Schizophrenia Research 193 (2018) 443–444
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Central serotonergic function in patients with predominantly negative symptoms of schizophrenia Keywords: Serotonin LDAEP Auditory evoked potentials Schizophrenia Positive symptoms Negative symptoms
Negative symptoms are extremely debilitating in the long-term course of schizophrenia. Because of the successful treatment of negative symptoms using serotonergic substances an involvement of the serotonergic system has been suggested. The “serotonergic paradox” describes that serotonergic agonists as well as antagonists can be used in the treatment of negative symptoms which led to the conclusion that there may be one common final effect (Silver, 2004). The loudness dependence of auditory evoked potentials (LDAEP) is a method of measuring central serotonergic activity (Juckel et al., 1997; O'Neill et al., 2008) with low serotonergic activity indicated by high LDAEP amplitudes and vice versa. Schizophrenic patients exhibit a weaker LDAEP than healthy controls (Gudlowski et al., 2009; Juckel et al., 2003; Park et al., 2010). Wyss et al. (2013) found higher LDAEP in schizophrenic patients using dipole source analysis and a correlation of schizophrenic negative symptoms with the LDAEP of the right hemisphere. As these results contradicted most earlier findings, we aimed at replicating the study. 30 adult schizophrenia patients (24 male, mean age 37.8 ± 9.5 years) without neuropsychiatric comorbidity were included in the study and compared to 30 healthy controls (24 male, mean age 37.00 ± 11.0 years). Patients and controls did not differ regarding age or gender. 13 patients received an antipsychotic monotherapy while 16 had a polypharmaceutic treatment. PANSS (mean PANSS positive score: 18.5 ± 4.8, mean PANSS negative score: 18.4 ± 6.6, mean PANSS general score: 38.4 ± 7.6), SANS (mean score 34.8 ± 19.1), BDI (mean score 15.8 ± 12.3), HAMD 21 (mean score 17.1 ± 6.8), BRMS (mean score 13.6 ± 5.4) and CDSS-G (mean score: 6.1 ± 3.9) scales were performed with all patients. Healthy subjects had to answer M.I.N.I., BDI (mean score 1.6 ± 2.6) and HAMD 21 (mean score 0.6 ± 0.9) questionnaires. For details about the procedures see Ostermann et al. (2012). Using SPSS®, it was shown that schizophrenic patients exhibited a lower LDAEP by tendency (LDAEP of schizophrenic patients: 0.193 ± 0.203, LDAEP of healthy controls: 0.294 ± 0.188, p = 0.051, t-test). If only male subjects were taken into consideration, LDAEP was significantly lower in the patient sample (p = 0.032).
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Both authors contributed equally to this article.
http://dx.doi.org/10.1016/j.schres.2017.05.041 0920-9964/© 2017 Elsevier B.V. All rights reserved.
There were significant negative correlations between LDAEP and PANSS negative score (r = − 0.423, p = 0.02; Fig. 1) as well as SANS score (r = −0.373, p = 0.042) and the SANS subscores of affective flattening (r = −0.379, p = 0.039), and alogia (r = −0.393, p = 0.032) using Spearman correlation coefficient. There were no correlations between LDAEP and positive or general schizophrenic symptoms nor concomitant depressive symptoms. The findings of reduced serotonergic activity in schizophrenic patients are in accordance to earlier studies (Gudlowski et al., 2009; Juckel et al., 2003; Park et al., 2010). Nevertheless, in an earlier study, we found stronger LDAEP in schizophrenic patients than in healthy controls (Wyss et al., 2013). Contradictory results may be due to the fact that the nature of serotonergic dysfunction in schizophrenia may be dependent on the brain area where serotonin concentration is measured. Moreover, Wyss et al. (2013) used dipole source analysis to examine the data whereas we employed single-electrode estimation. Thus, data may be difficult to compare. Wyss et al. only examined 13 patients and controls versus 30 patients and controls in our study. Although sample sizes have to be regarded critically in both studies, these might present a source of ambiguous results. The heterogeneity of the disease may also influence the results. It is important to consider different symptoms of psychiatric diseases rather than an entire syndrome complex (Ostermann et al., 2012). The importance of considering data of schizophrenic patients in this more distinct way may also be underlined by the fact that a lot of different neurotransmitters are involved in the pathogenesis of schizophrenia, such as dopamine or glutamate. There were negative correlations between LDAEP and negative symptoms. Wyss et al.'s (2013) study exhibited a positive correlation between LDAEP and negative symptoms, while our results are in line with another study by Gudlowski et al. (2009) who also found a negative correlation between LDAEP and negative symptoms. However, there are other studies which did not show any correlations or tendencies to positive correlations (Juckel et al., 2003). Despite differences in methodology, difficulties distinguishing between primary and secondary negative symptoms may also account for contradictory results in different studies (Silver, 2004). Regarding limitations, influence