Délivre les autorisations de mise sur le marché (AMM) et contrôle la publicité des médicaments.
FDA Agence pour le contrôle des aliments et des drogues (USA)
Cette agence américaine donne les autorisations US de mise sur le marché et publie des synthéses fournies
APA (Association des Psychiatres USA) : Régles de traitement des troubles bipolaires
En américain, of course
" La première ligne de traitement pour les dépressions bipolaires est le démarrage d'un traitement au Lithium ou au Lamictal (lamotrigine). Une monothérapie avec un anti-dépresseur n'est pas recommandée."
"2. Depressive episodes
The first-line pharmacological treatment for bipolar depression is the initiation of either lithium [I] or lamotrigine [II]. Antidepressant monotherapy is not recommended "
Algorithme TIMA de traitement de la dépression bipolaire
Cet algorithme donne, sous une forme explicite, les éléments du traitement de la dépression dans les troubles bipolaires. Il vient en complément de l'algorithme principal TIMA (sur la manie)
Bipolar: Overview, Course and Depression Relapse Prevention
Conférence "live" en format realnetwork
Am J Psychiatry 161:163-165, January 2004
Antidepressant Treatment in Bipolar Versus Unipolar Depression
S. Nassir Ghaemi, M.D., Klara J. Rosenquist, B.S., James Y. Ko, A.B., Claudia F. Baldassano, M.D., Nicholas J. Kontos, M.D., and Ross J. Baldessarini, M.D.
Cet article examine des enregistrements cliniques des résultats de traitementsdes dépressions par antidépresseurs obtenus sur des patients bipolaires et unipolaires. L'usage des antidépresseurs pour les patients bipolaires a un ratio coût/bénéfice défavorable, y compris avec les antidépresseurs modernes.
OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar depression. METHOD: The authors analyzed clinical records for outcomes of antidepressant trials for 41 patients with bipolar depression and 37 with unipolar depression, similar in age and sex distribution. RESULTS: Short-term nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%) depression. Manic switching occurred only in bipolar depression but happened less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle acceleration occurred only in bipolar depression (25.6%), with new rapid cycling in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss. Modern antidepressants, in general, did not have lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS: The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression.
Bipolar II Disorder: The Concept of Dysphoric Hypomania
Dr.
Suppes
Originally
webcast Tuesday, April 15, 2003
Conférence "live" in formar realnetwork
Le consensus sur le traitement des BPII n'existe pas pour le moment :
1).Démarrer en monothérapie avec un antidépresseur ? (fluoexetine -prozac- ou un autre)
2). Démarrer avec le lithium
3). Démarrer avec un anti-convulsivant (Divalproex - lamotrigine -autre) ?
C'est les études avec le lamotrigine (lamictal) qui donnent les meilleurs résultats pour l'instant, mais de nouvelles études sont nécessaires pour avoir une opinion ferme.
Un test en ligne permet de vérifier si l'on a bien compris les principaux points de la présentation.
Congratulations, you have passed the CME test for "CME Test: Bipolar II Disorder: The Concept of Dysphoric Hypomania - Dr. Trisha Suppes" (score 80 %).
NIMH - Institut National (US) de la santé mentale
http://www.nimh.nih.gov/publicat/bipolar.cfm (révisé en avril 2004) Extrait
Traitement de la dépression bipolaire. (traduction)
La recherche [et l'expérience] a montré que les personnes souffrant de troubles bipolaires risquent de basculer dans la manie ou l'hypomanie ou de développer des cycles rapides, durant le traitement avec des médicaments antidépresseurs. Cependant les médicaments thymorégulateurs sont nécessaires, seuls ou en combinaison avec les antidépresseurs, pour protéger les bipolaires de ce risque de bascule. Le lithium [théralithe] et le valproate [depakote] sont les médicaments thymorégulateurs les plus utilisés aujourd'hui. Cependant les recherches continuent à évaluer le potentiel thymorégulateur de nouvelles médications :-
Les
neuroleptiques atypiques, incluant la
clozapine(Clozaril, Leponex), olanzapine (Zyprexa), risperidone
(Risperdal), quietiapine(Seroquel) et ziprazidone(Geodon, Zeldox) sont
étudiés comme traitements possibles pour les
troubles
bipolaires. Les
résultats suggérent que la clozapine peut
être
utile comme
thymorégulateur pour les personnes qui ne
répondent
pas au
lithium ou aux autres thymorégulateurs. D'autres recherches
ont
apportyé la preuve de l'efficacité de
l'olanzapine
(zyprexa) pour la
manie aigüe, une indication qui a reçu
l'approbation de la
FDA.
L'olanzapine peut aussi être utile dans le traitement de la
dépression
psychotique.
Si l'insomnie
est un problème, des benzodiazépines
telles que le clonazepan (Klonopin, Rivotril) ou lorazepan (Ativan,
Temesta) peuvent être utiles pour promouvoir un meilleur
sommeil.
Toutefois, ces médicaments peuvent être
sources de dépendance,
et sont de
préférence prescrits sur une
courte période. D'autres types de médicaments
sédatifs comme le
zolpidem (Ambien, Stilnox) sont maintenant prescrits dans cet usage.
Des changements
dans le traitement peuvent être
nécessaires durant l'évolution de la maladie
bipolaire.
Un psychiatre
doit guider tous les changements dans le type de médicaments
et
les
doses prescrites.
Il faut
impérativement parler au psychiatre
de tous
les médicaments prescrits, ainsi que de tous les
suppléments "naturels"
absorbés. C'est important car certains
médicaments ou
suppléments
alimentaires peuvent avoir des effets secondaires pris
simultanément
avec votre traitement [alcool, cannabis ..]
Pour
réduire les possibilités de
rechute ou de
développer un nouvel épisode, il est important de
suivre
strictement le
traitement. Parlez à votre docteur si vous avez quelques
doutes
à
propos de votre traitement.
Treatment of Bipolar Depression
Research has shown that people with bipolar disorder are at risk of switching into mania or hypomania, or of developing rapid cycling, during treatment with antidepressant medication.16 Therefore, "mood-stabilizing" medications generally are required, alone or in combination with antidepressants, to protect people with bipolar disorder from this switch. Lithium and valproate are the most commonly used mood-stabilizing drugs today. However, research studies continue to evaluate the potential mood-stabilizing effects of newer medications.-
Atypical antipsychotic
medications, including clozapine (Clozaril®),
olanzapine (Zyprexa®),
risperidone (Risperdal®),
quetiapine (Seroquel®),
and ziprasidone (Geodon®),
are being studied as possible treatments for bipolar disorder. Evidence
suggests clozapine may be helpful as a mood stabilizer for people who
do not respond to lithium or anticonvulsants.17
Other research has supported the efficacy of olanzapine for acute
mania, an indication that has recently received FDA approval.18
Olanzapine may also help relieve psychotic depression.19
If insomnia is a problem, a
high-potency benzodiazepine
medication such as clonazepam (Klonopin®)
or lorazepam
(Ativan®)
may be helpful to promote better sleep. However, since these
medications may be habit-forming, they are best prescribed on a
short-term basis. Other types of sedative medications, such as zolpidem
(Ambien®),
are sometimes used instead.
Changes to the treatment
plan may be needed at various times
during
the course of bipolar disorder to manage the illness most effectively.
A psychiatrist should guide any changes in type or dose of medication.
Be sure to tell the
psychiatrist about all other prescription
drugs, over-the-counter medications, or natural supplements you may be
taking. This is important because certain medications and supplements
taken together may cause adverse reactions.
To reduce the chance of
relapse or of developing a new episode,
it
is important to stick to the treatment plan. Talk to your doctor if you
have any concerns about the medications.
16Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biological Psychiatry, 2000; 48(6): 558-72.
17Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. American Journal of Psychiatry, 1999; 156(8): 1164-9.
18Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs TG, David SR, Toma V. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. American Journal of Psychiatry, 1999; 156(5): 702-9.
19Rothschild AJ, Bates KS, Boehringer KL, Syed A. Olanzapine response in psychotic depression. Journal of Clinical Psychiatry, 1999; 60(2): 116-8.
World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for Biological Treatment of Bipolar Disorders, Part I: Treatment of Bipolar Depression
World J Biol Psychiatry (2002) 3, 115 - 124
Heinz Grunze1, Siegfried Kasper2, Guy Goodwin3, Charles Bowden4, David Baldwin5, Rasmus Licht6, Eduard Vieta7, Hans-Jürgen Möller1, WFSBP Task Force on Treatment Guidelines for Bipolar Disorders8
1 Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany
2 Department of General Psychiatry, University of Vienna, Vienna, Austria
3 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom
4 Department of Psychiatry, University of Texas Health Science Center, San Antonio, USA
5 Department of Mental Health, University of Southampton, Royal South Hants Hospital,
Southampton, United Kingdom
6 Psychiatric Hospital, Aarhus University, Risskov, Denmark
7 Department of Psychiatry, Hospital Clinic, Barcelona, Spain
8 WFSBP Task Force on Treatment Guidelines for Bipolar Disorders:
Siegfried Kasper (Chairman; Austria), Guy Goodwin (Co-Chairman; United Kingdom), Charles Bowden (Co-Chairman; USA), Heinz Grunze (Secretary; Germany), Hans-Jürgen Möller (WFSBP Past-President; Germany) Hapog Akiskal (USA), Herve Allain (France), Jose Ayuso-Gutierrez (Spain), David Baldwin (United Kingdom), Peer Bech (Danmark), Otto Benkert (Germany), Michael Berk (South Africa), Istvan Bitter (Hungary), Marc Bourgeois (France), Graham Burrows (Australia), Joseph Calabrese (USA), Giovanni Cassano (Italy), Marcelo Cetkovich-Bakmas (Argentina), John Cookson (United Kingdom), Delcir da Costa (Brasil), Mihai George (Romania), Frank Goodwin (USA), Gerado Heinze (Mexico), Teruhiko Higuchi (Japan), Robert Hirschfeld (USA), Cyril Hoeschl (Czech Republik), Edith Holsboer-Trachsler (Switzerland), Kay Jamison (USA), Cornelius Katona (United Kingdom),
Martin Keller (USA), Parmanand Kulhara (India), David Kupfer (USA), Yves Lecruibier (France), Brian Leonhard (Ireland), Rasmus Licht (Danmark), Odd Lingjaerde (Norway), Henrik Lublin (Denmark), Mario Maj (Italy), Julien Mendlewicz (Belgium), Philip Mitchell (Australia), Stuart Montgomery (United Kingdom), Charles Nemeroff (USA), Willem Nolen (The Netherlands), David Nutt (United Kingdom), Eugene Paykel (United Kingdom), Michael Philipp (Germany), Robert Post (USA), Stanislaw Puzynski (Poland), Zoltan Rihmer (Hungary), Janusz Rybakowski (Poland), Peer Vestergaard (Denmark), Eduard Vieta (Spain), Jörg Walden (Germany), Peter Whybrow (USA), Kazuo Yamada (Japan)
Introduction
Bipolar disorder is an under-diagnosed (Ghaemi et al 2000b; Kasper et al 2002a) and, when insufficiently treated, devastating illness (Simpson and Jamison 1999). In contrast to unipolar depression, bipolar disorder seems to have a worldwide prevalence within a relatively narrow range. Multinational studies have revealed a lifetime prevalence rate of about 1.6 % for bipolar I disorder (Weissman et al 1996), and for the spectrum of bipolar disorders classified as Bipolar I and II a prevalence of 5.5 % (Angst 1995). Some groups, such as young patients with psychotic depression, are especially likely to be misdiagnosed at index episode: up to 50 % of patients hospitalised with an index episode of depression may turn out to be bipolar in the long run (Goldberg et al 2001) (Figure 1). Together with increasing evidence of associated genetic polymorphism, e.g. in the expression of genes encoding for transporters and receptors of biogenic amines (Kelsoe et al 1996; Waldman et al 1997), the epidemiological figures support the assumption that bipolar disorder has a strong hereditary component and that prevalence is relatively insensitive to variations in personal or social adversity. Thus, it will be assumed that an optimised biological, mostly psychopharmacological, treatment may bring similar benefits across cultures.
Despite this argument, there are multiple guidelines and strategies for the treatment of bipolar disorder worldwide which place different emphases on different kinds of treatments. Obviously, this cannot be due to inherent biological diversities but to different traditions in treatment and different attitudes towards particular agents. Accordingly, the evidence upon which different approaches are based is relatively limited.
For the bipolar spectrum, these treatment guidelines may differ even more, as even the nosological issue is far from being solved (Akiskal and Pinto 1999; Baldessarini 2000)
Methods
The aim of this guideline is to bring together different views on the appropriate pharmacological treatment of bipolar disorder from scientifically well-respected experts and representatives of all continents. In order to achieve this aim, an extensive literature search was conducted up to February 2002, using MEDLINE and EMBASE, as well as other sources, e.g. book articles and abstract volumes of recent key conferences. Additionally, several national treatment guidelines from 1997 onwards were analysed for additional references. The evidence found was summarised and categorised to reflect its susceptibility to bias (Shekelle et al 1999). Each pharmacological treatment suggestion was evaluated with respect to its efficacy, safety (side effect profile and, particularly for bipolar depression, switch risk), practicability of use and availability in different countries. In view of the large diversity in pricing for medications worldwide, daily treatment costs were not taken into consideration.
Given the existing paucity of scientifically well-designed studies in bipolar affective disorders (Ghaemi et al 2000a), it was decided, in contrast to existing guidelines for more rigorously studied disorders, to use less rigid criteria and also to take any long-term clinical experience with a drug more into account. After a vigorous discussion at the World Congress of Biological Psychiatry in Berlin, July 2001, grading of evidence was based on the Schizophrenia Patient Outcome Research Team (PORT) treatment recommendations (Lehman and Steinwachs 1998). These recommendations combine evidencebased elements and clinical experience and have also been used in the WFSBP guidelines on unipolar affective illness (Bauer et al 2002a,b):
(p 117) The acute treatment of bipolar depression
• Antidepressants
There is a large body of clinical studies that support the efficacy of the different available antidepressants in treating symptoms of unipolar depression, even in refractory patients (McConville et al 1998; Nelson 1998a,b). Especially with new antidepressants, trials are methodologically sophisticated and every single antidepressant that has been registered during the last two decades would gain a clear Level A for efficacy. However, this is unfortunately only true for unipolar depression. Bipolarity is regrettably an exclusion criterion in most antidepressant trials of the last two decades.
