|Year : 2017 | Volume
| Issue : 1 | Page : 26-35
A retrospective study of late-onset bipolar disorder: A comparison with early and intermediate onset
Sandeep Grover, Swapnajeet Sahoo, Subho Chakrabarti, Ajit Avasthi
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||20-Jun-2017|
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Aim: To evaluate the sociodemographic, clinical, and treatment characteristics profile of late-onset (LO) bipolar affective disorder (BPAD) (onset ≥50 years) and compare the patients with LO BPAD with early age of onset (10–25 years) and intermediate age of onset (26–40 years) BPAD for the demographic features, illness characteristics, and treatment characteristics. Methodology: In this retrospective study, data (demographic features, clinical characteristics, and treatment characteristics) of 115 patients with LO BPAD (onset ≥50 years) were extracted and were compared with 93 patients with intermediate-onset (IO) (26–40 years) and 130 patients with early-onset (EO) (10–25 years) BPAD groups. Results: Patients with LO BPAD differ from EO and IO BPAD in having higher rates of family history of mental disorders, higher rates of comorbid psychiatric disorders (especially substance use disorders) and physical illnesses, higher rates of suicidal ideations, lower rates of suicidal attempts, higher rates of Type-II BPAD, lower prevalence of psychotic symptoms during the episodes, shorter interepisodic duration, higher use of combination of mood stabilizers and antidepressants, lower preference of lithium, higher preference for valproate, and lower use of benzodiazepines. In addition, patients with LO BPAD differed from those with EO BPAD in having higher rates of having a depressive-manic illness pattern, longer duration of depressive episodes, and lower number of manic episodes. Patients with LO BPAD differed significantly from IO BPAD in having lower number of episodes and more often use of antipsychotic monotherapy during the acute phase. Conclusions: LO BPAD differs from IO and EO BPAD on several of the clinical characteristics. Treatment preferences by the clinicians for LO BPAD also differ from EO and IO BPAD.
Keywords: Bipolar disorder, comparison, late onset
|How to cite this article:|
Grover S, Sahoo S, Chakrabarti S, Avasthi A. A retrospective study of late-onset bipolar disorder: A comparison with early and intermediate onset. J Geriatr Ment Health 2017;4:26-35
|How to cite this URL:|
Grover S, Sahoo S, Chakrabarti S, Avasthi A. A retrospective study of late-onset bipolar disorder: A comparison with early and intermediate onset. J Geriatr Ment Health [serial online] 2017 [cited 2020 Sep 24];4:26-35. Available from: http://www.jgmh.org/text.asp?2017/4/1/26/208606
| Introduction|| |
Bipolar affective disorder (BPAD) is a severe mental disorder seen across all age groups, including elderly. Based on the age of onset of the disorder, many authors have attempted to categorize the patients with BPAD as early onset (EO) and late onset (LO)., However, there is lack of consensus on the age cutoff used to divide the study sample into EO and LO BPAD. Yet, in the recent years, few studies have used a cutoff of 50 years for age of onset to categorize the patients into EO and LO.,,,,,
Overall, when compared to the data available for BPAD in adult population, the data involving elderly are significantly less. In terms of prevalence rates, the National Institute of Mental Health Epidemiological Catchment Area Study reported annual prevalence rate of BPAD to be 0.1% among those aged >65 years and which was significantly lower than 1.4% reported for those aged 18–44 years and 0.4% for those aged 45–64 years and also has highlighted the fact that there is a relative lack of information about bipolar disorder in elderly persons compared with late-life depression.,
Age of onset of BPAD has recently become an area of interest of many researchers. There is growing evidence that the LO BPAD is different from EO BPAD in terms of treatment needs and outcomes. Data on LO BPAD are mostly available in the form of retrospective chart reviews and cross-sectional studies. There are very few prospective and/or longitudinal studies in this regard. Older studies suggested that patients with LO BPAD usually have longer episodes, shorter interepisodic intervals, less intense features,, more hostility, irritability, and mixed features., In terms of treatment, these patients may respond preferentially to anticonvulsant medications. However, more recent longitudinal studies suggest that LO BPAD patients have fewer and milder manic symptoms compared to the EO BPAD, have a higher chance of having irritable rather than elated mood, and attain remission quicker with a more favorable outcome. Studies which have compared LO BPAD with EO BPAD have demonstrated that individuals with EO BPAD have a more severe form of illness, are more likely to experience psychotic symptoms, and have a poorer prophylactic lithium response., Recent reports also suggest that LO BPAD is strongly associated with organic brain disease,,, whereas EO cases are more likely to be associated with a family history of mood disorder.,
More recently, some authors have proposed that patients with BPAD, more particularly, BPAD Type-I (BPAD-I), can be aggregated into three subgroups on the basis of age of onset, i.e., EO, intermediate onset (IO), and LO, and studies have evaluated different phenomenological correlates in these subgroups.,,, However, the issue of similarities and differences between those with EO and LO is still not well settled and there is need to expand these data. A thorough internet search showed limited number of studies on LO BPAD. In this background, this retrospective study aimed to evaluate the sociodemographic, clinical, and treatment outcome profile of those BPAD patients who had an onset of illness after the age of 50 years and compare these variables with those with early age of onset and intermediate age of onset BPAD groups.
