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• Volume 11, Issue 5
• Investigating the impact of HIV on patients with first episode psychosis: a study protocol for a longitudinal cohort study
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• http://orcid.org/0000-0002-4436-2025 Usha Chhagan 1 ,
• http://orcid.org/0000-0002-5882-100X Vuyokazi Ntlantsana 1 ,
• Andrew Tomita 2 , 3 ,
• http://orcid.org/0000-0002-8154-790X Thirusha Naidu 4 ,
• http://orcid.org/0000-0001-5417-5920 Bonginkosi Chiliza 1 ,
• Saeeda Paruk 1
• 1 Department of Psychiatry , School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
• 2 KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP) , College of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
• 3 Centre for Rural Health, School of Nursing and Public Health , College of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
• 4 Department of Behavioural Medicine , College of Health Sciences, University of KwaZulu-Natal , Durban , South Africa
• Correspondence to Dr Usha Chhagan; uchhagan{at}hotmail.com

Introduction South Africa (SA) has a high HIV prevalence and limited mental healthcare resources. Neuropsychiatric complications such as psychosis onset in people living with HIV (PLWHIV) remains poorly understood. The study aims to compare the socio-demographic, clinical, substance use, cognitive and trauma profile of PLWHIV presenting with first episode psychosis (FEP) to those with the condition but without HIV.

Methods and analysis This study will compare presentation, course, and outcome of a cohort of PLWHIV and FEP with a control group recruited over a 3-year period. We will prospectively test the hypothesis that the 2 groups are socio-demographically, clinically and cognitively distinct at illness presentation, with higher trauma burden and poorer outcomes in those with the dual burden of HIV and FEP. FEP participants, confirmed by a structured neuropsychiatric interview, will have their socio-demographic, psychosis, mood, motor, trauma and substance use variables assessed. A neuropsychological battery will be completed to assess cognition, while quality of life, psychotic symptoms and HIV markers will be measured at 3, 6 and 12 months.

Ethics and dissemination The study protocol has been reviewed and ethics approval obtained from the Biomedical Research Ethics Committee (BC 571/18) of the University of KwaZulu-Natal. The results from this investigation will be actively disseminated through peer-reviewed journal publications and conference presentations.

• schizophrenia & psychotic disorders
• HIV & AIDS
• mental health

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/bmjopen-2020-046593

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Strengths and limitations of this study

This study will be among the first to examine the interacting roles of HIV, substance use and trauma in a first episode psychosis (FEP) study in Africa.

The study may provide valuable insight into the long-term impact of HIV infection on psychosis presentation which is poorly understood in low-and-middle-income countries.

Findings from this study will contribute towards baseline data to guide future studies of patients with FEP.

The study is hospitals-based, and this may introduce sample bias and limit generalisability to community samples.

Randomised controlled trial design is not possible given that study monitors disease progression.

Introduction

Psychiatric illness in the presence of HIV and AIDS has been linked to negative health behaviours and poorer clinical outcomes. 1 The prevalence of HIV among those with serious mental illness (SMI) ranges from 1% to 24%. 2 Left untreated, mental disorders in people living with HIV (PLWHIV) result in poorer quality of life, greater interpersonal difficulties, increased suicide risk and poor adherence to antiretroviral therapy.

Psychotic disorders are associated with a significant burden of disease, with affected persons often relying on limited public sector mental health resources in low-and-middle-income countries (LMICs). 3 There is a lack of research on HIV and psychosis in LMICs, particularly sub-Saharan Africa (SSA), despite this region accounting for more than two-thirds of the world’s HIV-positive population. 4 While research from high-income countries has demonstrated that there is a bi-directional relationship between HIV/AIDS and mental illness, there may be differences in the way this relationship is expressed in SSA. 5 There is much needed cross-cultural insight into the relationship between HIV/AIDS and psychosis. Culture may influence the patients’ perception and experience of psychosis as well as the clinical presentation. This highlights the need to explore the impact of culture on psychosis. 6 Studies have also shown variations in the socio-demographic and clinical profile of those with dual burden of HIV and first episode psychosis (FEP) compared with those with psychosis only. 7

Socio-demographic profile of PLWHIV and first episode psychosis

There is limited literature on the association of HIV and FEP, with previous studies mainly describing HIV prevalence rates or clinical profiles. 8 A Ugandan study by Lundberg and colleagues 9 found that HIV-positive patients with mental illness were more likely to be women and older (40–49 years). A KwaZulu-Natal (KZN) Province, SA, study of patients with FEP reported a higher HIV prevalence in less educated individuals; however, this was a small sample. 8 In a more recent chart review of patients with psychosis admitted to a psychiatric hospital in SA, HIV-infected patients with psychotic disorders were more likely to be women (74.0%), younger than 50 years (94.0%) and less likely to have secondary education than HIV-negative patients with psychotic disorders (56.0% vs 72.0%). 10

PLWHIV and psychosis symptomatology

In a review of the literature, grandiose, persecutory and somatic delusions were the most common psychotic symptoms, followed by hallucinations and mood symptoms in PLWHIV with FEP. 11 An Italian study found that HIV infection increased the severity of symptoms (more frequently paranoid delusions), was associated with a greater impairment in attention and concentration, and had decreased depressive symptoms. 7 In addition, PLWHIV and psychosis are more likely to be diagnosed as having a psychosis secondary to another medical condition than a primary psychotic disorder, and have more comorbid medical disorders and increased haematological test abnormalities. 10 A study in Gauteng province, SA, found that among PLWHIV presenting to psychiatry services, 23 individuals were diagnosed with psychosis due to another medical condition while only two were diagnosed with schizophrenia. 12 However, there is extremely limited literature on HIV and psychosis symptomatology, particularly from Africa. 8 13 This suggests a hiatus in the current literature on understanding the nature and severity of psychotic symptoms in PLWHIV, particularly in the African context. There is a need for systematic studies of larger cohorts with standardised tools to better understand how HIV may potentially influence psychosis presentation and course, as well as HIV disease outcomes.

PLWHIV and FEP and cognition

Cognitive impairment is well established in both psychotic disorders and HIV infection, being exacerbated in psychotic patients with HIV. 13 Being HIV positive is traditionally associated with a sub-cortical cognitive impairment, the prevalence of cognitive deficits being reported to range from 4% to 99% in a systematic review of HIV research in SSA. 5

De Ronchi et al 7 described cognitive screen deficits in a sample of 22 patients with FEP living with HIV in Italy. Participants had impaired attention and concentration on the Mini Mental State Examination (MMSE) but no other differences on cognitive impairment. A study of cognitive dysfunction among 156 HIV infected and 322 HIV non-infected patients with psychosis in Uganda assessed them with the MMSE and a neuropsychological battery. They found that PLWHIV and psychosis were more cognitively impaired than HIV-negative psychotic patients at baseline, and although there was some improvement with treatment, they remained more impaired at 6 months, suggesting that HIV worsened cognitive dysfunction in psychosis. 13 While earlier studies have suggested that psychosis and impairment in cognition were later manifestations of HIV, the Ugandan study demonstrated that both these conditions occur early, as shown by the average CD4 count of 305 cells/µL and the intermediate WHO staging of disease presentation. In addition, impairment in cognition also remained, despite an improvement in the psychotic symptoms. 13 Further research is warranted to establish the impact of HIV and psychosis on cognition, and whether HIV-related cognitive changes are associated with increased risk for psychosis or modifies psychosis onset or course.

PLWHIV and FEP and substance use

Studies traditionally suggest an association between substance use in FEP patients and HIV infection. 1 Substance use patterns vary across the different regions of SA. This may be related to both ethnic and socioeconomic differences. 14 Davis et al confirmed both the growing pattern of substance use as well as the trend of psychiatric comorbidity in KwaZulu-Natal (KZN). The rates of substance use in this province were also significantly higher than that reported in studies of the general population in SA. 14 Another study of patients with FEP in KZN, SA, reported lower rates of self-reported substance use among HIV-positive than HIV-negative patients with mental illness, 8 which was further supported by a retrospective chart review of patients with psychosis. 10 This may suggest that either substance use/misuse may not be a significant factor in HIV transmission in the KZN context, or that the study results were limited by under-reporting or the small sample size. Thus, while the international literature suggests that PLWHIV and mental illness may be vulnerable to substance use, this has not been borne out in the local KZN studies and warrants further research.

PLWHIV and FEP and trauma

Trauma, particularly early life trauma, is also recognised as an environmental risk factor for psychosis. 15 A South African study investigated the association between a history of traumatic experiences and the clinical features of FEP. Duration of untreated psychosis, age of and symptoms at onset were assessed in 54 psychotic patients, while 22% were HIV infected. Almost half of the study subjects had witnessed (49%) or directly experienced serious physical assault (45%), both events being associated with positive psychotic symptoms. 16

The trauma experienced may influence psychosis and HIV outcomes, as found in a systematic review, that hallucinations and delusions were more severe in people with a history of childhood trauma. 17 In addition, Leserman 18 reported on the negative association of HIV, stress and depression on the course of HIV in terms of decreasing the CD4 lymphocytes, increasing the viral load and having greater risk for premature mortality.

Exposure to violence and resultant trauma is of major public health concern. In SA, the mortality rate secondary to violence was estimated at 73/100 000. 19 20 While much research on early trauma has been conducted in developed countries, there is a need to examine the association of trauma and FEP in developing countries. 19–21

Course of comorbid HIV and psychosis

PLWHIV and psychosis are more likely to develop comorbid medical disorders, experience side effects of antipsychotic medication, develop metabolic syndrome secondary to ART, have longer length of hospital stay and readmission rates, and have poorer quality of life. 1 10 However, this has not been tested prospectively in the patients with FEP in the African context with the recent wide availability of ART.

The aim of the study is to investigate trends in clinical, substance use, cognitive and trauma presentations in individuals experiencing first episode of psychosis over time, and to compare presentation, course and 12-month outcomes between those with and without HIV.

Patients referred to the participating psychiatry units will be screened by the respective treating doctors for eligibility for recruitment into the study. The patients with FEP must fulfil the inclusion criteria and will be referred to the designated investigator at each unit. Once written informed consent has been obtained, the protocol for data capture will be followed, as per the list outlined in figure 1 and table 1 , the same protocol being followed for outpatients and inpatients. The clinical examination and psychiatric tests, which take approximately 2 hours, will be undertaken by the investigators who are all medical practitioners. Patient baseline assessments will be undertaken within 6 weeks of treatment during their outpatient visit or following admission to the respective units at baseline. A physical examination, body mass index and waist circumference measure will also be obtained by a medical practitioner. Where possible, collateral information from a next of kin, with the participant’s consent, will also be sought. The follow-up visits will be done at 3, 6 and 12 months as outpatients, and the participants will be reimbursed for travel costs. Attempts will be made to coincide each of these with scheduled clinic follow-up visits and will be performed by the same initial interviewer at each psychiatry outpatient department.

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List of all study procedures used in the patient assessment.

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Objectives and measures used at each visit in HIV-infected and non-infected participants

The cognitive battery assessment, which takes approximately 2 hours, will be administered by a clinical psychologist, at the 3-month and 12-month visits. Translation services will also be available for patients who require isiZulu translation during the interviews.

Following collating the data for steps 1–13 in figure 1 and table 2 , 22–33 we will perform steps 14 and 15 after voluntary counselling and testing. The required HIV tests, CD4 count and viral load if HIV positive, as per the protocol, will be taken by a medical practitioner at each site. HIV testing will be carried out at baseline for all participants as well as at each visit for HIV-negative participants. A patient with a positive HIV test will be referred to the HIV clinic at the site for further management. Other investigations, such as lipid profile, which are part of routine care, will be captured from the clinical records.

Cognitive test battery and domains to be tested

We are keen to explore impact of pathways of care on socio-demographic and clinical variables. Rehabilitation programmes are limited as many sites lack a multidisciplinary team to support this; however, standard of care includes medication, supportive therapy, psycho-education, referral to psychology if indicated and management of comorbid substance use.

Study design and setting

The comparative cohort study will be in keeping with a quantitative, descriptive and longitudinal 12-month design of adult patients presenting with FEP that are either HIV infected or non-infected. The study will take place in the eThekwini District, one of 11 in KZN Province, with an estimated population of 3 442 361 people. The district has a high HIV burden, with an estimated 650 000 people living with the virus in 2018. 34 In addition, there are only five hospitals in the municipality with psychiatric services managed by a psychiatrist, at which the study will be conducted. The hospitals selected are the four general hospitals with specialist psychiatric services situated in eThekwini: Addington, King Edward VIII, Prince Mshiyeni and RK Khan Hospitals, and at King Dinuzulu Hospital, which serves as the psychiatric hospital for the area. All hospitals have inpatient and outpatient psychiatric services and receive referrals from within the district as well as from urban and rural areas as far south as the Eastern Cape Province and northern KZN.

Eligibility criteria

Inclusion criteria.

