A clinical case series of switching from antipsychotic polypharmacy to monotherapy with a second-generation agent on patients with chronic schizophrenia

Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 361 – 369 www.elsevier.com/locate/pnpbp

A clinical case series of switching from antipsychotic polypharmacy to monotherapy with a second-generation agent on patients with chronic schizophrenia Takefumi Suzuki*, Hiroyuki Uchida, Koichiro Watanabe, Gohei Yagi, Haruo Kashima Department of Neuropsychiatry, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan Accepted 14 November 2003

Abstract Second-generation antipsychotic medications have become popular as a treatment for schizophrenia. The authors investigated 25 chronic subjects who had previously been treated with high-dose antipsychotic polypharmacy without amelioration. All patients had a history of having been treated with an antipsychotic polypharmacy regimen of the total daily chlorpromazine equivalent dose exceeding 1000 mg/day for more than 6 weeks. They were subsequently switched to a second-generation antipsychotic monotherapy. Other psychotropic medications were simplified at the same time. For successful patients whose symptoms showed at least minimal improvement, the medical chart was reviewed retrospectively. After completed switching, the patients were followed up for 12 weeks, when final evaluation was made. The Global Assessment of Functioning score improved from 32 to 47. The number of antipsychotic medications and total psychotropic medications were significantly reduced from 3.5 to 1.1 and 6.8 to 2.6, respectively. Also, the antipsychotic dose was significantly minimized from 2203 to 619 mg/day. Eleven of eighteen inpatients were discharged and the other four were better enough to be ready for discharge. By showing successful cases, the authors suggest a possibility of antipsychotic monotherapy with a second-generation agent even for those patients who had been treated with high-dose antipsychotic polypharmacy in vain. D 2003 Elsevier Inc. All rights reserved. Keywords: Antipsychotic monotherapy; Antipsychotic polypharmacy; High-dose therapy; Schizophrenia; Switching

1. Introduction There have been many guidelines or algorithms on the treatment of schizophrenia (American Psychiatric Association, 1997; Lehman and Steinwachs, 1998; Miller et al., 1999; McEvoy et al., 1999; Taylor et al., 2001). At the same

Abbreviations: BPD, bromperidol; CGI, Clinical Global Impression; CPZ, chlorpromazine; CYP 450, cytochrome P450; D2, dopamine D2 receptor; DOI, duration of illness; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; F-D, fluphenazine decanoate; F-E, fluphenazine enanthate; FPZ, fluphenazine; GAF, Global Assessment of Functioning; GI, Global Impression; HPD, haloperidol; HP-D, haloperidol decanoate; 5-HT2A, serotonin 5-HT2A receptor; LPZ, levomepromazine; MSP, mosapramine; OLZ, olanzapine; PPZ, perphenazine; PRS, perospirone; PMZ, pimozide; PCZ, propericiazine; QTP, quetiapine; RIS, risperidone; SLP, sulpiride; SOI, severity of illness; STP, sultopride; TMP, timiperone; ZTP, zotepine. * Corresponding author. Tel.: +81-3-3353-1211x62453; fax: +81-35379-0187. E-mail address: [email protected] (T. Suzuki). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2003.11.006

time, there is a growing popularity for the second-generation antipsychotic medications (Kupfer and Sartorius, 2002). Although typical antipsychotic agents still have a considerable role in treating schizophrenia, considering high prescription rate (Leslie and Rosenheck, 2002; Sernyak et al., 2003), the effectiveness of second-generation antipsychotics is being consolidated from various reports (Marder and Meibach, 1994; Tollefson et al., 1997; Purden et al., 2000; Conley and Mahmoud, 2001; Csernansky et al., 2002; Volavka et al., 2002). It might then follow that switching from typical to a second-generation antipsychotic medications is efficacious. Support for this view is appearing in the literature (Kinon et al., 2000; Voruganti et al., 2002). Taken together, the current suggestion can be summarized to treat patients with a single second-generation agent at the lowest possible dose (Miller et al., 1999; Taylor et al., 2001). In Japan, antipsychotic polypharmacy has been a rule rather than the exception for treatment of patients with schizophrenia. This peculiar situation is evident from various reports. A survey revealed that an average number of

