Psychosomatics 42:247-251, June 2001
© 2001 The Academy of Psychosomatic Medicine
Changes in Lymphocyte Subsets in Depressed HIV-Infected Patients Without Antiretroviral Therapy
Alessandra Alciati, M.D.,
Angelita Ferri, M.D.,
Simona Rozzi, M.D.,
Antonella D'Arminio Monforte, M.D.,
Fabrizia Colmegna, M.D.,
Isabel Valli, and
Carmen Mellado, M.D.
Received May 4, 2000; revised November 27, 2000; accepted November 29, 2000. From the Departments of Psychiatry and Infectious Diseases, L. Sacco Hospital, Milan. Address reprint requests to Dr. Alciati, Ospedale L.Sacco, Department of Psychiatry, Via G.B. Grassi, 74 20157 Milano, Italy.
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ABSTRACT
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The authors studied the effects of major depression on lymphocyte subsets by comparing depressed and matched control subjects in a population of HIV-seropositive outpatients not treated with antiretroviral therapy. Twelve patients with major depression, as determined by the Structured Clinical Interview for DSM-III-R, were assessed in comparison with 15 matched nondepressed control subjects. Flow cytometric analysis of peripheral blood lymphocyte subsets together with immunological parameters were performed. In HIV-infected patients, major depression was significantly (P=0.001) associated with a reduction in natural killer cell absolute count and percentage. This report suggests that depression may alter the natural killer cell population that provides a cytotoxic defense against HIV infection.
Key Words: HIV/AIDS • Depression • Antiretroviral Therapy
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INTRODUCTION
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The extremely variable course of HIV infection is still unclear. Differences among virus strains and the host's immunological response do not explain exclusively the variability of survival rates.1 Psychological aspects have been proposed as possible cofactors in the progression of HIV disease.2 Among these, depression is a focus of attention because it is common, potentially modifiable, and has been associated with changes in the immune response. In physically healthy patients with major depression, the lymphoproliferative response to mythogens3 [phytohemagglutinin-P(PHA), concanavalin A (ConA), pokeweed mitogen (PWM)] and natural killer (NK) cell activity have been found to be reduced,4 although there is little agreement in the literature.
Immunological changes associated with depression could be amplified by the effects of HIV infection on the immune response. Nevertheless, no significant association between depressive symptoms and changes in lymphocyte subsets count has so far been demonstrated. Total lymphocyte count,5 CD8+ count,6 CD8+ percentage,7 CD4+ count,8 and CD4+ percentage,9 which are considered the most important serological markers of the progression of the disease, do not differ in depressed and nondepressed HIV-infected patients. Moreover no association has been found among depression, NK cell count,5 and CD4/CD8 ratio9 changes.
Some of the instruments used for the assessment of depression in HIV patients may lead to an overestimation of depressive symptoms because some of the items in these instruments characterize depression by the presence of somatic complaints that could be caused by the infection itself, such as weight loss, insomnia, and fatigue. Also, these instruments do not usually evaluate the severity or the time of onset of these symptoms and may characterise as depression the transient reaction to changes in the individual's clinical state.
In some studies that use operational diagnostic criteria and structured interviews to make a diagnosis, depression is often examined in its different syndromal expressions, including major depression, dysthymia, and adjustment disorder with depressed mood. When only major depression is examined, the severity of the depression is not usually assessed.
To investigate the relationship between depression and immunological parameters, we studied only patients who received a DSM-III-R diagnosis of major depression that was considered clinically severe [as assessed by the 21-item Hamilton Rating Scale for Depression (Ham-D)  20] and who were not taking antiretroviral therapy.
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METHODS
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Subjects
All subjects were recruited from a group of HIV-seropositive patients in the Department of Infectious Diseases Out-Patients Service at the L. Sacco Hospital, Milan, Italy. HIV status was determined by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot testing.
The data for the current study were obtained from participants enrolled in a larger, ongoing longitudinal study, the overall goal of which is to determine the effect of depression on immune parameters and disease progression in HIV-seropositive patients.
Eligibility criteria for this study included being between 18 and 55 years old, becoming aware of HIV-seropositive status within the last 6 months, and having a white blood cell count of at least 2,000 cells/mm3.
All potential study participants were screened to exclude patients with intravenous drug use for the last 5 years, notable medical illness (heart, lung, kidney, liver, thyroid, and gastrointestinal diseases; cancer, diabetes, and arthritis) or neurological illness (stroke, seizure, head injury), past treatment for alcoholism or current heavy alcohol consumption (more than 60 drinks/month), and those meeting the 1987 Centers for Disease Control (CDC) criteria for acquired immunodeficiency syndrome (AIDS).
Beginning in 1994, HIV-seropositive patients who met DSM-III-R criteria10 for major depression and nondepressed HIV-seropositive control subjects (matched on the basis of age, gender, risk factors, length of illness, and CDC stage) were examined at 3-month intervals for signs and symtoms of AIDS and psychiatric and immunological status.
