Does a Presynaptic Dopamine Surplus Cause Psychosis?
12 April 2012. A meta-analysis of dopamine imaging studies in schizophrenia reports elevated presynaptic dopamine function. By contrast, no change in dopamine transporter activity and a small, antipsychotic-dependent increase in dopamine 2/3 (D2/3) receptor availability were found. The study, published online April 2 in the Archives of General Psychiatry, suggests that future antipsychotic drugs might target the presynaptic regulation of dopamine synthesis and release, rather than block D2 receptors, as most current drugs do.
The dopamine hypothesis is schizophrenia’s most venerable (see SRF Hypothesis), and was initially based on the observation that antipsychotic drugs are dopamine antagonists. The hypothesis posits that hyperactive dopamine signaling in subcortical brain regions is responsible for the positive symptoms of the illness, and has been bolstered by findings of increased striatal D2/3 receptor density and dopamine in postmortem tissue (Mackay et al., 1982), and elevations in cerebrospinal fluid (CSF) dopamine levels (Widerlöv et al., 1988). Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies have enabled the in-vivo measurement of dopamine function in the illness, and the large number of these studies affords the opportunity for meta-analysis.
Probing dopamine function
Led by Oliver Howes of King’s College London, U.K., researchers in the current study combed databases for PET and SPECT dopaminergic imaging studies published between 1960 and 2011. The researchers limited their meta-analysis to studies of striatal dopamine function, since this region can be reliably imaged and is where dopamine dysfunction in schizophrenia has been linked to illness onset, symptom severity, and treatment response (Laruelle et al., 1999). Howes and colleagues analyzed different aspects of dopaminergic function in schizophrenia using three separate meta-analyses measuring: 1) presynaptic function (including dopamine synthesis capacity, dopamine release, and synaptic dopamine levels); 2) dopamine transporter availability; and 3) D2/3 receptor availability.
A total of 17 studies examining 231 patients and 251 control subjects were included in the meta-analysis of presynaptic dopamine function, which found a significant elevation with a large effect size in schizophrenia subjects. Importantly, this effect does not seem to be mediated by antipsychotics, as a similar result was obtained after exclusion of medicated subjects. This elevation is likely due to a functional change in dopamine synthesis and release, rather than a change in axon terminal or neuron number, since there is no evidence that dopamine terminal density and neuron number are altered in schizophrenia (Taylor et al., 2000; Bogerts et al., 1983).
By contrast, no significant difference was observed between the 152 schizophrenia subjects and 132 controls used in a second meta-analysis of dopamine transporter availability. This finding persisted when antipsychotic-treated subjects were excluded. Unlike the analysis of presynaptic dopaminergic functioning, moderate to large heterogeneity between studies was observed, likely due to differences in the radiotracers utilized across studies.
The largest sample size (337 patients and 324 controls) was available to examine D2/3 receptor availability, and a significant elevation was observed. However, the effect size was much smaller than for presynaptic dopamine function, and appeared to be due to antipsychotic treatment, as no difference was seen between control antipsychotic-free schizophrenia subjects. Moreover, moderate to large heterogeneity between studies was present, and in over half of the iterations of a leave-one-out analysis, there was no difference between patients and controls, indicating that the difference was not robust.
Overall, the results of this in-vivo meta-analysis support the dopamine hypothesis of schizophrenia, and point to a specific abnormality in presynaptic dopamine function. Interestingly, this effect appears to be specific to schizophrenia, as alterations are not observed in non-psychotic affective and anxiety disorders (Howes et al., 2007). Howes and colleagues also examined subregions of the striatum, finding that presynaptic function was elevated in the putamen but not the caudate. Neither dopamine transporter nor D2/3 receptor availability was altered in either subregion alone. More work will be needed to address whether the presynaptic alterations are also present in other brain regions besides the striatum.
Implications for treatment
Since all current antipsychotics block D2 receptors, the results of the present study suggest that these treatments are acting downstream of the major dopamine abnormality, and thus that new drugs should target presynaptic dopamine synthesis and release. Interestingly, reserpine and α-methylparatyrosine, drugs that reduce presynaptic dopamine levels, can ameliorate psychotic symptoms (Hollister et al., 1955; Abi-Dargham et al., 2000), suggesting that this mechanism may be useful in schizophrenia.
