A possible antiviral action of lithium carbonate in herpes simplex virus infections

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A Possible Antiviral Action of Lithium Carbonate in Herpes Simplex Vires Infections Jay D. Amsterdam, Greg Maislin, and Janusz Rybakowski

There has been considerable interest in the possibility that some psychotropic medications may possess antiviral activity. Several clinical observations suggest that lithium may inhibit the reactivation of latent herpes simplex virus, thereby reducing the number of recurrent infections. We performed a retrospective study examining the pt4~tative antiviral activity of various psychotropic agents in 177 subjects receiving lithium prophylaxis and a comparison group of 59 subiects receiving other antidepressant drugs for affective illness. Chronic lithhm~ administration resulted in a significant red:,/ction in the mean rate of recurrent labial he~'pes i,ffections when compared to the pretreatment period (p < 0.001). In contrast, the mean rate of herpes i~¢'ections was unchanged in patients taking other antidepressants (p = 0.53). Although the overall reduction in herpes infections was not ,significantly different between groups, the proportion of subjects reporting a reduction in infection rate was greater in the lithium group (71%) compared with those receiving other antidepressams (52%) (p = C'.07). These data compliment prior in vitro an( eli,deal studies demonstrating a potential amiviral activity for lithium carbonate.

Introduction There is considerable interest in the possibility that some psychiatric disorders may be caused by viral infections (Gaidusek and Zigas 1957; Torrey et al. 1982; Jones et al. 1985; Amsterdam et a! !985: Crow 1987), and that a variety of psychotropic medications may possess antiviral activity (Chang 1975; Wunderlich e,~ al. 1980; Bohn et al. 1993; Shaskan et al. 1985; Patou et al. 1986). Several lines of evidence suggest ~hat ~ithium salts may possess antiviral activity, especially toward herpes simplex virus (Skinner et al. 1980; Buchan et al. 1988). There have been several clinical observations indicating that lithium may inhibit the reactivation of latent herpes simplex virus, thereby reducing the number of recurrent infections (Lieb 1979; Skinner 1983; Gilis 1983; Amsterdam et al. 1988). Furthermore, several in vitro studies have found that lithium chloride can inhibit the replicatien of herpes simplex virus by interfering with viral DNA synthesis at tissue concentrations that allow host cell DNA replication (Skinner et al. 1980; Hartiey 1983; Patou ct al. 1986; Buchan et al. 1988). In view of these interesting reports, we

1"-Iti : l i l ~ t [ , F l i z t t , From the Depression Research Unit, Department of Psychiatry, Univel~ity of Pe.nnsylvania School of M~dicine, n,-:°o.,.,.k:.~ PA (J.D.A., G.M.), ~e Wistar Institute, Philadelphia, PA (J.D.A.); and the Department of Psychiatry, Medical Academy of Bydgoszcz, Bydgoszcz, Poland ($.R.). Address reprint requests to: Jay D. Amsterdam, M.D., Depression Research Unit, itospital of the University of Permsylvaaia. 3400 Spruce Street, Philadelphia, PA 19104. Received Febreary 25, 1989; revised April 21, 1989.

@ 1990 Society of Biological Psychiatry

0006-3223/90/$03.50

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Table i. Descriptive Features of Subjects

Men Women Mean (+SD) age (years) Duration of treatment (months) Average mean ( ± SD) daily dose (nag) Average mean (±SD) lithium level (mF_~./liter)

Lithium grout; (N = 177)

Other antidepressant" groups (N = 59)

68 109 46 ± 13 101 ± 67

20 39 48 _ 15 55 ± 54

1123 ± 357 0.80 ± 0.9

°Tricyclic ,'mtideptessants, monoamine oxidase inhibitors, trazodone, fluoxetine.

performed a ,,~trospective study examining the putative antiviral activity of various psychotropic agents in a group of affeetive disorder p~tients receiving lithium prophylaxis and a comparison group receiving ~ variety of other antidepressant medications.

