Geo— earth. Don—sounds like… down. To earth. Geo…Don. A drug name is born.
Welcome to the Frontier Psychiatrists newsletter. It is a leading health-satire-regulatory enthusiasm newsletter.
This article is another in my series about one drug or another. Prior installments include Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc.
Geodon: Drug, Interrupted.
Geodon—trade name, ziprasidone—is yet another “atypical antipsychotic” medicine. The other term is “second generation” antipsychotic. They have been growth products and profitable, if not so cost-effective1. Geodon has been only modestly effective in both bipolar illness and schizophrenia2. Here is what the FDA label says about Geodon:
GEODON is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of GEODON to prolong the QT interval and may consider the use of other drugs first (5.3)
GEODON is indicated as an oral formulation for the:• Treatment of schizophrenia. (1)
• Acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder.
• Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate.
And Ladies, in Case You Were Wondering If Involuntary Intramuscular Injection Was an Option for Your Man, Geodon Won’t Disappoint!
GEODON as an intramuscular injection is indicated for the following:
• Acute treatment of agitation in schizophrenic patients.
Those are the indicated conditions. Today, I learned that the entire back and forth between Pfizer and the FDA is available for this and all drugs! All study protocol violations are available. In the trial that gained approval for the use of Geodon as an augmentation agent in bipolar disorder patients who are already taking lithium or depakote (but, importantly, would later be prescribed alone or in combination with other non-studied agents), here is what happened at one particularly problematic study site:
The dirty little secret about antipsychotic medications? They aren’t THAT anti….psychotic. The whole class of dopamine-blocking antipsychotic medications have lesser standards by which they are judged for approval.
Most medications for psychiatric conditions have a “50% Reduction in Symptoms on Some Standard Rating Scale” compared to inactive placebo pills as a threshold.
“Is your intervention demonstrating efficacy in the “50% less miserable” range?”
This is the gold standard for good enoughness in depression medicine FDA approval trials. But… given the limited efficacy of antipsychotic medicines, the threshold was… adjusted for their approval.
The research rating scale of choice for symptoms in psychotic illnesses like schizophrenia is the Positive and Negative Syndrome Scale or PANSS. This is not my favorite. I am not your average person. I have personal favorites among psychometric assessments. What change in the PANSS is considered acceptable in a drug intended to treat the symptoms of schizophrenia? A 20-30% reduction in symptoms.
Yes, antipsychotics are judged effective by less stringent criteria than all other psychiatric medicines. And despite a lack of warnings by professionals like myself, withdrawal effects are commonly noted (in samples with the potential for bias3).
With a class-wide reduced expectation for antipsychotics— medicines we depend on to provide relief of serious suffering—Geodon was milquetoast in research trials for schizophrenia…only the higher dose performed better than the placebo in phase III:
The percentage of patients who were classified as responders based on a PANSS reduction of ≥30% was significantly greater than that for placebo only for the 160 mg/day group, as was also the case for classification as responder based on a final CGI-I score of ≤2.
Subsequently, the landmark CATIE study compared a variety of antipsychotic medications…
Over the 18 months of the study, 79% of those assigned to ziprasidone would stop taking it. That “churn rate” would make even a Venture-backed wellness company cringe. There is not a lot of “product-market fit” between people for whom ziprasidone is intended and ziprasidone. Some risks were immediately apparent, unique, or worse with Geodon when introduced compared to other agents.
The FDA reviewer for the drug wrote a helpful article on it! I’ll quote from him:
The sponsor (Pfizer) summitted about 40 clinical pharmacology and PK studies including QT prolongation studies. There were four capsules formulation at that time: 20, 40, 60, and 80 mg and one intramuscular (IM) strength in another New Drug Administration (NDA) that came subsequent to oral route. The drug has to be given with food to increase the bioavailability to 60% (two-fold increase).
In 2014, a new warning from the FDA about Geodon, echoing its clozapine-esque heritage with life-threatening adverse effects, was released:
Geodon ….is associated with a rare but serious skin reaction that can progress to affect other parts of the body. A new warning has been added to the Geodon drug label to describe the serious condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
The bottom line about Geodon
It’s ok. It is not great. Do not expect miracles— if you keep taking it.
It’s poorly absorbed without food. You need to eat with it. The twice-daily dosing of Geodon is fiction in practice, too— no one takes drugs as reliably twice a day as once a day, and even less reliably if you need food in your stomach to be absorbed.
People in research studies with schizophrenia stop taking Gedon almost 80% of the time. It can’t be GREAT if people don’t keep taking it. It is not appropriate to blame that on “non-compliant patients”. I have friends with schizophrenia and patients with schizophrenia. They remember to check their text messages, call me, chat, and do other things in life that are worth it. Geodon only makes the “include in life” cut 21% of the time.
It is very sedating:
I think that Geodon isn’t that anti-psychotic for an antipsychotic.
From the FDA trials on bipolar disorder, but still…Keep an eye on the P values on the far right of these tables— and if they are greater than or less than 0.05.
Note—non-significant when it comes to “positive symptoms.”
Note—again, non-significant when it comes to “positive symptoms”
“Gedon— makes many sleepy, but it doesn’t do much to ameliorate their suffering.” In the process, it leads to higher healthcare costs:
“Gedon is an expensive, weak sauce that will rarely kill you, except sometimes, and then.. horribly from DRESS syndrome.”
My most meta-point from this exercise follows.
I’m a psychiatrist. I am a theoretical expert in these medications. I have published on some of these treatments. I coauthored papers with giants like John Kane and Christoph Correll, who I consider excellent mentors. The failings? They are all mine, but I doubt I am alone.
It was only today while writing this article you are reading now, that I read the actual FDA review process notes on this medicine. Perhaps medical training should include a year of investigative journalism or newsletter muck-rakery? Doctors can make up our own minds. We rarely do—mea culpa!— to the degree we could.
Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct;63(10):1079-87. doi: 10.1001/archpsyc.63.10.1079. PMID: 17015810.
Patkar A, Gilmer W, Pae CU, Vöhringer PA, Ziffra M, Pirok E, Mulligan M, Filkowski MM, Whitham EA, Holtzman NS, Thommi SB, Logvinenko T, Loebel A, Masand P, Ghaemi SN. A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One. 2012;7(4):e34757. doi: 10.1371/journal.pone.0034757. Epub 2012 Apr 24. PMID: 22545088; PMCID: PMC3335844.
Not to be a jerk, but although the authors published one significant outcome in this small study for depression, they found that other endpoints, in mania, treated with an antipsychotic, almost all of which successfully treat mania, that was…well…not significant…which is almost a more significant finding. By the way, the “antidepressant effects” of ziprasidone in bipolar disorder did not replicate.
Read, J. (2022). The experiences of 585 people when they tried to withdraw from antipsychotic drugs. Addictive Behaviors Reports, 15, 100421. https://doi.org/10.1016/j.abrep.2022.100421
I can think of very few patients I've met with chronic psychotic disorders who have found long-term success with ziprasidone. Maybe it is just coincidence or I'm misremembering, but I'm convinced it just doesn't work as well.