Keywords

Introduction

Multiple sclerosis (MS) is a relatively common chronic disabling central nervous system disease affecting 1 in 1,000 people in western countries [1]. Patients with MS appear to have higher lifetime prevalence rates of psychiatric symptoms and disorders compared with the general population (Table 8.1) [2–13].

Table 8.1 Lifetime prevalence rates of psychiatric disorders in MS patients and the general population [2–13]
Full size table

Corticosteroids and beta interferon that are used to treat MS are also associated with an increased risk of neuropsychiatric side effects, from mood disorders to psychotic symptoms. Those side effects induce the need for patient education about psychiatric comorbidities and for regular psychiatric evaluation.

Psychiatric disorders in MS patients are associated with decreased adherence to treatment, impaired functional status, and quality of life. The reported rates of completed suicide in persons with MS are also high, and suicidality seems to be associated with psychiatric disorders [14].

This context highlights the importance of screening, diagnosing, and treating MS patients suffering from psychiatric comorbidities.

In this chapter, we will focus on the pharmacological treatments for each of the psychiatric conditions.

Drug Treatment of Depression in Multiple Sclerosis

Depression is the commonest psychiatric disorder in MS patients but remains underdiagnosed and undertreated. Major depressive disorder (MDD) in patients with MS does not relate directly to disability progression or to longer disease duration. The reported risk factors are female sex, age below 35 years, family history of major depression, and high stress levels. Multiple sclerosis patients also experience fatigue and cognitive dysfunction, both of which can worsen depression and be worsened by depression [14].

Despite the high prevalence of MDD in MS and although antidepressant (AD) use is common among patients with MS, the literature on the effectiveness of antidepressants in MS is limited.

Three double-blind controlled studies evaluated the impact of desipramine (a tricyclic antidepressant, TCA), sertraline, and paroxetine (two widely used selective serotonergic recapture inhibitors, SSRIs) in depressed MS patients [15–17]. Only the last one was placebo-controlled and the three samples were relatively small (n = 28, n = 22 and n = 42, respectively). The antidepressant effect was moderate for sertraline (effect size: d = 0.46, p = 0.047) (findings presented in Minden et al. [2]), inconsistent for desipramine (according to the depression scales that were used), and comparable to the placebo for paroxetine. Desipramine is associated with a high level of side effects (postural hypotension, dry mouth, and constipation) that patients are not always able to tolerate.

A few open-label trials using SSRIs (sertraline, fluvoxamine, and fluoxetine), serotonin norepinephrine reuptake inhibitors (SNRIs) (duloxetine), reversible inhibitors of monoamine oxidase A (RIMAs) (moclobemide), and mirtazapine were also published [18,19]. Those studies showed the effects on depressive symptoms, evaluated with specific depression scales, and demonstrated better tolerance of SSRIs compared to TCA among MS patients.

According to those studies, antidepressants seem to reduce depressive symptoms in MS patients and should be considered for treating MDD in this population. However in an evidence-based perspective, the available literature provides insufficient evidence to support or refute the efficacy and use of TCAs and SSRIs for depressive symptoms and MDD in MS patients [2]. In this specific population, the evaluation of the balance between efficacy and risks has to be very cautious.

In their guidelines for the management of patients with mood disorders and selected comorbid medical conditions [20], the Canadian Network for Mood and Anxiety Treatments (CANMAT) considered that the use of antidepressants in this population should be strongly considered (recommendation level 2). However, due to issues with fatigue, orthostatic hypotension, balance, cognitive issues, and bladder problems, antidepressants with significant sedating or anticholinergic side effects should be avoided (recommendation level 3).

Electroconvulsive therapy (ECT) is an option in the case of treatment-resistant depression. In depressed MS patients treated with ECT, the neurological status of those patients can deteriorate, raising the question of whether ECT is a risk factor for disease exacerbation [21].

Summary

  • Antidepressants are largely used in MS patients with depressive symptoms or MDD, nevertheless empirical data are lacking.

