Nghiên cứu đặc điểm lâm sàng bệnh tâm thần phân liệt đáp ứng kém với thuốc an thần kinh cổ điển và kết quả điều trị bằng thuốc clozapine tt tiếng anh

MINISTRY OF EDUCATION

MINISTRY OF DEFENSE

AND TRAINING
MILITARY MEDICAL UNIVERSITY

PHUNG THANH HAI

STUDY ON CLINICAL FEATURES OF SCHIZOPHRENIC
PATIENTS, WHO RESPOND POORLY TO CLASSIC
ANTIPSHYCHOTIC DRUGS
Specialism: Neuroscience
Code: 9720159

SUMMARY OF MEDICAL DOCTORAL THESIS

HANOI - 2019


THE WORK HAS BEEN SUCCESSFULLY COMPLETED AT
MILITARY MEDICAL UNIVERSITY – MINISTRY OF DEFENSE

Science Supervisors:
1. Prof. PhD Cao Tien Duc
2. Associate. Prof. PhD Bui Quang Huy

Opponent 1: Associate. Prof. PhD
Opponent 2: Associate. Prof. PhD
Opponent 3: Associate. Prof. PhD

The thesis will be protected before the doctoral thesis review
Broad in Military Medical University – Ministry of Defense
By date month 2019

This thesis can be found at the library:
1. Military Medical University library – Ministry of Defense
2. National library of Vietnam


1
BACKGROUND
I. The urgency of the project:
Schizophrenia is a clinical syndrome of variable, but
profoundly disruptive, psychopathology that involves cognition,
emotion, perception, and other aspects of behavior. The expression of
these manifestations varies across patients and over time, but the
effect of the illness is always severe and is usually long lasting. The
disorder usually begins before age 25, persists throughout life, and
affects persons of all social classes.
In the United States, the lifetime prevalence of schizophrenia is
about 1 percent, and in Vietnam, it is 0.47% of the population.
Classic neuroleptics are often used for treatment. According to
Kaplan H.I. et al. (1994), about 60 - 70% of schizophrenia patients
respond well to classic neuroleptics and the remaining 30-40% of
these patients make a poor response. The classic neuroleptiques and
should be replaced by atypical neuroleptiques such as Risperidone,
Olanzapine, ... but Clozapine is the most effective.
Stephen M.S. (2003) stated that we have to quantify blood
levels of the drug in order to have a proper drug regulation.
Bui Tien Dung (2011) studied Clozapine treatment for chronic

schizophrenia but the results were limited and no research has been
done about the response to poor treatment with classic neuroleptics
and the determination of the plasma concentration of Clozapine to
assess the effectiveness of treatment.
II. The aim of the thesis:
1. Review clinical features of schizophrenia in patients who
respond poorly to classic neuroleptiques.


2
2. Evaluate results of treatment by clozapine for schizophrenic
patients, who respond poorly to classic neuroleptiques, under the
PANSS scale.
3. Comment on the relationship between plasma levels of
clozapine and treatment results of schizophrenic patients, who
respond poorly to classical neuroleptique, under the PANSS scale.
III. Practical significance and new contributions of the project:
- The average age of schizophrenia patients is 32.08 ± 8.91
years. The average duration of schizophrenia is 23.64 ± 6.32 years;
The average age of onset is 23.64 ± 6.32 years and the number of
relapses is 23.64 ± 6.32 years.
- Clinical symptoms of schizophrenia, which respond poorly to
Haloperidol: 60.66% are paranoid type; social withdrawal (78.69%);
diminished emotional range (62.29%); emotional blunting (54.10%);
poverty of speech (52.46%); slow thinking (91.80%); poor personal
hygiene, withdrawal from work-related situations, diminished sense
of purpose, diminished social drive (100%).
- The treatment of schizophrenic patients with clozapine under
the PANSS scale through T4, T6 and T8 was very statistically
significant with p<0.001. The average dose of Clozapine is 228.69 ±

40.48 mg/day and the average plasma level is 319.35 ± 129.81 ng/ml.
III. Structure of the project:
The project is presented in 134 pages, 40 tables of data and 8
charts. The content includes 2 pages of background, 32 pages
overview, 18 pages of subjects and methodology, 39 pages of study
results, 39 pages of discussion, 2 pages of conclusion, 1 page of
proposal. 110 documents of references (11 of Vietnamese documents
and 99 of foreign documents).


