Pone.0044415 1.5

Cognitive Dysfunction among HIV Positive and HIVNegative Patients with Psychosis in Uganda Noeline Nakasujja1,2*, Peter Allebeck2, Hans Agren3, Seggane Musisi1, Elly Katabira4 1 Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda, 2 Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden, 3 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden, 4 Department of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda Background: Cognitive impairment is an established phenomenon in HIV infected individuals and patients that havepsychosis. However there is need to establish the severity of the impairment if patients are co morbid with both conditions.
Aim: To compare cognitive function among HIV positive individuals and HIV negative individuals with psychosis.
Methods: We recruited patients with psychosis at two national referral hospitals. A standardized demographicsquestionnaire and psychiatric, physical, and laboratory assessments were conducted. Types of psychosis were diagnosedusing the Mini International Neuropsychiatric Inventory-PLUS while cognitive functioning was determined using the Minimental state examination (MMSE) and a neuropsychological test battery. Follow-up assessments on cognitive function andseverity of psychiatric illness were performed at 3 and 6 months. Pairwise comparison and multivariable logistic regressionanalysis were used to determine the differences between the HIV positive and HIV negative individuals.
Results: There were 156 HIV positive and 322 HIV negative participants. The mean age was 33 years for the HIV positivegroup and 29 years for the HIV negative group (p,0.001). The HIV positive individuals were almost three times (OR = 2.62 CI95% 1.69–4.06) more likely to be cognitively impaired on the MMSE as well as the following cognitive tests:- WHO-UCLAAuditory Verbal Learning Test (OR 1.79, 95% CI 1.09–2.92), Verbal Fluency (OR 3.42, 95% CI 2.24–5.24), Color Trails 1 (OR 2.03,95% CI 1.29–3.02) and Color Trails 2 (OR 3.50 95% 2.00–6.10) all p = 0.01. There was improvement in cognitive function atfollow up; however the impairment remained higher for the HIV positive group (p,0.001).
Conclusion: Cognitive impairment in psychosis was worsened by HIV infection. Care plans to minimize the effect of thisimpairment should be structured for the management of individuals with HIV and psychosis.
Citation: Nakasujja N, Allebeck P, Agren H, Musisi S, Katabira E (2012) Cognitive Dysfunction among HIV Positive and HIV Negative Patients with Psychosis inUganda. PLoS ONE 7(9): e44415. doi:10.1371/journal.pone.0044415 Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan Received January 9, 2011; Accepted August 7, 2012; Published September 6, 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone forany lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: Source of funding: Makerere University-Swedish International Development Cooperation Agency/Department for Research Cooperation cooperationgrant. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
CD4 count and were of older age [11]. While the severity ofimpairment may decrease with antiretroviral therapy (ART), the Cognitive dysfunction in patients having primary psychiatric prevalence of any degree of cognitive impairment even after the illness like schizophrenia has been well documented [1,2]. The use this medication remains as high as 40–70-% [12,13].
cognitive functioning of an individual with psychosis is affected by The debilitation that occurs in HIV positive individuals who are a number of factors including the severity of psychosis and anti cognitively impaired hinders their management as they may fail to psychotic medication being taken [3]. In many patients the adhere to their treatment regimen, the situation being further cognitive impairment is not secondary to delusions or effects of worsened if the person has a psychotic condition. In resource hallucinations but may rise from the lack of motivation the patients constrained settings, lack of clear guidelines at primary care experience [4]. Though cognitive dysfunction does not occur in all centers and the scarcity of ART results in delayed treatment [14] patients with psychosis [5], the dysfunction is common among creating a dilemma in the management of HIV and related patients with HIV associated psychosis, [6,7].
conditions like psychosis, even when there is evidence that ART The prevalence of HIV dementia among HIV positive improves the symptoms of psychosis and cognitive impairment individuals has decreased from 30–40% before the introduction [12,15]. Understanding the level of cognitive function in patients of highly active antiretroviral therapy to 10–15% in settings with that develop psychosis would create insight into ways of managing adequate access to the medication [8,9,10]. In Uganda, ambulant them. This study set out to compare the cognitive deficits among patients attending an HIV outpatient clinic were found to have an psychotic HIV positive and psychotic HIV negative individuals.
