Every day we are faced with prescribing dilemmas that don’t have ready answers. Instant or extended release? Brand or generic? With food or without? How should we adjust dosing to account for drug interactions, age, gender, ethnicity, or genetic testing results? Our new textbook Prescribing Psychotropics: From Drug Interactions to Pharmacogenetics is packed with answers to questions like these, and in this issue, we’ve reprinted some of our favorites.

Bupropion SR, XL, or Aplenzin?

When bupropion first came out in 1985, it caused a big problem. The drug creates a risk of seizures that is dose dependent, and it was launched with a liberal maximum dosage of 600 mg/day. Patients could push that dose even higher by accidentally doubling up on their pills, an easy mistake to make with bupropion’s immediate-release formulation that required TID dosing. The result was an alarming 3% risk of seizures, and the drug was withdrawn after less than a year on the market.

Bupropion was re-released in 1989 with a more cautious maximum daily dose of 450 mg. At this dose, the seizure risk fell to 0.4%, and at 300 mg it was 0.1%, about the same as the risk with SSRIs and close to the rate of new-onset seizures in the general population (0.08%). Later, extended-release formulations reduced those rates even further by smoothing over the peak plasma levels and lowering the chance of accidental double dosing. With those improvements, bupropion now has one of the lowest epileptogenic potentials of all antidepressants. In a 2018 meta-analysis, clomipramine had the highest seizure risk, followed by amitriptyline, venlafaxine, citalopram, sertraline, trazodone, mirtazapine, paroxetine, bupropion, escitalopram, fluoxetine, and duloxetine (Steinert T and Fröscher W, Pharmacopsychiatry 2018;51(4):121–135).

While the extended-release formulation is a safer option, there are now three versions to choose from: sustained release (SR), extended release (XL), or Aplenzin—which is a new, branded version of bupropion. Aplenzin has similar pharmacokinetics to bupropion XL, but it uses a different binding agent: hydrobromide instead of hydrochloride. Both bupropion XL and Aplenzin can be dosed once a day, but XL is generally less expensive than Aplenzin because it is generic—and for this reason, we recommend prescribing XL over the newer product.

Bupropion also has a reputation for causing anxiety and mild agitation, and this is where the immediate-release formulation still has a role. Those problems improve with slow titration, and immediate-release bupropion allows that with its low 75 mg dose. Starting there and raising by 75 mg every week is useful in sensitive populations, like the young, the old, and those with anxiety or bipolar disorders.

CARLAT TAKE

Bupropion is probably safer and better tolerated in its extended-release forms, although the immediate release is useful for slow titrations. Most of the time, bupropion XL is preferred.

Better lithium dosing

Most patients prefer extended-release lithium over the immediate-release lithium carbonate, and for good reason. The extended-release versions cut the rate of many side effects in half, including nausea, tremor, and possibly cognitive dulling and urinary frequency. However, if your patient complains of diarrhea as a side effect, consider switching to immediate-release lithium, which is less likely to cause this problem.

There are two versions of extended-release lithium—lithium ER (Lithobid) and CR (Eskalith)—and they have slightly different pharmacokinetics. Lithium CR releases slower and has a smoother peak than lithium ER. In theory, that might improve tolerability, and some patients appreciate that CR allows them to take their dose with fewer pills (it comes as 450 mg, while ER is 300 mg). The kidneys also appreciate the smoother peaks of these formulations, as renal impairment is linked to high serum levels of lithium. It may be possible to avoid renal problems altogether by keeping the serum level within the recommended maintenance range of 0.6–0.8 mmol/L (0.6–0.8 mEq/L). In a 12-year cohort study, every level above that range raised the risk of renal impairment, but the kidneys were spared when the levels stayed within those limits (Clos S et al, Lancet Psychiatry 2015;2:1075–1083).

Another way to reduce lithium’s renal risks is to give the entire dose at night. That strategy worked better than BID dosing in a few controlled studies, and it makes sense with lithium’s half-life of 18–24 hours (Girardi P et al, Drugs R D 2016;16(4):293–302). But wait. Didn’t we just say that the kidneys do better when lithium’s levels are spread out? The kidneys are finicky organs. They like their lithium levels low, and they also like to get a break from lithium for part of each day. Dosing in the evening with an extended-release formulation satisfies both ends.

CARLAT TAKE

Extended-release lithium is better tolerated than immediate-release lithium, unless the side effect in question is diarrhea. To protect the kidneys, give lithium all at night and avoid levels above 0.8 mmol/L.

Olanzapine: Swallowed or dissolved?

Orally disintegrating medications are usually prescribed when patients have difficulty swallowing, but olanzapine ODT (Zyprexa Zydis) has two other purported advantages. In emergency settings, the ODT is thought to provide rapid relief of agitation by dissolving quickly in the mouth. In theory, this route also lowers the risk of weight gain because the medication is absorbed in the oral mucosa and goes directly into the systemic circulation, allowing it to bypass the appetite-regulating serotonin receptors in the gut. Sounds plausible, but how well do these ideas hold up?