Methods

Subjec:s Descriptive features of the subject groups are shown in Table 1. A total of 236 patients were evaluated: 177 were receiving lithium carbonate and 59 were taking other antidepress}u;.~ts on a chronic basis. All subjects were treated on the Depression Research Unit at the Hospital of the University of Pennsylvani,a or the Affective Diseases Unit, Medical Academy of Bydgoszcz, Poland, and all met Research Diagnostic Criteria (Sp;tzer et al. 1978) for either past or present primary major depressive disorder, endogenous or bipolar subtype, l~c,ne of the patients had psychotic features and none weze demented. Subjects received psychotropic medication for a minimum of 12 months, and evaluations were performed in a consecutive, nzturalistic fashion with some patients in a midst of an affective episode and other euthymic. Several litlAum subjects also received concomitant antidepressant or tranquilizer medication during an affeetive episode, and an occasional patient in both groups used concomitant medication for severe insomnia or medical illnesses like hypothyroidism, mild essential hypertension, and diabetes mellitus. All of the subjects were in good #lysical health, and none had a history of significant renal, hepatic, neurological, cardiovascular, or hematological/immunological disease. After- info."rued consent was obtained, each subject was given a structured interview to assess the presence (and past history) of a series of infectious diseases. In addition, estimat~:s of the recurrence rates of herpesvirus infections were obtained. Responses were recorded on a standardized report form for pooled data analyses.

Statistical Procedures Subjects with labial herpes infections at any time before or during drug treatment constituted the primary study group. We calculated the proportion of subjects with any reduction in the numi:er of occurrences per year, as well as the mean within subject changes in infection r~:tes in the lithium and nonlithium groups. A chi-square stvtistic

A~ltiviral Action of Lithium in Herpes

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Table 2. Analysis of the Mean Frequency of Herpes Infections Per Year

Lithium Other antidepressants

Pretreatment

Dunng treatment

Difference

1.61 -+ 2 . 0 4 2.58 _ 3 . 0 9

0 . 8 0 -- 2 . 5 6 2.10 -- 4 . 8 6

0 . ~ 2 __ 1.81 p < 0.001 o 0 . 4 8 __ 3 . 9 2 p = 0.53 s

t = 1.50 df - 36.2 p ffi 0 . 1 4 ~Wilcoxon Sign Rank Test p :Wflcoxon Sign Rank Test p 'Wilcoxon Rank Sum Testp r e , s a l o n was 1.04 (2.41) (t --

t = 130 d f = 32.3 p = 0.20

t = 0.42 d f = 30.9 p = 0.08 c

< 0.0001. < 0.08. = 0.36; estimated difference after adjustment for confounding variables using multiple linear 1.60, df -- 64, p --- 0.12).

was used to test for differences in uhe proportions, and the odds ratio (with 95% confidence interval) was used to measure the magnitude of group differences. Pooles t-test or t-tests for unequal variances were used to examine the significance of group differences in the mean change in yearly lecurrence rates of berpes infections. Tests were repeated using the Wilcoxor~ rank stem for nonparamet~ic data. The withingroup treatment effects over time were examined using the paired t-test ahd Wilcoxon sign rank test. Because of the retrospective nature of the data, we constructed a model comparing lithium versus nonlithium differences adjusted for a variety of potentially confounding variables including age; concomitant medication; concurrent medical illness; history of rubeola (measles), rubella (German measles), myxovirus (mumps), Herpes zoster (chi:kenpox), Epstein-Barr virus (mononucleosis), and hepatitis infcvtion; allergies to drugs, food, and pollens; and the average number of"flu-like" colds per year prior to treatment. The test was constructed using a logistic regression model with any reduction in herpes infections as the dependent variable and the aforementioned factors as independent variables. This analysis was repeated for the ~nean change in Herpes infection rates using multiple linear regression. Finally, we separated out those patients who reported never having experienced labial herpes infection prior to treatment to determine if there was a difference in the propo~ion of patients with a first-time occurrence during treatment.

