i1523-5998-9-3-214

TM

PRETEST AND OBJECTIVES

Prim Care Companion J Clin Psychiatry 2007;9(3) 173

Articles are selected for credit designation on the basis of the CMEInstitutes assessment of the needs of readers of The Primary CareCompanion, with the purpose of providing readers with a curriculumof CME articles on a variety of topics throughout each volume.There are no prerequisites for participation in this CME activity.To obtain credit, please study the designated article and completethe Posttest and Registration Form.

CME Objective

After studying the ACADEMIC HIGHLIGHTS, you should be able to: Evaluate patients for the presence of subthreshold depressive

symptoms and modify treatment strategies to resolve them.

Target Audience

The target audience for this activity is psychiatrists and otherhealth professionals.

Accreditation Statement

This activity has been planned and implemented in accordance withthe Essential Areas and Policies of the Accreditation Council forContinuing Medical Education through the joint sponsorship of theUniversity of California, Irvine School of Medicine and the CMEInstitute of Physicians Postgraduate Press, Inc. The University ofCalifornia, Irvine School of Medicine is accredited by the ACCMEto provide continuing medical education for physicians.

Credit Designation

The University of California, Irvine School of Medicine designatesthis educational activity for a maximum of 1 AMA PRA Category 1Credit(s)TM. Physicians should only claim credit commensurate withthe extent of their participation in the activity.

Date of Original Release/Review

This educational activity was released in June 2007 and is eligiblefor AMA PRA Category 1 Credit through June 30, 2009. The latestreview of this material was February 2007.

This pretest is designed to facilitate your study of the material.

1. Patients with recurrent major depressive disorder whocontinue with long-term maintenance pharmacotherapymay have fewer recurrences and a longer time to depressiveepisode recurrence than those who discontinue medication.a. Trueb. False

For Pretest answers and Posttest, see pages 250251.

Answers to Vol. 7, No. 2 Posttest 20051. c 2. b 3. c 4. b 5. b

To receive your credit certificate immediately for freeGo to www.PSYCHIATRIST.com and

complete this activity online.

LETTERS TO THE EDITOR(continued)

238 Vitamin B12 Deficiency Manifested as Mania:A Case Report.German Jorge Gomez-Bernaland Milagros Bernal-Perez

239 Case Report: Bupropion-InducedClaustrophobia.Jodie V. Malhotra andCynthia A. Mascarenas

239 Is There an Alternative to Seclusionor Mechanical Restraint?Branimir Margetic, Branka Aukst-Margetic,and Adela Matusin

240 Massive Epistaxis and SubconjunctivalHemorrhage Due to Combination ofParoxetine and Limaprost Alfadex:A Case Report.Nobuhiro Sugiyama, Daimei Sasayama,and Naoji Amano

241 The Tolerability of Oral-Loaded ValproateAfter Remission of Acute Mania inJapanese Patients With Bipolar Disorder.Kiyomi Shinohara, Yasumasa Okamoto,Hiroaki Jitsuiki, Hidehisa Yamashita,Shigeru Morinobu, and Shigeto Yamayaki

BOOK REVIEWS 242

PSYCHIATRIC BRIEFS 244

INFORMATION FOR AUTHORSsee www.PrimaryCareCompanion.com forinformation

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ACADEMIC HIGHLIGHTSTM


Preventing Recurrent Depression:Long-Term Treatment for Major Depressive Disorder

T his ACADEMIC HIGHLIGHTS sectionof The Primary Care Companionto The Journal of Clinical

Psychiatry presents the highlights of theclosed roundtable meeting PreventingRecurrent Depression: Long-TermTreatment for Major DepressiveDisorder, which was held on July 9,2006, during the Collegium InternationaleNeuropsychopharmacologicum (CINP)meeting in Chicago, Ill. This report wasprepared by the University of California,Irvine School of Medicine, and the CMEInstitute of Physicians Postgraduate Press,Inc., and was supported by an educationalgrant from Wyeth Pharmaceuticals.

The roundtable meeting was chairedby David L. Dunner, M.D., from theCenter for Anxiety and Depression,Mercer Island, Wash., and the Departmentof Psychiatry and Behavioral Sciences(professor emeritus), University ofWashington, Seattle. The faculty werePierre Blier, M.D., Ph.D., from theDepartment of Psychiatry and theDepartment of Cellular MolecularMedicine, Institute of Mental HealthResearch, University of Ottawa, andthe Mood Disorders Research Program,Royal Ottawa Hospital, Ontario, Canada;Martin B. Keller, M.D., from theDepartment of Psychiatry and HumanBehavior, Brown University School ofMedicine, and Butler Hospital,Providence, R.I.; Mark H. Pollack, M.D.,from the Department of Psychiatry,Harvard Medical School, and the Centerfor Anxiety and Traumatic StressDisorders, Massachusetts GeneralHospital, Boston; Michael E. Thase,M.D., from the University of PittsburghSchool of Medicine and the WesternPsychiatric Institute and Clinic,Pittsburgh, Pa., and the Universityof Pennsylvania School of Medicine,Philadelphia, Pa.; and John M. Zajecka,M.D., from the Depression TreatmentResearch Center, Rush University MedicalCenter, Chicago, Ill.

Faculty disclosures appear at the endof the article.

The opinions expressed herein arethose of the faculty and do not necessarilyreflect the views of the CME provider,publisher, or the commercial supporter.

Major depressive disorder (MDD)is potentially a long-term or evenlifelong illness for many patients,and maintenance therapy is designedto prevent relapse in patients with re-current depression who have achievedremission. Patients who have residualsymptoms, ongoing psychosocialstressors, or comorbid illnesses areamong the suitable candidates formaintenance treatment. In the fol-lowing discussion, experts in the treat-ment of depression address topicsrelevant to maintenance treatment:length of treatment, pharmacotherapydosage, psychotherapy, and electro-convulsive therapy (ECT). Sugges-tions are also offered for improvingsubthreshold depressive symptoms andtreatment adherence.

