Chapter 10

Drug treatment of psychiatric

symptoms occurring in the context
of other disorders

General principles of prescribing in HIV

People living with HIV (PLWH) may experience symptoms of mental illness due to a
variety of factors (see Box 10.1). In practice, several of these factors may coexist within
an individual.

Box 10.1 Factors contributing to the development of psychiatric symptoms in people living with HIV1

■■ Primary (or pre-existing) psychiatric disorders

■■ Neurobiological changes caused by HIV in the central nervous system (CNS)
■■ Other infections or CNS tumours
■■ Antiretroviral drugs and other medical treatments (see Drugs for HIV‘in this section)
■■ Alcohol or substance misuse
■■ Adverse psychosocial factors (e.g. stigma)
■■ Awareness of a chronic disease requiring strict adherence to medication

When prescribing psychotropics, the following principles should be adhered to:

■■ Start with a low dose and titrate according to tolerability and response.
■■ Select the simplest dosing regimen possible. (Remember that the patient’s drug regi-
men is likely to be complex already.)
■■ Select an agent with the fewest side effects. Drug interactions, medical comorbidities
and any ongoing substance misuse must be considered.
■■ Ensure that management is conducted in close cooperation with the HIV specialists
and the rest of the multidisciplinary team.

The Maudsley® Prescribing Guidelines in Psychiatry, Fourteenth Edition. David M. Taylor,

Thomas R. E. Barnes and Allan H. Young.
© 2021 David M. Taylor. Published 2021 by John Wiley & Sons Ltd.
 778  The Maudsley® Prescribing Guidelines in Psychiatry

Although most psychotropic agents are thought to be safe in PLWH, definitive data are
lacking in many cases, and this group may be more sensitive to higher doses, side effects
CHAPTER 10

and interactions.2 Patients with advanced HIV disease are more likely to suffer exagger-
ated adverse reactions to psychotropic medication.

Schizophrenia
In general, there is no difference between the pharmacological treatment of schizophre-
nia in PLWH and the treatment of an uninfected person,3 but some specific considera-
tions should be kept in mind. PLWH are more susceptible to extrapyramidal side effects
(EPSEs)2 due to HIV invasion into basal ganglia, particularly during advanced illness.
Hence, second‐generation antipsychotics (SGAs), such as quetiapine, risperidone and
aripiprazole have been suggested as first-line choices for the treatment of psychosis
unrelated to dementia or delirium.4 The possible additive metabolic effects of antipsy-
chotics and antiretrovirals require close monitoring. QT interval prolongation can be a
complication of HIV progression, co-morbidities, antiretrovirals, as well as antipsy-
chotics.5 Drug interactions are discussed further in this section.
There are limited published reports of clozapine use for treatment-resistant schizo-
phrenia in PLWH.6–8 Clozapine can be used in people with refractory schizophrenia and
HIV with the aim of achieving control of the viral load. A multidisciplinary approach
is required in such cases.6,8
However, close monitoring of the white cell count is required since, clozapine, certain
antiretroviral therapy (ART), and the HIV virus itself can all have suppressive effects on
the bone marrow.6,8 Clozapine may also be helpful in the treatment of individuals with
HIV-associated psychosis with drug-induced parkinsonism.9

Delirium
Organic causes should be identified and treated. Short-term symptomatic treatment
may include low-dose SGAs (e.g. risperidone4). There have been few RCTs in delirious
patients with AIDS; earlier studies document the efficacy of typical antipsychotics,10
and low-dose haloperidol was the agent of choice in one consensus study.4 However,
first‐generation antipsychotic (FGAs) should be used cautiously given the increased
susceptibility to EPSEs in this patient group.10 Benzodiazepines should be used cau-
tiously as they may worsen delirium (except when alcohol or benzodiazepine with-
drawal is the precipitating factor).10

Depression
Depression in PLWH is common, with an estimated prevalence of 20–40%.11 It
may be a consequence of HIV infection or a pre-existing disorder. Studies suggest
that depression comorbid with HIV is associated with poor adherence to ART and
reduced viral suppression.12 Antidepressants are more effective than placebo in the
treatment of depression in PLWH12 and may improve adherence to ART,13 but there
is a gap in research comparing antidepressant types in this patient group. Selective
serotonin reuptake inhibitors (SSRIs) are preferable as first-line agents. Escitalopram/
Drug treatment of psychiatric symptoms occurring in the context of other disorders  779

citalopram4,14 have lower risk of pharmacokinetic interactions. Further treatment

follows standard protocols for depression. A study of escitalopram found no differ-

