Non-adherence remains the big issue in psychotic illness for society, patients, doctors and payers

Russ Pendleton BSc (Hons) Psychology, MBA, looks at the issues facing schizophrenia and bipolar disorder treatment today and how adherence contributes significantly to poorer outcomes for patients in pharmaphorum’s CNS themed month.

An introduction to non-adherence and psychotic illnesses

The main issue in the battle against Psychosis (the florid symptoms of schizophrenia and mania in particular) is not the effectiveness or tolerability of the antipsychotic agents, it is the supposedly simple task of keeping the patient on medication. There are a number of issues that impact on adherence to long-term, daily, prophylactic medicine. While this is a commonplace issue, it can have severe impact when a patient’s overall wellbeing is critically dependent on the medicine. While forgetting to take your antihypertensive or lipid-lowering agent occasionally is not very hazardous, failure to take their medication could prove much more damaging for psychotic patients. Up to 97% of schizophrenic patients suffer from lack of insight into their own symptoms1. In simple terms, the condition often involves suspiciousness, paranoia and misunderstanding of what is real and what is imagined. All these symptoms and aspects of the condition result in patients struggling even more than the rest of us to adhere to oral daily drug therapy.

Non-adherence rates are extremely high with oral daily schizophrenia therapy. Research shows that around 45% of these sufferers will have become non-adherent enough to relapse within one year of their first episode and around 75% of patients are non-adherent within two years of being discharged from hospital2, the consequences of which are medically and economically severe with 69% of patients with poor adherence suffering a relapse3.

Typically, new patients are treated and after a few months begin to think that they are cured. As a consequence, patients feel they don’t need the therapy any longer and stop taking their medications for a few days each week. Initially, the adverse effects are not visible and the non-adherence continues. Unfortunately the symptoms of the condition – e.g. lack of insight, paranoia, suspiciousness, all begin to re-emerge. Finally the patient is considered to have had a relapse and is often re-hospitalised taking them back to square one again.

Some patients, who have one episode, stay on their medication and never relapse for the rest of their lives. However, the statistics suggest that this is the minority, representing just around 22% of sufferers4. What this means is that a substantial proportion of patients suffer a chaotic and frightening life with a condition that is forever relapsing and remitting. Additionally, florid schizophrenia may be a neurotoxic state. These patients can also suffer a steady decline in cognitive function and memory.

“Research shows that around 45% of these sufferers will have become non-adherent enough to relapse within one year of their first episode”

Current treatment

The only answer for these non-adherent patients currently is for them to be given once weekly, once every two weeks or once monthly injectable drugs. Not only are these long-acting injectables (LAIs) expensive, there are issues around application and storage. However, many patients are so desperate, and dependent on medication, that these LAIs are the best option.

These injections are typically given in the thigh or buttocks with a large diameter needle. The solutions are often thick and oily and sit uncomfortably in the muscle, creating muscle stiffness and could also lead to muscle necrosis (muscle death) around the injection site(s). There are insurance issues for physicians approaching patients with needles, and for physicians asking patients to undress for the injection which make offering the injections costly for physicians (especially in the USA). Patients have to visit the clinic to ensure they are given their therapy on time every week, fortnightly or once a month. They endure all these downsides to ensure the symptoms of their condition do not return.

At the beginning of therapy, antipsychotic drugs take a few days to make a difference to symptoms and only at that stage do patients start to accept that treatment matters. During this acute phase of the illness, when patients may require sedation to calm down – even just to get to sleep – they are often given an injectable sedative, usually to speed up the response. This can lead to long-term negative associations with hypodermic syringes in the mind of the patient.

For some sufferers, this combination of issues mount up – they fall out of favour with the LAI therapy, slowly missing appointments, or putting them back a few days each month, until eventually they too reach such a decreased level of drug in their blood that they relapse. Studies suggest that for some LAIs, up to around 27% of patients relapse within one year5. At two years, the rate of patients treated successfully can be as low as 57%6, posing a very real danger that could lead to a relapse.

Although some studies with LAIs demonstrate an improvement in relapse prevention compared to oral once daily therapy, the relapse rate percentages in other studies are still high. Non-adherence remains the biggest cost driver at present in schizophrenia treatment. Non-adherence costs much more than the schizophrenia drug budget, first episode clinical budget or any other cost item related to the condition. Aside from this societal issue, it remains the single biggest cause of misery for these sufferers. Payers recognise that improvements in adherence would have a material impact on relapse rates, which is a major driver of product innovation in the treatment of schizophrenia and bipolar disorders.

“Non-adherence remains the biggest cost driver at present in schizophrenia treatment.”

The way forward

Leading clinicians believe that adherence is the major factor in schizophrenia and bipolar disorder treatment today and contributes significantly to poorer outcomes for patients. The way forward could be to offer a once weekly oral therapy with supervised dosing which aims to provide a very real benefit in relapse prevention for those patients struggling to comply with daily oral treatment but who are not ready for injectable therapy.

The number of patients who would potentially benefit from a sustained-release, once- weekly oral antipsychotic would likely be significant. A once weekly oral tablet, with few side effects and supervised dosing would result in improved relapse rates, more comfort for patients and less overall cost. This approach may result in fewer individuals lost to the remitting and relapsing course of the illness.


1. World Health Organisation, 1973, Report of the International Pilot Study of Schizophrenia, Geneva

2. Weiden PJ et al., 1995, Psychiatr Serv, ‘Postdischarge medication compliance of inpatients converted from an oral to a depot neuroleptic regimen’. Vol 46 (10): 1049–1054

3. Morken G et al., 2008, BMC Psychiatry, ‘Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia’, Apr 30, 8: 32–38

4. Shepherd M et al, 1989, Psychological Medicine Monograph Supplement 15, ‘The Natural History of Schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics’

5. NICE (UK), 2009, ‘Economic Model – cost effectiveness of pharmacological interventions for people with schizophrenia’. NICE clinical guidelines no. 82

6. Encephale, 2005, ‘Cost effectiveness analysis of schizophrenic patient care settings: impact of an atypical antipsychotic under long-acting injection formulation’, Edition Mar-Apr; 31(2): 235-46



About the author:

Russ Pendleton is the Commercial Vice President for Zysis, a Company that develops innovative psychiatry treatments. The lead program from Zysis is a ground-breaking and unique once weekly oral formulation of aripiprazole. Russ has worked in the field of Psychiatry, Neurology and Neuroscience for the last 20 years. He has initiated, grown and continues to run the International Forum of Psychosis and Bipolarity, the Global Addiction Association and the World Association of Neuro-technology all of which have world-leading annual conferences.

Russ has successfully created and out-licensed a psychiatry treatment in 2006 with Rune Healthcare and is currently working on progressing new treatments with the rest of the Zysis team. Prior to developing his own initiatives more fully, Russ worked in commercial and medical roles for various pharmaceutical companies over a 14 year span – companies now known as AstraZeneca, Abbott and Sanofi. He has an MBA from Nottingham University and studied Psychology, Greek and Roman Culture, Maths and Medicine at undergraduate level.

Closing thought: What else can be done to tackle non-adherence in patients with psychotic illnesses?