Effects of lithium on auditory evoked potentials in healthy subjects

Brief Reports

B!O]..,PSYCHIATRY 1990;27:552-555

Hallcher LM, Sherman WR (1980): The effect of lithium ion and other agents on the activity of myo-inositol-l-phosphatase from bovine brain, Biol Chem 255: i0896-10901. Honchar MP, Olney JW, Sherman WR (1983): Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 220:323325. Mork A, Geisler A (1987): Effects of lithium on calmodulin-stimulated adenylate cyclase activity in cortical membranes from rat brain. Pharmacol Toxico! 60:17-23. Newman M, Klein E, Birmaher B, Feinsod M, Belmaker RH (1983): Lithium at therapeutic cGncentrations inhibits human brain noradrena!ine-sen-

555

sitive cyclic AMP accumulation. Brain Res 278:380--381. Oppenheim G, Ebstein RP, Belmaker RH (1979): Effect of lithium on the physostigmine-induced behavioural syn&ome and plasma cyclic GMP. J Psychiatry Res 15"133-138. Taussky H, Shorr E, Kurzmann GA (1953): A microeolofimetric method for the determination of inorganic phosphorus. YBiol Chem 202:675-681. Vilsen B, Andersen JP~ Petersen J, Jorgensen PL (1988): Occlusion of 22Na~ and S6Rb+ in membrane-bound and soluble protomeric units of Na, K-ATPase. In Stein WD (ed), The Ions Pumps: Structure, Functions aad Regulation. New York: Allan R. Liss, pp 33-38.

Effects of Lithium on Audlto.y Evoked Potentials in Healthy Subjects •

r

U. Hegerl, W.M. Herrmann, G. Ulrich, and B. Mgller-Oedinghausen

Introduction In the past, the effects of lithium on averaged evoked potentials (AEP) have been studied mainly iv psychiatric patients. However, only studies on healthy subjects would allow a .di-. rect assessmem or" the neurophysiological ef-

From the Departmentof Psychiatry, Free Universityof Berlin, Laboratories of Clinical Fsychopharmacologyand Clinical Psychophysiology, Berlin, ~.G. Addres.~reprint requests, to Dr. med. U. Hegerl, PsychiatrischeKlinik tier Freiet~ Unive,:sit~tBerlin, Labor for Klinische Psychopharmakologie,Eschenallee3, D-1000 Berlin 19, West Germany. Received October 21, 1988; ~¢ised August 5, 1989. Supported by a grant from the "Deutsche Forsch,Jngsgemeinschaft" (DFG, MU 477/6-1).

© 1990 Society of Biological Psychiatry

fects of lithium in the absence of contaminating factors, such as psychopathological change or therapeutic response. We investigated AEP in healthy subjects who underwent 10 days of lithium ~dministration. Of particular interest were ff~e possible effects of liti~ium on the N l latency and on the slope of the amplitude/stimulus intensi~y fuaction (ASF) of the N~/P2 component, because in earlier stu~es we have s~ggested that these two variables might be useft~! ~.s early predictors of the response to lithium prophylaxis; any direct effect of lithium on either bI~ iatency or ASF might thus interfere with their possible p.~edictive quality (Hegerl et al. 1987).

0006-3223/90/$03.50

556

Brief Reports

BIOL PSYCHIATRY 1990;27:555-560

Materials and M e t h o d s

Subjects Eleven male volunteers (age 20-35 ye~s) with a normal alpha-electroencephalogram were included in this open study after an extensive clinical examination (electrocardiogram, laboratory tests, physical examination) and after written informed consent. The study was approved by the institutional ethics committee. The subjects were paid for their participation. One subject was removed from the study because routine drug urine screening indicated the use of street drugs. The AEP data of another subject were lost because of technical problems, thus 9 subjects remained for the final evaluation.