Dr. Dunner: We are going todiscuss some issues that arise whentreating MDD over the long term andattempting to prevent recurrent depres-sion. Let us begin by talking about thedifference between continuationtherapy and maintenance therapy.

Continuation Therapy andMaintenance TherapyDifferences

Dr. Keller: Continuation therapyis intended to prevent relapse, thatis, to suppress the symptoms of a cur-rent depressive episode from whichthe patient has not fully recovered(Figure 1).1 Usually, continuationtherapy lasts 4 to 6 months after apatient has responded in the acutephase of treatment.2

Dr. Dunner: Yes, in continuationtherapy studies, typical study design isto include patients who responded toan antidepressant during the acute

phase and then to continue somepatients on antidepressant therapyand switch others to placebo. Antide-pressant continuation therapy is invariably more effective than placebo,illustrating the need for continuationtherapy with all treatments, includingpsychotherapy. For example, a reviewby Keller and Boland3 stated that therisk of relapse is greatest during thefirst 6 months after recovery and foundthat continuation therapy with antide-pressant medications was effective(Table 1).38

Dr. Keller: In contrast to contin-uation therapy, maintenance therapyis a treatment designed to prevent re-currence, or the development of a newepisode, once an acute episode and thecontinuation treatment phase are over(see Figure 1).1 According to guide-lines established by Hirschfeld,9 theduration of maintenance therapy is 6 to24 months.

Dr. Thase: If other, more curativetreatment options are not available,maintenance therapy may be neededfor an indefinite amount of time forcertain patients; maintenance therapymay translate into lifelong treatment.

Clinical Characteristics forMaintenance TherapyCandidacy for MajorDepression

Dr. Dunner: Which patients shouldreceive maintenance treatment for ma-jor depression, and which should not?

Dr. Thase: The key characteristicsthat qualify a patient with major de-pression for maintenance therapy arethe number of prior episodes the pa-tient has had and the frequency ofrecurrence. Patients who have had 2

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Prim Care Companion J Clin Psychiatry 2007;9(3)216

episodes within several years or alifetime history of 3 or more episodeswould be likely to show the greatestbenefit from longer-term, preventivetherapy.

Dr. Keller: I would consider any-one who has had 2 lifetime episodesin addition to the current episode to bea candidate; however, we need to alsouse good judgment when determiningpatients eligibility for maintenancetherapy and consider remission and riskfactors for recurrence.

Dr. Zajecka: Only patients whohave achieved remission and a scoreof less than 7 on the Hamilton RatingScale for Depression (HAM-D)10 or 10on the Montgomery-Asberg Depres-sion Rating Scale (MADRS)11 shouldbe considered for maintenance treat-ment. Additionally, some other clinicalcharacteristicsfor example, residualsymptoms or pregnancyshould betaken into account when supportingmaintenance therapy candidacy.

Dr. Pollack: Ongoing psychosocialstressors and comorbidities should beconsidered too.

Dr. Dunner: Seasonal affectivedisorder (SAD) should also be con-sidered.

Dr. Keller: Patients who have at-tained remission but are not asympto-maticthat is, 1 or 2 symptoms stillpersistare at high risk for relapseand should continue to receive main-tenance treatment.12,13 These persistentsymptoms, or residual symptoms, inmajor depression may include diffi-culties in concentrating, sleep distur-bances, subtle decreases in energylevel, and minor persistent anxietysymptoms.

Dr. Thase: Patients who have re-sidual depressive symptoms also tendto have a more severe course of illness,a greater burden of psychiatric andmedical comorbidity, higher relapserates, higher risk of suicide attempt,and poorer social functioning than

those patients who are asympto-matic.1416

Dr. Blier: A 12-year study byJudd and colleagues17 showed thatpatients with residual subthresholdsymptoms, when compared withasymptomatic patients, had a moresevere course of illness, had morechronic depressive episodes, and hada relapse or recurrence of the nextmajor depressive episode more than 3times faster.

Dr. Thase: Thus, proper assess-ment of patients residual symptomsis essential to treat depression duringthe maintenance phase of therapy tooptimize patient outcome.

Dr. Dunner: Evidence-based as-sessments such as the Beck Depres-sion Inventory (BDI),18 the PatientHealth Questionnaire (PHQ-9),19 andthe Quick Inventory of DepressiveSymptomatology (QIDS)20 help clini-cians accurately determine patientssymptom severity. When physiciansuse oral evaluations without ratingscales, patients have a tendency to tellthe physician that they feel fine.

Dr. Pollack: Should treatment becontinued in patients who meet thecriteria for remission but who are in-volved in chaotic or stressful life situ-ations or life events?

Dr. Dunner: Ongoing psychoso-cial stressors may negatively affectpatients daily functioning. Simonsand colleagues21 found that the per-ceived impact of life stressors mayinitiate or prolong depressive episodesfor patients who have been diagnosedwith depression.

Dr. Keller: The Camberwell Col-laborative Depression Study22 exam-ined stressful variables for people whoare in a first or second depressive epi-sode. The results indicated that indi-viduals who have low income are athigher risk for relapse, as are those inan acrimonious relationship.

