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How to prevent the malignant progression of bipolar disorder

Abstract

There is increasing recognition that, in a high percentage of cases, bipolar disorder is a progressive illness. Multiple types of sensitization (or increased reactivity to repetition of the same stimulus) drive illness progression. One of the clearest is that of episode sensitization, where increased numbers of prior episodes are associated with: faster recurrences; more dysfunction; disability; social, educational, and employment deficits; suicide; medical comorbidities; cognitive dysfunction; and an increased incidence of dementia in old age. Repetition of stressors and bouts of substance abuse can also result in sensitization. Each type of sensitization appears to have an epigenetic basis, such that preventing sensitization should minimize the accumulation of adverse epigenetic chemical marks on DNA, histones, and microRNA. New data emphasize the importance of early, consistent intervention after an initial manic episode. The cognitive dysfunction associated with a first episode improves only if there are no further episode recurrences during the next year. A randomized study has also shown that comprehensive multimodal prophylactic intervention for 2 years leads to improvements in illness course extending over a total of 6 years. Intensive treatment of the earliest stages of bipolar disorder can thus exert lasting positive effects on the course of illness.

Sensitization; kindling; epigenetic; stress; depression


Introduction

Many of the clinical characteristics of bipolar disorder show sensitization (increases in pathological behavioral reactivity to repetition of the same stimuli) rather than tolerance or downregulation (Box 1). This includes sensitization to recurrent stressors, mood episodes, and bouts of substance abuse. Each type of sensitization also shows cross-sensitization to the other two, resulting in a downward spiral of illness progression.11. Post R. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992;149:999-1010.

2. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016.
-33. Post RM. Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord.2016;18:315-24.

Box 1
Bipolar disorder is a multifaceted progressive illness.

While stress, episodes, and bouts of substance abuse sensitize, the unfolding of recurrent mood episodes shows a pattern resembling that of amygdala kindling. In kindling, repeated stimulation of the amygdala results in increasingly long and complex afterdischarges which culminate in unilateral, then bilateral, full-blown seizures in response to a previously subthreshold stimulus. Following enough seizures so triggered, spontaneous seizures also begin to occur. While kindling is a nonhomologous model for affective episodes, the course of mood episodes proceeding from multiple recurrences precipitated by stressors to those that occur more spontaneously is analogous to the progressive unfolding and progression of amygdala-kindled seizures.44. Post RM. Preventing sensitization and kindling-like progression in the recurrent affective disorders.In:ChiccettiD, ed. Developmental psychopathy. Hoboken: John Wiley & Sons; 2016.p. 971-96. In this fashion, the sensitization and kindling preclinical models help conceptualize different aspects of biochemical, physiological, and behavioral aspects of illness progression in the affective disorders.

The sensitization phenomena and the kindling-like illness progression of affective episodes also emphasize the importance of early and sustained prophylactic intervention before the illness becomes increasing complex and treatment-resistant, a phenomenon that occurs both in the clinical realm and in the animal models. Moreover, since minor behavioral abnormalities and partial unilateral seizures are part of the progression to full-blown amygdala-kindled seizures, preventing these earliest manifestations can prevent progression to a full-blown episode. The hope is that, by analogy, preventing the early subsyndromal symptoms of the affective disorders could preclude the emergence of full-blown affective episodes. Importantly, if the pharmacological dissociations revealed in the kindling model are pertinent to those in the affective disorders, the data indicate that different drugs are effective at different stages of disease progression. For example, drugs such as carbamazepine and lamotrigine, which are highly effective in preventing full-blown amygdala-kindled seizures, are not effective against the initial stages of kindling development.22. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016.,44. Post RM. Preventing sensitization and kindling-like progression in the recurrent affective disorders.In:ChiccettiD, ed. Developmental psychopathy. Hoboken: John Wiley & Sons; 2016.p. 971-96. Conversely, benzodiazepines, which prevent early- and mid-phase seizures, are not effective against late spontaneous ones, while phenytoin shows the opposite pattern. Thus, caution must be taken in inferring that drugs effective against full-blown manic or depressive episodes would necessarily be effective in the earliest phase of affective illness evolution.

