Notes sur les conséquences et complications des troubles

 

croco        Notes sur les conséquences et complications A.I.T.B.
Jeudi 11 décembre 2003  : Conséquences et complications
et jeudi 2 décembre 2004

maj du 11 septembre 2008

   Les principaux documents de référence sont indiqués en fin. Il n'est pas question d'être exhaustif sur un tel sujet, aussi a-t-on privilégie les documents récents faisant autorité (rapports de recherche) et les rares documents en français.  La presse de vulgarisation médicale a été volontairement écartée.

Introduction    Notes   Références

INTRODUCTION

    Trois sujets de préoccupation : le suicide, les autres comorbidités, l'évolution à long terme de la maladie.

A).  Suicide

Le suicide est le principal risque des troubles bipolaires. En 2004 des controverses se sont élevées sur l'impact des SRI (AD) sur les suicides. Et la FDA(l'organisme américain de contrôle de la santé publique) a imposé l'écriture d'une mise en garde sur toutes les boîtes de SRI.. La prescription des AD a été aussi fortement restreinte chez les enfants et adolescents aux USA.    Voir aussi les notes sur la conférence 03.
  Il est à noter que le lithium, qui réduit le risque de suicide, n'est plus prescrit en premiére intention dans les hopitaux que dans 5% des cas, malheureusement ! On voit ici le poids de l'industrie pharmaceutique. En référence des résumés d'études sur le sujet..

 comorbidité

Dans le cadre de STEP-BD, la prévalence des idées suicidaires a été étudiée Les idéees suicidaires sont significativement plus nombreuses parmi les patients qui prennent un neuroleptique de deuxième génération que parmi les autres  (26 percent et 17 percent) et ceux qui prennent un antidépresseur et ceux qui n'en prennent pas (25 percent et 14 percent).

B). AUTRES COMORBIDITES.

Les maldies cardio-vasculaires viennent ensuite. Le diabéte et autres syndrômes métaboliques apparaissent liés  au trouble bipolaire. Et  l'olanzapine a aggravé cet aspect des choses. Diabéte et trouble bipolaire
  Cet aspect des choses a été remarqué dès 2004 par les spécialistes de médecine interne, et non par les psychiatres qui renvoient systématiquement les malades prenant du poids  vers la diététicienne ! Ce syndrôme métabolique a pris une telle ampleur qu'un correctif, la metformine,  a été proposé pour être adjoint systématiquement a la prescription du zyprexa (olanzapine). metformine, correcteur du zyprexa

diabéte et trouble bipolaire
 Il faut aussi penser aux accidents survenus en phase maniaque
La dépression conjuguée au diabéte entraîne également un surcroit de mortalité par maladies cardio-vasculaires.

C). AGGRAVATION DE LA MALADIE.

    On rentre là au coeur du sujet. et dans une vraie polémique. La maladie dans son évolution naturelle voit ses cycles s'accélérer et on peut se poser la question de la qualité des traitements pratiqués. : accélérent-ils l'évolution à long terme sous prétexte de traiter des épisodes ?

   C'est un vrai sujet et on est obligé, en pratique, de répondre par l'affirmative, malheureusement. Les épisodes dépressifs sont traités usuellement (hélas, hélas, hélas) avec des AD et les épisodes maniaques avec des neuroleptiques à forte dose. Cela amplifie les phases suivantes (la métaphore de la bosse sur une plaque de tôle) Ces deux types de traitement sont même poursuivis en maintenance sous prétexte que l'on ne change pas un traitement qui a réussi. (cf la thése de medecine de Sandrine Gravier pour les neuroleptiques),  On est très loin, en pratique, des traitements préconisés par les conférences de consensus. La plupart des médecins traitent les crises - ils ont une excuse, quand même, on les paye pour cela - de maniére symptomatique , sans se préoccuper des conséquences sur le long terme.


 NOTES    
I.MORTALITE.   
50% des bipo ont fait des tentatives de suicide
  
15% des patients non traités se suicident
. Risques liés aux états mixtes  et en fin de manie.
   3 types d'états mixtes :
      - états mixtes proprement dits
      - manie dysphorique
      - dépressions mixtes (ou agitées)
Risque multiplié par 3 par rapport à la population générale.
Mais : bipo traité risque lègérement inférieur à la moyenne ! (meilleur suivi médical)
  Phase dépressive : suicide
  Phase maniaque : conduites à risque  11000 suicides authentifiés par an en France dont 1000 de bipolaires (estimation)
300 000 à 500 000 tentatives de suicide. Plusieurs millions avec idées suicidaires.
Risque divisé par 8 sous traitement aux sels de lithium.  Même si la protection contre de nouveaux épisodes est limitée dans certains cas, il a un effet anti-impulsif et anti-suicidaire.
Pas d'études de risque de suicide avec les autres médicaments.
Peu de moyens de prédiction sûrs. On peut avoir des indices mais pas de certitudes.
Il est anormal que certains psychiatres culpabilisent les parents après le suicide d'un de leurs enfants.

  • II. COMPLICATIONS CARDIO-VASCULAIRES ET ALCOOL.
Liées au stress.  Surconsommation de drogues et de tabac.

III  COMPLICATIONS SOCIALES
    - familiales : les bipolaires ont un parcours chaotique.

    - coût socio-économique (USA 12 MM $ ?)
    - perte d'intégration

IV.CONDUITES ASOCIALES. (aspects médico-légaux).
      20% des bipolaires ont des antécédants judiciaires.
      Etude de McElroy  sur les délits sexuels aux USA
ex d'abolition du discernement :
femme 65ans sans antécédants achetant un masque de clown et  un pistolet  en plastique et braquant  un bureau de poste.
ex  d'altération du discernement :
homme 35 ans réalisant et vendant des  "copies" de Dubuffet.
45 ans tags dans une petite ville de province.
directeur financier ayant détourné 20MF dans ses phases maniaques

V.AGGRAVATION DE LA MALADIE.
Par une accélération des cycles jusqu'à avoir des cycles rapides ou des états mixtes ou des formes circulaires avec absence de rémission . Beaucoup plus difficiles à traiter que les formes TBI ou TBII.
Les benzodiazépines (Anafranil,  etc..) ont une influence très néfaste en accélerant les cycles.
Amm US prévention des récidives : Lamictal, Lithium
Amm Fr prévention des récidives : Lithium, Zyprexa

VI.SEQUELLES POST-DEPRESSION OU POST-ACCES MANIAQUES
Les intervalles libres ne sont pas si libres que cela avec des persistance éléments sub-dépressifs et sub-maniaques.
Après un cycle les bipo se plaignent souvent de ne pas avoir récupéré toutes leurs facultés "d'avant".