..
The controlled evidence alone is unimpressive. Practice is guided by the indistinguishable similarity of depressive episodes with a unipolar and bipolar course. What is true for acute treatment of unipolar depression seems very likely to be true also for bipolar depression.
(p 119)• Tolerability
As always, tolerability and side effects pose distinct advantages and disadvantages for individual drugs in individual patients. Compared with lithium, valproate and carbamazepine, it appears that patients are most satisfied with lamotrigine as far as efficacy and side effects are concerned (J. Goldberg, data presented at the APA 2000). However, especially the risk of allergic reactions with lamotrigine and also carbamazepine should not be underestimated.
Switch risk
Many physicians, especially in North America, appear more concerned about the risk of a switch into mania than about maximal efficacy in treating depression. On the one hand, manic episodes can be devastating for the patient and his occupational and family life. On the other hand, insufficient treatment of depression may severely reduce the patients' functional capacities and put them at an increased risk of suicide. As far as the switch rates reported with mood stabiliser monotherapy are concerned, they appear to be between 0 and 5 %, with lithium probably being the most effective in switch prevention (Calabrese et al 1999b). The natural risk of a switch into mania during recovery from a bipolar depression has been estimated to be between 4 and 8 % (Angst 1985; Bunney et al 1972). Antidepressant monotherapy without an accompanying mood stabiliser, however, may increase this switch risk significantly (Lewis and Winokur 1982; Wehr and Goodwin 1987).
Recommendations
Considering the different aspects of efficacy, tolerability and safety, it appears that antidepressants are probably the most efficacious treatment, whereas mood stabilisers are the safest or most conservative treatment. There is probably not much difference in the tolerability of the new generation of antidepressants compared to that of the new generation of mood stabilisers like lamotrigine. When the central inherent risks of bipolar depression are kept in mind, i.e. switch into mania and suicide, it appears that a combination of antidepressants and mood stabilisers should usually be the treatment of choice from the beginning. First line antidepressants are SSRIs and perhaps bupropion, depending on availability; first line mood stabilisers are lithium (which may additionally have antisuicidal effects (Thies-Flechtner et al 1996)) and lamotrigine. However, the main practical problem with lamotrigine treatment is that rapid dose increase is unacceptable because it may lead to severe allergic complications. In the phase III multicenter study (Calabrese et al 1999a), first antidepressant effects were seen at a dosage of 50 mg, which is not reached before week three if lamotrigine dosage is increased according to the manufacturer's recommendations. However, the time to the development of an antidepressive action of lithium is probably not much different, which clearly limits its use as monotherapy in
bipolar depression (Montgomery et al 2000). Conventional antidepressants also have a delay of two weeks or more before they show full beneficial action, so additional symptomatic treatment with tranquilizers, e.g. lorazepam, may be needed to bridge this time gap, and may even accelerate response (Furukawa et al 2002). If there is pre-existing treatment with a mood stabiliser that has shown efficacy in preventing relapses in the past, physicians should continue with it, optimise the dosage and add an antidepressant if necessary. Optimisation of mood stabiliser treatment does not imply simply a predefined plasma level, but an optimal balance between efficacy and tolerability. If this initial treatment is not sufficient, there is little controlled evidence on which to base a further treatment decision. Some advocate the addition of a second mood stabiliser but, equally, substitution of the antidepressant may be considered. There is limited evidence that adding a second mood stabiliser to pre-existing mood stabiliser treatment may be as efficacious as adding an antidepressant (Young et al 2000). However, as far as tolerability is concerned, the addition of a modern antidepressant may be better tolerated than combination treatment with two mood
stabilisers (in the study by Young et al, a combination of lithium and valproate was used). When the decision to add either a second mood stabiliser or an antidepressant has to be made, analysis of the patient's history concerning previous switches or rapid cycling may be helpful. This recommendation may be slightly varied in patients with severe and psychotic depression, and in depression within a rapid cycling course of illness. In uncomplicated unipolar depression, the efficacy of SSRI and TCA appears the same (Geddes et al 2000). In severe and psychotic depression, however, a classical TCA or irreversible MAOI may be required as, at least in unipolar depression, they appear superior to SSRI in these conditions (Perry 1996). Additionally, augmentation
with an atypical antipsychotic may be beneficial. Besides treating psychotic symptoms and having good tolerability, trials both with olanzapine (Vieta et al 2001b; Rothschild et al 1999; Tohen et al 2000) and risperidone (Vieta et al 2001a) suggest reasonable antidepressant effects with these atypicals by themselves.
For depression within a rapid cycling course, the role of antidepressants is controversial. Some highlight the potential of antidepressants not only to induce a switch, but also to cause an increase in the number of episodes (Altshuler et al 1995), although the likelihood of the latter has been questioned (Coryell et al 1992). Given the negative view of ADs, in rapid cycling patients with mild to moderate depression without suicidal risk, mono- or combination therapy with two mood stabilisers may be considered. In more severe depression within a rapid cycling course, however, the addition of an antidepressant appears entirely reasonable. If an antidepressant is added, some authorities believe it should be discontinued as early as possible: in practice this may be difficult.
Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP).
Hantouche
EG, Akiskal HS,
Lancrenon S,
Allilaire JF,
Sechter D, Azorin JM, Bourgeois M, Fraud JP, Chatenet-Duchene L.
J
Affect Disord 1998 Sep;50(2-3):163-73
"BACKGROUND: This paper presents the methodology and clinical data in
mid-stream from a French multi-center study (EPIDEP) in progress on a
national sample of patients with DSM-IV major depressive episode (MDE).
The aim of EPIDEP is to show the feasibility of validating the spectrum
of soft bipolar disorders by practising clinicians. In this report, we
focus on bipolar II (BP-II). METHOD: EPIDEP involves training 48 French
psychiatrists in 15 sites; construction of a common protocol based on
the criteria of DSM-IV and Akiskal (Soft Bipolarity), as well as
criteria modified from the work of Angst (Hypomania Checklist), the
Ahearn-Carroll Bipolarity Scale, HAM-D and Rosenthal Atypical
Depression Scale; Semi-Structured Interview for Evaluation of Affective
Temperaments (based on Akiskal-Mallya), self-rated Cyclothymia Scale
(Akiskal), family history (Research Diagnostic Criteria); and
prospective follow-up. RESULTS: Results are presented on 250 (of the
537) MDE patients studied thus far during the acute phase. The rate of
BP-II disorder which was 22% at initial evaluation, nearly doubled
(40%) by systematic evaluation. As expected from the selection of MDE
by uniform criteria, inter-group comparison between BP-II vs unipolar
showed no differences on the majority of socio-demographic parameters,
clinical presentation and global intensity of depression. Despite such
uniformity, key characteristics significantly differentiated BP-II from
unipolar: younger age at onset of first depression, higher frequency of
suicidal thoughts and hypersomnia during index episode, higher scores
on Hypomania Checklist and cyclothymic and irritable temperaments, and
higher switching rate under current treatment. Eighty-eight percent of
cases assigned to cyclothymic temperament by clinicians (with a cut-off
of 10/21 items on self-rated cyclothymia) were recognized as BP-II.
Evaluation of this temperament by clinician and patient correlated at a
highly significant level (r=0.73; p <0.0001). Cyclothymia and
hypomania were also correlated significantly (r=0.51; p <
0.001).
LIMITATION: In a study conducted in diverse clinical settings, it was
not possible to assure that clinicians making affective diagnoses were
blind to the various temperamental measures. However, bias was
minimized by the systematic and/or semi-structured nature of all
evaluations. CONCLUSION: With a systematic search for hypomania, 40% of
major depressive episodes were classified as BP-II, of which only half
were known to the clinicians at study entry. Cyclothymic temperamental
dysregulation emerged as a robust clinical marker of BP-II disorder.
These data indicate that clinicians in diverse practice settings can be
trained to recognize soft bipolarity, leading to changes in diagnostic
practice at a national level." [Abstract]
Am J Psychiatry 2002 159: 1711-1717
"OBJECTIVE: This study explored whether "switching" (i.e., the direct transition from one mood polarity to the other) has significant prognostic implications in patients with bipolar disorder. METHOD: Bipolar disorder patients (N=97) whose first prospectively observed episode included at least one mood polarity switch and 97 bipolar disorder patients whose index episode was monophasic were compared with respect to several demographic and historical variables, symptomatic features of the index episode, time to recovery from the index episode, time spent in an affective episode during a prospective observation period, and psychopathological and psychosocial outcome at a 10-year follow-up interview. RESULTS: Patients whose index episode included at least two mood polarity switches spent significantly more time in an affective episode during the observation period and had a significantly worse psychopathological and psychosocial outcome 10 years after recruitment than those whose index episode included only one mood polarity switch or was monophasic. Patients whose polyphasic index episode started with depression spent a significantly higher proportion of time in an affective episode and had a significantly worse 10-year outcome than those whose polyphasic index episode started with mania or hypomania. Retention of the switching pattern throughout the observation period was seen in 42.4% of patients whose index episode started with mania and in 65.2% of those whose index episode started with depression. CONCLUSIONS: An index episode including at least two mood polarity switches, especially if starting with depression, is associated with a poor long-term outcome in patients with bipolar disorder. This pattern represents a significant target for new pharmacological and psychosocial treatment strategies. " Traitement de la dépression bipolaire Evaluation and management of breaktrough depressive episodes
Paul KECK. J. of Clin. Psychiatry 2004-65
Strategies for preventing the recurrence of bipolar disorder. SN Ghaemi, TB Pardo, DJ Hsu J. of Clin. Psychiatry 2004-65
p 20." Le traitement à long terme des troubles bipolaires avec des AD doit être considéré en terme de ratio de risques/bénéfices. Du côté des bénéfices, un traitement avec un AD ajouté peut améliorer les symptômes de dépression aigus dans le court terme. Dans le long terme, cependant, pour la prévention des épisodes futurs, les études suggérent que les AD sont inefficaces.
Du côté des risques, il y a le déclenchement de cycles rapides ou d'accéleration des cycles avec les AD. Les cycles rapides apparaissent chez 20 à 25% des patients traités avec les AD tricycliques (TCA). Dans les seules données d'observation comparant les nouveaux antidépresseurs avec les anciens antidépresseurs, nous trouvons que le taux de cycles rapides dans les troubles bipolaires est similaire entre les TCA et les IRS.
Les données sur les AD en traitement à long terme du trouble bipolaire montrent un manque d'éfficacité. Une revue des recherches sur l'usage à long terme des AD trouve 7 essais cliniques controlés en double aveugle qui montrent que l'inefficacité des AD en monothérapie ou comme traitement annexe."
Efficacy
and safety of fluoxetine
in treating bipolar II major depressive episode
Amsterdam
JD, Garcia-Espana F, Fawcett J, Quitkin FM,Reimherr
FW, Rosenbaum JF, Schweizer E, Beasley C
University
of Pennsylvania Medical Center, Philadelphia, USA. J
Clin Psychopharmacol 1998 Dec;
18(6):435-40
ABSTRACT
Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin FM,Reimherr FW, Rosenbaum JF, Schweizer E, Beasley C
University of Pennsylvania Medical Center, Philadelphia, USA. J Clin Psychopharmacol 1998 Dec; 18(6):435-40
ABSTRACT
As many as 45% of patients with major depressive episode also meet DSM-IV criteria for bipolar II (BP II) disorder. Although some clinicians advocate using a mood stabilizer in treating BP II depression, antidepressant monotherapy has been less well studied in this disorder. As part of a prospective, placebo-controlled, relapse-prevention study in 839 patients, the efficacy and safety of short- and long-term fluoxetine treatment in patients with BP II major depression compared with patients with unipolar (UP) major depression was retrospectively examined. Eighty-nine BP II patients (mean age, 41+/-11 years) were compared with 89 age- and gender-matched UP patients and with 661 unmatched UP patients (mean age, 39+/-11 years). All received short-term fluoxetine therapy at 20 mg daily for up to 12 weeks. Complete remission was defined as a final Hamilton Rating Scale for Depression score < or = 7 by week 9 that was then maintained for 3 additional weeks. Remitted patients were then randomly assigned to receive double-blind treatment with one of the following: (1) fluoxetine 20 mg daily for 52 weeks; (2) fluoxetine for 38 weeks, then placebo for 14 weeks; (3) fluoxetine for 14 weeks, then placebo for 38 weeks; or (4) placebo for 52 weeks. Antidepressant efficacy was similar in BP and UP patients during short-term therapy. Discontinuation for lack of efficacy was lower in BP II (5%) than in UP (12%) patients (p = not significant [NS]), whereas dropouts for adverse events were similar in BP II (11%) and UP (9%) patients. During long-term relapse-prevention therapy, relapse rates were similar in BP II and UP patients (p = NS). During short-term fluoxetine therapy, three BP II (3.8%) versus no matched UP (p = NS) and 0.3% unmatched UP (p = 0.01) patients had a "manic switch." During long-term fluoxetine therapy, one (2%) BP II and three (1%) unmatched UP patients (one taking placebo) had a manic switch (p = NS). In conclusion, fluoxetine may be a safe and effective antidepressant monotherapy for the short-term treatment of BP II depression with a relatively low manic switch rate. Fluoxetine may also be effective in relapse-prevention therapy in patients with BP II disorder.BOLDER II Study Confirms Therapeutic Potential of SEROQUEL in Bipolar Depression ALDERLEY PARK, England, October 21Antidepressants in Bipolar Disorder: Are They Safe? Are They Effective?
by S. Nassir Ghaemi, M.D.Some clinicians seem to think that antidepressants rank slightly below sliced bread in their all-around utility: Not only do they work for depression, but for anxiety disorders, post-traumatic stress, headaches and pain. They might even work for what Freud labeled "the normal misery of life," allowing patients to experience life without the slow sad bits, like a good Hollywood movie. This optimism may be misdirected, however, in the case of patients with bipolar disorder, for antidepressants may cause serious problems in individuals who suffer from bipolar depression.
