psy researches

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Editorial

Clinical Psychopharmacology Guidelines: Different Strokes for Different Folks

Dan J. Stein, Yu Xin, David Osser, Xiangyang Li, Kenneth Jobson 64

Reviews/Mini-reviews

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for

Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance

Treatment of Major Depressive Disorder and Treatment of Chronic Depressive

Disorders and Subthreshold Depressions

Michael Bauer, Peter C. Whybrow, Jules Angst, Marcio Versiani, Hans-Jrgen

Mller, WFSBP Task Force on Treatment Guidelines for Unipolar Depressive

Disorders 69

GABAergic Neurosteroid Modulation of Ethanol Actions

Rahul T. Khisti, Shannon N. Penland, Margaret J. VanDoren, A. Chistina Grobin, A.

Leslie Morrow87

Brief reports

Serotonin Platelet-Transporter Measures in Childhood Attention-

Deficit/Hyperactivity Disorder (ADHD): Clinical versus Experimental Measures

of ImpulsivityRobert D. Oades, Michael Slusarek, Silke Velling, Brigitta Bondy 96

Original Investigations/Summaries of Original Research

Rate of Oxygen Consumption in Seasonal and Non-Seasonal DepressionBoris B. Pinchasov, Oleg V. Grischin, Arcady A. Putilov 101

Viewpoints

Catatonia and ECT: Meduna's Biological Antagonism Hypothesis Reconsidered

Max Fink 105

Case Reports/Case Series

Side Effects after Phototherapy Implementation in Addition to Fluoxetine or

Sertraline Treatment: A Report of Two Cases

ukasz Swicicki, Tomasz Szafranski 109


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trials. The available database may be found lacking in the developing world, for example, inaddressing whether preventive interventions or redeployment of resources are more important thanthe implementation of treatment (Birch 1997; Woolf 1999). Also, studies showing the cost-efficacyof a particular agent may not apply in a different setting where medication costs are, for example,particularly high and hospitalization costs relatively low.

Important questions for clinical psychopharmacology in the developing world include whethertraditional medications or non-patented but readily manufactured agents are as effective asmarketed products, or whether certain older and cheaper medications are in fact as well tolerated asmore newly introduced agents. Again, rigorous guidelines may be useful in helping to optimizedecision-making.

Another contrast between the developed and developing world lies in the aim of guidelines. In thedeveloped world, guidelines have often been associated with an attempt to restrict unnecessary

overtreatment and to reimburse only appropriate treatment. In the developing world (and inprimary care), on the other hand, there is often a particular need to counter the underrecognitionand undertreatment of a disorder, so indirectly reducing costs.

There is a need for additional systematic research on how best to encourage evidence-basedmedicine, and on how best to develop and implement guidelines and algorithms. Data thatreporting the evidence or issuing practice guidelines does little to change clinical practice (Davis etal 1995) is sobering. Indeed, there are many reasons why best evidence is not always implemented(Boyle 1998; Freeman and Sweeney 2001). In the developed and developing world there may againbe important differences with regard to a number of relevant issues.

First, the specificity of the guideline. In order to be useful guidelines should be neither too specificnor excessively general (Rush 2001). In the developed world, however, the availability of super-specialized practitioners means that greater specificity (and incorporation of clinical experience) isuseful. In the developing world (and in primary care) relatively simple guidelines that succinctlyemphasize the most universally accepted (and clearly data-based) interventions may be needed inorder to maximize resources.

Second, guideline dissemination and implementation. Although print publications remain widelyused in the developed world, computerization and the internet are likely to play an increasinglyimportant role in the future dissemination and implementation of guidelines in clinical psycho-pharmacology (Stein et al 1994; Trivedi et al 2000). Nevertheless, in developing countries whereprint publications and computers are not always widely available, particularly in outlying areas,other modalities for educating clinicians will be necessary.

Third, cross-cultural differences in diagnosis and management. In the developed world, it isimportant to consider the different ways in which patients from different cultural backgrounds may

present and their varying preferences regarding treatment. In the developing world, on the other


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EDITORIAL

hand, many aspects of Western guidelines may require significant adjustment. Common diagnosesmay not fit neatly into DSM-IV categories, and there may be frequent use of a range of additionalinterventions (e.g. traditional medication).

Along the same lines, it is important that guidelines and algorithms in clinical psychopharmacologypromote rather than hinder the doctor-patient relationship. In both the developed and thedeveloping world, there is an important risk of patients feeling alienated by the scientific model andits emphasis on the evidence base. Certainly, patients throughout the world frequently turn toalternative and unproven approaches.

Nevertheless, we are optimistic that the development of guidelines and algorithms that aim atenhancing the practice of evidence-based medicine can be helpful for clinicians and patients. Evenwhen important data is lacking, such efforts may be useful in emphasizing the need for additionalresearch (Alderson and Roberts 2000). In addition, guidelines and algorithms may be useful tools for

educating managed care organizations, policy-makers, clinicians, students and consumers.

Optimism about psychiatric guidelines and algorithms is itself based on too little evidence at thispoint in time (Jaffe and Yager 1999; Katon et al 1995). In the United States, large-scale empiricalstudies of algorithms are currently under way, and these will contribute to our understanding of thevalue of the careful development and implementation of decision-tools for clinical psycho-pharmacology (Rush et al 1999). In developing countries, there is a relative dearth of research onsuch tools, and efforts to encourage the careful examination of their pros and cons should bestrongly encouraged.

Dan J. Stein1, Yu Xin2, David Osser3, Xiangyang Li3, Kenneth Jobson4

1 University of Stellenbosch, Cape Town, South Africa, and University of Florida, Gainesville, USA2 Beijing Mental Health Institute, Beijing, China3 Harvard University Medical School, Boston, USA4 International Psychopharmacology Algorithm Project, Tennessee, USA

Correspondence:Dan J. Stein, M.D., Ph.D.MRC Unit on Anxiety DisordersUniversity of StellenboschPO Box 19063Tygerberg 7505Cape TownSouth AfricaTel: +27 21 938 9161Fax: +27 21 933 5790

E-mail: [email protected]


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References

Alderson P, Roberts I (2000) Should journals publish systematicreviews that find no evidence to guide practice? Examples frominjury research. BMJ 320: 376-377.

Birch S (1997) As a matter of fact: Evidence-based decision-makingunplugged. Health Economics 6: 547-559.

Boyle PJ (1998) Getting Doctors to Listen: Ethics and OutcomesData in Context. Georgetown University Press, Washington, D.C.

Cook DJ, Greengold NL, Ellrodt AG, Weingarten SR (1997) Therelation between systematic reviews and practise guidelines. AnnInt Med 127: 210-216.

Davis DA, Thomson MA, Oxman AD, Haynes RB (1995) Changingphysician performance: A systematic review of the effects of

continuing medical education strategies. JAMA 274: 700-705.

Fawcett J, Stein DJ, Jobson KO (1999) (eds) Textbook of TreatmentAlgorithms in Psychopharmacology. John Wiley, Chichester.

Freeman AC, Sweeney K (2001) Why general practitioners do notimplement evidence: qualitative study. BMJ 323: 1100.

Grimshaw JM, Russell IT (1993) Effect of clinical guidelines onmedical practice: A systematic review of rigorous evaluation.Lancet 342: 1317-1322.

Institute of Medicine (1992) Guidelines for Clinical Practice: FromDevelopment to Use. National Academy Press, Washington, D.C.

Jaffe SL, Yager J (1999) APA practice guidelines: A pilot study of adistrict branch-based educational awareness: Awareness and

reactions. Academic Psychiatry 23: 9-13.

Jobson KO, Potter WZ (1995) International PsychopharmacologyAlgorithm Project. Psychopharmacol Bull 31: 457-459.

Katon W, Von Korff M, Lin E, Walker E, Simon GE, Bush T, RobinsonP, Russo J (1995) Collaborative management to achieve treatmentguidelines: Impact on depression in primary care. JAMA 273: 1026-1031.

Klein DF (1993) Clinical psychopharmacological practice: The needfor a developing research base. Arch Gen Psychiatry 50: 491-494.

Patterson RD (1999) The Harvard Psychopharmacology AlgorithmProject. Psychiatr Ann 29: 248-250.

Rosenberg W, Donald A (1995) Evidence based medicine: An

approach to clinical problem solving. BMJ 310: 1122-1126.

Rush AJ (2001) Clinical practice guidelines: Good news, bad news,

or no news? Arch Gen Psychiatry 50: 483-490.

Rush AJ, Crismon ML, Toprac MG, Shon S, Rago WV, Miller AL,Suppes T, Trivedi MH, Biggs MM, Shores-Wilson K, Kashner TM,

Altshuler KZ (1999) Implementing guidelines and systems of care:Experiences with the Texas Medication Algorithm Project (TMAP).J Pract Psychiatry Behav Health 5: 75-86.

Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS(1996) Evidence-based medicine: What it is and what it isn't. BMJ312: 71-72.

Shaneyfelt TM, Mayo-Smith MF, Rothwangl J (2001) Are guidelinesfollowing guidelines? The methodological quality of clinicalpractice guidelines in the peer-reviewed medical literature. JAMA281: 1900-1905.

