Bipolar II Disorder: The Concept of Dysphoric Hypomania

Dr. Suppes
Originally webcast Tuesday, April 15, 2003

Traitement de la dépression bipolaire. (traduction)

•    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

• 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.

Hantouche EG, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM, Bourgeois M, Fraud JP, Chatenet-Duchene L.
Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP).
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]

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

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.

Antidepressants 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 contact as evidence of potential collusion. Yet we know that clinical research would be a long time coming if it depended only on scarce "blue chip" funding such as the Medical Research Council or Wellcome.
All the major players can be seen as compromised. The drug companies are massive organisations that need reform (see BMJ 2004;329: 862[Free Full Text]) yet are struggling to innovate. Most new compounds are variations on a theme; and, paradoxically, most research occurs within the public sector.
Elsewhere, the academic research community needs money to survive. Universities encourage entrepreneurship, and research income is a major determinant of esteem. Commerce is not confined to psychopharmacology; some genetics presentations are based on data that cannot be shown because of patent issues. It is not inconceivable that the pursuit of truth might eventually be constrained by the bottom line and science "deprived of its epistemological character" (R Horton, "The dawn of McScience," New York Review of Books, 2004 March 11: 7-9). And prescribers are no better. Social psychological research has repeatedly shown that doctors misjudge the influence exerted on them by big pharma's gifts and representatives. We are all fallible.
The regulators work closely with industry; governments encourage this and often the same people rotate between sectors (poacher or gamekeeper by turns). Even patients' groups may be financed by industry.
Medawar and Hardon also emphasise what will be familiar to those who attend journal clubs: that published research is often of poor quality, and data may be deployed creatively. As Richard Horton, the editor of the Lancet, says in the New York Review of Books article, "Journals have devolved into information-laundering operations for the pharmaceutical industry."
This is a depressing book, offering few solutions. The last pages invoke Ivan Illich and his thesis that medicine is bad for society, fostering dependence on doctors and technology and robbing us of our autonomy—our belief in ourselves as basically healthy, capable human beings. My own view, for what it is worth, is that where national governments fund health care they have a legitimate interest in properly funding research into treatment. Until they do we will rely on committees sifting inadequate studies and meta-analyses of secondhand data.

---

Sean A Spence, reader in psychiatry

Des hauts et des bas qui perturbent votre vie. Michel ROCHET. Chiron 2002.
p62 "J'ai connu 3 psychiatres .. qui m'ont prescrit des antidépresseurs durant 4 ans. Durant ces années, j'ai fait le Yo-Yo et j'ai ainsi tout perdu : famille, travail, atgent, amis pour me retrouver seul avec le RMI" (témoignage)
p43 " vous prenez un antidépresseur, vous risquez de faire des phases très hautes : vous ne serez donc pas stabilisé, même avec le lithium et ferez le Yo-Yo".

Traité de psychiatrie. Kaspernik, Loo, Zarifian. 1982
p150 Sous l'influence des thérapeutiques symptomatiques actuelles, la guérison clinique est obtenue en quelques semaines, mais les rechutes fréquentes et précoces lors de l'arrêt ou de la diminution des traitements symptomatiques donnent à penser qu'il s'agit plus d'une suspension de la sémiologie que d'un véritable traitement; il parait donc nécessaire de maintenir ces thérapeutiques assez longtemps après la guérison clinique et d'en réduire la posologie progressivement et prudemment sous couvert d'une surveillance clinique attentive"


The dark side of bipolarity: detecting bipolar depression in its pleomorphic expressions.
Akiskal HS J Affect Disord. 2005 Feb;84(2-3):107-15.

The depressive expressions of bipolar disorders have long been neglected. Current data, from both clinical and epidemiologic studies, indicate that such expressions far exceed the manic forms in both cross-section and during follow-up course. Thus, mania occurs in 1% of the population at large; bipolar depression afflicts at least 5 times more people. Much of the new literature on this subject has emphasized its high prevalence, morbidity, and mortality. There has been relatively less attention paid to the phenomenology of bipolar depression as it presents clinically. This special issue (volume 84/2-3, 2005) is devoted to a systematic data-based in-depth examination of the different clinical expressions of bipolar depression including, among others, retarded depression, agitated and/or activated depression, mood-labile depression, irritable-hostile depression, atypical depression, anxious depression, depressive mixed state, and resistant depression. Both bipolar I (BP-I), and the more prevalent yet relatively understudied bipolar II (BP-II), are covered. We trust that this extensive coverage of the "darker" side of bipolarity will set the stage for a much needed renaissance in its complex phenotypic expressions-and its delimitation from unipolar depression (UP). The phenomenology of BP-I depression ranges from depressive stupor to agitated psychosis, whereas UP depression expresses itself in psychic anxiety, and insomnia, as well as retardation. BP-II compared with UP is more likely to have atypical features, mood lability, hostility, activation, biographical instability, multiple anxiety comorbidities, suicidal tendencies, and to be rated as less "objectively" depressed. These findings are complex and do not fully agree with the conventional characterization of BP as retarded and UP as anxious and agitated. The inconsistency between the conventional and the phenomenology described herein is largely due to depressive mixed states, which tend to destabilize BP-II, and may account for the "contradictory" relationships of affect, sleep, drive, and psychomotor activity in mood disorders. [Abstract]


