Background
The long-term goal of the treatment of schizophrenia is theprevention of recurrence. To achieve this goal, the continuationof medication is important.
Lack of adherence to medication regimens is a critical issue
in the treatment of schizophrenia and has serious impacts on
the course of the illness, including worsening of symptoms,relapse, suicidal attempts, repeated emergency room visits or
re-hospitalization, and poor functional outcomes (AscherSvanum et al., 2006).
Factors inhibiting medication adherence have been suggested
to be associated with 1) Patients’ poor understanding of theirdiseases, 2) unfavorable relationship between patients andhealthcare workers and 3) Side effects of drugs.
In this session, I would like to suggest how we can assess theadherence and how we can improve adherence in patients withschizophrenia, by indicating our research.

Non-adherence with Antipsychotics How Do We Assess and Assist These
Patients with Schizophrenia?
Hiroyuki Kamei 1), Manako Han-ya 1), Takahiro Hayashi 2),
Shigeki Yamada 2), Nakao Iwata 3)1) Faculty of Pharmacy, Meijo University, Nagoya, Japan2) Department of Pharmacy, Fujita Health University Hospital3) Department of Psychiatry, School of Medicine, Fujita Health University

Nagoya, Japan.

Evaluation of medication adherence

Study 1
Association between the psychiatric symptoms and illness
insight / medication adherence in patients with schizophrenia

DAI-10（Drug Attitude Inventory-10 Questionnaire）
1. For me, the good things about medication
outweigh the badYesNo

1

Objects
The long-term goal of the treatment of schizophrenia is the prevention ofrecurrence.
To achieve this goal, the continuation of medication is important.
We considered that the continuation of medication may require improvement ininsight /medication adherence, not improvement in symptoms by involuntaryMedication. We then evaluated the association between the severity of symptoms
and insight / medication adherence.

2. I feel weird, like a "zombie", on medication

Yes

No

1

3. I take medication of my own free choice

Yes

No

1

4. Medication makes me feel more relaxed

Yes

No1

5. Medication makes feel tired and sluggish

Yes

No

1

6. I take medication only when I am sick

Yes

No1

7. I feel more normal on medication

Yes

No

1

8. It is unnatural for my mind and body to becontrolled by medication

Yes

No1

9. My thoughts are clearer on medication

Yes

No1

10. By staying on medication I can prevent getting
sickYes

NoMethods
The subjects were comprised of 101 outpatients with schizophrenia.
Psychiatric symptoms were evaluated using BPRS and CGI,
illness insight using SAI, and drug adherence using DAI-10.
BPRS: Brief Psychiatric Rating Scale
CGI: Clinical Global Impression Scale
SAI: Schedule for Assessment of InsightDAI-10: Drug Attitude Inventory-10 Questionnaire

Total

Association between BPRS and CGI or SAI

740
41.4±14.8
36.7±10.5

Worse

n=75

n=101

WorseWorseWorse70

35640

6430

31.8±9.1

4.4±1.7

4.1±1.2
3.9±1.3

CGI4CGIBPRSNo association(r = －0.069)

BPRS

5No association(r = －0.189)

n=75

7560

50

110

Jpn. J. Clin. Psychopharmacol. 11: 1491-1498, 2008

Association between BPRS and CGI orDAI-10
n=101Score

3No significant difference
between three groups

3225No significant differencebetween three groups

Better30

20-10 -8

Better

-6-4-202468DAI-10

BPRS: Brief Psychiatric Rating Scale
CGI: Clinical Global Impression Scale
DAI-10: Drug Attitude Inventory-10 Questionnaire

10WorseBetter

Better10-10 -8

Better220① Positive ② Slightly positive ③ Negative-6-4-20246810

SAI *
Better

DAI-10WorseSpearman rank correlation
Jpn. J. Clin. Psychopharmacol. 11: 1491-1498, 2008*：「Do you think you have a mental diseas ?」「I think usually」＝Positive,「 I think sometimes 」＝Little positive,「I don’t think so」＝Negative

10① Positive ② Slightly positive ③ Negative

SAI *BPRS: Brief Psychiatric Rating Scale
CGI: Clinical Global Impression Scale
SAI: Schedule for Assessment of Insight
Jpn. J. Clin. Psychopharmacol. 11: 1491-1498, 20081

Association between SAI and DAI-10

Association between SAI and DAI-10

n=757n=101

Better1065.5±4.2

5.7±3.9856

DAI-10Association(r = 0.291)

4DAI-102430024681012141618202

Significant difference(*P < 0.05)

The patients who are not awareof their own disease show
a poor medication adherence.

*-2

1.8±4.0
1-4

Worse-60① Positive-8② Slightly positive③ Negative

SAI *-10SAIBetter

Worse
Spearman rank correlation

SAI: Schedule for Assessment of InsightDAI-10: Drug Attitude Inventory-10 Questionnaire

Jpn. J. Clin. Psychopharmacol. 11: 1491-1498, 2008

Conclusion of study 1
In terms of the long-term prognosis of schizophrenia, the continuation ofmedication by improving insight / medication adherence, not improvementin symptoms by involuntary medication, is important.
Involuntarymedication

As a result, we build a
different direction toimproving symptoms.

