Is there an alternative treatment to clozapine for paranoid schizophrenia?

Fråga: Is there an alternative treatment to clozapine for paranoid schizophrenia in a patient who previously have tried several other antipshycotic agents without sufficient effect.

Sammanfattning: As outlined above there are several different available treatment strategies. If the patient is responding poorly to adequately dosed treatment, the first option would be to control the blood drug concentrations of the treatment. Established therapeutic concentration intervals exist for both perphenazine and aripiprazole. If, despite blood drug concentrations within the therapeutic interval, the patient responds poorly to the treatment, change of medication could be an option. Under careful supervision, both regarding cardiac symptoms and blood drug concentrations, one could try treatment with clozapine again. An alternative could be an addition of lamotrigine to risperidone, haloperidol, olanzapine or flupenthixole. A final option would be to try one of the drugs the patient has not yet tried, e.g. melperone or paliperidone, although there is no evidence that these treatments are any better than those the patient has already tried.

Svar: Current first line treatment for psychosis is perphenazine, risperidone or zuclopenthixol. Second line treatment is with olanzapine. Clozapine is recommended for treatment resistant schizophrenia. For schizophrenia to be classified as treatment resistant, at least two antipsychotics must have been tried without effect despite adequate dose over an adequate period of time. In the current case, the patient has been treated with a number of typical and atypical antipsychotics: risperidone (Risperdal), olanzapine (Zyprexa), zuclopenthixol (Cisordinol Depot), ziprasidone (Zeldox), flupenthixol (Fluanxol), haloperidol (Haldol) and quetiapine (Seroquel). It is not clear how long the different treatments have been ongoing, or what doses have been used. According to the patient records, blood drug concentration has not been measured to ensure that the patient has received the correct dose. The patient´s symptoms have fluctuated in severity over time, but the patient has not been free of psychotic symptoms since 2006.

The only atypical antipsychotics available on the Swedish market today that patient has not used are sertindole and paliperidone. Sertindole is contraindicated in patients with a history of significant cardiovascular disease, heart failure, cardiac hypertrophy, arrhythmias or bradycardia (1), which would preclude its use in this case, given the patient´s medical history. Paliperidone is an active metabolite of risperidone (2). The few studies that have compared risperidone and paliperidone have shown that both drugs work equally well for the treatment of schizophrenia, and that paliperidone might possibly be better tolerated by patients (3-5).

The patient has not tried following older, typical antipsychotics: melperone, fluphenazine, prochlorperazine and chlorprothixene. Melperone has been shown to have some effect in patients unresponsive to clozapine (6), but should be used with care in patients with severe bradycardia, heart disease, or hereditary types of QT interval prolongation. It should not be combined with other antipsychotics, but could otherwise be a treatment option (7).

Clozapine-induced pericarditis is rare, with about 20 cases described in the scientific literature (6,8). In all these cases the pericarditis improved once clozapine was discontinued. Two cases of rechallenge, i.e. reinstitution of clozapine, have been reported. In both these cases the patients were followed carefully for cardiac symptoms, but had not relapsed in pericarditis 3 months and 2 years, respectively, after reinstatement of the treatment (9). One systematic review assessed whether it would be possible to reintroduce clozapine for potentially life-threatening side effects, such as neutropenia, agranulocytosis, neuroleptic malignant syndrome (NMS), myocarditis, pericarditis, and lupus erythematosus (9). It concluded that careful reinstatement is possible for neutropenia and NMS, but not after agranulocytosis or myocarditis. There were too few cases of pericarditis in order to reach a conclusion regarding this condition (9).

There are several scientific publications about treatment-resistant schizophrenia that does not respond to clozapine, and where addition of various drugs to the clozapine treatment has been tried (10). None of these are suitable for the patient in the question if clozapine is to be avoided. The scientific literature on treatment resistant schizophrenia where clozapine cannot be used is very limited, but there are studies that have seen some beneficial effect of adding lamotrigine to risperidone, haloperidol, olanzapine or flupenthixole (11). Serdolect Lundbeck. SPC (cited 2012-04-16) Invega Janssen. SPC (cited 2012-06-27) Pani L, Marchese G. Expected clinical benefits of paliperidone extended-release formulation when compared with risperidone immediate-release. Expert Opin Drug Deliv 2009;6(3):319-31. Li H, Rui Q, Ning X, Xu H, Gu N. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35(4):1002-8 Kim S-W, Chung Y-C, Lee Y-H, Lee J-H, Kim S-Y, Bae K-Y, Kim J-M, Shin I-S, Yoon J-S. Paliperidone ER versus risperidone for neurocognitive function in patients with schizophrenia: a randomized, open-label, controlled trial. Int Clin Psychopharmacol 2012;27:267-74 Crews MP, Dhillon GS, MacCabe JH. Clozapine rechallenge following clozapine-induced pericarditis. J Clin Psychiatry 201;71(7):959-61 Buronil Lundbeck. SPC (cited 2011-03-08) Markovic J, Momcilov-Popin T, Mitrovic D, Ivanovic-Kovacevic S, Sekuli S, Stojsic-Milosavljevic A. Clozapine-induced pericarditis. Afr J Psychiatry 2011;14:236-38 Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 2012;134(2-3):180-6 Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 2012;38(5):1003-11 Kerwin RW, Bolonna A. Management of clozapine-resistant schizophrenia. Adv Psychiatr Treatm 2005;11:101-6