Depressive mixed state: a feature of the natural course of bipolar II (and major depressive) disorder?
Benazzi F  Psychopathology. 2004 Sep-Oct;37(5):207-12.

BACKGROUND: Depressive mixed state (DMX), i.e., a combination of hypomanic and depressive symptoms during the same episode, has recently seen a rebirth of studies after Kraepelin's description. Kraepelin observed, in an inpatient sample, that DMX was related to the number of episodes and to duration of manic-depressive insanity (illness). STUDY AIM: The aim was to test Kraepelin's observations in a very different sample. METHODS: 563 consecutive outpatients with major depressive episode (MDE)--320 with bipolar II disorder and 243 with major depressive disorder--were interviewed, in a private practice, by the Structured Clinical Interview for DSM-IV as modified by Benazzi and Akiskal (2003). Hypomanic symptoms during MDE were systematically assessed in patients while off psychoactive drugs. DMX was dimensionally defined, following Akiskal and Benazzi (2003), as an MDE plus 3 or more combined hypomanic symptoms. Kraepelin's examples of DMX, i.e., agitated depression (MDE plus psychomotor agitation) and depression with flight of ideas (MDE plus racing thoughts) were also tested. Univariate and multivariate logistic regression was used to study associations. RESULTS: DMX was present in 49.5% of the patients. Multiple logistic regression of DMX versus MDE recurrences and duration of illness, controlled for age, found a strong and significant association only between DMX and duration of illness. The same association was found between agitated depression and duration of illness (but not in depression with racing thoughts). Limitation: There was only a single interviewer. DISCUSSION: The findings support Kraepelin's observation of a link between DMX and durations of illness, but not that between DMX and recurrences. Onset of DMX could be more related to the natural course of manic-depressive illness than to a kindling process. [Abstract]


Is depressive mixed state a transition between depression and hypomania?
Benazzi F  Eur Arch Psychiatry Clin Neurosci. 2004 Apr;254(2):69-75.

BACKGROUND: Depressive mixed states (DMX), described systematically by Kraepelin, have recently been found common among depressed outpatients, with possible important impact on treatment. Study aim was to find if DMX in bipolar II disorder was often a transition period between depression and hypomania, as suggested by Kraepelin. METHODS: 194 consecutive bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Hypomanic symptoms during the index MDE were systematically assessed. DMX was defined as a MDE plus > 2 hypomanic symptoms appearing during the MDE (not before it), following Akiskal and Benazzi (2003). History of depression-hypomania cycles and vice versa (without symptom-free intervals) was assessed. If DMX were a transition period, cycles should have been more common in bipolar II with DMX than in bipolar II without DMX. To test if there were differences between DMX with history of cycles and DMX without history of cycles, the two subgroups were compared on many clinical, family history, and temperamental variables. To test if there were differences between bipolar II with DMX and bipolar II without DMX, comparisons between the two subgroups were done on variables often reported to be typically found in bipolar disorders and to be diagnostic validators (young onset, many recurrences, atypical features of depression, bipolar family history, temperamental mood lability, gender). RESULTS: DMX was present in 70.1%, and history of cycles in 79.8%. In bipolar II without index DMX (n = 58) history of cycles was present in 86.2%; in bipolar with index DMX (n = 136) history of cycles was present in 77.2% (p = 0.175). DMX with cycles was not significantly different from DMX without cycles on all study variables (apart from agitation). Bipolar II with index DMX, versus bipolar II MDE without index DMX, had significantly more depressions with atypical features, temperamental mood lability, and more females, while age of onset, recurrences, and bipolar family history were not significantly different. LIMITATIONS: Single interviewer, cross-sectional assessment. CONCLUSIONS: Findings do not support Kraepelin's view of DMX as a transition period between depression and hypomania, and a distinction between DMX with and without cycles. Findings only partly support DMX as a distinct subtype of bipolar II, which seems to require temperamental mood lability for its onset during a bipolar II MDE. [Abstract]


Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression).
Benazzi F, Koukopoulos A, Akiskal HS   Eur Psychiatry. 2004 Apr;19(2):85-90.