3
CHAPTER 1: OVERVIEW
1.1. General issues about schizophrenia
Schizophrenia is a clinical syndrome of variable, but
profoundly disruptive, psychopathology that involves cognition,
emotion, perception, and other aspects of behavior. The expression of
these manifestations varies across patients and over time, but the
effect of the illness is always severe and is usually long lasting. The
disorder usually begins before age 25, persists throughout life, and
affects persons of all social classes. Both patients and their families
often suffer from poor care and social ostracism because of
widespread ignorance about the disorder. Although schizophrenia is
discussed as if it is a single disease, it probably comprises a group of
disorders with heterogeneous etiologies, and it includes patients
whose clinical presentations, treatment response, and courses of
illness vary. Clinicians should appreciate that the diagnosis of
schizophrenia is based entirely on the psychiatric history and mental
status examination. There is no laboratory measure for schizophrenia.
The lifetime prevalence of schizophrenia is about 1 percent,
which means that about 1 person in 100 will develop schizophrenia

during their lifetime. Schizophrenia is found in all societies and
geographical areas, and incidence and prevalence rates are roughly
equal worldwide.
1.2. Clinical features of schizophrenia, which poorly respond to
classic neuroleptics
According to Ngo Ngoc Tan et al. (2005) patients with
schizophrenia have positive symptoms and negative symptoms.
Patients with positive symptoms are said to have nondeficit
schizophrenia. The symptoms used to define deficit schizophrenia are


4
strongly interrelated, although various combinations of the six
negative symptoms in the criteria can be found.
According to Bui Quang Huy et al (2009), deficit patients have a
more severe course of illness than nondeficit patients, with a higher
prevalence

of

abnormal

involuntary

movements

before

administration of antipsychotic drugs and poorer social function
before the onset of psychotic symptoms. The onset of the first

psychotic episode is more often insidious, and these patients show
less long-term recovery of function than do nondeficit patients.
According to Sadock B.J. et al. (2007), when patients with acute
schizophrenia

are

administered

an

antipsychotic

medication,

approximately 60 percent will improve to the extent that they will
achieve a complete remission or experience only mild symptoms; the
remaining 40 percent of patients will improve but still demonstrate
variable levels of positive symptoms that are resistant to the
medications. Rather than categorizing patients into responders and
nonresponders, it is more accurate to consider the degree to which the
illness is improved by medication.
According to Bui Quang Huy et al (2009), before considering a
patient a poor responder to a particular drug, it is important to assure
that they received an adequate trial of the medication. A 4- to 6-week
trial on an adequate dose of an antipsychotic represents a reasonable
trial for most patients. Patients who demonstrate even a mild amount
of improvement during this period may continue to improve at a
steady rate for 3 to 6 months. It may be helpful to confirm that the
patient is receiving an adequate amount of the drug by monitoring the

plasma concentration.


5
Sadock B.J. et al. (2015) consideres, if the patient is responding
poorly, one may increase the dose above the usual therapeutic level;
however, higher doses are not usually associated with greater
improvement than conventional doses. Changing to another drug is
preferable to changing to a high dose. If a patient has responded
poorly to a conventional antipsychotic drug, it is unlikely that this
individual will do well on another conventional antipsychotic drug.
Changing to atypical antipsychotic drug is more likely to be helpful.
According to Bui Quang Huy et al (2016), clozapine is effective
for patients who respond poorly to conventional antipsychotic drugs.
Double-blind studies comparing clozapine to other antipsychotics
indicated that clozapine had the clearest advantage over conventional
drugs in patients with the most severe psychotic symptoms, as well as
in

those

who

had

previously

responded

poorly

to

other

antipsychotics. When clozapine was compared with chlorpromazine
in a severely psychotic group of individuals who had failed in trials
with at least three antipsychotics, clozapine was significantly more
effective in nearly every dimension of psychopathology, including
both positive symptoms and negative symptoms.
1.3. Treatment for schizophrenia who respond poorly to conventional
antipsychotic drug
If the patient is responding poorly, one may increase the dose
above the usual therapeutic level; however, higher doses are not
usually associated with greater improvement than conventional
doses. Changing to another drug is preferable to changing to a high
dose.


