양극성 장애 --＞ 조울증 2018년 nature

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25년동안 약물을 먹으며 관리중

최근 약물유발 파킨슨 증상을 약간 보이고 있어 

건생병사 4과제로 

약물을 끊고 치료하기 위한 방안 탐구중!!

1. nature  
2. nature reviews disease primers  
3. primers  
4. article

• Primer
• Published: 08 March 2018

Bipolar disorders

• Eduard Vieta, 
• Michael Berk, 
• Thomas G. Schulze, 
• André F. Carvalho, 
• Trisha Suppes, 
• Joseph R. Calabrese, 
• Keming Gao, 
• Kamilla W. Miskowiak & 
• Iria Grande 

Nature Reviews Disease Primers volume 4, Article number: 18008 (2018) Cite this article

•  
•  
•  
•  

Abstract

Bipolar disorders are chronic and recurrent disorders that affect >1% of the global population. Bipolar disorders are leading causes of disability in young people as they can lead to cognitive and functional impairment and increased mortality, particularly from suicide and cardiovascular disease. Psychiatric and nonpsychiatric medical comorbidities are common in patients and might also contribute to increased mortality. Bipolar disorders are some of the most heritable psychiatric disorders, although a model with gene–environment interactions is believed to best explain the aetiology. Early and accurate diagnosis is difficult in clinical practice as the onset of bipolar disorder is commonly characterized by nonspecific symptoms, mood lability or a depressive episode, which can be similar in presentation to unipolar depression.

Moreover, patients and their families do not always understand the significance of their symptoms, especially with hypomanic or manic symptoms. As specific biomarkers for bipolar disorders are not yet available, careful clinical assessment remains the cornerstone of diagnosis. The detection of hypomanic symptoms and longtudinal clinical assessment are crucial to differentiate a bipolar disorder from other conditions. Optimal early treatment of patients with evidence-based medication (typically mood stabilizers and antipsychotics) and psychosocial strategies is necessary.

양극성 장애는

전 세계 인구의 1% 이상이 앓고 있는

만성적이고 반복적인 장애입니다.

양극성 장애는

인지 및 기능 장애,

특히 자살과 심혈관 질환으로 인한 사망률 증가로 이어질 수 있어

젊은 층에서 장애를 일으키는 주요 원인입니다.

정신과적 및 비정신과적 의학적 동반 질환은

환자에게 흔하며

사망률 증가의 원인이 될 수도 있습니다.

양극성 장애는

가장 유전적인 정신질환 중 하나이지만,

유전자-환경 상호작용 모델이 그 원인을 가장 잘 설명하는 것으로 여겨지고 있습니다.

양극성 장애의 발병은 일반적으로

비특이적 증상,

기분 불안정 또는 우울 에피소드가 특징이며

단극성 우울증과 증상이 유사할 수 있기 때문에

임상에서 조기에 정확한 진단을 내리는 것은 어렵습니다.

또한 환자와 그 가족은

특히 hypomanic or manic symptoms의 경우

증상의 심각성을 항상 이해하지 못합니다.

양극성 장애에 대한 구체적인 바이오마커가 아직 없기 때문에

신중한 임상 평가가 진단의 초석으로 남아 있습니다.

양극성 장애를 다른 질환과 감별하기 위해서는

경조증 증상의 발견과 장기적인 임상 평가가 매우 중요합니다.

증거에 기반한 약물(일반적으로 기분 안정제 및 항정신병약물)과

심리사회적 전략으로 환자를

조기에 최적으로 치료하는 것이 필요합니다.

Bipolar disorders include several disorders of emotion, energy and thought that are characterized by biphasic mood episodes of mania or hypomania and depres‑ sion and are expressed as recurrent episodes of changes in energy levels and behaviour. Cognitive symptoms, especially altered reaction time, verbal and visual memory and executive function, are highly preval‎ent in patients and contribute to disability1 . Bipolar disorders have been traditionally classified either as part of the spectrum of psychoses (especially as part of the most severe end of the spectrum, which corresponds to the classic concept of manic–depressive psychosis) or as a mood disorder (an affective disorder), potentially as a continuum from unipolar depression to bipolar illness2 . The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‑5) created a category for ‘Bipolar and Related Disorders’; thus, bipolar disorders are not classified under either psychotic disorders or affective disorders3 .

However, bipolar disorder is classified under the mood disorders block in the International Classification of Diseases, 10th revision (ICD‑10)4 . In the DSM‑5, bipolar dis‑ orders are subclassified as bipolar I disorder, bipolar II disorder, cyclothymia and residual categories of atypi‑ cal forms that do not fit in the abovementioned sub‑ types. This subclassification depends on the severity and duration of manic (or hypomanic) and depressive episodes (FIG. 1). During manic episodes, hyperactivity, increased selfesteem, grandiosity, reduced need for sleep, expan‑ sive mood and behaviour and psychotic symptoms are common, whereas during depressive episodes, decreased energy, sadness, social withdrawal, hypersomnia and low selfesteem are the cardinal features. Psychosis can also occur during depressive episodes but occurs more frequently during mania. Hypomania is a milder and shorter form of mania, and individuals with hypomania have relatively intact judgement. Often, acute episodes of mood alterations can include symptoms at both poles (that is, mixed symptoms). Patients with bipolar disorders might be able to achieve full remission and have symptomfree periods, during which the disorder is assumed to be latent, with optimal management. However, in many cases, resid‑ ual and subthreshold symptoms persist in a pervasive way, making functional recovery difficult to achieve, especially after the second, third and subsequent epi‑ sodes. Management involves pharmacological and nonpharmacological treatments for acute phases in manic (or hypomanic) and depressive episodes and longterm therapy to prevent episode recurrence. In this Primer, we provide an overview of the cur‑ rent state of knowledge of bipolar disorders, including the epidemiology, pathophysiology, diagnosis, course of illness, treatment, prevention and psychosocial outcome of these disorders.

양극성 장애에는 

조증 또는 경조증과 우울증의 양극성 기분 에피소드가 특징이며 

에너지 수준과 행동의 변화가 반복적으로 나타나는 

여러 가지 감정, 에너지 및 사고 장애가 포함됩니다. 

인지 증상, 

특히 반응 시간, 언어 및 시각 기억력, 실행 기능의 변화는 

환자들에게 매우 흔하게 나타나며 장애를 유발합니다1 . 

양극성 장애는 

전통적으로 정신병 스펙트럼의 일부(특히 조울증 정신병의 고전적 개념에 해당하는 가장 심한 스펙트럼의 일부)로 분류되거나 

기분 장애(정서 장애)로 분류되어 왔으며, 

잠재적으로는 단극성 우울증에서 양극성 질환으로 이어지는 

연속체2 로 분류되어 왔습니다2 . 

정신 장애 진단 및 통계 편람 5판(DSM-5)에서는 

'양극성 및 관련 장애'라는 범주를 만들었으며, 

따라서 양극성 장애는 정신병적 장애나 정동 장애로 분류되지 않습니다3 . 

그러나 

양극성 장애는 국제질병분류 제10차 개정판(ICD-10)4 에서 

기분 장애 블록으로 분류됩니다.

 DSM-5에서 양극성 장애는 

양극성 I 장애, 양극성 II 장애, 조울증 및 위에서 언급한 하위 유형에 속하지 않는 

비정형 형태의 잔여 범주로 세분화됩니다. 

이 하위 분류는 

조증(또는 경조증) 및 우울증 에피소드의 중증도와 지속 기간에 따라 달라집니다(그림 1). 

조증 에피소드에서는 

과잉 행동, 자존감 증가, 과대망상, 수면 욕구 감소, 기분과 행동의 확장, 정신병적 증상이 흔히 나타나는 반면, 

우울 에피소드에서는 

에너지 감소, 슬픔, 사회적 위축, 과다수면, 낮은 자존감이 주요 특징입니다. 

정신병은 

우울증 에피소드 중에도 발생할 수 있지만 

조증 기간에 더 자주 발생합니다. 

경조증은 

더 경미하고 짧은 형태의 조증으로, 

경조증에 걸린 사람은 비교적 온전한 판단력을 가지고 있습니다. 

종종 급성 기분 변화의 에피소드에는 

두 극단의 증상(즉, 혼합 증상)이 모두 포함될 수 있습니다. 

양극성 장애를 가진 환자는 

최적의 관리를 통해 완전 관해에 도달하고 증상이 없는 기간을 가질 수 있으며, 

이 기간 동안에는 장애가 잠재되어 있는 것으로 간주됩니다. 

그러나 많은 경우, 

잔존 증상과 역치 이하의 증상이 만연하게 지속되어 

특히 두 번째, 세 번째 및 그 이후의 에피소드 이후에는 기능 회복이 어렵습니다. 

관리에는 

조증(또는 경조증) 및 우울증 에피소드의 급성기에 대한 

약리적 및 비약리적 치료와 

에피소드 재발을 예방하기 위한 장기 치료가 포함됩니다. 

이 입문서에서는 

양극성 장애의 역학, 병태생리, 진단, 질병의 경과, 치료, 예방 및 심리사회적 결과 등 

양극성 장애에 대한 최신 지식 현황을 개괄적으로 소개합니다.

Epidemiology

Bipolar disorders affect >1% of the global population5 . The estimated lifetime preval‎ence is 0.6% for bipolar I disorder, 0.4% for bipolar II disorder, 1.4% for sub‑ threshold manifestations of bipolar disorders and 2.4% for the broader bipolar spectrum of bipolar disorders5 . Some studies have suggested higher rates: for example, a global 12‑month preval‎ence of 1.5% and a lifetime preval‎ence of 2.1% for bipolar I disorder according to DSM‑5 criteria have been reported6 . The onset of bipolar disorders is independent of ethnicity, nationality and socioeconomic status. The preval‎ence of bipolar I dis‑ order is similar in men and women, but bipolar II disorder is more common in females7 . Bipolar disorders begin in youth, with a mean age of onset of ~20 years2 . An earlier age of onset has been associated with greater comorbidity and onset beginning with depression. Diagnosis and management usually commence in young adulthood8 . However, a 5‑year delay to diagnosis from the onset of symptoms has been shown in some studies, although variable data have been repor‑ ted8 . In addition, time to diagnosis is longer in patients with comorbidities and depressive onset polarity8 . Impor‑ tantly, the duration of untreated illness (that is, the time between the first episode and adequate management) drives prognosis, and a longer duration of untreated illness has been associated with an increased number of suicide attempts and a longer duration of illness9 . Estimates of the global burden of disease have shown that 5 of the top 20 causes of disability are due to mental illnesses10.

Bipolar disorders are the 17th leading cause of global burden of disease, after depression, anxiety disorders, schizophrenia and dysthymia10. Mental illness accounted for 32.4% of years lived with disability and 13.0% of disabilityadjusted life years out of all dis‑ orders included in the Global Burden of Disease Study10. Indeed, as a lifelong and recurrent illness, bipolar dis‑ orders often lead to functional impairment and reduced quality of life (see Quality of life)11. This burden extends to family members, with caregiver burden and depres‑ sion being common12. In addition, as bipolar disorders affect the economically active population, high costs to society are incurred in terms of direct healthcare costs and the costs of disability, of which the costs of disability predominate13. This impact is likely greatest in younger individuals, as bipolar disorders disrupt the attainment of agespecific developmental, relationship, educational and occupational milestones14

역학 

양극성 장애는 

전 세계 인구의 1% 이상에게 영향을 미칩니다5 . 

평생 유병률은 

양극성 제1형 장애의 경우 0.6%, 

양극성 제2형 장애의 경우 0.4%, 

양극성 장애의 역치 미만 증상의 경우 1.4%, 

광범위한 양극성 장애의 경우 2.4%로 추정됩니다5 . 

일부 연구에서는 더 높은 유병률을 제시하기도 합니다: 

예를 들어, DSM-5 기준에 따른 양극성 장애의 전 세계 12개월 유병률은 1.5%, 평생 유병률은 2.1%로 보고되었습니다6 .

 양극성 장애의 발병은 인종, 국적, 사회경제적 지위와는 무관합니다. 

양극성 장애의 유병률은 

남성과 여성에서 비슷하지만 

양극성 장애는 여성에서 더 흔합니다7 .

 양극성 장애는 

청소년기에 시작되며 

평균 발병 연령은 ~20 세입니다2 . 

발병 연령이 빠를수록 

동반 질환이 더 많고 우울증으로 시작되는 것과 관련이 있습니다. 

진단과 관리는 

보통 젊은 성인기에 시작됩니다8 . 

그러나 일부 연구에서는 다양한 데이터가 보고되었지만 

증상 발현 후 진단까지 5년이 지연되는 것으로 나타났습니다8 . 

또한 

동반 질환이 있고 우울증 발병 극성이 있는 환자의 경우 

진단까지 걸리는 시간이 더 깁니다8 . 

중요한 것은 

치료받지 않은 질병의 기간(즉, 첫 번째 에피소드와 적절한 관리 사이의 시간)이 예후를 좌우하며, 

치료받지 않은 질병의 기간이 길수록 

자살 시도 횟수가 증가하고 

질병의 유병 기간이 길어지는 것과 관련이 있습니다9 . 