First, let's note that bipolar depression is not as uncommon as many suppose. Based on data regarding mania from the Epidemiologic Catchment Area study (Regier and Kaelber, 1995), it is generally assumed that bipolar disorder occurs in only about 1% of the population. If we include bipolar II disorder (hypomania), however, the condition has been described in 2% to 5% of the population (Angst, 1998). If we compare this prevalence to the reported 5% to 10% prevalence of unipolar depression, then the ratio of unipolar to bipolar disorder is two to one, not five or more to one as the Catchment Area study would predict. Thus, of all patients who have mood disorders, one out of every three should be diagnosed with bipolar disorder; this would make it a very common condition. And, contrary to another popular misconception, the majority of patients with bipolar disorder are depressed, not manic. Since mania is required for the diagnosis of bipolar disorder, clinicians sometimes assume that bipolar patients are the same as manic patients. In fact, most bipolar patients are depressed most of the time, and their manic episodes are infrequent and short (Goodwin and Jamison, 1990).
Since bipolar patients are depressed most of the time, it is not surprising that they frequently are treated with antidepressants. Indeed, recent pharmacy data indicate that the most commonly prescribed class of medications for bipolar disorder is indeed antidepressants (IMS, 1998). Of the top four prescribed drugs for patients with bipolar disorder by psychiatrists, three are selective serotonin reuptake inhibitors. These three SSRIs are more commonly prescribed for patients with bipolar disorder than lithium or any of the atypical antipsychotic agents (IMS, 1998).
There are far fewer controlled studies of antidepressants in bipolar disorder than there are in unipolar depression. I recently reviewed the literature and noted that, in the past decade, over 4,000 patients with unipolar depression using antidepressants were studied in double-blind, placebo-controlled fashion, compared to only about 200 patients with bipolar depression (Ghaemi et al., in press [b]). Long-term outcome studies in bipolar depression with the newer antidepressants are practically nonexistent. We have almost no idea from controlled studies of the long-term effects of antidepressants in bipolar disorder. The short-term studies have shown benefit for only a few antidepressants, such as bupropion (Wellbutrin) and paroxetine (Paxil) (Sachs et al., 1994; Young et al., 1997). These two have been shown to have relatively lower rates of causing acute mania than tricyclic antidepressants. Still, no antidepressant has been proven safe or effective in the long-term treatment of bipolar disorder.
There is, however, a good deal of naturalistic clinical evidence that antidepressants can possess long-term risks in the treatment of bipolar disorder (Wehr and Goodwin, 1987). A number of studies suggest that antidepressants can cause rapid cycling and a long-term worsening of the course of bipolar illness (Altshuler et al., 1995; Wehr and Goodwin, 1979; Ghaemi et al., in press [a]). In this setting, antidepressants act as mood destabilizers, counteracting the benefits of mood stabilizers. Thus, chronic antidepressant treatment can interfere with the patient's ability to respond to mood stabilizers and may cause more mood episodes in the long run. This is why many bipolar researchers recommend that antidepressants be tapered off two to three months after recovery from the acute major depressive episode (Sachs, 1996). Unfortunately, clinical practice data suggest that this does not occur in the real world, and that clinicians do use antidepressants in the long-term treatment of bipolar disorder.
There is some room for doubt here, and indeed some clinicians and researchers argue that antidepressants are not too risky in the treatment of bipolar disorder, particularly in type II illness (Amsterdam, 1998; Amsterdam et al., 1998), and especially when used in low doses along with mood stabilizers (Baldessarini, 1996). My own clinical experience is that I frequently help patients with complicated bipolar disorder the most by discontinuing their antidepressants. For the minority of patients who continue to relapse into depression every time antidepressants are stopped, I sometimes need to continue long-term antidepressant treatment. In my experience, most patients with bipolar disorder do best with multiple mood stabilizers in the absence of long-term antidepressant use.
Further controlled research will help clarify this issue. In the meantime, when it comes to antidepressant use in bipolar disorder, I believe that we clinicians should adhere even more assiduously to the ancient Hippocratic maxim, primum non nocere.
Dr. Ghaemi is a research psychiatrist in the Psychopharmacology Program at Cambridge Hospital and is an instructor in psychiatry at Harvard Medical School.
References
Altshuler LL, Post RM, Leverich GS et al. (1995), Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 152(8):1130-1138 [see comments].
Amsterdam J (1998), Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol 18(5):414-417.
Amsterdam JD, Garcia-Espana F, Fawcett J et al. (1998), Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 18(6):435-440.
Angst J (1998), The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 50(2-3):143-151.
Baldessarini R (1996), Drugs and the treatment of psychiatric disorders: Antimanic and antidepressant agents. In: Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed., Hardman J, Limbird LE, Molinoff PB et al., eds. New York: McGraw-Hill, pp431-459.
Ghaemi S, Boiman E, Goodwin F (in press [a]) Diagnosing bipolar disorder and the effect of antidepressants. J Clin Psychiatry.
Ghaemi S, Sachs G, Goodwin F (in press [b]), What is to be done? Current clinical controversies in the diagnosis and treatment of bipolar disorder. World Journal of Biological Psychiatry.
Goodwin FK, Jamison KR (1990), Manic-Depressive Illness. New York: Oxford University Press.
IMS (1998), National Disease and Therapeutic Index. New Jersey: IMS America.
Regier DA, Kaelber CT (1995), The epidemiologic catchment area (ECA) program: studying the prevalence and incidence of psychopathology. In: Textbook in Psychiatric Epidemiology, Tsuang MT, Tohen M, Zahner GEP, eds.). New York: Wiley-Liss, pp133-157. Sachs GS (1996), Bipolar mood disorder: practical strategies for acute and maintenance phase treatment. J Clin Psychopharmacol 16(2 suppl 1):32S-47S.
Sachs GS, Lafer B, Stoll AL et al. (1994), A double-blind trial of bupropion versus desiprimine for bipolar depression. J Clin Psychiatry 55(9):391-393.
Wehr TA, Goodwin FK (1979), Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry 36(5):555-559.
Wehr TA, Goodwin FK (1987), Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 144(11):1403-1411.
Young ML, Pitts CD, Oakes R, Gergel IP (1997), A double-blind placebo-controlled trial comparing the effect of paroxetine and imipramine in the treatment of bipolar depression. Presented at the Second International Conference on Bipolar Disorder. Pittsburgh, Penn.
Antidepressants in bipolar disorder: the case for caution.
Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Bipolar Disord. 2003 Dec;5(6):421-33.
Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA and Harvard Medical School, Boston, MA 02139, USA. ghaemi@hms.harvard.edu
The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients).
Oxcarbazepine treatment of bipolar disorder.
Ghaemi SN, Berv DA, Klugman J, Rosenquist KJ, Hsu DJ. J. Clin Psychiatry. 2003 Aug;64(8):943-5.Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, Mass., USA. ghaemi@hms.harvard.edu
OBJECTIVE: To assess the effectiveness and safety of oxcarbazepine in bipolar disorder. METHOD: A chart review of naturalistic treatment with oxcarbazepine in 42 outpatients with DSM-IV bipolar disorder (10 males, 32 females; mean +/- SD age = 33.3 +/- 12.4 years; 25 with bipolar disorder type I, 4 with bipolar disorder type II, and 13 with bipolar disorder not otherwise specified) was conducted. Patients had received oxcarbazepine monotherapy or adjunctive therapy between April 2000 and April 2002. Treatment response was defined as a Clinical Global Impressions-Improvement scale score of 1 (marked improvement) or 2 (moderate improvement). RESULTS: Oxcarbazepine was moderately to markedly effective in 24 subjects (57%). Mixed symptoms were the most common indication (52% [22/42]). The mean oxcarbazepine dose was 1056.6 mg/day, and mean treatment duration was 16.2 weeks. Sedation (17/42, 40%) was the most common side effect, but 16 patients (38%) had no side effects. Twenty-two patients (52%) stopped treatment, mostly due to side effects (12/22). Males were more likely to respond than females (10/10 vs. 14/32, p =.006). Dose, bipolar subtype, indication, past nonresponse to mood stabilizers, concurrent mood stabilizer use, and monotherapy use of oxcarbazepine did not differentially predict response. CONCLUSION: Oxcarbazepine appeared effective in about one half of patients with bipolar disorder and was well tolerated.Medicines out of Control? Antidepressants and the Conspiracy of Goodwill - Charles MEDAWAR, Anita HARDON . Aksant
BMJ 2004;329:1350 (4 December), doi:10.1136/bmj.329.7478.1350
The treatment of depression has seldom been more controversial. The safety of new antidepressants is subject to radical reappraisal, while an unpleasant question looms: can we really trust scientific evidence? Medawar and Hardon give a detailed analysis of this quagmire, massively annotated with footnotes and verbatim quotations.
It is understandable that the references sometimes get lost or the argument wanders, for the problem is not focal but pervasive. Theirs is an indictment of "big pharma" (the drug industry), doctors (both as prescribers and researchers), the regulatory authorities, politicians, and, ultimately, the values of society itself. Building on the evidence that earlier treatments of "distress" (such as opium, barbiturates, and benzodiazepines) initially seemed benign, only to wreak havoc later, the authors locate a similar optimism among early accounts of some antidepressants (particularly the selective serotonin reuptake inhibitors or SSRIs).
However, they suggest that there is something different about the current debate—something that is about precision, semantics, or sleight of hand, depending on your viewpoint. The authors argue that SSRIs elicit "dependency," as evidenced by withdrawal phenomena, but that this has been obfuscated by terminology. If feeling worse or experiencing adverse reactions when stopping a drug constitutes dependence, then SSRIs produce it. However, an alternative vocabulary describes such withdrawal phenomena (note the connotation of addiction) as "discontinuation" reactions, a softer sounding term. Furthermore, classically dependence requires euphoria and tolerance (increasing the dose to get the same effect). SSRIs evoke neither of these phenomena, but the authors see this as special pleading.
They extend their critique to the failure of post-marketing surveillance procedures. Relatively few prescribers report adverse reactions, and low levels of reporting can foster the assumption that little is wrong. The authors term this the NERO (no evidence of risk equals evidence of no risk) fallacy.
Again, their question is whether the people monitoring the unwanted effects of SSRIs knowingly or unknowingly minimised the drugs' drawbacks. If these drugs encourage suicidal acts among some patients then calling such acts "non-accidental" really matters. The authors suggest that the classification of suicidal acts as non-accidental obscured the problems with paroxetine in particular. Here, much depends on the attribution of motives to others.
Throughout the book the authors describe detailed paper trails: naming names and meetings, quoting what the regulators said, who gave evidence, who declared an "interest" and left the room, who had shares in drug companies. A number of psychiatrists are named. A dilemma emerges. A committee needing an expert opinion will need someone who has worked in the area. Yet a psychopharmacology researcher may well have received grants from industry. If the expert leaves the room when the science is discussed (declaring a competing interest), then the level of discourse is diminished. Few recognised experts in psychopharmacology have never interacted with big pharma. This critique sees all such conta onal decision as to continued use of these agents.[5] Data from a study by Hsu and colleagues[6] suggest that antidepressant continuation does not lead to increased time in remission in bipolar disorder, compared with antidepressant discontinuation.Bipolar Disorder and Comorbid Conditions
The purpose of a study by Simon and colleagues[7] was to determine to what extent comorbid conditions are linked to the adequate use of mood stabilizers and other pharmacologic interventions. The first 1000 patients enrolled into a large 20-site study on bipolar disorder (STEP-BD) were included in this study. The treatments were rated for adequacy based on predecided criteria for mood stabilizer use as well as treatment of associated specific disorders (eg, attention-deficit/hyperactivity disorder [ADHD], substance abuse, anxiety disorders).
The rates of comorbidity were as follows: current anxiety disorder in 32%; lifetime substance abuse disorder in 48%; current alcohol use in 8%; current ADHD in 6%; current eating disorder in 2%; and past eating disorder in 8%.
With regard to pharmacologic interventions:
A total of 7.5% of the sample were not treated with any psychotropic medications.
A total of 59% were not on adequate mood stabilizers. The extent of adequate mood stabilizer treatment was not related to comorbid diagnosis or bipolar I or II status.
Only 42% of individuals with a current anxiety diagnosis were receiving adequate treatment for this disorder.
The presence of comorbid conditions was only minimally associated with the appropriateness or extent of psychopharmacologic intervention.
This as well as other studies have noted a high rate of comorbidity among patients with bipolar disorder.[8] Patients with manic depression and comorbid conditions have been found to have higher levels of ongoing subsyndromal symptoms.[9] The findings from this study indicate that these associated symptoms and syndromes are not being addressed adequately by the clinician, and they may not be detecting them at all. Alternatively, the clinician may have concerns about adding medications such as stimulants, benzodiazepines, or antidepressants in someone with bipolar disorder.
Lack of treatment of these associated conditions may lead to significantly poorer outcome. Panic and anxiety, for example, have been associated with increased risk of suicide and violence.[10] Substance abuse has consistently been associated with more difficult course of treatment and worse outcomes.[11] Thus, "treatment resistance" in some patients may not be due to the difficulties inherent in treating the bipolar syndrome but rather to the lack of comprehensive and aggressive treatment of the associated comorbid conditions. Furthermore, a very large proportion of patients (59%) were not receiving adequate mood stabilization and 7.5% were on no psychotropic agents. The lack of adequate treatment of both the mood instability as well as the lack of attention to other associated conditions indicates that a large majority of patients were being treated suboptimally.
Using Ziprasidone as Adjunctive Treatment in Bipolar Disorder
Atypical neuroleptics are increasingly being utilized in the treatment of bipolar disorder as both stand-alone agents as well as adjunctively. Weisler and colleagues[12] reported on the long- and short-term effectiveness of ziprasidone as an add-on agent. A total of 205 adult inpatients with bipolar I disorder, most recent episode manic or mixed, who were being treated with lithium were randomized to receive ziprasidone or placebo. Subjects were given 80 mg on day 1 and 160 mg on day 2. Doses were then adjusted to between 80 and 160 mg as tolerated by the patient. Significant improvement was noted as early as day 4 compared with placebo, and the improvement continued throughout the 21-day period of the acute study. A total of 82 subjects continued in a 52-week open-label extension study, and continued improvement occurred on several measures through the extension period. There were no increases noted in weight or cholesterol, while mean triglyceride levels dropped significantly. Thus, employing this atypical agent early in treatment is helpful in accelerating the response time.