Références (SGDG)

 
La Recherche HS n°18 Les médicaments du bonheur. Août 2004 p 24 ISRS Un risque trop vite effacé. La littérature médicale a occulté le risque suicidaire lié aux antidépresseurs. D. HEALY
   Cet article analyse de manière critique l'incidence de la prise des antidépresseurs modernes (les IRS) sur le risque suicidaire. Il apparait que les essais cliniques randomisés ont montré une augmentation considérable du risque suicidaire pour les molécules les plus connues :
   PROZAC  (par rapport à une molécule de comparaison)      risque multiplié par trois
   ZOLOFT (par rapport à un placebo)                                   risque multiplié par deux
   DEROXAT (par rapport à un placebo)                                risque multiplié par  sept


Rihmer Z, Pestality P.     Bipolar II disorder and suicidal behavior.Psychiatr Clin North Am 1999 Sep;22(3):667-73, ix-x

"Despite the fact that the nosologic position of bipolar II disorder continues to be debated, several lines of research indicate that it is a distinct nosologic category that should be separated from both bipolar I and unipolar major depression. This review of the authors' and others' work demonstrates that the lifetime risk of suicide attempts is highest in bipolar II and lowest in unipolar patients, whereas risk is intermediate in bipolar I patients. Moreover, two reports show that bipolar II patients are over represented among suicide victims. Clinicians must take great care in not missing this diagnosis, which, when untreated, has ominous prognostic implications."

Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network.
J Clin Psychiatry. 2003 May;64(5):506-15.
"BACKGROUND: Clinical factors related to suicide and suicide attempts have been studied much more extensively in unipolar depression compared with bipolar disorder. We investigated demographic and course-of-illness variables to better understand the incidence and potential clinical correlates of serious suicide attempts in 648 outpatients with bipolar disorder.
METHOD: Patients with bipolar I or II disorder (DSM-IV criteria) diagnosed with structured interviews were evaluated using self-rated and clinician-rated questionnaires to assess incidence and correlates of serious suicide attempts prior to study entry. Clinician prospective ratings of illness severity were compared for patients with and without a history of suicide attempt.
RESULTS: The 34% of patients with a history of suicide attempts, compared with those without such a history, had a greater positive family history of drug abuse and suicide (or attempts); a greater personal history of early traumatic stressors and more stressors both at illness onset and for the most recent episode; more hospitalizations for depression; a course of increasing severity of mania; more Axis I, II, and III comorbidities; and more time ill on prospective follow-up. In a hierarchical logistic regression, a history of sexual abuse, lack of confidant prior to illness onset, more prior hospitalizations for depression, suicidal thoughts when depressed, and cluster B personality disorder remained significantly associated with a serious suicide attempt.
CONCLUSION: Our retrospective findings, supplemented by prospective follow-up, indicate that a history of suicide attempts is associated with a more difficult course of bipolar disorder and the occurrence of more psychosocial stressors at many different time domains. Greater attention to recognizing those at highest risk for suicide attempts and therapeutic efforts aimed at some of the correlates identified here could have an impact on bipolar illness-related morbidity and mortality."


Dalton EJ, Cate-Carter TD, Mundo E, Parikh SV, Kennedy JL. Suicide risk in bipolar patients: the role of co-morbid substance use disorders.
Bipolar Disord. 2003 Feb;5(1):58-61.
"OBJECTIVE: Bipolar disorder is associated with a high frequency of both completed suicides and suicide attempts. The primary aim of this study was to identify clinical predictors of suicide attempts in subjects with bipolar disorder.
METHODS: We studied 336 subjects with a diagnosis of bipolar I, bipolar II, or schizoaffective disorder (bipolar type). The Structured Clinical Interview for DSM-IV (SCID-I) was administered and subsequently two expert psychiatrists established a diagnosis. Predictors of suicide attempts were examined in attempters and non-attempters.
RESULTS: The lifetime rate of suicide attempts for the entire sample was 25.6%. A lifetime co-morbid substance use disorder was a significant predictor of suicide attempts: bipolar subjects with co-morbid substance use disorders (SUD) had a 39.5% lifetime rate of attempted suicide, while those without had a 23.8% rate (odds ratio = 2.09, 95% CI = 1.03-4.21, chi2 = 4.33, df = 1, p = 0.037).
CONCLUSIONS: Lifetime co-morbid SUD were associated with a higher rate of suicide attempts in patients with bipolar disorder. This relationship may have a genetic origin and/or be explained by severity of illness and trait impulsivity."


Michaelis BH, Goldberg JF, Singer TM, Garno JL, Ernst CL, Davis GP.
Characteristics of first suicide attempts in single versus multiple suicide attempters with bipolar disorder.
Compr Psychiatry. 2003 Jan-Feb;44(1):15-20.
"Although suicidality remains highly prevalent among patients with bipolar disorder, little research exists examining the characteristics of successive attempts among individuals who make and survive a first suicide attempt. We compared bipolar subjects with a history of one suicide attempt to those with multiple attempts and assessed demographic characteristics, family histories, psychopathology, and clinical dimensions of suicidal behavior. Fifty-two DSM-IV bipolar patients (age 21 to 74 years) with a history of at least one suicide attempt were consecutively evaluated in the Bipolar Disorders Research Clinic of the New York Presbyterian Hospital. Circumstances surrounding each lifetime suicide attempt were assessed by direct interviews, questionnaires, and chart reviews along with family psychiatric histories, substance abuse histories, current psychopathology, and features of impulsivity and aggression. Multiple suicide attempts occurred in approximately two thirds of the study group. Single attempters were significantly more likely than multiple attempters to show high seriousness of intent at their first attempt (OR = 0.65, 95% CI = 0.43 to 0.99), and tended to be less likely than multiple attempters to exhibit mixed states at their first attempt (OR = 0.54, 95% CI = 0.28 to 1.01). Seriousness of intent was consistent across the first and second attempts (r =.48, P <.01) and second and third attempts (r =.74, P <.05). Single and multiple attempters differed in no other clinical or demographic characteristics studied. We conclude that multiple suicide attempts are common among bipolar patients. Those who survive an initial suicide attempt involving high seriousness of intent appear less likely than those with low intent to make subsequent attempts. Consequently, single attempters may represent a group more closely resembling those who complete suicide on a first attempt, in terms of the risk for death associated with their first attempt. However, multiple suicide attempts among bipolar patients are not necessarily associated with a higher risk for lethality in first suicide attempt survivors."

Simpson SG, Jamison KR. The risk of suicide in patients with bipolar disorders. J Clin Psychiatry 1999;60 Suppl 2:53-6; discussion 75-6, 113-6
"Patients with bipolar disorder have a high risk of committing suicide, but determining the exact risk is complicated. For many years, the lifetime suicide risk in bipolar disorder was accepted as 15%, but recent researchers have suggested that the lifetime suicide risk may be lower. The group of bipolar patients at highest risk of suicide are young men who are in an early phase of the illness, especially those who have made a previous suicide attempt, those abusing alcohol, and those recently discharged from the hospital. The risk is also increased in patients who are in the depressed phase of bipolar illness, who have mixed states, or who have psychotic mania.

