PsycARTICLES - Effects of Lithium Carbonate on the Memory and Motor Speed of Bipolar Outpatients

3/1/10 1:10 PMPsycARTICLES - Effects of Lithium Carbonate on the Memory and Motor Speed of Bipolar Outpatients

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Journal of Abnormal PsychologyFebruary 1987, Vol. 96, No. 1, 64–69

Effects of Lithium Carbonate on the Memoryand Motor Speed of Bipolar OutpatientsEric D. Shaw, Peter E. Stokes, J. John Mann, Alan Z. A. Manevitz

AUTHOR AFFILIATIONS

Eric D. Shaw Payne Whitney Clinic,Department ofPsychiatry, New YorkHospital-Cornell MedicalCenter, New York, NewYork

Peter E. Stokes Payne Whitney Clinic,Department ofPsychiatry, New YorkHospital-Cornell MedicalCenter, New York, NewYork

J. John Mann Payne Whitney Clinic,Department ofPsychiatry, New YorkHospital-Cornell MedicalCenter, New York, NewYork

Alan Z. A. Manevitz Payne Whitney Clinic,Department ofPsychiatry, New YorkHospital-Cornell MedicalCenter, New York, NewYork



Abstract

York

© 1987 American Psychological Association

CITATION

Shaw, E. D., Stokes, P. E., Mann, J. J., & Manevitz, A. Z. (1987). Effects of lithium carbonate on the memory and

motor speed of bipolar outpatients. Journal of Abnormal Psychology, 96, 64-69. doi: 10.1037/0021-843X.96.1.64

doi: 10.1037/0021-843X.96.1.64

We examined the effect of lithium on the memory and motor speed of 22 outpatients with affective disordersin remission. Patients were assessed weekly over a 5-week period starting at their current lithium dosage,twice during administration of a blind placebo, and twice after their lithium was blindly reinstated. Motorspeed was assessed using the finger tapping test. Memory was assessed using the Buschke selectivereminding protocol. Mood was assessed at each session to ensure remitted status by clinical interview, theHamilton Rating Scale for Depression, the Longitudinal Rating of Manic States Scale, and a subjective statequestionnaire. Weekly blood samples were also drawn to assess plasma lithium level by means of atomicabsorption spectrophotometry. The results indicated that lithium had a significant detrimental effect onmemory and motor speed: Performance improved when lithium was discontinued and declined when lithiumwas reintroduced. The implications for patient management and diagnosis in bipolar disorder are discussed.

Memory impairment has been reported anecdotally as the leading side-effect complaint of patients withaffective disorders on lithium prophylaxis (McCreadie & Morrison, 1985) and the primary reason why thesepatients discontinue treatment (Jamison & Akiskal, 1983). As with memory, other neuropsychological sideeffects of lithium treatment, such as problems with concentration and coordination, have been reportedanecdotally (Jamison & Akiskal, 1983), but experimental investigations of their existence have yieldedequivocal results. Experimental demonstration of lithium's specific neuropsychological side effects would haveimplications for patient diagnosis, psychoeducation, compliance, and management and might also lead tofurther understanding of the therapeutic mechanisms associated with lithium's prophylactic efficacy.

A number of authors have noted the detrimental effects of lithium on the verbal memory of normalvolunteers (Judd, Hubbard, Janowsky, Huey, & Takanashi, 1979 ; Karinol, Dalton, & Lader, 1978 ; Kropf &Muller-Oerlinghausen, 1979) and psychiatric patients (Christodoulou, Kokkevi, Lykouras, Stefanis, &Papadimitrou, 1981 ; Reus, Targum, Weingartner, & Post, 1979). Their consistent findings suggest thatlithium either inhibits the efficiency of transfer of verbal material from short-term to long-term storage orthe efficiency of retrieval of this material from long-term storage. Methodological challenges to these findingsincluded heterogenous clinical populations often diagnosed by uncertain criteria, wide variations in patientages and lithium levels, and the use of questionable control groups. The most serious methodological concernin this research has been the affective stability of patient groups assessed on and off lithium. The failure ofreserchers to control for affective state has confounded positive results linking lithium level to memorydifficulties and prevented a clearer understanding of the nature of the memory impairment.



