Schizophrenia: From the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers

Figures & data

Figure 1.  The proposed cortical-subcortical circuitry implicated in schizophrenia. Relevant dopaminergic, glutamatergic, and GABAergic projections are depicted with bulky, fine, and dotted arrows, respectively. The nucleus accumbens, which receives extensive dopaminergic input from the ventral tegmental area (VTA) of the midbrain and prominent excitatory input from cortical areas, the prefrontal cortex (PFC), the hippocampus, and the amygdala, is thought to play a crucial role in integrating prefrontal and limbic input. Inhibitory projections from the nucleus accumbens are sent to the ventral pallidum, which projects to specific nuclei of the thalamus, which in turn send excitatory projections to various regions of the PFC. Dopaminergic projections from the VTA also innervate the PFC. Interactions between the PFC, the amygdala, and the hippocampus are not depicted (adopted from Thompson et al. 2004).

Table I.  Imaging studies of striatal presynaptic dopamine parameters in drug-naive (DN), drug free (DF) and treated (T) patients with schizophrenia.

Parameter	Study	Number of Patients (DN/DF/T)	Radiotracer	P	Effect size
DOPA accumulation	Reith et al. 1994	5 (4/0/1)	[^18F]DOPA	<0.05	0.91
	Hietala et al. 1995	7 (7/0/0)	[^18F]DOPA	<0.05	1.54
	Dao-Castellana et al. 1997	6 (2/4/1)	[^18F]DOPA	NS	0.3
	Lindstrom et al. 1999	12 (10/2/0)	[^11C]DOPA	<0.05	0.77
	Hietala et al. 1999	10 (10/0/0)	[^18F]DOPA	<0.05	1.09
	Elkashef et al. 2000	19 (0/9/10)	[^18F]DOPA	<0.05	−0.65
	Meyer-Lindenberg et al. 2002	6 (0/6/0)	[^18F]DOPA	<0.02	1.96
	McGowan et al. 2004	16 (0/0/16)	[^18F]DOPA	0.001	1.6
Amphetamine-induced DA release	Laruelle et al 1996	15 (2/13/0)	[^123I]IBZM/amphetamine	<0.05	1.51
	Breier et al. 1997	18 (8/10/0)	[^11C]raclopride amphetamine	<0.05	1.73
	Abi-Dargham et al 1998	21 (1/20/0)	[^123I]IBZM/amphetamine	<0.05	1.07
Baseline DA concentration	Abi-Dargham et al. 2000	18 (8/10/0)	[^123]IBZM/AMPT	<0.05	1.43
dopamine transporter density	Laakso et al. 2000	9 (9/0/0)	[^18F]CFT	<0.05	0.11
	Laruelle et al. 2000	22 (2/22/0)	[^123]CIT	<0.05	−0.43
	Hsiao et al. 2003	12 (l2/0/0)	[^99mTc]TRODAT	NS	0.22

Effect size is calculated as (mean patients – mean controls)/standard deviation controls (adopted from Toda and Abi-Dargham 2007). Abbreviations used: DOPA: dihydroxyphenylalanine; AMPT:-α-methylparatyrosine; DA: dopamine; preDCA: precommissural caudate; IBZM: iodobenzamide; TRODAT is a tropane derivative.

Figure 2.  Schizophrenia-susceptibility genes and synaptic plasticity: The glutamatergic synapse with a hypothetical scenario in which genes (in italics) may have shared effects on synapses via influences on their formation, plasticity or signalling properties. Solid arrows point to direct interactions, dotted ones to indirect action. mGluR: metabotropic glutamate receptor, NMDA: ionotropic N-methyl-D-aspartate receptor, P5C: ▵1pyrroline-5- carboxylate; PRODH: proline dehydrogenase. (adopted from Harrison and Owen 2003).

Table II.  Glutamate parameters measured in brain tissue of schizophrenia patients

