Recommendations on diagnosis and treatment ... - Practical Neurology

REVIEW

Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis Yara Dadalti Fragoso,1 Tarso Adoni,2 Andrea Anacleto,1 Paulo Diniz da Gama,3 Marcus Vinicus Magno Goncalves,4 Andre Palma da Cunha Matta,5 Monica Fiuza Koncke Parolin6

1

Department of Neurology, MS Reference Center, Universidade Metropolitana de Santos, Santos, SP, Brazil 2 Department of Neurology, MS Reference Center, Hospital Sirio-Libanes, Sao Paulo, SP, Brazil 3 Department of Neurology, MS Reference Center, Pontificia Universidade Catolica de Sao Paulo, Campus Sorocaba, Sorocaba, SP, Brazil 4 Department of Neurology, MS Unit, Centro Hospitalar Unimed, Joinville, SC, Brazil 5 Department of Neurology, MS Reference Center, Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, RJ, Brazil 6 MS Reference Unit Curitiba, Neurology Clinic, Curitiba, PR, Brazil Correspondence to Professor Yara Dadalti Fragoso, Department of Neurology, MS Reference Center, Universidade Metropolitana de Santos, Rua da Constituicao 374, Santos, SP CEP 11015-470, Brazil; yara@ bsnet.com.br

To cite: Fragoso YD, Adoni T, Anacleto A, et al. Pract Neurol Published Online First: [ please include Day Month Year] doi:10.1136/practneurol2013-000735

ABSTRACT

Diagnostic criteria

Multiple sclerosis (MS) is frequently associated with depression. Yet there are few clinical trials on treating depression in MS and no agreed recommendations for its assessment and follow-up. We present evidence-based recommendations for several aspects of depression in MS, including screening for depression, recognition of other concomitant psychiatric conditions, suicide risk, disability, fatigue, cognition, adherence to treatment, the effect of drugs used to treat MS on depression and possible pharmacological treatments for depression in MS.

The diagnosis of depression uses DSM-IV criteria,9 that is, at least five of the following symptoms persisting for over two consecutive weeks, and unrelated to bereavement or drug abuse:

INTRODUCTION Depression is the commonest psychiatric manifestation of multiple sclerosis (MS), but remains underdiagnosed and undertreated.1 2 Perhaps half of the number of patients with MS have depression.3 Major depression in patients with MS does not relate directly to disability progression or to longer disease duration.3 The reported risk factors are female sex, age below 35 years, family history of major depression and a high stress levels.4–6 Patients with MS also experience fatigue and cognitive dysfunction, both of which can worsen depression and be worsened by depression.7 The negative feelings of depression can lead people to overestimate their cognitive difficulties and fatigue.7 Depression can also compromise adherence to disease-modifying drugs.8 There are few recommendations for screening for depression. Most patients with MS do not undergo extensive neuropsychological testing (figure 1). There are no guidelines in the literature on treating depression in MS.

Fragoso YD, et al. Pract Neurol 2014;0:1–6. doi:10.1136/practneurol-2013-000735

1. Depressed mood most of the day, nearly every day, as indicated either by subjective report (eg, feels sad or empty) or the observation of others (eg, appears tearful). 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3. Significant weight loss when not dieting, or weight gain (eg, a change of >5% of body weight in a month). 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day. 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day. 9. Recurrent thoughts of death (not just fear of dying), suicidal ideation, or a suicide attempt or specific plan for committing suicide.

