affective disorders in patients with multiple sclerosis

6
Affective Disorders in Patients with Multiple Sclerosis Pathophysiology and Approaches to Management Thomas F. Scott, 1 Carol Chieffe 2 and Tuna Burgut 1 1 Department of Neurology, Allegheny University Hospitals, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA 2 Allegheny Neurological Associates, Pittsburgh, Pennsylvania, USA Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 1. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432 2.1 Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 2.2 Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 2.3 Overlap Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 2.4 Euphoria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 4. Affective Disorders as a Symptom of Multiple Sclerosis Relapse . . . . . . . . . . . . . . . . . . . . 435 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 Abstract Affective disorders are commonly seen in the multiple sclerosis (MS) popu- lation. Symptoms of MS overlap heavily with symptoms of major depression; however, the diagnosis of major depression is sought using the same clinical criteria as in the general population. Treatment with pharmacological intervention appears to have a high rate of success, although controlled studies are lacking. Both tricyclic antidepressants and selective serotonin (5-hydroxytryptamine; 5- HT) reuptake inhibitors are commonly used in MS clinics and are generally well tolerated for treatment of major depression. Data concerning the efficacy of phar- macological intervention are limited yet compelling, and we consider antidepre- ssants an indispensable component of our drug armamentarium. Treatment of mania and bipolar disorder in the MS population is more problematic, primarily due to a paucity of literature on the subject. We have found both lithium and valproic acid (sodium valproate) to be effective and well tolerated in these pa- tients. Pharmacological treatment of more nonspecific types of mood instability in affected patients with MS appears to be reasonably effective as well, and in this situation we have successfully used both antidepressants and mood stabilis- ers. DISEASE MANAGEMENT CNS Drugs 1999 Dec; 12 (6): 431-436 1172-7047/99/0012-0431/$03.00/0 © Adis International Limited. All rights reserved.

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Page 1: Affective Disorders in Patients with Multiple Sclerosis

Affective Disorders in Patients withMultiple SclerosisPathophysiology and Approaches to Management

Thomas F. Scott,1 Carol Chieffe2 and Tuna Burgut1

1 Department of Neurology, Allegheny University Hospitals, Allegheny General Hospital,Pittsburgh, Pennsylvania, USA

2 Allegheny Neurological Associates, Pittsburgh, Pennsylvania, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4311. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4322. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

2.1 Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4332.2 Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4332.3 Overlap Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4332.4 Euphoria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4334. Affective Disorders as a Symptom of Multiple Sclerosis Relapse . . . . . . . . . . . . . . . . . . . . 4355. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Abstract Affective disorders are commonly seen in the multiple sclerosis (MS) popu-lation. Symptoms of MS overlap heavily with symptoms of major depression;however, the diagnosis of major depression is sought using the same clinicalcriteria as in the general population. Treatmentwith pharmacological interventionappears to have a high rate of success, although controlled studies are lacking.Both tricyclic antidepressants and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors are commonly used in MS clinics and are generally welltolerated for treatment of major depression. Data concerning the efficacy of phar-macological intervention are limited yet compelling, and we consider antidepre-ssants an indispensable component of our drug armamentarium. Treatment ofmania and bipolar disorder in the MS population is more problematic, primarilydue to a paucity of literature on the subject. We have found both lithium andvalproic acid (sodium valproate) to be effective and well tolerated in these pa-tients. Pharmacological treatment of more nonspecific types of mood instabilityin affected patients with MS appears to be reasonably effective as well, and inthis situation we have successfully used both antidepressants and mood stabilis-ers.

DISEASE MANAGEMENT CNS Drugs 1999 Dec; 12 (6): 431-4361172-7047/99/0012-0431/$03.00/0

© Adis International Limited. All rights reserved.

Page 2: Affective Disorders in Patients with Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory dis-order affecting the CNS and is believed to be trig-gered by an unknown aetiological agent, perhapsviral, in a genetically susceptible host. The chall-enge to physicians is to intervene in these dysimm-une processes to prevent disease progression and,equally importantly, to give symptomatic relief topatients experiencing the protean manifestations ofmultifocal CNS injury. From the earliest descriptionsof MS to the present, psychiatric manifestations ofthe disease have been considered paramount. Anti-depressants are among the most frequently usedpharmacological treatments recommended for pa-tients with MS.MS occurs in 0.1% of the population of the US

and is similarly common in Europe, with a femaleto male predominance at about 2 to 1.[1] The prev-alence of MS is somewhat less in other geographicareas, but this is essentially a worldwide disease.Patients with disabling multifocal or diffuse CNS

diseases, including MS, have a high rate of depres-sion. Disabling illnesses other than MS, which donot affect the CNS, are associated with a lower in-cidence of depression.[2] Lifetime incidence stud-ies examining depression in MS clinic populationsindicate approximately 50% of patients will deve-lop depression.[3,4] In a sample of 250 patients inour clinic, 17% received pharmacotherapy for thediagnosis of major depression over a follow-up pe-riod of 4 years.[5] Recurrence of major depressionafter discontinuation of pharmacotherapy is repor-ted to occur in 52% of patients within 2 years afterdiscontinuation.[5]