Dr. Zajecka: Comorbid medicalillnesses are also ongoing stressors.Patients who have illnesses such ascardiovascular disease, cancer, anddiabetes that put them at greater risk

Table 1. Continuation Studies of Relapse Rates of Antidepressants Versus Placeboa

Relapse RateStudy Drug Drug (%) Placebo (%)Montgomery et al4 Fluoxetine 26 57Montgomery and Dunbar5 Paroxetine 16 43Doogan and Caillard6 Sertraline 13 46Montgomery et al7 Citalopram 11 31Feiger et al8 Nefazodone 17 33aAdapted with permission from Keller and Boland.3

Figure 1. Response, Remission, Recovery, Relapse, and Recurrence of DepressionDuring Treatment Stagesa

aReprinted with permission from Kupfer.1

X

Normalcy

Symptoms

Syndrome

Response

Treatment Phases

RemissionRelapse Recurrence

Acute Continuation Maintenance

X

Recovery

Progression

toD

isorder

X

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than people without comorbid medicalillnesses for depression are also at highrisk for relapse and should be consid-ered for maintenance therapy.23

Dr. Pollack: Anxiety commonlypresents with depression, and mono-therapy may not be effective in treat-ing both disorders in maintenancetherapy. Instead, medication augmen-tation, such as adding benzodiazepinesto antidepressant treatment, may pre-vent or decrease the risk of relapse inthis population.24

Dr. Keller: Patients who are in theirsecond episode and have poor symp-tom control or concomitant substanceabuse are candidates for maintenancetreatment as well.

Dr. Dunner: Seasonal affectivedisorder is a recurrent depression, andpeople with SAD are candidates formaintenance therapy instead of annualtreatment.

Dr. Thase: Approximately 15% to25% of people with recurrent depres-sion have a fall-winter pattern of epi-sodes,25 making this a relatively preva-lent type of depression. Phototherapyand other chronobiological interven-tions may have added value for treat-ing patients with this disorder.26,27Light boxes can be purchased at fairlyreasonable prices relative to medica-tion cost. I favor phototherapy to treatpatients with mild symptomatologyand pharmacotherapy to treat patientswith more severe presentations of theillness.

Dr. Dunner: To prevent relapseor suicidal tendencies among patientswith more severe SAD, I prefer to pro-vide maintenance pharmacotherapyrather than to rely on patients to reportannually for phototherapy treatment.Concerning pharmacotherapy, bupro-pion has been shown to be efficaciousand is approved to treat SAD28; how-ever, studies of other medications havevarying results.2933

Dr. Zajecka: The point of treatingthis type of recurrent depression is tokeep the patient in remission through-out the entire year, which may requirethe use of phototherapy, pharmaco-

therapy, or augmentation, dependingon the individual patient.

Dr. Thase: Physicians should alsoprovide ongoing supportive moni-toring to their patients to minimize therisk of full-blown relapses.

Dr. Zajecka: Perhaps it is easierto identify patients who should notreceive maintenance therapy. An ex-ample of a patient who can discontinuetreatment is someone who has remittedfrom his or her first depressive epi-sode, which was precipitated by a clearstressor, and who has no family historyof depression. Another example is ayoung woman who has had 1 depres-sive episode, plans on having children,and does not want to take medication.Although any patient may be at risk forrelapse, I recommend discontinuingtreatment in these particular cases,keeping these patients under observa-tion, and being prepared to treat themagain if relapse occurs.

Dr. Dunner: The example of theyoung woman planning to have chil-dren raises an interesting questionabout the teratogenic risks of long-termpharmacotherapeutic treatments formajor depression.

Dr. Thase: The risk of a recurrenceof the mothers depression both duringand following pregnancy is substan-tial, while the risk of teratogenicity forthe fetus is uncertain. For example,Cohen and colleagues34 showed a 68%relapse rate among antidepressant-treated women who were euthymic atconception and discontinued antide-pressant medication during pregnancy,with a majority relapsing in the firsttrimester. There was also a 50% risk ofpostpartum depression.34 Therefore, inthe absence of alternative therapies,maintaining antidepressant medicationwill clearly result in better outcomesfor the mother as opposed to discon-tinuing pharmacotherapy.

Dr. Blier: Id like to stress thatpregnancy does not protect against de-pression. Maintenance antidepressanttherapy is necessary to prevent relapse,which may negatively impact both themother and the fetus.

Dr. Dunner: There is a lack ofdata for the use of antidepressantsduring pregnancy. Generally, no syn-drome is associated with the use ofthese agents. However, one study35found a significant association (oddsratio = 2.9; 95% confidence interval,1.3 to 6.5) between persistent pulmo-nary hypertension in infants and expo-sure to selective serotonin reuptakeinhibitors (SSRIs) after the 20th weekof gestation.

Dr. Blier: In a peer-reviewed edi-torial,36 I discussed the study by Cham-bers and colleagues35 that Dr. Dunnerjust mentioned, and I explained thatwhen the entire pregnancy was exam-ined, no significant association wasreported, illustrating the lack of evi-dence for SSRIs as posing a terato-genetic risk for pulmonary hyper-tension. Further, evidence37,38 thatparoxetine causes cardiac malforma-tions in infants has varied.

Dr. Keller: No adverse effects tothe fetus have been found with fluox-etine, indicating that this medicationmay be safe to treat women duringpregnancy.39

Dr. Thase: In general, the motherswell-being is better if she continues onantidepressant treatment during preg-nancy, but both the mother and fathershould be informed of any potentialrisk to the unborn child.

MaintenancePharmacotherapy

Dr. Dunner: Let us discuss thedata relating to the efficacy of mainte-nance pharmacotherapy for recurrentdepression. A review by Hirschfeld40found that approximately 60% of pa-tients at risk for recurrent depression,if left untreated, will have a depressiveepisode recurrence within 1 year; how-ever, if patients maintain antide-pressant treatment, between 10% and30% will experience a recurrence, sug-gesting prophylactic efficacy of anti-depressants in the treatment of recur-rent depression.

