The authors have declared that no competing interests exist.
Second-generation antipsychotics have relatively recently become available in long-acting intramuscular formulations (LAIs) and have been receiving a substantial amount of pharmaceutical industry promotion on the grounds that they improve treatment adherence in patients with psychotic illness. LAIs do have some drawbacks, however, which is the topic area covered by this review. A Global Scholar search of the nursing and medical literature reveals several factors that can negatively impinge on the clinical efficacy of LAIs: 1. The extent of training of injection personnel 2. The quality of surveillance of patient symptoms and side effects 3. The skilled use of the full range of injection techniques 4. The extent of drug accumulation over time 5. The potential loss of drug dose flexibility 6. The impact of exercise and temperature on drug distribution 7. The burden of the medication routine and the social burdens of LAIs 8. The safety of LAIs during pregnancy 9. The perceived coerciveness of LAIs 10. Issues of overdose and polypharmacy 11. Issues of cost 12. The important issue of responsibility for self-management of illness. Although the evidence is clinical and anecdotal, LAIs appear to work well for many patients, but their drawbacks are not negligible. Clinicians need to weigh individual risks and benefits when making treatment decisions.
Long-acting intramuscular formulations of antipsychotics medications (LAIs) have been in clinical use since the early 1960s for the treatment of schizophrenia and related conditions. Second-generation antipsychotic LAIs have been made available more recently. An LAI means that the active drug is injected into a large muscle from where it gradually disperses, usually over several weeks, into the bloodstream and, hence, into the brain where it attaches to target neuroreceptors that control the transmission of key neurochemicals. By partially blocking transmission, the drug prevents the emergence of psychotic symptoms. The assurance of a long duration of blockade offers many advantages for patients who suffer from chronic forms of psychosis. The injection obviates the task of taking oral medications on a daily basis, a problematic task for many individuals who are diagnosed with schizophrenia and related conditions. It is easy to forget to take the daily pills, to run out of pills before a new prescription can be filled, or to abandon pills altogether when side effects emerge, or when one decides that medication is not needed. Because stopping antipsychotic medication leads to a very high rate of psychotic relapse, relatively strict adherence to a prescribed regimen is usually critical to well-being. LAIs, which are consistently reported to markedly improve treatment adherence
The first step in undertaking this review was to search the nursing and medical literature in Google Scholar with the following search terms: Long-acting antipsychotic, depot antipsychotic, intramuscular antipsychotic. This initial probe was followed by a search of published guidelines relevant to the administration of long-acting intramuscular antipsychotics. By the end of both search strategies, several findings relevant to the effectiveness and safety of LAIS had emerged from the published literature. They were: 1. The person who administers the injection requires training and experience 2. Accurate symptom and side effect surveillance is critical to safety 3. The injection technique needs to be adjusted to specific individual needs and also to the specific nature of the injected compound 4. Drug accumulation over time can be a problem, but can also be a benefit 5. Dosing flexibility is lost when a person receives an LAI and no oral medication 6. Drug dispersal from the muscle site of the LAI is affected by exercise and by heat 7. LAIs pose specific treatment burdens on the patient 8. LAIs are not considered safe during pregnancy 9. LAIs may be perceived as coercive 10. LAIS lower the risk of overdose but increase the risk of polypharmacy 11. The cost of LAIs may be an issue for some patients 12. Personal agency and the possibility of self-management may be lost for patients on LAIs. This review summarizes what is known about these twelve topics in order to aid clinical decisions.
The importance of continuity, training, and experience in injection giving Long-acting intramuscular formulations have been reported to be more effective than orally administered drugs for patients with schizophrenia in both naturalistic studies and in clinical trials
In real life, a variety of people in a wide range of settings may be the ones to administer an LAI. It may be a community nurse in the patient’s home or a psychiatric nurse in a hospital clinic, or an office nurse in a family doctor’s practice. Sometimes, the primary physician or the psychiatrist gives the injection. The injection provider may be a different person from week to week; continuity in that role is difficult to maintain. The person may, or may not, be well-trained. Experience varies widely among real life injection givers, as does the amount of time they can spend with the patient, the depth of their knowledge about the patient’s background and illness, their ability to accurately detect changes in the patient’s mental state, and their ability to recognize drug side effects.