To determine if the ODT form of olanzapine works faster than the standard oral version, researchers compared them in 11 healthy people. Each subject received three versions of olanzapine 5 mg, about two weeks apart: regular olanzapine tablets, olanzapine ODT swallowed, and olanzapine ODT delivered sublingually.

After 10 minutes, both ODT forms were detectable in subjects’ serum, whereas it took 30 minutes for the tablet form to be detectable. There was no statistically significant difference between swallowing the ODT and allowing it to dissolve sublingually (Markowitz JS et al, J Clin Pharmacol 2006;46(2):164–171). The bottom line is that olanzapine ODT is a good choice for rapid control of agitation when patients are willing to take a pill, and it has the advantage of being very difficult to cheek because it dissolves almost instantaneously.

Turning to weight gain, the picture gets murkier. In the 2000s, there was hope that olanzapine might cause less weight gain in its ODT form, as nine open-label studies and case reports documented weight loss (half a pound a week, on average) after switching from standard olanzapine to ODT. Those hopes were dashed, however, when three randomized, placebo-controlled trials failed to find any difference in weight gain between the two formulations (Kusumi I et al, Prog Neuropsychopharmacol Biol Psychiatry 2012;36(2):313–317).

CARLAT TAKE

Olanzapine ODT is useful for acute control of agitation and psychosis, but it is no less likely to cause weight gain than regular olanzapine.

Dosing by half-life

When a manufacturer releases a medication, they usually base the dosing schedule on its half-life. A medication with a 24-hour half-life is dosed once a day (QD), a med with a 12-hour half-life is dosed twice a day (BID), and a drug with an eight-hour half-life is dosed three times a day (TID). However, as years go by, clinicians often end up ignoring recommended dosing intervals and simplifying the schedules to once a day. That makes dosing easier for patients to follow, but does it compromise the drugs’ efficacy?

A few studies have tested this out, comparing QD to BID dosing for antipsychotics and antidepressants with short half-lives (eg, trazodone, clozapine, quetiapine, and ziprasidone). In all cases we’re aware of, the two dosing strategies had the same clinical outcomes. Most likely, the drugs’ therapeutic benefits depend on downstream effects like neurotropic factors and receptor adaptation, and the brain doesn’t require constant steady-state exposure to the drug to achieve those effects (Yýldýz A and Sachs GS, J Affect Disord 2001;66(2–3):199–206).

However, changing the dosing interval does significantly impact side effects. Sedation improves with evening dosing, a strategy that has been successfully employed with antidepressant doses of trazodone, which can be given entirely at night. Other side effects may improve with divided dosing, particularly the side effects that worsen as a medication’s level peaks: nausea, dizziness, fatigue, orthostasis, and QTc prolongation.

CARLAT TAKE

Psychiatric medications with delayed benefits can usually be given once a day without loss of efficacy. This strategy improves some side effects like sedation. Other side effects, though, are alleviated by spreading out the dose and lowering the drug’s peak levels.

Do drugs with long half-lives take ­longer to work?

There’s a myth that drugs with long half-lives take longer to work than drugs with short half-lives. Apparently, this comes from misinterpreting the meaning of steady state. It’s true that meds with long half-lives take longer to reach steady state. For example, fluoxetine, in concert with its metabolite norfluoxetine, has a half-life of about two weeks and takes two and a half months to reach steady state. Nonetheless, fluoxetine works just as quickly as antidepressants with short half-lives (Gelenberg AJ and Chesen CL, J Clin Psychiatry 2000;61(10):712–721). Evidently, serotonin receptors aren’t waiting around for fluoxetine to reach steady state.

Antipsychotic-carbamazepine pairings

Many of the medications that are commonly paired with an antipsychotic will change the antipsychotic’s blood levels. Bupropion, duloxetine, valproate, and most SSRIs (except citalopram and escitalopram) raise some antipsychotic levels, while carbamazepine lowers nearly all of them. That’s a problem when you need to augment carbamazepine with an antipsychotic due to breakthrough mania. The worst choice in those cases is quetiapine. Carbamazepine not only lowers quetiapine levels by 80%, it speeds quetiapine’s conversion into norquetiapine, a compound with antidepressant properties that has been linked to manic switching (Rovera C et al, Drug Saf Case Rep 2017;4(1):13). Instead, choose asenapine, the only atypical antipsychotic with no significant carbamazepine interactions.

Asenapine has a catch, however. It may not waver in the face of carbamazepine, but it can raise levels of other psychotropics through CYP2D6 inhibition. Most other antipsychotics do not inhibit or induce the major metabolic enzymes, so don’t worry about upsetting other drug levels when adding them to a patient’s regimen.

CARLAT TAKE

Asenapine is a good choice for carbamazepine augmentation, but it may increase the levels of other psychotropics.