HIV dementia prevalence rate of 31% especially if they had low September 2012 | Volume 7 | Issue 9 | e44415 Cognitive Dysfunction in HIV Associated Psychosis cryptococcal antigen, toxo titers and Venereal Disease ResearchLaboratory (VDRL).
We consecutively recruited 478 patients who were admitted at The study interviews were carried out in the locally spoken Mulago and Butabika national referral hospitals in Kampala, language Luganda or English. The patients continued to receive Uganda between February 2008 and April 2009. Ethical approval routine psychiatric care in the hospital even after being enrolled for conduction of the study was received from the Uganda into the study. Three hundred seventy eight (79%) patients National Council for Science and Technology as well as the returned for the 3 month and 302 (63%) returned for the 6 months Makerere University Research and Ethics Committee.
visit. The loss to follow up at 6 months was 36.8%.
Individuals were included in the study if they had features of psychosis, were aged 18–59 years old, were resident within a radius of 30 km of the city centre, and gave written informed The data was analysized using STATA version 10, (StataCorp, consent to participate in the study. We excluded individuals who College Station, TX USA). Chi square test and Fishers exact test had any known medical condition other than HIV and its were used to determine the difference in type of psychiatric illness, complications e.g. syphilis that could be related to the manic MMSE scores and to evaluate differences on neuropsychological episode, a recent onset of severe headache or substance performance for the HIV positive and HIV negative groups. The dependency. The participants received a standardized demo- level of cognitive function was determined by the presence or graphics questionnaire, psychiatric, physical, and laboratory absence of impairment on specific cognitive domains. The likelihood of cognitive impairment was determined using logisticregression using a stepwise approach while controlling for age, gender, HIV status and educational level.
The Mini International Neuropsychiatric Inventory-PLUS (MINI-PLUS) instrument was used to diagnose psychiatric illnesses: mania, depression, schizophrenia and psychosis nototherwise specified (PSY NOS) [16]. The severity of the different The HIV positive individuals were older, mean (SD), 33 years disorders was determined at baseline, 3 and 6 months using the (8.24) than the HIV negative individuals 29 years (8.07); Young Mania Rating Scale (YMRS) [17], the Brief Psychiatric (p,0.001). Most individuals 372 (77.82%) had more than 7 years Rating Scale (BPRS) [18] and the Patient Health Questionnaire of education and there was no statistical difference between the (PHQ-9) [19]. The participants’ consent to continue in the study HIV positive and HIV negative groups p = 0.424. The average was again sought when the patients came for the follow up CD4 count in the HIV positive group was 305 cell/uL. Only 7(4%) of the HIV positive individuals were at WHO clinical stage4 i.e. AIDS. Only 43 (27.5%) HIV positive individuals were on ART at baseline and 52 (33.3%) were on it by the 6 month. Allpatients were taking antipsychotic medication that included The cognitive function for the HIV positive individuals was chlorpromazine, haloperidol stelazine and or an antidepressant tested using the International HIV Dementia Scale (IHDS) [20].
like a tricyclic antidepressant or fluoxetine depending on the Both HIV positive and HIV negative groups received a battery of disorder they were being treated for. We found that 67 (43%) of neuropsychological tests for evaluating the different cognitive the HIV positive individuals did not have a prior episode of mental domains. The tests included: WHO UCLA Auditory Verbal illness and pair wise comparison with the HIV negatives 88 (27%) Learning Test for verbal memory, learning and recall; Symbol who had no prior episodes was statistically significant, p,0.001.
