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SIRS 2012—The Interactive, the Progressive, and the Hippocampal

30 May 2012. At the closing session of the Schizophrenia International Research Society meeting on Wednesday afternoon in Florence, Italy, the society's president, Robin Murray of King’s College London, United Kingdom, pronounced, “I just loved this conference.” From the audience, Cynthia Shannon-Weickert of the University of New South Wales, Sydney, Australia, echoed this, calling it “the best SIRS meeting ever.” Not that the participants didn't have suggestions for improvement: one audience member mentioned a lack of emphasis on postmortem work at the meeting, but others countered that it was represented, just not as cohesively in the same sessions as in the past. About half of the audience consisted of graduate students, and one suggested a graduate student-specific activity at SIRS 2014 (also scheduled for Florence) that might nurture the large-scale collaborations that will surely be a mainstay of their future research.

Here, SRF brings you a sampling of other conference news, including gene-environment interactions contributing to schizophrenia risk, evidence for brain changes in the disorder, and mechanistic models of psychosis.

GxE = ?
In his plenary talk on Monday, Robin Murray ventured into the complicated topic of gene-environment interactions in psychosis. Ranking cannabis use as one of the best environmental leads, Murray reviewed the evidence for an interaction with catechol-O-methyltransferase (COMT), a gene whose protein regulates catecholamine levels, including dopamine. “So far, it’s not very encouraging,” he said, noting that the initial positive study in 2005 has not since been reliably replicated. However, a new possibility has turned up in the form of AKT1, a workhorse protein kinase, and single-nucleotide polymorphisms (SNPs) in the gene encoding it have, when combined with cannabis use, been found to increase risk for psychotic disorders (van Winkel et al., 2011). Murray reported a similar increase in risk for psychosis in a case-control study of 491 first-episode psychosis patients and 280 controls. Among those who used cannabis every day, the odds ratio jumped from two to seven. Murray noted that AKT1 lies downstream from both the cannabinoid receptor and the D2 subtype of the dopamine receptor, presenting a plausible mechanism for its involvement in the overactive dopamine signaling associated with psychosis. He cited the need to look toward gene-environment methods honed to study cancer, which can deal with thousands of genes at a time. “We are just beginning to bite into the edges of this,” Murray said.

How people react to their environment may influence their risk for developing a psychotic disorder. Inez Myin-Germeys followed with a plenary talk about the experience sampling method, in which people document their moods multiple times a day, in an effort to help define “reactive phenotypes.” She finds that how a person reacts to stress is associated with the well-known COMT Val158Met allele that influences dopamine levels in the synapse: negative reactions to stress were associated with the Met/Met genotype, but only among those with a psychotic disorder (Collip et al., 2011). Myin-Germeys also reported new data showing that this association between negative responses to stress and the Met/Met genotype was found in a stress task adapted for brain imaging among 14 subjects at genetic risk for psychosis. Subjects with the Met/Met genotype had the lowest increase in dopamine signaling in the prefrontal cortex, compared to the Val/Met or Val/Val genotypes.

Tracking brain changes
In a packed session about progressive brain change in psychosis on Sunday afternoon, Matthew Kempton of King’s College London, United Kingdom, reported his findings from a meta-analysis of antipsychotic-naïve people with schizophrenia. Brain imaging studies turn up evidence for progressive brain tissue loss in the disorder, but the nature of the link remains debated: does the shrinkage drive the disease, or does it reflect use of antipsychotic medications, or lifestyle (see SRF related news story)? To try to get around these confounds, Kempton rounded up 58 studies of antipsychotic-naïve people with schizophrenia, and focused on regions of interest measured in three or more studies. Compared to controls, the schizophrenia subjects showed significantly smaller total brain volumes, as well as gray matter and white matter volumes. More specifically, the caudate, thalamus, and hippocampus were each significantly smaller than in controls, consistent with the idea that reduced brain volumes were related to disease, rather than medication.

