multiple sclerosis is a chronic demyelinating disease of the central nervous system , affecting any part of the cns , but mostly white matter tracts in the cerebral hemispheres , optic nerves , brainstem , cerebellum , and spinal cord .
the prevalence of the disorder ranges between 2 and 150/100,000 depending on the country or specific population , affecting approximately 1 million people worldwide .
psychiatric symptoms in the context of ms were first noted by charcot , who described mania , hallucinations , and depression among other manifestations of the disease .
lifetime prevalence of major depression ranges from 19 to 54% , depending on the population sample and diagnostic criteria used [ 68 ] .
annual prevalence is estimated at 16% , and point prevalence of clinically significant depressive symptoms is as high as 50% .
the rate of depressive disorders in a pediatric population with demyelinating disease has been estimated at 27% . evidently , prevalence is considerably higher than in the general population or among patients with general medical conditions other than ms .
etiologic factors seem to be both biological and psychosocial , and risk factors have been reported to be female sex , age < 35 years , family history of major depression , and a high level of stress .
disease - modifying agents , interferon beta in particular , have also been suspected to induce depressive symptomatology [ 14 , 15 ] .
however , subsequent well - designed studies failed to prove a depressogenic effect , and pretreatment depressed mood was found to be the best predictor of subsequent depression [ 16 , 17 ] .
the importance of this clinical issue can not be underestimated , given its high frequency , the possible adverse effects of depression on disease course , cognitive functioning , treatment adherence , deleterious consequences on quality of life , and increased risk of suicide [ 22 , 23 ] .  
unfortunately , mental comorbidity and depression in particular are frequently underdiagnosed and undertreated , with reported rates of missed diagnosis around 2330% [ 6 , 24 ] and rates of inadequate treatment around 20%36% of those reporting depression [ 6 , 25 ] . in a cross - sectional community study of patients with ms by cetin et al . , 59% of the patients who had significant symptoms of depression were not taking medication , possibly due to missed diagnosis , denial of symptoms , or false reporting , whereas the rest 41% received inadequate treatment . in the whole sample ( n = 542 ) ,
28% of the patients were adequately treated for depression and therefore had achieved remission . in another study by mohr et al .
, 65.6% of depressed patients did not receive medication , 4,7% received subthreshold treatment , 26,6% received threshold , and only 3.1% received overthreshold , indicating that in most cases , therapy is not in accordance with treatment guidelines for depression .
given the fact that depression is a treatable condition , correct diagnosis and adequate treatment are issues of immense importance for the management of multiple sclerosis patients .
the present paper is focused on current knowledge on diagnosis , assessment , and therapeutic interventions for depression in the context of multiple sclerosis .
although the symptom of depressive mood is almost always experienced by patients suffering from disabling diseases , the syndrome of major depression , as defined by the classification systems of icd-10   and dsm - iv - tr , corresponds to a constellation of symptoms comprising depressive mood , anhedonia , fatigue , psychomotor retardation or restlessness , suicidal ideation or suicide attempt , feelings of guilt and worthlessness , and difficulty in concentrating , as well as vegetative symptoms , including altered sleep , appetite , and sexual arousal .
a common challenge for correctly diagnosing depression in the context of multiple sclerosis is distinguishing whether a certain symptom emanates from a depressive disorder or can be attributed to the demyelinating disease .
potential confounders are fatigue , insomnia , altered appetite , and impaired memory and concentration , and misjudgments will lead to false positives or false negatives .
varied presentations of depression , for example , unexplained somatic complaints , anxiety , or hopelessness instead of sadness , could also complicate diagnosis , especially in older persons . patients with ms might exhibit pathological laughter or crying occurring with bilateral forebrain disease , which poorly correlates with underlying mood . on the other hand
a way of disentangling the differential diagnosis in such cases is by paying attention to the cognitive and affective domains of the depressive symptomatology , for example , the depressive mood and depressive beliefs , which is also an approach adopted by assessment tools and rating scales for depression in the presence of a physical illness and multiple sclerosis in particular .
