The French cohort of the EMBLEM study followed over 24-months showed considerable use of antimanic combinations and concomitant treatments, in particular antidepressants. Mixed states were common and their illness prognosis was poorer compared to the pure mania patients.
Analysis of the EMBLEM cohort provides information on the follow-up, treatment and course of bipolar disorder over the 24-month period. With six out of ten patients in remission during the follow-up period, EMBLEM provides confirmation that long-term treatment of bipolar disorders brings lasting attenuation of bipolar symptoms. Following the difference observed between the rates of relapse and the rates of recurrence, it could be thought that once stabilization has been achieved, antimanic drugs are relatively efficacious in the long term, with lower rates of recurrence.
Characteristics of mixed states
The prevalence of MS at baseline in the French cohort of EMBLEM was 34% (n = 262), in line with two other cohorts EPIMAN  and EPIMAN-II-Mille  (respectively 37% and 30%), which used a different categorical definition, but higher than in the European EMBLEM cohort (24%). It could be considered that, in France, psychiatrists are more attuned to identifying the associated depressive symptoms.
The study confirms the characteristics that were previously associated with MS in studies involving small populations (except for the EPIMAN-II-Mille study): patients are predominantly female [5, 16], with a higher risk of suicide [7, 16], earlier appearance of bipolar symptoms, a higher occurrence of manic episodes and depressive episodes in the past 12 months  and rapid cycling . Comorbidity related to substance abuse and dependence commonly identified in the literature [4, 16, 18, 19] was not found; although there was no standardized instrument for addiction screening in the present study.
At 24 months, mixed state patients had a lower recovery rate than pure mania patients (36% vs. 46%, p = 0.006), with a comparable "simple" remission rate. This observation highlights the lasting nature of the functional issues associated with MS (significantly higher work impairment and dissatisfaction with life) and a residual clinical symptomatology showing significantly higher CGI-BP-depression and hallucination scores and more attempted suicides. The course of MS seems worse than in PM patients, with higher rates of recurrence and 1.5 times more MS experiencing recurrence, although these failed to reach significance.
These observations highlight the importance of systematic screening in mania co-occurring with depressive symptoms  and a specific course of care.
The observations also suggest, that for certain patients, the persistent nature of residual symptoms can have an effect on bipolar patients' quality of life and predispose relapse .
Antimanic treatment combinations
Treatments initiated for pure mania and mixed states in this study were characterized by a high proportion of combinations throughout the 24-month period, although less than one patient out of three maintained the same combination. Guidelines for treating an acute manic episode, however, recommend initiating monotherapy [1, 2]. The number of mixed state patients with a poorer prognosis and which are harder to stabilize could partly explain the high proportion of treatment combinations.
The study design suggested including an equivalent number of patients taking olanzapine and other oral antimanic drugs. Analysis of the medications prescribed does not, therefore, give a precise picture of current practice, especially as regards the use of the various antimanic drugs, but it can offer a better understanding of prescriptions of combinations with atypical antipsychotic agents. AAP agents are frequently prescribed in combination with anticonvulsants or lithium, with a higher proportion of AAP + anticonvulsants in PM patients and AAP + lithium in MS patients. A number of studies have highlighted a limited efficacy of lithium in MS patients [1, 19, 21]. Combinations of AAP and Lithium or Valproate are recommended for severe forms in several guidelines .
One of the important outcomes of this study was the frequent use of antidepressants and this was also seen in the European cohort . Similar prescription patterns of antidepressants in mania have already been reported [16, 23].
The use of antidepressants, however, is not indicated [1, 2] in the treatment of manic or mixed episodes, due to a risk of inducing mood switches  and rapid cycling . It is possible that in this cohort, the high occurrence of MS explains the high rate of prescription of antidepressants as much as the high rate of prescription of antidepressants can explain the transition to an MS.
A number of explications can be put forward for the level of antidepressant prescriptions, with in first position the frequent co-occurrence of depressive symptoms with manic states. Three times more antidepressants are prescribed for an MS episode than for a PM episode. Mixed-state episodes do not by themselves, however, explain the total number of prescriptions. 15% of PM patients were prescribed an antidepressant for the initial treatment of their episode, and more than one out of four over the 24 months. There are other reasons relating to why the physician prescribed or maintained an antidepressant, such as the continuation of a prescription for a previous depression, misgivings concerning a brutal discontinuation of antidepressants, anxiety concerning a depressive switch, the patient's insistence on maintaining his/her treatment and also certain psychopathological hypotheses which consider that mania constitutes a depressive equivalent which needs to be treated, etc.
Benzodiazepines (BZD) are also commonly prescribed, both initially and over the long term, especially for MS patients. BZDs are used when treating an acute episode of agitation [1, 2], but they are not recommended for long-term use. The brutal and disconcerting mood swings in the mixed states can contribute to the anxiety frequently experienced in such cases and can explain the high prescription levels [16, 18, 24]. For patients suffering from associated anxiety disorders, certain guidelines recommend using an atypical antipsychotic over the long term .
This was a prospective observational study, which is subject to the usual biases related to this kind of study, in particular observation biases. The effect of the study design, which requested investigators to include an equivalent number of patients prescribed olanzapine and those taking other antimanic drugs, was discussed above in the analysis of prescription patterns.
The post hoc dimensional definition of mixed states in the study is an important limitation that needs to be factored into the interpretation of the results. Although the inclusion criteria specified that mixed states should be included in the same way as pure mania episodes, MS diagnosis was not reported separately. The definition chosen is likely to include states that are significantly different to pure mixed states, especially as regards states associating depressive and manic symptoms to varying degrees, such as dysphoric mania or mixed depressions [4, 6, 17]. However, the chosen CGI-BP-mania and depression thresholds (>3) were strict enough for most of these states to be considered as pure mixed states. This post hoc analysis is important in that it confirms the frequency of a clinically-significant associated depressive symptomatology in mania and measures the effect on the course and treatment patterns of bipolar disorder.