| Methodology|| |
This retrospective study was carried out at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, providing services to a major part of North India. PGIMER is a multispecialty tertiary care teaching hospital having both outpatient and inpatient psychiatric services.
Patients can walk into the outpatient “walk in clinic” and get themselves registered. Treatment as necessary is started and patient is thereafter given an appointment for a detailed workup. On the day of detailed workup, a unique psychiatry number is allocated to the patient. The patient is initially evaluated in detail by a psychiatry resident (MD Psychiatry trainee), and then, the case is discussed with a consultant who clarifies the history, interviews the patient and family, makes a diagnosis, and formulates the plan of management. The diagnosis is made as per the International Classification of Diseases-10 criteria. To ensure continuity of care, the same team which had worked up the case in detail is involved in the follow-up of the case. Every time, the patient follows up and the treatment details are entered into the same treatment records.
Demographic and basic clinical data in the form of diagnosis made for all the patients seen in the 'walk-in clinic' and those assessed in detail are entered into a computer-based registry and data of these patients can be searched using the registration number or the unique psychiatry number.
For this study, data of patients allocated unique psychiatry number during the years from 2001 to 2014 were searched in the computer-based registry using the following variables, i.e., age 50 years or more at the time of registration and a diagnosis of BPAD, mania, and organic mood disorders. Initially, those aged 50 years or more were identified and then the search was further refined to above-stated diagnoses. Case notes of all these patients were manually searched to identify the patients who had one of the above-stated diagnoses with first episode starting after the age of 50 years. Whenever there was a doubt about this cutoff, the case was excluded from the study. Cases so identified formed the study sample. Their case notes were reviewed for the sociodemographic profile, clinical profile including the treatment details.
For comparison, data of two more groups were extracted. The first comparison group had diagnosis of BPAD with age of onset between 10 and 25 years (EO) and the second control group had age of onset between 26 and 40 years (IO).
Data were analyzed using Statistical Package for the Social Science Version 20 (SPSS for Windows, Version 14.0. Chicago, SPSS Inc.). Frequencies with percentages were generated for the categorical variables. Mean and standard deviation (SD) were computed for the continuous variables. Comparisons were done using independent samples t-test, Chi-square test, ANOVA with post hoc analysis (Scheffe), and Mann–Whitney U-test. Correlations were studied using Pearson's product moment correlation coefficient. P < 0.05 was considered statistically significant.
| Results|| |
During the study period (2001–2014), 115 cases of BPAD (Group I) with age of onset above 50 years were identified and their data were extracted. Group II included 93 cases of BPAD with age of onset between 26 and 40 years (intermediate age of onset), and Group III included 130 cases of BPAD with age of onset in between 10 and 25 years (EO BPAD).
Sociodemographic profile of study groups
In the LO BPAD group (Group I), four-fifth (80%) of the patients were male. Majority of the patients were in the age group of 60–69 years (42.6%) at the time of first presentation, followed by those aged 50–59 years (36.5%). Mean age at the time of presentation was 62.77 years (SD-7.66), with a range of 51–90 years with a median of 61 years. The mean number of years of education was 8.77 (SD-4.90) years. About half of the patients were employed (50.4%) at the time of presentation. Majority of them were Hindu (63.5%) by religion, belonged to nonnuclear family (57.4%), and came from urban background (68.7%) [Table 1]. When compared with the two other groups, patients in the LO BPAD group were less educated. In terms of marital status, patients in the LO group were more often married than the EO group. All the three groups did not differ in terms of family type and place of residence [Table 1].
