In the shadow of mania: Cognitive impairment and depression in bipolar disorder

Although manic or hypomanic episodes are the defining features of bipolar disorder (BD), depressive episodes are more prevalent and contribute more to the burden of illness;1 together with cognitive impairments, which are characteristic, yet often overlooked in BP, they remain unmet medical needs in this complex illness.In a Special Lecture at the AsCNP, experts provided insight into the nature of cognitive impairment in BD, highlighting similarities and differences to those seen in schizophrenia, and gave an update on emerging approaches to the management of cognitive impairment and depression in BD.

Cognitive impairments in bipolar disorder: A neuroprogressive trajectory

Suggesting a continuum rather than a dichotomy between schizophrenia and BD, Allan Young, Professor at King’s College London, UK, characterized the cognitive impairments typically seen in BD by outlining important similarities and differences to those seen in schizophrenia:

• On average, children who develop schizophrenia later in life have lower cognitive ability compared to their healthy peers, whereas children who later develop BD tend to have average to above-average premorbid cognitive ability.2

• In schizophrenia, impairments tend to be global across cognitive domains, while BD tends to affect specific cognitive domains.3

• While the cognitive decline tends to plateau after the first episode in schizophrenia, patients with BD experience a fall-off in cognitive functions with each mood episode, which is sustained during euthymia, resulting in a pattern of progressive or even accelerated decline over time.4


Patients with bipolar disorder experience a fall-off in cognitive functions with each mood episode, resulting in a pattern of progressive or even accelerated decline over time.


Professor Young noted that although the cognitive decline over the course of bipolar illness may appear to be related mostly to manic episodes, he noted this as likely an artifact due to the less clearly defined nature of depression, arguing that depressive episodes are at least as harmful for patients’ cognitive functions.




Depressive episodes may be at least as harmful for patients’ cognitive function as manic episodes.


Genetic data may provide a window into the nature of cognitive impairment

Professor Young continued explaining how genetic analyses have deepened our understanding of the behavioral observations. For instance, genome-wide association studies (GWAS) have found a polygenic overlap between schizophrenia and lower cognitive abilities, whereas either no or even a positive genetic correlation is seen in BD.5

According to the Professor, such data indicate that in schizophrenia, the illness and the cognitive impairment both seem to be explained by a general brain vulnerability rooted in genetic architecture, whereas the cognitive impairments in BD should likely be considered a symptom domain characteristic for the illness, and independent of mood symptoms.

Although early intervention may have the potential to arrest or even reverse neuroprogression, cognitive impairment has received little attention as a treatment target in BD, and currently no approved treatment exists, Professor Young said. He ended his talk highlighting the need for proper assessment of cognitive impairment when patients are not in a mood episode, and proposed management strategies that combine evidence-based and personalized cognitive remediation approaches with optimal pharmacotherapy, with anti-glucocorticoid agents6 as an example of a candidate pharmacological treatment.


Targeting bipolar depression – current challenges and future opportunities

Professor Lakshmi Yatham, University of British Columbia, Canada, continued the session pointing out the underestimated impact of bipolar depression, not only for neuroprogression but also for functional impairment, quality of life and risk of suicide.

He noted that although antidepressant treatment in combination with an antimanic agent – a mood stabilizer or an antipsychotic - is a common clinical strategy that may have some effect, this approach may not work for all patients; and importantly, adjunctive antidepressant treatment should not be used for maintenance treatment beyond the acute episode due to the risk of switching to mania or hypomania.7

The impact of bipolar depression is underestimated, not only for neuroprogression but also functional impairment, quality of life and the risk of suicide, and current treatment options are limited.

With the limited treatment options for bipolar depression, the Professor Yatham urged methodological advances to overcome the historical challenges in drug discovery, and also presented emerging evidence for future candidate approaches, including glutamatergic and anti-inflammatory agents, transcranial magnetic stimulation and light therapy,8 thus concluding the session on a hopeful note.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.


1. Tondo et al. Curr Neuropharmacol 2017 Apr;15(3):353-358

2. Koenen et al. Am J Psychiatry. 2009 Jan; 166(1): 50–57

3. Martinez-Aran et al. Bipolar Disord 2007

4. Lewandowski et al. Psychol Med 2011; 41:225-241

5. Smeland et al. Mol Psychiatry 2019. Published online 4 Jan 2019

6. Watson et al Biol Psychiatry 2012 Dec 1;72(11):943-9

7. McGirr et al. Lancet Psychiatry. 2016 Dec;3(12):1138-1146

8. Yatham et al. Bipolar Disord. 2018 Mar; 20(2): 97–170

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