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German Journal of Psychiatry

ISSN 1433-1055

Immunological Study of Manic Patients

Ahmed Mubarak, El Sayed Gad and w. f. a. a. Ibrahim


Departments of Neuropsychiatry and Biochemistry

Faculty of Medicine Tanta University

Tanta, Egypt

Corresponding author: Professor Ahmed Mubarak, MD, Department of Neuropsychiatry, Faculty of Medicine, Tanta University, Tanta, Egypt; e-mail: amobarak@future.com.eg

 


Abstract

twenty manic patients and 20 healthy control subjects were evaluated psychiatrically and immunologically by estimating immunoglobulins (IgG, IgM and immune complex). The aim was to compare these parameters in manic patients with those in healthy control subjects and to correlate them with the frequency and severity of manic attacks. This may help in understanding the relationship between bipolar disorder and the immune system.

A significant decrease in immunoglobulins IgG and IgM was found in patients as compared with controls (p<0.05), but there was no significant difference in the serum immune complex between patients and controls. In recurrent cases, a significant decrease was found in IgG (p<0.001) and IgM (p<0.05) when compared to first episode cases, whereas the immune complex showed non-significant differences (p>0.05). A positive correlation was found between the severity of symptoms and immunological parameters. This correlation was significant for IgG (p<0.001) and IgM (p<0.05).

Conclusions: increased immune response in acutely disturbed severe manic patients may not be due to the disease process, but may be a body reaction to counteract the stresses of this acute state. The low immunoglobulins found in recurrent cases support the findings of previous investigations, although we could not prove whether this is a cause or an effect. However, this should direct our attention towards considering compromised immunity as a part of the healthcare of this group of patients (German J Psychiatry 1999;2:48-60).

 

Key words: Immunological, mania, immunoglobulins

 

Received: Nov. 11, 1999

Published: Dec. 8, 1999


 

Introduction

Research into immune function in psychiatry is challenging because it represents an interface between two rapidly changing fields. Revitalization of interest in this area began with work demonstrating changes in immune function with stress (Schleifer et al. 1983). Recognition of immune system dysfunction in psychiatric patients, particularly those with affective disorder or schizophrenia, has led to some interesting hypotheses of the pathogenesis of these disorders, including infectious and autoimmune aetiologies. On the other hand, dysfunction of the immune system may be secondary to the primary disease process, to long-term pharmacological treatment, or a result of an unrecognised concurrent, but unrelated medical disorder (Delisi et al. 1984). The interaction between the central nervous system (CNS) and the immune system has been a major focus of research in the last three decades. Recent reviews have focused on the role of stress and psychiatric morbidity on immune dysfunction (Shaviy et al. 1985). Perez and Farrant (1988) have drawn parallels between the two systems; in serving functions of adaptation and defence both the CNS and the immune system discriminate between self and non-self and incorporate principles of recognition, learning memory and transmission of information (Pereze and Farrant, 1988). Blalock (1984) has suggested that the immune system functions as a sensory organ for external stimuli that cannot be detected by the nervous system (Blalock 1984). The combination of cognitive dysfunction and immune dysfunction in states such as affective illness is increasingly being recognised (Calabrese 1987).

The immune response can be modified by a person's state of mind. States such as bereavement, depression, loneliness, separation and loss, and learned helplessness have all been shown to depress immune function (Schlerfer, 1983; Camara and Danao, 1989).

Recent studies have revealed some interesting evidence and hypotheses for the pathogenesis of schizophrenia and other psychoses, including infectious and autoimmune aetiologies (Cow 1984). Bipolar patients have been reported to have an increased prevalence of thyroid autoantibodies, changes in circulating phenotypic lymphocyte profiles and may even present with leukocytosis and fever during mania (Kronfol et al. 1988, Haggerty et al. 1987).

In depressed patients the percentage of neutrophils is increased and lymphocytes and monocytes decreased, complement C3, C4 and IgM are also increased (Kronfol et al. 1989). Other studies have shown that although lymphocyte proliferation and neutrophil phagocytosis are significantly reduced, mononuclear phagocytosis is increased in depressed patients (O'Neill and Leonard 1990).

