People living with human immunodeficiency virus (PLWH) may experience symptoms of mental illness because of a variety of factors (Box 10.1). In practice, several of these factors may coexist within an individual.1
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When prescribing psychotropics, the following principles should be adhered to:
Although most psychotropic agents are thought to be safe in PLWH, definitive data are lacking in many cases. PLWH may be more sensitive to higher doses, adverse effects and to interactions.2 Patients with advanced HIV disease are particularly more likely to suffer exaggerated adverse reactions to psychotropic medication.
Treatment of HIV infection has evolved in recent years to include long-acting injectable antiretroviral therapy (ART) (e.g. cabotegravir/rilpivirine)3 aiming to improve adherence to and persistence with treatment.3 Ensuring continuous ART is crucial for a number of reasons including the fact that inflammation associated with untreated HIV can worsen pre-existing cognitive decline in people with psychosis. Successful treatment with ART is associated with a lower risk of mental health disorders.4 In those at high risk of psychiatric relapse and poor compliance with medicines, long-acting injections of both antipsychotics and antiretrovirals are available and could be used concurrently.
For most PLWH and comorbid psychosis, treatment is similar to that used in people without HIV5 but with some specific considerations. PLWH are more susceptible to extrapyramidal side effects (EPSEs) because HIV, a neurotropic virus, enters the brain and replicates in the basal ganglia leading to dopaminergic neuronal loss.6 In addition to this, both HIV and ART are implicated in metabolic abnormalities, hyperlipidaemia, weight gain and insulin resistance.7
Use of second-generation antipsychotics (SGAs) in PLWH has been shown to increase the cardiovascular risk and metabolic complications compared with those not on SGAs.8 Likewise, QT interval prolongation can be a complication of HIV progression, HIV comorbidities and use of antiretrovirals as well as antipsychotics.9 Pharmacokinetic interactions should be considered and are discussed further in this section. SGAs are clearly first-line options for the treatment of psychosis in PLWH although close physical health monitoring is essential, as is the use of preventative measures if required.
Clozapine is a treatment option in PLWH10, 11, 12 and comorbid treatment-resistant schizophrenia. Haematological abnormalities, including leukopenia, neutropenia, lymphopenia, thrombocytopenia and anaemias, are frequent complications of HIV13 as well as ART. Clozapine treatment may be erroneously interrupted if these are considered as clozapine-induced, with detrimental consequences for the treatment of both HIV and psychosis. The safe and effective management of the additive haematological, metabolic and cardiovascular effects of clozapine and ART and complex pharmacokinetic interactions require the close collaboration of specialist medical teams and pharmacists. Clozapine may also be helpful in the treatment of individuals with HIV-associated psychosis with drug-induced parkinsonism.14
Depression is the most common mental health disorder in PLWH, with prevalence estimated to be between 14% and 78%.1 Depressive symptoms can be a consequence of HIV infection or ART or of a pre-existing disorder. Untreated depression in PLWH is associated with reduced viral suppression and faster HIV illness progression.15 Antidepressants are more effective than placebo in the treatment of depression in PLWH16 and may improve adherence to ART.17 Selective serotonin reuptake inhibitors (SSRIs) are preferred as first-line agents. Escitalopram/citalopram18, 19 probably have lower risk of pharmacokinetic interactions, although one study found no difference between the efficacy of escitalopram and placebo, possibly because of a large placebo response.20 Electrocardiogram (ECG) monitoring is recommended when citalopram/escitalopram is co-administered with ART that prolongs the QT interval.9, 21 Mirtazapine is effective22, 23 and may be beneficial in coexisting HIV wasting and depression24 or in reducing methamfetamine use among active users.25 The serotonin-noradrenaline reuptake inhibitors (SNRIs) duloxetine and venlafaxine were found to be as effective as SSRIs for depressive symptoms in PLWH.26 Bupropion was effective with similar tolerability to SSRIs in a 6-week open-label study in a small number of HIV-positive, depressed out-patients.27
The adverse effect burden of tricyclic antidepressants (TCAs) may limit efficacy and compliance, although their use may be appropriate, particularly in patients troubled with insomnia, irritable bowel disease or painful neuropathy related to HIV or ART. Constipation and dry mouth are frequently reported in PLWH on TCAs.16 Monoamine oxidase inhibitors (MAOIs) are not recommended in PLWH.
