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 AttentionDeficit/Hyperactivity Disorder (ADHD): Clinical versus Experimental Measures of Impulsivity Robert D. Oades, Michael Slusarek, Silke Velling, Brigitta Bondy 96 Original Investigations/Summaries of Original Research Rate of Oxygen Consumption in Seasonal and Non-Seasonal Depression Boris 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

World J Biol Psychiatry (2002) 3, 64 - 67

Editorial
Clinical Psychopharmacology Guidelines: Different Strokes for Different Folks
In recent years there has been a growing focus on the importance of "evidence-based medicine" the conscientious and judicious use of current best evidence in making decisions about the care of individual patients (Rosenberg and Donald 1995; Sackett et al 1996). This focus is understandable, for many reasons. First, from a scientific point of view it is crucial that physicians are able to justify their decision-making. Similarly, from the perspective of both professional associations and consumer advocates, it is important that medical practice be of high quality. Finally, economic pressures to practice medicine as efficiently as possible are an important driving force. There are several different ways of encouraging the practice of evidence-based medicine. Particularly important is the development of clinical guidelines (Rush 2001; Woolf 1992). These have been issued by a range of governmental agencies, professional associations and specialty groups. Several questions arise, including whether the development of guidelines is itself scientific (Institute of Medicine 1992; Shaneyfelt et al 2001), whether their dissemination significantly improves clinical practice (Davis et al 1995; Grimshaw and Russell 1993), and how to choose between multiple, sometimes conflicting guidelines (Davis et al 1995). Guidelines can be supplemented with algorithms, or rule-based deductive systems that operate with inputs, sequences and outputs, and that help the clinician select information that is relevant to decision making. In our experience of developing algorithms for clinical psychopharmacology (Jobson and Potter 1995; Stein and Jobson 1996; Fawcett et al 1999; Patterson 1999), we have been impressed with the differences in the advantages and disadvantages of these cognitive tools across various clinical settings. In particular, we have noted that guidelines and algorithms in developed and developing countries may have different emphases and aims, and may require somewhat different approaches. Thus, in the developed world, there is a growing evidence-base of controlled medication trials for psychiatric disorders. These trials are typically conducted in academic research settings, and may be particularly relevant to the many specialized practitioners who work in such contexts. On the other hand, this database is often sponsored by the pharmaceutical industry, with the aim of showing short-term efficacy and tolerability for registration purposes (Klein 1993). A number of important biases may result, including the potential overestimation of the efficacy and tolerability of more recently introduced agents, and a relative failure to appreciate issues of effectiveness in generalist settings. Particularly important current questions, for example, are whether newer antidepressants are more quick acting, or whether new generation antipsychotics are more effective than older ones. Careful judgment is required to differentiate scientific advances from marketing hype. Guidelines based on systematic review of the literature (Cook et al 1997) can be helpful. In the developing world (and in some primary care settings), where fewer trials are undertaken, and where relevant effectiveness issues are not necessarily addressed by the data, there may be a temptation to emphasize evidence that emerges from clinical experience rather than from controlled

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trials. The available database may be found lacking in the developing world, for example, in addressing whether preventive interventions or redeployment of resources are more important than the implementation of treatment (Birch 1997; Woolf 1999). Also, studies showing the cost-efficacy of 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 whether traditional medications or non-patented but readily manufactured agents are as effective as marketed products, or whether certain older and cheaper medications are in fact as well tolerated as more newly introduced agents. Again, rigorous guidelines may be useful in helping to optimize decision-making. Another contrast between the developed and developing world lies in the aim of guidelines. In the developed world, guidelines have often been associated with an attempt to restrict unnecessary overtreatment and to reimburse only appropriate treatment. In the developing world (and in primary care), on the other hand, there is often a particular need to counter the underrecognition and undertreatment of a disorder, so indirectly reducing costs. There is a need for additional systematic research on how best to encourage evidence-based medicine, and on how best to develop and implement guidelines and algorithms. Data that reporting the evidence or issuing practice guidelines does little to change clinical practice (Davis et al 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 again be 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 specific nor excessively general (Rush 2001). In the developed world, however, the availability of superspecialized practitioners means that greater specificity (and incorporation of clinical experience) is useful. In the developing world (and in primary care) relatively simple guidelines that succinctly emphasize the most universally accepted (and clearly data-based) interventions may be needed in order to maximize resources. Second, guideline dissemination and implementation. Although print publications remain widely used in the developed world, computerization and the internet are likely to play an increasingly important role in the future dissemination and implementation of guidelines in clinical psychopharmacology (Stein et al 1994; Trivedi et al 2000). Nevertheless, in developing countries where print 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 is important 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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hand, many aspects of Western guidelines may require significant adjustment. Common diagnoses may not fit neatly into DSM-IV categories, and there may be frequent use of a range of additional interventions (e.g. traditional medication). Along the same lines, it is important that guidelines and algorithms in clinical psychopharmacology promote rather than hinder the doctor-patient relationship. In both the developed and the developing world, there is an important risk of patients feeling alienated by the scientific model and its emphasis on the evidence base. Certainly, patients throughout the world frequently turn to alternative and unproven approaches. Nevertheless, we are optimistic that the development of guidelines and algorithms that aim at enhancing the practice of evidence-based medicine can be helpful for clinicians and patients. Even when important data is lacking, such efforts may be useful in emphasizing the need for additional research (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 this point in time (Jaffe and Yager 1999; Katon et al 1995). In the United States, large-scale empirical studies of algorithms are currently under way, and these will contribute to our understanding of the value of the careful development and implementation of decision-tools for clinical psychopharmacology (Rush et al 1999). In developing countries, there is a relative dearth of research on such tools, and efforts to encourage the careful examination of their pros and cons should be strongly encouraged. Dan J. Stein1, Yu Xin2, David Osser3, Xiangyang Li3, Kenneth Jobson4
1 2 3 4

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

Correspondence: Dan J. Stein, M.D., Ph.D. MRC Unit on Anxiety Disorders University of Stellenbosch PO Box 19063 Tygerberg 7505 Cape Town South Africa Tel: +27 21 938 9161 Fax: +27 21 933 5790 E-mail: djs2@sun.ac.za

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References Alderson P, Roberts I (2000) Should journals publish systematic reviews that find no evidence to guide practice? Examples from injury research. BMJ 320: 376-377. Birch S (1997) As a matter of fact: Evidence-based decision-making unplugged. Health Economics 6: 547-559. Boyle PJ (1998) Getting Doctors to Listen: Ethics and Outcomes Data in Context. Georgetown University Press, Washington, D.C. Cook DJ, Greengold NL, Ellrodt AG, Weingarten SR (1997) The relation between systematic reviews and practise guidelines. Ann Int Med 127: 210-216. Davis DA, Thomson MA, Oxman AD, Haynes RB (1995) Changing physician 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 Treatment Algorithms in Psychopharmacology. John Wiley, Chichester. Freeman AC, Sweeney K (2001) Why general practitioners do not implement evidence: qualitative study. BMJ 323: 1100. Grimshaw JM, Russell IT (1993) Effect of clinical guidelines on medical practice: A systematic review of rigorous evaluation. Lancet 342: 1317-1322. Institute of Medicine (1992) Guidelines for Clinical Practice: From Development to Use. National Academy Press, Washington, D.C. Jaffe SL, Yager J (1999) APA practice guidelines: A pilot study of a district branch-based educational awareness: Awareness and reactions. Academic Psychiatry 23: 9-13. Jobson KO, Potter WZ (1995) International Psychopharmacology Algorithm Project. Psychopharmacol Bull 31: 457-459. Katon W, Von Korff M, Lin E, Walker E, Simon GE, Bush T, Robinson P, Russo J (1995) Collaborative management to achieve treatment guidelines: Impact on depression in primary care. JAMA 273: 10261031. Klein DF (1993) Clinical psychopharmacological practice: The need for a developing research base. Arch Gen Psychiatry 50: 491-494. Patterson RD (1999) The Harvard Psychopharmacology Algorithm Project. 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. BMJ 312: 71-72. Shaneyfelt TM, Mayo-Smith MF, Rothwangl J (2001) Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peer-reviewed medical literature. JAMA 281: 1900-1905. Stein DJ, Jobson KO (1996) Psychopharmacology algorithms: Pros and cons. Psychiatric Annals 26: 190-191. Stein DJ, Patterson B, Hollander E (1994) Expert systems for psychiatric pharmacotherapy. Psychiatric Annals 24: 37-41. Trivedi MH, Kern JK, Baker SM, Altshuler KZ (2000) Computerizing medication algorithms and decision support systems for major psychiatric 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-based medicine. JAMA 282: 2358-2365.

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

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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, Marcio Versiani4, Hans-Jrgen Mller5, WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders6
1 2 3 4 5 6

University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA Humboldt University of Berlin, Charit Medical Center, Department of Psychiatry, Berlin, Germany University of Zrich, Department of Psychiatry, Zrich, Switzerland Federal University of Rio de Janeiro, Department of Psychiatry, Rio de Janeiro, Brazil University of Munich, Department of Psychiatry, Munich, Germany 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)

Summary These practice guidelines for the biological treatment of unipolar depressive disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of the complete spectrum of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating patients with these conditions. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for depressive disorders, as well as from meta-analyses and reviews on the efficacy of antidepressant medications and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and was then categorized into four levels of evidence (A-D). The first part of these WFSBP guidelines on unipolar depressive disorders covered the acute and continuation treatment of major depressive disorder (Bauer et al 2002). This second part of the guidelines covers the management of the maintenance-phase treatment of

major depressive disorder, as well as the treatment of chronic and subthreshold depressive disorders (dysthymic disorder, double depression, minor depressive disorder and recurrent brief depression). These guidelines are primarily concerned with the biological treatment (including antidepressants, lithium, other psychopharmacological and hormonal medications, and electroconvulsive therapy) of young adults and also, albeit to a lesser extent, children, adolescents and older adults. Key words: major depressive disorder, chronic depressive disorders, dysthymic disorder, subthreshold depressive disorders, maintenance treatment, evidence-based guidelines, pharmacotherapy, antidepressants, lithium, ECT. Correspondence: PD Dr. med. Dr. rer. nat. Michael Bauer Department of Psychiatry Universittsklinikum Medizinische Fakultt der Humboldt-Universitt zu Berlin Campus Charit Mitte Schumannstr. 20/21 10117 Berlin Germany Tel: +49 30 4505 517001 Fax: +49 30 4505 517902 E-mail: mjbauer@mednet.ucla.edu

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Acknowledgements We would like to thank Dr. Jrgen Untzer, Los Angeles, USA, for valuable contributions in preparing the first draft of these guidelines; Dr. Christoph Hiemke, Mainz, Germany, for comments on pharmacokinetic aspects 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 1.1 1.2 1.3 1.4 2 2.1 2.1.1 2.1.2 2.2 2.2.1 2.2.1.1 2.2.1.2 2.2.1.3 2.2.2 2.2.3 2.2.4 2.2.5 2.3 2.4 2.5 2.6 2.7 2.7.1 2.7.2 3 3.1 3.2 3.2.1 3.3 4 5 Long-Term Treatment of Unipolar Depressive Disorders Introduction Goal and Target Audience of WFSBP Guidelines Methods of Literature Research and Data Extraction Evidence-Based Classification of Recommendations Maintenance-Phase Treatment of Major Depressive Disorder General Treatment Principles of Maintenance Treatment Goals and Indications Treatment Implementation Pharmacotherapy of Maintenance Treatment Evidence of Efficacy Antidepressants Lithium Carbamazepine and Other Mood Stabilizers Comparative Efficacy Tolerability and Side Effects of Maintenance Medications Treatment of Symptomatic Worsening and Recurrence Maintenance Treatment Options for Prophylaxis - Resistant Depression Duration and Discontinuation of Maintenance Treatment Switching from Unipolar Depression to Bipolar Disorder Electroconvulsive Therapy (ECT) Psychotherapy Maintenance-Phase Treatment of MDD in Special Age Groups Children and Adolescents Older Adults Treatment of Chronic Depressive Disorders Introduction Dysthymic Disorder Pharmacotherapy of Dysthymic Disorder Double Depression and Other Chronic Depressions Subthreshold Depressions 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 of Recommendations General Recommendations The long-term course of unipolar major depressive disorder (MDD) is characterized by high rates of recurrence and prolonged symptomatic chronicity. The primary goals of maintenance (prophylactic) treatment are to prevent a new episode of depression, a recurrence, suicide and development of chronicity. Consideration of the patients course of illness and treatment history is essential for the implementation of maintenance-phase treatment. Even though no definite recommendation can be given as to when prophylactic therapy should be initiated, it is clearly indicated in situations associated with a high risk of recurrence. For patients who have had 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. Adverse prognostic indicators for recurrence include a high number of previous episodes, residual symptoms at remission, previous longer episodes and chronicity, more severe previous episodes, onset early in life, concurrent dysthymic disorder ("double depression"), relapse after medication withdrawal, previous episode within the last year, concurrent substance abuse or anxiety disorders, and family history of major depressive disorder in first degree relatives. Key elements of long-term treatment of MDD include 1) psychoeducation, 2) pharmacotherapy, and 3) adherence monitoring. Adjunctive depression-targeted psychotherapy may be considered in individual patients. Because maintenance treatment requires compliance with medication, education and a close therapeutic alliance with patients and their families are essential. To prepare patients and their families for maintenance treatment, they should be informed about the following topics: typical course of the illness, treatment options, medication effects and side effects, use of (daily) selfreport instruments to track mood and early warning signs of relapse or recurrence, long-term perspectives, and projected end of treatment. Other principles of maintenance treatment are to distinguish between spontaneous symptomatic fluctuations ("blips") and "true" recurrences. In contrast to "blips", which are self-limited and do not require specific interventions, recurrences must be treated aggressively. It is also essential to regularly check adherence to medication and to detect breakthrough symptoms early on. Specific Treatment Recommendations The medications of first choice for the maintenance treatment of MDD are either the antidepressant with which remission was achieved

in the acute and continuation phase or lithium. Many patients receive antidepressants during the acute and continuation phase, and the best treatment recommendation to prevent recurrence of depression is to continue the antidepressant medication at the same dose during the maintenance phase. Randomized placebo-controlled studies (usually conducted for one or two years during maintenance treatment) indicate that tricyclic antidepressants (TCAs), irreversible monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) are effective in preventing recurrence of depression. Recent evidence suggests that the "newer" antidepressants have superior long-term efficacy and better tolerability compared to traditional antidepressants (e.g., TCAs). Another first choice medication for the maintenance treatment of MDD is lithium. With respect to lithium therapy, serum lithium levels of 0.5 to 0.8 mmol/L (mEq/L) determined 12 hours after the last lithium intake are usually recommended for maintenance treatment. However, the "optimal" serum lithium level may vary somewhat from patient to patient, in the range of 0.4 to 1.0 mmol/L, depending on individual effectiveness and tolerability of side effects. There is modest evidence that carbamazepine is an alternative medication in the maintenance treatment of MDD. Other mood stabilizers that are used for bipolar affective disorders (e.g., valproate [divalproex], lamotrigine or gabapentin) have not been studied in randomized controlled trials for the maintenance treatment of MDD. Periodic (maintenance) electroconvulsive therapy (ECT) has been recommended for patients who fully responded to ECT during the acute and continuation treatment phase and especially for those who are not eligible for or who do not respond to maintenance medication treatment. The duration of continuation treatment following acute treatment should be six to nine months. Treatment length required for maintenance is not yet fully determined. However, three years of maintenance therapy is most commonly appropriate for recurrent patients, particularly when an episode prior to the present one has occurred in the last five years or when remission has been difficult to achieve. Maintenance treatment for five to 10 years, or even indefinitely, is recommended for those patients at greater risk, particularly when two or three attempts to withdraw medication have been followed by another episode within a year. Although the amount of data from controlled studies is still limited, results clearly indicate efficacy of various antidepressants (TCAs, SSRIs and other "newer" antidepressants) for dysthymic disorder. Although the optimal length of pharmacotherapy for dysthymia has not been studied in a controlled design, a course of treatment with an antidepressant for at least two to three years is recommended, as in MDD.

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Although subthreshold depressive disorders are highly prevalent in the general population and in primary care settings, controlled treatment data involving pharmacotherapy is even more sparse than for dysthymic disorder. Given the limited data from controlled studies for subthreshold depressive disorders, evidencebased treatment recommendations cannot be given at this point. However, a treatment trial with one of the well-tolerated antidepressants is worth trying in more chronic and unremitting cases. Withdrawal of antidepressants and lithium after longer term use (e.g., longer than six months) should always be gradual, with dose reductions over at least three months. Abrupt cessation of antidepressants after longer term use can lead to withdrawal syndromes. Rapid, although not abrupt, withdrawal can lead to rebound relapse and recurrence. Where symptoms return during or after withdrawal, full-dose maintenance treatment should be initiated. 1 Long-term treatment of unipolar depressive disorders1

1.1 Introduction Major depressive disorder (MDD), in its classic form, presents as a recurrent disorder (Angst 1986; Judd 1997; Kiloh et al 1988). Major depressions that do not respond to treatment or that spontaneously remit will suffer subsequent relapses or recurrences. Fifty percent to 85% of the patients who have an episode will have another episode of major depression (Mueller et al 1999; Andrews 2001; American Psychiatric Association 2000). The likelihood of a recurrence increases with the number of previous depressive episodes and the severity of the current episode (Angst 1999). Patients who have had three episodes of major depression have a 90% chance of having another (NIMH Consensus Development Conference 1985). Among others, risk factors for recurrence of MDD are: prior history of multiple episodes of MDD, early age at onset, persistence of dysthymic symptoms after recovery from an episode of MDD, presence of an additional, non-mood psychiatric diagnosis, and presence of a chronic physical disorder (Kovacs et al 1997; American Psychiatric Association 2000). Factors that have been associated with increased severity of subsequent depressive episodes include a history or a prior episode complicated by serious suicide attempts, psychotic features or severe functional impairment (American Psychiatric Association 2000). In recent years it has become apparent that the long-term course of unipolar MDD is not only characterized by high rates of recurrence but also
1 It is emphasized that the treatment of dysthymic disorders, subthreshold depressions 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.

dominated by prolonged symptomatic chronicity (Judd 1997; Judd et al 1998). Most patients with MDD return to the premorbid level of functioning between episodes of major depression. However, in approximately 30% of the severe or hospitalized depressed patients, residual symptoms and social or occupational impairment persists. It is now well established that about one-third of patients suffering from severe major depression will have a chronic course marked by at least two years of illness (Keller et al 1986; Scott 1988; Nierenberg 2001; American Psychiatric Association 2000; Judd and Akiskal 2000). Epidemiological and prospective clinical followup studies have also documented that the typical course of unipolar MDD involves fluctuating symptoms in which depressive subtypes included in official diagnostic systems do not represent discrete disorders, but are stages along a dimensional continuum (spectrum) of symptomatic severity (Angst et al 2000; Judd and Akiskal 2000). The group of chronic depressive disorders encompasses four subtypes of depressive illness: major depressive disorder, recurrent, without full interepisodic recovery (in incomplete remission), major depressive disorder, currently in a chronic (duration of two years) episode (chronic major depressive disorder), dysthymic disorder, "double depression" (concurrent dysthymic disorder and major depression). The group of "subthreshold depressions" (depressive disorders not otherwise specified, NOS) includes depressive conditions in which the number, duration or quality of symptoms is insufficient to meet the DSM criteria for a diagnosis of major depression (American Psychiatric Association 1994a; Judd et al 1998; Akiskal and Cassano 1997; Angst and Merikangas 1997). Patients with an early onset and older adults suffering an initial depressive episode after the age of 60 appear to be at greater risk for the development of chronicity (Klerman and Weissman 1989). Individuals suffering from either dysthymia alone or "double depression" have significantly greater impairment in functioning than those with major depression alone, depressive symptoms or past episodes of major depression (Wells et al 1992). Residual (subthreshold) symptoms in the course of MDD are associated with a high risk for early episode relapse and a significantly more chronic future course of illness. Asymptomatic recovery from MDD is associated with significant delays in episode relapse and recurrence and a more benign course of illness (Judd and Akiskal 2000; Judd et al 2000). 1.2 Goal and target audience of WFSBP guidelines These WFSBP guidelines provide an update of contemporary knowledge of unipolar depressive disorders and evidence-based recommendations

