Opening the programme was Dr Roger McIntyre, Professor of Psychiatry and Pharmacology at the University of Toronto, with his hard-hitting account of the patient burden associated with this overlooked disease state. He highlighted that diagnoses of bipolar are often disputed from clinician to clinician but went on to point out that this stress for the patient is further exacerbated by delays when concurrent manic and depressive symptoms are present.

Dr McIntyre’s focus then shifted to the comorbidities associated with mixed state; co-morbidities which are both wide-ranging and severe. The first of these was excess weight and obesity, a state which is especially prevalent in patients suffering mania with depressive symptoms.

McIntyre went as far as to suggest that weight gain might have a reinforcing effect on concurrent symptoms, increasing the incidence of subclinical depression by constricting neural blood-flow. The marked tendency towards weight-related health problems is accompanied by a greatly higher prevalence of cardiovascular disease, higher rates of disability, unemployment and educational disruption.

These states, he concluded, combine to make bipolar one of the most lethal mental disorders regularly seen, and one in desperate need of attention and action.

Professor Alan Swann, following next, continued to emphasise bipolar disorder’s history of complexity by discussing its characterisation by the great Emil Kraepelin in the late 19th Century.

Kraepelin, Swann reminded us, did not just define the general concept of bipolar disorder, he also assigned it a symptom profile very similar to that of the mixed state concept now being espoused. This was comprised of six distinct states based on combinations of depressive or manic affect, thought and behaviour.

This, combined with the acknowledgement of mixed states in no fewer than four separate mental health guidelines during the late 20th century, meant that Swann believes the inclusion of the mixed specifier into DSM-5 should not be seen as an upheaval but as a timely recognition of a well-established principle.

Pure manic symptoms, he said, were vital to distinguish from the manic symptom of activation, present in mixed state. This activation, he believed, was one of the most deadly symptoms of a mixed state, as whilst the depressive aspects are obviously extremely damaging, they tend to rob the patient of the will to act. Mix these depressive symptoms with activation, however, and the addition of inner tension and the energy to act on feelings of hopelessness make a mixed state particularly dangerous.

That is why, Swann said, seeing past the obvious manic symptoms to identify any present subsyndromal depression is vital and could be achieved in one of several ways. The use of indicator symptoms such as anxiety, agitation or irritability was extremely useful, as was investigation for activation of the HPA axis – seen in mixed state but not pure mania.

However he also highlighted the MINI questionnaire, a diagnostic tool designed to detect concurrent symptoms, and suggested having it self-administered by patients. With a current 80% level of agreement between patient self-diagnosis and clinician confirmation, this he said, would give psychiatrists a clearer picture of patient type even before diagnosis, and thus more time to tailor treatment.

Treatment was the subject of the symposium’s final speaker, Professor Eduard Vieta, presenting an overview of existing treatments and their suitability for mixed-state. He emphasised the high prevalence of polypharmacy for this patient group but pointed to a lack of trial data as being to blame; low-powered trials with none focussed purely on mixed-state patients.

While the bulk of his data-rich presentation was raw statistics, a theme that particularly stood out was the weight of evidence for prescribing an antipsychotic, during a manic episode. There is little evidence in the field based on new DSM-5 criteria. Here asenapine* post-hoc data shows significant superiority to placebo in treating mania with depressive symptoms.

The data also demonstrated a significant difference vs. olanzapine, when DSM -5 definitions were applied to mild, moderate and, in one small group, severely depressed manic patient cohorts.¹

Professor Vieta closed with an assertion that long-term evidence was the next vital ingredient of a truly mixed-state-focussed treatment. He encouraged all his colleagues to focus on patient education in order to improve adherence, adoption and effectiveness and to allow gathering of this long-term data.

Mania with depressive symptoms is, without doubt, a complex area to diagnose and treat. However, the arguments and information put forward by these three experts makes it clear that attention is finally being paid and that the conversation, whilst only just beginning, is being steered by individuals with a clear vision for the future of bipolar I disorder.

*Indication: Moderate to severe manic episodes associated with bipolar I disorder in adults