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1. Bipolar disorder and resembling special psychopathological manifestations in multiple sclerosis: a review Apostolos Iacovides and Elias Andreoulakis 3rd Department of Psychiatry, Aristotle University of Purpose of review Thessaloniki, AHEPA General Hospital, Thessaloniki, Greece The higher prevalence of psychiatric disorders in multiple sclerosis (MS) compared with the general population is well documented, with depression being the leading disorder. Correspondence to Apostolos Iacovides, PhD, MD, Professor Psychiatry, Director of 3rd Department of Apart from depression, other psychiatric disorders and symptoms such as bipolar Psychiatry, Aristotle University of Thessaloniki, AHEPA disorder, pseudobulbar affect, euphoria sclerotica, anxiety and personality changes are General Hospital, 1, St Kyriakidi Str, Thessaloniki 54636, Greece also reported to be overpresented in MS patients. Psychiatric disorders in MS lead to Tel: +30 231 0994 626; fax: +30 231 0994 623; signiﬁcant disruption in patients’ family, work and social life, affecting patients’ quality of e-mail: email@example.com life in general. Moreover, they are reported to be associated with poorer adherence to Current Opinion in Psychiatry 2011, 24:336–340 MS medication. The literature concerning bipolar disorder and affect disorders in MS is rather scarce. The purpose of this article is to provide a critical review on the latter subject. Recent ﬁndings This review focuses upon the recent ﬁndings with regard to the epidemiology and the comorbidity rates of bipolar and affect disorders in MS, questions raised about the potential underlying mechanisms that could explain such a high comorbidity, diagnostic issues and the recent developments in the treatment of those psychiatric disorders in MS. Summary Despite the fact that the higher prevalence of psychiatric disorders in MS is well established, such disorders still remain underdiagnosed and undertreated. A shift in the clinical suspicion towards the psychiatric morbidity in MS patients and the optimal treatment of those disorders is fundamental. Keywords affect, bipolar, euphoria, mood, multiple sclerosis, pathological laughing and crying, pseudobulbar affect Curr Opin Psychiatry 24:336–340 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 0951-7367 The neuropsychiatric manifestations in MS fall into two Introduction broad categories: disorders of mood, affect and behavior The occurrence of psychopathological symptoms and on the one hand, and cognitive impairment on the signs in multiple sclerosis (MS) was underlined and other, with considerable overlapping between these systematically described as early as in 1877 by Charcot. two categories. As far as mood and affect disorders The psychopathological symptoms mentioned included are concerned, they are mainly represented by major pathological laughing and weeping (also variably termed depression, bipolar disorder, euphoria and PBA. nowadays ‘pseudobulbar affect’ (PBA), ‘emotional incontinence’, or – most recently – ‘involuntary The main body of the literature focuses on the comorbid emotional expression disorder’), euphoria, mania, depres- depression found in MS, whereas the bibliography sion and hallucinations. concerning bipolar disorder, euphoria sclerotica and PBA remains rather scarce. This disproportion obviously Psychiatric symptoms are regarded as occurring more reﬂects the fact that depression is the most frequent commonly during the evolution of MS. Although among psychiatric disorders seen in MS, with a lifetime there are a few case studies reporting such symptoms prevalence reaching 50% and a 12-month prevalence of as the initial manifestations of MS, this phenomenon is 15.7%, the latter being twice as high as in the general thought to be rather uncommon. According to Fermo population (odds ratio: 2.3) . et al. , the frequency of psychiatric symptoms among the presenting manifestations of MS ranges from 0.2 The purpose of this article is to provide a critical review of to 2%. the recent ﬁndings with regard to the relationship of MS 0951-7367 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/YCO.0b013e328347341dCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Bipolar disorder in multiple sclerosis Iacovides and Andreoulakis 337with mood and affect disorders beyond depression, Key pointsthat is, bipolar disorder, euphoria sclerotica and PBAin the ﬁelds of epidemiology, comorbidity, diagnosis, Bipolar disorder and special emotional psycho- pathological symptoms in multiple sclerosis.pathophysiology and treatment. Diagnostic features, prevalence, etiopathological factors. Comorbidity.Bipolar disorder Treatment.The lifetime prevalence of bipolar disorder in the generalpopulation is often estimated to be around 1%. However,Perala et al.  in a recent population study reported found to be reversed when chronic corticosteroida 0.24% life-prevalence, 0.31% for men and 0.18% therapy is concerned, with depression being the leadingfor