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for their treatment. They were developed by the authors and arrived at by consensus with the WFSBP Task Force on Unipolar Depressive Disorders consisting of 46 international researchers and clinicians. The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of recommendations that are clinically and scientifically meaningful. They were also intended to bring together the various opinions of scientifically respected experts and international representatives on the appropriate state-of-theart treatment of these disorders. There were a few aspects for which it was not possible to reach a consensus within the Task Force. In such cases, the Chairman and Co-Chairmen had to make a final decision. The most divergent opinions were in the following areas: the use of anticonvulsants in maintenance treatment, the effectiveness and positioning of lithium in the maintenance treatment of unipolar depressive disorders, and the positioning of psychotherapy in guidelines for the biological treatment of depressive disorders. These guidelines are intended for use in clinical practice by all physicians seeing and treating patients with these conditions. They should be considered as guidelines only because the ultimate judgement regarding a particular treatment procedure must be made by the responsible treating physician in light of the clinical picture presented by the patient and the diagnostic and treatment options available. These guidelines are primarily concerned with the biological (somatic) treatment (e.g., antidepressants, lithium, other psychopharmacological and hormonal medications, and electroconvulsive therapy) of unipolar depressive disorders in young adults, but also, albeit to a lesser extent, of children, adolescents and older adults. They do not address depressive disorders occurring in bipolar affective disorders (which are covered by separate WFSBP guidelines [Grunze et al In Press]). The management of the acute and continuation treatment of major depressive disorder was covered in Part 1 of the WFSBP guidelines (Bauer et al 2002). This second part of the guidelines covers the management of maintenance-phase treatment of major depressive disorder, as well as treatment of chronic depressive disorders and subthreshold depressive disorders. Psychotherapeutic treatment interventions are covered only briefly, but references are provided for further reading. Since the availability of medications, treatments and diagnostic procedures varies considerably across countries, the authors have included several different treatment options in the guidelines. 1.3 Methods of literature research and data extraction The data used for the development of these guidelines have been extracted from the follow-

ing sources: Agency for Health Care Policy and Research (AHCPR) Depression Guidelines Panel (AHCPR 1993); AHCPR Evidence Report on Treatment of Depression: Newer Pharmacotherapies (AHCPR 1999); American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Revision (American Psychiatric Association 2000); British Association for Psychopharmacology Revised Guidelines for Treating Depressive Disorders (Anderson et al 2000); Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments, CANMAT, Clinical Guidelines for the Treatment of Depressive Disorders (CANMAT 2000); Canadian Consensus Guidelines for the Treatment of Seasonal Affective Disorder (Lam and Levitt 1999); Deutsche Gesellschaft fr Psychiatrie, Psychotherapie und Nervenheilkunde, DGPPN, Praxisleitlinien in Psychiatrie und Psychotherapie, Affektive Erkrankungen (DGPPN 2000); American Academy of Child and Adolescent Psychiatry, Practice Parameters for the Assessment and Treatment of Children and Adolescents with Depressive Disorders (American Academy of Child and Adolescent Psychiatry 1998); The Cochrane Library; meta-analyses on the efficacy of antidepressant medications identified by a search of the MEDLINE database (until August 2001); major pertinent review articles identified by a search of the MEDLINE database and textbooks, and individual clinical experience by the authors and members of the WFSBP Task Force on Unipolar Depressive Disorders. With respect to quoting original data, only research articles published in peer-reviewed journals in English before August 2001 were considered. Evidence-based classification of recommendations The evidence found in the literature research and data extraction was summarized and categorized to reflect its susceptibility to bias (Shekelle et al 1999). Each treatment recommendation was evaluated with respect to the strength of evidence for its efficacy, safety and feasibility2. However, daily treatment costs were not taken into consideration due to the variability of medication costs worldwide. Four categories of evidence were used: Level A: Good research-based evidence to support the recommendation. This level is achieved if research-based evidence for efficacy is given from at least three moderately large, positive, randomized, controlled (double-blind) studies (RCT). In addition, at least one of these three studies must be a well-conducted, placebocontrolled study.
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 support the recommendation. This includes evidence of efficacy from at least two moderately large randomized, double-blind studies (this can be either two comparator studies or one comparator-controlled and one placebo-controlled study) or from one moderately large randomized, double-blind study (placebo-controlled or comparator-controlled) and one prospective, moderately large (sample size of 50 participants), open-label, naturalistic study. Level C: Minimal research-based evidence to support the recommendation. This level is achieved if one randomized, double-blind study with a comparator treatment and one prospective, open-label study/case series (with a sample size of 10 participants) showed efficacy, or at least two prospective, open-label study/case series (with a sample size of 10 participants) showed efficacy. Level D: Expert opinion-based (from authors and members of the WFSBP Task Force on Unipolar Depression) recommendations supported by at least one prospective, open-label study / case series (sample size 10 participants). No level of evidence: Expert opinion for general treatment procedures and principles. 2 2.1 Maintenance-phase treatment of major depressive disorder

Kupfer 1993). The consideration of the patients course of illness and treatment history is essential for the implementation of maintenance phase therapy. Even though no definite recommendation can be given as to when prophylactic therapy should be initiated, it is clearly indicated in situations associated with a high risk of recurrence (Brunello et al 1995; Angst 1999; Dawson et al 1998; Paykel 2001) (Table 1). In addition to these risk factors, patient preference, severity of functional impairments and side effects experienced during the continuation phase also play a role in determining whether or not maintenance treatment should be implemented (AHCPR 1993; American Psychiatric Association 2000). 2.1.2 Treatment implementation Key elements of long-term treatment of recurrent depressive disorders include 1) psychoeducation, 2) pharmacotherapy, and 3) adherence monitoring. Adjunctive depressiontargeted psychotherapy may be included in some cases. Because maintenance treatment requires compliance with medication, education and a close therapeutic alliance with patients and their families are essential (Kupfer 1993). Education does not only reduce treatment attrition, but also leads to a better outcome (Rush 1999). To prepare patients and their families for maintenance treatment, they should be informed about the following topics: typical course of the illness, treatment options, medication effects and side effects, use of (daily) self-report instruments to track mood and early warning signs of relapse or recurrence, long-term perspectives, and projected end of treatment. Patients should also be instructed to inform all of their doctors about all the medications they are taking. It is also important to inform the patient that several different treatments may need to be tried before the treatment that is best for them is identified. Other principles of maintenance treatment are to distinguish between spontaneous symptomatic fluctuations ("blips") and "true" recurrences. In contrast to "blips", which are self-limited and do not require specific interventions, recurrences must be treated aggressively. It is also important to regularly check adherence to medication and to detect breakthrough symptoms early on (Rush 1999). Recently, a relapse prevention program (a low intensity intervention including enhanced patient education, visits with a depression specialist, telephone calls, symptom monitoring) for depressed patients in primary care significantly improved antidepressant adherence and depressive symptoms outcome in a randomized controlled 12-month trial compared with usual primary care (Katon et al 2001). The frequency of visits may range from monthly visits to every three to six months in stable

General treatment principles of maintenance treatment 2.1.1 Goals and indications The goals of long-term, maintenance (prophylactic) treatment are to prevent a new episode of depression (a recurrence), suicide and development of chronicity. A recurrence is an episode that appears after a completely asymptomatic period (remission) has been achieved for a six-month period (recovery) (Frank et al 1991;
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 and medication monitoring (e.g., side effect assessment, medication blood levels). In unstable patients, more frequent visits are required. If the patient develops a medical condition while on maintenance treatment, potential drug-drug interactions should be considered. Patients/ families should also be instructed to inform the treating physician if and when signs of depression reoccur. 2.2 Pharmacotherapy of maintenance treatment 2.2.1 Evidence of efficacy Pharmacotherapy is the most studied treatment modality in the long-term maintenance treatment of recurrent unipolar depression. Among the therapeutic options available, antidepressant medications and lithium have received the most study. The majority of controlled trials investigating these medications in maintenance treatment demonstrated efficacy for relapse prevention (Level A) (Solomon and Bauer 1993; AHCPR 1993, 1999; Davis et al 1999). The medications of first choice for maintenance treatment in unipolar depression are either the antidepressant with which remission was achieved in the acute/continuation phase or lithium (NIMH Consensus Development Conference 1985; AHCPR 1993; Prien and Kocsis 1995; American Psychiatric Association 2000; Paykel 2001). Likely reasons why antidepressants may be preferred to lithium as prophylactic agents are that patients are usually treated with antidepressants during the acute/continuation phase and that patients usually prefer to use medication that does not require regular monitoring by blood tests (Figure 1). The final choice of prophylactic agent must depend on how individual patients respond to and tolerate treatment with antidepressants and lithium (Schou 1997). A patient's preference and their own or their family members experience with maintenance treatment should also be considered in the choice of the medication. 2.2.1.1 Antidepressants Many patients receive antidepressants during the acute and continuation phase, and the best treatment recommendation to prevent recurrence of depression is to continue the antidepressant medication that was effective during the acute and continuation phase of treatment at the same dose during the maintenance phase (Level B) (Frank et al 1993; Franchini et al 1998). In these two latter studies, the group of patients who received only half of the acute-phase dose of imipramine (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 (usually for one or two years during the maintenance phase) of antidepressants in the prophylactic treatment of depression indicate that TCAs

(amitriptyline, imipramine, nortriptyline, maprotiline) (Level A), MAOIs (phenelzine) (Level A) (Solomon and Bauer 1993; Montgomery 1994; AHCPR 1993, 1999; American Psychiatric Association 2000; Paykel 2001) and SSRIs (Level A) (citalopram [Hochstrasser et al 2001], fluoxetine [Gilaberte et al 2001], fluvoxamine [Terra and Montgomery 1998] and paroxetine [Montgomery and Dunbar 1993]) are effective in preventing recurrence of depression. 2.2.1.2 Lithium The use of lithium as a maintenance therapy for unipolar recurrent depression is well established (Level A) (Goodwin and Jamison 1990; Schou 1997; Dunner 1998; Coppen 2000; Paykel 2001). Two meta-analyses found evidence that lithium is more effective than placebo in preventing recurrence of unipolar depressive illness (Souza and Goodwin 1991; Burgess et al 2001), whereby the results were statistically significant in only one of these two studies (Souza and Goodwin 1991). Over the past decade, evidence has accumulated from retrospective and prospective studies that long-term lithium prophylaxis may reduce suicide risk and even normalize the high mortality rate (Level C) (Coppen et al 1990; Mller-Oerlinghausen 1992, 1994; Tondo et al 1997; Schou 2000). A randomized 2.5-year

Maintenance Treatment (MT)* with Antidepressant Effective in Acute and Continuation Phase

Recurrence (Breakthrough) during MT Treat Breakthrough Episode Diagnostic Reassessment Consider Treatment Optimization or Change in MT**

Switch to Antidepressant From Different Class

Switch to Lithium or Antidepressant + Li

Switch to Antidepressant From Different Class or Combine Two Different Antidepressants

Switch to Antidepressant From Different Class or Li + Antidepressant From Different Class 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.

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

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maintenance treatment study in patients with major affective disorder showed significantly fewer suicides and suicide attempts in the lithium group compared with the carbamazepine group (Thies-Flechtner et al 1996). Furthermore, clinical findings suggest that the antisuicidal property of lithium acts independently of its "classical" episode preventive effect (Schou 1997; Bocchetta et al 1998; Grof 1998). However, a meta-analysis found no definitive evidence as to whether lithium has an anti-suicidal effect since a small number of deaths and suicides, and the absence of suicidal behaviour, were present in 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 lithium intake are usually recommended for maintenance treatment (Schou 1989). However, the optimal serum lithium level may vary somewhat from patient to patient, in the range of 0.4 to 1.0 mmol/L, depending on individual effectiveness and tolerability of side effects (Schou 1989; Birch et al 1993). These recommended serum lithium levels are usually achieved with a daily dose of 800 or 900 mg (dosage varies depending on availability of lithium tablets) to 1200 or 1500 mg lithium carbonate (600 mg to 1000 mg for Asian patients) in patients 60 years of age or younger, or 400/450 mg to 800/900 mg lithium carbonate in older patients (Birch et al 1993). It is irrelevant for efficacy whether lithium tablets are administered once or twice daily. Some patients find that a single daily dose facilitates long-term treatment compliance and reduces side effects. In general, extended release forms of lithium are better tolerated. 2.2.1.3 Carbamazepine and other mood stabilizers Among the group of mood stabilizer medications that are used for the treatment of bipolar disorder, the most studied agent in open and comparator studies other than lithium is carbamazepine (Level C). Carbamazepine has been studied in small double-blind comparator trials with lithium in recurrent major depression (for more information on study results see Chapter 2.2.2 below) (Placidi et al 1986; Simhandl et al 1993). Recommended serum levels of 4 to 12 g/ml (17 to 50 mol/L), measured 12 hours after the last drug intake (and not sooner than five days after the last change in dosage unless toxicity is suspected), relate more to anticonvulsant activity than to mood stabilizing efficacy of recurrent affective disorders. However, serum carbamazepine levels can serve as guidelines for medication compliance and excessive adverse effects (Bezchlibnyk-Butler and Jeffries 1996). Maintenance doses average about 800-1600 mg/d, but may be lower in routine clinical practice. Because carbamazepine can induce its own hepatic metabolism (via cytochrome CYP450 isoenzymes), determinations of serum carbamazepine should be performed every

second week for the first two months after initial treatment, every second month for the next six months, and then at clinical discretion thereafter, or when there is a major change in the dosage or drug regimen. Induction of CYP3A4 by carbamazepine will also accelerate phase I reactions of drugs that are used in addition to carbamazepine, if they are metabolized via CYP3A4 (Spina et al 1996). If dose adaptation of concomitant drugs is also necessary, monitoring of drug concentrations in the serum can be useful. Other mood stabilizers (e.g., valproate [divalproex], lamotrigine or gabapentin) have not been studied in placebo-controlled or double-blind comparator trials for the maintenance treatment of unipolar depression (Davis et al 1999). 2.2.2 Comparative efficacy A relatively small number of studies have directly compared different medications for maintenance treatment in recurrent unipolar depression (Solomon and Bauer 1993). A metaanalysis of studies comparing lithium with other antidepressants showed no conclusive advantage for lithium in the prophylaxis of unipolar illness (Souza and Goodwin 1991). In one relatively small randomized, placebo-controlled, two-year maintenance study, lithium (serum level 0.8-1.2 mmol/L) was superior to imipramine (100-150 mg/day); the combination of lithium and imipramine was not superior to lithium alone (Kane et al 1982). Another, larger randomized, placebocontrolled, two-year study reported better maintenance effects for imipramine (the mean daily dosage at the start of the maintenance phase was 137 mg, range 75-150 mg/day) than lithium (the mean serum lithium level at the start of the maintenance phase was 0.66 mmol/L, range 0.43-1.05 mmol/L) (Prien et al 1984). In the latter study, the combination of imipramine and lithium was not more advantageous than imipramine alone in preventing depressive recurrences. However, in a later reanalysis of the data, the same authors concluded that the results of the latter study could be accounted for by alternative explanations that are a consequence of the study design (Greenhouse et al 1991). One randomized, prospective, open 2.5-year trial comparing lithium (average serum lithium level 0.59 mmol/L) with amitriptyline (average dosage 98 mg/day) found significantly better prophylactic efficacy for lithium (Greil et al 1996a). A randomized, three-year maintenance study in a group of patients with major affective disorder showed equal efficacy for lithium and carbamazepine (Placidi et al 1986); for these two medications, similar results were obtained in a randomized two-year study of unipolar depression (Simhandl et al 1993). Although the evidence for prophylactic efficacy of carbamazepine in unipolar depression is limited, results

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indicate that carbamazepine may be an alternative for those patients who do not tolerate or respond to maintenance treatment with lithium or antidepressants (Level C) (Figure 1). In the largest and probably most influential study on the use of antidepressants in maintenance treatment, a randomized three-year placebo-controlled trial, survival analysis showed full-dose imipramine (mean dose at randomization 215 mg/day) with or without Interpersonal Therapy (IPT; weekly for 12 weeks, then bi-weekly for eight weeks, and then monthly) to be the best maintenance treatment, followed by IPT with or without placebo, and then placebo (Frank et al 1990). In this study of highly recurrent unipolar depression, all patients enrolled in the three-year study had remitted on the combination of imipramine and IPT, and all had remained well for four months of continuation therapy prior to randomization. A subsequent additional two-year placebo-controlled study of the patients who completed the threeyear study (Frank et al 1990) showed that imipramine (average dose of 200 mg/day) was significantly better than placebo in preventing recurrence (Kupfer et al 1992). A number of more recent studies suggest that the "newer" antidepressants (see Part 1 of these guidelines [Bauer et al 2002]) have superior longterm efficacy and better tolerability compared with traditional TCAs (Level B) (Montgomery 1999). A randomized, placebo-controlled, twoyear study comparing the efficacy of mirtazapine with that of amitriptyline found that the time to relapse was significantly longer in the mirtaapine group (Montgomery et al 1998). Similarly, a double-blind one-year study reported significantly greater improvement in some of the outcome measures in the venlafaxine group compared with imipramine (Shrivastava et al 1994). 2.2.3 Tolerability and side effects of maintenance medications The long-term side effects and tolerability of medications are key considerations in maximizing adherence to treatment. Side effects should be as minimal as possible. Even mild to moderate side effects during maintenance treatment may lead to noncompliance, with the consequence of symptom worsening and increased risk of recurrence. Using medications with a more favourable side effect profile than the TCAs may facilitate patient compliance with pharmacotherapy, as long as these agents are effective in the maintenance treatment of depression. The "newer" antidepressants are associated with fewer long-term side effects than the older tricyclics and tetracyclics (for details about side effects of antidepressants see: Part 1 of these guidelines [Bauer et al 2002]; Peretti et al 2000; AHCPR 1993, 1999; American Psychiatric Association 2000).