Types of sensitization in the mood disorders

Stress sensitization

There is a robust literature indicating that childhood adversities, particularly when followed by further stressors in adulthood, are prime candidates for precipitating affective episodes.11. Post R. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992;149:999-1010.,55. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-9. While many candidate gene-environmental interactions associated with this phenomena have not been replicated, the fundamental observations of stressors in childhood predisposing to affective episodes later in adulthood are consistent and highly replicable.66. Border R, Johnson EC, Evans LM, Smolen A, Berley N, Sullivan PF, et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry. 2019;176:376-87. The bulk of these data are in unipolar depression, but also appear applicable to bipolar disorder, where childhood stressors are a clear-cut poor prognosis factor for early onset and a more adverse course of illness. Differences in types, timing, and duration of stressors may have important consequences for illness progression, but a history of verbal abuse (even in the absence of physical or sexual abuse) is associated with an early onset of bipolar disorder and a more adverse course of illness.77. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, et al. Verbal abuse, like physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder. Bipolar Disord.2015;17:323-30. As multiple affective episodes occur, the vulnerability to further episodes increases and, as in kindling, spontaneous episodes also begin to occur. The occurrence of early stressors is also a vulnerability factor for later development of PTSD, and is a potent risk factor for animals and humans developing and sustaining substance abuse.22. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016.,88. Post RM. The neurochemistry and epigenetics of ptsd: implications for therapeutics in trauma- and stressor-related disorders. In: Stoddard FJB, David M, Milad M, Ursano R, ed. Trauma- and stressor-related disorders. New York: Oxford University Press; 2018.p. 161-76.

Substance abuse sensitization

If animals are repeatedly given psychomotor stimulants, such as amphetamine or cocaine, they show progressive increases in motor activity and stereotypy in response to the same dose. This has an epigenetic mechanism, as revealed by the fact that the methylation inhibitor zebularine prevents sensitization.99. Anier K, Malinovskaja K, Aunurm-Helm A, Zharkovsky A, Kalda A. DNA methylation regulates cocaine-induced behavioral sensitization in mice. Neuropsychopharmacology. 2010;35:2450-61. Zebularine also prevents the effects of early-life stressors decreasing brain-derived neurotrophic factor (BDNF) in the prefrontal cortex, suggesting that some aspects of stress sensitization are also mediated by epigenetic mechanisms.1010. Roth TL, Lubin FF, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65:790-9. Epigenetic mechanisms are those associated with environmental events placing chemical tags on DNA, histones, and microRNA that can influence which genes are transcribed or inhibited.22. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016.,33. Post RM. Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord.2016;18:315-24. There is a high incidence of substance abuse in patients with bipolar disorder, and when the two co-occur, the course of illness is more difficult based on the convergence of additional stressors, episodes, and bouts of substance abuse as well as their cross-sensitization.1111. Post RM, Kalivas P. Bipolar disorder and substance abuse: pathological and therapeutic implications of their comorbidity and cross sensitization. Br J Psychiatry. 2013;202:172-6.,1212. Post RM. Mechanisms of sensitization to stress, affective episodes, and abused substances: implications for treatment and prevention. In: Swann AC, Moeller FG, Lijffijt M. Neurobiology of addictions. New York: Oxford University Press; 2016.p. 315-46. BDNF increases are seen in the nucleus accumbens following defeat stress-induced sensitization, cocaine sensitization, and in humans with depression. There is also some evidence that early-onset bipolar disorder and substance abuse share some genetic vulnerabilities.1313. Lin PI, Mcinnis MG, Potash JB, Willour V, MacKinnon DF, DePaulo JR, et al. Clinical correlates and familial aggregation of age at onset in bipolar disorder. Am J Psychiatry. 2006;163:240-6.

Episode sensitization

In some individuals with unipolar or bipolar depression, repeated episodes occur on average with increasingly shorter euthymic intervals and increasing severity and treatment resistance.1010. Roth TL, Lubin FF, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009;65:790-9. Greater numbers of prior episodes are also associated with increasing cognitive dysfunction.1414. Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012;46:561-73. Two episodes of unipolar or bipolar depression do not increase the risk of a diagnosis of dementia in old age, while four episodes double this risk, and each additional episode thereafter further increases the risk.1515. Kessing LV, Andersen PK. Evidence for clinical progression of unipolar and bipolar disorders. Acta Psychiatr Scand. 2017;135:51-64. Animal models of depression reveal epigenetic mechanisms underlying episode sensitization, and depressed individuals with histories of abuse in childhood have more epigenetic changes than those without such a history.33. Post RM. Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord.2016;18:315-24.,1212. Post RM. Mechanisms of sensitization to stress, affective episodes, and abused substances: implications for treatment and prevention. In: Swann AC, Moeller FG, Lijffijt M. Neurobiology of addictions. New York: Oxford University Press; 2016.p. 315-46.,1616. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12:342-8. Subthreshold symptoms of depression and mania can also be precursors to the emergence of more full-blown episodes; for this reason, as well as the possibility that they also contribute to illness progression on a clinical or mechanistic (epigenetic) basis, the importance of preventing subthreshold symptoms is also emphasized.