Stein DJ, Jobson KO (1996) Psychopharmacology algorithms: Prosand cons. Psychiatric Annals 26: 190-191.

Stein DJ, Patterson B, Hollander E (1994) Expert systems forpsychiatric pharmacotherapy. Psychiatric Annals 24: 37-41.

Trivedi MH, Kern JK, Baker SM, Altshuler KZ (2000) Computerizingmedication algorithms and decision support systems for majorpsychiatric disorders. Journal of Psychiatric Practice 6: 237-246.

Woolf SH (1992) Practice guidelines, a new reality in medicine: II.Methods of developing guidelines. Arch Intern Med 152: 946-952.

Woolf SH (1999) The need for perspective in evidence-basedmedicine. JAMA 282: 2358-2365.

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SummaryThese practice guidelines for the biological treatmentof unipolar depressive disorders were developed by aninternational Task Force of the World Federation ofSocieties of Biological Psychiatry (WFSBP). The goalfor developing these guidelines was to systematicallyreview all available evidence pertaining to thetreatment of the complete spectrum of unipolar de-

pressive disorders, and to produce a series of practicerecommendations that are clinically and scientifi-cally meaningful based on the available evidence.

These guidelines are intended for use by allphysicians seeing and treating patients with theseconditions. The data used for developing these

guidelines have been extracted primarily fromvarious national treatment guidelines and panels fordepressive disorders, as well as from meta-analysesand reviews on the efficacy of antidepressantmedications and other biological treatment inter-ventions identified by a search of the MEDLINEdatabase and Cochrane Library. The identifiedliterature was evaluated with respect to the strengthof evidence for its efficacy and was then categorizedinto four levels of evidence (A-D). The first part ofthese WFSBP guidelines on unipolar depressivedisorders covered the acute and continuationtreatment of major depressive disorder (Bauer et al2002). This second part of the guidelines covers themanagement of the maintenance-phase treatment of

major depressive disorder, as well as the treatment ofchronic and subthreshold depressive disorders(dysthymic disorder, double depression, minordepressive disorder and recurrent brief depression).These guidelines are primarily concerned with thebiological treatment (including antidepressants,lithium, other psychopharmacological and hormonalmedications, and electroconvulsive therapy) of youngadults and also, albeit to a lesser extent, children,adolescents and older adults.

Key words: major depressive disorder, chronicdepressive disorders, dysthymic disorder,subthreshold depressive disorders, maintenancetreatment, evidence-based guidelines,

pharmacotherapy, antidepressants, lithium, ECT.

Correspondence:PD Dr. med. Dr. rer. nat. Michael BauerDepartment of PsychiatryUniversittsklinikum Medizinische Fakultt der

Humboldt-Universitt zu BerlinCampus Charit MitteSchumannstr. 20/2110117 BerlinGermanyTel: +49 30 4505 517001

Fax: +49 30 4505 517902E-mail: [email protected]

World Federation of Societies of Biological Psychiatry

(WFSBP) Guidelines for Biological Treatment of Unipolar

Depressive Disorders, Part 2: Maintenance Treatment of

Major Depressive Disorder and Treatment of Chronic

Depressive Disorders and Subthreshold Depressions

Michael Bauer1,2, Peter C. Whybrow1, Jules Angst3, MarcioVersiani4, Hans-Jrgen Mller5, WFSBP Task Force on TreatmentGuidelines for Unipolar Depressive Disorders61 University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of

Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA2 Humboldt University of Berlin, Charit Medical Center, Department of Psychiatry, Berlin, Germany3 University of Zrich, Department of Psychiatry, Zrich, Switzerland4

Federal University of Rio de Janeiro, Department of Psychiatry, Rio de Janeiro, Brazil5 University of Munich, Department of Psychiatry, Munich, Germany6 WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders:

Peter C. Whybrow (Chairman; USA), Jules Angst (Co-Chairman; Switzerland), Marcio Versiani (Co-Chairman; Brazil), Michael Bauer

(Secretary; USA/Germany), Hans-Jrgen Mller (WFSBP Past-President; Germany)

Herve Allain (France), Ian Anderson (United Kingdom), Jos L. Ayuso-Gutierrez (Spain), David Baldwin (United Kingdom), Per Bech

(Denmark), Otto Benkert (Germany), Michael Berk (Australia), Istvan Bitter (Hungary), Marc L. Bourgeois (France), Graham Burrows

(Australia), Giovanni Cassano (Italy), Marcelo Cetkovich-Bakmas (Argentina), John C. Cookson (United Kingdom), Delcir da Costa

(Brasil), Mihai D. Gheorghe (Romania), Gerardo Heinze (Mexico), Teruhiko Higuchi (Japan), Robert M. Hirschfeld (USA), Cyril Hschl

(Czech Republic), Edith Holsboer-Trachsler (Switzerland), Siegfried Kasper (Austria), Cornelius Katona (United Kingdom), Martin B.

Keller (USA), Parmanand Kulhara (United Arab Emirates), David J. Kupfer (USA), Yves Lecrubier (France), Brian Leonard (Ireland),

Rasmus W. Licht (Denmark), Odd Lingjaerde (Norway), Henrik Lublin (Denmark), Julien Mendlewicz (Belgium), Philip Mitchell

(Australia), Eugene S. Paykel (United Kingdom), Stanislaw Puzynski (Poland), A. John Rush (USA), Janusz K. Rybakowski (Poland), Isaac

Schweitzer (Australia), Jrgen Untzer (USA), Per Vestergaard (Denmark), Eduard Vieta (Spain), Kazuo Yamada (Japan)

World J Biol Psychiatry (2002) 3, 69 - 86


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AcknowledgementsWe would like to thank Dr. Jrgen Untzer, Los Angeles, USA, for valuable contributions in preparing thefirst draft of these guidelines; Dr. Christoph Hiemke, Mainz, Germany, for comments on pharmacokineticaspects of maintenance treatment; Jacqueline Klesing and Ilka Lachmair, Munich, Germany, and Trina

Haselrig, Los Angeles, for excellent general and editorial assistance.

Table of Contents

Executive Summary of Recommendations

1 Long-Term Treatment of Unipolar Depressive Disorders

1.1 Introduction

1.2 Goal and Target Audience of WFSBP Guidelines

1.3 Methods of Literature Research and Data Extraction

1.4 Evidence-Based Classification of Recommendations

2 Maintenance-Phase Treatment of Major Depressive Disorder

2.1 General Treatment Principles of Maintenance Treatment

2.1.1 Goals and Indications

2.1.2 Treatment Implementation2.2 Pharmacotherapy of Maintenance Treatment

2.2.1 Evidence of Efficacy

2.2.1.1 Antidepressants

2.2.1.2 Lithium

2.2.1.3 Carbamazepine and Other Mood Stabilizers

2.2.2 Comparative Efficacy

2.2.3 Tolerability and Side Effects of Maintenance Medications

2.2.4 Treatment of Symptomatic Worsening and Recurrence

2.2.5 Maintenance Treatment Options for Prophylaxis - Resistant Depression

2.3 Duration and Discontinuation of Maintenance Treatment

2.4 Switching from Unipolar Depression to Bipolar Disorder

2.5 Electroconvulsive Therapy (ECT)

2.6 Psychotherapy

2.7 Maintenance-Phase Treatment of MDD in Special Age Groups

2.7.1 Children and Adolescents

2.7.2 Older Adults

3 Treatment of Chronic Depressive Disorders

3.1 Introduction

3.2 Dysthymic Disorder

3.2.1 Pharmacotherapy of Dysthymic Disorder

3.3 Double Depression and Other Chronic Depressions

4 Subthreshold Depressions

5 References

Tables and Figures

Table 1: Factors Associated with Increased Risk for Recurrence in Major Depressive Disorder page 74

Figure 1: Flow Chart Therapeutic Options for Maintenance Treatment of Major Depressive Disorder page 75


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Executive Summary ofRecommendations

General RecommendationsThe long-term course of unipolar major de-pressive disorder (MDD) is characterized by highrates of recurrence and prolonged symptomaticchronicity. The primary goals of maintenance(prophylactic) treatment are to prevent a newepisode of depression, a recurrence, suicide anddevelopment of chronicity. Consideration of thepatients course of illness and treatment historyis essential for the implementation of mainte-nance-phase treatment. Even though no definiterecommendation can be given as to whenprophylactic therapy should be initiated, it isclearly indicated in situations associated with ahigh risk of recurrence. For patients who havehad three or more episodes of major depression,and in patients with a high prior rate of

recurrence (e.g., two episodes within five years),longer term maintenance therapy is indicated.Duration may vary from three years to lifetime,but in general the more adverse the prognosis,the longer the maintenance therapy. Adverseprognostic indicators for recurrence include ahigh number of previous episodes, residualsymptoms at remission, previous longer episodesand chronicity, more severe previous episodes,onset early in life, concurrent dysthymic dis-order ("double depression"), relapse after medica-tion withdrawal, previous episode within the lastyear, concurrent substance abuse or anxietydisorders, and family history of major depressivedisorder in first degree relatives.