1. Pathophysiology

MS plaques commonly occur in frontal, tempo-ral and hypothalamic white matter and hence maydisrupt important limbic connections and cause de-pression. In some patients with MS, acutely evolv-ing depression may result from this interruption oflimbic connections. More slowly evolving affec-tive disorders may result from a neurochemical im-balance related to multiple chronic lesions. Multi-ple studies have documented a preponderance oflesions involving the limbic system in patients with

MS who also have affective disorders, as would beexpected. Honer et al.[6] found increased numbersof temporal lobe lesions in depressed patients withMS as compared with nondepressed patients withMS. Using a broader survey of psychological symp-toms in patients with MS, Reischies et al.[7,8] founda positive correlation with these symptoms and fron-tal lobe involvement. Similarly, we have found ‘hy-pofrontality’ on single photon emission computer-ised tomography imaging in a group of depressedpatients with MS (unpublished observations). Al-though total lesion load has not been correlated withdevelopment of depression in MS, total lesion load(as opposed to temporal and frontal lesion load) hasbeen correlatedwith cognitive dysfunction.[9,10] Cog-nitive dysfunction in MS has in turn been associ-ated with development of depression.[11]Although much evidence exists to support the-

ories of various mechanisms of dysimmunity in MS,the precise mechanisms of acute inflammation andchronic CNS injury in this disease remain to beelucidated. Efforts to link evidence of dysimmun-ity in depression with dysimmunity in MS can thusbe criticised as highly speculative. On a purely cli-nical basis, psychological stress and acute depres-sive states do not seem to induce MS relapses, yetdepression may certainly be a symptom of relap-se.[12]New knowledge of the relationship between de-

pression and MS may arise from the recent obser-vations that cytokine therapywith the β-interferonsmay induce depression in some patients.[13] The ex-tensive use of β-interferons in present practice, how-ever, argues against a strong relationship betweendepression and this therapy. Similarly, although cor-ticosteroid therapy may induce acute affective dis-orders, the majority of these disorders occur in othersettings.

2. Diagnosis

The diagnosis of affective disorders in the MSpopulation is usually made by neurologists or pri-mary care physicians through the process of a psy-chiatrically oriented interview, either formal or in-

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formal. A psychiatric review of symptoms shouldbe done at each patient visit.

2.1 Depression

An informal assessment of depressive symptomsmay be quickly obtained in a clinic setting usingself-administered instruments such as the CarrollScale.[14,15] The examiner may administer similar-ly brief yet accurate tests such as the Hamilton De-pression Rating Scale or the Beck Depression In-ventory to assess severity of illness.[16] Symptomsmay be sought as per criteria of DSM-IV.[17] Pa-tients who fulfil criteria for major depression aregood candidates for treatment. A history of relaps-ing major depression should also be sought and, ifpresent, many patients may be best treated withlifelong pharmacotherapy. Patients with depressedmood who do not fulfil diagnostic criteria for ma-jor depression may also be considered for treat-ment trials. Some of our patients do not meet DSM-IV criteria for depression yet complain of suicidalideation or report other symptoms indicating obvi-ous need for treatment.

2.2 Bipolar Disorder

Bipolar disorder, as defined diagnostically inDSM-IV, appears to be much less common thanmajor depression in the MS population. In our ex-perience patients rarely complain of classic cycles;however, rapid mood swings and cyclothymia arecommon.[5] Treatment of disabling mood swingsand irritability in the absence of a specific psychi-atric diagnosis such as major depression or bipolardisorder may improve the quality of life of manypatients. These complaints are very common amongpatients with MS and should be specifically sought.Although less common than patients with se-

vere mood swings of a more nonspecific nature,some patients will in fact meet criteria for the di-agnosis of bipolar disorder. In an epidemiologicalstudy performed by Schiffer et al.,[18] a greater thanexpected statistical association between bipolar af-fective disorder and MS was shown in an MS pop-ulation in Monroe County, New York, USA. Joffeet al.[19] reported an even higher rate of bipolar dis-

order after finding a 13% lifetime prevalence ratein a 100-patient group in an MS clinic in Toronto,Canada.