Male and female patients will be included if they are inpatients or outpatients, aged 18–45 years, have a first presentation to mental healthcare services for FEP meeting Diagnostic and Statistical Manual (DSM)-V criteria 35 (American Psychiatric Association (APA) 2013) for a psychotic disorder, are neuroleptic naive or minimally treated (maximum 6 weeks of psychotropic treatment in this first episode), and provide consent to participate.

Exclusion criteria

Patients will be excluded if they have been prescribed antipsychotics in the past or have had previous psychotic episode, an intellectual disability (assessed clinically or by chart review) or other significant general medical conditions that may be associated with FEP, for example, epilepsy or syphilis, have less than 7 years of formal schooling and refuse consent.

Participant selection and sampling strategy

All adult inpatients or outpatients with FEP meeting the inclusion criteria will be recruited to the study over a 3-year period. The sample size calculation was based on a log-rank test group. In order to achieve an 80% power to detect an OR of 1.857 (to maximise variability), in a design with three repeated measurements having a compound symmetry covariance structure when the proportion from group 2 is 0.500, the correlation between observations on the same subject is 0.500, and the alpha (significance) level 0.05 or 5%, a sample of 130 PLWHIV and FEP and 130 HIV negative with FEP will be required. In addition, this sample size accounts for and permits a 10% dropout rate over an anticipated 36-month accrual with a minimum follow-up of 12 months.

Data collection

The study will use a clinical interview, physical examination, several psychiatric tools and HIV-related haematological tests to measure variables. Baseline measures will be done within 6 weeks of first presentation and as soon as the participant is able to consent. Participants need to have responded to antipsychotic medication and will be assessed to have the capacity to consent by a treating and research doctor. The study (HIV+) and control groups (HIV−) will receive the same baseline assessments and follow-up at 3, 6 and 12 months, which are summarised in table 1 . The HIV-negative group will have HIV testing at each visit to re-confirm HIV status. The study procedures, with instruments, 36–46 that will be used are shown in the information in figure 1 . Data will be collected manually and captured electronically.

Clinical researchers with a medical background will administer the mental health diagnostic assessment, the MINI 7.02, Psychotic Disorders version, DSM-V 36 and diagnostic interview face-to-face, and will be supported by a trained research assistant who will facilitate the self-report questionnaires. All study personnel will be trained on initiation of the study with an annual refresher training on the different tools by psychiatrists with research and clinical experience. A medical doctor will conduct the clinical assessments, collect the biological specimens ( table 1 ), and conduct the HIV counselling and testing. We will use an HIV COBAS COMBI test to detect both HIV antibodies and p24 antigen. Standard pre-test and post-test counselling will be delivered in a culturally sensitive manner, while the CD4 count and viral loads will be measured at every visit among PLWHIV.

Participants will be given a return research appointment date and telephonic contact will be maintained between interviews. The study team (research assistant and clinician) will contact participants to remind them of appointments to limit their withdrawing from the study. For participants who do not arrive for their appointments, the research assistant will contact the patient to reschedule an appointment in the same week.

Data management and analysis

All participants will be allocated a participant identification number (PID) code at enrolment, which will be used on samples and documents over the 12-month study period. Data will be downloaded to a secure server and kept in a password-protected system. Laboratory results will be merged into the main dataset using the unique PID.

Data will be entered into SPSS V.24 and the analyses conducted using STATA V.15. The socio-demographic and clinical characteristics of participants will be summarised using means and SD continuous variables. For categorical variables, proportion (%) will be reported. Significant associations in contingency tables (cross tabulations) will be assessed using the standard Pearson’s χ 2 test. An independent samples t-test will be used for comparing differences in continuous variables between two groups. If there are more than three groups, we will use ANOVA methods. A p value less than 0.05 will be regarded as statistically significant. In addition, we may also apply growth mixture modelling to observe whether subsets of individuals follow distinct trajectories over time.

Patient and public involvement

No patients or members of the public were involved in the design, analysis or reporting of this current investigation.

Ethics and dissemination

Ethical approval to conduct the study was obtained from the Biomedical Research Ethics Committee of the University of KwaZulu-Natal (UKZN). The study will be conducted in accordance with South African Department of Health Research Ethics guidelines (2015) as well as the UKZN policy on Research Ethics. Recruitment of study participants will commence as full ethics approval was received from Biomedical Research Ethics Committee. No other independent ethics review was required.

All participants fulfilling the inclusion criteria will be selected for the study, from whom written, informed consent will be obtained. All potential participants will have the opportunity to participate, which will be made known to them in the information sheet. Where participants are unable to consent independently, adequate steps will be taken to ensure that legally acceptable proxy consent is obtained. All participants testing HIV positive at any point in the study will be referred for ART and support.

The results from this investigation will be actively disseminated through peer-reviewed journal publications and conference presentations. On completion of the peer-review process, we will provide feedback to clinicians at Department of Health for further discussion about enhanced treatment algorithm.

Potential risks

There will be minimal risk or discomfort to participants, with one test requiring bloods to be taken. The only active involvement of the participants is for them to provide verbal responses to assessment interviews and scales used for data collection. We acknowledge the potential risk of psychological distress to patients, as they may be directly affected by sensitive questions, for example, relating to trauma during the administration of the psychiatric scales. The study has a distress plan to support such patients, which entails referral to treating team if there is concern about relapse or danger to self or others. The sites have specialist psychiatric services, both inpatient and outpatient, with a team available to attend to any adverse event that may arise during the interview process.

Methodological challenges and study limitations

Several limitations may affect the study, including that it is hospital-based, which may introduce sample bias and limit the generalisability to community samples. Another limitation is the use of tools that have limited validity in the local South African context, as they have not been used previously. Language and cultural barriers in communication will be addressed by an available isiZulu translator. A further limitation of the observational nature of the study is the attendant lack of standardisation of treatment, for which will follow the Essential Drug List (EDL) for hospital level adults (Department of Health, 2015). Although patients will follow the same algorithm, they may be maintained on different medication, depending on the individual patient treatment response. The study will, however, provide an adequate sample representing the clinical profile of patients with FEP and PLWHIV in a resource-constrained setting.

Study progress and challenges

A challenge we anticipate is the loss of participant follow-up, which is generally a common failing in managing psychiatric patients, particularly in LMIC settings with challenging psychosocial circumstances. The 3-month, 6-month and 12-month follow-up appointments may remain difficult to sustain, despite supporting participants with travel costs for visits. Maintaining follow-up visits is a challenge we anticipated and for which we have a contingency strategy, this being that a research assistant will have regular communication with the recruited participants, confirming appointment dates, sending reminders and facilitating travel arrangements. Participants seroconverting to HIV positive status during the study will be referred to antiretroviral services for care but continue follow-up assessments, noting the change in their HIV status.

Study significance

We postulate that the course and outcome of HIV psychosis differs from that in an HIV-negative individual, and that this study may provide valuable insight into the impact of HIV infection on psychosis presentation and outcomes. Longitudinal comparative cohort studies of this nature are limited and have not been conducted locally in one of the highest HIV prevalence settings in Africa, hence the data will serve to introduce new knowledge on the topic, as well as form the baseline for future research and treatment. A clearer understanding of the association between HIV and psychosis may provide better insight into HIV as a neurotropic virus. The findings of this study will contribute towards improving the care and management of patients with FEP and HIV.

WHO reports that in 2020, psychiatric conditions are ranked the second leading cause of global disease burden after ischaemic heart disease. 47 In the South African context, this is even more pronounced by the additional burden of HIV infection and AIDS. With an approximate overall HIV prevalence rate of 11.2% (6.19 million) and an estimated 16.6% of the population (adults aged 15–49 years) being HIV positive, SA is in urgent need of interventions to address the related adverse consequences. Psychotic disorders are associated with a significant burden of disease and often use the limited mental health resources. Understanding the association between HIV and psychosis in the era of antiretroviral treatment is thus an urgent priority. Using the HIV psychosis as a potential model for schizophrenia may also improve our understanding of its neurobiology. The new knowledge, generated through this novel study, will enable an understanding of the interplay between HIV and psychosis at a fundamental level, centred at the international epicentre of the HIV pandemic.

In addition, in SA, substance use and trauma remain critical public health challenges that need to be further explored. Thus, the study of the bidirectional associations between HIV, substance use and traumatic experiences, psychosis onset and presentation in a low-income and middle-income setting is essential to better guide the strategic use of their limited resources. Early insights into the role of substance use and trauma in HIV infection and psychosis onset could be used to delay, modify or even prevent the onset of HIV psychosis. Furthermore, the interplay of these extraneous factors in genetically predisposed individuals has not been explored. This study will allow us to begin to understand the contribution of HIV to psychosis onset, increase awareness of the need for screening and care in a highly vulnerable group, while building research capacity.

In LMIC, 11.1% of the total burden of disease are attributable to mental disorders. 21 In addition to the high prevalence and morbidity associated with mental disorders, it has been shown that cultural influences impact significantly on and contribute to the risk for mental and other health concerns in developing countries. The results of this study will contribute to the development of management (investigation and treatment) algorithms in the South African resource-constrained health departments. Reference will be made to the differences identified between the HIV positive and HIV negative groups, facilitating appropriate tailored approaches to each sub-group. The benefits of these would include policy changes and streamlined cost-effective treatment plans that will be equally beneficial to patient and the health department.

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Contributors UC, VN, TN and SP conceived the study. UC, VN will collect data. AT performed the statistical analysis. SP and BC supervised the work undertaken. UC wrote the first draft. All authors have read and approved the final manuscript.

Funding This study is funded by National Research Foundation of South Africa (Grant no. 117858), South African Research Council SIR grant and a start-up grant from the Society for Biological Psychiatry Research Fund. Funding (Grant no. N/A) was also received from University of KwaZulu-Natal College of Health Sciences PhD Scholarship (Grant no. N/A). AT was funded by UK Global Challenge Research Fund (MR/T029803/1).

Disclaimer The opinions and findings presented are those of the authors and not a reflection of the funders.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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HIV and AIDS in Older Adults: Neuropsychiatric Changes

• Geriatric Disorders (JA Cheong, Section Editors)
• Published: 09 July 2022
• Volume 24 , pages 463–468, ( 2022 )

Cite this article

• Paroma Mitra   ORCID: orcid.org/0000-0003-1947-3564 1 , 2 ,
• Ankit Jain 3 &
• Katherine Kim 1 , 2  

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Purpose of Review

Patients diagnosed with HIV can now survive well into their old age. Aging with HIV is not only associated with comorbid medical illnesses but also with neuropsychiatric conditions that can range from cognitive changes to severe behavioral manifestations. This paper reviews mood, anxiety, and cognitive changes in older patients with HIV, as well as some of the treatment challenges in this population.

Recent Findings

Most recent findings show that untreated HIV illness over a long period of time may further worsen both preexisting neuropsychiatric illness and may cause new onset behavioral and cognitive symptoms. HIV induces immune phenotypic changes that have been compared to accelerated aging Low CD 4 counts and high viral counts are indicative of poor prognosis.

Evaluation for potential HIV infections may be overlooked in older adults and require screening. Older adults experience accelerated CD4 cell loss. Older adults endorsing new onset mood or cognitive changes must be screened for HIV infection. New onset neurobehavioral symptoms should be carefully screened for and treated simultaneously in patients with HIV infection.

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Mitra, P., Jain, A. & Kim, K. HIV and AIDS in Older Adults: Neuropsychiatric Changes. Curr Psychiatry Rep 24 , 463–468 (2022). https://doi.org/10.1007/s11920-022-01354-z

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New-onset psychosis in HIV-infected patients

Affiliation.

• 1 Department of Psychiatry, University of California, San Diego.
• PMID: 1894589

Background: Psychiatric symptoms and disorders are becoming increasingly evident in human immunodeficiency virus (HIV)-infected patients. As psychotic symptoms may be severe and require immediate behavioral management, the authors sought to determine the frequency and clinical characteristics of new-onset psychosis not obviously attributable to substance abuse or delirium in these patients.

Method: The authors reviewed the English-language literature since 1981 by means of the Index Medicus and MEDLINE for reports of new-onset psychosis in HIV-infected patients and also examined the charts of 124 HIV-infected patients who had been followed up at the San Diego Veterans Affairs Medical Center since 1984. Cases of substance-induced psychosis and delirium were excluded.

Results: Results reflect a combination of cases from the authors' study and cases of new-onset HIV-associated psychosis reported in the literature (N = 31). Results of the initial neurologic evaluation, including computed tomography (CT) scan and examination of the CSF, were normal in a majority of patients (CT = 12 of 23 patients; CSF = 10 of 14 patients). Psychotic symptoms improved with neuroleptic treatment although side effects were frequently seen. In some patients (N = 12) psychosis was the presenting manifestation of HIV infection or acquired immunodeficiency syndrome. A proportion of patients (N = 7 [23%]), especially those with an abnormal CT and EEG at the time of presentation with psychosis, tended to have a relatively rapid deterioration in cognitive and medical status. Differences between studies in population and method made it impossible to determine the frequency of new-onset psychosis in the general HIV-infected population.