Body Weight and the Impact of Mood Stabilizers
A study to evaluate weight changes and their negative effects on patient compliance and the effective treatment of bipolar disorder was presented by Sachs and colleagues.[13] Weight gain is a specific area of concern for both clinicians and patients. Previous studies have shown that weight gain is associated with lithium, valproate, carbamazepine, gabapentin, and olanzapine. This study focused on the use of lamotrigine and its effects on maintenance treatment of bipolar I disorder utilizing data from 2 studies of bipolar disorder I patients who recently experienced a depressive or manic episode. Patients were enrolled into 1 of 2 different protocols. Each protocol consisted of an 8- to 16-week, open-label study where lamotrigine was added to the "existing psychotropic regimen prior to gradual transition to lamotrigine monotherapy."
A total of 583 patients were randomized to up to 18 months of double-blind lamotrigine treatment (n = 227; 100-400 mg/day fixed and flexible dosing), lithium (n = 166; 0.8-1.1 mEq/L), or placebo (n = 190). Mean age was 43 years, and 55% of participants were female. Mean weight at randomization was similar among treatment groups: lamotrigine = 79.8 kg; lithium = 80.4 kg; and placebo = 80.9 kg. One third had previously attempted suicide, while the other two thirds had been hospitalized for psychiatric reasons.
This study showed that lamotrigine patients lost an average of 2.6 kg over the 18 months of treatment while patients treated with placebo and lithium gained 1.2 kg and 4.2 kg, respectively. Other results showed no statistically significant differences between lamotrigine and placebo in the number of patients experiencing >/= 7% weight change, >/= 7% weight gain, or >/= 7% weight loss. Patients taking lamotrigine experienced a > 7% weight loss (12.1%) compared with patients taking lithium (5.1%; 95% confidence interval [-13.68, -0.17]). Patients taking lamotrigine stayed in the trial for longer periods of time, increasing the chance of observing differences in weight in the lamotrigine group (lamotrigine, lithium, and placebo treatment groups: 101, 70, and 57 patient years, respectively). Lithium patients experienced statistically significant weight changes from randomization at week 28 compared with the placebo group (lithium: +0.8 kg ; lithium placebo: -0.6 kg). Statistically significant differences between lithium and lamotrigine were seen at week 28 through week 52 (lamotrigine: up to -1.2 kg; lithium: up to +2.2kg). This study concluded that patients with bipolar I disorder taking lamotrigine did not experience relevant changes in weight.
Bipolar Disorder and the Burden of Depression
A study by Fu and colleagues[14] was conducted to examine the frequency and economic burden to a managed care payer of depressive and main episodes in a bipolar population. Utilizing claims data between 1998 and 2002 for bipolar patients (ICD-9:296.4-296.8), episodes of care of depression and mania were characterized based on ICD-9 codes. Using t-tests and multivariate linear regression, these were compared with outpatient, pharmacy, and inpatient costs. Data were taken from a large US managed care database with medical and pharmacy administrative claims data from more than 30 health plans. Samples were gathered of 1 or more claims for bipolar disorder for patients aged 18-60 years with no comorbid diagnosis of epilepsy (ICD-9: 345.xx) with a continuous enrollment of at least 6 months prior to first episode and 1 year after the start of episode. Episodes were defined as started by the first claim for bipolar disorder preceded by a 2-month period without any bipolar-related healthcare claims and ended when there was a gap of greater than 60 days between prescription refills of bipolar medication. Episodes were classified as depressive or manic if more than 70% of the medical claims were related to depression or mania.
A total of 38,280 subjects were included with a mean age of 39 years; 62% of subjects were female. More than 70% of resource utilization was accounted for by hospitalizations and outpatient visits. The length of stay for mania (10.6 days) was higher (P < .001) than for depression (7 days). A total of 14,069 episodes were defined for 13,119 patients by applying continuous inclusion criteria and an episode definition algorithm. Episodes of depression occurred 3 times more frequently than manic episodes (n = 1236). Average outpatient ($1426), pharmacy ($1721), and inpatient ($1646) costs of a depressive episode were compared with outpatient ($863 [P < .0001]), pharmacy ($1248 [P < .0001]), and inpatient ($1736 [P = 0.54]) costs for a manic episode. It was shown that the cost of a depressive episode ($5503) was approximately double the cost of a manic episode ($2842) after controlling for age, gender, site of visit, and healthcare costs prior to the start of the episode. Bipolar depression appears to be a greater burden than mania. The prevention or delay of bipolar depression could result in cost savings to managed care providers.
Predicting Relapse in Bipolar Disorder
Because bipolar disorder is a recurrent and cyclic disease, early prediction of subsequent episodes is essential for optimal treatment. In a study by Tohen and associates,[15] a post-hoc analysis was conducted based on the pooled data from 2 bipolar maintenance studies. A total of 779 patients who were in a state of remission from manic or mixed episodes were followed for up to 48 weeks. Patients were treated with olanzapine (n = 434), lithium (n = 213), or placebo (n = 132) after completion of an acute open-label treatment study comparing lithium monotherapy with olanzapine-lithium combination therapy. There were several predictors of early relapse, including a history of rapid cycling, a mixed-index episode, frequency of episodes in the previous year, age of onset younger than 20 years, family history of bipolar disorder, female gender, and the lack of a hospitalization in the past year. The strongest predictors were a history of rapid cycling and a mixed-index episode. The identification of risk factors might help the clinician to identify those individuals most at risk for relapse and aid in the development of early intervention strategies.
A Decade of Pharmacologic Trends in Bipolar Disorder
There have been many new treatments for bipolar disorder introduced in the past decade. The most important development has been the introduction of numerous atypical agents and the numerous studies documenting their effectiveness. A study by Cooper and colleagues[16] looked at the trends in medication use between 1992 and 2002. Data were derived from a pharmacy prescription database of 11,813 patients. The findings were as follows:
The percentage of patients treated with a mood stabilizer has remained stable through the 10-year period at approximately 75%. The percentage of patients on lithium has decreased steadily, a trend paralleled by the increase in valproate. In 1999, valproate became the most widely prescribed mood stabilizer. Lamotrigine and topiramate have been increasing steadily since 1997 to 1998, while the use of carbamazepine has been decreasing steadily.
Antidepressant use has been relatively stable, varying between 56.9% and 64.3%.
Atypical neuroleptics were utilized in 47.8% of patients in 2002. Olanzapine was the most prescribed atypical medication in 2002, followed by risperidone, quetiapine, and ziprasidone. Clozaril use has decreased dramatically.
The overall trend indicates that mood stabilizing is still the mainstay of treatment; the atypical agents are becoming much more accepted as integral to the treatment of the bipolar patient.
References
Perlis RH, Miyahara S, Marangell LB, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55:875-881. Abstract Pardo TB, Ghaemi SN, El-Mallak RS, et al. Do antidepressants improve remission in patients with bipolar disorder? Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR25. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152:1130-1138. Abstract Post RM, Leverich GS, Nolen WA, et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord. 2003;5:396-406. Abstract Ghaemi SN, El-Mallakh RS, Baldassano CF, et al. Effect of antidepressants on long-term mood morbidity in bipolar disorder. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR771. Hsu DJ, Ghaemi SN, El-Mallakh RS, et al. Antidepressant discontinuation and mood episode relapse in bipolar disorder. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR26. Simon NS, Otto MW, Weiss RD, et al. Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR394 Sasson Y, Chopra M, Harrari E, Amitai K, Zohar J. Bipolar comorbidity: from diagnostic dilemmas to therapeutic challenge. Int J Neuropsychopharmacol. 2003;6:139-144. Abstract MacQueen GM, Marriott M, Begin H, Robb J, Joffe RT, Young LT. Subsyndromal symptoms assessed in longitudinal, prospective follow-up of a cohort of patients with bipolar disorder. Bipolar Disord. 2003;5:349-355. Abstract Korn ML, Plutchik R, Van Praag HM. Panic-associated suicidal and aggressive ideation and behavior. J Psychiatr Res. 1997;31:481-487. Abstract Salloum IM, Thase ME. Impact of substance abuse on the course and treatment of bipolar disorder. Bipolar Disord. 2000;2(3 Pt 2):269-280. Weisler R, Warrington L, Dunn J, Giller EL, Mandel FS. Adjunctive ziprasidone in bipolar mania: short and long-term data. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR358. Sachs G, Merideth C, Ginsburg L, et al. The long-term impact of mood stabilizers on body weight. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR74. Fu AZ, Krishnan AA, Harris SD. The burden of depression patients with bipolar disorder. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR556. Tohen M, Bowden CL, Calabrese JR, et al. Predictors of time to relapse in bipolar I disorder. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR800 Cooper LM, Zhao Z, Zhu B. Trends in pharmacologic treatment of patients with bipolar: 1992-2002. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR749.
Bipolar II Disorder: An Overview of Recent Developments
Author(s)
BMJ 2005;331:155-157 (16 July), doi:10.1136/bmj.331.7509.155
Efficacy of antidepressants in adults
1. Resident, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.2. Assistant Professor of Psychiatry, Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.3. Professor of Psychiatry, Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.Address for correspondence: Dr LN Yatham, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1
The National Institute for Health and Clinical Excellence (NICE) recently recommended that antidepressants, in particular selective serotonin reuptake inhibitors, should be first line treatment for moderate or severe depression.1 This conclusion has broadly been accepted as valid.2 The message is essentially the same as that of the Defeat Depression Campaign in the early 1990s, which probably contributed to the 253% rise in antidepressant prescribing in 10 years.1 From our involvement in commenting on the evidence base for the guideline we believe these recommendations ignore NICE data. The continuing concern that selective serotonin reuptake inhibitors may increase the risk of suicidal behaviourw1 w2 means there needs to be further consideration of evidence for the efficacy of antidepressants in adults as there has been in children.
Efficacy
Although the NICE meta-analysis of placebo controlled trials of selective serotonin reuptake inhibitors found significant differences in levels of symptoms, these were so small that the effects were deemed unlikely to be clinically important.1 The conclusion that the drugs had clinically important benefits was based on analysis of response and remission rates. However, in our comments on the draft guidelines, we pointed out that these categorical outcomes were derived from the same continuous data for symptoms scores that were found to show no clinically relevant effects. As NICE notes, "dichotomising scores into remission and non-remission creates an artificial boundary, with patients just over the cut-off score often being clinically indistinguishable from those just under the cut-off."1The hypothetical data in the figure show how small differences may be magnified by transformation of continuous data into categorical data.3 In this example, response was defined as a minimum 12 point improvement on the Hamilton rating scale for depression. Difference in mean change of scores between drug and placebo groups was 1 point. This scenario yields response rates of 50% in the drug condition and 32% in the placebo condition. Thus, if improvement is normally distributed and the criterion for response is close to the mean improvement rate (which it generally is), a very small difference in symptom score can push a large proportion of patients into different categories.
The small effects found on continuous measures are consistent with results of other recent meta-analyses of symptom scores. Khan et al found a 10% difference in levels of symptoms in two meta-analyses,4 5 and Kirsch et al included unpublished studies in their latest analysis and found an overall mean difference of 1.7 points on the Hamilton scale.6 No research evidence or consensus is available about what constitutes a clinically meaningful difference in Hamilton scores, but it seems unlikely that a difference of less than 2 points could be considered meaningful. NICE required a difference of at least 3 points as the criterion for clinical importance but gave no justification for this figure.1 The most commonly used 17 item version of the Hamilton scale has a maximum score of 52 and contains seven items concerning sleep and anxiety, with each item on sleep scoring up to 6 points. Hence any drug with some sedative properties, including many antidepressants, could produce a difference of 2 points or more without exerting any specific antidepressant effect. Other recent meta-analyses that present categorical outcomes also find modest differences of between 14% and 18% in improvement or response rates.w3-w5
Severity of depression
A key claim in the NICE guideline is that the superiority of antidepressants over placebo correlates positively with the severity of depression being treated. This belief is an old one. In 1958 Kuhn suggested that endogenous depression was more responsive to antidepressants than neurotic or reactive depression, which was generally regarded as less severe.7 Regression to the mean may account for this impression since it entails that people with more severe depression at baseline will show greatest overall levels of improvement. But it does not explain drug-placebo differences, because greater improvement among patients with more severe depression occurs regardless of whether they are treated with a drug or placebo.An early review of controlled trials found that evidence about whether endogenous symptoms predicted response was inconsistent.8 Recent evidence comes from post-hoc analysis in trials with otherwise negative resultsw6 w7 and from meta-analyses. The meta-analysis by Angst et al is often cited in support of the severity hypothesis, but severity effects were weak and mostly non-significant.9 Effects in another meta-analysis were more impressive, but data were provided only for investigational antidepressants and not established ones, where the evidence seemed to be weaker.10 In contrast, another recent meta-analysis found no relation between severity and antidepressant effect,11 and a meta-analysis of older studies showed that differences between antidepressants and placebo were smaller and non-significant in inpatient trials compared with outpatient trials.12 The NICE meta-analysis failed to find a consistent gradient of effect from "moderate" (Hamilton score 14-18) through "severe" (19-22) to "very severe" depression (
23).1 In fact, the middle group, which would generally be referred to as moderately depressed, tended to show larger effects than either of the other two, but numbers of studies were small.
Thus there seems to be little support for the suggestion that recent failure to find marked differences between antidepressants and placebo is due to recruitment of patients with mild depression that is less responsive to antidepressants.1 Indeed, in the meta-analysis by Kirsch et al, all but one of the trials were conducted in patients with severe to very severe depression according to NICE criteria.6 The possibility that patients in the mid-range of severity show a greater antidepressant response, as suggested by the NICE data and by Joyce and Paykel,8 would not be expected from a simple biological effect. It may indicate that this group is more susceptible to some methodological artefact such as infringement of the double blind (see below).
