Schizophrenia Research Forum - A Catalyst for Creative Thinking

New Genetic Variations Link Schizophrenia and Bipolar Disorder

27 September 2006. Schizophrenia and bipolar disorder are debilitating psychiatric diseases with considerable overlap. They share multiple symptoms, and there is evidence that both occur in the same extended families more often than predicted by chance. This has led to the theory that variations within certain genes can increase susceptibility to both diseases (see SRF live discussion). Though the search for such susceptibility variations can be extremely complex—carriers are most often completely normal, for example, making it difficult to trace who does and who does not have a disease variant—researchers in Europe and the U.S. have just added two new genetic loci to the list of those linking schizophrenia and bipolar disorder.

In an article published online September 19 in Human Molecular Genetics, a collaboration led by Hamid Mostafavi Abdolmaleky and Sam Thiagalingam at Boston University, and Ming Tsuang at Harvard University, and comprising researchers from those and several other institutions, reports that reduced methylation of a gene coding for membrane-bound catechol-O-methyltransferase (MB-COMT), an enzyme that plays a crucial role in degrading the neurotransmitter dopamine and other catecholamines, is a major risk factor for the two diseases. In addition, a paper published online September 12 in Molecular Psychiatry, by Giovanni Vazza and colleagues at the University of Padova in Italy, identifies a shared susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26. Together, the papers not only strengthen the connection between the two disorders, but the COMT data also help explain the molecular basis for both, as well as shedding light on how the environment may influence a person’s chance of developing schizophrenia or bipolar disorder.

Too much degradation?
The identification of COMT as a susceptibility locus is not unexpected. Two variants of the COMT gene, differing by a single letter of genetic code, were previously identified, and one of them, producing a valine instead of a methionine at amino acid position 158 of the protein, was linked to schizophrenia (see SRF related news story). But in finding that the COMT gene in schizophrenia and bipolar patients is poorly methylated, Abdolmaleky and colleagues add a new twist. While this chemical modification has no effect on the genetic code itself, it can dramatically change gene activity by preventing DNA from interacting with the machinery that converts the genetic code into protein. In keeping with this, the researchers found that in postmortem samples of dorsolateral prefrontal cortex taken from 35 schizophrenia and 35 bipolar patients, the promoter region of MB-COMT—the very switch that turns on and off the gene—is the one that is poorly methylated. (Note: separate promoters generate membrane-bound and soluble COMT from the same gene.)

In theory, hypomethylation of the MB-COMT gene promoter could lead to increased gene activity, elevated COMT enzyme in the brain, and increased degradation of dopamine, perhaps explaining the loss of this neurotransmitter in the brains of schizophrenia patients (see Akil et al., 1999 and SRF related news story). In support of this idea, Abdolmaleky and colleagues used a cell-based assay to confirm earlier data that hypomethylation of COMT does indeed lead to increased gene expression, and they also compared the amount of COMT mRNA in brain extracts from schizophrenia patients and age-matched controls. Quantitative DNA amplification following reverse transcription revealed that COMT mRNA levels in patients were significantly higher in patients than controls (almost threefold in samples from the Harvard Brain Tissue Resource Center, though not as great a difference in samples from the Stanley Medical Research Institute). The researchers also found an inverse relationship between the levels of COMT and dopamine receptor DRD1 expression that translates into an overall hypoexpression of DRD1 in patients. Taken together, the data suggest that COMT and DRD1 levels may conspire to deprive patients of sufficient dopaminergic transmission.

Like all susceptibility variations, the effect of the MB-COMT hypomethylation is not all-or-none. The researchers found that the gene promoter was hypomethylated in 40 percent of controls compared to 74 and 71 percent of schizophrenia and bipolar patients, respectively. Interestingly, when Abdolmaleky and colleagues separately measured methylation status in samples from the left and right hemispheres of the brain, they found that the patient/control differences were more pronounced in the left side of the brain. In controls, hypomethylation of the promoter only occurred 20 percent of the time in the left side of the brain as opposed to 59 percent in the right side. This seems to suggest that the left side may be more susceptible to changes in methylation status, which would fit with the important role of the left hemisphere in schizophrenia. The language center of the brain is located in the left hemisphere in most people, and many of the symptoms of the disease have been linked to loss of brain laterality and to language difficulties. The loss of brain laterality of MB-COMT promoter methylation in the patients is consistent with other evidence indicating that brain laterality is lost in schizophrenia and bipolar patients (e.g., Crow, 1990).

But the methylation link speaks to a much broader theme, namely the cross-talk between the environment and genetic regulation. Environmental stimuli can cause profound changes in gene expression and behavior due to methylation or demethylation of specific genes (see SRF related news story). This paper hints at a disease/environment nexus that impacts COMT methylation. In fact, the researchers addressed this issue, correlating alcohol use with MB-COMT promoter modification in the patients. They found that methylation was more likely in heavy and moderate alcohol consumers. However, this trend could not be tracked in controls, as heavy and moderate alcohol abuse was not frequent in the control subjects.

The authors note that the sample size in this study was fairly small. “Our analyses reported here provide a clear trend that needs to be further validated in a larger population in future studies,” they write. This includes their finding that the valine allele at position 158 of the COMT enzyme seems to be enriched in samples that also have the promoter hypomethylation. The valine variant is a more active enzyme than that with methionine at the same position, suggesting that patients may be doubly impacted, first by overproduction of the protein, and second, by the fact that the protein is more active than normal.

In the second paper, Vazza and colleagues report that an as-yet uncharacterized locus on a small segment of chromosome 15 links to schizophrenia, bipolar disorder, and schizoaffective disorder in a small group of families in northeastern Italy. The locus lies very close to the ST8SIA2 gene, coding for sialyltransferase 8B, which was recently linked to schizophrenia in a Japanese population (see Arai et al., 2005).

Vazza and colleagues performed genome-wide analysis on 57 individuals in 16 families originating from Chioggia, a “culturally closed” community on an island in the Venetian lagoon. Seven families had only schizophrenia patients, two families had only bipolar patients, and the other seven families had members with two or more of the three disorders. The researchers identified four potential susceptibility loci on chromosomes 1p36, 1q43, 4p14, and 15q26. Only the latter stood up to rigorous statistical analysis, giving a logarithm of odds score greater than 3.0.