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Dr. Keller: My colleagues and Icompleted a progression of studies41comprising a 10-week acute and a6-month continuation phase of treat-ment, leading up to a 2-year mainte-nance phase of pharmacotherapy inpatients with recurrent depression. Theacute phase of treatment included 1096patients who had at least 2 depressiveepisodes in addition to the current onewithin the past 5 years; those patientswho responded to venlafaxine or flu-oxetine and remained well progressedto the continuation phase of treatment.Patients who maintained a medicationresponse over the 6-month period oftreatment were then randomly assignedin a double-blind fashion to receivevenlafaxine or placebo for the mainte-nance phase of treatment. During thefirst and second years of the mainte-nance phase,41 patients taking venla-faxine had lower rates of recurrent de-pression as compared with patientstaking placebo (Figure 2).

Dr. Thase: In that progression ofstudies, doses up to 300 mg/day ofvenlafaxine were permitted, which ishigher than the approved dose forthe once-daily formulation; however, asecondary analysis of patients who re-ceived approved doses, i.e., 75 mg/dayto 225 mg/day, confirmed the preven-tive effect of venlafaxine.

Dr. Keller: Many of us have pa-tients with recurrent depression who,after almost 3 years of treatment, wantto discontinue antidepressant medica-

tion; however, as the progression ofstudies41 we have been discussingshowed, the risk for relapse seemed toincrease over time rather than decrease.This increased risk for relapse was alsoillustrated in Frank and colleaguesstudy42 that examined imipramine ver-sus placebo treatment in patients whohad 2 prior depressive episodes inaddition to the current episode overthe past 5 years. After 3 years, fewersymptoms recurred in imipramine-treated patients than in patients whoswitched to placebo (20% and 80%,respectively).

Dr. Dunner: Further evidence ofthe benefit of long-term maintenancetherapy is shown in a 2-year exten-sion43 of Frank and colleagues 3-yearstudy42; in the 2-year extension, pa-tients randomly assigned to placebohad substantially higher recurrencerates than those who remained on im-ipramine. Additionally, maintenancestudies of citalopram44 and sertraline45found that patients who remained onmedication treatment had a longer timeto depressive episode recurrence andfewer recurrences than those who wererandomly assigned to placebo.

Dr. Pollack: Data46 on panic disor-der suggest that many patients whostop their medication may relapse orhave recurrent symptoms but will re-spond when the treatment is restarted,although the response will be slowerthan during initial treatment. Regard-ing major depression, what is the

prospect of response to medicationreadministration once patients haveinitially responded to a particular drugand then subsequently discontinuedthat medication?

Dr. Zajecka: Patients who haveachieved full remission may respondbetter to medication reinitiation thanthose patients who only had a partialresponse to the medication before stop-ping it. Fava and colleagues47 foundthat, of patients who relapsed on pla-cebo and were reinitiated into fluoxe-tine therapy, 62% responded.

Dr. Thase: In a study48 of re-treatment conducted by my colleaguesat the University of Pittsburgh, the timeto response the second time was iden-tical to the time to response the firsttime. Further, the duration of subse-quent depressive episodes was greatlyreduced because of early detection.

Dr. Blier: Early detection is impor-tant, because remission could be moredifficult to attain if the patient is al-lowed to continue in the relapsed state.

Dr. Dunner: Is atypical depressiondifferent from other forms of depres-sion with regard to the need for main-tenance therapy?

Dr. Thase: Stewart and col-leagues49 studied patients diagnosedwith atypical depression who achievedremission for at least 6 months witheither phenelzine or imipramine andwho then continued pharmacotherapyor were switched to placebo for an-other 6 months. Phenelzine, a mono-amine oxidase inhibitor (MAOI),showed a clear protective effect duringthe subsequent 6-month maintenancephase while imipramine, a tricyclicantidepressant (TCA), did not. Patientswho continued to take imipraminewere nearly as likely to relapse as thosewho took placebo after imipraminetherapy, whereas patients who contin-ued taking phenelzine were 3 to 4 timesless likely to relapse than those whohad taken phenelzine and then placebo.Therefore, patients with atypical de-pression who respond to MAOItherapy are likely to get the same ben-efit from maintenance therapy as pa-

Figure 2. Comparison of Relapse Rates for Maintenance Venlafaxine Versus Placebofor Patients With Recurrent Depressiona

aData from Keller et al.41

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40

30

20

10

0

Rec

urre

nce

Rat

e, %

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End Year 1 End Year 2

VenlafaxinePlacebo

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tients with other forms of recurrent de-pression, even though having reversevegetative symptoms may increase pa-tients likelihood of responding to onetype of treatment (MAOIs) over an-other (TCAs).

Duration andDose of MaintenancePharmacotherapy

Dr. Dunner: In my understanding,the average duration of antidepressanttreatment in the United States remainsbelow that recommended by theAgency for Health Care Policyand Research Practice Guidelines(AHCPR),50,51 even though theseguidelines were developed almost adecade ago.52 According to theAHCPR Practice Guidelines50 for thetreatment of major depression, acuteepisodes of depression should betreated for almost a year and recurrentepisodes should be treated somewhatlonger. Physicians, as a group, are notclosely adhering to the establishedtreatment guidelines when using phar-macotherapy to treat depression.

Dr. Zajecka: Clinicians shouldperceive depression as potentially be-ing a lifelong illness that may requiretreatment indefinitely in many patientsrather than as an illness that can usu-ally be cured with a single, short courseof treatment like an antibiotic.

Dr. Dunner: Should a female col-lege student aged 20 who has recurrentdepressive episodes take an antidepres-sant forever?