전 세계 질병 부담에 대한 추정치에 따르면 

상위 20개 장애 원인 중 5개가 정신 질환으로 인한 것으로 나타났습니다10. 

양극성 장애는 

우울증, 불안 장애, 정신분열증, 기분부전증에 이어 

전 세계 질병 부담의 17번째 주요 원인입니다10. 

정신질환은 

글로벌 질병 부담 연구에 포함된 모든 장애 중 장애로 인한 

수명의 32.4%, 장애 조정 수명의 13.0%를 차지했습니다10. 

실제로 

양극성 장애는 평생 재발하는 질환으로 

기능 장애와 삶의 질 저하로 이어지는 경우가 많습니다(삶의 질 참조)11. 

이러한 부담은 

가족 구성원에게까지 이어져 

간병인의 부담과 우울증이 흔하게 발생합니다12. 

또한 

양극성 장애는 

경제 활동 인구에 영향을 미치기 때문에 

직접적인 의료 비용과 장애 비용 측면에서 사회에 높은 비용이 발생하며,

 이 중 장애 비용이 압도적으로 높습니다13. 

양극성 장애는 

연령별 발달, 관계, 교육 및 직업적 이정표 달성을 방해하기 때문에 

이러한 영향은 젊은 층에서 가장 클 수 있습니다14.

Comorbidities

Bipolar disorders are comorbid with other psychiatric disorders (including anxiety disorders, substance use disorders, attentiondeficit/hyperactivity disorder and personality disorders), which can make diagnosis and management of bipolar disorders more difficult; this comorbidity is also associated with poorer outcomes15. Nonpsychiatric comorbidities are similarly highly preva‑ lent in patients with bipolar disorders and include meta‑ bolic syndrome, diabetes mellitus, osteoporosis and fibromyalgia as well as other endocrine and cardiovascu‑ lar disorders16–18. Regarding metabolic syndrome, the principal drivers include an unhealthy lifestyle and use of antipsychotic medications rather than illness itself 19. The presence of comorbid disorders has been associated with a greater risk of premature mortality in patients with bipolar disorders than in the general population20. In addition, comorbid obesity is associated with poorer outcomes of bipolar disorders with lithiumbased or quetiapinebased treatment21. A laterinlife onset of mania might be suggestive of an underlying medical comorbidity22.

동반 질환 

양극성 장애는 

다른 정신과적 장애(불안 장애, 약물 사용 장애, 주의력 결핍/과잉 행동 장애, 성격 장애 포함)와 동반되어 있어 

양극성 장애의 진단과 관리를 더 어렵게 만들 수 있으며, 

이러한 동반 질환은 더 나쁜 결과와도 관련이 있습니다15. 

비정신과적 동반 질환은 

양극성 장애 환자에서 유사하게 높은 유병률을 보이며 

대사 증후군, 당뇨병, 골다공증, 섬유근육통 및 기타 내분비 및 심혈관계 질환16-18을 포함합니다. 

대사 증후군의 주요 원인은 

질병 자체보다는 건강에 해로운 생활 습관과 항정신병 약물의 사용입니다 19. 

동반 질환의 존재는 

일반 인구보다 양극성 장애 환자의 조기 사망 위험이 더 높은 것과 관련이 있습니다20. 

또한 

동반 비만은 

리튬 기반 또는 케티아핀 기반 치료를 받는 양극성 장애의 더 나쁜 결과와 관련이 있습니다21. 

조증의 노년기 발병은 

기저 질환이 있음을 암시할 수 있습니다22.

Suicide 

Among the affective disorders, bipolar disorders have the highest suicide rate23, which is up to 20‑times higher than the rate among the general population. Approximately onethird to onehalf of patients with bipolar disorders will attempt suicide at least once, and 15~20% of suicide attempts are lethal24. Risk factors for suicide attempts include a younger age at onset, female sex, depressive polarity, anxiety, substance abuse and personality dis‑ order comorbidity; risk factors for completed suicide include a firstdegree family history of suicide and male sex24. The risk of suicide is higher in untreated patients than those treated with antiepileptic drugs25. 

자살 

정동 장애 중 

양극성 장애의 자살률이 가장 높으며23, 

이는 일반 인구의 자살률보다 최대 20배나 높은 수치입니다. 

양극성 장애 환자의 약 1/3~1/2가 한 번 이상 자살을 시도하며, 

자살 시도의 약 15~20%는 치명적인 결과를 초래합니다24. 

자살 시도의 위험 요인으로는 

젊은 발병 연령, 여성, 우울 양극성, 불안, 약물 남용, 성격 장애 동반 질환 등이 있으며, 

자살 완료의 위험 요인으로는 1급 자살 가족력, 남성 성별 등이 있습니다24. 

자살 위험은 

항전간제 치료를 받은 환자보다 

치료받지 않은 환자에서 더 높습니다25. 

Mechanisms/pathophysiology

Genetics Bipolar disorders are genetically complex disorders with a multifactorial genesis: both genetic factors, such as common and rare variants, and environmental factors contribute26,27. The heritability of bipolar disorders is estimated to be up to 85%2 , which is one of the highest estimates for psychiatric disorders, although a multi‑ factorial model of gene–environment interaction is believed to best fit this disorder (FIG. 2).

기전/병태생리

유전학 양극성 장애는 

다인성 기원을 가진 유전적으로 복잡한 장애로, 

흔한 변이형 및 희귀 변이형과 같은 유전적 요인과 환경적 요인이 모두 기여합니다26,27. 

양극성 장애의 유전 가능성은 

최대 85%로 추정되며, 

이는 정신과 질환 중 가장 높은 추정치 중 하나이지만 

유전자-환경 상호작용의 다인자 모델이 이 장애에 가장 적합한 것으로 여겨집니다(그림 2).

Although early association studies focused on candidate genes, genome wide association studies (GWAS) have eval‎uated large numbers of common variants (singlenucleotide poly‑ morphisms) across the whole genome for associations with disease. These GWAS have produced longawaited robust and reproducible findings. Thus far, significant genetic associations have been detected in 18 regions throughout the genome, many of which have been replicated (TABLE 1). As the associated alleles have small effects (with ORs <1.3), very large case–control samples are needed to validate these findings. As sample sizes con‑ tinue to increase, in particular through the formation of large international consortia (such as the Consortium on Lithium Genetics), more robust findings are expected.

First pathway analyses have suggested major roles for calcium signal transmission, the glutamatergic sys‑ tem, hormone regulation, microRNAs and histone and immune pathways, although these data are prelimin‑ ary28,29. Interestingly, intracellular calcium signalling was suggested to have a role in the pathophysiology of bipolar disorders several decades ago30. In addition to the common variants detected in GWAS, rare variants can also be relevant for disease development if they have a high penetrance and, therefore, convey an increased risk of the disease. Rare variants are classified according to their genomic size into singlenucleotide variants, smaller insertions and deletions and larger copy number variants (CNVs; deletions or duplications of large DNA sequences of 1kb to 3Mb that often affect several genes). Thus far, the most extensive results are available for CNV studies, but compared with other neuropsychiatric conditions such as schizophrenia, autism spectrum disorder and intellectual disability, these studies in bipolar disorders have not produced robust results. Some studies showed the accumulation of rare CNVs in patients with bipolar disorders, especially in those with earlyonset disease31,32; however, these find‑ ings could not always be reproduced. One metaanalysis reported an association between three CNVs and bipolar disorders (duplications at 1q21.1 and 16p11.2 and dele‑ tions at 3q29 (REF. 33)) that had all previously been associ‑ ated with schizophrenia.

In addition to GWAS and CNV studies, nextgeneration sequencing approaches to bipolar disorders are expected to discover novel rare variants and corroborate previous findings. Two decades of intense genetic research into bipolar disorders have focused on improving our understanding of the aetiology and how the disorders overlap with other mental disorders such as schizophrenia or major depres‑ sive disorder34. At present, genetic variants that have been associated with bipolar disorders cannot be used to predict individual risk, the course of the disorders or the effects of medication. Furthermore, the polygenic nature of these disorders makes it unlikely that a deterministic prediction will be possible in the future35. Taking into account ongoing studies, we speculate that ~100 loci will be identified from GWAS for bipolar disorders and major depressive disorder combined, which will narrow the gap between these conditions and schizophrenia, for which >100 loci have been identified. The GWAS are complemented by CNV studies and nextgeneration sequencing approaches and, collectively, data from these studies should improve our understanding of the path‑ ways and mechanisms underlying bipolar disorders and related traits. In addition, these data could potentially spur the development of novel pharmacological targets or lead to innovative drug repurposing trials.

Although most genetic studies of bipolar disorders have focused on aetiology, another area of research — pharmacogenetics — has been attracting increasing attention. Pharmacogenetics is the influence of genetic variation on the pharmacokinetics and pharmaco‑ dynamics of pharmacological therapies and could, in principle, contribute to personalized medicine. Pharmacogenetics studies in bipolar disorders have mainly encompassed candidate gene studies with small samples and have focused on lithium response. Because of the small sample sizes of these studies and the dif‑ ferent phenotypic definitions applied, no robustly repli‑ cated findings have been produced36. The largest GWAS for lithium response included 2,563 patients from >20 clinical centres in 4 continents, was performed by the Consortium on Lithium Genetics and reported a significant association with a locus on chromosome 21, which encodes the long, noncoding RNAs AL157359.3 and AL157359.4 (REF. 37). In addition, a poorer response to lithium in patients with bipolar disorders who have a higher genetic loading for schizophrenia has been reported by the Consortium on Lithium Genetics38. Despite these data, research on pharmacogenetics is still in its infancy; further replication studies are necessary and causal associations between the associated markers and their expression‎ need to be eval‎uated. 

초기 연관성 연구는 후보 유전자에 초점을 맞추었지만, 게놈 전체 연관성 연구(GWAS)는 전체 게놈에 걸쳐 수많은 공통 변이(단일염기다형성)를 평가하여 질병과의 연관성을 확인했습니다. 이러한 GWAS는 오랫동안 기다려온 강력하고 재현 가능한 결과를 도출해냈습니다. 지금까지 게놈 전체에 걸쳐 18개 영역에서 중요한 유전적 연관성이 발견되었으며, 그 중 많은 부분이 복제되었습니다(표 1). 관련 대립 유전자의 영향력이 작기 때문에(OR <1.3), 이러한 결과를 검증하려면 매우 큰 규모의 사례 대조군 샘플이 필요합니다. 

특히 대규모 국제 컨소시엄(예: 리튬 유전학 컨소시엄)의 결성을 통해 

샘플 크기가 계속 증가함에 따라 

더욱 강력한 결과가 나올 것으로 예상됩니다.

리튬 치료는 양극성 장애의 재발 위험을 줄여줍니다. 조증 에피소드에 대한 예방 효과는 분명하지만 우울증 에피소드에 대한 예방 효과는 모호합니다.

첫 번째 경로 분석에서는 

칼슘 신호 전달, 글루탐산 시스템, 호르몬 조절, 마이크로RNA, 히스톤 및 면역 경로의 주요 역할이 제시되었지만, 

이러한 데이터는 예비 단계에 불과합니다28,29. 

흥미롭게도 

세포 내 칼슘 신호는 

수십 년 전에 양극성 장애의 병태 생리학에 중요한 역할을 하는 것으로 제안되었습니다30. 

GWAS에서 발견되는 일반적인 변이 외에도 희귀 변이도 높은 침투력을 가지고 있어 질병의 위험을 증가시키는 경우 질병 발생과 관련이 있을 수 있습니다. 희귀 변이는 게놈 크기에 따라 단일 뉴클레오티드 변이, 작은 삽입 및 결실, 큰 복제수 변이(CNV; 여러 유전자에 영향을 미치는 1kb에서 3Mb의 큰 DNA 서열의 결실 또는 중복)로 분류됩니다. 지금까지 CNV 연구에 대한 가장 광범위한 결과가 나왔지만 조현병, 자폐 스펙트럼 장애, 지적 장애와 같은 다른 신경정신과 질환에 비해 양극성 장애에 대한 이러한 연구는 확실한 결과를 도출하지 못했습니다. 일부 연구에서는 양극성 장애 환자, 특히 조기 발병 환자에서 희귀 CNV가 축적되는 것으로 나타났지만31,32, 이러한 결과를 항상 재현할 수는 없었습니다. 한 메타분석에서는 이전에 모두 정신분열증과 연관성이 있었던 세 가지 CNV(1q21.1과 16p11.2의 중복 및 3q29의 결실(참조 33))와 양극성 장애 사이의 연관성을 보고했습니다.

양극성 장애에 대한 차세대 시퀀싱 접근법은 GWAS 및 CNV 연구와 더불어 새로운 희귀 변이를 발견하고 이전 연구 결과를 확증할 것으로 기대됩니다. 

양극성 장애에 대한 20년간의 집중적인 유전 연구는 

양극성 장애의 원인과 이 장애가 

조현병이나 주요우울장애와 같은 다른 정신 장애와 어떻게 겹치는지에 대한 

이해를 높이는 데 초점을 맞춰왔습니다34. 

