Treatment of Depression Is Associated with Suppression of Nonspecific and Antigen-Specific TH1 Responses in Multiple Sclerosis

ORIGINAL CONTRIBUTION Treatment of Depression Is Associated With Suppression of Nonspecific and Antigen-Specific TH1 Responses in Multiple Sclerosis

David C. Mohr, PhD; Donald E. Goodkin, MD; Janeen Islar, BS; Stephen L. Hauser, MD; Claude P. Genain, MD

Objective: To examine the relationship between de- human myelin oligodendrocyte glycoprotein (MOG). Vari- pression, treatment of depression, and interferon gamma ability in immune assays was controlled using 8 nonde- (IFN-␥) production by peripheral blood mononuclear cells pressed healthy subjects who were enrolled at times cor- in patients with comorbid diagnoses of relapsing- responding with the enrollment of MS patients. remitting multiple sclerosis (MS) and major depressive disorder. Results: Results of the Beck Depression Inventory were significantly related to IFN-␥ production stimulated with Design: A randomized comparative outcome trial of three OKT3 or MOG at baseline (PՅ.03 for all). Level of de- 16-week treatments for depression. Assessments were con- pression, OKT3-stimulated IFN-␥ production, and MOG- ducted at baseline, week 8, and treatment cessation. stimulated IFN-␥ production all declined significantly over the 16-week treatment period (PՅ.03 for all). Among con- Setting: An academic outpatient treatment and clini- trols, there were no significant changes over time in OKT3- cal research center. or MOG-stimulated IFN-␥, or in depression (PՆ.25 for all). Patients: Fourteen patients who met the criteria for relapsing-remitting MS and major depressive disorder. Conclusions: These findings suggest that the production of the proinflammatory cytokine IFN-␥ by autoag- Interventions: Individual cognitive behavioral therapy, gressive T cells in relapsing-remitting MS is related to de- group psychotherapy, or sertraline therapy. pression and that treatment of depression may decrease IFN-␥ production. Thus, treatment of depression may pro- Main Outcome Measures: Depression was assessed vide a novel disease-modifying therapeutic strategy as well using the Beck Depression Inventory. Interferon gamma as a symptomatic treatment for patients with MS. productionbyperipheralbloodmononuclearcellswasmea- sured following stimulation with OKT3 or recombinant Arch Neurol. 2001;58:1081-1086