Conclusions: A common clinical feature noted in new-onset psychosis in HIV-infected patients was acute or subacute onset of symptoms, which included delusions, hallucinations, bizarre behavior, mood or affective disturbances, and mild memory or cognitive impairment. The etiological association of the HIV infection to the psychosis is yet to be established.

Publication types

• Research Support, U.S. Gov't, Non-P.H.S.
• Research Support, U.S. Gov't, P.H.S.
• AIDS Dementia Complex / diagnosis
• AIDS Dementia Complex / psychology
• Acquired Immunodeficiency Syndrome / complications*
• Acquired Immunodeficiency Syndrome / psychology
• Delirium / diagnosis
• Delirium / etiology
• Electroencephalography
• HIV Seropositivity / complications*
• HIV Seropositivity / psychology
• Hallucinations / diagnosis
• Hallucinations / etiology
• Neurocognitive Disorders / diagnosis
• Neurocognitive Disorders / etiology*
• Neurocognitive Disorders / psychology
• Neurologic Examination
• Neuropsychological Tests
• Tomography, X-Ray Computed

Grants and funding

• MH45294/MH/NIMH NIH HHS/United States

Treating psychosis in patients with HIV/AIDS

Drs. Diduch and Campbell are PGY-1 Pharmacy Practice Residents, Chillicothe Veterans Affairs Medical Center, Chillicothe, Ohio. Dr. Borovicka is Associate Professor, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio. Dr. Cunningham is Psychiatrist, Community Health Network, Indianapolis, Indiana. Dr. Thomas is Director, PGY-1 and PGY-2 Residency Programs, Clinical Pharmacy Specialist in Psychiatry, Chillicothe Veterans Affairs Medical Center, Clinical Associate Professor of Pharmacology, Ohio University College of Osteopathic Medicine, Chillicothe, Ohio.

Disclosures The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. S, age 56, has human immunodeficiency virus (HIV) and schizoaffective disorder. He presents to your clinic with increased auditory hallucinations, disorganized behavior, and worsened tremors that have begun to seriously disrupt his daily life. Mr. S is prescribed risperidone; however, he reports that he has not been taking it lately due to the tremor despite being controlled on his medication regimen for nearly 1 year. His Abnormal Involuntary Movement Scale (AIMS) score reveals an increased wrist rigidity compared with previous clinic visits. Mr. S has a 40 pack-year history of smoking and history of IV drug use. Furthermore, he has a medical history of type 2 diabetes mellitus, hypertension, and hyperlipidemia.

His medication regimen includes atazanavir sulfate, 200 mg/d, ritonavir, 100 mg/d, efavirenz/emtricitabine/tenofovir disoproxil fumarate, 600/200/300 mg/d, risperidone, 6 mg/d, bupropion extended-release, 300 mg/d, gabapentin, 600 mg/d, amlodipine, 5 mg/d, pravastatin, 40 mg/d, metformin, 1000 mg twice daily, and glipizide, 10 mg twice daily. Today, his laboratory findings show that his CD4 count is 405 cell/mm 3 , and his viral load is <40 copies/mL, indicating his HIV is well managed. A hepatitis C virus antibody test result is negative and serum creatinine level is 1.0 mg/dL. Total cholesterol is 212 mg/dL, high-density lipoprotein cholesterol is 43 mg/dL, low-density lipoprotein cholesterol is 121 mg/dL, and triglycerides level is 238 mg/dL. Electrocardiography reveals a QTc interval of 426 ms. Mr. S’s blood pressure is 105/65 mm Hg. Based on this clinic visit, the treatment team decides to change Mr. S’s antipsychotic.

Psychiatric illness and HIV/AIDS

There is a strong link between mental illness and HIV/AIDS; 50% or more of patients with HIV/AIDS have a comorbid psychiatric disorder. 1 The prevalence of mental illness in patients with HIV/AIDS is reported to be 8 times higher than in those without HIV/AIDS. 2 Depression, bipolar disorder, anxiety disorders, delirium, substance abuse, and schizophrenia have all been identified in persons receiving highly active anti­retroviral therapy (HAART). Patients with HIV/AIDS and psychiatric illness have a decreased quality of life, poor adherence to medications, faster disease progression, and increased mortality. Care of these individuals is complicated by the stigma of HIV/AIDS and the prevalence of the illness in underserved populations, as well as the need for complex medication regimens and the possibility of drug–drug interactions (DDIs). 1,2 If left untreated, psychiatric illness in patients with HIV/AIDS may lead to further transmission of HIV as a result of patients engaging in high-risk behaviors, along with poor adherence to HAART. 3

Individuals diagnosed with schizophrenia, schizoaffective disorder, and bipolar disorder are at greater risk for HIV infection. 3 Patients with HIV/AIDS with primary psychosis may have poor medication adherence rates due to illness-related confusion or paranoia about medications. Furthermore, they may lack the resources to manage the complications and stress related to living with HIV/AIDS.

New-onset, or secondary psychosis, has been reported in individuals with late-stage HIV/AIDS with CD4 counts <200 who have not been diagnosed with a psychotic disorder previously. 3 These patients may experience more persecutory and grandiose delusions rather than hallucinations. Neuropsychiatric symptoms in patients with HIV/AIDS may be due to the presence of HIV or other infections in the CNS, tumors, or other inflammatory illnesses. Medications that have been implicated in neuropsychiatric symptoms include efavirenz, rilpivirine, and other HAART regimens; interferon; metoclopramide; corticosteroids; muscle relaxants; and clonidine. It is possible that symptoms may continue even after the medications are discontinued. 3

Antipsychotics remain the treatment of choice for psychosis in HIV/AIDS, regardless of the cause of the symptoms. Many factors must be taken into consideration when choosing an antipsychotic, such as DDIs, adverse effect profiles, patient history of antipsychotic use, cost, and patient preference. Here we focus primarily on DDIs and adverse effect profiles.

Drug–drug interactions

When treating psychosis in patients with HIV/AIDS, it is crucial to consider potential DDIs. Many antipsychotics and antiretroviral medications utilize cytochrome P450 (CYP) enzymes for their metabolism. The CYP enzyme system is responsible for the oxidative reactions that constitute the phase I reactions necessary for the metabolism of most drugs. Inhibition and induction of CYP enzymes are among the most common causes of pharmacokinetic DDIs. Antipsychotics are predominately metabolized by CYP3A4, CYP1A2, and CYP2D6. 4

Continue to: The DDIs arise because...

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• March 1, 2024 | VOL. 19, NO. 3 CURRENT ISSUE pp.2-13

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Neurosyphilis With Psychosis as the Primary Presentation

• Lauren M. Nutile , M.D.

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Patients with neurosyphilis, which is now a rare disease because of the availability of antibiotics, can initially present with psychiatric symptoms instead of the more well-known physical findings, such as general paresis, tabes dorsalis, and Argyll Robertson pupils. A subset of patients with primarily psychiatric symptoms beginning later in life tend to be incorrectly diagnosed as having late-onset schizophrenia. This case report describes a 67-year-old female with psychiatric symptoms starting 8 years prior to presentation who was misdiagnosed with late-onset schizophrenia. Because her symptoms first appeared at the later age of 59, additional testing was performed to rule out a medical etiology. The patient was found to be positive for syphilis infection in the serum and cerebrospinal fluid. She displayed no other notable symptoms of syphilis aside from bizarre behaviors and paranoid delusions. This case demonstrates the importance of considering organic infectious diseases, such as syphilis, when psychosis initially presents at an older age.

Syphilis is an infection caused by the bacterium Treponema pallidum that has shown decreased prevalence because of the advent of penicillin ( 1 ). If the disease remains untreated, syphilis progresses through three stages. Primary syphilis involves development of a chancre about 2 to 3 weeks after exposure, and secondary syphilis is characterized by lymphadenopathy, fever, CNS involvement, and rash on the palms and soles that appears weeks to months after infection. Tertiary syphilis is an inflammatory process that can cause granulomatous tissues to form in the cardiovascular or central nervous system 1 to 30 years after exposure. The illness may remain latent for years in between stages ( 1 ). Neurosyphilis itself can be further broken down into an early stage involving meningeal and vascular structures and a late stage affecting the parenchyma of the brain and spinal cord ( 1 , 2 ).

Some of the psychiatric symptoms that have been described in untreated neurosyphilis patients include personality changes, aggressive behaviors, mania, auditory and visual hallucinations, illusions, frank paranoia, progressive cognitive impairment often leading to loss of employment, delirium, and persecutory delusions ( 1 – 7 ). Because of early treatment, only about 10% to 15% of primary syphilis cases progress to tertiary syphilis, and of these cases, less than 20% present with primary psychiatric symptoms ( 3 ). For these reasons, the diagnosis of neurosyphilis is often overlooked.

Few journal articles and case reports in the current literature describe psychosis as the first manifestation of syphilis. In fact, many patients over age 45 who present as psychotic are diagnosed with late-onset schizophrenia. Late-onset schizophrenia accounts for 15% to 20% of all diagnoses of schizophrenia and is typically associated with better premorbid functioning, fewer negative symptoms, and less severe neurocognitive impairment, compared with schizophrenia that presents at an earlier age ( 8 ). Late-onset schizophrenia usually responds to lower doses of antipsychotics, compared with higher doses.

Case Report

Ms. A was a 67-year-old female with a medical history significant for hypertension, controlled diabetes, chronic obstructive pulmonary disease, and misdiagnosed late-onset schizophrenia who presented to inpatient psychiatry under a temporary detention order because she was displaying bizarre behavior and responding to internal stimuli. She also appeared to be quite paranoid, carrying knives around with her for protection. Her symptoms were first noticed 8 years before, and she had been admitted to an outside psychiatric facility seven times over the past 2 years with a similar presentation. Ms. A was misdiagnosed with late-onset schizophrenia and had been treated with risperidone, haloperidol, and paliperidone. Her symptoms only minimally improved with antipsychotic treatment each time, and she had a history of noncompliance with medication in the outpatient setting, because she did not believe she had a psychiatric illness. Over 8 years, Ms. A's symptoms continued to worsen to the point where she could no longer maintain employment. She retired at age 62 and moved in with family members.

The differential diagnosis for the case was initially broad and included late-onset schizophrenia, schizoaffective disorder, unspecified psychosis, substance-induced psychosis, HIV-associated psychosis, hepatic encephalopathy, neurosyphilis, and other venereal diseases. Basic psychiatry screening labs, including complete blood count, basic metabolic panel, thyroid-stimulating hormone, lipid panel, liver function tests, hemoglobin A1c, urinalysis, and drug screen, were ordered when the patient was admitted. Given that Ms. A's symptoms did not manifest until age 60, further testing was ordered, including syphilis immunoglobulin G, HIV, hepatitis C, gonorrhea, chlamydia, trichomonas, and computerized tomography (CT) imaging of the head. Syphilis testing was found to be reactive, with rapid plasma reagin titer of >1:256. A noncontrast head CT showed nonspecific subcortical and periventricular white matter hypodensities ( Figure 1 ). The basic psychiatry labs noted above and HIV, hepatitis, and other sexually transmitted disease testing were all negative.

FIGURE 1. Head CT without contrast a

a Axial images sliced superiorly to inferiorly moving left to right. The arrows point out nonspecific subcortical and periventricular white matter hypodensities in this patient. Hypodensities in these areas have been previously described in patients with neurosyphilis. However, it cannot be ruled out that these findings could be due to chronic microvascular changes.

Ms. A's psychotic symptoms were addressed pharmacologically by starting paliperidone and titrating to 6 mg daily. She was overall calm and cooperative while interacting with staff members on the psychiatric unit. However, she was frequently observed responding to internal stimuli and smiling inappropriately when she thought she was alone. The patient was quite guarded and generally a poor historian. When she was told about her diagnosis of syphilis, Ms. A stated she thought she had syphilis a few years ago, but she could not recall for sure. Her family was unable to confirm or deny a prior diagnosis of syphilis.

To solidify a diagnosis of neurosyphilis, a lumbar puncture was performed by the neurology consult team. On venereal disease research laboratory testing, cerebrospinal fluid (CSF) was found to be reactive, with a titer of 1:4. The patient was then transferred to a medical specialty unit where she was started on 4 million units of intravenous penicillin every 4 hours for the treatment of neurosyphilis. A peripherally inserted central catheter line was placed for ease of treatment, and she completed a 12-day course of antibiotics. At the time of discharge from the medical unit, Ms. A was no longer displaying any paranoid behaviors nor was she speaking about any overt delusions. She was discharged home with family after completion of penicillin treatment and after being reevaluated by psychiatry. Oral paliperidone 6 mg daily was prescribed at discharge. Ms. A was advised to follow up with both her local outpatient psychiatrist and her primary care provider for further syphilis-related management.

