Prevalence of Depressive and Other Central Nervous System Symptoms in HIV-Infected Patients Treated with HAART in Spain

Abstract

This study was conducted to assess the prevalence of depressive symptoms, sleep disturbances, and subjective cognitive complaints in patients with HIV receiving highly active antiretroviral therapy. Participants completed the “Center for Epidemiological Studies Depression Scale” (CES-D) and a questionnaire on sleep disturbances and subjective cognitive complaints. Mean age of the 799 participants was 43.7 years and 67% were men. Adjusted prevalence of CES-D was 35.4% (95% confidence interval [CI]: 32.0-38.7), with no significant differences between gender and age groups. Sleep disturbances were more prevalent in older versus younger participants (74.0% [95% CI: 70.4-77.7] versus 63.3% [95% CI: 56.8-69.8]). Cognitive complaints were more prevalent in women (52.3% [95% CI: 46.4-58.2]) when compared with men (48.2% [95% CI: 44.7-51.6]). Hepatitis C virus coinfection was a strong predictor of depressive symptoms. Male gender and detectable viral load were independent risk factors for sleep disturbance. A higher CES-D score was an independent risk factor for sleep disturbance and cognitive complaints.

Keywords

HIV depression sleep disturbance cognitive complaints HAART

Introduction

In the pre-highly active antiretroviral therapy (HAART) era, depressive symptoms and mood disorders were known to be substantial problems for patients infected by HIV with or without AIDS.^1,2 Although there is some evidence indicating that with the introduction of HAART, the rates of mood disorders may have decreased, findings have been inconsistent, and mood disorders continue to be a substantial problem in both women and men with HIV.^3

–6 Major depression is one of the most common mood disorders in HIV-seropositive individuals, with rates of depression ranging from 8% to 67%.⁷ The wide variation in rates across studies may depend on the patient populations studied and the method of assessment. Furthermore, several studies have shown that up to 85% of patients living with HIV/AIDS report some depressive symptoms that may not reach diagnostic criteria for a major depression diagnosis.^8

–13

Attention to HIV-associated depression is important since its presence may be associated with HIV disease progression and mortality, after controlling for CD4 counts and viral load.¹⁴ Depression has also been shown to influence the quality of life¹⁵ and medication adherence,^9,15,16 being an independent risk factor for nonadherence to HAART regimens.^17
–19 Conversely, depressive symptoms and lack of treatment adherence are considered independent predictors of HIV clinical progression and mortality.¹⁶

Despite its high prevalence, HIV-associated depression is frequently unrecognized and undertreated.²⁰ As in other medical illnesses, physicians may fail to diagnose depression as they might consider it an expected reaction to illness or a declining functional status related to a major medical disease.²¹

There are some other symptoms that deserve attention in HIV-positive individuals, due to the elevated rates reported and the possible relationship with depressive symptoms and/or the progression of the infection. Sleep disturbance is an important issue for HIV-infected patients, with prevalence reports of 30% to 40%.²² Psychological morbidity seems to be a major determinant of insomnia, although other variables may play a role including antiretroviral medication, drug and alcohol use, and potentially a direct role of HIV in the brain. Sleep disturbance has been described in all stages of HIV-related illness and may lead to chronic fatigue, reduced physical and social functioning, and an overall reduction in quality of life.²³

HIV can cause a wide range of neurocognitive complications such as mental slowing, memory loss, and difficulties in complex tasks requiring executive functions.²⁴ After HAART, the prevalence of milder forms of HIV-associated neurocognitive disorders seems to have increased with reported prevalence between 20% and 50%.^25
–27 Many HIV patients report cognitive complaints in clinical interviews, and little data exist regarding the positive predictive value of cognitive complaints for the presence of minor cognitive deficits in HIV-positive patients. Subjective neurocognitive complaints are often correlated with depression or other psychological symptoms and do not seem to correlate with objective cognitive impairment as has been found in some medical conditions, such as multiple sclerosis and chronic fatigue syndrome.²⁸ ^,29 Rourke et al³⁰ shows that depression in HIV-infected patients is associated with cognitive complaints, whereas those with more severe objective impairment tend to underreport cognitive difficulties.