Analogy to progressive somatic mutations in cancer evolution

In cancer development and progression (for colon, breast, and lung malignancies), there appears to be an accumulation of a series of somatic mutations, typically involving loss of protective oncogenes or tumor suppressive factors and increases in cellular proliferative factors. Further mutations are associated with tumor invasion and metastasis. It would appear that a similar pattern of progressive epigenetic changes drives illness progression in the recurrent affective disorders. While the somatic mutations seen in cancer do not occur in the mood disorders, changes in gene expression driven by epigenetic mechanisms convey losses in neuroprotective factors (the “good guys”) and increases chemical alterations driving behavioral pathology (the “bad guys”). Each new episode tends to diminish the “good guys” and enhance the “bad guys,” shifting the ratio toward episode occurrence and reduced levels of compensatory mechanisms, such as thyrotropin-releasing factor and GABA inhibition. As in cancer progression, early treatment is easier and less complicated than at later stages.1212. Post RM. Mechanisms of sensitization to stress, affective episodes, and abused substances: implications for treatment and prevention. In: Swann AC, Moeller FG, Lijffijt M. Neurobiology of addictions. New York: Oxford University Press; 2016.p. 315-46.

Illness progression in the affective disorders (Box 1) appears to have multiple interacting mechanisms. There is evidence of neuroendocrine dysfunction, mitochondrial and oxidative stress, inflammation, and loss of neuroprotective factors.1414. Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012;46:561-73. Bipolar disorder should be viewed as a systemic illness affecting a wide variety of organs in the periphery and the brain. Among the most lethal is proneness to cardiovascular disease, which is associated with loss of a decade or more in life expectancy.

Prefrontal cortex microanatomy and function begins to fail as dendritic length and complexity decreases, synapses regress, and adult mushroom-shaped spines revert to immature spike-shaped spines. These changes are seen on autopsy in the prefrontal cortex of depressed patients and in animal models of depression.

New data on the effects of ketamine are revealing. Not only does ketamine exert rapid-acting antidepressant effects in animals and humans, but its IV administration is associated with normalization of spine, synapse, dendrite, and prefrontal cortical communication deficits within a few hours.1717. Devama S, Bang E, Wohleb ES, Li XY, Kato T, Gerhgard DM, et al. Role of neuronal VEGF signaling in the prefrontal cortex in the rapid antidepressant effects of ketamine. Am J Psychiatry. 2019;176:388-400. This process appears to be vascular endothelial growth factor (VEGF)-dependent, as inhibiting VEGF wipes out the antidepressant effects of ketamine and administration of VEGF into the prefrontal cortex reproduces the positive effects seen with ketamine. This effect may interact with BDNF and with many other downstream intracellular pathways and mechanisms, as noted above.

Defeat stress as a model of peripheral inflammation affecting the central nervous system

The defeat stress model of depression reveals the importance of inflammatory mechanisms.1818. Hodes GE, Menard C, Russo SJ. Integrating interleukin-6 into depression diagnosis and treatment. Neurobiol Stress. 2016;4:15-22.,1919. Niraula A, Witcher KG, Sheridan JF, Godbout JP. Interleukin-6 induced by social stress promotes a unique transcriptional signature in the monocytes that facilitate anxiety. Biol Psychiatry. 2019;85:679-89. Repeated exposure to a larger, aggressive, home-cage mouse for 10 days results in the intruder mouse becoming depressed, asocial, and anhedonic (not preferring sugar water). If the secretion of IL-6 from white cells is blocked, the animals do not become depressed. In addition, if IL-6 secretion from monocytes in the bone marrow is prevented, animals do not become depressed. After a second bout of defeat stress, primed monocytes are stored in the spleen; if IL-6 is blocked from these cells, depression-like behaviors do not occur. It appears that the IL-6 secreted into the blood crosses the blood-brain barrier in endothelial cells, activates microglia, and starts a cascade of inflammatory effects that result in activation of inflammasomes, secretion of IL-1 beta, and other downstream neurobiological changes associated with depression. Multiple studies and meta-analyses have linked increases in markers of inflammation – particularly IL-1, IL-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) – with bipolar disorder, as recently reviewed by Fries et al.2020. Fries GR, Walss-Bass C, Bauer ME, Texeira AL. Revisiting inflammation in bipolar disorder. Pharmacol Biochem Behav. 2019;177:12-9.

