Psychiatric Annals

CME Article 

Evoked Response Potential Endophenotypes Link Schizophrenia and Psychotic Bipolar Disorder

Nathaniel G. Hurwitz, MD; Daniel J. Aires, MD, JD

Abstract

It has long been debated whether psychotic bipolar disorder and schizophrenia represent two separate diseases (the “Krapelinian dichotomy”) or rather one disease with a spectrum of severity. Although many genetic and environmental factors contribute to developing functional psychotic illness, most genetic abnormalities first described in schizophrenia have now been linked with psychotic bipolar disorder. Recently, some parameters that differentiate patients diagnosed as schizophrenic from controls have begun to be measured in patients diagnosed with psychotic bipolar disorder. Although funding channels have long facilitated study of chronically mentally ill schizophrenia populations, new data point toward the need to broaden the field of enquiry to “psychosis,” which links psychotic bipolar disorder and schizophrenia.

Abstract

It has long been debated whether psychotic bipolar disorder and schizophrenia represent two separate diseases (the “Krapelinian dichotomy”) or rather one disease with a spectrum of severity. Although many genetic and environmental factors contribute to developing functional psychotic illness, most genetic abnormalities first described in schizophrenia have now been linked with psychotic bipolar disorder. Recently, some parameters that differentiate patients diagnosed as schizophrenic from controls have begun to be measured in patients diagnosed with psychotic bipolar disorder. Although funding channels have long facilitated study of chronically mentally ill schizophrenia populations, new data point toward the need to broaden the field of enquiry to “psychosis,” which links psychotic bipolar disorder and schizophrenia.

Daniel J. Aires. MD, JD, is Stiefel Professor of Dermatology, Director, Division of Dermatology, University of Kansas School of Medicine, 3901 Rainbow Blvd, M.S. 2025, Kansas City, KS 66160; or e-mail daires@kumc.edu.

Dr. Aires and Dr. Hurwitz have disclosed no relevant financial relationships.

It has long been debated whether psychotic bipolar disorder and schizophrenia represent two separate diseases (the “Krapelinian dichotomy”) or rather one disease with a spectrum of severity. Although many genetic and environmental factors contribute to developing functional psychotic illness, most genetic abnormalities first described in schizophrenia have now been linked with psychotic bipolar disorder. Recently, some parameters that differentiate patients diagnosed as schizophrenic from controls have begun to be measured in patients diagnosed with psychotic bipolar disorder. Although funding channels have long facilitated study of chronically mentally ill schizophrenia populations, new data point toward the need to broaden the field of enquiry to “psychosis,” which links psychotic bipolar disorder and schizophrenia.

Evoked response potential (ERP) studies can shed light on complex multi-factorial conditions, such as bipolar disorder, psychotic bipolar disorder, and schizophrenia. ERPs measure brainwaves via electrodes placed on a subject’s scalp. Most ERP research focuses on subclinical abnormalities, called “endophenotypes.” These ERP abnormalities arise in non-ill, as well as clinically ill, subjects. Endophenotypes are least common in the normal population, more common in clinically normal subjects with psychiatrically ill relatives, and most common in the mentally ill.

ERP findings can be thought of in terms of genetic, or “trait” markers, and functional status, or “state” markers. Both can help inform the debate as to whether schizophrenia and psychotic bipolar disorder are two separate illnesses or a single disorder with a spectrum of severity. If schizophrenia and psychotic bipolar disorder are separate, then their similar trait markers should segregate out and not be common to both groups and their relatives. If schizophrenia and psychotic bipolar disorder are a single disease, then trait markers should be found in schizophrenia and psychotic bipolar disorder, as well as their relatives.

The “state” argument requires assessment of where subjects are in the course of their disease. As in seizure disorder, acute episodes in bipolar disorder and psychotic bipolar disorder recur in a “kindling” pattern of increasing frequency and severity over time. The toxic effects of recurrent acute psychotic episodes can eventually result in chronic psychotic symptoms at baseline. In schizophrenia, interepisode remission and progressive neurocognitive decline have also been described. If schizophrenia is, in fact, severe psychotic bipolar disorder, then “state-dependent” components of endophenotypes should be similar in schizophrenia and late or severe psychotic bipolar disorder but different in early psychotic bipolar disorder. Intermediate-level psychotic bipolar disorder, or study groups containing various stages of psychotic bipolar disorder should show intermediate deficits — somewhere between schizophrenia and control groups.