However, as noted by the authors, several challenges with this treatment strategy remain. For example, given that part of the synthetic pathway for dopamine overlaps with that of norepinephrine, altering dopamine synthesis may create adverse side effects from abnormal norepinephrine signaling. Moreover, regional specificity of the drug target may be necessary to avoid worsening the negative and cognitive symptoms that are thought to result, in part, from alterations in frontal dopamine function through D1 receptors (see SRF related news story).—Allison A. Curley.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies. Arch Gen Psychiatry. 2012 Apr 2. Abstract
Comments on News and Primary Papers
Primary Papers: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.Comment by: Bryan Roth
Submitted 18 April 2012
Posted 18 April 2012
The dopamine hypothesis of schizophrenia, in various guises, has captivated the attention of, literally, a large army of psychiatric researchers for nearly 50 years (see, e.g., Carlsson and Lindqvist, 1963). Indeed, a PubMed search of the terms "schizophrenia" and "dopamine" elicits nearly 7,000 articles. Further, every approved antipsychotic drug modulates D2-dopamine receptors and—with the exception of aripiprazole, which is a functionally selective D2 agonist—is a D2 antagonist. Finally, despite nearly three decades of research and billions of dollars spent by the pharmaceutical industry, no drug that does not interact with D2 dopamine receptors has proven to be any more effective than haloperidol for non-treatment-resistant schizophrenia.
Despite this focused research on dopamine, dopamine receptors, and schizophrenia, no clear consensus has emerged regarding whether schizophrenia is associated with excessive dopaminergic neurotransmission. As succinctly stated many years ago:
“The dopamine hypothesis of schizophrenia is by definition supported by no direct evidence. No one has found anything conclusively abnormal about dopamine (DA) in body fluids or brains of schizophrenics….” (Snyder, 1976) (italics mine)
Now, Howes and colleagues provide a nice meta-analytic study and attempt to address this issue conclusively as well as make suggestions for treatment. Briefly, they find that individuals with schizophrenia have a significant enhancement of what they interpret to be presynaptic dopaminergic function. A much smaller increase in D2-dopamine receptors was also reported. Not being a statistician, I cannot comment on the validity of the approach or the conclusions, though I will provide a perspective on what this might mean for drug discovery with the assumption that their results are correct.
What does it mean for drug discovery if there is excessive presynaptic dopamine activity in schizophrenia?
In the paper the authors discuss the potential of presynaptic D2 agonists, selective inhibitors of dopamine synthesis, and the use of dopamine-depleting drugs like reserpine. All of these approaches have been attempted with varying degrees of success, though since all catecholamines share the same biosynthetic pathway it will be essentially impossible to selectively inhibit dopamine synthesis without altering the synthesis of norepinephrine and epinephrine. As well, neither selective targeting of presynaptic D2 receptors nor selective depletion of dopamine is likely to be a pharmacologically viable option.
An alternative approach might be to target receptors that regulate dopamine release presynaptically. Thus, drugs that inhibit the release of dopamine might be salutary for schizophrenia. A quick literature search reveals, however, that several failed drug classes had as their raison d’être inhibition of presynaptic dopamine release, including:
Although I list only these three classes of compounds (each of which is directed at a different molecular target implicated in regulating presynaptic dopamine release) there are likely many others in the public and private domains.
What I believe this means is that it is possible to create drugs which inhibit presynaptic dopamine release, but that the jury is still out as to whether these will offer any substantial advantage over drugs which target postsynaptic D2 signaling.
Carlsson A, Lindqvist M. Effect of chloropromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) . 1963 Jan 1 ; 20():140-4. Abstract
Gewirtz GR, Gorman JM, Volavka J, Macaluso J, Gribkoff G, Taylor DP, Borison R. BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology. 1994 Feb;10(1):37-40. Abstract
Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther. 1995 Jul;274(1):329-36. Abstract
Snyder SH. The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor. Am J Psychiatry. 1976 February; 133(2):197-202. Abstract
Spooren W, Riemer C, Meltzer H. Opinion: NK3 receptor antagonists: the next generation of antipsychotics? Nat Rev Drug Discov . 2005 Dec ; 4(12):967-75. Abstract
View all comments by Bryan Roth
Primary Papers: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
Comment by: Christoph Kellendonk
Submitted 18 April 2012
Posted 18 April 2012
The meta-analysis by Howes et al. once more confirms that there are abnormalities in the dopamine system in the striatum of patients with schizophrenia.
What is new is recent evidence about the location of the dopaminergic hyperfunction. Several high-resolution imaging studies performed in the last few years suggest it to be located in the head of the caudate rather than the ventral striatum. The head of the caudate receives projections from the dorsolateral prefrontal cortex, an area important for the cognitive symptoms of schizophrenia. These new findings contradict the widely accepted hypothesis that the dopaminergic hyperfunction in the striatum is mainly in the ventral or “limbic” striatum.
Another interesting new finding is that the abnormalities in the striatal dopamine system are already present in prodromal subjects. They therefore may occur early in the disease process and could be of primary origin. Obviously, to really understand the etiology of the disorder we would have to image the dopamine system at even earlier developmental stages—something that, due to practical and ethical reasons, is not currently possible.
View all comments by Christoph Kellendonk
Comments on Related News
Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?Comment by: Michael J. Frank
Submitted 19 February 2009
Posted 19 February 2009
McNab and colleagues provide groundbreaking evidence showing that cognitive training with working memory tasks over a five-week period impacts D1 dopamine receptor availability in prefrontal cortex. Links between prefrontal D1 receptor function and working memory are often thought to be one-directional, i.e., that better D1 function supports better working memory, but here the authors show that working memory practice reciprocally affects D1 receptors.