Increased vulnerability to child and adolescent bipolar disorder in the U.S. compared to Europe

Two-thirds of bipolar disorder cases in adults in the U.S. begin in childhood or adolescence (before age 19), while only one-third of cases begin this early in the Netherlands and Germany.2121. Etain B, Lajnef M, Bellivier F, Mathieu F, Raust A, Cochet B, et al. Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States. J Clin Psychiatry. 2012;73:e561-6.

22. Belleivier F, Etain B, Malafosse A, Henry C, Kahn JP, Elgrabli-Wajsbrot O, et al. Age at onset in bipolar I affective disorder in the USA and Europe. The world journal of biological psychiatry. World J Biol Psychiatry. 2014;15:369-76.
-2323. Post RM. New perspectives on the course and treatment of bipolar disorder. Minerva Psichiatr. 2017;58:40-53. This appears to be based on increases in both genetic and environmental vulnerability in the U.S. Early-onset illness is associated with the additional risk factor of longer delay to first treatment, and early onset and treatment delay are both independent risk factors for a poor outcome in adulthood. While some have argued that these transnational differences could be attributed to diagnostic differences, this does not appear to be the case. In the study of Mesman et al.,2424. Mesman E, Birmaher BB, Goldstein BI, Goldstein T, Derks EM, Vleeschouwer M, et al. Categorical and dimensional psychopathology in Dutch and US offspring of parents with bipolar disorder: a preliminary cross-national comparison. J Affect Disord. 2016;205:95-102. which claimed a similar incidence in the U.S. and the Netherlands, the category of bipolar disorder not otherwise specified (BP-NOS) was not included in the assessment, and BP-NOS represents the highest proportion of children with early onset bipolar disorder. Moreover, children with bipolar disorder from the U.S. were more ill than those from the Netherlands in terms of increased numbers of comorbidities. In our cohort, adults with bipolar disorder in the U.S. were more ill than their European counterparts, and so were their offspring,2525. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, et al. Age of onset of bipolar disorder: combined effect of childhood adversity and familial loading of psychiatric disorders. J Psychiatr Res. 2016;81:63-70.,2626. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, et al. More illness in offspring of bipolar patients from the U.S. compared to Europe. J Affect Disord. 2016;191:180-6. siblings, and spouses. In the 676 patients from the U.S. compared to the 292 from Europe, there was a significantly higher prevalence of anxiety disorders, alcohol abuse, substance abuse, rapid cycling, 20 or more prior episodes, and prospective nonresponders to naturalistic treatment, but fewer hospitalizations.22. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016. In addition, those from the U.S. have more obesity and a host or other medical problems compared to the Europeans.2727. Post RM, Altshuler LL, Leverich GS, Frye MA, Suppes T, McElroy SL, et al. More medical comorbidities in patients with bipolar disorder from the United States than from the Netherlands and Germany. J Nerv Ment Dis. 2014;202:265-70.

A bipolar spectrum disorder diagnosis occurs in 2.2% of adolescents in the U.S., yet only 20% of them are on any kind of treatment.2828. Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui L, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the national comorbidity survey replication--adolescent supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49:990-9. Thus, earlier recognition and treatment of youngsters with a bipolar spectrum diagnosis is urgently needed to stem the tide of multi-generational transmission of illness.2525. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, et al. Age of onset of bipolar disorder: combined effect of childhood adversity and familial loading of psychiatric disorders. J Psychiatr Res. 2016;81:63-70.,2929. Post RM, Altshuler LL, Kupka R, McElroy SL, Frye MA, Rowe M, et al. Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder. Bipolar Disord. 2018 Jun 21. doi: https://10.1111/bdi.12668. Online ahead of print.
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Axelson et al.3030. Axelson D, Goldstein B, Goldstein T, Monk K, Yu H, Hickey MB, et al. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study. Am J Psychiatry. 2015;172:638-46. indicated that 74% of the offspring of a parent with bipolar disorder developed a major psychiatric diagnosis at 8 years of follow-up. The problems of early-onset illness will only continue to worsen as data indicate the presence of a cohort effect for depression, bipolar disorder, and substance abuse.3131. Kessler RC, Angermeyer M, Anthony JC, DE Graaf R, Demyttenaere K, Gasquet I, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization's World Mental Health Survey Initiative. World Psychiatry. 2007;6:168-76.,3232. Post R, Kupka R, Keck PE Jr, McElroy SL, Altshuler LL, Frye MA, et al. Further evidence of a cohort effect in bipolar disorder: more early onsets and family history of psychiatric illness in more recent epochs. J Clin Psychiatry. 2016;77:1043-9.