The main objective of this study was to evaluate the prevalence of depressive symptoms in HIV-positive patients treated with HAART in Spain. Secondary objectives were to determine the prevalence of sleep disturbances and subjective cognitive complaints in this population. Additionally, independent risk factors associated with depressive and other central nervous system (CNS) symptoms were also analyzed.

Patients and Methods

Study Design

This was a probabilistic stratified multistage survey developed in Spain to determine the prevalence of depression (main objective) and other CNS symptoms (secondary objective) in HIV patients treated with HAART. The survey sampling frame was a national population of 60 000 HIV patients under HAART treatment, attending Spanish hospitals. In order to establish the prevalence of depressive symptoms in a representative probabilistic sample, we considered in advance a prevalence of depressive symptoms of 40%. A total of 573 surveys should be collected in order to determine the true prevalence with a confidence level, 1 – α, 0.95, and a relative error of 10%. Considering multistage design effect and nonresponse, sample size was increased up to 808 patients and the participants were recruited by 101 hospital and health centers in Spain. Prior to the sampling stages, the participating centers were stratified among the 17 Spanish Autonomous Communities (SAC). The number of centers enrolled per SAC was fixed proportionally to the number of HIV-infected patients censed in each SAC. In the first stage of sampling, centers in each SAC were randomly selected with probability proportional to the number of HIV-infected patient visits the last year. In the second stage, physicians were selected by simple random sampling among those attending HIV-infected patients in each selected center. In the third stage, each participating physician selected 8 HIV patients under treatment with HAART by systematic sampling among visits scheduled during the 1-month planned survey period per center. To maintain the probabilistic structure, physicians or patients who refused to participate were not reposited, and the survey was finally administered to 799 HIV-infected patients, from September to December 2008. The sampling fraction was 0.013 (0.011-0.021 depending on SAC considered).

Approval for the study was given by the Ethics Committee of Hospital Vall d’Hebrón (Barcelona, Spain), and written informed consent was obtained from each patient before survey administration.

Study Procedures

Demographic and medical data obtained from medical records included age, gender, time since estimated HIV infection, time since HIV diagnosis and/or AIDS diagnosis, current and nadir CD4 count, current HIV viral load, and time since hepatitis B virus (HBV), and hepatitis C virus (HCV) infection, if relevant. The use of concomitant drugs (antidepressants and HCV treatment) was also recorded.

The survey was self-administered and it was composed of 2 questionnaires. To measure depressive symptoms, we used the Spanish version of the 20-item Center for Epidemiological Studies Depression Scale (CES-D) developed by Radloff³¹ and translated and validated by Gonzalez et al³² in arthritis population and Vazquez et al³³ in the general population. Participants indicated how often, over the past week, they experienced each of the 20 symptoms described in the CES-D scale, ranging from 0 (never) to 3 (all the time). Scores of 16 or above on the total score are suggestive of clinical depression.³¹ The second questionnaire was designed specifically for this study and collected patients’ subjective reports pertaining to sleep disturbance and cognitive complaints. Sleep disturbance was considered if the patient answered “yes” to any of the 3 questions about difficulties in falling asleep, broken sleep, and bad dreams or nightmares during the night. Cognitive complaints were considered if the patient answered “yes” to the questions about difficulties in concentration at work, studies, or homework, and/or reported to forget things very often. Finally, sexual desire was explored with a single question, “Do you have loss of or diminished sexual desire?”

Statistical Analysis

Summary data are shown as mean ± standard deviation or median and first to third quartiles (Q1-Q3) for quantitative data, and as frequency and percentage for qualitative data. Raw and adjusted prevalence with its confidence interval of 95% (95% CI) was calculated for CNS disturbances in the total sample, as well as by sex. In order to study the prevalence in age groups, the sample was segmented by age tertiles to conform 3 groups, <40 years, 40 to 46 years, and >46 years, of approximately the same size. Student t test was used to compare mean groups and chi-square to compare proportions. Logistic regression analysis was performed in a subset of 411 patients, in which information was available on all variables involved, in order to study the predictors of CES-D score ≥16, sleep disturbance, and cognitive complaints. The set of independent variables included gender, age (years), time from HIV diagnosis (years), HCV coinfection (yes/no), viral load (undetectable/detectable), CD4 counts (cells/mm³), nadir CD4 count (cells/mm³), and CES-D score (the last one only in models with sleep disturbance and cognitive complaints as dependent variable). Bivariate odds ratio (OR) were calculated considering each independent variable and then a multivariate model was built, exploring with the forced entry method and then by conditional forward stepwise method, with probabilities of .05 and .10 for entry and exit variables, respectively. Statistical significance was set at P < .05. Statistical analyses were carried out using SPSS v15.0 software.

