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Combination of amisulpride and olanzapine in treatment-resistant schizophrenic psychoses
European Psychiatry 19 (2004) 56–58 www.elsevier.com/locate/eurpsy
Short communication
Combination of amisulpride and olanzapine in treatment-resistant schizophrenic psychoses Mathias Zink *, Fritz A. Henn, Johannes Thome Clinic of Psychiatry and Psychotherapy, Central Institute of Mental Health, P.O. Box 12 21 20, 68072 Mannheim, Germany Received 22 March 2003; received in revised form 9 September 2003; accepted 11 September 2003
Abstract Treatment-resistant schizophrenia often leads to combined application of antipsychotic drugs. We report first experience with the combination of olanzapine and amisulpride. Improvement of psychopathological state and side effects could be achieved, and drug doses were lower than under monotherapy. We thus conclude that this approach represents a useful therapeutic option. © 2003 Elsevier SAS. All rights reserved. Keywords: Schizophrenia; Antipsychotic drugs; Amisulpride; Olanzapine
1. Introduction
2. Subjects and methods
Up to 40% of patients with psychotic symptoms do not respond to conventional antipsychotic monotherapy [4]. Within the group of atypical antipsychotic drugs, olanzapine presents a receptor profile quite similar to clozapine [9]. Olanzapine may induce a significant gain of body weight, somnolence, anticholinergic effects and transient increases of liver enzymes [2]. In cases of treatment-resistant schizophrenia successful combinations with several antipsychotic drugs [3] have been reported. Amisulpride, another safe and efficient atypical antipsychotic drug [7], exhibits a unique pharmacological profile, which is characterized by a predominant interaction with D3/D2-dopamine receptors. The substance ameliorates negative symptoms and exerts only extremely small increase of body weight [6]. The combined application of antipsychotic drugs is an established step in the therapy of treatment-resistant schizophrenic psychoses [5]. This widespread clinical practice stands in contrast to some critical remarks in the literature focusing on unjustified use and lack of controlled clinical studies [3]. We performed this retrospective study aiming at the systematic outcome-evaluation of all patients, who received olanzapine and amisulpride in combination.
This open study was designed as a retrospective chart review (RCR) [3]. We examined the clinical records of the patients released from our hospital with the antipsychotic combination of amisulpride and olanzapine during the period January 1999 to December 2001. The following data were collected: gender, age, diagnoses (ICD-10, DSM IV), time of onset, number of hospitalizations, pharmacological background information (ineffective pharmacological treatment attempts, rational for the combination therapy, dosages, side effects) as well as scores of global assessment of functioning (GAF) and clinical global impression (CGI). The difference with respect to these psychometric scales between the day of hospitalization and the day of release reflects the clinical improvement.
* Corresponding author. E-mail address: [email protected] (M. Zink). © 2003 Elsevier SAS. All rights reserved. doi:10.1016/j.eurpsy.2003.09.002
3. Results Seven patients (five men, two women, age between 22 and 46 years, mean 30 years, Table 1) with an acute exacerbation of schizophrenia were treated with the combination of amisulpride (dose 200–800 mg, mean 485.7 mg) and olanzapine (dose 5–40 mg, mean 21.4 mg). This relatively small group represents about 0.8% of all inpatients in our clinic with schizophrenic psychoses within the three years 1999, 2000 and 2001. Every patient in this group had been unsuccessfully treated with one or more typical antipsychotic
Table 1 Case reports. Therapeutic effects are reflected in changes (D) of GAF and CGI-scales. Abbreviations: amis, amisulpride; beh, behaviour; BMI, body mass index; CGI, clinical global impression (severity of illness); cloz, clozapine; comb, combination; D, difference; del, delusions; EPMS, extrapyramidal motoric symptoms; FThD, formal thought disorder; GAF, global assessment of functioning; hall, hallucinations; hosp, hospitalization; improv, improvement; incompl, incompliance; NS, negative symptoms; olanz, olanzapine; PS, positive symptoms; rem, remission; refr, refractory; ther, therapy; TypAnt, typical antipsychotic drugs Age Gender ICD-10, DSM IV
m
F 20.0, 295.3
2 46
m
F 20.0, 295.3
21 and >6 hosp
3 35
m
F 20.0, 295.3
19 and >4 hosp
4 23
m
F 20.0, 295.3
20 and 3 hosp
5 23
f
