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Keywords:

  • AIDS;
  • CD4;
  • CD8;
  • depression;
  • highly active antiretroviral therapy;
  • viral load

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Abstract  This study investigated the relationships between lymphocyte subsets and viral load in AIDS patients with and without major depression. During a 7-year period, a total of 60 male hospitalized AIDS patients were recruited in this study. The diagnosis of major depression in patients was made by the same psychiatrist according to the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders criteria. All patients had data for CD4, CD8 and CD4/CD8, and only 42 patients had viral load data. Of 60 AIDS patients, 32 patients had received highly active antiretroviral therapy and received subsequent assessment of lymphocyte cell counts 1 month later. Using ancova with age adjustment, the authors found that patients with major depression (n = 22) had significantly lower CD8 cell counts than patients without major depression (n = 38). However, CD4 cell counts and CD4/CD8 ratios were not significantly different between these two groups. In addition, there was no significant difference in viral load between patients with major depression (n = 16) and patients without major depression (n = 26). Of 32 patients received highly active antiretroviral therapy, 14 patients with an antidepressant (e.g. fluoxetine 20 mg/day) had significantly decreased CD4 and not CD8 cell counts and significantly reduced CD4/CD8 ratios during a period of 1 month. In conclusion, these results suggest that AIDS patients with major depression had significantly lower CD8 cell counts and might have a more severe inflammation/immunity reaction than patients without major depression.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Many studies have found strong associations with lower CD4 T-lymphocyte cell count, greater viral load, progression to AIDS, and mortality.1–3 Patients receiving highly active antiretroviral therapy (HAART) can increase the CD4 cell count and reduce the viral load.4 Furthermore, depression was shown to be related to progression of HIV-1 disease to AIDS.5–10 In previous studies, the activation of the monocytic and lymphocytic arms of cell-mediated immunity (CMI) were also found in major depression, including increased T helper (CD4+), T suppressor (CD8+), interleukin (IL)-1 and IL-6.11–14

Depressive symptoms are common in patients who are serologically positive for HIV, and the rates of depressive symptoms were reported to range from 5% to 20%.15–18 A recent large epidemiologic study found that approximately one-third screened positive for major depression and one-quarter for dysthymia.19,20 Rabkin et al. found that rates of major depression in an AIDS cohort were generally in the 5–10% range.21 Psychiatric consultations due to major depression in hospitalized AIDS patients were in the reported range of 10–28%;22–24 this variation may result from the fact that several symptoms of major depression (e.g. weight loss, insomnia, and fatigue) are also in AIDS per se, which rendered underdiagnosis of major depression in this patient population.25–27 Of note, little is known about the relationships between lymphocytes, HIV viral load and major depression in patients with AIDS.28,29

In this study, the authors simultaneously investigated the relationships between lymphocyte subsets, HIV viral load and major depression in male AIDS patients who were hospitalized for psychiatric consultation.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Subjects and design

This study was conducted in the infectious-disease wards of Chang Gung Memorial Hospital at Linko and Kaohsiung, Taiwan, from October 1997 to September 2004. During this period, 102 male AIDS patients were hospitalized and only 68 (67%) were enrolled for psychiatry consultation. The reasons for psychiatry consultation included insomnia, anxiety, depression, psychosis and family problems. AIDS was defined according to the definition of the Center for Disease Control and Prevention.30 Each AIDS patient underwent routine laboratory examinations including hematology, blood chemistry, urine analysis and lymphocyte analyses the morning after hospitalization.

The psychiatric diagnoses were made based on the assessment with the Structured Clinical Interview for the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders Axis I Disorders by the same psychiatrist.31 Patients who had delirium states, dementia, schizophrenia or substance dependence were excluded from this study. The remaining AIDS patients were grouped into patients with major depression and patients without major depression.

All patients underwent lymphocyte subpopulation analyses for CD4 and CD8 cell counts and CD4/CD8 ratio by flow cytometry using commercially prepared monoclonal antibodies (Becton Dickinson, CA, USA) in the clinical laboratory of the hospitals. Only some patients received the examination of HIV viral load because the testing kits were not available at the early study stage. Serum HIV RNA viral load was determined by Amplicor HN-1 Monitor (Roche Diagnostics, Indianapolis, IN, USA).