Particular care is needed when considering fatigue as a criterion for depression, since many patients with MS have fatigue, and not always with depression. More than half of the number of patients with MS have hypersomnia and daytime sleepiness.10 Reduced ability to think in MS may also relate to cognitive disturbances and not necessarily to depression. Taking these possible confounding factors into consideration, the DSM-IV criteria are useful for screening patients with MS

1

REVIEW two questions as routine in every MS consultation may alert neurologists to cases requiring more extensive evaluation. Clinicians should ask all MS patients the two questions on depressive mood and anhedonia. If the answer is ‘no’ to both, the probability of depression is less than 2%. If the answer is ‘yes’ to both, the probability of depression is 99%. Concomitant psychiatric conditions

Figure 1 Diagram summarising the advice from the present review. Routine screening for depression can be simplified and, if necessary, more detailed assessment and neuropsychological testing carried out. Full lines in the arrows are advice from the authors, and dotted lines in the arrows are options if another condition is suspected. Patients with multiple sclerosis who present fatigue, cognitive disorders and inadequate adherence to treatment may have underlying depression.

who may require more extensive and specialised evaluation. Clinicians should be familiar with the DSM-IV criteria for depression, and remember that fatigue, hypersomnia and cognitive dysfunction in MS may confound the interpretation of these diagnostic criteria. Simple methods for screening for depression

There is no simple and perfect way to screen for depression. Most scales are not specific for MS, except for the recently reported MS Depression Rating Scale.11 Among the most used scales are the Beck Depression Inventory (BDI)12 and the Hospital Anxiety and Depression Scale (HADS).13 Both are relatively simple and can be used by clinicians during routine consultations, but they may not be as simple for the patient. BDI and HADS use gradations of given symptoms, ranging from practically never to always, with some options between these extremes. Having BDI and HADS as the screening scales may discourage clinicians from routinely looking for depression. Therefore, Spitzer et al’s14 two questions for depressed mood and anhedonia provides a simpler approach14: 1. During the past month, have you often been bothered by feeling down, depressed, or hopeless? 2. During the past month, have you often been bothered by little interest or pleasure in doing things?

This two-question instrument was 96% sensitive with a negative likehood ratio (LR) of 0.07 and a negative predictive value of 98%.15 This simple method correctly identified 99% of depressed patients with MS.16 Of course, the two questions do not replace BDI and/or HADS and do not come close to a full neuropsychological evaluation. However, including these 2

Anxiety: About half the number of patients with MS report anxiety17 18 Depression, female sex, low levels of self-efficacy, disability and stress increase its prevalence, but only depression is an independent predictor.17 The literature suggests that anxiety clearly associates with reduced health-related quality of life, unrelated to neurological disability.19 Obsessive compulsive disorder may affect as many as 16% of patients with MS.20 It is associated with bipolarity, depression and anxiety in the general population,21 but these associations have not yet been studied in patients with MS. Other psychiatric conditions that are also more frequent in MS than in controls include sleep impairment, somatisation, interpersonal sensitivity, anger–hostility, phobic anxiety, paranoid ideation, psychoticism, low self-esteem and distorted eating attitudes.22 Clinicians should be aware that patients with MS have greater risk of anxiety, bipolarity and obsessivecompulsive behaviour. Patients with MS who already have depression may also develop other less common, but equally distressing psychiatric symptoms. Suicide risk

Patients with MS have a considerably increased risk of suicide,23 relating to depression, and not to disability.24 Risk factors include depression, social isolation, lower income and younger age,25 26 as well as male sex, disability, a sense of hopelessness6 26 and loss of control.27 Effective treatment of depression reduces suicide risk28; unfortunately, most cases of severe depression and suicide ideation in MS remain undiagnosed and untreated.29 30 Clinicians should be alert to the risk of suicide in patients with MS. In patients with moderate to severe depression, suicide ideation must be assessed. Disability and depression

Lower quality of life with MS appears more a function of depression than of chronic disability.31 Disability itself does not seem to lead specifically to depression.32 While disability from an acute relapse may cause depression, it often persists after recovery from the disability.33 Depressed patients complain more about their disability-related executive impairment than do non-depressed patients.34


REVIEW Clinicians should suspect depression in MS patients who report a degree of disability out of keeping with their physical signs. Fatigue and depression in MS

