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Case 1: Discussion

Case Summary

In the clinical case outlined here, the patient's symptoms most likely resulted from a drug-drug interaction between lopinavir-ritonavir (Kaletra) and lamotrigine (Lamictal). Ritonavir significantly lowers lamotrigine levels[1,2] and thus likely resulted in subtherapeutic lamotrigine levels, which in turn led to a destabilization of the patient's bipolar disease. Most medical providers are not aware that ritonavir can significantly lower lamotrigine levels. Indeed, most are accustomed to ritonavir increasing the levels of other drugs. For patients on lamotrigine who are starting on an antiretroviral regimen that includes ritonavir, we recommend obtaining a baseline lamotrigine level and closely monitor lamotrigine levels for the subsequent several months, with adjustment of the lamotrigine dose based on the levels. In the clinical situation presented here, the patient could have alternatively received an antiretroviral regimen that did not contain ritonavir. For example, use of a raltegravir (Isentress)-based regimen would provide an equally effective regimen without impacting lamotrigine levels, but would require twice daily dosing of the raltegravir. Prescribing an efavirenz (Sustiva)-based regimen might be problematic in this patient, primarily because of the neuropsychiatric side effects with efavirenz that could potentially exacerbate her bipolar disorder.

Background

Simultaneously treating HIV-infected patients with antiretroviral medications and psychotropic medications is often complex and challenging[3]. The concomitant use of drugs from these two classes of medications commonly occurs in clinical practice and can result in unwanted drug-drug interactions and overlapping adverse effects, thereby leading to medication intolerance, problems with medication adherence, medication interruptions, worsening of psychiatric symptoms, and, rarely, hospitalization. It is important to note these complications can also potentially negatively impact both the antiretroviral treatment course and the management of the psychiatric disorder. Further, the management of a major psychiatric disorder plays an extremely important role in patients on antiretroviral therapy, particularly in relation to optimizing medication adherence. The following discussion will outline and summarize important drug-drug interactions that occur in clinical practice involving antiretroviral medications and psychotropic medications used as antidepressants and mood stabilizers.

General Principles of Interactions with Antiretrovirals and Psychotropic Medications

Numerous significant drug-drug interactions can potentially occur when coadministering psychotropic medications and antiretroviral medications [4,5]. If this occurs, it usually involves an interaction between the psychotropic medication and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The PIs and NNRTIs impact the metabolism of psychotropic medications predominantly via the hepatic cytochrome P450 enzyme system (CYP450). Some of the PIs inhibit the CYP3A4 or CYP2D6 isoenzymes in the P450 system, increasing the plasma levels of the psychotropic medications metabolized in this same pathway and potentially causing drug toxicity. Ritonavir has complex interactions and typically increases the plasma levels of drugs by inhibiting the CYP2D6[6] or CYP3A isoenzymes[7], but it can reduce plasma levels of other drugs by causing induction of the CYP2B6 isoenzyme[8]. The NNRTI medications efavirenz, etravirine (Intelence), and nevirapine (Viramune) cause induction of P450 enzymes[9], which may decrease plasma levels of the coadministered psychotropic drug. In contrast, the NNRTI delavirdine (Rescriptor), which is rarely used in clinical practice, inhibits P450 enzymes. The NNRTI rilpivirine (Edurant) is metabolized by CYP3A isoenzymes, but rilpivirine is unlikely to impact the levels of psychotropic medications. Similarly, the nucleoside reverse transcriptase inhibitors (NRTIs), integrase strand transfer inhibitors, and CCR5 receptor antagonists generally do not significantly alter the levels of psychotropic medications. The most important interactions involving antidepressant medications and antiretroviral medications are summarized in Figure 1 and Figure 2. With any known or suspected significant drug-drug interaction that may impact clinical outcome, close monitoring and dose adjustment of the psychotropic medication is warranted. In addition, multiple guidelines recommend avoiding the co-administration of St. John's wort and antiretroviral medications.

