Psychosomatics 48:286-289, July-August 2007
doi: 10.1176/appi.psy.48.4.286
© 2007 Academy of Psychosomatic Medicine
Are Anti-Nuclear Antibodies Common in Affective Disorders? A Review of the Past 35 Years
Brian Appleby, M.D.
Received August 26, 2006; revised October 27, 2006; accepted November 1, 2006. From The Johns Hopkins Hospital, Baltimore, MD. Address correspondence and reprint requests to Brian Appleby, M.D., The Johns Hopkins Hospital, Meyer 131, 600 North Wolfe St., Baltimore, MD 21287. e-mail: bappleb1{at}jhmi.edu
© 2007 The Academy of Psychosomatic Medicine
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ABSTRACT
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There has been debate in the literature about whether or not positive anti-nuclear antibody (ANA) titers are associated with affective disorders. Using specific search criteria, the author conducted a search of PubMed over the past 35 years. Four studies showed a positive correlation, whereas eight did not. Some of the positive studies have confounding factors. Given that the positive studies have confounding factors and that there are more negative studies than positive ones, it is logical to assume that there is no association between ANA titer and affective disorders until a properly controlled study is conducted.
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A CASE STUDY
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The patient is a 26-year-old married white woman with a past history of major depressive disorder. The patient’s depressive illness began 5 years ago, when her boyfriend broke up with her. She would frequently stay in bed, and she missed a large number of her college classes. At the time, she described feeling terrible and overwhelmed, and she eventually stopped caring about things. She became socially isolated and was started on sertraline, with positive results. One year later, she discontinued her medication without the supervision of a physician. The patient subsequently relapsed into another depression and was tried on numerous medications. Her current regimen includes venlafaxine and bupropion. She has been on the aforementioned medications for 3 years and still complains of extreme exhaustion, typically sleeping 12 hours/day on weeknights and 15–16 hours/day on weekends. She was evaluated by her primary medical physician, who did an extensive laboratory work-up for her extreme fatigue. Comprehensive metabolic profile, complete blood count, thyroid-stimulating hormone, and vitamin B12 levels were normal. However, the patient had a positive anti-nuclear antibody (ANA) test, with a 1:160 titer. The patient denies any rheumatologic symptoms, including rashes, joint pain, Raynaud’s phenomenon, and photosensitivity. The patient has no apparent rheumatological cause for her positive ANA titer.
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DISCUSSION
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Although known to be a good marker in immunoinflammatory connective tissue diseases,1 the role of ANAs in affective illness is confusing, to say the least. There have been multiple studies examining this phenomenon, but they have shown mixed results. Moreover, there has not been any recent literature published on the topic. The intent of this article is to critically analyze previous studies and to update the current literature on the subject of anti-nuclear antibodies in affective disorders. Once reviewed, clinicians will be better educated regarding the role of ANAs in psychiatric evaluation.
A search was conducted on PubMed, using the terms "anti-nuclear antibody AND depression," "anti-nuclear antibody AND affective," "ANA AND depression," and "ANA AND affective." Subsequent articles were read for clinical relevancy. Those articles that investigated ANA titers in patients with affective disorder were included in this study.
A search of the literature yielded a total of 12 studies that measured ANA levels in patients with affective disorders. Table 1 lists the studies and their results. As a benchmark, the rate of positive ANA tests in the normal population can reach up to 30%.2–4 This review found two studies that exceeded this rate and two studies that claimed a positive result when compared with their control group. The remaining studies noted ANA-positive test rates within the expected range.
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TABLE 1. Association Between Affective Disorder and Anti-Nuclear Antibody (ANA) Titer (Percent of Affective Patient Population Found to Have a Positive ANA Titer)
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The first study to note a correlation between ANA titers and psychiatric disorders was conducted by von Brauchitsch,5 who reported an astoundingly high positive ANA rate of 48%. This rate is much higher than in the normal population. Similarly, another study by Deberdt et al.6 found an ANA-positive rate of 28% in a population that comprised 84% women. They found that most of the patients who were ANA-positive had "manic-depressive illnesses." Treatment-resistance also tended to be associated with having a positive ANA test; 66.7% of ANA-positive patients had "bad or moderate" treatment results, as compared with 36.8% of the ANA-negative group. A study by Johnstone et al.7 also found a correlation between ANA tests and psychiatric illness;7 however, they also found a link between lithium ingestion and positive ANA tests. Of seven patients who were taking lithium, four had positive ANA tests. With the exception of mono-amine oxidase inhibitors, many other psychiatric drugs were also found to have a mild association with positive ANA tests. This led the authors to conclude that it may be the psychiatric medications, namely lithium, that induced the positive ANA tests and that they might not necessarily be caused by the illness. The most recent study that found a correlation between ANA titers and affective disorders was done in 1985 by Legros et al.8 The patients in this study were drug-free for at least 8 weeks, and their serum was tested for ANA and various immunoglobulins. They found elevated levels of ANA (15.6%) that were statistically significant. Interestingly, the only positive ANA tests were from female subjects.