Method

Previous studies have also attempted to document the effect of lithium on the visual-motor skills of patientand normal populations (Demers & Henninger, 1971 ; Judd et al., 1979 ; Squire, Judd, Janowsky, & Huey,1980). These investigations have concentrated almost exclusively on the deleterious effects of lithium onDigit Symbol subtest performance, and their findings have been hampered by methodological concernssimilar to those mentioned previously. In addition, the mixed nature of the neuropsychological functions thatcontribute to Digit Symbol performance make it difficult to interpret the source of these findings. Lithium'seffect may have been on motor speed, information-processing speed, short-term retrieval, or a combinationof functions that contribute to test performance.

Subjects

Twenty-eight outpatients with major affective disorders who had been maintained on lithium prophylaxisparticipated. Informed consent was obtained after a discussion of the procedures. Twenty-two patients (12males, 10 females) completed the protocol; 6 were eliminated due to significant mood change thatthreatened their remitted status. Twenty of these patients had a Bipolar Disorder, predominantly Manic, 1had a Recurrent Depressive Disorder, and 1 had a Bipolar Disorder, Mixed, according to the criteria of thethird edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association,1980). Patients had been maintained on lithium for a mean period of 9.4 ( SD = 5.8) years with a rangefrom 1 to 20 years, at a mean lifetime level of 0.80 ( SD = 0.23) millimoles per liter (mmol/l) with a rangefrom 0.40 to 1.20 mmol/l. Their mean age was 51.2 ( SD = 15.5) years with a range from 29 to 77 years.Patients had been hospitalized an average of 1.7 times during their lifetimes with a range from 0 to 9 times.Seven of these 22 patients were on medications in addition to lithium. None had had electroconvulsivetherapy within the last 9 years.

Because of the potential risk of the placebo period, an effort was made to include only patients with alengthy history of psychiatric stability, without predictable psychosocial stressors during the evaluation, andwho had previously been off lithium without relapse for at least 3 weeks. Patients with a history of suicideattempts, violence, or other potentially damaging consequences to themselves or others were alsodiscouraged from participation.

Measures

Motor speed was measured by the use of the Finger Oscillation, or Tapping, Test (Halstead, 1947), the mostwidely used test of manual dexterity (Lezak, 1983 , p. 520). Subjects tapped a telegraph-like metered key(distributed by the Neuropsychology Laboratory of Ralph Reitan) for five 10-s trials, with a brief restbetween trials, starting with their dominant hand. The score for each hand was the average of the five trials.Dodril and Troupin (1975) demonstrated the test's sensitivity to variations in levels of medication such asdiphenyl-hydantonin (Dilantin) and its relative immunity from repeated measures practice effects.

Memory was evaluated using the selective reminding protocol (Buschke, 1973 ; Buschke & Fuld, 1974). Thisprocedure for assessing verbal learning and memory has been widely used in repeated measures and otherdesigns to evaluate response to various drugs and therapies (Mohs, Davis, & Leverey, 1981 ; Yesavage,Lierer, Becker, & Holman, 1980) and specifically in the measurement of the effects of lithium on memory by



Lierer, Becker, & Holman, 1980) and specifically in the measurement of the effects of lithium on memory byReus et al. (1979) . It was administered by reading the subject a list of 16 unrelated words and then testingrecall immediately. The subject was then reminded of any word on the list not recalled on the immediatelypreceding trial. The procedure was repeated for 10 trials or until the entire list was repeated correctly.