ULTIPLE sclerosis sion.11,12 However, the psychoneuroim- (MS) is the most com- munology literature suggests that this mon chronic demy- relationship may be more complex. Stud- elinating disease of the ies have consistently found depression to central nervous sys- be associated with lowered natural killer tem in adulthood. Its cause is believed to cell activity and lowered numbers of natu- M1,2 be autoimmune. Depression, with a life- ral killer, B, T-helper (TH), and suppressor- time prevalence estimated at over 50%,3 cytoxic T cells.13,14 Depression may in- is more common in MS than in other duce abnormalities of immune functions chronic illnesses4,5 or neurological disor- that are relevant to MS, in which a con- ders.6,7 The etiology of depression in MS certed immune attack by cellular and hu- is likely multifactorial and may be attrib- moral factors directed against myelin con- uted to brain lesions,8 psychosocial stituents of the central nervous system losses,9,10 and/or immune dysregula- results in tissue destruction.2 tion.11,12 In the animal disease model of MS, From the Departments of Studies examining the relationship experimental allergic encephalomyelitis Psychiatry (Dr Mohr) and + − Neurology (Drs Mohr, between depression and immune dysregu- pathology is mediated by CD4 CD8 TH1 Goodkin, Hauser, and Genain lation in MS have assumed that the causal cells that are activated by the presenta- and Ms Islar), University of relationship is unidirectional, with im- tion of specific myelin antigens on major California, San Francisco. mune dysregulation causing depres- histocompatibility complex class II mol-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 SUBJECTS AND METHODS suppression.23 Peripheral blood mononuclear cells (106/mL) were cultured in RPMI-1640 medium (GIBCO, SUBJECTS Grand Island, NY) supplemented with 10% fetal bovine serum (BioWhittaker, Walkersville, Md), 4mM L-glutamine, Fourteen patients with MS were enrolled over 12 months 25mM Hepes buffer, 50-U/mL penicillin, and 50-µg/mL strep- through the University of California, San Francisco, Mul- tomycin. After 2 days, cells were resuspended in 1 mL of se- tiple Sclerosis Center after signing informed consent docu- rum-free X-VIVO-10 medium (BioWhittaker) with 1 µg of ments. These patients were involved in a larger clinical trial OKT3 antibody, and supernatants were collected after an ad- of treatments for depression in MS26,27 and met the criteria ditional 2 days. Suppression of IL-10 was achieved in a du- for clinically definite relapsing-remitting MS28,29 and ma- plicate set of tubes by adding 1 µg of IL-10. jor depressive disorder using the Structured Clinical In- Antigen-stimulated production of IFN-␥ and T-cell pro- terview for the Diagnostic and Statistical Manual of Mental liferative responses were assessed by standard 3-day pro- Disorders, Fourth Edition.30 Patients were excluded if at liferation assays39 using 2ϫ105 PBMCs in 96-well round- screening they had experienced an MS exacerbation within bottom plates after the following additions: no antigen the previous 30 days; had taken immunosuppressive medi- (control); myelin basic protein (MBP), 50 µg/mL; a recom- cation within the last 14 days; were receiving any treat- binant protein corresponding to the N-terminus domain ment for depression, including medication or psycho- of human myelin oligodendrocyte glycoprotein (MOG) aa therapy; or met the criteria for dementia, defined as 1-125, 10 µg/mL; and phytohemagglutinin, 2.5 µg/mL. Af- performing below the fifth percentile on 3 of the follow- ter 48 hours, 100 µL of supernatant was removed from each ing tests: Digit Span Test,31 Symbol Digit Modalities Test,32 well and stored at –80°C for cytokine assays. After me- Rey Auditory Verbal Learning Test,33 7/24 Test,32 Con- dium replacement, 0.5 µCi of tritiated thymidine was added. trolled Oral Word Association Test,33 brief Boston Nam- The wells were harvested 18 hours later. Stimulation in- ing Test,34 and California Card Sort Test.35 Patients were dex values were calculated as ratios of counts per minute not asked to participate in blood draws for this study if they in stimulated wells over counts per minute in unstimu- were using disease-modifying medications (interferon beta- lated (control) wells. 1a, interferon beta-1b, or copolymer I). Most patients in The concentrations of IFN-␥ and IL-4 in superna- the larger clinical trial were using one of the disease modi- tants were measured using enzyme-linked immunosor- fying drugs, and no patient ceased using MS medications bent assay kits according to the manufacturer’s instruc- for participation in the study. tions (Biosource International, Camarillo, Calif). The To control for variability in the immunological as- production of each cytokine was calculated as the differ- says, 8 nondepressed healthy control subjects were en- ence between the concentration in stimulated superna- rolled corresponding with the enrollment of MS patients. tant culture and that in unstimulated cultures. Concentra- tions below the threshold of detection for the assay INTERVENTIONS (5 pg/mL) were arbitrarily set at 0.

