The interviewee declares no conflict of interest.

Bipolar patients with mixed features present cases with transient psychotic symptoms, rapid-cycling features and prominent anger in the context of low mood and anhedonia. The significant therapeutic consequences indicate the need to increase diagnostic knowledge, especially from a long-term therapeutic perspective.

AZ: According to your point of view, what is the most relevant factor that increased antipsychotics prescription in recent times?

MF: Assuming we are dealing specifically with the increased prescription trend of second-generation antipsychotic (SGA) within the past decades, I would prompt-out more than just one single major factor accounting for this.

Specifically, sponsorship, the goal for better efficacy and tolerability profile over the first-generation class (not necessarily achieved in full for all the SGA compounds), and the increased awareness about the trans-nosological effect of many of the SGA compounds in line with the acknowledgment of the existence of “rarity zones” beyond the classic Kraepelin dichotomy, would all play a major explanatory role for the trend. Overall, the increased diagnostic sensitivity of many clinicians about the broad bipolar spectrum and the presence of peculiar specifiers and features playing a role in differential diagnosis and therapeutic response would represent the very major explanatory factor from my point of view.

What are the main difficulties for the diagnosis of bipolar depression with mixed features at the present time?

Thank you for your question, which poses major clinical concerns. Basically, many prescribing clinicians substantially disregard the relevance of given specifiers. Moreover, these latter are hampered by significant construct validity issues. This is with reference with the approach adopted by the DSM-5 mixed features specifiers which would seamlessly apply to either major depressive episodes in the context of major depression or bipolar depression, given that overlapping symptoms would not need to account for differential diagnosis. As proved by increasing amount of evidence, the systematic disregard of the mentioned overlapping features, namely, distractibility, irritability, and psychomotor agitation [DIP], would hinder the differential diagnosis of bipolar mixed depression over the claimed “unipolar” major depressive episode with mixed features. Huge therapeutic implications would solicit greater diagnostic awareness, especially from a long-term management perspective.

What are the clinical features of mixed bipolar depression most frequently attributed to another psychiatric disorder?

BD patients with mixed features would encompass cases with transient psychotic features, with rapid-cycling features, and prominent anger in the context of low mood and anhedonia. In case of unstable mixed features, borderline personality disorder would probably represent a preferred diagnosis for some psychiatrists. It substantially depends on the education and clinical background of the diagnosing clinicians. Yet, therapeutic approaches would differ and eventually led to sub-optimal response or even worsening of the course of illness over the time, which is compelling especially in the presence of suicidal behaviour.

What are the positive and negative contributions from DSM-V for bipolar depression diagnosis?

The DSM-5 posed greater attention about the impact of some course specifiers compared to the DSM-4. Beyond the afore mentioned questionable validity of some of these construct, clinicians are now more aware about the existence of multiple presentations of bipolar depression. In addition, the DSM-5 chapter about bipolar disorders now poses emphasis about the quantitative (yet not necessarily qualitative) relevance of depression over hypomania in the longitudinal course of BD. This is extremely relevant, as this would prompt out the prescribing clinicians to conscientiously prescribe antidepressants when a diagnosis of lifetime bipolar disorder is made, which is on turn often hindered by the predominant depressive polarity and recall bias many BD patients present and/or acquire over the time.

What are the most serious mistakes in the pharmacological treatment of mixed bipolar depression?

Antidepressant monotherapy. No doubt about this. Yet, I want to stress-out the fact that while the emerging role of some SGAs adjunctive therapy for bipolar depression with mixed features is intriguing, evidence-based treatments endorsed by well-established guidelines are yet to come basically due to publication bias at this time.

What are the key points to reduce polypharmacy in patients with bipolar depression?

A systematic review on polypharmacy in bipolar disorder (Fornaro M et al., 2016) attempted to address this question as well as the putative issues leading to polypharmacy in BD, which by the way it is the rule rather than the exception regardless the substantial lack of guidelines endorsement for most of the patients. Basically, lithium inversely correlated with psychotropic polypharmacy (permissive criterion of “two or more”). Selected SGAs (yet adjunctive to either lithium, valproate or carbamazepine in most of the cases) may probably inversely correlated with treatment-non-response and need for complex polypharmacy in BD when lifetime rapid-cycling and/or mixed features ascertained. Yet, further evidence is needed in support of this otherwise clinically suggestive hint.

What are the essential diagnostic tools to accurate distinguish bipolar depression from unipolar depression with mixed features?

Again, an excellent question herein. Some recent evidence adopting a Bayesian approaches (namely ROC analysis) proved that the afore mentioned DIP symptoms would significantly enhance specificity and discriminant diagnosis of bipolar depression with mixed features vs. major depression overall. Yet, ad-hoc validated instruments enhancing the discriminant validity of the DSM-5 specifiers are yet to come. Discriminant analysis and factorial analysis approaches have been highlighted by the BRIDGE-II-Mix study authors, yet a questionnaire needs further validation studies.

What are the main advantages and disadvantages for the use of second generation antipsychotics versus other drug types in mixed bipolar depression?

Once again, I want to stress-out that evidence-based treatment and standard guidelines prompt for further studies on the matter. Anyway, selected SGAs may reduce the need for the afore mentioned polypharmacy, which is inversely related with short- and long-term treatment adherence in BD. A key factor indeed in the management of manic-depressive illness. Some recent compounds with better cognitive and metabolic profile vs. other SGAs, particularly lurasidone for bipolar depression with mixed features and low-dose adjunctive asenapine for mania with mixed features currently represent the most intriguing avenues in my opinion.

What atypical antipsychotics are the most fundamental priority to investigate in future studies about mixed bipolar depression?

As stated above, I think that lurasidone would probably stand-out in the near future as one of the most intriguing option of the management of bipolar depression with mixed features. Yet, stating the need for an evidence-based approach, I would prompt for additional replication studied both for the acute and maintenance treatment of this special sub-group of bipolar patients. Moreover, all the randomized clinical trials leading to FDA (extended) approval of the drug, and made publicly available for lurasidone in BD (not necessarily with mixed features only), have been sponsored by the manufacturer. Therefore, independent RCTs specifically focusing on BD cases with mixed features (according both to the “measurement biased” DSM-5 specifiers and the alternative criteria accounting for the DIP symptoms as differential diagnostic features vs. unipolar mixed depression are urged), whereas post-hoc analysis of multi-purpose, sponsored RCTs are not enough conclusive on the matter in my opinion. It will take time and money by the manufacturer to designate the most appropriate consultants and investigators to emphasize the clinical needs a vast proportion of routine out- and in-patients still have.

What features should have the ideal drug for patients with mixed bipolar depression?

Ideally, the ideal drug for the treatment of mixed bipolar depression should reduce the clinical severity (or some sort of rating score) of the DIP symptoms as a primary goal. Yet again, the current DSM-5 approach is not helping on the matter.

This is major concern, especially considering that virtually every clinical trial registered in clinicaltrials.gov or EU clinical trials would base on the DSM-5 criteria, whereas the intriguing RDoC criteria need for NIMH funding are yet to be ubiquitously accepted, and possibly represent a matter of construct validity debate themselves.