• Rapid cycling bipolar disorder, cognitive impairment and anxiety, also relatively unexplored  

Many sub-aspects of the bipolar affective disorder disease including bipolar disorders (BDs) in children and older persons, rapid cycling BD, cognitive impairment and anxiety, are yet to be explored. 

These concerns were raised in a journals based article on ‘Update on bipolar affective disorder: Hi bipolar! Wait !!!! Do I really know you?’ which was authored by L. Amarakoon and R. Fernando and published in the Sri Lanka Journal of Psychiatry's 15th Volume's First Issue, last month (October).

The ancient illness, which psychiatrist E.W.G.M. Kraepelin named manic depressive psychosis, has developed in terminology and taxology over the years and is now known as BD according to the World Health Organisation's International Classification of Diseases, 11th Revision (ICD-11) (is a mental health condition that affects a person’s mood, energy, activity and thought and is characterised by manic or hypomanic and depressive episodes). 

The ICD-11 explains several subtypes of BD, namely bipolar type I, bipolar type II, cyclothymic (characterised by episodes consisting of hypomanic and depressive symptoms that do not meet the full criteria for bipolar or major depressive disorder), other specified bipolar or related disorders, and bipolar or related disorders unspecified (6A60 to 6A6Z). 

BD is known to be one of the top 10 leading causes of disability in the world (S. Chakrabarti's ‘BD in the ICD-11: A review of the changes, their basis, and usefulness’), with a lifetime prevalence of 1% for bipolar I and bipolar II collectively and 2-3% when the whole bipolar spectrum is considered (a British study – G.M. Goodwin, P.M. Haddad, I.N. Ferrier, J.K. Aronson, T.R.H. Barnes, A. Cipriani, D.R. Coghill, S. Fazel, J.R. Geddes, H. Grunze, E.A. Holmes, O. Howes, S. Hudson, N. Hunt, I. Jones, I.C. Macmillan, H. McAllister-Williams, D.R. Miklowitz, R. Morriss, M. Munafò, C. Paton, B.J. Saharkian, K. Saunders, J. Sinclair, D. Taylor, E. Vieta and A.H. Young's ‘Evidence based guidelines for treating BD: Revised third edition recommendations from the British Association for Psychopharmacology’). 

It is estimated that about 40 million individuals in the world have been diagnosed with BD (A.A. Nierenberg, B. Agustini, O. Köhler-Forsberg, C. Cusin, D. Katz, L.G. Sylvia, A. Peters and M. Berk's ‘Diagnosis and treatment of BD: A review’).

B. Nowrouzi, R.S. McIntyre, G. MacQueen, S.H. Kennedy, J.L. Kennedy, A. Ravindran, L. Yatham and V.D. Luca's ‘Admixture analysis of age at onset in first episode BD’ mentions two peaks in the age of onset of BD with the most common diagnosis being at 15-24 years of age, where about 70% of patients get the diagnosis, and another peak being at 45-54 years of age. Depression is the most frequent first presentation and dominates the BD illness by having about 75% of the total illness-related burden. Initial depressive presentations also delay the actual diagnosis and treatment of BD by about nine years. Apart from that, personality traits, substance use disorders, non-specific symptomatology and the inability to identify mood elevations also contribute to the delayed diagnosis of BD.

M.J. Gitlin, J. Swendsen, T.L. Heller and C. Hammen's “Relapse and impairment in BD" found that more than 50% of patients do not adhere to treatment, and that there is a reduction in life expectancy in about 12-14 years with a two-fold increase in cardiovascular mortality. Rates of relapse are found to be high despite treatment. The prevalence of tobacco smoking (45%), metabolic syndrome (a cluster of conditions that occur together, increasing the risk of heart disease, stroke and type two diabetes, and which include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride [a type of fat called lipids, that circulates in the blood] levels) (37%), obesity (21%) and type 2 diabetes (14%) also contribute to the increased mortality in BD. 