현재 양극성 장애와 관련된 유전적 변이는 개인의 위험도, 장애의 경과 또는 약물의 효과를 예측하는 데 사용할 수 없습니다. 또한, 이러한 장애의 다원성 특성으로 인해 향후 결정론적 예측이 가능할 것 같지 않습니다35. 현재 진행 중인 연구를 고려할 때, 양극성 장애와 주요 우울 장애를 합친 GWAS에서 약 100개의 유전자좌가 확인될 것으로 예상되며, 이는 100개 이상의 유전자좌가 확인된 조현병과의 격차를 좁힐 수 있을 것으로 예상됩니다. GWAS는 CNV 연구와 차세대 시퀀싱 접근법으로 보완되며, 이러한 연구 데이터를 종합하면 양극성 장애 및 관련 특성의 기저에 있는 경로와 메커니즘에 대한 이해를 향상시킬 수 있습니다. 또한, 이러한 데이터는 잠재적으로 새로운 약리학적 표적의 개발을 촉진하거나 혁신적인 약물 용도 변경 시험으로 이어질 수 있습니다.

양극성 장애에 대한 대부분의 유전학적 연구는 

병인학에 초점을 맞춰 왔지만, 

또 다른 연구 분야인 약물유전학이 점점 더 주목을 받고 있습니다. 

약물유전학은 

유전적 변이가 약물 요법의 약동학 및 약력학에 미치는 영향을 연구하는 것으로, 

원칙적으로 개인 맞춤 의학에 기여할 수 있습니다. 

양극성 장애에 대한 약물 유전학 연구는 

주로 소량의 샘플을 대상으로 한 후보 유전자 연구를 포함하며 

리튬 반응에 초점을 맞춰 왔습니다. 

이러한 연구의 표본 크기가 작고 서로 다른 표현형 정의가 적용되었기 때문에 강력하게 재현된 연구 결과는 나오지 않았습니다36. 4개 대륙 20개 이상의 임상 센터에서 2,563명의 환자를 대상으로 한 리튬 반응에 대한 최대 규모의 GWAS는 리튬 유전학 컨소시엄에서 수행했으며, 긴 비코딩 RNA인 AL157359.3 및 AL157359.4를 암호화하는 21번 염색체 유전자좌와 유의미한 연관성을 보고했습니다(참조 37). 또한 리튬 유전학 컨소시엄에서는 조현병의 유전적 부하가 높은 양극성 장애 환자에서 리튬에 대한 반응이 더 나쁘다고 보고했습니다38. 이러한 데이터에도 불구하고 약물 유전학에 대한 연구는 아직 초기 단계이므로 추가적인 복제 연구가 필요하며 관련 마커와 그 발현 사이의 인과 관계를 평가해야 합니다. 

Environmental and medical risk factors

Although bipolar disorders have high heritability, environmental factors that can modify the onset and course of the disorders should also be taken into account. In general, the literature on the role of environ‑ mental factors in bipolar disorders is limited, although several environmental factors have been identified. For example, perinatal risk factors such as caesarean section delivery 39, maternal influenza infection40, maternal smoking during pregnancy41 and high paternal age42 have been implicated in increasing the risk of bipolar disorders. Life events, particularly childhood adverse events, have classically been described as risk factors of bipolar disorders as well as predictors of a moretorpid course43,44. Drug misuse has the same role. Indeed, the consumption of cannabis or other drugs during adoles‑ cence might lead to the early onset of bipolar disorders and a moresevere course45. In addition, as most patients with bipolar disorders present with a depressive epi‑ sode, they receive treatment with antidepressants with‑ out mood stabilizers, which can induce hypomanic or manic episodes46. Thus, the use of antidepressants might ‘unmask’ bipolar disorders. Other therapies that have been associated with mood switches in bipolar disorders are corticosteroids, androgens, electroconvulsive therapy (ECT), isoniazid and chloroquine2 . Medical conditions that have been associated with risk of bipolar disorders are multiple sclerosis, stroke, systemic lupus erythema‑ tosus and endocrine disorders (such as Cushing syn‑ drome and Addison disease)2 . Indeed, subthreshold hypothyroidism has been closely associated with rapid cycling bipolar disorders47. In addition, change of season, in particular from winter to spring and from summer to autumm48, and increased light exposure49 have also been described as triggers of bipolar disorders as well as course predictors.

환경적 및 의학적 위험 요인 

양극성 장애는 

유전성이 높지만, 

장애의 발병과 경과를 변화시킬 수 있는 환경적 요인도 고려해야 합니다. 

일반적으로 

양극성 장애에서 환경적 요인의 역할에 대한 문헌은 제한적이지만, 

몇 가지 환경적 요인이 확인되었습니다. 

예를 들어 

제왕절개 분만39, 산모의 인플루엔자 감염40, 임신 중 산모의 흡연41, 아버지의 높은 연령42과 같은 주산기 위험 요인이 

양극성 장애의 위험을 높이는 것과 관련이 있는 것으로 밝혀졌습니다. 

생활 사건, 

특히 어린 시절의 부작용은 

고전적으로 양극성 장애의 위험 인자이자 더 심한 경과의 예측 인자로 설명되어 왔습니다43,44. 

약물 오남용도 같은 역할을 합니다. 

실제로 청소년기에 대마초 또는 기타 약물을 섭취하면 

양극성 장애가 조기에 발병하고 더 심각한 경과로 이어질 수 있습니다45. 

또한, 

대부분의 양극성 장애 환자는 

우울증 삽화를 동반하기 때문에 

기분 안정제를 제외한 항우울제로 치료를 받게 되는데, 

이는 경조증 또는 조증 삽화를 유발할 수 있습니다46. 

따라서 

항우울제 사용은 양극성 장애의 '가면'을 벗길 수 있습니다. 

양극성 장애의 기분 전환과 관련된 다른 치료법으로는 

코르티코스테로이드, 안드로겐, 전기 경련 요법(ECT), 이소니아지드 및 클로로퀸2 이 있습니다. 

양극성 장애의 위험과 관련이 있는 질환으로는 

다발성 경화증, 뇌졸중, 전신 홍반성 루푸스, 내분비 장애(쿠싱 증후군 및 애디슨병 등)2 등이 있습니다. 

실제로 역치 이하 갑상선 기능 저하증은 

급속 주기성 양극성 장애와 밀접한 관련이 있습니다47. 

또한, 

특히 겨울에서 봄으로, 

여름에서 가을로 바뀌는 계절 변화48와 빛 노출 증가49도 

양극성 장애의 유발 요인이자 경과 예측 인자로 알려져 있습니다.

Pathophysiology

Knowledge of the pathogenesis and pathophysio‑ logy of bipolar disorders has progressed rapidly with advances in molecular technologies. Historically, mood disorders were though to result from an imbalance in the monoamine neurotransmitter systems, includ‑ ing the serotonergic, noradrenergic and — in particu‑ lar — dopaminergic pathways2 . However, no singular dysfunction in these systems has been identified2 . Altered endocrine functions have been widely studied in mood disorders, including the analysis of hormone levels in the blood and urine and the eval‎uation of the neuroendocrine systems, particularly the hypothalamic– pituitary–thyroid axis and the hypothalamic–pituitary– adrenal axis2 (FIG. 2). The early rebound of cortisol in the dexamethasone suppression test has been generally reported in affective illness50. Current studies are more focused on the modulation of synaptic and neural plasticity in brain regions, such as the prefrontal cortex, hippocampus, amygdala and other regions of the limbic system, in bipolar disorder51,52 (FIG. 2). Indeed, dendritic spine loss has been reported in the prefrontal cortex in postmortem tissue from patients with bipolar disorders53. Cellular and molecular alterations that can alter neuronal interconnectivity are also under study in bipolar disorders, including mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation, oxidation, apoptosis and epigenetic changes54 (FIG. 2).

However, as this line of research is still in its early stages, whether dysfunction of these path‑ ways contributes to the development of bipolar disorder is not known. Other fields of research include those using induced pluripotent stem cells (iPSCs) derived from patients with bipolar disorders, which have been used to examine hyperexcitability in iPSCderived neur‑ ons55, or studies examining the possible role of the gut– brain axis56,57. Indeed, alterations in the gut microbiota composition or concentration might activate immuno‑ inflammatory processes, changes in neuronal membrane permeability and oxidative stress54. Given that the core phenotype of the disorders is a biphasic energy shift, the corresponding monitoring of phasic dysregulation in mood, sleep and behaviour is attracting attention. These neurobiological lines of research are aligned with the notion of the progressive course of bipolar disorders, which was first described by Kraepelin58 and recently encompassed by the concept of neuro‑ progression59. The shortening of the interepisode interval after each episode recurrence and the reduced probabil‑ ity of treatment response with progression in a subset of patients putatively result from neurobiological inter related processes in the brain60. Several hypotheses have been proposed to explain this concept of progression of bipolar disorders.

For example, the kindling hypothesis speculates that alterations in brain plasticity lead to a gradual sensitization to stressors, which increases vulner‑ ability to episode recurrence61. Moreover, the allostatic hypothesis proposes that repeated neurobiological stress, such as during an episode, requires biological adjust‑ ments that can increase allostatic load62, increasing the risk of further episodes and precipitating and accelerat‑ ing progressive illness.

Neuroprogression encompasses the pathological ‘rewiring’ of the brain that occurs in parallel to the clinical and neurocognitive deterioration during the course of bipolar disorders. Several alterations, including increased neurodegeneration, neuronal apop‑ tosis, neurotoxic susceptibility and altered neuroplasticity, which are driven by changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis, have been implicated in neuroprogression59. Neuroimaging changes in bipolar disorders are progressive and include grey matter loss in the left pars opercularis, left fusiform gyrus, left rostral middle frontal cortex and the hippcampus63,64. Staging models have been proposed according to the model of neuroprogression based on the number of relapses and functional impairment, although these are not currently used in clinical practice65,66 

병태생리학

양극성 장애의 발병 기전과 병태생리에 대한 지식은 

분자 기술의 발전과 함께 급속도로 발전해 왔습니다. 

역사적으로 기분 장애는 

세로토닌, 노르아드레날린 및 특히 도파민 경로를 포함한 

모노아민 신경전달물질 시스템의 불균형으로 인해 발생하는 것으로 여겨졌습니다2 . 

그러나 이러한 시스템에서 특별한 기능 장애는 확인되지 않았습니다2 . 

내분비 기능의 변화는 

혈액 및 소변의 호르몬 수치 분석과 신경내분비계, 

특히 시상하부-뇌하수체-갑상선 축 및 시상하부-뇌하수체-부신 축의 평가를 포함하여 

기분 장애에서 널리 연구되어 왔습니다2 (그림 2). 

덱사메타손 억제 검사에서 코르티솔의 조기 반등은 일반적으로 정서 질환에서 보고되었습니다50. 

현재 연구는 

양극성 장애에서 

전전두엽 피질, 해마, 편도체 및 기타 변연계 영역과 같은 

뇌 영역의 시냅스 및 신경 가소성 조절에 더 초점을 맞추고 있습니다51,52(그림 2). 

실제로 양극성 장애 환자의 사후 조직에서 

전전두엽 피질에서 수지상 돌기 손실이 보고되었습니다53. 

미토콘드리아 기능 장애, 

소포체 스트레스, 

신경 염증, 

산화, 

세포 사멸 및 후성 유전학적 변화를 포함하여 

신경세포 상호 연결성을 변화시킬 수 있는 세포 및 분자 변화도 양극성 장애에서 연구 중입니다54(그림 2).

mitochondrial dysfunction,

endoplasmic reticulum stress,

neuroinflammation,

oxidation,

apoptosis and epigenetic changes54 

그러나 이러한 연구 분야는 아직 초기 단계이므로 이러한 경로의 기능 장애가 양극성 장애의 발병에 기여하는지 여부는 알려져 있지 않습니다. 

다른 연구 분야로는 

양극성 장애 환자에서 유래한 유도만능줄기세포(iPSC)를 사용하여 

iPSC 유래 신경세포의 과흥분성을 조사하는 연구55 또는 

장-뇌 축의 가능한 역할을 조사하는 연구56,57 등이 있습니다. 

실제로 

장내 미생물 구성이나 농도의 변화는 

면역 염증 과정, 신경막 투과성 변화 및 산화 스트레스를 활성화할 수 있습니다54. 

이 질환의 핵심 표현형이 2상 에너지 전환이라는 점을 고려할 때 

기분, 수면 및 행동의 단계적 조절 장애에 대한 모니터링이 주목받고 있습니다. 

이러한 신경생물학적 연구 분야는 

Kraepelin58이 처음 설명한 양극성 장애의 진행 과정 개념과 일치하며, 

최근에는 신경 진행이라는 개념으로 포괄되고 있습니다59. 

각 에피소드 재발 후 

에피소드 간 간격의 단축과 일부 환자의 진행에 따른 치료 반응 가능성 감소는 

뇌의 신경생물학적 상호 관련 과정60에서 기인하는 것으로 추정됩니다. 

이러한 양극성 장애의 진행 개념을 설명하기 위해 몇 가지 가설이 제안되었습니다. 

