Ewa Papuć, Beata Pawłowska Review of literature on mood disorders in multiple sclerosis Multiple sclerosis is the most often demyelinating disease and also one of the most often neurological disorders affecting mostly young people in the third or fourth decades of their life. Three types of clinical course are typical for the disease: (1) relapsing-remitting multiple sclerosis with relapses throughout the duration of the disease, (2) secondary progressive multiple sclerosis with the beginning typical for relapsing-remitting course (usually lasting about 15 years) unavoidably followed by a progressive phase and (3) primary progressive multiple sclerosis with steadily worsening the condition from the beginnig [7,23,39]. Multiple sclerosis is mainly perceived as a disease of motor and sensory systems leading gradually to physical disability. But the disease is often accompanied by emotional changes [7,11,16,18,24,27,32]. One of the first authors who paid attention to psychological functioning of people with multiple sclerosis was Jean Marie Charcot, who first noted, about 130 years ago, in 1874, that emotional and intellectual changes accompany multiple sclerosis [8]. At the beginning of the twentieth century some authors even thought emotional disorders in multiple sclerosis to be the most important symptoms of the disease [9]. In those days  the most often mood disorder associated with multiple sclerosis was euphoria. Brown and Davies considered its frequency in multiple sclerosis patients to be about 71%, but the limitation of their study was a small group of patients [5]. Also other authors such as Cotrell and Wilson reported, on the basis of their study with 100 MS patients, that the frequency of euphoria was 63%, whereas only 10% of the patients were depressive [9]. Nowadays euphoria seems to be far rare than it was thought previously. According to Kahana in cerebral MS its frequency is estimated to be about 5% [20]. In the seventies of the 20th century some authors paid attention to depressive symptoms in multiple sclerosis. One of the first, who highlighted that was Surridge [37]. Presently the frequency of  depressive symptoms in multiple sclerosis is estimated to be from 25–54% [2,19,24,25,26,29,36]. In detecting depressive symptoms some difficulties may occur because certain depressive symptoms, such as chronic fatigue, memory loss, concentration problems may overlap with symptoms of MS. In some studies correlation between the severity of depression and degree of physical disability was investigated. Although widely investigated, this correlation is still unclear. In some studies a positive correlation was found [24,37], whereas in other studies such correlation was not confirmed [10,19,25]. According to Stenager, there is a tendency for depression to increase with worsening disability up to an EDSS score of 5–6, but patients with greater disability (score 7–9) in spite of severe brain damage show lower level of depression compared to mildly disabled patients [quot. after 24]. Also most studies confirm that depressive episodes coincide with neurological exacerbations [10,25,33], but there are still some studies which have not found this positive correlation. Joffe`s study, in which 100 multiple sclerosis patients were investigated, showed that there was no direct correlation between functional disability measured by Kurtzke scores and mood disorders [19]. These results were also confirmed by Rabins [quot. after 24]. It is also interesting that psychiatric disorders, among which depression is very common, can be the first symptoms of multiple sclerosis. It has been estimated that up to 16% of MS patients can present different psychiatric disorders before the diagnosis of MS [7]. In 1995 Pine investigated 2720 consecutive admissions to psychiatric units. Although his results showed that MS patients account for a small part of all psychiatric admissions, this patients can exhibit mania or manic psychosis more often than the rest of the inpatient population [28]. Pathogenesis of depression in MS It is still unclear whether mood disorders in multiple sclerosis can be psychological response to functional loss and physical disability or can be just a part of the disease. Some studies confirm endogenous explanation of the disease, other support reactive basis of these disorders. It is known that MS patients present more affective disorders than patients with other neurological deficits and comparable degree of disability [2,34]. However, Surridge has not detected a significant difference in severity of depression comparing 108 multiple sclerosis patients with patients with muscular dystrophy [37]. Also multiple sclerosis patients with demyelinating lesions located mainly in spinal cord suffer fewer depressive disorders despite their greater disability [32]. A comparison of 64 patients with multiple sclerosis and 23 patients with spinal cord injury revealed that less emotional disturbances were present in spinal cord injury group, who were more functionally disabled. This may suggest that depression in MS is not a direct reaction to functional loss. It has also been proved that psychological functioning in MS is connected with the course of the disease. A comparison of psychological functioning of patients with PP-MS and SP-MS was made by Vleugels. According to his study primary progressive patients, despite their greater disability measured with EDSS, longer disease duration and older age had better psychological functioning compared to secondary progressive patients. An attempt to explain this results was made with the use of magnetic resonance imaging. It turned out, on the basis of magnetic resonance images, that in primary progressive MS there tends to be less cerebral lesions and there are fewer new lesions over time. This suggest that primary progressive MS compared to secondary progressive is more a disease of a spinal cord than of the brain [39]. This also confirms the hypothesis that that depression in MS is not only reactive. Some authors also inform about strong association of MS and bipolar affective disorders. While the prevalence of affective disorders in general population is about 1%, its occurrence in Joffe`s study was 13% [19]. According to other studies this prevalence was about 3% [2]. Investigations of the last decade are attempts to find the explanation of mood disorders, emotional changes and deterioration in psychological functioning of MS patients. Studies on mood disorders in MS in the last decade are focused on looking for relationship between lesions site in central nervous system and the presence of depressive symptoms on the basis of MRI and SPECT. In most of these studies lesions located mainly in temporal lobes coexisted with depressive MS symptoms [14,15]. Honer compared MS patients with depressive disorders and MS controls matched in age and illness severity without mood disorders.  