Dr. Thase: There is a differencebetween forever and indefinitely.In the future, treatments that target thealtered pathologic mechanisms of re-current depression may be availableand may have a more curative effectthan the present medications, whichsuppress illness activity. Comparedwith currently available pharmaco-therapeutic options, it may be possibleto stop future treatments with fewerhazards. In the meantime, I recom-

mend that patients be advised to taketreatment one year at a time.

Dr. Dunner: Let us discuss dosagerecommendations for the maintenancephase.

Dr. Keller: Current evidence3 sug-gests that patients should be main-tained on the same dose of medicationthat was necessary to achieve recoveryor remission in the acute episode. Be-cause of the absence of a large studyusing first-line treatments that providesevidence of equal efficacy after low-ering the dosage of medication, I rec-ommend maintaining the original phar-macotherapeutic dose to promoteoptimal patient outcome.

Dr. Dunner: The dose that got youbetter keeps you better.

Dr. Dunner: A study53 examinedincreases in medication dosages for

patients who relapsed. In this study,patients with depression who re-sponded to fluoxetine continued treat-ment for 25 weeks with 20 mg/dayof fluoxetine or were switched to 90mg/week of fluoxetine or to placebo.Those who relapsed during this phaseof treatment had their doses of fluoxe-tine increased in the following man-ner: patients taking placebo were given20 mg/day of fluoxetine, patients tak-ing 20 mg/day were given 40 mg/day,and patients taking 90 mg/week re-ceived 90 mg/twice a week. A major-ity of those whose dose was increasedresponded (Figure 3).

Dr. Blier: As pharmacotherapy isprolonged, increases rather than de-creases in drug dosage may be neces-sary to elicit favorable outcomes forpatients.

Figure 3. Response Rates to an Increase in Fluoxetine Dosage Following Relapsein Patients With Recurrent Depressiona

aData from Schmidt et al.53

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80

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pons

e R

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20 mg/day to 40 mg/day 90 mg/weekly to 90 mg/twice weekly

Maintenance Psychotherapy

Dr Dunner: What are the data formaintenance psychotherapy?

Dr. Keller: We have been talkingabout pharmacotherapy, but I wantto emphasize that the proper treatmentof patients with recurrent depressionincludes the combination of pharm-acotherapy and at least one of thestructured psychotherapiesmainlycognitive-behavioral therapy (CBT) orcognitive-behavioral analysis system ofpsychotherapy (CBASP); to use medi-cation alone is insufficient treatment.13

Dr. Zajecka: In the early phases oftreatment, CBT may prevent relapse,even in patients who discontinue theirmedication.54,55

Dr. Keller: Compelling evidencefor the value of psychotherapy is pro-vided by a 3-phase studyacute, con-tinuation, and maintenance treatmentphases5658that used a modified formof CBT called CBASP. In the 12-weekacute phase of treatment,56 patients ran-domly assigned to CBASP plus phar-macotherapy had a greater improve-

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ment in psychosocial functioning andhigher remission rates than patientswho received pharmacotherapy or psy-chotherapy alone. In the 16-week con-tinuation phase of treatment,57 a greaternumber of patients maintained partialor full remission on the combinationtreatment (90%) as compared withthe pharmacotherapy (80%) or psy-chotherapy alone (82%). In the 1-yearmaintenance phase of treatment,58 pa-tients in the CBASP group had signifi-cantly fewer recurrences (p .03) thanthose patients in the assessment-onlygroup. Patients who receive psycho-therapy in the acute and continuationphases of treatment and achieve remis-sion may be at a lower risk for recur-rence during the maintenance phase oftreatment than those patients who donot receive psychotherapy.

Dr. Pollack: Is there any evidencethat CBT helps prevent relapse afterdiscontinuation of medication?

Dr. Thase: Yes. Fava and col-leagues conducted studies59,60 of main-tenance CBT following pharmaco-therapy discontinuation and found thatpatients who received CBT had lowerlevels of residual symptoms59 or lowerrelapse rates60 compared with thosewho did not receive CBT. These find-ings suggest that maintenance CBT of-fers a valid, nonpharmacotherapeuticalternative to the long-term use ofantidepressants.

Dr. Pollack: Have there been stud-ies that have added psychosocial treat-mentswhether CBT or other typesspecifically around the time whenantidepressants are being tapered to seeif that would decrease the risk of re-lapse, as has been demonstrated withpsychotherapy and benzodiazepines inpanic disorder?61

Dr. Thase: Fava and colleagues62,63developed a type of psychosocialtherapy called personal well-beingtherapy, which was shown63 to reduceresidual symptoms, decrease the risk ofrelapse, and facilitate the subsequentwithdrawal of antidepressant medica-tions. Another study64 used an emotion-focused modified form of CBT to

similarly reduce patients risk forrelapse. Both personal well-beingtherapy and emotion-focused therapyare promising strategies that have notyet been replicated by a multicentergroup of collaborators.

An implicit assumption existsthat all psychotherapies are the same.However, in a maintenance study,65 theamount of time that the psychothera-pist spent performing interpersonalpsychotherapy (IPT) with patients wasdirectly associated with whether IPTwas efficacious for relapse prevention.When the psychotherapy had degener-ated into supportive conversationaway from interpersonal theme areasthe value of IPT was identical to that ofplacebo. When the IPT remained fo-cused on key psychotherapy themes,the psychotherapy efficacy approachedthat of imipramine. Thus, IPT was ei-ther a useful preventive treatment oran ineffective treatment, based on thequality and focus of the therapy.

Dr. Keller: Finding qualified psy-chotherapists is one of the keys to suc-cessful outcomes.