One advantage of maintenance therapy with lithium is the long experience with this agent worldwide, making the risks of long-term treatment more clear. Specialized Lithium Clinics for the prophylactic long-term treatment of patients with affective disorders have been established for more than 30 years in many countries and have provided longitudinal assessments of the side effects of lithium treatment (Schou 1997). During the long-term use of lithium, regular laboratory monitoring of the serum lithium level (performed once to four times per year, and more frequently if clinically required, e.g., in the early stages of treatment, with older patients or after clinical changes have become apparent), thyroid function (e.g., TSH level) and renal function (creatinine) (e.g., once or twice a year) is recommended (Birch et al 1993; American Psychiatric Association 1994b; Schou 1997; Kleiner et al 1999). The purpose of measuring serum lithium levels is to ensure that high serum lithium levels are detected and lowered, and to ensure that steps are taken to prevent recurrence in case of abnormally low serum lithium levels. It is also important to educate patients and their families about the warning signs of lithium toxicity. Among the common side effects of lithium treatment are the development of hypothyroidism and goitre resulting from the interference of lithium with the synthesis and release of thyroid hormones from the thyroid gland (Lazarus 1998). The prevalence of overt ("clinical") hypothyroidism has been reported to be between 8% and 10% in patients taking lithium, compared to a prevalence of 0.5% to 1.8% reported in the general population (Kleiner et al 1999). Even higher rates have been estimated for the prevalence of subclinical hypothyroidism (in 23% of patients on lithium therapy compared to rates of up to 10.4% in the general population) (Kleiner et al 1999). In the past, many concerns have been raised about whether long-term lithium exposure may cause irreversible kidney damage. A recent comprehensive review stated that in the vast majority of patients, the tubular damage is not associated with significant changes in glomerular filtration rate (Gitlin 1999). Clinically important glomerular dysfunction resulting from lithium treatment is rare and is unrelated to the duration of lithium therapy (Schou 1997; Gitlin 1999). A small percentage of patients treated with lithium may develop rising creatinine concentrations after 10 years or more of treatment. However, in patients treated with lithium for 15 years or more, affection of both glomerular and tubular function seems to be more common (Bendz et al 1994). Side effects of lithium treatment are usually dose dependent and can often be prevented or relieved by a moderate reduction in dosage

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(American Psychiatric Association 1994b). Side effects may include: hand tremor (counteracted by a -blocker), goitre and hypothyroidism (additional administration of L-thyroxine [L-T4] to achieve euthyroid status), lowered renal concentrating ability and polyuria and/or polydipsia (warning against dehydration, possibly reduction of dosage), weight gain (moderate dieting and exercise), gastrointestinal problems (e.g., nausea, dyspepsia, loose stools; managed by administering lithium with meals, switching lithium preparations or dose reduction) and, rarely, memory impairment/mental slowness (dose reduction) (Birch et al 1993; American Psychiatric Association 1994b). The most difficult side effect to treat is polyuria, which may persist in rare cases. Management includes ensuring that the lithium dose is as low as possible, switching to another lithium formula, switching to a single daily dose or changing the time of day when the medication is taken. In severe cases of lithium-induced polyuria, treatment with amiloride, a potassium-sparing diuretic or a thiazide diuretic may be tried (Cave: risk of thiazideinduced hypokalemia) (Jefferson et al 1987). The most common side effects of carbamazepine include neurological symptoms (e.g., diplopia, blurred vision, fatigue, ataxia; usually doserelated, often transient and reversible with dosage reduction), skin rashes, mild leukopenia and thrombocytopenia (both usually reversible with dose reduction; they may reverse spontaneously with continued treatment, however, close monitoring is required), mild liver enzyme elevations and hyponatremia (American Psychiatric Association 1994b). Monitoring of laboratory values (blood count, liver enzymes, electrolytes) is recommended two to four times per year during maintenance treatment (Greil et al 1996b). Rare, idiosyncratic but potentially fatal side effects of carbamazepine (occurring usually in the first six months of treatment) include agranulocytosis, aplastic anaemia, hepatic failure, exfoliative dermatitis (e.g., StevensJohnson Syndrome) and pancreatitis (American Psychiatric Association 1994b). Because these idiosyncratic fatal side effects occur very rapidly, education of the patient about the signs and symptoms of hepatic, haematological or dermatological reactions, and instructions to report symptoms if they occur, are essential for treatment with carbamazepine. 2.2.4 Treatment of symptomatic worsening and recurrence Brief, mild depressive symptoms ("blips") frequently occur during maintenance treatment. They are self-limited and, in contrast to recurrences (breakthrough episodes), do not require specific interventions or a change in the maintenance treatment plan. Psychiatric management (e.g., including dose adjustment, reassurance) and additional short-term treatment with a benzodiazepine or hypnotic medication to treat

insomnia and/or anxiety, or an adjunctive course of psychotherapy to help address specific psychosocial stressors or stressful life events, may be useful (Rush 1999). Many patients have a somewhat predictable pattern of symptoms that appear during a prodromal phase of a full-blown recurrence. When a patient suffers a recurrence of a depressive episode despite ongoing maintenance treatment (breakthrough episode), physicians face a considerable challenge. Early intervention can shorten the length of the episode (Kupfer et al 1989). The "differential diagnosis" of a recurrence includes evaluation of occult substance abuse, occult physical illness (e.g., thyroid dysfunction), nonadherence to medication, and the possibility of adverse life events (Rush 1999). Patients experiencing a new depressive episode while taking a mood stabilizer or an antidepressant may benefit from treatment optimization (e.g., increase of serum level to the upper end of the therapeutic level, addition of thyroid hormone if thyroid function is low [particularly in lithium-treated patients], additional psychotherapeutic interventions and visits). If the patient does not improve with treatment optimization, another round of adequate acute phase treatment should be initiated followed by continuation treatment (see Part 1 of these guidelines [Bauer et al 2002]). The treatment plan for subsequent maintenance therapy should be reevaluated and a switch in the choice of the prophylactic medication should be considered (Figure 1). 2.2.5 Maintenance treatment options for prophylaxis-resistant depression There is growing recognition that prophylactic treatment of affective disorders may be inadequate in a substantial proportion of patients. The maintenance treatment of patients with recurrent depression who experience recurrences during prophylactic treatment with standard agents, e.g. lithium or antidepressants, is one of the most challenging issues in the treatment of these disorders. However, little data from formal studies is available to guide physicians in the maintenance treatment of patients suffering from recurrences during standard prophylactic treatment (Bauer and Helmchen 2000). An algorithm including some options for the maintenance treatment of patients with MDD is presented in Figure 1. Combining an antidepressant with lithium, or combining lithium with carbamazepine, or combining two different antidepressants, are among the possible options. Adjunctive treatment with thyroid hormone (Lthyroxine) in supraphysiological doses has also been suggested for maintenance treatment of patients with prophylaxis-resistant depression (Bauer et al 2001). However, it should be emphasized that evidence of the efficacy of these combinations and of thyroid augmentation is limited (Level D).

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2.3

Duration and discontinuation of maintenance treatment The optimal moment to discontinue a long-term medication is difficult to predict. Current evidence suggests that maintenance treatment should be continued as long as the risk of recurrence persists (Brunello et al 1995). That risk is often difficult to assess in the individual patient, particularly after a long period (years) of absence of symptoms/recurrence. It appears that the likelihood of a recurrence increases with the number of previous depressive episodes (Angst 1999). However, some authors have argued that there is a similar risk of recurrence whether medication is discontinued after months or years of pharmacotherapy (Thase 1999). There is good evidence from a controlled five-year study that patients who benefit the most from continued prophylaxis are those who receive active fulldose medication for at least five years (Level C) (Kupfer et al 1992). Thus, for some patients, maintenance treatment is required for very long periods (e.g., a decade), and for others it is required indefinitely (Rush and Kupfer 2001). Three years maintenance therapy is appropriate almost as a routine for recurrent patients, particularly where an episode prior to the present one has occurred in the last five years or where remission has been difficult to achieve. Maintenance for five years or indefinitely is recommended for those patients at greater risk, particularly where two or three attempts to withdraw medication have been followed by another episode within a year. Regardless of the reason for discontinuation, after long-term pharmacotherapy the patient should be educated about the risk of recurrence and its early warning signs. Three phenomena that may occur after discontinuing long-term antidepressant medications need to be distinguished: recurrence of episode (return of the original symptoms), rebound (return of original symptoms but with greater intensity; typically occurs if lithium or antidepressants are withdrawn too rapidly), and withdrawal (development of different symptoms related to drug stoppage; typically occurs if TCAs and SSRIs are abruptly stopped) (Paykel 2001). In clinical practice, antidepressants should always be withdrawn slowly after maintenance therapy. A tapering period of four to six months is recommended in long-term treated patients to allow the early detection of emerging symptoms and to minimize the risk of antidepressant medication discontinuation syndromes. During the period of discontinuation, the patient should be monitored more closely. And after the discontinuation is complete the monitoring should continue during the next couple of months (e.g., particularly for the next six months, which appear to be a period of high risk for recurrence; Rush and Kupfer 2001) to identify those in whom a relapse is likely. If the full depressive episode recurs during or after discontinuation, a

full therapeutic dosage should be readministered promptly (AHCPR 1993). Antidepressant discontinuation syndromes have received little systematic study. Thus, most of the recommendations in the literature and in these guidelines are based on anecdotal data or expert opinion. It is agreed that a common feature of antidepressant discontinuation syndromes is the onset of symptoms within a few days of stopping the antidepressant or, less commonly, within a few days of reducing the dosage (Haddad 2001). Discontinuation symptoms are more likely to occur when abruptly stopping the dosage. They have been described with all classes of antidepressants, including TCAs (particularly those with anticholinergic and serotonergic potency), irreversible MAOIs, SSRIs and venlafaxine (Lejoyeux and Ades 1997; Edwards and Anderson 1999). Data from a randomized controlled trial (RCT) showed that discontinuation symptoms are more common with a shorteracting SSRI, such as paroxetine, than with a longer-acting agent, such as fluoxetine (Rosenbaum et al 1998). Withdrawal phenomena (e.g., dizziness, balance and sensory disturbance, nausea or emesis, fatigue, headache, gait instability, irritability, vertigo or feeling faint, and insomnia) differ in pattern from those of depressive recurrence. Withdrawal is usually mild but may be serious for the irreversible MAOIs. Typically these symptoms subside with the reinstatement of the original drug (Haddad 2001). Although not supported by controlled data, discontinuation reactions appear less frequently in shorter courses of treatment (Anderson et al 2000). 2.4 Switching from unipolar depression to bipolar disorder A change of diagnosis over time from unipolar depression to bipolar disorder has been described in approximately 10% to 20% of patients (Angst et al 1978; Akiskal et al 1995; Solomon et al 1997). Antidepressants, particularly TCAs, precipitate mania in some patients with apparent unipolar depression (Altshuler et al 1995). Early age at onset of MDD, greater acuteness, pleomorphic psychopathology and high rates of substance abuse have been identified as clinical predictors of the switch to hypomania (Akiskal et al 1995). If a switch to mania occurs during the maintenance phase treatment in unipolar depression, rapid tapering of the antidepressant and concomitant treatment of the manic episode is essential (for more information on the treatment of bipolar disorder, see WFSBP Guidelines for the Treatment of Bipolar Disorder [Grunze et al In Press]). 2.5 Electroconvulsive therapy (ECT) Case reports and case series have reported on the successful use of ECT in the maintenance phase of treatment (Level D) (Nobler and Sackeim 2000). Periodic (maintenance) ECT has been re-

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commended for patients who fully responded during the acute treatment phase, and especially for those who are not eligible for or who fail to respond to maintenance medication treatment. Usually, about one or two ECT treatments per month is recommended. Due to the lack of controlled and well-defined outcome studies, the long-term risks of maintenance ECT studies are unknown. 2.6 Psychotherapy Similar to Part 1 (Bauer et al 2002), these guidelines focus on biological (somatic) treatments. Therefore, psychotherapeutic treatments alone or in combination with pharmacotherapy will only be mentioned briefly and no levels of evidence will be provided. Instead, references for further reading are given. Although maintenance psychotherapy as the sole treatment to prevent recurrence is less studied, and at this point not recommended as a first-line treatment unless the patient does not wish to or cannot take medication for some reason (e.g., pregnancy) (AHCPR 1993), it is a treatment option for some patients. Preliminary data suggest that cognitive behavioural therapy (CBT) may be an effective treatment for preventing recurrence in patients with recurrent major depression (Teasdale et al 2000; Jarrett et al 2001), including patients who have been successfully treated with antidepressant drugs (Fava et al 1998). There is some indication that patients with residual depression benefit from CBT for preventing recurrence (Fava et al 1998; Paykel et al 1999). Maintenance interpersonal psychotherapy (IPT-M) has also been suggested by others (Frank et al 2000). The effectiveness of combined antidepressant medication and psychotherapy has not been well studied in the maintenance phase. Some studies have failed to find the combination to be superior to either treatment modality alone in patients with mild to moderate depression (American Psychiatric Association 2000). If psychotherapy, e.g., cognitive behavioural therapy or interpersonal therapy, is combined with medication, maintenance phase treatment usually involves a decreased frequency of psychotherapeutic sessions compared to the acute and continuation phase (e.g., once a month). 2.7 Maintenance-phase treatment of MDD in special age groups 2.7.1 Children and adolescents The American Academy of Child and Adolescent Psychiatry (1998) emphasized that there are no published data from RCTs regarding maintenance treatment of children and adolescents with MDD. Because the clinical presentations, sequelae and natural course of depression in youths are similar to those of depression in adults, the general guidelines for treatment of adults also apply to the treatment of adolescents

(American Academy of Child and Adolescent Psychiatry 1998). 2.7.2 Older adults The efficacy and safety of nortriptyline in preventing recurrence of major depressive episodes in patients older than 59 were well determined in a three-year placebo-controlled maintenance study of nortriptyline combined with psychotherapy and nortriptyline monotherapy (Reynolds et al 1999a). Other controlled studies have also supported the efficacy of nortriptyline in preventing recurrence of major depressive episodes in older adults (Level A) (Georgotas et al 1989; Reynolds et al 1999b). Nortriptyline has been well tolerated in longterm maintenance studies of older adults. Except for a consistent increase in heart rate and dry mouth, no other adverse events were detected in comparison with placebo (Marraccini et al 1999). A similar robust maintenance effect was found with the MAOI phenelzine in a placebo RCT in older adults (Level C) (Georgotas et al 1989). The SSRIs are being studied as alternatives for nortriptyline in the maintenance treatment of recurrent depression in older adults (Reynolds et al 2001). In an open, 18-month study, paroxetine has been shown to be comparable to nortriptyline in preventing recurrences of depression in older adults (Level C) (Bump et al 2001). 3 Treatment of chronic depressive disorders

3.1 Introduction Undertreatment and social impairment are the most striking characteristics of chronic depressive disorders. Patients with chronic depression are often not treated, or treated inadequately (Keller et al 1995a). It has been estimated that the response rates for chronically depressed patients are equal to or slightly lower (40% to 55%) than those of nonchronic populations (Howland 1991), and relatively low placebo response rates have been reported in these patients (Rush and Thase 1997). When symptomatic improvement occurs with pharmacotherapy in chronic depression, it is associated with functional restoration (Miller et al 1998). This all indicates that patients with chronic depression may well benefit from medication treatment. There is also evidence from a controlled study that patients with major depression who have residual symptoms may improve with cognitive behavioural treatment (Fava et al 1994). Another study of patients with chronic depression found that patients with a combination of CBT and nefazodone were more likely to have a favourable response than patients with either treatment alone (Keller et al 2000). 3.2 Dysthymic disorder ICD-10 defines dysthymia broadly as a chronic depression of mood that does not currently fulfil

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the criteria for recurrent depressive disorder in terms of either severity or duration of individual episodes (WHO 1991). Similarly, DSM-IV characterizes dysthymic disorder as a chronic mild depressive syndrome that has been present for two years or longer (American Psychiatric Association 1994a). Individuals with dysthymia frequently have a superimposed major depressive disorder ("double depression") (see Chapter 3.3). Patients with "double depression" are less likely to have a complete recovery than are patients with major depressive disorder without dysthymia (American Psychiatric Association 2000). However, patients with "double depression" who are treated during a major depressive episode also benefit with respect to their dysthymia (Akiskal 1994). Dysthymia is a relatively common disorder with a median point prevalence of 2.1% across studies worldwide (Wittchen 2000). The lifetime prevalence has been estimated to be between 3.1% (Weissman et al 1988) and 6.4% (Kessler et al 1994). There is epidemiological evidence of high comorbidity (75%) with other psychiatric disorders, mostly major depression, anxiety disorders and substance abuse. 3.2.1 Pharmacotherapy of dysthymic disorder Traditionally, dysthymic disorder has not been the focus of pharmacotherapeutic interventions, given the chronicity and presumed nonbiological personality variables associated with it (Howland 1991). Psychotherapy and psychoanalysis were generally considered the treatment options of first choice, although these treatment modalities were not well studied in controlled designs. However, as a result of a series of placebo-controlled medication trials, this attitude has recently been changing (Shergill and Katona 2000). Among the antidepressants found to be superior to placebo were desipramine (Kocsis et al 1996; Miller et al 2001), fluoxetine (Hellerstein et al 1993), moclobemide (Versiani et al 1997), imipramine and sertraline (Thase et al 1996; Keller et al 1998b). In a double-blind study comparing phenelzine with imipramine, the MAOI was more effective (Vallejo et al 1987). Although the amount of data from controlled studies is still limited, a comprehensive review has confirmed the efficacy of various antidepressants in dysthymic disorder (Level A) (World Psychiatric Association Dysthymia Working Group 1995). A recent meta-analysis of 15 randomized controlled trials that used various drugs (mostly antidepressants, TCAs, SSRIs and MAOIs) versus placebo in the treatment of dysthymia showed that drugs are more effective than placebo, with no difference between and within classes of drugs (Lima and Moncrieff 2001). Although the optimal length of pharmacotherapy in dysthymia has not been studied in a

controlled design, a course of treatment with an antidepressant for at least two to three years is recommended. Patients treated with TCAs were more likely to report adverse events compared with those treated with placebo in placebocontrolled trials (Lima and Moncrieff 2001). Results of a randomized, double-blind study of sertraline and imipramine indicated that patients suffering from chronic major depression (i.e., unremitting major depression for at least two years or dysthymia with a concurrent major depression) can achieve a good therapeutic response with acute pharmacotherapy (Keller et al 1998a). In this study, both antidepressants were equal in overall efficacy, but sertraline was better tolerated. Thus, superior tolerability and better side effect profiles compared to the "older" antidepressants, e.g., TCAs, make the SSRIs and other "newer" antidepressants the prime candidates for the long-term treatment of dysthymia (Level A). Recommended doses for dysthymia are similar to those given for acute treatment of a major depressive episode. No systematic research has been undertaken to study treatment options for patients with dysthymia who do not respond to an adequate first trial. Under such circumstances, switching to an antidepressant of a different class seems to be an appropriate option. Geriatric dysthymia is an understudied condition (Kocsis 1998). In one placebo-controlled study, paroxetine showed moderate efficacy in reducing depressive symptoms in geriatric dysthymia (Williams et al 2000). 3.3. "Double depression" and other chronic depressions It has been estimated that chronic depressive disorders account for 30% to 35% of all cases of depression (Kessler et al 1994). As many as 25% of patients with major depression have coexisting dysthymia, and more than 50% of the patients with dysthymic disorder will develop a major depressive episode at some point in time after the onset of their dysthymia ("double depression") (Keller and Shapiro 1982; Keller et al 1995b). Patients with "double depression" have a particularly chronic and severe course of illness. In a study comparing outpatients with "double depression" to outpatients with episodic major depression, patients with "double depression" exhibited significantly greater impairment, more severe depressive symptoms, greater comorbidity, more personality disturbance, lower levels of social support, more chronic strains, and higher rates of bipolar II and nonbipolar affective disorders in first-degree relatives (Klein et al 1988). In addition, patients with "double depression" are significantly less likely to fully recover. Recent randomized controlled trials have shown several medications (desipramine, Kocsis et al 1996; imipramine and sertraline, Keller et al

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1998a; nefadozone, Keller et al 2000) to be efficacious in the treatment of chronic depression, including "double depression" (Level A). The basic principles of treatment for chronic depression involve adequate acute-phase medication dosing for an appropriate length of time. Once full remission is achieved, the continuation and maintenance of pharmacotherapy lowers the risk of relapse and recurrence (Kocsis et al 1996; Nierenberg 2001; Trivedi and Kleiber 2001). There is evidence that patients with chronic depression particularly benefit from a combination of pharmacotherapy and psychotherapy, as seen in the combination of nefadozone and cognitive behavioural analysis system of psychotherapy (CBASP) (Keller et al 2000). 4 Subthreshold depressions

general population and in primary care settings, thus having a substantial impact on the mental health system (Sherbourne et al 1994; Judd et al 1994, 1996). Controlled treatment data involving pharmacotherapy of these disorders is sparse. The majority of published studies are case reports, open label studies or retrospective analyses (Rapaport and Judd 1998; Stamenkovic et al 1998; Pini et al 1999). In one RCT of patients with recurrent brief depression, fluoxetine was not superior to placebo in preventing recurrences (Montgomery et al 1994). However, in an open-label study of fluoxetine, the frequency of recurrences was significantly lower (Stamenkovic et al 2001). In an RCT of minor depression, paroxetine showed higher response rates compared with maprotiline, but no placebo-comparison was included (Szegedi et al 1997). In an RCT in older adults with minor depression, paroxetine improved depressive symptoms to a greater degree and more rapidly than placebo plus clinical management (Williams et al 2000). Given the limited data from controlled studies for subthreshold depressive disorders, evidencebased treatment recommendations cannot be given at this point. Close monitoring and problem-solving therapy for recent onset cases may be useful, and a treatment trial with one of the well-tolerated antidepressants is worth trying in more chronic and unremitting cases. RCTs of antidepressants in well-defined populations are warranted. The same is true for the treatment of adjustment disorder with depressed mood (Jones et al 1999). Disclosure statement The preparation of these WFSBP guidelines has not been financially supported by any commercial organization.