Digit Modalities Test for visual motor coordination; Animal Recall The mean score on the MMSE was 20.32 (5.13) for the HIV for verbal fluency; the Digit Span backward (WAIS III) for positive and 22.87(4.79) for the HIV negative group. The mean working memory; Digit Span forwards(WAIS III) for attention; IHDS score was 5.8(2.3). The psychiatric diagnoses by gender are Color Trails 1 and Color Trails 2 for abstraction/executive and presented in table 1; mania was the commonest type of psychosis speed of information processing. Each test score was standardized for both males and females. Psy NOS occurred more in the HIV to normal, 1 or 2 standard deviations (sd) from the mean in positive group (p,0.001). There was no history of prior episodes of comparison to normative values of the general non HIV, non psychiatric illness in 10 (62.5%) of the HIV positive individuals psychotic population [21]. The three following categories of who had Psy NOS. At the baseline MMSE evaluation, there were cognitive impairment were created; normal if scores were not more cognitively impaired individuals within the HIV positive deviating from the mean; mild if an individual had 1.0 sd in any of group 64.7%vs 35.3% than in the HIV negative group 49.4% vs the tests up to a maximum of 6 tests and severe if an individual had 50.6%, (p,0.000). The HIV positive individuals were almost three I.0 sd in any of the tests and in addition had 2.0 sd in one or more times (OR = 2.62 CI 95% 1.69–4.06) as likely to be cognitively tests. The neuropsychological tests were repeated at 3 and 6 impaired. The females 270 (58.82%) were more impaired than the males 189 (41.18%), p = 0.018. All tested cognitive tests apart fromdigit span were more likely to be impaired in the HIV positive group (table 2). The odds of impairment on each of the tests are The HIV testing was done using DETERMINE I/II (Abbot presented in table 3. Adjusted odds revealed female gender (OR Japan Cp. Ltd, Minato-ku, Tokyo, Japan), it was validated using 2.89, 95% 1.05–7.92), p = 0.038 and older age (OR 1.62, 95% STAT PAK (ChemiBio Diagnostics System, Inc., Medford, USA) 0.59–4.45), p = 0.34 to be associated with cognitive impairment and UNIGOLD (Trinity Biotech Plc, Bray Co Wicklow, Ireland) (table 4). At the 3 months follow up, the mean MMSE score was test kits. HIV pre and post-test counseling was done for all 22.93 in the HIV positive group and 24.41 for the HIV negative patients. For individuals who were found to be HIV positive and group while at 6 months it was 22.15 and 24.25 respectively. The met criteria for starting ART, this treatment was initiated at the categories for the levels of cognitive impairment at follow up are HIV treatment clinics at Mulago or Butabika hospitals. Other summarized in table 5. There was also improvement in psychiatric laboratory evaluations included a full blood count, CD 4 count, September 2012 | Volume 7 | Issue 9 | e44415 Cognitive Dysfunction in HIV Associated Psychosis Table 1. Type of psychosis by gender.
*Major Dep: represents Major depressive disorder,{Psy NOS: represents Psychosis not otherwise specified.
doi:10.1371/journal.pone.0044415.t001 signifying a difference in the manifestation of psychosis for theHIV positive individual.
Cognitive impairment was found to be worse among HIV Cognitive impairment for both psychotic and non psychotic positive individuals with psychosis in comparison to HIV negative individuals occurs more often among HIV positive older patients individuals with psychosis. The impairment was worse among and more so in individuals of female gender [24,26] similar to To our knowledge this is the first study to use a standardized Our study had a higher representation of females compared to neuropsychological battery of tests to compare cognitive function males in the HIV positive group by almost three thirds, reflecting in HIV positive and HIV negative patients with psychosis. Most of what is seen in most African HIV clinic settings. Females are eager the studies have used only the MMSE to assess the level ofcognitive function, however this test does not specify the cognitivedomains that may be affected [22]. Even though previous studies Table 3. Estimated odds ratios of being impaired in specific have shown that individuals with primary psychosis can have cognitive impairment [23], we found that the severity of theimpairment is worse in HIV positive individuals even after thesymptoms of psychiatric illness decrease during follow up.
As has been observed in other studies in our setting [7,24] mania, was the commonest presentation of psychosis. Among individuals with depression, the statistical difference observed inthe HIV positive males and HIV negative males could be explained by the very low numbers of individual with the disorder.
