Injectable Antipsychotics

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© Springer Nature Switzerland AG 2020
O. FreudenreichPsychotic DisordersCurrent Clinical Psychiatryhttps://doi.org/10.1007/978-3-030-29450-2_18



18. Long-Acting Injectable Antipsychotics



Oliver Freudenreich1 


(1)
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

 


Keywords

Long-acting injectable antipsychoticsLAIsRelapse preventionBenefitsIndicationsHarm reductionPatient selectionLAI choiceContraindicationsInjection clinic



Essential Points






  • Preventing psychotic relapse is one of the most important goals of treatment for schizophrenia. Antipsychotics are highly effective to prevent relapse (NNT = 3) but only if taken.



  • Long-acting injectable antipsychotics (LAIs) reduce relapse and mortality in patients with schizophrenia. They should be the default option (i.e., patient need to opt out) for patients who require antipsychotic maintenance treatment in order to assure continuous care. Clinician attitude against LAIs more so than patient attitude is a major reason for the underuse of LAIs.



  • Patients who should preferentially receive LAIs include first-episode patients and schizophrenia patients with forensic histories.



  • There is benefit from making nonadherence readily transparent. It frees clinicians and families to focus on treatment issues other than adherence.



  • Consider LAIs as a harm reduction strategy to delay the inevitable as long as possible for patients unlikely to adhere to psychiatric treatment.



  • The LAI choice is determined by patient choice, taking into account side effects and injection frequency but not efficacy which is about equal between LAIs.



  • LAIs are no substitute for rehabilitation or a clozapine trial in refractory patients.



  • Make things convenient for patients but not too convenient. Rare contact with the treatment team risks treatment disengagement.



  • Setting up “injection clinics” which may be virtual allows for population-based management and safe care (e.g., guideline-concordant monitoring).




“Der Ball ist rund, und das Spiel dauert 90 Minuten.” [1]


(The (soccer) ball is round and the game (of soccer) lasts 90 minutes.)


–Josef “Sepp” Herberger (1897–1977); fabled coach of 1954 West German soccer team


Long-acting injectable antipsychotics (LAIs) are in important tool in the long-term management of schizophrenia so I dedicate a whole chapter to them. I already made the argument for the critical importance of relapse prevention for schizophrenia as an example of tertiary prevention in Chap. 9 on prevention and staging. While antipsychotics are highly effective in preventing relapse (NNT = 3) [2], the oral route of administration is often problematic, and many patients relapse because of insufficient adherence. In this chapter, I examine the benefits of long-acting preparations of antipsychotics over their oral pendants and make the case for the routine first-line use of LAIs for most patients with schizophrenia in order to assure continuous care [3] in the service of improved functional outcomes [4]. Despite the clear challenges with adherence to oral antipsychotics, many clinicians are ambivalent and persist in using oral antipsychotics, without offering LAIs to their patients [5]. Even if the resistance stems from patients, clinicians must learn communication skills to nudge patients toward a LAI [6]. Emphasizing procedure rather than benefit, for example, is a common mistake [5]. Sepp Herberger’s famous quote about the game of soccer (see epigraph) admonishes us to not lose sight of simple facts. In our case, that long-term management of schizophrenia is fundamentally simple: long-term remission matters, and LAIs are excellent tools to achieve this goal. Remembering what is at stake and being mentally prepared will allow you to effectively counter a patient’s arguments against the use of LAIs. If education is done well, the vast majority of patients will accept treatment with a LAI. In a clinical trial of LAI for first-episode patients termed PRELAPSE, only about 10% rejected study participation because of the injection, and over 90% of participants accepted the actual injection during the treatment phase [7].



Key Point


The more difficult and ultimately most important task for a psychiatrist is not the treatment of an acute episode of psychotic illness but keeping patients stable over time. LAIs are the most effective tool to achieve the goal of relapse-free remission and the best possible recovery. Clinicians need to convey this message to patients effectively.


Advantages over Oral Antipsychotics


To clinicians, it appears obvious that a monthly LAI offers an efficacy advantage with regard to relapse over oral pills that need to be taken daily (and can be forgotten daily). Several randomized trials have indeed confirmed the benefit of LAIs over oral antipsychotics, for both chronic [8] and first-episode patients [9]. However, there have been many more studies that failed to show that LAIs are better than oral medications to prevent relapse [10], an apparent efficacy paradox. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) was one such relapse prevention study that assigned patients to either LAI risperidone or an oral second-generation antipsychotic of the physician’s choice [11]. In this large and well-conducted trial, there was no difference between the two groups with regard to relapse. Rather than questioning the value of LAIs, PROACTIVE perhaps simply shows that good clinical care (provided not just to the LAI intervention group but also to the oral control treatment arm) makes a difference in patient outcomes. In addition, it may very well be one example where a randomized trial may not be the gold standard to answer a particular clinical question [12]. Patients in a clinical trial do not represent the typical clinic patient who you would like to transition to a long-acting injectable. Mirror-image studies (a design where you contrast an outcome pre- and post-intervention, in this case before and after a transition to LAIs) conducted in real-world clinical populations have uniformly confirmed the superiority of LAIs over oral antipsychotics [13].


A nationwide study in Sweden found a reduction in mortality for schizophrenia patients treated with second-generation antipsychotics compared to no treatment [14]. With the exception of oral aripiprazole, LAIs were better than their oral counterparts, reducing mortality by about 33% more. The mode of administration matters: this survival benefit is a very strong argument for using LAIs routinely.



Key Point


LAIs are more effective in reducing relapse and mortality compared to oral antipsychotics. Put differently, the route of administration of antipsychotics has survival benefits which would be newsworthy were it a cancer treatment.


