| Year (month) | Agent (brand) | Key milestone | Dosing interval |
|---|---|---|---|
| 1968 | Fluphenazine decanoate (Prolixin Decanoate) | First FDA-approved LAI antipsychotic (oral fluphenazine approved 1959) | q2–4+ wk, IM/SC |
| 1986 | Haloperidol decanoate (Haldol Decanoate) | Only other first-generation LAI approved in the US; one source cites 1984, likely reflecting non-US availability | q4 wk, IM |
| Oct 2003 | Risperidone microspheres (Risperdal Consta) | First second-generation LAI; bipolar I added May 2009 | q2 wk, IM |
| Aug 2009 | Paliperidone palmitate 1-month (Invega Sustenna) | First monthly second-generation LAI; schizoaffective disorder added Nov 2014 | q4 wk, IM |
| Dec 2009 | Olanzapine pamoate (Zyprexa Relprevv) | REMS required for post-injection delirium/sedation syndrome | q2–4 wk, IM |
| Feb 2013 | Aripiprazole monohydrate (Abilify Maintena) | Bipolar I maintenance added Jul 2017 | q4 wk, IM |
| May 2015 | Paliperidone palmitate 3-month (Invega Trinza) | First LAI dosed beyond monthly | q3 mo, IM |
| Oct 2015 | Aripiprazole lauroxil (Aristada) | Prodrug; 6- and 8-week regimens available | q4–8 wk, IM |
| 2018 | Aripiprazole lauroxil (Aristada Initio) | Single-day initiation regimen | Initiation only |
| Jul 2018 | Risperidone ER SC (Perseris) | First subcutaneous LAI antipsychotic | Monthly, SC |
| 2021 | Paliperidone palmitate 6-month (Invega Hafyera) | Longest dosing interval of any LAI | q6 mo, IM |
| 2023 | Risperidone ER IM (Rykindo) | Additional IM risperidone LAI | q2 wk, IM |
| Apr 2023 | Risperidone ER SC (Uzedy) | Schizophrenia; bipolar I added Oct 2025 | q1 or q2 mo, SC |
| 2023 | Aripiprazole 2-month (Abilify Asimtufii) | Schizophrenia and bipolar I maintenance | q2 mo, IM |
| 2024 (available Apr 2025) | Paliperidone palmitate (Erzofri) | Single 351 mg initiation injection; no day-8 dose | Monthly, IM |
References
| |||
Note: Abilify Maintena is listed by one review as February 2015, but other reviews give February 2013. Exact months for Aristada Initio (June 2018), Invega Hafyera (August 2021), Rykindo (January 2023), Abilify Asimtufii (April 2023), and Erzofri (July 2024) should be verified against Drugs@FDA. Fluphenazine enanthate (circa 1966–67, since withdrawn) and non-US depots (flupentixol, zuclopenthixol) are excluded.
```I finished a memoriam to a colleague today. He was one of the best psychiatrists I have known and I know a lot of excellent psychiatrists. He was able to integrate the technical and humanistic aspects of the field to provide very high-quality care and consultation to his colleagues. We both worked in the same acute care setting for a period of about 11 years. I was primarily an inpatient psychiatrist and he was outpatient. We both ran clinical trials but he was much more active in that area.
I am
mentioning him here because of his innovative practices that preceded
widespread adoption by years if not decades.
The first innovation was a large clinic for long-acting injectable
antipsychotic medications or LAIs. The
above table lists all of the current LAIs with their approval dates in the left
column. My colleague worked at our hospital from 1981-2002, so his LAI clinic
probably only had two available options fluphenazine decanoate and haloperidol
decanoate. The older LAIs had a more
significant side effect burden. For
optimal use, careful dose adjustment and in some cases therapeutic drug
monitoring was necessary. There was also a reluctance to prescribe these
medications because of a bias that most people would not want intramuscular
injections on a regular basis. He had a very large clinic patients taking these
medications and none of those factors were a problem. As an inpatient
specialist at the time – his patients were rarely hospitalized. We had monthly quality assurance (QA)
meetings that seemed more like surgical morbidity and mortality conferences,
but at no time did we discuss different outcomes by physician or clinic or the
potential advantages of the LAI clinic.
The QA meeting were focused on criticizing care rather than optimizing
it.
When
clozapine came out in 1990, it was strictly regulated in the state of
Minnesota. The only indication was
treatment resistant schizophrenia and a normal absolute neutrophil count (ANC). For the first several years it also required
approval by a PharmD at the state level. There had to be documentation that the
patient failed on 2 antipsychotics before they were allowed to use
clozapine. Clozapine also had a Risk
Evaluation and Mitigation Strategy (REMS) before they existed. Clozapine had a risk of agranulocytosis and
therefore every patient had to have a weekly blood draw and normal ANC before
they could get the next week supply of clozapine. Over the next decade, my colleague built up
and maintained what was probably the largest clozapine clinic in the
state. He was adept at treating all of
the side effects of this medication as well as administrative complications. I
can recall calling him in a panic one day when I found out that a patient I had
discharged on clozapine to another state missed the weekly ANC determination
but was still given the next week supply of medication.
