Third Department of Psychiatry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Center, Budapest, Hungary
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, Budapest, Hungary
First Department of Psychiatry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Abstract
Background
Important methodological questions still exist concerning the Dexamethasone Suppression Test (DST), including the possibility of a better way of interpreting it. The aim of the present study was to explore the feasibility of an alternative way of interpreting DST results.
Methods
A total of 50 patients with major depression aged 41.0 ± 11.4 years old participated in the study. Past and present suicide attempts were recorded. Psychometric assessment included the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Scale (HAS), the Newcastle Depression Diagnostic Scale (NDDS), the Diagnostic Melancholia Scale (DMS) and the General Assessment of Functioning (GAF) scale. The 1 mg DST protocol was used. Analysis methods included the chi square test and analysis of covariance (ANCOVA) with Fisher least significant difference (LSD) as post hoc tests.
Results
In all, 34 patients (68%) were suppressors, 16 (32%) were non-suppressors and 14 patients had cortisol values above 5 μg/dl at baseline. Baseline cortisol level did not influence the classical DST interpretation. A total of 18 patients (36%) showed an increase of their cortisol levels after dexamethasone administration and 32 patients (64%) showed a decrease. Reducers had less melancholic features, similar levels of depression, better sleep and less suicidal thoughts in comparison to increasers. No relationship of DST to suicidality was found.
Discussion
The present study explored the pattern of cortisol response to dexamethasone suppression and suggested an alternative way of coding and interpreting the DST on the basis of whether the cortisol levels remain stable or increase vs decrease after the administration of cortisol. The results put forward a complex way of understanding the relationship of the DST results with clinical symptoms.
Introduction
Although the dexamethasone suppression test (DST) was first described as a biological marker for depression
The aim of the present study was to investigate the relationship between suicidal behaviour and the temporal characteristics of the DST. The temporal characteristics of the DST concerned whether non-suppression was defined on the basis of either of 16.00 or 23.00 day 2 cortisol levels, or both. The current report is complementary to a recently published paper by Yerevanian
Materials and methods
Subjects
A total of 50 patients (15 males and 35 females) aged 21–60 years (mean 41.0, SD 11.4)) suffering from major depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)
All participants provided written informed consent; 14 of them fulfilled criteria for atypical features, 16 for melancholic features and 32 for somatic syndrome (according to the International Classification of Diseases (ICD)-10). Nine patients did not fulfil criteria for any specific syndrome.
All participants were inpatients or outpatients of the Third Department of Psychiatry, Aristotle University of Thessaloniki, University Hospital AHEPA, Thessaloniki Greece and come from a study sample used in the PhD thesis of an author (KNF). The study on this specific population has already produced a significant number of publications
All participants were free of any medication for at least 2 weeks prior to the first assessment and diagnosis. In no case was medication interrupted in order to include the patient in the study. In addition, all participants were physically healthy with normal clinical and laboratory findings, including electroencephalogram and thyroid function, and with no pathological findings from the opthalmological examination. There was a great effort to exclude all cases that might contribute to the production of confounding results due to special characteristics (for example, obesity, puerperium etc.). Additionally, a particular effort was made to exclude patients who exhibited alcohol or nicotine abuse.
No participant fulfilled the criteria for catatonic or psychotic features or for seasonal affective disorder. Additionally, no patient fulfilled the criteria for another DSM-IV axis-I disorder, except for generalised anxiety disorder and panic disorder, and none had a past history of manic or hypomanic episode. Axis II disorders were also registered.
All patients had history of no more than five distinct episodes including the present one (mean 1.16 ± 1.53).
It should be noted that all suicidal attempts were non-violent, and were performed by the swallowing of pills, drugs or poison. Rather, they had an impulsive character and no notes were prepared before attempts.
Clinical diagnosis
The Schedules for Clinical Assessment in Neuropsychiatry version 2.0 (SCAN v 2.0))
Laboratory testing
Laboratory tests included blood and biochemical testing, test for pregnancy, T3, T4 and thyroid-stimulating hormone (TSH), Â12 and folic acid, and electroencephalogram.