Results

Description of Participants

A total of 799 patients participated across 101 health centers. Baseline characteristics are shown in Table 1. Mean age of patients was 43.7 ± 8.7 years and 67.1% were men. In all, 152 patients (19.0%) had detectable HIV viral load (>50 copies/mL), 254 patients (31.8%) had HCV coinfection, and 40 patients (5.0%) were coinfected with HBV. Information about antidepressant treatment and CES-D score was collected on 696 patients. The use of antidepressant drugs was more prevalent in patients with CES-D score ≥16 (20%) compared to those with CES-D score <16 (2.6%; P < .0005).

Table 1.

Sample Characteristics

	Median	(Q1-Q3)	n	%
Age, y	43.0	(38.0-47.3)
Gender, male			474	67.1
Years from estimated HIV infection, n = 470	15	(8.0-20.0)
Years from HIV diagnosis, n = 579	10	(5.0-16.0)
Years from AIDS diagnosis, n = 288	7	(3.0-12.0)
CD4 counts, cells/mm³	514	(345-725)
Nadir CD4 counts, cells/mm³	247	(60-280)
HIV viral load ≥ 50 copies/mL			152	19.0
Copies/mL	247	(50-1471)
Log copies/mL	2.39	(1.70-3.17)
Years from HCV diagnosis, n = 254	11.5	(8.0-16.0)
Years from HBV diagnosis, n = 40	9.5	(4.3-13.8)

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; Q1 to Q3, 1st to 3rd quartile.

Prevalence of Depressive and Other CNS Symptoms

Raw and adjusted prevalence and its 95% CI of depressive and other CNS symptoms are shown in Table 2. The CES-D score ≥16 was considered as the cutoff and was reached or exceeded by 280 patients (35.0%). The adjusted prevalence was 35.4% (95% CI: 32.0-38.7). No significant differences were found related to gender or age group.

Table 2.

Prevalence of Depressive Symptoms, Sleep Disturbance, and Cognitive Complaints in HIV-Positive Patients under HAART Treatment

	Frequency	N	Raw, %	Adjusted, %	95% CI
Depressive symptoms^a	280	799	35.0	35.4	32.0-38.7
Men	154	474	34.9	32.8	27.0-38.6
Women	81	232	32.5	30.8	26.8-34.9
<40 years	76	234	32.5	31.9	25.9-37.9
40-46 years	93	266	35.0	35.4	29.2-41.5
>46 years	103	286	36.0	36.6	30.8-42.4
Sleep disturbances^b	557	799	69.7	70.3	67.2-73.5
Men	333	474	70.3	67.3	63.3-71.3
Women	157	232	67.6	63.4	57.7-69.1
<40 years	149	234	63.7	63.3	56.8-69.8
40-46 years	193	266	72.6	74.3	69.1-79.6
>46 years	207	286	72.4	74.1	69.2-79.0
Concentration difficulties^c	235	799	29.4	30.3	26.8-33.2
Men	129	474	27.2	25.9	22.0-29.7
Women	79	232	34.1	32.1	26.4-37.7
<40 years	61	234	26.1	27.3	21.6-32.9
40-46 years	79	266	29.7	29.8	24.1-35.5
>46 years	93	286	32.5	32.7	27.2-38.2
Memory impairment	301	784	37.7	38.3	34.9-41.8
Men	161	464	34.7	32.4	28.3-36.6
Women	103	228	45.2	43.5	37.3-49.6
<40 years	97	260	37.3	37.3	31.3-43.4
40-46 years	87	230	37.8	36.6	30.1-43.2
>46 years	112	281	39.9	39.9	34.0-45.7
Cognitive complaints^d	382	799	47.8	48.2	44.7-51.6
Men	210	474	44.3	42.0	37.7-46.4
Women	126	232	54.3	52.3	46.4-58.2
<40 years	104	234	44.4	44.8	38.4-51.3
40-46 years	132	266	49.6	49.1	42.7-55.5
>46 years	207	286	49.0	49.2	43.3-55.1

Abbreviations: CI, confidence interval; CES-D, Center for Epidemiological Studies Depression Scale.