F 20.0, 295.3
23 and 3 hosp
6 47
m
F 20.0, 295.3
36 and 3 hosp
7 22
f
F 20.0, 295.3
21 and 1 hosp
Refractory in the history
Psychopathological state before combination
First drug
Main Adjuvans Improvement of problem GAF and CGI (D)
BMI, length and weight
Side effects
Remarks
TypAnt cloz, olanz, comb of olanz and Benperidol TypAnt, partial rem with olanz
Del, auditory and cenesthetic hall, suicidality, NS Psychomotor inhibition, blunted affect
Olanz 30 mg
Refr PS
27.9, 1.65 m, 76 kg 20.3, 1.68 m, 57.2 kg
Body weight +5 kg Body weight +7.5 kg
Antiviral comedication and Biperiden
24.2, 1.70 m, 70 kg
Improv Comedication: Biperiden of EPMS
24.8, 1.80 m, 80.3 kg
Body Comedication: Sertralin weight +17.5 kg
19.4, 1.61 m, 50.2
Body weight +2.5 kg
21.2, 1.80 m, 68.6 kg
Body Comedication: Reboxetin weight +10.8 kg
23.7, 1.68 m, 67 kg
Rem of EPMS
Olanz 40 mg
Amis 600 mg
Partial rem of PS DGAF: +30, DCGI: –2 Improv of activity and affectivity DGAF: +22, DCGI: –2 Rem of PS, obsession and FThD DGAF: +35, DCGI: –3
After Amis rem of 200 mg PS refr NS TypAnt (EPMS) FThD, paranoid del, Amis Refr Olanz Risperidone, olanz, hall, compulsion, 400 mg PS, 5 mg amis intolerance of psychomotor EPMS cloz agitation, with disorganized beh amis-monotherapy and combinations TypAnt (EPMS), FThD, paranoid del, Olanz Refr Amis Improv of FThD partial rem with hypoactivity, 30 mg PS and 800 mg and PS, but olanz anhedonia, blunted NS incomplete Rem of affect NS, DGAF: +25, DCGI: –3 Olanz Refr Amis Rem of PS, refr NS, Risperidon (EPMS), Paranoid del, 20 mg PS and 400 mg DGAF: +30, DCGI: cloz (EEG), partial auditory and NS –2 rem with olanz cenesthetic hall, blunted affect, mutism, psychomotoric inhibition TypAnt (EPMS) Paranoid del, Amis Refr Olanz Rem of PS, improv cloz, EPMS with anhedonia, 200 mg PS and 15 mg of NS DGAF: +28, 800 mg amis hypoactivity, NS, DCGI: –2 blunted affect EPMS with amis-monotherapy TypAnt and FThD, paranoid del, Amis Rem of Olanz Rem of PS, improv Risperidone auditory hall, NS 800 mg PS 10 mg of NS DGAF: +35, (EPMS) with DCGI: –2 amis, refr NS and psychomotor agitation
M. Zink et al. / European Psychiatry 19 (2004) 56–58
1 36
Age at first manifestation and number of hosp 17 and >6 hosp
57
58
M. Zink et al. / European Psychiatry 19 (2004) 56–58
drugs and at least one atypical agent before. The reasons for the combination therapy included persistent positive (five patients) and/or negative symptoms (six patients). Lower individual drug doses could be used in combination therapy compared with monotherapy (reduction of olanzapine by 21% and amisulpride by 26%). The refractory symptoms markedly improved or remitted, as recorded by the GAF (increase from 36.9 to 66.1, D = +29.2) and by the severity of illness scale of CGI (reduction from 5.9 to 3.6, D = –2.3). Side effects such as body weight gain and extrapyramidal motoric symptoms were ameliorated by dose reduction. Nevertheless, the patients showed an average increased in body weight by 6.2 kg and two patients needed anticholinergic comedication due to extrapyramidal symptoms. Additionally, two further patients received antidepressant drugs. 4. Discussion Our study indicates that the combination of olanzapine with amisulpride represents a new therapeutic strategy in cases of treatment-resistant schizophrenic psychoses, which are a frequent clinical problem, although a generally accepted definition of “treatment-resistance” is difficult to give [5]. Combination therapies should only be considered, if several monotherapies including an atypical antipsychotic drug have proven to be ineffective [3]. From a pharmacological point of view, the highly selective blockade of D3/D2-receptors by amisulpride can supplement the relatively broad receptor interactions of olanzapine, which shows only moderate dopaminergic receptor blockade [9]. The neurobiological rationale of a combination therapy aims in a highly synergistic antipsychotic potency without increasing the risk of adverse effects. Pharmacokinetic interactions both as possible reasons for the clinical effect or as threat of toxicity seem unlikely, since amisulpride is largely cleared without metabolization by urinary excretion [1], whereas olanzapine is metabolized via cytochromes p450 [8]. In our study, a remarkable reduction of the daily olanzapine and amisulpride doses was possible, thereby minimizing side effects such as weight gain (five cases) or extrapyramidal symptoms (three cases). This increases patient’s compliance preventing exacerbations and subsequent hospitalizations. We did not observe any new side effects or unfavorable drug interactions.