Key elements of long-term treatment of MDDinclude 1) psychoeducation, 2) pharmacothe-rapy, and 3) adherence monitoring. Adjunctivedepression-targeted psychotherapy may be con-sidered in individual patients. Because mainte-nance treatment requires compliance withmedication, education and a close therapeuticalliance with patients and their families areessential. To prepare patients and their familiesfor maintenance treatment, they should beinformed about the following topics: typical

course of the illness, treatment options, medica-tion effects and side effects, use of (daily) self-report instruments to track mood and earlywarning signs of relapse or recurrence, long-termperspectives, and projected end of treatment.Other principles of maintenance treatment areto distinguish between spontaneous symptoma-tic fluctuations ("blips") and "true" recurrences.In contrast to "blips", which are self-limited anddo not require specific interventions, recurrencesmust be treated aggressively. It is also essential toregularly check adherence to medication and todetect breakthrough symptoms early on.

Specific Treatment RecommendationsThe medications of first choice for the mainte-nance treatment of MDD are either the anti-depressant with which remission was achieved

in the acute and continuation phase or lithium.Many patients receive antidepressants during theacute and continuation phase, and the best treat-ment recommendation to prevent recurrence ofdepression is to continue the antidepressant me-dication at the same dose during the mainte-nance phase. Randomized placebo-controlledstudies (usually conducted for one or two yearsduring maintenance treatment) indicate that tri-cyclic antidepressants (TCAs), irreversible mono-amine oxidase inhibitors (MAOIs) and selectiveserotonin reuptake inhibitors (SSRIs) are effectivein preventing recurrence of depression. Recentevidence suggests that the "newer" antidepres-sants have superior long-term efficacy and bettertolerability compared to traditional antidepres-sants (e.g., TCAs). Another first choice medica-tion for the maintenance treatment of MDD islithium. With respect to lithium therapy, serumlithium levels of 0.5 to 0.8 mmol/L (mEq/L)

determined 12 hours after the last lithium intakeare usually recommended for maintenance treat-ment. However, the "optimal" serum lithiumlevel may vary somewhat from patient topatient, in the range of 0.4 to 1.0 mmol/L, de-pending on individual effectiveness and tolera-bility of side effects. There is modest evidencethat carbamazepine is an alternative medicationin the maintenance treatment of MDD. Othermood stabilizers that are used for bipolaraffective disorders (e.g., valproate [divalproex],lamotrigine or gabapentin) have not beenstudied in randomized controlled trials for themaintenance treatment of MDD. Periodic (main-tenance) electroconvulsive therapy (ECT) hasbeen recommended for patients who fullyresponded to ECT during the acute and con-tinuation treatment phase and especially forthose who are not eligible for or who do notrespond to maintenance medication treatment.

The duration of continuation treatment follow-ing acute treatment should be six to ninemonths. Treatment length required for mainte-nance is not yet fully determined. However,three years of maintenance therapy is most com-monly appropriate for recurrent patients, parti-

cularly when an episode prior to the present onehas occurred in the last five years or whenremission has been difficult to achieve. Mainte-nance treatment for five to 10 years, or evenindefinitely, is recommended for those patientsat greater risk, particularly when two or threeattempts to withdraw medication have beenfollowed by another episode within a year.

Although the amount of data from controlledstudies is still limited, results clearly indicateefficacy of various antidepressants (TCAs, SSRIsand other "newer" antidepressants) for dys-thymic disorder. Although the optimal length ofpharmacotherapy for dysthymia has not beenstudied in a controlled design, a course of treat-ment with an antidepressant for at least twoto three years is recommended, as in MDD.

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Although subthreshold depressive disorders arehighly prevalent in the general population andin primary care settings, controlled treatmentdata involving pharmacotherapy is even moresparse than for dysthymic disorder. Given thelimited data from controlled studies forsubthreshold depressive disorders, evidence-based treatment recommendations cannot begiven at this point. However, a treatment trialwith one of the well-tolerated antidepressants isworth trying in more chronic and unremittingcases.

Withdrawal of antidepressants and lithium afterlonger term use (e.g., longer than six months)should always be gradual, with dose reductionsover at least three months. Abrupt cessation ofantidepressants after longer term use can lead towithdrawal syndromes. Rapid, although notabrupt, withdrawal can lead to rebound relapse

and recurrence. Where symptoms return duringor after withdrawal, full-dose maintenancetreatment should be initiated.

1 Long-term treatment of unipolardepressive disorders1

1.1 IntroductionMajor depressive disorder (MDD), in its classicform, presents as a recurrent disorder (Angst1986; Judd 1997; Kiloh et al 1988). Majordepressions that do not respond to treatment orthat spontaneously remit will suffer subsequentrelapses or recurrences. Fifty percent to 85% ofthe patients who have an episode will haveanother episode of major depression (Mueller etal 1999; Andrews 2001; American PsychiatricAssociation 2000). The likelihood of a recurrenceincreases with the number of previous depressiveepisodes and the severity of the current episode(Angst 1999). Patients who have had threeepisodes of major depression have a 90% chanceof having another (NIMH Consensus Develop-ment Conference 1985). Among others, riskfactors for recurrence of MDD are: prior historyof multiple episodes of MDD, early age at onset,persistence of dysthymic symptoms after

recovery from an episode of MDD, presence ofan additional, non-mood psychiatric diagnosis,and presence of a chronic physical disorder(Kovacs et al 1997; American Psychiatric Associa-tion 2000). Factors that have been associatedwith increased severity of subsequent depressiveepisodes include a history or a prior episodecomplicated by serious suicide attempts, psy-chotic features or severe functional impairment(American Psychiatric Association 2000).

In recent years it has become apparent that thelong-term course of unipolar MDD is not onlycharacterized by high rates of recurrence but also

dominated by prolonged symptomatic chronici-ty (Judd 1997; Judd et al 1998). Most patientswith MDD return to the premorbid level of func-tioning between episodes of major depression.However, in approximately 30% of the severe orhospitalized depressed patients, residual symp-toms and social or occupational impairmentpersists. It is now well established that aboutone-third of patients suffering from severe majordepression will have a chronic course marked byat least two years of illness (Keller et al 1986;Scott 1988; Nierenberg 2001; American Psychia-tric Association 2000; Judd and Akiskal 2000).Epidemiological and prospective clinical follow-up studies have also documented that the typicalcourse of unipolar MDD involves fluctuatingsymptoms in which depressive subtypes in-cluded in official diagnostic systems do notrepresent discrete disorders, but are stages alonga dimensional continuum (spectrum) of sympto-

matic severity (Angst et al 2000; Judd and Akiskal2000). The group of chronic depressive disordersencompasses four subtypes of depressive illness: major depressive disorder, recurrent, without

full interepisodic recovery (in incompleteremission),

major depressive disorder, currently in achronic (duration of two years) episode(chronic major depressive disorder),

dysthymic disorder, "double depression" (concurrent dysthymic

disorder and major depression).

The group of "subthreshold depressions" (depres-sive disorders not otherwise specified, NOS)includes depressive conditions in which thenumber, duration or quality of symptoms isinsufficient to meet the DSM criteria for a diag-nosis of major depression (American PsychiatricAssociation 1994a; Judd et al 1998; Akiskal andCassano 1997; Angst and Merikangas 1997).

Patients with an early onset and older adultssuffering an initial depressive episode after theage of 60 appear to be at greater risk for thedevelopment of chronicity (Klerman and Weiss-man 1989). Individuals suffering from either

dysthymia alone or "double depression" havesignificantly greater impairment in functioningthan those with major depression alone, depres-sive symptoms or past episodes of major depres-sion (Wells et al 1992). Residual (subthreshold)symptoms in the course of MDD are associatedwith a high risk for early episode relapse and asignificantly more chronic future course of ill-ness. Asymptomatic recovery from MDD is asso-ciated with significant delays in episode relapseand recurrence and a more benign course ofillness (Judd and Akiskal 2000; Judd et al 2000).

1.2 Goal and target audience of WFSBPguidelines

These WFSBP guidelines provide an update ofcontemporary knowledge of unipolar depressivedisorders and evidence-based recommendations

1 It is emphasized that the treatment of dysthymic disorders, subthreshold depres-

sions and other chronic depressive disorders does not involve only long-term

treatment but also acute treatment. However, for editorial reasons only, both

acute and long-term treatment issues are covered in Part 2 of these guidelines.


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for their treatment. They were developed by theauthors and arrived at by consensus with theWFSBP Task Force on Unipolar Depressive Dis-orders consisting of 46 international researchersand clinicians. The goal for developing theseguidelines was to systematically review allavailable evidence pertaining to the treatment ofunipolar depressive disorders, and to produce aseries of recommendations that are clinically andscientifically meaningful. They were also in-tended to bring together the various opinions ofscientifically respected experts and internationalrepresentatives on the appropriate state-of-the-art treatment of these disorders. There were a fewaspects for which it was not possible to reach aconsensus within the Task Force. In such cases,the Chairman and Co-Chairmen had to make afinal decision. The most divergent opinions werein the following areas: the use of anticonvulsantsin maintenance treatment, the effectiveness and

positioning of lithium in the maintenance treat-ment of unipolar depressive disorders, and thepositioning of psychotherapy in guidelines forthe biological treatment of depressive disorders.

