Staging in bipolar disorder: from theoretical framework to clinical utility

Abstract

Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an atrisk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end-stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage-specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage-specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at-risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative-type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.

Exploring the clinical utility of two staging models for bipolar disorder

“…Several markers for clinical disease progression were assessed. These were selected based on earlier recommendations including BD in parents, childhood physical abuse, childhood sexual abuse, age at onset, episode acceleration, increasing or decreasing episode severity and treatment resistance (Table ). Treatment resistance was operationalized as the currently used number of classes of pharmacotherapeutic interventions (use of classic mood stabilizer, antipsychotics, antidepressants).…”

“…Both models take a complementary perspective on illness progression, and are studied separately, but not in relationship to each other. External criteria have only been tested for each model separately.…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…The concepts of clinical progression and neuroprogression have provided the basis for the development of staging systems in BD 30. Overall, the staging models describe three broad clinical stages: (I) individuals at increased risk for developing BD due to family history as well as certain subsyndromal symptoms predictive of conversion into full‐blown BD; (II) patients with fewer episodes and optimal functioning in the interepisodic periods, and (III) patients with recurrent episodes as well as decline in functioning and cognition 31.…”

Current understandings of the trajectory and emerging correlates of cognitive impairment in bipolar disorder: An overview of evidence

“…In cross‐sectional studies explicitly comparing patients with a single mood episode to those with multiple episodes, larger cognitive impairments have generally been found in the latter irrespective of mood state . In the context of an absence of age differences between single and multi‐episode groups, this has been taken by some to indicate progressive cognitive dysfunction that may directly owe to the cumulative biological toxicity associated with repeated mood episodes—a key notion of the clinical staging framework . However, given evidence of cognitive dysfunction in adult first degree relatives of BD that frames cognitive impairment as the outcome of genetic liability, it is also plausible that more severe cognitive impairment in those with repeated episodes represents a marker of a more severe illness phenotype rather than a function of illness progression .…”