Kempton also reported a similar pattern of reductions (compared to controls) in first-episode patients who had been treated with antipsychotics, and in chronically ill patients. The average reduction did not differ among these three groups for total brain, gray matter, or hippocampus; however, the smaller caudate found in the antipsychotic-naïve group was not apparent in the first-episode or chronic group, which might indicate that the striatum could be particularly sensitive to antipsychotic medication. Kempton said that the length of untreated psychosis in these groups would be important to track, as it might influence the magnitude of the changes seen. Also, whether these reflect progressive changes afoot as the illness unfolds would best be explored in a longitudinal study—something Kempton said was just getting underway in a multicenter MRI study of people at high risk for psychosis.

In the same session, Neeltje van Haren of University Medical Center Utrecht, The Netherlands, reviewed her data for progressive brain changes associated with schizophrenia. Subdividing brain volume into its component area and thickness, van Haren has found that cortical thickness decreases over five years in schizophrenia (van Haren et al., 2011), but her preliminary data do not show a concomitant decrease in cortical surface area—though it was abnormally small at baseline. She suggested that surface area may reflect an aberrant neurodevelopmental program that is present before or at illness onset, whereas cortical thinning may emerge at illness onset and after.

The mechanics of psychosis
On Tuesday afternoon, Peter Woodruff of the University of Sheffield, United Kingdom, described his experiments probing the brain basis for auditory hallucinations by using healthy controls who experience these while falling asleep or waking up. Preliminary fMRI data show that the auditory cortex in this group has regions of enhanced sensitivity to sound, and that this might reflect altered top-down modulation of these areas by prefrontal cortex. Woodruff discussed these findings in light of the complex interplay between brain regions that predict and receive sensory input. When the brain erroneously identifies a predicted sound as an actual signal, auditory hallucinations might result (Nazimek et al., 2012).

A session sponsored by the International Congress on Schizophrenia Research (ICOSR) on Tuesday featured a systems neuroscience view. Anthony Grace of University of Pittsburgh, Pennsylvania, described his results from studies of the methyl-azoxymethanol acetate (MAM) model of schizophrenia, in which pregnant rats treated with MAM, a DNA methylating agent, give birth to offspring which exhibit a number of schizophrenia-esque abnormalities, including deficits in pre-pulse inhibition, reversal learning, social interaction, and increased locomotor response to amphetamine, suggestive of overactive dopamine signaling (see Grace lecture at the 2008 Society for Neuroscience meeting). In the brains of these rats, Grace finds a noisier hippocampus, with more spontaneously active neurons than that found in controls; this is accompanied by decreases in a kind of interneuron there, too, which suggests that their ability to dampen activity in the hippocampus is compromised. Because hippocampal hyperactivity trickles through the neural circuit to increase dopamine neuron activity, restoring the inhibitory action of these interneurons might help. Indeed, he finds that a drug that selectively potentiates a subtype of GABA receptor found in the hippocampus settles activity there to control levels, and also tempered the dopamine-dependent hyperlocomotion induced by amphetamine (Gill et al., 2011).

Grace presented new results showing that these MAM-treated rats were more sensitive to stress: they made more distress calls when given a foot shock, and they show abnormally high levels of cortisol, a stress hormone, compared to controls. Because cortisol can damage the hippocampus, Grace suggested that keeping stress levels in check may protect the hippocampus, and, consistent with this, he reported that MAM-rats given diazepam before and during puberty did not exhibit hyperlocomotion induced by amphetamine. He suggested that anything that helps control stress may help ward off transition to psychosis in humans.

Continuing with the hippocampal theme, Carol Tamminga of University of Texas Southwestern Medical School in Dallas presented a model for psychosis based on regional alterations in glutamate signaling within the hippocampus (Tamminga et al., 2012). In schizophrenia, imaging studies find increased baseline activity in the hippocampus, and postmortem studies find decreased levels of the GluN1 subunit of the NMDA receptor in the dentate gyrus subregion of the hippocampus. Tamminga hypothesized that a decrease in glutamate signaling within the dentate gyrus could lead to increased activity within its target, the CA3 subregion, through homeostatic plasticity. This would increase synaptic strength between the dentate gyrus and CA3, and Tamminga reported preliminary evidence for this in the form of increased BDNF mRNA and more dendritic spines in CA3 neurons in postmortem tissue in schizophrenia. An increase in sensitivity to input could render CA3, a region responsible for completing memories based on isolated features of that memory, prone to making spurious associations and generating the false content of psychosis. To test this model, Tamminga is developing transgenic mice with a “molecular lesion” of decreased GluN1 levels specific to the dentate gyrus.—Michele Solis.