Interactions Between Antidepressants and Antiretroviral Medications

  • Selective Serotonin Reuptake Inhibitors (SSRIs): The SSRIs are frequently used for the treatment of depression in HIV-infected patients. Commonly used SSRIs in the HIV clinical setting include citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). The SSRIs undergo metabolism primarily via the CYP2D6 pathway and can also inhibit the 2D6 enzyme to varying degrees. Although ritonavir is a potent inhibitor of CYP2D6, it does not generally cause clinically significant drug interactions with most SSRIs, except with fluvoxamine (Luvox), a medication rarely used in clinical practice. Fluvoxamine has multiple pathways of metabolism and may inhibit or induce certain CYP enzymes and thus should be avoided with concurrent PI or NNRTI administration. Several PIs, notably darunavir (Prezista) and fosamprenavir (Lexiva) can decrease the levels of certain SSRIs: darunavir lowers levels of sertraline and paroxetine, and fosamprenavir lowers paroxetine levels. The only well characterized NNRTI interaction with SSRIs involves efavirenz, which significantly lowers sertraline levels. Several reports have described patients developing the serotonin syndrome when concomitantly taking antiretroviral medications and SSRI antidepressants and[10] some experts recommend using the lowest effective SSRI dose when initiating treatment in a patient concomitantly receiving antiretroviral medications, with monitoring for toxicity and dose titration to achieve clinical response.
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): The antidepressants duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) may be used concurrently with PIs and NNRTIs, but similar to the SSRIs, we recommend using the lowest effect dose of these antidepressants when initiating treatment in patients who are receiving antiretroviral therapy.
  • Noradrenergic and Specific Serotonergic Antidepressants: Similar to the SSRIs, the lowest dose of mirtazapine (Remeron) should be used when initiating treatment in a patient concurrently taking antiretroviral therapy.
  • Combined Reuptake Inhibitors and Receptor Blockers: Nefazodone (Serzone), which is not often used in clinical practice, should be avoided in primary care settings due to its black box warning for potential hepatic failure and suicidality. Ritonavir markedly increases trazodone (Desyrel) levels and can cause clinically significant sedation, fatigue, and performance impairment[11].
  • Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs): Bupropion (Wellbutrin), is metabolized via CYP2B6 and thus can interact with ritonavir, which can induce CYP2B6 isoenzymes[12]. Reports documented a reduction in plasma levels of bupropion by approximately 50% when give concurrently with lopinavir/ritonavir or tipranavir plus ritonavir[13]. Similarly, efavirenz lowers buproprion levels by about 50%. Thus, with these combinations, the buproprion dose may need titration upward to achieve response.
  • Tricyclic Antidepressants: The tricyclic antidepressants are metabolized through the CYP2D6 isoenzyme and thus levels may be significantly increased with concomitant use of ritonavir. In this setting, we recommend close observation and limiting the maximum dose of the tricyclic. For example, in most cases the dose of amitriptyline should not exceed 100 mg.
  • Herbal Antidepressants: The herbal remedy Hypericum perforatum (St. John's wort) causes induction of the cytochrome P450 enzymes CYP3A4 and CYP2C9 and thus can significantly lower PI and NNRTI levels (and possibly maraviroc levels).

Mood Stabilizers and Antiretroviral Medications

  • Lamotrigine (Lamictal): Significant interactions can occur with lamotrigine, which is often used as a mood stabilizer, and the PI lopinavir-ritonavir (Kaletra). Specifically, the co-administration of lamotrigine and lopinavir-ritonavir causes a 50% decrease in the plasma levels of lamotrigine[1]. The probable mechanism occurs through by lopinavir-ritonavir's induction of glucuronidation, the primary route of lamotrigine metabolism. Other ritonavir-boosted PI regimens are likely to cause a similar interaction with lamotrigine. When using lamotrigine concomitantly with ritonavir, we recommend titrating the dose of lamotrigine to effect and monitoring lamotrigine plasma levels during the dose titration.
  • Valproic Acid (Depakene, Depakote): An interaction involving glucuronidation occurs between valproic acid and zidovudine (Retrovir). Specifically, valproic acid inhibits the UGTB7 isoenzyme responsible for the glucuronidation of zidovudine to its inactive derivative, 5'-glucuronyl zidovudine[15], resulting in an increase in plasma levels of zidovudine of approximately 80%. The dose of zidovudine does not routinely require adjustment, but patients should be monitored closely for zidovudine-related toxicity, particularly anemia. In addition, ritonavir can significantly lower valproic acid levels and patients concomitantly given a ritonavir-boosted antiretroviral regimen and valproic acid should have close monitoring for a decreased valproic acid effect[17].
  • Aripiprazole (Abilify): The psychotropic medication aripiprazole is primarly used as a mood stabilizer and more recently as adjunct therapy for depression. The plasma levels of aripiprazole, a CYP3A4 substrate, may increase in combination with PIs, but plasma levels may decrease with concurrent NNRTI administration. The lowest effective dose should be initiated and titrated to effect when given concurrently with PIs.
  • Carbamazepine (Tegretol): Coadministration of carbamazepine with efavirenz results in in a significant decrease in efavirenz levels and a decrease in carbamazepine levels, but no significant change in the level of the active carbamazepine metabolite[18]. Ritonavir increases serum concentrations of carbamazepine and clinical cases of carbamazepine toxicity have been reported[19,20]. Carbamazepine can lower levels of PIs and one report described antiretroviral failure as a result of carbamazepine[21].

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  • The following link will open in a new window.
    Figure 1. Drug-Drug Interactions with Antidepressants and NNRTIs
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 1
  • The following link will open in a new window.
    Figure 2. Drug-Drug Interactions with Antidepressants and Protease
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 2