Serotonin Levels in Newly-Infected HIV-Positive: A Preliminary Study

Abstract

Background:

HIV is still a global health concern worldwide and in 2021, a total of 27,000 newly infected cases were detected in the Indonesian population, specifically among adults. However, there is no available data found about serotonin levels in newly infected cases of HIV.

Objective:

This study aimed to preliminary investigate serotonin levels in newly-infected HIV-positive cases in the Indonesian population.

Methods:

A quantitative cross-sectional analytic design was used with a total of 54 newly-infected HIV-positive participants who were enrolled using the purposive sampling technique. The questionnaire, blood sampling, and ELISA methods for measuring serotonin were applied. Furthermore, the serotonin distribution was compared based on participants’ characteristics using the Mann-Whitney U test. The main effect of characteristics was also tested by the generalized linear model.

Results:

The mean serotonin level was low and did not differ based on participants’ characteristics.

Conclusion:

Low serotonin level is characteristic of people newly infected with HIV in Indonesia. This might be a manifestation of the depression stage, a consequence of infection, or the involvement in provoking HIV infection progression.

1. BACKGROUND

Approximately 1.5 million people were newly infected with HIV worldwide in 2021 and 66% were aged 15+ years old. Moreover, the Asia-Pacific region including Indonesia contributed 17.3% of the total new cases globally (1, 2).

A total of 27,000 newly infected cases were detected in the Indonesian population and the majority were adults. The number is still considered high although it has declined by 48% since the peak in 2007. Moreover, people living with HIV (PLWH) in Indonesia still experience a relatively high number of AIDS-related deaths and a slow increase in the coverage of people receiving antiretroviral treatment (ART) (2).

Living with an HIV-positive status is devastating and several studies reported that PLWH most suffers from depression or depressive symptoms (3–7). This is due to the awareness of their status and will continue to affect the quality of life (8), leading to suicide ideation and attempt (9). Although HIV mortality has reportedly declined since the implementation of ART (10, 11), the caution of HIV morbidity (10), and considerable death in course of treatment cannot be ignored (12, 13).

A previously published article by Dursun & Reveley shared insight into the link between serotonin and HIV infection (14). Serotonin regulation might be affected during HIV infection and has been linked to psychiatric symptoms such as depression (14–17). Launay et al. also found that HIV-infected people have low serotonin levels but there are limited studies on this topic (18). Meanwhile, several investigations focused more on the sole precursor of serotonin namely tryptophan (19, 20). There is also no available study on the Indonesian population about the serotonin profile in HIV-infected people, particularly in newly-infected cases.

2. OBJECTIVE

Therefore, this study aims to preliminary investigate the serotonin levels in people newly infected with HIV in Indonesia.

3. MATERIAL AND METHODS

Study design, location, and participants

This preliminary study was conducted in Makassar City, South Sulawesi, Indonesia, using a quantitative descriptive cross-sectional design. South Sulawesi ranks 6th rank among the provinces with the highest prevalence of PLWH in Indonesia, and Makassar provides substantial contributions in number (21). The participants were newly diagnosed HIV-positive individuals registered at the HIV/AIDS service unit for at least 2 months and taking ART, not in III/IV stage, have no opportunistic infection and psychiatric history. They were selected using the purposive sampling technique. This technique was used to successfully enroll 54 people. Furthermore, age was categorized into 13-19, 20-39, and 40-59 years old. Education was classified as low (elementary school or lower), middle (junior or senior high school), and high (diploma or above). Participants who work were classified as “have a job”.

Procedure and ethical considerations

Participants who indicated interest to participate were first asked to sign written informed consent and receive monetary compensation. They were then interviewed using a questionnaire consisting of basic demographic characteristics including gender, age, education, and occupation, as well as transmission history questions. Furthermore, 2 cc of blood was collected in heparinized vacutainer tubes by intravenous cannulation and stored immediately at -20°C after serum separation less than one hour after sampling. Serotonin was measured by the enzyme-linked immunosorbent assay (ELISA) method using Human Serotonin ELISA Kit Catalogue Number E1128Hu (Bioassay Laboratory Technology, Zhejiang, China). All procedures were approved by the Ethical Commission of the Faculty of Medicine, Universitas Hasanuddin, with approval number: 683/UN.4.6.5.31/PP36/2021.