^a Positive depressive symptoms were considered if CES-D score ≥16.

^bPositive sleep disturbance was considered if difficulties in falling asleep, one or more wake up at night, or bad dreams or nightmares were reported.

^cPositive concentration difficulties were considered if concentration problems at work, studies, or homework were reported.

^dPositive cognitive complaints were considered if any concentration disorder or memory troubles were reported.

On the basis of our questionnaire, the adjusted prevalence of sleep disturbance was 70.3% (557 of 706; 95% CI: 67.2-73.5) and the adjusted prevalence of cognitive complaints was 48.2% (382 of 706; 95% CI: 44.7-51.6). Concentration difficulties were reported by 235 patients, adjusted prevalence 30.3% (95% CI: 26.8-33.2), and memory difficulties were reported by 301 patients, adjusted prevalence 38.3% (34.9-41.8). With respect to sleep disturbances, there were no differences in prevalence by gender but were more frequent in patients older than 40 years compared with younger patients. Cognitive complaints (mainly memory difficulties) were more prevalent in women. Differences by age group were not found.

The relation of loss of or diminished sexual desire with other variables was studied. Loss of or decrease in sexual desire was independent of gender (P = .250) or HCV coinfection (P = .499). Patients with decreased sexual desire compared to patients with conserved sexual desire were older (45.6 ± 9.4 versus 41.9 ± 7.7; P < .0005) and showed higher mean CES-D scores (19.6 versus 11.2; P < .0005). Differences in time from HIV diagnosis were not found (P = .930).

Logistic regression analysis was done to study the prognostic risk factors for depressive symptoms, sleep disturbance, and cognitive complaints. Results of bivariate and multivariate models for each dependent variable are shown in Table 3. The HCV coinfection was an independent risk factor for CES-D score ≥16, OR 1.599 (95% CI: 1.025-2.429). Male sex (OR 1.853 [95% CI: 1.134-3.044]), detectable viral load (OR 2.069 [95% CI: 1.069-4.004]), and higher CES-D score (OR 1.091 [95% CI: 1.062-1.120]) were independent risk factors for sleep disorders. Higher CES-D score (OR 1.107 [95% CI: 1.081-1.113]) was an independent risk factor for cognitive complaints.

Table 3.

Bivariate and Multivariate Models of Association between Independent Variables and CES-D Score ≥16, Sleep Disturbance, and Cognitive Complaints

	Bivariate OR			Multivariate OR
Independent	P	OR	95% CI	P ^a	OR^b	95% CI
CES-D score ≥16
Sex	.994	0.998	0.647-1.540	.728
Age, y	.605	1.006	0.983-1.030	.516
Years from HIV Dx	.545	1.009	0.980-1.038	.675
HCV coinfection	.028	1.599	1.025-2.429	.028^b	1.599	1.025-2.429
Viral load	.814	1.063	0.636-1.777	.857
CD4 count	.395	1.000	1.000-1.000	.390
CD4 nadir	.742	1.000	0.999-1.001	.740
Sleep disturbance
Sex	.063	1.527	0.977-2.386	.014^b	1.853	1.134-3.044
Age, y	.080	1.024	0.997-1.051	.152
Years from HIV Dx	.667	1.007	0.976-1.038	.644
HCV coinfection	.025	1.706	1.068-2.725	.151
Viral load	.017	2.136	1.145-3.984	.031^b	2.069	1.069-4.004
CD4 count	.969	1.000	1.000-1.000	.561
CD4 nadir	.406	1.000	0.998-1.001	.569
CES-D score	<.0005	6.532	3.630-11.755	<.0005^b	1.091	1.062-1.120
Cognitive complaints
Sex	.254	0.783	0.515-1.192	.879
Age, y	.544	1.007	0.984-1.030	.993
Years from HIV Dx	.101	1.024	0.995-1.054	.241
VHC coinfection	.156	1.345	0.893-2.026	.815
Viral load	.432	0.819	0.497-1.349	.320
CD4 count	.146	1.000	1.000-1.001	.045
CD4 nadir	.790	1.000	0.999-1.001	.941
CES-D score	<.0005	1.107	1.081-1.113	<.0005^b	1.107	1.081-1.113