6
If a patient has responded poorly to a conventional DRA, it is
unlikely that this individual will do well on another DRA. Changing
to an SDA is more likely to be helpful.
Clozapine is effective for patients who respond poorly to
DRAs.

Double-blind

studies

comparing

clozapine

to

other

antipsychotics indicated that clozapine had the clearest advantage
over conventional drugs in patients with the most severe psychotic
symptoms, as well as in those who had previously responded poorly
to other antipsychotics. When clozapine was compared with
chlorpromazine in a severely psychotic group of individuals who had
failed in trials with at least three antipsychotics, clozapine was
significantly more effective

in nearly every dimension of

psychopathology, including both positive symptoms and negative
symptoms.
Clozapine was prepared by the pharmaceutical company Sandos
(USA) in 1961 and measureed in 1975. In 1989, Clozapine was more
effective than any neuroleptics in treating schizophrenia.
According to Sadock B.J. et al. (2007), clozapine is indicated
primarily for chronic schizophrenia and poor treatment-response
schizophrenia.
Bui Quang Huy et al. (2009) show that, the initial dose of 25 mg /
day for the first Point of time , increased the dose gradually by 25 mg / day
until treatment effects were observed.
Veith R. (2002) argues that it is necessary to treat patients with

schizophrenia who respond poorly to new neuroleptics. During the attack
period lasting 6-8 weeks, Risperidone should be used 4-6 mg / day,
Olanzapine 15-25 mg / day, Quetiapine 450-1000 mg / day and


7
Amisulpride 400-1200 mg / day. After that, consolidation treatment is
equal to ½ or 2/3 of the attack dose.
Clozapine has a number of side effects that make it a difficult
drug to administer. The most serious is a risk of agranulocytosis. This
potentially fatal condition occurs in approximately 0.3 percent of
patients treated with clozapine during the first year of exposure.
Subsequently, the risk is substantially lower. As a result, patients who
receive clozapine in the United States are required to be in a program of
weekly blood monitoring for the first 6 months and biweekly monitoring
for the next 6 months. After 1 year of treatment without hematological
problems, monitoring can be performed monthly
1.4. Clozapine plasma concentrations
There are many methods of quantifying Clozapine and/or its
metabolite in biological fluids (plasma, serum, blood, etc.), but highperformance liquid chromatography with ultraviolet detector (HPLV-UV)
or liquid chromatography with dual mass spectrometry (LC-MS / MS)
most commonly used.
Using UV or fluorescent detectors: this method has the advantage
that the device is quite popular; however, the disadvantage is that the high
quantitative limit, especially the amount of analyte in the mixture does not
meet the research requirements for plasma samples patients treated may
have very low blood levels. concomitant medications.
Mass spectrometry detector: the advantage is a satisfactory
quantitative limit (1.5 ng / mL for clozapine), which can be simultaneously
quantified with 16 NEUROLEPTICS drugs. For high sensitivity,

simultaneous analysis of multiple drugs and complex samples such as
plasma, Clozapine was quantified by double mass spectrometry (LC-MS /
MS) with high sensitivity, selectivity and peaks.


8
CHAPTER 2: SUBJECTS AND METHODOLOGY
2.1. Subjects
2.1.1. Characteristics of subjects
The subjects are 61 patients diagnosed schizophrenia who were
poorly responding to classic antipshychotic drugs. They were inpatients treated at 1National Psychiatric Hospital, Thuong Tin-Hanoi
from 2014 to 2017.
2.1.2. Grouping of subjects
Divided into 2 stages:
- Stage 1: including 61 4-week research patients with classic
antipshychotic drugs and evaluated by PANSS scale 2 of times:
+ The first PANSS (PANSS-T0): after admission, before using
classic antipshychotic drugs.
+ Second PANSS (PANSS-T4): patients treated with classic
antipshychotic drugs after 4 weeks without remission of symptoms
are called poor response to classic antipshychotic drugs. At this time,
the measure haloperidol plasma level.
- Stage 2: including 61 patients treated with clozapine in the
next 4 weeks as follows:
+ 61 patients treated with clozapine after 2 weeks were
assessed by PANSS scale (PANSS-T6).
+ 61 research patients treated with clozapine after 4 weeks
were assessed by PANSS scale (PANSS-T8).
+ In these 61 patients, randomized 30 patients to measure
clozapine plasma level of 3 times:

• The first measure: after 48 hours of taking clozapine (T4).
• Second measure: after 2 weeks of clozapine treatment (T6).
• Third measure: after 4 weeks of clozapine treatment (T8).