Methodological issues in antidepressant trials
Several commentators have suggested that the small effects of antidepressants compared with placebos may be attributable to methodological factors or selective presentation of data from antidepressant trials.w8-w10 These include concerns that trials of antidepressants may not be truly double blind. This is because participants may be able to detect differences between placebos and drugs because the drugs cause noticeable physiological effects including, but not limited to, recognised side effects. Other concerns include the validity of outcome measures, that discontinuation effects may confound continuation trials, and that results may be inflated by exclusion of people who withdraw early from the analysis. Evidence also shows that trials of antidepressants with negative results are less likely to be published than those with positive results and that, within published trials, negative outcomes may not be presented.13A neglected aspect of antidepressant trials is the substantial heterogeneity of their findings.12 Although many trials do find antidepressants are superior to placebo, many do not, including some of the largest and most well known landmark trials such as the Medical Research Council trial and the early National Institute for Mental Health trial.w11 w12 In addition, many trials find that substances as diverse as methylphenidate, benzodiazepines, and antipsychotics can have antidepressant effects, suggesting that these effects may be attributable to non-specific pharmacological or psychological mechanisms.w10
Summary points Recent meta-analyses show selective serotonin reuptake inhibitors have no clinically meaningful advantage over placebo
Claims that antidepressants are more effective in more severe conditions have little evidence to support them
Methodological artefacts may account for the small degree of superiority shown over placebo
Antidepressants have not been convincingly shown to affect the long term outcome of depression or suicide rates
Given doubt about their benefits and concern about their risks, current recommendations for prescribing antidepressants should be reconsidered
Effect of antidepressants
Longitudinal follow-up studies show very poor outcomes for people treated for depression both in hospital14 and in the community,15 and the overall prevalence of depression is rising despite increased use of antidepressants.16 Two studies that prospectively assessed outcome in depressed patients treated naturalistically by general practitioners and psychiatrists found that people prescribed antidepressants had a slightly worse outcome than those not prescribed them, even after baseline severity had been taken into account.17 18 No comparable studies could be found that showed a better outcome in people prescribed antidepressants.Some authors have suggested a causal association between increased antidepressant prescribing since 1990 and reduction of overall suicide rates observed in some countries.w13 w14 However, others have pointed out that falls in overall suicide rates started long before this period,w15-w17 and suicide rates have increased in some age groupsw15 and some countriesw18 despite increased antidepressant prescribing. Meta-analyses of data from controlled trials have not found reduced rates of suicide or suicidal behaviour in drug arms compared with placebo arms.4 5 w19 w20
Conclusions
The NICE review data suggest that selective serotonin reuptake inhibitors do not have a clinically meaningful advantage over placebo, which is consistent with other recent meta-analyses. In addition, methodological artefacts may account for the small effect seen. Evidence that antidepressants are more effective in more severe conditions is not strong, and data on long term outcome of depression and suicide do not provide convincing evidence of benefit. In children, the balance of benefits to risks is now recognised as unfavourable. We suggest this may also be the case for adults, given the continuing uncertainty about the possible risk of increased suicidality as well as other known adverse effects. This conclusion implies the need for a thorough re-evaluation of current approaches to depression and further development of alternatives to drug treatment. Since antidepressants have become society's main response to distress, expectations raised by decades of their use will also need to be addressed.
References w1-w20 are on bmj.comWe thank other members of the Critical Psychiatry Network who contributed to the response to the NICE depression review and especially Duncan Double, who coordinated the response.
Contributors and sources: Both authors have conducted separate meta-analyses of antidepressant trials and reviews of antidepressant literature. JM has recently obtained an MD in antidepressant research methodology. The article draws on these sources, as well as the data contained in the NICE review. JM and IK contributed to the response to the NICE review. JM had the idea to write the paper. JM and IK drafted and revised the current manuscript. JM will act as guarantor.
Competing interests: IK has received consulting fees from Squibb and Pfizer. JM is co-chair of the Critical Psychiatry Network.
(Accepted 11 May 2005)
- National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care. Clinical practice guideline No 23. London: NICE, 2004. www.nice.org.uk/page.aspx?o=235213 (accessed 24 May 2005).
- Middleton H, Shaw I, Feder G. NICE guidelines for the management of depression. BMJ 2005;330: 267-8.
[Free Full Text] - Kirsch I. St John's wort, conventional medication and placebo: an egregious double standard. Complement Ther Med 2003;11: 193-5.[CrossRef][ISI][Medline]
- Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Arch Gen Psychiatry 2000;57: 311-24.
[Abstract/Free Full Text] - Khan A, Khan SR, Leventhal RM, Brown WA. Symptom reduction and suicide risk in patients treated with placebo antidepressant clinical trials: a replication analysis of the Food and Administration Database. Int J Neuropsychopharmacol 2001;2: 113-8.
- Kirsch I, Moore TJ, Scoboria A, Nicholls SS. The emperor's new drugs: an analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prev Treat 2002;5.www.journals.apa.org/prevention/volume5/pre0050023a.html (accessed 20 May 2005).
- Kuhn R. The treatment of depressive states with G22355 (imipramine hydrochloride). Am J Psychiatry 1958;115: 459-64.[ISI][Medline]
- Joyce PR, Paykel ES. Predictors of drug response in depression. Arch Gen Psychiatry 1989;46: 89-99.[Abstract]
- Angst J, Scheidegger P, Stabl M. Efficacy of moclobemide in different patient groups: results of new subscales of the Hamilton Rating Scale. Clin Neuropharmacol 1993;16 (suppl 2): S55-62.[ISI][Medline]
- Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002;22: 40-5.[CrossRef][ISI][Medline]
- Kirsch I, Scoboria A, Moore TJ. Antidepressants and placebos: secrets, revelations, and unanswered questions. Prev Treat 2002;5. www.journals.apa.org/prevention/volume5/pre0050033r.html (accessed 20 May 2005).
- Moncrieff J. A comparison of antidepressant trials using active and inert placebos. Int J Methods Psychiatric Res 2003;12: 117-27.[ISI]
- Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326: 1171-3.
[Abstract/Free Full Text] - Tuma TA. Outcome of hospital treated depression at 4.5 years. An elderly and a younger cohort compared. Br J Psychiatry 2000;176: 224-8.
[Abstract/Free Full Text] - Goldberg D, Privett M, Ustun B, Simon G, Linden M. The effects of detection and treatment on the outcome of major depression in primary care: a naturalistic study in 15 cities. Br J Gen Pract 1998;48: 1840-4.[ISI][Medline]
- Fombonne E. Increased rates of depression: update of epidemiological findings and analytical problems. Acta Psychiatr Scand 1994;90: 145-56.[ISI][Medline]
- Brugha TS, Bebbington P, MacCarthy B, Stuart E, Wykes T. Antidepressants may not assist recovery in practice: a naturalistic prospective survey. Acta Psychiatr Scand 1992;86: 5-11.[Medline]
- Ronalds C, Creed F, Stone K, Webb S, Tomenson B. The outcome of anxiety and depressive disorders in general practice. Br J Psychiatry 1997;171: 427-33.[Abstract]
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Current Psychiatry Vol. 4, No. 7 / July 2005
Antidepressants for bipolar depression: Tips to stay out of trouble
When it makes sense to use them and for how long. Lee S. Altman, MDAssistant professor of psychiatry, University of Colorado Health Sciences Center, Denver, CO
In clinical practice, 50% to 80% of bipolar patients receive long-term antidepressants,1 although potential benefits probably outweigh risks in 20% to 40%. This gap suggests that psychiatrists could do more to stay out of trouble when prescribing antidepressants for patients with bipolar depression.
Antidepressants have not shown efficacy in long-term treatment, and evidence of their effectiveness in acute bipolar depression is limited. They appear to pose greater risk of switching and mood destabilization for some patients and certain types of bipolar illness, and some antidepressant classes are more worrisome than others.
Because carefully analyzing risks and benefits is essential when considering antidepressants for a patient with bipolar illness, this article clarifies that delicate balance and offers evidence-based recommendations for using antidepressants in bipolar depression.
ACUTE THERAPY
Clinical trials support antidepressants as the treatment of choice for unipolar depression, but less evidence supports efficacy and safety in acute bipolar depression. Depressive episodes predominate in bipolar disorder, with chronic subsyndromal symptoms being most characteristic.2,3 Compared with mania or hypomania, depressive episodes:
last longer and are more frequent
contribute to greater morbidity and mortality
pose a greater treatment challenge.
Antidepressants have shown benefit in multiple double-blind, bipolar depression trials and were as effective as mood stabilizers in one small study.4 Even so, no trials have found them more effective than mood stabilizers in acute bipolar depression.
Controlled trials. Two randomized, double-blind, placebo-controlled trials have examined antidepressant use in bipolar depression.5,6 The larger and better designed—a prospective 10-week study by Nemeroff et al6—examined 117 outpatients with type I bipolar disorder.
Subjects who had been taking lithium (serum levels 0.5 to 1.2 mEq/L) for ≥6 weeks and were experiencing moderate breakthrough depression then received paroxetine (mean dosage 32.6 mg/d), imipramine (mean dosage 166.7 mg/d), or placebo. Therapeutic response was defined as ≤7 on the Hamilton Rating Scale for Depression (HRSD) or ≤2 on the Clinical Global Impression (CGI) scale—normally considered criteria for depressive remission.
The authors hoped to show a statistically significant medication-placebo difference, but the antidepressants’ effects were similar to those of placebo. Thus, adding antidepressants to lithium conferred no added benefit, though the small sample size may have created a false negative.
Interestingly, a post-hoc analysis found different treatment outcomes when patients were separated into two groups by lithium serum levels:
low therapeutic (≤0.8 mEq/L)
high therapeutic (>0.8 mEq/L).
Adding antidepressants significantly reduced HRSD scores compared with placebo in the low lithium group but not in the high lithium group. Thus, therapeutic lithium levels may have moderate antidepressant effects, and adding antidepressants may help patients who cannot tolerate therapeutic lithium levels.
MAINTENANCE THERAPY
Antidepressants may have modest efficacy in acute bipolar depression, but they have not shown benefit—with or without mood stabilizers—in 7 studies of bipolar depression maintenance therapy. Most were double-blind, long-term trials comparing tricyclic antidepressants (TCAs) with lithium or adding TCAs to lithium; 3 were placebo-controlled.7 Antidepressants were not more effective than mood stabilizers such as lithium or lamotrigine in preventing bipolar depression.
Type II patients. For depression in type II bipolar disorder, the only data on using antidepressants as acute or maintenance therapy come from post-hoc analyses of unipolar depression trials and retrospective assessments of “manic switches.” No specific mania rating scales have been used.8,9
Long-term antidepressants. Two naturalistic studies by Altshuler et al10,11 explored continuing antidepressants as bipolar depression maintenance treatment. The larger trial11 included 84 patients (most with type I bipolar disorder) who experienced breakthrough depression while taking a mood stabilizer. This subset (15%) of the Stanley Foundation Bipolar Network had tolerated antidepressants at least 2 months without switching into hypomania/mania and remained in remission at least 6 weeks. None were rapid cyclers.
With counseling from clinicians, patients chose to continue or discontinue taking antidepressants. Relapse rates after 1 year were 70% in patients who stopped antidepressants after <6 months, compared with 24% in those who continued taking them for 1 year. The authors concluded that bipolar patients may benefit from staying on antidepressants at least 6 months and perhaps 12 or more months after depressive remission.
Keep in mind, however, that these findings may not apply to all bipolar patients. This study pertains to a minority of robust responders—none of whom were rapid cyclers—who tolerated the medication well and were not randomly assigned to continue or discontinue antidepressants. Other evidence suggests that depressed bipolar patients are three times more likely than unipolar patients (54% vs 16%) to develop tolerance to antidepressants.12
ANTIDEPRESSANT RISKS
Risks of using antidepressants in bipolar patients include acute switches into hypo/mania, usually within 8 weeks of starting an antidepressant, and new-onset mood destabilization—with cycle acceleration or rapid cycling—or worsening of pre-existing rapid cycling (Table 1).1
Table 1
Switches vs destabilization: Defining antidepressant risks
Risk
Definition
Acute switches to hypomania/mania
≤8 weeks by convention, unless dosage is increased
Mood destabilization
Cycle acceleration
Increase of ≥2 mood episodes while taking antidepressants, compared with a similar exposure time before treatment
Rapid cycling
≥4mood episodes in previous 12 months (new-onset or exacerbation of baseline pattern), according to DSM-IV-TR
Source: Reference 1
Switching risk. Some researchers have reported antidepressant-induced switches to be milder and more brief than spontaneous hypo/manias,13 whereas others have observed more-severe mixed14 and even psychotic episodes. Risk factors that may predispose patients to switching include:
personal or family history of switches or mood destabilization
family history of bipolar disorder
exposure to multiple antidepressant trials
history of substance abuse or dependence
early onset (age <25) and/or treatment of mood symptoms.15,16
True switch rates are difficult to estimate because clinical trials have used different switching definitions, durations, antidepressants (with or without mood stabilizers, and with different mood stabilizers), and cohorts (often excluding rapid cyclers). Except for the Nemeroff et al study,6 no prospective, double-blind, placebo-controlled studies have examined switch rates, and even this study was not large enough to detect statistically significant differences.
Thus we must rely on naturalistic evidence that is less rigorous but more applicable to clinical practice. This literature reveals switch rates of:
30% to 60% with TCAs and monoamine oxidase inhibitors (MAOIs)
15% to 27% with selective serotonin reuptake inhibitors (SSRIs), bupropion, and venlafaxine.
Average switch rates are thought to be approximately 40% with TCAs/MAOIs and 20% with the newer antidepressants.1 Preliminary data associate venlafaxine with higher switch rates than SSRIs or bupropion, so perhaps antidepressants with some noradrenergic effects (including TCAs) facilitate the switching phenomenon.17
Mood destabilization. Three randomized, controlled trials suggest that antidepressants—especially TCAs—increase the risk of cycle acceleration or rapid cycling in bipolar patients. The best designed study—sponsored by the National Institute of Mental Health—was a 10-year, prospective, double-blind trial of 51 rapid-cycling patients. The trial’s on-off-on design showed that 20% of these patients developed rapid cycling as a direct result of taking TCAs.18
Unfortunately, most randomized, controlled trials are not designed to show a relationship between antidepressants and mood destabilization. Observational literature is mixed but suggests that antidepressant use is associated with rapid cycling. Most evidence supports a relationship between antidepressants and long-term mood destabilization—especially cycle acceleration, which is believed to occur in approximately 20% of patients using TCAs or SSRIs.1
Are mood stabilizers protective? Some studies suggest that mood stabilizers may help protect against switches. Most of the evidence—using lithium and TCAs—suggests a 50% drop in switch rates when patients receive mood stabilizers with antidepressants. In one study, lithium was more protective than anticonvulsants for SSRI-induced mania, but the difference was not statistically significant.19
Because study data variability, we don’t know if some mood stabilizers are more effective than others in preventing antidepressant-related switching. This variability is likely caused by:
medication-specific factors (such as higher switch rates with TCAs and possibly dual-reuptake inhibitors than with SSRIs)
illness-specific factors (such as rapid cycling and cycle pattern)
patient-specific factors, already described. Mood stabilizers appear to be more protective against switching than against mood destabilization, in which their effects are less clear (Table 2).15
Table 2
Frequency of switching or mood destabilization with antidepressants
Bipolar risk
Causative agents
Frequency
Mood stabilizer effect
Acute switch
TCAs, MAOIs
~ 40%
Variably protective; apparent partial risk reduction ~ 50%
SSRIs, bupropion, venlafaxine
~ 20%
Mood destabilization
TCAs, SSRIs
~ 20%
Not as clearly protective against mood destabilization as against acute switching
TCAs: tricyclic antidepressants; MAOIs: monoamine oxidase inhibitors; SSRIs: selective serotonin reuptake inhibitors
Source: References 1, 15
TREATMENT RECOMMENDATIONS
How does a clinician decide which bipolar depressed patients should receive antidepressants?