Clinical profile of study groups
Nearly half (47.8%) of the patients of the LO BPAD group were in the episode of mania at the time of presentation and 43.5% were in the episode of depression at the time of presentation. In terms of longitudinal course, in the LO BPAD group, about one-third (35.7%) followed a course of depression-mania/hypomania-euthymia pattern, another one-third (32.2%) followed mania/hypomania-depression-euthymia pattern. About one-fifth (19.1%) of patients in the LO group had only manic/hypomanic course (recurrent mania) during the follow-up, and few patients did not have any recurrence after the first episode of mania/hypomania. Overall, only 10 (8.7%) patients of LO BPAD group were categorized as having bipolar disorder Type-II.
Family history of psychiatric disorders was present in about half (52.2%) of the patients in the LO BPAD group, with history of affective disorder present in 30.4% of the patients. About one-third (37.4%) had comorbid psychiatric/substance use disorders in the LO group, with alcohol use being the most common comorbidity. In terms of comorbid physical disorders, about three-fifth of the patients in the “LO” group had at least one comorbid physical disorder, with 30.4% of patients diagnosed with hypertension and one-fourth (25.2%) diagnosed with comorbid diabetes mellitus. Besides diabetes mellitus and hypertension, 44.4% of the patients had other chronic comorbid physical disorders, with hypothyroidism and coronary artery disease being the most common ailments. In terms of definite organic causes, which could have contributed to the affective illness, in only 18 cases (15.65%) of cases, the illness could be attributed to physical disorders such as hypothyroidism, cerebrovascular accident, head injury, or administration of steroids. Lifetime suicidal ideations were found in one-third of patients (34.8%) of “LO” group, but very few patients made suicidal attempt (2.6%).
As expected, the three study groups differed significantly with regard to age of onset. The mean age of onset for the LO group was 57 (SD-7.64) years. Compared to other two groups, patients in the LO group contacted the treatment services earlier. Compared to EO group, significantly higher percentage of patients in the LO group had depression as the first-lifetime episode and illness, followed a depression-mania-euthymia pattern. However, the LO group did not differ significantly from the “IO” group in terms of type of first episode in lifetime. In addition, compared to other groups, significantly higher proportion of patients in the “LO” group had “recurrent mania pattern” of illness, family history of mental illness, Type-II/organic bipolar, comorbid psychiatric disorder, comorbid physical illnesses, and lifetime suicidal ideations. However, compared to other two groups, fewer patients in the “LO” group had lifetime suicidal attempts and history of hospitalization. Suicidal ideations were noted in one of the episodes in one-third (35%) of the cases, with only a few (2.6%) having current or lifetime suicidal attempt. Only five cases had cognitive deficits at the time of assessment, and only two cases had been hospitalized in a psychiatric setup earlier due to their illness [Table 2].
The mean duration of illness evaluated (i.e., from the onset of first symptoms to the last contact with the treating agency) for the purpose of this study for the “LO” group was 63.14 (SD-64.35; range 1–352 months) months, with a median of 48 months with interquartile range of 12–84 months. This was shorter than the duration of illness evaluated for the other two groups [Table 3].
A total number of depressive episodes experienced by patients in the LO group during the period under study were 1.97 and that of mania, hypomania, and mixed were 2.35, 0.3, and 0.03, respectively. In general, the depressive episodes lasted longer than the manic episodes, with a mean of 3.22 months for the former and 1.97 months for the later. However, the mean numbers of episodes of mania with psychotic symptoms were significantly more than mean number of depressive episodes with psychotic symptoms. Overall, only 9 (7.8%) patients had psychotic symptoms during the depressive episodes and 27 (23.47%) patients experienced psychotic symptoms during the manic episodes. The mean interepisodic duration was 48.53 months.
When patients of LO BPAD were compared with other two groups, there was no difference in the mean number of depressive episodes per year under evaluation for the three groups. However, the duration of depressive episodes was longer for LO group, compared to EO group.