Mania in PLWH can be primary (pre-existing bipolar affective disorder) or, rarely, secondary (HIV mania' associated with late-stage HIV infection). Treatment of bipolar disorder in HIV is similar to that in the general population.27 Lithium is renally excreted and so cytochrome P450 (CYP) interactions are unlikely. However, its use can be problematic in renal impairment, something which is often seen in PLWH. Lithium may be used cautiously in PLWH for primary bipolar disorder with close monitoring to avoid development of toxicity. Carbamazepine should be avoided because of significant drug interactions with ART and the risk of blood dyscrasias.28 Valproate is a known teratogen and should not be used in women of childbearing age.29 Its use is also best avoided with other hepatotoxic drugs (e.g. nevirapine, rifampicin)28 and where there is infection involving the liver (e.g. hepatitis C, mycobacterium avium complex30). Mood-stabilising antipsychotics such as risperidone, quetiapine, aripiprazole and olanzapine may be preferred.
Secondary mania may infrequently be seen in advanced illness in the context of HIV-associated neurocognitive disorders or central nervous system (CNS) opportunistic infections. The primary aim is to identify and treat the potential underlying cause (infections, substance misuse, alcohol withdrawal, metabolic abnormalities). Secondary mania may respond to quetiapine, olanzapine, aripiprazole or ziprasidone31 but their efficacy has not been demonstrated in clinical trials.
Anxiety disorders, including generalised anxiety disorder, obsessive compulsive disorder, panic disorder and post-traumatic stress disorder (PTSD), are highly prevalent in PLWH.32 Treatment follows standard guidelines for the management of anxiety disorders, with SSRIs being the first-line options. Benzodiazepines may have some utility in the acute treatment of anxiety but require caution because of potential misuse, possible drug interactions and a higher risk of sedative and neurocognitive adverse effects in PLWH.33 Lorazepam is metabolised by non-CYP pathways, and so has a lower risk of interactions. Clonazepam has no active metabolites and so it may be a preferred short-term option for PLWH.34, 35 Buspirone may also be helpful.34
HAND encompasses three sub-disorders, ranging from the more common asymptomatic neurocognitive impairment (ANI) to a mild neurocognitive disorder (MND) and the more severe but less common HIV-associated dementia (HAD). Screening for cognitive impairment is recommended in PLWH using scales such as the MoCA or the three-item Cognitive Concerns Questionnaire.36 In 2023, the International HIV-Cognition Working Group published recommendations to better define the cognitive impairment in HIV.37
Treatment involves the use of ART with high CNS penetration effectiveness (e.g. raltegravir), aiming to achieve therapeutic levels in the CNS with minimal drug-related neurotoxicity. Cognitive rehabilitation is an essential treatment component. Effective treatment of depression is essential as is management of substance use disorders and physical health comorbidities. Psychostimulants, modafinil, memantine, lithium and valproate have been studied but there is currently no licensed treatment for HAND.38
Delirium in HIV can be difficult to differentiate from HAND, although onset of delirium is more acute and its severity may fluctuate. Organic causes should be identified and treated. Antipsychotics are probably not effective in treating delirium and so should only be used as a last resort in severe cases and when non-pharmacological measures fail.27 Early studies document the efficacy of haloperidol, but the lowest possible dose should be used given the high incidence of EPSEs, particularly in those with advanced HIV (e.g. doses used in delirium in palliative care may be considered).27 Benzodiazepines should be used cautiously as they may worsen delirium except when alcohol or benzodiazepine withdrawal is the precipitating factor.27
Substance use disorders are highly prevalent in PLWH. Commonly used substances include alcohol, stimulants (including cocaine and methamfetamine), benzodiazepines, opioids and cannabinoids. The potential for interactions between drug use and prescribed medicines should be considered. Treatment should be offered to PLWH with comorbid substance use disorders. Naltrexone is safe and effective for alcohol relapse prevention in PLWH,39 while acamprosate has not been studied in this population and has a high tablet burden. Methadone and buprenorphine are possible evidence-based options for opioid use disorder but care is required with ART drug interactions.27, 40
Pharmacokinetic interactions between antiretroviral drugs and psychotropics occur frequently and can be clinically significant. Potential interactions should be investigated for all patients receiving antiretrovirals and psychotropics concomitantly and include current prescribed medication, alternative/herbal treatments, recreational drugs and other non-prescribed medicines. Interactions are numerous and complex. Readers are directed to regularly updated online resources for information about individual pharmacokinetic interactions such as www.hiv-druginteractions.org (also available as an app).