There is an annual suicide rate of 0.9% in BD, where 15-20% of patients die by suicide, thus being the psychiatric disorder with the highest rate of completed suicide (M.A. Ilgen, A.S.B. Bohnert, R.V. Ignacio, J.F. McCarthy, M.M. Valenstein, H.M. Kim and F.C. Blow's ‘Psychiatric diagnoses and risk of suicide in veterans’ and M. Nordentoft, P.B. Mortensen and C.B. Pedersen's ‘Absolute risk of suicide after first hospital contact in mental disorder’). Two-thirds of people do not return to work in the year after hospitalisation due to a manic episode (S.M. Strakowski, P.E. Keck Junior, S.L. McElroy, S.A. West, K.W. Sax, J.M. Hawkins, G.F. Kmetz, V.H. Upadhyaya, K.C. Tugrul and M.L. Bourne's ‘12-month outcome after a first hospitalisation for affective psychosis’). Poverty, homelessness, and incarceration are commonly associated with the BD diagnosis (L.A. Copeland, A.L. Miller, D.E. Welsh, J.F. McCarthy, J.E. Zeber and A.M. Kilbourne's ‘Clinical and demographic factors associated with homelessness and incarceration among Veterans Affairs patients with BD’).

Paediatric BD 

Many controversies are still associated with BD among the young, from the diagnostic criteria to epidemiological research to management.

The American Psychiatric Association's ‘Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)’ emphasises the presence of unequivocal euphoria and an episodic course as peculiar features in pre-pubertal BD and the longitudinal clinical observation before diagnosis. The irritability in mood has been recognised in a new diagnosis, namely disruptive mood dysregulation disorder (DMDD), which is not a BD diagnosis and is more common than the BD diagnosis.

A definitive diagnosis should not be made in childhood before puberty and it is suggested to conceptualise this probable clinical presentation as ‘pre-pubertal miasma’ or a syndrome rather than BD. Also, when making the diagnosis of ‘adolescent BD’ in post-puberty, one has to be more cautious than in adults (G.S. Malhi, M. Jadidi and E. Bell's ‘The diagnosis of BD in children and adolescents: Past, present and future’).

Methodological errors in ‘case identification’ and issues in sampling (prevalence becomes high in juvenile centres) in paediatric BD studies have been criticised. Later, it was clinically identified that there were conditions like obsessive-compulsive disorder, attention-deficit-hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depressive disorders or conduct disorders, which were misidentified as BD.

BD in old age

Attention has been given to older age BD (OABD) as a complex subgroup due to the increased risk of physical comorbidities, cognitive impairment, poor psychosocial functioning and premature death associated with this condition. 

In the current terminology, OABD refers to patients with BD aged 50 years and over (M. Sajatovic, S.A. Strejilevich, A.G. Gildengers, A. Dols, R.K.A. Jurdi, B.P. Forester, L.V. Kessing, J. Beyer, F. Manes, S. Rej, A.R. Rosa, S.N. Schouws, S-Y. Tsai, R.C. Young and K.I. Shulman's ‘A report on OABD from the International Society for BDs Task Force’). However, there are two other terminologies used, namely, late onset BD (LOBD), where BD onset is equal to or more than 40 years and early onset BD (EOBD), where the illness onset is less than 40 years (A.J.M. Beunders, M. Orhan and A. Dols's ‘OABD’).