CHAPTER 10
ence from placebo15 possibly due to a large placebo response. ECG monitoring is
recommended when citalopram/escitalopram is co-administered with ARVs that
prolong the QT interval.5,11 Mirtazapine is effective,16,17 with relatively low risk of
drug interactions,18 and may be beneficial in coexisting HIV wasting and depres-
sion19 or in reducing methamphetamine use among active users.20 ‘Dual action’
antidepressants (duloxetine, venlafaxine) were are equally effective to SSRIs for
depressive symptoms in PLWH.21 Other agents (bupropion,22 trazodone) are effec-
tive but their utility is limited by drug interactions and side effects.
The side-effect burden of TCAs may limit efficacy and compliance, although their use
may be appropriate at times. Constipation and dry mouth are frequently reported in
PLWH on TCAs.12 MAOIs are not recommended in PLWH.

Interferon-alpha-induced depression in HIV/HCV co-infected patients

Citalopram has been shown to be an effective and well-tolerated treatment for emer-
gent depression;23 however, prophylactic use of citalopram (i.e. before depression
emerges) cannot be recommended.24

Bipolar affective disorder

Mania in PLWH can be primary (pre-existing bipolar affective disorder) or secondary
(‘HIV mania’ associated with late-stage HIV infection). PLWH may be more sensitive
to the side effects of mood stabilisers such as neurotoxicity with lithium,25 especially if
they have neurocognitive dysfunction.25,26 Lithium is renally excreted, and so CYP450
interactions are unlikely. However, it can be problematic in renal impairment, often
seen in PLWH. Lithium and tenofovir disoproxil fumarate (TDF) co-therapy was inves-
tigated in a randomised placebo controlled trial as both are associated with renal tubu-
lar toxicity. The incidence of nephrotoxicity was not increased during the 24 weeks of
the trial, but we cannot rule out the risk over long term.27 Lithium may be used cau-
tiously in PLWH for primary bipolar disorder with close monitoring, but avoided in
advanced HIV disease.28 Carbamazepine should be avoided because of significant drug
interactions with and the risk of blood dyscrasias.28 Valproate can be an alternative in
PLWH for bipolar disorder. Monitoring is required due to its risk of hepatotoxicity,
blood dyscrasias, pancreatitis and drug interactions. Valproate use is best avoided with
other hepatotoxic drugs (e.g. nevirapine, rifampicin).28 Mood-stabilising antipsychotics
such as risperidone, quetiapine and olanzapine are also an option.4

Secondary mania (‘HIV mania’)

Reports of secondary mania, typically occurring in advanced illness in the context of
HIV-associated neurocognitive disorders or CNS opportunistic infections,29 have
declined with the widespread use of effective antiretrovirals. The first aim is to identify
and treat the potential underlying cause (infections, substance misuse, alcohol with-
drawal and metabolic abnormalities). Secondary mania may respond to atypical
 780  The Maudsley® Prescribing Guidelines in Psychiatry

antipsychotics, quetiapine, olanzapine and aripiprazole (as there is lower risk of EPSEs).
A case report describes successful treatment of ‘HIV mania’ with ziprasidone.30
CHAPTER 10

Anxiety disorders
Anxiety disorders are highly prevalent in PLWH. Generalised anxiety, panic disorders
and PTSD are commonly reported. SSRIs are first-line options for anxiety and panic
disorders treatment in standard guidelines, as well as in PLWH3 (see ‘Depression’ in this
section for preferred options). Benzodiazepines may have some utility in the acute treat-
ment of anxiety but require caution because of the potential of misuse, possible drug
interactions and increased risk of neurocognitive impairment in PLWH.31
Lorazepam, oxazepam and temazepam are metabolised by non-CYP450 pathways,
hence have lower risk of interactions and may be preferred options for PLWH.32
Buspirone may also be useful.33