State-dependent ERP findings are also influenced by whether subjects are acutely decompensated, or are “well controlled,” in between episodes. A subtle but important distinction arises in that state markers will differ greatly between acutely symptomatic psychotic bipolar disorder and interepisode, well-controlled, early-intermediate, psychotic bipolar disorder but should vary less in decompensated versus baseline “schizophrenia” because of the greater baseline severity of patients diagnosed with schizophrenia. Because brain information is transmitted via electricity and ERPs are electrical measures, ERPs map brain events “at the speed of thought.” The discussion below is based on 50 years of a confused literature.

P50 Gating

P50 refers to brain activity approximately 50 msec after ERP stimulus. Typically, a second identical stimulus induces a smaller, “gated” response relative to the first. Gating is thought to be because of brain circuitry that helps people ignore irrelevant things. About 70% suppression of a second click’s P50 amplitude is considered normal “gating.” Unfortunately, many people’s P50s are not much larger than their “background” alpha rhythms, so P50 gating reliability is good only within a few labs. First described as a schizophrenia endophenotype, P50 gating deficits have since been found in psychotic bipolar disorder.

Martin et al studied the effect on P50 gating of a specific allelic variation in a region coding a promoter for the alpha-7 acetylcholine nicotinic receptor on chromosome 15 (CHRNA7). They compared 17 schizoaffective bipolar type patients with previously gathered data from 37 schizophrenia and 149 control subjects.1 CHRNA7 allelic variants were present in 28% controls, 35% of schizoaffective psychotic bipolar disorder patients, and 30% of schizophrenia patients. The CHRNA7 variant “trait” reduced P50 gating in controls and schizoaffective psychotic bipolar disorder but not schizophrenia. The lack of CHRNA7 effect on schizophrenia could reflect state effects of severe psychotic illness overwhelming small trait effects seen in controls and schizoaffective bipolar type patients. Importantly, as would be expected in the “single disease” model, overall P50 gating was significantly reduced in schizophrenia patients relative to controls and was also reduced in the schizoaffective psychotic bipolar disorder group but to a lesser extent.

Noting emerging data linking schizophrenia and affective psychosis, such as psychotic bipolar disorder, Franks et al studied P50 gating in 11 acutely psychotic manic patients, 10 euthymic bipolar patients, and 22 control subjects to compare them with a recently studied group of 75 schizophrenia patients, which included acute and stable schizophrenia patients.2 The acutely manic group was assessed during the first week of hospitalization and weekly afterward. The manic group showed significant gating impairment while the euthymic and control groups showed normal gating. Furthermore, suppression of gating correlated with Manic State Rating Scale scores. Importantly, acutely manic patients could not be distinguished from previously studied schizophrenia patients. Manic patients whose symptoms improved showed reduction in gating deficits, while those who did not improve showed sustained gating deficits. This shows that state-dependent P50 measures differ between acutely symptomatic bipolar disorder and interepisode, well-controlled bipolar disorder and also that acutely symptomatic bipolar disorder is indistinguishable from schizophrenia.

Sanchez-Morla et al studied 50 psychotic bipolar disorder patients (mean duration of illness (MDOI) 20 years), 92 stable schizophrenia diagnosed patients (MDOI 15.7 years) and 67 controls3 and found that gating impairment did not differentiate schizophrenia from psychotic bipolar disorder, but both differed from controls. This suggests that highly kindled psychotic bipolar disorder is indistinguishable from schizophrenia and supports the “single disease” theory.