However this significance was not observed when comparing the HIV positive and HIV negative groups without stratification for Males with a diagnosis of schizophrenia were more among HIV negative individuals. It has been shown that the prevalence of schizophrenia is more and also occurs earlier among males compared to females [25]. Psychosis NOS occurred more for the HIV positive population and the majority of the individuals who presented with the disorder had no prior episode of mental illness Table 2. Neuropsychological test performance among HIV positive and HIV negative individuals at baseline.
VLT RAI; Verbal Learning Test recall after interference.
*statistically significant.
Adjusted for all other covariates for each cognitive domain.
September 2012 | Volume 7 | Issue 9 | e44415 Cognitive Dysfunction in HIV Associated Psychosis Table 4. Odds ratios for cognitive impairment in patients with psychosis.
*Only gender, age and education level entered into the regression model for the different types of the psychosis.
doi:10.1371/journal.pone.0044415.t004 in seeking care and maintaining follow up compared to their male the participants experience interview fatigue more so if they have counter parts [27], in addition they are more affected by the HIV been started on antipsychotic treatments. However the evaluations scourge and hence tend to be more afflicted by the complications were carried out when the patients were usually calm enough and that arise from the infection [24]. However it remains important to on lower medication dosage, indeed in some situations if a look into other factors that may predispose females to the participant expressed a desire to rest, the interview would be development of HIV associated psychosis and co- occurring postponed to a time when they would feel comfortable to complete cognitive impairment. For instance, theories on the neurotoxin the evaluation. The improvement observed in performance could production, specifically kynurenic acid that has been found to be be a result of practice effects however the HIV positive group still higher in HIV individuals with psychosis [28,29], have not performed worse than the HIV negative group. The selection of highlighted any differences between males and females.
the study participants was cumulative and when the HIV negative A number of earlier studies emphasised that cognitive impair- group reached saturation, we continued with the recruitment of ment and psychosis were late manifestations of HIV disease [6,30].
the HIV positive group till the total sample size was achieved. This The onset of psychosis primarily resulting from the HIV virus may have affected the randomness of the sample selected.
attack of the brain tissue or through opportunistic infections However this occurred only in the last two months of the study.
[31,32,33,34]. Recent studies including the findings of this study We also did not test for motor performance since the patients were show that the two conditions can sometimes occur early as on antipsychotic medication whose side effects would have evidenced by the moderate level of CD4 count and the introduced bias in the observations made. We had an advantage intermediate WHO stages of disease manifestation [35]. Further- of having a large sample size which could cater for some of these more the cognitive impairment persists even when the symptoms individual differences. There was a considerable loss to follow up of psychosis improved. This finding underscores the importance of by 6 months but the large sample size allowed for statistical early initiation of antiretroviral therapy for HIV positive individual significance to be inferred from the number that came back for re who develop cognitive impairment or psychosis or both conditions since there is evidence that the situation can be alleviated by this In summary this study compared cognitive function in HIV positive and HIV negative individuals in a cohort of individuals There were some limitations to this study. Conduction of the with psychosis. The cognitive impairment was more pronounced neuropsychological assessments is usually elaborate and sometimes among the HIV positive individuals and especially so for the Table 5. Cognitive function in HIV positive and HIV negative patients at 3 and 6 months of follow up.
September 2012 | Volume 7 | Issue 9 | e44415 Cognitive Dysfunction in HIV Associated Psychosis females. Whereas there are explanations for the higher impair- ment in the HIV positive group there is a need for future research We wish to acknowledge the research assistants and the patients who to focus on the mechanism that brings about this difference with gender. Strategies that include measures for the early detection ofHIV in patients with psychosis, use of non sedating antipsychotics or the early initiation of ART treatment should be in place forimproved mental health care.
Conceived and designed the experiments: NN SM HA EK. Performed theexperiments: NN. Analyzed the data: NN. Wrote the paper: NN PA HASM EK.
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