Dr. Pollack: Although we all rec-ognize the efficacy of quality psy-chotherapy, the accessibility of theseinterventions may vary outside special-ized treatment centers.

Dr. Keller: Finding psychothera-pists who specialize in CBT or othermodified forms of psychotherapy canbe difficult, but the ideal treatment stillis implementing these interventionsinto patients treatment regimens. Pri-mary care physicians are the maintreaters of depression, and it is crucial

for these doctors to align themselveswith a competent therapist to whomthey can refer patients.

Dr. Thase: Primary care physiciansshould look for a therapist who re-sponsibly handles referrals, gives feed-back about patient well-being, seemsto get at least half of the patients bet-ter, and receives good ratings frompatients.

Dr. Pollack: Does anyone have anysuggestions to help physicians findsuitable therapists?

Dr. Dunner: I would like to recom-mend the Web site academyofct.org,through which cognitive-behavioralpsychotherapists trained by AaronBeck may be located.

Dr. Thase: Interpersonal psycho-therapy may be easier to learn thanBecks full cognitive therapy, so nurseclinical specialists and others who pro-vide that type of therapy may be morereadily available.

Dr. Blier: The cost of psycho-therapy can be a problem for patients.For example, a 1-hour session of CBTcan amount to the cost of a 1-monthprescription for an antidepressant,which can deter some patients fromparticipating in this treatment option.

Dr. Thase: If cost or locationpresents a problem, Internet-based ortelephone-based cognitive-behavioralpsychotherapies are possible alterna-tives, and they have been shown to beefficacious for some patients.6671However, online interventions shouldnot be used to replace psychotherapyadministered by an actual person, ifthat is an available option.

Maintenance Electroconvulsive Therapy

Dr. Dunner: What are the data re-garding maintenance ECT?

Dr. Thase: Maintenance ECTshould be used only as a last resort,that is, after patients have failed to re-spond to pharmacotherapy and psycho-therapy.72 Although ECT can be dra-matic, effective, and life-saving, it is

costly and life disrupting, so its placeas a third- or fourth-line treatment formost forms of depression is well justi-fied. However, where there is no alter-native to help patients avoid an epi-sode of depression, maintenance ECTcan be used. Maintenance ECT mayalso be useful for treatment-resistant

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patients for whom vagal nerve stimula-tion (VNS) is appropriate treatmentwhile they are waiting for the effects ofVNS to ensue.

Dr. Zajecka: In a small study,73patients who previously failed pharma-cotherapy and responded to acute ECTwere then randomly assigned to receiveeither placebo or imipramine. Thosepatients who received imipramine hada much lower rate of relapse (18%)

Additional Considerations for Maintenance Therapy

Dr. Blier: One factor that is oftenoverlooked in maintenance treatmenttrials is the issue of substance or al-cohol use or abuse. In general, patientswith dual diagnosis are not admittedinto treatment trials because this co-morbidity can decrease the remissionrate.75 Substance abuse can be a con-tributing factor for relapse, yet this co-morbidity is often neglected when treat-ing patients with recurrent depression.

Dr. Zajecka: Clinicians need to re-main cognizant of the high comorbiditybetween affective disorders and sub-stance use disorders.

Dr. Dunner: We need to discussthe topic of tachyphylaxis, or what hasbeen called drug tolerance or the poop-out phenomenon, and consider how todeal with this confounding situation ofapparent decreased medication effec-tiveness over time.

Figure 4. Pharmacotherapy Efficacy Following Electroconvulsive Therapya

aReprinted with permission from Sackeim et al.74

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Nortriptyline-LithiumNortriptyline-PlaceboPlacebo

0

than patients who received placebo(80%), indicating that patients mightnot have to receive ECT as a mainte-nance therapy after remission, even ifECT helped the depression remit.

Dr. Dunner: According to a studyby Sackeim et al,74 the combination ofnortriptyline and lithium followingECT treatment was superior to placeboor medication monotherapy in pre-venting relapse (Figure 4).

Dr. Zajecka: When the SSRIscame onto the market, some patientsachieved a good response or full re-mission but, after some time, were de-scribed as apathetic and amotivatedwith a decreased range of affective re-sponse. Some people explained thisexperience by saying the medicationstopped working. However, this phe-nomenon may be due to the fact thatif medicines too selectively increaseserotonin activity in the brain, theremay be a compensatory decrease ofnorepinephrine and dopamine. Toprevent this, physicians can start pa-tients on a serotonin-norepinephrinereuptake inhibitor (SNRI).76 Also, pa-tients may respond to adjunctive nor-adrenergic or dopaminergic agents inaddition to an SSRI.

Dr. Blier: I agree. After sustainedadministration of an SSRI, the atonic

activity of the norepinephrine neuronsin the locus ceruleus decreases quitemarkedlyranging from 30% to 70%,depending on the drug.77 My col-leagues and I have recently completedstudies (B. Guiard, Ph.D.; M. El-Mansari, Ph.D.; P. Blier, M.D., Ph.D.,unpublished data, 2006) showing thatthe serotonin neurons exert an inhibi-tory action on dopaminergic neuronsin the ventral tegmental area. There-fore, the way Dr. Zajecka proposedmanaging tachyphylaxis is consistentwith the neurobiological data.77

Dr. Dunner: Tachyphylaxis is apresentation of anhedonia, a lack ofmotivation, and loss of libido. Tachy-phylaxis should be distinguished froma true recurrence, which is a full returnof symptoms, versus this emotionalblunting phenomenon that may occurin patients who are euthymic. The termtachyphylaxis is sometimes used to de-scribe both conditions and, therefore,may be used too broadly and inappro-priately. Recurrence occurs with treat-ments other than SSRIs, such asTCAs42; studies have found that about1 in 4 patients who receive mainte-nance treatment for major depressionexperience a recurrence.78 Determin-ing if a patient has tachyphylaxis, re-currence, or a drug side effect is part ofthe differential diagnosis of patientswho experience these symptoms whiletaking an antidepressant.