Lithium and Suicide Risk in Bipolar Disorder  by Leonardo Tondo, MD, Ross J. Baldessarini, MD, and John Hennen, PhD
ABSTRACT

Can timely diagnosis and treatment of depression reduce the risk of suicide? Studies of treatment effects on mortality in major mood disorders remain rare and are widely considered difficult to carry out ethically. Despite close associations of suicide with major affective disorders and related comorbidity, the available evidence is inconclusive regarding for sustained reductions of suicide risk by most mood-altering treatments, including antidepressants. Studies designed to evaluate clinical benefits of mood-stabilizing treatments in bipolar disorders, however, provide comparisons of suicidal rates with and without treatment or under different treatment conditions. This emerging body of research provides consistent evidence of reduced rates of suicides and attempts during long-term treatment with lithium. This effect may not generalize to proposed alternatives, particularly carbamazepine. Our recent international collaborative studies found compelling evidence for prolonged reduction of suicidal risks during treatment with lithium, as well as sharp increases soon after its discontinuation, all in close association with depressive recurrences. Depression was markedly reduced, and suicide attempts were less frequent, when lithium was discontinued gradually. These findings indicate that studies of the effects of long-term treatment on suicide risk are feasible and that more timely diagnosis and treatment for all forms of major depression, but particularly for bipolar depression, should further reduce suicide risk.

INTRODUCTION

Risk of premature mortality significantly increases in bipolar manic-depressive disorders.(1-12) Mortal risk arises from very high rates of suicide in all major affective disorders, which are at least as great in bipolar illness as in recurrent major depression.(1, 2, 13-16) A review of 30 studies of bipolar disorder patients found that 19% of deaths (range in studies from 6% to 60%) were due to suicide.(2) Rates may be lower in never-hospitalized patients, however.(6, 11, 12) In addition to suicide, mortality is probably also increased due to comorbid, stress-related, medical disorders, including cardiovascular and pulmonary diseases. (3-5, 7, 10) High rates of comorbid substance use disorders contribute further to both medical mortality and to suicidal risk (11, 17), especially in young persons (18), in whom violence and suicide are leading causes of death.(11, 12, 19)

Suicide is strongly associated with concurrent depression in all forms of the common major affective disorders.(2, 9, 20, 21) Lifetime morbid risk for major depression may be as high as 10%, and lifetime prevalence of bipolar disorders probably exceeds 2% of the general population if cases of type II bipolar syndrome (depression with hypomania) are included. (2, 22, 23) Remarkably, however, only a minority of persons affected with these highly prevalent, often lethal, but usually treatable major affective disorders receive appropriate diagnosis and treatment, and often only after years of delay or partial treatment. (8 ,9, 22, 24-28) Despite grave clinical, social, and economic effects of suicide, and its very common association with mood disorders, specific studies on the effects of mood-altering treatments on suicidal risk remain remarkably uncommon and inadequate to guide either rational clinical practice or sound public health policy.(7, 8, 11, 12, 22, 29, 30)

In view of the clinical and public health importance of suicide in manic-depressive disorders, and the rarity of evidence proving that modern mood-altering treatments reduce suicide rates, an emerging body of research has been reviewed. It indicates a significant, sustained, and possibly unique reduction of suicidal behavior during long-term treatment with lithium salts. These important effects have not been demonstrated with other mood-altering treatments.

THERAPEUTICS RESEARCH IN SUICIDE

Despite broad clinical use and intensive study of antidepressants for four decades, evidence that they specifically alter suicidal behavior or reduce long-term suicidal risk remains meager and inconclusive.(9, 11, 17, 31-37) The introduction of selective serotonin reuptake inhibitors (SSRIs) and other modern antidepressants that are much less toxic on acute overdose than older drugs appears not to have been associated with a decrease in suicide rates.(34, 38) Instead, their introduction may have been associated with a shift toward more lethal means of self-destruction.(39) We found only one report of a significantly lower rate of suicide in depressed patients treated with antidepressants compared to placebo (0.65% vs 2.78% per year), with an even lower rate with an SSRI than with other antidepressants (0.50% vs 1.38% per year).(37) Nevertheless, suicide rates during antidepressant treatment in that study were far greater than the general population rate of 0.010% to 0.015% per year, uncorrected for persons with mood disorders and other illnesses associated with increased suicide rates.(40)

Bipolar depression accounts for much or most of the time one is stricken with bipolar disorder (24) and can be disabling or fatal.(2, 7, 11, 12) Remarkably, however, the treatment of this syndrome remains much less studied than depressive to manic, agitated or psychotic unipolar major depression.(24, 38, 41) Indeed, bipolarity is typically a criterion for exclusion from studies of antidepressant treatment, apparently to avoid risks of switching from depressive to manic, agitated or psychotic phases when patients are not protected with lithium or another mood-stabilizing agent.(38)

Reasons for the rarity of studies of the effects of modern psychiatric treatments on suicide rates are not entirely clear. Therapeutic research on suicide is appropriately constrained ethically when fatality is a potential outcome, and particularly when discontinuation of ongoing treatment is required in a research protocol. Treatment discontinuation is increasingly recognized as being followed by at least temporary, sharp increases in morbidity that may exceed the morbid risk associated with untreated illness. This evidently iatrogenic phenomenon has been associated with discontinuation of maintenance treatment with lithium (42-46), anti-depressants (47), and other psychotropic agents.(44, 48) Mortality can also increase following treatment discontinuation. (9, 11, 21, 22) Such reactions can complicate clinical management. Moreover, they may also confound many research findings in that typically reported "drug vs. placebo" comparisons may not represent straightforward contrasts of treated vs untreated subjects when placebo conditions represent discontinuation of an ongoing treatment.

Avoiding such risks, most studies of treatment effects on suicide have been naturalistic or have examined suicidal behavior post-hoc as an unintended outcome of controlled treatment trials. Such studies have provided evidence that maintenance treatment with lithium is associated with a strong, and possibly unique, protective effect against suicidal behavior in major affective disorders, and particularly in bipolar syndromes. (6, 8, 11, 12, 21, 22, 49-56) Moreover, lithium's protective effect may extend more broadly to all causes of mortality in these disorders, although this possibility remains much less studied. (2, 3, 5, 7)

SUICIDE RATES ON AND OFF LITHIUM

We recently evaluated all available studies of lithium and suicide since the emergence of long-term lithium maintenance treatment in manic depressive disorders in the early 1970s. Studies were identified by computerized literature searches and cross-referencing from publications on the topic, as well as by discussing the aims of the study with colleagues who have conducted research on lithium treatment or who may have had access to unpublished data on suicide rates in bipolar disorder patients. We sought data permitting estimates of rates of attempted or completed suicides in bipolar patients or mixed samples of patients with major affective disorders that included bipolar manic-depressives. Suicide rates during maintenance lithium treatment were compared with rates after discontinuation of lithium or in similar untreated samples when such data were available.

Suicide rates during long-term lithium treatment were determined for each study, and, when available, rates for patients discontinued from lithium or for comparable patients not treated with a mood stabilizer were also determined. Suicide rates during lithium treatment were not significantly greater with larger numbers of subjects or longer follow-up. However, many of the available reports were flawed in one or more respects. Limitations included: (1) a common lack of control over treatments other than lithium; (2) incomplete separation by diagnosis or provision of separate rates for suicide attempts and completions in some studies; (3) a lack of comparisons of treated and untreated periods within subjects or between groups; (4) study of fewer than 50 subjects/treatment conditions despite the relatively low frequency of suicide; (5) inconsistent or imprecise reporting of time-at-risk (the amount of time the patient was absent); and (6) selection of patients with previous suicide attempts that may show bias toward increased suicide rates in some studies. Some of these deficiencies were resolved by contacting authors directly. Despite their limitations, we believe that the available data are of sufficient quality and importance to encourage further evaluation.

