Dopaminergic Neurotransmission in Patients with Schizophrenia in Relation to Positive and Negative Symptoms

O. Pogarell; W. Koch; S. Karch; S. Dehning; N. Müller; K. Tatsch; G. Poepperl; H.-J. Möller

doi:10.1055/s-0032-1306313

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2012; 45(S 01): S36-S41
DOI: 10.1055/s-0032-1306313

Original Paper

Dopaminergic Neurotransmission in Patients with Schizophrenia in Relation to Positive and Negative Symptoms

O. Pogarell^*

¹Department of Psychiatry, University of Munich, Munich, Germany

,

W. Koch^*

²Department of Nuclear Medicine, University of Munich, Munich, Germany

,

S. Karch

¹Department of Psychiatry, University of Munich, Munich, Germany

,

S. Dehning

¹Department of Psychiatry, University of Munich, Munich, Germany

,

N. Müller

¹Department of Psychiatry, University of Munich, Munich, Germany

,

K. Tatsch

²Department of Nuclear Medicine, University of Munich, Munich, Germany

³Department of Nuclear Medicine, Municipal Hospital of Karlsruhe Inc., Karlsruhe. Germany

,

G. Poepperl

²Department of Nuclear Medicine, University of Munich, Munich, Germany

⁴Department of Nuclear Medicine, Katharinenhospital, Stuttgart, Germany

,

H.-J. Möller

¹Department of Psychiatry, University of Munich, Munich, Germany

› Author Affiliations

Abstract

Schizophrenia is a complex dynamic disorder comprising a wide range of neurobiological alterations including dopaminergic dysfunction. The aim of the study was to investigate dynamic changes of dopaminergic neurotransmission in patients with schizophrenia (n=8, mean age 25.4±5.8 years) in early stages of the disorder, compared to healthy control subjects (n=7, mean age 23.6±2.7 years). A dynamic IBZM SPECT protocol was used to assess the endogenous dopamine release following an amphetamine challenge. Subjects received a bolus activity of 175 MBq followed by a continuous infusion of 45 MBq/h [¹²³I]IBZM. SPECT scans were performed 2 h after bolus injection, and 1 h following the amphetamine challenge (0.3 mg/kg). Striatal IBZM binding to dopamine D2 receptors was assessed with a volume-of-interest (VOI) technique. The change in IBZM binding between pre- and post-challenge scans was used as a measure of endogenous dopamine release triggered by amphetamine. At baseline, patients showed higher mean striatal IBZM binding compared to controls (0.77±0.09 vs. 0.68±0.07, p=0.07). There was a statistically significant difference in IBZM binding between patients, with a predominance of negative vs. positive symptoms (0.84±0.08 vs. 0.71±0.04, p<0.05). Upon amphetamine challenge, mean IBZM binding decreased by about 4.9±7.6% in controls (n=7) compared to a mean of 12.4±5.8% in subjects with schizophrenia (p<0.05). In patients, paranoid symptoms showed a significant negative correlation with IBZM baseline binding, whereas there was a trend towards positive correlation with the decrease of IBZM binding under challenge. Negative symptoms showed positive associations with baseline IBZM binding. The data are in line with previous reports and contribute to the notion of a dynamic instability of the dopaminergic system in patients with schizophrenia, taking into account the psychopathology with respect to positive or negative symptoms.

Key words

schizophrenia - dynamic systems disorder - dopamine - IBZM SPECT - amphetamine challenge

