Introduction
As the general population of people with HIV continues to age, so accompanies the risk for polypharmacy (the use of multiple medications concurrently by a patient) due to increasing comorbidities. According to 2023 Centers for Disease Control and Prevention (CDC) data, 23.9 percent of all adults receive some form of mental health treatment, with those 65 years of age and older particularly impacted.1-2 When used alongside multiple-class agents against HIV, medications for mental health may cause complex medication interactions needing intervention. Navigating these interactions may have a host of outcomes, including but not limited to choosing an alternative therapy, altering a dose, or monitoring with increased frequency.
Adherence to all prescribed medications should be maximized whenever possible and any drug-drug interactions (which may exacerbate deleterious side effects) should be limited. A correlation has been proven between improved mental health medication adherence and antiretroviral therapy (ART) adherence among patients diagnosed with bipolar disorder; however, this was not reaffirmed when studied among patients with schizophrenia.3-4
Here, we discuss notable interactions between ART and several classes of mental health medications, including antidepressants, antipsychotics, benzodiazepines, and other miscellaneous mental health medications.
A Pharmacist’s Perspective
Pharmacists, as the medication experts of the health care team, are trained extensively in medication safety and efficacy. Particularly when interfacing with antiretrovirals (ARVs), pharmacists are adept to educate and intervene on dose or route optimization, medication appropriateness, and drug-drug or drug-food interactions.
Key to appropriate medication usage is a complete medication reconciliation that includes all prescription or non-prescription items that a patient may be taking. Accurate medication reconciliation can be used to identify potential drug-drug interactions that may prompt further patient counseling or therapeutic modification. Now, with the availability of long-acting injectable therapy for HIV, medication reconciliations have become even more important as these agents may be easily overlooked as they may not appear in a patient’s medication list (depending how the medication was acquired or the time since the most recent administration).
Selective Serotonin Reuptake Inhibitors, Serotonin-norepinephrine Reuptake Inhibitors, and Selected Miscellaneous Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be used for multiple indications including but not limited to the following: anxiety or depression, bipolar disorder (in specific situations), and obsessive compulsive disorder.5 Several other miscellaneous antidepressants that are not categorized as SSRIs or SNRIs but may be used for depression include bupropion, mirtazapine, trazodone, and tricyclic antidepressants (TCAs).5 The choice between individual agents will be guided by specific indication and then balanced between avoidance of certain unwanted side effects (e.g. sexual dysfunction) versus a potential benefit associated with a side effect (e.g. weight gain in an already underweight patient).5
As a class, SSRIs and SNRIs may cause serotonin syndrome (with additive risk among patients prescribed multiple serotonergic agents), sexual dysfunction, weight fluctuation, and QTc prolongation.5 Among the agents in these classes, paroxetine is the most likely to have anticholinergic effects and cause weight gain or sexual dysfunction.6 Among the miscellaneous antidepressants, notable agent specific adverse effects include seizures (with bupropion), sedation (with trazodone), weight gain and sedation (with mirtazapine), and general anticholinergic effects (with TCAs).5,7-9
Interactions between ART and SSRIs, SNRIs, and miscellaneous antidepressants
Protease Inhibitors10
Medications that require ritonavir or cobicistat boosting effects (including all protease inhibitors and elvitegravir) are expected to increase serum concentrations of all other medications processed through the Cytochrome P 450 3A (CYP3A) hepatic metabolic pathway. Within this class, medications whose concentrations may be increased include sertraline, paroxetine, duloxetine, venlafaxine, buspirone, trazodone, mirtazapine, and the TCAs.
When initiating any of these agents, the lowest dose should be selected with careful upwards titration to effect and concurrent safety monitoring. Conversely, if a boosted ARV is initiated in a patient maintained on one of these agents, it is reasonable to monitor more carefully for adverse effects or consider an empiric dose reduction with further modifications as necessary. Regardless, patients should be thoroughly counselled on the interaction and potential side effects that can occur.
NNRTIs11
Medications within the NNRTI class can have variable effects on other medications given the specific agent. Although more commonly used newer class agents such as rilpivirine or doravirine are solely CYP3A substrates (in short meaning that their concentrations will be affected by other medications but will not themselves affect other medications), multiple older agents may function as CYP3A inducers to increase metabolic activity of these enzymes thereby reducing concentrations of other administered medications. For example, efavirenz may decrease concentrations of citalopram, escitalopram, sertraline, bupropion, mirtazapine, or trazodone (but given limited usage of efavirenz, this interaction may not be common in practice).
