In 12 patients with affective disorders (ICD-10: F31, F32, F33), EEGs were recorded before and after 4.4 months of lithium treatment. Effects of lithium on the EEG were analyzed by power spectral analysis controlled for vigilance. We found (1) an increase in relative power in both delta and theta band which was related to the lithium plasma level, (2) a decrease in relative alpha power especially at occipital leads and (3) a reduction of the dominant alpha frequency. The changes in relative power were more pronounced in the right hemisphere, which is in contrast to the hypothesis of a site-specific localization of lithium effects only in left anterior regions. Copyright (C) 2000 S. Karger AG,Basel

Hegerl, Ulrich

Juckel, Georg

Mavrogiorgou, Paraskevi

Schröter, Andreas

Schulz, C.

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Universität München: Elektronischen Publikationen

Lithium-induced EEG changes in patients with affective disorders

C. Schulz

P. Mavrogiorgou

A. Schröter

U. Hegerl

G. Juckel

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Lithium-Induced EEG Changes in Patients with Affective Disorders

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Neuropsychobiology 2000;42(suppl 1):33–37Lithium-Induced EEG Changes inPatients with Affective DisordersC. Schulz P. Mavrogiorgou A. Schröter U. Hegerl G. JuckelSection of Neurophysiology and Outpatient Clinic for Relapse Prophylaxis in Affective Disorders,Department of Psychiatry, Ludwig-Maximilians-University, Munich, GermanyDr. Georg JuckelSection of Neurophysiology, Department of PsychiatryLudwig-Maximilians-University, Nussbaumstrasse 7D–80336 Munich (Germany)Tel. +49 89 5160 3321, E-Mail juckel@nk-i.med.uni-muenchen.deABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2000 S. Karger AG, Basel0302–282X/00/0425–0033$17.50/0Accessible online at:www.karger.com/journals/npsKey WordsLithium W Quantitative EEG W Power spectral analysis WAffective disorderAbstractIn 12 patients with affective disorders (ICD-10: F31, F32,F33), EEGs were recorded before and after 4.4 months oflithium treatment. Effects of lithium on the EEG wereanalyzed by power spectral analysis controlled for vigi-lance. We found (1) an increase in relative power in bothdelta and theta band which was related to the lithiumplasma level, (2) a decrease in relative alpha power espe-cially at occipital leads and (3) a reduction of the domi-nant alpha frequency. The changes in relative powerwere more pronounced in the right hemisphere, which isin contrast to the hypothesis of a site-specific localizationof lithium effects only in left anterior regions.Copyright © 2000 S. Karger AG, BaselIntroductionThe salt lithium was introduced in prophylaxis andtreatment of affective disorders in 1949. However, it iswell known that neurological side effects like tremor, atax-ia, seizures or EEG alterations occur even when using lith-ium at therapeutic levels.Starting with the first report of lithium-inducedchanges in EEG in 1949 [1], a number of studies usingvisual analysis of the EEG reported a reduction in alphawaves, an increase in delta and theta waves, an increase inparoxysmal activity and abnormalities in vigilance [2–4].Studies using quantitative EEG analysis described almostconsistently an increase of power in total, delta and thetabands and a slowing of dominant alpha frequency [5–10].Furthermore a focussing of lithium effects in left anteriorregions with intermitting slow waves is being discussed byUlrich [11].These findings are inconsistent and partly contradicto-ry. The studies are barely comparable among each otherbecause of the different recording and analysis methods,the different sample characteristics (healthy volunteers,bipolar or unipolar patients) and different medicationaspects (lithium