Drug-drug interactions: Avoid serious adverse events with mood stabilizers
In clinical practice, prescribed drug combinations are often uncontrolled experiments, with unknown potential for toxic effects.
HOW TO MINIMIZE DDI RISK
Use the acronym “LISTEN” (Table 1) to minimize DDI risk in patients taking combination therapies.16 The 6 steps in LISTEN can help you determine which drug or drugs you may discontinue before adding another.
We also recommend that you monitor therapeutic and toxic effects by checking serum drug levels, especially for drugs with a low therapeutic index. Lithium, for example, requires close mentoring of plasma concentration every 2 to 6 months and during dosage adjustments to avoid toxicity.17 Therapeutic drug monitoring has been shown to prevent adverse events from DDIs.16 For added safety, encourage patents to purchase all medications at one pharmacy and to enroll in that pharmacy’s DDI monitoring program.18
Keep in mind that systemic conditions may require a dosage change:
- Increased volume of distribution, as in patients who gain weight or total water volume, requires higher doses to maintain a constant therapeutic effect.
- Reduced clearance, as in patients with decreased renal or hepatic function, will likely require lower doses to prevent toxicity.19
LISTEN: 6 tips to minimize DDI risk
| L | Listeach drug’s name and dosage in the patient’s chart and in a note given to the patient. |
| I | Each drug should have a clear indication and well-defined therapeutic goal; discontinue any drug not achieving its goal |
| S | Make the regimen as simple as possible, with once- or twice-daily dosing. |
| T | When possible, treat multiple symptoms with a single drug, rather than multiple symptoms with multiple drugs |
| E | Educatepatients about polypharmacy, DDIs, and adverse events; assess all medications—including vitamins, minerals, herbs, dietary supplements, nonprescription products—and address potential DDIs |
| N | Avoid prescribing medications with a narrow therapeutic window. |
DDIsWITH MOOD STABILIZERS
Diagnoses of schizophrenia, anxiety disorders, and affective disorders are major risk factors for polypharmacy.20 DDIs are a particular concern in patients with bipolar disorder, given their complex treatment regimens.21
Interactions occur with the most commonly prescribed bipolar medications, including lithium and anticonvulsants (Table 2).17.21-25 Although atypical antipsychotics are also considered mood stabilizers in bipolar disorder, we will discuss their potential DDIs in a future article.
Table 2
Some drug-drug interactions with mood stabilizers
| Mood stabilizer | Drug interactions |
|---|---|
| Carbamazepine | ↑plasma clomipramine, phenytoin, primidone |
| ↑risk of neurotoxic side effects and confusional states with lithium | |
| Alters thyroid function with anticonvulsants | |
| ↓anticoagulant concentrations and↑bleeding risk | |
| ↓oral contraceptive reliability; can cause false-negative pregnancy tests | |
| ↑metabolism and may ↓efficacy of cancer chemotherapy (docetaxel, estrogens, paclitaxel, progesterone, cyclophosphamide) | |
| ↑aprepitant, granisetron metabolism and ↓efficacy | |
| ↑glipizide, tolbutamide metabolism | |
| Lithium | NSAIDs (ibuprofen, indomethacin, piroxicam) and COX-2 inhibitors ↑plasma lithium |
| ACE inhibitors ↑plasma lithium | |
| Calcium channel blockers and carbamazepine ↑lithium neurotoxicity | |
| SSRIs ↑diarrhea, confusion, tremor, dizziness, and agitation | |
| Acetazolamide, urea, xanthine preparations, alkalinizing agents such as sodium bicarbonate ↓plasma lithium | |
| Metronidazole ↑lithium toxicity | |
| Encephalopathic syndrome possible with haloperidol | |
| Lamotrigine | ↑concentration of carbamazepine’s epoxide metabolite |
| Carbamazepine, phenytoin, phenobarbital ↓plasma lamotrigine 40% to 50% | |
| ↑plasma sertraline | |
| ↓plasma valproic acid 25%; valproic acid doubles plasma lamotrigine and ↑rash risk | |
| Topiramate | ↑valproic acid concentrations 11%; valproic acid ↓plasma topiramate 14% |
| ↑plasma phenytoin up to 25%; phenytoin, carbamazepine ↓plasma topiramate by 40% to 48% | |
| ↓digoxin bioavailability | |
| ↓oral contraceptive efficacy | |
| Valproic acid | ↑plasma phenobarbital, primidone |
| ↓phenytoin clearance, volume distribution and ↑breakthrough seizure risk | |
| ↑serum concentration of antiepileptics, such as lamotrigine; absence status possible with clonazepam | |
| ↑= Increases ↓= Decreases | |
| ACE = angiotensin-converting enzyme; COX = cyclooxygenase | |
| NSAIDs = nonsteroidal anti-inflammatory drugs; SSRIs = selective serotonin reuptake inhibitors | |
| Source: References 17, 21-25 | |
LITHIUM: TOXICITY RISK
Lithium is excreted via the kidneys, so be cautious when using lithium in patients taking diuretics.17,22 Drugs that can lower serum lithium concentrations by increasing urinary lithium excretion include acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.17
Combining lithium with selective serotonin reuptake inhibitors can cause diarrhea, confusion, tremor, dizziness, and agitation.17 An encephalopathic syndrome has occurred in a few patients treated with lithium plus haloperidol.
Monitor lithium levels closely when bipolar patients start or stop nonsteroidal anti-inflammatory drugs (NSAIDs). Nonprescription ibuprofen can cause serious and even life-threatening serum lithium elevations by affecting lithium’s rate of tubular reabsorption.26 Indomethacin, piroxicam, and selective cyclooxygenase-2 (COX-2) inhibitors also increase plasma lithium concentrations.25
For patients taking lithium with heart drugs, angiotensin-converting enzyme (ACE) inhibitors may increase plasma lithium levels,17 and calcium channel blockers may increase the neurotoxicity risk.17,22 Using the anti-infective metronidazole with lithium may provoke lithium toxicity.
VALPROIC ACID: MONITOR CLEARANCE
Drugs that affect the expression of hepatic enzymes—especially glucuronosyltransferase—may increase clearance of valproic acid and its derivatives. Phenytoin, carbamazepine, or phenobarbital, for example, can double valproic acid clearance.
On the other hand, drugs that inhibit CYP-450 (such as antidepressants) have little effect on valproic acid concentration. Valproate can decrease plasma clearance of amitriptyline, so consider monitoring this tricyclic’s blood levels in patients also taking valproate.17
Because valproic acid can increase serum phenobarbital, monitor barbiturate concentrations when using these two drugs. A similar interaction occurs with primidone, which is metabolized into a barbiturate. Breakthrough seizures may occur with phenytoin, as valproic acid can reduce phenytoin clearance and apparent volume distribution by 25%.22
