Multiple sclerosis (MS) is one of the most common neurologic disorders affecting young adults. The suggestion of a possible relationship between depression and MS has existed for many years. [1-4] The historical explanation for observed ``depression'' in persons with MS is a reaction to a stressful illness with potential consequent impact on all aspects (e.g., family, social, work, independent self-care, and so on) of daily living. Other studies suggest that depressive symptoms in MS patients may be correlated with progressive neurologic disability. [2,5] However, more recent work suggests that it is the increasing and specific CNS involvement that results in depressive symptoms. [6,7]
To date, studies on MS and depression have been problematic for several reasons. It is crucial in such studies to differentiate between ``depressive symptoms'' and a ``major depressive illness,'' which are very different entities. Major depressive illness is a discrete, operationally defined psychiatric disorder involving a constellation of mental and physical symptoms, only one of which may be a depressed mood. [8] However, few of the studies on MS and depression have used standardized objective diagnostic criteria for depression, thus lacking the diagnostic rigor necessary to differentiate depressive symptoms from a major depressive illness. Further, there has been little attempt to control for possible confounding factors such as the degree of MS disability and bias in case ascertainment.
Our interest in the relationship between MS and depression arose because of the results of a Canadian study on causes of death among 3,125 MS patients attending two MS clinics (Vancouver, British Columbia, and London, Ontario). [9] The suicide rate among these individuals was 7.5 times the rate for the age-matched general population. [9]
The possible relationship between MS and depression is of importance in both the understanding of the etiologies of these two common conditions and the potential treatment. If data suggest a genetic ``link'' between the two, this could imply a potential common etiology. Conversely, if the data do not support such a link, it is highly likely that depression in conjunction with MS may result from structural/immunologic changes. Depression in MS may in fact be of a different etiology compared with that of depression in non-MS patients. This could have potential implications for treatment.
Two studies have addressed a possible genetic link between MS and depression. Joffe et al., [10] using the Schedule for Affective Disorders and Schizophrenia (SADS) [11] and strict psychiatric Research Diagnostic Criteria (RDC), [12] found that 42% of MS patients had a lifetime occurrence of major depression. The familial rate of depression in these MS patients' firstdegree relatives, as assessed using the Family History RDC (FHRDC), [13] did not differ from expectations for the general population of individuals having a depression but not MS. [10] They interpreted the data as evidence against a genetic link between MS and depression. In this study, [10] only follow-up patients were included, and their MS disability was not specified.
The second study that looked at a possible genetic link between MS and depression [14] assessed 50 MS patients, also with the SADS [11] and FHRDC. [12] Fifty-four percent of MS patients had a lifetime diagnosis of major depression. Of these, 44% had a family history of (1) depression, or (2) depression plus alcoholism, or (3) alcoholism but no depression in their first-degree relatives. They interpreted the data as suggesting a possible genetic link between depression and MS. However, a study published subsequent to this work found that first-degree relatives of a primary depression population have lifetime risks for depression or alcoholism, or both, approaching 50%. [15]
British Columbia provides a unique opportunity to look at the relationship between MS and depression for several reasons. First, Canada has a universal medical insurance plan that provides all individuals with essentially equal financial access to health care facilities such as MS clinics. This is a major reason why Canadian MS clinic populations are representative of the overall MS population rather than being a biased subsample. [16,17] The Vancouver MS Clinic serves the province of British Columbia. To date, assessments and longitudinal follow-up of over 3,000 individuals have been completed. Second, from 1988 to 1990, all consecutive, unrelated inpatients and outpatients presenting to the Mood Disorder Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken. [15] The subgroup of these individuals meeting DSM-III-R criteria (and RDC criteria) for depression and their first-degree relatives are the reference population.
The objectives of the present study were threefold: (1) determine the lifetime risk for a depression in a representative, well-defined group of MS patients; (2) compare morbidity risks for depression among first-degree relatives of MS patients with a current or lifetime diagnosis of a depression with those for first-degree relatives of MS patients not having a depression; and (3) compare morbidity risks for depression among first-degree relatives of MS patients (with and without depression) with morbidity risks for first-degree relatives of the reference population, i.e., index case had depression but no MS.
Methods.
Study group.
Index cases for the present study were consecutive, unrelated MS patients (both new referrals and patients seen for routine follow-up) with a diagnosis of MS according to recognized criteria [18,19] who attended the Vancouver MS Clinic during the period July 1, 1992, to June 30, 1993, inclusive. To avoid as many potentially confounding factors as possible in assessing the relationship between MS and depression, we excluded any MS Clinic patient who (1) had an Expanded Disability Status Scale [20] (EDSS) score of 6.5 or greater (requires more than one cane to walk); (2) was involved in any of the ongoing experimental therapeutic treatment trials being conducted by the Vancouver MS Clinic; (3) was attending the MS Clinic specifically because of an MS relapse; or (4) was engaged in substance abuse.