Patients were randomly assigned to 1 of 3 commonly used STATISTICAL ANALYSES 16-week treatments for depression: (1) individual cognitive behavioral therapy26,27 designed to improve coping skills, 36 All IFN-␥ production variables are reported in pico- (2) group psychotherapy designed to provide social sup- grams per milliliter and were analyzed as continuous port and facilitate emotional expression, or (3) psycho- variables, except those in which MOG was used as an pharmacological therapy with the commonly prescribed an- 37 antigen. Because approximately 70% of all MS patients tidepressant sertraline. do not react to MOG at any given point in time,37 the ASSESSMENT OF DEPRESSION IFN-␥ response to MOG was dichotomized at each assessment point as “response” or “no response.” Response was Level of depression were measured using the Beck Depres- defined as MOG-stimulated IFN-␥ production that ex- sion Inventory (BDI).38 ceeded 3 SDs above the mean production of unstimulated cells (19.1 pg/mL). IMMUNOLOGICAL ASSAYS For T-cell proliferative responses, a stimulated index value of 2.5 or greater was considered a positive response. Heparinized venous blood was collected at baseline, week Associations between 2 continuous variables were ana- 8, and treatment cessation. Blood was processed within 4 lyzed using Pearson correlations. Comparisons of continu- hours to obtain PBMCs (Ficoll Hypaque; Pharmacia Bio- ous variables across 2 groups were analyzed using t tests. tech, Uppsala, Sweden). Analyses of change over time were performed using analy- Nonspecific OKT3-stimulated production of IFN-␥ was sis of variance for continuous variables or the Cochran Q measured with and without interleukin 10 (IL-10) test for dichotomous variables.

ecules.2 In humans, analogous T-cell responses directed Interferon gamma (IFN-␥) is the main proinflam- against several myelin antigens have also been impli- matory cytokine produced by activated TH1 cells and is cated in the pathogenesis of MS.15,16 These pathogenic T- regarded as a major effector mechanism in the patho- cell responses could be modulated by the level of depres- genesis of MS.19 Administration of IFN-␥ has been re- sion. Cross-sectional and longitudinal studies have shown ported to trigger exacerbations.20 Increased production that increased depression is related to higher numbers of IFN-␥ has been shown to precede both MS exacerba- and proportions of CD4+ and CD8+ T cells.17,18 tions21 and the development of new magnetic resonance

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 imaging brain lesions22; it may also be associated with an acceleration of the disease course.23 Increased IFN-␥ Table 1. Levels of Depression and Cytokine Production* production has also been associated with severe depression in psychiatric inpatients.24,25 However, the nature of Baseline Week 8 Posttreatment the relationship between depression and the produc- Multiple Sclerosis Patients (n = 14) tion of IFN-␥ by myelin-specific T cells has not been ex- BDI 21.9 (6.4) 15.6 (4.9) 14.2 (9.1) amined in MS. Furthermore, the relationship between OKT3 IFN-␥, pg/mL 1177 (939) 702 (416) 575 (396) ␥ OKT3 IFN-␥ + IL-10, pg/mL 537 (484) 249 (224) 186 (204) IFN- and more common forms of depression that do OKT3 IL-4, pg/mL 56 (44) 28 (26) 44 (57) not require inpatient treatment remains unclear. In the current study, we used a longitudinal design Control Subjects (n = 8) BDI 3.6 (3.0) 2.5 (3.1) 4.1 (3.8) to examine the relationship between immune system re- OKT3 IFN-␥, pg/mL 808 (394) 869 (490) 736 (387) activity as measured by nonspecific and myelin antigen– OKT3 IFN-␥ + IL-10, pg/mL 2.8 (6.0) 0 (0) 0.4 (1.1) stimulated production of IFN-␥ in peripheral blood mono- OKT3 IL-4, pg/mL 12.8 (12.0) 7.9 (8.7) 5.6 (6.6) nuclear cells (PBMCs) and a standardized measurement of depression in patients with relapsing-remitting MS. De- *Values are mean (SD). BDI indicates Beck Depression Inventory; pression was manipulated through outpatient treat- IFN-␥, interferon gamma; and IL, interleukin. ment using either psychotherapy or sertraline. It was hy- pothesized that depression would be positively correlated to IL-4 production, MBP-stimulated variables, prolifera- with nonspecific and specific antigen-stimulated IFN-␥ tive responses, or IL-10 suppression of IFN-␥ produc- production, that depression and IFN-␥ production would tion (rϽ0.47, PՆ.10 for all). decline during the course of treatment for depression, and that changes in IFN-␥ production would be related to EFFECTS OF TREATMENT changes in depression. (WITHIN-SUBJECT CHANGE)

RESULTS Table 1 displays the values of the dependent variables over the course of treatment for depression. Because both PATIENT CHARACTERISTICS BDI and OKT3-induced IFN-␥ production were related to age, the effects of age were covaried out of outcome Of the 14 relapsing-remitting MS patients enrolled in the analyses for these measures. study, 10 (71%) were women and 4 (29%) were men. The average age was 47.4 years (range, 29-69 years). The mean Depression Expanded Disability Status Scale40 score was 3.6 (range, 0-6.5). The mean time since diagnosis was 11.3 years The BDI dropped significantly over the 16 weeks of treat- (range, 10 months–19.8 years). The mean (SD) BDI at ment for depression (F2,26=6.19, P=.006). The age co- baseline was 21.9 (6.35). Three patients experienced clini- variate was significant, with younger patients showing cal exacerbations: 1 patient at week 3, 1 patient at week greater improvement (Rao R=5.95, P=.01). There was 6, and 1 patient at week 8, coincident with the sched- no differential effect for treatment modality (P=.86). uled assessment and blood draw. OKT3-Stimulated Production of IFN-␥ BASELINE ANALYSES Nonspecific IFN-␥ production decreased significantly over Dependent Variables (BDI and Immune Variables) the course of treatment (F2,24=3.92, P=.03). The age co- and Demographic or Disease Variables variate was marginally related to change in IFN-␥ over time, with younger patients showing a greater decline in Age was related to BDI (r=−0.65, P=.01) and OKT3- IFN-␥ production (Rao R=3.58, P=.05). Interleukin-10 stimulated IFN-␥ (r=−0.69, P=.006). Dependent vari- suppression of OKT3-stimulated production of IFN-␥ in- ables were otherwise unrelated to demographic and dis- creased during treatment (F2,24=6.68, P=.005). There was ease variables, including age, sex, marital status, Expanded no significant differential effect for treatment modality Disability Status Scale, or time since diagnosis (PՆ.09 (P=.55). for all). MOG-Stimulated Production of IFN-␥ Depression and Immune Variables Values of MOG-stimulated IFN-␥ for responders dur- Baseline BDI was significantly related to OKT3- ing treatment are displayed in the Figure. Five patients stimulated IFN-␥ production (r=0.64, P=.01). Five pa- (36%) showed an IFN-␥ response to MOG at baseline tients showed a positive IFN-␥ response to MOG at base- while 9 (64%) did not. Three patients (21%) showed an line. Baseline BDI was significantly related to IFN-␥ IFN-␥ response to MOG at week 8 (these were different response to MOG, with nonresponders significantly less patients than those who showed a response at baseline), depressed (mean [SD] BDI, 19.2 [4.9]) than responders and no patients showed an IFN-␥ response to MOG at 26.8 [6.1]) (t=−2.55, P=.03). Among MOG responders, treatment cessation (1 patient who showed a response BDI was strongly correlated with IFN-␥ production to MOG at week 8 was experiencing an exacerbation at (r=0.87, P=.05). The BDI was not significantly related the time of the blood draw and was subsequently treated

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 4100 Table 2. Mean (SD) Stimulation Indices for T-Cell Proliferative Responses During the Course of Treatment*

Baseline Week 8 Posttreatment

900 ∗ Multiple Sclerosis Patients (n = 14) MBP, µg/mL 0.6 (0.2) 0.8 (0.4) 1.0 (0.5) PHA, µg/mL 91 (127) 40 (41) 113 (161) MOG, µg/mL 2.1 (2.1) 1.5 (1.8) 1.5 (1.9) Control Subjects (n = 8) 300 MBP, µg/mL 1.1 (0.7) 1.3 (0.7) 1.5 (0.8) , pg/mL

γ PHA, µg/mL 4.9 (7.7) 20.4 (25.7) 29.6 (39.6) MOG, µg/mL 1.1 (0.7) 1.6 (0.5) 1.5 (0.6)

*MBP indicates myelin basic protein; PHA, phytohemagglutinin; and MOG, myelin oligodendrocyte glycoprotein. 200

MOG-Stimulated IFN- MOG (PՆ.16 for all) (Table 2). There were no significant differential effects for treatment modality (PՆ.56 for all).

100 RELATIONSHIP OF CHANGE IN DEPRESSION TO CHANGE IN IMMUNE FUNCTION

Using slopes analysis, the relationship between change 0 in BDI and change in immune function was examined Baseline Week 8 Posttreatment for those variables for which significant within-subject changes had occurred. The change in BDI was signifi- Production of myelin oligodendrocyte glycoprotein (MOG)-stimulated interferon gamma (IFN-␥) production at baseline, at week 8, and cantly related to the change in OKT3-stimulated IFN-␥, posttreatment in 8 patients (5 who showed a response at baseline and 3 who (r⌬BDI and r⌬IFN-␥=0.56, P=.04). Change in BDI was not showed a response at week 8). Seven patients showed no response to MOG significantly related to change in IL-10 suppression of at any point. Asterisk indicates a blood sample taken from a patient experiencing an exacerbation. OKT3-stimulated IFN-␥ (P=.74). The relationship between change in MOG-stimulated IFN-␥ and change in BDI was not examined because there was no variability with prednisone). The reduction in the number of pa- in IFN-␥ response to MOG at treatment cessation (ie, no tients showing a response to MOG over the course of treat- patient showed an IFN-␥ response to MOG). ment was significant (Cochran Q, 5.0; P=.03). All patients who responded to MOG also showed significant ANALYSIS OF CONTROL SUBJECTS IL-10 suppression (Cochran Q, 5.0; P=.03). Because there were no responders to MOG at treatment cessation, evalu- Of the 8 control subjects in the study, 5 (62%) were women ation of differential effects for treatment modality would and 3 (38%) were men, which was not significantly differ- only reflect pretreatment differences. As this would be ent from the MS patients (P=.12). The control subjects were meaningless, these calculations were not performed. significantly younger (mean, 31.2 years; range, 23-41 years) than the MS patients (t20=3.75, P=.001). Table 1 displays MBP-Stimulated Production of IFN-␥ the BDI and IFN-␥ values for control subjects. There were no significant changes over time in the BDI, nonspecific There was no significant change over time in MBP- or antigen-specific IFN-␥ responses, IL-10–suppressed stimulated IFN-␥ (P=.15), nor was there any significant IFN-␥ responses, or IL-4 responses (PՆ.25 for all). With change in IL-10 suppression of MBP-stimulated IFN-␥ respect to proliferative responses, there was a nearly sig- (P=.49). There were no significant differential effects for nificant increase in phytohemagglutinin-stimulated pro- treatment modality (PՆ.53 for all). liferation (F3,12=3.16, P=.06). No other proliferative responses showed significant changes over the course of the Production of IL-4 study (PՆ.24 for all). These control subjects were used solely to control for variability in the assays. Because con- There was no significant change over the course of treat- trol subjects were not depressed and did not have MS, no ment in OKT3-, MOG-, or MBP-stimulated IL-4 (PՆ.22 analyses were performed comparing controls and MS pa- for all). There were no significant differential effects for tients for BDI or immunological variables. treatment modality (P=.55). COMMENT T-Cell Proliferation Assays This study found that among MS patients, depression was There were no significant changes in proliferative re- positively correlated with both nonspecific and antigen- sponses over time using MBP, phytohemagluttinin, or specific stimulated production of IFN-␥ by PBMCs. Fur-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 thermore, over the course of treatment for depression, IFN-␥ production.50,51 However, serotonin has been shown decreases in levels of depression were associated with de- to stimulate, rather than reduce, IFN-␥ production.52,53 creases in levels of IFN-␥ production. The stability of the Thus, the effect of depression and its treatment on IFN-␥ IFN-␥ production in the control subjects rules out the is likely the final result of multiple and conflicting path- possibility that these findings were caused by variability ways, which will require further investigation. in the assays. Thus, these results support the hypothesis Several limitations must be considered in interpret- that depression is associated with increased IFN-␥ pro- ing the data of our study: (1) Confidence in our find- duction, and that IFN-␥ production can be down- ings may have been limited by the small sample size. How- regulated by treating depression. The observed relation- ever, the effect sizes were robust, and the statistical ship between IFN-␥ production, depression, and treatment methods employed controlled for the effects of chance of depression may have particular salience for MS pa- based on sample size. Furthermore, our findings are con- tients as IFN-␥ has been implicated as a major factor in sistent with those of previous cross-sectional17,24 and lon- the pathophysiology of this disease.19-22 gitudinal18,25 studies. (2) We considered placebo treat- Behavioral and pharmacological treatments for de- ment of major depressive disorder unethical.54 In the pression were used in this study. Because several anti- absence of a placebo control condition, it is possible that depressants, including sertraline, have been shown to re- all patients showed unusually high autoimmune reac- duce IFN-␥ secretion in PBMCs,41 we analyzed the data tivity before treatment and that the observed changes re- to determine if treatment assignment was related to IFN-␥ flect the natural course of such reactivity independent production. Although the possibility of a relationship be- of treatment for depression. This interpretation, while not tween treatment modality and IFN-␥ production can- consistent with the existing literature,13,14,18,24,25,39,42,55 can- not be formally excluded, these data suggest that such a not be ruled out. (3) Because this study was of short du- relationship is unlikely. ration, we do not know if observed changes in IFN-␥ pro- Consistent with previous studies,39,42,43 we found that duction are of clinical significance. It will be of a substantial proportion of patients with MS exhibited considerable interest to examine whether the treatment positive reactivity to MOG at baseline. Although some of depression and reduction in IFN-␥ production are re- patients, including one who had an exacerbation, showed lated to clinical and/or imaging measures of progression an IFN-␥ response to MOG at week 8, all the patients and exacerbation. became nonresponders by the end of treatment. This find- None of the limitations invalidate the primary finding is potentially relevant to treatment strategies for MS. ings that depression is associated with IFN-␥ produc- Both clinical studies and experimental studies using ani- tion in MS and that treatment of depression is associ- mal models of experimental allergic encephalomyelitis ated with a reduction in nonspecific and antigen- suggest that heightened immune response to MOG may specific IFN-␥ production. These novel findings suggest trigger autoimmune demyelination in the central ner- that treating depression may be an important disease- vous system.44-46 Thus, our observation that treatment of modifying component in the treatment and manage- depression is associated with decreased T-cell respon- ment of relapsing-remitting MS. siveness to MOG suggests that amelioration of depression could be an important factor for down-regulating Accepted for publication December 11, 2000. autoaggressive T cells and therefore may be an impor- This research was supported by grant RG2719 A1/2 tant component in the management of patients with MS. from the National Multiple Sclerosis Society, New York, NY; Although the manipulation of depression through by grant R01 MH59708 from the National Institute of Men- treatment supports the argument that depression can cause tal Health, Bethesda, Md (Dr Mohr); by an award from the changes in IFN-␥ production, these findings do not rule Osher Center for Integrative and Complementary Medi- out the possibility that IFN-␥ production can cause de- cine, University of California, San Francisco (Dr Mohr); pression. It has been suggested that immune dysregula- and by Harry Weaver Neurosciences Scholarship JF 2087- tion in MS may cause depression,12 and the increased in- A-2 from the National Multiple Sclerosis Society (Dr Genain). cidence of depression during disease exacerbation11,47 is Corresponding author and reprints: David C. Mohr, consistent with this argument. Thus, the present findings PhD, Veterans Affairs Medical Center (116-A), 4150 Clem- might better be interpreted as supporting the notion that ent St, San Francisco, CA 94121 (e-mail: [email protected] the relationship between immune dysregulation and de- .edu). pression in MS is dynamic and reciprocal. While our finding that a reduction in levels of de- REFERENCES pression is associated with a reduction in IFN-␥ production is consistent with the existing literature,24,25 1. Anderson DW, Ellenberg JH, Leventhal CM, Reingold SC, Rodriguez M, Silber- potential mediating mechanisms are not understood. Abil- berg DH. 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