When a word was recalled on two consecutive trials, it was assumed to have entered long-term storage(LTS) on the first of these trials and was considered to be in permanent storage. The word was thereforescored as in LTS on all following trials irrespective of subsequent recall. Words recalled that had previouslyentered LTS were considered to be in long-term retrieval (LTR), and when words in LTS were recalledconsistently on all subsequent trials, they were scored as in consistent long-term retrieval (CLTR).Inconsistent LTR, or recall of words in LTS followed by subsequent recall failure, is traditionally scored asrandom long-term retrieval (RLTR) until CLTR is achieved, with the sum of CLTR and RLTR equal to LTR onany trial. Recall of a word that has not entered LTS or has not been recalled on two consecutive trials istraditionally scored as short-term recall (STR). The sum of STR and LTR are therefore traditionally equal tothe total number of words recalled (Σ recall) on each trial.

In order to accomplish several experimental goals, modifications to the traditional scoring system weremade. First, in order to compare individual subject performance in lithium and placebo conditions, summarymeasures of each session's performance were constructed. For the traditional measures of STR, LTS, LTR,CLTR, and Σ recall, the total number of words recalled by Trial 10 or at the trial when the entire list was firstrecalled was selected. Others (Hannay & Levin, 1985) have used the total number of words recalled across alltrials in each category to summarize session performance. Although this provides an accurate summarymeasure, it does not differentiate between subjects who recall many words early and consistently and thosewho may recall fewer words earlier but subsequently learn a larger proportion of the list. Because eachsession was terminated when the entire list was recalled, we also wished to be able to describe differencesbetween performances that required fewer trials to recall the complete list; that is, subjects learning the 16words in eight trials should be discriminated from those requiring 10 trials. Therefore the total number ofwords recalled by the final trial was also divided by the number of trials to list completion for each categoryto produce a measure of learning efficiency, or slope, of LTR (SLTR), CLTR (SCLTR) and Σ recall (SΣ recall).

Other investigators (Christodoulou et al., 1981 ; Karinol et al., 1978) found that lithium does not impedeimmediate recall. We used first-trial recall of each list as a measure of immediate recall in order to assessthe effects of lithium on the attention and concentration necessary for the initial phases of list learning.However, the Σ recall measure, which is the sum of STR and LTR, utilized the traditional definition of STR.

Kraemer, Peabody, Tinklenberg, and Yesavage (1983) discussed the critical issues of list content, list length,and trial number. Because of the impossibility of matching lists across numerous possible content factors,unmatched words were selected randomly from these authors' pools of common high- and low-imagerywords (eight words from each pool per five lists). A list was randomly assigned to each subject at each of fivesessions.

Serum lithium determinations were done on heparinized plasma samples obtained by weekly venipuncture invacutainers 8 to 12 hours following the last medication or placebo dose. Assay was performed on a PerkinElmer Atomic Absorption Spectrophotometer (Model 503) using air-acetylene mixture aspiration ofheparinized plasma diluted 1:11 with deionized water as per standard methods (Zettner, Rafferty, & Jarecki,1968). Detection limits are 0.005 mmol/l, and reproducibility within the usual therapeutic range, 0.5 to 1.5mmol/l, is excellent, with a coefficient of variation of less than 5%.



Results

Procedure

Subjects were administered the experimental battery at their current lithium dosage at the first of five weeklysessions, scheduled at the same time each week. They were subsequently tested twice on placebo and thentwice on lithium. This produced an on-off-off-on-on weekly lithium regimen in an attempt to obtain an effectand an effect reversal. Ten of the subjects were run double blind, and 12 were assessed in a single blind dueto the limited availability of the blind rater. Clinical interview, the Hamilton Rating Scale for Depression(Hamilton, 1964), the Longitudinal Rating of Manic States Scale (Petterson, Fyro, & Sedvall, 1973), and aself-rating visual analogue mood form in the format used by Karinol et al. (1978) and Judd (1979) were usedto ensure that subjects remained in remission. If significant mood variation occurred at any time during theprotocol, the patient was referred to his or her outpatient physician and the results were excluded. Criteriafor significant mood variation included the emergence of symptoms of depression or mania as reported bythe patient directly on clinical interview or as observed by the raters after completion of the mood evaluationmeasures. As noted above, 6 patients of the 28 starting the protocol were so eliminated due to significantvariation in their weekly mood ratings (Hamilton score > 9, Manic States score > 14). Subject mood wasevaluated and reevaluated at the beginning of all four subsequent experimental sessions.

