Melperone in treatment-refractory schizophrenia: a case series

Introduction

Clozapine is the treatment of choice in patients with refractory schizophrenia with response rates of 30–60% [Meltzer et al. 1989; Kane et al. 1988]. According to the National Institute for Clinical Excellence (NICE) guidelines for the treatment of schizophrenia, clozapine should be offered to patients who have not responded adequately despite sequential use of at least two different antipsychotics [National Institute for Clinical Excellence, 2009]. Nonetheless, a substantial proportion of patients show an inadequate response to clozapine. For such patients, NICE recommends the addition of a second antipsychotic. However, evidence suggests that the addition of a second antipsychotic to clozapine results only in marginal benefits [Barbui et al. 2009; Taylor and Smith, 2009].

Furthermore, clozapine is associated with a significant burden of side effects and requires close haematological monitoring. Many clozapine-related side effects such as hypersalivation, sedation and hypotension are often benign and transient; metabolic disturbances such as weight gain, diabetes and dyslipidaemia are more significant and have long-term health implications. Other adverse effects such as agranulocytosis, myocarditis and thromboembolism may be life threatening.

There is therefore a continuing need for viable alternatives to clozapine for the treatment of patients who are wholly or partially treatment refractory as well as for patients who are poorly tolerant of clozapine. Various options have been briefly investigated in trials and in clinical practice. Despite the paucity of evidence, high-dose antipsychotics and combinations are commonly used in such patients [Paton et al. 2008].

Melperone is a butyrophenone antipsychotic licensed as Buronil in many countries in Europe but not in the UK. It has antagonist activity at D₂ and 5HT_2A receptors and fulfils criteria for atypical antipsychotic drugs with its low rate of extrapyramidal side effects and tardive dyskinesia [Bjerkenstedt et al. 1979]. In addition, the ratio of dopamine D4/D2 occupancy for melperone has been shown to resemble the binding profile of clozapine [Lahti et al. 1993]. Melperone has been investigated in an open trial for the treatment of patients with refractory schizophrenia [Meltzer et al. 2001] and shown to significantly improve overall psychiatric status as measured by the Global Assessment Scale (GAS) [Endicott et al. 1976] although it did not significantly affect the Brief Psychiatric Rating Scale (BPRS) scores [Overall and Gorham, 1962].

There is very little clinical experience of the use of melperone in the UK as it is currently unlicensed. Recently, there has been interest in melperone as a possible alternative to clozapine. This retrospective case series examines the outcomes for patients with refractory schizophrenia treated with melperone at the South London and Maudsley NHS Foundation Trust where it was first used in the UK.

The South London and Maudsley NHS Foundation Trust provides a range of mental health and substance misuse services in the UK. It provides care and treatment for a local population of 1.1 million people in South London. In addition, there are specialist services for people from across the country. The National Psychosis Unit is one of such tertiary referral services for the treatment of patients with refractory schizophrenia and melperone was first used here in the UK in 2005. This is thus the first published evidence of the experience with melperone in the UK.

Method

Using the pharmacy database, we identified all patients prescribed melperone from April 2005 to July 2010. From patient medical notes we extracted relevant information on past antipsychotic treatments and reasons for prescribing of melperone. For patients treated and discharged from the National Psychosis Unit, we contacted the care team to find out what the current antipsychotic treatment was. The main outcome was to determine proportion of patients discharged on melperone: a proxy for acceptable treatment outcome.

Results

In total, 22 patients were treated with melperone. One patient was excluded as she was treated for less than a week. Tables 1 and 2 give patient characteristics.

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Table 1.

Patient characteristics: summary.

Parameter	Description
Sex	Male: 12
	Female: 9
Age	Range 20–63 years (mean age, 36 years)
Ethnicity	White: 11
	Black: 7
	Asian: 3
Diagnoses (as recorded in medical notes)	Schizophrenia: 13
	Schizoaffective disorder: 7
	Severe depression with psychotic symptoms: 1
Mean age of onset of illness	19 years; range 12–43 years
History of clozapine treatment	Yes: 18/21
Discharged on melperone	n = 3/21

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Table 2.

Patient characteristics and outcome.