Parameter	Method	Hippocampus	Cortex	Thalamus	Reference
NMDA receptor	Binding	▾	n.d.	▾	Kerwin et al. 1988; Kornhuber et al. 1989; Ibrahim et al. 2000
Glutamate	re-uptake	n.d.	▴	n.d.	Miyamoto et al. 2003
Glutamate	Release	n.d.	▾	n.d.	Miyamoto et al. 2003
GRIA1	Protein	▾▴	n.d.	n.d.	Eastwood et al. 1997
GRIA2/3	Protein	▾	n.d.	N.d.	Eastwood et al. 1997
NMDZ1	mRNA	▾	n.d.	▾	Gao et al. 2000; Ibrahim et al. 2000; Law and Deakin 2001
NMDE2	mRNA	▴	n.d.	▾	Gao et al. 2000; Ibrahim et al. 2000
NMDE3	mRNA	n.d.	n.d.	▾	Ibrahim et al. 2000
GRIA 1	mRNA	▾	n.d.	▾	Harrison et al. 1991; Eastwood et al. 1995; Ibrahim et al. 2000
GRIA 2	mRNA	▾		n.c.	Eastwood et al. 1995
GRIA 3	mRNA			▾	Ibrahim et al. 2000
GRIK2	mRNA	▾		▾	Ibrahim et al. 2000; Porter et al. 1997
VGluT1	mRNA	▾			Harrison et al. 2003; Eastwood and Harrison 2005
VGluT2	mRNA			▴	Smith et al. 2001a, b
EAA1	mRNA			▴	Ohnuma et al. 2000
EAA2	mRNA			▴	Ohnuma et al. 2000

Abbreviations: ▾decreased in schizophrenia vs. controls; ▴ increased in schizophrenia vs. controls; n.c. not changed; n.d. not detected; —, not measured. NMDA, N-methyl-d-aspartate; GRIA, AMPA-selective glutamate receptor (synonym GluR); NMDZ1, glutamate (N-methyl-d-aspartate) receptor subunit 1 (synonym NR1); NMDE2, glutamate [NMDA] receptor subunit epsilon-2 (synonym NR2B); NMDE3, glutamate [NMDA] receptor subunit epsilon-3 (synonym NR2C); GRIK5, glutamate receptor, ionotropic kainate 5 (synonym KA2); VGLUT, vesicular glutamate transporter; EAA, excitatory amino acid transporters (see UniProt/Swiss-Prot; pers. comm. E. Grünblatt).

Figure 3.  The reelin cascade in the aetiopathology of schizophrenia. Reelin binds to the very-low-density lipoprotein receptor (VLDLR) and APOE receptor 2 (APOER2) that results in the activation of the cytoplasmic DAB1 (adapter protein disabled 1). Phosphorylated DAB1 activates phosphatidylinositide 3-kinase (PI3K) and subsequently AKT (V-akt murine thymoma viral oncogene homologue). AKT activation inhibits the activity of glycogen synthetase kinase 3 β (GSK3β) resulting the inhibition of t phosphorylation that promotes microtubule stability. DAB1 also activates SRC family tyrosine kinases (SFKs) following NMDAR phosphorylation which potentiates NMDAR-mediated Ca2+ influx. Elevated Ca2+ activates cAMP-response element binding protein (CREB) that initiates expression of important genes for synaptic plasticity, neurite growth, and dendritic spine development (adopted from Herz and Chen 2006).

Table III.  Synopsis of selected characteristics of candidate endophenotypes in schizophrenia research (pers. comm. A. Jablensky)