2.3 Overlap Symptoms

The high incidence of disabling fatigue in pa-tients with MS should not lull physicians intoignoring this symptom as a possible feature of de-pression. As in other patients with depression, treat-ment of depression may improve overall energylevels in patients with MS. Similarly, many othersymptoms occur with high frequency in both pa-tients with MS and depression, and it is often dif-ficult to discern the relative contributions of eachdisorder to symptomatology (inactivity, cognitivedysfunction, sexual dysfunction). Overlapping sy-mptoms ofMS andmajor depression are illustratedin figure 1.

2.4 Euphoria

Althoughmuch of the early literature[18] and somemore recent literature[18] has indicated an unexpec-ted occurrence of euphoria in many patients withMS, this seems to be a less emphasised and lesscommonly reported aspect of neuropsychiatric MSas concepts on this subject have become more re-fined.[18] Some patients do appear inappropriatelyjovial, with symptoms of disinhibition indicating‘frontal’ behaviour. Frontal lobe lesions or discon-nection of important inputs to the frontal lobe arewell known substrates of pathological apathy, andare proposed in some of our patients who seem toalternate between states of inappropriately eleva-ted mood and markedly disinterested states. In ourexperience, patients with euphoria tend to be mod-erately or severely cognitively impaired.

3. Treatment

Antidepressants are among the most commonlyused medications in MS clinics. The paucity of con-trolled studies of antidepressants in patients withMS may in some ways reflect the high degree ofconfidence physicians have in prescribing thesemed-ications. There seems to be little doubt that they are

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highly efficacious. In the only controlled trial re-ported in this regard, Schiffer andWineman[20] foundthat depressed patients with MS responded betterto desipramine than placebo. After 5 weeks of treat-ment 11 of 13 patients in the desipramine groupimproved significantly, whereas only 6 of 14 pa-tients in the placebo group improved. Both groupsreceived psychotherapy. Similarly, in a previouslypublished report, we found 48 of 51 patients res-ponded well to treatment with antidepressants (withand without psychotherapy).[5] Treatment-resistantillness occurred in 2 patients with chronic relapsingdepressive illness prior to their diagnosis of MS,and in a third patient with fulminant and progres-sive disease. Anecdotal reports and small open-labelstudies of sertraline and fluoxetine attest to the util-ity of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in patients withMS who have major depression.[14,21] We found sta-tistically significant improvement in patients’ scoreson the Carroll Scale for depression at 3 weeks and3 months after initiating treatment with sertraline,which was generally well tolerated.[14] Since flu-oxetine and sertraline were among the first avail-able SSRIs we started over 100 MS patients onthese two medications in the early 1990s. Most ofthese patients have done well and have either beenweaned off medication, remained on their originalSSRI or have relapsed while off treatment and re-turned to their original SSRI.

The lower incidence of adverse effects seenwiththe SSRIs as compared with tricyclic antidepres-sants (TCAs) makes these agents the first-line ther-apy for major depression in MS.[5] Our experiencewith fluoxetine and sertraline indicate that theseSSRIs are particularly well tolerated. TCAs maybe substituted as first-line treatment in patients withpainful nocturnal paresthesias or urinary frequen-cy, given their positive effects on these symptoms.Contrary to our overall experience, there are some

indications in the available literature suggesting thatpatients with MS may have increased sensitivity toadverse effects fromantidepressants.[20] PatientswithMS, especially those with advanced disease, shouldbe treated gingerly, with initially low doses ofmed-ication. It may also be possible that lower doses ofantidepressants are needed to achieve therapeuticeffect.[5] Dosage ranges and adverse effects repor-ted among 51 consecutive patients treated in ourMS clinic for depression are listed in table I. In thisgroup only 3 of 44 SSRI-treated patients (7%) hadto discontinue SSRIs because of adverse effects.Only 1 patient was unable to tolerate either SSRIsor TCAs. Two of 13 patients were unable to toleratethe adverse effects of TCAs. In an attempt to min-imise adverse effects andmaximise response, someof our patients have been treated with combinationtherapy including SSRIs and TCAs. Combinationtherapy has also involved mood stabilisers [carba-mazepine, valproic acid (sodium valproate) and lith-ium] for patients with unipolar relapsing depressionor patients with irritability. We have found psych-otic depression to be rare in our clinic, and thesepatients are treated in conjunction with psychiatricconsultation, sometimes ultimately involving a com-bination therapy using antipsychotics and antide-pressants.We found a high rate of relapse of depression

among patients who discontinued their antidepres-sants. In our study 14 of 27 patients (52%) relap-sed, generally within the first year after discontin-uation.[5] This relapse rate approximates that of otherpatients with major depression. We have found thatrelapse or onset of depression often occurs in thesetting of exacerbation of motor and sensory symp-

Fatigue Cognitivedecline

Majordepression

Mooddyscontrol

Fig. 1. Overlap between symptoms of multiple sclerosis andmajor depression.