It is important to consider a wide differential in the case of an elderly patient who presents with psychosis as a primary symptom, including organic diseases such as neurosyphilis. Some aspects of Ms. A's case did fit with a diagnosis of late-onset schizophrenia, particularly her psychotic symptoms starting after age 45, female gender, few negative symptoms, and good premorbid functioning ( 8 ). There was the possibility that she developed both late-onset schizophrenia and neurosyphilis. However, the positive serum and CSF testing, as well as Ms. A's minimal improvement with antipsychotic treatment, suggested that her symptoms were more likely the manifestation of neurosyphilis.

Because tertiary syphilis is quite indolent and can remain dormant for years, the patient may have been originally exposed to the disease up to 30 years earlier. Neither Ms. A nor her family could confirm whether she had previously been diagnosed with syphilis. Her symptoms likely worsened over 8 years because the infection went untreated. In contrast to Ms. A's poor response to antipsychotics, her symptoms appeared to have responded well to neurosyphilis treatment, which typically includes 18 to 24 million units per day of aqueous crystalline penicillin for 10 to 14 days through intravenous administration ( 4 , 9 ). After 12 days of intravenous penicillin, she was no longer responding to internal stimuli or smiling inappropriately.

Although a positive response was seen with intravenous penicillin treatment, it was important to ensure that the patient follow up with primary care and neurology as well as psychiatry. The overall prognosis for patients with neurosyphilis is poor. Only some patients experience resolution of psychotic symptoms after intravenous penicillin treatment; the cure rate is estimated to be about 60% ( 5 , 8 ). Patients may require serial laboratory monitoring (or lumbar punctures) every 6 months for a span of 2 years ( 10 ). If CSF white blood cell count or serum venereal disease research laboratory levels do not decrease fourfold or normalize by the end of 2 years, then a proper treatment response has not occurred and retreatment is considered ( 7 , 9 ). Additionally, some case reports have found that neurosyphilis patients who present as psychotic do not have a good prognosis for symptom resolution ( 1 , 2 , 5 ). In these cases, continuation of antipsychotic treatment may be necessary. However, if a patient continues to do well and no longer displays psychosis, antipsychotic treatment should be discontinued, given potential adverse effects from psychotropics.

The case of Ms. A helps to demonstrate that we must consider medical causes when evaluating new-onset psychosis in an older patient, especially when symptoms do not improve with antipsychotic treatment. The diagnosis of neurosyphilis is rare, but about 60% of patients respond well with intravenous penicillin treatment if providers correctly diagnose the etiology. If additional testing had not been ordered for organic causes of psychosis, Ms. A likely would have continued the pattern of psychiatric admission, medication noncompliance, and worsening of symptoms. Neurosyphilis is not an infection to be missed.

Key Points/Clinical Pearls

Medical conditions, including neurosyphilis, should always be considered in the differential diagnosis for psychosis in elderly patients.

Patients exposed to syphilis can develop neurosyphilis many years after initial infection.

Neurosyphilis does not always present with classic symptoms of general paresis, tabes dorsalis, and ocular findings.

Proper treatment with intravenous penicillin G does not always resolve the psychiatric symptoms of neurosyphilis.

The patient described in this case report provided verbal consent to this publication.

The author confirms that details of the case have been disguised to protect patient privacy.

Dr. Nutile thanks Tushar Thakre, M.D., and Katie Adams, Pharm.D., who assisted by providing editing suggestions.

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Two key brain systems are central to psychosis, Stanford Medicine-led study finds

When the brain has trouble filtering incoming information and predicting what’s likely to happen, psychosis can result, Stanford Medicine-led research shows.

April 11, 2024 - By Erin Digitale

People with psychosis have trouble filtering relevant information (mesh funnel) and predicting rewarding events (broken crystal ball), creating a complex inner world. Emily Moskal

Inside the brains of people with psychosis, two key systems are malfunctioning: a “filter” that directs attention toward important external events and internal thoughts, and a “predictor” composed of pathways that anticipate rewards.

Dysfunction of these systems makes it difficult to know what’s real, manifesting as hallucinations and delusions. 

The findings come from a Stanford Medicine-led study , published April 11 in  Molecular Psychiatry , that used brain scan data from children, teens and young adults with psychosis. The results confirm an existing theory of how breaks with reality occur.

“This work provides a good model for understanding the development and progression of schizophrenia, which is a challenging problem,” said lead author  Kaustubh Supekar , PhD, clinical associate professor of psychiatry and behavioral sciences.

The findings, observed in individuals with a rare genetic disease called 22q11.2 deletion syndrome who experience psychosis as well as in those with psychosis of unknown origin, advance scientists’ understanding of the underlying brain mechanisms and theoretical frameworks related to psychosis.

During psychosis, patients experience hallucinations, such as hearing voices, and hold delusional beliefs, such as thinking that people who are not real exist. Psychosis can occur on its own and isa hallmark of certain serious mental illnesses, including bipolar disorder and schizophrenia. Schizophrenia is also characterized by social withdrawal, disorganized thinking and speech, and a reduction in energy and motivation.

It is challenging to study how schizophrenia begins in the brain. The condition usually emerges in teens or young adults, most of whom soon begin taking antipsychotic medications to ease their symptoms. When researchers analyze brain scans from people with established schizophrenia, they cannot distinguish the effects of the disease from the effects of the medications. They also do not know how schizophrenia changes the brain as the disease progresses. 

To get an early view of the disease process, the Stanford Medicine team studied young people aged 6 to 39 with 22q11.2 deletion syndrome, a genetic condition with a 30% risk for psychosis, schizophrenia or both. 

Kaustubh Supekar

Brain function in 22q11.2 patients who have psychosis is similar to that in people with psychosis of unknown origin, they found. And these brain patterns matched what the researchers had previously theorized was generating psychosis symptoms.

“The brain patterns we identified support our theoretical models of how cognitive control systems malfunction in psychosis,” said senior study author  Vinod Menon , PhD, the Rachael L. and Walter F. Nichols, MD, Professor; a professor of psychiatry and behavioral sciences; and director of the  Stanford Cognitive and Systems Neuroscience Laboratory .

Thoughts that are not linked to reality can capture the brain’s cognitive control networks, he said. “This process derails the normal functioning of cognitive control, allowing intrusive thoughts to dominate, culminating in symptoms we recognize as psychosis.”

Cerebral sorting  

Normally, the brain’s cognitive filtering system — aka the salience network — works behind the scenes to selectively direct our attention to important internal thoughts and external events. With its help, we can dismiss irrational thoughts and unimportant events and focus on what’s real and meaningful to us, such as paying attention to traffic so we avoid a collision.

The ventral striatum, a small brain region, and associated brain pathways driven by dopamine, play an important role in predicting what will be rewarding or important. 

For the study, the researchers assembled as much functional MRI brain-scan data as possible from young people with 22q11.2 deletion syndrome, totaling 101 individuals scanned at three different universities. (The study also included brain scans from several comparison groups without 22q11.2 deletion syndrome: 120 people with early idiopathic psychosis, 101 people with autism, 123 with attention deficit/hyperactivity disorder and 411 healthy controls.) 

The genetic condition, characterized by deletion of part of the 22nd chromosome, affects 1 in every 2,000 to 4,000 people. In addition to the 30% risk of schizophrenia or psychosis, people with the syndrome can also have autism or attention deficit hyperactivity disorder, which is why these conditions were included in the comparison groups.

The researchers used a type of machine learning algorithm called a spatiotemporal deep neural network to characterize patterns of brain function in all patients with 22q11.2 deletion syndrome compared with healthy subjects. With a cohort of patients whose brains were scanned at the University of California, Los Angeles, they developed an algorithmic model that distinguished brain scans from people with 22q11.2 deletion syndrome versus those without it. The model predicted the syndrome with greater than 94% accuracy. They validated the model in additional groups of people with or without the genetic syndrome who had received brain scans at UC Davis and Pontificia Universidad Católica de Chile, showing that in these independent groups, the model sorted brain scans with 84% to 90% accuracy.

The researchers then used the model to investigate which brain features play the biggest role in psychosis. Prior studies of psychosis had not given consistent results, likely because their sample sizes were too small. 

Vinod Menon

Comparing brain scans from 22q11.2 deletion syndrome patients who had and did not have psychosis, the researchers showed that the brain areas contributing most to psychosis are the anterior insula (a key part of the salience network or “filter”) and the ventral striatum (the “reward predictor”); this was true for different cohorts of patients.

In comparing the brain features of people with 22q11.2 deletion syndrome and psychosis against people with psychosis of unknown origin, the model found significant overlap, indicating that these brain features are characteristic of psychosis in general.

A second mathematical model, trained to distinguish all subjects with 22q11.2 deletion syndrome and psychosis from those who have the genetic syndrome but without psychosis, selected brain scans from people with idiopathic psychosis with 77.5% accuracy, again supporting the idea that the brain’s filtering and predicting centers are key to psychosis.

Furthermore, this model was specific to psychosis: It could not classify people with idiopathic autism or ADHD.

“It was quite exciting to trace our steps back to our initial question — ‘What are the dysfunctional brain systems in schizophrenia?’ — and to discover similar patterns in this context,” Menon said. “At the neural level, the characteristics differentiating individuals with psychosis in 22q11.2 deletion syndrome are mirroring the pathways we’ve pinpointed in schizophrenia. This parallel reinforces our understanding of psychosis as a condition with identifiable and consistent brain signatures.” However, these brain signatures were not seen in people with the genetic syndrome but no psychosis, holding clues to future directions for research, he added.

Applications for treatment or prevention

In addition to supporting the scientists’ theory about how psychosis occurs, the findings have implications for understanding the condition — and possibly preventing it.

“One of my goals is to prevent or delay development of schizophrenia,” Supekar said. The fact that the new findings are consistent with the team’s prior research on which brain centers contribute most to schizophrenia in adults suggests there may be a way to prevent it, he said. “In schizophrenia, by the time of diagnosis, a lot of damage has already occurred in the brain, and it can be very difficult to change the course of the disease.”

“What we saw is that, early on, functional interactions among brain regions within the same brain systems are abnormal,” he added. “The abnormalities do not start when you are in your 20s; they are evident even when you are 7 or 8.”

Our discoveries underscore the importance of approaching people with psychosis with compassion.

The researchers plan to use existing treatments, such as transcranial magnetic stimulation or focused ultrasound, targeted at these brain centers in young people at risk of psychosis, such as those with 22q11.2 deletion syndrome or with two parents who have schizophrenia, to see if they prevent or delay the onset of the condition or lessen symptoms once they appear. 

The results also suggest that using functional MRI to monitor brain activity at the key centers could help scientists investigate how existing antipsychotic medications are working. 

Although it’s still puzzling why someone becomes untethered from reality — given how risky it seems for one’s well-being — the “how” is now understandable, Supekar said. “From a mechanistic point of view, it makes sense,” he said.

“Our discoveries underscore the importance of approaching people with psychosis with compassion,” Menon said, adding that his team hopes their work not only advances scientific understanding but also inspires a cultural shift toward empathy and support for those experiencing psychosis. 

“I recently had the privilege of engaging with individuals from our department’s early psychosis treatment group,” he said. “Their message was a clear and powerful: ‘We share more similarities than differences. Like anyone, we experience our own highs and lows.’ Their words were a heartfelt appeal for greater empathy and understanding toward those living with this condition. It was a call to view psychosis through a lens of empathy and solidarity.”

Researchers contributed to the study from UCLA, Clinica Alemana Universidad del Desarrollo, Pontificia Universidad Católica de Chile, the University of Oxford and UC Davis.

The study was funded by the Stanford Maternal and Child Health Research Institute’s Uytengsu-Hamilton 22q11 Neuropsychiatry Research Program, FONDEYCT (the National Fund for Scientific and Technological Development of the government of Chile), ANID-Chile (the Chilean National Agency for Research and Development) and the U.S. National Institutes of Health (grants AG072114, MH121069, MH085953 and MH101779).

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Identification of plasma Long non-coding RNA biomarkers to differentiate acute / early infection vs long-term infection

2023 FDA Science Forum

Background:

Individuals with acute / early HIV-1 infection are often unaware that they are infected with HIV-1 and may be involved in high-risk behavior leading to transmission of HIV-1. Identifying individuals with acute / early HIV-1 infection is critical to prevent further HIV-1 transmission, as diagnosis can lead to several effective HIV-1 prevention strategies. With increasing use of PrEP, incident and acute cases may be negative for viral markers in plasma or serum. This will also apply to samples from latently infected individuals who are on long term ART. Identification of disease-stage specific non-viral host biomarkers would be useful as surrogate markers to accurately identify new HIV-1 infections in disease stages where viral markers are absent or undetectable by current HIV assays.