Though it lies close to the ST8SIA2 gene, this new 15q26 locus lies about 5Mb away. Furthermore, when Vazza and colleagues analyzed ST8SIA2 single nucleotide polymorphisms (SNPs) that were linked to schizophrenia in the Japanese study, they found no difference between SNP frequencies in the Chioggia population and control populations from other Italian regions. The data indicate that there may be another gene on chromosome 15q that confers susceptibility to schizophrenia and bipolar disorder.—Tom Fagan.

References:
Abdolmaleky HM, Cheng K-H, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, Pan H, Papageorgis P, Ponte JF, Sivaraman V, Tsuang MT, Thiagalingam S. Hypomethylation of MB-COMT Promoter is a Major Risk Factor for Schizophrenia and Bipolar Disorder. Hum. Mol. Genet. 19 September, 2006. Advanced online publication. Abstract

Vazza G, Bertolin C, Scudellaro E, Vettori A, Boaretto F, Rampinelli S, De Sanctis G, Perini G, Peruzzi P, Mostacciuolo ML. Genome-wide scan supports the existence of a susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26. Mol Psychiatry. 2006 Sep 12; [Epub ahead of print] Abstract

Comments on News and Primary Papers
Comment by:  Mary Reid
Submitted 28 September 2006
Posted 29 September 2006

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary ReidComment by:  Patricia Estani
Submitted 5 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

Comments on Related News


Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 5 November 2005
Posted 5 November 2005

The fact that the PRODH alteration studied in Gogos et al. leads to alterations in glutamate release, and this corresponds to deficits in associative learning and response to psychotomimetics, provides a nice parallel to the human condition. The Reiss paper examines humans with the 22q11.2 deletion, and shows that the COMT low-activity allele of this deletion syndrome correlates with cognitive decline, PFC volume, and development of psychotic symptoms. This is a nice addition to the Weinberger and Bilder papers about how COMT can lead to psychosis vulnerability.

View all comments by Anthony Grace

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Caterina Merendino
Submitted 5 November 2005
Posted 5 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Leboyer Marion
Submitted 6 November 2005
Posted 6 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anne Bassett
Submitted 7 November 2005
Posted 7 November 2005
  I recommend the Primary Papers

I echo Jeff Lieberman's comment regarding previous reports of a weak association between the Val COMT functional allele and schizophrenia. Notably, the most recent meta-analysis (Munafo et al., 2005) shows no significant association. Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al. (1999) have reported that there is no association between COMT genotype and schizophrenia, and Bearden et al. reported that Val-hemizygous patients performed significantly worse than Met-hemizygous patients on executive cognition ( 2004) and childhood behavioral problems (2005). Though important as an initial prospective study, there is a risk in the Gothelf et al. small sample size and multiple testing for type 1 errors. Certainly, there is little evidence, even in 22qDS, for COMT (or PRODH) as “key” risk factors for schizophrenia. There may be some evidence for small effects on cognitive or other measures. Regardless, there is not “extreme deficiency” in COMT activity in the many individuals with Met-hemizygosity in 22qDS, or Met-Met homozygosity in the general population.

Regarding the news item, there are a few widely held misconceptions about 22qDS. Our recent article (Bassett et al., 2005) shows that, accounting for ascertainment bias, the rate of schizophrenia was 23 percent, and congenital heart defects was 26 percent. Of the other 41 common lifetime features of 22qDS (found in 5 percent or more patients), neuromuscular palatal anomalies were common but overt cleft palate was so rare it did not meet inclusion criteria; intellectual disabilities ranged from severe mental retardation (rare) to average intellect (rare) with most patients falling in the borderline range of intellect; and on average, patients had nine of 43 common features. We propose clinical practice guidelines for adults with 22qDS which may be directly applicable to the 1-2 percent of patients with a 22qDS form of schizophrenia.

References:
Bassett AS, Chow EWC, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005 Nov 1;138(4):307-13. Abstract

Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry . 2004 Sep;161(9):1700-2. Abstract

Bearden CE, Jawad AF, Lynch DR, Monterossso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Feb;11(1):109-17. Abstract

Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug;10(8):765-70. Abstract

Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct 1;56(10):940-5. Abstract

View all comments by Anne Bassett

Related News: SfN 2005: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: SfN 2005: Nature or Nurture—Epigenetics in Neuronal Responses

Comment by:  Robert Fisher
Submitted 24 December 2005
Posted 3 January 2006

Dr. Eric Nestler at UT Southwestern Medical Center, Dallas, has long postulated addiction as a 50/50 percent split between genetic predisposition and biological changes as a result of substance abuse and the brain's accommodation to the same. I have found this particular hypothesis to be quite useful in treating addicts and alcoholics in inpatient and outpatient settings. They usually are able to easily grasp the concepts on a reasonably scientific level. This approach allows them to avoid guilt, shame, ect., that are typically strong predictors of success or failure in treatment. It is an even more successful tool in working with co-occurring Axis I disorders.

View all comments by Robert Fisher

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Andreas Meyer-Lindenberg
Submitted 15 May 2006
Posted 15 May 2006
  I recommend the Primary Papers

I think this is an interesting paper, as it shows that alterations in tonic dopaminergic stimulation can result in a pronounced and qualitative switch (LTD to LTP) in the behavior of prefrontal neurons. Although the concept of tonic versus phasic dopaminergic stimulation has been adopted widely by the schizophrenia research community, the majority of the preclinical work has focused on acute changes in dopamine concentration and on subcortical structures, especially the nucleus accumbens, and from my perspective as a clinical researcher, it is welcome to see some data that extend to prefrontal cortex and longer timescales, although it must be emphasized that this paper concerns results from rats, in slices in vitro, using tetanic stimulation, and that the pretreatment with dopamine lasted for 40 minutes only. With these caveats, it is exciting to see that pretreatment with dopamine after what the authors presume is a 4-hour period of neurotransmitter depletion during slice preparation produces LTP after a weak tetanic stimulus, compared to LTD that the same stimulus evoked without dopamine priming. Since LTD arose under conditions of relative dopamine depletion, which might reflect, at least in directionality, the situation in schizophrenia, these data suggest that functionally impairing qualitative changes in a neuronal response in prefrontal cortex of relevance for working memory function could result from quantitative reductions in extracellular (tonic) dopamine content. It is also of interest that the authors demonstrate that the LTP requires concurrent stimulation of metabotropic glutamate receptors, suggesting a mechanism by which widely studied risk genes for schizophrenia such as COMT and GRM3 could interact in impairing prefrontal cortex function.