The present study was explained to eligible patients as part of their MS Clinic visit. A patient unable to participate (in all cases, this was because of time constraints rather than refusal to participate) was replaced by the next consecutive eligible patient. Because of criteria for inclusion in the study, all approached patients were matched so those who could not participate did not have a different profile from the participants. In total, eight patients were unable to participate.
Research instrument.
The Structured Interview for the DSM-III-R, nonpatient edition (SCID) [21] (a semi-structured interview) was administered by a trained research nurse. The research nurse conducting the interviews was experienced in differentiating common physical problems of MS from those that truly reflect depressive symptomatology. The SCID is designed to generate all psychiatric diagnoses, both current and lifetime, although only the diagnosis of depression is included in the present study. The nonpatient edition is specifically targeted to nonpsychiatric patients such as outpatients attending medical clinics. Interrater reliability was ensured in training sessions with the study psychiatrists (J.A., R.A.R.) who also reviewed all SCIDs and assigned DSM-III-R diagnoses, again recognizing common MS physical problems such as excessive fatigue and the need for increased sleep.
Psychiatric diagnoses in first-degree relatives of MS index cases.
Familial aggregates of MS have long been observed. [22] The Vancouver MS Clinic protocol was set up so that all consecutive, unrelated MS patients would have detailed genetic histories taken and documented by the Clinic's geneticist (A.D.S.) with the use of multiple family informants. These family histories are updated annually (see reference 22).
During the study period, information on depression among relatives of MS index cases was routinely included as part of the family-history interview. The present study focused on first-degree relatives (parents, children, siblings) of MS index cases as data were most accurate for this group. For each relative reported to have a depression during the genetic interview, an appropriate FHRDC questionnaire(s) [23] was administered to the family informants. The FHRDC questionnaires are designed to systematically evaluate the diagnoses of Depression (mania and depression) and ``Non-Depression'' Psychiatric Diagnoses (alcoholism, drug abuse, sociopathy, schizophrenia, and other, including suicide with no clear psychiatric diagnoses).
With appropriate consents, each reportedly affected family member was contacted, if possible, and the FHRDC questionnaire(s) was administered during either a personal or a telephone interview. The family member or an appropriate next of kin was also approached to give the consents needed to obtain medical/psychiatric records, if available. As the study focused on first-degree relatives of index cases, compliance was 100%.
Once all available information (FHRDC questionnaires, medical/psychiatric records) was available on each reportedly ``affected'' relative of an MS index case, the data were reviewed by a psychiatrist (J.A. or R.A.R., or both) experienced in the differential diagnosis of depression. A ``best-estimate'' [23,24] diagnosis was made. (See reference 15 for more details on diagnostic methodology and inter-/intrarater reliability.)
Analyses.
I. Index cases.
There were two groups of index cases: (1) MS patients who also had a current or lifetime diagnosis of a depression based on the SCID interview, i.e., ``MS plus depression'' and (2) MS patients who did not also have a current or lifetime diagnosis of a depression based on the SCID interview, i.e., ``MS, no depression.'' These two groups were compared for gender, age at the time of the SCID interview, and age of MS onset. Chi-square and t-test analyses were performed. Differences were considered significant at the 5% level.
The rate and lifetime risk of depression was determined in the MS index cases using the product limit estimate of survival function. [25]
II. First-degree relatives of index cases and reference population.
Morbidity risks for depression among first-degree relatives were calculated with the maximum likelihood estimation (MLE) approach. [26] In the absence of accurate age-of-onset information of depression for the first-degree relatives, their age-of-onset distributions were assumed to be approximately the same as the age-of-onset distributions of the index cases. Morbidity risks were compared using the likelihood ratio test, [26] with differences significant at the 5% level.
To investigate a possible genetic link between MS and depression, morbidity risks for depression among first-degree relatives of ``MS plus depression'' index cases were compared with those for first-degree relatives of ``MS, no depression'' index cases.
Morbidity risks for relatives of index cases (``MS plus depression,'' ``MS, no depression,'' ``MS plus minus depression'') were compared with those for first-degree relatives of a reference population, referred to in this study as the comparison (REF) group, whose data were available from another study. [15] The REF group consisted of 2,840 first-degree relatives of 472 individuals diagnosed as having either a single (N equals 151) or recurrent (N equals 321) episode of depression.
Results.
I. Study groups.
Index cases.
The study group consisted of a total of 221 MS index cases (63 men, 158 women). Seventy-six MS index cases (20 men, 56 women) had a current or lifetime diagnosis of a depression (34.4% of total) based on the SCID interview and thus made up the ``MS plus depression'' group. The remaining 145 MS index cases (43 men, 102 women) did not have a current or lifetime diagnosis of a depression (65.6% of total) based on the SCID interview and thus made up the ``MS, no depression'' group. The ``MS plus depression'' and ``MS, no depression'' index cases did not differ significantly (p more than 0.05) according to gender, age at the time of the SCID interview, disability as estimated by the EDSS, or age of MS onset.
First-degree relatives of MS index cases.