PURPOSE: As psychotic agitated depression is now a well-described form of mixed state during the course of bipolar I disorder, we sought to investigate the diagnostic validity of a new definition for agitated (mixed) depression in bipolar II (BP-II) and major depressive disorder (MDD). MATERIALS AND METHODS: Three hundred and thirty six consecutive outpatients presenting with major depressive episodes (MDE) but without history of mania were evaluated with the Structured Clinical Interview for DSM-IV when presenting for the treatment of MDE. On the basis of history of hypomania they were assigned to BP-II (n = 206) vs. MDD (n = 130). All patients were also examined for hypomania during the current MDE. Mixed depression was operationally defined by the coexistence of a MDE and at least two of the following excitatory signs and symptoms as described by Koukopoulos and Koukopoulos (Koukopoulos A, Koukopoulos A. Agitated depression as a mixed state and the problem of melancholia. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:547-64): inner psychic tension (irritability), psychomotor agitation, and racing/crowded thoughts. The validity of mixed depression was investigated by documenting its association with BP-II disorder and with external variables distinguishing it from unipolar MDD (i.e., younger age at onset, greater recurrence, and family history of bipolar disorders). We analyzed the data with multivariate regression (STATA 7). RESULTS: MDE plus psychic tension (irritability) and agitation accounted for 15.4%, and MDE plus agitation and crowded thoughts for 15.1%. The highest rate of mixed depression (38.6%) was achieved with a definition combining MDE with psychic tension (irritability) and crowded thoughts: 23.0% of these belonged to MDD and 76.9% to BP-II. Moreover, any of these permutations of signs and symptoms defining mixed depression was significantly and strongly associated with external validators for bipolarity. The mixed irritable-agitated syndrome depression with racing-crowded thoughts was further characterized by distractibility (74-82%) and increased talkativeness (25-42%); of expansive behaviors from the criteria B list for hypomania, only risk taking occurred with some frequency (15-17%). CONCLUSIONS: These findings support the inclusion of outpatient-agitated depressions within the bipolar spectrum. Agitated depression is validated herein as a dysphorically excited form of melancholia, which should tip clinicians to think of such a patient belonging to or arising from a bipolar substrate. Our data support the Kraepelinian position on this matter, but regrettably this is contrary to current ICD-10 and DSM-IV conventions. Cross-sectional symptomatologic hints to bipolarity in this mixed/agitated depressive syndrome are virtually absent in that such patients do not appear to display the typical euphoric/expansive characteristics of hypomania-even though history of such behavior may be elicited by skillful interviewing for BP-II. We submit that the application of this diagnostic entity in outpatient practice would be of considerable clinical value, given the frequency with which these patients are encountered in such practice and the extent to which their misdiagnosis as unipolar MDD could lead to antidepressant monotherapy, thereby aggravating it in the absence of more appropriate treatment with mood stabilizers and/or atypical antipsychotics. [Abstract]


Validating Kraepelin's two types of depressive mixed states: "depression with flight of ideas" and "excited depression".
Akiskal HS, Benazzi F   World J Biol Psychiatry. 2004 Apr;5(2):107-13.

Despite a venerable classic tradition going back to at least Kraepelin, depressive mixed states (DMX) are not represented in official diagnostic manuals in psychiatry. We have operationalised this condition as a major depressive episode (MDE) with three or more intra-episode hypomanic signs and symptoms (DMX3). Of 320 consecutive bipolar II outpatients, presenting for MDE treatment and interviewed using the Structured Clinical Interview for DSM-IV, modified to permit the systematic evaluation of hypomanic features during the index MDE, 200 met our criteria for DMX3 (62.5%). When compared with the remaining non-DMX bipolar II, they had significantly earlier age at onset, higher percentage of females, atypical features and bipolar family history. Multivariate logistic regression ofintra-MDE hypomanic signs and symptoms found evidence supporting an "excited depression" subtype (defined by the core feature of psychomotor agitation, and further characterised by talkativeness, irritable mood and distractability) and a "depression with flight of ideas" subtype (defined by the core feature of racing/crowded thoughts, and further characterised by risky pleasurable impulses including, among others, those with intense sexual arousal). We thereby documented the existence of two distinct DMX subtypes which testify to the clinical acumen of Kraepelin (and his pupil Weygandt) who in 1899 described these two subforms of depressive mixed states in more severely ill hospitalised patients. [Abstract]


Presence of irritability during depressive episodes in bipolar disorder.
Deckersbach T, Perlis RH, Frankle WG, Gray SM, Grandin L, Dougherty DD, Nierenberg AA, Sachs GS  CNS Spectr. 2004 Mar;9(3):227-31.