Subjects with highly active antiretroviral therapy, psychiatric medication and follow up of lymphocyte cell analyses

All AIDS patients received HAART. The drugs used in HAART included nucleotide reverse transcriptase inhibitors (e.g. zidovudine, didanosine, zalcitabine, stavudine, lamivudine), protease inhibitors (e.g. indinavior, ritonavir, saquinavir, lopinavir), and non-nucleotide reverse transcriptase inhibitors (e.g. efavirenz, nevirapine). The combinations of these drugs for the individual patients were at the discretion of their infectious-disease physicians.

If patients had any physical illness (e.g. infection), the necessary drugs were also prescribed. If patients had major depressive disorder, fluoxetine 20 mg/day was suggested to be given. Sleep disturbance and anxious states were also relieved by adding hypnotic and anxiolytic drugs. Some patients also received follow up of their lymphocyte subpopulation analyses at 1 month after initiation of HAART. If patients simultaneously received the treatments of HAART and fluoxetine and completed the follow up at 1 month, the severity of depression was assessed according to the 17-item Hamilton Rating Scale for Depression.32 The definition of good response for the improvement of depression meant that the total score had reduced 50%. All patients were given informed written consent and education for illness and treatment when hospitalized and received psychiatric consultation.

Statistical analysis

All data are presented as mean ± SD. The levels of CD4, CD8, CD4/CD8 and viral load were evaluated between patients with and without major depression by ancova with age adjustment. Using paired t-test, the levels of CD4 and CD8 and the CD4/CD8 ratios were also compared in patients who received HAART with fluoxetine after 1 month treatment and patients received HAART without fluoxetine. An alpha value of P < 0.05 was set to define statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Baseline data of patients before highly active antiretroviral therapy

Out of 68 patients, five patients in states of delirium (one cerebral toxoplasmosis, two cytomegalovirus meningitis, one tuberculosis meningitis and one progressive multifocal leukoencephalopathy), one patient with schizophrenia and two patients with substance dependence were excluded in this study. The remained 60 AIDS patients were grouped into patients with major depression (n = 22) and patients without major depression (n = 38, including one dysthymia, 28 adjustment disorder with anxiety and depression, nine no definite psychiatric disorder). Table 1 presents demographic and lymphocyte data for these 60 patients.

Table 1.  Demographic and lymphocyte data of patients with or without major depression
 Age (years)CD4 (ul)CD8 (ul)CD4/CD8
Patients with major depression (n = 22)35.8 ± 9.488.8 ± 149.7511.9 ± 423.60.12 ± 0.13
Patients without major depression (n = 38)39.4 ± 9.1103.7 ± 164.5518.6 ± 372.50.15 ± 0.18
Total (n = 60)38.1 ± 9.398.2 ± 157.8516.2 ± 388.50.14 ± 0.17

Using ancova with age adjustment, AIDS patients with major depression had significantly lower CD8 cell counts than patients without major depression (F = 5.772; P = 0.020). However, there were no significant differences between patients with and without major depression for CD4 cell count (F = 2.005; P = 0.162) and CD4/CD8 ratio (F = 0.214; P = 0.646).

Of 42 patients with HIV viral load data available, 16 patients (38%) met and 26 patients (62%) did not meet criteria for major depression. Table 2 presents demographic and viral load data for these patients. Using ancova with age adjustment, there was no significant difference in HIV viral load between AIDS patients with major depression and without major depression (F = 0.080; P = 0.778).

Table 2.  Demographic and viral load data of patients with or without major depression
 Age (years)Viral load (RNA copies/mL)
Patients with major depression (n = 16)35.9 ± 10.173 957.9 ± 130 156.1
Patients without major depression (n = 26)39.9 ± 9.489 969.2 ± 126 596.9
Total (n = 42)38.4 ± 9.883 869.7 ± 126 618.1

Patients received highly active antiretroviral therapy with/without fluoxetine

Of 60 AIDS patients who were hospitalized, 32 patients received HAART and received the subsequent assessment of lymphocyte cell counts (CD4, CD8 and CD4/CD8) 1 month later. Table 3 shows the demographic data and lymphocyte cell counts for these 32 patients. There were significantly increased CD4 cell counts (t = 4.443, P = 0.000), CD8 cell counts (t = 3.876, P = 0.001) and CD4/CD8 ratios (t = 3.726, P = 0.001) after patients received HAART.