The first step in treating bipolar depression (Algorithm) is to provide optimal dosages of the patient’s mood stabilizers. Consensus guidelines20 suggest lithium or lamotrigine as first-line treatments for bipolar depression. Evidence also shows efficacy for atypical antipsychotics, including the olanzapine/fluoxetine combination (OFC)—FDA-approved for acute bipolar depression21—and quetiapine monotherapy.22 Dosages vary, but suggested ranges include:
lithium: 0.6 to 1.2 mEq/L; aim for approximately 0.8 mEq/L, but some data suggest 0.6 to 0.7 mEq/L may be sufficient
lamotrigine: 50 to 250 mg/d (the higher dosage is based on maintenance studies)
OFC: 6 to 12 mg olanzapine/25 to 50 mg fluoxetine
quetiapine: 300 to 600 mg/d.
The next step is an antidepressant risk/benefit analysis, weighing the considerable risks of switching/mood destabilization with the patient’s depressive illness severity, type of bipolar disorder (such as rapid cycling), and cycle pattern.
Algorithm
Recommended treatment of bipolar depression
Cycle patterns. In a naturalistic study, Macqueen et al23 used life chart data for 42 bipolar patients to assess how the mood state preceding a prospectively observed depressive episode affected treatment response:
A euthymic mood state in the previous 2 months represented a uniphasic pattern and an isolated depressive episode.
A preceding hypomanic/manic mood state indicated a biphasic pattern.
Approximately 60% of bipolar patients show a biphasic pattern, although the episode sequence is usually depression-hypomania/mania rather than hypomania/mania-depression. These authors included patients whose breakthrough depressive episodes were treated with an antidepressant or a putative mood stabilizer but not an atypical antipsychotic.
In patients treated with an antidepressant, the response-to-switch ratio was 10:1 for those previously euthymic, compared with a less beneficial 0.75:1 in previously hypomanic/manic patients. This small study suggests that a patient’s cycle pattern may help you decide whether to use an antidepressant for bipolar depression.
How to use antidepressants. As described, some depressed bipolar patients are better candidates for antidepressant therapy than others (Table 3).
Table 3
Antidepressants for bipolar depression? Consider ‘ideal patient’ traits
Severe depression refractory to optimal doses of ≥1 mood stabilizers
Uniphasic cycle pattern
Not rapid cycling
No history of switching or mood destabilization
No comorbid substance abuse
Use antidepressants cautiously and conservatively in a minority of bipolar patients (approximately 20% to 40%) and usually for short periods (discussed below). SSRIs or bupropion are first-line agents because:
they appear to be relatively less likely to cause switching than other antidepressant classes
controlled trials have examined these antidepressants in bipolar depression.
Depressed patients with very mild, nonrapid-cycling, bipolar II disorder and no more than three previous hypomanic episodes might be candidates for antidepressant monotherapy. In other bipolar patients, always use at least one mood stabilizer if you decide to use an antidepressant.
TREATMENT DURATION
No randomized, controlled trial has examined what duration of antidepressant treatment may be optimum for bipolar depression, but consensus guidelines recommend:
approximately 3 to 7 months, depending on depression severity
approximately one-half that duration (2 to 4 months) for rapid-cycling bipolar disorder.20
Because of the switching risk, one could also argue for a shorter treatment duration in patients with a biphasic cycle pattern—especially with an episode sequence of depression to hypomania/mania to euthymia.
Ideally, patients would stay on antidepressants no longer than the natural course of their depression (usually 2 to 6 months in bipolar depression), although it could be shorter in rapid cyclers. Approximately 15% to 20% of patients may have a robust initial response to antidepressants and need to be maintained on these medications, especially after several tapers and relapses have failed.
Related resources
Bipolar Clinic and Research Program. Massachusetts General Hospital. Includes tools for clinicians and the clinical site for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). www.manicdepressive.org.
Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.
Drug brand names
Bupropion • Wellbutrin Imipramine • Tofranil Lamotrigine • Lamictal Lithium • Lithobid, others Olanzapine/fluoxetine • Symbyax Paroxetine • Paxil Quetiapine • Seroquel Venlafaxine • Effexor Disclosures
Dr. Altman is a speaker for Forest Pharmaceuticals, Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.
References
Ghaemi SN, Hsu DJ, Soldani F, et al. Antidepressants in bipolar disorder: the case for caution. Bipolar Disorders 2003;5:421–33. Judd LL. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530–7. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60(3):261–9. Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry 2000;157:124–6. Cohn JB, Collins G, Ashbrook E, et al. A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 1989;4(4):313–22. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001;158(6):906–12. Ghaemi SN, Lenox MS, Baldessarini RJ. Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry 2001;62(7):565–9. Amsterdam JD, Garcia-Espana F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 1998;18:435–40. Amsterdam JD, Garcia-Espana F. Venlafaxine monotherapy in women with bipolar II and unipolar major depression. J Affect Disord 2000;59:225–9. Altshuler L, Kiriakos L, Calcagno J, et al. Impact of antidepressant discontinuation versus antidepressant continuation at 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry 2001;62:612–16. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry 2003;160:1252–62. Ghaemi SN, Rosenquist KJ, Ko JY, et al. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry 2004;161:163–5. Stoll AL, Mayer PV, Kolbrener M, et al. Antidepressant-associated mania: a controlled comparison with spontaneous mania. Am J Psychiatry 1994;151:1642–5. Zubieta JK, Demitrack MA. Possible bupropion precipitation of mania and mixed affective state. J Clin Psychopharmacol 1991;11(5):327–8. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disorders 2003;5:407–20. Goldberg JF, Whiteside JE. The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study. J Clin Psychiatry 2002;63:791–5. Post RM, Leverich GS, Nolen WA, et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disorders 2003;5:396–406. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry 1988;145:179–84. Henry C, Sorbara F, Lacoste J, et al. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry 2001;62:249–55. Keck PE Jr, Perlis RH, Otto MW, et al. The Expert Consensus Guideline Series: Treatment of bipolar disorder 2004. Postgrad Med 2004;1–120. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079–88. Calabrese JR. Quetiapine BOLDER study [presentation]. New York: American Psychiatric Association annual meeting, 2004. MacQueen GM, Young LT, Marriott M, et al. Previous mood state predicts response and switch rates in patients with bipolar depression. Acta Psychiatr Scand 2002;105:414–18.
Comparison of two-phase treatment with imipramine or fluvoxamine, both followed by lithium addition, in inpatients with major depressive disorder. Am J Psychiatry. 2004 Nov;161(11):2060-5.
Birkenhager TK, van den Broek WW, Mulder PG, Bruijn JA, Moleman P.
Department of Psychiatry, Erasmus Medical Centre, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. t.birkenhager@erasmusmc.nl
OBJECTIVE: This study was designed to compare the efficacy of two two-phase pharmacological treatment strategies for inpatients with DSM-IV major depressive disorder. METHOD: During phase I, patients participated in a double-blind study of the effects of imipramine versus fluvoxamine, with final evaluation of response 4 weeks after patients attained the target plasma level. In phase II, for patients without treatment response or with partial response in phase I, lithium was added to imipramine or fluvoxamine. Final evaluation of response was made 3 weeks after the patients attained the target plasma level of lithium (0.6-1.0 mmol/liter). RESULTS: One hundred thirty-eight patients were enrolled in the study. At the end of phase I, remission, defined as a final Hamilton Depression Rating Scale score < or =7, was achieved by 16 (23%) of 70 imipramine-treated patients and 10 (15%) of 68 fluvoxamine-treated patients. At the end of phase II, 41 (59%) of 70 imipramine-treated patients versus 27 (40%) of 68 fluvoxamine-treated patients qualified for remission, a significant difference in favor of the imipramine strategy. Only a small minority of both groups received concomitant medication. In both phase I and phase II, the discontinuation rate was low (5% and 10%, respectively). CONCLUSIONS: Imipramine with subsequent lithium addition is superior to a similar strategy with fluvoxamine for treatment of severely depressed inpatients. Both strategies were well tolerated.
Newly released top-line results from the BOLDER II (BipOLar DEpRession) study have underlined the potential for SEROQUEL (quetiapine fumarate) in the treatment of patients with major depressive episodes associated with bipolar disorder. In BOLDER II, SEROQUEL 300mg and 600mg doses achieved a statistically significant reduction in levels of bipolar depression compared with placebo (p<0.001), as measured by the change from baseline in MADRS* total score(1).
BOLDER II, an eight week, multi-centre, placebo-controlled study, reinforces the findings of the landmark BOLDER I study(2) published in American Journal of Psychiatry in July 2005, which first indicated a significant effect for SEROQUEL in treating major depressive episodes associated with bipolar disorder.
In BOLDER II, the significant reduction in MADRS total score was seen both in patients with bipolar I and bipolar II disorder, in patients with or without a rapid cycling course of illness, and as early as week one after randomisation. Significant improvements were also seen compared with placebo in the various secondary study endpoints among SEROQUEL-treated patients, including reduction of anxiety symptoms. In addition, more than half (53%) of patients receiving SEROQUEL achieved remission** from their bipolar depression symptoms. Importantly, SEROQUEL was shown to be well tolerated in BOLDER II with a similar safety profile seen to that in BOLDER I. The rate of serious adverse events was low and comparable in all treated groups. The most common adverse events reported in the trial were dry mouth, sedation, somnolence, dizziness and constipation, and there was a low incidence of treatment-emergent mania in the SEROQUEL-treated groups. As in BOLDER I, there was a low incidence of EPS (extrapyramidal symptoms) and minimal weight change reported in the study. Professor Joseph Calabrese, co-director of the National Institute of Mental Health Bipolar Research Center at University Hospitals of Cleveland and Case Western Reserve University says: "Patients with bipolar depression are underserved and understudied. The findings from the BOLDER II study are very encouraging and support the findings of BOLDER I, in showing the potential of SEROQUEL, as monotherapy, for the acute treatment for bipolar depression. Each of these two studies represent the largest placebo-controlled short-term studies ever conducted in bipolar depression. The beneficial risk:benefit profile of Seroquel seen in both studies could offer an important therapeutic value for both patients and physicians as we currently have only one FDA-approved therapy to treat depressive episodes associated with bipolar disorder." Bipolar disorder is a serious mental illness that affects approximately 3-4% of the adult population and is the sixth leading cause of disability in the world(3,4,5,6). Patients with bipolar disorder are symptomatic almost half of their lives, and approximately two-thirds of that time is spent in the depressed phase of the illness(7). Currently SEROQUEL is only approved for the treatment of mania associated with bipolar disorder. "BOLDER II shows that SEROQUEL may provide substantial clinical benefits to patients with bipolar disorder", commented Carolyn Fitzsimons, Seroquel Commercial VP. "Based on prior discussions with the FDA and the results of BOLDER II, AstraZeneca plans to file for a US licence extension for SEROQUEL in the treatment of depressive episodes associated with bipolar disorder around the end of this year (2005)." SEROQUEL has been licensed for the treatment of schizophrenia since 1997 and is available in 85 countries for the treatment of this condition. SEROQUEL is also licensed in 73 countries for the treatment of mania associated with bipolar disorder. * MADRS (Montgomery- Asberg Depression Rating Scale) measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation and restlessness. The MADRS score decreases as depression symptoms improve. ** Remission defined as a score of less than 12 on the MADRS scale (Montgomery-Asberg Depression Rating Scale) at any point in time during the study Notes to Editors All product names appear in upper case. SEROQUEL is a trademark of the AstraZeneca group of companies. SEROQUEL is currently not licensed for the treatment of bipolar depression. BOLDER II was an eight week, multi-centre, placebo-controlled trial conducted in the US which evaluated the efficacy of SEROQUEL (quetiapine) treatment at doses of 300 or 600mg in over 500 patients with bipolar disorder experiencing major depressive episodes. In BOLDER, the primary endpoint for bipolar depression was change in baseline on the MADRS (Montgomery- Asberg Depression Rating Scale). Bipolar depression and anxiety symptoms were assessed using the MADRS, HAM-D (Hamilton Rating Scale for Depression) and HAM-A (Hamilton Rating Scale for Anxiety Scale). AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of over $21.4 billion and leading positions in sales of gastrointestinal, cardiovascular, respiratory, oncology and neuroscience products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index. In Neuroscience, AstraZeneca is dedicated to providing medicines that have the potential to change patients' lives. The company already markets several products including SEROQUEL and ZOMIG. SEROQUEL, which has proven efficacy and a very favourable side effect profile, is the fastest growing of the leading atypical antipsychotics and the number one prescribed atypical in the United States with global sales of $2 billion in 2004; ZOMIG is a reliable migraine therapy and a leader within the triptan market. The Neuroscience pipeline includes leading approaches for the treatment of depression and anxiety, overactive bladder, dementia, stroke, pain control and anaesthesia. Further Information: For further information, please go to http://www.astrazenecapressoffice.com References: 1. BOLDER II study. AstraZeneca Data on File. 2. Calabrese JR et al. Am J Psychiatry 2005;162:1351-60. 3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC, American Psychiatric Association, 2000:385;395. 4. Hirschfield et al. Screening for bipolar disorder in the community J Clin Psychiatry. 2003:64;53-59 5. Lish JD, Dime-Meenan S, Whybrow PC et al. The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994:31;281-294. 6. World Health Organization and the World Bank. The Global Burden of Disease: Summary. Cambridge, Mass: The Harvard School of Public Health Harvard University Press, 1996. 7. Judd, Lll, Akiskal, HS, Schettler, PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar disorder. Arch Gen Psychiatry. 2002;59:530-537
Am J Psychiatry 162:1545-1546, August 2005
© 2005 American Psychiatric Association
Letter to the Editor
Antidepressants for Bipolar Depression
Atlanta, Ga.