These guidelines are intended for use in clinicalpractice by all physicians seeing and treatingpatients with these conditions. They should beconsidered as guidelines only because the ulti-mate judgement regarding a particular treatmentprocedure must be made by the responsibletreating physician in light of the clinical picturepresented by the patient and the diagnostic andtreatment options available.

These guidelines are primarily concerned withthe biological (somatic) treatment (e.g., anti-depressants, lithium, other psychopharmaco-logical and hormonal medications, and electro-convulsive therapy) of unipolar depressivedisorders in young adults, but also, albeit to alesser extent, of children, adolescents and olderadults. They do not address depressive disordersoccurring in bipolar affective disorders (whichare covered by separate WFSBP guidelines[Grunze et al In Press]). The management of theacute and continuation treatment of major

depressive disorder was covered in Part 1 of theWFSBP guidelines (Bauer et al 2002). This secondpart of the guidelines covers the management ofmaintenance-phase treatment of major depres-sive disorder, as well as treatment of chronicdepressive disorders and subthreshold depressivedisorders. Psychotherapeutic treatment interven-tions are covered only briefly, but references areprovided for further reading. Since the availa-bility of medications, treatments and diagnosticprocedures varies considerably across countries,the authors have included several differenttreatment options in the guidelines.

1.3 Methods of literature research anddata extraction

The data used for the development of theseguidelines have been extracted from the follow-

ing sources: Agency for Health Care Policy andResearch (AHCPR) Depression Guidelines Panel(AHCPR 1993); AHCPR Evidence Report onTreatment of Depression: Newer Pharmaco-therapies (AHCPR 1999); American PsychiatricAssociation (APA) Practice Guideline for theTreatment of Patients with Major DepressiveDisorder, Revision (American Psychiatric Asso-ciation 2000); British Association for Psycho-pharmacology Revised Guidelines for TreatingDepressive Disorders (Anderson et al 2000);Canadian Psychiatric Association and theCanadian Network for Mood and AnxietyTreatments, CANMAT, Clinical Guidelines forthe Treatment of Depressive Disorders (CANMAT2000); Canadian Consensus Guidelines for theTreatment of Seasonal Affective Disorder (Lamand Levitt 1999); Deutsche Gesellschaft frPsychiatrie, Psychotherapie und Nervenheil-kunde, DGPPN, Praxisleitlinien in Psychiatrie

und Psychotherapie, Affektive Erkrankungen(DGPPN 2000); American Academy of Child andAdolescent Psychiatry, Practice Parameters forthe Assessment and Treatment of Children andAdolescents with Depressive Disorders (Ameri-can Academy of Child and Adolescent Psychiatry1998); The Cochrane Library; meta-analyses onthe efficacy of antidepressant medications iden-tified by a search of the MEDLINE database (untilAugust 2001); major pertinent review articlesidentified by a search of the MEDLINE databaseand textbooks, and individual clinical expe-rience by the authors and members of theWFSBP Task Force on Unipolar DepressiveDisorders. With respect to quoting original data,only research articles published in peer-reviewedjournals in English before August 2001 wereconsidered.

1.4 Evidence-based classification ofrecommendations

The evidence found in the literature researchand data extraction was summarized and cate-gorized to reflect its susceptibility to bias(Shekelle et al 1999). Each treatment recommen-dation was evaluated with respect to the strengthof evidence for its efficacy, safety and feasibility2.

However, daily treatment costs were not takeninto consideration due to the variability ofmedication costs worldwide. Four categories ofevidence were used:

Level A: Good research-based evidence to supportthe recommendation. This level is achieved ifresearch-based evidence for efficacy is givenfrom at least three moderately large, positive,randomized, controlled (double-blind) studies(RCT). In addition, at least one of these threestudies must be a well-conducted, placebo-controlled study.

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2 It is emphasized that a graded efficacy evaluation has its limitations. The strength

of a recommendation reflects the scientific evidence on which it is based and not

necessarily its importance. Levels of recommendation only apply to treatment

and not to other aspects.


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Level B: Fair research-based evidence to supportthe recommendation. This includes evidence ofefficacy from at least two moderately largerandomized, double-blind studies (this can beeither two comparator studies or one compara-tor-controlled and one placebo-controlled study)or from one moderately large randomized,double-blind study (placebo-controlled or com-parator-controlled) and one prospective,moderately large (sample size of 50 parti-cipants), open-label, naturalistic study.

Level C: Minimal research-based evidence tosupport the recommendation. This level isachieved if one randomized, double-blind studywith a comparator treatment and one prospec-tive, open-label study/case series (with a samplesize of 10 participants) showed efficacy, or atleast two prospective, open-label study/caseseries (with a sample size of 10 participants)

showed efficacy.

Level D: Expert opinion-based (from authors andmembers of the WFSBP Task Force on UnipolarDepression) recommendations supported by atleast one prospective, open-label study / caseseries (sample size 10 participants).

No level of evidence: Expert opinion for generaltreatment procedures and principles.

2 Maintenance-phase treatment ofmajor depressive disorder

2.1 General treatment principles ofmaintenance treatment

2.1.1 Goals and indicationsThe goals of long-term, maintenance (pro-phylactic) treatment are to prevent a newepisode of depression (a recurrence), suicide anddevelopment of chronicity. A recurrence is anepisode that appears after a completely asymp-tomatic period (remission) has been achieved fora six-month period (recovery) (Frank et al 1991;

Kupfer 1993). The consideration of the patientscourse of illness and treatment history isessential for the implementation of maintenancephase therapy. Even though no definite recom-mendation can be given as to when prophylactictherapy should be initiated, it is clearly indicatedin situations associated with a high risk ofrecurrence (Brunello et al 1995; Angst 1999;Dawson et al 1998; Paykel 2001) (Table 1). Inaddition to these risk factors, patient preference,severity of functional impairments and sideeffects experienced during the continuationphase also play a role in determining whether ornot maintenance treatment should be imple-mented (AHCPR 1993; American PsychiatricAssociation 2000).

2.1.2 Treatment implementationKey elements of long-term treatment of re-current depressive disorders include 1) psycho-

education, 2) pharmacotherapy, and 3) ad-herence monitoring. Adjunctive depression-targeted psychotherapy may be included insome cases. Because maintenance treatmentrequires compliance with medication, educationand a close therapeutic alliance with patientsand their families are essential (Kupfer 1993).Education does not only reduce treatment attri-tion, but also leads to a better outcome (Rush1999). To prepare patients and their families formaintenance treatment, they should be inform-ed about the following topics: typical course ofthe illness, treatment options, medication effectsand side effects, use of (daily) self-report instru-ments to track mood and early warning signs ofrelapse or recurrence, long-term perspectives,and projected end of treatment. Patients shouldalso be instructed to inform all of their doctorsabout all the medications they are taking. It isalso important to inform the patient that severaldifferent treatments may need to be tried beforethe treatment that is best for them is identified.

Other principles of maintenance treatment areto distinguish between spontaneous symp-tomatic fluctuations ("blips") and "true" recurren-ces. In contrast to "blips", which are self-limited

and do not require specific interventions,recurrences must be treated aggressively. It is alsoimportant to regularly check adherence to medi-cation and to detect breakthrough symptomsearly on (Rush 1999).

Recently, a relapse prevention program (a lowintensity intervention including enhanced pa-tient education, visits with a depression specia-list, telephone calls, symptom monitoring) fordepressed patients in primary care significantlyimproved antidepressant adherence and depres-sive symptoms outcome in a randomized con-trolled 12-month trial compared with usualprimary care (Katon et al 2001).

The frequency of visits may range from monthlyvisits to every three to six months in stable

Table 1

Factors associated with increased risk for recurrence in major

depressive disorder

three or more episodes of major depression

high prior rate of recurrence (e.g., two episodes within five years)

previous episode in the last year

residual symptoms during continuation phase treatment

residual subsyndromal symptoms at remission

concurrent dysthymic disorder ("double depression")

severity of episodes (includes suicidality and psychotic features)

longer previous episodes

relapse after medication withdrawal

concurrent coexisting substance abuse

concurrent coexisting anxiety disorders

family history of major depressive disorder in first degree relatives

onset prior to age 30


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patients for (brief) psychiatric evaluation andmedication monitoring (e.g., side effect assess-ment, medication blood levels). In unstablepatients, more frequent visits are required. If thepatient develops a medical condition while onmaintenance treatment, potential drug-druginteractions should be considered. Patients/families should also be instructed to inform thetreating physician if and when signs ofdepression reoccur.

2.2 Pharmacotherapy of maintenancetreatment

2.2.1 Evidence of efficacyPharmacotherapy is the most studied treatmentmodality in the long-term maintenance treat-ment of recurrent unipolar depression. Amongthe therapeutic options available, antidepressantmedications and lithium have received the moststudy. The majority of controlled trials inves-

tigating these medications in maintenancetreatment demonstrated efficacy for relapseprevention (Level A) (Solomon and Bauer 1993;AHCPR 1993, 1999; Davis et al 1999).