The goal of this study was to identify a panel of host derived plasma Long non-coding RNAs (lncRNAs) that could serve as prognostic and predictive biomarker to detect early/acute HIV-1 infection. Methods: PCR arrays were used to identify differentially expressed lncRNAs in plasma samples from HIV-1 infected patients. The early and long-term HIV-1 infected patients were divided into five groups (control, Eclipse stage of HIV-1+, Pre seroconverted HIV-1+, Post seroconverted HIV-1+, Long-term HIV-1+, HIV-1 patients on antiretroviral (ART) treatment.

Preliminary results indicated that eleven lncRNAs (7 up and 4 down regulated) were differentially expressed between eclipse vs control group, 37 lncRNAs (35 up and 2 down regulated) were differentially expressed between pre seroconverted HIV-1+ vs control group, 4 lncRNAs were up regulated between post seroconverted HIV-1+ vs control group, 37 lncRNAs (35 up and 2 down regulated) were differentially expressed between long-term HIV-1+ vs control group and 23 lncRNAs were up regulated between ART-treated HIV-1+ vs control group

Conclusion:

In conclusion, lncRNA expression changes significantly in response to HIV-1 infection and during ART treatment. Our findings also highlight the potential of circulating lncRNA in the detection of both acute/early stages of HIV-1 infection, which may help to shorten the window period and facilitate early detection and treatment initiation. Initiating ART treatment at this stage would significantly reduce HIV-1 transmission. These differentially expressed lncRNA could be used as prognostic and diagnostic biomarkers for HIV infection, as well as to identify new therapeutic targets.

Disclaimer:

“This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.”

Download the Poster (PDF; 0.99 MB)

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In this 2-part podcast series, NAMI Chief Medical Officer Dr. Ken Duckworth guides discussions on early psychosis that offer insights from individuals, family members and mental health professionals.  Read the transcript . Note:  Content includes discussions on topics such as suicide attempts and may be triggering.

Most people think of psychosis as a break with reality. In a way it is. Psychosis is characterized as disruptions to a person’s thoughts and perceptions that make it difficult for them to recognize what is real and what isn’t. These disruptions are often experienced as seeing, hearing and believing things that aren’t real or having strange, persistent thoughts, behaviors and emotions. While everyone’s experience is different, most people say psychosis is frightening and confusing.

Psychosis is a symptom, not an illness, and it is more common than you may think. In the U.S., approximately  100,000  young people experience psychosis each year. As many as  3 in 100  people will have an episode at some point in their lives.

Early or first-episode psychosis (FEP) refers to when a person first shows signs of beginning to lose contact with reality. Acting quickly to connect a person with the right treatment during early psychosis or FEP can be life-changing and radically alter that person’s future. Don’t wait to take the first step and prepare yourself with information by reviewing these tip sheets:

What is Early and First-Episode Psychosis? Early Psychosis: What’s Going on and What Can You Do? Encouraging People to Seek Help for Early Psychosis Early Intervention: Tips for School Staff and Coaches

Early Warning Signs Before Psychosis

Early psychosis or FEP rarely comes suddenly. Usually, a person has gradual, non-specific changes in thoughts and perceptions, but doesn’t understand what’s going on. Early warning signs can be difficult to distinguish from typical teen or young adult behavior. While such signs should not be cause for alarm, they may indicate the need to get an assessment from a doctor.

Encouraging people to seek help for early psychosis is important. Families are often the first to see early signs of psychosis and the first to address the issue of seeking treatment. However, a person’s willingness to accept help is often complicated by delusions, fears, stigma and feeling unsettled. In this case, families can find the situation extremely difficult, but there are engagement strategies to help encourage a person to seek help.

It’s important to get help quickly since early treatment provides the best hope of recovery by slowing, stopping and possibly reversing the effects of psychosis. Early warning signs include the following:

• A worrisome drop in grades or job performance
• Trouble thinking clearly or concentrating
• Suspiciousness or uneasiness with others
• A decline in self-care or personal hygiene
• Spending a lot more time alone than usual
• Strong, inappropriate emotions or having no feelings at all

Signs Of Early Or First-Episode Psychosis

Determining exactly when the first episode of psychosis begins can be hard, but these signs and symptoms strongly indicate an episode of psychosis:

• Hearing, seeing, tasting or believing things that others don’t
• Persistent, unusual thoughts or beliefs that can’t be set aside regardless of what others believe
• Strong and inappropriate emotions or no emotions at all
• Withdrawing from family or friends
• A sudden decline in self-care

Such warning signs often point to a person’s deteriorating health, and a physical and neurological evaluation can help find the problem. A mental health professional performing a psychological evaluation can determine if a mental health condition is involved and discuss next steps. If the psychosis is a symptom of a mental health condition, early action helps to keep lives on track.

Psychosis includes a range of symptoms but typically involves one of these two major experiences:

Hallucinations  are seeing, hearing or feeling things that aren’t there, such as the following:

• Hearing voices (auditory hallucinations)
• Strange sensations or unexplainable feelings
• Seeing glimpses of objects or people that are not there or distortions

Delusions  are strong beliefs that are not consistent with the person’s culture, are unlikely to be true and may seem irrational to others, such as the following:

• Believing external forces are controlling thoughts, feelings and behaviors
• Believing that trivial remarks, events or objects have personal meaning or significance
• Thinking you have special powers, are on a special mission or even that you are God.

We are still learning about how and why psychosis develops, but several factors are likely involved. We do know that teenagers and young adults are at increased risk of experiencing an episode of psychosis because of hormonal changes in their brain during puberty.

Several factors that can contribute to psychosis:

• Genetics.  Many genes can contribute to the development of psychosis, but just because a person has a gene doesn’t mean they will experience psychosis. Ongoing studies will help us better understand which genes play a role in psychosis.
• Trauma.  A traumatic event such as a death, war or sexual assault can trigger a psychotic episode. The type of trauma—and a person’s age—affects whether a traumatic event will result in psychosis.
• Substance use.  The use of marijuana, LSD, amphetamines and other substances can increase the risk of psychosis in people who are already vulnerable.
• Physical illness or injury.  Traumatic brain injuries, brain tumors, strokes, HIV and some brain diseases such as Parkinson’s, Alzheimer’s and dementia can sometimes cause psychosis.
• Mental health conditions.  Sometimes psychosis is a symptom of a condition like schizophrenia, schizoaffective disorder, bipolar disorder or depression.

A diagnosis identifies an illness; symptoms are components of an illness. Health care providers draw on information from medical and family history and a physical examination to diagnose someone. If causes such as a brain tumor, infection or epilepsy are ruled out, a mental illness might be the reason.

If the cause is related to a mental health condition, early diagnosis and treatment provide the best hope of recovery. Research shows that the earlier people experiencing psychosis receive treatment, the better their long-term quality of life.

Early Or First-Episode Psychosis

Early treatment of psychosis, especially during the first episode, leads to the best outcomes.

Research has shown significant success using a treatment approach called Coordinated Specialty Care (CSC). CSC uses a team of health professionals and specialists who work with a person to create a personal treatment plan based on life goals while involving family members as much as possible.

CSC has the following key components:

• Case management
• Family support and education
• Psychotherapy
• Medication management
• Supported education and employment
• Peer support

SAMHSA maintains an  Early Serious Mental Illness (ESMI) Treatment Locator  as a source of information for family members who are seeking CSC programs in the US. Portions of their website are available in Spanish.

Psychosis Treatment

Traditional treatment for psychosis involves  psychotherapy  and  medication . Several types of therapy have successfully helped individuals learn to manage their condition. In addition, medication targets symptoms and helps reduce their impact.

Related Conditions

Psychosis can be related to several mental health conditions:

• Bipolar Disorder
• Schizoaffective Disorder
• Schizophrenia
• Substance use disorders /  Dual Diagnosis

Know the warning signs of mental illness

Learn more about common mental health conditions

NAMI HelpLine is available M-F, 10 a.m. – 10 p.m. ET. Call 800-950-6264 , text “helpline” to 62640 , or chat online. In a crisis, call or text 988 (24/7).

New research defines specific genomic changes associated with the transmissibility of the monkeypox virus

Mount Sinai scientists, in collaboration with researchers from the Carlos III Health Institute (ISCIII) in Madrid, Spain, have located and identified alterations in the monkeypox virus genome that potentially correlate with changes in the virus's transmissibility observed in the 2022 outbreak. The findings were published April 18 in Nature Communications.

Monkeypox virus (MPXV) is a double-stranded DNA virus that can infect animals and humans. MPXV causes a disease known as mpox, with symptoms that include fever, swollen lymph nodes, and a rash. Most cases are mild and tend to get better on their own; however, mpox can be very painful and may lead to permanent scarring. First encountered in 1958 in crab-eating macaque monkeys imported to Belgium, MPXV has caused sporadic human disease outbreaks since the 1970s in Central and Western Africa. In May 2022, multiple countries, including the United States, reported an increasing number of MPXV infections and associated disease, including clusters in cases potentially linked to super-spreading events in Belgium, Spain, and the United Kingdom. While the number of new cases associated with the 2022 spillover has decreased over time, cases of the disease are still occurring among unvaccinated individuals, including a current increase in Central Africa due to a new spillover. As the virus's circulation in humans increases, the risk of emergence of a more transmissible variant capable of becoming endemic in the human population increases.

"Biopreparedness and virological surveillance involves studying the causes that favor zoonotic spillover and facilitates human-to-human transmission. When we observe significant changes in basic epidemiological features of a viral agent like monkeypox, it should reinvigorate our interest in understanding those transmission conditions. The increasing number of cases currently happening in Africa, and the 2022 epidemic, should be clear alert signals," says Gustavo Palacios, PhD, Professor of Microbiology at the Icahn School of Medicine at Mount Sinai and a senior author of the study.

To carry out the study, researchers analyzed samples from 46 patients infected with MPXV whose diagnosis and sequencing were carried out at the ISCIII at the beginning of the 2022 mpox outbreak. The team performed high-quality sequencing of each study participant's complete monkeypox virus genome to determine possible correlations between genomic variations in the different groups of sequences and epidemiological links associated with the virus's ability to evolve, transmit, and infect.

According to the research team, recurrent observed genomic changes were located in areas of the genome that could be related to viral adaptation. Those specific locations would contribute to modulating the viral replication cycle, adaptability, and path of entry and egress. These alterations appear in areas known as low complexity genomic regions, which are particularly difficult to sequence and analyze, explaining why they were overlooked before. This highly sophisticated complete genome sequencing was made possible through the use of two advanced sequencing technologies: single-molecule long-read sequencing (to cover highly repetitive regions) and deep short sequencing reads (to provide accuracy and depth).

By detailing the genomic alterations within these repetitive genomic sequences and linking them to critical viral functions, researchers provide a plausible explanation for the heightened transmissibility observed during the 2022 mpox outbreak.

"These findings might be offering the first hints to help us understand the unique features of the strains associated with sustained human-to-human transmission, which has not ever been observed in these agents," says Dr. Palacios. "Better understanding of the doors that facilitate transmission of viral agents and impact their clinical presentations will enable us to develop more effective prevention and treatment strategies."

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Story Source:

Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine . Note: Content may be edited for style and length.

Journal Reference :

• Sara Monzón, Sarai Varona, Anabel Negredo, Santiago Vidal-Freire, Juan Angel Patiño-Galindo, Natalia Ferressini-Gerpe, Angel Zaballos, Eva Orviz, Oskar Ayerdi, Ana Muñoz-Gómez, Alberto Delgado-Iribarren, Vicente Estrada, Cristina García, Francisca Molero, Patricia Sánchez-Mora, Montserrat Torres, Ana Vázquez, Juan-Carlos Galán, Ignacio Torres, Manuel Causse del Río, Laura Merino-Diaz, Marcos López, Alicia Galar, Laura Cardeñoso, Almudena Gutiérrez, Cristina Loras, Isabel Escribano, Marta E. Alvarez-Argüelles, Leticia del Río, María Simón, María Angeles Meléndez, Juan Camacho, Laura Herrero, Pilar Jiménez, María Luisa Navarro-Rico, Isabel Jado, Elaina Giannetti, Jens H. Kuhn, Mariano Sanchez-Lockhart, Nicholas Di Paola, Jeffrey R. Kugelman, Susana Guerra, Adolfo García-Sastre, Isabel Cuesta, Maripaz P. Sánchez-Seco, Gustavo Palacios. Monkeypox virus genomic accordion strategies . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-46949-7

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Neuropsychiatric manifestations of HIV infection and AIDS

As the life expectancy of people living with HIV infection has increased (through recent advances in antiretroviral therapy), clinicians have been more likely to encounter neuropsychiatric manifestations of the disease. Some patients present with cognitive deficits due to an HIV-triggered neurotoxic cascade in the central nervous system. However, more patients present with a depressive spectrum disorder during the course of their illness, the underlying pathogenesis of which is not as well understood. This category of psychiatric disorders presents diagnostic challenges because of the many neurovegetative confounding factors that are present in association with HIV illness. As quality of life becomes a more central consideration in the management of this chronic illness, better awareness of these neuropsychiatric manifestations is paramount. This article reviews these clinical issues and the available psychopharmacologic treatment options.