View all comments by Andreas Meyer-Lindenberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Patricia Estani
Submitted 3 June 2006
Posted 3 June 2006
  I recommend the Primary Papers

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Terry Goldberg
Submitted 20 June 2006
Posted 20 June 2006

Matsuda et al. demonstrate that priming D1 and D2 receptors may induce LTP; otherwise, LTD develops. To elaborate, a weak tetanic stimulation and dopamine stimulation produces LTD. However, if dopamine is perfused for 12 to 40 minutes at D1 and D2 receptors and a tetanic stimulus is provided, LTP, a form of cellular learning associated with memory, develops. This study has potentially important implications for understanding the cause of prefrontally based failures in information processing in schizophrenia. It gives additional weight to arguments that reduced dopaminergic tone at the cortical level is responsible for at least some of the cognitive problems associated with the disorder.

It also helps make sense out of some otherwise anomalous data in the literature. For instance, in manipulations of several tests of purported attentional control and vigilance problems, findings appeared more consistent with difficulties in constructing a representation than with attention per se in target detection (e.g., Elvevag et al., 2000; Fuller et al., 2005).

One thing that I would certainly give an eyetooth to know is how the authors view their work in light of findings by Seamans and Goldman-Rakic on differences in the consequences of stimulation of D1 and D2 receptors (simplistically, that D1 activation promotes task-relevant information, while D2 stimulation may produce task-irrelevant information processing experienced as interference).

Caveat Emptor: I don’t have the expertise to comment on the slice preparation methodology.

References:

Elvevag B, Weinberger DR, Suter JC, Goldberg TE. Continuous performance test and schizophrenia: a test of stimulus response compatibility, working memory, response readiness, or none of the above? Am J Psychioatry 2000; 157:772-780. Abstract

Fuller RL, Luck SJ, McMahon RP, Gold JM. Working memory consolidation is abnormally slow in schizophrenia. J Abnorm Psychol 2005; 114:279-290. Abstract

View all comments by Terry Goldberg

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Satoru Otani
Submitted 22 July 2006
Posted 24 July 2006

In his June 20 comment, Dr. Goldberg raised an important question concerning our paper: how our results, showing the necessity of D1+D2 receptor coactivation for prefrontal LTP induction and priming, fit into the scheme proposed by Seamans et al., 2001, that is, the differential roles played by D1 and D2 receptors for prefrontal cortex (PFC) cognitive processes.

I think I have to first point out that the dependency of PFC long-term potentiation (LTP) induction (let alone "priming" now) on DA receptor subtypes may vary among subpopulations of PFC synapses. In ventral hippocampus (HC)-PFC synapses, LTP induction requires D1 but not D2 receptors (Gurden et al., 2000). This in vivo study fits with the idea that HC-PFC projection and its D1 receptor-mediated modulation are critical in spatial information processing (working memory) and encoding of this information. However, recent in vivo results of Yukiori Goto at the University of Pittsburgh (personal communication, but see Goto and Grace, 2005) indicate that LTP induction in cortico-cortical synapses in the PFC may be dependent on both D1 and D2 receptors, similar to our case. Dr. Goto found that while synaptic potentiation in the HC-PFC synapses indeed depends only on D1 receptors, potentiation in cortico-cortical synapses, stimulated by the electrode inserted in the superficial layer of the PFC as in our preparation, depends on the activation of both D1 and D2 receptors. Thus, it appears that DA receptor dependency of LTP induction differs between the HC projection input and the cortico-cortical input—the former dependent only on D1 receptors and the latter on D1+D2 receptors.

How significant this difference might be functionally is, of course, still an issue for speculation. It seems clear that working memory input from the HC (and strengthening of this input), which may depend only on D1 receptors, are critical for PFC cognitive function. But also, other cortical inputs, which are not necessarily related to the attention-driven working memory, may be as critical for the formation and achievement of goal-directed behavior, and strengthening of these cortical inputs may depend on D1+D2 receptors. Incidentally, Dr Goto also showed that the organization of a planned behavior tested in a modified radial-arm maze task requires not only intact HC-PFC connection but also the activation of both D1 and D2 receptors within the PFC (Goto and Grace, 2005). We are tempted to suggest that neuronal traces within the PFC necessary for the generation of goal-directed behavior may be heterogeneous both in their input origin and in their formation mechanism.

References:

Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21, 3628-3638. Abstract

Gurden H, Takita M, Jay TM. Essential role of D1 but not D2receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci. 2000 Nov 15;20(22):RC106. Abstract

Goto Y, Grace AA (2005) Retrospective and prospective memory processing in the hippocampal—prefrontal cortical network. Soc Neurosci Abstr 413.3.

View all comments by Satoru Otani

Related News: Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

Comment by:  Jeremy Seamans
Submitted 26 July 2006
Posted 27 July 2006

Drs. Goldberg and Otani raise some excellent points in their comments on the Matsuda et al. paper. As Dr. Otani alluded to in his latest comment, it is useful to define exactly what is being modulated under different experimental conditions and how this all relates to prefrontal cortex (PFC) function in general.

Dr Otani’s studies investigate synaptic plasticity induced by tetanic stimulation and how this process is modulated by tonic dopamine (DA). Long-term potentiation/long-term depression (LTP/LTD) induced by tetanic stimulation has provided us with perhaps the best model of the cellular basis of long-term memory and has been proposed to underlie, among other things, various aspects of long-term spatial memory and declarative memory. LTP is a long-lasting, passive, associational memory mechanism, unlike working memory that is transient in nature, relies on active processing and is not associational. Therefore, in PFC, it would be highly unlikely that LTP/LTD is the neural mechanism of working memory. However, to solve a working memory problem, one must manipulate newly acquired information within a certain context or based on a pre-learned rule. Perhaps the best example of how these processes relate can be found in White and Wise, 1999, and Wallis et al., 2001, who investigated the activation of PFC neurons in situations where two different abstract rules could be applied. PFC neurons showed different degrees of activation during a delay period depending on the preference of the neuron for a specific task rule. Therefore, stable long-standing rules regulate how strongly a cell in PFC exhibits short-term memory related activity. These rules were learned over time and were stable. LTP/LTD are as good mechanisms as any for their cellular basis. This implies that LTP/LTD-like mechanisms influenced the manner in which PFC neurons exhibited transient working memory related activity. Therefore, as shown by Matsuda et al. and suggested by others (e.g., Lisman and Grace, 2005), a long-term memory mechanism, perhaps involved in the formation of stable rules, is subjected to modulation by tonic and phasic DA. This long-term memory in turn regulates the online active processing of information in working memory.