The medications of first choice for maintenancetreatment in unipolar depression are either theantidepressant with which remission wasachieved in the acute/continuation phase orlithium (NIMH Consensus Development Confe-rence 1985; AHCPR 1993; Prien and Kocsis 1995;American Psychiatric Association 2000; Paykel2001). Likely reasons why antidepressants maybe preferred to lithium as prophylactic agents arethat patients are usually treated with anti-depressants during the acute/continuation phaseand that patients usually prefer to use medi-cation that does not require regular monitoringby blood tests (Figure 1). The final choice of pro-phylactic agent must depend on how individualpatients respond to and tolerate treatment withantidepressants and lithium (Schou 1997). Apatient's preference and their own or theirfamily members experience with maintenancetreatment should also be considered in thechoice of the medication.

2.2.1.1 AntidepressantsMany patients receive antidepressants during theacute and continuation phase, and the best treat-ment recommendation to prevent recurrence ofdepression is to continue the antidepressantmedication that was effective during the acuteand continuation phase of treatment at the samedose during the maintenance phase (Level B)(Frank et al 1993; Franchini et al 1998). In thesetwo latter studies, the group of patients whoreceived only half of the acute-phase dose ofimipramine (Frank et al 1993) or paroxetine(Franchini et al 1998), rather than the full dose,showed a significantly higher recurrence rate.Randomized placebo-controlled studies (usuallyfor one or two years during the maintenancephase) of antidepressants in the prophylactictreatment of depression indicate that TCAs

(amitriptyline, imipramine, nortriptyline, ma-protiline) (Level A), MAOIs (phenelzine) (LevelA) (Solomon and Bauer 1993; Montgomery1994; AHCPR 1993, 1999; American PsychiatricAssociation 2000; Paykel 2001) and SSRIs (LevelA) (citalopram [Hochstrasser et al 2001], fluo-xetine [Gilaberte et al 2001], fluvoxamine [Terraand Montgomery 1998] and paroxetine[Montgomery and Dunbar 1993]) are effective inpreventing recurrence of depression.

2.2.1.2 LithiumThe use of lithium as a maintenance therapy forunipolar recurrent depression is well established(Level A) (Goodwin and Jamison 1990; Schou1997; Dunner 1998; Coppen 2000; Paykel 2001).Two meta-analyses found evidence that lithiumis more effective than placebo in preventingrecurrence of unipolar depressive illness (Souzaand Goodwin 1991; Burgess et al 2001), whereby

the results were statistically significant in onlyone of these two studies (Souza and Goodwin1991). Over the past decade, evidence hasaccumulated from retrospective and prospectivestudies that long-term lithium prophylaxis mayreduce suicide risk and even normalize the highmortality rate (Level C) (Coppen et al 1990;Mller-Oerlinghausen 1992, 1994; Tondo et al1997; Schou 2000). A randomized 2.5-year

Maintenance

Treatment (MT)* with

AntidepressantEffective in Acute and

Continuation Phase

Recurrence (Breakthrough) during MTTreat Breakthrough EpisodeDiagnostic Reassessment

Consider Treatment Optimization or Change in MT**

Switch to Antidepressant

From Different Class

or

Combine Two

Different

Antidepressants

Switch to Antidepressant


or

Li + Antidepressant


or

Li + CBZ or CBZ

Abbreviations:CBZ = carbamazepine, MT = maintenance treatment, Li = lithium;

* Maintenance electroconvulsive therapy (ECT) is an option for patients responding

to ECT in the acute-phase treatment or who fail to respond to two or more

maintenance medication treatments

** Additional course of psychotherapy may also be considered.

Switch to

Antidepressant


Switch to Lithium

or

Antidepressant + Li

Figure 1Flow chart - Therapeutic options for maintenance treatment ofmajor depressive disorder


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maintenance treatment study in patients withmajor affective disorder showed significantlyfewer suicides and suicide attempts in thelithium group compared with the carbamaze-pine group (Thies-Flechtner et al 1996). Further-more, clinical findings suggest that the anti-suicidal property of lithium acts independentlyof its "classical" episode preventive effect (Schou1997; Bocchetta et al 1998; Grof 1998). However,a meta-analysis found no definitive evidence asto whether lithium has an anti-suicidal effectsince a small number of deaths and suicides, andthe absence of suicidal behaviour, were presentin the data analyzed (Burgess et al 2001).

Serum lithium levels of 0.5 to 0.8 mmol/L(mEq/L) drawn 12 hours after the last lithiumintake are usually recommended for mainte-nance treatment (Schou 1989). However, theoptimal serum lithium level may vary some-

what from patient to patient, in the range of 0.4to 1.0 mmol/L, depending on individual effec-tiveness and tolerability of side effects (Schou1989; Birch et al 1993). These recommendedserum lithium levels are usually achieved with adaily dose of 800 or 900 mg (dosage variesdepending on availability of lithium tablets) to1200 or 1500 mg lithium carbonate (600 mg to1000 mg for Asian patients) in patients 60 yearsof age or younger, or 400/450 mg to 800/900 mglithium carbonate in older patients (Birch et al1993). It is irrelevant for efficacy whetherlithium tablets are administered once or twicedaily. Some patients find that a single daily dosefacilitates long-term treatment compliance andreduces side effects. In general, extended releaseforms of lithium are better tolerated.

2.2.1.3 Carbamazepine and other moodstabilizers

Among the group of mood stabilizer medicationsthat are used for the treatment of bipolardisorder, the most studied agent in open andcomparator studies other than lithium is carba-mazepine (Level C). Carbamazepine has beenstudied in small double-blind comparator trialswith lithium in recurrent major depression (for

more information on study results see Chapter2.2.2 below) (Placidi et al 1986; Simhandl et al1993). Recommended serum levels of 4 to 12g/ml (17 to 50 mol/L), measured 12 hoursafter the last drug intake (and not sooner thanfive days after the last change in dosage unlesstoxicity is suspected), relate more to anticonvul-sant activity than to mood stabilizing efficacy ofrecurrent affective disorders. However, serumcarbamazepine levels can serve as guidelines formedication compliance and excessive adverseeffects (Bezchlibnyk-Butler and Jeffries 1996).Maintenance doses average about 800-1600mg/d, but may be lower in routine clinicalpractice. Because carbamazepine can induce itsown hepatic metabolism (via cytochromeCYP450 isoenzymes), determinations of serumcarbamazepine should be performed every

second week for the first two months after initialtreatment, every second month for the next sixmonths, and then at clinical discretionthereafter, or when there is a major change inthe dosage or drug regimen. Induction ofCYP3A4 by carbamazepine will also acceleratephase I reactions of drugs that are used inaddition to carbamazepine, if they are meta-bolized via CYP3A4 (Spina et al 1996). If doseadaptation of concomitant drugs is alsonecessary, monitoring of drug concentrations inthe serum can be useful.

Other mood stabilizers (e.g., valproate [dival-proex], lamotrigine or gabapentin) have not beenstudied in placebo-controlled or double-blindcomparator trials for the maintenance treatmentof unipolar depression (Davis et al 1999).

2.2.2 Comparative efficacy

A relatively small number of studies havedirectly compared different medications formaintenance treatment in recurrent unipolardepression (Solomon and Bauer 1993). A meta-analysis of studies comparing lithium with otherantidepressants showed no conclusive advantagefor lithium in the prophylaxis of unipolar illness(Souza and Goodwin 1991). In one relativelysmall randomized, placebo-controlled, two-yearmaintenance study, lithium (serum level 0.8-1.2mmol/L) was superior to imipramine (100-150mg/day); the combination of lithium and imi-pramine was not superior to lithium alone (Kaneet al 1982). Another, larger randomized, placebo-controlled, two-year study reported bettermaintenance effects for imipramine (the meandaily dosage at the start of the maintenancephase was 137 mg, range 75-150 mg/day) thanlithium (the mean serum lithium level at thestart of the maintenance phase was 0.66mmol/L, range 0.43-1.05 mmol/L) (Prien et al1984). In the latter study, the combination ofimipramine and lithium was not moreadvantageous than imipramine alone in pre-venting depressive recurrences. However, in alater reanalysis of the data, the same authorsconcluded that the results of the latter study

could be accounted for by alternative expla-nations that are a consequence of the studydesign (Greenhouse et al 1991). One random-ized, prospective, open 2.5-year trial comparinglithium (average serum lithium level 0.59mmol/L) with amitriptyline (average dosage 98mg/day) found significantly better prophylacticefficacy for lithium (Greil et al 1996a).

A randomized, three-year maintenance study ina group of patients with major affective disordershowed equal efficacy for lithium and carba-mazepine (Placidi et al 1986); for these twomedications, similar results were obtained in arandomized two-year study of unipolar depres-sion (Simhandl et al 1993). Although theevidence for prophylactic efficacy of carbamaze-pine in unipolar depression is limited, results


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indicate that carbamazepine may be an alter-native for those patients who do not tolerate orrespond to maintenance treatment with lithiumor antidepressants (Level C) (Figure 1).

In the largest and probably most influentialstudy on the use of antidepressants in main-tenance treatment, a randomized three-yearplacebo-controlled trial, survival analysisshowed full-dose imipramine (mean dose atrandomization 215 mg/day) with or withoutInterpersonal Therapy (IPT; weekly for 12 weeks,then bi-weekly for eight weeks, and thenmonthly) to be the best maintenance treatment,followed by IPT with or without placebo, andthen placebo (Frank et al 1990). In this study ofhighly recurrent unipolar depression, all patientsenrolled in the three-year study had remitted onthe combination of imipramine and IPT, and allhad remained well for four months of continua-

tion therapy prior to randomization. A sub-sequent additional two-year placebo-controlledstudy of the patients who completed the three-year study (Frank et al 1990) showed thatimipramine (average dose of 200 mg/day) wassignificantly better than placebo in preventingrecurrence (Kupfer et al 1992).