In the studies done by Debert et al.6 and Legros et al.,8 an association was made between positive ANA titers and gender. Almost all of Debert’s sample was female, and, in the study conducted by Legros et al., only women seroconverted. An additional study by Hornig et al.9 examined ANA tests in association with affective subtypes, active mood state, medications, age, and gender. They did not find a correlation with mood state or affective diagnosis; nor did they find one with medication. However, they did find a statistical difference between men and women, with women having more positive tests, leading to the conclusion that gender may have more influence on auto-antibodies than does psychiatric diagnosis.
The majority of the studies examining ANA titers in affective illness fail to find a correlation outside of the expected rate of seroconversion. For example, a study by Shopsin et al.10 tested patients after a medication washout period of 14 days. Subjects were also prescreened for other illnesses, including syphilis, that can cause a positive ANA. They found a positive ANA test rate that was within the expected range. Similarly, Ghose et al.3 found no difference in ANA titers between lithium-treated patients, psychiatric patients not treated with lithium, and the general population. Gastpar et al.,2 likewise, did not find an increased ANA titer in patients treated with lithium or neuroleptics. Two studies designed to catch undetected systemic lupus erythematosus (SLE) within the psychiatric population found no association between ANA titers and affective diagnosis.11,12 In fact, both studies also noted a preponderance of positive ANA tests in women. Some studies were unable even to obtain a positive ANA test from any psychiatric patient.13,14
Two studies that claim a positive result are still within the accepted range of 0–30% for seroconversion in a normal population. The studies that do find an association between ANA titers and affective disorders tend to be older studies. Perhaps because of this, the patient population was not prescreened for other illnesses that can cause a positive ANA, especially syphilis. Because the patient population was not prescreened, it is possible that the patients had other illnesses that could have resulted in a positive ANA titer. Hence their positive test would not be a true correlation to an affective illness, but, rather, to another disease.
The other complication with many of the studies is the concurrent or previous use of medications. Some of the previous studies have shown that lithium can cause a positive ANA titer.6 Chlorpromazine, a commonly used neuroleptic during the time of the studies, is also known to cause positive ANA titers.15 Little is known about what drugs were previously taken by patients in the study by Deberdt et al.6 Especially troubling are the assertions made in the article referring to the ANA-positive population as being more "manic depressive" in nature and also being treatment-resistant. These characteristics are often observed in the types of patients taking lithium. Although some of the articles did not see an increased incidence in positive ANA titer and lithium use, it should still be properly controlled for.
Although illness comorbidity and medications are important factors in analyzing the studies, perhaps the greatest factor is that of gender. Rheumatologic illnesses are, in fact, more common in women, and positive ANA tests are more common in older women.4 As some of the previous studies have shown, being a woman can be the greatest predictive factor for ANA titer. This is especially important because two of the studies predicting an association between ANA titer and affective illness also had a preponderance of women in their samples; 84% of the population in the study by Deberdt et al.6 were women. This is very important if the highest predictive factor is gender. In the study by Legros et al.,8 only women had a positive ANA titer. It could be that the sample was somehow biased, although there were relatively even numbers of men and women in the study.
Much has changed within psychiatry over the past 35 years. Diagnosis, although still done via mental status exam, is more precise and uniform with the aid of the Diagnostic and Statistical Manual of Mental Disorders–IV (DSM–IV). Many of the studies described depressions as being either endogenous or exogenous, neurotic or psychotic. Hence the current classification system differs from those in the past. Similarly, medications are likely used in a more systematic and goal-oriented fashion. Given that change, findings from those studies could not necessarily be carried over into our present-day diagnostic criteria.
Another confounding factor is that rheumatologic illnesses, which frequently result in a positive ANA test, are often comorbid with psychiatric disorders. Katz and Yelin16 studied patients with rheumatoid arthritis and reported that 15%–17% complained of depressive symptoms each year. The prevalence of depression is even higher in those patients with SLE (41%–81%).17 Symptoms of rheumatologic disorders can also mimic depression; for instance, lupus can be marked by extreme fatigue and, sometimes, psychosis.18 Oftentimes, psychiatric symptoms precede a diagnosis of lupus.11
Medications used to treat both rheumatologic and psychiatric conditions may also make a diagnosis difficult. Corticosteroids, which are used to treat many connective tissue diseases, may cause a secondary depression, as well as psychosis or mania.19 In contrast, many psychiatric drugs can cause a drug-induced lupus syndrome; these include carbamazepine, chlorpromazine, and lithium.20 Drug-induced lupus is characterized by an abrupt onset of joint pain and general symptoms.21 Compared with SLE, rashes are less prominent. The patients affected by this condition tend to be older, and there is an equal male-to-female ratio. Drug-induced lupus is also often accompanied by a positive ANA test. Hence, treating patients with rheumatologic disorders can be quite complicated, because the line between rheumatologic illness and psychiatric disorder may be blurred.