We hypothesized that if lithium negatively affected memory and motor speed, then subjects' performance onboth measures would be significantly improved from baseline at their minimum lithium plasma level atSession 3 (after 2 weeks on placebo) and would then significantly decline at maximum lithium plasma levelat Session 5 (back on lithium for 2 weeks). Overall, this pattern of results would then be statisticallydescribed by a significant quadratic function. We predicted the magnitude of the lithium plasma level effectto be sufficient to produce significant differences in the dependent measures between Sessions 1 and 3 andSessions 3 and 5, using paired T tests. We also assessed the possible contribution of potential biasing factorssuch as time on lithium, lithium level, and age by using repeated measures analyses of variance ( ANOVAS )as well as baseline correlational analyses.

Potential Biasing Factors

Single- versus double-blind procedure

Ten of the 22 subjects were run in a double-blind procedure. The remaining 12 subjects were run in asingle-blind procedure due to the limited availability of the blind rater. A repeated measures ANOVA showedno significant differences resulting from blind status in subjects' reactions to the lithium manipulation on themotor speed or memory measures: The largest nonsignificant F (4, 80) was 0.60. These data were thereforepooled for analyses. Weekly subject guesses of their medication status indicated that subjects were unable todistinguish between lithium and placebo at a rate in excess of that predicted by chance.

Subject attrition

The 6 subjects who failed to complete the protocol due to significant mood variation appeared to differ fromthe 22 subjects who completed the protocol only in terms of their history of past psychiatric hospitalizations.



the 22 subjects who completed the protocol only in terms of their history of past psychiatric hospitalizations.The former had been hospitalized an average of 2.3 times, whereas the latter had been hospitalized anaverage of 1.7 times during their lives.

Affective stability

As shown in Table 1

, there were no significant changes in the affective stability of the 22 remaining subjects, according torepeated measures ANOVA of scores on the Hamilton Depression and Manic States rating scales, across thefive weekly sessions.

Effect of Lithium on Motor Speed

Results of motor speed testing, pooled over dominant and nondominant hands, are displayed in Table 2



. A repeated measures ANOVA with a Greenhouse and Geisser (1959) correction to the degrees of freedomfor autocorrelation (McCall & Applebaum, 1973) indicated the presence of a significant quadratic function, F(2, 44) = 34.29, p < .00001 . In addition, significant differences in the directions predicted between the firstand third session means, t (21) = 4.17, p < .001 (two-tailed), and the third and fifth session means, t (21)= 2.74, p < .02 (two-tailed), were found.

Repeated measures ANOVAS were undertaken to determine whether initial lithium level (mean and mediansplit at 0.80 mmol/l), length of lithium treatment (median split at 10 years), subject age (median split at47.5 years), or sex affected motor speed response to the lithium manipulation. No significant effects forinitial lithium level, F (4, 80) = 1.80 , length of lithium treatment, F (4, 80) = .23 , subject age, F (4, 80) =0.24 , or sex, F (4, 80) = 1.05 , were found.

Effect of Lithium on Memory

The means and standard deviations of each memory category are displayed in Table 3

. The repeated measures ANOVA results with the prescribed mean contrasts are summarized in Table 4



.

The lithium manipulation affected all of the Buschke measures in the predicted manner, except for immediaterecall (IR) and STR, as indicated in Table 4

. Although subjects recalled significantly more words on placebo at Session 3 than at Session 1, there wasno significant reduction in IR performance at Session 5, after lithium had been reinstated for 2 weeks. Therewere also no significant differences for the prescribed mean contrasts at Session 3, t (21) = 1.23 , or Session5, t (21) = .73 , for STR.

http://psycnet.apa.org/index.cfm?fa=fulltext.printArticle&jcode=abn&vol=96&issue=1&format=HTML&page=64&language=eng#tbl4



Discussion

5, t (21) = .73 , for STR.