Abbreviations: CI, confidence interval; OR, odds ratio.

^aMultivariate forced entry P values.

^bMultivariate last step of forward stepwise entry P values and OR.

Discussion

We have designed a survey focusing on 3 of the most studied areas in HIV neuropsychiatry: depressive symptoms, sleep disturbance, and subjective cognitive complaints. We have found that in the HAART era, significant depressive symptoms based on the items of the CES-D scale are still very common in both HIV men and women in Spain (35.4% of the sample). Although there have been several studies in Europe, United States, and Africa regarding the prevalence of these symptoms, there is no current study in the Spanish HIV population. The prevalence of depression in patients with HIV/AIDS is higher than that in the general population, which has been established as 10.5% by the Global Burden of Disease study from the World Health Organization,³⁴ although this percentage may vary depending on age, gender, socioeconomic status, and/or comorbidity.³⁵ Ciesla’s meta-analysis³⁶ indicates that major depression rates for individuals with HIV infection are almost twice as high as in the general population.

Current studies in HIV-positive participants, most of them done in African countries, have found different rates of depressive symptoms ranging from 14% to 54%, probably as a result of different methodologies and the use of different instruments to assess depressive symptoms and different cutoff on the CES-D.^37
–39 The high prevalence of depressive symptoms in our study underscores the importance of screening for depression in outpatient clinics in Spain. Evidence shows that the prevalence of depression in the general population is higher among women than among men across all ages and ethnic groups.^40
–42 However, we have not found any difference between the prevalence of depressive symptoms and gender in our study, after controlling for the use of antidepressant treatment which was higher in women.

A single cause for the high prevalence of depression in the HIV population has not been identified, but a combination of genetic, biochemical, and environmental factors are hypothesized to contribute.⁴³ In addition, research suggests that HAART may affect mood as an adverse effect.⁴⁴ However, much has also been written about the role of HAART as a protective factor for the occurrence of depressive symptomatology.^45,46 In our study, we have not found any relation between viral load or markers of immune status (CD4 counts) and depressive symptoms and the only clinical variable that influences the risk of depression is HCV coinfection. Nevertheless, this effect cannot be attributed to the HCV medication because only 10.6% of the coinfected patients were taking peg-interferon plus rivabirine at the time of the study. This is in accordance with the results of other authors.⁴⁷ As social and psychological factors potentially play a greater role in the genesis of depression compared with the neuropathological effects of the HIV and/or HCV infection, these factors deserve further investigation.

Because depression may affect the global functioning of the participants and influence the progression of HIV infection, both detection and treatment of depression should be a major priority. However, one of our results is that at least 80% of patients with symptoms suggestive of clinical depression did not receive pharmacological treatment. This finding is consistent with the one found by Israelski et al²⁰ who showed that only 43% of the patients in their study were receiving concurrent psychiatric treatment.

We have found a higher prevalence of sleep disturbances (70.3%) compared with the prevalence of less than 20% in the general population.^48,49 The high prevalence could be explained by several specific factors of this population group such as HIV infection, HAART, and depressive symptoms. The signs and symptoms of depression are similar in HIV-infected and noninfected patients, although patients with HIV infection may more frequently have sleep and appetite disturbance.⁵⁰ In our study, a higher viral load and higher depressive symptomatology were independent risk factors for the presence of sleep disturbance, suggesting that there could be a double influence related to the virus and psychological morbidity. With respect to subjective cognitive complaints, 48.2% of the participants reported lack of concentration or memory difficulties, the last being predominantly in women. As in other studies, the only variable that was associated with the emergence of cognitive complaints is having more depressive symptoms.⁵¹ Other clinical variables such as HCV coinfection, higher viral load, disease duration, and nadir and current CD4 count did not seem to be the risk factors for the cognitive complaints in our study. There is a need to include in future studies an objective neuropsychological assessment and to explore the relationship between subjective cognitive complaints, depressive symptoms, and objective cognitive functioning.

