Abstract
Background:
In March 2015, pipotiazine palmitate depot antipsychotic was globally withdrawn due to the shortage of its active ingredient. Thus, all patients receiving this medication had to be switched to an alternative antipsychotic drug. In this study we set to evaluate the process of switching away from pipotiazine palmitate within our clinical service, and its impact on hospitalization.
Methods:
Demographic and clinical data on patients who were receiving pipotiazine palmitate in Northamptonshire at the time of its withdrawal were anonymously extracted from their electronic records and analyzed using descriptive statistics.
Results:
A total of 17 patients were switched away from pipotiazine palmitate at the time of its withdrawal, all of whom had a prior history of nonadherence with oral treatment. A total of 14 patients were switched to another depot antipsychotic drug, while three patients chose an oral alternative which they subsequently discontinued resulting in relapse and hospitalization. There was a five-fold increase in mean hospitalization among patients who completed a year after the switch.
Conclusion:
Switching away from pipotiazine palmitate was associated with significant clinical deterioration in patients who switched to an oral antipsychotic, whereas most patients who switched to another depot treatment maintained stability. Clinicians should exercise caution when switching patients with schizophrenia away from depot antipsychotic drugs, especially in cases of patients with a history of treatment nonadherence who prefer to switch to oral antipsychotics.
Keywords: hospitalization, long-acting injectable antipsychotics, pipotiazine palmitate, schizophrenia, switching antipsychotics
Introduction
Long-acting injectable (LAI) antipsychotics are commonly used to manage treatment nonadherence [Patel et al. 2009; Tiihonen et al. 2011], which is a major clinical conundrum and the main cause of relapse in schizophrenia [Lindenmayer et al. 2009].
Naturalistic mirror-image studies have consistently shown that LAIs reduce hospitalization, which is contrary to the findings of randomized controlled trials (RCTs) [Kishimoto et al. 2013]. This discrepancy, however, has been attributed to a non-consent bias, whereby those who consent to participating in an RCT are more likely than ‘real world’ patients to take their treatment whether it is a LAI or oral antipsychotic, resulting in equal outcomes in terms of hospitalization [Kane et al. 2013; Mustafa 2015a]. This methodological limitation, for instance, explains the stark contrast between the findings of naturalistic studies and RCTs in evaluating outcomes of community treatment orders (CTOs) [Burns et al. 2013; Rawala and Gupta, 2014].
Pipotiazine palmitate depot antipsychotic is a first generation LAI that was withdrawn in March 2015 due to a global shortage of its active ingredient, after being available for over four decades [Haddad et al. 2015]. Haddad and colleagues recommended that the decision to switch to an alternative antipsychotic should be made on individual basis in discussion with patients, taking into account their clinical risks and likelihood of nonadherence with oral treatment. Further, they advised clinicians to be vigilant regarding relapse for at least 12 months after the switch [Haddad et al. 2015].
In June 2016 we conducted a study evaluating the process of switching away from pipotiazine palmitate within our local mental health service in Northamptonshire. To the best of the author’s knowledge, no studies have previously been published on this subject. This study was approved by the local Clinical Audit and Effectiveness Committee.
Methods
A list of patients who were receiving pipotiazine palmitate at the time of its withdrawal was obtained from the hospital pharmacy and community mental health teams (CMHTs). Patients’ demographic and clinical data were anonymously extracted from their electronic records and analyzed using descriptive statistics. Hospitalization data were obtained only for patients who had received pipotiazine palmitate for at least 12 months, and who had subsequently been on an alternative treatment for at least another 12 months, in order to allow sufficient time to evaluate the risk of relapse, as suggested by Haddad and colleagues [Haddad et al. 2015].
Results
A list of 23 patients was collated. Six of them were excluded as we found they had discontinued pipotiazine palmitate prior to its withdrawal, through nonadherence. In our county (population nearly 700,000) 17 patients, who were stable on pipotiazine palmitate, discontinued it due to its global withdrawal in March 2015. In some cases, pipotiazine palmitate was stopped in late 2014 and early 2015 in anticipation of its withdrawal, whereas in others cases patients continued to receive it till later on in 2015 owing to the availability of local supplies. All cases of switching away from pipotiazine palmitate took place in the community.
A total of 13 (76.5%) patients were male while four (23.5%) were female. The majority of patients (11; 64.5%) were white British (WB), with four (23.5%) black and two (12%) Asian. A total of 13 (76.5%) patients had a diagnosis of schizophrenia while the remaining four (23.5%) patients had a schizoaffective disorder. Age ranged from 29 to 75 years with a mean age (SD) of 45 (13.6) years.
CMHTs provided care for the majority (15; 88%) of patients, 11 (64.5%) of whom had been under the care of the local Assertive Outreach (AO) service till its closure in 2014. Two (12%) patients were only treated by the psychiatric outpatient clinic. Three (17.6%) patients were under CTOs at the time of the switch, while the rest of the patients (14; 82.4%) were voluntary.
Prior to its withdrawal, pipotiazine palmitate treatment duration was 12 months or longer in 15 (88%) patients, eight months in one (6%) patient and seven months in one (6%) patient. A total of 15 (88%) patients received pipotiazine palmitate every four weeks, whereas two (12%) received it every two weeks. The monthly dose of pipotiazine palmitate ranged from 50 to 200 mg, with a mean (SD) dose of 92.4 (46.2) mg. All 17 (100%) patients had a documented history of nonadherence with oral treatment and hence were advised by their treating psychiatrists to switch to another LAI. Initially, 14 (82.4%) patients agreed to switch to another LAI, albeit in three cases this was arranged as a condition of their CTO, whereas three (17.6%) patients chose to switch to an oral alternative.