Repeated measures ANOVAS for the effect of initial lithium level, length of lithium treatment, subject age,and subject sex revealed no significant effect of these variables on the response of the memory measures tothe lithium manipulation: The highest nonsignificant F (4, 80) was 1.42. Nor were there significantcorrelations among these control variables and the memory measures at baseline: The largest nonsignificantcorrelation was −.34 ( df = 20).

A range of significant correlations (from .37, p < .05, to .48, p < .02, df = 20) among the motor speed andthe SCLTR and SLTR variables across all five testing sessions indicated that there was a close association intheir reaction to the effect of the lithium manipulation.

Medications in Addition to Lithium

As noted, 7 of the 22 patients were on medication in addition to lithium at the time of the protocol. Four ofthese subjects were on doses of a thyroid supplement, synthroid. One was on a low dose of a neuroleptic,thiothixene. Another subject was on an antihypertensive medication, lopressor, and another was on a low-dose cardiac medication, nitroglycerine. A repeated measures ANOVA revealed no significant differences inreaction to the lithium manipulation between subjects receiving or not receiving additional medication on anyof the dependent variables except IR: The largest, F (4, 80) was 1.72. The presence of medications inaddition to lithium appeared to have a significant interactive effect on IR, F (3, 63) = 2.85, p < .05 , suchthat the performance of these 7 patients improved and declined in response to lithium discontinuation andreinstatement, whereas the performance of patients on lithium alone improved on placebo but did not declinewith lithium reinstatement.

Discontinuation of lithium treatment resulted in a statistically significant improvement in combined handmotor speed. Resumption of lithium treatment significantly reversed this effect. This is the first report ofreversible lithium-induced motor speed impairment. Further data suggested that neither length of lithiumtreatment nor age was as critical to this motor speed effect as lithium level.

These results are consistent with earlier findings in the literature that describe lithium's deleterious effect onDigit Symbol performance (Demers & Henninger, 1971 ; Judd et al., 1979 ; Squire et al., 1980), and theysuggest that lithium's effects on this task may be substantively motoric.

Lithium's effect on list-learning ability appears largely on longer term retrieval measures. Although lithiumdiscontinuation significantly improved IR, lithium reinstatement did not reverse this effect within 2 weeksexcept in patients who were on additional medications. The presence of practice effects between Sessions 1and 3 may also have contributed to the initial improvement in IR. Nor did the lithium manipulationsignificantly effect STR. This relative lack of effect on shorter term memory functions is consistent with thefindings of Karinol et al. (1978) , who also failed to find any significant lithium effects on immediate retrievalin normals or in a mixed group of psychiatric patients.

Findings of significant lithium impairment of longer term versus immediate recall are also consistent with anumber of less controlled studies of normal and patient populations. For instance, Karinol et al. (1978) found



number of less controlled studies of normal and patient populations. For instance, Karinol et al. (1978) foundno impairment in immediate retrieval in 6 normal subjects who crossed from lithium to placebo after 7 days,but they did discover a significant difference in the ability of the lithium group to recall words learned 7 daysearlier. Kropf and Muller-Oerlinghausen (1979) also found that a normal volunteer lithium group could recallsignificantly fewer words learned in a pretest than could a control group after 14 days. In a study of 18bipolar patients on lithium, Christodoulou et al. (1981) found that a 16-day lithium placebo period had nosignificant effect on two short-term memory tasks—Digit Span and Wechsler Memory Scale (Wechsler, 1945)paired-associate performance. Although there was significant improvement in the number of errors made inBenton's (1974) Test of Visual Retention and Rey's (1964) immediate retrieval of unrelated words, no test oflonger term verbal retrieval was administered, nor were controls for practice included by retesting afterlithium was reinstated.

Our results are most consistent with those of Reus et al. (1979) , who compared 17 Bipolar, Manic patientson lithium to 7 who had discontinued treatment (5 due to pregnancy) for at least 3 weeks. These authorsfound no impact on STR but did find significantly worse CLTR in the lithium group.