Comme l'espérance de vie des personnes vivant avec le VIH a augmenté (grâce aux progrès récents de la thérapie aux antirétroviraux), les cliniciens sont maintenant plus susceptibles de faire face à des manifestations neuropsychiatriques de la maladie. Certains patients se présentent avec des déficits de la cognition attribuables à une cascade neurotoxique déclenchée par le VIH dans le système nerveux central. Plus de patients se présentent toutefois avec un trouble du spectre dépressif pendant leur maladie, dont on ne comprend pas aussi bien la pathogénèse sous-jacente. Cette catégorie de troubles psychiatriques pose des défis diagnostiques en raison des nombreux facteurs confusionnels neurovégétatifs associés à l'infection par le VIH. Comme la qualité de vie devient un facteur plus central dans la prise en charge de cette maladie chronique, il est primordial d'être plus conscient de ses manifestations neuropsychiatriques. Dans cet article, les auteurs passent en revue ces enjeux cliniques et les traitements psychopharmacologiques possibles.

Introduction

The Joint United Nations Programme on HIV/AIDS has estimated that, as of 2004, more than 40 million people worldwide were living with HIV virus type 1. 1 In North America, between 540 000 and 1.6 million adults and children are thought to be infected, and these are predominantly injection drug users and men who have sex with men. Far from over, this pandemic has also seen the number of women infected with HIV increase rapidly across the globe, and women now account for half of all people living with HIV worldwide. However, recent advances in the treatment of this retrovirus have increased the life expectancy of seropositive people, which makes it more likely that clinicians will encounter patients with neuropsychiatric manifestations of the disease.

The most common neurologic manifestations are minor cognitive and motor disorder (MCMD) and HIV-associated dementia (HAD). The most common psychiatric manifestations are depressive spectrum disorders. In both cases, the impact of these syndromes on seropositive patients is significant and appropriate intervention is required, the key to optimal treatment resting with early diagnosis and aggressive treatment. In this paper, we describe the major neuropsychiatric manifestations of HIV spectrum disease and also discuss the diagnosis and treatment of these types of conditions.

Neurologic manifestations of HIV infection

The first cases of HIV-related infections were reported in 1981, and the virus was identified 2 years later. 2 Neurologic complications were recognized very early in the epidemic. 3 It is now known that HIV can be isolated from the cerebrospinal fluid (CSF) and can also be found in brain tissue, which suggests that the virus can cross the blood–brain barrier. Sacktor et al 4 reported that when monotherapy was a mainstay of treatment (between 1990 and 1992), the mean incidence of HAD was 21.1 cases per 1000 person-years, whereas when highly active antiretroviral therapy (HAART) became the norm (between 1996 and 1998), the mean incidence of HAD decreased significantly, to 10.5 cases per 1000 person-years. 4 These authors also noted a concurrent decrease in the incidence of opportunistic central nervous system (CNS) infections for the same observation periods.

Another team of researchers found a decrease in prevalence rates of opportunistic CNS infections over the same period; however, using autopsy data, they found an increase in the prevalence of HIV encephalopathy in the post-HAART years. 5 This would suggest that despite improved therapeutic options and an apparent decrease in neurologic complications, HIV seems to continue to infiltrate the CNS.

The presence and action of HIV in the CNS are now much better understood. HIV crosses the blood–brain barrier by a Trojan-horse–type mechanism using macrophages it infects. 6 Once in the brain, HIV targets and infects glial cells, from which it later secretes neurotoxins that lead to neuronal damage and death. 7 The extent of this neuronal damage is thought to be linked to the level of clinical neurologic deficits. Postmortem neuropathologic examinations of HIV-positive patients have revealed the presence of virus in cortical and subcortical structures, namely the frontal lobes, the subcortical white matter and the basal ganglia. 8 , 9 Some authors have suggested that the caudate nucleus and the basal ganglia are the primary areas of pathogenesis. 10 , 11

The underlying mechanisms leading to neurocognitive impairment are now also better understood. 6 Recent evidence supports a mechanism by which neurotoxins released by periventricular macrophages and microglia trigger cytokine and chemokine release, 12 which in turn leads to modification of synaptic architecture in the cortex. 13 , 14 , 15 It is thought that apoptosis, or programmed cell death, is the most common mechanism resulting in cell loss. 16 , 17

People with severe neurocognitive deficits or HAD usually have higher plasma HIV viral load; however, an elevated viral load does not always lead to HAD, and HAD has been documented in the absence of elevated viral load. 7 , 18 , 19 Hence, correlates have been identified in the CSF. Generally, HIV viral loads in the CSF are similar to those in the serum. 20 However, elevation of levels of certain substances in the CSF has been positively correlated with the presence of severe neurocognitive deficits. These substances include β 2 -microglobulin, 21 neopterin, 22 quinolinic acid 23 and Fas receptors and Fas ligands. 24 The latter finding is interesting since Fas is associated with the execution of apoptotic programs. Nevertheless, these findings currently have no diagnostic value.

Although HIV may remain dormant in the CNS for many years, its mere presence might lead to subtle deficits in cognitive functioning. However, these deficits are not found in all patients, which has led some authors to suggest that peripheral triggers might be involved. 25 , 26 Much more research is needed before it can be determined which individuals or subgroups of individuals are more vulnerable to neurologic complications.

Neurocognitive deficits are manifestations of both direct and indirect effects of HIV on the CNS. 27 While it is generally agreed that people with advanced disease present with deficits in many cognitive domains, 28 , 29 , 30 , 31 there is conflicting evidence regarding whether similar deficits occur in asymptomatic individuals. For example, some investigators have found neuropsychologic deficits in asymptomatic patients, 32 , 33 , 34 , 35 , 36 whereas others have found similar levels of neurocognitive impairment in seropositive and match-controlled seronegative individuals. 37 , 38 In a review of 57 studies examining neurologic functioning, the median rate of neuropsychologic impairment based on test performance was 35% for seropositive and 12% for seronegative patients. 39 However, in another review of 36 cross-sectional studies and 9 longitudinal studies, more than half of the studies showed no significant differences in the results of neuropsychologic testing between symptomatic and asymptomatic participants as well as no baseline impairment in seropositive patients. 40 Although methodologic differences might help to explain the discordant findings, research suggests that when deficits are present in asymptomatic patients, they are subtle and limited to fewer cognitive domains. 28 , 40 When depressive symptoms are also present, psychomotor slowing accompanies verbal memory deficits, whereas when depressive symptoms are absent, only verbal and nonverbal cognitive deficits are evident. 41

As HIV disease progresses, additional cognitive domains often become impaired. Attention and concentration, as measured by dual task or divided attention paradigms, are decreased. 42 , 43 The presence of HIV in the fronto-subcortical circuitry and its deleterious impact on working memory means that executive function is also affected. 44 Learning and memory, as measured by information retrieval, are also impaired. 31

The most prominent and common neurocognitive deficit is psychomotor retardation. 7 Cognitive slowing can be seen with or without normal motor function. 29 Thus, HIV-seropositive patients should be assessed for these types of neurocognitive impairments in the presence of subjective or behavioural indications.

Diagnosis and treatment of neurologic manifestations of HIV infection

The American Academy of Neurology has put forth diagnostic criteria for HIV-associated MCMD ( Box 1 ) and HAD ( Box 2 ). 45 Whereas HAD is thought to represent neuronal death, MCMD is thought to be a lesser form of dementia on a continuum of cognitive deficits, representing neuronal dysfunction. The previous expression for this condition, AIDS dementia complex, has been dropped because seropositive patients not presenting with AIDS-defining criteria have presented with dementia. 46

Both MCMD and HAD are diagnoses of exclusion, and CNS pathology must be ruled out. For example, CNS infectious pathogens or tumours as well as metabolic causes of encephalopathy must be investigated before the cognitive and motor deficits can be attributed to HIV infection. Among the more frequent CNS infections are toxoplasmosis and progressive multifocal leukoencephalopathy, which is caused by the papovavirus, whereas non-Hodgkins CNS lymphoma is the most common cancer associated with neurocognitive changes. 47

Once opportunistic infections have been ruled out or treated if necessary, there are potentially 2 therapeutic options for neurocognitive deficits: diminish the effects of the virus on the CNS through better control of viral load or develop neuroprotective agents to shield the CNS from HIV-induced virotoxins. Unfortunately, antiretrovirals are not always successful in crossing the blood–brain barrier, but, as evidenced by the decrease in the incidence of HAD with the advent of HAART, they offer good results. 48 There are, in theory, neuroprotective agents against the virotoxins of HIV ( Table 1 ), 49 , 50 including pentoxyfilline, 51 , 52 nimodipine, 53 peptide T, memantine, 53 selegiline 54 and lexipafant. 55 However, supporting evidence is available only for selegiline as a potential therapeutic agent.

Traditional approaches to treating dementia in the course of HIV infection have also shown some success. Psychostimulants have been useful in treating both apathy and cognitive slowing in HAD. 56 , 57 , 58 Dopamine agonists have shown some success as well, 59 but there have been no controlled trials of cholinesterase inhibitors in treating dementia in HIV illness. Similarly, despite anecdotal evidence suggesting some success with agents such as donepezil, placebo-controlled trials have not yet been conducted.

Agitation and psychosis associated with dementia in HIV-infected patients are often treated with mood stabilizers and antipsychotics. In addition, the presence of cognitive slowing may be related to concurrent depressive symptoms. As such, an underlying depressive illness should be ruled out. These concerns are reviewed in the next section, which examines the impact of depression and other psychiatric illnesses on HIV disease and outlines the treatment of these psychiatric disorders.

Psychiatric manifestations of HIV infection

Recognizing the psychiatric manifestations of HIV disease can be complicated by the complex biologic, psychologic and social circumstances associated with this illness, and psychiatric symptoms often go unrecognized and untreated. 60 The significance of these findings is magnified by emerging evidence that certain symptoms, such as depression, may be associated with an increase in mortality rate among HIV-seropositive women 61 and with disease progression in HIV-seropositive men. 62 Here, we examine the main psychiatric conditions observed among HIV-seropositive patients, including mood disorders and psychosis.

Depression is one of the most common psychiatric disorders observed in people infected with HIV. Prevalence rates have shown wide variation, with estimates of between 4% and 22% for HIV-seropositive men and between 2% and 18% for HIV-seropositive women. 63 , 64 , 65 Earlier controlled studies found that the prevalence of major depression and other mood disorders was higher among asymptomatic HIV-seropositive men than in the general population 66 , 67 but was similar to that of HIV-seronegative gay men. 63 , 68

Most prevalence studies have focused on HIV-seropositive men, even though it is estimated that women constitute 50% of new cases of HIV infection worldwide 1 and that women account for more than 16% of all cases of HIV infection in the United States; 69 moreover, women report higher rates of depression than men in the general population. 70 Current estimates of depression among HIV-seropositive women range from 1.9% to 35% in clinical samples 71 , 72 and from 30% to 60% in community samples. 61 , 73

In addition, more recent studies with large sample sizes and controlled study designs have reported that HIV-positive women are at significantly greater risk for major depressive disorder than demographically matched HIV-negative women. Ickovics et al 61 reported chronic depressive symptoms in 42% and intermittent depressive symptoms in 35% of a sample of 765 HIV-positive women. In a clinical study of 93 HIV-seropositive women and 62 HIV-seronegative women, Morrison et al 74 found that the prevalence of major depressive disorders was significantly higher among HIV-positive women than among HIV-negative controls (19.4% v. 4.8%).

Whereas depression is increasingly recognized as a cause of increased morbidity and mortality in many chronic medical illnesses, it remains undiagnosed and untreated in the HIV-infected population. 60 , 75 In the context of HIV infection, the diagnosis of depressive disorders can be even more challenging because many vegetative symptoms of depression (e.g., fatigue, pain, anorexia and insomnia) are observed in many patients throughout the course of their HIV illness, even when depression is not present. However, in both the early and late phases of HIV disease, these symptoms correlate more closely with a mood disorder (when present) than with clinical correlates of infection. 76 The prominence of diminished mood in the morning coupled with anhedonia should alert clinicians to the presence of a major depressive disorder and should help distinguish it from demoralization or an adjustment disorder. 77 Clinical detection of depressive symptoms is even more important given a well-documented decrease in adherence to HAART in the context of depression. 78 , 79 , 80 Fortunately, recent studies have shown that the treatment of depressive symptoms in patients with HIV infection improves psychosocial functioning and quality of life. 81

Higher rates of mania have also been noted with progression of HIV infection. In early HIV infection, 1%–2% of patients experience manic episodes, 76 which is only slightly higher than the rate in the general population. However, after the onset of AIDS, 4%–8% of patients appear to experience mania. 82 , 83 This increased frequency of mania around the time of onset of AIDS has been closely associated with cognitive changes or dementia and is thought to be a secondary manic syndrome due to HIV infection of the CNS. In a 17-month chart review, among the 8% of patients with manic episodes, counts of helper/inducer lymphocyte (CD3+/CD4+) cells were significantly higher in those with a history of mood disorder, suggesting that mania may be a direct effect of HIV on the CNS. 82 In a case–control study of 19 patients with HIV-associated mania and 57 HIV-seropositive controls, AIDS dementia was significantly more common in patients with mania, which suggests a strong association between HIV neuropathology and manic symptoms. 83 Sometimes referred to as “AIDS mania,” this condition is phenomenologically different from the typical manic syndrome of bipolar disorder in both its symptom profile and severity, 76 and it is often characterized by irritability rather than euphoria.

