Psychosomatics 49:530-534, November-December 2008
doi: 10.1176/appi.psy.49.6.530
© 2008 Academy of Psychosomatic Medicine
Early-Onset Versus Late-Onset HIV-Related Secondary Mania in Uganda
Etheldreda Nakimuli-Mpungu, M.B.Ch.B., M.Med.,
Seggane Musisi, FRCP(C),
Steven Kiwuwa Mpungu, M.B.Ch.B., M.Sc., and
Elly Katabira, M.R.C.P., FRCP
Received August 5, 2006; revised November 23, 2006; accepted December 4, 2006. From the Departments of Psychiatry, Internal Medicine, and Clinical Epidemiology and Biostatistics, Makerere University Medical School. Send correspondence and reprint requests to Etheldreda Nakimuli-Mpungu, Johns Hopkins Bloomberg School of Public Health, Dept. of Mental Health, Baltimore, MD 21205. e-mail: ethelmpungu{at}yahoo.com
© 2008 The Academy of Psychosomatic Medicine
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ABSTRACT
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BACKGROUND: First-episode secondary mania in human immunodeficiency virus (HIV) infection has been described among samples of predominantly Caucasian, HIV-positive male patients in developed countries. OBJECTIVE: The goal of this study was to compare the demographic and clinical characteristics of HIV-positive patients with early-onset and late-onset first-episode secondary mania in HIV infection. There were previous findings of an association between late-onset mania and severe cognitive impairment. METHOD: Subjects were HIV inpatients with clinically-confirmed mania, who received standard demographic, psychiatric, physical, and laboratory assessments. Early-onset patients had CD4 cell counts >200 mm3; late-onset patients had CD4 cell counts  200 mm.3 RESULTS: There were no demographic or cognitive differences between early-onset and late-onset mania patients, and high rates of psychotic symptoms in both groups. However, late-onset patients had more manic symptoms. CONCLUSION: Late-onset HIV mania patients had more severe psychopathology and, thus, demonstrated a greater need for highly active retroviral therapy.
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INTRODUCTION
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First-episode secondary mania in human immunodeficiency virus (HIV) infection has been described among samples of predominantly Caucasian, HIV-positive male patients in developed countries.1–3 Recently, however, in a controlled study, the clinical presentation and correlates of first-episode secondary mania were described in a sample of HIV-positive patients in Uganda.4 Compared with HIV-negative patients with primary mania, HIV-positive patients with first-episode secondary mania were predominantly women, age 30–49 years, of low socioeconomic and education status. A significant number are divorced or widowed as a result of losing spouses to AIDS.
Clinically, the majority were more irritable, more aggressive, and had more disruptive behaviors, greater frequency of decreased need for sleep, more talkativeness, and higher rates of psychotic symptoms. As expected, they had more cognitive impairment and more immune suppression. These findings show that first-episode secondary mania in HIV-positive individuals and primary mania in HIV-negative individuals are clinically distinct syndromes.
Previous descriptions of HIV-positive patients with secondary mania occurred in patients with advanced HIV disease, with a mean CD4 count range of 43 to 100 per cubic millimeter. Interestingly, in this study, the HIV-positive patients had a mean CD4 count of 392, and 46% had CD4 counts <200 mm3, indicating that first-episode mania occurred in both early and advanced HIV disease.4 Previous researchers have examined differences between early-onset and late-onset mania in HIV infection and have found that the latter have a different manic-symptom profile and are more likely to have dementia or cognitive slowing. They proposed that the different demographic and symptom profile associated with early-onset and late-onset mania may reflect differences in pathophysiology.5
In this study, our sample specifically comprised HIV-positive patients who met criteria for secondary mania. The goal of this study was to compare the demographic and clinical characteristics of HIV-positive patients with early-onset and late-onset first-episode secondary mania in HIV infection, in order to determine whether baseline characteristics might provide insights into appropriate methods of assessment and management. Also, we sought to replicate previous findings of an association between late-onset mania and severe cognitive impairment.5 We also hypothesized that the demographic and clinical characteristics of patients with early-onset and late-onset first-episode secondary mania in HIV infection would be different.