The answer to the question within the title is a complicated one. There have been studies that do and do not show an association between ANA titers and affective illnesses. Moreover, the studies that do assert an association between the two may be methodologically flawed. When comorbid illnesses and medications are not controlled for, these confounding factors may result in a false positive rate of seroconversion. Similarly, many modern-day studies that have controlled for comorbidity and medications have not found an association between ANA and affective illness. Therefore, it would be prudent to assume that there is not a correlation between ANA and mood disorders until a properly-designed study has determined otherwise. A prospective study controlling for comorbid illness, medications, and gender would be ideal.
In summary, there is little evidence to support ordering an ANA test for the purpose of diagnosing an affective disorder. In contrast, an ANA test can be very helpful in cases where there is concern about rheumatologic illness. Symptoms of fatigue, malaise, joint pain, malar rash, photosensitivity, serositis, and neurologic symptoms would raise suspicions of a rheumatologic disease. Because the symptoms of these illnesses mimic affective disorders, an ANA can be useful to rule out a connective tissue disease. If the test is positive, the patient should then be referred to a rheumatologist for further evaluation.
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CONCLUSION
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There has been debate within the literature over whether or not ANA is correlated with affective disorders. In total, 12 studies have examined this question. Four studies have shown an association between the two, whereas the remainder of the studies have not. The studies that have found an association may have confounding factors. These include not screening for comorbid illnesses that can result in a positive ANA test and having a population mainly comprising women, who have higher rates of positive ANA. Also, many psychiatric medications, such as lithium and chlorpromazine, can cause positive ANA tests. Thus, their use should be accounted for in a study measuring ANA. Because there are more negative studies than positive ones and because the positive studies may be methodologically flawed, one can assume that, for psychiatric patients, the incidence of positive ANA titers is no different from that of the normal population. Thus, ANA titer should not be used to diagnose depression. Instead, it should be used to rule out rheumatologic illness when it is suspected.
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REFERENCES
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- Wilk AS: Anti-nuclear autoantibodies: clinical utility for diagnosis, prognosis, monitoring, and planning of treatment strategy in systemic immunoinflammatory diseases. Scand J Rheumatol 2005; 34:260–268[CrossRef][Medline]
- Gastpar M, Muller W: Auto-antibodies in affective disorders. Neuropsychopharmacol 1981; 5:91–97[CrossRef]
- Ghose K, Coppen A, Hurdle ADF, et al: Antinuclear antibodies, affective disorders, and lithium therapy. Pharmakopsychiat 1977; 10:243–245
- Kavanaugh A, Tomar R, Reveille J, et al: Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. Arch Pathol Lab Med 2000; 124:71–81[Medline]
- von Brauchitsch H: Antinuclear factor in psychiatric disorders. Am J Psychiatry 1972; 12:102–104
- Deberdt R, Van Hooren J, Biesbrouck M, et al: Antinuclear factor-positive mental depression: a single disease entity? Biol Psychiatry 1976; 11:69–74[Medline]
- Johnstone E, Whaley K: Antinuclear antibodies in psychiatric illness: their relationship to diagnosis and drug treatment. BMJ 1975; 2:724–725[Abstract/Free Full Text]
- Legros S, Mendlewicz J, Wybran J: Immunoglobulins, autoantibodies, and other serum protein fractions in psychiatric disorders. Eur Arch Psychiatr Neurol Sci 1985; 235:9–11[CrossRef][Medline]
- Hornig M, Amsterdam J, Kamoun M, et al: Autoantibody disturbances in affective disorders: a function of age and gender? J Affect Disord 1999; 55:29–37[CrossRef][Medline]
- Shopsin B, Sathananthan GL, Chan TL, et al: Antinuclear factor in psychiatric patients. Biol Psychiatry 1973; 7:81–87[Medline]
- van Dam AP, Wekking EM, Callewaert JAC, et al: Psychiatric symptoms before systemic lupus erythematosus is diagnosed. Rheumatol Int 1994; 14:57–62[CrossRef][Medline]
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- Fontana A, Storck U, Angst J, et al: An immunological basis of schizophrenia and affective disorders? Neuropsychobiology 1980; 6:284–289[Medline]
- Berglund S, Gottfries CG, Gottfries I, et al: Chlorpromazine-induced antinuclear factors. Acta Med Scand 1970; 187:67–74[Medline]
- Katz PP, Yelin EH: Prevalence and correlates of depressive symptoms among persons with rheumatoid arthritis. J Rheumatol 1993; 20:790–796[Medline]
- Moran MG: Psychiatric aspects of rheumatology. Psychiatr Clin Am 1996; 19:575–587[CrossRef]
- Harris E (ed): Kelley’s Textbook of Rheumatology, 7th Edition. Philadelphia, PA, WB Saunders, 2005, pp 1204-1205
- Moore D, Jefferson J: Handbook of Medical Psychiatry, 2nd Edition. Philadelphia, PA, Mosby, 2004, p 294
- Rakel R (ed): Textbook of Family Practice, 6th Edition. Philadelphia, PA, WB Saunders, 2002, p 979
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ABSTRACT
A CASE STUDY