Fatigue is defined as physical and/or mental weariness resulting from exertion, lack of energy or tiredness. It is common in central and peripheral neurological disorders.35 Fatigue in MS is perhaps the single most debilitating symptom, surpassing pain and even physical disability.36 Fatigue significantly impairs quality of life in MS.37 Half of all patients with MS report depression at some period of their lives,6 38 and fatigue affects at least 75%,36 persisting over time39; thus, many patients with MS have both.40 Tiredness and lack of energy—typical of depression and fatigue—correlate with sleep disturbances.41 A recent imaging study showed a pattern of diffuse grey matter atrophy that related to fatigue and depression in patients with MS.42 The presence of fatigue in MS should alert clinicians to the possibility of depression. Cognitive dysfunction and depression in MS

There is no standard method to assess cognition in patients with MS: over 30 tests are currently used.43 Depressed mood in MS may worsen cognition, and particularly attention and interest. Although some studies show no specific correlation between depression and cognitive dysfunction in MS,44 depression probably does affect cognitive performance.43 In fact, fatigue and depression are the main correlates of cognitive impairment in MS.45 46 Thus, depression may exaggerate the features of cognitive disability while not necessarily worsening performance. Unemployment and poor social life, sometimes (but not always) relate to physical disabilities, and may also negatively influence cognition leading to further isolation and frustration.47 Depression may influence cognitive performance, but also influences a patient’s interpretation of his/her cognitive dysfunction. Patients whose ‘memory’ complaints are prominent and apparently unrelated to their cognitive state, require screening for depression. Adherence to treatment

Patients with MS and depression are twice as likely not to adhere to disease-modifying drug treatment, particularly if they have not taken antidepressants for at least 6 months.8 48 In a large study in the King county (USA) population of patients with MS, 19% had excessive alcohol consumption, overuse of prescribed medications and illicit substance abuse, and particularly those with depression.49 Although there are no specific studies in MS, patients who consume alcohol are less likely to adhere to treatment because


they are concerned that the combination may be toxic.50 In a patient with MS and depression, clinicians should assess adherence to treatment at every consultation. Alcohol and drug consumption must also be addressed, since these habits may influence adherence.

Disease-modifying drugs (interferon-β, glatiramer acetate, natalizumab, fingolimod)

Disease-modifying drugs may induce or exacerbate depression, improve depression and not alter depression. This aspect of MS treatment needs investigation through long-term pharmacovigilance. There are only anecdotal reports and small case series, and no substantial conclusions. Interferon β: The leaflets accompanying interferon β 1a (subcutaneous and intramuscular) and 1b (subcutaneous) include warnings about their use in depression and/or previous psychiatric history. However, this is controversial. There are reports of severe depression and suicide attempts among MS patients treated with interferon β who had no prior psychiatric history.51 On the other hand, others have found no evidence to support interferon-β alone causing or exacerbating depression.52 Nonetheless, because of the apparently higher risk of depression in patients with MS treated with interferon β, this treatment requires screening for signs of depression and, if necessary, appropriate antidepressant treatment.53 Glatiramer acetate: The leaflet accompanying this medication specifies depression as an adverse effect. There are no data on the prevalence, characteristics or risk factors for depression in patients using glatiramer acetate. There is a hypothesised but unproven theory of potential antidepressant effects from glatiramer acetate.54 Overall, the risk of depression from glatiramer acetate apears no higher than with interferon-β, and in both the risk is small.5 However, as with interferon-β, it is sensible to screen patients who receive glatiramer acetate or signs of depression, and treat them appropriately if necessary. Natalizumab: A retrospective analysis on the depression data of the phase III SENTINEL study on natalizumab showed that a significant number of patients who entered the trial without depression developed a positive score for depression during the trial.55 On the other hand, a more recent phase IV study analysing fatigue in patients treated with natalizumab showed better scores for depression among treated patients.56 The leaflet accompanying the drug warns of depression as a potential adverse effect. Fingolimod: Fewer than 5% of patients using fingolimod develop depression,57 and depression is not among the 15 most common listed side effects of the drug. Studies analysing fingolimod’s adverse events found no significant differences in development or worsening of depression58 59 However, the leaflet 3