Statistical analysis

Univariate descriptive analysis was performed for basic characteristics and serotonin levels, while the potential confounding effect of respondents’ basic characteristics on serotonin levels was analyzed at bivariate and multivariate levels using the Mann-Whitney U test and Generalized linear model. For further interpretation of the results, several previous studies that reported serotonin levels were involved and compared using a one-sample t-test. The test was considered significant when the p-value is <0.05 at a 95% level of confidence. IBM SPSS for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA), was used to conduct all analyses.

4. RESULTS

Demographic characteristics

Table 1 shows that most respondents with newly-infected cases of HIV were male at 83.3%, 88.9% were aged 20-39 years old, 87.0% had sexual activity with males, 83.3% had low-middle education level, and 79.6% had a job.

Table 1. Characteristics of Participants.

Characteristics	Frequency (n=54)
	n	%
Gender
Male	45	83.3
Female	9	16.7
Age (category; years)
13-19	3	5.6
20-39	48	88.9
40-59	3	5.6
Transmission
Sexual activity with Male	47	87.0
Sexual activity with Female	7	13.0
Drugs/Inject	0	0.0
Transfusion	0	0.0
Education
Low-middle	45	83.3
High	9	16.7
Occupation
No Job	11	20.4
Have a Job	43	79.6

Serotonin level based on participants’ characteristics

Figure 1 shows the level of serotonin among the HIV-positive participants in this study. The mean±standard deviation (SD) in the total sample was 97.92±90.58. Most participants had serotonin levels <100 ng/ml with a mean±SD of 57.79±31.31, but two had extreme levels of 375.63 and 518.91 ng/ml, respectively.

Figure 1. Distribution of Serotonin Level in HIV-Positive Participants. a) Serotonin distribution based on frequency (N=54; Mean±SD=97.92±90.58). b) Serotonin distribution less or more than 100 ng/ml. Mean±SD of serotonin <100 ng/ml was 57.79±31.31 (n=39) and mean±SD of serotonin >100 ng/ml was 202.27±110.66 (n=15).

Based on participants’ characteristics, there was no difference in serotonin levels in relation to gender of male vs female; p=0.601; age category 13-19 vs 20-39 vs 40-59; p=0.334; transmission history of sexual activity with male vs female; p=0.461; occupation as in no job vs have a job, p=0.364, and education of low-middle vs high; p=0.905, as shown in Figure 2.

Figure 2. Distribution of Serotonin Level Based on Participants’ Characteristics. a) Serotonin level based on gender, b) serotonin level based on age categories, c) serotonin level based on transmission history, d) serotonin level based on occupation, and e) serotonin level based on education. The p-values were obtained using the Mann–Whitney U test with a 95% level of confidence (α=0.05). All p-values did not show a significant difference.

The test of model effect shows that there was no effect of gender (Wald χ²=2.516, df=1, p=0.113), age (Wald χ²=1.676, df=1, p=0.195), transmission history (Wald χ²=3.781, df=1, p=0.052), occupation (Wald χ²=1.336, df=1, p=0.248) and education (Wald χ²=0.118, df=1, p=0.731) on serotonin level of HIV-positive participants as presented in Table 2.

Table 2. Generalized Linear Models of Serotonin Levels Based on Participants’ Characteristics.

Variables	Tests of Model Effects (Type III)
	Wald Chi-Square	df	Sig.
Gender	2.516	1	0.113
Age	1.676	1	0.195
Transmission	3.781	1	0.052
Education	0.118	1	0.731
Occupation	1.336	1	0.248
(intercept)	19.996	1	<0.001

5. DISCUSSION

This study is the first to investigate serotonin levels in people newly infected with HIV in Indonesia. The results showed that the average serotonin level was low or under the standard value as about 39 out of 54 samples or 72.2% had <100 ng/ml. Moroianu et al. (22) reported that people with serotonin levels <100 ng/ml could be interpreted as depressed. The mean serotonin level in HIV-positive people did not differ compared to several depressed samples from previous studies, while opposite results were found in the healthy subjects as shown in Table 3. Therefore, it can be assumed that people diagnosed as newly-infected HIV-positive might experience depressive episodes.

Table 3. The Comparison of Serotonin Levels in HIV-Positive Participants with Depressed and Healthy Samples from Previous Studies Using a One-Sample T-Test.