This study has several limitations. First, although CES-D is a useful screening tool, it frequently yields false positives independently of the population in which it is applied.^52
–54 Second, questions concerning sleep disturbance and cognitive complaints have been extracted from other studies^5,55,56 and applied in the absence of specific psychometric tests. Third, lack of information affects our study in 3 ways, (a) we did not collect information concerning the number and type of HAART and treatment duration that could have affected depressive and other CNS symptoms, (b) we have not used structured or semistructured diagnostic interviews to diagnose depression that would offer superior reliability and validity and would have increased the quality of our study, and (c) because the survey was completed in the waiting room, the missing data could not be collected later. Finally, interpretations of the predictive associations between risk factors and outcomes remain difficult and prospective studies are needed to demonstrate causality.

We consider this study as one of special relevance, first, because of the probabilistic nature of the survey and a relatively large sample size with a fraction sampling higher than 0.01; second, due to the current interest in the mental health of patients with HIV infection, which includes the need for increased identification of mental illness as well as provision of psychiatric services in an accessible setting.

In summary, we have shown that 35.4% of HIV-positive patients receiving HAART treatment in Spain report depressive symptoms suggestive of depressive disorders. Since the prevalence of depression in patients with HIV/AIDS is much higher than in the general population, it would be important to evaluate carefully in future prospective studies whether this high prevalence could be related to the virus, HAART, or other social factors. In addition, it is necessary to assess how depression affects medical outcome, compliance, quality of life, and high-risk behaviors. Given that HAART therapies have greatly increased life expectancy and transformed HIV infection into a potentially chronic disease, physicians face a major long-term challenge to anticipate and manage distress and psychiatric disorders, all of which could result from a chronic infectious disease that requires lifelong treatment. Successful treatment for depressive symptoms could influence the reported rates of sleep difficulties and cognitive complaints and may significantly improve the quality of life. HIV caregivers should be sensitive to the possibility of depressive symptoms and other CNS symptoms in order to detect them early and to provide individualized care to patients with HIV.

Footnotes

Acknowledgments

The authors acknowledge Dr Jesús Garrido for the statistical analysis of the study and Dr Fernando Sánchez-Barbero (HealthCo, Spain) for assistance in the preparation of this manuscript.

Declaration of Conflicting Interests

Esteban Ribera has received honoraria, speaker’s fees, consultant fees, and funds for research from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Janssen-Cilag, MSD, Pfizer, Roche Farma, Schering Plough, and Glaxo Smith Kline.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Cochran

Mays

. Depressive distress among homosexually active African American men and women. Am J Psychiatry. 1994;151(4):524–529.

Drebing

Van Gorp

Hinkin

. Confounding factors in the measurement of depression in HIV. J Pers Assess. 1994;62(1):68–83.

Alciati

Starace

Scaramelli

. Has there been a decrease in the prevalence of mood disorders in HIV-seropositive individuals since the introduction of combination therapy? Eur Psychiatry. 2001;16(8):491–496.

Chan

Orlando

Joyce

. Combination antiretroviral therapy and improvements in mental health: results from a nationally representative sample of persons undergoing care for HIV in the United States. J Acquir Immune Defic Syndr. 2003;33(1):104–111.

Starace

Bartoli

Aloisi

. Cognitive and affective disorders associated to HIV infection in the HAART era: findings from the NeuroICONA study. Cognitive impairment and depression in HIV/AIDS. The NeuroICONA study. Acta Psychiatr Scand. 2002;106(1):20–26.

Rabkin

Ferrando

Lin

Sewell

McElhiney

. Psychological effects of HAART: a 2-year study. Psychosom Med. 2000;62(3):413–422.