The use of the nontraditional measures of memory efficiency, SLTR and SCLTR, indicated that lithium levelsignificantly affected not only the absolute number of words retrieved but also the number of trials necessaryto learn those words recalled. The criterion requiring only a single repetition of the entire list was somewhateasier than the traditional requirement for two consecutive list repetitions. But the use of 16 unrelated wordsand 10 versus 12 reminding trials probably made this task more difficult than traditional applications, whichfrequently utilize shorter lists and/or related words (Buschke & Fuld, 1974 ; Hannay & Levin, 1985 ; Kraemeret al., 1983). One of the strengths of the selective reminding test is that these features may be varied to suitvarious patient groups. But the use of the easier criteria for list learning and longer list length may limit thegeneralizability of these findings to other groups. Although Hannay and Levin (1985) noted the presence ofpractice effects for measures similar to those utilized in this protocol (Σ recall, LTR, and CLTR), they hadadministered an unrelated 12-word list to normal college students. The significant decrease in longer termmemory performance accompanying the reinstatement lithium indicates that if practice effects were present,they were offset between Sessions 3 and 5 by the lithium level effect.

Although, in our sample, time on lithium did not appear to significantly contribute to the robustness of thesefindings, future longitudinal studies of patients beginning lithium treatment will be required to determine howcritical length of treatment is to these effects. The close association of the memory and motor speed resultsduring the lithium manipulation suggests that these effects are part of a more generalized lithium effect. Butfurther research with biological markers such as thyroid stimulating hormone, nerve conductance velocity,cholinergic receptors, and electroencephalograms will also be necessary to clarify any central or othermechanisms underlying lithium's toxicology.

Selection Biases

The subject selection criteria we used suggest that our sample may have been a somewhat more compliant,less severely ill sample than other outpatient groups. In addition, 81.8% of our patients reported thepresence of what they thought were lithium-induced neuropsychological side effects, including difficultieswith memory and/or concentration, after they had entered the study.

Another important subject selection bias concerns the fact that these patients had been on lithiumsuccessfully for a mean of 9.4 years. They were therefore highly selected for their ability to adapt to lithium's



References

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Clinical Implications

In an earlier study of noncompliance (Jamison, Gerner, & Goodwin, 1979), clinicians rated side effects asamong the most important factors in lithium noncompliance, but they tended to focus on somatic effects(especially weight gain) rather than neuropsychological effects. Jamison et al. (1979) hypothesized that thissystematic lack of emphasis on neuropsychological effects, despite patient complaints, may be due tophysicians' reluctance to acknowledge neuropsychological changes or to attributions that such effects arecaused by an underlying affective illness rather than lithium.

The lack of previous reliable evidence to support the existence of these side effects may explain thereluctance of clinicians to attribute these to lithium. Because of estimates that up to 47% of patientsdiscontinue lithium against medical advice (Jamison et al., 1979) and because memory effects were the mostfrequently reported side effect leading to noncompliance in another clinic population (Jamison & Akiskal,1983), patient compliance may be improved by the prediction and explanation of these neuropsychologicalside effects or by serious consideration and evaluation of other similar patient complaints. However, althoughour results document the existence of statistically significant motor speed and longer term memory effects,the clinical generalizability of the magnitude of these effects cannot be determined. Although patients may beaware of such effects, the ability to tap 48 versus 54 times in 10 s or to recall from two to three additionalwords may have only a limited impact on patients' daily functioning. A careful evaluation of the extent of anyneuropsychological side effects and their impact on patient occupational, recreational, or other performancemay be necessary to determine their practical clinical significance for individual patients.

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The authors would like to acknowledge the important contributions of James Kocsis, Irving Alexander, PatLogue, Herbert Crovitz, Reid Goldstein, and Thomas Moore to this research and to thank RowellLaboratories for their donation of lithium carbonate and placebo capsules.



This work was partially completed as part of the first author's doctoral dissertation at the Department ofPsychology, Duke University.

Correspondence concerning this article should be addressed to Eric D. Shaw, 7309 Pomander Lane, ChevyChase, Maryland 20815

Received August 4, 1986

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PsycARTICLES - Effects of Lithium Carbonate on the Memory and Motor Speed of Bipolar Outpatients