Washington, D.C.
To the Editor: Meta-analysis represents an "observational study of studies." The benefits of random assignment and the removal of confounding bias within a sample are lost with meta-analysis, resulting in the problem of "heterogeneity" between study samples. Just as randomized clinical trials are more valid than observational studies, a meta-analysis of one to five randomized clinical trials is not necessarily more valid than one well-designed randomized clinical trial. This issue may be less relevant if studies agree, as it appears they did in the meta-analysis by Harm J. Gijsman, Ph.D., M.R.C.Psych., et al. (1). However, this apparent agreement hides important unexplored heterogeneity, which does not invalidate the meta-analysis but can lead to its misinterpretation.
For instance, the only placebo-controlled study that found no evidence of acute antidepressant response is the only study, to our knowledge (2), in which all patients received baseline lithium. Among other studies, one (3) nonrandomly assigned 37% of the patients in the antidepressant arm to lithium versus 21% in the placebo arm—a relative 77% increased lithium use in the antidepressant arm—hardly a fair assessment of fluoxetine versus placebo. Two compared antidepressant alone to placebo alone, and one large study (58.5% of all meta-analysis patients) (4) compared olanzapine plus fluoxetine to olanzapine alone ("placebo" improperly referred to olanzapine plus placebo). These studies may suggest acute antidepressant efficacy compared to no treatment or olanzapine alone but not compared to the most proven mood stabilizer, lithium, which is also the most relevant clinical issue.
Regarding antidepressant-induced mania, two studies comparing antidepressants without mood stabilizer to no treatment (placebo only) reported no mania in any patients: an oddity, if true, since it would suggest that even spontaneous mania did not occur while those patients were studied or that perhaps manic symptoms were not adequately assessed. As described, another study preferentially prescribed lithium more in the antidepressant group (3), providing possibly unequal protection against mania. Although the olanzapine-fluoxetine data suggest no evidence of switching while using antipsychotics, in our reanalysis of the lithium-plus-paroxetine (or imipramine) study, there was a threefold higher manic switching rate with imipramine versus placebo (risk ratio=3.14), with asymmetrically positively skewed confidence intervals (0.34–29.0). Combined with other studies reviewed that showed higher tricyclic antidepressant switching rates than other antidepressants, attention to this heterogeneity suggests that one cannot rule out antidepressant switching.
Finally, these short-term (up to 10 weeks) studies are only relevant, if at all, to the acute depressive episode. Contrary to the highly selective review in the discussion, they do not provide any evidence to support long-term maintenance use of antidepressants in bipolar disorder, which was previously shown ineffective in multiple randomized clinical trials in a systematic review (5).
In summary, our critique touches partly on the validity of this meta-analysis, but more importantly, on its generalizability due to unexplored heterogeneity. Apparent agreement among studies hides major conflicting results between the only adequately designed study using the most proven mood stabilizer, lithium, and the rest. It would appear that the rosy conclusions of the meta-analysis are premature when the clinical options involve use of proven mood stabilizers, such as lithium, with or without antidepressants.
References
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Goodwin GM:
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[Abstract/Free Full Text] - Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD: Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158:906–912[Medline]
- Cohn JB, Collins G, Ashbrook E, Wernick JF: A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 1989; 4:313–314[Medline]
- Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60:1079–1088; correction, 2004; 61:176[CrossRef]
- Ghaemi SN, Lenox MS, Baldessarini RJ: Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry 2001; 62:565–56
APA annual meeting. Toronto 23 mai 2006
A new study presented today at the 159th Annual Scientific Meeting of the American Psychiatric Association (APA) in Toronto, Canada identified five predictors for bipolar disorder risk in patients who have been unsuccessfully treated with antidepressants. Researchers concluded that significant risk factors of bipolar disorder among patients already diagnosed with major depression were anxiety, feelings of people being unfriendly, family history of bipolar disorder, a recent diagnosis of depression, and legal problems.
The study also found that forty-three percent of patients who responded positively to any three risk factors, screened positive for bipolar disorder using the Mood Disorder Questionnaire (MDQ), a validated screener for bipolar disorder. In addition, one-third of patients whose medication for their depression was not right for them and that they had been told by a doctor they had anxiety and felt people were unfriendly toward them, screened positive for bipolar disorder, using the MDQ.
Based on these findings, a brief assessment tool was derived that can be used to identify bipolar disorder risk.
"Bipolar depression may be difficult for both patients and doctors to identify because the symptoms are often confused with major depression," said Joseph R. Calabrese, M.D., Professor of Psychiatry, Case Western Reserve University and Director, Mood Disorders Program, University Hospitals of Cleveland. "Given the difficulty of diagnosing bipolar disorder, the five predictors identified in this study may help physicians better assess a patient's risk for bipolar disorder, which could lead to more effective treatment."
The study findings coincide with previous research that suggests nearly half of all patients who have bipolar disorder will first be diagnosed with major depression. Inappropriate treatment due to misdiagnosis can have a harmful effect on patients potentially making the illness harder to treat; antidepressants alone have been shown to induce mania or hypomania (a mild form of mania) in some patients with bipolar depression. Furthermore, people with untreated bipolar disorder can experience a greater frequency of manic and depressive episodes, causing significant disruption in their personal and professional lives.
"Many people with bipolar disorder face up to ten years of coping with symptoms before getting an accurate diagnosis," said Karl Ackerman, President of the Manic-Depressive and Depressive Association of Boston. "For me, it was twelve years. Looking back, I realize the anxiety I experienced along with my depression could have been another sign of bipolar disorder. These predictors can be useful for patients who are dealing with depression that isn't helped by medication."
"It's important for people who are suffering from depression to talk to their doctors about other experiences and symptoms over their lifetime -- especially times when they were feeling really well," said Gary Sachs, MD, Associate Professor of Psychiatry, Harvard Medical School and Director, Bipolar Disorder Clinic and Research Program, Massachusetts General Hospital. "Many patients with bipolar disorder go too long without a correct diagnosis. This can mean years lost to an illness that can be successfully managed when correctly diagnosed and treated. The predictors identified in this study may help physicians and patients identify depression associated with bipolar disorder rather than unipolar mood disorder."
Study Design
The study was designed to identify predictors of bipolar disorder risk among patients treated for major depression. Psychiatrists from community and private practice clinic settings randomly selected patients who were unsuccessfully treated with antidepressants. Patients self-reported demographics, family history, co-morbid health status, alcohol/drug use, legal problems, and current depression using the Centers for Epidemiologic Studies Depression (CES-D) scale. Screening for bipolar disorder was self-reported using the Mood Disorder Questionnaire (MDQ), a validated screening instrument for Bipolar I and II disorders.
Of the 602 patients enrolled in the study, 18.6% screened positive for bipolar disorder using the MDQ (MDQ+). Researchers identified five significant variables associated with bipolar disorder risk: the CESD item "people were unfriendly" (p<.001), co-morbid anxiety (p<.002), depression diagnosis within five years (p<.001), family history of bipolar disorder (p<.010), and legal problems (p<.026).
For patients with no risk factors (n=41), 2.4% screened positive for bipolar disorder using the MDQ. For patients endorsing "people were unfriendly" (n=103), 31.1% screened positive for bipolar disorder; adding co-morbid anxiety (n=82) the percent of MDQ+ patients increased to 35.4%; adding recent depression onset (n=17) increased MDQ+ rate to 41.2%; adding family history (n=4) increased MDQ+ rate to 75%; one hundred percent of patients endorsing all five factors (n=3) were MDQ+. Forty-three percent of patients who responded positively to any three risk factors, screened positive for bipolar disorder using the MDQ.
Researchers concluded that over one-third of patients who potentially experienced projection or rejection sensitivity determined by the endorsement of the CES-D item "people were unfriendly" as well as co-morbid anxiety were at risk for bipolar disorder. These two clinical features and recent depression onset, bipolar disorder family history and legal problems may prove useful indicators of bipolar disorder risk among patients with major depression who have been unsuccessfully treated with antidepressants.
STAR*D: The Results Begin to Roll in
As clinicians, we all recognize that many of the depressed patients we see do not adequately respond to our first treatment. What to do next for these individuals remains unclear, as there are few data from well-controlled replicated trials to guide us. In the absence of clear guidance from empirical research, we use what evidence is available, as well as case reports, our own clinical experience, and recommendations from experts.
This lack of evidence-based guidance was the primary motivation behind the development of The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This large study, funded at considerable cost by the National Institute of Mental Health and years in the making, has begun to yield results. Available clinical trials, many sponsored by the pharmaceutical industry and conducted in research centers (academic or private), generally focus on uncomplicated, nonchronic major depression; in this respect, they often do not reflect the clinical "real world." STAR*D was designed to be relevant to clinicians by including patients more typical of outpatient practice. The patients are drawn from psychiatric and primary care "real world" settings, and the exclusion criteria are much less restrictive than usual. Patients with chronic depression and other psychiatric and medical comorbidities are included, and outcomes focus on remission (a Hamilton Depression Rating Scale score of 7 or less) rather than just a decrease in symptom severity.
In this issue of the Journal, Fava and colleagues detail the Level 3 results of STAR*D. Their article follows an article published in the January issue of the Journal on the Level 1 results (1), and two articles published in the New England Journal of Medicine in March detailing the Level 2 results (2, 3). We can now begin to put STAR*D into context and examine what clinical guidance these results provide.
First, a brief overview of the study is worthwhile. In Level 1, over 4,000 patients with nonpsychotic major depression were entered into the study and given citalopram at doses of up to 60 mg. The primary outcome was remission, a relatively asymptomatic threshold. This first level approximates typical clinical practice in that the initial intervention was a selective serotonin reuptake inhibitor (SSRI). Level 2 included those patients who did not remit or could not tolerate citalopram. They were offered the option of switching to another treatment, or augmentation of the citalopram that they were taking. The switching options were sustained-release bupropion, sertraline or venlafaxine extended-release, and the augmentation options were bupropion sustained-release, buspirone, or cognitive behavior therapy (the cognitive behavior therapy results have not yet been published). Again, this level approximates clinical practice in that patients were able to express a preference for switching or for continuing citalopram and adding an augmenter. Level 3 included patients who did not achieve remission or could not tolerate the treatment that they received at Level 2. These patients were randomly assigned to mirtazapine or nortriptyline. This is the study conducted by Fava and colleagues, presented in this issue of the Journal. It is worthwhile to read each study in the order of publication, as there are many details not covered in this editorial that may affect how one interprets the importance of the data.
So what were the results, and what have we learned that we did not already know? The overall remission rate in Level 1 (all patients taking open-label citalopram) was 27.5%. No surprise here, as clinical trials with antidepressants typically report remission rates of 30% or less (4).
At Level 2, remission rates did not differ significantly among the three antidepressant switch strategies: 21.3% with bupropion sustained-release, 18.1% with sertraline, and 24.4% with venlafaxine extended-release. Level 2 remission rates were also similar across drug augmentation strategies: 29.7% achieved remission with citalopram plus bupropion sustained-release, and 30.2% achieved remission with citalopram plus buspirone, but buspirone was not tolerated as well as bupropion. Here, we do have some surprises and, perhaps, new clinical guidance.
In clinical practice today, it is popular to target our second-tier approaches at specific neurotransmitters (5). That is, if an SSRI does not help, try a drug that targets dopamine, norepinephrine, or some combination of serotonin, norepinephrine, and dopamine. Furthermore, there is some suggestive evidence that the dual uptake inhibitors (those antidepressants that inhibit norepinephrine and serotonin) are associated with somewhat higher remission rates (6). However, STAR*D suggests that our clinical practice of switching to another class of antidepressant may not be any more effective than switching to another SSRI. While this may be counterintuitive, and we would like to see replication of the finding, it does give some pause to our current thinking.
STAR*D may also suggest that augmentation is somewhat better than switching. The study was not designed to compare these two approaches directly, but it does appear that, in general, we may be better off augmenting than switching. These results are consistent with our current practice and expert guidelines. If someone has partially responded to an antidepressant, augmentation makes sense. Likewise, if there has been no response or if a patient has not tolerated the initial antidepressant, then switching makes more sense. Last, it appears that buspirone, as an augmentation strategy, was not tolerated as well as bupropion. Augmenting with buspirone is an approach that, in practice, is not as widely used as other strategies.
In Level 3, 114 patients were randomly assigned to mirtazapine (up to 60 mg/day) and 121 to nortriptyline (up to 200 mg/d) for up to 14 weeks of treatment. Remission rates did not differ between the treatment options: 12.3% with mirtazapine and 19.8% with nortriptyline. In addition, the treatments did not differ in tolerability. In truth, there was a numerical difference in remission rates between these two approaches, but with relatively few patients during this phase, the two arms of the study did not differ significantly. We are left wondering whether the difference was mere chance or if we really should be using tricyclic antidepressants, such as nortriptyline, more than we currently do.
It must be said that STAR*D is a laudable endeavor. The study is the largest randomized clinical trial in depression ever done, and it was very well done. The enrollment was efficient and included a large number of minorities, which is a rarity in clinical trials. The data from this study will continue to be published and, beyond this first wave, we will continue to see results that may affect our practice. Some will question whether or not the cost was worth what we have learned. Since we cannot know what would have come from this money spent elsewhere, there is no answer to this question. We are, however, left wanting guidance that this trial alone cannot give us.
Clinical trials tell us how groups of patients do on average. For an individual patient, a particular treatment may or may not work. These trials do not tell us which patient will respond to which treatment; they merely suggest what treatment is most likely to be helpful. Of course, we all want to know what treatment is right for a particular patient. For example, choosing an antibiotic for an individual patient requires knowledge of the causative organism and its sensitivity to various antibiotics, but we are not yet at a point in our understanding of depression where our technologies allow for such a detailed examination. We do not understand the pathophysiology and heterogeneity of the biology of depression sufficiently. The limits of our science also apply to our intervention research.
An issue that bedevils the design of such a large, long-term study is that treatments change, so establishing an evidence base for popular treatments is chasing a moving target. For example, there is considerable interest today in other approaches not tested in STAR*D, such as atypical antipsychotics (7), mood stabilizers (8), stimulants (5), and targeting specific residual symptoms (9). Each of these strategies is supported in clinical trials, case reports, and expert opinion. Unfortunately, it was not possible to test these approaches in STAR*D, and we are left wondering where these strategies belong in our clinical approach to depression.