Some of the key findings of the Global Aging and Geriatric Experiments in BD project are: There is no distinction between BD-I and BD-II in EOBD and LOBD; There is no difference in the severity of the manic and depressive symptoms in EOBD and LOBD; Mixed symptoms (e.g. simultaneous depressive and manic symptoms) are common in OABD, which is associated with worsened functionality; The female sex is associated with higher levels of anxiety, hypochondriasis and psychiatric hospitalisations and the male sex is associated with increased substance use disorders; On average, two or more physical comorbidities are present in OABD, so it is important to screen for cardiovascular risk factors and physical co-morbidities and to pay attention to lifestyle modifications; Cardiovascular diseases and some forms of cancers are increased in OABD; Lithium is effective and safe as a maintenance mono-therapy in OABD, and it is associated with less depressive symptoms, less rapid cycling and fewer cardiovascular co-morbidities compared to non-lithium users, while lithium users have also shown better cognitive functions than non-users; Individuals with OABD and on antipsychotics have more severe illness and frequent hospitalisations; There is low quality evidence for nutritional interventions (e.g. Vitamin D and B12) and improvement in cognitive, affective and overall outcomes in OABD; and that the OABD treatment plan should aim to improve personal and social functioning and the quality of life.

Rapid cycling BD

According to the ICD-11, rapid cycling BD (RCBD) has been defined as having at least four distinct mood episodes (major depressive, manic, hypomanic, or mixed episodes) during the previous 12 months in a person with bipolar I or bipolar II disorder. It can be considered a discrete BD pattern with a substantially increased illness related burden. Patients with RCBD have an early age at onset, a longer course of illness, greater episode burden, higher rates of substance abuse, increased suicidality, higher physical health issues and poorer psychosocial functioning (R. Strawbridge, S. Kurana, J. Kerr-Gaffney, S. Jauhar, K.R. Kaufman, N. Yalin and A.H. Young's “A systematic review and meta-analysis of treatments for RCBD”). The lifetime prevalence of RCBD ranges from 26% to 43% in patients diagnosed with BD (A. Miola, K.N. Fountoulakis, R.J. Baldessarini, M. Veldic, M. Solmi, N. Rasgon, A. Ozerdem, G. Perugi, M.A. Frye and A. Preti's ‘Prevalence and outcomes of RCBD: Mixed method systematic meta-review’). Being of the female sex, concomitant hypothyroidism and being treated with antidepressants are factors commonly associated with this condition (P.J. Harrison, P. Cowen, T. Burns and M. Fazel's ‘Shorter Oxford Textbook of Psychiatry’), while childhood maltreatment and genetic predisposition are being discussed as potential associations.

The detection and management of RCBD is often a significant clinical challenge to psychiatrists. There is a broad consensus that the treatment response is relatively poor in RCBD compared to non-RCBD. RCBD is a predictor of poor response to lithium maintenance treatment (T.P. Hui, A. Kandola, L. Shen, G. Lewis, D.P.J. Osborn, J.R. Geddes and J.F. Hayes's ‘A systematic review and meta-analysis of clinical predictors of the lithium response in BD’). M.A. Furio, D. Popovic, E. Vieta, Y. Stukalin, M. Hagin, C. Torrent, J-M. Azorin, J. Angst, C.L. Bowden, S. Mosolov, A.H. Young and G. Perugi's ‘Characterisation of RCBD patients presenting with major depressive episode within the BDs: The Improving Diagnosis, Guidance, and Education study’ suggests that patients with RCBD have to be treated with more medications and higher doses compared to non-RCBD patients. 

However, the 2023 updated National Institute for Health and Care Excellence (NICE) guidelines recommend using the same therapeutic interventions used in non-RCBD patients in the management of RCBD (‘BD: Assessment and management’). In contrast, The Maudsley Prescribing Guidelines in Psychiatry recommend a stepwise treatment strategy for RCBD (D.M. Taylor, T.R.E. Barnes and A.H. Young). This includes withdrawing antidepressants, evaluating and managing precipitants (thyroid dysfunction, alcohol use and external stressors, etc.), optimising mood stabilisers guided by plasma levels, combining mood stabilisers, and using adjunctive treatment options such as certain atypical antipsychotics. A certain atypical antipsychotic has been demonstrated to have a consistently large effect size across outcomes in managing RCBD. Data concerning the role of electroconvulsive therapy, hormonal treatments and specific psychotherapies in the management of RCBD are limited.