Procedure
Twelve patients with major depression who were HIV-seropositive and who were not taking an antiretroviral drug at the time of initial assessment were selected for this study. Informed consent was obtained from all subjects after the procedures were fully explained. Patients with depression were not included if they had been treated with a regimen of antidepressant, lithium, or neuroleptic drugs during the preceding 3 months.
A DSM-III-R diagnosis of major depression was made by use of the Structured Clinical Interview for DSM-III-R (SCID) at the subjects' entry into the study. Interrater reliability has been good (kappa=0.82).
Trained psychiatric clinicians further evaluated the severity of the subjects' depression with the 21-item Ham-D in which mild depression is defined by scores ranging from 7 to 12, moderate depression is defined by scores ranging from 13 to 20, and severe depression is defined by scores over 20. Only patients with a score of 20 or more on the 21-item Ham-D entered the study. The intraclass correlation coefficient for the raters was r=0.88
Each depressed patient was matched as closely as possible to a control HIV-seropositive nondepressed subject on the basis of the following factors: 1) gender, 2) age (within 5 years), 3) length of known period of HIV-seropositivity, 4) CDC stage, and 5) risk factors. All nondepressed HIV-seropositive control subjects met the same inclusion and exclusion criteria. They were interviewed with the SCID Nonpatients Version (SCID-NP) and Ham-D and had no current or past major psychiatric disorders. No subjects were taking an antiretroviral drug at the time of entry into the study.
Depressed and control subjects had no symptoms of active bacterial or viral infection. Depressed and control subjects were also free of medications known to affect immune response, recreational drugs, and heavy alcohol consumption for at least 2 weeks before immunological testing. There were no significant differences in alcohol consumption between the two groups.
Blood samples for immunological analysis were drawn between 8:30 and 9:30 A.M. by venipuncture from patients and control subjects after fasting for at least 10 hours. In 9 depressed patients and 12 control subjects, blood samples were drawn within 3 days from the psychiatric assessment. In the remaining 6 subjects, blood samples were obtained within 7–10 day of assessment.
Lymphocytes bearing CD4+ and CD8+ marker and NK cells, identified by using fluorescent monoclonal antibodies to stain for CD16 (Leu-11), were counted at each visit since the patient's initial assessment. The Leu-11 (CD16) marker is present on virtually all cells in the peripheral blood that are known to have functional NK activity.11
Serum level of the immune activation marker ß2 microglobulin was measured by a competition ELISA using a commercially available kit. HIV p24 antigen testing was performed.
Because the viral load determinations were not available in the cohort until July 1996, they were not included in the analysis. The HIV-positive patients not taking antiretroviral therapy were admitted to the study before this date.
The patients with depression underwent a treatment program with specific serotonin reuptake inhibitors (SSRI), receiving either sertraline (dose range=50–100 mg), fluoxetine (20–40 mg), fluvoxamine (50–200 mg), or paroxetine (20–40 mg). The control subjects did not receive any form of treatment.
Group means for continuous data were compared using Student t-test. All P values are two-tailed and statistical significance was set at 0.05.
Monoclonal Antibody and Flow Cytometry Technique
Peripheral blood samples were collected into Vacutainer (Bectan Dickinson) with EDTA. Monoclonal antibodies (Ortho Trio Systems, Inc.) were used to measure the predominant reactivity to the various lymphocyte subset. Monoclonal antibodies identify and enumerate T lymphocytes (CD3+), B lymphocytes (CD19+), and NK cells (CD16+/CD3-) simultaneously when using the Ortho ImmunoCount Flow Cytometry System. Whole blood was incubated with premixed fluorochrome-conjugated monoclonal antibodies for 15 min at room temperature in the dark. Erythrocytes were lysed and the absolute counts and percentage of positively stained lymphocytes were enumerated using the Ortho ImmunoCount Flow Cytometry System. Specific lymphocyte subset enumeration is achieved through acquisition and analysis using the Ortho ImmunoCount Flow Cytometry System that consist of Ortho Cytoronabsolute Laser Flow Cytometer and Ortho ImmunoCount II software.
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RESULTS
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We examined 27 subjects: 12 patients with major depression (8 men and 4 women) and 15 control subjects (11 men and 4 women). The age range for the depressed group was 26–52 years (mean±SD=33.75±7.07), and for the control patients the age range was 27–48 years (34.8±5.04). All the subjects were white.
One depressed patient and his matching control subject were in CDC stage IVC2, whereas all the other subjects were in CDC stage III. No patients had previously been hospitalized with a HIV-related complication. Of the patients, 58% had acquired HIV infection by intravenous drug use, 25% by homosexual intercourse, and 16% through heterosexual contacts.
There were no significant differences between depressed and nondepressed HIV-seropositive patients with respect to age (P=0.63), years of education (P=0.71), or time that HIV-positive status was known (P=0.26). The characteristics of depressed and matched nondepressed seropositive subjects are shown in Table 1.