The quantification of immunoglobulin concentrations in serum is a common way of measuring the humoral immune response of the CNS and the whole organism to infection. Quantitative and qualitative immunoglobulin abnormalities are commonly found in acute and persistent viral infection (Vaheri et al. 1982). Up to now several studies on immunoglobulin concentrations in patients with schizophrenic and affective disorders have revealed conflicting results (Delisi et al. 1981, Roos et al. 1985).

the aim of this investigation is to study specific immunological parameters in mania (IgG, IgM, immune complex) and to correlate these parameters with the frequency and severity of manic attacks. This will help in understanding the relationship between bipolar disorder and the immune system, a relationship which should be taken into account in the long-term healthcare of this group of patients.

 

subjects and methods

The patient group included 20 manic patients (females and males with age ranging from 17 to 35 years), diagnosed according to DSM-IV and ICD-10 criteria. The control group included 20 healthy individuals matched by age and sex to the patient group, with no previous history of any psychiatric disorders or any medical disease that can affect the immune system.

 

Table 1. Demographic data in patients and control cases

 

Patients

Control Subjects

t

p

Mean age

 

 

25.5 (SD 4.92)

 

25.16 (SD 3.99)

 

0.2

 

n.s.

sex :

 Male

 Female

No. (%)

11 (55)

9 (45)

No. (%)

10 (50)

10 (50)

?2

0.03

0.04

p

n.s.

n.s.

 

A history was obtained and a clinical psychiatric examination performed. The objective evaluation of the severity of manic symptomatology was done by using the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen 1987). All patients were evaluated clinically (history and clinical examination), searching for signs of immunological changes, e.g. recurrent viral infection and searching for any diseases that can affect immunity, e.g. sore throat, bronchitis, liver diseases, thyroid enlargement etc. Laboratory investigations: 1) Complete blood count: to exclude patients with anaemia, leucopenia, leucocytosis, eosinophilia or any other abnormal figures in blood count. 2) Thyroid function tests to exclude patients with increased T3 and T4 serum levels or to exclude patients with low serum T3 and T4 levels. 3) Renal function tests (blood urea and serum creatinine) to exclude patients with renal impairment. 4) Liver function tests: to exclude patients with liver affection, especially those with high liver enzymes or those with diminished albumin levels or high globulin levels. 5) Urine and stool analysis to exclude urinary tract infection or parasitic infestations. Exclusion criteria were patients with previous diseases that can affect immunity, e.g. rheumatic fever, rheumatoid arthritis, liver diseases, renal diseases, etc.; patients under medication for mania or those who stopped treatment for a period less than 6 months; patients who received any other medication such as oral contraceptives, nonsteroidal anti-inflammatory drugs, corticosteroids, anticonvulsants, and antidepressants, or had ECT during the preceding 6 months; patients with any history of fever during the preceding 3 months.

Immunological studies (Mancini, 1965)

(1) Estimation of serum immunoglobulin level including IgG and IgM was done by using the immuno­diffusion technique of Mancini (1965) using Norpartigen immuno­diffusion plates (Behring-Werke).

(2) Detection of circulating immune complexes was performed by precipitation with polyethylene glycol. Immunoglobulin levels are calculated in grammes/litre (G/L), immune complex is calculated by the degree of optical density (OD).

 

Results

 Psychiatric Evaluation

In Table 2, the clinical characteristics of the patients are given.

 

Table 2. Manic symptoms and course characteristics

 

No

%

Clinical Manifestations:

Mood Changes

Elevated:

Expansive:

Irritable

Inflated self-esteem:

Decreased need for sleep:

Talkativeness:

Flight of ideas:

Distractibility:

Hyperactivity:

Excessive involvement in pleasurable activities:

 

 

2

8

10

16

20

20

19

16

18

15

 

 

10

40

50

80

100

100

95

80

90

75

Course:

First episode:

Recurrent:

Type of episode:

Exclusively manic

Manic-depressive

 

11

9

 

14

6

 

55

45

 

70

30

 

 

 

 

 

 

Table 3. Symptom severity in cases with first episode and recurrent cases (t =3.51; df =18; p<0.01)

 

Mean CASH score (SD)

First Episode (11)

36.46 (SD 3.86)

Recurrent (9)

27.89 (SD 6.90)

 

Cases with first episode showed a significantly higher severity score than recurrent cases (Table 3).

