Updated guidance from the National Institute of Health and Clinical Excellence recommends better discussion of treatment with patients and individual therapeutic trials of antipsychotics
Schizophrenia is a major mental health disorder characterised by abnormalities of thought, ideation (delusion), perception (hallucination) and emotion. The lifetime prevalence for schizophrenia is between 0.4–1.4%; at any time it affects approximately 5 per 1,000. Schizophrenia is reported in all countries and whilst there is little variation in the overall incidence of schizophrenia, the course and outcome differ across populations and cultures. Onset occurs at any age, but is more common in late adolescence and the early twenties and unusual prior to puberty. Prevalence is similar in males and females. Antipsychotics are the main medication used to treat schizophrenia since the introduction of chlorpromazine in 1952. NICE has recently, in March 2009, published a clinical guideline on the ‘Core Interventions in the Treatment and Management of Schizophrenia in Adults in Primary and Secondary Care’ updating previous guidance issued in 2002.,
Broad NICE treatment recommendations
The NICE guideline issued in 2002 recommended that the second-generation, so-called atypical antipsychotics, should be used as first-line treatments mainly due to a reduced incidence of extrapyramidal side-effects. The revised guidance, however, does not recommend a particular medicine, or class of medication, but highlights the role of patient choice; it recommends that the choice of medicine should be a joint decision between the service user and healthcare professional.
The decision should consider the adverse event profile, particularly in respect to extrapyramidal and metabolic adverse events, and if appropriate involve the carer.
The new guidelines have been heavily influenced by two major new studies; CATIE and CUTLASS., In CATIE 1,493 people with chronic schizophrenia from 57 sites in the USA, were randomised to the typical anti-psychotic, perphenazine, or one out of four atypicals (olanzapine, quetiapine, risperidone or ziprasidone, which is not available in the UK).
Both patient and treating clinician were blind to the treatment. The overall conclusion from CATIE was that there was little difference in overall effectiveness between anti-psychotics, including the typical perphenazine, and all anti-psychotics were associated a high frequency of adverse events.
In CUTLASS 227 people with schizophrenia, or a related disorder, were randomised to a typical, or an atypical antipsychotic chosen by the clinician caring for the patient. The trial was designed to test effectiveness in “real-life” conditions and was conducted across 14 Mental Health trusts in the UK. CUTLASS concluded that there was no difference in the effect of typicals and atypicals on the symptoms of schizophrenia, quality of life measures, and the overall associated costs of care. The revised guidance recommends that treatment with an antipsychotic should be viewed as an “individual therapeutic trial”. Before treatment is commenced the indication for treatment, potential risks and benefits, and the anticipated time for symptoms to respond and adverse events to occur should be recorded. People with schizophrenia frequently lack insight into the presence of a mental illness and the need for treatment, including, the need for treatment with an antipsychotic should be carefully explained.
Antipsychotics should be commenced at a low dose, so that patients can be monitored for possible adverse effects, following a complete discussion about possible adverse events. Efficacy, adverse events, adherence and physical health should be regularly monitored and recorded whilst the dosage is gradually increased within the BNF dose range. The “individual therapeutic trial” should be continued for 4 to 6 weeks at the optimum dose. The rationale for medication changes including the use of doses above BNF limits should be recorded.
Schizophrenia is associated with physical health issues and increased mortality, and according to the Office of National Statistics 62% of people with psychosis experience a physical condition compared to 42% of people without psychosis., Thus the revised NICE guidance recommends that the physical health of people with schizophrenia should be monitored, at least annually, by GPs and primary care healthcare professionals. This monitoring should focus on an assessment of cardiovascular disease risk, because people with schizophrenia are a greater risk of cardiovascular disease compared to the general public. Primary care should also develop and utilise case registers to monitor the mental and physical health of people with schizophrenia.
Treatment Resistant Schizophrenia
Treatment resistant schizophrenia (TRS) is fairly common and around 20 to 33% of people with schizophrenia fail to respond to standard antipsychotics, and the guidance makes a number of recommendations on the care pathways for treatment resistant schizophrenia.