예를 들어, 

불쏘시개 가설 kindling hypothesis은 

뇌 가소성의 변화가 스트레스 요인에 대한 점진적인 민감성으로 이어져

 에피소드 재발에 대한 취약성을 증가시킨다는 가설입니다61. 

또한, 

동조성 가설 allostatic hypothesis  은 

에피소드와 같은 반복적인 신경생물학적 스트레스는 동조성 부하를 증가시켜62 

추가 에피소드의 위험을 증가시키고 

진행성 질환을 촉발하고 가속화할 수 있는 생물학적 조절을 필요로 한다고 제안합니다. 

신경 진행은 

양극성 장애가 진행되는 동안 임상적 및 신경 인지적 악화와 병행하여 발생하는 

뇌의 병리학적인 ' ewiring'을 포괄합니다. 

Neuroprogression encompasses the pathological ‘rewiring’ of the brain that occurs in parallel to the clinical and neurocognitive deterioration during the course of bipolar disorders. 

염증성 사이토카인, 

코르티코스테로이드, 

뉴로트로핀, 

미토콘드리아 에너지 생성, 

산화 스트레스 및 신경 발생의 변화로 인한 신경 퇴화 증가, 

신경 세포 아포토시스, 

신경 독성 감수성 및 신경 가소성 변화를 포함한 여러 가지 변화가 신경 진행과 관련이 있습니다59. 

양극성 장애의 신경 영상 변화는 

진행성이며 

좌측 안와, 좌측 방추이랑, 좌측 복측 중전두피질 및 해마63,64의 회백질 손실을 포함합니다. 

재발 횟수와 기능 장애를 기준으로 

신경 진행 모델에 따라 병기 모델이 제안되었지만 

현재 임상에서는 사용되지 않습니다65,66. 

Diagnosis, screening and prevention

The classic and easily recognized bipolar disorder is bipolar I disorder, which is characterized by episodes of mania. Other bipolar disorders include bipolar II disorder and cyclothymia. The diagnosis of each disorder is based on different sets of behaviour and thought, which are divided somewhat arbitrarily on the degree of dis‑ ruption in these areas. Additional characteristics include the development of psychotic symptoms. In general, two sets of diagnostic criteria are used: the DSM‑5 of the American Psychiatric Association and the ICD‑10 of the WHO4 . Updates to the ICD‑10 (that is, the ICD‑11) are expected in the near future; thus, the relative differences and utility of the ICD‑11 and the DSM‑5 remain to be determined. For the purposes of this Primer, we focus on the DSM‑5.

진단, 검사 및 예방 

고전적이고 쉽게 인식되는 양극성 장애는 

조증 에피소드가 특징인 양극성 I 장애 bipolar I disorder 입니다. 

다른 양극성 장애로는 

양극성 II 장애와 양극성 조울증 bipolar II disorder and cyclothymia 이 있습니다. 

각 장애의 진단은 

다양한 행동과 사고의 집합을 기반으로 하며, 

이러한 영역의 파열 정도에 따라 다소 자의적으로 나뉩니다. 

추가적인 특징으로는 

정신병적 증상의 발현이 있습니다. 

일반적으로 두 가지 진단 기준이 사용되는데, 미국 정신의학회의 DSM-5와 WHO의 ICD-10이 그것입니다4. 가까운 시일 내에 ICD-10(즉, ICD-11)에 대한 업데이트가 예정되어 있으므로 ICD-11과 DSM-5의 상대적인 차이점과 유용성은 아직 결정되지 않았습니다. 이 입문서에서는 DSM-5에 초점을 맞추고 있습니다.

Classification

Bipolar I disorder.

As previously mentioned, bipolar I disorder is characterized by episodes of mania67 (BOX 1). In the DSM‑5, bipolar I disorder met twice the mini‑ mum criteria required to be recognized as a separate disorder, and diagnosis of bipolar I disorder was among the disorders with the highest interrater reliability in field trials68,69.

분류 

양극성 제1형 장애. 

앞서 언급한 바와 같이, 

양극성 I 장애는 조증 삽화67(박스 1)가 특징입니다. 

DSM-5에서 양극성 I 장애는 별도의 장애로 인정받는 데 필요한 미니맘 기준의 두 배를 충족하며, 양극성 I 장애 진단은 현장 시험에서 평가자 간 신뢰도가 가장 높은 장애 중 하나였습니다68,69.

The diagnosis of bipolar I disorder requires only a history of mania or the presence of mania (BOX 1); episodes of major depression are not required (BOX 2). In fact, ~5% of patients with bipolar I disorder have been estimated to experience only manic episodes (unipolar mania), although some of these patients might develop episodes of major depression later in life and can have subclinical depression. Hypomanic symptoms can occur in patients with bipolar I disorder (BOX 1) and might represent increasing instability for the patient and indi‑ cate that more intervention is needed to improve stabil‑ ity (for example, medication switching). Psychosis can also occur in individuals with bipolar I disorder and has been estimated to occur in up to 75% of patients with an acute manic episode2 . In a longterm follow‑up study of nearly 13 years, patients with bipolar I disorder were found to be symptomatically ill in 47.3% of followup weeks; patients had depressive symptoms during 31.9% of follow‑up weeks and patients had manic or hypo‑ manic symptoms for 8.9% of follow‑up weeks70. Sub‑ syndromal symptoms were threetimes more frequent than syndromal episodes70.

양극성 제1형 장애의 진단에는 

조증 병력 또는 조증의 존재만 있으면 되며(박스 1), 

주요 우울증의 에피소드는 필요하지 않습니다(박스 2). 

실제로 

양극성 제1형 장애 환자의 약 5%는 

조증 삽화(단극성 조증)만 경험하는 것으로 추정되지만, 

이러한 환자 중 일부는 나중에 주요 우울증 삽화가 나타날 수 있으며 무증상 우울증이 있을 수 있습니다. 

경조증 증상은 양극성 장애(박스 1) 환자에게서 발생할 수 있으며, 

환자의 불안정성이 증가하여 안정성을 개선하기 위해 더 많은 개입(예: 약물 전환)이 필요하다는 것을 나타낼 수 있습니다. 

정신병은 양극성 장애 환자에서도 발생할 수 있으며, 

급성 조증 에피소드가 있는 환자의 최대 75%에서 발생하는 것으로 추정됩니다2 . 

약 13년에 걸친 장기 추적 연구에서 

양극성 제1형 장애 환자는 47.3%의 추적 주에 증상이 있는 것으로 나타났으며,

 31.9%의 추적 주에 우울 증상을, 8.9%의 추적 주에 조증 또는 경조증 증상을 보인 환자가 있었습니다70. 

아증후군은 증후군의 증상보다 3배 더 빈번하게 나타났습니다70.

조증 
조증은 비정상적으로 지속적으로 기분이 들뜨거나 과민한 상태가 지속되고 목표 지향적인 활동이나 에너지가 비정상적으로 지속적으로 증가하는 뚜렷한 기간으로 정의됩니다. 이 기간은 1주일 이상 지속되며 거의 매일, 또는 입원이 필요한 경우 일정 기간 동안 하루의 대부분 동안 나타납니다. 기분 장애가 사회적 또는 직업적 기능에 현저한 장애를 일으키거나 자신 또는 타인에 대한 위해를 예방하기 위해 입원이 필요할 정도로 심각하거나 정신병적 특징이 있어야 합니다. 또한 해당 에피소드가 물질(예: 남용 약물, 약물 또는 기타 치료)의 생리적 영향이나 다른 의학적 상태에 기인하지 않아야 합니다. 조증 기간 동안 다음 증상 중 3개 이상(기분만 짜증스러운 경우 4개 이상)이 상당한 정도로 나타나며 평소 행동과 눈에 띄는 변화를 나타냅니다: - 부풀려진 자존감 또는 거만함 - 수면 필요성 감소(예: 3시간만 자도 개운한 느낌) - 평소보다 말이 많거나 계속 말을 해야 한다는 압박감 - 생각이 '경주'하는 듯한 주관적인 경험 또는 아이디어의 비행 - 주의 산만함(중요하지 않거나 관련 없는 외부 자극에 너무 쉽게 주의가 끌림), 보고되거나 관찰된 대로 - 목표 지향적 활동(사회적으로, 직장에서, 학교에서 또는 성적으로) 또는 정신 운동 동요(즉, 목적 없는 비목표 지향적 활동)의 증가 - 고통스러운 결과를 초래할 가능성이 높은 활동에 과도하게 관여(예: 무절제한 구매 행위, 성적 무절제한 행위 또는 어리석은 사업 투자에 참여) 

경조증 
경조증은 위와 같이 조증에 대해 정의되지만, 증상이 직업적 또는 사회적 장애를 일으키지 않는, 즉 중증도가 낮은 증상에 대한 기준이 더 낮습니다. 정의에 따르면, 증상이 입원이 필요할 만큼 심각하지 않으며 정신병적 증상이 아닙니다. 에피소드 기준을 충족하는 데 필요한 기간은 4일 이상이며, 다른 사람들이 관찰할 수 있을 정도로 일상적인 기능에 변화가 있어야 합니다. 경조증 기간 동안 정신병적 증상이 나타나면(우울증은 아니지만) 해당 에피소드를 조증으로 분류합니다. DSM-5, 정신 장애의 진단 및 통계 편람, 제5판3 .

Bipolar II disorder.

Bipolar II disorder is character‑ ized by at least one hypomanic episode and one major depressive episode (BOXES 1,2). Symptoms must not be due to substance or medication use, or to other psychiatric or medical conditions. The course of illness is usually characterized by substantial and often prolonged periods of depression and periodic hypomanic symp‑ toms. Perhaps because of this burden of depression, the overall degree of functional impairment and suicide risk is about the same for patients with bipolar II disorder as for those with bipolar I disorder5 . The differential diagnosis of bipolar II disorder is often complicated by the dominance of depressive features. Several longitu‑ dinal studies have suggested that bipolar II disorder is a stable diagnosis that persists throughout the lifetime of an individual71,72. Psychotic symptoms can occur during bipolar II depressive episodes and have been reported in up to 50% of patients2 . In a longterm follow‑up study of 13 years, patients with bipolar II disorder were symptomatically ill in 53.9% of followup weeks. Patients had symp‑ toms of depression in 50.3% of followup weeks and hypomania in 1.3% of followup weeks. Subsyndromal symptoms were threetimes more frequent than major depressive symptoms73.

양극성 II 장애.

양극성 II 장애는 

최소 한 번의 경조증 에피소드와 한 번의 주요 우울증 에피소드가 특징입니다(박스 1,2). 

증상은 

약물이나 약물 사용, 

기타 정신과적 또는 의학적 질환으로 인한 것이 아니어야 합니다. 

질병의 경과에는 

일반적으로 상당 기간의 우울증과 주기적인 경조증 증상이 장기간 지속되는 것이 특징입니다. 

이러한 

우울증의 부담 때문인지 

양극성 장애 II 환자의 전반적인 기능 장애 정도와 자살 위험은 

양극성 장애 I 환자와 거의 동일합니다5 . 

양극성 장애의 감별 진단은 

종종 우울 증상이 우세하기 때문에 복잡합니다. 

여러 장기 연구에 따르면 

양극성 II 장애는 

개인의 일생 동안 지속되는 안정적인 진단이라고 합니다71,72. 

양극성 II형 우울 삽화 동안 정신병적 증상이 발생할 수 있으며 

최대 50%의 환자에서 보고되었습니다2 . 

13년에 걸친 장기 추적 연구에서 양극성 장애 환자는 추적 주수의 53.9%에서 정신병적 증상을 보였습니다. 

추적 관찰 주수의 50.3%에서 우울증 증상이, 추적 관찰 주수의 1.3%에서 경조증 증상이 나타났습니다. 

서브증후군은 주요 우울 증상보다 3배 더 빈번하게 나타났습니다73.

Cyclothymia.

Cyclothymia is a historically important diagnosis that describes everything from tempera‑ ment to a prodrome of bipolar disorders. Cyclothymia is defined as mood instability for >2 years with both hypomanic and depressive symptoms that do not meet the criteria for hypomanic or depressive episodes. Some studies estimate that ≥30% of people diagnosed with cyclothymia develop a bipolar disorder, predominantly bipolar II disorder74.

사이클로티미아. 

조울증은 

조증부터 양극성 장애의 전조증상까지 모든 것을 설명하는 

역사적으로 중요한 진단명입니다. 

조증은 

경조증 또는 우울증 삽화의 기준을 충족하지 않는 경조증과 

우울 증상이 모두 2년 이상 지속되는 기분 불안정증으로 정의됩니다. 

일부 연구에 따르면 

조울증 진단을 받은 사람의 30% 이상이 

양극성 장애, 주로 양극성 II 장애로 발전하는 것으로 추정됩니다74.

Other specified bipolar and unspecified bipolar and related disorders.