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antipsychotics for schizophrenic patients in 1993 was 2.6 and the percentage of patients treated with a single antipsychotic was only 10.4% (Yamauchi et al., 1998). Another report from Ito et al. (1999) indicated that the rate of antipsychotic polypharmacy exceeded 90%. A more recent study showed the rate of 84.9% for schizophrenia (Inagaki et al., 2001). With respect to the dose of antipsychotic medications, higher doses are generally considered inappropriate (Putten et al., 1990; Volavka et al., 1995), and maintenance chlorpromazine equivalent dose of 300 – 600 mg per day is recommended (Lehman and Steinwachs, 1998). However, an average daily dose of 1066 mg is reported (Inagaki et al., 2001), based on data from 476 chronic patients hospitalized in Japanese public hospitals. The reason to bring about antipsychotic high-dose polypharmacy appears simple. Most plausible rationale to validate using such regimen seems to be troublesome behaviors that patients show owing to their internal symptoms, such as command auditory hallucinations. Many patients however may be maintained after dose increment and what is likely is that the dose may be increased more on the next episode of problematic behaviors. They then will be judged difficult cases. When the dose finally exceeds 1000 mg of chlorpromazine equivalent, but the patient remains unresponsive for more than 6 weeks, and two more medications from other chemical classes failed to ameliorate symptoms, they are finally evaluated as treatment-resistant subjects (Kane et al., 1988), for whom clozapine may be indicated, which exerts substantial efficacy (Wahlbeck et al., 1999). Regrettably, this compound is still unavailable in Japan. Although some rational combinations of antipsychotics have been suggested, and a recent trend in favor of antipsychotic polypharmacy has been pointed out (Clark et al., 2002), the evidence is not still fully established to date (Freudenreich and Goff, 2002). In this report, the authors present patients who had been treated with high-dose antipsychotic polypharmacy without much relief, who were then subsequently switched to a second-generation antipsychotic monotherapy with much amelioration of their symptoms. They had been treated with high-dose antipsychotic polypharmacy with reasons but inadequate treatment response ensued. By showing successful instances, however, the authors specifically intend to suggest a possibility of antipsychotic monotherapy even for those who had a history of being treated with high-dose antipsychotic polypharmacy in vain.

2.1. Subjects

2. Methods

Table 1 Relative potency of antipsychotic medications

Before switching antipsychotic medications, full description for the purpose and the procedure was provided. Written informed consent was then obtained from all subjects as a part of the routine work in the event of medication change.

All patients had been suffering from chronic schizophrenia, according to DSM-IV (American Psychiatric Association, 1994), and all had been treated with antipsychotic medications. To be eligible for selection, patients had to have a history of being treated with more than 1000 mg of daily antipsychotic medications (chlorpromazine equivalent) for more than 6 weeks. This dose is often cited as one of the criteria of treatment-resistance (Kane et al., 1988), but as is evident from the introduction and the results below, Japanese psychiatrists in particular often use combination of antipsychotic (as well as psychotropic) medications. Eventually, all cases had been treated with antipsychotic polypharmacy and the total chlorpromazine equivalent dose exceeded 1000 mg/day. Relative potency of antipsychotic medications is shown in Table 1 (revised from Inagaki et al., 1999), and the total dose was determined for each subject. Those with active somatic complications, mental retardation severe enough to prevent them from giving informed consent, history of neurological disorders, and substance abuse were excluded. 2.2. Study design This study is a description of cases in which retrospective medical chart review was performed for successful switch. Their severity had been worse than markedly ill (SOI of more than five). Because of unsatisfactory therapeutic response, antipsychotic medications of patients were switched to monotherapy with a second-generation agent in a cross-taper fashion. Psychotropic medications other than antipsychotic medications were also switched into a simple regimen to the extent that the dose and their content were judged to be less complicated than the baseline. Patients originally had been free from obvious adverse events due to medications, which indicates that this study was not intended to address the changes of objective adverse effects after switching, although subjective side effects might have been implicated. While switching antipsychotic medications, the dose of the selected second-generation antipsychotic was within the suggested range (Kupfer and Sartorius, 2002). They were maintained on the same antipsychotic medication for at least 12 weeks after the completion of switching. As many symptoms can emerge as a result of discontinuation (Weiden et al., 1997), the risks following abrupt

RIS 1 TMP 1.3 HPD 2 BPD 2 FPZ 2 PMZ 4 PRS 8 PPZ 10 PCZ 20 MSP 33 QTP 66 CPZ 100 LPZ 100 SLP 200 STP 200 CPZ 100 mg/day = HPD 2 mg/day = HP-D 30 mg/4w = F-D 7.5 mg/2w = F-E 7.5 mg/2w Second-generation antipsychotics are shown in italics.