Table 3.  Demographic and lymphocytes data of patients with or without antidepressant drug (baseline and follow up)
 Age (years)CD4CD8CD4/CD8
  • *

     P < 0.05, paired t-test.

Patients with antidepressant drug (n = 14)34.9 ± 10.1   
 Baseline 124.9 ± 179.2621.6 ± 485.70.15 ± 0.16
 Follow up 197.5 ± 172.1950.4 ± 665.10.23 ± 0.20
 P-value 0.037*0.0740.018*
Patients without antidepressant drug (n = 18)38.72 ± 9.2   
 Baseline 108.3 ± 171.2550.6 ± 424.50.15 ± 0.17
 Follow up 221.2 ± 238.9978.2 ± 619.50.23 ± 0.25
 P-value 0.001*0.003*0.020*
Total (n = 32)37.1 ± 9.7   
 Baseline 115.6 ± 172.0581.6 ± 446.10.15 ± 0.16
 Follow up 210.8 ± 209.4966.0 ± 629.40.23 ± 0.23
 P-value 0.000*0.001*0.001*

Of 32 patients receiving HAART, 18 were without major depression and did not receive fluoxetine. They also showed significantly increased CD4 cell counts (t = 3.834, P = 0.001), CD8 cell counts (t = 3.537, P = 0.003) and CD4/CD8 ratios (t = 2.556, P = 0.020). The 14 patients with major depression who had received fluoxetine 20 mg/day, had also significantly increased CD4 cell counts (t = 2.322, P = 0.037) and CD4/CD8 ratios (t = 2.692, P = 0.018) and not CD8 cell counts (t = 1.944, P = 0.074). Of 14 patients, eight patients (57%) had a good response in depression and six patients did not have a good response.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The most important finding in this study is that AIDS patients with major depression had significantly lower CD8 T cell counts than patients without major depression. This finding supports the hypothesis that natural killer (NK) cell and CD8 T-lymphocyte populations might be possible mechanisms linking depression and HIV disease progress or AIDS.6,33 In addition, some studies also found that a subpopulation of activated CD8 cells have been correlated with cytotoxic activity and with HIV disease progression.2,3,34

Another important finding is that patients with fluoxetine had significantly increased CD4 cell counts and CD4/CD8 ratios and not CD8 cell counts. However, there were significant increased CD4, CD8 cell counts and CD4/CD8 ratio in patients without fluoxetine. The difference between these groups was that patients with fluoxetine treatment did not increase the level of CD8 cell counts. Evans et al.28 had suggested depression might have a negative impact on innate immunity. Examination of killer cell, CD8 cell and the use of antidepressant drugs should be useful in the discussion of relationships between depression, immunity and HIV disease progression. Therefore, the physicians should increase abilities to detect depressive disorders and allow the patients to accept the diagnosis and receive adequate therapy.

The current data shows that there was no significant difference in viral load between patients with major depression and patients without major depression. This result was not compatible with a previous finding by Evans et al.28 They found that depressed HIV-positive patients had higher viral load and reminded the authors to assess the direct effects of depression on HIV medication adherence.28

Some studies suggested that depression promotes inflammatory processes.35 In contrast, some studies found that inflammatory process contribute to depression. The inflammatory mediators induce sickness behaviors (e.g. anorexia, anhedonia and insomnia) which were similar with depressive symptoms.36 The activation of the lymphocytic arm of cell-mediated immunity (CMI) could be involved in major depression, including T helper (CD4+) and T suppressor (CD8+).11,12,14

Besides the disease course and the theory of inflammatory process, the changes of CD4, CD8 or CD4/CD8 might be related to the effects of antiretroviral and antidepressant therapy. These drugs almost all influenced the activity of cytochrome P450 (CYP450) enzymes including 3A4 and 2D6.10,37 The risk of serotonin syndrome was noted in patients with the treatment of HAART and antidepressants simultaneously.37 Some studies did not find that antidepressants could significantly affect CD4 cell counts including fluoxetine, paroxetine and imipramine.38–41 However, their HIV-positive patients were not all in the AIDS stage and the duration of treatment was longer than the current data.