REVIEW accompanying the drug lists depression as a potential adverse effect of the drug. Patients with MS must be screened for depression before and during treatment with disease-modifying drugs. Treating depression in MS

Pharmacological treatment: Despite the high prevalence of depression in patients with MS and the potential danger of suicide, there are remarkably few methodologically sound papers on the subject. A Cochrane review32 identified only two studies, one using paroxetine60 and the other using desipramine.61 Each included only small patient numbers and shortterm treatment. Adverse events were frequent, while several patients dropped out or were lost to follow-up. It is difficult to draw definite conclusions from these studies, but both drugs showed only a trend toward improving depression in MS. The confidence intervals were wide and there were no statistically significant differences between any of the drugs and placebo for any of the outcomes.32 There have been open trials treating depression in MS using sertraline,62 moclobemide and fluoxetine,63 64 and duloxetine.65 Again, these were isolated studies with small numbers of patients and relatively short follow-up. The tendency to use selective serotonin receptor reuptake inhibitor is justified since tricyclic antidepressants could induce somnolence, reduce cognitive performance and exacerbate fatigue. Non-pharmacological treatment: Individual cognitive-behavioural therapy, group psychotherapy, or sertraline were compared in an open trial on depressive patients with MS.66 There were no significant differences between these treatments, although the samples were small and the drop-out rate was around 20%. At least over the short term, individual cognitive behavioural therapy seems a good nonpharmacological alternative to treat depression in MS.67 There are no evidence-based guidelines to treat patients with MS who present with depression; the choice depends upon the efficacy and tolerability of the drugs used to treat depression generally. CONCLUSION Despite the well-recognised high risks of depression among patients with MS, including suicide ideation, there are few high-quality studies of its management. While awaiting adequate clinical trials, we recommend that depression should be actively investigated in every patient with MS and treated with efficient antidepressants as necessary. Contributors All authors have contributed equally to the paper. Their names are in alphabetical order of the last surname, except for YDF who designed the study, compiled results and wrote the paper.

4

Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Katharine Harding, Cardiff, UK.

REFERENCES 1 Marrie RA, Horwitz R, Cutter G, et al. The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated. Mult Scler 2009;15:385–92. 2 Skokou M, Soubasi E, Gourzis P. Depression in multiple sclerosis: a review of assessment and treatment approaches in adult and pediatric populations. ISRN Neurol 2012;2012:427102. 3 Chwastiak L, Ehde DM, Gibbons LE, et al. Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Am J Psychiatry 2002;159:1862–8. 4 Patten SB, Metz LM, Reimer MA. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult Scler 2000;6:115–20. 5 Patten SB, Fridhandler S, Beck CA, et al. Depressive symptoms in a treated multiple sclerosis cohort. Mult Scler 2003;9:616–20. 6 Feinstein A. Multiple sclerosis and depression. Mult Scler 2011;17:1276–81. 7 Kinsinger SW, Lattie E, Mohr DC. Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in patients with multiple sclerosis. Neuropsychology 2010;24:573–80. 8 Tarrants M, Oleen-Burkey M, Castelli-Haley J, et al. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult Scler Int 2011;2011:271321. 9 American Psychiatric Association. DSM-IV Diagnostic and statistical manual of mental disorders. 4th edn. 2000, text rev. 10 Bøe Lunde HM, Aae TF, Indrevåg W, et al. Poor sleep in patients with multiple sclerosis. PLoS ONE 2012;7:e49996. 11 Quaranta D, Marra C, Zinno M, et al. Presentation and validation of the multiple sclerosis depression rating scale: a test specifically devised to investigate affective disorders in multiple sclerosis patients. Clin Neuropsychol 2012;26:571–87. 12 Beck AT, Beamesderfer A. Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry 1974;7:151–69. 13 Herrmann C. International experiences with the Hospital Anxiety and Depression Scale—a review of validation data and clinical results. J Psychosom Res 1997;42:17–41. 14 Spitzer RL, Williams JB, Kroenke K, et al. Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME-MD 1000 study. JAMA 1994;272:1749–56. 15 Whooley MA, Avins AL, Miranda J, et al. Case-finding instruments for depression: two questions are as good as many. J Gen Int Med 1997;12:439–45. 16 Mohr DC, Hart SL, Julian L, et al. Screening for depression among patients with multiple sclerosis: two questions may be enough. Mult Scler 2007;13:215–19. 17 Garfield AC, Lincoln NB. Factors affecting anxiety in multiple sclerosis. Disabil Rehabil 2012;34:2047–52. 18 Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler 2007;13:67–72. 19 Poder K, Ghatavi K, Fisk JD, et al. Social anxiety in a multiple sclerosis clinic population. Mult Scler 2009;15:393–8.