OLZ 2.5 ZTP 66

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withdrawal of antipsychotics are reported (Viguera et al., 1997) and especially because the authors simplified other psychotropics as well at the same time, medication change was conducted gradually with caution. Here, the definition of a second-generation antipsychotic medication was in accordance with Kupfer and Sartorius (2002), who specified RIS (optimal dose range 2 – 8 mg), OLZ (5– 20 mg), QTP (150 – 750 mg), ZTP (75 – 450 mg) as such. Clozapine, ziprasidone, sertindole and amisulpiride are still unavailable in Japan. The authors also included PRS (12 – 48 mg), which was synthesized in Japan and has the activity both against D2 and 5-HT2A receptors (Onrust and McClellan, 2001). As differences among second-generation antipsychotics are not well-established, though some reports on this point are appearing in the literature (Purden et al., 2000; Conley and Mahmoud, 2001; Volavka et al., 2002), the authors classified all five compounds as such. 2.3. Assessments Patients were evaluated weekly with the CGI (Guy, 1976) (SOI and GI) and the GAF (American Psychiatric Association, 1994). These ratings and medication switching were performed by a single experienced psychiatrist. Final evaluation was made 12 weeks after the completion of switching. To be eligible for inclusion, the increase in the GAF score of at least 10 and the CGI of at least one point improvement (decrease) were necessary. All subjects eventually enjoyed a drastic alleviation of their symptoms (e.g. discharged from a hospital, moved from a closed ward to an open one) after switching. 2.4. Data analyses The baseline and the final status were compared by the Wilcoxon signed-rank test with regards to the GAF score, the SOI, the number and the dose of antipsychotic agents as well as the total number of psychotropic medications. A p value of < 0.01 was considered significant (two-tailed).

3. Results A total of 25 cases were identified. Demographic variables are shown in Table 2. There were 18 inpatients and 14 male subjects. Eleven subjects were classified as delusional, eight disorganized, three residual, two undifferentiated and one catatonic subtype, according to DSM-IV. As is evident, the initial GAF score of 32 and SOI of 5.8 on the average indicate that patients had been suffering from severe schizophrenia. And a mean DOI of 16.8 years indicates long-standing psychoses. Accordingly, they had exhibited poor social functioning. Table 3a shows the past maximum medication status of each patient before switching.

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Table 2 Demographic data of patients Mean F SD (minimum – maximum) Age (years) Duration of illness Total number of admission (years) Total duration of admission (years) Education (years)a Global Assessment of Functioningb Severity of Illnessc Number of antipsychotic medications Total dose of antipsychotic medications Number of total psychotropic medications

40.8 F 13.0 (21 – 67) 16.8 F 12.7 (2 – 52) 4.4 F 4.3 (1 – 20) 4.6 F 6.5 (0.5 – 33) 12.0 F 2.6 (6 – 16) 31.5 F 7.8 (15 – 51) 5.8 F 0.5 (5 – 7) 3.5 F 1.0 (2 – 5) 2203 F 1085 (1050 – 5183) 6.8 F 1.7 (3 – 11)

a

Education of 12 years means that a patient graduated from a high school. b GAF score of 31 – 40 means that a patient have some impairment in reality testing or communication or major impairment in several areas, such as work or school, family relations, judgement, thinking, or mood. c SOI of 6 (5.8) indicates severe illness.

The fact that the patients had been treated with high-dose antipsychotic polypharmacy shows that they had not been successfully treated as recommended. Two facts specifically are orthy of comment. First, what is remarkable is the total dose of antipsychotic medications. They were 2203 mg/day on the average. The recommended dose of daily antipsychotic medication is about 300– 600 mg in the maintenance phase (Baldessarini et al., 1988; Lehman and Steinwachs, 1998). This result indicates that the principle of pharmacotherapy for schizophrenia, which notes using the lowest possible dose of a simple medication regimen (Miller et al., 1999; Taylor et al., 2001), can be ignored in a real-world clinical setting. Higher dose therapy has been judged inappropriate by recent studies (Putten et al., 1990; Volavka et al., 1995). Also of note is antipsychotic polypharmacy. They had been treated with 3.5 antipsychotics on the average. Second, the problem of psychotropic polypharmacy is highlighted. Table 3a clearly demonstrates this common practice. The average of number of total psychotropic agents was 6.8 before switching. The final medication status is presented in Table 3b. The dose and the number of antipsychotic medications were significantly reduced to 619 ( p < 0.0001) and to 1.1 ( p < 0.0001), respectively, and the clinical status resulted in significant improvement. The GAF score jumped up from 32 to 47 ( p < 0.0001) and the SOI moved from 5.8 to 4.6 ( p < 0.0001). The resultant GI was 2.4 (Table 4). Although formal ratings were not performed, patients were classified with regards to the five domains (Lindenmayer et al., 1994) of improvement. Seven patients got better on negative symptoms, six on positive, five on cognitive ones while four improved in terms of excitement and the three others on anxiety/ depression. Of note is the fact that in 11 out of 18 inpatients, switching high-dose polypharmacy to a second-generation