Domain/Tests	Association with disorder	Effect size	Trait stability/State independence	Heritability/Segregation within Families	Underlying neurobiology/genetics
a) Cognition
Attention	SZ patients consistently worse than controls. CPT-IP associated with negative symptoms; CPT-DS associated with cognitive disorganization	CPT-IP d = 1.51 CPT-DS d = 1.29 (WAFSS)	Test-retest: CPT-IP r = 0.56 (SZ) 0.73 (C) CPT-DS r = 0.65 SZ) 0.72 (C) Both stable across clinical states	Twin studies: CPT-IP h^2=0.39–0.49 (C) CPT-DS h^2=0.51–0.57 (C) CPT-DS λr=9 (sibs) λr=12 (parents)	Linkage to 6p24 (WAFSS). Association with the 22q11 deletion syndrome
Continuous Performance Task (CPT)
Identical Pairs (CPT-IP): working memory load
Degraded Stimulus (CPT-DS): perceptual disambiguation
Verbal declarative memory (VDM)	The most consistently found deficit in SZ patients. VDM deficits related to negative symptoms	d = 1.41–2.39	Test-retest: r = 0.62–0.64 (SZ) r = 0.74–0.88 (C)	Twin studies: h^2=0.47–0.63 (C) h^2=0.21–0.49 (SZ) Mild deficits in unaffected family members.	VDM deficits associated with decreased volume of hippocampus; association with DISC1 reported.
WMS-III LM
CVLT
RAVLT
Working memory (WM)	Consistently found deficits in SZ patients	LNS > 1.4 SD (SZ vs controls) LNS d = 0.66 (unaffected family members vs controls)	Constancy over time; Minimal correlation with positive symptoms; moderate correlation with negative symptoms.	Twin studies: h^2=0.43–0.49 (C) h^2=0.36–0.42 (SZ)	WM deficits associated with DLPFC and posterior parietal dysfunction. Likely role of COMT rs 4680 (Val^158/108Met) and DISC1.
Online maintenance of information:
Spatial delayed response
Digits forward
Maintenance + manipulation
N-back tasks
Digits backward
Letter-number sequencing (LNS)
Face memory and emotion processing	Frequently found deficits in SZ patients	No published data	Possibly stable trait; more data required.	Twin studies: h^2=0.33 (faces) h^2=0.37 (emotion) Mild deficits in unaffected family members	Associations (fMRI): Faces: right fusiform gyrus and frontotemporal circuitry. Emotion: amygdala and hippocampus. Genetic association not known.
Face recognition tasks
Emotion recognition tasks
b) Neurophysiology/psychophysiology
Sensory gating	SZ patients fail to attenuate response to second (test) stimulus.	Amplitude: d = 0.78 Suppression ratio: d = 0.54 (WAFSS)	Test-retest: r = 0.66–0.73 Suppression deficit present in both acutely psychotic and stabilized patients. Clozapine reduces deficit.	Twin studies: h^2=0.53–0.68 Unaffected relatives and high-risk subjects show less suppression than controls, but data are inconsistent.	Cholinergic activation of hippo-campal CA3/CA4 interneurons inhibits the firing of pyramidal neurons. Involvement of temporoparie-tal and prefrontal circuits likely. Association with CHRNA7.
P50 event-related potential (suppression ratio and amplitude difference)
Failure of automatic inhibition	SZ patients are deficient in automatic inhibition of startle. The response is influenced by atypical an-tipsychotics and nicotine. DA agonists reduce, NMDA antagonists increase PPI.	Not available	Test-retest: r > 0.90 Longitudinal stability of PPI across clinical states has been little investigated.	Twin studies: h^2>0.50 PPI deficits found in unaffected family members. Males produce greater PPI than females. PPI in Asians > Caucasians	PPI regulated by a limbic cortico-striato-pallido-pontine circuit interacting with the primary startle circuit at the pons reticular nucleus. PPI is abnormal in the 22q11 deletion syndrome. Possible role of the D2-like receptor G-protein and hippocampal α5 subunit of the GABAa receptor.
Prepulse inhibition of startle reflex (PPI)
Stimulus deviance detection	Deficit is present in the majority of SZ patients (not ameliorated by atypical antipsychotics). Presence of MMN deficit in first-episode patients uncertain.	d∼1.0 (meta-analysis) d = 0.74 (WAFSS)	Test-retest: r = 0.78 (duration MMN) r = 0.53 (frequency MMN) Intraclass r = 0.9 over 1 year.	No formal h^2 estimates available. Abnormality is present in a proportion of unaffected family members.	MMN is reduced in the 22q11 deletion syndrome. Possible association with rs4680 (COMT).
Mismatch negativit (MMN): Formation of an early (pre-attentive) auditory memory trace; automatic comparison process. MMN tests the integrity of the primary auditory memory network.
Working memory updating/stimulus salience evaluation	Amplitude decrement and increased latency in SZ patients: one of the most consistent findings in the disorder.	Meta-analysis: d = 0.89 (amplitude) d = 0.59 (latency) WAFSS: d = 0.91 (amplitude)	Test-retest: r = 0.81–0.91 (2 weeks) r = 0.59–0.61 (1–2 years)	Twin studies: h^2=0.60 Unaffected family members similar to probands. Familial deficit most evident for P3a.	Amplitude decrement correlated with smaller left superior temporal gyrus. Genetic linkage to 6p24. Possible association with DISC1 and DRD2.
Auditory P300 event-related potential Composite of: P3a (frontal); P3b (parietal)
Saccadic dysfunction	SZ patients: increased error rate; longer latencies to correct AS; reduced spatial accuracy	d = 0.99 (patients vs controls, WAFSS) d = 0.99 (relatives vs controls)	Test-retest: r = 0.87 (2 years) COGS inter-site study: r = 0.77–0.96 Deficit stable across clinical states	Twin studies: h^2=0.57 Error rate in unaffected family members: inconsistent data	Sensorimotor reprogramming; DLPFC, lateral interparietal area, supplementary eye field neurons. Linkage to 22q1 1–12 (COMT effect?)
Antisaccade task (AS) Inhibition of reflexive prosaccade; performance of antisaccade to a mirror location
c) Neuroimaging
3-D computational cortical surface maping	Hippocampal volumes: Probands < unaffected co-twins < healthy subjects. Decrease in hippocampal size associated with cognitive deficit (memory dysfunction)	Not available	Not available	Twin studies: h^2=0.42	Hippocampal volume is environment- and activity-dependent. Possible role of DISC1, brain-derived neuro-trophic factor (BDNF) and translin-associated factor X (TRAX) genes.
Reduced hippocampal volumes
Corpus callosum morphology	Vertical (upward) displacement	Not available	Not available	Present in both affected and unaffected family members. Putative neuro-anatomical marker of biological vulnerability for SZ.	Genetic/neurodevelopmental origin likely.
fMRI response to working memory tasks	Exaggerated activation in right DLPFC in unaffected family members. Inefficient WM processing, similar to deficit in SZ patients.	Not available	Not available		Possible role of rs4680 (COMT).