Table 1 summarizes available data concerning rates of suicides and attempts among manic-depressive patients on or off lithium, based on previously reported (6) and new, unpublished meta-analyses. The results indicate an overall reduction of risk by nearly seven fold, from 1.78 to 0.26 suicide attempts and suicides per 100 patient-years at risk (or percent of persons/year). In another more recent, quantitative meta-analysis (L.T., unpublished, 1999), we evaluated fatality rates ascribed to suicide in the same studies as well as in additional previously unreported data kindly provided by international collaborators. In the latter analysis, based on results from 18 studies and more than 5,900 manic-depressive subjects, we found a similar reduction of risk from a suicide rate averaging 1.83 ± 0.26 suicides per 100 patient-years in patients not treated with lithium (either after discontinuing or in parallel groups not given lithium) to 0.26 ± 0.11 suicides per 100 patient-years in patients on lithium.

IMPLICATIONS OF FINDINGS

The present findings derived from the research literature on lithium and suicide risk indicate substantial protection against suicide attempts and fatalities during long-term lithium treatment in patients with bipolar manic-depressive disorders, or in mixed groups of major affective disorder subjects that included bipolar patients. While this evidence is strong and consistent overall, the relative infrequency of suicide and limited size of many studies required pooling of data to observe statistically significant effect that was not found in several individual studies. Large samples and lengthy times-at-risk, or pooling of data across studies, are likely to be required in future studies of treatment effects on suicide rates.

It is also important to emphasize that the observed, pooled, residual risk of suicides while on lithium, though much lower than without lithium treatment, is still large, and greatly exceeds general population rates. The average suicide rate during lithium maintenance treatment, at 0.26% per year (Table 1), is more than 20 times greater than the annual general population rate of about 0.010% to 0.015%, which also includes suicides associated with psychiatric illnesses.(11, 40) The evidently incomplete protection against suicide associated with lithium treatment may reflect limitations in the effectiveness of the treatment itself and, very likely, potential noncompliance to long-term maintenance therapy.

Since suicidal behavior is closely associated with concurrent depressive or dysphoric mixed states in bipolar disorder patients (9, 11, 20), it is likely that residual risk for suicide is associated with incomplete protection against recurrences of bipolar depressive or mixed mood states. Lithium has traditionally been considered to provide better protection against mania than against bipolar depression.(27, 38) In a recent study of more than 300 bipolar I and II subjects, we found that depressive morbidity was reduced from 0.85 to 0.41 episodes per year (a 52% improvement) and time ill was reduced from 24.3% to 10.6% (a 56% reduction) before vs during lithium maintenance treatment.(23) Improvements in mania or hypomania were somewhat larger, at 70% for episode rates and 66% for percentage of time manic, with even greater improvement in hypomania in type 11 cases (84% fewer episodes and 80% less time hypomanic). Corresponding suicide rates fell from 2.3 to 0.36 suicide attempts per 100 patient-years (an 85% improvement) during vs before lithium maintenance treatment. (9, 20) The present findings indicate an 85% to crude sparing of completed suicides and attempts (1.78 to 0.26% per year; see Table 1). These comparisons suggest that protective effects of lithium rank: suicide attempts or suicides³ hypomania>mania>bipolar depression. Since suicide is closely associated with depression (11, 20), it follows that better protection against bipolar depression must be a key to limiting suicidal risk in bipolar disorders.

It is not clear whether reduction of suicide rates during lithium maintenance reflects simply the mood-stabilizing effect of lithium, or if other properties of lithium also contribute. In addition to protection from recurrences of bipolar depressive and mixed-mood states closely associated with suicidal behavior, important associated benefits of lithium treatment possibly also contribute to reduction of suicide risk. These may include improvements in overall emotional stability, interpersonal relationships and sustained clinical follow-up, vocational functioning, self-esteem, and perhaps reduced comorbid substance abuse.

An alternative possibility is that lithium may have a distinct psychobiological action on suicidal and perhaps other aggressive behaviors, possibly reflecting serotonin-enhancing actions of lithium in limbic forebrain. (38, 57) This hypothesis accords with growing evidence of an association between cerebral deficiency of serotonin functioning and suicidal or other aggressive behaviors. (58-59) If lithium protects against suicide through its central serotonergic activity, then proposed alternatives to lithium with dissimilar pharmacodynamics may not be equally protective against suicide. Specifically, mood-stabilizing agents that lack serotonin enhancing properties, including most anti-convulsants (27, 38), might not protect against suicide as well as lithium. It would be unwise clinically to assume that all putative mood-stabilizing agents provide similar protection against suicide or other impulsive or dangerous behaviors.

For example, findings from recent reports from a multicenter European collaborative study challenge the assumption that all effective mood-altering treatments have a similar impact on suicide rates. This study found no suicidal acts among bipolar and schizoaffective disorder patients maintained on lithium, whereas carbamazepine treatment was associated with a significantly higher rate of suicides and suicide attempts in 1% to 2% of subjects per year-at-risk. (60, 61) Patients assigned to carbamazepine had not been discontinued from lithium (B. Müller-Oerlinghausen, written communication, May 1997), which might otherwise have increased risk iatrogerically. (8, 42-46) A similar rate of suicide attempts to that found with carbamazepine in bipolar patients was also found among patients with recurrent unipolar depression who were maintained long-term on amitriptyline, with or without a neuroleptic. (60, 61) These provocative observations regarding carbamazepine and amitriptyline indicate the need for specific assessments of other proposed alternatives to lithium for their potential long-term protection against suicidal risk in bipolar disorder patients.

 

Several drugs are used empirically to treat bipolar disorder patients, although they remain largely untested for long-term, mood-stabilizing effectiveness. In addition to carbamazepine, these include the anticonvulsants valproic acid, gabapentin, lamotrigine, and topiramate. Sometimes calcium channel-blockers, such as verapamil, nifedipine, and nimodipine, are employed, and newer, atypical antipsychotic agents including clozapine and olanzapine are increasingly used to treat bipolar disorder patients, encouraged in part by an assumption that risk of tardive dyskinesia is low. The potential antisuicide effectiveness of these agents remains unexamined. An exception to this pattern is clozapine, for which there is some evidence of antisuicidal and perhaps other antiaggressive effects, at least in patients diagnosed with schizophrenia. (62) Clozapine is sometimes used, and may be effective, in patients with otherwise treatment-unresponsive major affective or schizoaffective disorders (63, 64), but its antisuicidal effects in bipolar disorder patients have yet to be investigated. Contrary to the hypothesis that serotonergic activity may contribute to antisuicidal effects, clozapine has prominent antiserotonin activity, particularly at 5-HT2A receptors (65, 66), suggesting that other mechanisms may contribute to its reported antisuicidal effects.

EFFECTS OF DISCONTINUING LITHIUM ON SUICIDE RISK

Another factor to consider in interpreting the findings pertaining to effects of lithium treatment on suicide rates is that most of the studies analyzed involved comparisons of suicide rates during vs after discontinuing long-term lithium treatment. In a recent international collaborative study, we found that clinical discontinuation of lithium maintenance treatment was associated with a sharp increase in suicidal risk in a large, retrospectively analyzed sample of bipolar I and II patients.(8, 9, 20, 21, 46) Rates of suicide attempts had decreased by more than six-fold during lithium maintenance treatment, compared to years between onset of illness and the start of sustained maintenance treatment (Table 2). In these patients, nearly 90% of life-threatening suicide attempts and suicides occurred during depressive or dysphoric mixed-mood states, and previous severe depression, prior suicide attempts, and younger age at onset of illness significantly predicted suicidal acts.