During the last decade, there has been growing interest in understanding the importance of depressive symptoms that do not reach the threshold for major depressive disorder (Angst and Ernst 1993; Sherbourne et al 1994; Pini et al 1999; Angst et al 2000; Geiselmann and Bauer 2000; Sadek and Bona 2000). The term "subthreshold depression" is now generally defined as a patient who suffers from a cluster of depressive symptoms, of which the number, duration or quality is insufficient to meet the DSM criteria for a diagnosis of major depression (Sadek and Bona 2000). Subthreshold depression includes those patients who meet criteria for minor depressive disorder (MinD), recurrent brief depressive disorder (RBD) (Angst and Hochstrasser 1994) and subsyndromal symptomatic depression (SSD) (Judd et al 1994). In DSM-IV, these disorders fall under the category of depressive disorders not otherwise specified (NOS). The essential feature of MinD is one or more period of depressive symptoms that is identical to major depressive episodes in duration, but that involves fewer symptoms and less impairment (DSM-IV, American Psychiatric Association 1994a). Individuals whose presentation meets the criteria for minor depressive disorder would be diagnosed as having "adjustment disorder with depressed mood" if the depressive symptoms occur within three months of the onset of a psychological stressor (DSM-IV). In RBD, the number and severity of symptoms are identical to those in major depressive episodes and last at least two days, but less than two weeks. Judd et al (1994) defined subsyndromal symptomatic depression (SSD) as the simultaneous presence of any two or more symptoms of depression, but excluding anhedonia and depressed mood, which are present for most or all of the time, and are at least two weeks in duration. These symptoms are associated with evidence of social dysfunction occurring in individuals who do not meet criteria for diagnoses of minor depression, major depression, and/or dysthymia. It should be emphasized that these subthreshold depressive disorders are highly prevalent in the

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GABAergic Neurosteroid Modulation of Ethanol Actions

Rahul T. Khisti, Shannon N. Penland, Margaret J. VanDoren, A. Chistina Grobin, A. Leslie Morrow
Departments of Psychiatry and Pharmacology and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, North Carolina, USA
Summary Systemic administration of ethanol elevates plasma and cerebral cortical GABAergic neuroactive steroids. The increase in neurosteroids is responsible for specific behavioural and electrophysiological actions of ethanol in rodents. This article recapitulates the current knowledge of the novel interaction between ethanol and neurosteroids and addresses the potential mechanism for ethanol-induced increase in brain neurosteroid levels. Ethanol-induced increase in the cortical neurosteroid content is modified by neurosteroid biosynthesis inhibitors and completely prevented by adrenalectomy in male rats. In line with this, adrenalectomy prevented the anticonvulsant and hypnotic effects of acute ethanol administration. It is speculated that acute ethanol administration might resemble acute stress and increase neuroactive steroids due to activation of hypothalamic-pituitary adrenal axis. Ethanolinduced increases in neuroactive steroids might be responsible for the antidepressant, anxiolytic, spatial learning deficits and drug discriminatory actions in rodents. Thus ethanol-induced increases in neuroactive steroids represent a novel mechanism of ethanols action, responsible for several pharmacological and behavioural actions of ethanol. The development of new therapeutic strategies for alcoholism may arise based on the novel interaction between ethanol and neurosteroids in the brain. Key words: 3-hydroxy-5-pregnan-20-one, allopregnanolone, DHEA, alcohol. Correspondence: A. Leslie Morrow, Ph.D. Bowles Center for Alcohol Studies CB#7178, 3027 Thurston Bowles Bldg. University of North Carolina at Chapel Hill Chapel Hill, NC 27599-7178 USA Tel: +1 919 966 7682 Fax : +1 919 966 9099 E-mail: morrow@med.unc.edu Central effects of ethanol Ethanol has potent and ubiquitous effects on the function of the central nervous system (CNS). Different neurotransmitter and neuromodulator systems, including -aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), serotonin, adenosine and opioid systems, are directly or indirectly modified by ethanol administration. Among these modulatory systems, the effect of ethanol on GABAergic neurotransmission is the most potent and the most controversial. Acute ethanol administration mimics some of the actions of positive allosteric modulators of GABAA receptors, such as the benzodiazepines and barbiturates. Similar to these GABAergic modulators, ethanol elicits anxiolytic, sedative/hypnotic, anticonvulsant and motor incoordinating effects (Majchrowicz 1975; Frye et al 1981). Furthermore, ethanol causes impairments in cognitive processing (Matthews et al 1995; Givens and McMahon 1997), and at high concentrations ethanol acts as an anaesthetic and respiratory depressant (Sellers and Kalant 1976). Substantial evidence supports the supposition that ethanol enhances GABAergic neurotransmission. Ethanol intoxication and anxiolysis are respectively reduced and blocked by inverse agonists at GABAA receptors (Suzdak et al 1986b; Glowa et al 1988; Becker and Hale 1991), while the GABAA receptor agonists potentiate ethanol-induced anxiolysis (Ho and Yu 1991). At physiologically relevant concentrations (20-60 mM), ethanol potentiates muscimol-stimulated Cl- uptake in cerebral cortical synaptoneurosomes of rats (Suzdak et al 1986a; Morrow et al 1988), mouse cerebellar microsacs (Allan and Harris 1987) and cultured rat spinal cord neurons (Ticku and Burch 1980). Similar to ethanol-induced behavioural effects, ethanol potentiation of GABAA receptor-mediated Clinflux is blocked by Ro15-4513 and GABAA receptor antagonists (Suzdak et al 1986a; Suzdak et al 1988; Mehta and Ticku 1988). Despite the plethora of data linking ethanol action to GABAA receptors, electrophysiological studies are inconclusive in finding a direct interaction and suggest that ethanol may have indirect actions, possibly involving activation of kinases (for a review see Grobin et al 1998). Recently, our group (Morrow et al 1999) suggested a novel role for the neurosteroid 3-hydroxy5-pregnan-20-one (3,5-THP or allopregnanolone) in certain pharmacological and behavioural effects of ethanol. 3,5-THP is a ring-A

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reduced metabolite of progesterone which rapidly alters CNS excitability through specific positive allosteric interaction with a steroid recognition site on GABAA receptors (Paul and Purdy 1992). In this review we discuss recent discoveries in the functional and behavioural interactions of ethanol and GABAergic neurosteroids. GABAergic neurosteroids The terms "neuroactive steroids" and "neurosteroids" are commonly used for steroids that interact with neurotransmitter receptors (Paul and Purdy 1992). The actions of classical steroid hormones at the genome require a time lag of several minutes to hours and are limited by the rate of protein synthesis (McEwen 1991), while the modulatory effects of neuroactive steroids occur within milliseconds to a few seconds. The concentration of some neuroactive steroids in the brain far exceeds that found in plasma (Baulieu 1981), and persists in the brain even after ablation of gonadal or adrenal glands. Neurosteroids have actions at various receptors, including the ligand-gated receptors GABAA, NMDA, kainate, nicotinic acetylcholine, 5-HT3 receptors, voltage-gated channels like Ca+2, and other receptors such as sigma1 and oxytocin (Rupprecht and Holsboer 1999). However, the action of the 3,5- and 3,5-reduced metabolites of progesterone and deoxycorticosterone at GABAA receptors occurs with nanomolar potency, stereoselectivity and greater efficiency than actions at any other sites (Paul and Purdy 1992; Lambert et al 1995). Based on their actions at the GABAA receptors, the neurosteroids are classified as GABAA receptor agonists or antagonists. Endogenous neurosteroids having potent agonistic action at GABAA receptors include 3,5THP, 3-hydroxy-5-pregnan-20-one (pregnanolone), 3,21-dihydroxy-5-pregnan-20-one (5THDOC) and 3,21-dihydroxy-5-pregnan-20one (5-THDOC), whereas dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PS) are antagonists (Majewska and Schwartz 1987; Majewska et al 1990) Many investigators have suggested that these neurosteroids together help to regulate CNS excitability. The most direct evidence for this hypothesis shows that inhibition of the biosynthesis of GABAergic agonist neurosteroids diminishes normal GABA receptor electrophysiological responses to muscimol in vivo (Pinna et al 2000). Effect of ethanol on neurosteroid content Several studies have shown that 3,5-THP plays an important role in the complex interactions between ethanol and GABAA receptors. Systemic ethanol administration to male and female rats elicits a marked increase in plasma and cerebral cortical 3,5-THP levels (Morrow et al 1999). Plasma and cerebral cortical 3,5-THP levels in male rats are elevated by 600% and 700% above

controls, respectively. On the other hand, in female rats tested during the estrus phase, ethanol increased 3,5-THP levels in plasma by 157% and in cerebral cortex by 234%. These increases in brain 3,5-THP levels are sufficient to enhance GABA-mediated neurotransmission in brain (Morrow et al 1987; Morrow et al 1990) and exhibit behavioural effects including antianxiety and anticonvulsant actions in animal models (Crawley et al 1986; Devaud et al 1995). Similarly, ethanol also increases 3,5-THP and 3,21-dihydroxy-5-pregnan-20-one (THDOC, tetrahyrodeoxy-corticosterone) in cerebral cortex and hippocampus, in both alcohol-naive Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats (Barbaccia et al 1999). Ethanol elevates cerebral cortical 3,5-THP levels in male rats in a dose- and time-dependent manner (VanDoren et al 2000). The effects of ethanol on cerebral cortical 3,5-THP levels is biphasic, similar to the effects of ethanol on GABAA receptor-mediated chloride uptake in cerebral cortical synaptoneurosomes (Suzdak et al 1986a). At doses greater than 3 g/kg, ethanol produces a smaller effect on cortical 3,5-THP than 2 or 3 g/kg doses. The time course of the effect of acute ethanol administration on 3,5THP suggests that 3,5-THP contributes to the effects of systemic ethanol administration 20 to 120 minutes following administration, and reaches a plateau between 40 to 80 minutes after administration. Neurosteroid 3,5-THP contributes to specific effects of ethanol Morrow and colleagues (Morrow et al 1987, 1990) have shown that cerebral cortical concentrations of 3,5-THP above 50 nM (or approximately 6 ng/g tissue) potentiate GABAA receptormediated chloride flux leading to the hypothesis that ethanol induction of 3,5-THP in cortex contributes to the pharmacological effects of ethanol in vivo. When the steroid-specific biosynthetic inhibitor finasteride was administered before moderate doses (2 g/kg, 20 % v/v in saline) of ethanol, blocking synthesis of 3,5THP from 5-DHP (5-dehydroprogesterone), increases in cortical 3,5-THP levels were partially reversed (VanDoren et al 2000). This partial reduction in 3,5-THP levels may be due to the fact that finasteride only partially inhibits the type 1 5-reductase enzyme in vivo (Tian 1996; Stuart et al 2001). Alternatively, the release of endogenous stores of 3,5-THP may contribute to increases in 3,5-THP levels. However, since finasteride reduced the effects of ethanol (2.0 g/kg) on 3,5-THP levels to concentrations that would be expected to lack pharmacological activity, effects of finasteride on ethanol-induced pharmacological actions were predicted. Ethanol inhibition of spontaneous neural activity in brain Ethanol inhibits spontaneous neural electro-

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physiological activity in several brain areas including the medial septum, inferior colliculus, substantia nigra reticulata and cerebral cortex (Breese et al 1993). To examine if 3,5-THP contributes to ethanol-induced effects on neurons in the brain, spontaneous firing rates of medial septum/diagonal band of Broca neurons (MS/DB) were investigated (VanDoren et al 2000). In this region, ethanol significantly reduces spontaneous firing rates 40-50%, an effect that was observed 15 minutes following ethanol injection and sustained for up to 55 minutes. This time course corresponds closely to the time course of ethanol-induced elevation in 3,5-THP levels in cerebral cortex. Finasteride pretreatment completely blocked the effect of ethanol on spontaneous firing rate (VanDoren et al 2000). In addition, the effect of exogenous 3,5-THP administration was not altered by finasteride pretreatment, suggesting that finasteride pretreatment does not alter the response of MS/DB neurons to GABA-mediated inhibition per se. Therefore, it is likely that finasteride pretreatment prevents the formation of 3,5THP that normally mediates or modulates the effect of ethanol on MS/DB neurons. Anticonvulsant effects of ethanol To determine if 3,5-THP contributes to the anticonvulsant effects of ethanol, we investigated the effect of finasteride pretreatment on ethanols ability to increase bicuculline seizure thresholds (an anticonvulsant effect). Finasteride completely prevented the anticonvulsant effect of ethanol (2 g/kg) 40 minutes following systemic administration (VanDoren et al 2000). Moreover, finasteride did not alter seizure thresholds 10 minutes after ethanol administration, when ethanol does not produce an anticonvulsant effect and 3,5-THP levels are not elevated to effective concentrations. These data support the hypothesis that ethanol induction of 3,5-THP levels in the cortex mediates or modulates the anticonvulsant effects of ethanol via GABAA receptors. Motor incoordination and muscle relaxation Several behavioural effects of ethanol can be observed within minutes of systemic administration, preceding ethanol induction of 3,5THP, including muscle relaxation and motor incoordination. These effects can be detected and measured by the Majchrowitz Intoxication Scale (Majchrowicz 1975) or the aerial righting reflex (Givens and Breese 1990). Finasteride did not block ethanol-induced muscle relaxation or motor incoordination as measured on the Majchrowitz Intoxication Scale or by the aerial righting reflex (unpublished data). Indeed, finasteride enhanced these effects of ethanol at some time points. Since finasteride reduces some effects of ethanol and increases other effects of ethanol, it appears that 3,5-THP may contribute to specific behavioural effects of ethanol.

However, the mechanisms for finasteride enhancement of ethanols motor effects are unknown. Differential regulation of 3,5-THP biosynthesis across brain regions (Mellon and Deschepper 1993) may be an important factor, as ethanol-induced motor incoordination may involve brain areas where 3,5-THP biosynthesis and finasteride actions have not been studied. It is also possible that finasteride administration may increase levels of other GABAA receptor neurosteroids by altering the steroid biosynthetic pathway. Hence, it is not yet clear whether GABAergic neurosteroids contribute to the motor-incoordinating effects of ethanol. Hypnotic effects of ethanol Sleep problems are more common among alcoholics than among non-alcoholics (Aldrich 1998; Ehlers 2000). During both drinking periods and withdrawal, alcoholics commonly experience problems falling asleep and decreased total sleep time. In the laboratory, ethanolinduced loss of righting reflex has been used for several years as a crude index to study the sedative-hypnotic actions of ethanol. Several neurotransmitters and neuromodulators, including GABA, glutamate and adenosine, are involved in the ethanol-induced loss of righting reflex in rodents. Among the different neuroactive substances implicated in ethanol-induced loss of righting reflex, research on the involvement of 3,5-THP is of increasing interest and importance. It is widely known that sedative hypnotic effects of ethanol are potentiated and antagonized respectively by GABAA receptor agonists and antagonists (Martz et al 1983). It has been previously shown that administration of high doses of 3,5-THP or its precursors to rodents induces a loss of righting reflex and anaesthesia (Mok et al 1993; Korneyev and Costa 1996). Waking cerebral cortical levels of 3,5-THP correlate with ethanol-induced sleep time (VanDoren et al 2000). These findings suggest for the first time that neurosteroids, including 3,5-THP, may be important in the sedativehypnotic actions of ethanol. We investigated the effects of systemic administration of biosynthetic inhibitors of 3,5-THP such as finasteride and SKF 105111 on ethanolinduced loss of righting reflex. Finasteride had no effect on ethanol-induced sleep time and did not alter cerebral cortical 3,5-THP levels at hypnotic ethanol doses (Morrow et al 2001a). It has been previously shown that systemic administration of SKF 105111 to mice reduces the loss of righting reflex induced by the potent GABAA receptor agonists pentobarbital and muscimol, by reducing brain levels of 3,5-THP (Matsumoto et al 1999; Pinna et al 2000). However, there are equivocal reports about the effect of SKF 105111 on ethanol-induced loss of righting reflex. Guidotti et al (2001) showed that systemic administration of SKF 105111 to mice significantly reduces the duration of loss of

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righting reflex induced by ethanol. On the contrary, Atzorii et al (2001) presented evidence that SKF 105111 does not modulate ethanolinduced loss of righting reflex in mice. We found that prior administration of SKF 105111 (50 mg/kg, i.p.) to rats receiving ethanol did not significantly reduce sleep time, but instead increased the latency for the animals to induce sleep (Table 1). Moreover, SKF 105111 did not reduce cerebral cortical 3,5-THP levels (data not shown). These findings suggest that systemic administration of biosynthetic inhibitors may not alter ethanol-induced increases in cerebral cortical 3,5-THP at hypnotic doses of ethanol.
Table 1 Finasteride, SKF 105111 and NPI-113 do not alter ethanol-induced loss of righting reflex. Finasteride (25 mg/kg, s.c., 4 and 1.5 hr before ethanol), SKF 105111 (50 mg/kg, i.p., 15 min prior to ethanol) and NPI 113 (15, 30 or 45 mg/kg, i.p., 15 min prior to ethanol) were administered, followed by ethanol (3.5 g/kg, 20 % v/v, i.p.) administration. Duration of loss of righting reflex was determined at the point when the rat regains the ability to right itself three times in one minute (n = 5-7/group). Animals that failed to lose righting reflex were not included in the study. Treatments Dose Duration of LORR (min SEM) 96.8 19 126.0 17 66.51 8.78 73.86 7.37 100.0 8.0 86.0 12.0 99.0 8.0 123.0 15.0

