical dopamine release through dysregulation of stress-sensitive regions of the cortex such as ACC.

Of course, much work remains to be done. In humans, it is hard to prove a causal relationship among social exclusion/social defeat, dopamine functioning, and increased risk for psychosis. Nevertheless, the work of Gevonden and colleagues elegantly shows that the study of high-risk populations such as minorities using experimental paradigms in order to investigate the neural underpinnings of the development of psychosis is highly promising.

References:

Selten JP, Cantor-Graae E. Social defeat: risk factor for schizophrenia? The British journal of psychiatry: the journal of mental science Aug 2005;187:101-102. Abstract

Selten JP, van der Ven E, Rutten BP, Cantor-Graae E. The social defeat hypothesis of schizophrenia: an update. Schizophrenia bulletin Nov 2013;39(6):1180-1186. Abstract

van Os J, Rutten BP, Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophrenia bulletin Nov 2008;34(6):1066-1082. Abstract

Akdeniz C, Tost H, Meyer-Lindenberg A. The neurobiology of social environmental risk for schizophrenia: an evolving research field. Social psychiatry and psychiatric epidemiology Apr 2014;49(4):507-517. Abstract

Tidey JW, Miczek KA. Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain research May 20 1996;721(1-2):140-149. Abstract

Gevonden M, Booij J, van den Brink W, Heijtel D, van Os J, Selten JP. Increased Release of Dopamine in the Striata of Young Adults With Hearing Impairment and Its Relevance for the Social Defeat Hypothesis of Schizophrenia. JAMA psychiatry Oct 1 2014. Abstract

Stefanis N, Thewissen V, Bakoula C, van Os J, Myin-Germeys I. Hearing impairment and psychosis: a replication in a cohort of young adults. Schizophrenia research Jul 2006;85(1-3):266-272. Abstract

van der Werf M, van Winkel R, van Boxtel M, van Os J. Evidence that the impact of hearing impairment on psychosis risk is moderated by the level of complexity of the social environment. Schizophrenia research Sep 2010;122(1-3):193-198. Abstract

Fors A, Abel KM, Wicks S, Magnusson C, Dalman C. Hearing and speech impairment at age 4 and risk of later non-affective psychosis. Psychol Med Oct 2013;43(10):2067-2076. Abstract

Lederbogen F, Kirsch P, Haddad L, Streit F, Tost H, Schuch P, Wüst S, Pruessner JC, Rietschel M, Deuschle M, Meyer-Lindenberg A. City living and urban upbringing affect neural social stress processing in humans. Nature . 2011 Jun 23 ; 474(7352):498-501. Abstract

Akdeniz C, Tost H, Streit F, Haddad L, Wüst S, Schäfer A, Schneider M, Rietschel M, Kirsch P, Meyer-Lindenberg A. Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk. JAMA Psychiatry . 2014 Jun ; 71(6):672-80. Abstract

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