We've got the drug, now invent the disease
What’s the difference between Parkinson’s Disease Psychosis (PDP) and just regular psychosis?
That depends who you ask, but the answer made a lot of difference to Acadia Pharmaceuticals when they wanted to get their new drug, Nuplazid (pimavanserin) approved to treat PDP.
PDP didn’t officially exist until 2013, when it first appeared as a diagnosis in the Diagnostic and Statistical Manual (DSM-5), the “Bible” of psychiatric diagnosis. When the previous edition, DSM-IV, came out in 1994, the psychosis seen in some Parkinson’s patients was not considered to be distinct from the psychosis anyone else might experience. The fifth and most recent edition includes PDP under the heading, “Psychotic Disorder Due to Another Medical Condition.”
Three years later, in 2016, the FDA approved Nuplazid as the first ever (and still the only) drug licensed to treat PDP.
Dopamine, delusions, & dyskinesia
The problem with PD is that one of the main drugs used to treat it, Levadopa, is known to affect dopamine levels in the brain. It is widely accepted that Levadopa (as well as many of the other drugs also used to treat PD) can cause psychosis. One solution to that is reducing the dosage of Levadopa and seeing if the hallucinations and delusions fade away. Sometimes that helps; at other times, the PD symptoms intensify and an alternative treatment is needed.
What were doctors doing prior to 2016 when desperate relatives of people with Parkinson's Disease appealed to them for help with the hallucinations, delusions, and paranoia that can often appear during treatment for PD? The patients were given other antipsychotic drugs — and there are quite a few of them to choose from — with varying degrees of success.
The next problem is that almost all antipsychotics also affect dopamine levels in the brain. This is why many people who take them develop tics, various kinds of involuntary movements which are clinically known as tardive dyskinesia and are sometimes permanent, even after withdrawing from the drugs. While some consider that a price worth paying for subduing psychosis, in the case of Parkinson’s, the motor function is already so disrupted that making it worse is extremely undesirable.
Safe and effective!
This set of circumstances is what gave Acadia its opening. While there are a few antipsychotics (such as clozapine and quetiapine) that primarily affect serotonin levels in the brain rather than dopamine and don’t impair motor function, Acadia claimed that Nuplazid had no effect whatsoever on dopamine levels and therefore didn’t have any negative effect on motor function. The clinical trial it presented to the FDA confirmed their claim, and the FDA agreed that,
As an antipsychotic, this drug is pharmacologically different from the approved antipsychotics because it appears to lack the usual dopamine blockade that other drugs in the class have. This relative lack of dopamine blockade is pharmacologically important in Parkinson’s disease patients because these patients have a relative dopamine deficiency as part of their primary disease process.
This meant that PD patients could continue taking Levadopa and add on Nuplazid to treat hallucinations, delusions, and so forth.
Well, almost...
Unfortunately for many PD patients suffering from hallucinations, delusions, and paranoia, Nuplazid wasn’t always so good at addressing psychosis. Studies revealed that clozapine and quetiapine were often better. But it was worse than that. Within the first year of Nuplazid’s approval, almost 300 deaths were connected with use of the drug, and the numbers have continued to rise ever since.
The FDA appears unconcerned. In 2018, it published a review of all the post-marketing reports of deaths and serious adverse events related to Nuplazid, concluding that,
Based on an analysis of all available data, FDA did not identify any new or unexpected safety findings with Nuplazid, or findings that are inconsistent with the established safety profile currently described in the drug label. After a thorough review, FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis. [emphasis added]
We expected the deaths, so that's okay...
The key words in the above statement are “new” and “unexpected.” The deaths weren’t unexpected at all, and they weren’t new, as they had been seen before. Where? In Nuplazid’s clinical trial.
It took the FDA just 6 months (less than the usual 10) to approve Nuplazid, which was fast-tracked through the licensing process due to its “breakthrough” status and allegedly also due to pressure from the general public. The FDA also agreed that a single successful clinical study lasting 6 weeks was enough to approve the drug, even though only 199 people were enrolled, of whom 105 took Nuplazid and 94 were given placebo.
What’s more, Acadia conducted 3 unsuccessful clinical trials for Nuplazid before finally coming up with a 4th whose results were good enough for the FDA. Even then, the benefits of Nuplazid over placebo were extremely modest, and 10 people dropped out of the Nuplazid group due to the side effects (versus 2 in the placebo group).