Acuff

Archambeault

Greenberg

. Mental health care for people living with of affected by HIV/AIDS: a practical guide. In: Rockville MD: Research Triangle Institute. 1999.

Gibbie

Mijch

Ellen

. Depression and neurocognitive performance in individuals with HIV/AIDS: 2-year follow-up. HIV Med. 2006;7(2):112–121.

Bouhnik

Preau

Vincent

. Depression and clinical progression in HIV-infected drug users treated with highly active antiretroviral therapy. Antivir Ther. 2005;10(1):53–61.

10.

Lima

Geller

Bangsberg

. The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART. AIDS. 2007;21(9):1175–1183.

11.

Fumaz

Munoz-Moreno

Molto

. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38(5):560–565.

12.

Ferrando

. Diagnosis and treatment of psychiatric disorders in HIV-infected patients. New Dir Ment Health Serv. 2000;2000(87):25-35.

13.

Tate

Paul

Flanigan

. The impact of apathy and depression on quality of life in patients infected with HIV. AIDS Patient Care STDS. 2003;17(3):115–120.

14.

Ickovics

Hamburger

Vlahov

. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA. 2001;285(11):1466–1474.

15.

Trepanier

Rourke

Bayoumi

Halman

Krzyzanowski

Power

. The impact of neuropsychological impairment and depression on health-related quality of life in HIV-infection. J Clin Exp Neuropsychol. 2005;27(1):1–15.

16.

Villes

Spire

Lewden

. The effect of depressive symptoms at ART initiation on HIV clinical progression and mortality: implications in clinical practice. Antivir Ther. 2007;12(7):1067–1074.

17.

Ammassari

Antinori

Aloisi

. Depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy among HIV-infected persons. Psychosomatics. 2004;45(5):394–402.

18.

Carrieri

Raffi

Lewden

. Impact of early versus late adherence to highly active antiretroviral therapy on immuno-virological response: a 3-year follow-up study. Antivir Ther. 2003;8(6):585–594.

19.

Starace

Ammassari

Trotta

. Depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31(suppl 3):S136–S139.

20.

Israelski

Prentiss

Lubega

. Psychiatric co-morbidity in vulnerable populations receiving primary care for HIV/AIDS. AIDS Care. 2007;19(2):220–225.

21.

Perez-Stable

Miranda

Munoz

Ying

. Depression in medical outpatients. Underrecognition and misdiagnosis. Arch Intern Med. 1990;150(5):1083–1088.

22.

Robbins

Phillips

Dudgeon

Hand

. Physiological and psychological correlates of sleep in HIV infection. Clin Nurs Res. 2004;13(1):33–52.

23.

Reid

Dwyer

. Insomnia in HIV infection: a systematic review of prevalence, correlates, and management. Psychosom Med. 2005;67(2):260–269.

24.

McArthur

Brew

Nath

. Neurological complications of HIV infection. Lancet Neurol. 2005;4(9):543–555.

25.

Cysique

Maruff

Brew

. Prevalence and pattern of neuropsychological impairment in human immunodeficiency virus-infected/acquired immunodeficiency syndrome (HIV/AIDS) patients across pre- and post-highly active antiretroviral therapy eras: a combined study of two cohorts. J Neurovirol. 2004;10(6):350–357.

26.

Robertson

Smurzynski

Parsons

. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21(14):1915–1921.

27.

Woods

Moore

Weber

Grant

. Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev. 2009;19(2):152–168.

28.

Altay

Toner

Brooker

Abbey

Salit

Garfinkel

. The neuropsychological dimensions of postinfectious neuromyasthenia (chronic fatigue syndrome): a preliminary report. Int J Psychiatry Med. 1990;20(2):141–149.

29.

Maor

Olmer

Mozes

. The relation between objective and subjective impairment in cognitive function among multiple sclerosis patients--the role of depression. Mult Scler. 2001;7(2):131–135.

30.

Rourke

Halman

Bassel

. Neurocognitive complaints in HIV-infection and their relationship to depressive symptoms and neuropsychological functioning. J Clin Exp Neuropsychol. 1999;21(6):737–756.

31.