of other neurotransmitters like dopamine, acetylcholine, glutamate or noradrenaline on LDAEP have to be taken into consideration (Juckel et al., 2007; O'Neill et al., 2007). Although several studies reported that there are no correlations between LDAEP and antipsychotic medication (Gudlowski et al., 2009; O'Neill et al., 2008; Ostermann et al., 2012; Park et al., 2010) medication effects cannot be ruled out. Age and gender of the participants may be influencing factors, although their effects might rather be improbable (Gudlowski et al., 2009; Juckel et al., 2003, 2007; Park et al., 2010). Smoking and attention deficits might also have influenced the results. The study shows that schizophrenic patients have an increased central serotonergic activity and the higher the serotonergic activity the stronger are schizophrenic negative symptoms. Thus, the present study underlines the importance of central serotonergic function in schizophrenic negative symptoms while positive symptoms are not
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Central serotonergic function in patients with predominantly negative symptoms of schizophrenia to serotonergic and noradrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder. J. Clin. Psychiatry 68 (8), 1206–1212. O'Neill, B.V., Croft, R.J., Leung, S., Oliver, C., Phan, K.L., Nathan, P.J., 2007. High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans. Psychopharmacology 195 (1), 85–93. O'Neill, B.V., Croft, R.J., Nathan, P.J., 2008. The loudness dependence of the auditory evoked potential (LDAEP) as an in vivo biomarker of central serotonergic function in humans: rationale, evaluation and review of findings. Hum. Psychopharmacol. 23 (5), 355–370. Ostermann, J., Uhl, I., Köhler, E., Juckel, G., Norra, C., 2012. The loudness dependence of auditory evoked potentials and effects of psychopathology and psychopharmacotherapy in psychiatric inpatients. Hum. Psychopharmacol. 27 (6), 595–604. Park, Y.M., Lee, S.H., Kim, S., Bae, S.M., 2010. The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34 (2), 313–316 (17). Silver, H., 2004. Selective serotonin re-uptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia. Expert. Opin. Pharmacother. 5 (10), 2053–2058. Wyss, C., Hitz, K., Hengartner, M.P., Theodoridou, A., Obermann, C., Uhl, I., Roser, P., Grünblatt, E., Seifritz, E., Juckel, G., Kawohl, W., 2013. The loudness dependence of auditory evoked potentials (LDAEP) as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms. PLoS One 8 (7): e68650 (12). http://dx.doi.org/10.1371/journal.pone.0068650.
Fig. 1. Correlation between LDAEP and PANSS negative score.
correlated to serotonin. It seems to be of utmost importance to agree on standard methods of measuring and analyzing LDAEP as the contradictory results of other studies might be an artifact of methodological differences. As serotonergic dysfunction could be shown in subgroups of negative symptoms it may be assumed that negative symptoms are a heterogeneous group of symptoms with different pathomechanisms. Longitudinal challenge studies with 5HT agonists and antagonists and further differentiation of 5HT receptor subtypes will be necessary to clarify this question. Conflict of interest No conflicts of interests have to be declared. Contributors I. Uhl, P. Roser, C. Norra and G. Juckel designed and performed the study. I. Uhl and G. Juckel wrote the first draft. A. Kulik, A. Theodoridou, C. Wyss, M. Brüne and W. Kawohl contributed to recruitment of patients, performing data analyses and discussion of the data. All authors have approved the final version.
I. Uhl A. Kulik P. Roser Department of Psychiatry, Ruhr University, LWL University Hospital Bochum, Germany A. Theodoridou C. Wyss Psychiatric University Hospital, Zürich, Switzerland C. Norra M. Brüne Department of Psychiatry, Ruhr University, LWL University Hospital Bochum, Germany W. Kawohl Psychiatric University Hospital, Zürich, Switzerland Corresponding authors at: Department of Psychiatry, Ruhr-University Bochum, LWL Hospital Bochum, Alexandrinenstr. 1, 44791 Bochum, Germany.
Acknowledgement
No conflicts of interests have to be declared. References Gudlowski, Y., Ozgürdal, S., Witthaus, H., Gallinat, J., Hauser, M., Winter, C., Uhl, I., Heinz, A., Juckel, G., 2009. Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity. Schizophr. Res. 109 (1–3), 141–147. Juckel, G., Molnár, M., Hegerl, U., Csépe, V., Karmos, G., 1997. Auditory-evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats. Biol. Psychiatry 41 (12), 1181–1195. Juckel, G., Gallinat, J., Riedel, M., Sokullu, S., Schulz, C., Möller, H.J., Müller, N., Hegerl, U., 2003. Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity. Schizophr. Res. 64 (2– 3), 115–124. Juckel, G., Pogarell, O., Augustin, H., Mulert, C., Müller-Siecheneder, F., Frodl, T., Mavrogiorgou, P., Hegerl, U., 2007. Differential prediction of first clinical response
G. Juckel Department of Psychiatry, Ruhr University, LWL University Hospital Bochum, Germany Corresponding authors at: Department of Psychiatry, Ruhr-University Bochum, LWL Hospital Bochum, Alexandrinenstr. 1, 44791 Bochum, Germany. E-mail address:
[email protected] 19 March 2017