One commonly used pathway for schizophrenia that fails to respond to a single antipsychotic is the use of more than one antipsychotic. However, there is no robust evidence supporting the use of anti-psychotic polypharmacy. The vast majority of the clinical trials utilised monotherapy, and any open trials using polypharmacy are uncontrolled and subject to bias. Polypharmacy may decrease efficacy; one study that compared clozapine with clozapine plus risperidone in refractory schizophrenia, indicated that combination treatment worsened outcomes. Polypharmacy increases the risk of adverse events and drug interactions, and decreases adherence, partly due to an increase in complexity of the regime and any anti-cholinergic induced cognitive impairment. Polypharmacy is associated with antipsychotic doses above BNF levels, and a 50% increase in movement disorders compromising a major benefit of atypicals. In a 10 year study reduced survival was associated with neuroleptic polypharmacy probably via an increase in adverse events. A second study showed that every additional antipsychotic prescribed increased the relative risk of dying 2.50 times (95% CL 1.46-4.30). Therefore, the revised guidance recommends that the use of more than one antipsychotic should be avoided, except for short periods of time, such as, when swapping antipsychotics. The revised guidance supports the principle from the 2002 guidance that clozapine should be utilised in TRS. The 2009 guidance states that if symptoms do not respond to treatment with adequate doses of at least two other antipsychotics, one of which must be a second generation antipsychotic, clozapine should be offered. If symptoms fail to respond to clozapine the diagnosis, adherence levels and the use of psychological treatments should be considered. Additionally, the blood level of clozapine should be checked to confirm that it is within the therapeutic range. Finally, a second antipsychotic should be utilised to augment clozapine for a trial period of 8 to 10 weeks.
Long acting depot neuroleptics
Long-acting depot antipsychotics, which are widely used in schizophrenia, are administered by deep intramuscular injection usually into the buttock. The active molecule is slowly released resulting in relatively stable plasma levels and allowing the intra-muscular injection to be administered every few weeks. The main advantage of such preparations is that covert non-adherence, both non-intentional and intentional, can be easily identified and, if identified, measures can be taken. However, this method of administering medication lacks flexibility, achieving the optimal dose is time-consuming, and the process of receiving the injection may be stigmatising. The new guidance recommends that depot/long-acting injectable antipsychotics should be considered if there is a need to avoid covert non-adherence, or if the service-user expresses a preference. Due to the delay in obtaining therapeutic blood levels long-acting depot antipsychotics should not be used to treat an acute episode of psychosis.
Since publication of the 2002 guidance, the first long acting injectable atypical neuroleptic has become licensed in the UK, and Risperdal Consta® was included in the review. The revised guidance concluded that from the limited data, that compared the safety and efficacy of long-acting risperidone to oral risperidone, and placebo, there was no evidence that long-acting risperidone was more effective, or better tolerated, than oral risperidone. Furthermore, the guidance does not differentiate between long-acting risperidone injection and typical depots.
Future research priorities
The new guidance identified a number of future research priorities. First, further long-term, direct comparisons of the safety and efficacy of the different anti-psychotics, both oral and depot products are required; these studies should assess the long-term risk versus benefits of the treatments. In addition, large-scale, observational, survey-type trials with qualitative components should investigate the service-users’ experience of treatment with medication, including satisfaction, preferences and quality of life measures. The guidance also recommends that further studies involving clozapine should be conducted; in particular the efficacy of augmentation of clozapine with a second antipsychotic, where TRS has failed to fully respond to clozapine monotherapy, should be studied. The effect of clozapineon hostility, violence and suicide rates should also be further investigated.
The recently updated NICE guidance on the treatment of schizophrenia has some key differences to previous guidance published in 2002. In particular, reflecting key evidence from two important studies, rather than recommending a class of medication, the guidance highlights the importance of patient choice. Treatment should be tailored to the individual balancing adverse events and efficacy. The guidance also discusses the potential roles of clozapine and long-acting injectable neuroleptics. Finally, NICE highlight the need for more research into developing effective treatments for this very debilitating disorder.
1. Cannon M, et al. JNNP 1996,60,604-613.
2. Gelder M, et al. New Oxford Textbook of Psychiatry. Volume 1.Oxford University Press 2003.
3. NICE Guidelines 82. March 2009.
4. NICE Guidelines 1. December 2002.
5. Lieberman JA, et al. NEJM 2005,353,1209-23.
6. Jones PB, et al. Arch psyc 2006,63,1079-87.
7. Roberts L, et al. FP 2007,24,34-40.
8. Singleton N, et al. Int Rev Psychatr 2003,15,65-73.
9. Honer WG, et al. NEJM 2006;354:472-82.
10. Carnahan RM, et al. Acta Psychiatrica Scandinavica 2006,113,135-141.
11. Waddington JL, et al. BJP 1998,173,325-9.
12. Joukamaa M, et al. BJP 2006,188,122-127.