In contrast, many investigators have proposed that DA is also able to directly modulate working memory related activity. As noted by Dr. Goldberg, in addition, we have suggested that the mode of modulation is different for D1 and D2 receptors in PFC. Like task rules, DA appears to modify the strength of delay-period activity (e.g., Sawaguchi, 2001). Furthermore, the modulation of synaptic currents by DA, especially via D1 receptors, is very long-lasting and has been termed “late potentiation” and in fact shares aspects of the late phase of LTP (Huang and Kandel, 1995). However, unlike stable task rules, DA levels can change quickly and dynamically, and as a result, delay-period activity may be increased or decreased depending on the level of DA and the differential activation of D1 and D2 receptors, even if the same task rule is being implemented. The dynamic modulation of DA levels depends on a variety of factors such as intrinsic motivation, stress, and even the strength of the active memory trace (Phillips et al., 2004).

Therefore, DA modulates LTP/LTD, which in turn may be involved in the rule-dependent modification of delay-period activity. DA can also directly modulate the ionic currents involved in actually generating delay-period activity. Although this modulation can be long-lasting, DA levels and activation of different DA receptors change dynamically and the mode of modulation could continuously vary based on a variety of intrinsic and task-dependent variables.

Perhaps one implication of all this for schizophrenia would be that dysfunction of DA-dependent modulation of LTP/LTD would lead to an inability to accurately store or implement the appropriate rule for a given situation. In contrast, dysfunction of the direct DA modulation of ionic and synaptic currents could lead to more immediate issues such as distractability or pathologically focused processing of information within working memory (Seamans et al., 2001; Seamans and Yang, 2004).

References:

Huang YY, Kandel ER. D1/D5 receptor agonists induce a protein synthesis-dependent late potentiation in the CA1 region of the hippocampus. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2446-50. Abstract

Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron. 2005 Jun 2;46(5):703-13. Review. Abstract

Phillips AG, Ahn S, Floresco SB. Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task. J Neurosci. 2004 Jan 14;24(2):547-53. Abstract

Sawaguchi T. The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci Res. 2001 Oct;41(2):115-28. Abstract

Seamans JK, Gorelova N, Durstewitz D, Yang CR. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci. 2001 May 15;21(10):3628-38. Abstract

Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004 Sep;74(1):1-58. Review. Erratum in: Prog Neurobiol. 2004 Dec;74(5):321. Abstract

Wallis JD, Anderson KC, Miller EK. Single neurons in prefrontal cortex encode abstract rules. Nature. 2001 Jun 21;411(6840):953-6. Abstract

White IM, Wise SP. Rule-dependent neuronal activity in the prefrontal cortex. Exp Brain Res. 1999 Jun;126(3):315-35. Abstract

View all comments by Jeremy Seamans

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Andreas Meyer-Lindenberg
Submitted 8 February 2007
Posted 8 February 2007

This fascinating paper contributes to our mechanistic understanding of a fundamental nonlinearity governing the response of prefrontal neurons during working memory to dopaminergic stimulation: the “inverted U” response curve (Goldman-Rakic et al., 2000), which proposes that an optimum range of dopaminergic stimulation exists, and that either too little or too much dopamine impairs tuning, or the relationship between task-relevant (“signal”) and task-irrelevant (“noise”) firing of these neurons. On the level of behavior, this is predicted to result in impaired working memory performance outside the optimum middle range, and this has been confirmed in a variety of species. This is a topic of high relevance for schizophrenia where prefrontal dysfunction and related cognitive deficits, and dopaminergic dysregulation, have long been in the center of research interest (Weinberger et al., 2001), and may be linked (Meyer-Lindenberg et al., 2002). In particular, evidence for abnormally decreased dopamine levels in prefrontal cortex would predict that patients with schizophrenia are positioned to the left of the optimum. This line of thought has recently received impetus from genetic studies on COMT, the major enzyme catabolizing dopamine in prefrontal cortex (Tunbridge et al., 2004). Neuroimaging studies have shown that genetic variants with high COMT activity are positioned to the left, those with lower activity nearer the optimum of the inverted U curve, and that this position predicts nonlinear response to amphetamine stimulation (Mattay et al., 2003), as well as interactions between dopamine synthesis and prefrontal response (Meyer-Lindenberg et al., 2005). Variants with sub- (Egan et al., 2001; Nicodemus et al., 2007) or superoptimal (Gothelf et al., 2005) stimulation were associated with schizophrenia risk. Task-related and task-unrelated prefrontal function reacted in opposite ways to genetic variation in dopamine synthesis, suggesting a tuning mechanism (Meyer-Lindenberg et al., 2005). Recently, interacting genetic variants in COMT have also been found to affect prefrontal cortex function in an inverted U fashion (Meyer-Lindenberg et al., 2006).

A seminal contribution to the cellular mechanisms of the inverted U curve is the paper by Williams (one of the authors of the current study) and Goldman-Rakic in Nature 1995 (Williams and Goldman-Rakic, 1995). In this work, dopamine D1 receptor antagonists were used and shown to increase prefrontal cell activity in low levels, whereas high levels inhibited firing. This implicated a mechanism related to D1 receptors and suggested that the neurons studied were to the right of the optimum on the inverted U curve, that is, their dopamine stimulation was excessive. The present study, from Amy Arnsten’s lab at Yale, further defines the cellular mechanisms underlying the inverted U curve in recordings from PFC neurons of awake behaving monkeys exposed to various levels of stimulation by a dopamine 1 receptor agonist. A spatial working memory paradigm was used, enabling the determination of the degree to which the neurons were tuned by comparing the firing rate to stimuli in the preferred spatial stimulus direction (“signal”) to the firing rate to nonpreferred stimuli (“noise”). The authors recorded both from neurons that were highly tuned (supposedly receiving optimum stimulation) and neurons that were less tuned. As would be predicted from the model, highly tuned neurons did not improve, or worsened, during stimulation, while weakly tuned neurons became more focused in their activity profile. It is not quite clear to me why the previous paper (Williams and Goldman-Rakic, 1995) found neurons that were predominantly to the right of the optimum, while this work identified neurons using a similar paradigm that were either to the left or near the optimum. Perhaps it is because Williams and Goldman-Rakic (Williams and Goldman-Rakic, 1995) screened neurons for a response to the D1 antagonist first. In both studies, extracellular dopamine was not actually measured, meaning that the state of basal stimulation can only be inferred indirectly from the response to the iontophoresed agonist or antagonist. Importantly, the effect of D1 stimulation was always suppressive; effects on tuning were due to the fact that the reduction in response to the signal and the noise were different in extent, such that for weakly tuned neurons and low levels of D1 stimulation, the noise firing was more suppressed than that of the signal, resulting in increased signal to noise. In a second set of pharmacological experiments, which included validation in a rat working memory model, the authors show that these effects are cAMP, but not PKC-dependent, suggesting a preferential cellular mechanism through Gs-proteins, which might be useful for exploration of more specific drug targets.