Comments on Related News


Related News: Interpret With Care: Cortical Thinning in Schizophrenia

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 4 January 2012
Posted 4 January 2012

Plump Enough
Thanks for your thought-provoking review of structural MRI changes in schizophrenia. I had a couple of quick comments.

You make the statement that, "Though cortical thickness itself is below the resolution of typical MRI, image analysis algorithms can now infer thickness across the entire cortical sheet as it winds its way throughout the brain." I thought sMRI gathers information for about 2 mm cubed or so. So maybe the point to make is that cortex thickness is not below the resolution, but the putative change in thickness is below the resolution. It would be interesting to know if the putative change in cortical thickness in schizophrenia could be better viewed with 3T or 7T scanners.

Also, I wonder how to interpret decreases in volume over five years that seem to be as much as 5 percent in some areas. How long could this continue to be progressive at this rate, and what would be the final cortical volume expected in the final decade of life? For example, if the DLPFC BA46 is about 3,500 microns thick, then a 5 percent loss/five years over 20 years would leave you with about 2,850 microns, and that would be about a 20 percent decrease in thickness. While postmortem studies may be limited, as Karoly points out, certainly we know that the frontal cortex is still "plump enough" to define cyto-architecturally, and to examine at the histological level. We also consider that there is about a 10 percent loss in cortical thickness in people with schizophrenia. Certainly, the cortex does not degenerate completely as would be expected with relentless progression of loss and accumulated deterioration of cortical grey matter over time.

Thus, this is an interesting issue, but many questions remain. Is there a lot of case-to-case variability that underlies these averages such that some cases lose more cortical volume and some do not lose any at all? Could it be that, while there is cortical volume loss, there are some patients in whom this loss slows or even reverses naturally over the course of the disease? What is the physical substrate of such cortical volume loss in people with schizophrenia? Can we prevent cortical volume loss over time, and would this be beneficial to patient outcomes?

View all comments by Cynthia Shannon Weickert

Related News: Meta-Analysis Finds Antipsychotics Help Prevent Relapse in Schizophrenia

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 23 May 2012
Posted 23 May 2012

Since the John Davis meta-analysis in the 1970s (the second meta-analysis in medicine; see Davis, 1975), there is little doubt that drug beats placebo in relapse prevention. What is terrific here are the details on aspects of course that are addressed and more information on the risk side to complement benefit. I will comment on two findings. First, depot beats oral. Especially in the United States, we need to move depot into an attractive option and first-line approach (assuming oral administration of the same compound supports safety in the individual). Second, I have thought that there is little evidence for second-generation antipsychotics being superior to first-generation antipsychotics (clozapine excepted) in efficacy and effectiveness, and that the strongest case for second-generation antipsychotics was better relapse prevention. This meta-analysis failed to support this supposed advantage, and I have to adjust my view in this regard.

The van Os and Howes commentary merits a serious and thoughtful read. It gives emphasis to how early and modest the field is in discovery for the psychopharmacology of schizophrenia. In the 60 years since chlorpromazine, progress has been narrow, not very innovative, and not very robust.

References:

Davis JM. Overview: maintenance therapy in psychiatry: I. Schizophrenia. Am J Psychiatry . 1975 Dec ; 132(12):1237-45. Abstract

View all comments by William Carpenter

Related News: SIRS 2012—Psychological and Social Treatment for Schizophrenia

Comment by:  Lewis Kirshner
Submitted 18 June 2012
Posted 20 June 2012

The field seems to be cautiously returning to look seriously at psychotherapeutic approaches. Paying attention to forms of cognition and affect has been a traditional form of therapy, and it seems foolish to ignore the clinical experiences of its many practitioners, despite conceptual problems of past work. We also have the benefits of studies indicating the effects of trauma on subsequent psychosis and developmental research on attachment and language that may mediate early neglect or trauma. Problems in development of TOM in insecure attachment may point to specific vulnerabilities.