Psychosis is a recognized but — relative to the mood disorders — uncommon psychiatric manifestation of AIDS. 84 , 85 Even less commonly, antiretroviral therapy may precipitate psychosis. For example, there have been anecdotal reports of psychosis associated with ganciclovir 86 , 87 and efavirenz. 88 Psychosis was found more frequently in patients with AIDS-related neurocognitive impairments. 69 Using chart reviews, Navia and Price 89 found that 15% of 46 patients with HAD experienced psychotic symptoms. These findings were supported by data from the San Diego HIV Neurobehavioural Research Center suggesting that HIV-infected patients with psychosis exhibited greater neurocognitive impairments than HIV-positive controls without psychosis. 84

Treatment of psychiatric manifestations of HIV infection

Although a growing body of evidence supports the importance of treatment of mood disorders in HIV disease, controlled studies of somatic therapies are often lacking in this population, with polypharmacy and drug–drug interactions often presenting as complicating factors.

Tricyclic antidepressants

Numerous studies have reported the efficacy of tricyclic antidepressants (TCAs) for the treatment of HIV-seropositive patients with depressive disorders. 90 , 91 Rabkin et al, 92 in a double-blind, randomized, placebo-controlled trial of 97 HIV-seropositive patients, demonstrated the effectiveness of imipramine in the treatment of depression. At 6 weeks of treatment, 74% of the imipramine group and 26% of the placebo group showed improvement of depressive symptoms without changes in CD3+/CD4+ cell counts. It is important to note, however, that more than one-third of the subjects in that study discontinued treatment because of anticholinergic side effects. Elliott et al, 93 using a similar design, compared imipramine, paroxetine and placebo in 75 HIV-positive subjects. The 2 antidepressants were equally efficacious at 6, 8 and 12 weeks and were significantly more efficacious than placebo. Again, attrition due to side effects was 48% with imipramine, 20% with paroxetine and 24% with placebo.

Selective serotonin reuptake inhibitors

As suggested by the Elliott et al study described above, 93 selective serotonin reuptake inhibitors (SSRIs) are as effective as TCAs in the treatment of depression in HIV-seropositive patients, and they have a more favourable side effect profile. Rabkin et al, in an extension of their TCA study, 92 enrolled HIV-seropositive subjects with depression in whom treatment with imipramine had failed (because of lack of efficacy or intolerability of side effects) in a 12-week open- label trial of fluoxetine. 94 Although the baseline depression severity scores on the Hamilton Rating Scale for Depression (HAM-D) (mean 12.5) were lower than scores for the imipramine trial (mean 15.8), 83% of subjects treated with fluoxetine at 15–60 mg/day exhibited significant reductions in HAM-D scores. Although it did not alter CD3+/CD4+ cell counts, fluoxetine was well tolerated by subjects. In another study, Rabkin et al 95 used a randomized, placebo-controlled design to compare the efficacy of fluoxetine and placebo for treatment of depression in HIV-seropositive patients. Seventy-four percent of the subjects responded to fluoxetine, whereas 47% responded to placebo, but an intention-to-treat analysis showed that the differences between groups were less remarkable.

Ferrando et al 96 compared paroxetine, fluoxetine and sertraline in a 6-week open trial in 33 symptomatic HIV-seropositive subjects. Eighty-three percent of the subjects reported improvements in depression and somatic symptoms related to HIV disease. Only 73% of subjects completed the study because of complaints of agitation, anxiety and insomnia at weeks 1 and 3. Because of the limited sample size, no differences in efficacy could be ascertained. In another 6-week trial of paroxetine in 10 HIV-positive patients with major depression, significant improvements in HAM-D scores were noted between weeks 2 and 6. 97 Overall, these studies seem to show that SSRIs are effective in reducing depressive symptoms in HIV-seropositive patients and may be better tolerated than traditional TCAs.

Newer antidepressant agents

Recent studies suggest that several of the newer antidepressant agents may be useful for the treatment of depression in HIV-seropositive patients. In an open trial of nefazodone in 15 outpatients, the response rate was 73% and there were few adverse effects. 98 However, reports of nefazodone-induced liver toxicity 99 may be relevant, given that many patients with HIV infection also have hepatitis B and C infection. Mirtazapine has also shown some benefit for patients with HIV infection, promoting weight gain and decreasing nausea; however, its sedating side effects can be problematic. In a recent 6-week open-label, flexible-dose trial of sustained-release buproprion in 20 HIV-seropositive depressed men and women, 12 patients attained remission at a mean dose of 265 mg/day. Fourteen of the patients reported some adverse events, and 5 patients discontinued the study because of side effects (panic attacks, agitation and irritability). 100

Reboxetine, a selective norepinephrine reuptake inhibitor that is currently marketed in Europe, was studied in an open trial of 20 HIV-seropositive men with depression. 101 At 12 weeks, the 15 patients completing the trial showed at least a 50% reduction in symptoms at a dose of 8 mg/day. The 5 patients who discontinued the study did so because of side effects of insomnia, shivering and sweating. Overall, these open trials of newer antidepressants suggest efficacy similar to that observed in the controlled trials of TCAs and SSRIs, but controlled trials of the newer agents have lacked HIV-seropositive subjects.

Psychostimulants and novel agents

Methylphenidate and dextroamphetamine have been used in the treatment of depression in chronic medical illness, and both have been studied in placebo-controlled trials in patients infected with HIV. Fernandez et al 58 compared treatment response of desipramine and methylphenidate in 15 subjects, with both drugs leading to improvements of 50%. However, the desipramine-treated patients exhibited more side effects including dry mouth, anxiety and insomnia, consistent with previous studies of imipramine. 92 , 93

Wagner et al, 102 in an open trial of dextroamphetamine treatment of 24 patients with AIDS and depression who exhibited debilitatingly low energy levels, found a response rate of 75%. Improvements in mood and energy coincided with significant reductions in HAM-D scores, which were noted as early as week 2. Although systematic follow-up evaluations were not available, the treatment effects were maintained over 2 years. A placebo-controlled trial of dextroamphetamine showed a significant improvement in initiative and mood in 73% of depressed patients assigned to the drug and 25% of those receiving placebo. 103 These observations warrant further study.

HIV-associated reductions in testosterone levels have been correlated with changes in mood, appetite and sexual function. 104 Studies examining the effects of testosterone supplementation on depression 104 , 105 and the adrenal steroid dehydroepiandrosterone 106 have shown promise for improving mood as well as anabolic and androgenic parameters. Exercise may also augment improvement in psychologic and nutritional status in HIV-seropositive patients receiving testosterone therapy. 107

Mood stabilizers

Recent studies examining the efficacy of mood stabilizers for the treatment of manic symptoms in HIV-infected patients indicate that AIDS-associated manic states are responsive to available anti-manic agents, but patients are more prone to neurocognitive side effects. 108 , 109 The results of these mainly open trials should be interpreted with caution as they are limited by small sample sizes and other methodologic difficulties.

When mood stabilizers are used to treat HIV-infected patients, knowledge of the metabolic pathways of psychotropic agents and the influence of particular agents on overall drug metabolism is important. For example, carbamazepine may interact with antiretrovirals. As a potent inducer of CYP3A enzymes, carbamazepine may increase the metabolism of protease inhibitors such as indinavir 110 and non-nucleoside reverse transcriptase inhibitors such as delavirdine. 111 Conversely, because ritonavir is a potent enzymatic inhibitor of the CYP3A system that may raise serum levels of carbamazepine, carbamazepine toxicity is possible when these 2 drugs are used together. 112 In addition, medical conditions or treatments occurring during the course of HIV illness, such as hypoalbuminemia or administration of antibiotics, could elevate the free drug concentration of valproic acid.

In a case series of HIV-seropositive gay men, lithium was not well tolerated, and signs and symptoms of toxicity developed in 8 out of 10 patients, 7 of whom needed to stop treatment. 108 Dehydration and fluid shifts associated with diarrhea have also been reported. 90

Antipsychotic agents

The use of antipsychotic agents in the treatment of mood disorders and psychotic disorders in HIV-infected patients is less well studied. Reports indicate that HIV-seropositive patients may be more sensitive to the extrapyramidal side effects associated with dopamine receptor antagonists. This may be related to the psychomotor slowing associated with HIV infection. 84 In a case series of 21 patients with psychotic symptoms (12 of whom had mania with psychotic features), risperidone was efficacious and produced fewer side effects than conventional neuroleptics, although some studies have reported increased sensitivity to both older and newer antipsychotic agents. 113 An open-label study using clozapine reported improvements in psychotic symptoms in HIV-infected patients without extrapyramidal symptoms. 114 Clearly, controlled trials are needed in this area.

Psychopharmacology summary

The studies reviewed above point to the need for more controlled trials of psychopharmacologic agents for psychiatric disorders in people living with HIV, but they also provide support for the efficacy of these agents in the treatment of mood disorders. A recent study by Vitiello et al, 115 however, points out that even when psychiatric disorders are recognized, they may remain untreated. In a study of the prevalence and patterns of use of psychotropic medications, for which these authors used a probability sample of 1561 HIV-seropositive patients with a diagnosis of major depression or dysthymia, only 43% of subjects reported ever receiving antidepressant medication. They also noted that African-American HIV-seropositive patients with depression were less likely to receive antidepressant medications than any other ethnic group. This is especially concerning given that this group is overrepresented in the HIV-infected population.

In the treatment of HIV-infected patients, strategies similar to those that apply for treatment of psychiatric disorders in the general population should be followed. Knowledge of the metabolic pathways of psychotropic agents as well as the major antiretrovirals are useful because of potential adverse drug–drug interactions. Reassuringly, there are no absolute contraindications specific to this patient population other than an increased sensitivity to side effects, which has been widely reported. 90 , 116

The use of nontraditional agents (such as herbal agents) to treat psychiatric symptoms must also be monitored in HIV-seropositive patients. An open-label study revealed that the serum concentration of the protease inhibitor indinavir, metabolized by the 3A4 isoenzyme system, was markedly reduced by the administration of St. John's wort, a 3A4 inducer. 117 This reduction in indinavir levels was significant enough to potentially cause drug resistance and treatment failure. Similar caution should be exercised with concomitant use of alcohol or recreational drugs such as Ecstasy: alcohol can increase the risk for pancreatitis, 118 and Ecstasy has proven nearly fatal in combination with ritonavir. 119

Psychoneuroimmunology of HIV infection

Despite the development of effective combination antiretroviral therapies for HIV that have lengthened the life expectancy of HIV-infected patients, there continues to be wide variability in the course of HIV disease, specifically in the length of time before diagnosis of AIDS or death. These findings have prompted investigators to look at other factors that might influence the disease, such as stress, depression and other psychosocial factors.

Evidence has been mounting that chronic stress and dysfunctional coping may affect the immune system, exerting potentially harmful effects on cellular immunity, 120 , 121 , 122 , 123 but studies assessing the effects of depression on immunity in HIV-positive patients have yielded conflicting results. 124 , 125 , 126 One research group has shown significant effects of stress on cellular immune parameters, 127 and depressive symptoms (especially in the presence of severe stress) were related to declines in several lymphocyte subsets (NK cells and CD16, CD56 and CD8 cytotoxic suppressor cells) over a 2-year period in HIV-seropositive men. 128

Additional evidence is emerging from longitudinal studies to suggest that depression is associated with disease progression or death in HIV-infected subjects. Among 7 prospective studies with long-term follow-up, 6 studies found that depression was associated with HIV disease progression 62 , 129 , 130 and death. 61 , 131 , 132 However, no relation was found between baseline depression and progression to AIDS or decline in CD4 lymphocytes in the Multicenter AIDS Cohort Study. 133 Other major longitudinal studies with shorter follow-up periods have shown no relation of stress and depression to changes in CD4 cell counts. 124 , 125

While most studies have focused on men, recent data support the negative impact of depressive symptoms on immunity in women. Ickovics et al 61 have shown that depression among women infected with HIV is associated with HIV disease progression and mortality. Furthermore, depressive symptoms have been shown by another group to be significantly associated with higher counts of activated T cells (CD8+, CD38+, DR+) and higher viral loads, all of which are associated with advancing HIV disease. 134 Major depression was also associated with reductions in NK cell activity. 134

Conclusions

People infected with HIV have a better life expectancy today than in the early days of the epidemic, mostly because of recent advances in antiretroviral therapy. Although the relations among neuropsychiatric symptoms, neuroendocrine peptides and the immune system remain unclear, the emergence of neuropsychiatric complications during HIV infection or AIDS can have serious effects if they are not identified promptly. Whether these complications are due to the direct or indirect effects of HIV on the brain or to the effects of stress and depression, careful diagnosis and treatment are necessary. Continued investigation to elucidate potential causal mechanisms holds the promise of refinement of existing therapies and development of new treatment options.