REVIEW 20 Foroughipour M, Behdani F, Hebrani P, et al. Frequency of obsessive-compulsive disorder in patients with multiple sclerosis: a cross-sectional study. J Res Med Sci 2012;17:248–53. 21 Shabani A, Alizadeh A. The specific pattern of obsessive-compulsive symptoms in patients with bipolar disorder. JRMS 2008;13:48–54. 22 Sarısoy G, Terzi M, Gümüş K, et al. Psychiatric symptoms in patients with multiple sclerosis. Gen Hosp Psychiatry 2013;35:134–40. 23 Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology 2013;81:184–92. 24 Flood S, Foley FW, Zemon V, et al. Predictors of changes in suicidality in multiple sclerosis over time. Disabil Rehabil 2013. [Epub ahead of print] 25 Brønnum-Hansen H, Stenager E, Nylev Stenager E, et al. Suicide among Danes with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005;76:1457–9. 26 Pompili M, Forte A, Palermo M, et al. Suicide risk in multiple sclerosis: a systematic review of current literature. J Psychosom Res 2012;73:411–17. 27 Gaskill A, Foley FW, Kolzet J, et al. Suicidal thinking in multiple sclerosis. Disabil Rehabil 2011;33:1528–36. 28 Bourdette D. Depression is a treatable cause of suffering among multiple sclerosis patients and can result in suicide. Neurology 2002;59:E6–7. 29 Turner AP, Williams RM, Bowen JD, et al. Suicidal ideation in multiple sclerosis. Arch Phys Med Rehabil 2006;87:1073–8. 30 Wallin MT, Wilken JA, Turner AP, et al. Depression and multiple sclerosis: review of a lethal combination. J Rehabil Res Dev 2006;43:45–62. 31 Göksel Karatepe A, Kaya T, Günaydn R, et al. Quality of life in patients with multiple sclerosis: the impact of depression, fatigue, and disability. Int J Rehabil Res 2011;34:290–8. 32 Koch MW, Glazenborg A, Uyttenboogaart M, et al. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev 2011;(16):CD007295. 33 Moore P, Hirst C, Harding KE, et al. Multiple sclerosis relapses and depression. J Psychosom Res 2012;73:272–6. 34 Hanssen KT, Beiske AG, Landrø NI, et al. Predictors of executive complaints and executive deficits in multiple sclerosis. Acta Neurol Scand 2013. [Epub ahead of print] 35 Cantor F. Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis. PMR 2010;2:399–405. 36 Krupp L. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler 2006;12:367–8. 37 Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci 2002;205:51–8. 38 Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry 2005;76:469–75. 39 Téllez N, Río J, Tintoré M, et al. Fatigue in multiple sclerosis persists over time: a longitudinal study. J Neurol 2006;253:1466–70. 40 Johansson S, Ytterberg C, Hillert J, et al. A longitudinal study of variations in and predictors of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008;79:454–7. 41 Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep 2010;33:1061–7. 42 Gobbi C, Rocca M, Riccitelli G, et al. Influence of the topography of brain damage on depression and fatigue in