Psychometric assessment
Assessment included the Hamilton Depression Rating Scale (HDRS) and subscales
On the basis of clinical and psychometric data, patients were divided into three groups. The first included those without death thoughts (no thoughts of death at all or wondering whether life has no meaning), the second included those with no specific thoughts about death (afraid that they will die or wish to die) and finally the third included truly suicidal patients (thinking about or planning suicide). We created a new categorical variable, named the Death Thoughts Rating, by attributing a score of 0 for members of the first group, 1 for the second and 2 for the third group; this is somewhat different from the rating of the HDRS item 3.
Data concerning personal and family history and stressful life events
The family history method
Dexamethasone Suppression Test
The DST
Statistical analysis
The following grouping methods were used:
• The two classical groups, that is suppression vs non-suppression on the basis of the 5 μg/dl cut-off level.
• Two groups on the basis of whether cortisol values increased or decreased after dexamethasone administration (increasers vs decreasers)
• Groups defined by the interaction of the above two grouping methods.
• Two groups defined by the presence or not of a recent suicide attempt (within the last month).
• Two groups defined by the presence or not of a suicide attempt ever in the past
• Three groups defined by the Death Thoughts Rating variable (A: no thoughts of death, B: non-specific thoughts of death and C: suicidal ideation).
These patient groups were compared using:
• Crosstabulation frequencies between groups using the chi square test.
• Three analysis of covariance (ANCOVA) tests were performed, with the two ways to define DST results as grouping variable (in a yes/no format) and a third with their combination, and the following as dependent variables: age at onset, number of episodes, number of melancholic and atypical criteria met, GAF, HDRS (and its subscales: depressed index, anxiety index, non-specific index and sleep index)
The Fisher least significant difference (LSD) test was used for the post hoc comparisons. For these comparisons the p < 0.05 level was used to define significance.
Results
In all, 34 patients (68%) were suppressors and 16 (32%) were non-suppressors with the use of the 5 μg/dl cut-off point. It is to be noted that 14 (28%) patients had cortisol values above 5 μg/dl at baseline. The results of the DST test with the patients categorised according to their baseline cortisol values (above and below 5 μg/dl) are shown in table
Dexamethasone Suppression Test (DST) results with patients categorised according to their baseline cortisol values
Suppressors
Non-suppressors
Baseline cortisol < 5 μg/dl (n = 36):
Day 2, 16:00
32 (88.88%)
4 (11.12%)
Day 2, 23:00
27 (75%)
9 (25%)
Either at 16:00 or 23:00
25 (69.44%)
11 (30.56%)
Baseline cortisol > 5 μg/dl (n = 14):
Day 2, 16:00
9 (64.28%)
5 (35.72%)
Day 2, 23:00
12 (85.71%)
2 (14.29%)
Either at 16:00 or 23:00
9 (64.28%)
5 (35.72%)
Overall (n = 50)
34 (68%)
16 (32%)
Some patients showed an increase of their cortisol levels after dexamethasone administration while others experienced a reduction. The respective frequencies are shown in table
Changes in cortisol levels after dexamethasone administration
Day 2, 16:00
Day 2, 23:00
Either or both
Baseline cortisol < 5 μg/dl (n = 36):
Increased or unchanged
12 (33.34%)
13 (30.56%)
14 (38.88%)
Increased
6 (16.67%)
10 (27.78%)
Unchanged
6 (16.67%)
1 (2.78%)
Decreased
24 (66.66%)
25 (69.44%)
Baseline cortisol > 5 μg/dl (n = 14):
Increased or unchanged
4 (28.57%)
1 (7.14%)
4 (28.57%)
Increased
4 (28.57%)
1 (7.14%)
Unchanged
0 (0%)
0 (0%)
Decreased
10 (71.43%)
13 (92.86%)
Overall (n = 50):
Increased or unchanged
16 (32%)
12 (24%)
18 (36%)
Increased
10 (20%)
11 (22%)
Unchanged
6 (12%)
1 (2%)
Decreased
34 (68%)
38 (76%)
Relationship between increasers vs reducers and non-suppressors vs suppressors
Non-suppressors
Suppressors
Total
Increasers
15
3
18
Decreasers
1
31
32
Total
16
34
50
On testing the two different DST classifications with ANCOVA, the results were as follows: for the classical DST non-suppression (either at 16.00 or at 23.00) the ANCOVA showed a significant effect (Wilks L = 0.199; F = 5.632, effect = 20; error = 28; p = 0.00002). The post hoc results are shown in table
Analysis of covariance (ANCOVA) post hoc test for the classical Dexamethasone Suppression Test (DST) definition
DST suppressors
DST non-suppressors
p Value
Mean
SD
Mean
SD
GAF
48.74
13.97
58.13
13.65
0.021
DMS Endogenous axis
3.88
2.92
6.13
3.03
0.011
HDRS Depressive Index
10.97
2.76
8.63
2.31
0.005
Death Thoughts Rating
1.00
0.70
0.56
0.73
0.044
DMS, Diagnostic Melancholia Scale; GAF, General Assessment of Functioning; HDRS, Hamilton Depression Rating Scale.