In striking contrast, after discontinuing lithium (typically at the patient's insistence following prolonged stability) rates of suicides and attempts increased 14-fold overall (Table 2). In the first year after discontinuing lithium, affective illness recurred in two thirds of patients, and rates of suicide attempts plus fatalities increased 20-fold. Suicides were nearly 13 times more frequent after discontinuing lithium (Table 2). Of note, at times later than the first year off lithium, suicide rates were virtually identical to those estimated for the years between onset of illness and the start of sustained lithium maintenance. These findings strongly suggest that lithium discontinuation carries added risk, not only of early recurrence of affective morbidity, but also of a sharp increase in suicidal behavior to levels well in excess of rates found before treatment, or at times later than a year after discontinuing treatment. These increased suicidal risks may be related to a stressful impact of treatment discontinuation itself that may have contributed to most of the contrasts shown in Table 1 between subjects treated with lithium vs subjects who discontinued lithium use.(8)

If stopping lithium is followed by added suicide risk associated with recurrence of bipolar depression or dysphoria, then slow discontinuation of treatment may reduce the incidence of suicide. Encouraging preliminary findings indicated that, after gradual discontinuation of lithium over several weeks, suicidal risk was reduced by half (Table 2).(9, 21) The median time to first recurring episodes of illness was increased an average of four times after gradual vs rapid or abrupt discontinuation of lithium and the median time to bipolar depression was delayed by about threefold. (8, 45, 46) The apparent protective effect of gradually discontinuing lithium against suicidal risk may reflect the highly significant benefits of gradual discontinuation against early recurrences of affective episodes as a key intervening variable.(8)

CONCLUSIONS

Several points arising from this overview of the association of long-term lithium treatment with reduced suicide risk should be emphasized. First, the evidence reviewed provides strong, consistent support for the conclusion that suicide rates are much lower during long-term treatment with lithium than after stopping this treatment for patients with bipolar and perhaps other major recurrent affective or schizoaffective disorders. Second, these findings also indicate that much-needed studies of the therapeutics of suicide are feasible, at least based on naturalistic comparisons involving varied treatment conditions. Perhaps even controlled comparisons of clinically plausible alternative treatments can be carried out, as has been done to compare lithium and carbamazepine.(60, 61) Third, it is important to emphasize that the average protective effect of lithium is far from complete, and suicide rates during lithium treatment greatly exceed those in the general population. Fourth, the effect of lithium against suicide is not known to generalize to other effective or experimental mood-altering therapies, nor to conditions other than manic-depressive syndromes and perhaps some schizoaffective conditions, all of which require long-term studies comparing clinically and ethically plausible alternative treatment options.

In contrast to lithium, there is remarkably little information available concerning effects of alternative treatments on suicidal behavior, other than preliminary indications that carbamazepine may not be as effective as lithium in limiting suicidal risk in patients with bipolar or schizoaffective disorders (60-61), and that clozapine may have antisuicidal effects in patients with chronic psychotic disorders.(62) While it is plausible to expect a suicide-reducing benefit of effective antidepressant treatments in patients with major affective disorders, information supporting this hope remains remarkably limited and either inconclusive or negative. (11, 17, 30, 35-37)

Finally, if the impression is valid that lithium exerts less consistent protection against bipolar depression than against hypomania or mania, it follows that better protection against bipolar depression is a key to further limiting suicidal risk in bipolar disorders. The striking paucity of studies of treatment effectiveness in bipolar depression and the close association of suicidality and depression or dysphoria in bipolar disorders emphasize the need for improved identification and timely, sustained treatment of patients at increased risk of suicide with all forms of major depression, but particularly of bipolar depression

Dr. Tondo is research associate at McLean Hospital, Harvard Medical School, in Boston, MA; assistant professor of psychiatry in the Department of Psychology at the University of Cagliari in Sardinia, and director of the outpatient clinic Centro Lucio Bini, a Stanley Foundation International Research Center, in Cagliari, Sardinia, Italy.

Dr. Baldessarini is professor of psychiatry and neuroscience at Harvard Medical School in Boston; director of the Laboratories for Psychiatric Research, Bipolar & Psychotic Disorders Program, and the Psychopharmacology Program, at the McLean Division of Massachusetts General Hospital in Belmont, MA; a founding director of the International Consortium for Bipolar Disorders Research.

Dr. Hennen is instructor in psychiatry at Harvard Medical School in Boston and chief of the Biostatistics Laboratory of the Bipolar & Psychotic Disorders Program at McLean Hospital.

Acknowledgements: Completion of this article was supported by awards from the National Alliance for Research on Schizophrenia and Depression, the Theodore & Vada Stanley Foundation, and the American Foundation for Suicide Prevention (LT); and by National Institutes of Health Career Investigator Award MH-47370, the McLean Private Donor Neuropharmacology Research Fund, a grant from the Bruce J. Anderson Foundation, and an award from Solvay Corporation (RJB).

This article was previously published in Primary Psychiatry. 1999;6(9):51-56


Symbyax Shown to Reduce Symptoms Associated With Suicidal Thinking in Patients With Bipolar Depression
Those with Early-Onset of Bipolar Disorder Also Shown More Likely to Respond to Symbyax Treatment

May 05, 2004 -- New data show that Symbyax™ (olanzapine and fluoxetine HCl) reduced the symptoms associated with suicidal ideation (having thoughts of suicide), a predictor of suicidal behavior, in bipolar depressed patients within the first week of treatment. Another study demonstrated that having an early onset of bipolar disorder tripled the likelihood that a patient might respond to Symbyax. These findings were presented today at the annual meeting of the American Psychiatric Association.

Symbyax is the first and only FDA-approved treatment for the depressive phase of bipolar disorder.

"These data provide hope to patients whose lives are disrupted by bipolar depression, a devastating and difficult condition to treat that often results in suicide or suicide attempts," said Terence A. Ketter, M.D., associate professor of psychiatry and behavioral sciences, and chief, Bipolar Disorders Clinic, Stanford University School of Medicine. "The rapid reduction of symptoms associated with suicidal ideation suggests the potential benefit of Symbyax among bipolar depressed patients, who are at high risk of taking their own lives."

Suicidal Ideation Study

An eight-week analysis of 688 people that compared Symbyax (n=73), olanzapine (n=299) and placebo (n=316) in the treatment of bipolar I depression showed:

  • Suicidal ideation, as measured by the Montgomery-Asberg Depression Rating Scale item 10 (MADRS-10), was significantly reduced in bipolar depressed patients by the first week of Symbyax treatment compared to patients receiving placebo or olanzapine.
  • Symbyax significantly improved the symptoms of apparent sadness, reported sadness, pessimistic thoughts, and inner tension - four MADRS items correlated to suicidal ideation - within one week compared to placebo.

Olanzapine is not indicated for bipolar depression.