These categories replace the ‘not otherwise specified’ category in the DSM‑IV75. The other specified bipolar and related disorders are short duration hypomanic episodes (2–3 days) and major depressive episodes, hypomanic episodes with insuffi‑ cient symptoms and major depressive episodes, hypo‑ manic episodes without prior major depressive episode, and shortduration cyclothymia (<2 years). Individuals with shortduration hypomanic episodes and major depressive episodes should be followed up. By contrast, the category ‘unspecified bipolar and related disorders’ is intended for temporary use, such as in emergency room settings in which insufficient evidence and infor‑ mation are available but the individual’s behaviour and history suggest a diagnosis that falls into the bipolar and related disorders category3

기타 특정 양극성 및 상세불명의 양극성 및 관련 장애. 

이 범주는 DSM-IV75의 '달리 명시되지 않음' 범주를 대체합니다. 기타 특정 양극성 및 관련 장애는 단기간 경조증 삽화(2~3일) 및 주요 우울 삽화, 불충분한 증상이 있는 경조증 삽화 및 주요 우울 삽화, 이전 주요 우울 삽화가 없는 경조증 삽화, 단기간 조울증(2년 미만)입니다. 단기간의 경조증 삽화와 주요 우울 삽화가 있는 사람은 추적 관찰을 받아야 합니다. 반면 '상세불명의 양극성 및 관련 장애' 범주는 응급실 환경과 같이 증거와 정보가 불충분하지만 개인의 행동과 병력이 양극성 및 관련 장애 범주에 속하는 진단을 시사하는 경우3에 일시적으로 사용하기 위한 것입니다.

Substance-induced and medication-induced bipolar and related disorders. 

This category includes symp‑ toms of bipolar disorders such as mood instability and mania that are caused by any substance, medication or medical conditions. Examples include a cocaine induced or amphetamineinduced manic episode or a medical condition (such as hyperthyroidism) causing manic symptoms. The difference between this group of diagnoses and the other categories is that when the causal element is removed, bipolar symptoms should not recur.

물질 유발 및 약물 유발 양극성 장애 및 관련 장애. 

이 범주에는 물질, 약물 또는 의학적 상태에 의해 유발되는 기분 불안정 및 조증과 같은 양극성 장애의 증상이 포함됩니다. 예를 들면 코카인으로 인한 조증 에피소드 또는 암페타민으로 인한 조증 에피소드 또는 조증 증상을 유발하는 의학적 상태(예: 갑상선 기능 항진증)가 포함됩니다. 이 진단 그룹과 다른 범주의 차이점은 원인 요인이 제거되면 조울증 증상이 재발하지 않는다는 것입니다.

Specifiers.

Specifiers are used to provide additional detail about the nature of the symptoms of an episode or throughout the course of the disorder (BOX 3). New additions to the DSM‑5 bipolar and related disorders category include the specifiers ‘with anxious distress’ and ‘with mixed features’. Other specifiers were contin‑ ued from the DSM‑IV to DSM‑5, such as ‘with rapid cycling’, ‘with melancholic features’ or ‘with atypical features’ during depressive episodes and ‘with psychotic features’. Other specifiers include ‘with peri‑ partum onset’ and ‘with seasonal pattern’, which can be used for depressive and hypomanic or manic symp‑ toms. Specifiers to be considered for inclusion in future updates to the DSM include predominant polarity (that is, either manic or depressive polarity), the pres‑ ence of cognitive impairment, family history of bipolar disorders and age at onset (for example, using 18 years of age as a cutoff to define early onset). The ‘with mixed features’ specifier can, for the first time, be used for symptoms of major depressive dis‑ order or bipolar disorders. This specifier refers to the possibility that individuals in a manic episode can simultaneously experience symptoms of depression or, conversely, that patients can experience hypomanic symptoms during a depressive episode (BOX 3). The possibility of mixed symptoms is important for diag‑ nosis and management for a number of reasons, not least of which is because mixed symptoms are associated with a more torpid course of disease and a higher likeli‑ hood of suicide2 . However, this specifier, which replaced the DSM‑IV ‘mixed episode category’ that required the simultaneous occurrence of a full manic and a full depressive episode, has not been without controversy76. Indeed, although European and North American litera‑ ture recognizes that mixed symptoms can occur across the range of mood symptoms experienced by patients with bipolar disorders, a debate on how to define mixed features remains77.

지정자.
지정어는 삽화 증상의 특성 또는 장애의 경과에 대한 추가 세부 정보를 제공하는 데 사용됩니다(박스 3). DSM-5 양극성 및 관련 장애 범주에 새로 추가된 지정자에는 '불안 장애가 있음' 및 '혼합된 특징이 있음'이 포함됩니다. 우울 삽화 중 '빠른 주기', '우울한 특징이 있음' 또는 '비정형적 특징이 있음', '정신병적 특징이 있음'과 같은 다른 지정자는 DSM-IV에서 DSM-5로 계속 유지되었습니다. 

다른 지정자에는 우울증과 경조증 또는 조증 증상에 사용할 수 있는 '분만 전후 발병' 및 '계절적 패턴'이 포함됩니다. 향후 DSM 업데이트에 포함될 것으로 고려되는 지정자에는 우세한 양극성(조증 또는 우울증 양극성), 인지 장애의 존재, 양극성 장애의 가족력, 발병 연령(예: 조기 발병을 정의하기 위해 18세를 컷오프로 사용) 등이 포함됩니다. '혼합된 특징 포함' 지정자는 처음으로 주요우울장애 또는 양극성 장애의 증상에 사용할 수 있습니다. 이 지정자는 조증 에피소드에 있는 개인이 우울증 증상을 동시에 경험할 수 있거나 반대로 우울 에피소드 중에 경조증 증상을 경험할 수 있는 가능성을 나타냅니다(박스 3). 혼합 증상의 가능성은 여러 가지 이유로 진단 및 관리에 중요한데, 그중에서도 혼합 증상은 질병의 경과가 더 나빠지고 자살 가능성이 더 높기 때문입니다2 . 그러나 완전한 조증과 완전한 우울 삽화가 동시에 발생해야 했던 DSM-IV의 '혼합 삽화 범주'를 대체한 이 규정은 논란의 여지가 없었습니다76. 실제로 유럽과 북미의 문헌에서는 양극성 장애 환자가 경험하는 다양한 기분 증상 범위에서 혼합 증상이 발생할 수 있음을 인정하고 있지만, 혼합 증상을 어떻게 정의할지에 대한 논쟁이 여전히 남아 있습니다77.

Diagnostic work-up

Possibly one of the most important factors in the diag‑ nosis of bipolar disorders is that individuals are typically very conscious of and sensitive to their depressive symp‑ toms but do not recognize their hypomanic or manic symptoms. One question to ask patients is whether they have periods of depressive symptoms in which they have excessive energy or periods of extreme irritability and high activity, as this question can help the patient recognize symptoms other than depression. Indeed, the identification of past or current hypomanic or manic symptoms in patients who present with depression is critically important. Asking individuals about changes in activity and energy levels, not just mood, is also impor‑ tant, as changes in energy and activity levels might be more of a signifier of bipolar disorders than changes in mood78,79. Along this line, increasing activity or energy is actually required for bipolar mania diagnoses in DSM‑5. In addition to asking patients about a history of depression and other types of episodes, including family members or partners in the eval‎uation is crucial, given that the patient might be unable to effectively observe or identify changes in their own behaviour, energy or mood. Owing to the high lifetime potential for suicide in patients with bipolar disorders, screening patients for suicide intent or plan is very important24. Several screening instruments that may be of possi‑ ble benefit include life charting80 (which can be used for mania, hypomania and depression), the Young Mania Rating Scale81 and the Hypomania/Mania Symptom Checklist (HCL‑32)82,83. Screening tools for bipolar disorders such as the Mood Disorders Questionnaire and HCL‑32 are often used but have low sensitivity and specificity, especially in the community setting84. Major depressive episodes are similar in bipolar disorders and major depressive disorder, although mixed features are more common in patients with bipolar disorders than in those with major depression85. Several selfreport questionnaires for the eval‎uation of depression are available, including the Patient Health Questionnaire‑9 (PHQ‑9) or the Inventory of Depressive Symptomatology (IDS)86. In addition, cliniciandriven forms are available, including the Hamilton Rating Scale for Depression and the clinician version of the IDS87. As previously discussed, patients tend to be more aware of depres‑ sive symptoms than manic symptoms; thus, the use of selfreport and cliniciandriven forms for mania and hypomania is key to assess these symptoms.

진단 검사 

양극성 장애 진단에서 가장 중요한 요인 중 하나는 

일반적으로 개인이 자신의 우울 증상을 매우 의식하고 민감하지만 

경조증이나 조증 증상을 인식하지 못한다는 점입니다. 

환자에게 물어볼 수 있는 질문 중 하나는 

과도한 에너지로 우울한 증상을 보이는 기간이나 극도로 짜증스럽고 활동량이 많은 기간이 있는지 여부인데, 

이 질문은 환자가 우울증 이외의 증상을 인식하는 데 도움이 될 수 있기 때문입니다. 

실제로 

우울증 환자의 과거 또는 현재 경조증 또는 조증 증상을 파악하는 것은 매우 중요합니다. 

에너지 및 활동 수준의 변화가 기분 변화보다 

양극성 장애의 징후일 수 있기 때문에 

기분뿐만 아니라 활동 및 에너지 수준의 변화에 대해 개인에게 질문하는 것도 중요합니다78,79. 

이러한 맥락에서 

DSM-5의 양극성 조증 진단에는 실제로 활동량이나 에너지의 증가가 필요합니다. 

환자가 자신의 행동, 에너지 또는 기분 변화를 효과적으로 관찰하거나 식별하지 못할 수 있으므로 

환자에게 우울증 및 기타 유형의 에피소드 병력에 대해 물어보는 것 외에도 

가족이나 파트너를 평가에 포함하는 것이 중요합니다. 

양극성 장애 환자의 경우 평생 자살할 가능성이 높기 때문에 

환자의 자살 의도 또는 계획을 선별하는 것은 매우 중요합니다24. 

도움이 될 수 있는 선별 도구로는 

조증, 경조증, 우울증에 사용할 수 있는 라이프 차트80, 

젊은 조증 평가 척도81, 경조증/조증 증상 체크리스트(HCL-32)82,83 등이 있습니다. 

기분 장애 설문지 및 HCL-32와 같은 양극성 장애 선별 도구는 자주 사용되지만 

민감도와 특이도가 낮으며, 

특히 지역사회 환경에서는 더욱 그렇습니다84. 

주요 우울 삽화는 양극성 장애와 주요 우울 장애에서 비슷하지만, 

양극성 장애 환자에서 주요 우울증 환자보다 혼합된 특징이 더 흔합니다85. 

우울증 평가를 위한 자가 보고 설문지로는 

환자 건강 설문지-9(PHQ-9) 또는 우울 증상 인벤토리(IDS)86 등 여러 가지가 있습니다. 

또한 해밀턴 우울증 평가 척도(Hamilton Rating Scale for Depression)와 임상의용 버전 IDS87 등 임상 중심의 양식도 사용할 수 있습니다. 앞서 논의했듯이 환자는 조증 증상보다 우울 증상을 더 잘 인식하는 경향이 있으므로 조증 및 경조증에 대한 자가 보고 및 임상 중심 양식을 사용하는 것이 이러한 증상을 평가하는 데 중요합니다.

Prevention

Some studies have suggested that early interventions in highrisk children and adolescents alter the course and development of bipolar disorders88. These early interven‑ tions represent an emerging field, and those individuals at highest risk, such as children or adolescents with sub‑ syndromal manic symptoms or children of patients with bipolar disorders, are providing important new informa‑ tion. The possible role of environmental factors (such as diet, physical activity and smoking, as well as stress, substance abuse or neurological insult) in the develop‑ ment of bipolar disorders is increasingly appreciated43. However, this work is still very early on in its develop‑ ment. Some groups are trying to identify the earliest bio‑ logical symptoms of bipolar disorders and interventions that could change the course of illness.

예방

일부 연구에 따르면 

고위험군 아동 및 청소년에 대한 조기 개입이 양극성 장애의 경과와 발달에 변화를 가져온다고 합니다88. 

이러한 조기 개입은 새롭게 떠오르는 분야이며, 아증후성 조증 증상을 보이는 아동이나 청소년 또는 양극성 장애 환자의 자녀와 같이 고위험군에 속하는 사람들은 중요한 새로운 정보를 제공하고 있습니다. 

양극성 장애의 발병에 있어 환경적 요인(식이, 신체 활동, 흡연, 스트레스, 약물 남용, 신경학적 모욕 등)의 역할이 점점 더 중요해지고 있습니다43. 

그러나 이 연구는 아직 개발 초기 단계입니다. 

일부 그룹에서는 양극성 장애의 초기 생물학적 증상과 질병의 경과를 바꿀 수 있는 개입을 파악하기 위해 노력하고 있습니다.

Management

Bipolar disorders are highly recurrent, even when correctly diagnosed and treated. The effective treatment of acute depressive and hypomanic or manic symptoms and the prevention of relapses are essential accord‑ ing to several international guidelines, including the Canadian Network for Mood and Anxiety Treatments, the International College of Neuropsychopharmacology and the British Association for Psychopharmacology89–91. Accordingly, management of patients with bipolar dis‑ orders involves the acute treatment of manic or hypo‑ manic episodes in addition to maintenance therapy to prevent relapses and further episodes. 

