Prescribing for Medication Refractory Schizophrenia
Prescribing for Medication Refractory Schizophrenia
Clinical outcomes in schizophrenia are often disappointing: a third of patients are resistant to standard pharmacological interventions, fewer than one in eight individuals fully recover, and data are particularly disheartening for negative and cognitive symptoms. Clozapine is the most effective antipsychotic for more treatment naïve and medication refractory patients, but half will not show significant improvement on it. There is limited evidence for polypharmacy – including augmentation of clozapine - or above licensed dose use of antipsychotics, and both increase side effects. Naturalistic – or partially naturalistic - studies such as CATIE and CUTLASS confirmed clozapine's superior efficacy (although this was not the primary outcome for the CATIE study, and assignment to clozapine in the phase II part was not randomised), and the absence of any significant effect on negative or cognitive symptoms; but were able to offer little pragmatic guidance for post-clozapine treatment. Guidelines provide extensive lists of potential post-clozapine strategies, including the use of other drug classes including mood-stabilisers and anti-depressants - but recognise the frank inability to select between them. Clinicians are thus faced with an unenviable but relatively common challenge of treating patients resistant to first and second line treatments in the absence of robust data to further guide them.
Three critical issues occur in the "post-clozapine" literature: study methodologies; heterogeneity of psychosis outcomes; and a medication accumulation bias. The research gold standard remains the double-blinded randomised controlled trial (RCT), but trial participants are less representative of clinical populations with respect of co-morbidity, insight and capacity to consent, and anticipated drug class effects are underpowered to elicit the well-recognised subpopulations of full-, partial-, and non-responders. Trials typically evaluate a single compound against placebo, with fewer head-to-head trials, and very few data on adjunct treatments. It is perhaps not surprising that there is little agreement about clinical, pharmacological or demographic factors associated with outcomes. Clinical opinion with respect to individual patient presentations – that is specific symptom profiles and local prescribing culture - often dictates choice and duration of treatment, with wide geographical variation, often contrary to evidence. Finally patients typically accrue increasing medications, with management often comprising addition of new medication, with existing (or previously added) ones seldom discontinued for fear of causing destabilisation. However remission often does not occur and such polypharmacy is more likely to become the rule rather than the exception.
We describe a naturalistic study of outcomes in 153 treatment refractory inpatients on a specialist tertiary psychosis service, the National Psychosis Service (NPS) at the Maudsley and Bethlem Royal Hospitals, London, UK. The admission criteria to the service are analogous to those of the United Kingdom's Department of Health definition and guidelines for specialist services (Table 1). Such criteria give broad descriptions of how a treatment refractory illness might manifest, for example through high symptom burden and/or significant impact on social functioning, as well as illustrate anticipated prior pharmacological and psychological interventions and durations. However they act as guidance, and can be superseded by the clinical judgement of the referring or assessing psychiatrist; for example, whilst it would ordinarily be anticipated that a referred patient would have had previous psychological intervention(s), it is recognised that there can be circumstances wherein this would have been untenable; furthermore "high symptom burden" and "significant impact on functioning" are not further quantified, but designed to allow a clinical discretion in interpretation. We have previously reported upon the nature of, and the clinical and psychosocial improvements demonstrated by, this service, but briefly, the National Psychosis Unit is a 23 bedded unit, staffed with Consultant Psychiatrists, junior doctors, specialist clinical psychologists, mental health nurses, a social worker and occupational therapy staff members. Staff work closely within an interdisciplinary setting with weekly in-depth multiprofessional ward reviews of each patient. All patients are offered specialist psychological input, family therapy, and a range of occupational therapy. It is sited within the Bethlem Royal Hospital, South London, in extensive landscaped grounds, with access to swimming, a gym, and a range of occupational therapy activities. There is ready access to specialised pharmacy, haematology, and cardiology input, and it has a close association with the Psychosis Clinical Academic Group at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, enabling very close links with field-leading research. Herein we set out to evaluate: a) the feasibility of rationalising pharmacological treatment; b) to identify the most common medications prescribed on discharge (as a posited index of their optimal tolerated treatment); c) exploratory analysis of medication(s) associated with overall outcomes and specific symptom domains.
