Feb 5, 2014 - Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis. Yara Dadalti Fragoso,1 Tarso Adoni,2 Andrea ...
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
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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
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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
Fragoso YD, et al. Pract Neurol 2014;0:1–6. doi:10.1136/practneurol-2013-000735
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
Fragoso YD, et al. Pract Neurol 2014;0:1–6. doi:10.1136/practneurol-2013-000735
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.
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Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Katharine Harding, Cardiff, UK.
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