Lithium was the first medication approved by the US FDA for the treatment of acute mania and since then, for adults, ten medications have been approved by the FDA for the treatment of acute mania, three for the treatment of bipolar depression and six for maintenance therapy (TABLE 2). For children and adolescents, five medications are approved for acute mania by the FDA (TABLE 2). The approvals of most of these therapies were based on results from randomized, doubleblind, placebocontrolled studies using DSM‑IV diagnostic criteria, although some medications have also been used or studied for treatment without FDA approval. However, importantly, results from pivotal clinical trials are not necessarily generaliz‑ able to the realworld population because most patients with comorbidities, especially those with substance use disorders, were excluded from these trials92. Indeed, one example of this limitation is the lack of superior‑ ity of quetiapine (extendedrelease) compared with placebo in reducing depressive symptoms in patients with multiple comorbidities93. Comorbidities in bipolar disorders are frequent, and appropriate treatments for these conditions represent an urgent unmet need. Despite available therapies for bipolar disorders, treat‑ ment loses effectiveness when adherence is uncertain. Thus, enhancing adherence is one of the cornerstones in the management of patients with bipolar disorders. In addition, balancing shortterm and longterm effec‑ tiveness and safety for all drugs in patients with bipolar disorders is essential94

관리
양극성 장애는 정확하게 진단받고 치료하더라도 재발률이 높습니다. 캐나다 기분 및 불안 치료 네트워크, 국제 신경정신약물학회, 영국 정신약물학회89-91 등 여러 국제 가이드라인에 따르면 급성 우울증 및 경조증 또는 조증 증상의 효과적인 치료와 재발 예방이 필수적입니다. 따라서 양극성 장애 환자 관리에는 조증 또는 경조증 에피소드의 급성 치료와 더불어 재발 및 추가 에피소드를 예방하기 위한 유지 요법이 포함됩니다. 

리튬은 

미국 FDA에서 급성 조증 치료제로 승인한 최초의 약물이며, 

이후 성인의 경우 급성 조증 치료제로 10개, 

양극성 우울증 치료제로 3개, 

유지 요법으로 6개 약물이 FDA에서 승인되었습니다(표 2). 

소아 및 청소년의 경우, 5개의 약물이 급성 조증 치료제로 FDA의 승인을 받았습니다(표 2). 이러한 치료법의 승인은 대부분 DSM-IV 진단 기준을 사용한 무작위, 이중맹검, 위약 대조 연구 결과를 기반으로 이루어졌지만, 일부 약물은 FDA 승인 없이도 치료를 위해 사용되거나 연구된 바 있습니다. 그러나 중요한 것은 대부분의 동반 질환이 있는 환자, 특히 약물 사용 장애가 있는 환자는 이러한 임상시험에서 제외되었기 때문에 중추적인 임상시험의 결과를 실제 인구에 일반화할 수 없다는 점입니다92. 실제로 이러한 제한의 한 예로 여러 동반 질환이 있는 환자의 우울 증상 감소에 있어 위약에 비해 케티아핀(서방형)의 우월성이 부족하다는 점을 들 수 있습니다93. 양극성 장애의 동반 질환은 빈번하게 발생하며, 이러한 질환에 대한 적절한 치료법은 시급한 미충족 수요를 나타냅니다. 양극성 장애에 대한 치료법이 있음에도 불구하고 치료 순응도가 불확실할 경우 치료 효과는 떨어집니다. 따라서 치료 순응도를 높이는 것은 양극성 장애 환자 관리의 초석 중 하나입니다. 또한 양극성 장애 환자의 모든 약물에 대해 장단기 효과와 안전성의 균형을 맞추는 것이 필수적입니다94.

Treatment of acute mania

Pharmacological therapy is the cornerstone treatment for acute mania (TABLE 2), although nonpharmacological treatments can be used in patients with treatment resistant and severe mania. The treatment for hypo‑ mania has scarcely been addressed, and pharmacological approaches for mania have been assumed. Differences in the reported efficacy of the FDAapproved therapies for the treatment of mania in adults are small, especially on the basis of data from head‑to‑head comparison studies, although some multipletreatment network metaanalyses have suggested a stronger efficacy of some therapies95,96. By contrast, the adverseeffect pro‑ files of therapies for mania is widely variable97 (TABLE 2).

A morerecent metaanalysis supports that when a patient does not respond after 1–2 weeks, a different medication should be considered98. The combination of a mood stabilizer and an antipsychotic, especially for moresevere illness, may be a better choice than either medication alone99. In children and adolescents, the antipsychotic risperidone had a higher efficacy than lithium and divalproex sodium but was associated with moresevere metabolic adverse effects100. Despite several antipsychotics showing superior‑ ity to placebo at reducing manic symptoms (such as haloperidol and paliperidone monotherapy), none has been approved for this indication95. Several other investigated therapies, such as lamotrigine, eslicarba‑ zepine  and topiramate monotherapy or combined gabapentin and mood stabilizer, were not superior to placebo95. Other drug classes, including NSAIDs (cele‑ coxib), dopamine agonists (bromocriptine), protein kinase C inhibitors (tamoxifen) and xanthine oxidase inhibitors (allopurinol), have also been studied in acute mania as monotherapy or adjunctive therapy99. The sample sizes of those studies were small, and the results were generally inconclusive. ECT as a monotherapy or an adjunctive therapy to pharmacological treatments can also be used for the treatment of acute mania, especially in patients with refractory mania or those with aggressive behaviour and/or psychosis101. Two studies showed the efficacy of repetitive transcranial magnetic stimulation of the right prefrontal cortex for the treatment of acute mania in adults, although one study in adolescents was ineffec‑ tive102,103. In addition, dysfunction of the circadian sys‑ tem is thought to be a main factor for the onset of mania and, accordingly, one study showed an effect of blue lightblocking glasses (when used as an additive to standard pharmacological treatment) in reducing manic symptoms compared with standard treatment alone104. Cognitive–behavioural therapy (CBT) was suggested to improve the severity of manic symptoms in one metaanalysis105.

급성 조증 치료

급성 조증의 치료는 

약물 치료가 기본이지만(표 2), 

치료에 내성이 있는 중증 조증 환자에게는 비약물적 치료가 사용될 수 있습니다. 

저조증에 대한 치료는 거의 다루어지지 않았으며, 

조증에 대한 약리학적 접근이 가정되어 왔습니다. 

일부 다중 치료 네트워크 메타분석에서는 일부 치료법의 효능이 더 강력하다고 제안했지만, 특히 일대일 비교 연구 데이터를 기반으로 한 성인 조증 치료를 위해 FDA 승인을 받은 치료법의 보고된 효능의 차이는 작습니다95,96. 반면, 조증 치료의 부작용 효과는 매우 다양합니다97(표 2).

더 많은 메타분석에 따르면 환자가 

1-2주 후에도 반응하지 않으면 다른 약물을 고려해야 한다고 합니다98. 

특히 중증 질환의 경우 

기분 안정제와 항정신병 약물을 병용하는 것이 

두 가지 약물을 단독으로 사용하는 것보다 더 나은 선택이 될 수 있습니다99. 

소아 및 청소년의 경우 항정신병 약물인 

리스페리돈은 리튬 및 디발프로엑스 나트륨보다 효능이 더 높았지만 

더 심각한 대사 부작용과 관련이 있었습니다100. 

할로페리돌 및 팔리페리돈 단독 요법과 같이

 조증 증상 감소에 위약보다 우수한 효과를 보이는 항정신병 약물이 몇 가지 있지만, 

이 적응증에 대해 승인된 약은 없습니다95. 

라모트리진, 에슬라카르바 제핀, 토피라메이트 단독 요법 또는 가바펜틴과 기분 안정제 병용 요법 등 여러 가지 다른 연구 요법도 위약보다 우월하지 않았습니다95. NSAID(셀레콕시브), 도파민 작용제(브로모크립틴), 단백질 키나아제 C 억제제(타목시펜), 잔틴 산화효소 억제제(알로푸리놀) 등 다른 약물 계열도 급성 조증에서 단독 요법 또는 보조 요법으로 연구되었습니다99. 이러한 연구의 표본 크기가 작았고 결과는 일반적으로 결정적이지 않았습니다. 단독 요법 또는 약물 치료의 보조 요법으로서 ECT는 특히 불응성 조증 환자나 공격적 행동 및/또는 정신병 환자에서 급성 조증 치료에도 사용할 수 있습니다101. 성인의 급성 조증 치료를 위한 우측 전전두엽 피질의 반복적 경두개 자기 자극이 효과가 있다는 두 건의 연구가 있었지만, 청소년을 대상으로 한 연구는 효과가 없었습니다102,103. 또한 일주기 시스템의 기능 장애는 조증 발병의 주요 요인으로 생각되며, 이에 따라 한 연구에서는 청색광 차단 안경(표준 약물 치료의 보조제로 사용 시)이 표준 치료 단독에 비해 조증 증상을 감소시키는 효과가 있는 것으로 나타났습니다104. 한 메타분석에서는 인지 행동 치료(CBT)가 조증 증상의 중증도를 개선하는 것으로 나타났습니다105.

Treatments for acute depression

Although patients with bipolar disorders spend more time in depression than in mania or hypomania, fewer studies focus on depression, and only three medica‑ tions — all antipsychotics — have been approved by the FDA for bipolar depression. Patients with depression are more sensitive to, but less tolerant of, pharmacological treatments — especially antipsychotics — than they are during mania106. Accordingly, a lower starting dose and slower titration might be necessary for patients with depression. In addition, antipsychoticinduced meta‑ bolic abnormalities have become a major concern, and monitoring weight changes and metabolic profiles at each healthcare visit should be routine. Notably, shortterm weight gain cannot accurately predict longterm weight gain97 and selfreported weight change is unreliable107. Given the limited number of approved medications for bipolar depression, offlabel use of therapies, or com‑ binatorial therapy, is common. In this context, some treatments, including anticonvulsants (such as divalproex and lamotrigine), olanzapine monotherapy and com‑ bined lithium and lamotrigine therapy, were superior to placebo in reducing the severity of depressive symp‑ toms in patients with bipolar disorders108. In addition, quetiapine–lamotrigine combination therapy was superior to quetiapine alone109. Lurasidone, which is approved by the FDA for the treatment of bipolar depres‑ sion in adults, has shown compelling results in acute depression in trials in children and adolescents with bipolar disorders110. Little evidence supports the possible benefits of anticonvulsants (such as levetiracetam, topiramate and gabapentin), thyroid hormone, acetylcholinesterase inhibitors, acetyll‑carnitine, pregnenolone, naltrex‑ one or lisdexamfetamine, either as adjunctive therapy or monotherapy, for bipolar depression. However, studies with a small sample size have shown efficacy of pramipexole, ketamine and scopolamine for bipolar depression. Antiinflammatory agents such as NSAIDs, N‑acetylcysteine, omega‑3 polyunsaturated fatty acids and pioglitazone might also have antidepressant effects in bipolar depression when used adjunctive to conventional therapy111. The controversy surrounding the efficacy of anti‑ depressants in acute bipolar depression and the risk of mood switching to hypomanic episodes, manic episodes or mixed states, particularly with monotherapy, remains unsettled46. One metaanalysis of 15 trials including a total of 2,373 patients showed that antidepressants were not superior to placebo treatment112, although another meta analysis that focused on adjunctive secondgeneration antidepressants reported only positive effects113,114. How‑ ever, agomelatine treatment was not superior to pla‑ cebo in patients with bipolar depression115. In addition, an increased risk of switching to mania or hypomania and cycle acceleration has been reported with stimulantlike agents and pramipexole. A traditional mood stabilizer should be started first, before antidepressants or other drugs that can induce switching to mania, and manic or hypomanic switching should be monitored closely when using maniaprovoking agents. Nonpharmacological treatments for bipolar depres‑ sion include ECT, repetitive transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimu‑ lation, lifestyle interventions and psychotherapies. ECT is commonly used for treatmentrefractory depression and is effective for the treatment of both bipolar depres‑ sion and unipolar depression116. Indeed, ECT had a significantly higher responder rate than algorithmbased pharmacological treatments in patients with treatment resistant bipolar depression117. Psychotherapy, such as psychoeducation, CBT, familyfocused therapy, dia‑ lectical behaviour therapy, mindfulnessbased CBT and interpersonal and social rhythm therapy, might be useful primarily as adjunctive treatments for managing bipolar depression118. However, the usefulness of each intervention has been studied only in specific patients with specific symptoms of bipolar disorders105,119. In chil‑ dren and adolescents, family psychoeducation, in addi‑ tion to skill building and CBT, might be effective for bipolar depression120.

