MILITARY MEDICAL UNIVERSITYPHUNG THANH HAI STUDY ON CLINICAL FEATURES OF SCHIZOPHRENIC PATIENTS, WHO RESPOND POORLY TO CLASSIC... Review clinical features of schizophrenia in patients wh
Trang 1MILITARY MEDICAL UNIVERSITY
PHUNG THANH HAI
STUDY ON CLINICAL FEATURES OF SCHIZOPHRENIC PATIENTS, WHO RESPOND POORLY TO CLASSIC
Trang 2Science 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
Trang 3I The urgency of the project:
Schizophrenia is a clinical syndrome of variable, butprofoundly disruptive, psychopathology that involves cognition,emotion, perception, and other aspects of behavior The expression ofthese manifestations varies across patients and over time, but theeffect of the illness is always severe and is usually long lasting Thedisorder usually begins before age 25, persists throughout life, andaffects persons of all social classes
In the United States, the lifetime prevalence of schizophrenia isabout 1 percent, and in Vietnam, it is 0.47% of the population.Classic neuroleptics are often used for treatment According toKaplan H.I et al (1994), about 60 - 70% of schizophrenia patientsrespond well to classic neuroleptics and the remaining 30-40% ofthese patients make a poor response The classic neuroleptiques andshould 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 bloodlevels of the drug in order to have a proper drug regulation
Bui Tien Dung (2011) studied Clozapine treatment for chronicschizophrenia but the results were limited and no research has beendone about the response to poor treatment with classic neurolepticsand the determination of the plasma concentration of Clozapine toassess the effectiveness of treatment
II The aim of the thesis:
1 Review clinical features of schizophrenia in patients who
respond poorly to classic neuroleptiques
Trang 42 Evaluate results of treatment by clozapine for schizophrenicpatients, who respond poorly to classic neuroleptiques, under thePANSS scale.
3 Comment on the relationship between plasma levels ofclozapine and treatment results of schizophrenic patients, whorespond 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 ± 8.91years 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 ofrelapses is 23.64 ± 6.32 years
- Clinical symptoms of schizophrenia, which respond poorly toHaloperidol: 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 personalhygiene, withdrawal from work-related situations, diminished sense
of purpose, diminished social drive (100%)
- The treatment of schizophrenic patients with clozapine underthe PANSS scale through T4, T6 and T8 was very statisticallysignificant 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 8charts The content includes 2 pages of background, 32 pagesoverview, 18 pages of subjects and methodology, 39 pages of studyresults, 39 pages of discussion, 2 pages of conclusion, 1 page ofproposal 110 documents of references (11 of Vietnamese documentsand 99 of foreign documents)
Trang 5CHAPTER 1: OVERVIEW 1.1 General issues about schizophrenia
Schizophrenia is a clinical syndrome of variable, butprofoundly disruptive, psychopathology that involves cognition,emotion, perception, and other aspects of behavior The expression ofthese manifestations varies across patients and over time, but theeffect of the illness is always severe and is usually long lasting Thedisorder usually begins before age 25, persists throughout life, andaffects persons of all social classes Both patients and their familiesoften suffer from poor care and social ostracism because ofwidespread ignorance about the disorder Although schizophrenia isdiscussed as if it is a single disease, it probably comprises a group ofdisorders with heterogeneous etiologies, and it includes patientswhose clinical presentations, treatment response, and courses ofillness vary Clinicians should appreciate that the diagnosis ofschizophrenia is based entirely on the psychiatric history and mentalstatus 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 schizophreniaduring their lifetime Schizophrenia is found in all societies andgeographical areas, and incidence and prevalence rates are roughlyequal worldwide
1.2 Clinical features of schizophrenia, which poorly respond to classic neuroleptics
According to Ngo Ngoc Tan et al (2005) patients withschizophrenia have positive symptoms and negative symptoms.Patients with positive symptoms are said to have nondeficitschizophrenia The symptoms used to define deficit schizophrenia are
Trang 6strongly interrelated, although various combinations of the sixnegative 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 higherprevalence of abnormal involuntary movements beforeadministration of antipsychotic drugs and poorer social functionbefore the onset of psychotic symptoms The onset of the firstpsychotic episode is more often insidious, and these patients showless 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 willachieve a complete remission or experience only mild symptoms; theremaining 40 percent of patients will improve but still demonstratevariable levels of positive symptoms that are resistant to themedications Rather than categorizing patients into responders andnonresponders, it is more accurate to consider the degree to which theillness 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 assurethat they received an adequate trial of the medication A 4- to 6-weektrial on an adequate dose of an antipsychotic represents a reasonabletrial for most patients Patients who demonstrate even a mild amount
of improvement during this period may continue to improve at asteady rate for 3 to 6 months It may be helpful to confirm that thepatient is receiving an adequate amount of the drug by monitoring theplasma concentration