Results Overall, 90 of 236 subjects reported the presence of recurrent labial herpes infections: 63 of 177 (36%) on litifium and 27 of 59 !,46%) on other antidepressants (X 2 ~:- 1.94; p = 0.16) (Table 3), agreeing with prior data from the literature (Ship et al. 1977). The mean pretreatment recurrence rate for l~,~bial herpes infections (1.6 ± 2.6 episodes per year) significantly diminiehed during treatment (0.8 _+ 1.8 episodes per year) (p < 0.001). In contrast, there was no significant change in the rne~ rec,Jrrence rate of herb'¢.~infections before or during ~eatment with other antidepressant~i (p = 0.6) (Table 2). However, the statistical significance of the difference in these reductir~ns could not be estimated. Overall, 45 (71%) lithium subjects reported a decrease in the recurrence rate of herpes infections, whereas only 18 subjects (29%) experienced no change or an increased frequency of infections. In contrast, 14 (52%) s::bjects t-,firingother amidepressav.ts reported a decreased rate of herpes infections, and 13 (48%) reported no c[:ange or an increased number of

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Table 3. Analysis of Proportions Proportion with l~t,~al herpes infections Lithium 36% (63/1 t7) Other antidepressants 46% (27/59)

p = 0.16

Proportion with a reduction in ccc~rrence rate Lithium 71% (45/63)

p = 0.if7

2.3 (0.95.9) °

Other antidepressants 52% (14/27) Proportion with a reductionin recurrencerate by logisticregressionanalysisb Lithium 70% (42/60) p = 0.02 Oilier antidepressants 40% (8/12) ~oportion with first occurrencedaring treatment Lithium 3% (4/118) Other antidepress~nts 11% (4/36) P = 0"09d

3.5 (1.210.0) ° 3.6 (1.012.6y

"Odds ratio and 95% confidence intervals. bLogistic regression inclu,~ing age; vse of other medications; other illness--measles, German measles, mumps, ch~,.ken pox, mononuci:osis, hepatitis; allergies t,.~medications, food, and pollens; and number of flu colds per year prior to treatn, e~,t. CAdjusted odds ratio and 96% confidence interval. nOne-sided Fisher's Exact Test.

infections. Thus, there was a modest trend for more lithium subjects ~o have a reduction in the frequency of herpes infections (Xe = 3.21; p = 0.07) (Table 3). The ratio comparing the odds of a reduction in infections within the lithium group to that of a reduction in nonlithium subjects was 2.3 (0.9-5.9). The statistical significance of the difference in proportions was 0.07, iMicating that evidence of a difference (before adjusting for potentially confounding variables) was modest. Complete data on the possible confounding vaaiables was not available for 10 subjects, and they could not be included in the logistic regression model. ~Iowever, the remaining patients had an unadjusted odds ratio of 3.5 (1.2--10.0) and an adjusted ratio of 3.6 (1.112.6) (Table 3) suggesting that the group comparisons were actua|ly unaffected by these factors. Thus, the clinical variables (e.g., age and other infections) did not represent a confounding influence on the trend for a difference in herpes infection rates between the lithium and nonlithium groups. There were more non-lithium subjects having a primary labial herpes infection during treatment (11%) compared with subjects receiving lithium (3%), although this difference tailed to achieve statistical significance (p < 0.09; one-sided t test) (Table 3). F':~ally, we observed a small, but statistically significant decrease in the mean yearly rate of common "fl~-like" colds reported by lithium patients (p < 0.0001) as well as in those taking other antidepressant drugs (p < O.u5~ suggesting ,,,,~,'t-~'*h-e,"~",,,.... ,,,.,"' in affective state per se may also diminish the likelihood of viral infections. .

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Discussion Herpes simplex virus is an ubiquitous agent causing a variety of illnesses in humans (Corey and Spear 1986). The most frequent clinical manifestation of the reactivated latent virus is o, al labial herpes which affects approximately 40% of the population (Ship et al. 1977); therefore, our observation in affective disorders patients a~ees with trois estimate. Althol,igh recurrence rates for labial herpes infections may vary between individuals, in mos~ cases they remain fairly constant over years (Ship et al. 1977). There have been several clinical case reports (Lieb 1979; Lieb 1981; Girls 1983), and

