Symptoms that should be taken seriously

Psychiatric comorbidity in multiple sclerosis is common, with significant impact on quality of life. This should result in consequences for counseling and treatment. Interdisciplinary collaboration is required.

Comorbidity is the presence of an additional disease in a patient with a particular index disease. Multiple sclerosis is one of the most common neurological disorders of early and middle adulthood. The early onset of the disease and the long duration of illness often lead to work restrictions and incapacity at a young age and can result in psychosocial and economic burdens. These in turn, along with etiologic factors and iatrogenic influences, cause many patients to develop comorbidities over the course of their lives. Concomitant psychiatric disorders (especially unipolar and bipolar affective disorders, but also anxiety disorders and psychosis) represent the most common comorbidity in patients with multiple sclerosis and are found in up to 60% of patients [1].

The various psychiatric comorbidities of multiple sclerosis are the result of multiple interactions of endogenous (genetic), therapeutic, and external factors. Numerous other biological factors such as brain organic disorders, structural brain lesions, drug influences, effects of relapse events and stress on mood and behavior, neurochemical and neuroendocrine factors, and psychoreactive and psychosocial moments condition the psychiatric comorbidity of patients with multiple sclerosis [2]. While psychiatric comorbidities can be difficult to diagnose, they are usually readily amenable to therapy. Adequately implemented therapy for comorbid psychiatric disorders can at least indirectly alleviate some of the burden of illness and thereby contribute to an increase in functional level and quality of life.

Depression and multiple sclerosis

Depressive disorder is among the most common psychiatric comorbidities of multiple sclerosis, with a 1-year prevalence rate of approximately 15% in patients older than 18 years and up to 25% in patients aged 18 to 45 years. Compared to the general population, the risk of developing depression is about five times greater in people with MS. The estimated average lifetime prevalence is approximately 30-50% [3]. Despite these high prevalence rates and the strong impact of depressive symptomatology on the quality of life of MS patients, depressive disorders are underdiagnosed and undertreated in MS patients. The reasons for this are, on the one hand, that depression in MS patients often occurs in a rather subtle way and can thus easily be overlooked. On the other hand, symptoms such as fatigue, sleep disturbances, psychomotor slowing, memory or concentration disorders can also occur in other disorders.

Suicide risk is increased approximately 7.5-fold in patients with MS compared with the general population and is higher than in other neurological or chronic conditions [4]. Additional risk factors for suicide include male sex, young age at onset, first five years after diagnosis, current or previous depressive episodes, self-injurious behavior, social isolation, substance abuse, or recent deterioration in functioning. The relationship between MS and depressive disorders, including the influence of disease activity, severity, and duration of MS disease, is complex and much remains unexplained. Depression could be a consequence of the neuropathologic process of MS, a response to the psychosocial stress associated with an MS diagnosis, or both. A genetic predisposition to depressive disorders in people with MS seems unlikely given the lack of evidence for increased rates of depression in first-degree relatives of depressed patients with MS [5]. Etiologic factors associated with comorbid depression include disturbances in endocrine control of hypothalamic-pituitary-adrenocortical axis function, effects of disease-modifying drugs, and regional brain changes (in frontal and temporal lobes and limbic system).

Regarding therapy of comorbid depressive disorder in MS patients, selective serotonin reuptake inhibitors (SSRIs) and antidepressants with combined serotonergic and noradrenergic properties have proven to be the agents of choice in the clinical setting [6,7]. However, randomized-controlled trials investigating pharmacotherapeutic treatment options for depression in MS are scarce. Other pharmacotherapeutic options include, for example, low-dose tricyclic antidepressants (e.g., desipramine) [8], whereas lithium is used particularly for refractory depression. Finally, psychotherapeutic measures such as cognitive-behavioral therapy should also be considered [9]. This is especially true for primary psychoreactive depression, which is relatively common in the context of coping, adjustment, and self-esteem regulation disorders. Accordingly, patients with active coping strategies and stable psychosocial support are less likely to suffer from depression [10]. Finally, drugs for the treatment of fatigue with potential mood elevating effects such as amantadine and ^Modasomil® should also be considered [11,12].