A number of more recent studies suggest that the"newer" antidepressants (see Part 1 of theseguidelines [Bauer et al 2002]) have superior long-term efficacy and better tolerability comparedwith traditional TCAs (Level B) (Montgomery1999). A randomized, placebo-controlled, two-year study comparing the efficacy of mirtazapinewith that of amitriptyline found that the timeto relapse was significantly longer in the mirta-apine group (Montgomery et al 1998). Similarly,a double-blind one-year study reported signifi-cantly greater improvement in some of theoutcome measures in the venlafaxine groupcompared with imipramine (Shrivastava et al1994).

2.2.3 Tolerability and side effects ofmaintenance medications

The long-term side effects and tolerability of

medications are key considerations in maxi-mizing adherence to treatment. Side effectsshould be as minimal as possible. Even mild tomoderate side effects during maintenancetreatment may lead to noncompliance, with theconsequence of symptom worsening and in-creased risk of recurrence. Using medicationswith a more favourable side effect profile thanthe TCAs may facilitate patient compliance withpharmacotherapy, as long as these agents areeffective in the maintenance treatment ofdepression. The "newer" antidepressants areassociated with fewer long-term side effects thanthe older tricyclics and tetracyclics (for detailsabout side effects of antidepressants see: Part 1 ofthese guidelines [Bauer et al 2002]; Peretti et al2000; AHCPR 1993, 1999; American PsychiatricAssociation 2000).

One advantage of maintenance therapy withlithium is the long experience with this agentworldwide, making the risks of long-termtreatment more clear. Specialized LithiumClinics for the prophylactic long-term treatmentof patients with affective disorders have beenestablished for more than 30 years in manycountries and have provided longitudinalassessments of the side effects of lithiumtreatment (Schou 1997).

During the long-term use of lithium, regularlaboratory monitoring of the serum lithium level(performed once to four times per year, and morefrequently if clinically required, e.g., in the earlystages of treatment, with older patients or afterclinical changes have become apparent), thyroidfunction (e.g., TSH level) and renal function(creatinine) (e.g., once or twice a year) is re-commended (Birch et al 1993; American

Psychiatric Association 1994b; Schou 1997;Kleiner et al 1999). The purpose of measuringserum lithium levels is to ensure that high serumlithium levels are detected and lowered, and toensure that steps are taken to prevent recurrencein case of abnormally low serum lithium levels.It is also important to educate patients and theirfamilies about the warning signs of lithiumtoxicity. Among the common side effects oflithium treatment are the development of hypo-thyroidism and goitre resulting from theinterference of lithium with the synthesis andrelease of thyroid hormones from the thyroidgland (Lazarus 1998). The prevalence of overt("clinical") hypothyroidism has been reported tobe between 8% and 10% in patients takinglithium, compared to a prevalence of 0.5% to1.8% reported in the general population (Kleineret al 1999). Even higher rates have beenestimated for the prevalence of subclinicalhypothyroidism (in 23% of patients on lithiumtherapy compared to rates of up to 10.4% in thegeneral population) (Kleiner et al 1999).

In the past, many concerns have been raisedabout whether long-term lithium exposure maycause irreversible kidney damage. A recent

comprehensive review stated that in the vastmajority of patients, the tubular damage is notassociated with significant changes in glo-merular filtration rate (Gitlin 1999). Clinicallyimportant glomerular dysfunction resultingfrom lithium treatment is rare and is unrelatedto the duration of lithium therapy (Schou 1997;Gitlin 1999). A small percentage of patientstreated with lithium may develop rising crea-tinine concentrations after 10 years or more oftreatment. However, in patients treated withlithium for 15 years or more, affection of bothglomerular and tubular function seems to bemore common (Bendz et al 1994).

Side effects of lithium treatment are usually dosedependent and can often be prevented orrelieved by a moderate reduction in dosage

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(American Psychiatric Association 1994b). Sideeffects may include: hand tremor (counteractedby a -blocker), goitre and hypothyroidism(additional administration of L-thyroxine [L-T4]to achieve euthyroid status), lowered renal con-centrating ability and polyuria and/or polydipsia(warning against dehydration, possibly reduc-tion of dosage), weight gain (moderate dietingand exercise), gastrointestinal problems (e.g.,nausea, dyspepsia, loose stools; managed byadministering lithium with meals, switchinglithium preparations or dose reduction) and,rarely, memory impairment/mental slowness(dose reduction) (Birch et al 1993; AmericanPsychiatric Association 1994b). The most diffi-cult side effect to treat is polyuria, which maypersist in rare cases. Management includes ensur-ing that the lithium dose is as low as possible,switching to another lithium formula, switchingto a single daily dose or changing the time of day

when the medication is taken. In severe cases oflithium-induced polyuria, treatment with amilo-ride, a potassium-sparing diuretic or a thiazidediuretic may be tried (Cave: risk of thiazide-induced hypokalemia) (Jefferson et al 1987).

The most common side effects of carbamazepineinclude neurological symptoms (e.g., diplopia,blurred vision, fatigue, ataxia; usually dose-related, often transient and reversible withdosage reduction), skin rashes, mild leukopeniaand thrombocytopenia (both usually reversiblewith dose reduction; they may reverse spon-taneously with continued treatment, however,close monitoring is required), mild liver enzymeelevations and hyponatremia (American Psy-chiatric Association 1994b). Monitoring oflaboratory values (blood count, liver enzymes,electrolytes) is recommended two to four timesper year during maintenance treatment (Greil etal 1996b). Rare, idiosyncratic but potentiallyfatal side effects of carbamazepine (occurringusually in the first six months of treatment)include agranulocytosis, aplastic anaemia, hepa-tic failure, exfoliative dermatitis (e.g., Stevens-

Johnson Syndrome) and pancreatitis (AmericanPsychiatric Association 1994b). Because these

idiosyncratic fatal side effects occur very rapidly,education of the patient about the signs andsymptoms of hepatic, haematological or derma-tological reactions, and instructions to reportsymptoms if they occur, are essential fortreatment with carbamazepine.

2.2.4 Treatment of symptomaticworsening and recurrence

Brief, mild depressive symptoms ("blips")frequently occur during maintenance treatment.They are self-limited and, in contrast to recurren-ces (breakthrough episodes), do not requirespecific interventions or a change in the mainte-nance treatment plan. Psychiatric management(e.g., including dose adjustment, reassurance)and additional short-term treatment with abenzodiazepine or hypnotic medication to treat

insomnia and/or anxiety, or an adjunctivecourse of psychotherapy to help address specificpsychosocial stressors or stressful life events,may be useful (Rush 1999).

Many patients have a somewhat predictablepattern of symptoms that appear during aprodromal phase of a full-blown recurrence.When a patient suffers a recurrence of adepressive episode despite ongoing maintenancetreatment (breakthrough episode), physiciansface a considerable challenge. Early interventioncan shorten the length of the episode (Kupfer etal 1989). The "differential diagnosis" of arecurrence includes evaluation of occult sub-stance abuse, occult physical illness (e.g., thyroiddysfunction), nonadherence to medication, andthe possibility of adverse life events (Rush 1999).Patients experiencing a new depressive episodewhile taking a mood stabilizer or an anti-

depressant may benefit from treatment opti-mization (e.g., increase of serum level to theupper end of the therapeutic level, addition ofthyroid hormone if thyroid function is low[particularly in lithium-treated patients], addi-tional psychotherapeutic interventions andvisits). If the patient does not improve withtreatment optimization, another round of ade-quate acute phase treatment should be initiatedfollowed by continuation treatment (see Part 1of these guidelines [Bauer et al 2002]). Thetreatment plan for subsequent maintenancetherapy should be reevaluated and a switch inthe choice of the prophylactic medicationshould be considered (Figure 1).

2.2.5 Maintenance treatment options forprophylaxis-resistant depression

There is growing recognition that prophylactictreatment of affective disorders may be inade-quate in a substantial proportion of patients. Themaintenance treatment of patients with re-current depression who experience recurrencesduring prophylactic treatment with standardagents, e.g. lithium or antidepressants, is one ofthe most challenging issues in the treatment ofthese disorders. However, little data from formal

studies is available to guide physicians in themaintenance treatment of patients sufferingfrom recurrences during standard prophylactictreatment (Bauer and Helmchen 2000). An algo-rithm including some options for the mainte-nance treatment of patients with MDD ispresented in Figure 1. Combining an anti-depressant with lithium, or combining lithiumwith carbamazepine, or combining two differentantidepressants, are among the possible options.Adjunctive treatment with thyroid hormone (L-thyroxine) in supraphysiological doses has alsobeen suggested for maintenance treatment ofpatients with prophylaxis-resistant depression(Bauer et al 2001). However, it should be em-phasized that evidence of the efficacy of thesecombinations and of thyroid augmentation islimited (Level D).


