Consensus Meeting

ECNP Consensus Meeting March 2000 Nice: Guidelines for Investigating Efficacy in Bipolar Disorder

Anxiety symptoms are prevalent in bipolar disorder (BD) even during periods of remission and impede treatment efficacy, prognosis and functional capacity. This highlights a pressing clinical need to identify novel effective anxiety treatments. This systematic review aimed to evaluate the evidence within the field.

Following PRISMA guidelines, we conducted a systematic search on PubMed, PsycInfo, EMBASE and Cochrane Library for randomised controlled trials (RCTs) targeting anxiety in remitted BD patients.

We identified 10 RCTs investigating the effects of psychological or pharmacological treatments on anxiety in remitted BD patients. Two studies of transdiagnostic personalised cognitive behavioural therapy (CBT) found a treatment-related reduction in anxiety. This evidence was preliminary given small sample size and use of self-report measures in a single-blind trial design, respectively. The remaining six psychological intervention trials provided more preliminary evidence due to several methodological challenges. The two pharmacological studies found anxiolytic effects of add-on olanzapine or methylene blue to lithium treatment, respectively. Nevertheless, this evidence should be interpreted with caution given high drop-out rates and substantial side-effects that may have impeded blinding.

We did not conduct a quantitative meta-analysis.

There is preliminary evidence for beneficial effects of modified CBT and add-on pharmacotherapy on residual anxiety in BD. Future trials should pre-screen participants for anxiety, define one clinician-rated anxiety measurement as a primary outcome, and employ intention-to-treat analysis to assess treatment effect. This will advance treatment development and enable personalised approaches to address residual anxiety in BD, which has great clinical relevance.

Le lithium est un traitement de première intention dans les troubles de l’humeur et pourtant son usage décline, sans doute par crainte des effets secondaires et des contraintes de surveillance. Le monitoring plasmatique est essentiel pour la tolérance et l’observance. Nous avons donc comparé cette surveillance en pratique clinique avec les recommandations en recensant l’ensemble des dossiers hospitaliers et ambulatoires comportant une prescription de lithium sur un an. Le critère principal était l’adéquation aux recommandations de la surveillance de la fonction thyroïdienne, rénale, de la calcémie et de la lithiémie, sans oublier la présence ou non d’un diabète insipide néphrogénique. Quatre-vingt-dix-sept patients (soit 12,5 % de la file active suivie pour trouble unipolaire, bipolaire ou schizo-affectif) ont été retenus avec 30 % d’entre eux en totale adéquation. Les taux d’adéquation et le délai moyen du dernier contrôle étaient respectivement de : 50 % et 14 mois pour la fonction thyroïdienne ; 65 % et 16 mois pour la calcémie ; 63 % et 11,7 mois pour la fonction rénale ; 66 % et 4,7 mois pour la lithiémie. Quatre découvertes de diabète insipide étaient répertoriées. Cette étude confirme les résultats préalables de l’enquête de la National Patient Safety Agency au Royaume-Uni. L’importance d’une amélioration des pratiques est soulignée, via la formation, la psychoéducation et la mise à disposition d’outils de suivi en possession du patient. De façon concomitante, la fréquence de surveillance et le risque pour chaque paramètre sont discutés à la lumière des données récentes de la littérature, dans l’objectif de substituer aux appréhensions générales vis-à-vis de ce traitement des critères objectifs de décision personnalisée.

Lithium is one of mood disorder pharmacotherapy cornerstone. Despite being described as first line agent by most of guidelines, its prescription have declined since several years probably due to the fear of side effects which predominantly depend on posology and regular plasmatic controls. Thus, we compared monitoring advised in recommendations and clinical practice in our Teaching Hospital.

A retrospective transversal pharmacoepidemiological study was conducted. Principal judgment criterion was adequation between guidelines and naturalistic data concerning biologic parameters – thyroid and renal functions, lithium plasmatic concentration, calcemia, presence of diabetes insipidus. A maximum of medical records containing a lithium prescription were selected.

Ninety-seven patients (12.5% of mood disorder active file in our Teaching Hospital) were retained. Among them, 30% presented complete adequation concerning all biologic parameters. Adequation and mean delay of control were for each parameters respectively: thyroid function, 50% and 14 months; calcemia, 65% and 16 months; renal function, 63% and 11.7 months; lithium plasmatic level, 66% and 4.7 months. Four diabetes insipidious have been notified.

