How important are long-acting antipsychotics in schizophrenia treatment?

The clinical stability of patients with schizophrenia can be improved by several factors, with antipsychotic therapy being the single most important factor in reducing relapse.

Improving the clinical stability of schizophrenic patients has received a lot of interest. Factors including maintenance antipsychotics,¹ family therapy,^2,3 assertive community treatment,⁴ as well as supporting housing⁵ and employment⁶ have been shown to enhance clinical stability. On the other hand, sub-optimal medication adherence¹ and substance use disorders⁷ can be seen to hinder clinical stability.

Associate Professor Zafar Sharif, Columbia University College of Physicians and Surgeons, and Director of the Psychotic Disorders Treatment Research Program at St. Luke’s-Roosevelt University Hospital in New York, said that antipsychotic therapy "has been proven to be the single most important thing that we can do as clinicians in improving the outcome of these [schizophrenic] patients."

For those patients treated with conventional antipsychotics the rate of relapse remains significantly lower than those receiving placebo. In a study published in the American Journal of Psychiatry, greater than 65% of patients had not relapsed following 18 months of treatment with conventional antipsychotics compared to less than 20% for those receiving placebo.⁸

Professor Sharif, said "for each successive relapse, recovery can be slower and less complete, there is an increased risk of self-harm and homelessness, loss of self-esteem, social and vocational disruption, a greater use of healthcare resources, as well as an increased burden on families and caregivers." Hence the prevention of relapse is critical in the optimal management of the schizophrenic patient and "especially important in the first 5-10 yrs of the illness" said Professor Sharif.

Considering the importance of medication compliance in the prevention of relapse, a recent literature review examined the prevalence of and risk factors for medication non-adherence in patients with schizophrenia. This looked at 39 studies published between 1980 and 2000. They found a range of reported non-adherence rates (20-89%), depending upon the assessment method and patient sample used. When adherence was strictly measured, defined as "taking medication as prescribed at least 75% of the time," the mean non-adherence rate was 49.5%.⁹

An observational study (n=2230) examined the relationship between medication compliance and relapse after first hospitalisation. The mean follow-up was 3.6 years. This study found that 36% of patients discontinued medication within 30 days of hospitalisation. For those discontinuing medication there was a 10-fold increase in mortality.¹⁰

The consequences of interruptions to antipsychotic therapy can be disastrous. In a study evaluating suicide attempt rate in schizophrenic patients, those with a greater than 30 day interruption to atypical antipsychotic medication had a suicide attempt rate per 10,000-person years of 72 compared to a rate of only 20 for those patients with no interruption.¹¹

Risk of hospitalisation has also been shown to increase with increasing interruption to therapy.¹²

It has been widely assumed that atypical antipsychotics improve treatment adherence. However, studies have found that there is little difference in adherence rates between oral conventional and atypical antipsychotics. In an article published in the American Journal of Psychiatry, the authors used pharmacy refill records to compare outpatient adherence in veterans receiving conventional (haloperidol and perphenazine) versus atypical (risperidone, olanzapine and quetiapine) antipsychotics. Adherence was calculated by analysing refill records for up to 12 months. This study found no difference in the 12-month adherent fill rate however the authors acknowledged that the use of samples, stored medications, medications purchased without insurance, and medications provided by hospital pharmacies may limit the accuracy of the results.¹³

There are several reasons why patients are non-compliant with their medications. Those at most risk for partial adherence include patients who are early in the disease progression, have lack of insight,¹⁴ disorganised thinking,¹⁵ substance abuse, a negative view of medication,¹⁴ history of relapse/rehospitalisation,^16-18 infrequent outpatient clinical contact, previous non-adherence and those with poor planning at discharge from the hospital.¹⁴

Professor Sharif said the two most important reasons for lack of medication compliance were "lack of insight, where the patient doesn’t think that they are sick and may deny the presence of the illness" and "cognitive deficits, meaning they have difficulty remembering to do things and difficulty executing tasks without being told to do it."

Unfortunately, Professor Sharif said "there is no real accurate way to assess whether a patient is taking their medications or not." He said "there are limitations with taking blood levels as patients just need to have taken the medication within the last day or two to get a decent blood level", also looking at pharmacy data is "labour intensive and can’t be done in routine clinical practice." He said "in clinical settings probably the best way to assess compliance is if someone is living with the person … who can provide information on what the patient is doing in terms of medication adherence."

One of the interventions to address poor compliance includes the use of long acting injectable antipsychotics. Professor Sharif said "the most reliable way to get a patient to take medication is to switch them over to an injectable antipsychotic."

The benefits of depot antipsychotic medications include improved adherence and the prevention or delay of relapse,^19,20 the early identification of non-adherence, clear attribution of cause of relapse or non-response, regular interactions between patient and healthcare provider and improved global functioning.²¹

Depot medication also avoids first-pass metabolism, thereby producing predictable and stable plasma levels as well as avoiding abrupt discontinuation of treatment if the injection is missed. Studies have shown this route of administration to be preferred by many patients,²² with patients less likely to discontinue medication for any reason.^23,24

Professor Sharif said "the advantages of an injectable are that you as a clinician are completely aware of how much medication you are giving, how frequently you are giving it, and how much of it is in the patient’s system. That allows you to then make judgements about whether the medication is working effectively, what the side effect profile is of that dose, do you need to reduce the dose, increase the dose or change it. All these decisions become evidence based because you know exactly what your patient is taking. The second advantage of injectables is that if your patient becomes non adherent, they don’t show up for the injection. As soon as they don’t show up for the injection you immediately recognise that the patient has become non compliant and then you can activate the system of care to intervene to prevent a relapse from occurring."

A relapse prevention study using Risperdal Consta (risperidone) found the overall incidence of patients meeting any 1 of the 5 criteria for relapse was 22% in the group administered 25mg and 15% in those receiving 50 mg. A 12 week clinical trial assessing safety and tolerability found discontinuation rates due to adverse events were actually lower in the Risperdal Consta arm (11%) than in the placebo arm (13%).²⁵ The most common adverse events included insomnia, psychotic disorder not otherwise specified, headache and anxiety with an overall discontinuation rate of 5.9% due to adverse events.²⁶ The overall incidence of EPS-related adverse events with 25mg was similar to placebo and this is the recommended starting dose.²⁷

Prof Sharif said "For most patients, repeated relapses are detrimental such that early and effective intervention is critical to limit long term morbidity/mortality. Poor adherence is the most important actionable factor in driving relapse and practitioners should systematically evaluate each schizophrenia patient’s risk for poor adherence. As part of management, the appropriateness of injectable antipsychotics should be considered."

Professor Sharif said that schizophrenia can be "very difficult to treat and it is easy to become discouraged, and then in subtle ways to communicate that to patients. Keeping hope and keeping optimism is sometimes not emphasised enough in treating this population."

References

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