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METHOD
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Patients were recruited as part of the Primary Mania Versus HIV-Related Secondary Mania in Uganda study, which was conducted to compare the clinical presentation and correlates of HIV-positive patients with first-episode secondary mania with those of HIV-negative patients with primary mania. Methods for this study are described in detail elsewhere.4 Psychiatrists attached to the wards where patients were admitted clinically confirmed a diagnosis of mania by DSM–IV criteria.6 The manic symptoms at the time of admission were rated on the Young Mania Rating Scale (YMRS)7 by research assistants (psychiatric clinical officers) who had received training in the use of this scale. The patients were treated with typical antipsychotic drugs, and, when they gained insight and were stable enough to communicate, research assistants explained the study procedures and asked the patients to provide written informed consent to participate. For those who did not consent, any data collected previously were discarded.
Patients were eligible for the study if they were at least 18 years old. They were excluded if they were found to have a medical condition other than HIV/AIDS and its complications that could be related to the manic episode. The Alcohol Use Disorders Identification Test (AUDIT)8 was used to exclude those with alcohol dependence. Also, patients were clinically assessed, and those who met DSM–IV criteria6 for delirium, substance use, and dependence disorders were excluded from the study, as well as those patients who were in puerperium.
Those who gave informed consent underwent routine standard psychiatric, physical, and laboratory assessments. Among demographic variables, we examined age at assessment, gender, education status (primary education-or-less versus some secondary education-or-more), marital status (single, married, widowed, divorced/separated), socioeconomic status as indicated by number of rooms in the house in which they lived (1–2 rooms versus >2 rooms), and loss of sexual partner/spouse to AIDS (Yes or No). Among clinical characteristics, we examined source of referral (self-referral, referral from general hospital, or referral from police); length of hospitalization (1–2 weeks versus >2 weeks); frequency of HIV-related symptoms; manic symptoms as rated by the YMRS (total YMRS scores and individual manic symptom scores); measures of cognitive impairment, assessed by the Mini-Mental State Exam (MMSE);9 and measures of immune status, such as CD4 cell counts. The patient’s medical records were reviewed, and the following were noted: physical diagnosis, investigations done, and physical examination findings. HIV status was noted from past medical records or self-reports of HIV status. For those patients whose HIV-serostatus was not known, pretest counseling was given before HIV serology was done. WHO clinical staging of HIV/AIDS10 was used to stage all HIV-positive patients. Secondary mania was diagnosed according to a modified form of the criteria of Krauthammer and Klerman11 initially used by Ellen et al.1: no clear previous personal or 2) family history of affective disorder. The patients were grouped according to whether the first-episode secondary mania occurred when their CD4 count was 200 mm3 (late onset) or >200 mm3 (early onset).
Statistical Analysis
Statistical analysis was carried out with a commercial software package (SPSS, Version 11.5). First, we calculated frequencies of various clinical and demographic variables. Bivariate-level analyses were conducted to identify demographic and clinical variables that were significantly associated with late-onset, first-episode secondary mania. Within the bivariate statistics, we used chi-square tests or Fisher’s exact test for qualitative variables, independent-sample t-tests for continuous variables, and Spearman’s rank test for correlation coefficients for cases of two quantitative variables.
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RESULTS
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Overall, 61 HIV-positive patients met criteria for first-episode secondary mania. Of these, 28 (46%) had CD4 cell counts <200 mm3 (late-onset mania), whereas 33 (54%) had had CD4 cell counts  200 mm3 (early-onset mania).
There were no differences in demographic variables between the two groups of patients. There were no differences between the two groups regarding sources of referral ( 2=0.72; p=0.69) or length of hospitalization. (2=2.5; p=0.11) However, patients with late-onset mania were more likely to have lost a sexual partner to HIV/AIDS than patients with early-onset secondary mania (2=12.24; p=0.002).
Clinically manic symptoms reported by the HIV-positive patients were comparable, although there were unusually high rates of psychotic symptoms in both groups: visual hallucinations (late-onset: 96%, versus early-onset: 88.2%; 2=1.12; p=0.29), auditory hallucinations; (76% versus 55.9%; 2=1.12; p=0.29), and paranoid delusions; (96% versus 88.4%; 2=1.1; p=0.29). However, when manic symptoms were assessed with the YMRS, HIV-positive patients with late-onset secondary mania had higher manic symptom scores, as shown in Table 1.
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TABLE 1. Association Among Manic Symptom Scores on the Young Mania Rating Scale (YMRS) and Immunological Status, Mean (Standard Deviation)
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Cognitive impairment, as indicated by MMSE score, was found in both groups of patients, with no significant differences. Late-onset patients had a mean MMSE score of 21.3 (standard deviation [SD]: 3.4), and early-onset patients had a mean MMSE score of 22.08 (SD: 3.8). Using cutoff points provided by Crum et al.,12 we categorized MMSE scores of 21–24 as indicating mild impairment (late-onset: N=16; 68%) versus early-onset (N=22; 63.5%; Fisher’s exact test=0.9; p=0.82); a score of 16–20 indicated moderate impairment (late: N=5 [17.4%] versus early: N=5; [14.3%]; Fisher’s exact test=0.35; p=0.88) and a score of 15, severe impairment (late: N=1 [3.6%]) versus early: (N=1 [2.2%]; Fisher’s exact test=0.18; p=0.90).