Olincy and Martin studied 15 patients diagnosed with non-psychotic bipolar disorder, 29 with psychotic bipolar disorder, 22 with schizoaffective psychotic bipolar disorder type, 36 with schizophrenia, as well as 42 controls.4 Number of episodes and MDOI were not described. The schizoaffective psychotic bipolar disorder group had significantly more positive and negative mood symptoms than either bipolar group. Symptom severity data were not available for schizophrenia. Schizophrenia showed the largest gating deficits, psychotic bipolar disorder showed smaller deficits, and non-psychotic bipolar disorder did not show reduced gating compared with controls. Importantly, a history of psychosis at any time was associated with impaired gating, regardless of diagnosis. This also points toward a single disease with a severity spectrum.

P300 Amplitude

The most common ERP paradigm is the auditory oddball, so named because it involves a sequence of two tones: a less frequent “oddball” tone, about 20% of stimuli, and a more frequent “standard” tone (80%). Subjects press a button upon detecting the oddball (target) but not the standard (non-target) tones. The oddball target P300 is linked to the decision process, which relies on memory to compare the incoming tone with stored “target” and “non-target” tone information.

Some data support “trait” contributions to P300. Most comparative studies across diagnoses involve many families, and each family may have its own different vulnerability factors. Hennah et al reported an important finding within one large family with many psychiatrically ill members. A breakpoint on chromosome 1 at 1q42.2 resulted in disruption of two specific genes, disrupted in schizophrenia 1 and 2 (DISC1 and DISC2). Of the 77 family members studied, 34 carried the translocation between chromosomes 1 and 11, t(1;11). Within this family, 18 t(1;11) family members were diagnosed with either schizophrenia, bipolar disorder, or recurrent major depression. No normal karyotype family member manifested major mental illness. Translocation carriers (not psychiatrically ill) showed P300 reductions compared with non-carriers as well as healthy unrelated controls. This shows a powerful trait factor affecting P300 conferring non-specific major mental illness.5

Analysis of five twin studies yielded 60% meta-heretability for P300 amplitude.6 Reduced P300 amplitude has been shown in relatives of schizophrenia and psychotic bipolar disorder probands7,8 — a P300 trait similarity between schizophrenia and psychotic bipolar disorder.

Many cross-sectional studies and studies of only two time points report either invarient or state-dependent changes in P300 amplitudes in schizophrenia. Mathalon et al measured P300 and Brief Psychiatric Rating Scale scores in 34 schizophrenia patients on multiple occasions at varying intervals and medication states. Amplitudes were consistently reduced relative to controls (trait). Within schizophrenia, amplitudes tracked longitudinally with symptoms, consistently reducing when patients were more symptomatic and increasing (toward normal) with improvement. This convincingly demonstrates trait as well as state dependence in schizophrenia.9

O’Donnell et al studied 13 manic or mixed bipolar patients, 12 schizophrenia patients, and 24 controls.10 Eleven of the bipolar disorder patients were inpatients with acute symptoms at the time of testing, whereas only five schizophrenia patients were in the hospital. MDOI was 14 years for bipolar disorder and 17.6 years for schizophrenia. P300 was significantly reduced in patients compared with controls, with no significant difference between bipolar disorder and schizophrenia, supporting the single disease theory.

Bestelmeyer et al studied 21 schizophrenia and 19 bipolar disorder patients; all were interepisode, stable outpatients.11 Mean duration of illness for schizophrenia and BP were 18.9 and 22.7, respectively, suggesting advanced disease in both groups. P300 amplitude was non-differential between the schizophrenia and psychotic bipolar disorder groups, leading authors to conclude, “It appears that the P300 may be a marker for functional psychosis in general rather than being specific to schizophrenia.”

Some groups have reported left-lateralized P300 amplitude deficits in schizophrenia, whereas others have not been able to replicate this finding. McCarley et al studied 15 first-episode schizophrenia patients and 18 first-episode affective psychosis patients, of whom 17 were psychotic bipolar disorder, and 15 controls.12 It should be mentioned that of the 15 labeled schizophrenia, 60% (9) had previously been prescribed “either antipsychotic, antidepressive, or mood-stabilizing medication.” This raises the possibility that most schizophrenia-labeled subjects may in fact have had previous mood episodes. Left posterior superior temporal gyrus (LPSTG) volumes were greatest in control (0.480 +/− .047), smaller in psychotic bipolar disorder (0.456 +/−.070) and smallest in schizophrenia (0.406 +/− .055). P300 varied significantly with LPSTG in schizophrenia. They did not report whether, as would be expected, a directionally similar but smaller and non-significant association was found in the psychotic bipolar disorder subjects.

