Cognition and suicidality in bipolar disorder

Bipolar disorder, characterised by alternating manic or hypomanic episodes with depressive episodes, disproportionately affects men and exhibits a familial predisposition. Its chronic nature and variable course often lead to functional, occupational, and cognitive impairments, resulting in substantial direct and indirect costs.

Mortality rates are elevated due to both natural causes, such as cardiovascular disease and diabetes, and suicide. Despite clinically euthymic periods, patients with bipolar disorder experience markedly impaired quality of life, particularly those with a history of suicide attempts.

SUICIDALITY

Bipolar I disorder is defined by manic episodes, while Bipolar II involves hypomanic and major depressive episodes. These disorders have estimated global lifetime prevalences of 0.6-1.0% and 0.4-1.1%, respectively, with varying rates across countries. Early onset, often before age 25, is common, and depressive symptoms typically accompany manic presentations.

Individuals with bipolar disorder face a remarkably heightened suicide risk, approximately 20 to 30 times higher than the general population, with the highest suicide risk among psychiatric disorders. However, suicide rates vary concerning bipolar disorder subtypes, gender, age, and illness severity.

Despite inconsistencies, bipolar disorder patients face a substantial suicide risk, with annual attempt rates estimated at 400–1400/100,000, translating to a 30- to 60-fold increase compared to the general population. Roughly one-third to one-half of bipolar patients attempt suicide, with 15 to 20% dying by suicide.

The risk of suicide varies among different phases of bipolar disorder, with major depressive episodes presenting the highest risk, followed by mixed episodes, and finally, manic episodes associated with the lowest risk. Individuals with rapid cycling bipolar disorder face a heightened risk compared to those without rapid cycling patterns.

Moreover, the risk of suicide escalates with prolonged illness duration and untreated periods, attributed to the increased frequency and duration of depressive episodes within the bipolar course. This underscores the significance of timely intervention and management, particularly targeting depressive symptoms, to mitigate suicide risk in bipolar patients.

COGNITIVE DEFECTS

Recent decades have seen heightened scholarly interest in cognitive deficits among patients with bipolar disorder, irrespective of their illness phase. Research consistently highlights significant impairments in verbal memory, attention, language, and executive function during manic, depressive, and mixed states. Cognitive decline often commences early in the disorder's course and may manifest in the prodromal phase and among first-degree relatives.

While the trajectory of cognitive function throughout the disease remains uncertain, studies suggest a correlation between cognitive impairment severity and the frequency of manic episodes or hospitalisations. It is posited that progressive cognitive decline may primarily affect a subgroup experiencing frequent manic episodes.

Identifying and intervening early with targeted strategies could mitigate symptoms in these individuals. Medications used to manage acute episodes generally enhance cognition via symptom alleviation, but their impact during euthymia remains unclear. Nevertheless, effective mood stabilisation likely benefits cognitive function, given its independent association with fewer affective episodes.

TREATMENT OPTIONS

Lithium

Lithium, the gold-standard treatment for bipolar disorder, reduces self-harm and suicidality. Studies suggest minor negative impacts on cognitive function, particularly in verbal learning, memory, and creativity. It may negatively affect psychomotor speed but not attention. In patients recovering from their first manic episode, lithium improves cognitive performance, particularly in verbal fluency.

Compared to quetiapine, lithium shows greater improvement in verbal fluency. Additionally, lithium-treated patients exhibit better working memory compared to valproate-treated patients but still show impairment compared to healthy controls. Overall, lithium also appears to enhance cognition in manic patients.

Anticonvulsants

Anticonvulsants with diverse pharmacological actions, are mostly an effective tool in bipolar disorder treatment.

Lamotrigine, approved for depressive relapse prevention, improves working and verbal memory in pediatric patients.
Valproate, effective for acute mania, shows deficits in cognitive function compared to other anticonvulsants and lithium.
Carbamazepine, used for manic and mixed states, causes cognitive deficits including memory impairment and reduced verbal fluency, potentially mitigated by controlled-release formulations.

Antipsychotics

Antipsychotics are integral in bipolar disorder treatment due to their varied therapeutic effects. While they may negatively impact verbal memory, this association may be influenced by patient characteristics.

Second-generation antipsychotics (SGAs), like quetiapine, demonstrate efficacy in acute mania and bipolar depression, with quetiapine showing favorable cognitive profiles compared to other SGAs.
Olanzapine, commonly adjunctive in mania treatment, improves cognitive function and may relate to better tolerability.
Risperidone enhances occupational functioning and cognitive flexibility when combined with mood stabilizers.
Lurasidone improves cognition in bipolar I depression, while aripiprazole shows mixed results across studies.
Asenapine's cognitive effects are minimally explored in bipolar II disorder.
Limited data exist on ziprasidone and cariprazine's cognitive impacts.

Antidepressants

Antidepressants are mainly used in combination therapy for bipolar disorder due to the risk of manic switching. Assessing their cognitive effects in bipolar disorder is challenging, with limited research available.

Studies suggest venlafaxine may positively impact verbal memory, while intravenous ketamine may improve cognition in bipolar depression.
Fluoxetine, recommended in bipolar disorder, shows lasting improvements in attention, memory, and overall cognitive performance in other psychiatric conditions, though reversible memory loss is rare.

A note on vitamin D

Individuals with bipolar disorder commonly experience somatic comorbidities like hypertension and diabetes due to lifestyle factors, medication side effects, and neuroinflammatory processes. Vitamin D, crucial for somatic and psychological health, undergoes complex metabolism to its active form, 1,25(OH)2D, with neuroprotective and antioxidant effects. It activates tyrosine hydroxylase gene expression, involved in catecholamine synthesis, thus impacting psychiatric disorders. This underscores the importance of adequate vitamin D levels in managing both somatic and psychological aspects of bipolar disorder.

CONCLUSION

In conclusion, bipolar disorder presents a complex clinical picture characterised by mood fluctuations, cognitive impairments, and heightened suicide risk. Despite advancements in treatment options, including lithium, anticonvulsants, antipsychotics, and antidepressants, managing the disorder's diverse manifestations remains challenging.

Understanding the intricate interplay between somatic comorbidities, cognitive deficits, and mood instability is crucial for providing comprehensive care. Additionally, emerging evidence suggests a potential role for vitamin D in mitigating neuroinflammatory processes and improving cognitive function, highlighting the importance of considering adjunctive treatments beyond conventional pharmacotherapy.

REFERENCES

McIntyre, RS, et al, 2020. Bipolar disorders. Lancet 2020; 396: 1841–56.

Miller, JN, et al, 2020. Bipolar Disorder and Suicide: a Review. Current Psychiatry Reports; 22:6.

Späth, Z, et al, 2023. Vitamin D Status in Bipolar Disorder. Nutrients 2023, 15, 4752.