It’s nice when we can get our patients better with a single medication, but that’s not always possible. Sometimes the right combination of meds can do the trick, but studies of polypharmacy are scarce. In this article we dig through that research, small and limited as it is, to highlight a few useful combinations where the drug interaction can benefit your patient.

Stimulants with clonidine or guanfacine
Stimulants can raise blood pressure, which tends to be a problem as patients age. Adding an antihypertensive is a common solution, and two alpha-agonists, clonidine (Kapvay) and guanfacine (Intuniv), have FDA approval for both hypertension and ADHD. It sounds like a match made in heaven—but what do the data show?

This strategy was tested out in a randomized controlled trial in 207 children ages 7–14. It compared the combination of dex-methylphenidate XR (Focalin XR, 5–20 mg/day, average 15 mg/day) and guanfacine (1–3 mg/day, average 0.03 mg/kg/day) with each of those meds on their own. After 2 months, the combination strategy treated ADHD more effectively than either of the monotherapy arms. Side effects were also more favorable. The combined treatment had less blood pressure elevations than stimulant alone, and less fatigue than guanfacine ­monotherapy.

The combined treatment also had less QTc prolongation. That’s important, as QTc prolongation is partly responsible for the rare cases of sudden cardiac arrest on stimulants. In contrast, other ADHD augmentation strategies—bupropion, atomoxetine, and modafinil—can further elevate both blood pressure and QTc.

There was no apparent downside to this strategy, but the benefits were not very large, and neither drug completely reversed the side effects of the other (McCracken JT et al, J AACAP 2016;55(8):657–666).

TCPR recommendation: Combining stimulants and guanfacine (and possibly clonidine) is a sensible strategy in ADHD, particularly when cardiac risks are present.

Dopamine agonists and SSRIs
The dopamine agonists pramipexole (Mirapex) and ropinirole (Requip) are FDA-approved for restless leg syndrome (RLS) and have antidepressant qualities in their own right. Of the two, pramipexole is better studied in depression and has worked in small, controlled trials of both bipolar and unipolar depression. Further, in one trial, patients with hard-to-treat MDD who received pramipexole combined with an SSRI/SNRI achieved better response than patients taking an SSRI/SNRI and placebo (Cusin C et al, J Clin Psychiatry 2013;74(7):e636–e641).

In terms of side effects, serotonergic medications can sometimes cause RLS (Debattista CB et al, J Clin Psychopharm 2000;20(2):274–275). Pramipexole can treat SSRI-induced RLS. That benefit, along with its ability to augment SSRIs in treatment-resistant depression, makes this an intriguing combination.

When using pramipexole, starting low (around 0.125–0.25 mg per day) and increasing the dose slowly (by 0.25 mg every week) helps reduce nausea and orthostasis, two common side effects with this drug. Sedation is also possible, and there have been rare reports of visual hallucinations and compulsive behaviors such as gambling (Aiken CB, J Clin Psychiatry 2007;68(8):1230–1236).

TCPR recommendation: When patients complain of restless legs on serotonergic antidepressants, try a low dose of pramipexole for RLS. The dose can be raised if depressive symptoms ­persist.

Lithium and carbamazepine
Lithium and carbamazepine might not be the first drugs you’d think about combining, given that they both have significant adverse reactions and potential toxicity. But there are reports that these drugs can cancel out some of each other’s side effects. In particular, they have opposite effects on sodium and white blood count. Carbamazepine can lower sodium by raising SIADH, whereas lithium raises sodium by causing the opposite syndrome, diabetes insipidus. Small studies have concluded that lithium protects against hyponatremia on carbamazepine (Vieweg V et al, Am J Psych 1987;144(7):943–947).

In addition, carbamazepine can cause a potentially dangerous neutropenia, while lithium increases white blood cell production. In a placebo-controlled study, lithium successfully reversed the neutropenia that was induced by carbamazepine (Kramlinger KG and Post RM, Am J Psych 1990;147(5):615–620).

Beyond side effect neutralization, there may be an efficacy advantage with this combination. There are open-label studies of patients who did not respond to lithium or carbamazepine alone but who then responded to the two drugs together (Lipinski JF et al, Am J Psych 1982;139(7):948–949). The combination is particularly helpful in rapid-cycling bipolar disorder (Strömgren LS, Comprehensive Psych 1990;31(3):261–265).

This combination is not without its risks. Lithium and carbamazepine can have additive effects toward hypothyroidism, and there are rare reports of neurotoxicity even with normal plasma levels of each drug (Kim MD et al, Jefferson J Psych 1988;6(2):63–72).

TCPR recommendation: For patients with rapid-cycling or treatment-resistant bipolar disorder, the combination of carbamazepine and lithium can be effective, even if neither of those meds worked on their own. Lithium can help reverse drops in white blood cells, neutrophils, and sodium caused by carbamazepine.

Clozapine and fluvoxamine
Clozapine is one of the less friendly atypicals when it comes to weight gain, diabetes, and triglycerides. Most of those metabolic side effects are not due to clozapine itself but to its metabolite, norclozapine. Fluvoxamine (Luvox) blocks the conversion of clozapine into norclozapine by inhibiting the CYP1A2 enzyme. In theory, combining these drugs creates a more tolerable version of clozapine.

This strategy has been used since the 1990s, but it wasn’t tested in a randomized controlled trial until this year. In that study, 85 patients with schizophrenia were given clozapine either as monotherapy (300 mg/day) or in combination (clozapine 100 mg/day with fluvoxamine 50 mg/day). After 3 months, the combination group had significantly less weight gain, insulin resistance, glucose, and triglycerides compared to clozapine monotherapy. The combined group also had greater improvement on the PANSS psychopathology scores.

Serum levels of clozapine were similar in both groups, but as predicted, the norclozapine metabolite was lower in the combination group (Lu ML et al, Schizophrenia Research 2018;193:126–133).

TCPR recommendation: For patients who need to stay on clozapine but have significant side effects with the medication, you could consider carefully adding fluvoxamine. However, drug interactions are difficult to predict, so check a clozapine level before and after adding fluvoxamine, and follow it regularly while using them together.

TCPR Verdict: When polypharmacy is needed, look for combinations that reduce the side effect burden instead of raising it.