This work has interesting implications for our understanding of prefrontal function in schizophrenia. Since dopamine stimulation was found to be almost exclusively suppressive, cortical dopamine depletion in schizophrenia would be predicted to lead to relatively increased, but inefficient (untuned) cortical cognitive response, as has indeed been observed (Callicott et al., 2000). However, it is an open question precisely how cortical physiology assessed by imaging relates to these cellular events. The data by Arnsten suggest that each patch of prefrontal cortex will contain a population of neurons at various states of tuning that will respond differently to drug-induced or cognitively related changes in extracellular dopamine, with some improving, some decreasing their tuning. Depending on whether imaging signals and tasks are more sensitive to overall firing rate, or to specific signal-to-noise properties, the resulting blood flow change might be quite different. Perhaps this contributes to some of the puzzling discrepancies between hypo- and hyperactivation both being observed in comparable tasks and regions of prefrontal cortex in schizophrenia.

References:

1. Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301. Review. No abstract available. Abstract

2. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry. 2001 Dec 1;50(11):825-44. Review. Abstract

3. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. Abstract

4. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

5. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. Epub 2003 Apr 25. Abstract

6. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

7. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29. Abstract

8. Nicodemus KK, Kolachana BS, Vakkalanka R, Straub RE, Giegling I, Egan MF, Rujescu D, Weinberger DR. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet. 2007 Feb;120(6):889-906. Epub 2006 Sep 28. Abstract

9. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. Abstract

10. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry. 2006 Sep;11(9):867-77, 797. Epub 2006 Jun 20. Abstract

11. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995 Aug 17;376(6541):572-5. Abstract

12. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex. 2000 Nov;10(11):1078-92. Abstract

View all comments by Andreas Meyer-Lindenberg

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Terry Goldberg
Submitted 6 April 2007
Posted 6 April 2007

In this landmark study, Arnsten and colleagues used a full dopamine agonist in awake behaving monkeys to make key points about the inverted U response at the cellular level and how this maps to the behavioral level. There were a number of surprises. The first was that stimulation of the D1 receptor had consistently suppressive effects on neuronal firing during delays in a working memory task. The second was that when responses were optimized, suppressive effects differentially affected non-preferred directional neurons, rather than preferred direction neurons. Thus, it appeared that noise was reduced rather than signal amplified. Too much D1 stimulation resulted in suppression of both classes of neurons.

The implications of this work are important because it suggests that there is a neurobiological algorithm at work that can reliably produce this unexpected physiological pattern (perhaps as the authors suggest on the basis of baseline activity). It remains to be elucidated whether the D1 receptor effects are mediated by glutamatergic neurons or GABA interneurons, or both. There is another layer of complexity to the story. As Arnsten and colleagues note, possible excitatory influences of D1 stimulation may not have been observed because endogenous dopamine had already triggered this process. It is unclear if D2 receptors in the cortex have a role in shaping or terminating this activity.

Last, it is tempting to speculate about the implications of these findings for other types of tasks that engage prefrontal cortex in humans. What does tuning mean in the context of tasks like the N Back which demands updating, the ID/ED test from the CANTAB, which involves suppression of salient distractors at early set shifting stages, or a task which demands heavy doses of cognitive control like the flanker task, all of which have been shown to be sensitive to manipulations of the dopamine system (Goldberg et al., 2003; Jazbec et al., 2007; Diaz-Asper et al., in press; Blasi et al., 2005)?

View all comments by Terry Goldberg

Related News: Biology of Reinforcement—Dopamine Linked to Three Separate Reward Paths

Comment by:  Patricia Estani
Submitted 16 November 2007
Posted 16 November 2007
  I recommend the Primary Papers

Related News: Epigenetic Analysis Finds Widespread DNA Methylation Changes in Psychosis

Comment by:  Dennis Grayson
Submitted 26 March 2008
Posted 27 March 2008
  I recommend the Primary Papers

The paper by Mill et al. is one of the first comprehensive attempts to examine changes in methylation across the entire genome in patients with various diagnoses of mental illness. The study is well designed, extensive, and uses fairly new technology to examine changes in methylation profiles across the genome. In the frontal cortex, the authors provide evidence for psychosis-associated differences in DNA methylation in numerous loci, including those involved in glutamatergic and GABAergic transmission, brain development, and other processes linked with disease etiology. Methylation in the frontal cortex of the BDNF gene is correlated with a non-synonymous SNP previously associated with major psychosis. These data provide further support for an epigenetic origin of major psychosis, as evidenced by DNA methylation-induced changes likely important to gene expression.

In many ways, this seems reminiscent of the trend in genetics several years ago when the inclination was to move from single gene loci association and linkage studies to genomewide scans. The only downside of the approach is that what one gains in information, one (at least initially) loses in biology. That is given the wealth of new findings uncovered; we now need to go back and examine these results in light of what we know regarding gene function in neurobiology and cognition. Of course, this is the trend, now that microarrays have increased our capacity to look at all things at the same time. The flipside is that it will take several large-scale studies of this sort to better understand which findings are replicable and which are not. That is, do the results of the Mill paper agree with data obtained and carried out by laboratories using the methyl DIP or MeCP2 ChIP assays coupled with microarrays. While these experiments ask different questions, the implication is that there may be some degree of overlap in comparing these different methodologies. While this may be premature, there is a sense that this information will be available shortly.