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Table 3a Detailed information of 25 patients before switching Sex

Age

In- or out-patient

DOI (years)

Education (years)

Total number of admission

1

M

36

inpatient

15

12

3

2 3

F F

33 46

inpatient inpatient

8 23

16 12

4

F

46

inpatient

16

5

M

26

inpatient

6

M

48

7

F

8

Total duration of admission (years)

Initial GAF

Initial SOI

Past maximum antipsychotic medications (total CPZ equivalent dose)

Other psychotropic medications

4

31

6

biperiden 6, nitrazepam 10, flurazepam 15

3 2

3 4

35 30

5 6

12

1

2

25

6

2

9

2

1

21

6

HPD 36, BPD 36, RIS 9, FPZ 6, LPZ 50, F-E 25 mg/2w (5183) BPD, 48, HPD 27, OLZ 20, ZTP 150 (4777) RIS 12, FPZ 18, OLZ 20, MSP 150, HP-D 100 mg/4w (3688) HPD 36, FPZ 10, MSP 150, CPZ 450, LPZ 25 (3230) HPD 27, CPZ 175, TMP 18, LPZ 25 (2935)

inpatient

23

12

2

6

15

7

HPD 36, STP 1500, CPZ 350 (2900)

28

inpatient

8

12

3

3

30

6

BPD 27 CPZ 600 OLZ 20 (2750)

M

43

outpatient

18

12

2

1.5

51

5

HPD 36, CPZ 325, FPZ 3, LPZ 100 (2375)

9

M

54

inpatient

36

12

8

3

41

5

10 11

M M

28 21

inpatient inpatient

11 4

9 9

4 2

4 0.5

30 21

6 6

BPD 36, HPD 6, QTP 100, SLP 100, PPZ 4 (2342) HPD 27, CPZ 700, LPZ 10 (2060) HPD 12, ZTP 300, STP1800, LPZ 50 (2005)

12 13 14

M M M

37 65 39

outpatient inpatient outpatient

19 35 14

12 9 16

1 4 4

1 33 1.5

34 25 30

6 6 6

15 16

F F

34 37

outpatient inpatient

6 7

16 12

2 3

1 2

40 25

5 6

BPD 30, FPZ 3, SLP 500, PMZ 3 (1975) HPD 27, ZTP 150, PMZ 6, LPZ 50 (1777) BPD 24, CPZ 350, LPZ 50, F-D 25 mg/4w (1767) BPD 24, RIS 4, CPZ 100 (1700) HPD 18, OLZ 15, CPZ 50 (1550)

17 18 19

F F M

58 37 67

outpatient outpatient inpatient

22 9 52

6 14 16

5 4 10

7 1.5 8

45 31 37

5 6 6

BPD 30, CPZ 50 (1550) BPD 18, ZTP 200, RIS 3 (1503) HPD 27, CPZ 150 (1500)

20

F

32

inpatient

3

16

2

3

27

6

BPD 18, QTP 300, CPZ 50, LPZ 25 (1430)

21 22

M F

25 46

inpatient outpatient

2 22

9 12

1 20

2 6

30 31

6 6

HPD 21, PRS, perospirone; 24, LPZ 25 (1375) STP 1800, CPZ 400 (1300)