An influential body of empirical and theoretical research suggests that an optimal level of prefrontal D1 receptor stimulation is required for working memory function (e.g., Seemans and Yang, 2004).
Because acute pharmacological targeting of prefrontal D1 receptors reliably alters working memory, causal directionality from D1 to working memory remains evident. Nevertheless, these findings cast several other studies in a new light. Namely, when a population exhibits impaired (or enhanced) working memory and PET studies indicate differences in dopaminergic function, it is no longer clear which variable is the main driving factor. For example, those who engage in cognitively demanding tasks on a day-to-day basis may show better working memory and dopaminergic correlates may be reactive rather than causal. Finally, the possibility cannot be completely discounted that the observed changes in D1 receptor binding may reflect a learned increase in prefrontal dopamine release; this would explain the general tendency for D1 receptor availability to decrease with cognitive training, due to competition with endogenous dopamine.
The McNab study also finds that only cortical D1 receptors, and not subcortical D2 receptors, were altered by cognitive training. The significance of this null effect of D2 receptors is not yet clear.
First, all tasks used in the training study involved recalling the ordering of a sequence of stimuli and repeating them back when probed.
While clearly taxing working memory, these tasks did not require subjects to attend to some stimuli while ignoring other distracting stimuli, and did not require working memory manipulation. Both manipulation and updating are characteristics of many working memory tasks, particularly those that depend on and/or activate the basal ganglia. Indeed, previous work by the same group (McNab and Klingberg,
2008) showed that basal ganglia activity is predictive of the ability to filter out irrelevant information from working memory. Similarly, Dahlin et al. (2008) reported that training on tasks involving working memory updating leads to generalized enhanced performance in other working memory tasks, and that this transfer of learned knowledge is predicted by striatal activity. These results are consistent with computational models suggesting that the basal ganglia act as a gate to determine when and when not to update prefrontal working memory representations and are highly plastic as a function of reinforcement. Thus, future research is needed to test whether training on filtering, updating, or manipulation tasks leads to changes in striatal D2 receptor function.
McNab, F. and Klingberg, T. (2008). Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience, 11, 103-107. Abstract
Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L. & Nyberg, L. (2008).
Transfer of learning after updating training mediated by the striatum.
Science, 320, 1510-1512. Abstract
Seamans, J.K. and Yang, C.R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1-57. Abstract
View all comments by Michael J. Frank
Related News: Cognition and Dopamine—D1 Receptors a Damper on Working Memory?
Comment by: Terry Goldberg
Submitted 3 March 2009
Posted 3 March 2009
This is an important article that describes profound changes in the dopamine D1 receptor binding potential after working memory training in healthy male controls. The study rests on prior work that has demonstrated changes in brain volume with practice (e.g., Draganski and May, 2008), and dopamine can be released at the synapse in measurable amounts even during, dare I say, fairly trivial activities (e.g., playing a video game (Koepp et al., 1998). The present study demonstrated that binding potential of D1 receptors decreased in cortical regions (right ventrolateral frontal, right dorsolateral PFC, and posterior cortices) with training, and the magnitude of this decrease correlated with the improvement during training. Binding potential of D2 receptors in the striatum did not change. Unfortunately, D2 receptors in the cortex could not be measured with raclopride.
Two points come to mind. One is theoretical—how long would such a change remain, i.e., is it transient or is it fixed? This has implications for understanding practice-related phenomena and their transfer or consolidation. The second is technical. A number of studies have shown that practice can change not only the magnitude of a physiologic response, but also its location (see Kelly and Garavan for a review, 2005). Thus, the circuitry involved in learning a task may be different than the circuitry involved in implementing a task after it is well learned. By constraining areas to those activated in fMRI during initial working memory engagement, it is possible that other critical areas were not monitored for binding potential changes.
Draganski B, May A. Training-induced structural changes in the adult human brain. Behav Brain Res . 2008 Sep 1 ; 192(1):137-42. Abstract
Kelly AM, Garavan H. Human functional neuroimaging of brain changes associated with practice. Cereb Cortex . 2005 Aug 1 ; 15(8):1089-102. Abstract
Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature . 1998 May 21 ; 393(6682):266-8. Abstract
View all comments by Terry Goldberg
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.
Abi-Dargham A, Kegeles LS, Martinez D, Innis RB, Laruelle M. Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naÃƒÆ’Ã†â€™Ãƒâ€ Ã¢â‚¬â„¢ÃƒÆ’Ã¢â‚¬Å¡Ãƒâ€šÃ‚Â¯ve 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 Akdeniz, Andreas 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.
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, WÃƒÂ¼st 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, WÃƒÂ¼st S, SchÃƒÂ¤fer 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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