Predictors of Response Study

In addition, a statistical analysis performed on acute phase data from a double-blind, randomized clinical trial comparing Symbyax (n=86), olanzapine (n=370) and placebo (n=377) in patients with bipolar depression found:

  • Having an early onset of bipolar disorder (prior to age 20) tripled the odds of response to Symbyax among patients with bipolar depression. Response was defined as a greater than 50 percent decrease in Montgomery-Asberg Depression Rating Scale (MADRS) total score.
  • Early onset was the only independent variable evaluated that was significant for predicting response to Symbyax among patients with bipolar depression.

"Since bipolar disorder often emerges in late adolescence or early adulthood, the high rates of response among bipolar depressed patients who had early onset suggests that Symbyax may work well in this large, well-defined population," said Robert W. Baker, M.D., associate medical director, USMD Neurosciences, Eli Lilly and Company.

About Bipolar Disorder
Bipolar disorder typically emerges in adolescence or young adulthood, and episodes continue intermittently throughout life, often disrupting work, school, family, and social life.
Patients with the disease have a higher risk of committing suicide than those with other psychiatric or medical disorders, and without effective treatment, bipolar disorder can lead to suicide in nearly 20 percent of cases. The relative risk of suicide among patients with bipolar depression has been shown to be nearly 35 times greater than among patients in the manic phase of bipolar disorder.

Bipolar disorder, also known as manic-depressive illness, affects an individual's mood, behavior, and thinking. Unlike many illnesses, symptoms may be quite different at various phases of the illness. Treatment is challenging because some therapies that are effective for one phase of the illness may be counterproductive for another. For example, antidepressant treatments can precipitate manic episodes.

Bipolar disorder is a complex mental illness characterized by debilitating mood swings ranging from episodes of deep depression (feelings of extreme guilt, sadness, anxiety and, at times, suicidal thoughts) to episodes of mania (abnormal euphoria, elation and irritability), interspersed with periods of normal mood. Patients with bipolar disorder spend more than three times longer in the depressive phase than in the manic phase of the disorder and take longer to recover from it.

More than 2.5 million Americans live with a diagnosis of bipolar disorder but recent research indicates the real number may be as high as 10 million. The results of untreated bipolar disorder can be catastrophic. According to the National Institute of Mental Health, nearly one in every five people with the illness commits suicide. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability in the world.

Important Information About Symbyax

The most common treatment-emergent adverse event associated with Symbyax (vs. placebo) in clinical trials was somnolence (22 vs. 11%). Other common events were: weight gain (21 vs. 3%), increased appetite (16 vs. 4%), asthenia (15 vs. 3%), peripheral edema (8 vs. 1%), tremor (8 vs. 3%), pharyngitis (6 vs. 3%), abnormal thinking (6 vs. 3%) and edema (5 vs. 0%).

Contraindications - Symbyax should not be used with an MAOI or within at least 14 days of discontinuing an MAOI. At least five weeks should be allowed after stopping Symbyax before starting an MAOI. Thioridazine should not be given with Symbyax or within at least five weeks after stopping Symbyax. Symbyax is contraindicated in patients with known hypersensitivity to the product or any component of the product.

Hyperglycemia and diabetes mellitus - Hyperglycemia, in some cases associated with ketoacidosis, coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.

Cerebrovascular adverse events (CVAE), including stroke, in elderly patients with dementia - Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of CVAE in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

Orthostatic hypotension - Symbyax may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. Particular caution should be used in patients with known cardiovascular disease, cerebrovascular disease, or those predisposed to hypotension.

Allergic events and rash - In premarketing trials, the overall incidence of rash or allergic events with Symbyax was similar to that with placebo (4.6%, 26/571 vs. 5.2%, 25/477). In fluoxetine clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. If rash or other possibly allergic phenomena appear for which an alternative etiology cannot be determined, immediate discontinuation is recommended.

Concomitant use - Caution should be used when prescribing medications that contain olanzapine or fluoxetine HCl with Symbyax.

Abnormal bleeding - Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of Symbyax with NSAIDs, aspirin, or other drugs that affect coagulation.

Mania/hypomania - Because of the cyclical nature of bipolar disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with Symbyax.

Prolactin and serum sodium - As with other drugs that antagonize dopamine receptors, Symbyax elevates prolactin levels, and a modest elevation persists during administration; however, possibly associated clinical manifestations were infrequently observed. Hyponatremia has been observed in premarketing studies of Symbyax, but the incidence of serum sodium levels occurring below the reference range was statistically insignificant compared with placebo (2%, 10/500 vs. 0.5%, 2/380); none of these patients had a treatment-emergent level less than 130 mmol/L.

Transient, asymptomatic elevations of hepatic transaminase - In premarketing trials, statistically significant ALT (SGPT) elevations (>3 times the upper limit of the normal range) were observed in 6.3% (31/495) of patients exposed to Symbyax compared with 0.5% (2/384) of the placebo patients and 4.5% (25/560) of olanzapine-treated patients. None of these patients developed jaundice. Periodic assessment of transaminases is recommended in patients with significant hepatic disease.

Weight gain - In clinical studies, the mean weight gain for Symbyax-treated patients was statistically significantly greater than placebo-treated (3.6 kg vs. -0.3 kg) and fluoxetine-treated (3.6 kg vs. -0.7 kg) patients but was not statistically significantly different from olanzapine-treated patients (3.6 kg vs. 3.0 kg). Fourteen percent of Symbyax-treated patients met criterion for having gained >10% of their baseline weight.

Special populations and elderly - Dysphagia was observed infrequently in premarketing studies, but as with other psychotropic drugs, Symbyax should be used cautiously in patients at risk for aspiration pneumonia. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. In 2 clinical studies in patients with Alzheimer’s disease, two olanzapine-treated patients died from aspiration pneumonia, with one of these patients experiencing dysphagia. As with other CNS-active drugs, Symbyax should be used with caution in elderly patients with dementia. The lowest starting dose should be considered in patients with hepatic impairment.

As with all medications that contain an antipsychotic, the following considerations should be taken into account when prescribing Symbyax:

Neuroleptic malignant syndrome (NMS) - as with all antipsychotic medications, a rare condition known as NMS has been reported with olanzapine. If signs and symptoms appear, immediate discontinuation is recommended.

Tardive dyskinesia (TD) - as with all antipsychotic medications, prescribing should be consistent with the need to minimize the risk of TD. If its signs and symptoms appear, discontinuation should be considered.

Seizures - occurred infrequently in premarketing clinical trials (4/2066, 0.2%). Confounding factors may have contributed to many of these occurrences. Symbyax should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Such conditions may be more prevalent in patients age 65 years or older.

Source: Eli Lilly Press Release

 

Bipolar Patients With Suicidal Behavior: Toward the Identification of a Clinical Subgroup
Frederic Slama, M.D.; Frank Bellivier, M.D., Ph.D.; Chantal Henry, M.D., Ph.D.; Angela Rousseva, M.D.; Bruno Etain, M.D.; Frederic Rouillon, M.D.; and Marion Leboyer, M.D., Ph.D. (J Clin Psychiatry 2004;65:1035-1039)

Background: Suicide is the most severe and frequent complication of bipolar disorder, but little is known about the clinical characteristics of bipolar patients at risk of suicide. The purpose of this study was to identify those characteristics.