There were many factors which could confound the present results, including duration of HIV infection, presence of other concurrent systemic diseases, the duration of follow up for lymphocytes assessments, referral bias and small sample sizes. In addition, the current subjects simultaneously checked the lymphocytes and viral load, but not all patients had the data of lymphocytes and viral load simultaneously. So the relationship between lymphocytes and viral load could not be acquired. The authors only compared the differences of lymphocytes or viral load in patients with/without major depression, respectively. In future, a larger sample size is needed to test the authors’ results after controlling for other confounding factors and to clarify the association between depression and immunity in AIDS patients.

In conclusion, these results suggest that AIDS patients with major depression had significantly lower CD8 cell counts and might have a more severe inflammation/immunity reaction than patients without major depression.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
    Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann. Intern. Med. 1996; 124: 654663.
  • 2
    Liu Z, Cumberland WG, Hltin LE, Kaplan AH, Detels R, Giorgi JV. CD8+ T-lymphocytes activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J. Acquir. Immune. Defic. Syndr. 1998; 18: 332340.
  • 3
    Giorgi JV, Hultin LE, McKeating JA et al. Shorter survival in advanced human immunodeficiency virus Type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 1999; 179: 859870.
  • 4
    Autran B, Carcelain G, Li TS et al. Positive effects of combined antiretrioviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112116.
  • 5
    Lykersos CG, Hoover DR, Guccione M et al. Changes in depressive symptoms as AIDS develops. Am. J. Psychiatry 1996; 153: 14301437.
  • 6
    Leserman J, Petitto JM, Perkins DO, Folds JD, Golden RN, Evans DL. Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus infected men. Arch. Gen. Psychiatry 1997; 54: 279285.
  • 7
    Leserman J, Petitto JM, Golden RN et al. Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. Am. J. Psychiatry 2000; 157: 12211228.
  • 8
    Leserman J, Petitto JM, Gu H et al. Progression to AIDS, a clinical AIDS condition, and mortality: psychosocial and physiological predictors. Psychol. Med. 2002; 32: 10591073.
  • 9
    Leserman J. HIV disease progression: depression, stress, and possible mechanisms. Biol. Psychiatry 2003; 54: 295306.
  • 10
    Cruess DG, Petitto JM, Leserman J et al. Depression and HIV infection: impact on immune function and disease progression. CNS Spectr. 2003; 8: 5258.
  • 11
    Maes M, Lambrechts J, Bosmans E et al. Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody. Psychol. Med. 1992; 22: 4553.
  • 12
    Maes M, Smith R, Scharpe S. The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 1995; 20: 111116.
  • 13
    Maes M, Bosmans E, Jongh RD, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9: 853858.
  • 14
    Schleifer SJ, Keller SE, Bartlett JA. Depression and immunity: clinical factors and therapeutic course. Psychiatry Res. 1999; 85: 6369.
  • 15
    Stern RA, Singer NG, Silva SG et al. Neurobehavioral functioning in a nonconfounded group of asymptomatic HIV-seropositive homosexual men. Am. J. Psychiatry 1992; 149: 877906.
  • 16
    Perkins DO, Stern RA, Golden RN, Murphy C, Naftolowitz D, Evans DL. Mood disorders in HIV infection: prevalence and risk factors in a non-epicenter of the AIDS epidemic. Am. J. Psychiatry 1994; 151: 233236.
  • 17
    Lipsitz JD, Williams JB, Rabkin JG et al. Psychopathology in male and female intravenous drug user with and without HIV infection. Am. J. Psychiatry 1994; 151: 16621668.
  • 18
    Atkinson JJ, Grant I, Kennedy CJ, Richman DD, Spector SA, McCutchan JA. Prevalence of psychiatric disorders among men infected with human immunodeficiency virus: a controlled study. Arch. Gen. Psychiatry 1988; 45: 859864.