Vehicle + ethanol Finasteride + ethanol Vehicle + ethanol SKF105111 + ethanol Vehicle + ethanol NPI 113 + ethanol

3.5 g/kg 25 mg/kg + 3.5 g/kg 3.5 g/kg 50 mg/kg + 3.5 g/kg 3.5 g/kg 15 mg/kg + 3.5 g/kg 30 mg/kg + 3.5 g/kg 45 mg/kg + 3.5 g/kg

THP. Ethanol selectively produces a significant dose-dependent impairment in the use of the previously learned spatial information (Matthews et al 1995). It is possible that ethanol stress might impair performance on learning and memory tasks by increasing 3,5-THP concentrations in brain. Like ethanol, the neurosteroid 3,5-THP selectively impairs spatial memory in rats. Intracerebroventricular infusion or subcutaneous administration of 3,5-THP has been shown to impair performance on several tasks, including spatial working memory tasks (Reddy and Kulkarni 1998; Ladurelle et al 2000). Acute ethanol administration and acute allopregnanolone administration produced strikingly similar impairments in spatial memory performance in the Morris water task. Furthermore, the spatial memory deficit is selective in that no significant alteration in non-spatial memory performance is found with either drug. The hippocampus is critical for spatial memory performance in a variety of tasks such as the Morris water maze. However, the hippocampus is not critical for performance on non-spatial learning and memory tasks (Morris et al 1982; Packard et al 1989; Matthews et al 1995). Previously, it has been shown that acute ethanol administration and 3,5-THP administration alter hippocampal neurophysiology (Steffensen and Henriksen 1992; Givens 1995; Wang et al 2000) and impair spatial learning and memory performance (Gibson 1985; Matthews et al 1995; White et al 1997; Morato et al 2001). While not conclusive, the striking correlation between the spatial memory impairments produced by ethanol and allopregnanolone suggest that ethanol's actions may involve changes in 3,5-THP levels in the hippocampus. Drug discrimination Drug discrimination procedures examine whether the interoceptive effects produced by a test drug are similar to a training drug, indicating common pharmacological mechanisms (Overton 1974). This procedure is commonly used to identify potential receptors that mediate the stimulus effect of drugs on the CNS (Colpaert 1986; Holtzman 1990). Recently, the discriminative stimulus properties of 3,5-THP and 5THDOC have been assessed in the rat. According to their GABA agonist activity, both neurosteroids substituted for the interoceptive cues of diazepam, pentobarbital and ethanol (Ator et al 1993). Similar effects are found with other GABAergic neurosteroids including 3,5-THP and 3,5-THP (Bowen et al 1999). Acute administration of 3,5-THP, 3,5-THP, 3,5THDOC and the low efficacy steroid 3,5-THP resulted in complete substitution of 80% to 100% and 40% to 67% of the animals tested in the 1 vs. 2 g/kg dose of ethanol discriminations, respectively (Bowen et al 1999). Data from male and female cynogolous monkeys (Macaca fasicularis) confirm the data from in vitro studies showing that configuration of the hydroxyl group at the C3 position determines ethanol-like

In addition to these biosynthetic inhibitors, systemic administration of NPI 113, a partial agonist of neurosteroid sites on GABAA receptors, did not block ethanol-induced loss of righting reflex (Penland et al 2001). However, when ethanol was administered to adrenalectomized (ADX) rats there was a 90% reduction in the duration of loss of righting reflex in ADX compared to SHAM ADX rats (data not shown). Furthermore, waking cerebral cortical 3,5-THP levels of ADX rats were remarkably lower compared to the SHAM ADX rats (data not shown). Collectively, these findings suggest that ethanol-induced increases in brain neurosteroids may contribute to the hypnotic effects of ethanol in vivo. Cognitive function Ethanol and other stressors have long been known to disrupt contextual or spatial memory. Stressors are known to increase endogenous brain levels of neurosteroids, including 3,5-

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discriminative effects (Ator et al 1993; Grant et al 1996). Accordingly, 3,5-THP and androsterone produced discriminative stimulus effects similar to those of ethanol in male and female monkeys trained to self-administer 1 g/kg of ethanol (88% and 100%, respectively) and 2 g/kg of ethanol (83% and 80%, respectively) (Grant et al 1996). More recently, it was shown that 3,5-THP and pentobarbital infused into the nucleus accumbens substitutes for the discriminative stimulus effects of ethanol (Hodge et al 2001). It was suggested that GABAA receptors in the nucleus accumbens play a more influential role in the discriminative stimulus effects of ethanol (Hodge et al 2001). Thus, neurosteroids produce discriminative stimulus effects similar to ethanol, consistent with the hypothesis that neurosteroids mediate several GABAergic effects of ethanol. Other behaviours Ethanol increases brain levels of 3,5-THP to a pharmacologically relevant concentration (VanDoren et al 2000). It was recently shown that the anxiolytic action of ethanol is blocked by both systemic and intrahippocampal administration of antagonists at the peripheral diazepam binding inhibitor receptor (Morato et al 2001). Both systemic and intrahippocampal administration of Ro5-4864 markedly antagonized the anxiolytic action of ethanol (Morato et al 2001). The intrahippocampal administration of PK 11195 blocked anxiolytic actions, whereas its systemic administration had no effect on them. Recently, Bitran presented evidence that intracerebroventricular administration of PK 11195 antagonizes the anxiolytic action of ethanol by reducing brain levels of neurosteroids, including 3,5-THP (data presented at the Annual Conference of the Research Society of Alcoholism, Montreal, Canada, 2001). Similarly, Khisti and Chopde (personal communication) demonstrated the involvement of 3,5-THP in the antidepressant action of acute systemic ethanol administration to mice as revealed by the forced swim test. They found that acute ethanol administration led to decreased immobility, and withdrawal from chronic ethanol administration resulted in increased immobility in the forced swim test. The immobility associated with ethanol withdrawal could be reversed by sub-antidepressant doses of 3,5THP, suggesting sensitization to its antidepressant effects. It is noteworthy that ethanol withdrawal in human patients increases the incidence of depression, as well as decreasing the levels of neuroactive steroids, including 3,5THP (Romeo et al 1996). Since finasteride only partially reduces 3,5THP levels and does not block all the behavioural effects of ethanol, it would be premature to suggest the clinical use of such compounds for ethanol dependence. Investigation of other inhibitors of 5-reductase, such as SKF 105111,

which inhibits both type 1 and type 2 subtypes of 5-reductase (Levy et al 1989), might give more insight towards the complex interaction between ethanol and 3,5-THP. However, the usefulness of steroid biosynthetic inhibitors may be limited by potential pharmacokinetic interactions with ethanol as well multiple potential side effects that may arise due to inhibition of other steroid biosynthetic pathways. Mechanisms of ethanol-induced elevations in brain neurosteroid levels Plasma levels of the 3,5-THP and THDOC precursors progesterone and corticosterone are also elevated following systemic ethanol administration, but do not correlate (r = 0 for progesterone; r = 0.18 corticosterone) with the cerebral cortical levels of 3,5-THP (VanDoren et al 2000). This suggests that effects of ethanol administration on 3,5-THP concentrations in cerebral cortex may involve mechanisms that are distinct from the regulation of plasma steroid levels. To investigate whether increases in cerebral cortical 3,5-THP are mediated by release of an endogenous pool of steroid from the adrenal glands, we investigated the effect of ethanol in ADX and sham-operated male rats. Interestingly, we found that cerebral cortical levels of 3,5THP in sham-operated rats were considerably

16

Saline Ethanol (2 g/kg, 20 % v/v, i.p.)

14

Cerebral cortical 3, 5-THP (ng/g)

12

10

0 SHAM ADX ADX

Figure 1 Adrenalectomy attenuates ethanol-induced increase in cerebral cortical 3,5-THP levels. Adrenalectomized (ADX) and shamadrenalectomized (SHAM ADX) rats were injected with ethanol (2 g/kg; 20 % v/v, i.p.) and were decapitated after 40 minutes. The data represents mean SEM of cerebral cortical 3,5-THP levels in six to seven rats per group.

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higher than in the ADX rats (Figure 1). These results suggest that ethanol acts as an acute stressor, causing the activation of the hypothalamic pituitary adrenal (HPA) axis, and induces the release of 3,5-THP and progesterone into the circulation, elevating brain 3,5-THP levels. Ethanol-induced increases in levels of progesterone and corticosterone also suggest a nonspecific activation of steroid biosynthesis and/or adrenal release. Ethanol could increase 3,5THP levels via several mechanisms, including modulation of biosynthesis, catabolism or release of endogenous steroid pools. If pregnane steroid biosynthesis is activated non-specifically by ethanol, an increase in plasma or brain levels of DHEA or its sulphated congener, DHEAS, might be predicted due to elevations of the precursor pregnenolone. However, systemic ethanol administration does not alter DHEA or DHEAS concentrations 60 minutes after systemic ethanol administration (Morrow et al 2001b). This lack of effect of ethanol on DHEA and DHEAS levels is consistent with the idea that androstane steroids are regulated differently than pregnane steroids. However, Robel and Baulieu (Robel and Baulieu 1995) have reported that DHEA(S) clears rapidly in the brain under the influence of ethanol. It has also been reported that ethanol markedly increases the metabolic conversion of DHEAS to 5-androstene-3,17-diol monosulphate (Andersson et al 1986). Hence, ethanol may transiently alter DHEA or DHEAS levels, although this possibility remains untested. Figure 2 illustrates the steroid biosynthetic pathways modulated by ethanol and by activation of the HPA axis, indicating many potential sites of ethanol modulation. Acting as an acute stressor, ethanol is known to increase corticotrophin releasing factor (CRF) in the hypothalamus, which subsequently increases adrenocorticotrophic hormone (ACTH) release from the pituitary into the circulation (Rivier 1996). Increased ACTH may increase the influx of cholesterol through the mitochondrial membrane by increasing the endogenous peptide, diazepam binding inhibitor peptide (DBI) (Cavallaro et al., 1992). The increase in cholesterol might lead to increases in a number of precursor neuroactive steroids, including progesterone and 5-DHP, the immediate precursor of 3,5-THP. Several possible mechanisms for the ethanol-induced increase in brain neurosteroids like 3,5-THP have been explored. Table 2 shows the effects of systemic pretreatment with the biosynthetic inhibitors finasteride, indomethacin and trilostane on ethanol-induced increases in cerebral cortical 3,5-THP. These biosynthetic enzyme inhibitors either moderately or completely fail to inhibit the ethanol-induced increase in cortical 3,5-THP content. The type II 5-reductase inhibitor finasteride was the only enzyme inhibitor that reduced the ethanol-induced increase in cerebral cortical 3,5-THP. The

3-hydroxysteroid dehydrogenase (3-HSD) inhibitor indomethacin, paradoxically, increased cerebral cortical concentrations of 3,5-THP, and the 3-hydroxysteroid dehydrogenase inhibitor trilostane did not have an effect on cerebral cortical 3,5-THP levels. Similarly, systemic pretreatment with PK 11195, an antagonist at DBI receptors, antialarmin, an antagonist at the CRF receptor and NPI-113, a partial agonist of neurosteroid sites on GABAA receptors, did not prevent ethanol-induced increases in 3,5-THP levels in cortex (Table 2).
ETHANOL
CHOLESTEROL CRF receptors CRF A C T H f
(inner mitochondrial membrane)

DBI

MDR

CHOLESTEROL
(inner mitochondrial membrane)

P450scc PREGNENOLONE b 3-HSD CORTICOSTERONE PROGESTERONE c 5-reductase 5 - DHP d 3-HSD

3, 5 - THP e GABAA receptor

Figure 2 Schematic diagram of steroid biosynthetic pathways involved in ethanol-induced increases in cerebral cortical 3,5-THP. Systemic administration of ethanol acts as a stressor and increases CRF content in brain, which in turn releases ACTH from pituitary gland into the plasma. Increased plasma ACTH may subsequently increase DBI levels. Increased DBI increases the influx of cholesterol from outer mitochondrial membrane to the inner mitochondrial membrane thereby leading to the cascade of neuroactive steroid biosynthesis. This is the rate-limiting step in steroid biosynthesis. The biosynthesis of neuroactive steroids is regulated by different enzymes acting at various stages. The alphabetical labels represent drugs used for investigating the mechanism of ethanol-induced increases in cerebral cortical 3,5-THP levels. The dotted lines represent the possible feedback inhibition. a = PK11195; b = trilostane; c = finasteride and SKF 105 111; d = indomethacin; e = NPI 113; f = antialarmin; MDR = peripheral mitochondrial diazepam binding inhibitor receptor; P450scc = cytochrome P450 side chain cleavage; 3-HSD = 3-hydroxysteroid dehydrogenase; 3-HSD = 3-hydroxysteroid dehydrogenase.

The lack of effect of neurosteroid biosynthesis inhibitors on ethanol-induced increases in 3,5-THP levels may indicate that ethanolinduced elevations in brain levels of neurosteroids are not dependent on de novo biosynthesis in brain. However, the possibility exists that ethanol has pharmacokinetic interactions with steroid biosynthesis inhibitors and interferes with their inhibitory activity in vivo.

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Further studies are needed to determine if ethanol directly alters the activity of neurosteroid biosynthetic enzymes in brain, as this mechanism may contribute to ethanol-induced elevations in neurosteroid concentrations.
Table 2 Differential effects of steroid biosynthetic enzyme inhibitors, CRF and diazepam binding inhibitor (DBI) receptor antagonists on ethanol-induced increases in cerebral cortical 3,5-THP levels. Saline or ethanol (2 g/kg, 20 % v/v, i.p.) was administered, and 3,5-THP levels were measured in cerebral cortex 1 hr after ethanol administration. Trilostane (inhibitor of the conversion of pregnenolone to progesterone) was administered 30 mg/kg, i.p. 1 hr before ethanol. The 5-reductase inhibitor finasteride was administered 25 mg/kg, s.c., 4 and 1.5 hr before ethanol. The 3-hydroxysteroid dehydrogenase inhibitor indomethacin was administered 0.1 mg/kg, i.p., 20 min before ethanol. CRF receptor antagonist antialarmin (20 mg/kg, i.p.) and the antagonist of mitochondrial DBI receptors, PK 11195 (6 mg/kg, i.p), were administered to separate groups of rats 15 min before ethanol. Cortical 3,5-THP levels were significantly decreased only with finasteride pretreatment and significantly increased with indomethacin pretreatment. No significant effects on blood alcohol concentration (BAC) were found. Treatments Dose (i.p.) Cortical % ethanol 3,5-THP response (ng/g) 2.3 1.1 9.8 0.9 10.4 1.0 5.9 1.0* 14.9 0.9* 12.4 2.5 8.6 0.7 100.0 0.0 105.0 9.3 59.9 10.1 151.9 9.0 BAC (mg/dl)

THP prior to ethanol administration. If 3,5THP mediates behavioural actions of acute ethanol administration, then reinstating the peripheral stores of 3,5-THP precursor in ADX rats should reinstate the behavioural effects of ethanol in vivo. Hence, the effects of ethanol may involve elevations in neurosteroid precursors and effects on biosynthesis of GABAergic neurosteroids from these precursors. Further studies are needed to address these possibilities. Summary and outlook This review discusses the potential role of GABAergic neurosteroids in diverse pharmacological, physiological and behavioural actions of ethanol. Ethanol-induced increases in cerebral cortical 3,5-THP may be responsible for several important acute and chronic actions of ethanol. Ethanol-induced increases in cerebral cortical levels of neurosteroids are responsible, at least in part, for several behavioural effects of ethanol, including its hypnotic, reinforcing, anticonvulsant, anxiolytic and antidepressant actions. The actions of neurosteroid intermediaries represent a novel mechanism of ethanol action. Further studies will be required to address several important issues, including the mechanisms that underlie ethanol-induced elevations in 3,5-THP and the relevance of this effect to all of ethanols actions in the brain. Understanding these potential mechanisms for the ethanol-induced increase in cerebral cortical neurosteroid levels would be extremely valuable in the future design and development of new therapies for alcoholism.

Saline Ethanol Trilostane + ethanol Finasteride + ethanol Indomethacin + ethanol Antialarmin + ethanol PK 11195 + ethanol

2 g/kg 30 mg/kg + 2 g/kg 25 mg/kg + 2 g/kg 0.1 mg/kg + 2 g/kg 20 mg/kg + 2 g/kg 6 mg/kg + 2 g/kg

232 12.0 153 21.0 172 7.9 163 14.0

125.9 25.4 245 23.2 87.8 6.8 236 7.8

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BRIEF REPORT

Serotonin Platelet-Transporter Measures in Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Clinical versus Experimental Measures of Impulsivity
Robert D. Oades1, Michael Slusarek1, Silke Velling1, Brigitta Bondy2
1 2

University Clinic for Child and Adolescent Psychiatry, Essen, Germany Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany
Introduction Severe attention-deficit/hyperactivity disorder (ADHD) in children is usually treated with psychostimulant drugs, such as methylphenidate. Some improvement may be seen in up to 80% of patients (Swanson et al 1998). Clinical response is interpreted in terms of enhancing a hypoefficient dopamine system (Malone et al 1994), particularly in children with the hyperactive/impulsive subtype (DSM-IV). An alternative noradrenergic theory (Heilman et al 1991) may account for depressed activity in systems using noradrenaline as transmitter (Oades 1987) and be especially pertinent to the inattentive subtype (Lockwood et al 2001). But, interpretations here may be complicated by changes in other colocalised modulators like neuropeptide Y (Oades et al 1998). Past reviews considered catecholaminergic alterations as primary, to the exclusion of serotonergic systems (Oades 1987; Zametkin and Rapaport 1987). This is surprising in view of the widely acknowledged attribution of changed serotonin (5-HT) transmission to some forms of impulsivity (Soubrie 1986), and the high heritability for the ADHDcombined subtype for which impulsivity is a core feature (Rutter et al 1999). Further, in an animal model of ADHD (dopamine transporter knockout), hyperactive responsivity is modulated by the synaptic availability of serotonin (Gainetdinov et al 1999). In a non-ADHD context (e.g. borderline personality disorder, suicide), impulsivity in terms of abrupt bursts of behaviour and aggression has been associated with reduced 5-HT activity (e.g. lower CSF levels of 5-HIAA: Kavoussi et al 1997). In aggressive children with ADHD there are also indications from provoked prolactin release for reduced 5-HT activity (Halperin et al 1997). Further, as in attempted suicide in adults (Engstrom et al 1999), in ADHD patients reduced HVA/5-HIAA ratios may be related to poor cognitive and inhibitory control (Oades 2002). Thus, one might predict that features leading to the reduced synaptic availability of 5-HT would relate to impulsive reactivity: but it will be noted that low HVA/5-HIAA ratios would result from increased 5-HT metabolism. As the 5-HT transporter prominently controls the availability of 5HT in the synapse, an exploration of the binding characteristics of platelet 5-HT transporters, a model for the central transporter receptor

Summary Impulsivity in terms of aggression, suicide or poor cognitive control has been associated with low synaptic availability of serotonin (5-HT) in adults and children. However, characteristics of the 5-HT transporter have not been studied in children with attention-deficit/hyperactivity disorder (ADHD: combined type), where impulsivity is a core symptom. Here, we explored in 20 children with ADHD the relationship of the density (Bmax) and affinity (Kd) of the platelet 5-HT transporter measured with [3H]paroxetine to both clinical ratings of impulsivity (Conners Parent Questionnaire), and an experimental measure of impulsivity (the ability to withhold a prepotent response in the "stop-signal" paradigm). Decreases of affinity (increased Kd) correlated with a low probability of response inhibition, but not with the clinical ratings of impulsivity. However, ratings of distractibility and impulsivity correlated with the experimental measure of response-inhibition. In contrast, increased transporter affinity (low Kd) correlated modestly with higher ratings of aggressive and externalising behaviour. Bmax was not associated with any behavioural score. We conclude that the synaptic availability of 5-HT is under the control of the 5-HT transporter binding site affinity and that low affinity may be related to cognitive impulsivity (distractibility). Increased affinity of the transporter may also be related to conduct disturbance. Key words: childhood ADHD, distractibility, externalising behaviour, impulsivity, serotonin, transporter. Correspondence: Robert D. Oades, Ph.D. Clinic for Child and Adolescent Psychiatry University of Essen Virchowstr. 174 45147 Essen Germany Tel: +49 201 7227 468 Fax: +49 201 7227 302 E-mail: oades@uni-essen.de Acknowledgement We are very grateful to Ms Alexandra Schieler for her help with the biochemical assay.