급성 우울증 치료 
양극성 장애 환자는 조증이나 경조증보다 우울증에 더 많은 시간을 보내지만, 우울증에 초점을 맞춘 연구는 더 적고, 양극성 우울증에 대해 FDA의 승인을 받은 약물은 단 세 가지(모두 항정신병약물)에 불과합니다. 우울증 환자는 조증 환자에 비해 약물 치료, 특히 항정신병약물에 더 민감하지만 내약성이 낮습니다106. 따라서 우울증 환자에게는 더 낮은 시작 용량과 더 느린 적정이 필요할 수 있습니다. 또한 항정신병 약물로 인한 대사 이상은 주요 관심사가 되었으며, 의료기관을 방문할 때마다 체중 변화와 대사 프로필을 모니터링하는 것이 일상화되어야 합니다. 특히, 단기 체중 증가는 장기 체중 증가를 정확하게 예측할 수 없으며97, 자가 보고된 체중 변화는 신뢰할 수 없습니다107. 양극성 우울증에 대해 승인된 약물의 수가 제한되어 있기 때문에 치료제의 오프라벨 사용 또는 이원적 치료가 일반적입니다. 이러한 맥락에서 항경련제(디발프로엑스 및 라모트리진 등), 올란자핀 단독 요법, 리튬과 라모트리진 병용 요법 등 일부 치료법은 양극성 장애 환자의 우울 증상의 중증도를 줄이는 데 위약보다 우수한 효과를 보였습니다108. 또한, 케티아핀-라모트리진 병용 요법은 케티아핀 단독 요법보다 우수했습니다109. 성인 양극성 우울증 치료제로 FDA의 승인을 받은 루라시돈은 양극성 장애가 있는 소아 및 청소년을 대상으로 한 임상시험에서 급성 우울증에 대한 강력한 결과를 보여주었습니다110. 항경련제(레베티라세탐, 토피라메이트, 가바펜틴 등), 갑상선 호르몬, 아세틸콜린에스테라아제 억제제, 아세틸카르니틴, 프레그네놀론, 날트렉스원 또는 리스덱삼페타민을 보조 요법이나 단독 요법으로 양극성 우울증에 사용할 경우의 이점을 뒷받침하는 증거는 거의 없습니다. 그러나 표본 규모가 작은 연구에서도 프라미펙솔, 케타민, 스코폴라민이 양극성 우울증에 효과가 있는 것으로 나타났습니다. NSAID, N-아세틸시스테인, 오메가-3 고도불포화지방산, 피오글리타존과 같은 항염증제도 기존 치료에 보조적으로 사용할 경우 양극성 우울증에 항우울 효과가 있을 수 있습니다111. 급성 양극성 우울증에서 항우울제의 효능과 특히 단독 요법에서 저조증 삽화, 조증 삽화 또는 혼합 상태로의 기분 전환 위험에 대한 논란은 여전히 해결되지 않은 상태입니다46. 총 2,373명의 환자를 포함한 15건의 임상시험을 대상으로 한 메타분석에서는 항우울제가 위약 치료보다 우월하지 않은 것으로 나타났지만112, 보조적인 2세대 항우울제에 초점을 맞춘 또 다른 메타분석에서는 긍정적인 효과만 보고되었습니다113,114. 그러나 양극성 우울증 환자에서 아고멜라틴 치료는 플라세보보다 우월하지 않았습니다115. 또한, 각성제와 프라미펙솔은 조증 또는 경조증으로 전환될 위험이 증가하고 주기가 빨라지는 것으로 보고되었습니다. 항우울제나 조증 전환을 유발할 수 있는 다른 약물을 사용하기 전에 전통적인 기분 안정제를 먼저 시작해야 하며, 조증 유발 약물을 사용할 때는 조증 또는 경조증 전환을 면밀히 모니터링해야 합니다. 양극성 우울증에 대한 비약물적 치료법에는 ECT, 반복적 경두개 자기 자극, 심부 뇌 자극, 미주 신경 자극, 생활 습관 중재 및 심리 치료가 포함됩니다. ECT는 일반적으로 치료 불응성 우울증에 사용되며 양극성 우울증과 단극성 우울증 치료에 모두 효과적입니다116. 실제로 ECT는 치료 저항성 양극성 우울증 환자에서 알고리즘 기반 약물 치료보다 훨씬 더 높은 반응률을 보였습니다117. 정신교육, CBT, 가족 중심 치료, 인지행동 치료, 마음챙김 기반 CBT, 대인관계 및 사회적 리듬 치료와 같은 심리치료는 주로 양극성 우울증 관리를 위한 보조적 치료로 유용할 수 있습니다118. 그러나 각 개입의 유용성은 양극성 장애의 특정 증상을 가진 특정 환자에서만 연구되었습니다105,119. 소아 및 청소년의 경우, 기술 습득 및 CBT와 더불어 가족 심리 교육이 양극성 우울증에 효과적일 수 있습니다120.

Maintenance treatment

Considering the recurrent and chronic nature of bipolar disorders, optimal longterm management requires a preventive strategy that includes pharmacological treat‑ ments, psychological therapies and lifestyle approaches121 shortly after onset122. Pharmacotherapy (most com‑ monly a mood stabilizer alone or in combination with an antipsychotic or an antidepressant123) in addition to tailored psychosocial interventions can decrease the risk of relapse, improve treatment adherence and reduce the number and length of hospitalizations90. Lithium remains one of the most effective drugs for the prevention of both manic and depressive episodes, and one network metaanalysis reported a risk ratio of 0.62 (95% credible interval 0.53–0.72) for the risk of mood relapse or recurrence compared with placebo124. In addition, lithium monotherapy and combined lithium–valproate therapy were found to be more likely to prevent relapses in patients with bipolar I disorder than valproate monotherapy, regardless of the severity of illness in the BALANCE study125. However, adjunc‑ tive lithium to optimized personalized treatment had no additional benefit compared with optimized personal‑ ized treatment alone126. Nevertheless, the lithium plus optimized personalized treatment group had less expo‑ sure to secondgeneration antipsychotics and the sub‑ sequent adverse effects126. Despite the effectiveness of lithium, this drug has been associated with a decline in renal function and the development of hypothyroid‑ ism and hypercalcaemia following longterm use124,127.

Quetiapine and combined quetiapine–lithium and quetiapine–divalproex therapy have also been suggested as suitable therapies for the maintenance treatment of patients with bipolar disorders on the basis of data from metaanalyses124,128. Indeed, no clinically meaningful differences were found between lithium treatment or treatment with quetiapine and adjunctive personal‑ ized treatment in the CHOICE study129. Nevertheless, these data should be interpreted with caution, as treat‑ ments were initiated during an acute episode in most trials (mostly during an acute manic episode) and the polarity of the episode affects the potential of the treatment to prevent further episodes of the similar polarity 130. Furthermore, many industryled trials were enriched designs, which may inflate the efficacy of the studied drug91. Evidence for pharmacological maintenance therapies in children and adolescents is practically limited to the acute treatment of manic and mixed episodes108. Pharmacological maintenance treatment should be aligned with the patient’s predominant polarity, which is defined as the pole at which a patient has at least twice as many episodes as at the other pole. However, polarity is not observed in all patients. Predominant polarity has prognostic value and clinical and therapeutic implica‑ tions131.

The polarity index is a metric used to classify maintenance therapies and categorizes therapies as those with a predominant antimanic prophylactic profile and those with an antidepressant prophylactic profile (FIG. 3). For example, patients with a depressive predominant polarity (mostly those with bipolar II disorder) might have a better response to lamotrigine and are more likely to require adjunctive antidepressants. Conversely, patients with a manic predominant polarity (mostly those with bipolar I disorder) have a better response to atypical antipsychotics such as risperidone92,132,133. Quetiapine and lithium have a polarity index nearest to 1, reflecting a nearequal efficacy in preventing manic and depressive episodes. For nonpharmacological treatment, psychoeducation has shown longlasting prophylactic effects in individuals with bipolar disorders who attended group psychoeduca‑ tion for 6 months134. Indeed, at 5‑year follow‑up, patients who received psychoeducation had a longer time to recurrence, had fewer recurrences, spent less time in an episode and had reduced duration of hospitalization135. CBT136, interpersonal and social rhythm therapy137 and familyfocused therapy138 have also reported efficacy for bipolar maintenance therapy. Recently, functional remediation (a restoring psychosocial therapy that uses ecological neurocognitive techniques) has improved functioning in patients with bipolar I disorder139 and patients with bipolar II disorder140 with psychosocial functional impairment. Moreover, improvement in psychosocial functioning has been shown to remain after 1‑year followup141. Internetbased approaches and appli‑ cations are gaining traction and are starting to be used in clinics13,142. In general, CBT, familyfocused therapy and psychoeducation have a more antidepressant than antimanic prophylactic effect, whereas caregiver group psychoeducation has a more antimanic effect143. Valproate and carbamazepine are not recommended for the treatment of women of childbearing age as they increase the risks of spina bifida and low IQ in off‑ spring89. In this subpopulation, preconception counsel‑ ling and planning are crucial to avoid the teratogenic effects of drugs, in particular during the first trimester, and the abrupt cessation of a treatment, which imply an undeniable risk of recurrences of a mood episode in the mother.

유지 치료
양극성 장애의 반복적이고 만성적인 특성을 고려할 때, 

최적의 장기 관리를 위해서는 

발병 직후부터 약물 치료, 

심리 치료 및 생활 습관 접근법121을 포함하는 

예방 전략이 필요합니다122. 

맞춤형 심리사회적 개입과 더불어 

약물 요법(대부분 기분 안정제 단독 또는 항정신병약물 또는 항우울제와 병용123)은 

재발 위험을 줄이고 치료 순응도를 개선하며 

입원 횟수 및 기간을 줄일 수 있습니다90. 

리튬은 

조증 및 우울증 삽화 예방에 가장 효과적인 약물 중 하나로, 

한 네트워크 메타분석에서는 위약 대비 기분 재발 또는 재발 위험에 대한 위험비가 

0.62(95% 신뢰구간 0.53-0.72)로 보고된 바 있습니다124. 

또한, BALANCE 연구125에서는 

질환의 중증도에 관계없이 

리튬 단독 요법과 리튬-발프로에이트 병용 요법이 

발프로에이트 단독 요법보다 양극성 장애 환자의 재발을 예방할 가능성이 더 높은 것으로 나타났습니다. 

그러나 

최적화된 개인 맞춤형 치료에 리튬을 추가하는 것은 

최적화된 개인 맞춤형 치료 단독 요법에 비해 추가적인 이점이 없었습니다126. 

그럼에도 불구하고 리튬과 최적화된 개인 맞춤형 치료를 병용한 그룹은 2세대 항정신병 약물에 대한 노출과 그에 따른 부작용이 더 적었습니다126. 

리튬의 효과에도 불구하고 

이 약물은 장기 사용 시 

신장 기능 저하와 갑상선 기능 저하증 및 고칼슘혈증 발생과 관련이 있습니다124,127.

케티아핀과 케티아핀-리튬 및 케티아핀-디발프로엑스 병용 요법도

 메타분석 데이터를 기반으로 양극성 장애 환자의 유지 치료에 적합한 치료법으로 제안되었습니다124,128. 

실제로 CHOICE 연구129에서는 

리튬 치료 또는 케티아핀 치료와 보조적인 개인 맞춤형 치료 간에 임상적으로 의미 있는 차이가 발견되지 않았습니다. 

그럼에도 불구하고 대부분의 임상시험에서 

치료가 급성 삽화(대부분 급성 조증 삽화) 중에 시작되었고 

삽화의 극성이 유사한 극성의 추가 삽화를 예방하는 치료의 가능성에 영향을 미치기 때문에 

이러한 데이터는 신중하게 해석해야 합니다. 

또한, 많은 산업계 주도 임상시험이 강화된 설계로 진행되어 연구 대상 약물의 효능이 부풀려질 수 있습니다91. 소아 및 청소년의 약물 유지 요법에 대한 증거는 조증 및 혼합 삽화의 급성 치료로 실질적으로 제한되어 있습니다108. 약물학적 유지 치료는 환자의 우세 극성에 맞춰야 하며, 이는 환자가 다른 극성보다 최소 두 배 이상 많은 에피소드가 있는 극성으로 정의됩니다. 그러나 모든 환자에서 극성이 관찰되는 것은 아닙니다. 우세 극성은 예후적 가치와 임상적 및 치료적 의미가 있습니다131.