intoxication, lithium monotherapy andlithium combined with neuroleptics).The purpose of our study was first to evaluate theeffects of lithium on relative power, dominant frequenciesand absolute power of the EEG spectra, controlled forvigilance, in the course of long-term lithium treatment inpatients with affective disorders. Secondly, we were inter-ested whether the hypothesis of site-specific effects of lith-ium in the left frontal region is replicable using quantita-tive EEG analysis.CGIDelta34 Neuropsychobiology 2000;42(suppl 1):33–37 Schulz/Mavrogiorgou/Schröter/Hegerl/JuckelTable 1. Description of the studied patients with affective disordersPatient data n 12Age 59B13 yearsSex (F/M) 5/7ICD-10 F31: n = 1F32: n = 2F33: n = 9T1 T24.2B1.4 2.5B0.8Analyzed 2-second EEG segments 52B16 52B18MedicationAD (number of patients) 9 9NL 3 –No medication 3 –Lithium plasma level – 0.67B0.17 mmol/lAD = Antidepressives; NL = neuroleptics.Table 2. Relative power of the EEG data at T1 (before lithium treat-ment) and T2 (under lithium treatment)ElectrodepositionMean T1%Mean T2%WilcoxontestF3-C3 11.4B7.2 11.9B11.5 n.s.F4-C4 10.7B8.4 13.1B12.7 n.s.C3-P3 8.4B5.4 10.5B7.4 n.s.C4-P4 6.9B3.1 9.6B6.5 0.06P3-O1 9.1B9.5 10.7B8.8 n.s.P4-O2 8.6B6.9 11.9B10.9 n.s.Theta F3-C3 18.9B8.2 21.8B9.2 n.s.F4-C4 16.8B7.2 21.5B7.6 0.02C3-P3 17.6B6.1 23.0B9.8 0.04C4-P4 15.4B5.3 24.0B11.1 0.00P3-O1 16.5B9.2 23.6B10.4 0.02P4-O2 16.6B7.6 23.0B10.3 0.02Alpha F3-C3 38.1B20.2 39.1B20.7 n.s.F4-C4 39.5B19.7 39.3B21.4 n.s.C3-P3 55.5B13.7 50.6B16.8 0.07C4-P4 59.2B12.9 51.3B16.7 0.02P3-O1 59.0B22.4 52.8B19.3 0.04P4-O2 58.4B20.0 52.4B20.9 0.03Beta F3-C3 31.5B19.5 27.2B21.5 n.s.F4-C4 33.0B20.2 26.0B15.5 0.08C3-P3 18.4B6.8 16.0B4.8 n.s.C4-P4 18.5B6.7 15.0B6.1 0.06P3-O1 15.4B11.0 12.9B3.6 n.s.P4-O2 16.5B11.6 12.7B3.8 n.s.MethodEEG was obtained from 12 patients with affective disorders(ICD-10: F31, F32, F33) of the Outpatient Clinic for Relapse Pro-phylaxis in Affective Disorders who were included in a prospectivestudy. EEG was recorded before lithium treatment (T1) and 4.4 B3.5 months after baseline under lithium (T2). The patients had ana-lyzable recordings for quantitative EEG analysis at both time points.The age of the patients (5 females, 7 males) ranged from 38 to 76years (mean 59 B 13 years). Before lithium treatment (T1), 3patients were treated with neuroleptics and antidepressants, 6 pa-tients had antidepressive treatments without other psychotropicdrugs, and 3 patients were not treated with any psychotropic medica-tion. At T2, 3 patients were only treated with lithium, and 9 patientsreceived additional antidepressive medication (table 1).For EEG recording, patients were seated with eyes closed in acomfortable chair located in a quiet room. Digital EEG was recordedby electrocaps with the international 10/20 configuration and by useof Cz as reference. The recordings were amplified and filtered by theBEST system with a low-pass filter of 70 Hz and a high-pass filter of0.5 Hz; the sampling rate was 256 Hz. For quantitative EEG analysis,two experienced neurophysiologists visually selected artifact-free 2-second segments (52 B 16 segments at T1, 52 B 18 segments at T2),controlled for vigilance. At least 50% occipital alpha rhythm had tobe present in each segment.Fast Fourier transformation was performed in the BEST systemfor bipolar electrode pairs F3-C3, F4-C4, C3-P3, C4-P4, P3-O1 and P4-O2. Absolute and relative power, and the dominant frequency fordelta (2–3.5 Hz), theta (3.5–8 Hz), alpha (8–12 Hz) and beta bands(12–32 Hz) were calculated and statistically compared for T1 and T2,using nonparametric Wilcoxon tests.The lithium plasma level was correlated (Pearson correlationcoefficients) with relative theta and relative alpha power at T2, withthe difference in relative theta and relative alpha power between T1and T2 and with the dominant frequency in the alpha band at T2.ResultsA significant increase of relative power under lithiumtreatment was found in the theta band at all electrodepositions (F4-C4, C3-P3, C4-P4, P3-O1 and P4-O2) exceptfor left frontocentral F3-C3 (table 2). A strong increase inrelative theta power from T1 to T2 was related to a highlithium plasma level (F3-C3: r = 0.81, p ! 