women, with a difference in sexes which was not mood disorder. These drug-induced hypomanic or manicstatistically signiﬁcant. Moreover, the lifetime prevalence symptoms are dose dependent, often occur during theof bipolar disorder showed no signiﬁcant difference ﬁrst few weeks of the therapy and are reversible withamong age groups, being 0.22, 0.36, 0.23, 0.14% in dose reduction or treatment discontinuation. A preven-age groups of 30–44, 45–54, 55–64 and over 65 years, tive beneﬁt of lithium and phenytoin against the steroid-respectively. With regard to the prevalence and induced mood disturbances has been reported. However,comorbidity rates of bipolar disorder in MS in particular, Jefferies  points out the lack of sufﬁcient clinical trialsthey have been reported to range from 0.3 to 32% [4–7]. investigating the effective treatment of manic episodesThe great variability in the sample sizes, the prospective in MS patients in particular.or retrospective planning and the evaluation methodsused in each study could account for such a diversity Concerning neuroimaging ﬁndings, corticosteroid usein the reported rates. However, the particularly high rates has been associated with changes in the temporal lobereported in earlier studies are no longer supported in .recent population studies and have declined to 0.3–2.4%[8,9]. Most recently, Marrie et al.  in a large population Interferon (INF) has been another medication implicatedstudy (8983 patients with MS) reported a prevalence rate in side effects concerning mood. Depression is regardedof 2.4% for bipolar disorder in MS . Conclusively, bipolar as a potential side effect of the use of INF (particularlydisorder seems to be two to three times more frequent in INF-a, but also INF-b), especially, though not necess-MS than in the general population. arily, in patients with a previous history of depression. The mechanism of the action of INF-b in inducingThe relationship of bipolar disorder and MS, though depression has not been thoroughly investigated yet.well established, remains complex. The cause of such Fragoso et al.  reported 11 cases of severe depressiona high comorbidity is regarded as being multifactorial. It with suicidal ideation in patients under INF-b therapy.is attributed to a variety of factors, such as the medication In some of the cases, depression was accompanied byused in MS, the demyelination brain lesions, genetics, psychotic or manic behavior, leading them to suggestor, ﬁnally, the psychological reactions and adjustment that there might be a psychiatric syndrome associateddifﬁculties – associated with premorbid personality with INF-b therapy that goes beyond depression.vulnerabilities – to the chronic, severe and progressivecharacter of the disease (the latter particularly concerning With regard to the investigation of a potential causalthe appearance of depression in MS). association between demyelinating lesions due to MS and the appearance of bipolar disorder, there areAmong medication used in MS implicated in inducing some studies that investigated the morphological ﬁndingshypomanic or manic episodes are the corticosteroids, in MRI patients who exhibited bipolar disorder orbaclofen, dantrolene, tizanidine and illicit drugs . similar symptoms. Plaques in bilateral temporal hornHowever, the medication side effects alone cannot fully areas  and ubiquitous white matter changes account for the higher comorbidity between mania or were reported. According to Fazzito et al. , thehypomania and MS. psychiatric disorders shown in MS patients are thought to be secondary to temporal lobe demyelinatingAs far as the corticosteroids are concerned, mood disturb- lesions, though the physiopathology still remains notances are reported to be the most common psychiatric fully known.side effects associated with them. Brown , in the mostrecent study on the subject, stated that hypomania and Concerning two newer medications applied in MS,mania have been reported as the most common mood mitoxantrone and natalizumab, there is not sufﬁcientchanges during acute corticosteroid therapy, whereas evidence regarding their potential psychiatric side effectsdepression comes in second place. This relation has been to date.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
338 Medical comorbidity Another hypothesis stated is that of a genetic relationship between MS and bipolar disorder – reﬂecting a potential Pseudobulbar affect common genetic susceptibility – based on ﬁndings from This terminology points out the importance of bulbar familial bipolar disorder and MS studies, in which high nuclei in the brain stem thought to be implicated in similarity concerning the human leukocyte antigen controlling emotional expression, whereas the alternative (HLA) system genes, particularly of class II (DR, DQ), terms used – mentioned in the introduction section – was found [16–18]. mainly focus on the phenomenology of this entity. PBA is an affective disinhibition syndrome, a condition in which Finally, concerning the treatment