Variable	Mean ± SD	Test-value	Sample	City/Country	p-value	References
Serotonin	84.48±57.91	95.10±71.11	Depression patient	Semarang/Indonesia	0.192	(23)
		70.77±46.23	Depression patient	Romania	0.094	(22)
		73.75±n.a	Depression patient	India	0.187	(16)
		79.8±52.60	Depression patient	Korea	0.562	(24)
		179.30±177.78	Healthy people	Ubud/Indonesia	<0.001	(25)
		154.17±20.90	Healthy people	Denpasar/Indonesia	<0.001	(26)
		119±n.a	Healthy people	California/USA	<0.001	(27)
		114.54 ± 51.10	Healthy people	Normandy/France	<0.001	(28)
		185 ± 68.0	Healthy people	Los Angeles/USA	<0.001	(29)

Furthermore, no significant difference was found in the proportion of serotonin levels based on participants’ characteristics and there was no confounding effect. Low serotonin has been linked with depression occurrence (15,16,30), while depression is also associated with HIV (31, 32). Several studies reported that depression or depressive symptoms were found more dominantly in HIV-positive people than in the general population or HIV-negative (3–7). Therefore, low serotonin levels might be the manifestation of depression stage in HIV-positive people.

Serotonin dysregulation during HIV infection might be a consequence of the infection itself as proposed by Dursun & Reveley (14). HIV-positive people experience impaired immune systems and central nervous systems due to persistent viral infection (14, 17, 33–35). One of the possible mechanisms might involve the cytokinergic-monoaminergic mechanism. During viral infection, the increased proinflammatory cytokines including TNF-α, IL-1B, IL-6, and viral proteins induce indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) through kynurenine pathway which can diminish tryptophan availability, thereby decreasing serotonin production (14, 17, 36).

Another possibility is that serotonin might provoke the progression of HIV infection in individuals. Several studies reported that serotonin plays a significant role in HIV infection progression (37,38). In sufficient levels, it can inhibit or suppress viral infection development (38) and modulate immune function (37). Therefore, this suggests that under low serotonin circumstances, people might be at risk of developing HIV during the viral infection period.

Despite the possible biological rationale for the results, other possible explanations might also include psychological and sociocultural factors such as a sense of hopelessness, social support, isolation, and stigmatization (17,31,32,39). These factors might contribute to the rationality of the link between serotonin and HIV.

The small sample size and simple study design are limitations of this study that impact inadequacy in explaining the causal effect between serotonin level and HIV. Although value comparison was conducted using the mean value of some reported studies in different countries including Indonesia, the different demographical characteristics particularly ethnic heterogeneity should be cautious.

However, this preliminary study could propose some health implications as follows: a) low serotonin might be a potential biomarker in HIV-depression co-occurrence, b) the serotonin dysregulation affected by a viral infection can be anticipated with medication such as an antidepressant or non-medication therapies (i.e., supportive coaching), and c) there is a need to improve self- or public health awareness and prevention due to the potential involvement of low serotonin level in HIV infection progression. Therefore, further investigations are needed specifically in the Indonesian population due to the lack of information regarding this phenomenon.

6. CONCLUSION

Low serotonin level is found more dominantly in people newly infected with HIV in Indonesia. This might be a manifestation of the depression stage, a consequence of infection itself, or the involvement in provoking HIV infection progression. Based on the results, some health implications have also been proposed.

Informed Consent Statement:

All participants were informed and signed informed consent about subject of the study.

Author's Contribution:

M.Y.T­—Substantial contribution to conception and design, acquisition of data, and analysis and data interpretation; drafting the article; critically revising and approval final version to be published. A.A.M.—Substantial contribution to conception and design, acquisition of data, and analysis and data interpretation; drafting the article; critically revising and approval final version to be published. K. S. K.— Substantial contribution to conception and design and acquisition of data; critically revising and approval final version to be published. R. H. M.— Substantial contribution to conception and design and acquisition of data; critically revising and approval final version to be published. F. H.— Substantial contribution to conception and design and acquisition of data; critically revising and approval final version to be published.

Conflicts of interest:

There are no conflicts of interest.

Financial support and sponsorship:

We thank the Indonesia Endowment Funds for Education (LPDP) for supporting the funding of this research with grand number 0001447/TRP/D/PDD-2020.