High-risk individuals can be identified by presently available clinical characteristics

Genetic vulnerability is a crucial risk factor for the onset of bipolar disorder, and Stahl et al.3333. Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51:793-803. have identified 30 loci with genome-wide significance, but we are still a long way from being able to use genetics as a reliable predictor of bipolar disorder. However, if a positive family history of bipolar disorder in parents and grandparents is accompanied by a history of adversity in childhood, the likelihood of early-onset illness is further enhanced. If these two vulnerabilities are also accompanied by prodromal symptoms, risk is further amplified.3434. Post R, Chang K, Frye M. Paradigm shift: preliminary clinical categorization of ultrahigh risk for childhood bipolar disorder to facilitate studies on prevention. J Clin Psychiatry. 2013;74:167-9. The ready identification of individuals at high and very high risk gives credence to efforts at early intervention and prevention. Many variables associated with good health can be introduced in high-risk individuals, including good diet, exercise, weight management, and sleep hygiene.3535. Post RM, Yatham LN, Vieta E, Berk M, Nierenberg AA. Beyond evidence-based treatment of bipolar disorder: rational pragmatic approaches to management. Bipolar Disord. 2019;21:650-9. In those who are already prodromal, family-focused therapy (FFT) or one of its many closely aligned therapies is highly effective and should be offered more consistently.3636. Miklowitz DJ, Schneck CD, Singh MK, Taylor DO, George EL, Cosgrove VE, et al. Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. J Am Acad Child Adolesc Psychiatry. 2013;52:121-31.,3737. Fristad MA, Verducci JS, Walters K, Young ME. Impact of multifamily psychoeducational psychotherapy in treating children aged 8 to 12 years with mood disorders. Arch Gen Psychiatry. 2009;66:1013-21.

There are mixed data for omega-3-fatty acids helping to ward off a diagnosis of schizophrenia in those who are prodromal, and parallel studies should be conducted in bipolar disorder. The potential protective effects of safe and well-tolerated supplements – such as folate, vitamin D3, N-acetylcysteine, acetyl-L-carnitine, and phosphatidylcholine – all deserve to be further studied, but such studies are not given high priority or are being funded by the NIMH and other regulatory and funding bodies. This should change based on both current need and clinical and theoretical support, but also on the basis that more formal neurobiological markers eventually will be found and replicated. When these markers become available, one would still need to proceed with studies of what types of primary and secondary prevention are effective in these high-risk individuals.

Consistent long-term prophylaxis required after the first manic episode

The types and consistency of intervention after the occurrence of a first manic episode needs major revision. Studies reveal the cognitive and structural deficits that occur with first mania are resolved over the next year only on the condition that no further episodes occur.3838. Kozicky JM, Torres IJ, Silveira LE, Bond DJ, Lam RW, Yatham LN. Cognitive change in the year after a first manic episode: association between clinical outcome and cognitive performance early in the course of bipolar I disorder. J Clin Psychiatry. 2014;75:e587-93.,3939. Demmo C, Lagerberg TV, Kvitland LR, Aminoff SR, Hellvin T, Simonsen C, et al. Neurocognitive functioning, clinical course and functional outcome in first-treatment bipolar I disorder patients with and without clinical relapse: a 1-year follow-up study. Bipolar Disord. 2018;20:228-37. Preventing further episodes in the year after a first manic episode is no easy task, and the types and aggressiveness of treatment needed to achieve this end require further study.