Sex	Age (years)	Ethnicity	Age of onset (years)	Duration of illness (years)	Previous history of clozapine	Reason for melperone	Duration of melperone treatment (months)	Reason for stopping melperone	Antipsychotic before melperone	Antipsychotic after melperone	Current antipsychotic (July 2010)
M	30	Black	14	21	Y	Intolerance to clozapine - hypertension	7	Ineffective	Clozapine	Amisulpride	Clozapine
F	51	Asian	24	23	Y	Intolerance to clozapine - seizures	3	Ineffective	Olanzapine +  Amisulpride	Clozapine	Clozapine
M	26	Black	18	3	N	Low ANC* and ineligible for clozapine	11	Ineffective	Olanzapine + Amisulpride	Zuclopenthixol decanoate	Quetiapine + Amisulpride
M	33	Black	19	14	Y	Refused clozapine	3	Ineffective	Pipothiazine palmitate + Olanzapine	Clozapine	Clozapine
M	43	White	18	21	Y	Refused clozapine	3	Refused	Risperidone + Amisulpride	Aripiprazole	Clozapine + Amisulpride
F	32	Asian	21	7	Y	Intolerance to clozapine – neutropenia	9	Refused, EPSE	Olanzapine + Aripiprazole	Clozapine	Risperidone Consta + Olanzapine
M	38	White	24	9	Y	Noncompliance with clozapine	5	Ineffective	Amisulpride + Olanzapine	Clozapine	?? lost to follow up
M	60	White	43	16	Y	Hypersaliva-tion on clozapine	1	Adverse effects	Clozapine	Olanzapine	Risperidone
F	23	White	14	8	Y	Intolerance to clozapine – constipation	2	Ineffective Adverse effects	Clozapine	Olanzapine	Olanzapine
F	30	Black	14	11	Y	Insufficient response to clozapine	7	Non compliance	Clozapine	Quetiapine	Clozapine Sulpiride
F	44	White	21	20	Y	Non compliance with clozapine	5	Ineffective	Haloperidol	Clozapine	Clozapine
M	33	White	19	13	Y	Intolerance to clozapine – neutropenia	4	Ineffective	Haloperidol	Clozapine	Clozapine Amisulpride
F	23	White	16	2	N	Low ANC and ineligible for clozapine	6	Ineffective	Risperidone	Risperidone	Risperidone Consta Olanzapine
M	20	Black	12	5	Y	Intolerance to clozapine pericarditis	11	Ineffective	Olanzapine	Clozapine	Clozapine
F	33	White	16	13	Y	Intolerance to clozapine Myocarditis		Discharged on melperone	Zuclopenthixol decanoate	Discharged on melperone	Melperone
F	24	White	16	3	Y	Insufficient response to clozapine	4	Discharged on melperone	Chlorpromazine risperidone	Not known	Lost to follow up
M	63	White	39	19	Y	Noncompliant with clozapine	4	Ineffective	Risperidone + Amisulpride	Clozapine	Risperidone
M	34	White	19	10	N	Refused clozapine	2	Ineffective	Zuclopenthixol Haloperidol	Clozapine	Olanzapine
M	46	Black	22	21	Y	Noncompliant	2	Refused	Risperidone	Flupentixol Decanoate	Flupentixol Decanoate
M	31	Asian	14	12	Y	Intolerance to clozapine – neutropenia	12	Ineffective	Olanzapine	Amisulpride	Amisulpride
F	41	Black	15	22	Y	Intolerance to clozapine. Sedation and weight gain		Discharged on melperone	Aripiprazole	Discharged on melperone	Melperone

ANC, absolute neutrophil count.

This sample comprised patients with severe and treatment-refractory illness. The average age of onset of illness was 19 years of age. Almost all patients (18/21, 86%) had a prior exposure to clozapine. Of these, 10 patients had discontinued it because of adverse effects, 6 because of noncompliance with medication or blood tests and 2 patients because of inadequate response. Three patients had no prior exposure to clozapine. In two patients, this was because they had low baseline neutrophil counts and so they were ineligible for clozapine treatment. The third patient had not been exposed to clozapine because of a refusal to comply.

Discussion

Although the data on the efficacy of melperone in treatment-resistant schizophrenia are rather limited, it was initially perceived in our unit as ‘clozapine without blood tests’ and an option particularly for refractory patients who refused clozapine or those who were intolerant to the various adverse effects observed with clozapine.

The sample treated comprised a cohort of patients with severe refractory psychotic disorders, with a relatively early onset of psychotic illness and mean duration of antipsychotic treatment of 13 years. The majority of patients had been previously treated on clozapine, hence there is some selection bias although it is noteworthy that of the sample who discontinued melperone, more than half were subsequently re-exposed to clozapine with therapeutic benefits. This is in contrast to the findings by Meltzer and colleagues who found that nonresponders to melperone generally did not respond to clozapine treatment [Meltzer et al. 2001].

Of 21 patients treated, only three patients (14%) were discharged on melperone (the primary outcome measure). One patient was lost to follow up and two patients remain clinically stable on long-term treatment. Of these, one patient has a diagnosis of schizoaffective disorder, depressive type. She had remained well on clozapine for 2 years but discontinued due to weight gain and sedation and suffered a relapse of her illness. She was tried on other medications without success and refused to go back on clozapine, hence the trial of melperone. She remains on melperone treatment in addition to sodium valproate, mirtazapine and venlafaxine in the community. The second patient on long-term treatment with melperone has a diagnosis of severe depressive episodes with psychotic symptoms. She was previously treated on clozapine but developed myocarditis. She failed to respond to other antipsychotic and antidepressant combinations as well as to ECT treatment. She is currently in a rehabilitation unit on treatment with melperone in combination with lithium, lamotrigine and mirtazapine.

Limitations

This is a rather small retrospective case notes review including only 21 patients. There may be bias in the sample population as more than half (13/21) the patients were treated in a tertiary referral centre and most had previous exposure to clozapine. There were no formal clinical assessments or ratings of psychopathology nor systematic evaluation of melperone tolerability and adverse effects.

Conclusions

This is the first attempt to evaluate the efficacy of melperone in the treatment of refractory psychotic illness in a naturalistic setting. Although it may be a worthwhile option in a very few patients, our results indicate a low overall success rate with melperone in patients with treatment refractory psychotic illness. Melperone should probably not be seen as an alternative for patients for whom clozapine is not suitable. Routine ECG monitoring should be considered at doses greater than 300 mg daily.