Finally, I would like to focus on recent findings regarding the methylation of the reelin promoter. These authors (Mill et al.) and Tochigi and colleagues (Tochigi et al., 2008) have found that the reelin promoter is not hypermethylated in patients with schizophrenia. In fact, Tochigi et al., 2008, found that the reelin promoter is not methylated at all using pyrosequencing. However, several groups (Grayson et al., 2005; Abdolmaleky et al., 2005; Tamura et al., 2007; Sato et al., 2006) have shown that the human reelin promoter is methylated in different circumstances. Interestingly, there is little consensus in the precise bases that are methylated in these latter studies. Our group (Grayson et al., 2005) performed bisulfite treatment of genomic DNA and sequencing of individual clones. Moreover, we analyzed two distinct patient populations. The clones were sequenced at a separate facility. What was intriguing was that the baseline methylation patterns in the two populations was different, and yet several sites stood out as being relevant in both. We mapped methylation to the somewhat rare CpNpG sites proximal to the promoter. Interestingly, these bases were located in a transcription factor-rich portion (Chen et al., 2007) of the promoter and in a region that shows 100 percent identity with the mouse promoter over a 45 bp stretch. We have also been able to show that changing one of these two bases to something other than cytosine reduces activity 50 percent in a transient transfection assay. So the question becomes, How do we reconcile these disparate findings regarding methylation? As suggested by Dr. McCaffrey, the answer may lie in regional differences that arise due to the nature of the material available for each study. We have found a degree of reproducibility by using human neuronal precursor (NT2) cells for many of our studies. At the same time, this cell line is somewhat artificial and cannot be used to reconcile differences found in human tissue. Perhaps it might be prudent to examine material taken by using laser capture microdissection to enrich in more homogenous populations of neurons/glia. In moving ahead, it might be best to now focus on the mechanism for these differences in methylation patterns and try to understand the biology associated with the new findings (Mill et al., 2008) as a starting point.

References:

Abdolmaleky HM, Cheng KH, Russo A, Smith CL, Faraone SV, Wilcox M, Shafa R, Glatt SJ, Nguyen G, Ponte JF, Thiagalingam S, Tsuang MT. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):60-6. Abstract

Chen Y, Kundakovic M, Agis-Balboa RC, Pinna G, Grayson DR. Induction of the reelin promoter by retinoic acid is mediated by Sp1. J Neurochem. 2007 Oct 1;103(2):650-65. Abstract

Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9341-6. Abstract

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008 Mar 1;82(3):696-711. Abstract

Sato N, Fukushima N, Chang R, Matsubayashi H, Goggins M. Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers. Gastroenterology. 2006 Feb 1;130(2):548-65. Abstract

Tamura Y, Kunugi H, Ohashi J, Hohjoh H. Epigenetic aberration of the human REELIN gene in psychiatric disorders. Mol Psychiatry. 2007 Jun 1;12(6):519, 593-600. Abstract

Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N, Kato T. Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry. 2008 Mar 1;63(5):530-3. Abstract

View all comments by Dennis Grayson

Related News: Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

Comment by:  Alastair Cardno
Submitted 7 April 2009
Posted 7 April 2009
  I recommend the Primary Papers

The results of the family/adoption study by Lichtenstein et al. (2009) and our twin study (Cardno et al., 2002) are remarkably similar. Using a non-hierarchical diagnostic approach, the genetic correlation between schizophrenia and bipolar/mania was 0.60 in the family/twin study and 0.68 in the twin study. The heritability estimates were somewhat lower in the family/adoption (~60 percent) than twin study (~80 percent), but can still be said to be substantial and similar for both disorders.

When we adopted a hierarchical approach, with schizophrenia above mania, we found no monozygotic twin pairs where one twin had schizophrenia and the other had bipolar/mania, but with their considerably larger sample, Lichtenstein et al. (2009) were able to confirm a significantly elevated risk for bipolar disorder in siblings of probands with schizophrenia (RR = 2.7), even when individuals with co-occurrence of both disorders were excluded.

I think there is a potentially interesting link between the family/adoption and twin studies focusing mainly on non-hierarchical diagnoses: Owen and Craddock’s (2009) commentary on the family/adoption study, where they advocate a dimensional approach, and Will Carpenter’s SRF comment regarding the value of domains of psychopathology. The non-hierarchical approach (where individuals can have a diagnosis of both schizophrenia and bipolar disorder during their lifetime) could be viewed as a form of dimensional/domains of psychopathology approach, with schizophrenia and bipolar disorder each having a dimension of liability, and there is now evidence from family, twin, and adoption analyses that these dimensions are correlated, i.e., that there is some overlap in etiological influences.

If schizophrenia and bipolar disorder share some causal factors in common, what might be the implications for the unresolved status of schizoaffective disorder? Our twin study suggested that the genetic (but not environmental) liability to schizoaffective disorder is entirely shared with schizophrenia and mania, defined non-hierarchically (Cardno et al., 2002). If so, and if schizophrenia and bipolar disorder share some genetic susceptibility loci in common, while other loci are not shared, then risk of schizoaffective disorder (or perhaps the bipolar subtype) could be elevated either by the coincidental co-occurrence of non-shared susceptibility loci, or by the occurrence of loci that are common to both disorders.

In this case, any loci that influence risk of schizoaffective disorder (bipolar subtype?) should also increase risk of schizophrenia and/or bipolar disorder, and this model would be refuted if any relatively specific susceptibility loci for schizoaffective disorder were confidently identified.

Some further outstanding issues:



References:

Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 2002;159:539-545. Abstract

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-9. Abstract

Owen MJ, Craddock N. Diagnosis of functional psychoses: time to face the future. Lancet 2009;373:190-191. Abstract

View all comments by Alastair Cardno

Related News: With Two Affected Parents, Schizophrenia Risk in Offspring Skyrockets

Comment by:  Peter Propping
Submitted 16 March 2010
Posted 16 March 2010

The study by Gottesman et al. is extremely important. Its value derives from the fact that the incidences come from a registry-based ascertainment of cases and from a country with national health insurance. Thus, the usual selective influences on ascertainment can largely be excluded. The empirical risk figures derived from this dual-mating study are much higher than in offspring where only one parent was affected by either schizophrenia or bipolar disorder. In the present study, however, the risk figures were somewhat lower than reported in some earlier studies (conducted in Germany, the United States, and the United Kingdom), where the cases had been ascertained through clinical admissions (Kahn, 1923; Kallman, 1938; Schulz, 1940; Elsässer, 1952; Lewis, 1957; Gershon et al., 1982). The major explanation is likely to be the ascertainment bias in the earlier studies.

Interestingly, this study found somewhat higher risks for both schizophrenia and bipolar disorder in the offspring of matings where one parent had schizophrenia and the other bipolar disorder. This points to a genetic overlap between the predispositions to the two diseases. An overlap is also suggested by recent molecular studies (e.g., Steinberg et al., 2010). If a genetic association has been found with one of the two disorders, it should also be tested in the other disorder.