9
2.1.3. Selection criteria
- The patients diagnosed as schizophrenia according to
ICD.10F standard in 1992 about mental disorders and act. Include,
chapter F2, section F20.
- Poor response to classic antipsychotic drugs by Sadock B. J.
(2015).
2.2. Study method
2.2.1. Study design
- The study was prospective, cross-sectional, analyzed in order
to know the clinical features of patients with schizophrenia, who
poorly respond to classic antipshychotic drugs.
- Analysis of clinical characteristics of all 61 studied patients.
- Analysis of plasma haloperidol and clozapine concentrations
of these patients
- Relationship between clinical features, PANSS scores and
plasma clozapine concentration.
- Quantify clozapine concentrations at three times:
+ 1st time: 2 days after taking clozapine.
+ 2nd time: 2th week of clozapine treatment.
+ 3nd time: 4th week of clozapine treatment.
2.2.2. Study sample size:
Select all schizophrenic patients, who poorly respond to classic
antipshychotic drugs.
2.3. Ethics in research

- The study did not affect the patient's treatment results.
- Ensure the privacy of patients during the study process.
- Patients do not have to pay any extra money for research
2.4. Data processing method
- The data were analyzed by STATA 12.0.
- The results are presented by Tables and Charts.


10
CHAPTER 3: RESULTS
3.1. The general characteristic of the research subjects
Table 3.1 Current age of research subjects
Index
n
%

Age
≤20 years
21-30 years
31-40 years
>40 years
Total

5
8.20
25
40.98
19
31.15
12

19.67
61
100.00
Average age = 32.08 ± 8.91 years
Table 3.1 shows that the age group ≤ 20 years old accounts for
the lowest rate (8.20%) and the age group from 21-30 years old
accounts for the highest rate (40.98%). The remaining ages are from
31-40 years old (31.15%) and the age group is over 40 years old
(19.67%). The average age of patients was 32.08 ± 8.91 years.
3.2 Clinical features schizophrenia, who responds poorly to
classic antipsychotic drugs
Table 3.4 The duration of schizophrenia
Index
n
%
Duration
≤ 5 years
23
37.71
6-10 years
20
32.79
11-15 years
9
14.75
>15 years
9
14.75
Total
61

100.00
The average duration = 23.64 ± 6.32 years
Table 3.4 shows that, the duration of illness ≤5 years accounted
for the highest proportion (37.71%), followed by 6-10 years
(32.79%), 11-15 years and >15 years is the lowest (14.75%).


11
Table 3.9 Negative symptoms of subjects
Index

No

Symptoms

n=61

%

1

Emotional blunting

15

24.59

2

Inappropriate affect

33

54.10

3

Poverty of speech

32

52.46

4

Curbing of interests

38

62.29

5

Diminished sense of purpose

30

49.18

6

Diminished social drive

48

78.69

Table 3.9 shows the diminished social drive, the highest rate
(78.69%) and the lowest is emotional blunting (24.59%).
Table 3.18 Symptoms of anormal behaviors
Num

Index
Symtoms

(n=61)

%

1

Eccentric behavior

34

55.74

2

Social withdrawal

39

63.93

3

Aggressive behavior

36

59.02

4

Bulimia

2

3.29

5

Leaving home wandering

41

67.21

6

Suicide

2

3.29

Table 3.18 shows that leaving home wandering accounts for
the highest proportion (67.21%) and the lowest rate is bulimia and
suicide (3.29%).


12
3.3. The results of treatment of schizophrenia respond poorly to
classic pshychotic drugs under PANSS scale
Table 3.27 Relationship between dose of Clozapine and PANSS score
Clozapine

Time

PANSS scale
Total score PANSS
(1)

T4

T6

T8

(n=61)

(n=61)

(n=61)

27.11 ± 4.24

N - PANSS (3)

29.25 ± 1.90 26.97 ± 2.07

G - PANSS (4)

64.64 ± 2.87

40.38 ± 2.15 31.87 ± 1.87

S - PANSS (5)

13.23 ± 1.12

6.25 ± 0.72

6.00 ± 0.00

Anergia (6)

9.38 ± 1.82

7.47 ± 1.26

6.52 ± 0.81

13.20 ± 1.87

8.08 ± 0.94

7.26 ± 0.73

disturbance

(7)

(T4 –
T6)

p
(T6 – T8)

134.23 ±5.68 87.21 ± 3.65 64.59 ± 2.88

P - PANSS (2)

Thought

p

13.62 ± 1.47 12.52 ± 1.29

p<0.001

14.20 ± 1.60

Activation (8)

12.72 ± 0.95

6.49 ± 0.62

5.84 ± 0.37

Paranoid bellig. (9)

13.59 ± 1.28 6.59 ± 0.82

5.85 ± 0.36

Depression (10)

12.54 ± 1.18 8.59 ± 1.19

7.82 ± 0.56

p<0.001

p<0.05

p<0.001

The association between the dose of Clozapine and the PANSS
scale in patients with schizophrenia shows that the all respondents
were significantly different in the three surveys with p<0.001.


13
Table 3.28 Relationship between dose of Clozapine and P-PANSS
Clozapine

Time
T4

T6

T8

p

p

(n=61)

(n=61)

(n=61)

(T4 – T6)

(T6 – T8)

3.11±1.97

1.56±0.50

1.18±0.39

3.97±0.89

2.46±0.53

1.98±0.13

P3 Hallucinations

2.98±1.87

1.52±0.50

1.20±0.40

P4 Excitement

4.20±0.51

2.05±0.28

1.84±0.37

P5 Grandiosity

3.69±0.50

1.75±0.47

1.36±0.48

P6 Suspiciousness

4.72±0.80

2.13±0.34

1.88±0.32

P7 Hostility

4.44±0.59

2.15±0.40

1.98±0.13

P- PANSS
P1 Delusions
P2

Conceptual

disorganization

p<0.001

p<0.001

p<0.01

When comparing the three surveys of P-PANSS, showed a
significant difference with p<0.001.
Table 3.29 Relationship between dose of Clozapine and N-PANSS
Clozapine

Time
N-PANSS

T4

T6

T8

p

p

(n=61)

(n=61)

(n=61)

(T4–T6)

(T6–T8)

p<0.001

p<0.001

N1 Blunted affect

1.51±0.81 1.87±1.28 1.33±0.47

N2 Emotional withdrawal

4.72±0.55 4.21±0.66 2.02±0.13

N3 Poor rapport

4.62±0.49 4.31±0.59 2.02±0.13

N4 Passive/apathetic social
withdrawal
N5

Difficulty in abstract

thinking
N6 Lack of spontaneity and
flow of conversation
N7 Stereotyped thinking

4.84±0.61 4.44±0.53 2.23±0.42
4.82±0.39 4.47±0.57 2.28±0.45
4.56±0.53 3.95±0.28 2.33±0.47
4.18±0.46 3.70±0.49 2.00±0.00

Table 3.29 The three surveys of N-PANSS were very diverse.
N2, N3, N5, N6 and N7 were statistically significant differences with
p<0.001.


14
Table 3.30 Relationship between dose of Clozapine and G-PANSS
Clozapine
Time
G-PANSS

T4

T6

(n=61)

(n=61)

T8

p

p

(n=61)

(T4 – T6)

(T6 – T8)