Compared to other two groups, patients in the EO group had significantly higher number of manic episodes per year and lower number of manic episodes with psychotic symptoms. Those with LO BPAD had significantly higher number of manic episodes per year when compared to IO group. Total numbers of lifetime episodes were highest for the IO group and this was significantly higher when compared to other two groups. The mean duration of interepisodic duration was significantly shorter for the LO BPAD group, compared to IO group. In terms of at least one-lifetime episode with psychotic symptoms, significantly lower proportion of patients in the LO group exhibited the same.
In terms of management of acute episodes, most preferred strategy in the “LO” group was to use a combination of conventional mood stabilizer and an antipsychotic medication and this was followed by use of combination of conventional mood stabilizer along with antidepressant.
In terms of maintenance treatment, in the “LO” group, about half (50.4%) of the patients were managed with conventional mood stabilizers only. A quarter of patients received a conventional mood stabilizer along with an antipsychotic or an antidepressant medication. About one-fourth were managed with only antipsychotic medications.
As shown in [Table 4], in terms of conventional mood stabilizers, about half (52.2%) of the patients in the “LO” group were prescribed valproate during the maintenance phase.
In terms of type of antipsychotic used during the acute phase and then continued in maintenance phase, about two-third (64.3%) of LO patients received an antipsychotic medication with olanzapine being the most common medication, followed by risperidone and quetiapine. In terms of combination, in 40% of patients, antipsychotics were given along with the mood stabilizers. Slightly more than one-third (38.3%) of the patients were also prescribed antidepressant medications at some point of their illness, with escitalopram being the most commonly used medication, closely followed by sertraline and bupropion. In most cases (35 out of 44 cases), antidepressants were given under the cover of a mood stabilizer, and in 5 cases, these were given along with an antipsychotic medication. Few patients (n = 6) in the LO group also received electroconvulsive therapy during the acute phase treatment. Mean dose of lithium in those prescribed lithium (n = 22) was 634 mg (SD-159.9) with a median of 600 mg/day, mean dose of valproate in those prescribed valproate (n = 60) was 887.50 mg (SD-215.82) with a median of 1000 mg/day, and mean dose of carbamazepine in those prescribed carbamazepine (n = 3) was 466.66 mg (SD-115.47) with a median of 400 mg/day. During the acute phase, compared to other two groups, lower percentage of patients in the LO group received benzodiazepines.
When compared to other two groups (EO and IO groups), patients with “LO” group were less often prescribed mood stabilizer only or a combination of mood stabilizer and an antipsychotic medication during the acute phase. However, they were more often prescribed a combination of a mood stabilizer and antidepressant medication. During the maintenance phase, compared to EO group, patients in “LO” group were less often prescribed a combination of mood stabilizer and an antipsychotic medication. Among the conventional mood stabilizers, compared to the other two groups, patients in LO group were less often prescribed lithium and more often prescribed valproate. Overall, carbamazepine was not preferred much in all the three groups. Dose of lithium used in the “LO” group was comparable to that used in other two groups; however, the dose of valproate was slightly lower in the “LO” group, compared to the other two groups. Compared to other two groups, patients in LO group more often received electroconvulsive therapy in the acute phase.
| Discussion|| |
There is limited information on the LO BPAD, with lack of data from India and other eastern countries. Accordingly, there is a need to expand the data on this topic. The present study aimed to evaluate the sociodemographic and clinical profile of patients with LO BPAD and to compare the same with EO and IO BPAD patients. The included 115 cases of LO BPAD registered with our services over the period of 14 years.
Previous studies have reported a female preponderance in LO BPAD patients ,, and being more educated  as compared to EO BPAD patients. However, the present study suggests that compared to EO and IO BPAD, there were higher proportions of males in the LO BPAD group and the duration of education was also lower than other two groups. The difference in education between the three groups can be understood as a cohort effect in the Indian context, where the literacy rates have improved over the years. Overall, if one looks at previous studies from our center on patients with BPAD,,, these in general suggest male preponderance in Indian setting, compared to females, more males are brought for treatment. Possibly, this could have affected the findings of gender. The majority of the patients in the LO and IO BPAD groups were married and employed when compared to the EO group. Higher married proportion of patients in LO and IO groups is understandable considering the fact that in general, marriage is universal in the Indian setting, more stable, and the age of marriage in Indian setting is going up.