One hint of an effective strategy would be the greater use of lithium. Berk et al.4040. Berk M, Daglas R, Dandash O, Yücel M, Henry L, Hallam K, et al. Quetiapine v. lithium in the maintenance phase following a first episode of mania: randomised controlled trial. Br J Psychiatry. 2017;210:413-21. reported that, in first-episode bipolar patients randomized to a year of lithium or quetiapine, those on lithium did better in every respect: fewer episodes of mania and depression, better functioning and cognition, and fewer abnormalities on brain imaging. Moreover, Hafeman et al.4141. Hafeman DM, Rooks B, Merranko J, Liao F, Gill MK, Goldstein TR, et al. Lithium versus other mood-stabilizing medications in a longitudinal study of bipolar youth. J Am Acad Child Adolesc Psychiatry. 2019 Jul 29;S0890-8567(19)31399-1. doi: https://10.1016/j.jaac.2019.06.013. Online ahead of print.
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found lithium superior to other mood stabilizers in long-term follow up, mirroring the results of Geller et al.4242. Geller B, Tillman R, Bolhofner K, Zimerman B. Pharmacological and non-drug treatment of child bipolar I disorder during prospective eight-year follow-up. Bipolar Disord. 2010;12:164-71. and the findings of Goldstein et al.4343. Goldstein BI, Birmaher B, Carlson GA, DelBello MP, Findling RL, Fristad M, et al. the international society for bipolar disorders task force report on pediatric bipolar disorder: knowledge to date and directions for future research. Bipolar Disord. 2017;19:524-43. that treatment with lithium resulted in fewer patients acquiring substance-abuse comorbidities.

One of the strongest studies supporting the need for early, comprehensive, long-term specialty treatment is that of Kessing et al.4444. Kessing LV, Hansen HV, Hvenegaard A, Christensen EM, Dam H, Gluud C, et al. Treatment in a specialised out-patient mood disorder clinic v. standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial. Br J Psychiatry. 2013;202:212-9. They randomized adolescents and young adults with a manic hospitalization to receive 2 years of comprehensive specialty clinic treatment or treatment as usual (TAU) in the community, which, in the study setting of Denmark, is free and usually of exceptionally high quality. Those randomized to the specialty clinic not only had fewer relapses over the next 2 years, but this continued over a total of 6 years, even though all patients had returned to TAU after the first 2 years. Specialty-clinic treatment included psychotherapy, pharmacotherapy, psychoeducation, mood charting, and recognition of early symptoms that might signal a relapse. One can conclude that early comprehensive treatment can moderate the long-term course of bipolar disorder and change it for the better. However, making such comprehensive treatment available to every patient with bipolar disorder will require massive shifts in medical and public health practice in the U.S. and elsewhere.2323. Post RM. New perspectives on the course and treatment of bipolar disorder. Minerva Psichiatr. 2017;58:40-53.,3535. Post RM, Yatham LN, Vieta E, Berk M, Nierenberg AA. Beyond evidence-based treatment of bipolar disorder: rational pragmatic approaches to management. Bipolar Disord. 2019;21:650-9.

Early treatment may require judicious complex combinations to achieve and maintain remission

Many texts and treatment guidelines emphasize the use of monotherapy as a sufficient approach to bipolar disorder. However, in controlled studies of pharmacoprophylaxis, remission is rarely achieved with monotherapy, and more complex regimens typically need to be utilized and further studied. Viral load in HIV/AIDS cannot be reduced to negligible levels without triple antiviral therapy, and the complexity of pharmacological treatment required to maintain bipolar disorder patients requires further study. As in HIV/AIDS, more complex combination treatments targeting different transmitter systems may be required.

We already know from studies measuring reduction in bipolar illness reoccurrence that combination therapy is consistently more effective than monotherapy. Such systematic combination studies include those of lithium and valproate; lithium and carbamazepine; lithium and lamotrigine; lithium and nimodipine; quetiapine and lamotrigine; and all of the anticonvulsants as augmented by atypical antipsychotics.2323. Post RM. New perspectives on the course and treatment of bipolar disorder. Minerva Psichiatr. 2017;58:40-53.,3535. Post RM, Yatham LN, Vieta E, Berk M, Nierenberg AA. Beyond evidence-based treatment of bipolar disorder: rational pragmatic approaches to management. Bipolar Disord. 2019;21:650-9.,4545. Post R, Leverich G. Treatment of bipolar illness: a casebook for clinicians and patients. New York: WW Norton and Company Inc;2008. What other supplements and drugs need to be added to achieve and maintain the desired goal of remission is not known, but should be a high priority for further study.

