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ICOSR 2011—The Kraeplinian Dichotomy Revisited, Again

As part of our ongoing coverage of the 2011 International Congress on Schizophrenia Research (ICOSR), 2-6 April, in Colorado Springs, Colorado, we bring you session summaries from some of the Young Investigator travel award winners. For this report, we thank Brandon Abbs of Brigham and Women’s Hospital, Boston, Massachusetts.

2 May 2011. One of the 3 April morning sessions was entitled, “Was Kraepelin Misguided About the Absolute Distinction Between Schizophrenia and Bipolar Disorder?” Session Chair Charles Nemeroff of the University of Miami, Florida, began with an overview of the similarities and differences between bipolar disorder and schizophrenia, starting with similarities in the presence of psychotic symptoms. Psychotic symptoms accompany bipolar disorder between 55 percent and 90 percent of the time, can include delusions and hallucinations, distractibility, disorganized thought, and can be accompanied by affective symptoms of depression and mania. More generally, bipolar disorder and schizophrenia show similar rates of prevalence in epidemiological studies, concordance rates in twin studies, abnormal brain structure (specifically, increased ventricles) in morphology studies, and genetic regulation in genomewide-association studies.

While there are similarities in the chronic dysfunction associated with the disorders, there are differences in the prodromal/premorbid, onset, and treatment periods. Bipolar disorder does not seem to have a prodromal period or be associated with a measurable loss of function prior to illness onset. At onset, patients with schizophrenia often retreat and develop a “curious indifference” to maintaining social connections, while bipolar disorder shows grandiosity and social engagement. Valproate and other mood stabilizers and anticonvulsants are effective in bipolar disorder but not schizophrenia, including lithium, which promotes growth in the hippocampus, caudate, and frontal cortex. Conversely, antipsychotics are effective in schizophrenia but do not promote growth in the hippocampus, and antidepressants do not “switch” patients with schizophrenia into a manic state. Nemeroff concluded with an insight into the genetic aspects of the disorder by pointing out that genes often confer risk for different non-psychiatric conditions by affecting the same system, which segued into Daniel Weinberger’s presentation.

Weinberger, from the National Institute of Mental Health (NIMH), Bethesda, Maryland, argued that it is not surprising that genes confer risk to multiple disorders, as there is no genetic or evolutionary validity to psychiatric diagnostic criteria. However, genes do directly impact the function of brain systems that support information processing; therefore, genes that confer risk for both bipolar disorder and schizophrenia should also affect the brain systems underlying the disorders. He focused on the affective-emotional, declarative, and working memory systems, and the underlying anatomical targets were the hippocampus and dorsal lateral prefrontal cortex (DLPFC). The bipolar disorder- and schizophrenia-risk-associated alleles of the genes DISC1 and CACNA1C were shown to relate to function in both of these areas in separate tasks, suggesting that they have a non-specific association with brain function. Furthermore, Weinberger suggested that the molecular signaling pathways underlying system function are in a position to affect the development and function of multiple systems through multiple genes. For example, DISC1 expression was shown to be mediated by the NKCC1 gene (presumably acting on GABA systems that can affect dendrite and cell growth), and the effects of BDNF and COMT genes were shown to be dependent upon whether or not subjects also had risk-associated alleles on the AKT1 gene, which can affect BDNF and COMT effects through changes to Akt signaling. Having just a risk allele for BDNF, COMT, and AKT1 alone did not impact brain function, and risk for schizophrenia was additive; each risk-associated allele added some degree of risk for schizophrenia, with the maximum risk in those who had all three risk alleles.

Genes that confer risk for schizophrenia and bipolar disorder can also be expressed differently throughout development, as Weinberger demonstrated with the GRM7 gene. In bipolar disorder, the gene is silent during fetal development, while in schizophrenia there is increased expression across the lifespan, including during fetal development. This suggests an early developmental etiology for schizophrenia that is not necessarily found in bipolar disorder. Weinberger concluded with an anecdote about an old study that looked at bipolar disorder and schizophrenia patients who had been institutionalized for 50 years in Bethlam Hospital, London. The groups were similar in symptomatology and epidemiology, but the schizophrenia patients had not achieved the educational or employment status of their fathers by the time of their first episode, while bipolar disorder patients had. This again suggests that during an earlier developmental or premorbid period, bipolar disorder and schizophrenia may look the most dissimilar.

Philip Harvey of the University of Miami continued the session, showing that when one controls for premorbid functioning, bipolar disorder shows the same magnitude of chronic and ever-present cognitive impairment as schizophrenia, and bipolar disorder with psychosis shows greater impairment than bipolar disorder without psychosis. These impairments are in the same cognitive domains; therefore, bipolar disorder and schizophrenia show the same cognitive impairments but with a different magnitude of severity (schizophrenia > bipolar disorder with psychosis > bipolar disorder without psychosis). Meta-analyses show that this impairment is also related to functional outcome to the same degree in bipolar disorder and schizophrenia, and predictors of residential independence are determined by cognitive ability rather than diagnosis, environment, or education. These results again suggest differences in premorbid functioning and learning, or compensation, for developmental cognitive impairments.

Cameron Carter, University of California, Davis, gave the final talk, which refined the differences in brain structure and function in bipolar disorder and schizophrenia as shown in neuroimaging. He pointed out that bipolar disorder has a unique pregenual anterior cingulate gyrus structural abnormality, which is involved in emotional control, while schizophrenia has more extensive abnormalities in DLPFC, which is involved in cognitive control and working memory. These volumetric differences are also present on measures of cortical thickness, particularly in bipolar disorder-1. From a functional point of view, schizophrenia shows different patterns of activation in the DLPFC, ventral lateral PFC (VLPFC), and amygdala or medial temporal lobe. Schizophrenia shows less activation in DLPFC and amygdala, and greater activation in VLPFC, while bipolar disorder shows the opposite. Pairing these data with performance on an AX-CPT task, Carter concluded that schizophrenia may involve a developmental cognitive impairment, while bipolar disorder may involve a developmental emotional impairment, thus refining the theme of differences in early development and the premorbid/prodromal period in bipolar disorder and schizophrenia.—Brandon Abbs.

Comments on Related News

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Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.


Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover