Indian J. Psychiat* 1994,36(2), 61-66.

TILAK VENKOBA RAO ORATION PSYCHOIMMUNOLOGY AND FUNCTIONAL PSYCHOSES: THE INDIAN SCENE S.C.TIWARI Mr. Chairperson, co-chairperson, my teachers a) in vivo effects of antibrain on the sitting in this august audience, members of our bioelectrical activity of brain structures and be­ society, distinguished guests, ladies and gentlemen: havior (Mihailovic & Jankovic, 1961); This morning in beautiful city of Lucknow, I have b) the speculation that schizophrenia is an im­ been selected to deliver the "Tilak Venkoba Rao munological disorder (Health & Krupp, 1967); oration" which is indeed a land mark step in my c) the modulation of learning and memory by career for a variety of reasons. I am fortunate that I means of antibrain antibodies (Jankovic, 1985); am delivering this oration in the city of my alma d) alterations in immune status following viral mater where I have grown worthy of this oration. I infections and the proposed viral hypothesis of owe a lot to my alma mater and to my revered teachers particularly Prof. B.B. Sethi who brought schizophrenia (Torrey et al, 1978); about a revolution in biological psychiatric research e) the correlation between cerebral atrophy of at Lucknow center. I have never met Tilak but as unknown origin and cell mediated immunity much as I know about him, he was a worthy son of (Jankovic et al, 1977). worthy parents Prof. Venkoba Rao and Dr.(Smt.) The first three experimental and clinical studies Parvathi Devi. I pay my regards to 'Tilak and I am have dealt with the activity of antibrain antibodies sure that the institution of this award after his name (e.e. humoral immunity), the fourth with both will always encourage behaviorists to research humoral and cellular immunity, whereas the last one newer areas in the field of biological psychiatry. relates to the role of cellular immunity in the Before I deliberate upon the main body of oration, I pathogenesis of psychiatric disorders (Jankovic, must thank my parents and my parents-in-law who 1985). These findings provided the much needed are also sitting in audience for this prestigious day theoretical basis for imm unologic research in mental of my career without whose blessings this achieve­ disorders. Though inconclusive, these investigations ment could not have been possible. Lastly, I must have been instrumental in at least heralding a new thank my wife Smt. Shweta Tiwari who is also era of scientific inquiry into the hitherto unknown present here and whose love and constant en­ etiopathogenesis of mental disorders. couragement and sacrifice has enabled me to see the The development of immunological research in dawn of this momentous day in my life. psychiatry has an uneven history. A preliminary BACKGROUND outline of the 's capability to resist infections was delineated by the end of the 19th My interest in psychoimmunological studies was century. However, investigations of the relationship triggered off by my first research work on the viral between the central nervous and immune systems hypothesis of functional psychoses, which was prin­ began after almost three decades with Sir Thomas cipally an immunological study and also because of Lewis' study of the "Triple Response" in !920. This curiosity to observe etiological correlates of mental was followed in the next two decades by disorders in the laboratory test-tube. Speransky's (Pavlov's colleague) conditioning The term 'immunopsychiatry' (or psychoim- studies exhibiting the effect of the CNS on im- munology) was introduced by Jankovic to denote the munopathologic phenomena and by Selye's descrip­ involvement of immune processes, both humoral tion of the CNS - pituitary - adrenal axis effects on and cell mediated, in the pathogenesis of certain the immune function at many levels. mental disorders. The term did not appear de novo, This initial period of enthusiasm was followed by but because of certain important observations which a major swing away from the study of the nervous made it imperative: system's possible influence on the immune system, because of the then gathering evidence that the im­ mune system can function independently and 61 S.CTIWARI autonomously, and this negative phase lasted for a immunological studies at a number of centers (Kol- quarter century or so (Waksman, 1985). However, zaskina et al, 1980). In recent years, two conferences with subsequent developments in molecular biology devoted entirely to ', Immunity and Mental and , both in terms of understanding Disorders' were organized with the help of the and methodological innovations, a large body of W.H.O. (Louvain, Belgium, 1983; Montreal, experimental evidence has gathered during the last Canada, 1984), and the results have been published two decades which points towards the existence of in two monographs (Morozov, 1983; Kurstak et al, complex interactions between the nervous and the 1987). immune systems (Felten et al, 1985). With this In the assessment of over and underactive im­ knowledge, psychoimmunology has not looked mune responses, both humoral and cell mediated back; since then the development of immunological immunological parameters have been investigated. research in psychiatry has run parallel to that of In addition, other biological parameters which arc immunology, reflecting methodological and thought to be linked with the immune system, such theoretical advances made in the latter field. as hormones, neurotransmitters, enzymes, etc., have also been investigated. There is an exhaustive list of RESEARCH STRATEGIES such investigations, but they have mainly been car­ Immune alterations manifest either into overac­ ried out in Western countries. This reflects the ac­ tive or into underactive immune responses. If the cessibility to resources, methodological and source of immunogen is endogenous, the resultant technological advancements etc. In India, these is­ immune disorder is autoimmunity in the case of an sues have played a detrimental role in research overactive , and malignancy in the development in almost every field of medical case of an underactive response. If the source of science including psychoimmunology. Isolated immunogen is exogenous, the resultant im­ studies are available from a few centers and the munological disorder is an in case of overac­ majority of work in this area has been carried out by tive immune response and infection in the case of an us at Lucknow. Only functional psychoses have underactive immune response. Investigative been investigated in India, though other mental dis­ strategies in psychoimmunology have progressed orders such as stress related disorders, drug addic­ along these four lines. The majority of research in tions, etc. have been investigated elsewhere in the psychoimmunology commenced in the 1960's, world. What follows is the narration of our activities though evidence of a dysfunctional immunological and future plans in this field. system in psychiatric disorders were already present since the early llXX)'s. Both immune overactivity PSYCHOIMMUNOLOGICAL RESEARCH: and underactivity have been extensively inves­ THE INDIAN SCENE tigated. The I "70'sand 1980's have seen revitalized activities in this area with the appearance of new Contribution of Lucknow center: centers in which involvement of the immune system The very first study in this area in India was in endogenous psychoses has been extensively ex­ carried out at Lucknow center and it reported that all amined. cases of schizophrenia studied had atypical lym­ phocytes (Sethi & Sethi, 1971). The study did not A number of centers across the globe are examin­ attempt to differentiate between T and B lym­ ing these matters, but the contributions and coor- phocytes, nor were their functional aspects inves­ dinaiing activities of the W.H.O. in promoting tigated. Perhaps, the study was not planned from an immunological research in psychiatry deserves spe­ immunological perspective. cial mention, 'lhe division of mental health of the The second study in the country was also carried W.H.O. has. since 1078, organized one or two sym­ outat Lucknow center in 1976-77 by Dr.R.S. Pandey posia each year as part of the World Congress of and colleagues. This work had the autoimmune Biological Psychiatry, at which results of research hypothesis in the background and overactive im­ in this field ;ire discussed. A program entitled 'An- mune response was investigated in schizophrenic tithymic AntiNxlics in Schizophrenia', involving subjects employing antigens specifically prepared seven research centers, tixik place between 1973 and from different area of brain tissue. A total of 54 1978 under lhe aegis of lhe W.H.O. The results of schizophrenic and 27 non-schizophrenic medical this program are set out in a joint publication and patients were studied. Antigens were prepared from have served as the basis for further development of the frontal cortex, structures of the limbic system, 62 PSYCHOIMMUNOLOGY & FUNCTIONAL PSYCHOSES and parts of the extrapyramidal system from a 35 & 1990). Essentially, it was a negative study and the year old man who had died 2 hours after an results were neither in favor of an underactive im­ automobile accident. Antibodies against these an­ mune response, nor in favor of the viral hypothesis tigens (antibrain antibodies) were studied in the of schizophrenia and depression. Instead, part of the serum and CSF of experimental and control subiects. results favored an overactive immune response and It was found that antibrain antibodies were thus provided some supportive evidence for the present in the serum and CSF of 48.1% of the autoimmune hypothesis. Nonetheless, some of the schizophrenic patients and in none of the control observations deserve special mention. subjects, with high titres of antibrain antibodies Of the depressives in this study, 33.7% had raised being present only in serum. There was no sig­ total CSF proteins - a pattern also noticed in nificant difference in the antigenicity of the three neurological patients. Serum IgG was significantly antigens. Further, it was found that antibodies were higher in depressives and in neurological controls, more commonly found in serum and CSF of those whereas serum IgA was significantly higher in schizophrenics who had a longer duration of illness, schizophrenia, depression and neurological con­ more episodes, positive family history for trols. IgM was within normal limits. In the CSF, IgG schizophrenia, and who received the diagnosis of was detected in all subjects, and was significantly chronic undifferentiated schizophrenia (Pandey et higher in schizophrenics, depressives and neurologi­ al. 1981). The study results favored the autoimmune cal subjects, whereas IgA was detected in the CSF hypothesis for schizophrenia. There is no other of only 23% depressives and 25% neurological report of this nature from the Indian subcontinent. patients and IgM was detected only 25% of There is an enormous amount of literature on this neurological patients. issue from western countries, but till date the status The hemagglutination inhibition (HI) antibodies of the autoimmune hypothesis remains controversial against rubella , tested in the lowest and highest (Ganguly et al, 1987; Koljaskina & Prilipko, 1988). dilutions of 1:20 and 1:1280 respectively, were Psyche-immunology became the area of my inter­ found in the serum of all the subjects and the in­ est in the late 1970's when the viral hypothesis of cidence of seropositive cases and the geometric functional psychoses was regaining ground (Torrey mean of titres were found to be higher (but et al, 1978). The first study which 1 planned was on not statistically significant) in schizophrenic, immunoglobulins and viral antibodies in depressive and neurological subjects as compared to schizophrenic and depressive patients (Tiwari, surgical controls. HI antibodies were not detected in 1982). This, my maiden attempt, explored the pos­ the CSF of any of the subjects. The complement sibility of an underactive immune response in func­ fixing (CF) antibodies against , tional psychoses. I had two objectives in mind, the tested in lowest and highest dilutions of 1:8 and first being to study the pattern of immunoglobulins 1:256 respectively, were found to have a pattern and anti-viral antibodies in the serum and CSF of similar to HI antibodies and these two were not schizophrenic and depressive patients, and the detected in the CSF of any of the subjects. The second being to study the relationship between ill­ immunoglobulin levels were found to be significant­ ness variables and immunological parameters. ly higher in the serum of schizophrenics and depres­ The sample for the study comprised of 30 sives and had a direct relationship with the total schizophrenics, 30 depressives, 20 controls (non- duration (longer duration) of illness, number of psychiatric, non-neurological surgical patients episodes (more episodes) and positive family his­ scheduled to be operated under spinal anaesthesia), tory. and, in addition, 20 neurological controls of either When an infectious agent, such as a virus, is unknown, multiple, or doubtful etiology. All suspected to be the cause of a particular diseased patients and controls were recruited following strin­ state, the immune response is usually expected to be gent inclusion and exclusion criteria. Total CSF hypoactive. However, in this study, an almost op­ protein, humoral immunoglobulins G, A and M an­ posite trend was noticed, thus apparently refuting the tibodies against rubella (hemagglutination inhibi­ viral hypothesis of schizophrenia and depression. tion antibodies) and against cytomegalovirus However, it is known that certain viruses in certain (complement fixing antibodies) in the serum and circumstances trigger an autoimmune response CSF of all subjects were investigated. Part of the either by affecting the B lymphocyte or the T lym­ results have been published (Tiwari etal, 1984,1969 phocyte regulatoryfunction . Do, then, the increased

63 S.CTIWARI immunoglobulins in this study indicate the presence similar in patients and controls. After 2 weeks of of viral infections? As anti-viral antibodies were not treatment, chlorpromazine did not produce any sig­ detected and T cells were not investigated in thk> nificant change in the immunological parameters, study, no conclusions can be drawn. Do these obser­ but after 4 weeks there was a significant rise in vations, then, favor the autoimmune hypothesis? For absolute T and counts, though humoral im­ an , there should be, besides munoglobulins and PHA skin test did not show any elevated immunoglobulins, presence of various significant change. On the other hand, haloperidol auto-antibodies, depressed levels of serum comple­ invoked immunopotentiation after only 2 weeks of ment, immune complexes in the serum, depressed treatment as evidenced by significantly increased levels of T suppressor cells, etc. None of these and T and B cell counts. The variables were investigated and, therefore, any in­ trend was maintained at the end of 4 weeks treatment ference about autoimmunity will be far fetched. as well. In addition, at the end of 4 weeks, there was a significant elevation of serum IgM levels. PHA The results of the study, however, did indicate skin test, however, remained unaltered. that depressives in many immunological aspects resembled neurological patients who were of either Both imipramine and amitriptyline were found to unknown, multiple, or doubtful etiology (Guillian- be immunopotentiating and except for serum IgG Barre syndrome (6), motor neurone disease (4), and PHA skin test, all other immunological idiopathic epilepsy (5), cerebellar ataxia (3) and parameters (IgA, IgM and absolute T and B cell Parkinson's disease (2) (a total of 20 patients). This counts) showed significant elevation after 2 and 4 was the most important finding of the study and weeks of treatment. To test whether clinical im­ provides enough ground for future immunological provement in patients was the result of im­ research. munopotentiation by psychotropic drugs, the Our second major work in the area of psychoim- improved schizophrenics and depressives were munology was the result of our previous work and compared with non-improved groups and it was the unconfirmed reports in the literature that found that the immunological profile of the two psychotropic drugs have an adverse effect on im­ groups did not differ. mune function. The work in this direction was car­ This study raised some important questions. Is ried out in 1987-88 and was entitled, 'A study of the immune profile unrelated to schizophrenic and effects of psychotropic drugs on humoral and cell depressive psychopathology? Is immunopotentia­ mediated immune responses in schizophrenics and tion a non-specific phenomenon, particularly in depressives'. The work was carried out by Dr. D.K. terms of clinical improvement? Is immunopotentia­ Agarwalla, a postgraduate psychiatry student, under tion in any way related to the course and outcome of my co-supcrvisorship and part of the results have schizophrenic and depressive pathology? These is­ been published (Agarwalla et al, 1991). Thirty sub­ sues remain unanswered by our study. It may be jects (12 drug naive and 18 total drug free for 3 speculated that there is a non-specific im­ months) each of schizophrenia and depression were munopotentiation by psychotropic drugs used in the recruited along with 15 healthy volunteers (controls) study in the initial phase of treatment which might for the study. In al! of these subjects, quantitative return back to the preexisting state during the later assessment of the immune system was done by course of therapy, or else, if the elevation persists, it assaying the humoral (IgO, IgA and IgM) and cel­ is simply non-specific. Perhaps, a long term study lular (T and B lymphocyte) fractions in peripheral might answer some of these questions. blood, qualitative assessment of immune function was done in vivo by the PHA (Phenyl hemag­ These findings indicate that neuroleptics and an­ glutinin) skin test. Both the quantitative and qualita­ tidepressants cause immunomodulation, more tive assessment was done at base line, and after 2 and specifically immunopotentiation. This observation 4 weeks in schizophrenics and depressives, while it and reports of immunomodulation in the literature was done only once in controls. (Vertanian & Koljaskina, 1987) inspired us to take up the third work in the field of psychoimmunology To study the effects of psychotropic drugs, in 1989-90. Dr. Sanjay Agarwal, another chlorpromazine and haloperidol were administered postgraduate student, carried out the work entitled to schizophrenics, and tmipramine and amitnptylinc 'Role of an immunomodulator in the treatment of were administered to depressives. The results of the schizophrenics', under my co-supervisorship. It was study showed that pretreatment immune profile was based on the observation that there is a hyperrespon-

64 PSYCHOIMMUNOLOGY & FUNCTIONAL PSYCHOSES sive B cell functioning (increased production of Varanasi, under the supervisorship of Dr. I. Sharma humoral immunoglobulins) in schizophrenics due to (personal communication). The results are yet to be diminution in regulatory activity of T suppressor published. I am not aware of any other work in this cells, secondary to a reduction in the number of T field by any other center in the country. suppressor cells. This led to the hypothesis that by use of an immunomodulator, T suppressor cell CURRENT ACTIVITIES AT LUCKNOW CENTER functioning can be corrected which will eventually AND FUTURE DIRECTIONS correct the hyperresponsive B cell functioning (Ver- Another study which has been planned is about tanian & Koljaskina, 1987). This work of ours was the genetic aspects of psychoimmunology. the result of this hypothesis, and we attempted to Schizophrenic and depressive probands with family study the efficacy of an immunomodulating agent, history of illness in their first degree relatives are to levamisole, using the agent as adjunct to neurolep­ be investigated. In particular, T suppressor cells are tics in the treatment of schizophrenia. to be studied which have almost conclusively been shown to play a role in autoimmune diseases. Thirty four schizophrenics, recruited following rigorous inclusion and exclusion criteria, underwent Till date, inspite of concerted and sincere efforts, a six weeks trial in which eighteen patients (ex­ no definite direction could be delineated, except that perimental group) received levamisole and in our most recent work, we could detect decreased chlorpromazine alone following randomization. T suppressor cell numbers. This observation and Chlorpromazine was given in a dose of 15 mg/kg findings of increased levels of immunoglobulin does body weight per day for the study period, and indicate the possibility of an autoimmune aetiology levamisole in the dose of 150 mg twice a week of schizophrenia. Further, in our first study, we throughout the study. Immunological parameters found similarities between depressives, (IgG, IgA IgM and C3,C4 complements, T cells, B schizophrenics, and neurological controls of un­ cells and T suppressor cells) were studied on day 0 known, doubtful or of multiple etiology, particularly (baseline) and on days 21 and 42. These observa­ with Guillian-Barre syndrome for which a viral tions have been very encouraging. The study etiology is proposed. With these findings we stand revealed that T suppressor cells are decreased in at a crossroad, and are eager to pursue both roads, number in chronic schizophrenics. On treatment i.e. that of autoimmunity and of a viral hypothesis. with levamisole, this decrease is corrected and the No doubt, the future of psychoimmunology is schizophrenics showed corresponding clinical im­ promising and several avenues are open for further provement as well. Moreover, the coefficient of research. Besides autoimmunity and infection correlation revealed that this increase in T suppres­ (viral?), the other roads which could be travelled are sor cell number is significantly correlated with the that of immunogenetics and allergic / hypersen­ improvement in the psychosis. The observations sitivity reactions in the understanding of the com­ thus indirectly support the autoimmune hypothesis plex aetiopathology of functional psychoses. of schizophrenia and also provide evidence that Internationally, this area is being pursued vigorously chronic schizophrenics respond better to conven­ and all aspects of immune function including tional neuroleptics when treated in combination with genetic, biochemical, endocrinal etc., are being in­ levamisole. The only lim iting factor in the study was vestigated. India is rich with fresh and untreated a small sample size, and there is obviously a need patient populations with adequate climatic varia­ for a larger study. tions and, therefore, the country should provide the most fertile ground for psychoimmunologicai re­ OTHER INDIAN CONTRIBUTIONS search. Only a few other workers have attempted psychoimmunologicai studies in schizophrenia. Rao REFERENCES and associates at N1MHANS, Bangalore, studied serum immunoglobulins in schizophrenics as com­ Agarwalla, D.K., Agarwal, A.K., Tiwari, S.C., pared to controls (Rao et al, 1985). The investigators Dalai, P.K., Bahuguna, L.K. & Kumar, A. studied the effects of treatment and illness profile on (1991) Astudy of nature and impact of treatment immunoglobulins. It was a negative study and no on lymphocyte sub-populations among association / correlation could be established. A schizophrenics and depressives. Indian Journal similar work has been carried out at the Department of Psychiatry, 33,3, 206-211. of Psychiatry, Institute of Medical Sciences, BHU, 65 S.C.HWARI

Felten, D.L., Felten, S. Y., Carlson, S.L., Olschow- Rao, N., Gopinath, I. V.L., Jayasimha, P.S., Rana, ka, J Ji. & Llvnat, S. (1985) Noradrenergic and N.S., Rao, B.S. & Subba Krishna, D.K. (1985) peptidergic innervation of lymphoid Tissue. Serum immunoglobulins and schizophrenia. In­ Journal of Immunology, 135, 2, 761-765. dian Journal of Psychiatry, 27, 325-328. Ganguly, R., Rabin, B.S., Kelly, R.H., Lyte, M. & Sethi, N. & Sethi, B.B. (1971) Relationship of Ragu, U.K. (1987) Clinical and laboratory atypical lymphocytes and psychiatric disorders. evidence of autoimmunity in acute Indian Journal of Psychiatry, 13, 97-105. schizophrenia. Annals of New York Academy of Tlwari, S.C, Lai, N., Trivedi, J.K., Sayeed, J. & Science, 676-685. Bahuguna, L.M. (1984) Immunoglobulin Pat­ Health, R.G. & Krupp, I.M. (1967) Schizophrenia terns in schizophrenic patients. Indian Journal of as an immunological disorder. Demonstration of Psychiatry, 23, 223-228. antibrain globulins by fluorescent antibody tech­ Tlwari, S.C, Lai, N., Trivedi, J.K. & Venna, S.L. niques. Archives of General Psychiatry, 16, 1-9. (1989) Relationship of immunoglobulins with Jankovic, B.D., Jakulic, S. & Horvat, J. (1977) the number and duration of schizophrenic Cerebral atrophy: An immunological disorder. episodes. Indian Journal of Medical Research, Immunology (Suppl.), 135. 90,229-232. Koljaskina, G.I. (1980) Antithymic immune factor Tlwari, S.C, Lai, N., Trivedi, J.K., Chaturvedi, in schizophrenia. Neuropsychobiology, 6,6,349- U.C, Venna, S.L. & Bahuguna, L.M. (1990) 355. Immunoglobulins and viral antibodies in depres­ KoUaskina, G.I. & Prilipko, L.L. (1988) Im­ sive patients. Indian Journal of Psychiatry, 32, munological research on endogenous psychoses. 318-323. Geneva: World Health Organization. Torrey, E.F., Paterson, M.R., Branuon, W.L., Kurstak, N., Lipovski, Z. & Morozov, P. (1987) Carpenter, W.T., Post, R.M. & Kammen, Viruses, immunity and Mental disorders. Lon­ D.P.W. (1978) Immunoglobulins and viral an­ don: Plenum Medical Book Company. tibodies in psychiatric patients. British Journal of Mlhailovic, L.J. & Jankovic, B.D. (1961) Effects Psychiatry, 132, 342-348. of intraventricularly injected anti-n caudate an­ Vertanian, E. & Koljaskina, G.L(1987) A tibody on the electrical activity of the cat brain. psychiatrist's view of neuroimmunomodulation. Nature, 192,665. The neuroimmune interaction and mechanism. Morozov, P. (1983) Research on the viral Annals of New York Medical Sciences, 496, 660- hypothesis of mental disorders. Basel: Karger. 668. Pandey, R.S., Gupta, A.K. & Chaturvedi, U.C. Waksman, I.J. (1985) From neuroimmunology to (1981) Autoimmune model of schizophrenia immunopsyeniatry. Journal of Immunology, with special reference to antibrain antibodies. (Suppl.), 135-161. Biological Psychiatry, 16, 1123-1136.

S.C.Tiwari, Assistant Professor in Neuropsychiatry, Department of Psychiatry, K.G. 's Medical College, Lucknow. This oration was delivered at the 45th Annual Conference of the Indian Psychiatric Society held at Lucknow on 7th January 1993.

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