Because a correlation ofsymptom and insight /medication adherence is
not observed, it is noteffective at first to demand
symptom improvement by
involuntary medication.

Improvement
in症状悪化
symptoms
NoassociationNo
association

Improvementofアドヒアランス
medication不良
adherence

Improvement of
病識欠如
insightAssociation

Good communication
to patients

We at first improveinsight / medication
adherence by the goodcommunication with thepatients.

MEMS: Medication Event Monitoring
SystemAn MEMS cap
mounted with an
IC tip recording
the opening date
and time

Data collection
at every visit tohospitalCount in theinternet center*：「Do you think you have a mental disease ?」「I think usually」＝①Positive,「 I think sometimes」＝ ②Slightly positive,「I don’t think so」＝③Negative* p<0.05 vs. ① Positive or ② Slightly positive
Jpn. J. Clin. Psychopharmacol. 11: 1491-1498, 2008

Study 2
Medication event monitoring system (MEMS) trial toevaluate the adherence of patients with schizophrenia
in JapanObjects
In order to accurately detect the medication adherence of patients withschizophrenia, for the first time in Japan a study that examines the consistency ofmedication adherence when using MEMS was conducted as a multicenter study,
in which one university hospital and six mental hospitals participated.
Methods
The subjects were comprised of 50 outpatients with schizophrenia.
Medication adherence and its tendencies were continuously monitored for up toa period of 6 months after discharge from hospital by using MEMS.
The endpoint was the continuing treatment.

Antipsychotics

RisperidoneOlanzapine
Aripiprazole
Blonanserin
Timiperone
Quetiapine

PC
Medicine bottle with
the MEMS cap

Perospirone
Haloperidol

Data reading device

2Patients medication pattern - Case ①

Patients medication pattern – Case ②

Time of Day

Time of Day
Date

DateMedication compliance is high, and time of taking medicine is constant

The days when medicine is not taken at all,in the latter half, in particular increases

Final status: Good compliance in taking medication
Patient background : Male, 38 years old / schizophrenia
paranoid type
Average of medication compliance ：98 %The time of taking medicine range ：46.9 min

Final status: Poor medication
Patient background : Female, 36 years old / schizophrenia paranoid type
Average of medication compliance ：55 %The time of taking medicine range ：212.9 min

Time course in the ratio of the patients with good adherence

Patients medication pattern – Case ③

Date
The days when medicine was not taken increase,and the time of taking medicine is not constantFinal status: Dropout (re-hospitalization)
Patient background : Male, 41 years old / schizophrenia paranoid type
Average of medication compliance ：66 %The time of taking medicine range ：253.4 min

20% of all patientsworsen after thefirst month

The ratio of patients with good adherenceTime of Day

The medicine compliance worsens with timeDischarge

12The compliancegradually worsens
subsequently

3456(months)

Good adherence ：the average value from MEMS is over than 75 %Time course in the ratio of the patients with good adherence

MEMS study

The ratio of patients with good adherence

The medicine compliance worsens greatly just after discharge

worsen greatly by
the first week justafter discharge

12 (24%)6 (12%)

Good compliance服薬良好32(64%)

服薬不良
Poor compliance
脱落
Dropped outn = 50Discharge

1234(weeks)

Good adherence ：the average value from MEMS is over than 75 %Good adherence ：the average value from MEMS is over than 75 %3

Method (1)Study 3The subjects checked symptoms that had concerned them in the Self-Report
Symptom Check Sheet. Pharmacists then conducted a questionnaire survey toevaluate the subjects’ degree of recognition regarding side effects, and clarify
whether or not a physician had been informed of their symptoms.

Investigation of the current state regarding side effects,
which are less likely to be noted, in pharmacotherapy forschizophrenia

Body Check Sheet
Please check the presence or absence of the following symptoms in your recent daily life:□ I become sleepy during the daytime (I cannot think clearly).
□ I have difficulties in getting up in the morning.
□ I feel restless and uneasy.
□ My appetite has grown.
□ I have gained weight.
□ I am lactating.
□ I do not have sexual desires.

Objects
・It is essential to improve adherence for the continuous taking of
medication, and the side effects of antipsychotics are partially
responsible for poor adherence.
・Some of the side effects of antipsychotics are not noted by healthcare
workers or patients, and some are less likely to be identified for various
reasons, such as patients being unwilling to tell. There is a concern thatsuch side effects may result in decreased adherence, and the taking ofdrugs may be discontinued.
・In this study, we investigated the current state regarding the side effectsof antipsychotics, which are less likely to be noted, and the backgroundcauses.

Females□ I have menstrual irregularities/amenorrhea.
Males□ I cannot ejaculate.
□ I do not have erections.
□ I have a feeling of fullness in my chest (I feel stiffness in my chest).
□ Others
Please write down what you would like to tell your physician

Method (3)Details of the questionnaire for each symptom checked

Method (2)Details of the questionnaire for each symptom checked(1) Do you think the symptom is caused by the side effects ofyour medication?
Yes, I do.
The symptom may not be caused by the side effects of my medication.
I am not sure.