3 of those 10 people “dropped out” because they died.
... and they had nothing to do with the drug in any case
The FDA agreed with Acadia that the deaths were all “unrelated” to Nuplazid because the causes of death were different each time:
There is no unifying mechanism for the observed SAEs [serious adverse events]/deaths. Many of the SAEs including deaths were considered by the investigators to be unrelated or unlikely related to drug.
The FDA also pointed out (correctly) that other antipsychotics can also cause death, which it seemed to feel was a mitigating factor for Nuplazid:
Regarding safety, it is true that this drug has the same unfortunate serious adverse events (SAEs) including death as the other atypical antipsychotics, although there were only 4 on-treatment deaths in the 6-week controlled trials database, and there is an imbalance (3 to 1) in the drug and the placebo groups.
Approve now, test later
The vote that approved Nuplazid was not unanimous — it went 12 – 2 in favor of the new drug. Dr. Paul Andreason, who has since left the FDA, cast one of the “against” votes, protesting the drug's mortality rate as seen in the clinical trial.
The treatment more than doubled the risk of death and/or serious adverse events in [Nuplazid’s] pivotal trial.
To date, over 700 people are believed to have died due to Nuplazid.
One committee member who voted in favor allegedly made a “plea” to the FDA to “consider a large observational study so we can ensure that, once it goes into real-world use, the benefits will outweigh the risks.”
The FDA has yet to conduct that observational study, but other researchers have shown interest in comparing mortality rates linked to Nuplazid with those linked to other antipsychotic drugs. There are 5 such studies, all observational rather than properly designed, randomized, and blinded, but their results still have some value. Two out of the five studies show Nuplazid to be slightly less lethal than other antipsychotics; the other three show no significant difference.
Curiously, one of the FDA members who voted in favor of Nuplazid explained that “she wouldn’t have voted for the drug’s approval if there had been a safe and effective alternative on the market.”
PDP is 'unique' even though we can't quite define it...
Neither clozapine nor quetiapine are FDA-approved to treat PDP; they are only licensed for schizophrenia (and sometimes also acute mania and various forms of depression). Whether or not one can truly distinguish between schizophrenia and PDP is a controversial issue. Some researchers believe that PDP is “unique”:
The psychosis associated with PD, mostly hallucinations and delusions, is unique. Unlike those with primary psychotic disorders, visual hallucinations are more frequent than auditory ones. Episodes tend to occur at the end of the day and in dim light. Delusions can be both persecutory or jealousy based. Of note, people with PDP tend to have a clear sensorium. They do not present as cognitively muddled or cloudy, which should be considered when contemplating PDP treatment.
Others say that while there are “no standardized diagnostic criteria for psychosis associated with Parkinson's disease,” PDP is nonetheless something very different from non-PD psychosis (and also has very gloomy prospects):
PDP is associated with a poor prognosis of chronic psychosis, nursing home placement, and death...
Findings suggest that PDP may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorderor drug intoxication.
However, other researchers dispute these claims and suggest that PDP is a sham diagnosis created in order to open a niche for a specialized drug to treat it. They define PDP as Parkinson’s Disease plus psychosis, pointing out that the diagnostic criteria are simply psychotic features plus Parkinson’s Disease, and noting that there is evidence to suggest that Levadopa may not actually be a cause of psychosis after all.
... but Nuplazid can be used in schizophrenia too!
After Acadia acquired breakthrough status for Nuplazid based on its being a unique treatment for a distinct condition, Acadia started testing Nuplazid for use in schizophrenia, in the exact same dose as it was giving for Parkinson’s Disease Psychosis, which was supposedly something else entirely.
This time around, however, the attempt failed — Nuplazid crashed in its phase 3 trial when the placebo did just as well as the drug.
“We are disappointed the trial did not meet its primary endpoint given the significant unmet need in patients with negative symptoms of schizophrenia,” said Steve Davis, Chief Executive Officer of Acadia.
Davis was right in claiming that people with schizophrenia have many unmet needs. All the drugs offered, including Nuplazid, have a terrible side-effect profile and promise no hope of recovery, only “management.”
Meanwhile, Acadia can console itself with the estimated $1 billion per year it is making managing Parkinson’s patients.