References:

Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, Andreassen OA, Sigurdsson E, Thorgeirsson TE, Böttcher Y, Olason P, Ophoff RA, Cichon S, Gudjonsdottir IH, Pietiläinen OPH, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Athanasiu L, Suvisaari J, Lonnqvist J, Paunio T, Hartmann A, Jürgens G, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Breuer R, Möller H-J, Giegling I, Glenthøj B, Rasmussen HB, Mattheisen M, Bitter I, Réthelyi JM, Sigmundsson T, Fossdal R, Thorsteinsdottir U, Ruggeri M, Tosato S, Strengman E, GROUP, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Walshe M, Bramon E, Vassos E, Li T, Fraser G, Walker N, Toulopoulou T, Yoon J, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MN, Rietschel M, Peltonen L, Rujescu D, Collier DA, Stefansson H, St Clair D, Stefansson K. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2010 Jan 5. Abstract

Kahn E (1923). Studien über Vererbung und Entstehung geistiger Störungen. IV. Schizoid und Schizophrenie im Erbgang. Springer: Berlin.

Kallmann FJ (1938). The genetics of schizophrenia. Augustin: New York.

Schulz B (1940). Kinder schizophrener Elternpaare. Z Ges Neurol Psychiat 168:332-81.

Elsässer G (1952). Die Nachkommen geisteskranker Elternpaare. Thieme: Stuttgart.

Lewis AJ (1957). The offspring of parents both mentally ill. Acta Genet 7:349-65. Abstract

Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI Jr, Goldin LR, Bunney WE Jr. (1982). A family study of schizoaffective, bipolar I, bipolar II, unipolar and normal control probands. Arch Gen Psychiat 39:1157-67. Abstract

View all comments by Peter Propping

Related News: With Two Affected Parents, Schizophrenia Risk in Offspring Skyrockets

Comment by:  Jehannine Austin
Submitted 19 March 2010
Posted 19 March 2010

The study recently published by Irving Gottesman and colleagues in the Archives has—as the authors point out—potentially important clinical implications. Using Denmark’s national registry data (>2.6 million individuals), the researchers calculated the cumulative incidences (to age 52) of psychiatric diagnoses in offspring of couples where one or both had previously been diagnosed with schizophrenia or bipolar disorder. The results clearly show that the probability of developing psychiatric illness is higher among offspring of individuals who have one parent with schizophrenia or bipolar disorder than among those who have no affected parents, and that the probability of developing psychiatric illness is highest among those who have both parents affected.

Probabilities that children will develop psychiatric disorders are of considerable interest amongst individuals with severe mental illnesses like schizophrenia and bipolar disorder. Further, American Psychiatric Association practice guidelines (American Psychiatric Association, 2002) for the treatment of individuals with bipolar disorder who are considering having children suggest that genetic counseling (which incorporates provision and discussion of risks for children to be affected) may be useful. Accordingly, Gottesman’s group points out that the probabilities documented in their paper may be useful for individuals with psychiatric disorders with regard to personal decision-making about issues such as childbearing. Indeed, we have previously shown that perceived risk for offspring to develop psychiatric illness may influence childbearing decisions (Austin et al., 2006).

It becomes relevant to question how the risks for offspring of individuals with psychiatric illness to develop severe mental illnesses are perceived by affected individuals. In an online survey, we asked 250 individuals with a history of psychotic illness or bipolar disorder what they thought was the chance for an individual with one affected parent to develop psychosis. We found that 43 percent of this group indicated that they thought the chance was 50 percent or greater (unpublished data).

Other commentary on this article highlighted that the probability of severe mental illness “skyrockets” when both parents are affected. But, for a sizable proportion of affected individuals who dramatically overestimate the chance for offspring to be affected, the figures derived by Gottesman’s group will actually be reassuring or lower than anticipated.

The figures reported by Gottesman’s group are a welcome resource for those of us who seek to provide individuals with severe mental illness with the most accurate probability estimates possible for these outcomes in the context of genetic counseling. As the authors point out, however, the probability figures they generated are “applicable to groups of people, not to the individuals themselves.” These figures are a useful foundation for the derivation of individualized probability estimates, in a manner that has been described elsewhere (Austin et al., 2008; Austin and Peay, 2006). No matter how reliable the study from which such probabilities are generated, however, they remain probabilities and, as John Adams writes, “Estimates of the probability of particular harms are quantified expressions of ignorance” (Adams, 2003). Essentially, we can’t say for sure whether a particular individual will develop severe mental illness or not.

References:

American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 Suppl):1-50. Abstract

Adams J. Risk and morality: three framing devices. In RV Ericson and A Doyle (Eds.), Risk and Morality. Toronto: University of Toronto Press, 2003:87-103.

Austin J, Smith GN, Honer WG. The genomic era and perceptions of psychotic disorders: Genetic risk estimation, associations with reproductive decisions and views about predictive testing. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):926-8. Abstract

Austin JC, Peay HL. Applications and limitations of empiric data in provision of recurrence risks for schizophrenia: A practical review for healthcare professionals providing clinical psychiatric genetics consultations. Clin Genet. 2006;70(3):177-87. Abstract

Austin JC, Palmer CG, Rosen-Sheidley B, Veach PM, Gettig E, Peay HL. Psychiatric disorders in clinical genetics II: Individualizing recurrence risks. J Genet Couns. 2008;17(1):18-29. Epub 2007 Dec 11. Abstract

View all comments by Jehannine Austin

Related News: Schizophrenia and Bipolar With Psychosis Share Cognition, Connectivity

Comment by:  Jose GoikoleaEduard Vieta
Submitted 18 July 2013
Posted 18 July 2013

The recent publication of two papers from the B-SNIP group in the American Journal of Psychiatry provides additional high-quality data supporting a dimensional model for psychotic disorders, different from the current Kraepelinian categorical model. These two papers focus on two different putative endophenotypes for schizophrenia and bipolar disorder, namely, cognitive performance and white matter integrity. Interestingly, both endophenotypes show quite similar results.

The work of the B-SNIP group is praiseworthy. Consisting of six centers across the United States, the group has studied quite a large sample of patients with psychotic disorders (schizophrenia, schizoaffective, and psychotic bipolar disorder) using both current categorical diagnostic criteria and a dimensional Schizo-Bipolar Scale approach. Besides that, the group assesses relatives without psychotic or affective disorders, which is essential for further understanding the underlying genetic basis and identifying endophenotypes for these disorders.