In addition to the obviously highly relevant benefits for relapse prevention and mortality reduction, LAIs have other advantages that are less apparent. Perhaps most importantly for all stakeholders, LAIs allow for an open discussion of adherence as nonadherence is readily apparent when a patient misses an injection. It frees families to be family and not the adherence police (an unthankful role for any parent), and it frees clinicians to focus on issues other than trying to figure out adherence. It allows for informed decisions if there are symptoms as opposed to trying to make a notoriously difficult guess about partial adherence. Many patients are quite receptive when they hear that there is a preparation of their medicine where they do not have to remember to take a pill every day. With longer preparations available or in development, LAIs are even more convenient (but see limitations below).


The REMIND trial reminded us that our usual tools to assist motivated patients remember taking oral medications for chronic conditions (i.e., a pillbox) are imperfect [15]. In this large, pragmatic trial, patients who were taking up to three medications for chronic conditions either received pillboxes (some with reminder functions) or they did not. Only 15% of patients achieved optimal adherence, with no better adherence in the patients who were provided pillboxes. Even in motivated patients, LAIs may therefore be the practically better option if we want to avoid inadvertent adherence. Simple, low-cost reminders alone may not do it. Be careful transitioning patients back to oral medications “to increase autonomy” after they have been stabilized on LAIs. LAIs may just be what is needed to achieve stability.


Patient Selection


In the old days, first-generation LAI were reserved for patients who had failed oral medications. For many clinicians, LAIs represented a treatment of last resort, often reserved for patients with “no insight.” Patients often perceived the use of LAIs as punitive. This thinking is slowly shifting. The NICE Schizophrenia Guideline suggests offering LAIs to patient (1) who prefers such treatment after an acute episode and (2) where avoiding covert nonadherence (either intentional or unintentional) to antipsychotics is a clinical priority [16]. An even stronger argument can be made (see above) that LAIs should be the preferred mode of administration for any patient who requires maintenance treatment, given their established efficacy and survival advantages over oral medications. At a minimum, LAIs should be presented to all patients as a choice on par with oral antipsychotics. In addition, patient groups who are very likely to discontinue antipsychotics or who have much to lose if there is a psychotic relapse should be prioritized for LAIs. Examples are first-episode patients who are trying to piece their lives back together after their first psychiatric hospitalization or patients at high-risk for criminal offending when they are psychotic. Long-term follow-up studies [17, 18] and randomized trials [9] have clearly established that LAIs are effective medications to prevent early relapse in young first-episode patients. LAIs to assure medication persistence may be even more important for first-episode patients who use substances [19]. PRIDE (Paliperidone Palmitate Research in Demonstrating Effectiveness) showed the benefit on reducing arrest rates if patients with criminal histories were given a long-acting injection prior to hospital discharge [8]. Table 18.1 summarizes clinical indications for LAIs that have face validity.


Table 18.1

Indications for LAIs




























Routine care for maintenance phase of schizophrenia


Strong considerations


First-episode schizophrenia


High-risk for forensic offending


Serious illness course


Partial adherence due to co-morbid drug use


Rule-out treatment-refractory schizophrenia


Others


Maintenance phase of bipolar disorder


Harm reduction in nonadherent patients


Court-ordered antipsychotic maintenance treatment


While lithium remains the most gold standard mood stabilizer for all phases of bipolar disorder, antipsychotics, including long-acting antipsychotics, are increasingly used to manage bipolar disorder [20]. Particularly second- and third-generation antipsychotics are now routinely used and recommended to manage acute mood episodes and to prevent relapse [21]. Perhaps not surprisingly, a large Finnish cohort study found that, in bipolar patients, long-acting injectables were more effective in reducing psychiatric (and medical) hospitalizations than their oral counterparts [22].



Key Point


Consider LAIs the treatment of choice for all patients, at all disease stages (first episode, chronic). LAIs should be the default option, where patients need to opt out.


Harm Reduction


Discharge patients unlikely to adhere to psychiatric treatment on a long-acting injectable antipsychotic. I had learned about this approach first when I visited a hospital in Addis Ababa where the very pragmatic psychiatrists described this as a common discharge plan when long-term follow-up could not be guaranteed in resource-poor settings of rural Ethiopia. In that way, it bought families a few months of normalcy.



Tip


LAIs can be used as a risk mitigation strategy [23]: if adherence is unlikely, a longer-acting antipsychotic preparation delays relapse after medication discontinuation.


If LAIs are not an option, consider an oral antipsychotic with a long half-life such as cariprazine which has an effective half-life of the active moiety of 1 week [24]. In one analysis of a cariprazine relapse prevention study where patients received either cariprazine or placebo after acute stabilization, placebo relapse was delayed by several weeks compared to antipsychotics with shorter half-lives. This property may buy clinicians more time to address adherence, particularly partial adherence [25].


Contraindications to LAIs


LAIs are not a good option for all patients with schizophrenia (see Table 18.2). LAIs are not a substitute for clozapine if patients have treatment-refractory schizophrenia. It turns out that clozapine has real-world effectiveness for relapse prevention that mirrors those of LAIs [26]. They also pose risks related to their long half-life: once administered, an injection cannot be taken away which can result in difficult-to-manage situations (e.g., if NMS develops or the patient experiences severe akathisia). LAIs can therefore only be given to patient known to tolerate the oral pendant which requires an oral treatment period prior to giving an injection. However, side effects may only become apparent weeks later. Be careful with loading strategies and avoid overshooting, particularly when using the decanoates as you may cause severe EPS [27]. NMS appears to be rare with second-generation LAIs. In a review of a clinical trials database for long-acting paliperidone, only 1 patient out of 5000 (which translates to less than 0.1% incidence per year) experienced an episode of NMS from which he recovered [28].
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Aug 14, 2021 | Posted by in PSYCHIATRY | Comments Off on Injectable Antipsychotics

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