Method: We studied 307 prospectively recruited DSM-IV-diagnosed bipolar I or II patients from November 1994 through October 2001. Semi-structured diagnostic interviews (the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies) were used to determine the diagnosis of bipolar disorder and its lifetime description, lifetime comorbid Axis I disorder diagnoses, familial history of psychiatric disorders and demographic characteristics.

Results: One hundred twenty-nine bipolar patients (42%) had made at least 1 suicide attempt in their life. Lifetime history of suicidal behavior was associated with history of suicidal behavior in first-degree relatives but not with a familial history of mood disorder. Early age at onset of mood disorder, total number of previous depressive episodes, alcohol and tobacco use, social phobia, antidepressant-induced mania, and personal history of head injury were associated with suicidal behavior. No association was observed with gender or diagnosis of bipolar I or II disorder. Social phobias, tobacco use, and personal history of head injury were no longer associated with suicidal behavior in the multivariate analysis.

Conclusion: Bipolar patients with early age at bipolar disorder onset, high number of depressive episodes, personal history of antidepressant-induced mania, comorbid alcohol abuse, and suicidal behavior constitute a clinical subgroup at risk of suicidal behavior. This information, as well as familial history of suicide behavior, should improve suicide risk assessment in bipolar patients.


  Corrélations entre lithium et suicide
M.J.DONNER J. Clin Psychiatry 2004, 65, [supl 10] 5-10


Prevalence and Consequences of Metabolic Syndrome in Bipolar Disorder
By Dale A. D'Mello, MD, Supriya Narang, MD, and Gina Agredano, MD

January 2007, Vol. XXIV, No. 1

http://www.psychiatrictimes.com/showArticle.jhtml?articleID=196901885

Patients with bipolar disorder suffer a disproportionate burden of cardiovascular illness compared with others in the general population.1,2 While the pathogenesis of this excess morbidity is undetermined, biologic, behavioral, and sociodemographic factors have been implicated.3 Bipolar disorder is commonly associated with disrupted circadian rhythms,4 insomnia,5 breathing-related sleep disorders,6 immune function disorders,7 and hyperactivity of the sympathetic adrenal medullary8 or hypothalamic-pituitary- adrenal axes.9 All of these seemingly disparate phenomena are now known to have dire metabolic consequences.3 For instance, sustained hypercortisolemia is associated with visceral obesity and subsequent insulin resistance.10 Not surprisingly, several previous studies have established that the prevalence of metabolic disorders is alarmingly high among patients with bipolar disorder (Table 1).11-16 Furthermore, medications that are commonly used in the management of bipolar disorder are now known to contribute to weight gain, dyslipidemia, and diabetes.2

We recently conducted a study to examine the prevalence and clinical correlates of metabolic disorders in a cohort of hospitalized patients with bipolar disorder.

Methods

We recruited 41 patients with bipolar disorder, who were consecutively admitted to the psychiatric unit of a general hospital in central Michigan in a manic or mixed state during calendar years 2004 and 2005. All of the patients received the customary physical examination, laboratory tests, and comprehensive psychiatric evaluations. Following informed consent, we retrieved demographic and clinical information. Demographic data included age, sex, and ethnicity. Clinical information included height, weight, body mass index (BMI), blood pressure, fasting plasma glucose levels, and a serum lipid panel. Other clinical information included the psychiatric diagnosis, the list of discharge medications, the age of onset, and duration of psychiatric illness. We used the Young Mania Rating Scale (YMRS) scores, hospital length of stay (LOS), and number of days hospitalized in the preceding 5 years as measures of illness severity.

We used the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) diagnostic criteria to establish the diagnosis of metabolic syndrome (Table 2).17 We used a BMI value of 25 or greater as an inclusion criterion rather than the customary waist circumference value of greater than 40 inches in men and greater than 35 inches in women. Patients who met 3 or more of the diagnostic criteria were considered to have metabolic syndrome. The data were entered into a statistical software program (SYSTAT Version 11) for analysis. The mean values for age, BMI, systolic and diastolic blood pressure, high-density lipoprotein cholesterol, serum triglycerides, fasting plasma glucose, LOS, and YMRS scores were computed. The patients were then grouped according to the presence of obesity, hypertension, dyslipidemia, diabetes or prediabetes, or metabolic syndrome.

The prevalence of metabolic syndrome was calculated for the entire cohort of patients and in both sex sub- groups. Finally, each component of metabolic syndrome was correlated with the severity of illness assessed by the LOS and the admission YMRS score.

Results

There were 41 patients in the study: 17 men and 24 women. The mean age of the sample was 41 (SD = 11) years. The mean LOS was 16 (SD = 10) days. The mean YMRS score was 36 (SD = 9). The mean BMI was 31 (SD = 8).

Fifty-six percent of the sample met modified NCEP-ATP III criteria for metabolic syndrome, 41% were obese, 71% had dyslipidemia, 62% were hypertensive, and 48% were diabetic or prediabetic (Figure 1). The mean LOS and YMRS scores were numerically higher in patients with obesity, dyslipidemia, diabetes or prediabetes, and metabolic syndrome than in individuals without these metabolic disorders (Figure 2 and Figure 3). However, perhaps because of the small sample size, the differences in values did not achieve statistical significance. At the time of discharge, the patients were typically maintained on combinations of mood stabilizers and antipsychotic medication, but the cross-sectional nature of this study precluded making a valid correlation between psychotropic compounds and metabolic effects.

Discussion

In the present study, the prevalence of metabolic syndrome in patients hospitalized with bipolar disorder (56%) was dramatically higher than the prevalence observed in community samples (25%).18 The magnitude of comorbid metabolic disorders correlated positively with the severity of the mood disorder.

This suggests that patients with more severe mood disorders may be more susceptible to metabolic conditions such as visceral obesity, hypertension, dyslipidemia, and diabetes. Future studies using larger patient populations are needed to confirm this finding.

If metabolic disorders such as obesity, diabetes, dyslipidemia, and hypertension are in fact common complications of mood disorders, as they appear to be, then perhaps early and effective interventions in bipolar disorder may prevent the development of these metabolic consequences.2 Primary preventive measures such as regular physical exercise and dietary counseling should be routinely incorporated into the long-term treatment plan for patients.2

Medications used in the treatment of bipolar disorder are commonly associated with weight gain.19-21 Antipsychotic drugs have been implicated in new-onset diabetes and in dyslipidemia.22,23 In addition, divalproex sodium is associated with polycystic ovarian syndrome.24 Current treatment guidelines require that psychiatrists routinely screen for the presence of obesity, dyslipidemia, hypertension, and dysglycemia.22 Considering the emerging recognition of the true enormity of the metabolic consequences of bipolar disorder, drugs with an advantageous metabolic profile should be considered as first-line therapy in the long-term management of this condition.

Dr D'Mello is associate professor in the department of psychiatry at Michigan State University in East Lansing. He reports that he has received speakers honoraria from Bristol-Myers Squibb, Pfizer, Janssen, and AstraZeneca and served as a consultant for Pfizer.

Dr Narang is a psychiatrist in private practice in Batesville, Ark. She reports that she has no conflicts of interest concerning the subject matter of this article.