G1 Somatic concern

3.84±0.66 3.39±0.56

G2 Anxiety

3.92±0.59 3.38±0.61 1.90±0.30

G3 Guilt feelings

3.77±0.50 4.31±0.59

1.97±0.18

G4 Tension

4.69±0.53 2.85±0.44

2.00±0.00

3.84±0.37 2.95±0.22

2.00±0.00

G6 Depression

3.87±0.34 2.93±0.36

1.98±0.13

G7 Motor retardation

3.93±0.31 2.29±0.49

2.18±0.43

G8 Uncooperativeness

4.43±0.56 2.31±0.50

1.98±0.13

G5

Mannerisms

and

posturing

G9

Unusual

thought

content

1.97±0.36

p<0.001

p<0.001

p<0.05

p<0.001

4.49±0.50 2.34±0.48 2.00±0.00

G10 Disorientation

1.00±0.00 1.00±0.00

1.00±0.00

G11 Poor attention

4.57±0.49 2.47±0.50

2.33±0.47

p < 0,05

4.64±0.52 2.74±0.44

2.28±0.45

p<0.001

4.28±0.58 2.11±0.32

2.00±0.00

G14 Poor impulse control 4.82±0.39 2.08±0.28

2.03±0.18

p>0.05

G15 Preoccupation

3.74±0.44 2.16±0.37

2.00±0.00

p<0.01

4.82±0.39 2.51±0.54

2.25±0.43

p<0.001

G12 Lack of judgment
and insight
G13

Disturbance

of

volition

G16

Active

avoidance

social

0

p<0.001

0

p<0.01


15
Table 3.30 shows that, The relationship between the dose of

Clozapine and the G-PANSS shows that the three surveys had
significant differences with p<0.001.
Table 3.31. Relationship between dose of Clozapine and S-PANSS
Clozapine

Time
T4

T6

T8

p

p

S-PANSS

(n=61)

(n=61)

(n=61)

(T4 – T6)

(T6 – T8)

S1 Angry

4.43±0.56

2.11±0.32

2.00±0.00

4.21±0.49

2.08±0.28

2.00±0.00

4.59±0.50

2.05±0.22

2.00±0.00

S2

p<0.01

Exasperated

when satisfaction of
requests

was

p<0.001

p<0.05

delayed
S3 Mood unstable

p>0.05

Table 3.31 For the three surveys of S-PANSS there were
significant differences with p<0.001. Remaining at T6 and T8 shows
that it is very diverse as S1 with the difference of pT6 - T8 <0.01; S2
is different from pT6 - T8 <0.05 and even S3 has no difference (pT6 T8>0.05).


16
3.4. Relationship between dose and Clozapine plasma level under
PANSS scale
Table 3.38 Relationship between Clozapine plasma level and
PANSS scores
Time

PANSS scale
Total

Clozapine concentration (ng/ml)
T4

T6

T8

p

p

(n = 30)

(n = 30)

(n = 30)

(T4 – T6)

(T6 – T8)

PANSS 136.20±4.9

score (1)

5

87.37±2.87 64.47±2.93

P-PANSS (2)

28.07±4.39 13.87±1.65 12.80±1.40

N-PANSS (3)

9.25±1.90

27.00±1.66 14.13±1.57

G-PANSS (4)

4.64±2.87

40.33±2.04 31.53±1.87

S-PANSS (5)

3.23±1.12

6.17±0.59

6.00±0.00

Anergia (6)

9.70±1.74

7.73±1.11

6.53±0.78

3.77±2.03

8.33±0.96

7.43±0.77

2.97±0.89

6.57±0.63

5.83±0.38

3.73±1.28

6.67±0.99

5.87±0.35

2.50±1.17

8.43±1.25

7.70±0.60

Thought
disturbance (7)
Activation (8)
Paranoid

bellig.

(9)
Depression (10)

Table

3.38

the

relationship

between

p<0.001

p>0.05
p<0.001

p<0.001

plasma

clozapine

concentration and PANSS scores showed that there were significant
differences with pT4-T6<0.001 and pT6-T8<0.001. Particularly, T6 and
T8 at S-PANSS found no statistical significance (pT6 - T8>0.05).


17
Table 3.39 Relation between Clozapine plasma level and P-PANSS
Tim
e

Clozapine concentration (ng/ml)
T4

T6

T8

p

p

(n = 30)

(n = 30)

(n = 30)

(T4–T6)

(T6–T8)

3.47±1.96

1.63±0.49

1.20±0.41

3.90±0.80

2.43±0.50

2.00±0.00

P3 Hallucinations

3.40±1.85

1.63±0.49

1.27±0.45

P4 Excitement

4.20±0.55

2.00±0.26

1.83±0.38

P5 Grandiosity

3.80±0.48

1.83±0.46

1.33±0.48

P6 Suspiciousness

4.80±0.80

2.17±0.38

1.93±0.25

P7 Hostility

4.50±0.63

2.17±0.46

1.97±0.18

P-PANSS
P1 Delusions
P2

Conceptual

disorganization

p<0.001

p<0.001

p<0.05
p<0.001
p<0.05

Table 3.39 the relationship between plasma concentrations of

clozapine and P- PANSS in patients with schizophrenia showed that
these different levels such as group P4-PANSS, P6-PANSS and P7PANSS in T6 and T8 with pT6-T8<0.05. Remaining all have a clear
difference in T4 and T6; T6 and T8 with pT4-T6<0.001 and pT6T8<0.001.