Dr. Thase: Another explanation fortachyphylaxis is that the patients im-provement has been attributed to theactive medication when in reality thepatient remitted spontaneously or re-sponded to the placebo effect. Perhapsthe phenomenon is sometimes due topatients not being as adherent to theirmedication regimen as they say thatthey are.

Dr. Keller: What guidance canwe give clinicians in encouragingtheir patients to remain adherent tomedication?

Dr. Blier: Nonadherence is an im-portant consideration in maintenancetherapy. Approximately 50% of pa-tients stop their medication prema-

220

ACADEMIC HIGHLIGHTS


turely and do not take it beyond 3months.7981 Physicians should work toenhance patients comfort level to en-sure they adhere to treatment recom-mendations.

Dr. Dunner: Why do patients be-come nonadherent during this phase oftreatment? (Table 2).

Dr. Keller: The obvious factors arethat patients believe that they will re-main euthymic after going off medica-tion, or that the medication does notproduce the desired outcomes, or thatserious adverse events or side effectsoccurred while taking the medication.

Dr. Thase: Persistent sexual dys-function, particularly when the patientwas not aware that the medicationcould cause this adverse event, may bea strong motivator in stopping main-tenance pharmacotherapy.82 Manypatients in whom sexual dysfunctionoccurs are reluctant to discuss sucha private issue with their physicianand instead simply stop taking theirmedication.

Dr. Zajecka: Comorbid substanceabuse may be a contributing factor tomedication discontinuation, as well.

Dr. Dunner: Weight gain is an-other factor for medication discon-tinuation.82

Dr. Thase: Weight gain is often agradual process. Many antidepressantsare weight neutral or even cause initialweight loss, but by the time patientsreach the maintenance phase of treat-ment, some notice a substantial weightgain.

Dr. Blier: I recommend imple-menting exercise regimens, not only tocontrol this long-term weight gain, butalso as a beneficial maintenance treat-

ment option for patients, especiallythose with less severe depression orwho are coming out of depression.

Dr. Dunner: Informing patients ofthe high risk of recurrence for peoplewith multiple depressive episodes mayencourage adherence in maintenancetherapy patients.83 If a patient has had3 or more depressive episodes, the like-lihood is 95% that another depressiveepisode will occur within the next 2years.84

Dr. Keller: Comparing mainte-nance treatment for depression to thatfor diabetes or hypertension can alsohelp encourage patients to take theirmedication to stay well, rather thanjust to get well. Also, patients shouldmonitor their own moods using estab-lished self-rating scales such as theBDI,18 PHQ-9,19 and the QIDS.20 Byself-monitoring their moods, patientswill know firsthand exactly how theyare doing, which can help them evalu-ate the course of their depression.

Dr. Dunner: If patients want to stoppharmacotherapy, I suggest their medi-cation be tapered and self-monitoringof their moods introduced to help themidentify the return of symptoms. Self-monitoring can help patients get backon medication treatment in a timelymanner and realize that lowering thedose may cause some return of symp-toms. Even if patients have achievedremission, continued self-monitoring isnecessary to ensure that they remaineuthymic.

Conclusion

Dr. Dunner: To conclude, somepatients may experience recurring de-pressive episodes throughout theirlives unless maintenance therapy isused to prevent relapse. Treatmentshould include both psychotherapy andpharmacotherapy, and medication dos-age typically should not be decreasedafter remission. Physicians shouldmonitor patients for comorbidities,tachyphylaxis, and nonadherence totreatment.

Drug names: bupropion (Wellbutrin andothers), citalopram (Celexa and others),fluoxetine (Prozac and others), imipramine(Tofranil and others), lithium (Eskalith,Lithobid, and others), nortriptyline (Pamelor,Aventyl, and others), paroxetine (Paxil,Pexeva, and others), phenelzine (Nardil),sertraline (Zoloft and others), venlafaxine(Effexor and others).

Disclosure of off-label usage: The chair hasdetermined that, to the best of his knowledge,no investigational information aboutpharmaceutical agents that is outside U.S.Food and Drug Administrationapprovedlabeling has been presented in this activity.