Table 1 shows pipotiazine palmitate treatment regime, immediate alternative antipsychotic drug and the antipsychotic drug at 12 months from the switch.
Table 1.
Alternative antipsychotic drug.
| Patient | Pipotiazine palmitate | Immediate alternative to piportil depot | Subsequent antipsychotic |
|---|---|---|---|
| 1 | 75 mg four weekly | Test dose of zuclopenthixol decanoate then changed to haloperidol decanoate | Haloperidol decanoate; 150 mg four weekly |
| 2 | 50 mg four weekly | One dose of paliperidone palmitate then changed to flupenthixol decanoate | Flupenthixol decanoate; 120 mg two weekly |
| 3 | 75 mg four weekly | Two doses of olanzapine pamoate then changed to flupenthixol decanoate | Flupenthixol decanoate; 120 mg weekly |
| 4 | 75 mg four weekly | Olanzapine pamoate | Olanzapine pamoate; 405 mg monthly |
| 5 | 100 mg four weekly | Haloperidol decanoate | Haloperidol decanoate; 100 mg four weekly |
| 6 | 75 mg four weekly | Oral risperidone | Zuclopenthixol decanoate; 300 mg two weekly |
| 7 | 150 mg four weekly | Paliperidone palmitate | Clozapine; 400 mg per day |
| 8 | 100 mg two weekly | Risperidone depot | Risperidone depot; 37.5 mg two weekly |
| 9 | 50 mg four weekly | Fluphenazine decanoate | Fluphenazine decanoate; 25 mg two weekly |
| 10 | 150 mg four weekly | Oral risperidone | Clozapine; 400 mg per day |
| 11 | 100 mg four weekly | Fluphenazine decanoate | Fluphenazine decanoate; 50 mg two weekly |
| 12 | 50 mg four weekly | Zuclopenthixol decanoate | Zuclopenthixol decanoate; 200 mg two weekly |
| 13 | 50 mg four weekly | Aripiprazole depot | Aripiprazole depot; 300 mg monthly |
| 14 | 100 mg four weekly | Aripiprazole depot | Aripiprazole depot; 400 mg monthly* |
| 15 | 60 mg four weekly | Flupenthixol decanoate | Flupenthixol decanoate; 80 mg four weekly* |
| 16 | 50 mg four weekly | Flupenthixol decanoate | Flupenthixol decanoate; 40 mg two weekly* |
| 17 | 80 mg two weekly | Oral olanzapine | Paliperidone palmitate; 100 mg monthly |
Patients who did not complete 12 months following the switch (for all other patients subsequent antipsychotic was at 12 months).
At the time of conducting the study, 12 (70.5%) patients had received pipotiazine palmitate for at least 12 months and also completed at least 12 months since the switch, amongst them the three patients who switched to oral antipsychotics. Seven (41%) patients were not hospitalized either the year before or the year after the switch, all of them switched to a LAI, including the three patients who were subject to CTOs. Only four (23.5%) patients were hospitalized in the year after the switching, including the three (17.6%) patients who switched to oral antipsychotics. For those 12 patients, there were three admissions (46 bed-days) in the year before the switch compared with six admissions (283 bed-days) in the year after. In the three patients who switched to oral antipsychotics, hospitalization increased from one admission (19 bed-days) in the year before the switch to five admissions (144 bed-days) in the year after.
Discussion
In Northamptonshire, an English county with a population of nearly 700,000, only 17 patients were receiving pipotiazine palmitate at the time of its global withdrawal. Compared with, for instance, the 410 patients receiving pipotiazine palmitate in Scotland [Haddad et al. 2015], this may suggest a considerable geographical variation in its use, and possibly the use of LAIs in general. The list of patients was obtained from the dispensing hospital pharmacy, as well as CMHT staff who administer LAIs at their local ‘depot clinics’, making it unlikely that any cases were missed.
The majority of patients had received care from the local Assertive Outreach (AO) service, highlighting their history of nonadherence with treatment. The low admission rate in this patient group prior to the switch emphasizes the potential role for LAIs in reducing hospitalization. Amongst those who switched to an LAI, only one patient was hospitalized. The use of CTO seemed to ensure adherence with LAI and was associated with non-hospitalization in the year before and the year after the switch, which is consistent with other observational evidence [Mustafa 2015b; Rawala and Gupta, 2014]. Conversely, all three patients who chose to switch to oral antipsychotics subsequently discontinued treatment resulting in relapse and hospitalization. Twelve months later, two of them were receiving LAIs and one was on clozapine. This finding is in line with the study by Barnes et al. [2013] which showed that switching from a LAI to an oral antipsychotic was associated with poorer clinical and functional outcomes at a one year follow up.
In summary, switching away from pipotiazine palmitate was associated with considerable clinical destabilization in patients who chose to switch to an oral alternative. In most cases, patients who switched to another LAI maintained stability, although in one case the switch was associated with a treatment resistant relapse necessitating the use of clozapine. In addition to the cost of increased hospitalization (by 515%) associated with the switch, five (29%) patients were subsequently receiving the more costly newer LAI antipsychotics, suggesting that on a national scale switching away from pipotiazine palmitate may have resulted in significant financial implications for mental healthcare services at a time of austerity.
Clinicians should exercise caution when switching patients with schizophrenia away from LAIs, especially those with a history of treatment nonadherence who prefer to switch to oral antipsychotics.
Due to the study’s retrospective design, small sample size and lack of a control group, the results must be interpreted tentatively. The role of chance and other confounding factors that may have influenced the results, such as comorbid substance misuse and health service reforms, could not be ruled out.
Footnotes
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The author has attended educational events sponsored by Eli Lilly, Janssen, Lundbeck and Otsuka.
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