18
Table 3.40 Relation between Clozapine plasma level and N-PANSS
Time

N- PANSS
N1 Blunted affect
N2

Emotional

withdrawal
N3 Poor rapport
N4 Passive/apathetic
social withdrawal
N5

Difficulty

in

abstract thinking
N6

Lack

Clozapine concentration (ng/ml)
T4

T6

T8

p

p

(n = 30)

(n = 30)

(n = 30)

(T4–T6)

(T6–T8)

2.10±1.54

1.93±1.28

1.37±0.49

p<0.05

4.80±0.41

4.40±0.72

2.00±0.00

4.67±0.48

4.33±0.60

2.03±0.18

4.73±0.52

4.43±0.57

2.20±0.41

4.80±0.41

4.33±0.61

2.27±0.45

4.50±0.51

3.97±0.18

2.27±0.45

4.20±0.48

3.60±0.56

2.00±0.00

p<0.001

p<0.01
p<0.001

of

spontaneity and flow

p<0.001

of conversation
N7

Stereotyped

thinking

Table 3.40 the relationship between plasma concentrations of
clozapine and N-PANSS in patients showed that a significant
difference between T6 and T8 with pT6-T8<0.001. Particularly in T4
and T6 shows N2-PANSS, N3-PANSS, N5-PANSS, N6-PANSS and
N7-PANSS with pT4-T6<0.001; N4-PANSS with pT4-T6<0.01 and
N1-PANSS with pT4-T6<0.05.

19
CHAPTER 4: DISCUSSION
4.1 General characteristic of subjects:
- Age of the subjects:
Table 3.1 age group 21-30 years old has the highest rate of
40.98% and the lowest age is ≤ 20 years old (8.20%). This data is
suitable for Trinh Van Anh (2018).
4.2. Clinical features of schizophrenia who respond poorly to
classic neuroleptics
- Durations of schizophrenia
Table 3.4 shows that, the duration of illness ≤5 years accounted
for the highest proportion (37.71%), followed by 6-10 years
(32.79%), 11-15 years and >15 years is the lowest (14.75%).
According to Mohammad S. (2005), the average disease duration
of a group of 11 patients treated with Clozapine was 9.7±3.1 years.
As for the group of patients treated with classic neuroleptics, the
average duration of the disease is 8.6±3.7 years.
- Negative symptoms of schizophrenia
Table 3.9 shows the diminished social drive, the highest rate
(78.69%) and the lowest is emotional blunting (24.59%).
This result is consistent with the study of Bui Tien Dung and
shows that the negative symptoms of schizophrenia patients are very
diverse and very common.
- Anormal behaviors symptoms
Table 3.18 shows that leaving home wandering accounts for the
highest proportion (67.21%) and the lowest rate is bulimia and
suicide (3.29%).

20
This result is consistent with Meltzer HY (1989), the author said
that 2/3 of patients have wandering behavior, strange behavior.
4.3. The results of treatment of schizophrenia respond poorly to
classic pshychotic drugs under PANSS scale
- Relationship between dose of Clozapine and PANSS score
The association between the dose of Clozapine and the PANSS
scale in patients with schizophrenia shows that the all respondents
were significantly different in the three surveys with p<0.001.
This result is consistent with Mohammed S. (2005), Pierre-Michel
L. and CS. (2002), Dragan B.R. and CS. (2009), Janakiraman R. and
CS. (2005) and Bui Tien Dung (2011).
- Relationship between dose of Clozapine and P-PANSS
Table 3.28 shows that When comparing the three surveys of PPANSS, showed a significant difference with p<0.001
This result is consistent with Varunide S. and CS. (2010) and Bui
Tien Dung (2011).
- Relationship between dose of Clozapine and N-PANSS
Table 3.29 shows, the three surveys of N-PANSS were very
diverse. N2, N3, N5, N6 and N7 were statistically significant
differences with p<0.001.
This result is consistent with Dragan B.R. and CS. (2009) and Bui
Tien Dung (2011).
- Relationship between dose of Clozapine and G-PANSS
Table 3.30 shows that, the relationship between the dose of
Clozapine and the G-PANSS shows that the three surveys had
significant differences with p<0.001.
This result is consistent with Janakiraman R. and CS. (2005) and
Bui Tien Dung (2011).