This study represents all patients treated with the combination of olanzapine and amisulpride over a period of 3 years, representing 0.8% of 859 patients suffering from schizophrenic psychoses. These numbers underline the fact that the indication for a combined therapy was restricted to severe cases. Because only inpatients were included, long-term efficiency and benefits of the outlined therapy have to be further evaluated in prospective and randomized studies. Nevertheless, the results of our study are encouraging and prove the clinical benefit of olanzapine–amisulpride combination in treatment-resistant schizophrenic psychoses.
Acknowledgements The authors thank patients, nursing stuff and physicians of the Department of Psychiatry of the Central Institute of Mental Health for clinical treatment of inpatients and W. VanSyckel for text revision.
References [1] [2] [3]
[4]
[5] [6]
[7]
[8]
[9]
Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000;38(5):393–414. Conley RR, Meltzer HY. Adverse events related to olanzapine. J Clin Psychiatry 2000;61(Suppl 8):26–9 [discussion 30]. Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30. Hellewell JS. Treatment-resistant schizophrenia: reviewing the options and identifying the way forward. J Clin Psychiatry 1999;60 (Suppl 23):14–9. Koshino Y. Algorithm for treatment-refractory schizophrenia. Psychiatry Clin Neurosci 1999;53(Suppl):S9–S13. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, Lemperiere T, et al. Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001;44(1):41–6. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159:180–90. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes p450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996;41(3):181–6. Stephenson CM, Pilowsky LS. Psychopharmacology of olanzapine. A review Br J Psychiatry 1999;38(Suppl):52–8.
Short communication
Combination of amisulpride and olanzapine in treatment-resistant schizophrenic psychoses Mathias Zink *, Fritz A. Henn, Johannes Thome Clinic of Psychiatry and Psychotherapy, Central Institute of Mental Health, P.O. Box 12 21 20, 68072 Mannheim, Germany Received 22 March 2003; received in revised form 9 September 2003; accepted 11 September 2003
Abstract Treatment-resistant schizophrenia often leads to combined application of antipsychotic drugs. We report first experience with the combination of olanzapine and amisulpride. Improvement of psychopathological state and side effects could be achieved, and drug doses were lower than under monotherapy. We thus conclude that this approach represents a useful therapeutic option. © 2003 Elsevier SAS. All rights reserved. Keywords: Schizophrenia; Antipsychotic drugs; Amisulpride; Olanzapine
1. Introduction
2. Subjects and methods
Up to 40% of patients with psychotic symptoms do not respond to conventional antipsychotic monotherapy [4]. Within the group of atypical antipsychotic drugs, olanzapine presents a receptor profile quite similar to clozapine [9]. Olanzapine may induce a significant gain of body weight, somnolence, anticholinergic effects and transient increases of liver enzymes [2]. In cases of treatment-resistant schizophrenia successful combinations with several antipsychotic drugs [3] have been reported. Amisulpride, another safe and efficient atypical antipsychotic drug [7], exhibits a unique pharmacological profile, which is characterized by a predominant interaction with D3/D2-dopamine receptors. The substance ameliorates negative symptoms and exerts only extremely small increase of body weight [6]. The combined application of antipsychotic drugs is an established step in the therapy of treatment-resistant schizophrenic psychoses [5]. This widespread clinical practice stands in contrast to some critical remarks in the literature focusing on unjustified use and lack of controlled clinical studies [3]. We performed this retrospective study aiming at the systematic outcome-evaluation of all patients, who received olanzapine and amisulpride in combination.