Ham-D scores for patients with depression ranged from 24 to 38. No patients with depression showed melancholic features. The mean Ham-D for patients with depression was 29.7±4.69; for the control subjects the mean Ham-D was 3.6±1.9. Eight of the 12 depressed patients had no prior history of major depression, and 4 of 11 patients (36%) reported that at least one family member suffered from depression (one subject was adopted after birth and never knew his parents). The reported duration of depressive symptoms before the psychiatric assessment ranged from 1 month to more than 3 months.
Data on absolute count and percentage of lymphocyte subsets and serological markers of HIV progression in depressed and nondepressed patients are shown in Table 2.
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DISCUSSION
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The results of our study, in agreement with previous studies, show that major depression in HIV-infected patients is not associated with significant changes in CD4 and CD8 lymhocyte cells, absolute count or percentage, or in CD4/ CD8 ratio.
However, our data do demonstrate a clear relationship between severe depression and a reduction in counts and percentage of NK lymphocytes labeled by Leu-11 monoclonal antibodies in HIV-seropositive non-AIDS patients not treated with antiretroviral therapy. Major depression in otherwise healthy individuals has been associated with a suppression of various aspects of the immune response. Recent data have shown that the severity of depression may be an important variable in the expression of depression-related immune alterations, thus suggesting that negative studies may reflect findings from less severely depressed patients.
A growing body of literature focusses on changes in NK cells, a subset of large granular lymphocytes that are involved in the natural resistance against viral infection and tumor growth. Several studies have shown relationships between depression and decreased NK cell number12,13 and activity.14 These effects are particularly marked in patients who are severely depressed15 or who exhibit melancholia.16 Moreover, the reduced NK cell activity associated with major depression may be abrogated with symptom remission.17 In HIV-infected patients, stress-related changes in NK population have been examined, but these studies have yielded discrepant findings.
Evans5 reported that HIV-positive patients with more stressful life events had fewer NK lymphocytes, and Goodkin18 found that life stressors helped predict progression to AIDS but were not associated with NK cell activity.
Sahs19 concluded that NK CD56 cell number is not related to the measures of psychological distress in homosexual men with and without HIV infection. On the contrary, Leserman20 produced the first prospective data showing that stress and depressive symptoms, especially when they occur jointly, are associated with a decreased number of NK and CD8 lymphocytes in HIV-infected men.
NK cell numbers and activity in HIV-seropositive patients with major depression are less frequently examined, and our results provide some of the first evidence of NK cell number reduction in depressed subjects not treated with antiretroviral therapy. This finding is notable in light of NK activity in immune response. In fact, NK cells are an important component of the cellular immune system. They are capable of destroying pathogens or tumor cells without direct assistance from other cell types and without prior exposure to an antigen.21
In addition to nonselective cytotoxic activity of NK cells, there is evidence that HIV-1–infected CD4+T cell lines are susceptible to NK cell-mediated cytotoxicity.22,23 NK cells have also been shown to lyse cells infected by pathogens and to eliminate pathogens that activate the HIV-1 transactivator of viral transcription (Tat) infectivity gene.24
In conclusion, our results confirm that severe depression in HIV-infected subjects has no measurable effect on the number of CD4+ and CD8+ T cells. However, we found that there is a relationship between severe depression and a reduction in NK cell population.
These results suggests a specific effect on NK cells that could relate to unique aspects of NK cell regulation and/or possible differential effects of major depression-related dysfunction such as alterations in hypothalamic-pituitary-adrenal axis on NK and T cells.
Given that NK cells may provide a defense against opportunistic infection and control over HIV,25 the lowering of this cell population due to major depression may have clinical relevance for the course of HIV infection.
In two previous studies evaluating the influence of depression on the progression of HIV infection,8,26 a cohort of asymptomatic seropositive homosexual men were examined every 6 months by the self-administered rating scale Center for Epidemiologic Studies Depression Scale (CES-D), considering as "depressed," individuals showing a score of 16 or higher. Although no association between the CES-D score and the onset of AIDS or the time of death has been found, in one these studies8 the presence of depression appeared to determine a more rapid decline in CD4 cell count. It is important to point out that the CES-D is not a clinical tool for depressive disorders. Its sensitivity for DSM-III-R major depression is in the 80–90% range, with a specificity in the 70–80% range.27
A review, with meta-analytic techniques, of 19 published studies28 concluded that depressive symptoms are not associated with alterations in putative markers of HIV progression or with increases in objectively defined HIV morbidity and mortality. Prospective studies using structured diagnostic interviews and operational diagnostic criteria are critical for gaining a better understanding of the effects of depression on immune parameters and HIV disease progression.
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J. D. Hartzell, I. E. Janke, and A. C. Weintrob
Impact of depression on HIV outcomes in the HAART era
J. Antimicrob. Chemother.,
August 1, 2008;
62(2):
246 - 255.
[Abstract]
[Full Text]
[PDF]
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ABSTRACT
INTRODUCTION