  • Selective serotonergic recapture inhibitors and SNRIs can be considered as a first-line option according to the efficacy/risk balance.

  • In treatment-resistant patients, ECT should be considered with caution related to the risk of neurological deterioration in the presence of active disease.

  • Antidepressants combined with cognitive behavioral therapy (CBT) is considered to be of interest to meet the particular needs of each individual patient whenever possible [22].

Drug Treatment of Bipolar Disorder in Multiple Sclerosis

In a study using standardized diagnostic tools and a case–control design, compared with controls, MS patients had a significantly higher lifetime prevalence of bipolar disorder type I (p = 0.005) and bipolar disorder type II (p < 0.0001) [23]. Because of this high prevalence, the CANMAT considered that people with MS should be monitored for hypomanic and manic symptoms while they are being treated with antidepressant medications (recommendation level 4) [20].

Despite the impact of this co-morbidity, no specific clinical trials of pharmacologic interventions for these patients can be found in the literature. A few anecdotal reports underline interest in the various strategies for the treatment of bipolar disorder including benzodiazepines [24], second-generation antipsychotics [25], or lithium [26].

For most of the patients, the choice of treatment must be based on the recommendations used in general psychiatry. For the treatment of acute mania, risperidone, aripiprazole (two second-generation antipsychotics), and valproate (an anticonvulsant) are considered as a grade 1 recommendation (Category A evidence and good risk–benefit ratio) [27]. Lithium (formerly considered to be a “gold standard”) is only a grade 2 recommendation. For the treatment of acute bipolar depression, quetiapine is the only drug considered to be a grade 1 recommendation [28]. Lithium, lamotrigine (an anticonvulsant), aripiprazole, and quetiapine are considered as a grade 1 recommendation for long-term treatment of bipolar disorder [29].

For Ameis and Feinstein [18], according to different case reports, anticonvulsants should be less effective on psychiatric symptoms in MS patients, compared with their usual efficacy. This has to be confirmed by specific studies.

In MS patients, the balance between efficacy and risk must be considered [18]:

  • Lithium is not always well tolerated: the increase of diuresis induced by this compound, coupled with bladder dysfunction observed in MS, can make the patient incontinent.

  • Second-generation antipsychotics are better tolerated than neuroleptics in terms of extrapyramidal side effects, but MS patients may be more sensitive to neurological side effects and must be regularly monitored.

  • Anticonvulsants may induce sedation, dizziness, headaches, ataxia, tremors, nausea, constipation, and weight gain that may increase the disability associated with MS.

One of the specificities of MS patients is that some of them develop mania or hypomania secondary to treatment with steroids/ACTH prescribed for exacerbations of neurological symptoms [30]. Patients with a previous history of depression or a family history of depression must be considered to be at risk. Clinicians must consider using reduced doses of steroids/ACTH or adding lithium prophylaxis when treating high-risk patients.

Summary

  • Multiple sclerosis patients are at high risk of developing bipolar disorder.

  • Lithium, anticonvulsants, and second-generation antipsychotics must be considered for the treatment of acute phases (mania and depression) and for long-term maintenance treatment of bipolar disorder in MS patients.

  • The specificity of the different side-effect profiles has to be taken into account.

  • The iatrogenic effect of steroids/ACTH on mood has to be considered, high-risk patients have to be identified, and a prophylactic use of a mood stabilizer has to be considered.

Drug Treatment of Anxiety in Multiple Sclerosis

Generalized anxiety disorder appears to be the most common anxiety disorder in MS patients with 18 % of patients meeting the criteria for this disorder and more than half of these patients not receiving any treatment [31]. Panic disorder and obsessive–compulsive disorder may also be much more common. The advent of injectable disease-modifying treatments for MS induces an increase in “self-injection anxiety.” If specific cognitive behavioral therapies have been developed for “self-injection anxiety,” no studies on the pharmacological approach of anxiety have been published.

