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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 high-
performance 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 in-
patients 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 5 8.20
21-30 years 25 40.98
31-40 years 19 31.15
>40 years 12 19.67
Total 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 n=61 %
Symptoms
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
Index
Num (n=61) %
Symtoms
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
p
T4 T6 T8 p
(T4 –
PANSS scale (n=61) (n=61) (n=61) (T6 – T8)
T6)
Total score PANSS
134.23 ±5.68 87.21 ± 3.65 64.59 ± 2.88
(1)
P - PANSS (2) 27.11 ± 4.24 13.62 ± 1.47 12.52 ± 1.29 p<0.001
N - PANSS (3) 29.25 ± 1.90 26.97 ± 2.07 14.20 ± 1.60
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 p<0.05
p<0.001
Anergia (6) 9.38 ± 1.82 7.47 ± 1.26 6.52 ± 0.81
Thought disturbance
13.20 ± 1.87 8.08 ± 0.94 7.26 ± 0.73
(7)
p<0.001
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
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
Time Clozapine
T4 T6 T8 p p
P- PANSS (n=61) (n=61) (n=61) (T4 – T6) (T6 – T8)
P1 Delusions 3.11±1.97 1.56±0.50 1.18±0.39
P2 Conceptual
3.97±0.89 2.46±0.53 1.98±0.13
disorganization
P3 Hallucinations 2.98±1.87 1.52±0.50 1.20±0.40 p<0.001
p<0.001
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<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
Time Clozapine
T4 T6 T8 p p
N-PANSS (n=61) (n=61) (n=61) (T4–T6) (T6–T8)
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
4.84±0.61 4.44±0.53 2.23±0.42
withdrawal
p<0.001 p<0.001
N5 Difficulty in abstract
4.82±0.39 4.47±0.57 2.28±0.45
thinking
N6 Lack of spontaneity and
4.56±0.53 3.95±0.28 2.33±0.47
flow of conversation
N7 Stereotyped thinking 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 T8 p p
T4 T6
G-PANSS (n=61) (T4 – T6) (T6 – T8)
(n=61) (n=61)
G1 Somatic concern 3.84±0.66 3.39±0.56 1.97±0.36
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 p<0.001
G5 Mannerisms and
3.84±0.37 2.95±0.22 2.00±0.00
posturing p<0.001
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 p<0.05
G8 Uncooperativeness 4.43±0.56 2.31±0.50 1.98±0.13
G9 Unusual thought p<0.001
4.49±0.50 2.34±0.48 2.00±0.00
content
G10 Disorientation 1.00±0.00 1.00±0.00 1.00±0.00 0 0
G11 Poor attention 4.57±0.49 2.47±0.50 2.33±0.47 p < 0,05
G12 Lack of judgment
4.64±0.52 2.74±0.44 2.28±0.45 p<0.001
and insight
G13 Disturbance of
4.28±0.58 2.11±0.32 2.00±0.00 p<0.01
volition p<0.001
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
G16 Active social
4.82±0.39 2.51±0.54 2.25±0.43 p<0.001
avoidance
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
Time Clozapine
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 p<0.01
S2 Exasperated
when satisfaction of
4.21±0.49 2.08±0.28 2.00±0.00 p<0.001 p<0.05
requests was
delayed
S3 Mood unstable 4.59±0.50 2.05±0.22 2.00±0.00 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 Clozapine concentration (ng/ml)
T4 T6 T8 p p
PANSS scale (n = 30) (n = 30) (n = 30) (T4 – T6) (T6 – T8)
Total PANSS 136.20±4.9
87.37±2.87 64.47±2.93
score (1) 5
P-PANSS (2) 28.07±4.39 13.87±1.65 12.80±1.40 p<0.001
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 p>0.05
Anergia (6) 9.70±1.74 7.73±1.11 6.53±0.78 p<0.001
Thought
3.77±2.03 8.33±0.96 7.43±0.77
disturbance (7)
Activation (8) 2.97±0.89 6.57±0.63 5.83±0.38 p<0.001
Paranoid bellig.
3.73±1.28 6.67±0.99 5.87±0.35
(9)
Depression (10) 2.50±1.17 8.43±1.25 7.70±0.60
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).