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(Cheetham et al 1993), and their relationship to impulsivity in children with ADHD was conducted. Children were recruited from those presenting to a newly advertised screening programme, from which the subgroup tested were those recommended to receive medication, for which a blood sample was necessary. The screening programme allowed clinical ratings of impulsivity, as well as an experimental measure of the (in)ability to withhold a prepotent response at short notice (stop-paradigm: Slusarek et al 2001), to be compared with 5-HT transporter measures. Methods Twenty children with a pervasive hyperkinetic disturbance (ICD-10: WHO 1991), equivalent to the combined type (DSM-IV 314.01), were recruited. Biochemical data were obtained from 13 boys and three girls (mean age 10.4 years [y], standard deviation [sd] 2.4, range 7.2-14.5y) with a performance IQ of 87.4 (sd 14.0). Two had a simple hyperkinetic disorder (F90.0) and 14 a hyperkinetic disorder of social behaviour (F90.1 that includes elements of DSM-IV 313.81); of these, four had a secondary emotional disturbance (two with F93.8, one 94.1 and one 43.25). After receiving approval for the study from the faculty Ethics Committee, the children provided oral and the parents written informed consent to participation. The parents completed the Child Behavior Checklist (CBCL: Achenbach and Edelbrock 1983) and the Conners Parent rating scale (Goyette et al 1978). The sum score for Conners ratings was 20.8 (sd 1.27). Exclusion criteria included the diagnosis of learning disorders, a score of <17 on the Conners scale and a T score <60 on the CBCL attention scale. The present analysis was restricted to the CBCL scales for internalising (mean 68.9, sd 1.8), externalising (mean 71.8, sd 1.6) and aggressive behaviour (mean 75.9, sd 2.1), and to four of the ten items on the Conners scale relevant to impulsivity (i.e. C1 activity [mean 2.3, sd 0.21], C2 impulsivity [mean 2.3, sd 0.18], C5 fidgeting [mean 2.1, sd 0.20], C6 distractibility [mean 2.4, sd 0.16]). The stop-signal task was a forced-choice reaction time (RT) task. In the primary task children were asked to respond quickly and accurately with a left or right computer key when they saw an "X" appear to the left or right of a fixation point on the computer screen. After 20 trials to allow familiarisation with the task and 10 further trials for calculation of the individual mean RT, the secondary task was introduced. Here a "stopsignal" was presented with an auditory 1 kHz, 500 ms tone on 25% of 192 trials after the target. The stop-signal was presented 50, 200, 350 or 500 ms before the expected response. The interstimulus interval was 7 seconds. The stop-signal reaction time (SSRT) is the time between presen-

tation of the stop-signal and the inhibition of response, estimated from the RT distribution in the primary task (Logan 1994). Logans probability of inhibition (p-inhibit) was also calculated for each of the different stop-signal delays. Data for the 50 and 500 ms intervals did not distinguish ADHD from healthy children due to floor and ceiling effects, respectively. Thus analysis here is restricted to the 200 and 350 ms intervals. Platelets were prepared from platelet-rich plasma (25 ml EDTA blood) and stored as pellets at 80C prior to analysis of 5-HT transporter binding features after the method of Maguire et al (1993). After thawing and homogenisation of the pellets in hypotonic lysis buffer, cells were washed in Tris-HCl (70 mmol/l) and solubilized in an assay buffer (Tris HCl 50 mmol/l; NaCl 120 mmol/l; KCl 5 mmol/l; pH 7.5). Binding was performed using six different concentrations of 3Hparoxetine (0.2-5 nmol/l). Unspecific binding was assessed by 1 mol/l fluoxetine in parallel experiments. The assay was carried out in a final volume of 250 l incubating for two hours at 20C. The reaction was stopped through rapid filtration (GF/F filter Whatman) and radioactivity measured in a Beckman scintillation counter. Spearman correlation coefficients were calculated for comparisons of clinical and experimental behavioural indices with biochemical measures. Linear regression analyses with up to a maximum of three variables to predict impulsivity and the biochemical measures were used to seek support for the exploratory correlations. Results The mean platelet count for the children was 266 x103/l (sd 58.7, range 189-386). The mean values for Bmax and Kd were 3682 fmol/mg protein (sd 2684.2) and 0.424 nmol/l (sd 0.356), respectively. The experimental indices on the stop-signal task (p-inhibit) were 0.33 and 0.54 (SSRT 468 and 488 ms) for the 200 and 350 ms intervals, respectively. Comparative values from healthy children for p-inhibit were 0.46 and 0.80 (SSRT 225 and 235 ms) at 200 and 350 ms, respectively. The clinical, experimental and biochemical measures were not associated with the age or the IQ of the children. There were no significant correlations for the Bmax of the 5-HT transporter with either the clinical ratings or the experimental measures (p-inhibit/SSRT). However, Figure 1 shows that on the stop-signal task, decreasing p-inhibit correlated with increasing Kd values (i.e. decreasing affinity). Similar associations were found for the SSRT (Figure 1). Kd was not associated with any of the Conners clinical ratings. However, the experimental p-inhibit measures at 350 ms on the stop-signal task showed a modest relationship to the scales

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of impulsivity (r = -0.51, p = 0.05) and distractibility (r = -0.46, p = 0.08).

Probability of response inhibition (stop-signal 200 ms before) vs. Kd affinity (of paroxetine binding) 1.4 R = -0.57, p = 0.027 [SSRT R = +0.63, p = 0.011 Bmax/p 200 NS R = +0.08]

Further, we noted a modest correlation for increasing externalising and aggressive behaviour with lower Kd values for the 5-HT transporter: increasing affinity correlated similarly with both ratings: r = -0.4, p = 0.04). Discussion This preliminary study of the potential contribution of the 5-HT transporter binding site to measures of impulsivity in children with ADHD throws up three points of interest. First, the relevant features of the transporter in the platelet model are not the number or density of binding sites (Bmax) but its affinity (Kd). Increasing difficulty with inhibiting response in the stop-signal task was correlated with decreasing receptor affinity. Second, while clinical ratings of impulsivity were not related to the transporter (Kd), they and, to a greater extent, ratings of distractibility were associated with the experimental likelihood of withholding a response. Third, there was a modest correlation between increasing affinity of the transporter receptor and increasing disruptive behaviour. This last finding seems to support reports that indices of lower 5-HT activity coincide with the expression of violent behaviour (see Introduction). This preliminary investigation did not attempt to compare diagnosis-dependent differences for 5-HT transporter measures. However, the Bmax values were comparable with reports from impulsive and non-impulsive adult suicide attempters (Verkes et al 1998), normal 11- to 12year-old male and female children (Sigurdh et al 1999) and adolescents with conduct disorder (Unis et al 1997). The Kd values were also comparable, except that the median value cited by Sigurdh et al was somewhat lower, probably reflecting minor methodological differences (personal communication, October 2001). We are unable to say if the higher values in the present study and that of Unis et al reflect the related disorders of ADHD (here) and conduct disorder (Unis et al) How should differences of Kd be interpreted? Reductions of binding site affinity should normally be off-set by increased receptor capacity. It may be assumed that where this does not occur, more 5-HT remains available in the synapse. If this increase is associated with impulsivity then it stands in contrast to studies in adult subjects (see Introduction). For an alternative explanation the question then shifts to whether the association with a decreased likelihood of response inhibition reflects a relationship to impulsivity? It seems intuitive to describe a reduced ability to inhibit a response tendency as one that reflects an impulsive disposition, one that is not planned, poorly controlled, inaccurate or maladaptive (Solanto et al

1.0

Affinity Kd

0.6

0.2

-0.2 0.0 0.2 0.4 0.6 0.8 1.0

Probability (at 200 ms) of inhibiting a response

Probability of response inhibition (stop-signal 350 ms before) vs. Kd affinity (of paroxetine binding) 1.4 R = -0.67, p = 0.006 [SSRT R = +0.62, p = 0.014 Bmax/p 350 NS R = +0.15]

1.0

Affinity Kd

0.6

0.2

-0.2 0.0 0.2 0.4 0.6 0.8 1.0

Probability (at 350 ms) of inhibiting a response

Figure 1 The affinity (Kd) of the 5-HT transporter binding site (nmol/l) is plotted against the probability of inhibiting a response in the "stopsignal" task, where stop-signal intervals of 200 ms and 350 ms before the expected mean response time for 16 ADHD children are shown in the top and bottom diagram, respectively. (The single high Kd value is attributable to a 10-year-old girl with a mild comorbid disturbance of bonding.)

Linear regressions confirmed that the experimental measures (p-inhibit at 200 and 350 ms) tended to predict Kd for the 5-HT transporter (pinhibit-350, partial correlation 0.50, p = 0.06, R2 48.9) but Conners and CBCL ratings made no significant contribution. Indeed the biochemical measures (Kd, Bmax, F[2,12] = 4.2, p = 0.04) predicted p-inhibit-350 on the stop-signal task (Kd, partial correlation 0.63, p = 0.014, R2 3.7), and Conners ratings (fidgeting, impulsivity, distractibility; F[3,11] = 4.0 p = 0.038) contributed similarly to an explanation of the pinhibit-350 measure, (distractibility: partial correlation 0.57, p = 0.038, R2 37.4).

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2001). But, this description could apply to rapid responses to an irrelevant distractor, that would normally be inhibited. Thus, it would also be possible to describe unusually fast reactions to the stop-signal as reflecting an impulsive disposition of the subjects. It is instructive that the clinical ratings that predicted p-inhibit closest were those of distractibility, albeit that the relationship was negative. Thus, the least distractible children were most likely to inhibit a response. Those who were less likely to inhibit responses (the more distractible) showed a lower 5-HT transporter affinity with putatively greater synaptic availability of 5-HT. This is consistent with a report of an association of poorer signal detection indices on sustained attention tasks with 5-HT metabolism (Oades 2000). Clearly a new and larger sample of children should be examined to test this proposal with a contrast of 5-HT measures in those rated high or low on distractibility and impulsivity ratings, backed up with continuous performance test measures of commission errors (impulsive cognition). Thus an apparent conflict with the literature on 5-HT and impulsivity may be resolved in terms of the information processing involved in the experimental measures. The apparent increased affinity (lower synaptic 5-HT availability) in those with more externalising and aggressive behaviour is concordant with the literature. Children with a stable diagnosis of ADHD, especially those with the combined subtype, are likely to show marked conduct disturbance (August et al 1998; Faraone et al 1998). But both hyperactive and non-hyperactive children with conduct disturbance are likely to show impulsive behaviour (Taylor 1998). Thus, our evidence of differential associations of types of impulsive cognition and impulsive aggression with features controlling the availability of 5-HT warn against premature use of adjunctive serotonergic medication without detailed consideration of the individuals symptoms. While it may seem likely that antagonists (of the uptake or the postsynaptic site) could be beneficial in some circumstances (disruptive behaviour), inappropriate use could exacerbate the patients tendencies to poor stimulus-response control with potential longterm consequences for risk-taking behaviour and substance misuse.

treatments. Neuropharmacol 32: 737-743. Engstrom G, Alling C, Blennow K, Regnell G, Traskmann-Bendz L (1999) Reduced cerebrospinal HVA concentrations and HVA/5HIAA ratios in suicide attempters monoamine metabolites in 120 suciide attempters and 47 controls. Eur Neuropsychopharmacol 9: 399-405. Faraone SV, Biederman J, Weber W, Russell RL (1998) Psychiatric, neuropsychological and psychosocial features of DSM-IV subtypes of attention-deficit/hyperactivity disorder: results from a clinically referred sample J Am Acad Child Adolesc Psychiatry 37: 185-193. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical effect of psychostimulants on hyperactivity. Science 283: 397-401. Goyette CH, Conners CK, Ulrich RF (1978) Normative Data on the Revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychology 6: 221-236. Halperin JM, Newcorn JH, Kopstein I, McKay KE, Schwartz ST, Siever LJ, Sharma V (1997) Serotonin, aggression and parental psychopathology in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36: 1391-1398. Heilman KM, Voeller KKS, Nadeau SE (1991) A possible pathophysiological substrate of attention deficit hyperactivity disorder. J Child Neurology 6: 76-81. Kavoussi R, Armstead P, Coccaro EF (1997) The neurobiology of impulsive aggression. Psychiat Clin N Am 20: 395-403. Lockwood KA, Marcotte AC, Stern C (2001) Differentiation of attention-deficit/hyperactivity disorder subtypes: application of a neuropsychological model of attention. J Clin Exp Neuropsychology 23: 317-330. Logan GD (1994) On the ability to inhibit thought and action: a users guide to the stop signal paradigm. In: Dagenbach D, Carr T (eds) Inhibitory processes in attention, memory and language. Academic Press, San Diego, pp 189-240. Maguire K, Tuckwell V, Pereira A, Dean B, Singh B (1993) Significant correlation between 14C-5-HT uptake and 3Hparoxetine binding to platelets from healthy volunteers. Biol Psychiatry 34: 356-360. Malone MA, Kershner JR, Swanson JM (1994) Hemispheric processing and methylphenidate effects in ADHD. J Child Neurology 9: 181-189. Oades RD (1987) Attention deficit disorder with hyperactivity (ADDH): contribution of catecholaminergic activity. Prog Neurobiology 29: 365-391. Oades RD (2000) Differential measures of sustained attention in children with attention-deficit/hyperactivity or tic disorders: relations to monoamine metabolism. Psychiat Res 93: 165-178. Oades RD (2002) Dopamine (DA) may be hyper with respect to noradrenaline (NA) metabolism, but hypo with respect to serotonin (5-HT) metabolism in ADHD children. Behav Brain Res 130: 97-102 Oades RD, Daniels R, Rascher W (1998) Plasma neuropeptide-Y levels, monoamine metabolism, electrolyte excretion and drinking behavior in children with attention-deficit hyperactivity disorder. Psychiatry Res 80: 177-186.

References Achenbach TM, Edelbrock CS (1983) Manual for the Child Behavior Checklist and revised Child Behavior Profile. University of Vermont, Burlington. August GJ, Braswell L, Thuras P (1998) Diagnostic stability of ASDHD in a community sample of school-aged children screened for disruptive behavior. J Abnorm Child Psychology 26: 345-356. Cheetham SC, Viggers JA, Slater NA, Heal DJ, Buckett WR (1993) [3H] Paroxetine binding in rat frontal cortex strongly correlates with [3H] 5HT uptake: effect of administration of various antidepressant Rutter M, Silberg J, OConnor T, Simonoff E (1999) Genetics and child psychiatry: II empirical research findings. J Child Psychol Psychiatry 40: 19-55. Sigurdh J, Spigset O, Allard P, Mjrndal T, Hgglf B (1999) Binding of [3H]lysergic acid diethylamide to serotonin 5-HT2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy children, adolescents and adults. Neuropsychobiol 40: 183-187. Slusarek M, Velling S, Bunk D, Eggers C (2001) Motivational effects on inhibitory control in children with ADHD. J Am Acad Child

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Adolesc Psychiatry 40: 355-363. Solanto MV, Abikoff H, Sonuga-Barke E, Schachar R, Logan GD, Wigal T, Hechtman L, Hinshaw S, Turkel E (2001) The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD. J Abnorm Child Psychology 29: 215228. Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9: 319-364. Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJS, Jensen PS, Cantwell DP (1998) Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 351: 429-432. Taylor E (1998) Clinical foundations of hyperactivity research. Behav Brain Res 94: 11-24. Unis AS, Cook EH, Vincent JG, Gjerde DK, Perry BD, Mason C, Mitchell J (1997) Platelet serotonin measures in adolescents with conduct disorder. Biol Psychiatry 42: 553-559. Verkes RJ, Van der Mast RC, Kerkhof AJFM, Fekkes D, Hengeveld MW, Tuyl JP, Van Kempen GMJ (1998) Platelet serotonin, monoamne oxidase activity and [3H]paroxetine binding related to impulsive suicide attempts and borderline personality disorder. Biol Psychiatry 43: 740-746. WHO [World Health Organization] (1991) Tenth revision of the International Classification of Diseases, Chapter V (F): Mental and Behavioural Disorders (including disorders of psychological development). Clinical Descriptions and Diagnostic Guidelines. Huber, Bern. Zametkin AJ, Rapoport JL (1987) Neurobiology of attention deficit disorder with hyperactivity: where have we come in 50 years? J Am Acad Child Adolesc Psychiatry 26: 676-686.