This open study was designed as a retrospective chart review (RCR) [3]. We examined the clinical records of the patients released from our hospital with the antipsychotic combination of amisulpride and olanzapine during the period January 1999 to December 2001. The following data were collected: gender, age, diagnoses (ICD-10, DSM IV), time of onset, number of hospitalizations, pharmacological background information (ineffective pharmacological treatment attempts, rational for the combination therapy, dosages, side effects) as well as scores of global assessment of functioning (GAF) and clinical global impression (CGI). The difference with respect to these psychometric scales between the day of hospitalization and the day of release reflects the clinical improvement.
* Corresponding author. E-mail address: [email protected] (M. Zink). © 2003 Elsevier SAS. All rights reserved. doi:10.1016/j.eurpsy.2003.09.002
3. Results Seven patients (five men, two women, age between 22 and 46 years, mean 30 years, Table 1) with an acute exacerbation of schizophrenia were treated with the combination of amisulpride (dose 200–800 mg, mean 485.7 mg) and olanzapine (dose 5–40 mg, mean 21.4 mg). This relatively small group represents about 0.8% of all inpatients in our clinic with schizophrenic psychoses within the three years 1999, 2000 and 2001. Every patient in this group had been unsuccessfully treated with one or more typical antipsychotic
Table 1 Case reports. Therapeutic effects are reflected in changes (D) of GAF and CGI-scales. Abbreviations: amis, amisulpride; beh, behaviour; BMI, body mass index; CGI, clinical global impression (severity of illness); cloz, clozapine; comb, combination; D, difference; del, delusions; EPMS, extrapyramidal motoric symptoms; FThD, formal thought disorder; GAF, global assessment of functioning; hall, hallucinations; hosp, hospitalization; improv, improvement; incompl, incompliance; NS, negative symptoms; olanz, olanzapine; PS, positive symptoms; rem, remission; refr, refractory; ther, therapy; TypAnt, typical antipsychotic drugs Age Gender ICD-10, DSM IV
m
F 20.0, 295.3
2 46
m
F 20.0, 295.3
21 and >6 hosp
3 35
m
F 20.0, 295.3
19 and >4 hosp
4 23
m
F 20.0, 295.3
20 and 3 hosp
5 23
f
F 20.0, 295.3
23 and 3 hosp
6 47
m
F 20.0, 295.3
36 and 3 hosp
7 22
f
F 20.0, 295.3
21 and 1 hosp
Refractory in the history
Psychopathological state before combination
First drug
Main Adjuvans Improvement of problem GAF and CGI (D)
BMI, length and weight
Side effects
Remarks
TypAnt cloz, olanz, comb of olanz and Benperidol TypAnt, partial rem with olanz
Del, auditory and cenesthetic hall, suicidality, NS Psychomotor inhibition, blunted affect
Olanz 30 mg
Refr PS
27.9, 1.65 m, 76 kg 20.3, 1.68 m, 57.2 kg
Body weight +5 kg Body weight +7.5 kg
Antiviral comedication and Biperiden
24.2, 1.70 m, 70 kg
Improv Comedication: Biperiden of EPMS
24.8, 1.80 m, 80.3 kg
Body Comedication: Sertralin weight +17.5 kg
19.4, 1.61 m, 50.2
Body weight +2.5 kg
21.2, 1.80 m, 68.6 kg
Body Comedication: Reboxetin weight +10.8 kg
23.7, 1.68 m, 67 kg
Rem of EPMS
Olanz 40 mg
Amis 600 mg
Partial rem of PS DGAF: +30, DCGI: –2 Improv of activity and affectivity DGAF: +22, DCGI: –2 Rem of PS, obsession and FThD DGAF: +35, DCGI: –3
After Amis rem of 200 mg PS refr NS TypAnt (EPMS) FThD, paranoid del, Amis Refr Olanz Risperidone, olanz, hall, compulsion, 400 mg PS, 5 mg amis intolerance of psychomotor EPMS cloz agitation, with disorganized beh amis-monotherapy and combinations TypAnt (EPMS), FThD, paranoid del, Olanz Refr Amis Improv of FThD partial rem with hypoactivity, 30 mg PS and 800 mg and PS, but olanz anhedonia, blunted NS incomplete Rem of affect NS, DGAF: +25, DCGI: –3 Olanz Refr Amis Rem of PS, refr NS, Risperidon (EPMS), Paranoid del, 20 mg PS and 400 mg DGAF: +30, DCGI: cloz (EEG), partial auditory and NS –2 rem with olanz cenesthetic hall, blunted affect, mutism, psychomotoric inhibition TypAnt (EPMS) Paranoid del, Amis Refr Olanz Rem of PS, improv cloz, EPMS with anhedonia, 200 mg PS and 15 mg of NS DGAF: +28, 800 mg amis hypoactivity, NS, DCGI: –2 blunted affect EPMS with amis-monotherapy TypAnt and FThD, paranoid del, Amis Rem of Olanz Rem of PS, improv Risperidone auditory hall, NS 800 mg PS 10 mg of NS DGAF: +35, (EPMS) with DCGI: –2 amis, refr NS and psychomotor agitation