Both studies obtain similar results for each endophenotype: Both schizophrenia and bipolar disorder show abnormalities (in cognition and in white matter integrity) compared to healthy controls. There are no qualitative differences in these abnormalities; that is, they share a similar pattern of disturbance, although it is more severe (cognition) or widespread (white matter) in schizophrenia. These disturbances are shared to a lower degree by unaffected relatives, supporting their validity as endophenotypes, even if this is much clearer for relatives of schizophrenia subjects. Undoubtedly, these results support the notion of a single nosological entity with a dimensional nature. On the “schizophrenia edge” of the continuum, a more severe or widespread impairment as well as more abnormalities in unaffected relatives would be found.

However, there are some comments that should be taken into account for a fair interpretation of the results. First of all, the diagnosis of schizoaffective disorder has become somehow a test itself to validate the categorical versus dimensional model for psychotic disorders. The paper by Hill et al. compares the schizoaffective group with the healthy control group and with the other proband groups. The conclusions seem to support the dimensional model, as schizoaffective probands show an intermediate cognitive performance between schizophrenia and bipolar disorder without qualitative differences. Instead, for unclear reasons, the DTI paper splits the schizoaffective group in manic type merged with the bipolar group, and depressive type merged with the schizophrenia group, losing an opportunity to analyze this perspective.

Second, it is a shame that non-psychotic bipolar 1 patients have not been included in these studies. This represents a bias toward the psychotic view, whereas the inclusion of the non-psychotic bipolar subjects would have provided a second enriching view from the “affective” perspective. This second supplementary approach would be more likely to identify possible endophenotypic features that might differentiate schizophrenia from bipolar disorder. In fact, in light of these two papers, schizophrenia and bipolar disorder could be understood as the same disease, bipolar just being a less severe phenotype. Although there is quite large evidence that schizophrenia and bipolar disorder share different genetic, neurobiological, and cognitive features, and that a mixed categorical and dimensional approach may be much closer to reality, differences between both disorders should still be kept in mind. For instance, the unique clinical features of the most prototypical euphoric mania or the circadian rhythm disturbances in bipolar disorder are likely to be based on neurobiological features specific to bipolar disorder that are not yet completely understood or identified.

View all comments by Jose Goikolea
View all comments by Eduard Vieta

Related News: Schizophrenia and Bipolar With Psychosis Share Cognition, Connectivity

Comment by:  Ole A. Andreassen, SRF AdvisorMartin Tesli
Submitted 3 September 2013
Posted 4 September 2013

The two reports from the B-SNIP consortium elegantly address Kraepelin’s dichotomy in psychosis and provide evidence using a large sample that there are overlapping cognitive deficits across psychotic bipolar disorder and schizophrenia (Hill et al., 2013), and similar patterns of connectivity abnormalities (as measured by diffusion tensor imaging, or DTI) in the two disorders (Skudlarski et al., 2013). Both phenotypes are also found in relatives, supporting the idea that the cognitive and DTI measures are true "endophenotypes."

The finding that cognitive dysfunction in schizophrenia and psychotic bipolar disorder depends more on psychosis than a diagnostic group is a nice replication of our previous findings (Simonsen et al., 2011). This is reassuring and further suggests that it is a robust phenomenon, as the neuropsychological test batteries used in the two studies were quite different. The severity of the deficits is also comparable between the two studies.

The current study also investigated the familiality of cognitive dysfunction, which was quite high, with deficits also seen in non-psychotic relatives of both bipolar disorder and schizophrenia. Quite interestingly, the cognitive deficits were more associated with cluster A (psychosis-like) personality traits in relatives of bipolar disorder than in schizophrenia. This further strengthens the argument that there is a continuum of psychosis across these disorders which is heritable.

The paper by Skudlarski et al. reports brain imaging investigations (DTI) from the same sample. Decreased fractional anisotropy was found in multiple brain regions in schizophrenia and psychotic bipolar disorder subjects, and to a smaller extent in their relatives, than in healthy controls. These findings seem consistent, as 15 out of 18 regions have been previously reported in schizophrenia and 10 out of 21 in bipolar disorder. Further, the current results are in line with the continuum model of psychotic disorders and the polygenic architecture reported in recent mega-analyses (Lee et al., 2013).

Intriguingly, the authors found fractional anisotropy to be even better correlated with the "Schizo-Bipolar Scale" than with disease category. This proves the utility of cross-diagnostic clinical dimensions when investigating potential neurobiological mechanisms in psychiatric disorders. To bring this a step further, it would be interesting to know whether this clinical scale also correlates with fractional anisotropy (or neurocognition) within the bipolar disorder or the schizophrenia sub-sample separately.

In the perspective of the psychosis continuum model, it seems slightly contradictory that the investigators did not include schizoaffective disorder as a disease category on its own. Instead, they split this diagnostic group in two, classifying the depressed subgroup in the schizophrenia group and the manic subgroup in the psychotic bipolar disorder group. As a rationale for this classification, the authors reported controversial validity of the diagnostic status of schizoaffective disorder. If this controversy led to a split of the schizoaffective group in the paper by Skudlarski et al., why did the same controversy lead to the inclusion of schizoaffective disorder as its own category in the study by Hill et al.? Both approaches could potentially have been applied in both studies to actually explore this controversy in terms of neurocognition and white matter integrity.

Both studies support the hypothesis that reduced white matter integrity and impaired neurocognition are intermediate phenotypes in psychotic disorders. However, it might be debated whether these two features are causative in nature or merely correlate with the clinical symptomatology. Does reduced white matter integrity cause reduced neurocognition, which in turn gives rise to psychotic symptoms, or are the two latter phenomena independent but correlating effects of the former? Future studies should aim at disentangling these levels of correlating phenomena in biological psychiatric research. In line with this, it would be interesting to investigate the relationship between DTI measures and structural and functional MRI. Is the currently reported reduced white matter integrity reflected in the reductions identified with sMRI? And what consequences do these impairments have for brain activity as assessed with fMRI? Lastly, can these alterations be explained by genetic risk variants individually or in aggregate?

In summary, these two statistically well-powered studies have provided robust evidence for the continuum model in psychotic disorders. This is in accordance with findings from molecular genetics, brain imaging, and clinical studies. Now it is time to look for mechanisms behind these correlations.

References:

Hill SK, Reilly JL, Keefe RS, Gold JM, Bishop JR, Gershon ES, Tamminga CA, Pearlson GD, Keshavan MS, Sweeney JA. Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study. Am J Psychiatry . 2013 Jun 17. Abstract

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