Both of these
clinics were early innovations based on both current discussions and how LAIs
are discussed in treatment guidelines.
Clozapine is now widely regarded as the most effective antipsychotic
medication with secondary applications in movement disorders. The REMS strategy
has been reduced to the point that it is done but is no longer mandatory and it
is no longer for the entire period of tie while using clozapine. Some
guidelines have incorporated additional indications such as one failed
antipsychotic or significant suicide risk.
Since better tolerated second generation LAIs have been developed the
indications have expanded to include bipolar disorder. I have personally seen patients with clear
bipolar disorder who have been stabilized on newer LAIs when nothing else
worked.
My main point
in discussing these two clinics is that they were in place and working 10-15
years before these modalities were being discussed as not being widely enough
deployed or not being utilized early enough in treatment. My colleague was focused on providing that
level of care and establishing therapeutic relationships with his patients. He
was always available for consultation and discussion. We had humorous conversations about the
personal embarrassment of polypharmacy but how some people seemed to need
it. We discussed the best ways to treat
depression with comorbid schizophrenia.
We covered movement disorders that were barely discussed in the
literature (tardive torticollis) and patient with hematological malignancies
who needed clozapine. Acute care
psychiatry can become a series of desperate situations and it is always good to
have a colleague who can reassure you that there is nothing else that can be
done.
In addition
to the clinics my colleague was also an investigator in 80 clinical trials for Alzheimer’s
Disease, Schizophrenia, Obsessive Compulsive Disorder, Major Depression,
Tourette’s Syndrome, Post Traumatic Stress Disorder, and Generalized Anxiety
Disorder. Although most were medication trials many involved psychotherapy and
quality of life outcomes. He was also a
speaker and between 1991 and 2001 gave over 200 invited presentations for grand
rounds, regional psychiatric and community meetings, and pharmaceutical
presentations.
It was not
until after I had finished writing my tribute that I thought of a piece written
by Atul Gawande about another Minnesota physician. In that piece he describes how pediatrician
Warren Warwick may have made the Minnesota Cystic Fibrosis Center at
Fairview-University Children’s hospital – the top center in the country. He being that discussion after a long introduction
of how physicians were rated on outcomes, the need for transparency in those
ratings, and how most physicians would either not want to see the results or be
reluctant to accept the results. Evidence Based Medicine (EBM) is introduced as
the standard, but it takes more than that.
All of the top cystic fibrosis centers used the same guidelines,
procedures, and medicines. Why was it that Warwick had consistently better
results in terms of much lower mortality rates.
Gawande observes
a couple of Warwick’s sessions with patients. In the dialogue he is doing much
more than a review of symptoms. He is actively exploring and confronting the
patient about their CF care. Gawande
suggests that “more nebulous factors like aggressiveness and consistency
and ingenuity can matter.” As
I read about the interaction it seemed like supportive psychotherapy to
me. The only element missing was an explicit statement about the therapeutic
alliance, but that was implied by Dr. Warwick’s: “What have you been doing to
make us the best CF program in the country?’
I am sure
that my colleague was much less direct.
He knew what his patients needed and he know that it included more than
medicine. He was able to discuss anything
with them. Years after he left, those same people would approach me in the
hallway and ask: “Have you heard from him?
How is he doing?” They all knew
he wanted the best for them and that they could problem solve with him and get
his support.
Gawande’s piece
still contains important observations 22 years later. It also has implications for psychiatry. Gawande
was writing at that time about a country wide network of 117 CF. Even before his essay these centers had
reduced CF mortality significantly from and average life expectancy of 10 in
1962 to 33 in 2003. At the best center
lifespan was 47. The questions come down
to can the reasons for these differences be measured reliably, is it a question
of a bell curve distribution of outcomes and how static is that curve, and how
important are the intangibles?
I was in a
managed care organization that attempted to measure process outcomes. One of the criticisms of psychiatry is that
there are no “hard outcomes.” Having
completed an extensive review of antidepressants and suicide risk I know that
is not true. Death and hospitalization are
both hard outcomes in psychiatry. The paradox in current healthcare measurement-based
care is that all care in the US is based on rationing. No amount of rationalization will convince me
that rationed care has quality or optimizing outcomes as a goal. Care in many of these settings is observably bad - even compared with care I personally received in 1969.
But what
would happen if we approached care like my later colleague. What if we developed networked clinics based
on LAIs or clozapine, or specific diagnostic groups. What if the goal was cooperative elevation of
the field and enhanced collegial consultation instead of avoiding difficult
problems and rationing care? What if it
was possible to learn intangibles and psychotherapy hat would enhance the
treatment process instead of the continued silo based practices?
These are
additional thoughts I had as I commemorated my colleague. They are things I wished I had asked him when
he was around.
George Dawson, MD, DFAPA
Gawande
A. The Bell Curve. The New Yorker. November 29, 2004: https://www.newyorker.com/magazine/2004/12/06/the-bell-curve
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