Notably, the McCarley group subsequently studied a larger group of 26 first-episode affective, of whom 24 were psychotic bipolar disorder, 53 first-episode schizophrenia, and 29 controls, and examined gray-matter volumes in the left temporal pole, which includes the LPSTG.13 They found that the schizophrenia and affective psychosis/psychotic bipolar disorder groups had significantly reduced left temporal pole gray matter volume relative to controls, with no difference between the two psychosis groups. They, unfortunately, did not measure P300 amplitudes.

In the 2002 paper, McCarley’s group ascribed P300 effects to gray matter loss in schizophrenia patients. Multiple imaging studies have shown left lateral volume loss in psychotic bipolar disorder. Stanfield et al showed that in familial bipolar disorder, psychosis associated with left temporal gray matter reductions.14 Chen et al found that left temporal gray matter reduction associated with psychosis in bipolar disorder.15 Kasai et al reported reduced left temporal pole gray matter in first-episode schizophrenia and first-episode affective (mainly manic) psychosis.13 Qiu et al found the same pattern and degree of abnormal left planum temporale thinning in psychotic bipolar disorder and schizophrenia.16 All of these link psychotic bipolar disorder with schizophrenia. Although left-lateralized P300 amplitude reduction has yet to be demonstrated in psychotic bipolar disorder, it may only be a matter of time.

Conclusion

All people have better and worse moods. All clinicians who have followed patients through first-break psychotic episodes know the extreme anxiety, sensitivity to expressed emotion, and blatant mood alteration that herald and accompany this cataclysmic event. Mood is universal and influences sleep architecture, nerve growth factor and other plasticity factors,17 so it is difficult to imagine a lack of interaction between mood and psychosis vulnerability factors. Acknowledging mood focuses attention away from studying chronically ill and medicated populations and toward translational use of ERP markers first studied in those populations.

Longitudinal stability is key in managing chronic diseases such as diabetes, seizure disorder, and functional psychosis. As in seizure disorder, acute episodes in bipolar disorder and psychotic bipolar disorder recur in a “kindling” pattern of increasing frequency and severity over time.18 In schizophrenia, kindling has not been studied, but it is now widely known that patients show acute episodes superimposed on a larger pattern of gradually declining inter-episode baseline. The absence of lab testing negatively differentiates clinical psychiatry from other medical fields. ERPs are developmental markers.19 If, as some studies suggest, left-temporal P300 amplitude reduction identifies subgroups with severe mental illness, children from families with such vulnerability factors could be followed longitudinally for early evidence of endophenotypic variation. Interventions could then be started early, which might alter disease progression.

As with genetic studies, the most-replicated ERP findings in schizophrenia research were subsequently sought and found in psychotic bipolar disorder. P50 gating was first described in schizophrenia and subsequently demonstrated in psychotic bipolar disorder. P300 amplitude reduction too is a highly replicated finding in schizophrenia, which has since been shown in psychotic bipolar disorder, and recently in unaffected relatives of psychotic bipolar disorder probands. This argues for a single disease with a broad spectrum of severity.