0.01; F4-C4: r =0.61, p ! 0.05). In the alpha band, the relative power wasunchanged at F3-C3 and F4-C4 and reduced at the central-parieto-occipital electrodes (C4-P4, P3-O1 and P4-O2). Fig-ure 1 shows that relative theta power at C4-P4 increased by8.6% and relative alpha power decreased by 7.9% underlithium treatment. The relative power in the delta bandwas slightly increased at all electrodes without statisticalsignificance. The relative power of the beta band was gen-erally reduced, but also without statistical significance.The analysis of the dominant frequency revealed a gen-eral slowing of the EEG in the total band at the electrodesLithium-Induced EEG Changes Neuropsychobiology 2000;42(suppl 1):33–37 35Fig. 1. Changes in relative theta and alpha power at electrode pairC4-P4 before and under lithium treatment.Fig. 2. Changes in the dominant frequency of the alpha band beforeand under lithium treatment. For each electrode position, the aver-aged dominant frequency is displayed.C4-P4 and P4-O2 under lithium therapy. The dominantalpha frequencies were significantly slower at leads F3-C3,F4-C4, C3-P3, C4-P4 and P4-O2, except for P3-O1 (fig. 2).Figure 3 presents the power spectra of 1 patient, demon-strating the slowing of the dominant alpha frequencyunder long-term lithium treatment. In the delta, theta andbeta bands, no significant changes of the dominant fre-quency were found.A statistically significant increase in absolute powerwas only found in the theta band at F3-C3, F4-C4, C3-P3,C4-P4 and P3-O1.DiscussionThe aim of our study was to examine the effects oflong-term treatment with lithium on the EEG in patientswith affective disorders. Increased relative theta powerand decreased relative alpha power under lithium treat-ment were found for both hemispheres with slightly high-er significance for the right hemisphere. In addition, a sig-nificant correlation between lithium plasma level andincrease of the theta power from T1 to T2 was found.Slowing of the dominant frequency in the alpha band wasobserved at all leads except the left occipital electrode.Taking these findings together, the hypothesis of typicalEEG alterations in anterior regions of the left hemisphere[11] cannot be supported. It seems more likely that lithi-um affects the CNS without any preference of region. Thiscorresponds well to findings on the way of action of lithi-um, indicating that lithium acts unspecifically on neuron-al cells in the whole brain by influencing second-messen-ger mechanisms.It is unlikely that our above-mentioned findings are theresult of improved psychopathology. The CGI score of thepatients improved by 1.7 points from T1 to T2. Studiesconcerning the EEG of depressive patients described en-hanced delta, theta and alpha activity compared to nor-mals [12–14]. Thus, with improvement in psychopatholo-gy, an acceleration of the dominant alpha frequency com-bined with an increase in relative alpha power and adecrease in relative theta activity has to be expected. Withrespect to the improvement in our group of patients in theCGI score, we had to expect a decrease of theta activity andan increase of alpha power at T2 due to the psychopatholo-gy. However, the outcome of our examination was theopposite. At T2, we found increased relative theta power,decreased relative alpha power and slowing of the domi-nant alpha frequency at T2 under lithium therapy. There-fore, these EEG