Full Text

References

References
1 Kleinman JE, Law AJ, Lipska BK et al. Genetic neuropathology of schizophrenia: new approaches to an old question and new uses for postmortem human brains. Biol Psychiatry 2011; 69: 140-145
2 Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006; 7: 818-827
3 Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963; 20: 140-144
4 Carlsson A, Waters N, Holm-Waters S et al. Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 2001; 41: 237-260
5 Angrist B, van Kammen DP. CNS stimulants as a tool in the study of schizophrenia. Trends Neurosci 1984; 7: 388-390
6 Andreasen NC. Positive and negative symptoms: historical and conceptual aspects. Mod Probl Pharmacopsychiatry 1990; 24: 1-42
7 Glick ID, Lemmens P, Vester-Blokland E. Treatment of the symptoms of schizophrenia: a combined analysis of double-blind studies comparing risperidone with haloperidol and other antipsychotic agents. Int Clin Psychopharmacol 2001; 16: 265-274
8 Glick ID, Suppes T, DeBattista C et al. Psychopharmacologic treatment strategies for depression, bipolar disorder, and schizophrenia. Ann Intern Med 2001; 134: 47-60
9 Andreasen NC, Flaum M, Swayze VW et al. Positive and negative symptoms in schizophrenia. A critical reappraisal. Arch Gen Psychiatry 1990; 47: 615-621
10 Andreasen NC, Flaum MA. Schizophrenia and related psychotic disorders. Hosp Community Psychiatry 1990; 41: 954-956
11 Ruhrmann S, Schultze-Lutter F, Klosterkotter J. Early detection and intervention in the initial prodromal phase of schizophrenia. Pharmacopsychiatry 2003; 36 (Suppl. 03) S162-S167
12 Strous RD, Alvir JM, Robinson D et al. Premorbid functioning in schizophrenia: relation to baseline symptoms, treatment response, and medication side effects. Schizophr Bull 2004; 30: 265-278
13 Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660-669
14 Davis KL, Kahn RS, Ko G et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-1486
15 Bender W, Albus M, Moller HJ et al. Towards systemic theories in biological psychiatry. Pharmacopsychiatry 2006; 39 (Suppl. 01) S4-S9
16 Tretter F. Mental illness, synapses and the brain – behavioral disorders by a system of molecules within a system of neurons?. Pharmacopsychiatry 2010; 43 (Suppl. 01) S9-S20
17 Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 1999; 13: 358-371
18 Laruelle M, Abi-Dargham A, Gil R et al. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999; 46: 56-72
19 Tretter F, Scherer J. Schizophrenia, neurobiology and the methodology of systemic modeling. Pharmacopsychiatry 2006; 39 (Suppl. 01) S26-S35
20 an der Heiden U. Schiszophrenia as a dynamical disease. Pharmacopsychiatry 2006; 39 (Suppl. 01) S36-S42
21 Abi-Dargham A, van de Giessen E, Slifstein M et al. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry 2009; 65: 1091-1093
22 Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 2000; 31: 371-384
23 Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 1998; 42: 211-221
24 Laruelle M, Abi-Dargham A, van Dyck CH et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235-9240
25 Soares JC, Innis RB. Neurochemical brain imaging investigations of schizophrenia. Biol Psychiatry 1999; 46: 600-615
26 Patel NH, Vyas NS, Puri BK et al. Positron emission tomography in schizophrenia: a new perspective. J Nucl Med 2010; 51: 511-520
27 Erritzoe D, Talbot P, Frankle WG et al. Positron emission tomography and single photon emission CT molecular imaging in schizophrenia. Neuroimaging Clin N Am 2003; 13: 817-832
28 Schmitt GJ, la Fougere C, Dresel S et al. Dual-isotope SPECT imaging of striatal dopamine: first episode, drug naive schizophrenic patients. Schizophr Res 2008; 101: 133-141
29 Schmitt GJ, Meisenzahl EM, Frodl T et al. Increase of striatal dopamine transmission in first episode drug-naive schizophrenic patients as demonstrated by [(123)I]IBZM SPECT. Psychiatry Res 2009; 173: 183-189
30 Laruelle M, Abi-Dargham A, van Dyck CH et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med 1995; 36: 1182-1190
31 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276
32 Wittchen HU, Zaudig M, Fydrich T. Strukturiertes klinisches Interview für DSM-IV Achse I und II - SKID. Göttingen, Germany: Hogrefe; 1997
33 Pogarell O, Koch W, Popperl G et al. Acute prefrontal rTMS increases striatal dopamine to a similar degree as D-amphetamine. Psychiatry Res 2007; 156: 251-255
34 Chang LT. A method for attenuation correction in radionuclide computed tomography. IEEE Trans Nucl Sci 1978; 25: 638-642
35 Koch W, Radau PE, Hamann C et al. Clinical testing of an optimized software solution for an automated, observer-independent evaluation of dopamine transporter SPECT studies. J Nucl Med 2005; 46: 1109-1118
36 Kung HF, Alavi A, Chang W et al. In vivo SPECT imaging of CNS D-2 dopamine receptors: initial studies with iodine-123-IBZM in humans. J Nucl Med 1990; 31: 573-579
37 Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 2000; 20: 423-451
38 Kay SR, Opler LA. The positive-negative dimension in schizophrenia: its validity and significance. Psychiatr Dev 1987; 5: 79-103
39 Rolls ET, Loh M, Deco G et al. Computational models of schizophrenia and dopamine modulation in the prefrontal cortex. Nat Rev Neurosci 2008; 9: 696-709
40 Winterer G, Egan MF, Kolachana BS et al. Prefrontal electrophysiologic “noise” and catechol-O-methyltransferase genotype in schizophrenia. Biol Psychiatry 2006; 60: 578-584
41 Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004; 27: 683-690
42 Durstewitz D, Seamans JK. The computational role of dopamine D1 receptors in working memory. Neural Netw 2002; 15: 561-572
43 Durstewitz D, Seamans JK. The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-O-methyltransferase genotypes and schizophrenia. Biol Psychiatry 2008; 64: 739-749
44 Durstewitz D, Seamans JK, Sejnowski TJ. Neurocomputational models of working memory. Nat Neurosci 2000; 3 (Suppl) 1184-1191
45 Abi-Dargham A, Gil R, Krystal J et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761-767
46 Buchsbaum MS, Christian BT, Lehrer DS et al. D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia. Schizophr Res 2006; 85: 232-244
47 Slifstein M, Narendran R, Hwang DR et al. Effect of amphetamine on [(18)F]fallypride in vivo binding to D(2) receptors in striatal and extrastriatal regions of the primate brain: Single bolus and bolus plus constant infusion studies. Synapse 2004; 54: 46-63