M. Zink et al. / European Psychiatry 19 (2004) 56–58
1 36
Age at first manifestation and number of hosp 17 and >6 hosp
57
58
M. Zink et al. / European Psychiatry 19 (2004) 56–58
drugs and at least one atypical agent before. The reasons for the combination therapy included persistent positive (five patients) and/or negative symptoms (six patients). Lower individual drug doses could be used in combination therapy compared with monotherapy (reduction of olanzapine by 21% and amisulpride by 26%). The refractory symptoms markedly improved or remitted, as recorded by the GAF (increase from 36.9 to 66.1, D = +29.2) and by the severity of illness scale of CGI (reduction from 5.9 to 3.6, D = –2.3). Side effects such as body weight gain and extrapyramidal motoric symptoms were ameliorated by dose reduction. Nevertheless, the patients showed an average increased in body weight by 6.2 kg and two patients needed anticholinergic comedication due to extrapyramidal symptoms. Additionally, two further patients received antidepressant drugs. 4. Discussion Our study indicates that the combination of olanzapine with amisulpride represents a new therapeutic strategy in cases of treatment-resistant schizophrenic psychoses, which are a frequent clinical problem, although a generally accepted definition of “treatment-resistance” is difficult to give [5]. Combination therapies should only be considered, if several monotherapies including an atypical antipsychotic drug have proven to be ineffective [3]. From a pharmacological point of view, the highly selective blockade of D3/D2-receptors by amisulpride can supplement the relatively broad receptor interactions of olanzapine, which shows only moderate dopaminergic receptor blockade [9]. The neurobiological rationale of a combination therapy aims in a highly synergistic antipsychotic potency without increasing the risk of adverse effects. Pharmacokinetic interactions both as possible reasons for the clinical effect or as threat of toxicity seem unlikely, since amisulpride is largely cleared without metabolization by urinary excretion [1], whereas olanzapine is metabolized via cytochromes p450 [8]. In our study, a remarkable reduction of the daily olanzapine and amisulpride doses was possible, thereby minimizing side effects such as weight gain (five cases) or extrapyramidal symptoms (three cases). This increases patient’s compliance preventing exacerbations and subsequent hospitalizations. We did not observe any new side effects or unfavorable drug interactions.
This study represents all patients treated with the combination of olanzapine and amisulpride over a period of 3 years, representing 0.8% of 859 patients suffering from schizophrenic psychoses. These numbers underline the fact that the indication for a combined therapy was restricted to severe cases. Because only inpatients were included, long-term efficiency and benefits of the outlined therapy have to be further evaluated in prospective and randomized studies. Nevertheless, the results of our study are encouraging and prove the clinical benefit of olanzapine–amisulpride combination in treatment-resistant schizophrenic psychoses.
Acknowledgements The authors thank patients, nursing stuff and physicians of the Department of Psychiatry of the Central Institute of Mental Health for clinical treatment of inpatients and W. VanSyckel for text revision.
References [1] [2] [3]
[4]
[5] [6]
[7]
[8]
[9]
Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000;38(5):393–414. Conley RR, Meltzer HY. Adverse events related to olanzapine. J Clin Psychiatry 2000;61(Suppl 8):26–9 [discussion 30]. Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30. Hellewell JS. Treatment-resistant schizophrenia: reviewing the options and identifying the way forward. J Clin Psychiatry 1999;60 (Suppl 23):14–9. Koshino Y. Algorithm for treatment-refractory schizophrenia. Psychiatry Clin Neurosci 1999;53(Suppl):S9–S13. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, Lemperiere T, et al. Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001;44(1):41–6. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159:180–90. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes p450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996;41(3):181–6. Stephenson CM, Pilowsky LS. Psychopharmacology of olanzapine. A review Br J Psychiatry 1999;38(Suppl):52–8.