HIV-associated neurocognitive disorders

In the current era of effective antiretrovirals, the incidence of severe HIV-associated
cerebral disease has declined dramatically; however, more subtle forms of HIV-
associated neurocognitive disorders (HAND) remain prevalent.34,35 Risk factors include
comorbidities (e.g. HCV coinfection), HIV infection itself and patient genetic factors.
HAND encompasses three sub-disorders, ranging from more common, asymptomatic
neurocognitive impairment (ANI), to more severe less common, HIV-associated demen-
tia (HAD) disorders. Screening for cognitive impairment is recommended in PLWH.11
CogState or the HIV dementia scale have been used though may not identify ANI.35
Symptoms include apathy, irritability, inertia, lack of spontaneity, social withdrawal,
psychomotor slowing, complaints of diminished attention and concentration, emo-
tional lability, and occasionally, ‘HIV mania’.29
The main treatment is antiretroviral therapy with high CNS penetration effectiveness
(CPE) aiming at reaching good levels in the CNS with minimal drug-related neurotoxicity.
Further adjunctive treatments have been studied (minocycline, memantine, selegiline, lith-
ium, valproate, lexipafant, nimodipine, psychostimulants, natalizumab interferons, etc.).36
In a recent study paroxetine was associated with neurocognitive improvements (after
adjusting for depression),37 while a trial of rivastigmine patch was negative. Further
studies are needed to confirm the effects of these adjunctive treatments for HAND.

Interactions between antiretroviral drugs and psychotropics

Pharmacokinetic interactions between antiretroviral drugs and psychotropics occur fre-
quently and can be clinically significant. Potential interactions should be checked for all
patients receiving antiretrovirals and psychotropics concomitantly. Drug history for
checking drug interactions should include current prescribed medication, alternative/
herbal treatments, recreational drugs and other non-prescribed medicines.34
Readers are directed to regularly updated online resources for information about indi-
vidual pharmacokinetic interactions:
■■ www.hiv-druginteractions.org (also available as an App)
■■ www.hivinsite.ucsf.edu
Drug treatment of psychiatric symptoms occurring in the context of other disorders  781
Pharmacodynamic interactions may also occur, usually through overlapping adverse
effects.
Potential pharmacodynamic interactions are shown in Table 10.1.
Table 10.1 Potential pharmacodynamic interactions with antiretrovirals.38
Potential adverse effect
Bone marrow suppression
Bone mineral density reduction
Creatine kinase (CK) elevations
ECG changes
Cardiovascular effects
Renal effects
Gastrointestinal disturbances
Seizure(s)
Metabolic abnormalities such as
hypertriglyceridaemia,
hypercholesterolaemia, insulin
resistance, hyperglycaemia and
hyperlactataemia
CHAPTER 10
Implications for
Implicated antiretroviral drug(s) 32,39,40 psychotropic prescribing
Zidovudine (anaemia, neutropenia) Concurrent use with certain
psychotropics (e.g.
clozapine) may increase the
risk of myelosuppression/
neutropenia
Tenofovir disoproxil fumarate May compound the
(Tenofovir alafenamide has smaller effect reductions in bone mineral
on BMD) density possible with
prolactin elevating
antipsychotics
Dolutegravir, emtricitabine, raltegravir May be important to
acknowledge associated link
if diagnosis of NMS is being
considered
Atazanavir, darunavir, efavirenz, lopinavir, May increase risk of
rilpivirine, ritonavir, saquinavir arrhythmias associated with
certain psychotropic drugs
Abacavir, darunavir/ritonavir, lopinavir/ Cardiovascular events (e.g.
ritonavir MI) occurred in some
cohorts
Tenofovir disoproxil fumarate Proteinuria,
(if regime includes ritonavir, risk is hypophosphatemia,
increased) glycosuria, hypokalaemia,
renal tubular
Atazanavir, darunavir, dolutegravir, May compound
didanosine, elvitegravir/cobicistat, gastrointestinal disturbances
fosamprenavir, indinavir, lopinavir, associated with certain
nelfinavir, raltegravir, saquinavir, tipranavir, psychotropics (e.g. SSRIs)
zidovudine
Darunavir, efavirenz, maraviroc, ritonavir, May increase seizure risk
saquinavir, zidovudine associated with certain
psychotropic drugs
All combination antiretroviral therapy May compound risk of
metabolic adverse effects
associated with certain
psychotropic drugs
(particularly SGAs)
 782  The Maudsley® Prescribing Guidelines in Psychiatry