the use of two screening questions   has been proposed for detecting major depressive disorder in the context of ms and primary care setting , which correspond to depressive mood (  during the last two weeks , have you often been bothered by feeling down , depressed , or hopeless ?  ) and anhedonia (  during the past two weeks , have you often been bothered by little interest or pleasure in doing things ?  ) .
at least one affirmative response on either question was used as a criterion of having mdd .
this approach was shown to have a positive predictive value of 71.7% , with a rate of 27.3% of false positives .
however , two thirds of false positives were shown to have subthreshold depression , which again should alert the clinician for the need of treatment .
using the yale single question   is even less time consuming , but this tool seems to lack sensitivity , as it could not identify 34.7% of patients who were depressed by beck depression inventory criteria . on the other hand , it appears to be quite specific , that is , depression can be ruled out when it does not exist .  
the beck depression inventory   is an objective self - report assessment tool comprising 21 items , and one of the most commonly used for patients with multiple sclerosis .
recommended cutoff point is set at 13 , though 30% of patients with depression will be missed in this way .
concerns regarding the length of the instrument as well as the inclusion of items corresponding to neurovegetative symptoms , which might lead to overdiagnosis , have led to the implementation of shorter forms , such as the 7-item beck depression inventory - fast screen ( bdi - fs ) .
validity of the instrument has been documented for the population of patients with multiple sclerosis .   the hospital anxiety and
depression scale   is a self - assessed questionnaire consisting of 14 items , suitable for use in persons with medical conditions , if items corresponding to somatic symptoms are omitted , and recently validated for people with multiple sclerosis .   the center for epidemiologic studies depression rating scale ( ces - d ) , comprising 20 items , has been used with a cutoff point of 16 ( > 15 ) , as likely to correspond to significant depression , recognizing 74.5% of depressed persons [ 9 , 45 ] .
another useful scale is the chicago multiscale depression inventory that was developed to assess depression in ms and other chronic diseases .
it is a 42-item self - reporting questionnaire consisting of three subscales , mood , physical malfunctioning , and self - criticism , the first of which is recommended for ms .
the validity of the use of the hamilton rating scale for depression   has been examined in one study .
the authors conclude that the whole or part of the scale can be used , depending on study design .
the depressive mood scale ( ehd , echelle d ' humeur dpressive ) is an 11-item french questionnaire specifically designed and validated for the assessment of depression in ms , focusing on mood changes rather than somatic symptoms .
the zung self - rating depression scale ( zsrd )   is a 20-item tool that has been shown to have good construct validity for measuring depression in medically ill populations   and has been used for patients with ms [ 53 , 54 ] , as well as the montgomery - asberg rating scale ( madrs ) , a widely known clinician - rated assessment tool for depression , consisting of 10 items .   in pediatric populations , researchers
most frequently use the child depression inventory for identifying depression in samples with ms [ 57 , 58 ] .
the presence of depression can also be documented by applying the kiddie - sads interview .
the utility of detecting depression partly depends on the efficacy and availability of treatments as well as willingness of patients to receive treatment . in a recent study ,
less than 30% of depressive individuals who were prompted to receive treatment did so , and possible explanations for this were distorted beliefs of depression being inevitable , practical problems , or the depression itself [ 60 , 61 ] .
concluding , identifying depression , though not sufficient to ensure effective treatment , is a necessary first step towards proper management of depressed patients with multiple sclerosis .
a comprehensive treatment plan for depression should include pharmacotherapy , psychotherapy , or cognitive behavioural therapy in specific or combination therapy . screening for suicidal intend is incremental due to the high cumulative lifetime risk for suicide .
treating depression has been found to improve adherence , cognitive disturbances , fatigue , quality of life , and possibly disease course , by decreasing production of cytokine .
there is a growing body of evidence regarding the neuroprotective effects of antidepressants such as fluoxetine   and phenelzine .
furthermore , escitalopram has been found to reduce stress - related relapses in a recent open - label , randomized , controlled study .  
treatment guidelines have been most recently reported by the canadian network for mood and anxiety disorders ( canmat ) , based on up - to - date literature .