In the 1970s, one of my patients was receiving long-acting fluphenazine decanoate every three weeks to treat long-standing psychotic illness. When the patient started a 9 to 5 rehabilitation program, I was unable to see her after hours so an evening-shift nurse offered to see the patient, administer the injection, and act as a liaison between the hospital and the rehabilitation program. The nurse and I met regularly to discuss the patient’s progress. After a few months, I was told that the patient was not doing well in the program. The rehabilitation staff complained that she was “acting hysterical, grimacing at male patients in a flirtatious way, inappropriately winking at them.” The nurse talked to the patient about this behavior, but it got worse rather than better. Eventually, the rehabilitation program asked the patient to leave and I was able to see her again. The grimacing and winking and inappropriate behavior turned out to be drug-induced tardive dyskinesia, unrecognized by the nurse and by the rehabilitation personnel. Signs of tardive dyskinesia in the 1970s were not infrequently dismissed as “hysterical”
In real life, patients with long standing psychotic symptoms are difficult to engage in counseling and are often seen only summarily by their psychiatrists – infrequently and for very brief appointments. When patients are taking oral medication, pharmacists require the periodic renewal of the prescription, which guarantees periodic face-to-face visits with the doctor. When patients receive depot injections, hospital regulations sometimes allow written prescription renewals without face-to-face meetings. Months may go by before a patient’s symptoms and side effects are medically checked. This, of course, can be corrected by training the nurse who gives the injections to monitor medical symptoms and adverse effects, and by changing hospital regulations to require all psychiatrists to see their patients regularly whether on medication or not.
A memory that stands out for me is that of a patient who had been coming for monthly depot injections for two years without telling anyone at the clinic of a lesion on her breast and without anyone noticing her severe weight loss until her breast cancer had become inoperable.
The perfection of proper technique for administering long acting injections of antipsychotics requires training and practice
Depending on the skill and experience of the injector, injections can be painful, can sometimes by accident enter a blood vessel
Long-acting injections are usually given every two, three, or four weeks on the assumption that the muscle store is depleted at the end of that period. Antipsychotics being lipophilic drugs, however, a portion of the drug is stored in the body’s lipid repositories and can accumulate there over time
A 40 year old woman who had been on depot antipsychotic injections for ten years joined Weight Watchers and lost 40 pounds in three months. Accumulated drug from her dwindling fat stores entered her blood stream and, in turn, her brain, which led to the development of very distressing extrapyramidal symptoms, side effects of her medications. She didn’t know what they were because she had never before experienced side effects.
Such experiences and currently available brain imaging data raise the possibility that, in some patients, the dosing interval of LAI antipsychotics may – and should - be extended beyond the currently recommended time period
Depending on chance events and exposure to stresses, the dose of antipsychotics often needs to be adjusted up or down. Depot treatment leaves little room for such adjustments
In 1963 when I was a resident in psychiatry, I worked on a unit that evaluated new drugs and we tested the first long acting injection, fluphenazine enanthate, expected to be effective for two weeks. The first person we gave it to (I no longer remember the dose we gave but it was probably the one recommended at the time – 25 mg) developed unmanageable akathisia. She paced up and down the ward non-stop day and night and no sedative or anticholinergic or antihistaminic drugs were able to help. This continued for two months, far longer than the anticipated two weeks. The memory of that patient and her distress has made me very careful about prescribing long-acting antipsychotic medication.
The effect of exercise and heat Because injections are usually given into the gluteal muscle, exercising the leg will increase the flow of drug from muscle to bloodstream and will increase side effects. I have previously written about my experience with a patient to whom this happened
Mohammed et al.
With respect to (A), medication routines, many people prefer coming for a monthly injection to the responsibility of remembering to take pills once or more times a day
The social burden of injections (E above) refers to the need to explain to others why one has to be away from school or work or social engagements in order to receive periodic injections. Most patients are unwilling (and have reason to be) to share their need for psychiatric care with employers
Most psychosis treatment guidelines recommend
Some patients, though far from all, perceive depot antipsychotics as being more coercive than oral medications
On the plus side, when a person is receiving depot injections, there is no risk of committing suicide by taking an overdose. This advantage is reduced, however, by the fact that people on injections are often prescribed concomitant oral medications as well. Polypharmacy is more common in those prescribed an LAI
Cost of the newer injectables is high and can be a major problem for patients when the injection is not covered by insurance or by the hospital pharmacy budget. This is, of course, true for all relatively new medications. For hospitals or clinics, there is also the cost of storage of injectables, some requiring refrigeration. To this needs to be added the cost of extra staffing of “depot clinics”
The most important quarrel with the practice of depot injections is that, while putting an emphasis on patient compliance, the LAI takes away a measure of autonomy and makes it difficult for the person to learn by experience
Long-acting medications take months to achieve steady states after dose adjustments so that the patient remains passive vis à vis his or her treatment
This review, while citing some results from randomized clinical trials, has relied mainly on qualitative reports and clinical observation. This is an important limitation of the generalizability of the findings, a limitation that clinicians must bear in mind when making clinical decisions. Despite wide use, the findings of this review suggest that LAIs have drawbacks, which, in some instances, may be serious. A background concern is that the increasing enthusiasm for LAIs is based not on newly discovered cost effectiveness evidence for these formulations
A thorough reading of the relevant literature confirms that long-acting antipsychotics have proven effective in schizophrenia and related psychotic disorders probably because of the stability of dose administration and the increase in treatment adherence