HIV-related symptoms were rated with WHO criteria for diagnosis of AIDS in an adult in Africa.10 HIV-positive patients with a CD4 count <200 cells/mm3 were more likely to have WHO Clinical Stage 3 or 4 HIV/AIDS than those with a CD4 count >200 cells/mm3 (84% versus 25%, respectively [2=43.32; p<0.001]). Spearman’s correlation coefficient between WHO Clinical Stage 3 and 4 and CD4 count of<200 was significant (p<0.001; correlation coefficient = –0.541).
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DISCUSSION
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Our study showed that among HIV-positive patients who met criteria for secondary mania, patients with early-onset and late-onset mania had comparable sociodemographic characteristics. In both groups, patients were predominantly women in the 30–49 age-group, although the female-to-male ratio was higher among the late-onset manic patients (10:1 versus 4:1). In both groups, the patients were of low socioeconomic and educational status. They had comparable marital status, although patients with late-onset mania were more likely to have lost a sexual partner to AIDS. In previous descriptions of HIV-positive patients with mania, those with early-onset and late-onset mania were still comparable in their demographic profiles.5 However, unlike our study, previous studies included manic patients with personal or family histories of mood disorders, and those found that HIV-positive patients with early-onset mania were more likely to have a family history of mood disorder.5
Clinically, consistent with previous findings,5 patients with late-onset secondary mania had more YMRS manic symptoms. They were more irritable and had a more decreased need for sleep than patients with early-onset secondary mania. However, in contrast to previous findings, our patients with late-onset secondary mania had more disruptive behaviors, and were more energetic and more talkative. In our study, regardless of the level of CD4 cell counts, cognitive impairment was present in both groups of HIV-positive patients. Contrary to previous findings,5 there was no association between late-onset secondary mania and severe cognitive impairment. Previous researchers have reported that HIV-positive patients with late-onset mania had psychomotor slowing, were less talkative, and had cognitive slowing.3,5,13 Possible explanations for this difference could be the small sample sizes in previous studies or methodological differences between our study and previous studies; however, this finding is not surprising. Although, in Uganda, a high rate of dementia (30%) has been reported for HIV-positive patients attending an HIV clinic in Mulago hospital, these patients had a mean CD4 cell count of 217 mm3, indicating that a significant proportion of patients with dementia may have had CD4 counts >200.17 Also, HIV dementia has been reported among HIV-positive patients with higher CD4 counts who were on highly-active antiretroviral drugs.18 These findings are consistent with reports that the HIV virus invades the CNS early in the course of HIV infection, which results in a proportion of HIV patients’ developing a variety of cognitive syndromes.
These findings underscore the importance of neuropsychological assessment and treatment of patients with first-episode mania. Both groups of patients reported unusually high rates of psychotic symptoms, indicating a severe manic state, which would be more expected among the HIV-positive patients with late-onset mania. One may argue that this may indicate contamination with cases of HIV-associated delirium. Estimated rates of delirium in HIV patients range from 43% to more than 65% in AIDS.14 However, as in previous studies,1,2 patients who had alteration in level of consciousness, an inability to focus or shift attention, and diurnal fluctuation of symptoms, which are characteristic of delirium, were excluded. Also, differences in population characteristics could account for such a finding. Some cross-cultural studies have shown a higher prevalence of psychotic features among Africans with mood disorders than their counterparts in Europe.15,16
There are many limitations to this study. First, reports of personal and family history of mental illness are limited by the potentially distorting influence of retrospective recall-bias. Given the small sample size and the hospital setting in which the study was done, results may not be generalizable beyond this study population. Also, subtle differences between the two groups may have been missed. Patients were not assessed for brain pathology, which is recommended as part of the standard medical work-up for new-onset psychiatric syndromes in individuals with HIV infection. However, all individuals studied had a neurological examination and were found to be fully conscious, without focal neurological signs.
Finally, the MMSE was designed to screen for cortical dementia, such as Alzheimer disease, and it is therefore less sensitive for detecting subcortical dementia, such as HIV dementia. Within the context of these limitations, to our knowledge, this is the first study to compare the demographic and clinical characteristics of first-episode, early-onset versus late-onset secondary mania in a sample of HIV-positive patients in Africa.