Cognitive impairment

Cognitive functioning in BD predicts future general functioning better than affective symptomatology. It is also postulated that cognitive functioning is associated with social and occupational functioning. The cognitive impairment in BD is found to be persistent in euthymic (a normal, tranquil mental state or mood, specifically, a stable mental state or mood in those affected with BD, and one that is neither manic nor depressive) states (M. Sanches, I.E. Bauer, J.F. Galvez, G.B. Zunta-Soares and J.C. Soares's ‘The management of cognitive impairment in BD: Current status and perspectives’), and there is significant cognitive impairment in patients with recurrent episodes compared to patients with a single episode (B.T. Baune and G.S. Malhi's ‘A review on the impact of cognitive dysfunction on social, occupational, and general functional outcomes in BD’). Cognition and emotional regulations are intricately linked, and the executive functions are mainly affected in BD.

K.W. Miskowiak, I. Seeberg, M.B. Jensen, V. Balanzá-Martínez, C.d.M. Bonnin, C.R. Bowie, A.F. Carvalho, A. Dols, K. Douglas, P. Gallagher, G. Hasler, B. Lafer, K.E. Lewandowski, C. López-Jaramillo, A. Martinez-Aran, R.S. McIntyre, R.J. Porter, S.E. Purdon, A. Schaffer, P. Stokes, T. Sumiyoshi, I.J. Torres, T.E.V. Rheenen, L.N. Yatham, A.H. Young, L.V. Kessing, K.E. Burdick and E. Vieta's ‘Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for BDs Targeting Cognition Task Force’ found that cognitive remediation shows the most consistent cognitive benefits, and that pharmacologically, a certain wakefulness-promoting medication and a certain antipsychotic have early positive results. There is an association between executive functioning and emotional regulation. J.M. Koay and A.V. Meter's ‘The effect of emotion regulation on executive function’ seeks to improve working memory (which is a part of executive functioning) with the aim of improving emotional regulation and cognition.

Anxiety

Anxiety disorders are seen in nearly half of bipolar patients (F.S. Goes's ‘The importance of anxiety states in BD’ and M.S. Spoorthy, S. Chakrabarti and S. Grover's ‘Comorbidity of bipolar and anxiety disorders: An overview of trends in research’). The lifetime prevalence of anxiety disorders among adults with BD ranges from 41% to 47%. Among anxiety disorders, panic disorder had the highest lifetime prevalence (17-22%), followed by generalised anxiety disorder (13-20%), social phobia (13-20%), specific phobias (11%) and agoraphobia (8%). The DSM-V and ICD-11 classification systems encourage clinicians to identify anxiety symptoms in bipolar patients and specify using the ‘with anxious distress’ and ‘with prominent anxiety symptoms’ specifiers, respectively, to plan treatment and monitoring.

The presence of co-morbid anxiety disorder in bipolar patients is associated with more adverse consequences, such as having more frequent and severe depressive episodes, the longer duration of illness, increased substance abuse, higher rates of suicidal attempts, and a greater likelihood of treatment non-response (R.N. Jensen, C. Csillag and M. Vinberg's ‘Anxiety in patients with bipolar affective disorder’ and K. Latalova, J. Prasko, A. Grambal, P. Havlikova, D. Jelenova, B. Mainerova, D. Kamaradova, M. Ociskova, Z. Sedlackova and A. Sandoval's ‘BD and anxiety disorders’). Though there is a significant influence of anxiety symptoms on the course and outcome of BD, the identification and effective management of anxiety disorders in bipolar patients often remain neglected.

There is a considerable risk of using standard treatments for anxiety disorders, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in bipolar patients, due to the risk of mood destabilisation and manic switch. In general, mood stabilisation is the priority over addressing anxiety disorders in bipolar patients. Following the initial standard treatment with second-generation antipsychotics and mood stabilisers, antidepressants can be used to manage anxiety symptoms with caution and close monitoring (C.A. Ott's ‘Treatment of anxiety disorders in patients with co-morbid BD’).