Managing mixed mood states by maintaining a maintenance mindset?

Another flaw in the human character is that everybody wants to build and nobody wants to do maintenance.

Hocus Pocus, Kurt Vonnegut (1922–2007)

The management of mixed mood states is difficult for several reasons. First, mixed states are poorly and variably defined, with Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) failing to capture clinical reality (Sani and Swann, 2020). Second, because mixed states have been under-recognised, research informing management is extremely modest as compared to other acute presentations (mania and bipolar depression). And third, the management of mixed states is inherently complex because it entails treating diverse symptoms across separate dimensions (Cuomo et al., 2020).

Recent guidelines for the management of mood disorders are among the first to provide specific advice for the management of acute mixed presentations; details can be found both in the comprehensive document (Malhi et al., 2021) and a recently published summary (Malhi et al., 2020). In this editorial, drawing on the similarities and differences between maintenance therapy and acute mixed presentations, we discuss the principles of management with a view to providing a framework for navigating these complex presentations.

Commonalities

Strategy

In the management of mixed states and bipolar disorder maintenance therapy, the principal goal is to achieve mood stability. This is somewhat different to the goals when treating acute mania and bipolar depression, where the initial aims are to ameliorate current symptoms, achieve remission and then recovery. In other words, treatment is focused on reducing symptoms from one particular polarity of mood. In contrast, in mixed states and maintenance therapy, it is necessary to address the full spectrum of symptoms from both mania and depression and take into consideration the possibility that treatment of one set of symptoms may exacerbate others. In both phases of bipolar disorder, it is important to institute lifestyle interventions that restore chronobiological rhythms, in particular sleep hygiene, and to cease medications and substances that may exacerbate changes in mood. It is also important to provide appropriate psychoeducation, so as to ensure an appreciation of the long-term goals of treatment.

Treatment

Tailoring pharmacological management requires careful appraisal – the components of which are similar for both acute mixed states and maintenance therapy. In both instances, it is helpful to determine whether the individual has a bipolar mixed presentation (where there is no predominance of either mania or depression), or a unipolar mixed presentation, such as mixed mania or mixed depression (where the symptoms are predominantly manic or depressive, respectively). Therefore, a thorough assessment of predominance, pattern of illness and prior responsiveness, along with a detailed characterisation of current presenting symptoms and any precipitants, is critical. It is also useful to review the full spectrum of symptoms according to the Activity, Cognition and Emotion (ACE) model (Malhi et al., 2018), which places necessary emphasis on recognising individual symptoms within domains that can then be targeted with specificity, instead of treating broad depressive and manic syndromes. Clearly, this requires a more sophisticated approach to assessment and appraisal at the outset, but in terms of management it is more likely to be successful and achieve greater functional recovery.

Comparing the Choices recommended for the management of mixed states and maintenance in bipolar disorder, it is clear that there is significant overlap (see Malhi et al., 2021, Figures 30 and 32). For example, for the treatment of bipolar mixed states, where there is no predominance of either mania or depression, lithium, valproate and quetiapine (either as monotherapy or in combination) are common to both. Similarly, aripiprazole is advocated for both mixed mania and maintenance therapy, where a recurrence of manic symptoms is more likely than that of depression. However, there is a subtle difference between the management of mixed depression and prophylaxis for bipolar depression, with lamotrigine being given preference over lurasidone for long-term management; although lurasidone can be combined with lamotrigine for maintenance therapy, especially if depression is likely to recur.

Given these commonalities, the key point for consideration is that not only are the appraisal and formulation of acute mixed states and maintenance therapy similar, but that as a consequence of these shared elements, the approach to management is comparable. In other words, when managing acute mixed presentations, it is helpful to bear in mind long-term maintenance therapy because many of the same considerations and principles determine treatment choice. It is also important to note that once an individual has experienced a mixed mood state, it is likely that this will recur, and this also needs to be factored into the planning of long-term management. To this end, it is essential that the symptom profile of the patient is meticulously mapped, and to achieve this, a longitudinal perspective is fundamental and may require a number of assessments over a period of time. A detailed and comprehensive assessment, both of the phenomenology and past treatments, will also provide insights as to which therapies have been helpful for particular symptoms and symptom domains, and which interventions are perhaps more prone to exacerbating the illness.

Differences

Clearly, the acuity of a mixed state presentation distinguishes its treatment from the long-term management of bipolar disorder, where the focus is more so on maintaining wellness and preventing the recrudescence of symptoms. Therefore, when managing acute mixed states, it is important to identify those symptoms that require urgent attention, while simultaneously maintaining awareness that some symptoms and perhaps whole symptom domains are likely to respond more swiftly than others. For example, marked agitation requires prompt attention and usually it can be dealt with swiftly by administering sedating medications such as benzodiazepines and/or atypical antipsychotics. However, cognitive and emotional symptoms generally take much longer to respond fully and may in some instances be transiently exacerbated by treatments that reduce anxiety and agitation. Such competing actions make the management of acute mixed states challenging and it is here that an approach similar to that of maintenance therapy can be helpful – for example, utilising mood-stabilising medications alongside those that have acute effects.

Conclusion and future directions

As underscored in the recent College guidelines, the key to successfully managing bipolar disorder is long-term maintenance therapy (Malhi et al., 2021). However, in practice, the management of acute episodes of bipolar disorder has generally received greater attention, even though, in order to prevent future episodes, it is maintenance therapy that needs to be optimised. At the same time, mixed states have been largely overlooked, and only recently has there been a resurgence of interest in these more complex and challenging presentations that impact a significant proportion of patients with mood disorders. Mixed states are at the nexus of major depressive and bipolar disorders and create the phenomenal continuity that poses difficulties for our current therapeutic armamentarium, which has been largely developed to treat distinct phases of illness. And therefore, presently, the management of mixed mood states is necessarily complicated. But hopefully, with further research, more targeted therapies will emerge and a better understanding of how to optimally manage mixed states will be achieved. In the meantime, modelling the management of mixed states along the same lines as that of instituting maintenance therapy may be useful, especially as most patients eventually need to have treatments that maintain long-term mood stability and therefore acute management inevitably graduates to maintenance therapy.

Future clinical research needs to inculcate more sophisticated dimensional models of symptoms and syndromes into evaluation and diagnosis. It also needs to adopt a longitudinal perspective and make this integral to the management of complex presentations, such as mixed mood states, where competing contingencies are often the norm. Studies need to be undertaken that explore how therapies can be used to target specific components of a mood disorder (e.g. symptoms or domains) and also determine the optimal sequencing of treatments to achieve mood stability. Such new knowledge is necessary to develop a nuanced approach to the management of mixed states and further refine the maintenance therapy of bipolar disorders.