References:

Berry K, Barrowclough C, Wearden A. Attachment theory: a framework for understanding symptoms and interpersonal relationships in psychosis. Behav Res Ther . 2008 Dec ; 46(12):1275-82. Abstract

Fonagy P, Target M. Playing with reality: I. Theory of mind and the normal development of psychic reality. Int J Psychoanal . 1996 Apr ; 77 ( Pt 2)():217-33. Abstract

Heins M, Simons C, Lataster T, Pfeifer S, Versmissen D, Lardinois M, Marcelis M, Delespaul P, Krabbendam L, van Os J, Myin-Germeys I. Childhood trauma and psychosis: a case-control and case-sibling comparison across different levels of genetic liability, psychopathology, and type of trauma. Am J Psychiatry . 2011 Dec ; 168(12):1286-94. Abstract

Lysaker PH, Outcalt SD, Ringer JM. Clinical and psychosocial significance of trauma history in schizophrenia spectrum disorders. Expert Rev Neurother . 2010 Jul ; 10(7):1143-51. Abstract

Read J, Gumley J. Can attachment theory help explain the relationship between childhood adversity and psychosis? Attachment New Directions in Psychotherapy. Relational Analysis. 2008;2:1-35.

View all comments by Lewis Kirshner

Related News: Meta-Analysis Finds Antipsychotics Help Prevent Relapse in Schizophrenia

Comment by:  Wolfgang Gaebel
Submitted 21 June 2012
Posted 22 June 2012
  I recommend the Primary Papers

Antipsychotics are (generally) effective in relapse prevention—however, evidence-based indicators for more individualized treatment are needed.

Leucht and colleagues (Leucht et al., 2012) conducted a new, highly comprehensive, but also very differentiated meta-analysis on the relapse preventive efficacy of antipsychotic drugs as compared to placebo, which is now published in The Lancet. In addition, detailed comments are provided by van Os and Howes (van Os and Howes, 2012) in the same issue. As in former reviews addressing this topic, the results clearly underline that antipsychotics are (generally) effective in preventing relapse in schizophrenia compared to placebo with average one-year relapse rates of 27 percent versus 64 percent, an estimated risk ratio of 0.4, and a number of 3 needed to treat (to benefit) patients. On the other hand, and despite this high-grade evidence, many patients with schizophrenia still show cognitive, affective, motivational, or "functional" deficits and impairments in the longer illness course. This indicates that antipsychotics are not so effective in all symptom domains and contributes to the notion by some researchers that schizophrenia is still a "poor outcome" disorder, in particular as compared to other mental disorders (Jobe and Harrow, 2005). Thus, further efforts are needed to develop drug and other treatment strategies to affect the illness course more comprehensively. In this regard, a more uniform and broadly accepted definition of "relapse" would be very helpful. For example, the consensus-based definition of "remission" (Andreasen et al., 2005) has stimulated a large amount of research and enables a better comparison of results across studies.

Some other aspects are noteworthy to address. First, it is still unclear how long antipsychotic treatment has to be maintained, especially after a first episode. A comparison of evidence-based treatment guidelines from different countries developed on highest-quality criteria yielded no or inconsistent recommendations regarding the duration of maintenance treatment (Gaebel et al., 2011). In the last years, different trials compared maintenance treatment (MT) with (stepwise) drug discontinuation (mostly supplemented by early drug intervention based on early signs for relapse, i.e., targeted intermittent treatment/IT) in the long-term treatment of first-episode patients. Whether drug treatment was discontinued after six months (Wunderink et al., 2007), after one year (Gaebel et al., 2011), or, as just published, after two years (Emsley et al., 2012; observational design after drug discontinuation), risk for relapse did noticeably increase after drug discontinuation (up to fivefold after one year compared to further MT). On the other hand, a considerable proportion of patients remains stable under intermittent treatment (in the Gaebel et al., 2011, trial, about 50 percent after MT in the first year). In addition, a relevant proportion of patients (about 20 percent) remain relapse free and develop only one illness episode also if drug treatment was suspended (e.g., Harrow et al., 2012).