BACKGROUND: This study examined the prevalence of irritability in patients with bipolar I disorder during an episode of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) major depression who do not meet criteria for a mixed episode. METHOD: A chart review of 111 patients with bipolar I disorder treated at the Massachusetts General Hospital Bipolar Clinic between 1998 and 2000 identified 34 patients who met criteria for a DSM-IV major depressive episode in the absence of (1) mood elevation and/or (2) irritability associated with any additional above threshold DSM-IV symptoms of mania. Data gathered from the charts utilized prospective ratings made routinely at each clinic visit using the Clinical Monitoring Form (CMF), a structured assessment instrument which includes modified versions of the mood modules of the Structured Clinical Interview for DSM-IV. Data from these 34 patients were reviewed to determine the presence of irritability. RESULTS: The frequency of abnormal irritability in these 34 patients followed a bimodal distribution: 26% of the patients showed abnormal irritability > or =75% of the time, compared with 68% of the patients with abnormal irritability < or =30% of the time. Of the high-irritability patients, psychomotor agitation was rated as definitely present to a significant degree in 44%. Talkativeness and distractibility were rated present but subthreshold in one patient each. All other symptoms of DSM-IV mania were absent. CONCLUSION: Approximately 25% of patients with bipolar I disorder who meet criteria for a DSM-IV major depressive episode also experienced substantial irritability in the absence of associated symptoms of mania. Our results suggest that abnormal irritability is not limited to mania or mixed states. [Abstract]

Antidepressant-induced dysphoria found in bipolar patients

EI-Mallakh and Karippot J Affect Disord 2005; 84: 267–272
               
17 Mar 2005
Preliminary study findings suggest that a triad of dysphoric mood, irritability, and middle insomnia that is frequently associated with occupational and social dysfunction can occur in some bipolar patients who are receiving antidepressants.
Over the last three decades, evidence has accumulated suggesting the induction of mania or rapid cycling in some patients as a result of antidepressant treatment, observe Rif EI-Mallakh and Anoop Karippot from the University of Louisville School of Medicine in Kentucky, USA.
In previous studies, they noted a phenomenon that was probably related to rapid cycling, the presence of a chronic, dysphoric, irritable state in bipolar patients receiving long-term antidepressant treatment.
To investigate this further, the researchers assessed six type I bipolar patients who had received antidepressants, including paroxetine, sertraline, fluoxetine, and divalproex, continuously for an average of 6.6 years and had developed chronic irritable dysphoria.
As reported in the Journal of Affective Disorders, all the patients responded well to antidepressant treatment during their index depressive episode and this response persisted for at least several months. However, they all had recurrent depressive symptoms while still taking the antidepressants.
Significant dysphoria, irritability, and middle insomnia were evident in the patients, and they also exhibited severe social and occupational dysfunction.
Prior to discontinuing their antidepressant treatment, five patients had stopped working, two had lost their homes, and one had declared bankruptcy. In addition, two patients had terminated long-term relationships, while two had significant relationship problems.
The researchers found minimal change in the clinical status of the patients immediately after they stopped treatment, but, after about 2 months, there was a gradual decline in dysphoria, irritability, and middle insomnia as well as other symptoms.
Occupational recovery returned relatively late in the course of recovery, but was still associated with difficulties.
Noting that as rapid cycling accelerates, the course of bipolar illness is altered from episodic to chronically continuous, EI-Mallakh and Karippot suggest that "antidepressant-associated chronic irritable dysphoria may be a milder manifestation of this phenomenon."

antidepressant-associated chronic irritable dysphoria (acid) in bipolar disorder: a case series (Abstract)

Rif. S. EI-Mallak Anoop Karippot    Received 28 July 2003; accepted 18 August 2004 Volume 84, Issue 2, Pages 267-272 (February 2005)
Source: J Affect Disord 2005; 84: 267–272

Background
Antidepressants administered to bipolar subjects may induce manias, mixed states, or rapid cycling. More recently, we have noted that long-term use of antidepressants may induce a chronic dysphoric, irritable state.