23

F

50

inpatient

22

12

10

4

35

6

24 25

M M

25 60

inpatient inpatient

6 37

12 12

2 11

1 12

35 33

6 6

HPD 8, RIS 4, FPZ 3, HP-D 100 mg/4w (1283) HPD 18, CPZ 150, LPZ 25 (1075) HPD 18, CPZ 150 (1050)

biperiden 6, estazolam 2 biperiden 6, bromazepam 6 biperiden 3 biperiden 6, flunitrazepam 2, promethazine 12.5, phenobarbital 40 carbamazepine 900, promethazine 75, estazolam 6, bromovalerylurea 0.5, amobarbital 0.2 carbamazepine 300 promethazine 150, flunitrazepam 2 biperiden 9, promethazine 12.5, phenobarbital 40, estazolam 3 biperiden 4, bromazepam 2, promethazine 25 biperiden 6 biperiden 6, promethazine 75, phenobarbital 120, flunitrazepam 2 biperiden 6, nitrazepam 10 biperiden 8, flunitrazepam 2, hydroxyzine 100 carbamazepine 400, biperiden 4, flunitrazepam 4, phenobarbital 80, promethazine 25 biperiden 4, flurazepam 15 biperiden 6, trihexyphenydil 6, promethazine 25, phenobarbital 80, flunitrazepam 4 biperiden 4 biperiden 4, nitrazepam 10, bromocriptine 7.5 biperiden 6, carbamazepine 400, nitrazepam 1, imipramine 10 biperiden 3, promethazine 50, quazepam 30, bromazepam 15, clonazepam 1.5, flunitrazepam 4, phenobarbital 110 biperiden 3, flunitrazepam 2 carbamazepine 600, biperiden 3, promethazine 50, phenobarbital 160, amobarbital 0.1, bromovalerylurea 0.3 carbamazepine 300, biperiden 4, flunitrazepam 2 biperiden 6, promethazine 25, nitrazepam 10 biperiden 2, lorazepam 3, phenobarbital 30

BPD, bromperidol; CPZ, chlorpromazine; F-D, fluphenazine decanoate; F-E, fluphenazine enanthate; FPZ, fluphenazine; HPD, haloperidol; HP-D, haloperidol decanoate; LPZ, levomepromazine; MSP, mosapramine; OLZ, olanzapine; PMZ, pimozide; PPZ, perphenazine; QTP, quetiapine; RIS, risperidone; SLP, sulpiride; STP, sultopride; TMP, btimeperone, ZTP, zotepine.

T. Suzuki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 361–369

Case no.

T. Suzuki et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 361–369

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Table 3b Detailed information of 25 patients after switching Case no.

Maximum dose of an atypical antipsychotic

Final antipsychotic medication (dose)

Final psychotropic medications

Final GAF

Final SOI

GI

Comment

1

OLZ 30

OLZ 30 (1200)

valproate 1200

43

5

2

2

QTP 500

QTP 500 (758)

lorazepam 2

51

4

2

3

ZTP 350 (HP-D100 mg/4w)

ZTP 350 HP-D100 mg/4w (864)

carbamazepine 800, lorazepam 6

45

5

2

4

RIS 6

RIS 3 (300)

quazepam 15

50

4

2

5

PRS 36

PRS 36 (450)

diazepam 10, zopiclone 15

40

5

2

6

RIS 8

RIS 8 (800)

carbamazepine 1000, lorazepam 4

31

6

2

7

RIS 7

RIS 6 (600)

lorazepam 7, carbamazepine 200

40

5

3

8

QTP 400

QTP 400 (606)

lorazepam 1

59

4

3

9

QTP 500

QTP 500 (758)

trazodone 25, lorazepam 2

57

4

2

10

OLZ 20

OLZ 20 (800)

lorazepam 2

45

5

2

11

RIS 4

RIS 3 (300)

lithium 600, diazepam 10, brotizolam 0.5

50

4

2

12

QTP 500

QTP 400 (606)

lorazepam 4

51

4

2

13

OLZ 20

OLZ 20 (800)

flunitrazepam 2 hydroxydine 75

37

5

3

14

RIS 6

RIS 6 (600)

carbamazepine 600, lorazepam 5

41

5

3

15

QTP 300

QTP 300 (455)

lorazepam 2

55

4

2

16

OLZ 20

OLZ 20 (800)

diazepam 15, zopiclone 7.5

51

4

2

17

RIS 6

RIS 5 (500)