The mean age of onset of the illness in the LO BPAD group was 57 (SD-7.64; range: 50–85) years, which is slightly less than the mean age of onset (68.2 years; SD-3.9; range 60–72) reported in some of the earlier studies., The time lag or the mean time from the onset of symptoms to the presentation to our setup was shortest for the LO group in our sample. Previous studies, which have compared the three study groups, have also reported similar findings.,,, BPAD-I was the most common subtype in all the three groups, which is in accordance with the existing literature. However, the present study suggests that compared to other groups, higher percentage of patients in the LO group had BPAD-II. This finding is also supported by some of the studies from the west which suggest that LO is more benign when compared to the other groups.,
Most of the studies from the west suggest that polarity of the first episode is depressive in most BPAD patients,,, and more depressive episodes and possibly milder manic symptomatology are seen especially in the LO BPAD patients.,, In contrast, to these findings, the present study suggests that in all the three groups, higher proportion of patients had mania as the first episode, and these findings are in line with some of the Indian studies, which have evaluated the course of BPAD.,, However, it is also possible that this finding could have been influenced by recall bias or gender distribution. In the present study, higher proportion of patients were male and it is well known that manic episodes are more common in males.,,
There is lack of consensus with respect to prevalence of psychotic symptoms during the various phase of illness, with some studies suggesting lower prevalence of psychotic symptoms in the elderly group, whereas others suggest that psychotic symptoms are more common in the elderly onset BPAD patients., Findings of the present study support the earlier group of studies.
In general, majority of the studies suggest that LO BPAD is nonfamilial , whereas occasional studies suggest that patients with LO BPAD have high rates of family history of affective disorders. Findings of the present study support the latter group of studies. Some of the authors suggest that higher prevalence of family history in the LO group could be due several methodological issues such as older individuals have a greater number of older first-degree relatives who have an increased exposure to the genetic and environmental factors, thereby leading to more predispositions to psychiatric disorders. The higher prevalence of family history in LO group could also be influenced by higher awareness about illness in these families and hence bringing these patients for treatment.
Compared to other two groups, prevalence of comorbid psychiatric illness was more in the LO BPAD group, with substance use disorder (alcohol > tobacco > opioid) being the most common disorders. Previous studies from other parts of the world suggest lifetime substance abuse rate of around 29% in a subgroup of elder bipolar individuals, resulting in more hospital admissions compared to the younger bipolar., Majority of previous studies have demonstrated an increased prevalence of neurological illnesses (dementia and cerebrovascular disease) and physical illness (endocrine/metabolic/respiratory) in patients with LO BPAD.,, Findings of the present study also suggest that about three-fifth of LO patients had at least one comorbid physical illness, with hypertension, diabetes mellitus, coronary artery disease, and benign hypertrophy of prostate being the common ones. These findings signify that a substantial proportion of LO BPAD individuals have medical burden of physical illness which needs to be addressed too. In the present study, 6.1% of cases in the LO BPAD group had history of some kind of brain insult (brain injury/encephalitis/cerebrovascular accident) which indicates that a brain insult in early or middle ages may be associated with higher risk of LO BPAD. Several case reports/series also suggest the role of brain injury/insult in causing secondary mania/BPAD in older individuals due to anoxic encephalopathy/thalamic damage.,,,
It has been well reported that the elderly individuals have the highest suicide rates of all age groups., However, very few studies have evaluated the suicidal attempts in the LO BPAD group and have found that as compared to EO BPAD, though the suicide rate is low, the elderly are at greater risk of completed suicide., In the present study too, though suicidal ideation was present more in the LO BPAD group (34.8%), very few attempted suicide (2.6%) was just the reverse in the EO BPAD group.
Studies of the long-term course of LO BPAD have been rare. However, the existing literature suggests that as compared to EO BPAD, LO BPAD patients have a milder form of illness, less number of episodes, and less likely to be hospitalized for an episode.,, There is very less evidence to suggest that older people have more frequent or longer episodes  and some studies have even found no difference in the number of depressive/manic episodes per year in both the two groups. In the present study, we could not find any difference in the mean number of depressive episodes per year in the three groups, but duration of depressive episodes was longer for LO group as compared to EO group. However, the LO group had significantly higher number of manic episodes per year and less no of episodes in lifetime as compared to the other two groups.