References

  1. Martin LF, Leonard S, Hall MH, Tregellas JR, Freedman R, Olincy A. Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(5):611–614. doi:10.1002/ajmg.b.30470 [CrossRef]
  2. Franks RD, Adler LE, Waldo MC, Alpert J, Freedman R. Neurophysiological studies of sensory gating in mania: comparison with schizophrenia. Biol Psychiatry. 1983;18(9):989–1005.
  3. Sanchez-Morla EM, García-Jiménez MA, Barabash A, et al. P50 sensory gating deficit is a common marker of vulnerability to bipolar disorder and schizophrenia. Acta Psychiatr Scand. 2008;117(4):313–318. doi:10.1111/j.1600-0447.2007.01141.x [CrossRef]
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  5. Hennah W, Thomson P, Peltonen L, Porteous D. Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness. Schizophr Bull. 2006;32(3):409–416. doi:10.1093/schbul/sbj079 [CrossRef]
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  7. Bramon E, McDonald C, Croft RJ, et al. Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study. Neuroimage. 2005;27(4):960–968. doi:10.1016/j.neuroimage.2005.05.022 [CrossRef]
  8. Schulze KK, Hall MH, McDonald C, et al. Auditory P300 in patients with bipolar disorder and their unaffected relatives. Bipolar Disord. 2008;10(3):377–386. doi:10.1111/j.1399-5618.2007.00527.x [CrossRef]
  9. Mathalon DH, Ford JM, Pfefferbaum A. Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study. Biol Psychiatry. 2000;47(5):434–449. doi:10.1016/S0006-3223(99)00277-2 [CrossRef]
  10. O’Donnell BF, Vohs JL, Hetrick WP, Carroll CA, Shekhar A. Auditory event-related potential abnormalities in bipolar disorder and schizophrenia. Int J Psychophysiol. 2004;53(1):45–55. doi:10.1016/j.ijpsycho.2004.02.001 [CrossRef]
  11. Bestelmeyer PE, et al. The P300 as a possible endophenotype for schizophrenia and bipolar disorder: evidence from twin and patient studies. Psychiatry Res. 2009;169(3):212–219. doi:10.1016/j.psychres.2008.06.035 [CrossRef]
  12. McCarley RW, Salisbury DF, Hirayasu Y, et al. Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Arch Gen Psychiatry. 2002;59(4):321–331. doi:10.1001/archpsyc.59.4.321 [CrossRef]
  13. Kasai K, Shenton ME, Salisbury DF, et al. Differences and similarities in insular and temporal pole MRI gray matter volume abnormalities in first-episode schizophrenia and affective psychosis. Arch Gen Psychiatry. 2003;60(11):1069–1077. doi:10.1001/archpsyc.60.11.1069 [CrossRef]
  14. Stanfield AC, Moorhead TW, Job DE, et al. Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder. Bipolar Disord. 2009;11(2):135–144. doi:10.1111/j.1399-5618.2009.00666.x [CrossRef]
  15. Chen X, Wen W, Malhi GS, Ivanovski B, Sachdev PS. Regional gray matter changes in bipolar disorder: a voxel-based morphometric study. Aust N Z J Psychiatry. 2007;41(4):327–336. doi:10.1080/00048670701213229 [CrossRef]
  16. Qiu A, Vaillant M, Barta P, Ratnanather JT, Miller MI. Region-of-interest-based analysis with application of cortical thickness variation of left planum temporale in schizophrenia and psychotic bipolar disorder. Hum Brain Mapp. 2008;29(8):973–985. doi:10.1002/hbm.20444 [CrossRef]
  17. Walker MP. The role of sleep in cognition and emotion. Ann N Y Acad Sci. 2009;1156:168–197. doi:10.1111/j.1749-6632.2009.04416.x [CrossRef]
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  19. Ponton C, Eggermont JJ, Khosla D, Kwong B, Don M. Maturation of human central auditory system activity: separating auditory evoked potentials by dipole source modeling. Clin Neurophysiol. 2002;113(3):407–420. doi:10.1016/S1388-2457(01)00733-7 [CrossRef]

CME Educational Objectives

  1. Recognize ERP endophenotypes, such as P50 and P300.

  2. Cite the implications of ERP P50 data for distinctions between schizophrenia and bipolar disorder.

  3. Define the implications of ERP P300 data for distinctions between schizophrenia and bipolar disorder.

Authors

Daniel J. Aires. MD, JD, is Stiefel Professor of Dermatology, Director, Division of Dermatology, University of Kansas School of Medicine, 3901 Rainbow Blvd, M.S. 2025, Kansas City, KS 66160; or e-mail daires@kumc.edu.

Dr. Aires and Dr. Hurwitz have disclosed no relevant financial relationships.

10.3928/00485713-20100303-06

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