New FDA Approval: Nuplazid

Drug

Pimavanserin [Nuplazid]

Indication

The treatment of hallucinations and delusions associated with psychosis in Parkinson's Disease

How it Works

Nuplazid is an atypical antipsychotic that is both an inverse agonist and antagonist at 5HT-2A receptors. It also (to a lesser extent) hits 5HT-2C receptors. Confused on the difference between an inverse agonist and an antagonist? An inverse agonist inactivates (shuts off) an active receptor. An antagonist binds to an inactive receptor and prevents it from becoming active. A common inverse agonist is Benadryl (and other antihistamines). Anyway, Nuplazid does both. It inactivates active receptors. And it prevents inactive receptors from becoming active. 

How does Nuplazid actually work in treating hallucinations in Parkinson's Disease? Not a clue. Unfortunately science doesn't know. This is par for the course for many of our drugs that work in the brain.

In general, we're looking at a big neurotransmitter balancing act. Dopamine is low in patients with Parkinson's. So we give agents that increase dopamine to try to correct this imbalance. However, too much dopamine causes hallucinations and psychosis. We're increasingly finding that other neurotransmitters have their role in this ecosystem as well. In this case, specifically shutting off certain serotonin receptors seems to help alleviate the psychosis. Because science?

Notable Adverse Effects

That box is pretty darn black...

For starters, like other antipsychotic agents, Nuplazid has a black box warning for an increased risk of death for dementia related psychosis in elderly patients. So Nuplazid can only be used for Parkinson's related psychosis. And you're going to have a good long discussion about the benefits and risks if the patient is elderly. 

Then, like some other atypical antipsychotic agents, Nuplazid can prolong the QT interval. For the pharmacy students out there, you'll want to make note of that. QT questions have a habit of popping up on the NAPLEX. They tend to show up as additive drug interactions where several QT prolonging agents are combined in one patient. Or they might show up as part of a CYP inhibition interaction. 

Speaking of drug interactions, Nuplazid is a 3A4 substrate. So you'll have to be mindful of strong inhibitors and inducers. 

Other notable adverse effects are peripheral edema (swelling of legs, ankles and feet) and confusion. It also causes hallucinations (you might remember them as the thing Nuplazid is supposed to treat....it's kind of like how arrhythmia drugs can all cause arrhythmia). 

Current Place in Therapy

Here's the thing. Nuplazid was approved from a placebo controlled trial involving an experimental group of only 202 people. Over 90% of them were Caucasian. So data is sparse and not all that generalizable. There is no renal adjustment, but it also hasn't been studied in severe renal failure (CrCl < 30 ml/min). And it hasn't been studied at all in patients with liver disease. This limits the usefulness of Nuplazid. 

That said, psychosis in Parkinson's Disease is a serious issue. Depending on where you get your stats from, it affects up to 40% of Parkinson's patients to one degree or another. And treatment options are somewhat limited.

In general, we first try to restore dopamine balance (because too much dopamine tends to cause psychosis). This is accomplished by lowering the doses of the current drug regimen. Typically you'd start by reducing the "supplemental" meds. The anticholinergics. The COMT inhibitors. The dopamine agonists. If all of that fails, you can try lowering the actual dopamine (Sinemet typically). 

Of course, you have to monitor carefully. You don't want to go so far that Parkinson's symptoms return. 

If all of that fails, then you bring on board the antipsychotics. You will practically never use a typical (first generation) antipsychotic here. Remember that they cause a strong (and specific) dopamine blockade, which is the last thing you want in a Parkinson's patient. First generation antipsychotics can cause "pseudoparkinsonism" which is exactly what it sounds like. They can produce the symptoms of Parkinson's Disease in healthy patients. So they're a no-no. 

Atypical antipsychotics are what we use in Parkinson's. The most studied and recommended are quetiapine [Seroquel] and clozapine [Clozaril]. Seroquel is far and away your best choice here (Clozaril probably is worthy of an entire tl;dr pharmacy post by itself, actually...). 

Anyway, now you have Nuplazid that fits in here too. In our opinion, you'd use it only in patients that failed Seroquel (and are bad candidates for Clozaril). There's just too little data (and too much cost) associated with Nuplazid in comparison.