Trang 7Sadock B.J et al (2015) consideres, if the patient is respondingpoorly, one may increase the dose above the usual therapeutic level;however, higher doses are not usually associated with greaterimprovement than conventional doses Changing to another drug ispreferable to changing to a high dose If a patient has respondedpoorly to a conventional antipsychotic drug, it is unlikely that thisindividual 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 antipsychoticsindicated that clozapine had the clearest advantage over conventionaldrugs in patients with the most severe psychotic symptoms, as well as
in those who had previously responded poorly to otherantipsychotics When clozapine was compared with chlorpromazine
in a severely psychotic group of individuals who had failed in trialswith at least three antipsychotics, clozapine was significantly moreeffective in nearly every dimension of psychopathology, includingboth 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 doseabove the usual therapeutic level; however, higher doses are notusually associated with greater improvement than conventionaldoses Changing to another drug is preferable to changing to a highdose
Trang 8If a patient has responded poorly to a conventional DRA, it isunlikely 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 toDRAs Double-blind studies comparing clozapine to otherantipsychotics indicated that clozapine had the clearest advantageover conventional drugs in patients with the most severe psychoticsymptoms, as well as in those who had previously responded poorly
to other antipsychotics When clozapine was compared withchlorpromazine in a severely psychotic group of individuals who hadfailed in trials with at least three antipsychotics, clozapine wassignificantly more effective in nearly every dimension ofpsychopathology, including both positive symptoms and negativesymptoms
Clozapine was prepared by the pharmaceutical company Sandos(USA) in 1961 and measureed in 1975 In 1989, Clozapine was moreeffective than any neuroleptics in treating schizophrenia
According to Sadock B.J et al (2007), clozapine is indicatedprimarily for chronic schizophrenia and poor treatment-responseschizophrenia
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 / dayuntil treatment effects were observed
Veith R (2002) argues that it is necessary to treat patients withschizophrenia who respond poorly to new neuroleptics During the attackperiod lasting 6-8 weeks, Risperidone should be used 4-6 mg / day,Olanzapine 15-25 mg / day, Quetiapine 450-1000 mg / day and
Trang 9Amisulpride 400-1200 mg / day After that, consolidation treatment isequal to ½ or 2/3 of the attack dose.
Clozapine has a number of side effects that make it a difficultdrug to administer The most serious is a risk of agranulocytosis Thispotentially fatal condition occurs in approximately 0.3 percent ofpatients treated with clozapine during the first year of exposure.Subsequently, the risk is substantially lower As a result, patients whoreceive clozapine in the United States are required to be in a program ofweekly blood monitoring for the first 6 months and biweekly monitoringfor the next 6 months After 1 year of treatment without hematologicalproblems, monitoring can be performed monthly
1.4 Clozapine plasma concentrations
There are many methods of quantifying Clozapine and/or itsmetabolite 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 advantagethat the device is quite popular; however, the disadvantage is that the highquantitative limit, especially the amount of analyte in the mixture does notmeet the research requirements for plasma samples patients treated mayhave very low blood levels concomitant medications
Mass spectrometry detector: the advantage is a satisfactoryquantitative limit (1.5 ng / mL for clozapine), which can besimultaneously quantified with 16 NEUROLEPTICS drugs For highsensitivity, simultaneous analysis of multiple drugs and complex samplessuch as plasma, Clozapine was quantified by double mass spectrometry(LC-MS / MS) with high sensitivity, selectivity and peaks
Trang 10CHAPTER 2: SUBJECTS AND METHODOLOGY
2.1 Subjects
2.1.1 Characteristics of subjects
The subjects are 61 patients diagnosed schizophrenia who werepoorly responding to classic antipshychotic drugs They were in-patients treated at 1National Psychiatric Hospital, Thuong Tin-Hanoifrom 2014 to 2017
2.1.2 Grouping of subjects
Divided into 2 stages:
- Stage 1: including 61 4-week research patients with classicantipshychotic drugs and evaluated by PANSS scale 2 of times:+ The first PANSS (PANSS-T0): after admission, before usingclassic antipshychotic drugs
+ Second PANSS (PANSS-T4): patients treated with classicantipshychotic drugs after 4 weeks without remission of symptomsare called poor response to classic antipshychotic drugs At this time,the measure haloperidol plasma level
- Stage 2: including 61 patients treated with clozapine in thenext 4 weeks as follows:
+ 61 patients treated with clozapine after 2 weeks wereassessed by PANSS scale (PANSS-T6)
+ 61 research patients treated with clozapine after 4 weekswere assessed by PANSS scale (PANSS-T8)
+ In these 61 patients, randomized 30 patients to measureclozapine 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)
Trang 112.1.3 Selection criteria
- The patients diagnosed as schizophrenia according toICD.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 classicantipshychotic 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
Trang 12CHAPTER 3: RESULTS 3.1 The general characteristic of the research subjects
Table 3.1 Current age of research subjects
3.2 Clinical features schizophrenia, who responds poorly to classic antipsychotic drugs
Table 3.4 The duration of schizophrenia
The average duration = 23.64 ± 6.32 years
Table 3.4 shows that, the duration of illness ≤5 yearsaccounted for the highest proportion (37.71%), followed by 6-10years (32.79%), 11-15 years and >15 years is the lowest (14.75%)
Trang 13Table 3.9 Negative symptoms of subjects
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