17
Table 3.39 Relation between Clozapine plasma
level and P-PANSS
Tim Clozapine concentration (ng/ml)
e
T4 T6 T8 p p
(n = 30) (n = 30) (n = 30) (T4–T6) (T6–T8)
P-PANSS
P1 Delusions 3.47±1.96 1.63±0.49 1.20±0.41
P2 Conceptual
3.90±0.80 2.43±0.50 2.00±0.00 p<0.001
disorganization
P3 Hallucinations 3.40±1.85 1.63±0.49 1.27±0.45
p<0.001
P4 Excitement 4.20±0.55 2.00±0.26 1.83±0.38 p<0.05
P5 Grandiosity 3.80±0.48 1.83±0.46 1.33±0.48 p<0.001
P6 Suspiciousness 4.80±0.80 2.17±0.38 1.93±0.25
p<0.05
P7 Hostility 4.50±0.63 2.17±0.46 1.97±0.18
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 P7-
PANSS 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 pT6-
T8<0.001.
18
Table 3.40 Relation between Clozapine plasma level and N-PANSS
Time Clozapine concentration (ng/ml)
T4 T6 T8 p p
N- PANSS (n = 30) (n = 30) (n = 30) (T4–T6) (T6–T8)
N1 Blunted affect 2.10±1.54 1.93±1.28 1.37±0.49 p<0.05
N2 Emotional
4.80±0.41 4.40±0.72 2.00±0.00
withdrawal p<0.001
N3 Poor rapport 4.67±0.48 4.33±0.60 2.03±0.18
N4 Passive/apathetic
4.73±0.52 4.43±0.57 2.20±0.41 p<0.01
social withdrawal
N5 Difficulty in p<0.001
4.80±0.41 4.33±0.61 2.27±0.45
abstract thinking
N6 Lack of
spontaneity and flow 4.50±0.51 3.97±0.18 2.27±0.45 p<0.001
of conversation
N7 Stereotyped
4.20±0.48 3.60±0.56 2.00±0.00
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.
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 high-
performance 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 in-
patients 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.
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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 5 8.20
21-30 years 25 40.98
31-40 years 19 31.15
>40 years 12 19.67
Total 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 n=61 %
Symptoms
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
Index
Num (n=61) %
Symtoms
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
p
T4 T6 T8 p
(T4 –
PANSS scale (n=61) (n=61) (n=61) (T6 – T8)
T6)
Total score PANSS
134.23 ±5.68 87.21 ± 3.65 64.59 ± 2.88
(1)
P - PANSS (2) 27.11 ± 4.24 13.62 ± 1.47 12.52 ± 1.29 p<0.001
N - PANSS (3) 29.25 ± 1.90 26.97 ± 2.07 14.20 ± 1.60
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 p<0.05
p<0.001
Anergia (6) 9.38 ± 1.82 7.47 ± 1.26 6.52 ± 0.81
Thought disturbance
13.20 ± 1.87 8.08 ± 0.94 7.26 ± 0.73
(7)
p<0.001
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
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
Time Clozapine
T4 T6 T8 p p
P- PANSS (n=61) (n=61) (n=61) (T4 – T6) (T6 – T8)
P1 Delusions 3.11±1.97 1.56±0.50 1.18±0.39
P2 Conceptual
3.97±0.89 2.46±0.53 1.98±0.13
disorganization
P3 Hallucinations 2.98±1.87 1.52±0.50 1.20±0.40 p<0.001
p<0.001
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<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
Time Clozapine
T4 T6 T8 p p
N-PANSS (n=61) (n=61) (n=61) (T4–T6) (T6–T8)
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
4.84±0.61 4.44±0.53 2.23±0.42
withdrawal
p<0.001 p<0.001
N5 Difficulty in abstract
4.82±0.39 4.47±0.57 2.28±0.45
thinking
N6 Lack of spontaneity and
4.56±0.53 3.95±0.28 2.33±0.47
flow of conversation