biperiden 2

55

4

3

Switch to QTP, ZTP, PRS was ineffective. Although disorganization persisted, discharged from the hospital and now taking part in day-care activity more regularly than ever before. Much reduced bothersome positive symptoms. Became able to take part in occupational therapy. Ready to be discharged. Required about 6 weeks for switch. Much reduced frequency of short-acting intramuscular haloperidol, owing to auditory hallucination. Much relief in subjective positive symptoms but wanted to continue HP-D. Ready for discharge. Required about 10 weeks for switch. Monotherapy with HPD was possible, but left much to be desired such as severe withdrawal. Much improvement ensued and ultimately discharged. Became able to move from a closed to an open ward. Subsequently discharged with almost same medication regimen. Required about 8 weeks for switch. Monotherapy with BPD and OLZ ended in vain. Became free from chronic seclusion and able to go out from a closed ward alone. Less behavioral disturbances such as mutilation, yelling due to positive symptoms. Required about 12 weeks for switch. Showed transient irritability at first, became less compliant and more active in the end. Chronic constipation, hemorrhoid got better. Much better subjective mood. Required about 4 weeks for switch. Much less suicidality and avolition, although persecution persisted. Better clinical status led to discharge. Required about 2 weeks for switch. ZTP monotherapy was ineffective. Better status led to discharge. Problem of compliance was overcome. Because carbamazepine caused skin rash, he had been treated with as high as 2650 mg in the absence of mood stabilizing agents. Discharged from the hospital. Required about 16 weeks for switch. BPD monotherapy left much to be desired. Much better volition, less polydipsia and no enuresis. Became able to participate in day-care activity. Monotherapy with HPD resulted in stuporous status. Much reduced negative symptoms and going out from a closed ward alone became possible. Less severity in all domains. Much reduced use of medical resources such as ambulance and emergency visits. Required about 16 weeks for switch. Less suicidality and nonspecific complaints. Less subjective side effects and retained menstruation. Showed similar response like older brother (case 8). Required about 4 weeks for switch. PCZ monotherapy was ineffective and caused severe orthostatic hypotension. Much better cognitive function and negative symptoms. Ultimately discharged from the hospital. Less positive symptoms. Better compliance. Required about 4 weeks for switch. (continued on next page)

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Table 3b (continued) Case no.

Maximum dose of an atypical antipsychotic

Final antipsychotic medication (dose)

Final psychotropic medications

Final GAF

Final SOI

GI

Comment

18

OLZ 20

OLZ 10 (400)

lorazepam 2

41

5

3

19

OLZ 10

OLZ 10 (400)

lorazepam 3

49

4

2

20

RIS 4

RIS 3 (300)

lorazepam 10, quazepam 15

59

4

2

21

PRS 32

PRS 28 (350)

biperiden 2, lorazepam 4

40

5

3

22

QTP 600

QTP 600 (909)

45

5

3

23

ZTP 250 (HP-D 100 mg/4w)

ZTP 250, HP-D 100 mg/4w (712)

lorazepam 6, flurazepam 30, flunitrazepam 4 lithium 600, lorazepam 2

50

5

2

24

RIS 4

RIS 4 (400)

lorazepam 3

51

4

2

25

OLZ 20

OLZ 15 (600)

lorazepam 3

45

5

3

FPZ monotherapy was ineffective. Reduced commanding auditory hallucination. Much less subjective adverse events. Much more ADL and reduced aggression. Ready for charge. Required about 4 weeks for switch. Better enough to be discharged. Relatively resistant to benzodiazepines, but such was not the case with respect to antipsychotics. Required about 4 weeks for switch. Less positive symptoms and better depressive symptoms. Became able to participate in day-care activity. Discharged from the hospital. Required about 3 weeks for switch. Frequent admission became unnecessary. Retained regular menstruation. Required about 6 weeks for switch. Monotherapy with FPZ, HPD, PMZ all resulted in vain. Treatment with ZTP alone was also ineffective, partially validating combination regimen. Much more volition led to discharge. Became able to maintain single life. Tolerable positive symptoms. Frequent admission became unnecessary. Able to be discharged. More compliant. Tolerable positive symptoms. Required about a week for switch. Less disorganization. Acceptable positive symptoms and better ADL. Ready for discharge. Required about a week for switch.

BPD, bromperidol; CPZ, chlorpromazine; F-D, fluphenazine decanoate; F-E, fluphenazine enanthate; FPZ, fluphenazine; HPD, haloperidol; HP-D, haloperidol decanoate; LPZ, levomepromazine; MSP, mosapramine; OLZ, olanzapine; PMZ, pimozide; PPZ, perphenazine; PRS, perospirone; QTP, quetiapine; RIS, risperidone; SLP, sulpiride; STP, sultopride; TMP, btimeperone, ZTP, zotepine.

