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.

CHAPTER 10
Potential pharmacodynamic interactions are shown in Table 10.1.

Table 10.1 Potential pharmacodynamic interactions with antiretrovirals.38

Implications for
Potential adverse effect Implicated antiretroviral drug(s) 32,39,40 psychotropic prescribing

Bone marrow suppression Zidovudine (anaemia, neutropenia) Concurrent use with certain
psychotropics (e.g.
clozapine) may increase the
risk of myelosuppression/
neutropenia

Bone mineral density reduction Tenofovir disoproxil fumarate May compound the
(Tenofovir alafenamide has smaller effect reductions in bone mineral
on BMD) density possible with
prolactin elevating
antipsychotics

Creatine kinase (CK) elevations Dolutegravir, emtricitabine, raltegravir May be important to

acknowledge associated link
if diagnosis of NMS is being
considered

ECG changes Atazanavir, darunavir, efavirenz, lopinavir, May increase risk of

rilpivirine, ritonavir, saquinavir arrhythmias associated with
certain psychotropic drugs

Cardiovascular effects Abacavir, darunavir/ritonavir, lopinavir/ Cardiovascular events (e.g.

ritonavir MI) occurred in some
cohorts

Renal effects Tenofovir disoproxil fumarate Proteinuria,

(if regime includes ritonavir, risk is hypophosphatemia,
increased) glycosuria, hypokalaemia,
renal tubular

Gastrointestinal disturbances 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

Seizure(s) Darunavir, efavirenz, maraviroc, ritonavir, May increase seizure risk

saquinavir, zidovudine associated with certain
psychotropic drugs

Metabolic abnormalities such as All combination antiretroviral therapy May compound risk of
hypertriglyceridaemia, metabolic adverse effects
hypercholesterolaemia, insulin associated with certain
resistance, hyperglycaemia and psychotropic drugs
hyperlactataemia (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

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