Medication In the morning (75 rain after breakfast) and in the evening, at 12-ar intervals, subjects received tablets containing 339 mg lithium sulfate; the dosages were adapted to the preceding lithium blood levels. Blood samples for the determination of the lithium plasma, levels were drawn daily in the morning prior to lithium administration. After 10 days of this lithium regimen (study day 10), lithium plasma levels were in the range of 0.63--0,84 retool/liter (mean 0.71 retool/liter), Lithium medication was then combined with a nonsteroidal anfiir,.flamma~orydrag for an additional 10 days; all medication then ceased. During the period of lithium adminis~ tratiop, the subjects were hospitalized under strict and constant medical surveillance. A foUow-up examination took place 2 weeks after the termination of medication.

in random order by headphone. We recorded with gold-plated cup electrodes from C,, C~, C4, and 1 cm above the outer comer of the left eye, referenced to linked mastoid electr<,~es. For artefact suppression, all trials were e'~tomatically excluded from averaging if at any pohlt during the averaging period the voltage exceeded + 50 IxV in any of th~ i,',.~.~rleads. About 80 responses were averaged :~ ~ach intensity level. Peak-to-peak amplitudes (PI/N~, NI/P2), and the P~, Nm, and P2 amplitudes with reference to a zero baseline were measured with a cursor spot program on a screen. The P~ was defined as the most positive amplitude, with a la|ency of >45 msec, and occurred before the N~ c~mponent; the peak N~ was the most negative amplitude value during the 55-140-msec pev.'od, and the subsequent peak P~. the most positive amplitude during the 100-235-msec period. In Figure 1, the AEP (C~) at four intensity levels are shown for one subject, recorded before and during lithium administration. Additionally, the P~ and N~ latencies were measured for all leads after averaging the four responses to the four respective stimulus intensities. Details of tbe recording proced:~re have be~n described elsewhere (Hegerl et al. 1989).

Analysis of Data A measure of the rate of amplitude increase with

increasing stimulus intensities was obtained by fitting a s~aight line ~o the amplitude values at each intensity level using the least square technique. The slope of the line thereby indicates the amplitude change due to increasing stimulus intensity. The effects of the lithium medication were probed by analysis of vaxiance with two repeated Recording Procedure factors (factor 1: lead C~, C3, (:4; factor 2: reAEP were recorded before lithium (study day cording A, B. C). AEP v~fiables during lithium 0, recording A), after 10 days of lithium admin- administration (recording B) were compared with istration (studyday I0, recordingB), and 2 weeks the two drug-free conditions (recordings A and after the termination of medication (recording C) by calculating the F r,~tios for the contrasts C). For all subjects, the recordings were per- [(B - A) + (B - C ) ] . The statistics were formed in the morning within the same hour. confirmatory concerning Af~Fslope (N~/P2 comBinaural clicks(52, 62, 72, 82 dB HL; stimulus ponent) and N~ latency; the o~er variables were duration 0.9 msec; ISI 2. I sec) were presented analyzed in an exploratory way. p < 0.05 was

Brief Reports

BIOL PSYCHIATRY 1990;27:555-5.~0

=

recording

V/div

A

recording B

--~--

J

I

ITI 0

I

I

I

I00

I

557

---

72 dB

I

180

260

ms

0

100

180

260

Figure 1. AEP (C,) at four intensity levels in a single subject recorded before (recording A) and after (recording B) a 10 day litl-dum administration.

assumed to be the level of statistical significance. Results Effects of lithium on AEP are s~mmarized in Table 1. Under lithium (recor~ng B), pronounced increases of the P~ and P#N~ amplitude, as well as significant but less pronounced increases of the N~ and N,/P2 amplitude, were found. The P2 amplitude did not change under lit.hium (T~,ble 2). Regarding !atencies~ an increase of the P~ latency under lithium (recording B) was noted

(Table 2). Possible effects of intensity on amplitudes were tested ~y analysis of variance wi~ two repeated measurement factors (factor 1: lead Cz, C3, C4; factor 2: intensity level 1, 2, 3, 4). Intensity effects (recording A) were significant for P,IN~ amplitude (F~/24: 10.5; p = 0.0008), N~/P2 amplitude ( F ~ : 15.6; p = 0.0001), and P2 amplitude (F3/24: 6.20; p = 0 . 0 2 ) : indicating an amplitude increase with increasing stimulus intensity, but not for the P, amplitude (F3~24: 1.26; p = 0.31,~. ASF slopes of the Ps, Ps!N~, NJP2, and P2 ~mplitude were not significantly chang~ in re-

Table 1. Effects of Lithium on AEP Variables° ASF slopes

Latencies

Amplitudes Pt

N,

P2

t

0

p = 0.003

p = O.O1

P!

t p = 0.04

°An~ysisof variance, onhogonal contrast, N -- 9.