There is dearth of data in the form of randomized controlled studies on pharmacological treatment of the LO BPAD patient, and due to this, there are several methodological and conceptual issues in making specific recommendations., Role of antidepressants in the treatment of acute depressive phase of BPAD is controversial in view of risk of switch to mania  and the same principles apply to the LO BPAD group too. In the present study too, in the LO BPAD group, very few individuals were administered antidepressants alone (4.3%), or if administered, these were given under cover of either a mood stabilizer (28.7%) and/or an antipsychotic (6.1%). This suggests that practice of pharmacotherapy in patients in LO BPAD is influenced by recommendations made for other age groups.
Some atypical antipsychotics such as quetiapine  and aripiprazole  have been shown to be efficacious in management of mania in LO BPAD as an antimanic agent. Previous studies and recent meta-analysis had also proved antimanic efficacy of olanzapine ,,, and risperidone ,, in adult patients. In the present study, majority of patients were treated with olanzapine, followed by risperidone in all the three groups. The preference of olanzapine and risperidone is in general in line with the prescription patterns in our setup , and India. However, these prescription patterns can be considered worrying as it has been shown that use of atypical antipsychotics in elderly is associated with sudden deaths,, and due to the same, there is a black box warning for the same.,
Previous retrospective  and prospective, observational studies  involving LO or elderly patients with BPAD suggest that combination therapy of mood stabilizer and antipsychotic is more common than monotherapy in the acute phase treatment, but they tend to be maintained well on antipsychotics/lithium than the EO and middle-onset BPAD patients. The prescription patterns which were noted in the present study are also in similar lines. Only one-third of the patients received monotherapy with mood stabilizers, antipsychotics, or antidepressants in the LO BPAD group, and majority of the patients received one of the combinations. However, in the maintenance phase, about half of the LO BPAD patients were managed with mood stabilizers only. Further, the present study suggests that compared LO BPAD groups, patients with EO and IO BPAD had more combinations during the acute phase. Previous studies which have compared pharmacological treatment between EO and LO BPAD patients.,,
Lithium is considered to be one of the most efficacious medications for all acute phases of illnesses;, however, data on the use of lithium among elderly are limited. In general, it is suggested that lithium should be used cautiously among elderly patients, dose should be kept lower than the doses used in adult populations, and the levels must be closely monitored.,, Due to these, it is less preferred among elderly patients., The present study suggests that compared to other groups, valproate is more often preferred in the LO group and lithium is less preferred. In the present study, it is also possible that higher prevalence of physical morbidity, organicity, and substance use comorbidity in the LO group could have also led to lower prescription rates of lithium and higher rates of use of valproate as there is some evidence to support these preferences., Lower use of benzodiazepines in the LO group is also guided by the existing literature which suggests increase risk of falls and cognitive deficits among elderly with use of benzodiazepines.,
The present study is limited by retrospective nature of data collection, lack of use of standardized diagnostic interview, hospital-based study, and small sample size. The present study did not evaluate the effectiveness of various treatments but just provides information on prescription patterns. Future studies following prospective study designs will help in understanding the differences of LO BPAD with EO and IO BPAD.
| Conclusions|| |
The present study suggests that patients with LO BPAD differ from EO and IO BPAD in terms of having lower level of education, being married (difference seen only between LO and EO), more often having DMI illness pattern (difference seen only between LO and EO), having higher rates of family history of mental disorders, higher rates of comorbid psychiatric disorders (especially substance use disorders) and physical illnesses, higher rates of suicidal ideations, lower rates of suicidal attempts, higher rates of BPAD-II, having longer duration of depressive episodes (difference seen only between LO and EO), lower prevalence of psychotic symptoms during the episodes, lower number of manic episodes (difference seen only between LO and EO), lower number of episodes (difference seen only between LO and IO), shorter interepisodic duration, more often use of antipsychotic monotherapy during the acute phase (difference seen only between LO and IO), higher use of combination of mood stabilizers and antidepressants, lower preference of lithium, higher preference for valproate, and lower use of benzodiazepines.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]