antipsychotic monotherapy led to discharge from a hospital and in four others showed a clinical status improved enough to be ready for discharge (83% in total). The number of total psychotropic medications was reduced to 2.6, which was also significant ( p < 0.0001). On top of that, the use of anti-parkinsonian drugs was significantly minimized. All patients had been prescribed them at baseline but 23 (92%) could be managed without them in the end. Also evident, however, is the fact that no patient could be treated with a single antipsychotic alone. Lorazepam, where necessary, suffices as a benzodiazepine for 16 out of 23 (70%) cases (only two subjects did not need that). Thirteen subjects (52%) had a history of being tried on some second-generation antipychotics. But the strategy had mostly been an add-on procedure and a change to monotherapy had not been implemented afterwards. And in 17 subjects (68%), the dose of the main medication alone, which accounts for the most relative potency, had exceeded 1000 mg/day. Past maximum medication in Table 3a means subjects’ past most complicated medication regimen with which patients had been treated for more than 6 weeks in the past. This does not necessarily mean their medication status just before switching. A total of seven subjects (No. 4, 6, 12, 13,

16, 18, 23) were first converted to monotherapy by a typical agent with resultant unsatisfactory status, then switched to second-generation agents. ZTP monotherapy was ineffective for case No. 10 but subsequent change to OLZ was effective. One case (No. 1) was first switched to QTP then ZTP, PSR and OLZ 20 mg, all of which resulted in failure. Only after OLZ was

Table 4 Results after switching Mean F SD (minimum – maximum) Global Assessment of Functioninga Severity of Illness Number of antipsychotic medications Total dose of antipsychotic medications Number of total psychotropic medications Global Impressionc a

31.5 F 7.8 (15 – 51) ! 47.2 F 7.1 (31 – 59)b 5.8 F 0.5 (5 – 7) ! 4.6 F 0.6 (4 – 6)b 3.5 F 1.0 (2 – 5) ! 1.1 F 0.3 (1 – 2)b 2203 F 1085 (1050 – 5183) ! 619 F 231 (300 – 1200)b 6.8 F 1.7 (3 – 11) ! 2.6 F 0.7 (2 – 4)b 2.4 F 0.5 (2 – 3)

GAF score of 41 – 50 means serious symptoms or any serious impairment in social, occupational, or school functioning. b < 0.0001 by the Wilcoxon signed rank test. c GI of 2 and 3 means much and minimal improvement, respectively.

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increased to 30 mg, added with valproate, he could finally be discharged in a better status. For the remaining 16 patients, who were directly switched to a second-generation drug, the approximate period of medication switching was 6.4 weeks on the average (range 1 –16 weeks), although minor dose reduction or adjustment of benzodiazepines, etc., could follow over a period of subsequent weeks. The final results in Table 4 represent patients’ status 12 weeks after the completed switch. Although monotherapy with a second-generation drug was sought, haloperidol decanoate was necessary for two subjects (No. 3, 23).

4. Discussion 4.1. Clinical implications The major difference between this report and other switching studies (Kinon et al., 2000; Voruganti et al., 2002) is that we specifically dealt with patients who had been treated with high-dose antipsychotic polypharmacy without success. To be sure, there had been reasons to bring about such a medication regimen, presumably unsatisfactory therapeutic response, such as problematic behavior and aggression. What should be acknowledged is that a history of being treated with antipsychotic polypharmacy at high doses does not necessarily indicate treatment-resistance. However, of note is the fact that nine subjects (36%) had been tried on monotherapy without success. In addition, in 17 patients (68%), the amount of the main antipsychotic alone had exceeded 1000 mg, for whom monotherapy with that medication only had been very unlikely to work. The principal finding is that those who suffer from severe schizophrenia can be treated with a second-generation agent within the recommended dosage. And 23 out of 25 subjects (92%) were treated with a second-generation antipsychotic monopharmacy. Although antipsychotic monotherapy was aimed, two other patients needed haloperidol decanoate. The important point that the authors want to emphasize is, during the switching process, if we set the target dose of a second-generation antipsychotic based solely on the relative potency of chlorpromazine equivalence, the results could be completely different. For example, in the case of No. 4, if we increased RIS up to 32 mg/day, the dose of which is calculated from Table 1, possible adverse effects, especially extrapyramidal side effects, could have prevented the switching. Eventually, she developed sialorrhea at 6 mg. Interindividual differences such as CYP 450 polymorphisms might be more relevant (Chou et al., 2000), but a report suggests higher haloperidol levels in Asian males compared with Caucasian males at a fixed dose, although no differences were found among females (Zhang-Wong et al., 1998). What deserves consideration is if a patient is treated with antipsychotic megadose therapy for a long time, for example