Data were available for a total of 1,207 first-degree relatives of the 221 MS index cases. Table 1 breaks down this number according to gender and relationship to the MS index case.
Table 1. Number of first-degree relatives of index cases according to gender and ``depression'' status of the MS index case
II. Cumulative risk estimates for a depression among MS index cases.
As shown in the Figure 1, the age-corrected cumulative risk for a depression among the MS index cases was 50.3% (SE equals 5.7%), by age 59 years.
Figure 1. Cumulative lifetime risk for a depression in 221 MS index cases.
III. Morbidity risk estimates for a depression among first-degree relatives of MS index cases.
Morbidity risk estimates for the first-degree relatives of each group of index cases, i.e., (1) ``MS plus depression,'' (2) ``MS, no depression,'' (3) all MS (``MS plus minus depression''), and (4) REF group, were calculated using the aforementioned MLE approach.
As shown in Table 2, first-degree relatives of MS index cases consistently showed a significantly lower risk for developing a depression than did first-degree relatives of the REF group: (1) ``MS plus depression'' versus REF, G2 equals 12.20, p less than 0.001, df equals 1; (2) ``MS, no depression'' versus REF, G2 equals 36.58, p less than 0.001, df equals 1; and (3) ``MS plus minus depression'' versus REF, G2 equals 43.79, p less than 0.001, df equals 1. First-degree relatives of ``MS plus depression'' index cases did not have significantly different risks for depression than did first-degree relatives of ``MS, no depression'' index cases (p equals 0.1).
Table 2. Results of maximum likelihood estimates for risk of depression among the two study groups (MS plus depression; MS, no depression), the combined group (MS plus depression) and a reference population (REF)
Discussion.
The present study differs from others in the literature as it utilizes a representative sample of MS index cases, strict psychiatric diagnostic criteria, and FHRDC for compiling family-history information on depression among first-degree relatives of MS index cases, as well as controls for the degree of MS disability (as measured by the EDSS), reasons for clinic attendance (e.g., those having an MS relapse or participating in a therapeutic trial), and uses a structured interview specifically designed for nonpsychiatric patients (the SCID). To the best of our knowledge, no other single study has incorporated all six of these factors. In addition, our study population was more than twice as large as the studies in the literature, e.g., references 10 and 14.
It would be understandable for patients with chronic debilitating illnesses to also have higher rates of depression compared with controls. However, the rate of depression among MS index cases has consistently been higher than those found for patients with other chronic debilitating illnesses. Wells et al. [27] found that the lifetime prevalence of depression in a group of patients with chronic medical disorders was 12.9%, higher than the 9.7% in the general population but much lower than the rates of 42 to 54% for MS found in the present study and in earlier works. [10,14]
Results from the present study show that there is a high rate (50.3% lifetime rate by age 59) of depression among MS clinic patients based on SCID interviews designed to differentiate depressive symptoms from a major depressive illness. Morbidity risks for a depression among first-degree relatives of these MS index cases, regardless of whether or not the MS index case had a current or lifetime diagnosis of a depression, were consistently markedly lower than the risks for first-degree relatives of a reference population, i.e., depression but no MS. If a clear genetic link exists between depression and MS, one would expect the morbidity risk for first-degree relatives of the ``MS plus depression'' index cases to be very similar to the morbidity risk for first-degree relatives of the REF group. However, the present study did not find this Table 2.
In conclusion, the results of the present study suggest that the high rate of depression among MS index cases does not appear to have a clear genetic basis, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS (see reference 15).
Acknowledgments
We would like to thank Doug Keller, Rudy Young, Kelly Grant, and Theresa Janze for their valuable assistance with this project.
Footnotes
-
.AB.-The objectives of the present study were (1) to ascertain the lifetime risk of a depression in a representative group of multiple sclerosis (MS) patients, (2) to assess the morbidity risks for depression among first-degree relatives of these MS patients, and (3) to compare these familial risks for first-degree relatives of MS patients with those for first-degree relatives of a primary depression population, i.e., depression but no MS. We psychiatrically evaluated 221 MS patients (index cases) using a structured clinical interview for the DSM-III-R and calculated the rate and lifetime risk of depression for these index cases using the product limit estimate of survival function. We obtained psychiatric histories for all first-degree relatives of index cases, and we calculated morbidity risks for depression for these relatives using the maximum likelihood approach and compared the risks using the likelihood ratio tests. Index cases had a 50.3% lifetime risk of a depression. Morbidity risks for depression among first-degree relatives of index cases were decidedly lower when compared with morbidity risks among first-degree relatives of the reference population. Although there appears to be a very high rate of depression among MS patients, the data for their first-degree relatives do not support a clear genetic basis for this depression, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS.| NEUROLOGY 1996;46:628-632
- Copyright 1996 by the Advanstar Communication Inc.
REFERENCES
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Alert Me
Recommended articles
Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis
Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study
Neocortical volume decrease in relapsing–remitting MS patients with mild cognitive impairment
Risk of Parkinson's disease among first-degree relatives