Radloff

. The CES-D Scale. A self-report depression scale for research in the general population. Appl Psychol Measure. 1977;4:454–463.

32.

Gonzalez

Stewart

Ritter

Lorig

. Translation and validation of arthritis outcome measures into Spanish. Arthritis Rheum. 1995;38(10):1429–1446.

33.

Vazquez

Blanco

Lopez

. An adaptation of the Center for Epidemiologic Studies Depression Scale for use in non-psychiatric Spanish populations. Psychiatry Res. 2007;149(1-3):247–252.

34.

Murray

CJL

López

. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press; 1996.

35.

Kessler

Berglund

Demler

. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–3105.

36.

Ciesla

Roberts

. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry. 2001;158(5):725–730.

37.

Kaharuza

Bunnell

Moss

. Depression and CD4 cell count among persons with HIV infection in Uganda. AIDS Behav. 2006;10(4 suppl):S105–S111.

38.

Myer

Smit

Roux

Parker

Stein

Seedat

. Common mental disorders among HIV-infected individuals in South Africa: prevalence, predictors, and validation of brief psychiatric rating scales. AIDS Patient Care STDS. 2008;22(2):147–158.

39.

Nakasujja

Skolasky

Musisi

. Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda. BMC Psychiatry. 2010;10:44.

40.

Alonso

Angermeyer

Bernert

. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004;(420):21–27.

41.

Bebbington

. Sex and depression. Psychol Med. 1998;28(1):1–8.

42.

Patten

Wang

Williams

. Descriptive epidemiology of major depression in Canada. Can J Psychiatry. 2006;51(2):84–90.

43.

Schatzberg

. Pathogenesis of mood disorders. In: Stein

DJ KK

Schatzberg

, ed. The American Psychiatric Publishing Textbook of Mood Disorders. Washington DC: American Psychatric Press Inc; 2006.

44.

Des Jarlais

Carael

M. AIDS

1999. Behavioral and social science: overview. AIDS. 1999;13(suppl A):S235–S237.

45.

Judd

Cockram

Komiti

Mijch

Hoy

Bell

. Depressive symptoms reduced in individuals with HIV/AIDS treated with highly active antiretroviral therapy: a longitudinal study. Aust N Z J Psychiatry. 2000;34(6):1015–1021.

46.

Low-Beer

Chan

Yip

. Depressive symptoms decline among persons on HIV protease inhibitors. J Acquir Immune Defic Syndr. 2000;23(4):295–301.

47.

Braitstein

Montessori

Chan

. Quality of life, depression and fatigue among persons co-infected with HIV and hepatitis C: outcomes from a population-based cohort. AIDS Care. 2005;17(4):505–515.

48.

Ohayon

. Prevalence and comorbidity of sleep disorders in general population. Rev Prat. 2007;57(14):1521–1528.

49.

Vela-Bueno

De Iceta

Fernandez

Prevalence of sleep disorders in Madrid, Spain. Gac Sanit. 1999;13(6):441–448.

50.

Penzak

Reddy

Grimsley

. Depression in patients with HIV infection. Am J Health Syst Pharm. 2000;57(4):376–386.

51.

Millikin

Rourke

Halman

Power

. Fatigue in HIV/AIDS is associated with depression and subjective neurocognitive complaints but not neuropsychological functioning. J Clin Exp Neuropsychol. 2003;25(2):201–215.

52.

Pandya

Metz

Patten

. Predictive value of the CES-D in detecting depression among candidates for disease-modifying multiple sclerosis treatment. Psychosomatics. 2005;46(2):131–134.

53.

Covic

Pallant

Tennant

Cox

Emery

Conaghan

. Variability in depression prevalence in early rheumatoid arthritis: a comparison of the CES-D and HAD-D Scales. BMC Musculoskelet Disord. 2009;10:18.

54.

Breslau

. Depressive symptoms, major depression, and generalized anxiety: a comparison of self-reports on CES-D and results from diagnostic interviews. Psychiatry Res. 1985;15(3):219–229.

55.

Price

Yiannoutsos

Clifford

. Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS. 1999;13(13):1677–1685.

56.

Simioni

Cavassini

Annoni

. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243–1250.