In the absence of a large body of systematic data,3535. Post RM, Yatham LN, Vieta E, Berk M, Nierenberg AA. Beyond evidence-based treatment of bipolar disorder: rational pragmatic approaches to management. Bipolar Disord. 2019;21:650-9. one needs to be extremely careful when instituting complex treatment regimens, using slow, incremental dose escalation of each new agent; titrating effectiveness against the emergence of any side effects is crucial to achieving an efficacious and well-tolerated regimen. Patients should be encouraged to conduct systematic daily life charting of mood, medications, and side effects, which may be particularly important in achieving an optimal regimen. Personal calendars and mood charts can be copied from Post & Leverich4545. Post R, Leverich G. Treatment of bipolar illness: a casebook for clinicians and patients. New York: WW Norton and Company Inc;2008. or downloaded from http://www.bipolarnews.org (click on mood chart or personal calendar).

Later stages of illness require more complex treatment

We can try to ameliorate many of the episode-driven difficulties with cognition and function by engaging in more optimal treatment of bipolar illness from the outset. However, a great many patients already present with multiple episodes, cognitive dysfunction, and treatment resistance, and these later-stage characteristics need to be dealt with aggressively.33. Post RM. Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord.2016;18:315-24.,2323. Post RM. New perspectives on the course and treatment of bipolar disorder. Minerva Psichiatr. 2017;58:40-53.,4545. Post R, Leverich G. Treatment of bipolar illness: a casebook for clinicians and patients. New York: WW Norton and Company Inc;2008.,4646. Post RM. Myriad of implications of acetyl-l-carnitine deficits in depression. Proc Natl Acad Sci U S A. 2018;115:8475-7. In many instance, this is likely to involve multiple medications22. Post RM. Depression as a recurrent, progressive illness: need for long-term prevention. In: Strain JJ, Blumenfield M. Depression as a systemic illness.Oxford: Oxford University Press;2016. (almost all off-label) targeting the medical and psychiatric comorbidities that commonly accompany bipolar disorder (Box 2). When combinations are administered carefully, their side-effect burden can even be lower than when trying to achieve a complete response with high doses of a single substance. Comorbid anxiety and substance abuse complicate treatment, need to be addressed specifically, and will usually require further medications. Similarly, diabetes, obesity, and other elements of the metabolic syndrome often accompany bipolar disorder, and, along with smoking, convey a great risk for early loss of life expectancy, primarily because of cardiovascular disease.4747. Kessing LV, Vradi E, McIntyre RS, Andersen PK. Causes of decreased life expectancy over the life span in bipolar disorder. J Affect Disord. 2015;180:142-7. Treatment and prevention of the comorbidities of bipolar disorder require specific attention and will often mandate increasingly complex approaches.

Box 2
Drugs targeting multiple comorbidities in bipolar disorder.

Conclusions

Bipolar disorder is a progressive, potentially lethal medical illness that all too often is not given the attention and respect that is required to moderate its course. Like a malignancy that is not adequately dealt with in a timely fashion, bipolar disorder can progressively evolve to a more treatment-refractory and pernicious stage. Such a progression can involve the accumulation of and sensitization and cross-sensitization to stressors, mood episodes themselves, and bouts of substance abuse. Each of these appears to have underlying neurobiological mechanisms driven by epigenetic changes in DNA, histones, and microRNA. Since these are environmentally driven changes, they are amenable to efforts at prevention and treatment. Early attempts at stress reduction and modulation, as well as episode and substance abuse treatment and prevention, would appear to be critical to preventing a malignant transformation of bipolar disorder from a manageable illness to an incapacitating and treatment-resistant one.

A new round of research, academic, and public health attention will be required to more adequately and properly treat this illness. Given the likelihood that this will not be readily achieved in the near future, it behooves each physician to attempt to provide the type of early and comprehensive treatment that Kessing et al.4444. Kessing LV, Hansen HV, Hvenegaard A, Christensen EM, Dam H, Gluud C, et al. Treatment in a specialised out-patient mood disorder clinic v. standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial. Br J Psychiatry. 2013;202:212-9. documented as essential to a more benign outcome.

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Publication Dates

  • Publication in this collection
    22 June 2020
  • Date of issue
    Sep-Oct 2020

History

  • Received
    24 Jan 2020
  • Accepted
    6 Feb 2020
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