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World J Biol Psychiatry (2002) 3, 101 - 104

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ORIGINAL INVESTIGATION/SUMMARY OF ORIGINAL RESEARCH

Rate of Oxygen Consumption in Seasonal and Non-Seasonal Depression

Boris B. Pinchasov, Oleg V. Grischin, Arcady A. Putilov
Institute for General Pathology and Human Ecology, Siberian Branch, Russian Academy of Medical Sciences, Novosibirsk, Russia
Summary Most depressives suffer from weight loss, anorexia and insomnia, while for winter depressives the typical symptoms are weight gain, carbohydrate craving, overeating, oversleeping and extreme lack of energy. It is important to know whether winter depressives differ from most other depressives on measures of energy regulation. In wintertime, we evaluated the rate of oxygen consumption in relationship to neuro-vegetative depressive symptoms in 92 Siberian women. The seated subjects underwent oxyspirography in the mid-morning (1.5 hours after a standard breakfast). It was found that the oxygen consumption rate was similar in non-depressed women (n=25) and depressed women with non-seasonal depression (n=27). The comparatively lower values were obtained in women with winter depression (n=40). This finding supports the suggestion that the behaviour disturbances typical for winter depression may represent a physiological feedback loop to energy conservation. Key words: seasonal affective disorder, non-SAD, atypical depressive symptoms, oxygen consumption, energy regulation. Correspondence: Arcady Putilov, Ph.D. Institute for Medical and Biological Cybernetics SB RAMS 2, Timakova Street Novosibirsk 630117 Russia Tel: +7 3832 321256 Fax: +7 3832 325558 E-mail: putilov@cyber.ma.nsc.ru Acknowledgments We wish to thank Prof. Alexandra M. Shurgaja for helpful discussion of the design of this study. We are also grateful to Mrs. Nataljya Schriener for technical assistance. Introduction Winter depression is the most common form of Seasonal Affective Disorder (SAD). It is a cyclic mood and neuro-vegetative disturbance with regular autumn/winter depressions and nondepressed periods in spring/summer (Rosenthal et al 1984a). This form of depression is typically associated with such behavioural disturbances as hyperphagia, increased appetite, weight gain, carbohydrate craving, hypersomnia, difficulty waking up in the morning, daytime sleepiness, lack of energy and fatigability (Rosenthal et al 1984a; Rosenthal and Hefferman 1986). In contrast, the well-known distinctive features of endogenous and melancholic subtypes of Major Depressive Disorder are anorexia, loss of weight, decreased appetite, hyposomnia or insomnia, early morning awakening, psychomotor agitation and anxiety (Spitzer et al 1978; Zimmerman et al 1989). It is important to know how depressives with typical and atypical symptoms compare on measures of energy regulation (Gaist et al 1990). In their pioneer study, Gaist et al (1990) suggested that the depressive symptoms of SAD could be construed as having an energy-conserving function. Patients with winter depression were predicted to have a low level of resting energy expenditure. However, the study revealed that, contrary to the prediction, a group of seven female and three male subjects with winter depression showed significantly higher resting metabolic rates compared to a group of five female and four male controls. Our earlier Siberian SAD studies (Putilov 1999; Pinchasov et al 2000) provided evidence for lower metabolic rates in female patients with winter depression compared to healthy and nonseasonally depressed females. In particular, we found lower values of resting metabolic rate (Putilov 1997; Putilov and Danilenko 1999), a lower rate of resting oxygen consumption (Pinchasov et al 2000), and a lower rate of oxygen consumption right after submaximal physical exercise (Putilov et al 1991; Neschumova et al 1994; Schergin et al 1996). In the recent study we evaluated the midmorning rate of oxygen consumption in a sample of female patients and controls that was much larger than those reported earlier. In

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addition to comparison of individuals with and without depression, these samples provide comparison of two symptomatically different groups of depressives with winter and with nonseasonal patterns in order to evaluate whether symptoms specific for winter depression could be construed as having an energy conservation function. Material and methods The investigation was carried out in the winter months at the hospital of the Siberian Branch of the Russian Academy of Medical Sciences (Novosibirsk). Non-depressed individuals were mostly recruited from the medical staff. Other non-depressed individuals and all individuals with the symptoms of winter and non-seasonal depression were participants of the programme of preventive health care for the residents of Yakutia and Novosibirsk. They were selected through the admission tests performed on the first day of a two-week medical examination, and through their attending psychologists in the first week of medical examination. A history of seasonal difficulties was elicited by self-administration of the Seasonal Pattern Assessment Questionnaire (Rosenthal et al 1984b). The depressed seasonals fulfilled the criteria for a winter pattern of seasonal difficulties. The criteria of Rosenthal et al (1984a) were applied for the final diagnosis of SAD. The depressed and non-depressed non-seasonals did not meet the criteria for SAD or subsyndromal SAD (Kasper et al 1989a,b). The history of depression and dysthymia was ruled out for nondepressed individuals. Individuals with nonseasonal depression met the criteria for a major or minor depressive disorder or dysthymia (Spitzer et al 1978; American Psychiatric Association 1994), but denied a seasonal pattern of their depression. In total, 92 female individuals - 40 with seasonal depression, 27 with non-seasonal depression and
Table 1

25 healthy controls - volunteered to participate as subjects of this investigation. They gave informed consent for the psychiatric and physiological testing procedures, but were unaware of the main physiological purpose of the study (comparison of energy regulation in seasonals and non-seasonals). Nobody was on antidepressants before the study, and nobody was engaged in regular sports or other physical activities. Mood was rated with the 21-item Hamilton Depression Rating Scale (HDRS; Hamilton 1967). Additionally, the subjects self-rated their symptoms with the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale: Seasonal Affective Disorder Version (SIGH-SAD) (Williams et al 1988). It incorporates both the HDRS and 8-item Addendum for such atypical depressive symptoms as hypersomnia, carbohydrate craving, increased appetite, increased eating, weight gain, fatigue, type B diurnal variation and social withdrawal (Rosenthal and Heffernan 1986). Atypical balance (Terman et al 1996), reflecting the relative dominance of the atypical symptoms, was calculated as a percentage of the total depression score (100*Addendum score/combined SIGH-SAD score). Analysis of gas exchange was based on a widely accepted approach (Ferrannini 1988; Branson 1990). The procedure was carried out with an oxyspirograph SG-1M (a closed-circuit system with continuous absorption of carbon dioxide and conveyance of oxygen). A subject went into the laboratory mid-morning, 1.5 hours after the standard breakfast. She was asked to sit in the upright position and breathe through a mask for 10 minutes. The expired gas was sampled over the last three minutes and analyzed for oxygen consumption. Mean values and standard deviations for the main outcome measures are listed in Table 1. The values in the three diagnostic groups (depressed SAD, depressed non-SAD and nondepressed individuals) were compared with one-

Comparison of age, psychopathologic scores, body weight and oxygen consumption in the three diagnostic groups Index SAD n=40 mean (SD) Age, years HDRS, score Addendum SIGH-SAD, score Atypical balance, % Body weight, kg Oxygen consumption, ml/min The same, per kg body weight 38.7 (11.5) 19.6 (4.9) 9.4 (2.9) 32.5 (8.0) 73.3 (15.7) 228.6 (30.8) 3.2 (0.6) Depressed Non-SAD n=27 mean (SD) 36.2 (7.8) 20.4 (4.4) 5.8 (2.3) 21.8 (6.7) 66.3 (13.2) 245.0 (26.3) 3.8 (0.7) Non-depressed n=25 mean (SD) 35.5 (10.6) 5.6 (1.7) 2.1 (1.1) 27.1 (12.3) 69.4 (14.3) 249.7 (24.1) 3.7 (0.6) F One-way ANOVA DF p

10.6 109.3 73.5 11.5 1.9 5.2 7.9

2/89 2/89 2/89 2/89 2/89 2/89 2/89

0.426 0.000 0.000 0.000 0.154 0.007 0.001

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way ANOVAs (Table 1). Post hoc Tukey HSD tests for unequal n (Spjotvoll/Stoline tests) were then used to evaluate the significance of inter-group differences. Two-tailed statistical significance was accepted at p<0.05. Results The three diagnostic groups did not differ significantly with respect to age and body weight (Table 1). In particular, one-way ANOVA of data on body weight did not reveal a significant grouping effect. According to the subsequent post hoc Tukey test, the difference between the two groups of depressed subjects was insignificant (p=0.196), although the non-seasonal depressives were, on average, lighter than the seasonal depressives by approximately 10% (Table 1). All psychiatric ratings were considerably better in the non-depressed subjects (the ANOVAs gave p<0.001 for both the HDRS and addendum score). The groups of depressed subjects were identical on the HDRS score (Tables 1), and differed on an atypical balance, reflecting a prevalence of atypical symptoms (Tukey test showed highly significant difference, p<0.001). One-way ANOVAs of absolute and relative rates of oxygen consumption (expressed either in milliliters per min or per min*kilogram body weight) yielded the significant grouping effects. Both absolute and relative values were lower in the depressed SAD females compared to female non-seasonals, either with or without depression (Table 1). These results were confirmed by a post hoc Tukey test that showed less than 0.05 level of significance for the difference between winter depressives and non-depressed individuals on both absolute and relative values of oxygen consumption rate. Besides, winter depressives differed from non-SAD depressives on the relative value (p <0.01), and tended to differ on the absolute value (p=0.076). In general, the level of depression measured with HDRS was independent of depression type, but, in accordance with our expectations, the depressed seasonals reported many more atypical depressive symptoms than the depressed non-seasonals. The patients with seasonal and non-seasonal symptoms differed significantly on the relative index of oxygen consumption, while the two groups of non-seasonals were similar on the indexes of oxygen consumption. Discussion In the present study we compared resting oxygen consumption in Siberian women who were either asymptomatic or who had depressive symptomatology of the seasonal or non-seasonal type. Overall, the results indicate that, on average, the group of women with seasonal

depressive symptoms expended less energy compared to the women in the non-seasonal groups. These results are in line with previous findings of our group, i.e., with the results of a comparison of SAD females with healthy females on such metabolic measures as resting and exercising metabolic rates (Putilov 1997, 1999). The difference between depressed seasonals and non-seasonals observed in the present study cannot be attributed to a selection bias, because, unlike healthy controls, the depressed individuals were recruited from the same clinic population. The results of Siberian studies contradict the results of the pioneer study by Gaist et al (1990). However, in the American study female subjects were analyzed together with male subjects despite considerable gender differences in resting metabolic rate. We used the data from Table 1 of the Gaist et al study (1990) to calculate a coefficient of correlation between resting metabolic rate and atypical balance in seven female SAD patients. (The small size of the male subgroup [n=3] does not allow a similar calculation for male patients with SAD.) The correlation in the female subgroup was negative (-0.94, p<0.0016) indicating a link between atypical depressive symptomatology and low energy expenditure. Therefore, data on female SAD patients are in accordance with other data of Siberian studies on the association between the symptoms of winter depression and reduced metabolic rate, while energy expenditure in male SAD subjects requires further exploration. The biochemical background of the energy conservation strategy in winter depression is not clear. Some of the atypical depressive symptoms resemble those of hypothyroid patients, but studies of a possible link between hypothyroidism and SAD gave discrepant results. Although no evidence was provided for low levels of triiodothyronine, thyroxine and thyrotropin (Kasper et al 1989a; Joffe et al 1991; Danilenko et al 1992; Danilenko and Putilov 1993; Bauer et al 1993), the reports on impaired responses of the hypothalamic-pituitary-thyroid axis to endocrine and light stimuli (Raitiere 1992; Danilenko and Putilov 1993; Coiro et al 1994; Oren et al 1996) could suggest a contribution of mild thyroid deficiency to the genesis of abnormal behavioural and physiological traits of winter depressives. In sum, the main finding of this study suggests that SAD patients experiencing the atypical depressive symptoms expend less energy when compared with either healthy controls or nonseasonally depressed patients. The alteration of energy-regulating systems appears to be relevant to the pathophysiology of seasonal depression. In fact, atypical depressive symptoms such as hyperphagia, weight gain, carbohydrate craving,

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fatigue and hypersomnia might be considered as the psycho-vegetative signs of a general adaptive mechanism aimed at the conservation of energy in winter.

action of bright light on human activity and mood. Doctor of Science Dissertation. Medical University of Siberia, Tomsk. Putilov AA, Danilenko KV (1999) The sympatho-adrenal and energy-regulating systems in winter depression. In: Holick MF (ed) Biological Effects of Light: 1998. Kluwer Academic Publishers, Boston, Dordrecht, London, pp 455-458. Putilov AA, Danilenko KV, Volf NV, Cherepanova VA, Palchikov VE, Neschumova TV, Zolotarev DY, Senkova NI (1991) Chronophysiological aspects of light treatment or seasonal affective disorder: Siberian studies. Light Treatment Biol Rhythms 3: 43-45. Raitiere MN (1992) Clinical evidence for thyroid dysfunction in patients with seasonal affective disorder. Psychoneuroendocrinology 17: 231-241. Rosenthal NE, Heffernan MM (1986) Bulimia, carbohydrate craving, and depression: A central connection? In: Wurtman RJ, Wurtman JJ (eds) Nutrition and the Brain, 7. Raven Press, New York, pp 139-165. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin RK, Davenport Y, Mueller PS, Newsome DA, Wehr TA (1984a) Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41: 72-80. Rosenthal NE, Bradt GH, Wehr TA (1984b) Seasonal Pattern Assessment Questionnaire. National Institute of Mental Health, Bethesda, MD. Schergin SM, Danilenko KV, Putilov AA (1996) Biological and psychic effects of bright light in seasonal affective disorder. In: Holick MF (ed) Biological Effects of Light: 1995. Walter de Gruyter & Co, Berlin, New York, pp 409-411. Spitzer R, Endicott J, Robins F (1978) Research Diagnostic Criteria: Rationale and Reliability. Arch Gen Psychiatry 35: 773-782. Terman M, Amira L, Terman JS, Ross DC (1996) Predictors of response and nonresponse to light treatment for winter depression. Am J Psychiatry 153: 1423-1429. Williams JBW, Link MJ, Rosenthal NE, Terman M (1988) Structured Interview Guide for the Hamilton Depression Rating Scale: Seasonal Affective Disorder Version (SIGH-SAD). New York State Psychiatric Institute, New York. Zimmerman M, Black DW, Coryell W (1989) Diagnostic criteria for melancholia: The comparative validity of DSM-III and DSM-III-R. Arch Gen Psychiatry 46: 361-368.

References American Psychiatric Association (1994) DSM IV: Diagnostic and Statistical Manual of Mental Disorders, 323, 4th Edition. American Psychiatric Press, Washington, D.C. Bauer MS, Kurtz J, Winokur A, Phillips J, Rubin LB, Marcus JG (1993) Thyroid function before and after four-week light treatment in winter depressives and controls. Psychoneuroendocrinology 18: 437-443. Branson RD (1990) The measurement of energy expenditure: instrumentation, practical considerations, and clinical application. Respir Care 35: 640-659. Coiro V, Volpi R, Marchesi C, De Ferri A, dAmato L, Caffarri G, Davolio M, Rossi E, Caffarra P, Chiodera P (1994) Lack of seasonal variation in abnormal TSH secretion in patients with seasonal affective disorder. Biol Psychiatry 35: 36-41. Danilenko KV, Putilov AA (1993) Diurnal and seasonal variations in cortisol, prolactin, TSH and thyroid hormones in women with and without seasonal affective disorder. J Interdisc Cycle Res 24: 185-196. Danilenko KV, Putilov AA, Russkikh GS, Duffy LK (1992) Diurnal and seasonal variations of blood melatonin, serotonin, histamine, cortisol, T3 and T4 in seasonal affective disorder. In: Biol Rhythms and Medications: Fifth Int Conf Chronopharmacology (Amelia Island, Florida, July 12-16, 1992). Abst. No VIII-11. Ferrannini E (1988) The theoretical bases of indirect calorimetry: A review. Metabolism 37: 287-301. Gaist PA, Obarzanek E, Skwerer RG, Duncan CC, Shultz PM, Rosenthal NE (1990) Effects of bright light on resting metabolic rate in patients with seasonal affective disorder and control subjects. Biol Psychiatry 28: 989-996. Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6: 278-296. Joffe RT, Levitt AJ, Kennedy SH (1991) Thyroid function and phototherapy in seasonal affective disorder. Am J Psychiatry 148: 393. Kasper S, Rogers SLB, Yancey A, Schulz PM, Skwerer RG, Rosenthal NE (1989a) Phototherapy in individuals with and without subsyndromal seasonal affective disorder. Arch Gen Psychiatry 46: 837-844. Kasper S, Wehr TA, Bartko JJ, Gaist PA, Rosenthal NE (1989b) Epidemiological findings of seasonal changes in mood and behavior: A telephone survey of Montgomery County, Maryland. Arch Gen Psychiatry 46: 823-833. Neschumova TV, Danilenko KV, Putilov AA (1994) Characteristics of response of the cardiovascular system in seasonal affective disorder and light therapy. Human Physiology 20(3): 189-192. Oren DA, Levendosky AA, Kasper S, Duncan CC, Rosenthal NE (1996) Circadian profiles of cortisol, prolactin, and thyrotropin in seasonal affective disorder. Biol Psychiatry 39: 157-170. Pinchasov BB, Shurgaja AM, Grischin OV, Putilov AA (2000) Mood and energy regulation in seasonal and non-seasonal depression before and after midday treatment with physical exercise or bright light. Psychiatry Res 94: 29-42. Putilov AA (1997) "Owls", "Larks" and Others: About Clocks Inside Us and Their Influence on Our Health and Character. Novosibirsk University Press, Novosibirsk, and Soverschenstvo Publishing House, Moscow. (In Russian) Putilov AA (1999) Chronophysiological mechanisms mediating

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Catatonia and ECT: Meduna's Biological Antagonism Hypothesis Reconsidered

Max Fink
Department of Psychiatry, SUNY at Stony Brook, and Albert Einstein College of Medicine, New York, USA
Summary Catatonia is a motor syndrome with abnormalities in neuroendocrine regulation. Both the motor syndrome and the neuroendocrine abnormalities respond rapidly to electroconvulsive therapy (ECT). This rapid efficacy supports a neuroendocrine hypothesis of the mode of action of ECT and encourages neuroendocrine studies of catatonia. Key words: catatonia, electroconvulsive therapy, neuroendocrine, mode of action. Correspondence: Max Fink, M.D. Professor of Psychiatry and Neurology Emeritus, School of Medicine, SUNY at Stony Brook Professor of Psychiatry, Albert Einstein College of Medicine P.O. Box 457 St. James New York 11780-0457 USA Tel: +1 631 862 6651 Fax: +1 631 862 8604 E-mail: mafink@attglobal.net Introduction The remission rate for severely ill, non-psychotic, unipolar depressed patients with electroconvulsive therapy (ECT) is 84%. It is 95% for those with psychotic depression, and successful courses of treatment usually complete within three weeks (Petrides et al 2001, Birkenhger et al, In Press). It would be difficult to imagine a condition for which ECT would be more effective, but catatonia is such a condition. It remits with three or four treatments in less than one week. Treatment failure is rare (Fink 1997; Fink and Taylor In Press). Does such a rapid response reflect a more direct benefit of seizures in catatonia than in depression? Does it offer a clue to the mode of action of ECT? Laszlo Meduna sought patients with dementia praecox for experiments with camphor-induced seizures. The first patients met Kraepelinian criteria for the catatonic variety of the illness. Meduna was remarkably successful in relieving catatonia and psychosis, a finding that so excited the clinical world that convulsive therapy quickly became the dominant treatment of the severely psychiatrically ill (Meduna 1985). The selection of catatonic patients was fortuitous, however, for had he selected patients with other forms of dementia praecox, he would have had poorer clinical results (Fink and Sackeim 1996). Meduna, a neuropathologist, found a paucity of glia in the brains of patients with dementia praecox, and an abundance of glia in those with epilepsy. He concluded that inducing seizures in patients with dementia praecox would increase glia and thereby reverse the psychosis. He explained his successful experience as the result of a biological antagonism between epilepsy and psychosis. Many critics consider this concept inadequate. But, if we focus on Meduna's observations that seizures relieve catatonia (erroneously equated with the psychosis of dementia praecox), we can look at the concept of biological antagonism with more encouraging data. Catatonia Catatonia is a syndrome of motor behaviours that accompany disorders in thought, mood and cognition. Stupor, mutism, negativism, stereotypy, staring, echophenomena and rigidity are readily identifiable catatonic features (Fink 1997; Fink and Taylor In Press).