N,

P2

P,

PI/N,~

Nt/P2

P2

0

0

0

0

0

558

BIOL PSYCHIATRY 1990;27:555-560

Brief Reports

Table 2. Amplitudes and Latencies (mean 4- SD; N = 9) Before Eithium (A), After 10 Days of Lithium Administration (B), and 2 Weeks After Lithium Discontinuation (C) Recording A P~ amplitude

(~V) N, amplitude (pN)

P2 amplitude (ttV) P~ latency (msec) N~ latency (msec)

P2 latency (msec)

Cz

C3 C4 Cz C3 C,t Cz C3 C,, C~ C3 C4 Cz C3 C4 C~ C3 C,,

2.8 2.1 2.1 2.8 2.0 2.7 5.6 4.6 ,L8 57.3 57.3 53.3 91.9 94.8 95.3 167.3 172.8 181.1

-± ± ± ± ± ± ± ± ± ± 4± ± ± ± ± ±

2.1 1.1 1.4 1.7 1.4 1.5 2.8 2.0 2.1 2.0 3.2 8.4 11.0 12.2 15.7 24.3 5.7 17.2

Recording B (lithium) 4.9 3.5 3.4 3.3 3.2 3.5 6.1 4.7 5.0 58.5 59.0 58.9 97.5 107.3 104.3 169.2 168.6 181.3

cording B during lithium medication as compared with the recordings A and C. Discussion Under lithium, marked amplitude increases of the P~, and N i components were found. It might be argued that the amplitude increases at recording B in this open study were not effects of lithium but of factors related to retesting. This, however, appears rather unlikely because in an earlier study on healthy subjects tested twice the first day and retested 3 weeks later (Hegerl et al. 1988, 1989) we found no retest influence oa the P~ amplitude, and a decrease of the N~/P2 amplitude at the second, compared to the first and third recording. These results (unpublished data) support the view that the amplitude increases under lithium, observed in t.he present study, cannot be ascribed to any retest effect. Furthermore, these results in healthy subjects are in agreement with results obtained in patients. In a placebo-controlled study involving 12 depressive patients during lithium medication, Strau-

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.8 1.4 1.7 3.0 2.0 2.2 2.8 2.3 2.1 1.9 3.0 3.2 17.6 7.6 15.5 18.6 11.9 13.2

Recording C 2.9.4- 1.0 1.9 -4- 0.9 1.7 ± 1.2 1.5 ± 1.8 1.5 ± 1.4 1.9 ± 1.5 6.4 ± 2.4 4.7 ± 1.7 4.9 - 1.9 58.0 - 3.2 53.7 ± 8.,.~ 54.0 ± 8.0 91.0 -+ 10.7 96.3 ± 6.9 94.? ± 6.6 176.8 ± 34.3 170.0 ± 9.4 187.0 ± 21.2

Analysis of variance [contrast (B - A) + (B - C)] Fw8~: 18.47 p - 0.003 Fw8~: 9.69 p - 0.01 Fw8~: 0.08 p = 0.79 Fws~: 5.87 p = 0.04 Fw8~: 3.05 p = 0.12 Fw,): 0.53 p ffi 0.49

manis et al. (1981) found an amplitude it,crease of early positive AEP components (P3o, Ps0). Heninger (1978) also described an amplitude increase of AEP components, which probably conesponds to the P~ and Ni components as defined by our methodology. Using somatosensory-evoked potentials, amplitude increases of early components during lithium medication have been a consistent and apparently lithium-specific finding in psychiattic patieuts (Straumanis et al. 1981; Buchsbaum et al. 1979; Heninger 1978; Heninger and Demers 1971). Studying patients with visualevoked potentials, increases of the P~/N, component (Fenwick and Robertson 1983) and of the N~ component (McKnew et al. 1981) were found in some studies, but not hi others (Heninger 1978; Buchsbaum et al. 1977; Greenhill et al. 1973). Our results indicate that lithium-induced amplitude increases of the P~ and N, components of AEP do occur not only in m~icdepressive patients, but also in healthy subjects, and thus should be regarded as direct pharmacological effects of subchronic lithium

Brief Reports

559

BIOL PSYCHIATRY 1990;27:555-560

18.0.

16.0. >

• :~ 14.0' "o ...,,

Q.

E

12.0

I .,,,m

z

Q.

lO.O

8.0

6.0"

4.0.

2.0.