 I want to avoid inconveniencing physicians

 I thought that changing to other medication would make no difference I do not want more types of medication

Symptoms checked in the Self-Report Symptom Check Sheet
Number of patients who have checked
40
60
80
100
120
140
96

160

155

8183(5) To patients who answered “The symptom has remained untreated,” doyou think this kind of sheet would help you tell a physician about symptoms
that concern you (remain untreated)?
 Yes, I do.
 No, I don’t.

Questionnaire survey after filling in the Self-Report
Symptom Check Sheet
Q1. Do you think the symptom is due to the side effectsof your medication?

1304752180
172767454

 There is no time to tell a physician

 Side effects are inevitable to suppress the symptom

Yes, I have been concerned about the symptom, but it has remained
untreated.
Yes, I have been concerned, and informed a physician of thesymptom.
No, I have not really been concerned.

Sexual dysfunction
性機能障害
Sleepinessduring thedaytime昼間眠気Weight gain
体重増加Restlessness
そわそわDry mouth Physicians have never asked me I am satisfied with my medication at the moment(3) Has the symptom concerned you?

20

 I’m unwilling to tell a physician/it is humiliating

 I am afraid to tell a physician (e.g., the physician may get angry)(2) Do you want to change your medication because of the symptom?
Yes, I do.
No, I don’t.

0(4) To patients who answered “The symptom has remained untreated,”
why has it remained untreated? (multiple answers)

Yes, I do.
No, I don’t.
Unknown106

外来患者(n=171)

1005743
口喝
Increased appetite
入院患者(n=139)
93
48
45
食欲増進
Difficulties
in getting
up in the morning81
43
38
朝起床できない
Tremor of the48
25
23
hands手足の震え
and feet
47
Constipation便秘2423Inability to articulate432518
呂律が回らない
Dark blue = Outpatient
Sialorrhea
34
1420
Light blue = Inpatient流涎Itching sensation
3 16 19of the feet
足がむずむずする
n=310 (multiple answers)
Insomnia
不眠 2 4 6Others
54
3420
その他
n=310（複数回答）

25%

37%
薬の副作用である
薬の副作用ではない38%

不明
n=310

4

Q3. Has the symptom concerned you?
Q2. Do you want to change your medication
because of the symptom?

Yes, I have been concerned about the symptom,

気になっていたが、我慢していた
but it has remained untreated.

Yes, I have been concerned, and informed a

気になって、医師に伝えていた
physician of the symptom.
Yes, I do.
No, I don’t.

21%

気にならない思う

No, I have not been concerned.

24%

思わない

48%

79%

28%

n=310

n=310

Q4. To patients who answered “The symptom has remained untreated,”
why has it remained untreated?

言いにくい
医師に申し訳ない
症状を抑えるために仕方ない
その他

I’m unwilling to tell a physician/it is humiliating
Physicians have never asked me
There is no time to tell a physician
I want to avoid inconveniencing physicians
聞いてくれない
言う時間がないI am afraid to tell a physician (e.g., the physician may get angry)
I am伝えるのが怖い
satisfied with my medication at今の薬が気に入っている
the moment
Side他の薬に変えても同じ
effects are inevitable to suppress
the symptom薬の種類が増える
I thought that changing to other medication would make no difference
I do not want more types of medication

Q5. To patients who answered “The symptom has remained
untreated,” does a check sheet help you tell your physician
about the symptom?

Yes, I do.
No, I don’t.

20%

はい2%
6%

いいえ

13%

12%
21%

An unfavorable relationshipbetween patients and physicians

80%

19%

n=310

12%

7%

4%

(49%)

n=310

4%

Discussion
・A large number of patients were not aware that symptoms
concerning them were caused by the side effects of theirmedications. Also, some patients had not reported theirsymptoms to physicians for various reasons, such as they had
been unwilling to tell, and they had not been asked byphysicians. The undisclosed symptoms included: weight gain,increased appetite, sexual dysfunction, inability to articulate,sialorrhea, etc. These findings suggest that side effects that areless likely to be disclosed mainly because of an unfavorable
relationship between patients and physicians, and improvementin such a relationship may lead to the disclosure of side effects.
・Using a number of methods, such as the Self-Report Symptom
Check Sheet, pharmacists actively collect information on
symptoms which patients are unwilling to disclose, and give
physicians feedback, which is considered to help improve themedication adherence of each patient.

Conclusion
1) Pharmacists sufficiently inform the patients with schizophrenia
about their disease and have the patients understand theneed for the medicine well.

Pharmacists suggest supporting the patients withschizophrenia by listening to and actively discerning
their complaints about medication.
3) Pharmacists explain to patients that it is important tosufficiently understand the risks/benefits of treatment
and early detection/treatment of side effects.
2)4) It is a great contribution to improving patients’ daily life when
the intervention of these pharmacists improve adherence inpatients with schizophrenia.

56