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.4041
Potential adverse effect | Implicated antiretroviral drug(s)214243 | Implications for psychotropic prescribing |
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Bone marrow suppression | Zidovudine (anaemia, neutropenia) | Concurrent use with certain psychotropics (e.g. clozapine) may increase the risk of myelosuppression/neutropenia |
Bone mineral density (BMD) reduction | Tenofovir disoproxil fumarate (TDF) (tenofovir alafenamide has smaller decline of BMD) NNRTIs, PIs, INSTIs: decreases in BMD following any regimen | May compound the reductions in BMD 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 | Efavirenz, rilpivirine, saquinavir/ritonavir: QT prolongation Atazanavir, lopinavir saquinavir: PR prolongation | May increase risk of arrhythmias associated with certain psychotropic drugs |
Cardiovascular effects | Abacavir, darunavir/ritonavir, lopinavir/ritonavir | Cardiovascular events (e.g. myocardial infarction) occurred in some cohorts |
Renal effects | TDF (risk increased if used with ritonavir) Tenofovir alafenamide: less impact on renal function versus TDF Atazanavir (kidney stones, tubo-interstitial nephritis) | Proteinuria, hypophosphataemia, glycosuria, hypokalaemia, renal tubular |
Gastrointestinal disturbances | Atazanavir, darunavir, dolutegravir, didanosine, elvitegravir/cobicistat, fosamprenavir, indinavir, lopinavir, nelfinavir, raltegravir, saquinavir, tipranavir, zidovudine | May compound gastrointestinal disturbances associated with certain psychotropics (e.g. SSRIs) |
Seizure(s) | Darunavir, efavirenz, maraviroc, ritonavir, saquinavir, zidovudine | May increase seizure risk associated with certain psychotropic drugs (e.g. clozapine) |
Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia | All combination antiretroviral therapy Raltegravir, elvitegravir, dolutegravir: greater risk of weight gain | May compound risk of metabolic adverse effects associated with certain psychotropic drugs (particularly SGAs) |
INSTIs, integrase strand transfer inhibitors; NMS, neuroleptic malignant syndrome; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors.
Psychiatric adverse events have been reported with most antiretroviral drugs, but a causal relationship remains uncertain for many. Efavirenz has been most commonly implicated, and HIV guidelines suggest avoiding its use in patients with psychiatric comorbidity.
Table 10.2 summarises the most important psychiatric adverse effects of antiretroviral drugs. Note that this is not an exhaustive list and readers are directed to the summaries of product characteristics/product labelling for greater detail.
Table 10.2 Summary of Psychiatric Adverse Drug Reactions (ADRs) with Antiretroviral Drugs.21405
Drug | Adverse psychiatric effects/comments |
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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 |
Tenofovir alafenamide | Insomnia |
Zidovudine | Sleep disturbance, vivid dreams, agitation, mania, depression, psychosis, delirium. Psychiatric ADRs are usually dose-related. Onset varies widely, from <24 hours to 7 months. |
Non-nucleoside reverse transcriptase inhibitors | |
Efavirenz | Somnolence, insomnia, abnormal dreams, impaired concentration, depression, psychosis, suicidal ideation. Symptoms usually subside or diminish after 2-4 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 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, raltegravir | Insomnia, depression, suicidal ideation (particularly with dolutegravir and symptoms may appear within first months of treatment) |
Bictegravir | Depression incidence similar to dolutegravir (though suicidality greater for dolutegravir) but further data required |
Cabotegravir | Limited data but incidence appears low - also long acting and so effects may be prolonged |
A 2023 systematic review concluded that dolutegravir-based regimens led to higher discontinuation rates due to neuropsychiatric adverse effects compared with those treated with bictegravir, emtricitabine and tenofovir alafenamide. Antiretroviral regimen choice should evidently take into account the individual's risk factors for developing neuropsychiatric adverse effects.46
CNS, central nervous system; GHB/GBL, gamma hydroxybutyrate/gamma butyrolactone.