Method
A case series is presented in which six type I bipolar subjects receiving antidepressants continuously for several years developed chronic irritable dysphoria.
Results
A triad of dysphoric mood, irritability, and middle insomnia that is frequently associated with occupational and social dysfunction can occur in some bipolar patients receiving antidepressants for at least 3 years. Typically, initial treatments with antidepressants for the index episode were effective. Over time, depressive symptoms returned and would transiently improve with dose increase or change of agents. Ultimately, the dysphoria and associated symptoms became chronic and resulted in dysfunction. Concomitant mood stabilizer did not appear to alter this pattern. Discontinuation of antidepressants was associated with a slow and gradual improvement in these symptoms over the ensuing year.
Conclusion
Additional studies are required to investigate safety of long-term use of antidepressants in bipolar illness.

Depression, the predominant mood in bipolar disorder II, responds to atypical antipsychotics

Dr. Heinz Grunze, Ludwig-Maximilians-Universität, Munich, Germany
17th European College of Neuropsychopharmacology   : 2004-10-10 to 2004-10-13: Stockholm,Sweden

 Although most of the research in bipolar disorder focuses on the treatment of mania, depression is the prevalent mood, particularly for patients with bipolar disorder II, according to Dr. Grunze.
"These patients have symptoms almost half of the days of any given year, and three times more of those days are spent living with depression than with hypomania or mania," he said.
"The most serious risk for such patients is suicide. That risk is higher than in patients with unipolar depression." Because patients with bipolar disorder II have a higher ratio of depression to mania than to patients with bipolar disorder I, their risk is even higher, he added.
Nevertheless, research on the treatment for bipolar depression is underfunded, as is research on treatment of bipolar disorder II, Dr. Grunze said. "A literature search back to 1994 showed that, of double-blinded, randomized, controlled trials in bipolar disorder, none have involved bipolar disorder II."
Therefore, treatment strategies for depression are particularly limited, he noted. The older tricylic antidepressants, such as imaprimine, are of no benefit. The selective serotonin reuptake inhibitors can address depression, but entail the risk of mood conversion from depression to hypomania, mania, or rapid cycling.
As in other phases of bipolar disorder, several atypical antipsychotics seem to be effective at addressing depression without the safety risks involved with antidepressants. One open trial involving risperidone for depression in bipolar disorder II showed that 60% of patients were asymptomatic after 6 months of treatment.
In a recent double-blinded, randomized controlled trial, the BipOLar DepRession (BOLDER) study, investigators assessed the role of quetiapine for bipolar depression. They recruited 504 bipolar patients, two-thirds with bipolar disorder I and one-third with bipolar disorder II. All patients were experiencing depression symptoms at the time they were enrolled in the study. The investigators randomized patients to one of three treatment arms: 300 mg daily of quetiapine, 600 mg daily of quetiapine, or placebo.
The investigators then studied the patients for 8 weeks. Throughout the study, patients in both quetiapine groups had improved scores on the Mania and Depression Rating Scale (MADRS) as well as on both the Hamilton-Depression and Hamilton-Anxiety scores (p<0.01). The difference in effect was noticeable by the first week of the study, said Dr. Grunze.
The conventional wisdom is that, after patients are stable, lithium is a more effective mood stabilizer in bipolar disorder I, and lamotrigene is more effective in bipolar disorder II. More randomized controlled trials involving patients with bipolar disorder II that can confirm such assumptions.
"The future is showing an emerging role for both lamotrigene and atypical antipsychotics for patients with bipolar disorder II," Dr. Grunze concluded.

 

FDA accepts weakened antidepressant warning

BMJ  2005;330:620 (19 March), doi:10.1136/bmj.330.7492.620-a  Jeanne Lenzer        New York
New "black box" warnings will appear this month in the United States on antidepressant labels about the risk of increased suicidality among children using the drugs.  The warnings initially advised by the US Food and Drug Administration, however, have been weakened by industry, say critics.
An FDA advisory panel that met last September ( BMJ 2004;329: 702[Free Full Text]) urged the FDA to demand the new black box warnings. The FDA issued a labelling recommendation in October that read "Antidepressants increase the risk of suicidal thinking and behaviour (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders."
The revised text reads "Antidepressants increased the risk of suicidal thinking and behaviour (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders."
The FDA also deleted a sentence in the warnings section (separate from the black box) that . . . [Full text of this article]

La prescription et le coût des AD en Angleterre