Analysis of covariance (ANCOVA) post hoc test for the reducers/increasers Dexamethasone Suppression Test (DST) definition
Fisher least significant difference (LSD) test, p value
Reducers (R)
Single level Inreasers (SI)
Both levels Increasers (BI)
R vs SI
R vs BI
SI vs BI
Mean
SD
Mean
SD
Mean
SD
No of atypical features
0.94
0.98
1.53
0.74
1.00
1.00
0.037
NS
NS
No of melancholic features
2.25
1.52
2.20
1.61
4.00
1.73
NS
0.046
NS
HDRS
26.38
5.97
23.00
3.93
29.00
3.61
0.047
NS
NS
HDRS Depressive Index
10.84
2.93
8.87
2.33
10.33
2.08
0.026
NS
NS
HDRS Sleep Index
3.41
2.11
3.47
1.46
6.00
0.00
NS
0.025
0.036
Death Thoughts Rating
1.00
0.72
0.40
0.51
1.67
0.58
0.005
0.003
NS
Baseline cortisol
5.16
5.70
4.18
3.23
3.80
2.75
Cortisol day 2, 16:00
1.94
4.29
3.77
3.89
7.17
1.46
Cortisol day 2, 23:00
1.58
2.71
5.16
3.65
7.00
1.66
HDRS, Hamilton Depression Rating Scale; NS, not significant.
For the combination of the two DST interpreting methods into a single grouping variable with three levels (suppressors and reducers vs non-suppressors and increasers vs other combinations) the ANCOVA showed again a significant effect (Wilks L = 0.129; F = 2.403; effect = 40; error = 54; p = 0.001). The post hoc results are shown in table
Analysis of covariance (ANCOVA) post hoc test for the combined Dexamethasone Suppression Test (DST) definition
Fisher least significant difference (LSD) test, p value
Suppressors and reducers (SR)
Other (O)
Non-suppressors and increasers (NSI)
SR vs O
O vs NSI
SR vs NSI
Mean
SD
Mean
SD
Mean
SD
N1971
-5.02
19.30
-0.54
14.69
-19.55
18.44
NS
0.013
0.026
End DMS
3.82
3.02
4.17
2.37
7.30
2.87
NS
0.007
< 0.001
HDRS depressive index
11.00
2.84
9.00
2.76
9.50
2.32
0.041
NS
NS
DMS, Diagnostic Melancholia Scale; HDRS, Hamilton Depression Rating Scale; NS, not significant.