It turned out that MS group with mood disorders had greater number of laesions in the temporal lobes [15]. Pujol on the other hand, revealed that demyelinating plaques in the white matter of left hemisphaere, near insula, in the left arcuate fasciculus region are mainly responsible for depressive symptoms [15]. Some drugs used in the therapy of MS are also thought to be responsible for mood disorders. There are some evidence that depression may be a side effect of steroids treatment. In 1993 Alam proved that patients treated with methylprednisolone (500 mg per day) can suffer from depression of mild intensity [1]. Another drug used in MS treatment was interferon beta introduced to MS therapy in the nineties of the 20th century. Results of studies on the influence of interferon beta on mood disorders are not unequivocal. Some authors inform about higher risk of depression in patients treated with interferon beta compared to placebo group. But a European mulitcentre trial on interferon beta treatment in secondary progressive MS revealed that depression was present more often in patients not treated with interferon [12]. Other studies checking the influence of interferon on the level of depression measured with Beck Depression Inventory also have not confirmed this influence [3,4,17]. Genetic basis of depression in multiple sclerosis was also taken into consideration. Study made by Minden in 1989 on 50 patients with MS revealed that 54% of them were depressive in certain periods of their life, and 44% of these patients had first degree relatives with depressive symptoms. According to the authors of these study such results may suggest genetic basis of depression in MS. On the contrary, in 1996 Sadovnick presented results of his research on 221 patients with MS. The results confirmed a very high risk of depression in patients with MS, but the data for their first degree relatives have not supported a genetic basis for depression [31]. It is known that depression is connected with higher risk of suicide. Since depressive symptoms in multiple sclerosis are very common, this risk is also high in MS patients. In 1991 Sadovnick, in his research on the group of 3126 patients, revealed that the proportion of suicides among MS patients was 7.5 times higher than for the age-matched general population [30]. Another study, which involved 5525 MS patients, revealed that the risk of suicide was twice as much as estimated for general population. The probability of suicide was highest in a group of men and in men with the first relapse before they were 30 years old (35). On the other hand there are also studies which have not confirmed the higher risk of suicide in multiple sclerosis patients [33]. Other reported in literature psychiatric disorders accompanying MS, apart from depression and euphoria, are labile mood, pathological crying and laughing, irritability, nervousness and memory deficits [2,10]. According to Feinstein`s study the prevalence of pathological crying and laughing is about 10% in MS. These disorders are most often observed in patients with greater physical disability (EDSS>6.5), longer disease duration (>10 years) and with secondary progressive clinical course of the disease [13].  The prevalence of concentration problems in MS is estimated to be about 26%, sleep disturbances, anxiety and irritability have prevalence about 20%. In Arias` study emotional liability was present in 30% of patients. It was associated with older age, inability to work and greater disability on EDSS [2]. Treatement of depression in MS Not very much studies have been made on the efficiency of depression treatment in MS. Several clinical reports suggested that tricyclic antidepressants and cognitive-behavioral therapy may be effective means of managing depressive symptoms in multiple sclerosis [36]. The effectiveness of desimipramine in one of the studies was evaluated as high, but the limitation of this treatment were side effects typical for tricyclic antidepressants [quot. after 18]. Research made by Scott in 1995 on 10 depressive patients with MS showed that sertraline in a dose of 100 mg per day is not only effective but also well tolerated in treatment of major depression. None of the patients involved into the study with sertraline experienced side effects. Studies made by Scott on the effectiveness of different antidepressive drugs in MS showed high effectiveness of these drugs in 51 among 52 patients involved into the study. At the same time withdrawal of this treatment was connected with high risk of depression relapse [33]. Tricyclic antidepressants and selective serotonine reuptake inhibitors (SSRI) were also used in treatment of pathological laughing and crying [quot. after 18]. Conclusions Although neuropsychological aspects of multiple sclerosis are a subject of interest in the last years, in everyday clinical practice these aspects of the disease remain unrecognized or ignored. Scales commonly used for measuring disability in multiple sclerosis such as expanded disability status scale introduced by Kurtzke in 1983 (EDSS) do not take emotional disorders and cognitive deterioration of these patients into account; they focus on physical disability mainly [22]. Scales used for assessment of MS patients, created in the last years measure also their psychological functioning. An example can be Mulitiple Sclerosis Functional Composite Measure (MSFC) [39]. As for depression treatment, in the last years a great progress has been made in introducing new groups of antidepressive drugs, so that nowadays depressive symptoms in different somatic disorders can and should be succesfully treated with minimal side effects. The aim of this article was to stress the need to place more attention on clinical detection and treatment of psychopathological disorders in multiple sclerosis patients. 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To cite this article: Papuć E., Pawłowska B., Review of literature on mood disorders in multiple sclerosis [in:] Niebrój L., Kosińska M., Unemployment and Health Care, Katowice: Wyd. SAM 2004, p. 127-131