Adverse psychiatric effects of antiretroviral drugs

CHAPTER 10

Psychiatric adverse events have been reported with many antiretroviral drugs, but a
causal relationship remains uncertain. Efavirenz has been most commonly implicated,
and HIV guidelines suggest avoiding its use in patients with psychiatric illness.32,34,39
Table 10.2 summarises the most important psychiatric adverse effects of antiretrovi-
ral drugs. Note that this is not an exhaustive list; readers are directed to the SPCs/
product labelling for other possible adverse effects. The differential diagnosis of psychi-
atric side effects is covered elsewhere in the Guidelines. Monitoring of people on medi-
cines with psychiatric side effects would be recommended.

Table 10.2 Summary of psychiatric adverse drug reactions (ADRs) with antiretroviral drugs.32,39–41

Drug Adverse psychiatric effects/comment

Nucleoside reverse transcriptase inhibitors

Abacavir Depression, anxiety, nightmares, labile mood, mania, psychosis. Very few cases
reported; in all reported cases, the patient rapidly returned to baseline after
discontinuing drug

Didanosine Lethargy, nervousness, anxiety, confusion, sleep disturbance, mood disorders,

psychosis, mania. Very rare

Emtricitabine Confusion, irritability, insomnia

Zidovudine Sleep disturbance, vivid dreams, agitation, mania, depression, psychosis, delirium.
Psychiatric ADRs are usually dose-related. The onset varies widely, from <24 hours to
7 months

Non-nucleoside reverse transcriptase inhibitors

Efavirenz Somnolence, insomnia, abnormal dreams, impaired concentration, depression, psychosis,

and suicidal ideation. Symptoms usually subside or diminish after 2 to 4 weeks. However,
subtler, long-term neuropsychiatric effects may occur. Can exacerbate psychiatric
symptoms; avoid in patients with a history of psychiatric illness

Etravirine Sleep disturbance

Nevirapine Visual hallucinations, persecutory delusions, mood changes, nightmares and vivid
dreams, depression. A small handful of cases have been reported. Onset of symptoms
was within the first couple of weeks. Symptoms all resolved on discontinuation of
nevirapine

Rilpivirine Depression, suicidality, sleep disturbances. A similar adverse effect profile to efavirenz
but a lower incidence of each event. May exacerbate psychiatric symptoms; consider
avoiding in patients with a history of psychiatric illness

Integrase strand transfer inhibitors

Dolutegravir, elvitegravir Depression and suicidal ideation (symptoms infrequently exacerbated in patients with
and raltegravir pre-existing psychiatric conditions)

CCR5 Antagonist

Maraviroc Depression, insomnia

Drug treatment of psychiatric symptoms occurring in the context of other disorders  783