effects seem to be induced by lithium.On the other hand, the EEG alterations found in ourstudy could be the result of changes in the medication oth-er than lithium. At baseline, 9 patients were treated withantidepressants, 3 of them additionally with neuroleptics.At T2, 9 patients under lithium treatment were still onantidepressants, but none of the patients received neuro-leptics anymore. Neuroleptic-induced EEG changes areassociated with an increase of slow activity in the deltaand theta band and a decrease of alpha activity [14, 15].Stopping medication with neuroleptics should lead to a1236 Neuropsychobiology 2000;42(suppl 1):33–37 Schulz/Mavrogiorgou/Schröter/Hegerl/JuckelFig. 3. Example of the EEG power spectrumin 1 patient with affective disorder. The lineat 9.5 Hz and 8.5 Hz respectively indicatesthe dominant alpha frequency before (a) andunder (b) lithium treatment.decreased theta activity and an increased activity in thealpha band. However, we did not find such changes in ourstudy. Under lithium treatment without any neurolepticadditional medication, theta activity was found to beincreased and alpha activity was reduced. Because thenumber of patients treated with antidepressants did notvary from T1 to T2, the effects of this medication on theEEG may be negligible. Thus, it is unlikely that thechanges in the EEGs of our patient group can be explainedby changes in neuroleptic or antidepressive medication.Furthermore, the correlation between the lithium plas-ma level and the increase in theta power is an additionalargument that the change in theta power observed in thisstudy was induced by lithium.Lithium-Induced EEG Changes Neuropsychobiology 2000;42(suppl 1):33–37 37References1 Corcoran A, Taylor C, Page LH: Lithium poi-soning from the use of salt substitute. J AmMed Assoc 1949;139:685–688.2 Czernik A: EEG-Veränderungen unter langjäh-riger Lithiumbehandlung. Psychiatr Clin 1978;11:189–197.3 Helmchen H, Kanowski S: EEG-Veränderun-gen unter Lithiumtherapie. Nervenarzt 1971;42:144–148.4 Small JG, Milstein V, Medlock CE: ClinicalEEG findings in mania. Clin Electroencepha-logr 1997;28:229–235.5 Bente D, Scheuler W, Ulrich G, Müller-Oer-linghausen B: Effects of lithium on the EEG ofhealthy subjects and psychiatric patients:Methods, results and hypothesis; in HerrmannWM (ed): EEG in Drug Research. Stuttgart,Fischer, 1982.6 Müller-Oerlinghausen B, Hamann S, Herr-mann WM, Kropf D: Effects of lithium on vigi-lance, psychomotoric performance, and mood.Pharmakopsychiatr Neuropsychopharmakol1979;12:388–396.7 Ulrich G, Frick K, Stieglitz RD, Müller-Oer-linghausen B: Interindividual variability oflithium-induced EEG changes in healthy vol-unteers. Psychiatr Res 1986;20:117–127.8 Ulrich G, Herrmann WM, Hegerl U, Müller-Oerlinghausen B: Effect of lithium on the dy-namics of electroencephalographic vigilance inhealthy subjects. J Affective Disord 1990;20:19–25.9 Thau K, Rappelsberger P, Lovrek A, PetscheH, Simhandl C, Topitz A: Effect of lithium onthe EEG of healthy males and females. 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B: Interindividual variability of lithium-induced EEG changes in healthy volunteers. Psychiatr Res

EEG-Veränderungen unter langjähriger Lithiumbehandlung. Psychiatr Clin

Effect of lithium on the dynamics of electroencephalographic vigilance in healthy subjects.

Effects of lithium on vigilance, psychomotoric performance, and mood.

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Psychiatrische Elektroenzephalographie.

Right hemisphere abnormalities in major depression: Quantitative electroencephalographic findings before and after treatment.

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Lithium-induced EEG changes in patients with affective disorders

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