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2.3 Duration and discontinuation ofmaintenance treatment

The optimal moment to discontinue a long-termmedication is difficult to predict. Currentevidence suggests that maintenance treatmentshould be continued as long as the risk ofrecurrence persists (Brunello et al 1995). Thatrisk is often difficult to assess in the individualpatient, particularly after a long period (years) ofabsence of symptoms/recurrence. It appears thatthe likelihood of a recurrence increases with thenumber of previous depressive episodes (Angst1999). However, some authors have argued thatthere is a similar risk of recurrence whethermedication is discontinued after months or yearsof pharmacotherapy (Thase 1999). There is goodevidence from a controlled five-year study thatpatients who benefit the most from continuedprophylaxis are those who receive active full-dose medication for at least five years (Level C)

(Kupfer et al 1992). Thus, for some patients,maintenance treatment is required for very longperiods (e.g., a decade), and for others it isrequired indefinitely (Rush and Kupfer 2001).Three years maintenance therapy is appropriatealmost as a routine for recurrent patients, parti-cularly where an episode prior to the present onehas occurred in the last five years or whereremission has been difficult to achieve. Mainte-nance for five years or indefinitely is recommen-ded for those patients at greater risk, particularlywhere two or three attempts to withdrawmedication have been followed by anotherepisode within a year.

Regardless of the reason for discontinuation,after long-term pharmacotherapy the patientshould be educated about the risk of recurrenceand its early warning signs. Three phenomenathat may occur after discontinuing long-termantidepressant medications need to be dis-tinguished: recurrence of episode (return of theoriginal symptoms), rebound (return of originalsymptoms but with greater intensity; typicallyoccurs if lithium or antidepressants are with-drawn too rapidly), and withdrawal (develop-ment of different symptoms related to drug

stoppage; typically occurs if TCAs and SSRIs areabruptly stopped) (Paykel 2001). In clinicalpractice, antidepressants should always be with-drawn slowly after maintenance therapy. Atapering period of four to six months isrecommended in long-term treated patients toallow the early detection of emerging symptomsand to minimize the risk of antidepressantmedication discontinuation syndromes. Duringthe period of discontinuation, the patient shouldbe monitored more closely. And after the dis-continuation is complete the monitoring shouldcontinue during the next couple of months (e.g.,particularly for the next six months, whichappear to be a period of high risk for recurrence;Rush and Kupfer 2001) to identify those inwhom a relapse is likely. If the full depressiveepisode recurs during or after discontinuation, a

full therapeutic dosage should be readministeredpromptly (AHCPR 1993).

Antidepressant discontinuation syndromes havereceived little systematic study. Thus, most of therecommendations in the literature and in theseguidelines are based on anecdotal data or expertopinion. It is agreed that a common feature ofantidepressant discontinuation syndromes is theonset of symptoms within a few days of stoppingthe antidepressant or, less commonly, within afew days of reducing the dosage (Haddad 2001).Discontinuation symptoms are more likely tooccur when abruptly stopping the dosage. Theyhave been described with all classes of anti-depressants, including TCAs (particularly thosewith anticholinergic and serotonergic potency),irreversible MAOIs, SSRIs and venlafaxine(Lejoyeux and Ades 1997; Edwards andAnderson 1999). Data from a randomized con-

trolled trial (RCT) showed that discontinuationsymptoms are more common with a shorter-acting SSRI, such as paroxetine, than with alonger-acting agent, such as fluoxetine (Rosen-baum et al 1998). Withdrawal phenomena (e.g.,dizziness, balance and sensory disturbance,nausea or emesis, fatigue, headache, gait insta-bility, irritability, vertigo or feeling faint, andinsomnia) differ in pattern from those ofdepressive recurrence. Withdrawal is usuallymild but may be serious for the irreversibleMAOIs. Typically these symptoms subside withthe reinstatement of the original drug (Haddad2001). Although not supported by controlleddata, discontinuation reactions appear lessfrequently in shorter courses of treatment(Anderson et al 2000).

2.4 Switching from unipolardepression to bipolar disorder

A change of diagnosis over time from unipolardepression to bipolar disorder has been describedin approximately 10% to 20% of patients (Angstet al 1978; Akiskal et al 1995; Solomon et al1997). Antidepressants, particularly TCAs, pre-cipitate mania in some patients with apparentunipolar depression (Altshuler et al 1995). Early

age at onset of MDD, greater acuteness, pleo-morphic psychopathology and high rates ofsubstance abuse have been identified as clinicalpredictors of the switch to hypomania (Akiskal etal 1995). If a switch to mania occurs during themaintenance phase treatment in unipolardepression, rapid tapering of the antidepressantand concomitant treatment of the manicepisode is essential (for more information on thetreatment of bipolar disorder, see WFSBP Guide-lines for the Treatment of Bipolar Disorder[Grunze et al In Press]).

2.5 Electroconvulsive therapy (ECT)Case reports and case series have reported on thesuccessful use of ECT in the maintenance phaseof treatment (Level D) (Nobler and Sackeim2000). Periodic (maintenance) ECT has been re-


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commended for patients who fully respondedduring the acute treatment phase, and especiallyfor those who are not eligible for or who fail torespond to maintenance medication treatment.Usually, about one or two ECT treatments permonth is recommended. Due to the lack ofcontrolled and well-defined outcome studies, thelong-term risks of maintenance ECT studies areunknown.

2.6 PsychotherapySimilar to Part 1 (Bauer et al 2002), these guide-lines focus on biological (somatic) treatments.Therefore, psychotherapeutic treatments aloneor in combination with pharmacotherapy willonly be mentioned briefly and no levels ofevidence will be provided. Instead, references forfurther reading are given.

Although maintenance psychotherapy as the

sole treatment to prevent recurrence is lessstudied, and at this point not recommended as afirst-line treatment unless the patient does notwish to or cannot take medication for somereason (e.g., pregnancy) (AHCPR 1993), it is atreatment option for some patients. Preliminarydata suggest that cognitive behavioural therapy(CBT) may be an effective treatment for pre-venting recurrence in patients with recurrentmajor depression (Teasdale et al 2000; Jarrett etal 2001), including patients who have beensuccessfully treated with antidepressant drugs(Fava et al 1998). There is some indication thatpatients with residual depression benefit fromCBT for preventing recurrence (Fava et al 1998;Paykel et al 1999). Maintenance interpersonalpsychotherapy (IPT-M) has also been suggestedby others (Frank et al 2000).

The effectiveness of combined antidepressantmedication and psychotherapy has not beenwell studied in the maintenance phase. Somestudies have failed to find the combination to besuperior to either treatment modality alone inpatients with mild to moderate depression(American Psychiatric Association 2000). If psy-chotherapy, e.g., cognitive behavioural therapy

or interpersonal therapy, is combined with medi-cation, maintenance phase treatment usuallyinvolves a decreased frequency of psychothera-peutic sessions compared to the acute andcontinuation phase (e.g., once a month).

2.7 Maintenance-phase treatment ofMDD in special age groups

2.7.1 Children and adolescentsThe American Academy of Child and AdolescentPsychiatry (1998) emphasized that there are nopublished data from RCTs regarding mainte-nance treatment of children and adolescentswith MDD. Because the clinical presentations,sequelae and natural course of depression inyouths are similar to those of depression inadults, the general guidelines for treatment ofadults also apply to the treatment of adolescents

(American Academy of Child and AdolescentPsychiatry 1998).

2.7.2 Older adultsThe efficacy and safety of nortriptyline inpreventing recurrence of major depressiveepisodes in patients older than 59 were welldetermined in a three-year placebo-controlledmaintenance study of nortriptyline combinedwith psychotherapy and nortriptyline mono-therapy (Reynolds et al 1999a). Other controlledstudies have also supported the efficacy ofnortriptyline in preventing recurrence of majordepressive episodes in older adults (Level A)(Georgotas et al 1989; Reynolds et al 1999b).Nortriptyline has been well tolerated in long-term maintenance studies of older adults. Exceptfor a consistent increase in heart rate and drymouth, no other adverse events were detected incomparison with placebo (Marraccini et al 1999).

A similar robust maintenance effect was foundwith the MAOI phenelzine in a placebo RCT inolder adults (Level C) (Georgotas et al 1989).

The SSRIs are being studied as alternatives fornortriptyline in the maintenance treatment ofrecurrent depression in older adults (Reynolds etal 2001). In an open, 18-month study, paroxe-tine has been shown to be comparable to nor-triptyline in preventing recurrences of depres-sion in older adults (Level C) (Bump et al 2001).

3 Treatment of chronic depressivedisorders

3.1 IntroductionUndertreatment and social impairment are themost striking characteristics of chronic depres-sive disorders. Patients with chronic depressionare often not treated, or treated inadequately(Keller et al 1995a). It has been estimated thatthe response rates for chronically depressedpatients are equal to or slightly lower (40% to55%) than those of nonchronic populations(Howland 1991), and relatively low placeboresponse rates have been reported in thesepatients (Rush and Thase 1997). When sympto-

matic improvement occurs with pharmaco-therapy in chronic depression, it is associatedwith functional restoration (Miller et al 1998).This all indicates that patients with chronicdepression may well benefit from medicationtreatment. There is also evidence from a con-trolled study that patients with major depressionwho have residual symptoms may improve withcognitive behavioural treatment (Fava et al1994). Another study of patients with chronicdepression found that patients with a combina-tion of CBT and nefazodone were more likely tohave a favourable response than patients witheither treatment alone (Keller et al 2000).