Capsid Inhibitors12
The capsid inhibitor lenacapavir is a moderate inhibitor of CYP3A and therefore can increase concentrations of other medications processed through this pathway (including, but not limited to, buspirone or trazodone). As with the boosted agents, clinicians may choose lower doses with subsequent titration to effect.
Antipsychotics
Antipsychotic medications can be classified as either first or second generation, with second generation antipsychotics (SGAs) generally more prevalent in clinical practice.13 SGAs are used for multiple on- and off-label indications with varying evidence supporting their use. While all SGAs are indicated for schizophrenia, some individual agents are additionally indicated for bipolar disorder, concomitant therapy for depression, and agitation related to psychiatric disorders or dementia.13 Common off-label uses may include anxiety, delirium, or insomnia.13
Although SGAs are far less associated with the neuromuscular effects previously seen with first-generation antipsychotics (ex. tardive dyskinesia, dystonia, neuroleptic malignant syndrome), the class still carries significant side effects, namely a metabolic syndrome comprised of central obesity, hypertension, dyslipidemia, and hyperglycemia.13 The risks for this syndrome vary between agents, with clozapine and olanzapine as the greatest offenders.14
The SGAs can cause QTc prolongation, however this is an additive reaction that increases with concomitant prolonging agents of any class (including rilpivirine).13,15 First generation antipsychotics are more likely to affect the QT interval, but ziprasidone carries the highest prolonging risk among the SGAs.14 Other notable adverse effects within the class include sedation with quetiapine and clozapine as well as akathisia with lurasidone, risperidone, and aripiprazole.14
Interactions between ART and antipsychotics
Protease Inhibitors10
As before, medications that require ritonavir or cobicistat boosting effects will increase concentrations of other CYP3A metabolized compounds given their significant inhibitory effect on the pathway. Lumateperone and lurasidone, for example, should both be avoided in a patient prescribed ritonavir or cobicistat given the risk for accumulation of the parent drug and active metabolites. Other antipsychotics, however, have specific recommendations for titration and dose adjustments when concomitantly administered with a booster. Clinicians should initiate aripiprazole and brexpiprazole at 25 percent of the recommended dose and iloperidone at 50 percent of the recommended dose for the specific indication and titrate slowly as necessary.
Other notable recommendations for concomitant boosted ARVs include empiric dose reductions of quetiapine to one-sixth of the maintenance (with subsequent re-titration if necessary) and anticipated increased concentrations of ziprasidone (alongside the potential risk for QTc prolongation). Specific titration recommendations for cariprazine exist: If a patient begins cariprazine while already maintained on a booster, the dose should start at 1.5 mg on days one and three with a subsequent titration to a maximum daily dose of 3 mg. Alternatively, if the patient is being initiated on a booster while on maintenance cariprazine, the maintenance dose should be halved.
NNRTIs11
Several agents in the NNRTI class, such as efaverinz and etravirine, are inductive to the CYP3A pathway and are therefore expected to decrease concentrations of antipsychotic agents (e.g. aripiprazole, brexpiprazole, iloperidone, lurasidone, clozapine, risperidone, haloperidol, quetiapine, and ziprasidone). Cariprazine and lumateperone are unique in that they should both be completely avoided with these inductive agents due to the risk of poor efficacy. Alternatively, newer class agents such as rilpivirine and doravirine are CYP3A substrates alone and are not expected to have a similar interaction.
Capsid Inhibitors12
Specific dosing recommendations are available for coadministration of brexpiprazole, lumaterperone, or lurasidone with the capsid inhibitor lenacapavir given its moderate CYP3A inhibitory activity. Brexpiprazole should be initiated at 25 percent of the usual staring dose; special consideration should additionally be given towards patients who are known to carry polymorphisms signifying poor metabolic activity of cytochrome P450 2D6, as brexpiprazole is metabolized by both the CYP2D6 and CYP3A4 enzymatic pathways. Patients receiving lumateperone and lenacapavir together should be capped at a maximum daily dose of 21 mg (50% of the typical dose) due to this inhibitory activity. Lurasidone doses should be halved if lenacapavir is initiated and subsequently titrated to an optimal range of 20 to 80 mg daily.
Although no specific recommendations exist, lenacapavir may increase systemic concentrations of other medications such as quetiapine. In such instances, patients should be closely monitored for efficacy and potential adverse effects.