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We identify many forms of catatonia (Fink and Taylor 2001, In Press). A retarded form, labelled the Kahlbaum Syndrome or benign stupor, is common. An excited form is described as catatonic excitement or delirious mania. An acute form with fever and autonomic instability, often with a fatal outcome, is labelled malignant, lethal or pernicious catatonia. When catatonia is associated with specific toxic agents, it is labelled as the neuroleptic malignant syndrome (NMS) and the toxic serotonin syndrome (TSS). Catatonia occurs in patients suffering from mood disorders (mania and depression), systemic medical illnesses, toxic states, and psychosis (schizophrenia). In modern diagnostic classification systems, however, catatonia is restricted to a feature of schizophrenia and its recognition compels this diagnosis (American Psychiatric Association 1980). This limitation has been properly criticized and it is more reasonable to define catatonia as a syndrome akin to a delirium or to delusions, features of diverse illnesses and not specific to a single disorder (Fink and Taylor In Press). Catatonia is identified when two or more motor signs are present for 24 hours or longer in patients with disturbances in mood, thought or cognition. Many consider catatonia to be rare, to have disappeared with the introduction of psychotropic drugs, or to be limited to patients with chronic psychiatric illnesses. Perhaps the most surprising finding of recent research is that 7% to 15% of the acutely ill patients admitted to psychiatric hospitals exhibit catatonia. Often they exhibit four or more signs, facilitating the identification (Fink and Taylor In Press). The first effective treatment for catatonia, the opening shot of the 20th century psychopharmacology revolution, was intravenous amobarbital, described by Bleckwenn (1930). In 1934, Laszlo Meduna began his experiments to resolve the psychosis of dementia praecox by inducing seizures with intramuscular injections of camphor at three- to four-day intervals (Meduna 1985). His 1935 report encouraged worldwide interest (Meduna 1935). By 1938, an electrical induction of seizures was developed, laying the foundation for modern ECT. A few decades later, diazepam and lorazepam substituted for the barbiturates because of their greater safety, establishing their use in the treatment algorithms for catatonia (Fink and Taylor In Press). In developing the DSM and ICD classifications, the psychiatric disorders were separated by the phenotypic description of signs, symptoms and course of illness (American Psychiatric Association 1980). But another way to classify disorders is not by the overt symptoms and signs, but by the response of patients to different psychoactive agents. This method was used by Klein

and Fink to describe the various behaviour patterns in hospitalized patients randomly treated with either imipramine or chlorpromazine (Klein and Fink 1962a,b). A more recent example is in the report by Glassman and his co-workers who separated patients with psychotic depression from those with the nonpsychotic forms by their failure to respond to well-controlled treatment with imipramine. These patients did respond to ECT (Glassman et al 1975). This observation was quickly confirmed and by 1980 an updated DSM-III classification system recognized an entity of psychotic depression (296.34) (American Psychiatric Association 1980). In addition to their poor response to antidepressant drugs alone, such patients had abnormal neuroendocrine regulations that reversed with adequate treatment. Psychotic depression is now envisioned as a disease entity separate from non-psychotic depression (Petrides et al 2001; Rothschild and Schatzberg 1992). Catatonia treatments For more than half a century, patients with catatonia have been labelled as suffering from dementia praecox, catatonic type (DSM-III, 295.2) (American Psychiatric Association 1980). This classification is unfortunate because it leads to treatment with antipsychotic drugs and denies consideration of more effective treatments. Not only are these medicines often unhelpful, but they worsen catatonia (Fink 1997; Fink and Taylor In Press). Barbiturates relieve catatonia. The immediate efficacy of amobarbital galvanized a psychiatric profession dominated by psychodynamic explanations of psychopathology. The success of the treatment encouraged a biological explanation for a dramatic psychopathological state of catatonia that had been interpreted only in psychodynamic terms (Bleuler 1924). Lorazepam and diazepam, recent replacements for the barbiturates, are rapidly effective in more than 85% of the patients with catatonia. The relief afforded is dose dependent, however, and some reports of failure may be the consequence of inadequate dosing (Fink and Taylor In Press). The anticonvulsant carbamazepine also relieves catatonia (Fink and Taylor In Press). The most dramatic relief of catatonia, however, is with ECT. The induction of two to three seizures is almost always rapidly effective. But a routine schedule of two or three treatments a week may be unsuccessful. In the more severely ill, especially those with the malignant and delirious forms of the illness, daily treatments are required (Arnold and Stepan 1952; Fink and Taylor In Press; Philbrick and Rummans 1994; Fink 1999). Bilateral electrode placement needs to be used. Because benzodiazepines in high doses are often given first, patients coming to

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ECT often have high seizure thresholds. The energy parameters must be adjusted to assure adequate treatments, and this is best done by examining the seizure EEG, now an integral part of modern ECT devices (Fink and Taylor In Press). The efficacy of ECT in relieving the NMS form of catatonia encouraged the argument that this neurotoxic syndrome was a type of malignant catatonia, rather than a special instance of dopaminergic blockade akin to malignant hyperthermia (Fink 1996). The benzodiazepines are also effective in relieving NMS (Fink 1997; Fink and Taylor In Press). Central actions of the agents that relieve catatonia The brain effects of barbiturates and benzodiazepines are usually pictured in neurohumoral terms. While many brain systems are immediately altered, the sedative and hypnotic effects are seen to be mediated through the inhibitory properties of GABA (Paul 1995). These compounds impede the passage of currents so that more energy is needed to stimulate succeeding synapses. The reduced ability of electric currents to elicit overt motor seizures reflects a rise in seizure thresholds. A similar rise in seizure thresholds occurs during the course of ECT (Abrams 1997). Seizure durations shorten with repeated seizure inductions. ECT has also been used to end an ongoing status epilepticus (Fink et al 1999). The impact of catatonia or its treatment on brain or serum GABA is largely unstudied, however, so we are left with our speculations. The dramatic picture of catatonia and its rapid relief argues that catatonia is the final common outcome pathway for abnormal brain seizure activity. Catatonia is prominent in patients with epilepsy, and non-convulsive status epilepticus is part of its differential diagnosis. Against such an association, however, is the failure to demonstrate EEG seizure activity in catatonic patients (Fink and Taylor In Press). ECT is most effective in those patients with a neuroendocrine abnormality, such as an abnormal dexamethasone suppression test or a diminished thyroid-stimulating hormone response to thyrotropin releasing hormone (Fink 1999, 2000). These abnormalities disappear with effective treatment. The persistence of neuroendocrine abnormalities, or their recurrence, is the harbinger of a poor clinical outcome or a recurrence of the illness. While reports of neuroendocrine testing in patients with catatonia are few, we note the extensive studies of thyroid function by Gjessing in patients with periodic catatonia (Fink and

Taylor In Press; Gjessing 1976). Fluctuating phases of catatonia were associated with changes in weight and in measures of thyroid activity. Catatonic features are common in patients with psychotic depression (Fink and Taylor In Press). Their neuroendocrine measures are grossly abnormal, improving with effective treatment. This neuroendocrine relationship has led some investigators to assess and report that massive doses of progesterone receptor antagonists elicit as quick a reversal of psychotic depression as is induced with ECT (Belanoff et al 2001). Conclusion The delineation of psychotic depression as a psychiatric disorder separate from schizophrenia allowed effective treatments to be developed. The recent rediscovery of catatonia as a motor syndrome among mood and systemic medical disorders suggests that it be separated from its connection to schizophrenia. It also should be studied for its neuroendocrine relationships. The neuroendocrine hypothesis of the mode of action of ECT has an important corollary in catatonia. The biological antagonism of dementia praecox and epilepsy hypothesized by Meduna still warrants study, not in the terms available to him in his studies of brain glia, but in terms of the new neuroendocrine science. The efficacy of interventions that affect the brain's GABAergic systems in relieving catatonia, especially malignant catatonia, argues for a neuroendocrine basis for this syndrome. It is a constructive update to Meduna's hypothesis that became the basis for modern ECT.

References Abrams R (1997) Electroconvulsive Therapy. 3rd. Ed. Oxford University Press, New York. American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders. Third Edition. Washington, D.C. Arnold OH, Stepan H (1952) Untersuchungen zur Frage der akuten tdliche Katatonie. Wr Zeitschrift fr Nervenheilkunde 4: 235-287. Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Schatzberg AF (2001) Rapid Reversal Of Psychotic Major Depression Using C-1073 (Mifepristone). Abstracts, ACNP Meeting, Dec 12, 2001. Birkenhger TK, Pluijms EM, Lucius SAP (in press) ECT response in delusional versus non-delusional depressed inpatients. J Affective Dis. Bleckwenn WJ (1930) The production of sleep and rest in psychotic cases. Arch Neurol Psychiatry 24: 365-372. Bleuler E (1924) Textbook of Psychiatry. Macmillan, New York. Fink M (1996) Neuroleptic malignant syndrome. One entity or two? Biol Psychiatry 39: 1-4. Fink M (1997) Catatonia. In: M. Trimble, J Cummings (eds) Contemporary Behavioural Neurology. Butterworth/Heinemann, Oxford, UK, pp 289-309.

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Fink M (1999) Electroshock: Restoring the Mind (pp 157). Oxford University Press, New York. Fink M (2000) Electroshock Revisited. Am Scientist 88: 162-167. Fink M, Sackeim HA (1996) Convulsive therapy for schizophrenia? Schizophrenia Bull 22(1): 27-39. Fink M, Taylor MA (2001) The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci 251 (Suppl 1): 8-13. Fink M, Taylor MA (In Press) Catatonia: A Clinician's Guide to Diagnosis, Treatment and Neurology. Cambridge University Press, Cambridge, UK. Fink M, Kellner CH, Sackeim HA (1999) Intractable seizures, status epilepticus, and ECT. JECT 15: 282-284. Gjessing R (1976) Contributions to the Somatology of Periodic Catatonia. Pergamon Press, Oxford. Glassman AH, Kantor SJ, Shostak M (1975) Depression, delusions, and drug response. Am J Psychiatry 132: 716-719. Klein DF, Fink M (1962a) Behavioral reaction patterns with phenothiazines. Arch Gen Psychiatry 7: 449-459. Klein DF, Fink M (1962b) Psychiatric reaction patterns to imipramine (Tofranil). Am J Psychiatry 119: 432-438. Meduna L (1935) Versuche ber die biologische Beeinflussung des Ablaufes der Schizophrenie: Camphor und Cardiozolkrmpfe. Z Ges Neurol Psychiatr 152: 235-262. Meduna L (1985) Autobiography. Convulsive Ther 1: 43-57, 12138. Paul S (1995) GABA and glycine. In: FE Bloom, DJ Kupfer (eds) Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, pp 87-94. Petrides G, Fink M, Husain MM, Knapp R, Rush AJ, Mueller M, Rummans TA, O'Connor KM, Rasmussen KG, Bernstein HJ, Biggs M, Bailine SH, Kellner CH (2001) ECT remission rates in psychotic versus non-psychotic depressed patients: A CORE report. JECT 17: 244-253. Philbrick KL, Rummans TA (1994) Malignant catatonia. J Neuropsychiatry Clin Neurosci 6: 1-13. Schatzberg AF, Rothschild AJ (1992) Psychotic (delusional) major depression: Should it be included as a distinct syndrome in DSMIV? Am J Psychiatry 149:733-745.

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Side Effects after Phototherapy Implementation in Addition to Fluoxetine or Sertraline Treatment: A Report of Two Cases
wicicki1, Tomasz Szafran ukasz S ski2
1 2

II Department of Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland III Department of Psychiatry, Institute of Psychiatry and Neurology, Warsaw, Poland
Introduction Seasonal affective disorder (SAD) is commonly treated with bright white light of 2500 - 10000 lux intensity. Phototherapy is regarded as a safe method of treatment, and its efficacy has been confirmed by many controlled studies. It is also used as a supplementary strategy in the management of depressive episodes in the course of affective disorders without a seasonal pattern, as wicicki 2001). well as schizoaffective disorders (S Symptoms such as pain in the eyeball, transient sleeping disorders, increased irritability and development of anxiety were reported occasionally (Levitt et al 1993; Kogan and Guilford 1998; Gallin et al 1995), and single cases of shift from the depressive into hypomanic stage were also reported (Labbate et al 1994). One case study provides a description of suicidal attempts of three patients treated with light (PraschakRieder et al 1997). There is some good evidence in the literature for the role of serotonin in the mechanism of action of bright white light, some of which will be mentioned in the last chapter of this paper. Some of the most direct evidence is derived from the tryptophan depletion paradigm, showing constantly that the beneficial effects of bright light therapy can be reversed by lowering the serotonin-precursor tryptophan (the same is true for SSRI medications) (Neumeister et al 1997, 1998a,b, 1999). The interaction between phototherapy and antidepressive agents has not yet been described in the available literature. The authors present two patients in whom such an interaction probably did occur. Case 1 Mr. A, a 45-year-old man being treated for dysthymia in an outpatient setting. The patient had suffered from mild depressive episodes for a long time, since his university years. The episodes never developed into the full syndrome of recurrent depressive disorder, however, they subjectively affected the quality of the patient's life and significantly lowered his ability to work. In the past the patient had abused alcohol, for about four years. His drinking had the pattern of alcoholic bouts. He continued to abuse alcohol despite the apparent adverse consequences for both his health and social functioning. He had never been treated for alcohol dependence, and remained fully abstinent for three years. He was administered 20 mg/day of fluoxetine for over a year before receiving light treatment. The treat-

Summary Serotonergic-type side effects (like diarrhoea, hyperthermia, nausea, confusion) were seen after phototherapy in patients receiving fluoxetine or sertraline. Phototherapy was discontinued and symptoms completely resolved. In the authors' opinion, the symptoms were likely to be associated with specific interaction (serotonin effect potentialisation). To the authors knowledge this is the first report concerning such an effect. Key words: phototherapy, serotonin uptake inhibitors, adverse effects. Correspondence: wicicki, M.D. ukasz S Institute of Psychiatry and Neurology 1/9 Sobieskiego Str. 02-957 Warsaw Poland Tel: +48 22 642 66 11 Fax: +48 22 642 53 75 E-mail: swiecick@ipin.edu.pl

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ment was tolerated very well, and no adverse symptoms were reported. He was generally satisfied with the effects of the drug, but in the autumn of 1996 he started to complain of difficulty in falling asleep, anxiety and lack of energy. The decision to introduce phototherapy was then made. The course of treatment included 14 sessions with a light intensity of 10000 lux, for 30 minutes. After the third session the patient complained of diarrhoea, anxiety, tremor in his hands, and states described by him as a "feeling of disorientation and confusion - he did not know where he was". Phototherapy was discontinued, and without any medical intervention the described symptoms remitted within two to three days. The patient continued the fluoxetine regimen, 20 mg/day. About two months later phototherapy was restarted at the patient's request. However, the treatment was ceased for good after the second session due to the occurrence of diarrhoea. At the same time the patient continued to receive fluoxetine, which was effective and well-tolerated. Further treatment with SSRI agents was also tolerated well. Case 2

1998). The Serotonin Syndrome Scale consists of nine items (agitation, disorders of orientation, myoclonus, hyperreflexia, tremor, dizziness, hyperthermia, sweating, diarrhoea), each rated from "0" to "3". The maximum score is 27, and a serotonin syndrome is supposed to be present when the total score is greater than six. The assessed lithium plasma concentration was 0.57 mmol/l, blood count was normal, the results of laboratory tests of glucose blood level, creatinine, electrolytes, thyroid hormones and transaminases were also within the normal range, and ECG did not reveal any abnormalities. On the fourth day after the onset of the symptoms blood pressure was elevated to 150/110 mmHg, whereas on the other days it remained within normal limits. Over a couple of days a slight increase in body temperature was recorded. Following the onset of the above mentioned symptoms, the light treatment was discontinued and sertraline was withdrawn. Seven days later all the symptoms had resolved completely. Mrs. B was placed on a regimen of moclobemide, 300 mg/day. After four weeks she recovered and was discharged from the hospital. Discussion

Mrs. B, a forty-year-old married woman with a 15-year history of schizoaffective disorder, including seven hospitalisations. After the last hospitalisation she received 1000 mg/day of lithium carbonate, and under this medication remission of symptoms lasted for two years. She was readmitted to hospital due to elevated mood, increased drive, irritability and sleeplessness. The treatment with lithium carbonate, 1000 mg/day, was supplemented with levomepromazine. The patient's mental state improved and she was transferred from the full-time psychiatric ward to a day clinic. After seven weeks of treatment she started to complain of depressed mood, decreased activity and lack of appetite. Having had suicidal ideation she was readmitted to the full-time psychiatric ward. She continued her lithium, and mianserine was started at 90 mg/day. Six weeks later, due to lack of improvement, the antidepressant was switched to sertraline, 150 mg/day. Administration of lithium, 1000 mg/day, was continued (plasma level: 0.89 mmol/l). She also received 2 mg/day of estazolam to treat her insomnia. After four weeks of treatment the patient's symptoms still included depressed mood, low activity level and lack of appetite. Too early awakening time (disturbance of sleep-wake schedule) and lower mood in the morning hours (compared with the rest of the day) were also reported. Phototherapy was initiated. After the third session the patient's mood improved, and she became more active and started to care about the way she looked. After the fifth phototherapy session diarrhoea, increased sweating and sleeplessness occurred, and the patient complained of "anxiety in the chest". These symptoms scored seven points on the Serotonin Syndrome Scale (Hegerl et al

In both cases presented above patients received agents with serotonergic activity to manage their depressive symptoms, and the treatment was tolerated well. After introduction of phototherapy the patients developed clinical symptoms that may be related to serotonergic hyperactivity such as diarrhoea, anxiety, tremor, disorientation, increased sweating and elevated body temperature. This interpretation seems to be supported by the relationship between the timing of the phototherapy administration and the occurrence of the symptoms, while no change in the pharmacological treatment was made. However, objective assessment of serotonergic system activity was not possible in either of the cases. Excessive consumption of carbohydrates, as a process of self-regulation of the serotonin level in the central nervous system, provided the basis for one of the hypotheses referring to biological explanations for SAD, assuming dysregulation of seasonal serotonin metabolism. Some patients revealed the need to consume large amounts of carbohydrates, which, according to them, tended to improve their mood and general activity level (Wurtman and Wurtman 1989; Rosenthal et al 1989; Krauchi et al 1990, 1992). Other authors (Wallin and Rissanen 1994) also mention frequent co-occurrence of SAD and disorders related to serotonergic system dysfunction, such as pre-menstrual syndrome, alcohol abuse and obesity. In patients suffering from SAD and whose symptoms have remitted during the course of

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phototherapy, a tryptophan depletion diet (which slows down serotonin synthesis) leads to rapid relapse of depressive symptoms (Lam et al 1996). In the study by Jacobsen et al (1994), 10 patients with SAD received meta-chlorphenylpiperazine (m-CPP, a relatively selective 5-HT2 receptor agonist). Secondary to this agent they showed increased activity level and elated mood, whereas the healthy controls responded by developing bradykinesia. After one week of phototherapy, responses of the group with SAD and healthy controls to the m-CPP were comparable. This may imply that phototherapy normalises serotonin transmission. The observations presented by the authors may support the claim of some research groups (i.e., Neumeister et al 1997, 1998a,b; Danilenko et al 1994) that enhancement of serotonergic transmission is vital for phototherapy to be effective. They also indicate the need for clinical studies into the level of central serotonergic system activity during the course of phototherapy. To the authors' best knowledge, the occurrence of adverse symptoms of this kind during a course of phototherapy and concomitant treatment with an antidepressive agent with serotonergic activity has not been reported in the literature. Phototherapy is generally regarded as a rather safe method of treatment. It seems, however, that the potential for occurrence of side effects due to hyper-stimulation of the serotonergic system should be recognised. There is also a need for further evaluative research into the serotonergic system activity using objective methods.

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wicicki (2001) Zastosowanie fototerapii w leczeniu depresji w przebiegu niesezonowych zaburzen afektywnych. [Phototherapy in non-seasonal affective disorders]. Psychiat Pol 35 (2): 211-218. Wallin MS, Rissanen AM (1994) Food and mood: relationship between food, serotonin and affective disorders. Acta Psychiatr Scand Suppl 377: 36-40. Wurtman RJ, Wurtman JJ (1989) Carbohydrates and depression. Scientific American 260: 68-75.

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