References

CHAPTER 10
1. Nanni MG, et al. Depression in HIV infected patients: a review. Curr Psychiatry Rep 2015; 17:530.
2. Hill L, et al. Pharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychotics.
Ann Pharmacother 2013; 47:75–89.
3. Cohen M, et al. Comprehensive textbook of AIDS psychiatry: a paradigm for integrated care. Oxford University Press, Oxford, England; 2017.
4. Freudenreich O, et al. Psychiatric treatment of persons with HIV/AIDS: an HIV-Psychiatry Consensus Survey of Current Practices.
Psychosomatics 2010; 51:480–488.
5. Liu J, et al. QT prolongation in HIV-positive patients: review article. Indian Heart J 2019; 71:434–439.
6. Nejad SH, et al. Clozapine use in HIV-infected schizophrenia patients: a case-based discussion and review. Psychosomatics 2009;
50:626–632.
7. Sanz-Cortés S, et al. A case report of schizophrenia and HIV: HAART in association with clozapine. J Psychiatric Intensive Care 2009;
5:47–49.
8. Whiskey E, et al. Clozapine, HIV and neutropenia: a case report. Ther Adv Psychopharmacol 2018; 8:365–369.
9. Lera G, et al. Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism. Mov Disord 1999;
14:128–131.
10. Watkins CC, et al. Cognitive impairment in patients with AIDS - prevalence and severity. HIV/AIDS (Auckland, NZ) 2015; 7:35–47.
11. European AIDS Clinical Society. Guidelines Version 10.1 October 2020. 2020; http://www.eacsociety.org/files/guidelines_10.1-english.pdf.
12. Eshun-Wilson I, et al. Antidepressants for depression in adults with HIV infection. Cochrane Database System Rev 2018; 1:Cd008525.
13. Gokhale RH, et al. Depression prevalence, antidepressant treatment status, and association with sustained HIV viral suppression among
adults living with HIV in care in the United States, 2009-2014. AIDS Behav 2019; 23:3452–3459.
14. Currier MB, et al. Citalopram treatment of major depressive disorder in hispanic HIV and AIDS patients: a prospective study. Psychosomatics
2004; 45:210–216.
15. Hoare J, et al. Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized,
double-blind, placebo-controlled study. J Nerv Ment Dis 2014; 202:133–137.
16. Patel S, et al. Escitalopram and mirtazapine for the treatment of depression in HIV patients: a randomized controlled open label trial. ASEAN
J Psychiatry 2012; 14.
17. Elliott AJ, et al. Mirtazapine for depression in patients with human immunodeficiency virus. J Clin Psychopharmacol 2000; 20:265–267.
18. Adams JL, et al. Treating depression within the HIV ‘medical home’: a guided algorithm for antidepressant management by HIV clinicians.
AIDS Patient Care STDS 2012; 26:647–654.
19. Badowski M, et al. Pharmacologic management of human immunodeficiency virus wasting syndrome. Pharmacotherapy 2014;
34:868–881.
20. Coffin PO, et al. Effects of mirtazapine for methamphetamine use disorder among cisgender men and transgender women who have sex with
men: a placebo-controlled randomized clinical trial. JAMA Psychiatry 2020; 77:246–255.
21. Mills JC, et al. Comparative effectiveness of dual-action versus single-action antidepressants for the treatment of depression in people living
with HIV/AIDS. J Affect Disord 2017; 215:179–186.
22. Currier MB, et al. A prospective trial of sustained-release bupropion for depression in HIV-seropositive and AIDS patients. Psychosomatics
2003; 44:120–125.
23. Laguno M, et al. Depressive symptoms after initiation of interferon therapy in human immunodeficiency virus-infected patients with chronic
hepatitis C. Antivir Ther 2004; 9:905–909.
24. Klein MB, et al. Citalopram for the prevention of depression and its consequences in HIV-hepatitis C coinfected individuals initiating
pegylated interferon/ribavirin therapy: a multicenter randomized double-blind placebocontrolled trial. HIV Clin Trials 2014; 15:161–175.
25. Ferrando SJ. Psychopharmacologic treatment of patients with HIV/AIDS. Current psychiatry reports 2009; 11:235–242.
26. El-Mallakh RS. Mania in AIDS: clinical significance and theoretical considerations. Int J Psychiatry Med 1991; 21:383–391.
27. Decloedt EH, et al. Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral
therapy: analysis from a randomized placebo controlled trial. AIDS Res Ther 2017; 14:6.
28. Gallego L, et al. Psychopharmacological treatments in HIV patients under antiretroviral therapy. AIDS Rev 2012; 14:101–111.
29. Singer EJ, et al. Neurobehavioral Manifestations of Human Immunodeficiency Virus/AIDS: Diagnosis and Treatment. Neurol Clin 2016;
34:33–53.
30. Spiegel DR, et al. The successful treatment of mania due to acquired immunodeficiency syndrome using ziprasidone: a case series. J
Neuropsychiatry Clin Neurosci 2010; 22:111–114.
31. Saloner R, et al. Benzodiazepine use is associated with an increased risk of neurocognitive impairment in people living with HIV. J Acquir
Immune Defic Syndr 2019; 82:475–482.
32. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living
with HIV. Department of Health and Human Services. 2017; https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
33. Brogan K, et al. Management of common psychiatric conditions in the HIV-positive population. Curr HIV/AIDS Rep 2009; 6:108–115.
34. Waters L, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015 (2016 interim
update). 2016; http://www.bhiva.org/documents/Guidelines/Treatment/2016/treatment-guidelines-2016-interim-update.pdf.
35. Carroll A, et al. HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment. F1000Res 2017;
6:312.