21
- Relationship between dose of Clozapine and S-PANSS
Table 3.31: For the three surveys of S-PANSS there were
significant differences with p<0.001. Remaining at T6 and T8 shows
that it is very diverse as S1 with the difference of pT6 - T8 <0.01; S2
is different from pT6 - T8 <0.05 and even S3 has no difference (pT6 T8>0.05). This result is consistent with Dragan B.R. (2009).
4.4. Relationship between dose and Clozapine plasma level under
PANSS scale
- Relationship between Clozapine plasma level and PANSS
scores
Table

3.38

the

relationship

between

plasma

clozapine

concentration and PANSS scores showed that there were significant
differences with pT4-T6<0.001 and pT6-T8<0.001. Particularly, T6
and T8 at S-PANSS found no statistical significance (pT6 - T8>0.05).
This result is consistent with Hussein R. and CS. (1999) and Sukhtej
S. and CS. (2016).
- Relation between Clozapine plasma level and P-PANSS

Table 3.39 the relationship between plasma concentrations of
clozapine and P- PANSS in patients with schizophrenia showed that
these different levels such as group P4-PANSS, P6-PANSS and P7PANSS in T6 and T8 with pT6-T8<0.05. Remaining all have a clear
difference in T4 and T6; T6 and T8 with pT4-T6<0.001 and pT6T8<0.001.
This result is consistent with Hussein R. and CS. (1999), Sukhtej S.
and CS. (2016).
- Relation between Clozapine plasma level and N-PANSS
Table 3.40 the relationship between plasma concentrations of
clozapine and N-PANSS in patients showed that a significant


22
difference between T6 and T8 with pT6-T8<0.001. Particularly in T4
and T6 shows N2-PANSS, N3-PANSS, N5-PANSS, N6-PANSS and
N7-PANSS with pT4-T6<0.001; N4-PANSS with pT4-T6<0.01 and
N1-PANSS with pT4-T6<0.05.
According to Hussein R. (1999), in patients who responded to
Clozapine after 4 weeks of treatment, the N-PANSS score was from
30.9 ± 4.7 to 17.6 ± 3.9 points; In the group of patients who did not
respond to treatment, N-PANSS scores from 31.5 ± 4.0 to 28.5 ± 5.2
points [109].
Sukhtej S. and CS. (2016) studied 28 patients with treatmentresistant schizophrenia, treated with clozapine at 289.28 mg/day, and
mean plasma clozapine concentrations of 206.54μg/l. Before
treatment, the patient's N-PANSS score was 19.07±7.66, after 1
month of N-PANSS point treatment was 12.03±3.84 and after 2
months, it was only 10.78±2.58 points [110].


23
CONCLUSION

Study on 61 patients with schizophrenia, poor response to
classic antipshychotic drugs at the Central Psychiatric Hospital I,
Hanoi, we have the following conclusions:
1. Clinical features schizophrenia responds poorly to classic
antipshychotic drugs:
- The majority of patients are paranoid type (60.66%). The highest
rate (78.69%) of negative symptoms is diminished social drive,
leaving home wandering accounts for 67.21
2. The results of treatment of schizophrenia respond poorly to
classic pshychotic drugs under PANSS scale
- The association between the dose of Clozapine and the Total
PANSS scores in patients with schizophrenia shows that the all
respondents were significantly different in the three surveys with
p<0.001. The average score of PANSS scale is reduced from T4
(134.23±5.68 points); to T6 (87.21±3.65 points) and T8 (64.59±2.88
points).
- Relationship between dose of Clozapine (228.69±40.48mg/day)
and P-PANSS, N-PANSS, G-PANSS, S-PANSS showed a significant
difference with p<0.001
3. Relationship between dose and Clozapine plasma level under
PANSS scale
- Relationship between Clozapine plasma level (T4: 272.68 ±
143.3ng/ml; T6: 319.35±129.81ng/ml and T8: 319.34±138.71ng/ml)
and Total PANSS scores showed that there were significant
differences with pT4-T6<0.001 and pT6-T8<0.001. Particularly, T6
and T8 at S-PANSS found no statistical significance (pT6 - T8>0.05).