Miscellaneous Mood Disorder Medications
Miscellaneous mood disorder medications include lithium, lamotrigine, oxcarbazepine, carbamazepine, and valproic acid. These agents are well established, with known interactions and adverse effects. While utilized most often in bipolar disorder or adjunctively in certain mood disorders, several carry an additional indication for seizure disorders. Lithium and valproic acid are notable as narrow therapeutic index drugs which require serum level monitoring and are particularly prone to the inductive or inhibitory effects of other medications.16
Of note: Oxcarbazepine, carbamazepine, and lamotrigine all carry significant risk of severe rash.16 To mitigate risk, lamotrigine should be titrated slowly, and HLA-B*1502 genetic testing is recommended prior to carbamazepine initiation.16
Interactions between ART and miscellaneous mood disorder medications
When considering specific agents, carbamazepine is particularly notable for its drug-drug interaction potential as it is both a strong CYP3A inducer and substrate and will autoinduce its own metabolism, which may extend past the drug’s discontinuation.17 Given these interactions and rash risk, the alternative oxcarbazepine has proved an option of greater clinical usage. Nevertheless, oxcarbazepine is a moderate CYP3A4 inducer.18
Protease Inhibitors11
Differing from the other characterized interactions discussed here, concomitant use of protease inhibitors is expected to decrease concentrations of selected agents in this class. When given alongside ritonavir, lamotrigine and valproic acid concentrations are expected to be reduced due to hepatic (non-CYP) glucuronidation induction; this interaction may require higher than typical doses of the agent to achieve desired symptomatic control.
Given their CYP3A inductive effects, carbamazepine and oxcarbazepine directly counteract the boosting (or inhibitory) effects of cobicistat or ritonavir, thus their associated agents will not achieve therapeutic concentrations. As a result, carbamazepine should be completely avoided in this instance; oxcarbazepine, as a moderate inducer is not contraindicated, butclose virologic monitoring for potential breakthrough is indicated.
INSTIs, NNRTIs, Capsid Inhibitors, CCR5 antagonist, GP120 antagonist11-12, 19-21
Several other classes are not recommended to be given with carbamazapine or oxcarbazapine given their CYP3A inductive risk. These include: INSTIs, NNRTIs, the capsid inhibitor lenacapavir, the CCR5 antagonist maraviroc, and the gp120 antagonist fostemsavir.
Benzodiazepines
Benzodiazepines, despite regular use in clinical practice, carry known risks with long-term usage including, but not limited to, tolerance effects or addictive potential. Ideally, these agents should be used as a bridge for symptomatic control during concomitant titration to an effective dose of a SSRI or SNRI. However, these medications are prescribed for a multitude of on- and off-label indications.22 With long-term use, dependence and paradoxical anxiety can occur; benzodiazepines must be titrated off slowly to avoid the risk of withdrawal or seizure. 22
Interactions between ART and benzodiazepines
Protease inhibitors10
Given strong CYP3A inhibitory effect by the boosting agents, lorazepam, oxazepam, or temazepam are preferred benzodiazepine agents as they are not processed by this metabolic pathway and will maintain a predictable non-boosted effect. Alternatively, medications such as alprazolam, clonazepam, and diazepam do undergo metabolism through the CYP3A pathway and should generally be avoided with concomitant boosters due to accumulation risk. Midazolam is contraindicated per guidelines as it is almost exclusively metabolized by CYP3A with subsequent concentrations significantly increased.
NNRTIs11
Efavirenz, given its inductive potential on the CYP pathways, is expected to decrease concentrations of both alprazolam and diazepam. Of note, midazolam concentrations may be variably effected in the presence of efavirenz and should be avoided.
Capsid Inhibitors12
Lenacapavir is expected to increase concentrations of alprazolam, clonazepam, and midazolam due to its moderate CYP3A4 inhibition. Patients who receive both medications should be monitored closely for adverse reactions secondary to the benzodiazepine agent (e.g. excess sedation) and titrated slowly to effect.
Conclusion
Identifying and counseling on interactions between mental health medications and ARVs may help maximize adherence, minimize adverse effects, and prevent patient harm. Although not as common in today’s clinical practice, boosting agents used with protease inhibitors or elvitegravir carry the highest risk for medication interactions given strong CYP3A inhibition. Multidisciplinary team members (including pharmacists) stand ready to assist with medication interactions and provide recommendations for resolution.
Multiple additional resources exist for medication interaction information, namely the HIV Interaction Checker through the University of Liverpool (www.hiv-druginteractions.org) as well as within the United States HIV Clinical Guidelines (www.hivinfo.nih.gov). As a good rule, when in doubt, ask a pharmacist for help!