3.2 Dysthymic disorderICD-10 defines dysthymia broadly as a chronicdepression of mood that does not currently fulfil

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the criteria for recurrent depressive disorder interms of either severity or duration of individualepisodes (WHO 1991). Similarly, DSM-IVcharacterizes dysthymic disorder as a chronicmild depressive syndrome that has been presentfor two years or longer (American PsychiatricAssociation 1994a). Individuals with dysthymiafrequently have a superimposed major depres-sive disorder ("double depression") (see Chapter3.3). Patients with "double depression" are lesslikely to have a complete recovery than arepatients with major depressive disorder withoutdysthymia (American Psychiatric Association2000). However, patients with "double depres-sion" who are treated during a major depressiveepisode also benefit with respect to theirdysthymia (Akiskal 1994).

Dysthymia is a relatively common disorder witha median point prevalence of 2.1% across studies

worldwide (Wittchen 2000). The lifetime pre-valence has been estimated to be between 3.1%(Weissman et al 1988) and 6.4% (Kessler et al1994). There is epidemiological evidence of highcomorbidity (75%) with other psychiatric dis-orders, mostly major depression, anxietydisorders and substance abuse.

3.2.1 Pharmacotherapy of dysthymicdisorder

Traditionally, dysthymic disorder has not beenthe focus of pharmacotherapeutic interventions,given the chronicity and presumed nonbiologi-cal personality variables associated with it (How-land 1991). Psychotherapy and psychoanalysiswere generally considered the treatment optionsof first choice, although these treatment modali-ties were not well studied in controlled designs.However, as a result of a series of placebo-con-trolled medication trials, this attitude has recent-ly been changing (Shergill and Katona 2000).

Among the antidepressants found to be superiorto placebo were desipramine (Kocsis et al 1996;Miller et al 2001), fluoxetine (Hellerstein et al1993), moclobemide (Versiani et al 1997), imi-pramine and sertraline (Thase et al 1996; Keller

et al 1998b). In a double-blind study comparingphenelzine with imipramine, the MAOI wasmore effective (Vallejo et al 1987). Although theamount of data from controlled studies is stilllimited, a comprehensive review has confirmedthe efficacy of various antidepressants indysthymic disorder (Level A) (World PsychiatricAssociation Dysthymia Working Group 1995). Arecent meta-analysis of 15 randomized con-trolled trials that used various drugs (mostlyantidepressants, TCAs, SSRIs and MAOIs) versusplacebo in the treatment of dysthymia showedthat drugs are more effective than placebo, withno difference between and within classes ofdrugs (Lima and Moncrieff 2001).

Although the optimal length of pharmaco-therapy in dysthymia has not been studied in a

controlled design, a course of treatment with anantidepressant for at least two to three years isrecommended. Patients treated with TCAs weremore likely to report adverse events comparedwith those treated with placebo in placebo-controlled trials (Lima and Moncrieff 2001).Results of a randomized, double-blind study ofsertraline and imipramine indicated thatpatients suffering from chronic major depression(i.e., unremitting major depression for at leasttwo years or dysthymia with a concurrent majordepression) can achieve a good therapeuticresponse with acute pharmacotherapy (Keller etal 1998a). In this study, both antidepressantswere equal in overall efficacy, but sertraline wasbetter tolerated. Thus, superior tolerability andbetter side effect profiles compared to the "older"antidepressants, e.g., TCAs, make the SSRIsand other "newer" antidepressants the primecandidates for the long-term treatment of

dysthymia (Level A).

Recommended doses for dysthymia are similarto those given for acute treatment of a majordepressive episode. No systematic research hasbeen undertaken to study treatment options forpatients with dysthymia who do not respond toan adequate first trial. Under such circum-stances, switching to an antidepressant of adifferent class seems to be an appropriate option.

Geriatric dysthymia is an understudied condi-tion (Kocsis 1998). In one placebo-controlledstudy, paroxetine showed moderate efficacy inreducing depressive symptoms in geriatricdysthymia (Williams et al 2000).

3.3. "Double depression" and otherchronic depressions

It has been estimated that chronic depressivedisorders account for 30% to 35% of all cases ofdepression (Kessler et al 1994). As many as 25%of patients with major depression have co-existing dysthymia, and more than 50% of thepatients with dysthymic disorder will develop amajor depressive episode at some point in timeafter the onset of their dysthymia ("double

depression") (Keller and Shapiro 1982; Keller et al1995b). Patients with "double depression" have aparticularly chronic and severe course of illness.In a study comparing outpatients with "doubledepression" to outpatients with episodic majordepression, patients with "double depression"exhibited significantly greater impairment, moresevere depressive symptoms, greater comor-bidity, more personality disturbance, lower levelsof social support, more chronic strains, andhigher rates of bipolar II and nonbipolar affec-tive disorders in first-degree relatives (Klein et al1988). In addition, patients with "double depres-sion" are significantly less likely to fully recover.

Recent randomized controlled trials have shownseveral medications (desipramine, Kocsis et al1996; imipramine and sertraline, Keller et al


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1998a; nefadozone, Keller et al 2000) to beefficacious in the treatment of chronic depres-sion, including "double depression" (Level A).The basic principles of treatment for chronicdepression involve adequate acute-phase medi-cation dosing for an appropriate length of time.Once full remission is achieved, the continua-tion and maintenance of pharmacotherapylowers the risk of relapse and recurrence (Kocsiset al 1996; Nierenberg 2001; Trivedi and Kleiber2001). There is evidence that patients withchronic depression particularly benefit from acombination of pharmacotherapy and psycho-therapy, as seen in the combination of nefado-zone and cognitive behavioural analysis systemof psychotherapy (CBASP) (Keller et al 2000).

4 Subthreshold depressions

During the last decade, there has been growing

interest in understanding the importance of de-pressive symptoms that do not reach the thres-hold for major depressive disorder (Angst andErnst 1993; Sherbourne et al 1994; Pini et al1999; Angst et al 2000; Geiselmann and Bauer2000; Sadek and Bona 2000). The term "subthres-hold depression" is now generally defined as apatient who suffers from a cluster of depressivesymptoms, of which the number, duration orquality is insufficient to meet the DSM criteriafor a diagnosis of major depression (Sadek andBona 2000). Subthreshold depression includesthose patients who meet criteria for minor depres-sive disorder (MinD), recurrent brief depressive disor-der (RBD) (Angst and Hochstrasser 1994) and sub-syndromal symptomatic depression (SSD) (Judd et al1994). In DSM-IV, these disorders fall under thecategory of depressive disorders not otherwisespecified (NOS). The essential feature of MinD isone or more period of depressive symptoms thatis identical to major depressive episodes induration, but that involves fewer symptoms andless impairment (DSM-IV, American PsychiatricAssociation 1994a). Individuals whose presenta-tion meets the criteria for minor depressive dis-order would be diagnosed as having "adjustmentdisorder with depressed mood" if the depressive

symptoms occur within three months of the on-set of a psychological stressor (DSM-IV). In RBD,the number and severity of symptoms are identi-cal to those in major depressive episodes and lastat least two days, but less than two weeks. Juddet al (1994) defined subsyndromal symptomaticdepression (SSD) as the simultaneous presence ofany two or more symptoms of depression, butexcluding anhedonia and depressed mood,which are present for most or all of the time, andare at least two weeks in duration. These symp-toms are associated with evidence of socialdysfunction occurring in individuals who do notmeet criteria for diagnoses of minor depression,major depression, and/or dysthymia.

It should be emphasized that these subthresholddepressive disorders are highly prevalent in the

general population and in primary care settings,thus having a substantial impact on the mentalhealth system (Sherbourne et al 1994; Judd et al1994, 1996).

Controlled treatment data involving pharmaco-therapy of these disorders is sparse. The majorityof published studies are case reports, open labelstudies or retrospective analyses (Rapaport and

Judd 1998; Stamenkovic et al 1998; Pini et al1999). In one RCT of patients with recurrent briefdepression, fluoxetine was not superior to placeboin preventing recurrences (Montgomery et al1994). However, in an open-label study of fluo-xetine, the frequency of recurrences was signifi-cantly lower (Stamenkovic et al 2001). In an RCTof minor depression, paroxetine showed higherresponse rates compared with maprotiline, butno placebo-comparison was included (Szegedi etal 1997). In an RCT in older adults with minor

depression, paroxetine improved depressivesymptoms to a greater degree and more rapidlythan placebo plus clinical management(Williams et al 2000).

Given the limited data from controlled studiesfor subthreshold depressive disorders, evidence-based treatment recommendations cannot begiven at this point. Close monitoring andproblem-solving therapy for recent onset casesmay be useful, and a treatment trial with one ofthe well-tolerated antidepressants is worth tryingin more chronic and unremitting cases. RCTs ofantidepressants in well-defined populations arewarranted. The same is true for the treatment ofadjustment disorder with depressed mood (Joneset al 1999).

Disclosure statementThe preparation of these WFSBP guidelines hasnot been financially supported by any commer-cial organization.

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