 

Immunological studies

A significant decrease of the immunoglobulins IgG and IgM was found in patients compared with the control subjects (p<0.05), but no significant difference in serum immune complex (p>0.05; Table 4). There was a significant decrease in IgG (p<0.001) and IgM (p<0.05) in recurrent cases compared with those cases presenting with their first episode, while immune complex showed non-significant differences (p>0.05; Table 5).

A positive correlation was found between the severity of symptoms and immunological parameters. This correlation was significant for IgG (p<0.001) and IgM (p<0.05) but not significant for immune complex (p>0.05; Fig. 2-4).

 

Table 4. Immunological findings in patients and control subjects (t test, df=38)

Factor

Cases

Controls

t

p

IgG (g/l); mean (SD)

22.19 (1.91)

26.63 (7.83)

2.19

p<0.05

IgM (g/l); mean (SD)

2.39 (0.51)

3.02 (0.84)

2.15

p<0.05

Immune complex (OD); mean (SD)

0.92 (0.08)

0.91 (0.05)

0.10

p>0.05 (n.s.)

 

 

table 5. Immunological findings in cases with first episode and cases with recurrent episode (t test, df=38)

 

First episode

Recurrent episode

t

p

IgG(g/l), mean (SD)

31.71 (6.06)

20.43 (4.57)

4.6

p<0.001

IgM(g/l), mean (SD)

30.41 (0.68)

2.55 (0.81)

2.57

p<0.05

Immune complex (OD), mean (SD)

0.95 (0.14)

0.87 (0.13)

1.24

p>0.05 (n.s.)

 

 

 

 

 

 

 

 

Discussion

Immunological studies in mania are rare, which in 1988 led kronfol and House to claim that the immune state of mania had never been investigated.

there are many conflicting results concerning the immunology of bipolar disorders in previous studies, Weisse (1992) reported no difference in lymphocyte function or numbers of T and B cells and antibody production between bipolar patients and a control group, suggesting that bipolar patients do not exhibit reduced immune function. Rapaport (1994) reported that there was no evidence of immune activation in euthymic bipolar subjects and that they did not differ significantly from normal volunteers, neither lithium treatment nor gender differences seeming to alter this finding. On the other hand, Leonard and Song (1996) reported a significant increase in the levels of IgM, but not IgG in depressed patients, while Maes (1995) found significantly higher plasma levels of IgG in major depressed subjects than in normal controls.

Leonard and Song (1996) reported that serum concentrations of IgG and IgM are increased in depressed patients. Maes et al. (1997) reported that plasma IgG was significantly lowered in manic patients, either medicated or not, and reported no significant alteration in plasma IgM. All of the studies mentioned above had different methodologies and consequently produced different conclusions.

In our study, the elevation of immunoglobulins in the acute severe form of the disease could be regarded as an acute body reaction to the illness, an explanation adopted by Kronfel and House in 1989. This elevation in immunoglobulins may explain how manic patients tolerate the physical stresses like cold and physical effort during the acute phase of the disease. In this respect, Maes et al. (1997) reported no relationship between the presence of an acute phase response and the aetiology of mania.

Lowered immunoglobulins in patients with recurrent episodes than in control subjects were found by previous studies (schlerfer, 1983; camara and Danoo, 1989). The relationship of immune system to bipolar disorder may be a complex one. The neurotransmitter systems, e.g. the dopamine system, may be a common factor affecting the mesolimbic system and implicated in psychotic processes, or even the manic core itself, and at the same time the hypothalamo-pituitary adrenocortical axis and consequently the immune system. Whether or not the decrease in immunoglobulins is a cause or an effect needs further research in large-scale prospective studies on the role of the immune system in the pathogenesis of mania.

From this study we can conclude that an increased immune response in acutely disturbed severe manic patients may not be due to the disease process, but to an acute phase body reaction to counteract the stresses of this acute state.

Although it was not possible to determine whether the low immunoglobulins found in recurrent cases were a cause or an effect, this finding should direct our attention towards considering compromised immunity as a part of the healthcare of this group of patients.