Dr Agredano is a resident in the department of family practice at the Natividad Medical Center in Salinas, Calif. She reports that she has no conflicts of interest concerning the subject matter of this article.

Drugs Mentioned in This Article
Divalproex (Epival, Depakote)

References

1. Krishnan KR. Psychiatric and medical comorbidity of bipolar disorder. Psychosom Med. 2005;67:1-8.

2. Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293:2528-2530.

3. McIntyre RS, Konarski JZ, Misener VL, Kennedy SH. Bipolar disorder and diabetes mellitus: epidemiology, etiology, and treatment implications. Ann Clin Psychiatry. 2005;17:83-93.

4. Yamamoto H, Nagai K, Nakagawa H. Additional evidence that the suprachiasmatic nucleus is the center for regulation of insulin secretion and glucose homeostasis. Brain Res. 1984;304:237-241.

5. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005;165:863-867.

6. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol. 2005;99: 1998-2007.

7. Tsai SY, Yang YY, Kuo CJ, et al. Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania. J Affect Disord. 2001; 64:185-193.

8. Swann AC, Secunda SK, Koslow SH, et al. Mania: sympathoadrenal function and clinical state. Psychiatry Res. 1991;37:195-205.

9. Watson S, Gallagher P, Ritchie JC, et al. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry. 2004;184:496-502.

10. Basat O, Ucak S, Ozkurt H, et al. Visceral adipose tissue as an indicator of insulin resistance in nonobese patients with new onset type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2006;114:58-62.

11. Lilliker SL. Prevalence of diabetes in a manic-depressive population. Compr Psychiatry. 1980;21:270-275.

12. Cassidy F, Ahearn E, Carroll BJ. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry. 1999;156:1417-1420.

13. Regenold WT, Thapar RK, Maran C, et al. Increased prevalence of type 2 diabetes mellitus among inpatients with bipolar I and schizoaffective disorders independent of psychotropic drug use. J Affect Disord. 2002; 70:19-26.

14. Basu R, Brar JS, Chengappa KN, et al. The prevalence of the metabolic syndrome in patients with schizoaffective disorder'bipolar subtype. Bipolar Disord. 2004;6:314-318.

15. Fagiolini A, Kupfer DJ, Houck PR, et al. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry. 2003;160:112-117.

16. Fagiolini A, Frank E, Scott JA, et al. Metabolic syndrome in bipolar disorder: findings from the bipolar disorder center for Pennsylvanians. Bipolar Disord. 2005;7:424-430.

17. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary: the third report of the National Cholesterol Education Program (NCEP). JAMA. 2001;285:2486-2497.

18. Alexander C, Landsman P, Teutsch S, Haffner S. NCEP-defined metabolic syndrome, diabetes and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52: 1210-1214.

19. Mackin P, Watkinson HM, Young AH. Prevalence of obesity: glucose homeostasis disorders and metabolic syndrome in psychiatric patients taking typical or atypical drugs: a cross sectional study. Diabetologia. 2005;48: 215-221.

20. Morriss R, Mohammed FA. Metabolism, lifestyle and bipolar affective disorder. J Psychopharmacol. 2005;19:94-101.

21. Marken PA, Pies RW. Emerging treatments for bipolar disorder: safety and adverse effect profiles. Ann Pharmacother. 2006;40:276-285.

22. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care. 2004;27:596-601.

23. Gergerlioglu HS, Savas HA, Celik A, et al. Atypical antipsychotic usage-related higher serum leptin levels and disabled lipid profiles in euthymic bipolar patients. Neuropsychobiology. 2006;53:108-112.

24. Verrotti A, Greco R, Latini G, Chiarelli F. Endocrine and metabolic changes in epileptic patients receiving valproic acid. J Pediatr Endocrinol Metab. 2005;18:423-430.

Evidence-Based References

    * Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care. 2004;27:596-601.

    * Fagiolini A, Frank E, Scott JA, et al. Metabolic syndrome in bipolar disorder: findings from the bipolar disorder center for Pennsylvanians. Bipolar Disord. 2005;7:424-430.


Diabète, dépression : un cocktail explosif

Par Destination Santé  
vendredi 9 mars 2007, 9h00

C'est connu, diabète de type 2 et dépression peuvent être à l'origine de complications cardio-vasculaires. Mais lorsqu'ils se combinent, le cocktail devient... détonant. Par rapport à un dépressif, un patient à la fois diabétique et dépressif aurait ainsi un risque de mortalité majoré de 30%.

Le Pr Anastasia Georgiades et ses collègues du Duke University Medical Center aux Etats-Unis, ont suivi près de 1 000 cardiaques pendant 4 ans. Leur objectif, évaluer le sur-risque de mortalité chez les patients cumulant diabète de type 2 et dépression.

Résultat, une surmortalité de 20% à 30% a été observée chez ces malades, en comparaison avec le reste de la cohorte qui ne souffrait si l'on ose dire, que de dépression. « Nos données dévoilent une importante interaction entre les 2 pathologies », observent les auteurs. « Le diabète de type 2 et la dépression révèlent un effet synergique que nous ne comprenons pas encore très bien. » Autrement dit, le cumul de ces 2 facteurs de risque aurait sur notre santé, des conséquences encore plus graves que lorsqu'ils agissent séparément. Aujourd'hui en France, 3 millions de personnes souffrent d'un diabète de type 2. Et un enfant sur six est obèse. C'est deux fois plus qu'il y a 10 ans...

Source : American Psychosomatic Society, 09 mars 2007


Suicidal Ideation and Pharmacotherapy Among STEP-BD Patients

Joseph F. Goldberg, M.D., Michael H. Allen, M.D., David A. Miklowitz, Ph.D., Charles L. Bowden, M.D., Carrie J. Endick, C.S.W., Cheryl A. Chessick, M.D., Stephen R. Wisniewski, Ph.D., Sachiko Miyahara, M.S., Kemal Sagduyu, M.D., Michael E. Thase, M.D., Joseph R. Calabrese, M.D. and Gary S. Sachs, M.D.
Psychiatr Serv 56:1534-1540, December 2005

OBJECTIVE: Little is known about the effects of lithium on suicidal ideation or about the possible antisuicidal effects of divalproex, second-generation antipsychotics, or antidepressants among persons with bipolar disorder.

METHODS: Using a cross-sectional design, the authors examined patterns of psychotropic drug use relative to suicidal ideation among 1,000 patients with bipolar disorder in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

RESULTS: The presence of suicidal ideation was similar between patients who were taking any lithium and those who were not (22.2 percent and 25.8 percent, respectively) and between those who were taking any divalproex and those who were not (20.3 percent and 21.5 percent). Suicidal ideation was significantly more prevalent among patients who were taking a second-generation antipsychotic than those who were not (26 percent and 17 percent) and those who were taking an antidepressant and those who were not (25 percent and 14 percent). After other variables had been controlled for, lithium prescriptions were significantly more common among patients who had suicidal ideation.

CONCLUSIONS: Among patients with bipolar disorder who have suicidal ideation, antidepressants and second-generation antipsychotics appear to be prescribed by community practitioners more often than other medications, with lithium reserved for those with more severe illness characteristics.



 



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