of bipolar disorder in mood (emotional experience) and affect (emotional MS, bipolar disorder is usually treated with lithium or expression) are not in concordance. It is characterized anticonvulsants . However, no sufﬁcient data are by spontaneous, involuntary and uncontrollable outbursts available regarding the effect of mood stabilizers such of contextually inappropriate crying or laughing that as carvamazepine or valproic acid, because there are no are inconsistent with the patient’s underlying mood, controlled trials of their use in treating manic symptoms disproportionate or incongruent to the patient’s in MS in particular. underlying feelings or to external triggers. Uncontrollable crying seems to be more common than laughing. Never- Apart from bipolar depression, individual symptoms theless, the patient’s insight is spared. This emotional of euphoria and PBA have also been reported in MS incontinence is perceived as ego-dystonic by the patient, patients. causes signiﬁcant social embarrassment and urges the patient to voluntarily control it, though inadequately. What makes it superﬁcially similar to bipolar disorder Euphoria is that such an emotional lability (though the latter Euphoria can be deﬁned as ‘a ﬁxed state of well being, tends to be regarded as a distinct entity) could be despite the presence of considerable physical morbidity’. misinterpreted as being a manifestation of a mixed mood This deﬁnition points out the lack of insight regarding episode or even a rapid-cycling bipolar disorder. the severity of the illness, which results in an elevated However, what mainly distinguishes the two entities is affect and an overoptimistic attitude. Compared with the disassociation of the affect and the underlying mood, hypomania or mania, euphoria looks similar concerning resulting in emotional expression incongruent or dispro- the presence of elevated affect but is distinguished by the portionate to the underlying emotional experience or to lack of hyperactivity, pressured speech, racing thoughts, the external stimuli, the shorter duration of such episodes grandiosity ideas and so on. compared with a more sustained underlying emotional state in mood episodes and, ﬁnally, the fact that such an There are no studies investigating the prevalence rate of outburst is ego-dystonic and causes signiﬁcant distress to this entity in the general population. The estimates of the patient, who feels unable to control it. Moreover, PBA euphoria’s prevalence in MS are declining throughout can also be distinguished from a bipolar disorder mood time. Initially, in the 1920s, euphoria had been episode by the lack of speciﬁc symptoms and signs such overestimated – reported to be found in over two-thirds as hyperactivity, poor sleep, pressured speech and so on. of MS patients and regarded as the speciﬁc psychopatho- However, although distinct entities, PBA and a mood logical trait of MS. In 1990, Rabins  summarized the disorder – particularly depression – could also coexist, at mean prevalence rate of euphoria in MS to 25% among a rate as high as 50% . the studies they investigated. Later on, Diaz-Olavarieta et al.  reported that euphoria was present in 13% of There are no studies concerning the prevalence rate of 44 MS patients studied compared with 0% of 25 control PBA in the general population. PBA is not exclusively individuals . found in MS but can also be found in other neurological disorders such as amyotrophic lateral sclerosis, the Regarding the stage of the illness, euphoria seems to cerebellar type of multiple system atrophy, cerebro- occur in the later stages of MS . It is reported to be vascular disease, Parkinson’s disease, traumatic brain associated with signiﬁcant cognitive impairment, heavy injury, dementia, migraine, progressive supranuclear total load of brain demyelinating lesions, especially in the palsy and mass lesions, particularly in the cerebellopon- frontal lobe, signiﬁcant cerebral atrophy and ventricular tine junction . Haussleiter et al.  summarized enlargement [20,22] and reduced global gray matter PBA prevalence rate in MS to a mean of 10%. However, volume . most recently, Strowd et al.  reported a prevalence rate ranging from 7 to 52% and a mean occurrence of one Euphoria mainly remains untreated, as it does not such episode every 2 days (3.6 days per week) . PBA cause any distress to patients that would make them in MS is generally regarded to occur in the chronic– seek help. progressive type of MS and seems to be associated withCopyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