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prior in vitro studies (Skinner et al. 1980; Hartley 1983; Buchan et al. 1988) indicating an anti-herpesvirus action for lithium ion. For example, Skinner et al. (1980) added lithium chloride to herpes-infected baby hamster kidney cells and observed a substantial reduction in virus replication at a lithium concentration of 5 raM, with complete inhibition of viral replication at 30 raM. Lithiuin also reduced viral DNA replication at 7.5 mM (a concentration permitting host cell replication) and completely inhibited viral DNA replication at 30 raM. Other proposed mechanisms for the antiviral action of lithium include replacing magnesium ion as an enzyme cofactor in viral protein synthesis (Bach and Specter 1988), inhibition of viral DNA polymerase (Skinner et al. 1980), -alterations in lymphecyte and macrophage functiolJ (Ffiedenberg and Marx 1980), ~ reduction of Tsuppressor lymphocyte activity (Shenkman et al. 1978; Lieb 1981), altered prostaglandin El and free fatty acid synthesis (Horrobin 1985; Horrobin et al. 1988), and altered host cell membrane dynamics reducing the likelihood of viral penetration into the cell (Bohn et a|. i983; Gosztonyi and Ludwig 1984; Shaskan et al. 198~). Furthc~Trl~re, the antiviral activity of lithium appears to be limited to ~e lithium ion per se, affecting primarily DNA viruses with litth~ effect on RNA viral agents (Skinner et al. 19~,q: Buchan et al. 1988). Recently, howe~ter, antiviral activity has also been reported for sulpiride (Patou et ai. 1986), tfifluoperaziL~e (Patou et al. 1986), chlorpromazine (Chang 1975; ~rizonova et al. 1982; Bohn et ai. 1983; Patou et al. 1986), and haloperidol (Wunde-I;oh et 81. 1980). In clinical stucCOes,Skinner (1983) co~pared lithium succinate ointmcat to placebo in 73 women with recurrent genital herpes infections and observed a greater reduction i~ symptoms and viral excretion in the lithium group. More recently, we reported that oral lithium carbonate could reduce the recurrence rates of genital herpes infections when compared to placebo treatment (Amsterdarr~ et al. 1988). Because the reactivation of latent he~pesvirus has often been attributed to stress (Landm a n n et al. i984; Glaser et al. 1985; Schleifer et al. 1985), we specuhted that the beneficial effect of psychotropic medication on mood stability might enhavce the overall immunol?gical stares of the individual and diminish the number of viral infec:ions (Fernandez an~" Fox 1980; Sengar et al. 1982; Kiecolt-Glaser et al. 1985). Although we did not directly n~easure immunocompetence in our subjects, both treatment groups did report a diminished frequcacy of viral infections with improvement in their affective disorder. However, the observation that the lithium-treated patients had a somewhat greater reduction in herpes infections compared with the nonlithium subjects (p = 0.07) suggests the addition of a specific anti-herpesvirus action for lirhmm. Several caveats need to be considered in the interpretation of these data. For example, our use of retrospective, patient-reposed information has obvious limitations~ and a prospective study documenting the frequcn:y of labial infections and serum antibody titers would have been more ideal. Furthermore, there might have been o~er clinical variables that were not examined in ~e present study, which could have accounted for our observation. In conclusion, ihc present results indicate that long-term lithium administration significantly reduces the frequency of recurrent labial herpes i~fections when compared to the pretreatment period (p < 0.001). Furthermore, alth~ugh ,~gubjects in both medication groups reported fewer herpes infections during treaune~t, this trend was more evident in the lithium subjects compared with those taking other antidepressants (p = 0.07). These data compliment prior in vitro and clinic~ studies demonstrating a pot~,~tial antiviral activity for lithium. Future, prospective stt:dies will help to ch~fy the: potential clinical utility of lithium in che management of recurrent herpesvirus infections.

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This work was supported by The Jack Warsaw Fund for Research in Biological Psychiatry, Hosp~t,',.,~of the University of Pemlsylvania, Philadelphia, PA. The authors extend special recognition to William Dyscn, M.D. and Larry Potter, B.S. for their assistance in obtaining ~ e clinical data, and to Ms. Kathryn Pochi for her assistance in the prepara~on of this manuscript.

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