N7 Stereotyped thinking 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 T8 p p
T4 T6
G-PANSS (n=61) (T4 – T6) (T6 – T8)
(n=61) (n=61)
G1 Somatic concern 3.84±0.66 3.39±0.56 1.97±0.36
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 p<0.001
G5 Mannerisms and
3.84±0.37 2.95±0.22 2.00±0.00
posturing p<0.001
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 p<0.05
G8 Uncooperativeness 4.43±0.56 2.31±0.50 1.98±0.13
G9 Unusual thought p<0.001
4.49±0.50 2.34±0.48 2.00±0.00
content
G10 Disorientation 1.00±0.00 1.00±0.00 1.00±0.00 0 0
G11 Poor attention 4.57±0.49 2.47±0.50 2.33±0.47 p < 0,05
G12 Lack of judgment
4.64±0.52 2.74±0.44 2.28±0.45 p<0.001
and insight
G13 Disturbance of
4.28±0.58 2.11±0.32 2.00±0.00 p<0.01
volition p<0.001
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
G16 Active social
4.82±0.39 2.51±0.54 2.25±0.43 p<0.001
avoidance
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
Time Clozapine
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 p<0.01
S2 Exasperated
when satisfaction of
4.21±0.49 2.08±0.28 2.00±0.00 p<0.001 p<0.05
requests was
delayed
S3 Mood unstable 4.59±0.50 2.05±0.22 2.00±0.00 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 Clozapine concentration (ng/ml)
T4 T6 T8 p p
PANSS scale (n = 30) (n = 30) (n = 30) (T4 – T6) (T6 – T8)
Total PANSS 136.20±4.9
87.37±2.87 64.47±2.93
score (1) 5
P-PANSS (2) 28.07±4.39 13.87±1.65 12.80±1.40 p<0.001
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 p>0.05
Anergia (6) 9.70±1.74 7.73±1.11 6.53±0.78 p<0.001
Thought
3.77±2.03 8.33±0.96 7.43±0.77
disturbance (7)
Activation (8) 2.97±0.89 6.57±0.63 5.83±0.38 p<0.001
Paranoid bellig.
3.73±1.28 6.67±0.99 5.87±0.35
(9)
Depression (10) 2.50±1.17 8.43±1.25 7.70±0.60
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).
17
Table 3.39 Relation between Clozapine plasma
level and P-PANSS
Tim Clozapine concentration (ng/ml)
e
T4 T6 T8 p p
(n = 30) (n = 30) (n = 30) (T4–T6) (T6–T8)
P-PANSS
P1 Delusions 3.47±1.96 1.63±0.49 1.20±0.41
P2 Conceptual
3.90±0.80 2.43±0.50 2.00±0.00 p<0.001
disorganization
P3 Hallucinations 3.40±1.85 1.63±0.49 1.27±0.45
p<0.001
P4 Excitement 4.20±0.55 2.00±0.26 1.83±0.38 p<0.05
P5 Grandiosity 3.80±0.48 1.83±0.46 1.33±0.48 p<0.001
P6 Suspiciousness 4.80±0.80 2.17±0.38 1.93±0.25
p<0.05
P7 Hostility 4.50±0.63 2.17±0.46 1.97±0.18
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 P7-
PANSS 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 pT6-
T8<0.001.
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Table 3.40 Relation between Clozapine plasma level and N-PANSS
Time Clozapine concentration (ng/ml)
T4 T6 T8 p p
N- PANSS (n = 30) (n = 30) (n = 30) (T4–T6) (T6–T8)
N1 Blunted affect 2.10±1.54 1.93±1.28 1.37±0.49 p<0.05
N2 Emotional
4.80±0.41 4.40±0.72 2.00±0.00
withdrawal p<0.001
N3 Poor rapport 4.67±0.48 4.33±0.60 2.03±0.18
N4 Passive/apathetic
4.73±0.52 4.43±0.57 2.20±0.41 p<0.01
social withdrawal
N5 Difficulty in p<0.001
4.80±0.41 4.33±0.61 2.27±0.45
abstract thinking
N6 Lack of
spontaneity and flow 4.50±0.51 3.97±0.18 2.27±0.45 p<0.001
of conversation
N7 Stereotyped
4.20±0.48 3.60±0.56 2.00±0.00
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.