Background
Clinical outcomes in schizophrenia are often disappointing: a third of patients are resistant to standard pharmacological interventions, fewer than one in eight individuals fully recover, and data are particularly disheartening for negative and cognitive symptoms. Clozapine is the most effective antipsychotic for more treatment naïve and medication refractory patients, but half will not show significant improvement on it. There is limited evidence for polypharmacy – including augmentation of clozapine - or above licensed dose use of antipsychotics, and both increase side effects. Naturalistic – or partially naturalistic - studies such as CATIE and CUTLASS confirmed clozapine's superior efficacy (although this was not the primary outcome for the CATIE study, and assignment to clozapine in the phase II part was not randomised), and the absence of any significant effect on negative or cognitive symptoms; but were able to offer little pragmatic guidance for post-clozapine treatment. Guidelines provide extensive lists of potential post-clozapine strategies, including the use of other drug classes including mood-stabilisers and anti-depressants - but recognise the frank inability to select between them. Clinicians are thus faced with an unenviable but relatively common challenge of treating patients resistant to first and second line treatments in the absence of robust data to further guide them.
Three critical issues occur in the "post-clozapine" literature: study methodologies; heterogeneity of psychosis outcomes; and a medication accumulation bias. The research gold standard remains the double-blinded randomised controlled trial (RCT), but trial participants are less representative of clinical populations with respect of co-morbidity, insight and capacity to consent, and anticipated drug class effects are underpowered to elicit the well-recognised subpopulations of full-, partial-, and non-responders. Trials typically evaluate a single compound against placebo, with fewer head-to-head trials, and very few data on adjunct treatments. It is perhaps not surprising that there is little agreement about clinical, pharmacological or demographic factors associated with outcomes. Clinical opinion with respect to individual patient presentations – that is specific symptom profiles and local prescribing culture - often dictates choice and duration of treatment, with wide geographical variation, often contrary to evidence. Finally patients typically accrue increasing medications, with management often comprising addition of new medication, with existing (or previously added) ones seldom discontinued for fear of causing destabilisation. However remission often does not occur and such polypharmacy is more likely to become the rule rather than the exception.
Aim
We describe a naturalistic study of outcomes in 153 treatment refractory inpatients on a specialist tertiary psychosis service, the National Psychosis Service (NPS) at the Maudsley and Bethlem Royal Hospitals, London, UK. The admission criteria to the service are analogous to those of the United Kingdom's Department of Health definition and guidelines for specialist services (Table 1). Such criteria give broad descriptions of how a treatment refractory illness might manifest, for example through high symptom burden and/or significant impact on social functioning, as well as illustrate anticipated prior pharmacological and psychological interventions and durations. However they act as guidance, and can be superseded by the clinical judgement of the referring or assessing psychiatrist; for example, whilst it would ordinarily be anticipated that a referred patient would have had previous psychological intervention(s), it is recognised that there can be circumstances wherein this would have been untenable; furthermore "high symptom burden" and "significant impact on functioning" are not further quantified, but designed to allow a clinical discretion in interpretation. We have previously reported upon the nature of, and the clinical and psychosocial improvements demonstrated by, this service, but briefly, the National Psychosis Unit is a 23 bedded unit, staffed with Consultant Psychiatrists, junior doctors, specialist clinical psychologists, mental health nurses, a social worker and occupational therapy staff members. Staff work closely within an interdisciplinary setting with weekly in-depth multiprofessional ward reviews of each patient. All patients are offered specialist psychological input, family therapy, and a range of occupational therapy. It is sited within the Bethlem Royal Hospital, South London, in extensive landscaped grounds, with access to swimming, a gym, and a range of occupational therapy activities. There is ready access to specialised pharmacy, haematology, and cardiology input, and it has a close association with the Psychosis Clinical Academic Group at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, enabling very close links with field-leading research. Herein we set out to evaluate: a) the feasibility of rationalising pharmacological treatment; b) to identify the most common medications prescribed on discharge (as a posited index of their optimal tolerated treatment); c) exploratory analysis of medication(s) associated with overall outcomes and specific symptom domains.
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