use of antidepressants is strongly recommended , as well as psychotherapies emphasizing coping strategies rather than insight .
drugs with significant sedating or anticholinergic side effects , such as tricyclic antidepressants , should rather be avoided , due to issues with fatigue , orthostatic hypotension , balance , cognitive disturbances , and bladder problems .
patients should also be monitored for manic or hypomanic symptoms , while on antidepressant medication , as the prevalence of bipolar disorder is quite elevated in ms , presumably two to three times higher than in the general population .should depression emerge during treatment with interferon beta , the latter needs not necessarily be discontinued , but the depression should be adequately treated instead . despite the high burden of depression in multiple sclerosis patients , few trials have been published regarding this particular population , and only two of them were double blind , randomized , placebo controlled , and meeting certain standards of quality , as already observed by koch et al . .
the first one examined the efficacy of desipramine versus placebo and found a trend in favor of desipramine .
the second demonstrated greater efficacy of paroxetine versus placebo , with 78.6% versus 42.1% of patients exhibiting response , respectively , but the difference did not reach significance , probably because of underpowering of the study and dosing and duration issues .
another problem faced by both studies was missing data or patients who were lost at followup . in another study by mohr et al .
, sertraline was found to be equally effective with cognitive behavioural therapy , and both of them were more efficacious than supportive - expressive therapy in a sample of 63 depressed patients with multiple sclerosis .
open - label studies have demonstrated efficacy of sertraline , fluvoxamine , moclobemide , and fluoxetine .
a few case reports deal with the usefulness of ect for severe or refractory depression in ms ; however , concerns have been raised that ect might mediate neurological deterioration by altering the number or size of the cns plaques and/or periplaque edema [ 79 , 80 ] .
it has been postulated that the presence of contrast - enhanced lesions might predict deterioration , and therefore , a gadolinium - enhanced mri is suggested , but this observation is based on a report of only three patients , one of whom deteriorated after ect sessions .
psychotherapy has long been considered an important treatment option for the management of depression in patients with ms , with approaches focusing on coping skills showing superiority over insight - oriented therapies .
cognitive behaviour therapy ( cbt ) helps patients to correct distorted cognitive appraisal of the environment and core beliefs that lead to maladaptive behaviour , and change the connection between life events and learned reactions such as depression beliefs . regarding multiple sclerosis in particular , which imposes progressively increasing physical difficulties and challenges in everyday living , together with cognitive impairment , cbt can help maximize the development of the patients ' coping skills . in line with this observation , individual ( cbt )
has been found more beneficial than supportive expressive therapy ( set ) , administered either as usual   or by telephone .
telephone - administered psychotherapy or counseling is particularly appealing because of the frequent physical disability , which represents an obstacle to receiving therapy otherwise . for similar reasons , computerized forms of cbt are also available [ 86 , 87 ] .
, there still may be some patients who would benefit more by insight - oriented , psychodynamic psychotherapy , which focuses on the management of psychological defenses and unconscious psychic activity [ 82 , 88 ] .
the effectiveness of mindful - based intervention ( mbi ) which is based on the nonjudgmental awareness of everyday moments has also been recently demonstrated .
individual preference and needs , cognitive performance , and availability of therapist should help the clinician choose among the above diverse psychotherapeutic approaches .
the prevalence of depression in patients is remarkably high , yet it is still frequently underdiagnosed and undertreated .
patients who are not treated are not expected to improve and are at risk for further deterioration .
more and better designed studies for therapeutic interventions , particularly in the pediatric populations , are clearly needed .
 multiple sclerosis is a chronic demyelinating disease affecting one million people worldwide , with a significant burden of psychiatric comorbidity . 
 depression is the commonest psychiatric manifestation but still remains largely underdiagnosed and undertreated . 
 the present work reviews current knowledge on diagnosis , assessment , and somatic and psychotherapeutic treatment interventions for depression in adult and pediatric populations of patients with multiple sclerosis . 
1. Introduction
2. Diagnosis and Assessment
3. Treatment Approaches
4. Concluding Remarks 