There are other significant findings indicating that different patients respond differently to similar treatment strategies. Although efficacy of antipsychotics in general is proven, a distinct proportion of patients suffers from partial remission, symptom recurrence, or relapse despite antipsychotic treatment. This applies also to depot treatment, which minimizes adherence problems, although some patients do relapse, as once again shown in a recent placebo-controlled trial not yet included in the Leucht review (Kane et al., 2012). Similarly, the inconclusive results regarding abrupt versus stepwise drug discontinuation and the development of a "supersensitivity" psychosis represent (to a great extent) different effects in different patients. This corresponds to a finding of our own discontinuation trial, in which assured pre-treatment with antipsychotics and an excellent treatment response have been predictors for deterioration in the case of drug discontinuation (Gaebel et al., 2011). It seems that some patients do very well with antipsychotics (often mistaken by themselves as not being in need of drugs), and that they are the ones who should be recommended to rather maintain than to discontinue treatment.

Based on the Vulnerability-Stress-Coping-model for schizophrenia, many influencing factors contribute to illness development and course. Accordingly, schizophrenia represents a heterogeneous illness due to various pathogenetic factors. Thus, different effects in different patients to similar treatment strategies are to be expected. On the other hand, different antipsychotics do also show some differences in efficacy on different symptom domains (Leucht et al., 2009), as well as in side effect and receptor profiles (Correll, 2010). Thus, besides developing new drugs and other treatment strategies, research should also focus on matching the right patient to the right treatment strategy. This requires the availability of valid (i.e., evidence-based) indicators to enable effective individual treatment decisions. This could be clinical indicators (like symptom characteristics, response, adherence, etc.) or biological markers such as genetic variants, neurophysiological, chemical, or functional parameters (among others). For example, Mössner et al. (Mössner et al., 2009) analyzed data from the first-episode study incorporating the above-mentioned discontinuation trial (Gaebel et al., 2011) regarding genetic characteristics and drug response. They found that response in the negative symptom domain is different according to a common polymorphism (-1019C/G) located in the promoter region of the serotonin (5-HT) 1A receptor gene only for the SGA risperidone (as compared to haloperidol). Other observational trials show similar effects, but well-controlled RCTs are needed to provide sound evidence. Accordingly, we are now preparing a trial in which patients with primary negative symptoms are randomly allocated to different SGAs to investigate response differences in the negative symptom domain in relation to their (-1019C/G) polymorphisms.

References:

Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, Davis JM (2012). Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 379:2063-71. Abstract

van Os J, Howes OD (2012). Antipsychotic drugs for prevention of relapse. Lancet. 2012; 379):2030-1. Abstract

Jobe TH, Harrow M. Long-term outcome of patients with schizophrenia: a review. Canadian Journal of Psychiatry. 2005; 50, 892-900. Abstract

Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 2005;62:441-449. Abstract

Gaebel W, Riesbeck M, Wobrock T (2011): Schizophrenia guidelines across the world: a selective review and comparison. Int Rev Psychiatry. 23: 379-87. Abstract

Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry, 2007, 68:654-61. Abstract

Gaebel W, Riesbeck M, Wölwer W, Klimke A, Eickhoff M, von Wilmsdorff M, Lemke M, Heuser I, Maier W, Huff W, Schmitt A, Sauer H, Riedel M, Klingberg S, Köpcke W, Ohmann C, Möller HJ; German Study Group on First-Episode Schizophrenia (2011): Relapse prevention in first-episode schizophrenia: Maintenance vs. intermittent drug treatment with prodrome-based early intervention. Results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. 72: 205-18. Abstract

Emsley R, Oosthuizen PP, Koen L, Niehaus DJ, Martinez G (2012). Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin Psychiatry. 73: e541-e547. Abstract

Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med. 2012 Feb 17:1-11. Abstract

Kane JM, Sanchez R, Perry PP, Jin N, Johnson BR, Forbes RA, McQuade RD, Carson WH, Fleischhacker WW. Aripiprazole Intramuscular Depot as Maintenance Treatment in Patients With Schizophrenia: A 52-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry 2012;73(5):617-624. Abstract

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet; 373: 31-41. Abstract

Correll CU (2010). From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry. 25 Suppl 2:S12-21. Abstract

Mössner R, Schuhmacher A, Kühn KU, Cvetanovska G, Rujescu D, Zill P, Quednow BB, Rietschel M, Wölwer W, Gaebel W, Wagner M, Maier W (2009). Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet Genomics;19:91-4. Abstract

View all comments by Wolfgang Gaebel