Faculty disclosure: In the spirit of fulldisclosure and in compliance with all ACCMEEssential Areas and Policies, the faculty forthis CME article were asked to complete astatement regarding all relevant financialrelationships between themselves or theirspouse/partner and any commercial interest(i.e., a proprietary entity producing healthcare goods or services consumed by, or usedon, patients) occurring within the 12 monthsprior to joining this activity. The CME Institutehas resolved any conflicts of interest thatwere identified. The disclosures are asfollows: Dr. Dunner has received grant/research support from Eli Lilly, Pfizer,GlaxoSmithKline, Wyeth, Bristol-MyersSquibb, Forest, Cyberonics, Janssen, Novartis,and Otsuka; is a consultant or advisory boardmember for Eli Lilly, Pfizer, GlaxoSmithKline,Wyeth, Bristol-Myers Squibb, Corcept,Janssen, Novartis, Shire, Somerset, Otsuka,Siemens, and Roche; and is on the speakersbureau for Eli Lilly, Pfizer, GlaxoSmithKline,Wyeth, Forest, Cyberonics, and Sanofi-Aventis. Dr. Blier is President of MedicalMultimedia, Inc.; is a contract employee ofForest, Janssen, and Steelbeach Productions;is a consultant for Biovail, Eli Lilly, Forest,Janssen, Lundbeck, Organon, Sepracor, Wyeth,Sanofi-Aventis, and Pfizer; is on the speakersbureau for Cyberonics, Eli Lilly, Forest,Janssen, Lundbeck, Organon, and Wyeth; andhas received grant/research support from EliLilly, Forest, Janssen, Lundbeck, Mitsubishi,Organon, Wyeth, and AstraZeneca. Dr. Kelleris a consultant for or has received honorariafrom Collegium, Cypress Bioscience,Cyberonics, Eli Lilly, Forest, Janssen,Organon, Otsuka, Pfizer, Pharmastar, Sepracor,Vela, and Wyeth; has received grant/researchsupport from Eli Lilly, Forest, Pfizer, andWyeth; and is on the advisory boards forAbbott, Bristol-Myers Squibb, Cyberonics,Cypress Bioscience, Eli Lilly, Forest,GlaxoSmithKline, Janssen, Novartis, Organon,Pfizer, Sepracor, and Wyeth. Dr. Pollack is aconsultant for and is on the advisory boardsfor AstraZeneca, Brain Cells, Bristol-MyersSquibb, Cephalon, Forest, GlaxoSmithKline,Janssen, Jazz, Eli Lilly, Medavante,Neurocrine, Novartis, Otsuka, Pfizer, Predix,Roche, Sanofi, Sepracor, UCB Pharma, andWyeth; has received grant/research supportfrom Bristol-Myers Squibb, Cephalon, Forest,GlaxoSmithKline, Janssen, Eli Lilly, NationalAlliance for Research on Schizophrenia andDepression, National Institute on Drug Abuse,National Institute of Mental Health, Pfizer,Sepracor, UCB Pharma, and Wyeth; is on

Table 2. Reasons Patients May BecomeNonadherent During MaintenancePharmacotherapy

Patients believe they will remain wellMedication does not produce the desired

outcomeSerious adverse events or side effects occur

Persistent sexual dysfunctionWeight gain and other metabolic

risk factorsPresence of comorbid substance abuse

221

ACADEMIC HIGHLIGHTS


the speakers bureau for Bristol Myers Squibb,Forest, GlaxoSmithKline, Janssen, Eli Lilly,Pfizer, Solvay, and Wyeth; and has equity inMedavante. Dr. Thase is a consultant for or ison the advisory boards for AstraZeneca,Bristol-Myers Squibb, Cephalon, Cyberonics,Eli Lilly, GlaxoSmithKline, Janssen,Neuronetics, Novartis, Organon, Sepracor,Shire, and Wyeth; and is on the speakersbureau for AstraZeneca, Bristol-Myers Squibb,Cyberonics, Eli Lilly, GlaxoSmithKline,Organon, Sanofi-Aventis, and Wyeth. Dr.Zajecka has received grant/research supportfrom AstraZeneca, Bristol-Myers Squibb,Eli Lilly, Forest, McNeil, Novartis, PamLab,and Somaxon; is a consultant for or is on theadvisory boards for Abbott, Biovail, Bristol-Myers Squibb, Eli Lilly, Otsuka, PamLab,and Wyeth-Ayerst; and is on the speakersbureau for Abbott, AstraZeneca, Bristol-MyersSquibb, Cyberonics, Eli Lilly, Pfizer,GlaxoSmithKline, and Wyeth-Ayerst. Thisarticle has been peer-reviewed to make sureit is evidence-based and has fair balance.

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For the CME Posttest for this ACADEMIC HIGHLIGHTS, see pages 250251.

223

POSTTESTTM


ACADEMIC HIGHLIGHTS pp. 214223

1. All of the following patients in remission from majordepression should be considered for long-term maintenancetreatment except:a. A young man with an alcohol problem who has had 2 previous

major depressive episodes, has a family history of depression, anddoes not want to be on medication

b. A middle-aged woman with minor persistent anxiety symptomswho has had several previous major depressive episodes with afall/winter pattern and is in an acrimonious relationship

c. A young woman planning to have children who does not want tobe on medication, has had one major depressive episode, and hasno family history of depression

d. An elderly man with diabetes who has had 3 previous majordepressive episodes

2. According to data, approximately what percent of patientswith recurrent major depression, if left untreated, will havea depressive episode recurrence within 1 year?a. 4b. 23c. 60d. 95

3. During long-term maintenance pharmacotherapy forrecurrent major depressive disorder, all of the followingstrategies can be helpful in preventing relapse except:a. Self-monitoring by the patientb. Receiving online psychotherapyc. Reducing medication dosaged. Ongoing supportive monitoring by the clinician

4. According to research, patients receiving structuredpsychotherapy in addition to maintenance pharmacotherapyas long-term treatment for major depressive disorder haveall the following except:a. Reduced residual symptomsb. Better psychosocial functioningc. A greater chance of maintaining partial or full remissiond. A greater likelihood of relapse if medication is discontinued

5. Which of the following strategies can help patients adhere tolong-term maintenance pharmacotherapy for majordepressive disorder?a. Education about the risks of relapse if medication is discontinuedb. Forewarning about sexual dysfunctionc. Implementing an exercise programd. All of the above

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Circle the one correct answer for each question.1. a b c d 4. a b c d

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3. a b c d

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Hospital Private Practice Resident Intern

Deadline for submissionFor a credit certificate to be issued, please complete thisRegistration Form no later than June 30, 2009. Onlinesubmissions will receive credit certificates immediately. Faxedor mailed submissions will receive credit certificates within6 to 8 weeks.

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THE PRIMARY CARE COMPANION TO THE JOURNAL OF CLINICAL PSYCHIATRY, Volume 9 Number 3CME PretestCME ArticleAcademic Highlights: Preventing Recurrent Depression: Long-Term Treatment for Major Depressive Disorder

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