1. Comorbid migraine in major depressive disorder suggests
a subgroup related to bipolar disorder
K. Gordon-Smith 1, P. Ridley 3, A. Perry 1 S. Knott 1, L. Forty 2, N. Craddock 2, I. Jones 1,2, L.A. Jones 1
1Department of Psychological Medicine, University of Worcester, UK
2Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK
3College of Medical and Dental Sciences, University of Birmingham, UK
Background
It has been hypothesised that patients with major depressive disorder (MDD) and migraine may represent a subgroup of individuals due to differences in their clinical characteristics when compared to those with MDD without migraine.  
Female gender, longer depressive episodes, greater severity of depressive symptoms, greater seasonal variation in symptoms, greater number of depressive episodes, higher prevalence of cyclothymic and irritable temperaments and agoraphobia have been found to be associated with migraine in MDD (Hung et al., 2005; Oedegaard and Fasmer, 2005).
Previous small-scale studies suggest the specific clinical characteristics associated with presence of migraine in MDD may overlap with those of bipolar disorder.
Results
The presence of migraine in MDD was associated with female gender (77% vs 57%, p<0.001), younger age of onset (23 vs 27 years, p=0.002), history of attempted suicide (38% vs 23%, p=0.002), and more panic/agoraphobia symptomatology (6 vs 4, p<0.001) (Table1).
Female gender (OR=2.44, p=0.006) and younger age of onset (OR=0.97, p=0.013) remained significant in a multivariate model.
There were no significant differences between the scores of participants with and without migraine on any scale of the TEMPS-A.
For two of the three clinical characteristics found to be significantly different between the MDD+m and MDD-m groups, the characteristics of the MDD+m group were significantly more similar to one or both of the BPI and BPII groups compared to the MDD-m group (age at onset and history of suicide attempt) (Table 2).
Aims
In a large UK sample with broad and rich clinical descriptions:
Compare a broad range of clinical characteristics in participants who have MDD with and without migraine.
Explore possible similarities between those characteristics associated with the presence of migraine in MDD and those in bipolar disorder.
Table 1. Lifetime demographic and clinical characteristics of participants with major depressive disorder with and without migraine
MDDR-
migraine
(n=218)
MDDR+
(n=134)
p-value
Age at interview, median (IQR)
51 (40-59)
49 (40-56)
p=0.070
Sex (Female), % (n)
56.9% (124)
76.9% (103)
p<0.001
Family history of affective disorder, % (n)
82.1% (138)
92.1% (105)
p=0.017
Age of illness onset, median (IQR)
27 ( )
23 ( )
p=0.002
Episodes per year of illness, median (IQR)
( )
( )
p=0.415
Attempted suicide, % (n)
22.7% (49)
38.3% (51)
Ever a tobacco smoker, % (n)
52.7% (68)
47.9% (101)
p=0.386
Heaviest alcohol consumption over recommended limit, % (n)
47.2% (101)
41.9% (54)
p=0.336
GSM-V: panic/agoraphobia, median (IQR)
4 (2-6)
6 (5-7)
GSM-V: social anxiety, median (IQR)
7 (4-9)
8 (5-10)
p=0.119
GSM-V: Obsessive compulsive, median (IQR)
4 (2.25-6)
p=0.960
HCL-32 total, median (IQR)
17 (13-20)
17 (11-21)
p=0.662
MDDR= recurrent major depressive disorder; IQR = inter-quartile range; GSM-V = General 5-Spectrum Measure; HCL-32 = Hypomania Checklist. Significant results at p<0.01 are shown in bold. Numbers vary for each variable due to missing data.
Methods
Participants
Subset of participants with a lifetime DSM-IV diagnosis of recurrent MDD (MDDR) assessed for the presence of migraine (n= 352) who were recruited to an ongoing programme of research into the genetic and non-genetic determinants of bipolar disorder (BD) and related mood disorders (Bipolar Disorder Research Network, BDRN).
Clinical Assessment
Lifetime psychiatric history – details of illness course were collected via semi-structured interview (Schedules for Clinical Assessment in Neuropsychiatry) and review of medical case notes.
Modified General Spectrum Measure 5 (GSM-V) –self-report measure of panic/agoraphobia, social anxiety and obsessive compulsive symptomatology.
Hypomania Checklist (HCL-32) – self report measure of hypomanic/manic symptoms.
Temperament Assessment
Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) –self-report questionnaire measuring cyclothymic, depressive, irritable, hyperthymic and anxious temperaments.
Migraine Assessment
An 11 item self-report headache questionnaire based on the International Headache Society’s diagnostic criteria was used to make a lifetime diagnosis of migraine.
MDDR without migraine
(MDDR-m) n=218
MDDR with
migraine
(MDDR+m) n=134
Table 2: Characteristics associated with the presence of migraine in major depressive disorder: relationship with bipolar disorder
MDDR-
migraine
(n=218)
MDDR+
(n=134)
BPI (n=364)
BPII (n=43)
p-value
Post-hoc analysis
Median age of illness onset, years (IQR) 27
( ) 23
( )
(18-31) 21
(15-31)
p<0.001
MDDR+m, BPI and BPII < MDDR-m (p<0.005)
Attempted suicide, % (n)
22.7%
(49)
38.3%
(51)
39.8% (135)
32.6% (14)
MDDR+m and BPI > MDDR-m (p<0.003)
GSM-V: Median panic/agoraphobia score (IQR) 4
(2-6) 6
(5-7)
(2-7) 5
(4-6)
MDDR+m> BPI and MDDR-m (p<0.001)
MDDR= recurrent major depressive disorder; BPI=bipolar I disorder; BPII=bipolar II disorder; IQR = Inter-quartile range; GSM-V = General 5-Spectrum Measure. Significant results at p<0.01 are shown in bold.
Statistical Analysis
Chi-squared and Mann-Whitney U tests were used to compare demographic, clinical and temperament measures between the MDDR-m and MDDR+m groups. Due to the number of comparisons, a stringent significance level of p<0.01 was employed.
All demographic and lifetime clinical course variables significant at p<0.05 were included as explanatory variables in a binary logistic regression model, with presence of migraine as the outcome variable.
All clinical characteristics found to be significantly associated (p<0.01) with the presence of migraine in MDDR were then compared between MDDR+m and MDDR-m individuals and two further groups of individuals with bipolar I disorder (BPI; n=364) and bipolar II disorder (BPII; n=43).
All categorical variables were analysed by chi-squared tests, with each pair of groups being analysed independently by post-hoc chi-squared tests. Continuous variables were compared by Kruskal-Wallis tests, with differences between each pair of groups being assessed by post-hoc Mann-Whitney U tests. A significance level of 1% (p<0.01) was employed for all variables.
Conclusions
The presence of migraine in MDD delineates a subgroup of individuals with a more severe illness course.
The clinical presentation of this subgroup more closely resembles that of bipolar disorder than that of MDD without migraine.
The presence of migraine in major depression may be a marker of a specific subgroup that could be useful in future research.
Limitations
Relied on participant self-report of migraine, temperament and anxiety symptoms.
Sample size was not large enough to stratify the MDDR+m group by presence/absence of aura.
Acknowledgements
We would like to thank all of the participants who have kindly given their time to participate in our research and all the mental health professionals who were involved in the recruitment of participants.