0.0

I

I

"

recording

recording

recording

A

B

C

(lilhium)

I

Figure 2. PdNi amplitudes of the 9 subjects before lithium (A), after 10 days of lithium administration (B), and 2 weeks after lithium discontinuation (C).

administration. Effects of lithium on latencies were less pronounced. Our findings of an increase of the P t latency during lithium medication has not yet been reported. Latency increases of the N,, P2, and 1)3 components of AEP, however, have been noted during lithium medication in patients (Heninger 1978; Shagass et al. 1982). We were unable to find statistically significant effects of lithium on the ASF slopes of the Pro, PI/N,, NI/P2, and P2 amplitudes of AEP. The findings in the literature conceming effects of lithium on ASF slopes (Buchsbaum et al. 1971, 1977, 1979; Greenhill et al. 1973; Hubbard et al. 1980; Zerbi et al. 1984) are incons,;stent and confined to visual and somatosensory-evoked potentials. Therefore, it appears more likely that

the increased ASF slopes observed in lithium responders as compared with nonresponders (Hegerl et al. 1987) are related to the process or disposition of "response" per se, and should not be seen as a direct effect of lithium itself.

References Buchsbaum MS, Goodwin F, Murphy D, Borge G (1971): AER in affective disorders. Am J Psychiatry 128:19-25. Buchsbaum MS, Lavine R, Davis G, Goodwin F, Murphy D, Post R (1979): Effects of lithium on somatosensory evoked potentials and preaiction of clinical response in patients with affective illness. In Cooper T, Gershon S, Kline N, Schou M (eds), Lithium-Controversies and Unresolved

560

BIOL PSYCHIATRY

Brief Repor~:s

1990;27:555-560

Issues. New Jersey: Excerpta Medica, pp 685- Heninger GR (1978): Lithium carbonate and brain function. Arch Gen Psychiatry 35:228-223. 702. Buchsbaum MS, Van Kammen D, Murphy D (1977): Heninger GR, Demers R (1971): Lithium effects on the EEG and somatosensory evoked response in Individual differences in average evoked rerelation to sodium metabolism. Electroencepha~sponses to d- and l-amphetamine with and without ogr Clin Neurophysiol 31:289-290. lithium carbonate in depressed patients. Psychopharmacology (Berlin) 51:129-135. Hubbard R, Judd L, Huery L, Kripke D, Janowsky D, Lewis A (1980): Visual cortical evoked poFenwick O, Robertson R (1983): Changes in the vistentials in alcoholics and normals maintained on ual evoked potentials to pattern reversal with lithlithium carbonate: Augmentation and reductio~ ium medication. Electroencephalogr Clin New phenomena. Adv Exp Med Biol 126:573rophysiol 55:538-545. 577. Greenhill L, Rieder R, Wender P, Buchsbaum MS, Zahn T (1973): Lithium carbonate in the treatmeii~ McKnew DH, Cytryn L, Buchsbaum MS, et al (1981): of hyperactive children, Arch Gen Psychiatry Lithium in children of lithium-responding parents. 28:636-640. Psychiatry Res 4:171-180. l-ieged U, Ulrich G, M~ller-Oedinghausen B (1987): Shagass CH, Straumanis J, Roemer R (1982): PsyAuditory evoked potentials and response to lithchotropic drugs and evoked potentials. In Buser ium prophylaxis. Pharmacopsychiatry 20:213-216. P, Cobb W, Okuma T (eds), Kyoto Symposia (EEG, Suppl 36). Amsterdam: Elsevier Biomedical Press, Hegerl U, Prochno J, Ulrich G, Miiller-Oerlinpp 538-548. ghausen B (1988): Are auditory evoked potentials suitable for pre,licting the response to lith- Straumanis J, Shagass CH, Roemer R. Mendels J, ium prophylaxis? A study on the effects of Ramsey A (1981): Cerebral evoked potential repeated measurement, age, gender, and personchanges produced by treatment with lithium carality on the amplitude/stimulus intensity funcbonate. Biol Psychiatry 6:113-129. tion in healthy volunteers. Pharmacopsychiatry Zerbi F, Bezzi, G, Tosca P, Fenoglio L, Romani A, 21:336-337. Spagliardi R (1984): Potenziali evocati visivi: Un Hegerl U, Prochno J, Ulrich G, Miiller-Oerlinghaupossible marker neurofiologico predittivita della sen B (1989): Sensation seeking and auditory respos'ta ai sali di litio. Riv Spec Freniatr 106:1718evoked potentials. Biol Psychiatry 25:179.-190. 1725.