  • 19
    Bing EG, Burnam MA, Longshore D et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch. Gen. Psychiatry 2001; 58: 721728.
  • 20
    Cruess DG, Evans DL, Repetto MJ, Gettes D, Douglas SD, Petitto JM. Prevalence, diagnosis, and pharmacological treatment of mood disorders in HIV disease. Biol. Psychiatry 2003; 54: 307316.
  • 21
    Rabkin JG, Ferrando SJ, Jacobsberg LB, Fishman B. Prevalence of axis I disorders in an AIDS cohort: a cross-sectional, controlled study. Compr. Psychiatry 1997; 38: 146154.
  • 22
    Bear JW. Study of 60 patients with AIDS or AIDS-related complex requiring psychiatric hospitalization. Am. J. Psychiatry 1989; 146: 12851288.
  • 23
    Snyder S, Reyner A, Schmeidler Bogursky E, Gomez H, Strain JJ. Prevalence of mental disorders in newly admitted medical inpatients with AIDS. Psychosomatics 1992; 33: 166170.
  • 24
    Huang TL, Leu HS. Psychiatric characteristics of HIV-infected patients with cocktail therapy. Taiwanese J. Psychiatry 2000; 14: 125131 (in Chinese).
  • 25
    Perkins DO, Leserman J, Stern RA et al. Somatic symptoms and HIV infection: relationship to depressive symptoms and indicators of HIV disease. Am. J. Psychiatry 1995; 152: 17761781.
  • 26
    Griffin KW, Rabkin JG, Remien RH, Williams JBW. Disease severity, physical limitations and depression in HIV-infected men. J. Psychosom. Res. 1997; 44: 219227.
  • 27
    Kalichman SC, Rompa D, Cage M. Distinguishing between overlapping somatic symptoms of depression and HIV disease in people living with HIV-AIDS. J. Nerv. Ment. Dis. 2000; 188: 662670.
  • 28
    Evans DL, Ten Have TR, Douglas SD et al. Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am. J. Psychiatry 2002; 159: 17521759.
  • 29
    Cole SW, Kemeny ME, Fahey JL, Zack JA, Naliboff BD. Psychological risk factors for HIV pathogenesis: mediation by the autonomic nervous system. Biol. Psychiatry 2003; 54: 14441456.
  • 30
    Centers for Disease Control 1992. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. M.M.W.R. 41 (RR-17), 1–19.
  • 31
    First MB, Spitzer RL, Gibbon M, Williams JBW. User’s Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version. American Psychiatric Press, Washington DC, 1997.
  • 32
    Hamilton M. Development of a rating scale for primary depressive illness. Br. J. Soc. Clin. Psychol. 1967; 6: 278296.
  • 33
    Evans DL, Leserman J, Perkins DO et al. Stress-associated reductions of cytotoxic T lymphocytes and natural killer cells in asymptomatic HIV infection. Am. J. Psychiatry 1995; 152: 543550.
  • 34
    Ho HN, Hultin LE, Mitsuyasu RT et al. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J. Immunol. 1993; 150: 30703079.
  • 35
    Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of depression is associated with suppression of nonspecific Th1 responses in multiple sclerosis. Arch. Neurol. 2001; 58: 10811086.
  • 36
    Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav. Immun. 2001; 15: 724.
  • 37
    DeSilva KE, Le Flore DB, Marston BJ, Rimland D. Serotonin syndrome in HIV-infected individuals receiving antiretroviral therapy and fluoxetine. AIDS 2001; 15: 12811285.
  • 38
    Elliot AJ, Karina KK, Bergam K, Russo J, Claypoole K, Roy-Byme PP. Randomized, placebo-controlled trial of paroxetine versus immipramine in depressed HIV-positive outpatients. Am. J. Psychiatry 1998; 155: 367372.
  • 39
    Ferrando SJ, Rabkin JG, De Moore GM, Rabkin R. Antidepressant treatment of depression in HIV-seropositive women. J. Clin. Psychiatry 1999; 60: 741746.
  • 40
    Rabkin JG, Rabkin R, Harrison W, Wagner G. Effect of immipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am. J. Psychiatry 1994; 151: 516523.
  • 41
    Rabkin JG, Wagner G, Rabkin R. Fluoxetine treatment for depression in patients with HIV and AIDS. A randomized, placebo-controlled trial. Am. J. Psychiatry 1999; 156: 101107.