Contributors: All authors contributed substantially to drafting and revising the article, and each gave final approval for the article to be published.

Competing interests: None declared for Drs. Dubé, Benton and Cruess. Dr. Evans has received grants and/or research support from Cephalon, GlaxoSmithKline and the National Institute of Mental Health. He is on the speakers' bureau for AstraZeneca, Eli Lilly, GlaxoSmithKline and Wyeth and has acted as a consultant with Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, Janssen Pharmaceutica, Novartis, Pfizer, GlaxoSmithKline, Somerset and Wyeth.

Correspondence to: Dr. Benoit Dubé, Assistant Professor of Clinical Psychiatry and Assistant Director, Office of Education, Department of Psychiatry, University of Pennsylvania, 3535 Market St., 2nd Floor, Philadelphia PA 19104; fax 215 746-7203; ude.nnepu.dem.liam@ebudeb

Submitted Mar. 22, 2004; Revised Dec. 31, 2004; Accepted Feb. 1, 2005

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Chinese Company Under Congressional Scrutiny Makes Key U.S. Drugs

Lawmakers raising national security concerns and seeking to disconnect a major Chinese firm from U.S. pharmaceutical interests have rattled the biotech industry. The firm is deeply involved in development and manufacturing of crucial therapies for cancer, cystic fibrosis, H.I.V. and other illnesses.

A WuXi Biologics facility in Wuxi, China. WuXi AppTec and an affiliated company, WuXi Biologics, have received millions of dollars in tax incentives to build sprawling research and manufacturing sites in Massachusetts and Delaware. Credit... Imaginechina Limited, via Alamy

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By Christina Jewett

• April 15, 2024

A Chinese company targeted by members of Congress over potential ties to the Chinese government makes blockbuster drugs for the American market that have been hailed as advances in the treatment of cancers, obesity and debilitating illnesses like cystic fibrosis.

WuXi AppTec is one of several companies that lawmakers have identified as potential threats to the security of individual Americans’ genetic information and U.S. intellectual property. A Senate committee approved a bill in March that aides say is intended to push U.S. companies away from doing business with them.

But lawmakers discussing the bill in the Senate and the House have said almost nothing in hearings about the vast scope of work that WuXi does for the U.S. biotech and pharmaceutical industries — and patients. A New York Times review of hundreds of pages of records worldwide shows that WuXi is heavily embedded in the U.S. medicine chest, making some or all of the main ingredients for multibillion-dollar therapies that are highly sought to treat cancers like some types of leukemia and lymphoma as well as obesity and H.I.V.

The Congressional spotlight on the company has rattled the pharmaceutical industry, which is already struggling with widespread drug shortages now at a 20-year high . Some biotech executives have pushed back, trying to impress on Congress that a sudden decoupling could take some drugs out of the pipeline for years.

WuXi AppTec and an affiliated company, WuXi Biologics grew rapidly, offering services to major U.S. drugmakers that were seeking to shed costs and had shifted most manufacturing overseas in the last several decades.

WuXi companies developed a reputation for low-cost and reliable work by thousands of chemists who could create new molecules and operate complex equipment to make them in bulk. By one estimate, WuXi has been involved in developing one-fourth of the drugs used in the United States. WuXi AppTec reported earning about $3.6 billion in revenue for its U.S. work.

“They have become a one-stop shop to a biotech,” said Kevin Lustig, founder of Scientist.com, a clearinghouse that matches drug companies seeking research help with contractors like WuXi.

WuXi AppTec and WuXi Biologics have also received millions of dollars in tax incentives to build sprawling research and manufacturing sites in Massachusetts and Delaware that local government officials have welcomed as job and revenue generators. One WuXi site in Philadelphia was working alongside a U.S. biotech firm to give patients a cutting-edge therapy that would turbocharge their immune cells to treat advanced skin cancers.

The tension has grown since February, when four lawmakers asked the Commerce, Defense and Treasury Departments to investigate WuXi AppTec and affiliated companies, calling WuXi a “giant that threatens U.S. intellectual property and national security.”

A House bill called the Biosecure Act linked the company to the People’s Liberation Army, the military arm of the Chinese Communist Party. The bill claims WuXi AppTec sponsored military-civil events and received military-civil fusion funding.

Richard Connell, the chief operating officer of WuXi AppTec in the United States and Europe, said the company participates in community events, which do not “imply any association with or endorsement of a government institution, political party or policy such as military-civil fusion.” He also said shareholders do not have control over the company or access to nonpublic information.

Last month, after a classified briefing with intelligence staff, the Senate homeland security committee advanced a bill by a vote of 11 to 1: It would bar companies from receiving government contracts for work with Wuxi, but would allow the companies to still obtain contracts for unrelated projects. Government contracts with drugmakers are generally limited, though they were worth billions of dollars in revenue to companies that responded to the Covid-19 pandemic.

Mr. Connell defended the company’s record, saying the proposed legislation “relies on misleading allegations and inaccurate assertions against our company.”

WuXi operates in a highly regulated environment by “multiple U.S. federal agencies — none of which has placed our company on any sanctions list or designated it as posing a national security risk,” Mr. Connell said. WuXi Biologics did not respond to requests for comment.

Smaller biotech companies, which tend to rely on government grants and have fewer reserves, are among the most alarmed. Dr. Jonathan Kil, the chief executive of Seattle-based Sound Pharmaceuticals, said WuXi has worked alongside the company for 16 years to develop a treatment for hearing loss and tinnitus, or ringing in the ear. Finding another contractor to make the drug could set the company back two years, he said.

“What I don’t want to see is that we get very anti-Chinese to the point where we’re not thinking correctly,” Dr. Kil said.

It is unclear whether a bill targeting WuXi will advance at all this year. The Senate version has been amended to protect existing contracts and limit supply disruptions. Still, the scrutiny has prompted some drug and biotechnology companies to begin making backup plans.

Peter Kolchinsky, managing partner of RA Capital Management, estimated that half of the 200 biotech companies in his firm’s investment portfolio work with WuXi.

“Everyone is likely considering moving away from Wuxi and China more broadly,” he said in an email. “Even though the current versions of the bill don’t create that imperative clearly, no one wants to be caught flat-footed in China if the pullback from China accelerates.”

The chill toward China extends beyond drugmakers. U.S. companies are receiving billions of dollars in funding under the CHIPS Act, a federal law aimed at bringing semiconductor manufacturing stateside.

For the last several years, U.S. intelligence agencies have been warning about Chinese biotech companies in general and WuXi in particular. The National Counterintelligence and Security Center, the arm of the intelligence community charged with warning companies about national security issues, raised alarms about WuXi’s acquisition of NextCODE, an American genomic data company.

Though WuXi later spun off that company, a U.S. official said the government remains skeptical of WuXi’s corporate structure, noting that some independent entities have overlapping management and that there were other signs of the Chinese government’s continuing control or influence over WuXi.

Aides from the Senate homeland security committee said their core concerns are about the misuse of Americans’ genomic data, an issue that’s been more closely tied to other companies named in the bill.

Aides said the effort to discourage companies from working with WuXi and others was influenced by the U.S. government’s experience with Huawei, a Chinese telecommunications giant. By the time Congress acted on concerns about Huawei’s access to Americans’ private information, taxpayers had to pay billions of dollars to tear Huawei’s telecommunication equipment out of the ground.

Yet WuXi has far deeper involvement in American health care than has been discussed in Congress. Supply chain analytics firms QYOBO and Pharm3r, and some public records, show that WuXi and its affiliates have made the active ingredients for critical drugs.

They include Imbruvica, a leukemia treatment sold by Janssen Biotech and AbbVie that brought in $5.9 billion in worldwide revenue in 2023. WuXi subsidiary factories in Shanghai and Changzhou were listed in government records as makers of the drug’s core ingredient, ibrutinib.

Dr. Mikkael A. Sekeres, chief of hematology at the University of Miami Health System, called that treatment for chronic lymphocytic leukemia “truly revolutionary” for replacing highly toxic drugs and extending patients’ lives.

Janssen Biotech and AbbVie, partners in selling the drug, declined to comment.

WuXi Biologics also manufactures Jemperli, a GSK treatment approved by the Food and Drug Administration last year for some endometrial cancers. In combination with standard therapies, the drug improves survival in patients with advanced disease, said Dr. Amanda Nickles Fader, president of the Society of Gynecologic Oncology.

“This is particularly important because while most cancers are plateauing or decreasing in incidence and mortality, endometrial cancer is one of the only cancers globally” increasing in both, Dr. Fader said.

GSK declined to comment.

The drug that possibly captures WuXi’s most significant impact is Trikafta, manufactured by an affiliate in Shanghai and Changzhou to treat cystic fibrosis, a deadly disease that clogs the lungs with debilitating, thick mucus. The treatment is credited with clearing the lungs and extending by decades the life expectancy of about 40,000 U.S. residents. It also had manufacturers in Italy, Portugal and Spain.

The treatment has been so effective that the Make-A-Wish Foundation stopped uniformly granting wishes to children with cystic fibrosis. Trikafta costs about $320,000 a year per patient and has been a boon for Boston-based Vertex Pharmaceuticals and its shareholders, with worldwide revenue rising to $8.9 billion last year from $5.7 billion in 2021, according to a securities filing .

Trikafta “completely transformed cystic fibrosis and did it very quickly,” said Dr. Meghan McGarry, a University of California San Francisco pulmonologist who treats children with the condition. “People came off oxygen and from being hospitalized all the time to not being hospitalized and being able to get a job, go to school and start a family.”

Vertex declined to comment.

Two industry sources said WuXi plays a role in making Eli Lilly’s popular obesity drugs. Eli Lilly did not respond to requests for comment. WuXi companies also make an infusion for treatment-resistant H.I.V., a drug for advanced ovarian cancer and a therapy for adults with a rare disorder called Pompe disease.

WuXi is known for helping biotech firms from the idea stage to mass production, Dr. Kolchinsky said. For example, a start-up could hypothesize that a molecule that sticks to a certain protein might cure a disease. The company would then hire WuXi chemists to create or find the molecule and test it in petri dishes and animals to see whether the idea works — and whether it’s safe enough for humans.

“Your U.S. company has the idea and raises the money and owns the rights to the drug,” Dr. Kolchinsky said. “But they may count on WuXi or similar contractors for almost every step of the process.”

WuXi operates large bioreactors and manufactures complex peptide, immunotherapy and antibody drugs at sprawling plants in China.

WuXi AppTec said it has about 1,900 U.S. employees. Officials in Delaware gave the company $19 million in tax funds in 2021 to build a research and drug manufacturing site that is expected to employ about 1,000 people when fully operational next year, public records and company reports show.

Mayor Kenneth L. Branner Jr. of Middletown, Del., called it “one of those once-in-a-lifetime opportunities to land a company like this,” according to a news report when the deal was approved.

In 2022, the lieutenant governor of Massachusetts expressed a similar sentiment when workers placed the final steel beam on a WuXi Biologics research and manufacturing plant in Worcester. Government officials had approved roughly $11.5 million in tax breaks to support the project. The company announced this year that it would double the site’s planned manufacturing capacity in response to customer demand.

And in Philadelphia, a WuXi Advanced Therapies site next to Iovance Biotherapeutics was approved by regulators to help process individualized cell therapies for skin cancer patients. Iovance has said it is capable of meeting demand for the therapies independently.

By revenue, WuXi Biologics is one of the top five drug development and manufacturing companies worldwide, according to Statista , a data analytics company. A WuXi AppTec annual report showed that two-thirds of its revenue came from U.S. work.

Stepping away from WuXi could cause a “substantial slowdown” in drug development for a majority of the 105 biotech companies surveyed by BioCentury , a trade publication. Just over half said it would be “extremely difficult” to replace China-based drug manufacturers.

BIO, a trade group for the biotechnology industry, is also surveying its members about the impact of disconnecting from WuXi companies. John F. Crowley, BIO’s president, said the effects would be most difficult for companies that rely on WuXi to manufacture complex drugs at commercial scale. Moving such an operation could take five to seven years.

“We have to be very thoughtful about this so that we first do no harm to patients,” Mr. Crowley said. “And that we don’t slow or unnecessarily interfere with the advancement of biomedical research.”

Julian E. Barnes contributed reporting, and Susan C. Beachy contributed research.

Christina Jewett covers the Food and Drug Administration, which means keeping a close eye on drugs, medical devices, food safety and tobacco policy. More about Christina Jewett

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