Anxiety disorders and MS

Uncertainty about the course of the disease may promote the development of anxiety. The lifetime prevalence of anxiety disorders in people with MS is generally estimated at 36%, with generalized anxiety disorder (F41.1), panic disorder (F41.0), obsessive-compulsive disorder (F42), and social anxiety disorder (F40.10), in particular, being among the most common. Newly diagnosed MS, increasing disease activity, perception of pain, fatigue, or sleep disturbances are risk factors for the development of anxiety disorders in MS. Female gender, social isolation, prior suicidal ideation, a past or present diagnosis of a depressive episode, and alcohol/psychoactive substance abuse were also identified as risk factors [13].

The most important substances for drug therapy of anxiety disorders in MS patients are antidepressants such as selective serotonin reuptake inhibitors. Venlafaxine, pregabalin, gabapentin, and beta-blockers may be considered as additional treatment options for refractory cases. Benzodiazepines should be saved for the treatment of acute and severe anxiety disorders, given their sedative properties, cognitive side effects, and dependence potential [14]. Non-pharmacological treatment approaches include stress management programs and cognitive behavioral therapy [15].

Bipolar affective disorders and MS

The 1-year prevalence of bipolar affective disorder in MS is reported to be 0.99% for bipolar I and 7.5% for bipolar II disorders in a case-control study [16]. Bipolar I disorder is characterized by manic episodes, which may be preceded or followed by depressive episodes, and by intervening stable phases. Characteristics of a manic episode include hyperactivity, increased speech, decreased need for sleep, unrestrained behavior, or exaggerated self-evaluation [17]. Bipolar II disorders are characterized by hypomanic episodes that result in less pronounced social and occupational functioning impairments. Unlike depression, a shared genetic vulnerability (MS and bipolar affective disorder) is likely based on reports of familial clustering of both disorders. Furthermore, an association of the two syndromes due to local MS-related brain lesions is also discussed, although no definite statements can be made in this regard in view of the currently thin data situation [18,19]. Psychological adjustment processes in combination with certain personality traits and coping mechanisms are discussed as further etiological factors. In addition, manias induced by steroids and other drugs have also been described in patients with MS.

In the treatment of bipolar disorder, the primary goal is to reduce the severity and frequency of the episodes of illness, and a combined approach of medication and psychotherapy has proven effective. To date, no separate management strategies exist for the treatment of affective disorders in MS, so equally as in other patients without an additional MS diagnosis, lithium is among the most important mood stabilizers.

Psychosis and MS

Psychotic symptoms can be expected to occur in about 2-4% of people with MS – a rate about three times higher than in the general population [20]. MS-associated changes in periventricular white matter and temporal and frontotemporal areas have been hypothesized in the genesis of psychotic symptoms [20], although recent imaging or neuropathology studies are lacking.

Treatment of psychotic MS patients, similar to patients without MS, is primarily with neuroleptics, although caution should be exercised in the choice of psychotropic agent due to the potential for side effects (especially extrapyramidal symptoms).

Pseudobulbar affect and euphoria

About 10% of all MS patients suffer from pseudobulbar affect disorder (PBA for short). This is understood as pathological, i.e. inappropriate to the respective situation and uncontrollable laughter and crying. Despite its high prevalence, PBA often remains misdiagnosed or underdiagnosed. Although the exact etiology of this condition remains unknown to date, PBA is thought to result from a disconnection of brain structures and/or a disruption of neurotransmitter systems involved in emotion regulation. Differential diagnosis should exclude depressive disorder or other psychiatric disorders [2].

An exaggerated sense of well-being, cheerfulness, confidence, often associated with an excessive feeling of vitality – euphoria for short – is an established phenomenon in MS with prevalence rates up to 25%. The occurrence of euphoria has been associated with disease progression and the extent of neuropathological lesions, particularly in the frontal lobe, although recent imaging studies are also lacking [2].

Take-Home Messages

Neuropsychiatric signs and symptoms are common in multiple sclerosis and appear both before neurological diagnosis and, far more often, during disease progression.
The genesis of psychiatric comorbidity in multiple sclerosis is diverse.
Psychiatric comorbidity has immediate clinical consequences for patient counseling and treatment and exerts a significant impact on their quality of life.
Ideally, diagnosis and treatment are carried out by close interdisciplinary collaboration of neurologists and psychiatrists and, if necessary, neuropsychologists.
In everyday clinical practice, psychiatric disorders in patients with MS are often given too little attention and, above all, are far too rarely treated consistently.

Acknowledgements: Prof. Dr. phil. P. Brugger and PD Dr. med. C. Müller-Pfeiffer for their careful review of the article.

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