The comparison of the relationship the two DST definitions have with suicidality and thoughts of death is shown in tables
Dexamethasone Suppression Test (DST) suppression vs non-suppression and increasers vs reducers rates in the different suicidal behaviour groups, Yates corrected chi square tests
Suppressors (n = 34)
Non-suppressors (n = 16)
Chi square
Increasers
Reducers
Chi square
n
%
n
%
p Value
n
%
n
%
p Value
Recent suicide attempt
5
14.70
0
0.00
0.266
2
11.11
3
9.37
0.844
Ever suicide attempt
11
32.35
2
12.50
0.135
4
22.22
8
25.00
0.825
Death thoughts rating:
0.074
0.305
No death thoughts
8
23.53
9
56.25
6
33.33
11
34.37
Non-specific thoughts of death
18
52.94
5
31.25
6
33.33
16
50.00
Suicidal ideation
8
23.53
2
12.50
6
33.33
5
15.62
Combined Dexamethasone Suppression Test (DST) definitions in the different suicidal behaviour groups, Yates corrected chi square tests
Suppressors and reducers (SR) (n = 28)
Other (O) (n = 12)
Non-suppressors and increasers (NSI) (n = 10)
Chi square, p-value
n
%
n
%
n
%
SR vs O
O vs NSI
SR vs NSI
Recent suicide attempt
3
10.71
2
16.66
0
0.00
0.602
0.542
0.692
Ever suicide attempt
9
32.14
2
16.66
2
20.00
0.315
0.723
0.385
Death thoughts rating:
0.573
0.851
0.312
No death thoughts
7
25.00
5
41.67
5
50.00
Non-specific thoughts of death
15
53.57
5
41.67
3
30.00
Suicidal ideation
6
21.43
2
16.67
2
20.00
Discussion
The present study explored the pattern of cortisol response to dexamethasone suppression and suggested an alternative way of coding and interpreting the DST on the basis of whether the cortisol levels remain stable or increase vs decrease after the administration of cortisol. In the current study sample, 34 patients (68%) were suppressors and 16 (32%) were non-suppressors with the use of the classic 5 μg/dl cut-off point. The use of both the 16:00 and 23:00 day 2 cortisol values seems to be important otherwise significant false results appear. With the use of the new suggested increasers/reducers dexamethasone test (IRDT), 18 patients (36%) had unchanged or showed an increase of their cortisol levels vs 32 patients (64%) who showed a decrease. The two classification methods overlap significantly but they are not identical and for 24% of patients are classified differently. Although several patients had high (above 5 μg/dl) baseline cortisol values, it seems that this does not influence the post dexamethasone values.
The classical DST interpretation leads to the conclusion that DST suppressors are patients that are less endogenous, with lower functioning, and with higher suicidal thoughts in comparison to non-suppressors. These results are by themselves peculiar and do not fit with the classical definition and concept of depression. By comparison, reducers had less melancholic features, similar levels of depression, better sleep and less suicidal thoughts in comparison to increasers. Suppressors and reducers were less endogenous and with lower depression in comparison to non-suppressors and increasers. Since anxiety was not assessed in the current study but several HDRS items include a strong anxiety component, and the HDRS anxiety index was calculated, it is unlikely that the presence of anxiety is hidden behind the peculiarity of results. However, it is possible that the combined use of the two methods to interpret the DST could isolate a subgroup of depressed patients at high risk to show suicidal behaviour.
Our current study reported that 10% of depressed patients from the study sample had recently attempted suicide and 26% had attempted at least once in the past. Additionally, 46% were experiencing some kind of thoughts of death and 20% were experiencing suicidal ideation at interview time. Concerning suicidality, no method reported in the current study, showed a strong potential in correlating with history of suicidal acts or present suicidal ideation.
DST non-suppression has originally been associated with the endogenous, melancholic and psychotic type of depression
Most previous studies conducted on the association of DST non-suppression and suicidal behaviour concluded that DST non-suppression is related to suicidal ideation and to future suicide rather than committed suicide
DST suppression has been associated previously with suicide
Investigating the different non-suppressor groups with distinct temporal characteristics and in relation to absolute cortisol levels could give deeper insight into the associations of DST and characteristics of depression and suicidal behaviour. However, further research on larger numbers is necessary in this area, although it does appear promising.
Compared to the beginnings of research on DST when it was conceived as being related to endogenous and melancholic depression
Conclusion
The results of our study, especially in the light of the previous literature on DST, indicate that the relationship between DST and clinical symptomatology is very complex, and also that methodological problems and contradictions often halt the possibility of drawing all data and conclusions from studies and of comparing the results. Specific characteristics of the response to dexamethasone administration should be taken into account in a more complex way when analysing the relationship between DST and clinical symptoms in order to avoid missing a possible existing relationship.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
KNF designed the protocol, gathered and analysed the data and contributed to interpretation and the draft and the final paper. XG contributed in the analysis of the data and to interpretation and the draft and the final paper. ZR contributed in the analysis of the data and to interpretation and the draft and the final paper. CF and AI contributed in the design of the protocol, the gathering of the data and the final paper.