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toms of MS. Patients may require adjustments to-wards higher doses of antidepressants over suchperiods of exacerbating motor and sensory symp-toms.No large patient series is available regarding treat-

ment outcomes in patients who have both MS andbipolar disease. In a series of 7 patients, Hutchin-son et al.[22] found it necessary to use antipsychoticsin most patients to control mania. Some patientswere then stabilised on lithium for prophylactic the-rapy. Other anecdotal reports also describe the con-trol of mania with antipsychotics, and subsequentprophylactic therapy with lithium, carbamazepineor valproic acid.[23-25] Brief manic episodes mayoccur in the setting of corticosteroid therapy andmay be treated similarly.[26]Even fewer reports are available concerning the

utility of nonpharmacological intervention in pa-tients with MS with affective disorders. Counsel-ling and behavioural therapy undoubtedly have apositive impact on patients with depression in ourclinics, but this has not been examined systemati-cally. There was some suggestion in the previouslymentioned study by Schiffer and Wineman[20] thatpsychotherapy was effective, though inferior to psy-chotherapy plus medication.Another nonpharmacological intervention, elec-

troconvulsive therapy (ECT), was recommendedand given to one of our patients, but had to be aban-doned because of post-ECT apnoea.[27] One otherpatient in our clinic has been maintained on a long

term basis with ECT and combination pharmaco-therapy to control severe relapsing depression. ECTwas successfully given to a patient reported by Co-ffey et al.,[28] who also reviewed 11 other anecdotalcases.

4. Affective Disorders as a Symptom ofMultiple Sclerosis Relapse

The appearance or recurrence of psychiatric sy-mptoms as a manifestation of MS exacerbation (i.e.new inflammatory lesions) has been anecdotallyreported but not systematically studied. We repor-ted a seemingly random occurrence of psychiatricsymptoms in relation to periods of exacerbation ina large patient group in our clinic, but such studieswould ideally be performed in conjunction withfrequent magnetic resonance imaging (MRI) scan-ning to detect otherwise silent limbic lesions.[5]Wehave encountered 1 patient with a fairly suddenonset of severe depression which was initially re-fractory to medication, in whom MRI scanning re-vealed a large enhancing (acute) frontal lobe le-sion. This patient responded well to combinationtherapy with high-dose corticosteroids and antide-pressants. Kwentus et al.[29] reported a similar casein which spinal fluid evidence of disease activityparalleled manic behaviour. These cases suggestthat in some patients, perhaps those with severerefractory psychiatric symptoms, repeat MRI scan-ning is indicated before consideration of cortico-steroid therapy.

Table I. Commonly used medications, dosages and adverse effects for patients with a history of antidepressant use for depression in theAllegheny Multiple Sclerosis Treatment Center, Pittsburgh, Pennsylvania, US

Medications Daily dose ranges (mg) Adverse effects reported

Selective serotonin reuptake inhibitors Altered mental status, nausea, insomnia,palpitations, anorgasmia, decreased libido,drowsiness, euphoria, malaise

Sertraline 50-150

Fluoxetine 20-40

Paroxetine 10-30

Tricyclic antidepressants Drowsiness, dry mouth, malaise, urinary retention,constipationNortriptyline 25-150

Amitriptyline 25-75

Imipramine 25-100

Desipramine 25-75

Doxepin 25-100

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Adverse effects of corticosteroid therapy, parti-cularly mania but also psychosis, are fairly commonin the MS population. It is difficult to distinguishadverse effects of corticosteroids from psychiatricmanifestations of new and old demyelinating le-sions. In patients who are considered to be poorcandidates for corticosteroid discontinuation, con-comitant treatment with mood stabilisers is sug-gested.

5. Conclusion

Although we have presented an outline of howaffective disorders have been managed in our MSclinic, our methods have yet to be formalised. Dif-ferent approaches to screening and treatment of thesedisorders should be considered, and compared in aprospective fashion. The impact of psychotherapyand behavioural approaches to treatment in this pop-ulation is particularly understudied. Comparativetrials of different pharmacological interventions arealso lacking.

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Correspondence and reprints: Dr Thomas F. Scott, Suite 206,East Wing, 420 East North Avenue, Pittsburgh, PA 15212,USA.E-mail: [email protected]

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