43

44

45

46

47

48

49

50

51

52

53 54

55

56

57

58

59

60

patients with multiple sclerosis. Mult Scler 2013. [Epub ahead of print] Engel C, Greim B, Zettl UK. Diagnostics of cognitive dysfunctions in multiple sclerosis. J Neurol 2007;254(Suppl 2):1130–4. Mattioli F, Bellomi F, Stampatori C, et al. Depression, disability and cognitive impairment in multiple sclerosis: a cross sectional Italian study. Neurol Sci 2011;32:825–32. Heesen C, Schulz KH, Fiehler J, et al. Correlates of cognitive dysfunction in multiple sclerosis. Brain Behav Immun 2010;24:1148–55. Sundgren M, Maurex L, Wahlin Å, et al. Cognitive impairment has a strong relation to nonsomatic symptoms of depression in relapsing-remitting multiple sclerosis. Arch Clin Neuropsychol 2013;28:144–55. Pöttgen J, Dziobek I, Reh S, et al. Impaired social cognition in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84:523–8. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. Eur J Neurol 2009;256:568–76. Bombardier CH, Blake KD, Ehde DM, et al. Alcohol and drug abuse among persons with multiple sclerosis. Mult Scler 2004;10:35–40. Kalichman SC, Amaral CM, White D, et al. Alcohol and adherence to antiretroviral medications: interactive toxicity beliefs among people living with HIV. J Assoc Nurses AIDS Care 2012;23:511–20. Fragoso YD, Frota ERC, Lopes JS, et al. Severe depression, suicide attempts, and ideation during the use of interferon beta by patients with multiple sclerosis. Clin Neuropharmacol 2010;33:312–16. Borras C, Rio J, Porcel J, et al. Emotional state of patients with relapsing–remitting MS treated with interferon beta-1b. Neurology 1999;52:1636–9. Parfenov V, Schluep M, Du Pasquier R. Assessing risks of multiple sclerosis therapies. J Neurol Sci 2013;332:59–65. Tsai SJ. Glatiramer acetate could be a potential antidepressant through its neuroprotective and anti-inflammatory effects. Med Hypotheses 2007;69:145–8. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–23. Svenningsson A, Falk E, Celius EG, et al. Natalizumab treatment reduces fatigue in multiple sclerosis. Results from the TYNERGY trial; a study in the real life setting. PLoS ONE 2013;8:e58643. Cohen JA, Barkhof F, Comi G, et al. TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362: 402–15. Kappos L, Radue EW, O’Connor P, et al. FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362: 387–401. Ziemssen T, Meergans M, Tracik F, et al. Results of the interim analysis of a non-interventional registry study to establish long-term safety and pharmacoeconomic data on fingolimod (Gilenya®) in multiple sclerosis patients (PANGAEA). Poster presented at 28th ECTRIMS. October 2012, Lyon, France. Ehde DM, Kraft GH, Chwastiak L, et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry 2008;30:40–8.

5

REVIEW 61 Schiffer RB, Wineman NM. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psych 1990;147:1493–7. 62 Scott TF, Nussbaum P, McConnell H, et al. Measurement of treatment response to sertraline in depressed multiple sclerosis patients using the Carroll scale. Neurol Res 1995;17:421–2. 63 Barak Y, Ur E, Achiron A. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J Neuropsychiatry Clin Neurosci 1999;11:271–3. 64 Barak Y, Achiron A, Shoshani D, et al. Fluoxetine treatment of depression in patients suffering from multiple sclerosis. Human Psychopharmacol 1998;13:66–7.

6

65 Solaro C, Bergamaschi R, Rezzani C, et al. Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin Neuropharmacol 2013;36:114–16. 66 Hart S, Fonareva I, Merluzzi N, et al. Treatment for depression and its relationship to improvement in quality of life and psychological well-being in multiple sclerosis patients. Qual Life Res 2005;14:695–703. 67 Firth N. Effectiveness of psychologically focused group interventions for Multiple Sclerosis: a review of the experimental literature. J Health Psychol 2013. [Epub ahead of print]