Abbreviations. SZ, schizophrenia; C, controls; DLPFC, dorsolateral prefrontal cortex; WAFSS, Western Australian family study of schizophrenia.

Table IV.  CSF proteins and lipids involved in the pathophysiology of schizophrenia. Several CSF proteins and lipids are important in transport, nerve cell excitability, nerve cell growth and neuron secretion. These functions of lipids may have significant physiologic ramifications in schizophrenia (pers. comm. A. Fonteh)

Proteins	Lipid substrates and metabolites	Functions or putative mechanisms of action
apolipoproteins, apolipoprotein receptors, ATP-cassette binding proteins, LCAT, CETP	Phospholipids, cholesterol, fatty acids	Uptake and transport of lipids, nerve cell growth/regeneration
δ-6 or F-5-desaturases, elongase	Polyunsaturated fatty acids (1PUFA)	Synthesis of ^1PUFAs, membrane fluidity, receptor function
Cycloxygenases, lipoxygenases, monoxygenases, prostaglandin synthases	Polyunsaturated fatty acids (AA, EPA, DHA), prostaglandins, leukotrienes	Signal transduction, lipid mediators of inflammation and pain, neurotransmission
Phosphoinositide kinases	Phosphotidylinositols, phosphoinositides	Signalling molecules, receptor function, vesicle formation, fusion, trafficking exocytosis, neurotransmitter secretion
Transferases, transacylases, phospholipases (PLA2, PLC, PLD), platelet-activating factor-acetyl hydrolases (PAFAH), sphingomyelinase	Phospholipids, lyso-phospholipids, sphin-gosine-1-phosphate, diacylglycerols, phos-phatidic acid, inositol phosphates, endocan-nabinoids, platelet-activating factor	Physical properties of cell membranes, endocytosis, vesicle formation, secretion, plasticity, precursors of lipid mediators of inflammation and pain, signalling molecules
Fatty acid amide hydrolase (FAAH), monoglyceride lipases	Fatty acid amides (e.g., arachidonoyl etha-nolamide, AEA), and fatty acyl glycerols (e.g., arachidonoyl-glycerol) known as en-docannabinoids	Signalling molecules, ligands of G-protein-coupled receptors (CB1 and CB2) receptor. Implicated in pain, depression, cognition, sleep, synap-tic plasticity, feeding and behavioural effects

Abbreviations. LCAT, lecithin-cholesterol acyl transferase; CETP, cholesterol ester transfer protein; PUFA, polyunsaturated fatty acids; AA, arachidonic acid; EPA, eicisapentaenoic acid; DHA, docosahexaenoic acid; CB, cannabinoid.

Figure 4.  Chromosomal susceptibility loci for schizophrenia derived by meta-analyses of genomewide linkage scans, and proposed risk genes (pers. comm. M. Gawlik).

Table V.  Candidate genes for schizophrenic psychoses and strength of the biological evidence

		Weighting the evidence (0–5 + )* for
gene	Chromosomal localisation	genetic association with schizophrenia	linkage to gene locus	biological function	altered espiession in schizophrenia
RGS4	1q23.3	+++	+++	synaptic signalling	yes
DISC1	1q42.2	++++	++	neuional migrating	not known
DTNBP1 (Dysbindin)	6p22.3	+++++	++++	glutamate release	yes
NRGl(Neuregulin)	8p12	+++++	++++	neuronal migration, glutamate signalling	yes
d-amino-acid oxidase (DAO)	12q24	+++	++	glutamate signalling	not known
d-amino-acid oxidase activator (G72/G30)	13q33.2	+++	++	glutamate signalling	not known
AKT1	14q32.33	+	+	synaptic signalling	yes
COMT	22q11	++++	++++	dopamine metabolism	yes

*according to Harrison and Weinberger (2005); chromosomal localisation acc. to UCSC database (genome.ucsc.edu/)

Note: effect size does not exceed “minor gene” effects (estimated OR 1.5–1.8).

Figure 5.  The potential role of cytokines in the pathophysiology of schizophrenia (pers. comm. YK Kim).

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