STAR*D is valuable because it examines, in a systematic way, response and remission in a sequential approach for those patients who do not remit with standard treatment. Furthermore, it is valuable because it avoids some of the limitations in generalizability and external validity of most previous studies. It has also added some novel findings to the literature from which we derive our clinical guidance, but in the end, this first wave of data from STAR*D will not greatly affect the prescribing practices of most clinicians. The study has confirmed much of what we suspected, based on industry and federally sponsored clinical trials, case reports, and expert opinion. STAR*D does not answer all of our questions, but progress in science is incremental, and STAR*D has added incrementally to the evidence base for the use of antidepressants. However, while it is asking too much of any study, we are left wanting more—more attention to other current options, more certainty, and, in the end, more guidance.
Address correspondence and reprint requests to Dr. Menza, Robert Wood Johnson Medical School, Department of Psychiatry, University of Medicine and Dentistry of New Jersey, 671 Hoes Lane, D207A, Piscataway, NJ 08854; menza{at}umdnj.edu (e-mail). Dr. Menza has received research support from the National Institute of Neurological Disorders and Stroke, Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, Eli Lilly, Sanofi-Aventis, Sepracor, and Takeda. He has served as a consultant for NIMH, the National Institute of Neurological Disorders and Stroke, Forest Laboratories, Eli Lilly, Sanofi-Aventis, Sepracor, and Takeda. He has been a speaker for Eli Lilly, Sanofi-Aventis, Sepracor, and Takeda. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.
REFERENCES
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Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G,
Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM,
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STAR*D: What Have We Learned?
A. John Rush, M.D.
STAR*D represents a 7-year effort by literally hundreds of people and thousands of patients. Future reports will
- compare longer-termoutcomes of the various randomized treatments (e.g., does cognitivetherapy prevent relapse better than medication as either a switchor augmentation strategy?);
- identify which patients benefitfrom which treatments (e.g., do different patients [definedby different clinical features or genetic polymorphisms] responddifferently to different treatments?); and
- determine whetherdifferent treatment sequences (in steps 1 to 4) are preferredfor some but not other patients (1). At this point, however,we can ask, "What have we learned so far?"
This highly representative clinical sample of depressed outpatients has revealed that major depression is often chronic, severe, and associated with substantial general medical and psychiatric comorbidity. Two-thirds of patients had at least one concurrent general medical condition; two-thirds had at least one other psychiatric disorder; nearly 40% had their first depressive episode before age 18; over half reported a mood disorder in at least one first-degree relative; and over half met criteria for anxious features (2, 3). In addition, patients in primary care and psychiatric settings with major depression did not differ clinically except for slightly higher rates of general medical conditions in primary care settings, and slightly higher rates of prior suicide attempts in psychiatric settings (4).
In terms of treatment tactics, STAR*D developed and implemented easily applied methods to enhance the quality of care in both daily practice and in clinical trials in representative groups of patients. This so-called "measurement-based care" entailed the routine use of simple paper-and-pencil symptom and side effect measures at each treatment visit, along with guidance based on these measures to recommend timely dose or treatment changes. A likely consequence of this high-quality, consistent care was that outcomes in primary care and psychiatric settings were not different (5).
Longer times than expected were needed to reach response or
remission. In fact, one-third of those who ultimately
responded did so after 6 weeks (and half of
those who ultimately remitted did so after 6
weeks) (5).
These results suggest that stopping a
vigorously dosed treatment for patients who report little benefit
by 6 weeks is ill-advised. Itemized symptom measures (as
opposed to a global judgment) might well detect a benefit (e.g.,
25%–45% reduction in baseline symptom severity) that
many patients may not report if asked for their global impression.
If a modest improvement (e.g., 
20% reduction) is present,
a dose increase (if tolerated) at 6 weeks or simply further
exposure (up to 10 weeks) may help a sizable number of
patients to at least respond, if not achieve remission, by 12
weeks.
As for treatment strategies, we found that patients had clear preferences about their acceptance of augmentation versus switching at both the second and third levels in STAR*D (6). Those who fared better in the prior step and who evidenced minimal intolerance preferred augmentation, while those with little benefit or substantial intolerance with the prior treatment preferred to switch. Whether augmentation is best even if the initial treatment is minimally effective could not be evaluated in the STAR*D design.
As for specific medications at the second step, results suggest that either a within-class switch (e.g., citalopram to sertraline) or an out-of-class switch (e.g., citalopram to bupropion-SR) is effective, as was a switch to a dual-action agent (e.g., venlafaxine-XR). While bupropion-SR and buspirone were not different as augmentation options in the second-step treatment according to 17-item Hamilton Rating Scale for Depression scores, secondary measures (e.g., tolerability, symptom change from baseline to exit in the 16-item, clinician-rated Quick Inventory of Depressive Symptomatology) recommended bupropion-SR over buspirone. Thus, substantial pharmacologic differences between the second-step medications did not translate into substantial clinical differences in efficacy.
The cognitive therapy findings at the second step were both encouraging and disappointing. There was no difference between cognitive therapy as a switch or as augmentation strategy versus medication as a switch or augmentation strategy (7). Yet cognitive therapy may well be treating a group that is not particularly medication responsive (8). However, far fewer patients than expected elected randomization that included cognitive therapy—perhaps because of the need for additional copayments, the fact that some patients were already seeing a therapist, or the need to visit yet another provider at another site. Thus, future work to enhance the delivery and convenience of obtaining cognitive therapy is needed. Much as 7-Eleven has found, convenience sells. Inconvenience is an obstacle.
In the third medication step (Level 3), a medication switch was far less effective than was a medication switch at the second step according to scores on the 16-item, self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR16). In addition, a change in presumed mechanism of action at the third medication switch step (mirtazapine versus a third reuptake blocker, nortriptyline) did not produce different outcomes.
At the third medication augmentation step (Level 3), T3 augmentation did as well or better than lithium, suggesting that T3 deserves stronger consideration than many expected and confirming the value of T3 (9) in less resistant patients. Higher doses of lithium might have been more effective, but even at the doses used, tolerability was an issue.
Finally, in the fourth medication step (Level 4), we expected a better result than we obtained with tranylcypromine—perhaps because the Level 3 medication had to be discontinued for a washout period before tranylcypromine could be started or because lower than desired tranylcypromine doses were used (although tolerability was an issue with tranylcypromine). In these rather treatment-resistant Level 4 patients, results also provided the first evidence of tolerability and at least modest efficacy with the combination of venlafaxine-XR plus mirtazapine.
Finally, subject attrition was substantial, despite the extra staffing provided by the Clinical Research Coordinators, patient education, and the availability of cost-free treatment. Most patients who left the study were not in remission. Methods to enhance retention and to achieve earlier remission in more patients are clearly needed.
Our initial follow-up findings (10) revealed: 1) remission at entry into the follow-up phase was consistently associated with a better prognosis than was simple improvement at entry into the follow-up phase after the first, second, and third treatment steps; 2) patients and clinicians are less willing to push for remission in patients with greater levels of resistance, since more patients at follow-up entry were not in remission after more prior unsuccessful acute treatment trials; and 3) regardless of remission status at follow-up entry, higher relapse rates were found among those who required more acute treatment trials (i.e., for those with greater levels of resistance).
These findings validate the importance of remission (not simply response) as a clinically meaningful endpoint, given the lower relapse rates for those who were in remission at entry into the follow-up phase than among those who had not achieved remission (10). These results also indicate that patients with treatment-resistant depression deserve very diligent follow-up care. These follow-up results also highlight the need to focus future trials on longer-term outcomes to examine the durability of earlier improvement and to identify the best treatments for patients who relapse over time.
The decreasing likelihood of remission with later treatment steps (14% and 13% after steps 3 and 4 versus 37% and 31% after steps 1 and 2, respectively) (10) has policy implications. Logically, primary care providers are well positioned—if given the time, staff support, and reimbursement support to deliver high-quality, measurement-based care—to conduct the first two treatment steps. Thereafter, more complex drug regimens are likely needed; the gains are likely to be lower; and the evidence base is truly sparse. Perhaps these steps are best left to specialists.
STAR*D results also raise important research design and treatment issues. Why not include more broadly representative patients in placebo-controlled efficacy trials that are used to develop treatments? Presently, symptomatic volunteers who are not fully representative of actual patients commonly populate these early efficacy trials. Unlike self-declared patients seen in practice settings, these subjects often have minimal medical or psychiatric comorbid conditions, nor are they chronically ill. Thus, efficacy trial findings may not generalize to actual practice. If we could protect patient safety and ensure internal validity in such efficacy trials, results would be more directly applicable to our patients, who are less likely to improve spontaneously than symptomatic volunteers. Such patients would reduce placebo response rates and thereby reduce the likelihood of failed trials.
From a treatment perspective, STAR*D results raise the question of whether combination (two antidepressants) or augmentation (one antidepressant and another agent to augment its effect) might be more effective (achieve remission faster in more patients) than several sequenced monotherapy steps. STAR*D found very reasonable safety and tolerability for several combination/augmentation options, but it did not compare such options (which are commonly used in practice) with monotherapies at different steps, except at Level 4. On the other hand, a large proportion of patients chose randomization to combinations/augmentations. Since remission must be the goal of treatment—a notion clearly supported by the STAR*D follow-up results—different combinations/augmentations at the first or second steps might well increase remission rates in more patients, either because different drugs target different patients or because the combination/augmentation is simply a pharmacologically more powerful and broader spectrum antidepressant.
The gap between what we do in practice and what we know is very large. We insist that remission is our goal, yet we do not routinely carefully measure symptoms in practice to determine if remission occurs. Yet we know that "better but not remitted" consistently leads to a worse prognosis than full remission. We often underdose or poorly titrate medication. Finally, we often combine treatments in practice, yet very few trials have assessed either safety or efficacy of these efforts. Analogous to treating hypertension, diabetes, or many other medical conditions, our patients deserve every chance to reach remission. "Less hypertensive" is not the goal of treatment of hypertension. Nor should "less depressed" be the goal for our depressed patients.
Finally, on a personal note, large efforts like STAR*D are the ultimate exercise in "delayed gratification." But at the end of the day, the journey—the process of working with outstanding investigators and committed staff and patients—is its own unique reward. No single trial can answer more than a few specific questions, but such efforts can develop new clinical or research methods and raise important questions for further study. I and all of my colleagues are extremely grateful for the chance to contribute a small bit in a large and challenging area. Most important, we wish to thank all of our patient participants and the clinical staffs for their commitment to making STAR*D a reality.
Address correspondence and reprint requests to Dr. Rush, Department
of Psychiatry, University of Texas Southwestern Medical
Center at Dallas, 5323 Harry Hines Blvd.,
Dallas, TX 75390-9086; john.rush@utsouthwestern.edu
(e-mail).
Dr. Rush has served as an advisor, consultant, or speaker for or received research support from Advanced Neuromodulation Systems, Inc.; Best Practice Project Management, Inc.; Bristol-Myers Squibb Company; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals, Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems, Inc.; Jazz Pharmaceuticals; Merck & Co., Inc.; the National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Personality Disorder Research Corp.; Pfizer Inc.; the Robert Wood Johnson Foundation; the Stanley Medical Research Institute; the Urban Institute; and Wyeth-Ayerst Laboratories Inc. He has equity holdings in Pfizer Inc and receives royalty/patent income from Guilford Publications and Healthcare Technology Systems, Inc. Dr. Freedman reviewed this editorial and found no evidence of influence from these relationships.
- Murphy SA, Oslin DW, Rush AJ, Zhu J: Methodological challenges in constructing effective treatment sequences for chronic psychiatric disorders. Neuropsychopharmacology 2006; advance online publication, 8. Nov 2006; doi:10.1038/sj.npp.1301241
- Fava M, Alpert JE, Carmin CN, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K, Morgan D, Schwartz T, Balasubramani GK, Rush AJ: Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D. Psychol Med 2004; 34:1299–1308[CrossRef][Medline]
- Fava M, Rush AJ, Alpert JE, Carmin CN, Balasubramani GK, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K: What clinical and symptom features and comorbid disorders characterize outpatients with anxious major depressive disorder: a replication and extension. Can J Psychiatry 2006; 51:823–835[Medline]
- Gaynes BN, Rush AJ, Trivedi M, Wisniewski SR, Balasubramani GK, Spencer DC, Petersen T, Klinkman M, Warden D, Schneider RK, Castro DB, Golden RN: A direct comparison of presenting characteristics of depressed outpatients from primary vs. specialty care settings: preliminary findings from the STAR*D clinical trial. Gen Hosp Psychiatry 2005; 27:87–96[CrossRef][Medline]
- Trivedi MH,
Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G,
Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM,
Balasubramani GK, Fava M: Evaluation of outcomes with citalopram for
depression using measurement-based care in STAR*D: implications for
clinical practice. Am J Psychiatry 2006; 163:28–40
[Abstract/Free Full Text - Wisniewski SR, Fava M, Trivedi MH, Thase ME, Warden D, Niederehe G, Friedman ES, Biggs MM, Sackeim HA, Shores-Wilson K, McGrath PJ, Lavori PW, Rush AJ: Which second step treatments are acceptable to depressed outpatients and their clinicians? A STAR*D report. Am J Psychiatry (in press)
- Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther JF, Fava M, Nierenberg AA, McGrath P, Warden D, Niederehe G, Rush AJ: Cognitive therapy as a second-step treatment: a STAR*D report. Am J Psychiatry (in press)
- Schatzberg AF,
Rush AJ, Arnow BA, Banks PL, Blalock JA, Borian FE, Howland R, Klein
DN, Kocsis JH, Kornstein SG, Manber R, Markowitz JC, Miller I, Ninan
PT, Rothbaum BO, Thase ME, Trivedi MH, Keller MB: Chronic depression:
medication (nefazodone) or psychotherapy (CBASP) is effective when the
other is not. Arch Gen Psychiatry 2005; 62:513–520
[Abstract/Free Full Text] - Joffe RT, Singer W, Levitt AJ, MacDonald C: A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry 1993; 50:387–393[Abstract]
- Rush AJ,
Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D,
Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum
JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term
outcomes in depressed outpatients requiring one or several treatment
steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–1917
[Abstract/Free Full Text]