The study confirms previous findings of the National Patient Safety Agency in U.K. and highlights the clear difference between clinical practices and recommendations. Thyroid function should be better assessed because of dysregulation frequency, mood consecutive destabilization and possible supplementation. Dyscalcemia and diabetes insipidious need also particular caution because they are probably less known and can lead to treatment cessation. In the contrary, renal risk have probably been overestimated in the past and should not conduct physicians to avoid lithium on the condition that overdoses are avoided and other risk factors (interactions, cardiovascular and metabolic condition) are taken into account. Lithium plasmatic level is very important because of dose-dependant side effects and should be assessed every time treatment is changed.

Some progress could be done with patient better information and psycho-education, but also better practitioner formation. However, recent scientific evidence concerning biological monitoring is in evolution and should be taken into account for a more personalized risk evaluation.

Bipolar depression poses a great burden on patients and their families due to its duration, associated functional impairment, and limited treatment options. Given the complexity of the disorder and the advances in treatment, a number of clinical guidelines, consensus statements and expert opinions were developed with the aim to standardize treatment and provide clinicians with treatment algorithms for every-day clinical practice. Unfortunately, they often led to conflicting conclusions and recommendations due to limitations of the available literature. As findings emerge from research literature, guidelines quickly become obsolete and need to be updated or revised. Many guidelines have been updated in the last 5 years, after the last review of bipolar disorder (BD) treatment guidelines.

The purpose of this work is to systematically review guidelines, consensus meetings and treatment algorithms on the acute treatment of bipolar depression updated or published since 2005, to critically underline common and critical points, highlight limits and strengths, and provide a starting point for future research

The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta Medica/EMBASE, databases were searched using “depression”, “bipolar”, “manic-depression”, “manic-depressive” and “treatment guidelines” as key words

The search returned 204 articles. Amongst them, there were 28 papers concerning structured treatment algorithms and/or guidelines suggested by official panels. After excluding those guidelines that were not performed by scientific societies or international groups and those published before 2005, the final selection yielded 7 papers When looking into guidelines content, the results indicate a trend to the gradual acceptance of the use of the atypical antipsychotic quetiapine as monotherapy as first-line treatment. Antidepressant monotherapy is discouraged in most of them, although some support the use of antidepressants in combination with antimanic agents for a limited period of time. Lamotrigine has become a highly controversial option.

The management of bipolar depression is complex and should be differentiated from management of unipolar depression. Guidelines may be useful instruments for helping clinicians to choose and plan bipolar depression treatment by integrating the more updated scientific knowledge with every-day clinical practice and patient-specific factors; however, a further effort is needed in order to improve guidelines implementation in clinical practice. The latest updates on treatment guidelines for bipolar depression give priority to novel treatment approaches, such as quetiapine, over more traditional ones, such as lithium or antidepressants. Lamotrigine is a controversial option.

DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk – probably over 10% – that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression.

Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments.

Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD).

Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity.

Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be > 20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D > 24 at baseline.

There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures.

Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit–risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls.

The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6–8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time.

To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring.

Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a ‘relapse prevention’ design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct.

The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative.

Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is ‘time to intervention for a new episode’ for discontinuation designs.

This article attempts to summarize the current status of our knowledge and practice in the acute treatment and prophylaxis of bipolar depression. For prophylactic treatment, our knowledge about lithium firmly supports its usefulness against bipolar depression and its specific effectiveness for suicidal prevention. Valproic acid and carbamazepine could be effective, too, while lamotrigine which seems to be preferably effective against depression but not mania. The FDA has approved the olanzapine–fluoxetine combination and quetiapine monotherapy for the treatment of acute bipolar depression. The usefulness of antidepressants in bipolar depression is controversial both for acute and prophylactic treatment; guidelines suggest their cautious use and always in combination with an antimanic and mood stabilizer agent, because in some patients they may induce switching to mania or hypomania, mixed episodes and rapid cycling. Data on psychosocial intervention are restricted to the maintenance phase. Electroconvulsive therapy and transcranial magnetic stimulation are additional options for refractory patients. Bipolar depression seems to be a more difficult condition to treat than mania. Most patients need complex combination treatment although the published evidence on this type of treatment is limited.

Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania.

A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5–20 mg/day) to divalproex sodium (500–2500 mg/day) for bipolar manic or mixed episodes (N = 251). Young Mania Rating Scale (YMRS) scores ≥ 20 were required for inclusion. Patients were classified at study entry as “rapid cyclers” if they experienced ≥ 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline.

A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p = 0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p < 0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific.

Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account.

Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.