The main pharmacological agents that can be used for anxiety disorders in the general population [32] must be considered in MS patients. Selective serotonergic recapture inhibitors, SNRIs, noradrenergic and specific serotonergic antidepressants (NaSSAs), TCAs, monoamine oxidase inhibitors (MAOIs), and RIMAs have demonstrated their efficacy in the treatment of anxiety disorders. Selective serotonergic recapture inhibitors and SNRIs are usually preferred as initial treatments, since they are generally safer and better tolerated. Benzodiazepines may be useful as adjunctive therapy, particularly for acute anxiety or agitation or while waiting for the onset of adequate efficacy of SSRIs. Due to concerns about possible dependency, sedation, and cognitive impairment, those compounds should be restricted to short-term use. Several anticonvulsants and atypical antipsychotics have demonstrated efficacy in some anxiety and related disorders, but are generally recommended as second-line, third-line, or adjunctive therapies.

The choice of medication should take into consideration the evidence for efficacy and safety/tolerability specifically in MS patients. Selective serotonergic recapture inhibitors and SNRIs may induce sexual dysfunction, drowsiness, and fatigue that can be particularly disabling for these patients.

Summary

  • Anxiety disorders are frequent in MS patients and have to be screened.

  • Selective serotonergic recapture inhibitors and SNRIs can be considered as the cornerstone of the pharmacological treatment of anxiety disorders.

  • The choice of the compound must rely on the efficacy and safety profile.

Drug Treatment of Psychosis in Multiple Sclerosis

The prevalence of psychotic disorders is higher in MS patients, with epidemiologic evidence of an association between MS and psychotic disorders in the general population [13].

There are only a few case reports describing the efficacy of neuroleptics or second-generation antipsychotics in the treatment of psychosis in MS [18]. Neuroleptics induced more neurological side effects and a higher risk for tardive dyskinesia in MS patients [33]. Consideration should be given to the fact that those patients may be more sensitive than general psychiatry patients to developing antipsychotic extrapyramidal symptoms or tardive dyskinesia.

Second-generation antipsychotics have a better risk–benefit balance with a specific interest of ziprasidone, risperidone, and aripiprazole [34]. They can be considered as a first-line treatment for MS patients with psychosis. There is no data suggesting that one second-generation antipsychotic is better than another. Clozapine is not a first-line treatment owing to the risk of agranulocytosis and the need for active blood monitoring.

Summary

  • Psychotic symptoms are more prevalent in MS patients compared with the general population.

  • Second-generation antipsychotics must be considered as a first-line treatment in MS patients with psychosis.

  • MS patients may be more sensitive to extrapyramidal side effects that have to be monitored.

General Considerations

Adherence to Treatment

Multiple sclerosis patients with psychiatric comorbidities are more likely not to adhere to disease-modifying drug treatment and psychotropic treatment [14]. This can have a dramatic effect in terms of outcome and quality of life. There is a need to optimize adherence to psychotropic treatment:

  • Clinicians must assess adherence at every consultation.

  • Psychoeducation programs focusing on treatment adherence have to be developed and implemented.

Needs for Future Research

Despite the high prevalence of psychiatric disorders in MS patients and their consequences, there is a real lack of evidences to define precise pharmacological strategies. Large, methodologically rigorous, randomized, placebo-controlled studies must be conducted in this population to evaluate pharmacologic therapies with strong evidence of efficacy and widespread use for treating emotional disorders in individuals with MS [2]. This may include systematic examinations of combinations of pharmacologic and non-pharmacologic therapies.

Conclusion

Multiple sclerosis is frequently associated with psychiatric comorbidities. The drug management of these disorders is a challenge for clinicians because they can have an impact on the prognosis of MS, the adherence to treatment, and the quality of life of patients. The first step in the management of all patients with MS is the need to systematically assess and screen psychiatric comorbidities (especially MDD, bipolar disorder, general anxiety disorder, and psychotic disorder). The second step (pharmacological strategies) will select and introduce a compound as a first-line option according to the safety profile of the patient. Due to lack of evidence, most of the recommendations are based on guidelines for the treatment of psychiatric disorders in the general population. Specific studies and consequently clinical practice guidelines for patients with MS and psychiatric comorbidities are needed.