Bipolar disorder in multiple sclerosis Iacovides and Andreoulakis 339severe disability, cognitive impairment and longer depression, suggests that PBA and depression are distinctdisease duration, whereas no correlation has been found entities, although they often co-occur in MS patients .with MS relapses . Treatment with anticonvulsants such as lamotrigine has also been reported . A novel treatment [dextro-Concerning the pathophysiology of PBA, a three- methorphan–quinidine (DMQ)] with a combinationstructured model was originally proposed: the cortex of dextromethorphan (DM), a s-1 receptor agonist inhi-being the controller, the bulbar nuclei as the physiologi- biting glutaminergic signaling and quinidine (Q), usedcal effector and the hypothalamus in an integrating role as a CYP2D6 inhibitor in order to increase plasma levels. The role of the prefrontal cortex in PBA pathophy- of dextromethorphan, which is vulnerable to extensivesiology has been pointed out, based on the poorer metabolism by CYP2D6, has also been pointed out asperformance of the MS patients group in speciﬁc tasks beneﬁcial recently . According to Wortzel et al. ,which are regarded as being mediated by this region and the SSRIs are the recommended ﬁrst-line pharma-the fact that this region is regarded as taking part in cotherapy for PBA. When SSRIs turn out to be not wellkeeping emotional expression compatible with social tolerated or ineffective, alternative treatments such ascontexts . Findings concerning not only the interrup- those mentioned above should be considered. However,tion of cortical inhibition of postulated laughing and Strowd et al. , based on the lack of large well con-crying centers in the upper brainstem but also the trolled clinical trials concerning the treatment of PBA,dysfunction resulting from lesions in the cerebro- posed the issue that antidepressants might be helpfulponto-cerebellar pathways, which are thought to be in treating coexisting depression, but not sufﬁcient ininvolved in appropriate adjustment to social and treating PBA, raising implications for a better tailoredcognitive context, provided a further link of PBA to pharmacological treatment of PBA.the cerebellum . Moreover, the case of a 46-year-old woman, suffering from idiopathic Parkinson’s disease,who exhibited pseudobulbar crying induced by stimu- Conclusionlation in the region of the subthalamic nucleus was Despite the fact that the coexistence of psychopatho-reported . Recent studies implicate widely dispersed logical symptoms in MS is well established, most oflesions including bilateral medial inferior frontal, bilateral the affected patients are still underdiagnosed and under-inferior parietal and brainstem regions and also basal treated. A shift concerning the clinical suspicion andganglia [33,34]. Summarizing, Parvizi et al.  in the the treatment of psychiatric disorders in MS seemsmost recent and thorough review on the subject con- fundamental, as they can have a considerable impactcluded that basis pontis is the only identiﬁed anatomical on the patients’ quality of life and also on the MSsite in which a discrete lesion can cause PBA. Other treatment adherence.anatomical sites also implicated in the pathophysiology ofPBA are the prefrontal cortex and anterior cingulate, the In the reverse direction, because psychopathologicalinternal capsula, the thalamus and subthalamic nucleus, symptoms and signs might represent, though not verythe cerebral peduncles and the cerebellum . often, the ﬁrst clinical manifestations of MS – even in the absence of neurological clinical ﬁndings, or in the pre-Regarding the neurochemistry of PBA, neurotransmitters sence of ‘mild’ ones – MS should be also be consideredsuch as serotonin, dopamine, noradrenaline and gluta- in the differential diagnosis in some people presentingmate appear to be implicated in the pathophysiology of with such symptoms as euphoria, pseudobulbar affect orPBA. However, although the role of serotonergic systems even a manic episode with atypical features, cognitiveseems better established, the role of nonserotonergic impairment, peripheral physical ﬁndings or a lack ofsystems still remains speculative . response to the standard bipolar disorder treatment.Regarding the treatment of PBA, several types of Acknowledgementspsychotropic drugs have been applied. Amantadine and The authors have no conﬂicts of interest to declare.levodopa , tricyclic antidepressants (TCAs) such asamitriptyline  and nortriptyline , selective sero-tonin reuptake inhibitors (SSRIs) such as ﬂuoxetine , References and recommended readingcitalopram  and sertraline , serotonin–norepi- Papers of particular interest, published within the annual period of review, have been highlighted as:nephrine reuptake inhibitors (SNRIs) such as duloxetine of special interest, venlafaxine  and revoxetine  and other of outstanding interest Additional references related to this topic can also be found in the Currentantidepressants such as mirtazapine . The response World Literature section in this issue (p. 363).to the treatment with antidepressants has been reported 1 Fermo SL, Barone R, Patti F, et al. Outcome of psychiatric symptomsto be quite rapid, within a few (often 1–3) days. Such presenting at onset of multiple sclerosis: a retrospective study. Mult Sclera difference in the response rate, compared with 2010; 16:742–748.Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
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