 

references

Andreasen,.N.: Comprehensive Assessment of symptoms and History CASH Department of psychiatry, University of Iowa. College of Medicine. 1987

Blalock, J.E. :The immune system as a sensory organ. Journal of Immunology, 1984; 132:1067-1070.

Calabrese, J.R., Kling, M.A. and Gold, P.W.: Alteration in immunocompetence during stress, bereavement and depression; Focus on neuroendocrine regulation. American Journal of psychiatry, 1987; 144:1123-1134.

Camara, G.E. and Danao, C.T.: The Brain and the Immune system. A psychosomatic network, Psychosomatic Medicine, 1989; 30:140-145.

Cow, T.J.: Are-evaluation of the viral hypothesis: is psychosis the results of retroviral integration at a site close to the cerebral dominance gene? British Journal of psychiatry, 1984; 145:243-253.

Delisi, L.E., Cathering King, A. and Targum, S.: Serum Immunoglobulin Concentrations in patients Admitted to an Acute psychiatric in patient service. British Journal of psychiatry, 1984; 145:661-666.

Delisi, L.E., Weinberger, D.R., Potkin, S., Necker, L.M., Shilling, D.J. and Wyatt, R.J.: Quantitative determination of immunoglobulin in CSF. and plasma of chronic schizophrenic patients. British Journal of psychiatry, 1981; 13:5130518.

Haggerty, J.J., Simon, J., Evans, D.C. and Nemeroff, C.B.: Relation ship of serum TSH concentration and antithyroid antibodies to diagnosis and DST response in psychiatric patients. American Journal of Psychiatry, 1987; 144:1491-1493.

Kronfol, Z. and House, D.J.: Immune function in Mania. Biological Psychiatry, 1988; 24:341-343.

Kronfol, Z. and House, J.D.: Lymphocyte mitogenesis, immunoglobulin and complement levels in depressed patients and normal controls. Acta psychiatrica Scandenavia, 1989; 80 : 142-147.

Leonard, B.E. and Song, C.: Stress and the Immune system in the Etiology of Anxiety and Depression. Pharmacology Biochemistry and Behavior, 1996; 54:299-303.

Maes, M.: Evidence for an immune response in major depression: A review and hypothesis. Progress in Neuro-psychopharmacological and Biological Psychiatry 1995; 19:11-38.

Maes, M., Delange, J., Ranjan, R., Mettzer, Y.H., Desnyder, R., Cooremans, W. and Scharpe, S. : Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Research, 1997; 66:1-11.

Mancini, G Carbonara, A. O. and Hermans, J. F.: Immunochemical quantitations of antigens by single radial immunodiffusion. Immunochemistery, 1965; 2: 235-254.

O’Neill, B. and Leonard, B.C. : Abnormal Zymosan induced neutrophil chemiluminescence as a marker of depression. Journal of Affective Disorder, 1990; 19:265-272.

Perez, M. and Farrant, J.: Immune Reaction and Mental Disorder. Psychological Medicine, 1988; 18:11-13.

Rapaport, H.M.: Immune parameters in euthymic bipolar patients and normal volunteers. Journal of Affective Disorders, 1994; 32:149-156.

Rapaport, M.H., Schmidt, M.E., Risinger, R. and Maji, H.: The Effects of prolonged Lithium Exposure on the Immune system of Normal control subjects: Serial serum soluble Interleukin-2 Receptors and Anti-thyroid Antibody Measurements. Biological psychiatry, 1994; 35:761-766.

Schleifer, S.J., Keller, S.E., Camarino, M., Thornton, J.C. and Stein, M.M.: Suppression lymphocyte stimulation following bereavement. Journal of American Medical Association, 1983; 374-377.

Shavity, Y. Terman, G.W., Martin, F.A., et al. : Stress, Opioid peptides, the immune system and cancer. Journal of Immunology, 1985; 135 (Suppl): 834 - 837.

Vaheri, A., Keski Oza, J., Salonen, E.M. & Kostkiniemi, M.C.: Cerebrospinal fluid IgG bands and virus specific IgG IgM and IgA antibodies in herpes simplex virus encephalitis. Journal of Neuroimmunology, 1982; 3:247-261.

Weisse, S.C.: Depression and Immunocompetence: A Review of the Literature. Psychological Bulletin, 1992; 3:475-489.