In summary, HIV-positive patients with early-onset and late-onset secondary mania have comparable demographic characteristics and levels of cognitive impairment. However, HIV-positive patients with late-onset secondary mania have more severe psychopathology. These findings show that late-onset secondary mania is clinically distinct from early-onset secondary mania. The correlation of WHO Clinical Stage 3 and 4 and a measure of CD4 cell count of <200 further emphasizes our earlier recommendation that in low-income countries where the costs of measures of immune status such as CD4 cell counts are prohibitive, secondary mania in AIDS may be used as an indicator to initiate highly-active antiretroviral therapy.4 Also, these findings underscore the importance of neuropsychological assessment and treatment of HIV-related secondary mania, regardless of HIV disease stage.
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ACKNOWLEDGMENTS
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This study was supported in part by the Uganda Ministry of Health, Support to the Health Center Strategic Plan Project (funded by the African Development Bank), the Makerere University Faculty of Medicine SIDA/SAREC Project, and an APA/AstraZeneca Young Minds in Psychiatry International Award, 2004, to Dr. Nakimuli-Mpungu.
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REFERENCES
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- Ellen SR, Judd FK, Mijch AM, et al: Secondary mania in patients with HIV infection. Aust N Z J Psychiatry 1999; 33:353–367[CrossRef][Medline]
- Mijch AM, Judd FK, Lyketsos CG, et al: Secondary mania in patients with HIV infection: are antiretroviral drugs effective? J Clin Neuropsychiatry Clin Neurosci 1999; 11: 475-480
- Lyketsos CG; Hanson AL, Fishman M, et al: Manic syndrome early and late in the course of HIV. Am J Psychiatry 1993; 150:326–327[Abstract/Free Full Text]
- Nakimuli-Mpungu E, Musisi S, Kiwuwa S, et al: Primary mania versus HIV-related secondary mania in Uganda. Am J Psychiatry 2006; 163:1349–1354[Abstract/Free Full Text]
- Lyketsos CG, Schwartz J, Fishman M, et al: AIDS mania. J Neuropsychiatry Clin Neurosci 1997; 9:277–279[Abstract/Free Full Text]
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., International Version, Washington, DC, American Psychiatric Association, 1995
- Young RC, Biggs JI, Ziegler VE, et al: A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133:429–435[Abstract/Free Full Text]
- Folstein MF, Folstein SE, McHugh P: Mini-Mental State: a practical method for grading the cognitive function state of patients for the clinician. J Psychiatr Resid 1975; 12:189–198
- Saunders JB, Aasland OG, Babor TF, et al: Development of the Alcohol Use Disorders Identification Test (AUDIT): World Health Organization Collaboration Project on Early Detection of Persons with Harmful Alcohol Consumption, II. Addiction 1993; 88:791–804[CrossRef][Medline]
- Interim WHO Clinical Staging of HIV/AIDS and HIV/AIDS Case Definitions for Surveillance, African Region, 2005. http://www.who.int/entity/hiv/pub/guidelines/clinical staging.pdf; accessed Feb. 4, 2006
- Krauthammer C, Klerman GL: Secondary mania: manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry 1978; 35:1333–1339[Abstract/Free Full Text]
- Crum RM, Anthony JC, Bassett SS, et al: Population-based norms for the Mini-Mental State Exam by age and educational level. JAMA 1993; 269:2386–2391[Abstract/Free Full Text]
- Kieburtz K, Zettelmaier AE, Ketonen L, et al: (1991) Manic syndromes in AIDS. Am J Psychiatry 1991; 148:1068–1070[Abstract/Free Full Text]
- American Psychiatric Association: American Psychiatric Association Practice Guidelines for the Treatment of Patients with HIV/AIDS. Washington, DC, American Psychiatric Publishing, 2001
- Makanjuola ROA: Manic disorder in Nigerians. Br J Psychiatry 1982; 141:459–463[Free Full Text]
- Segal J, Douki S: CANMAT guidelines for bipolar disorder: commentary from the African perspective. Bipolar Disord 2005; 7(suppl 3):77-82
- Sacktor NC, Wong M, Nakasujja N, et al: The International HIV Dementia Scale: a new, rapid screening test for HIV dementia. AIDS 2005; 19:1367–1374[Medline]
- Lucette AJ, Cysique PM, Brew BJ: Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 2006; 66:1447–1450[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