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in case No. 2, without much amelioration, should we feel the dose is too high because of the dose of 4777 mg/day, which everybody will admit to be high in dose and uniformly reduce the dose? Or shall we switch to another antipsychotic medication, add some other psychotropic medications, increase the dose and the number of medications because the clinical response is unsatisfactory (the patient had actually been suffering from command hallucination severe enough to interfere with her life)? The truth would be case-dependent, considering side effects and clinical status (e.g. possibility of hurting self or others), but the last option, in the absence of subsequent trial to monotherapy, will be certain to bring about polypharmacy. If a patient is not relieved by such a medication regimen, she or he is a candidate for switching. Prudent caution should be exercised on the dose of the selected second-generation antipsychotic medication, regardless of the prior total dose, and the dose of a second-generation agent should be within the recommended range, at least in the first trial of that medication. The dose and the relative potency of medications are very crucial, as these factors exert direct effect on outcome. For example, conflicting results are derived from the studies comparing RIS and OLZ, depending on the dose of each medication (Tran et al., 1997; Conley and Mahmoud, 2001). When switching to a second-generation medication within the recommended range fails, the next step to take needs more thoughtful judgement. This may include changing to clozapine (Kane et al., 1988; Wahlbeck et al., 1999) or increasing the dose of the second-generation antipsychotic medication (Launer, 1998). Case No. 1 is the only one patient treated outside the recommended range of up to 20 mg of OLZ. After sequential failure to respond to three second-generation agents and only after increasing the dose of OLZ to 30 mg with adjunctive valproate did amelioration result. We however have to admit that so-called treatmentresistant cases do exist and there are some options (in other words, no consensus has been made to date) for these difficult populations (Buckley et al., 2001). Case No. 6 was surely judged to have been treatment-refractory, though maybe not treatment-resistant, because he had been chronically secluded for more than a year and admitted for more than 5 years lately. He had been treated with various antipsychotic medications at high doses without success. He was, however, very successfully switched to a much simpler medication regimen. Although there apears to be a recent trend for antipsychotic polypharmacy (Clark et al., 2002), newer antipsychotics have the potential to revise polypharmacy, even when clozapine is unavailable. Eventually, 55% of cases had been tried on at least one of the second-generation antipsychotics in the past. Regrettably enough, though, they had been used as an add-on therapy without subsequent trial of monotherapy in our sample.

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This practice has been criticized as groundless and may increase the risk of side effects (Stahl, 1999). We have to remember that reduced adverse effects are the most prominent strength of the second-generation antipsychotic medications (Kupfer and Sartorius, 2002). To date, the efficacy of even theoretical antipsychotic combination therapy has not been fully substantiated (Freudenreich and Goff, 2002). 4.2. Limitations Retrospective design, lack of control group as well as uniform method of switching and extensive evaluations, small number of patients, indication of successful subjects only are the main drawbacks of this report. The most important question is the representativeness of our sample. So as to demonstrate real effectiveness, prospective studies with multiple fixed-dose design will be necessary. Psychotropic polypharmacy was also common. This is no exception for our cases. Some guidelines suggest using concomitant psychotropic medication, based on the clinical situation. One example may be applying antidepressants in case of depressive symptoms or benzodiazepines in the event of agitation (McEvoy et al., 1999). But when and how long to treat such symptoms still remain to be clarified. One clear advantage of the second-generation antipsychotics is that anti-parkinsonian medications can often be spared, which is evident by our cases. Ninety-two percent of subjects were managed without them. All patients however need adjunct medication, mostly lorazepam. This means genuine monopharmacy, that is to treat a patient with a single antipsychotic alone, was not possible. The authors however think this is an unavoidable result considering severe baseline severity, complicated medication regimen and in light of the fact that psychotropic polypharmacy (combination of medications with different mechanisms of action) is also increasing in frequency (Clark et al., 2002).

5. Conclusion Even those with chronic schizophrenia who had been treated with high-dose antipsychotic polypharmacy without clinical relief could still be candidates for switching to a second-generation antipsychotic monotherapy. During the switching process, the target dose of the second-generation agent should be within the recommended range, instead of targeting the dose determined by the relative potency.

Acknowledgements This work was partially funded by the Ome-Keiyu Hospital in Tokyo, Japan. The authors thank Dr. N. Ootsuka and Dr. M. Kamisada for their ongoing support.

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