극성 지수는 유지 요법을 분류하는 데 사용되는 지표로, 우세한 항우울제 예방 프로필을 가진 요법과 항우울제 예방 프로필을 가진 요법으로 분류합니다(그림 3). 예를 들어, 우울 우위 극성을 가진 환자(대부분 양극성 장애 환자)는 라모트리진에 더 좋은 반응을 보일 수 있으며 보조 항우울제가 필요할 가능성이 더 높습니다. 반대로 조증 우세 극성을 가진 환자(대부분 양극성 I 장애 환자)는 리스페리돈과 같은 비정형 항정신병 약물에 더 잘 반응합니다92,132,133. 케티아핀과 리튬은 극성 지수가 1에 가까워 조증 및 우울증 에피소드를 예방하는 데 거의 동일한 효능이 있음을 반영합니다. 비약물적 치료의 경우, 정신교육은 6개월 동안 그룹 정신교육에 참여한 양극성 장애 환자에게 장기적인 예방 효과가 있는 것으로 나타났습니다134. 실제로 5년 추적 관찰 결과, 심리교육을 받은 환자는 재발까지 걸리는 시간이 길고, 재발 횟수가 적으며, 에피소드에 소요되는 시간이 짧고, 입원 기간도 감소했습니다135. CBT136, 대인관계 및 사회 리듬 치료137, 가족 중심 치료138도 양극성 유지 치료에 효과가 있는 것으로 보고되었습니다. 최근에는 기능적 교정(생태학적 신경인지 기법을 사용하는 심리사회적 회복 치료)을 통해 양극성 제1형 장애139 환자와 양극성 제2형 장애140 환자 중 심리사회적 기능 장애가 있는 환자의 기능이 개선되었습니다. 또한, 심리사회적 기능의 개선은 1년 추적 관찰 후에도 유지되는 것으로 나타났습니다141. 인터넷 기반 접근 방식과 응용 프로그램이 주목을 받고 있으며 클리닉에서 사용되기 시작했습니다13,142. 일반적으로 CBT, 가족 중심 치료 및 정신 교육은 항우울제보다 항우울 예방 효과가 더 큰 반면, 간병인 그룹 정신 교육은 항우울 효과가 더 큽니다143. 발프로에이트와 카바마제핀은 가임기 여성의 척추 이분증과 낮은 IQ의 위험을 증가시키므로 가임기 여성의 치료에는 권장되지 않습니다89. 이 하위 집단에서는 특히 임신 초기에 약물의 기형 유발 효과와 갑작스러운 치료 중단을 피하기 위해 임신 전 상담과 계획이 중요하며, 이는 산모에게 기분 장애가 재발할 수 있는 명백한 위험을 의미합니다.

Quality of life

Bipolar disorders are associated with reduced quality of life that can be more severe than that which occurs in other mood or anxiety disorders144. Poor quality of life correlates with depressive symptoms more than manic or hypomanic symptoms144. In addition, poor quality of life is associated with residual depressive symptoms that can occur during remission145 and the high comorbidity of bipolar disorders with anxiety disorders146. Quality of life also comprises individuals’ perceptions of their position in life in the context of their culture, value system, per‑ sonal goals, expectations and standards147. Thus, quality of life depends not only on clinical remission but also on functional recovery148. Accordingly, poor quality of life is closely associated with sociooccupational disabil‑ ity, including reduced academic attainment and work‑ force capacity149 and difficulties with activities of daily living150, employment status and personal relationships. Indeed, the unemployment rate is 4–10‑times higher151 and the divorce and separation rate is 2–3‑times higher in patients with bipolar disorders than in the general population152. The frequent onset of bipolar disorders around 20 years of age interferes with ageappropriate educational, social and developmental tasks as well as the development of a sense of self and identity153.

Thus, the fairly early onset is a key reason for academic underattainment and poor vocational integration108. Other contributors to poor occupational outcomes in patients with bipolar disorders include the presence of persistent cognitive impairment, including impairments in memory and executive function — notwithstanding that people with the highest premorbid intellectual functioning are at greatest risk of developing the dis‑ order154 (FIG. 4). Substantial cognitive impairment has been reported in 50–70% of patients during periods of remission155,156. Patients with cognitive impairment have poorer quality of life, increased stress and lower work capacity than patients who are cognitively intact, despite comparable levels of subsyndromal mood symp‑ toms155,156. Indeed, metaanalyses have indicated that impairments in memory and executive function are stronger contributors to poor occupational outcome than residual mood symptoms157. Functional remediation is a recently developed psychological intervention that aims to restore psycho‑ social functioning in patients with several disorders and has shown beneficial effects on functional capacity that persist for ≥1 year after treatment completion in patients with bipolar disorders139,141. No clinically avail‑ able treatments for cognitive dysfunction in patients with bipolar disorders are currently available, although preliminary evidence points to potential superiority of lithium compared with alternatives158. Several candi‑ date treatments, including erythropoietin, mifepristone, Nacetylcysteine159, cognitive remediation therapy160 and lurasidone, have been studied and have shown benefi‑ cial effects, mostly for the treatment of cognitive impair‑ ment161. Treatments targeting cognitive and functional impairments could increase quality of life in patients with bipolar disorders by enhancing academic attain‑ ment, work capacity and social relations and are a major strategic focus for the next decade.

삶의 질

양극성 장애는 다른 기분 장애나 불안 장애에서 발생하는 것보다 더 심각한 삶의 질 저하와 관련이 있습니다144. 삶의 질 저하는 조증 또는 경조증 증상보다 우울 증상과 더 관련이 있습니다144. 또한, 삶의 질 저하는 관해 기간 동안 발생할 수 있는 잔류 우울 증상145 및 양극성 장애와 불안 장애의 높은 동반 질환146과 관련이 있습니다. 삶의 질은 또한 문화, 가치 체계, 개인별 목표, 기대 및 기준의 맥락에서 삶의 위치에 대한 개인의 인식으로 구성됩니다147. 따라서 삶의 질은 임상적 관해뿐만 아니라 기능적 회복에도 영향을 미칩니다148. 따라서 삶의 질 저하는 학업 성취도 및 노동력 능력 감소149, 일상 생활 활동150, 고용 상태 및 개인 관계의 어려움 등 사회직업적 장애와 밀접한 관련이 있습니다. 실제로 조울증 환자의 실업률은 일반인보다 4~10배 높고151 이혼 및 별거율은 2~3배 높습니다152. 20세 전후의 잦은 양극성 장애 발병은 연령에 맞는 교육, 사회 및 발달 과업뿐만 아니라 자아 및 정체감의 발달을 방해합니다153.

따라서 상당히 이른 발병은 학업 성취도 저하와 직업 통합 저하의 주요 원인입니다108. 양극성 장애 환자의 직업적 결과가 좋지 않은 다른 원인으로는 기억력 및 실행 기능 장애를 포함한 지속적인 인지 장애의 존재를 들 수 있는데, 이는 병전 지적 기능이 가장 높은 사람들이 장애 발병 위험이 가장 높음에도 불구하고154 (그림 4). 관해 기간 동안 환자의 50~70%에서 상당한 인지 장애가 보고되었습니다155,156. 인지 장애가 있는 환자는 비슷한 수준의 아증후성 기분 증상에도 불구하고 인지적으로 온전한 환자보다 삶의 질이 떨어지고 스트레스가 증가하며 업무 능력이 떨어집니다155,156. 실제로 메타분석에 따르면 기억력과 실행 기능의 장애가 잔존 기분 증상보다 직업적 성과 저하에 더 큰 영향을 미치는 것으로 나타났습니다157. 기능적 치료는 여러 장애를 가진 환자의 정신-사회적 기능 회복을 목표로 하는 최근 개발된 심리적 개입으로, 양극성 장애 환자의 경우 치료 완료 후 1년 이상 지속되는 기능적 능력에 유익한 효과가 있는 것으로 나타났습니다139,141. 현재 양극성 장애 환자의 인지 기능 장애에 대해 임상적으로 사용할 수 있는 치료법은 없지만, 예비적 증거에 따르면 리튬이 다른 대안에 비해 잠재적으로 우월한 것으로 나타났습니다158. 에리스로포이에틴, 미페프리스톤, 나세틸시스테인159, 인지 개선 요법160 및 루라시돈을 포함한 여러 가지 후보 치료법이 연구되었으며, 대부분 인지 장애 치료에 유익한 효과를 보였습니다161. 인지 및 기능 장애를 표적으로 하는 치료법은 양극성 장애 환자의 학업 성취도, 업무 능력 및 사회적 관계를 향상시켜 삶의 질을 높일 수 있으며 향후 10년 동안 주요 전략적 초점이 될 것입니다.

Outlook

Over the past 30 years, the traditional concept of ‘bipolar disorder’ has evolved into a range of interconnected con‑ ditions that vary in terms of severity, frequency and polar‑ ity of mood shifts. Severe affective psychoses and milder syndromes, such as cyclothymia, are now recognized under the umbrella term of bipolarity and might share some common aspects of their pathophysiology and response to treatments108. In addition, the general ado‑ lescence onset (and, in rare cases, before puberty) is now recognized, although there is an ongoing controversy regarding the underdiagnosis versus overdiagnosis of bipolar disorders in children in certain countries162.

전망
 지난 30년 동안 '양극성 장애'라는 전통적인 개념은 기분 변화의 심각성, 빈도 및 극성 측면에서 다양한 상호 연결된 개념으로 발전해 왔습니다. 양극성 장애라는 포괄적인 용어 아래 중증 정동장애와 조울증과 같은 경증 증후군은 병리 생리와 치료에 대한 반응에서 몇 가지 공통된 측면을 공유할 수 있습니다108. 또한, 특정 국가에서는 소아 양극성 장애의 과소 진단과 과잉 진단에 대한 논란이 계속되고 있지만, 일반적으로 사춘기 이전(드물게는 사춘기 이전)에 발병하는 것이 인정되고 있습니다162.

Study design and experimental techniques

Regarding the genetics and pathogenesis of bipolar disorders, we need to widen our horizon and use new techniques and strategies. Diagnostic criteria should still be studied, focusing on the biology underlying the course, outcome and recovery of these disorders. Sample sizes of pharmacogenetics studies should be increased, and genomic approaches should be complemented using other techniques, such as epigenomics, proteo‑ mics, transcriptomics and metabolomics. In addition, research should include populations from around the world to develop a global overview of the genetic and environmental liability factors for bipolar disorders. The analysis of big actimetric (that is, data from non‑ invasive monitoring of human rest or activity cycles) and biomarker data using machine learning techniques may enable a probabilistic approach from a multifactor‑ ial perspective involving more variables than can be managed by a clinician alone. Psychiatry will be increas‑ ingly computerized, which might be particularly helpful for bipolar disorders, as the disease courses can be seem‑ ingly chaotic and unpredictable to the human eye. Above all, these endeavours must adhere to the idea of data sharing, fostering collaboration between clinicians and basic scientists that should offer hope to and potentially cure millions of patients. 

연구 설계 및 실험 기법 

양극성 장애의 유전학 및 발병 기전과 관련하여 우리는 시야를 넓히고 새로운 기술과 전략을 사용해야 합니다. 이러한 장애의 과정, 결과 및 회복의 근간이 되는 생물학에 초점을 맞추어 진단 기준을 연구해야 합니다. 약물유전학 연구의 샘플 크기를 늘리고 후성유전체학, 단백질체학, 전사체학, 대사체학 등 다른 기술을 사용하여 게놈 접근법을 보완해야 합니다. 또한 양극성 장애의 유전적 및 환경적 책임 요인에 대한 글로벌 개요를 개발하기 위해 전 세계 인구가 연구에 포함되어야 합니다. 머신러닝 기법을 이용한 빅 액티메트릭(인간의 휴식 또는 활동 주기에 대한 비침습적 모니터링 데이터) 및 바이오마커 데이터를 분석하면 임상의가 혼자서 관리할 수 있는 것보다 더 많은 변수를 포함하는 다인자적 관점에서 확률론적 접근이 가능할 수 있습니다. 정신의학은 점점 더 전산화될 것이며, 이는 특히 조울증과 같이 인간의 눈으로 보기에 혼란스럽고 예측하기 어려운 질병의 경과에 도움이 될 수 있습니다. 무엇보다도 이러한 노력은 데이터 공유라는 개념을 준수해야 하며, 임상의와 기초 과학자 간의 협력을 촉진하여 수백만 명의 환자에게 희망을 주고 잠재적으로 치료할 수 있어야 합니다. 

Staging and stage-specific treatments

Awareness of the importance of staging bipolar dis‑ orders is increasing, which will establish more tailored pharmacological and psychological treatments. Interest in early intervention is also increasing. Early intervention needs to be minimally invasive and almost free of adverse effects, given the nonspecific prodromal symptoms and the high risk of false positives163. After confirmed diag‑ nosis, speaking openly about disease with patients and their families is important, as is implementing long term treatment strategies and psychoeducation. For patients in late stages of these disorders, interventions used for treatmentrefractory patients might be the most effective117,164

병기 및 단계별 치료
양극성 장애 병기 구분의 중요성에 대한 인식이 높아지면서 보다 맞춤화된 약물 및 심리 치료가 확립되고 있습니다. 조기 개입에 대한 관심도 증가하고 있습니다. 조기 개입은 비특이적인 전구 증상과 위양성 위험이 높기 때문에 최소한의 침습적이고 부작용이 거의 없어야 합니다163. 확진 후에는 장기적인 치료 전략과 심리 교육을 실시하는 것과 마찬가지로 환자 및 가족에게 질병에 대해 공개적으로 이야기하는 것이 중요합니다. 이러한 장애의 말기 환자에게는 치료 불응성 환자에게 사용되는 개입이 가장 효과적일 수 있습니다117,164

New therapies and personalized treatment

Improvements in our understanding of the pathophysio‑ logy of bipolar disorders are expected and should lead to more accurate diagnosis and improved treatments. The traditional randomized placebocontrolled trial para‑ digm needs to be challenged if we are to progress towards precision psychiatry166,167. This progress requires improv‑ ing our ability to define a condition through molecular psychopathology168 and specific biomarkers; currently, most available biomarkers are approximate correlates of systemic stress or chronic brain damage54. The stratifica‑ tion of patients using other specifiers (such as predomin‑ ant polarity or early onset), which are absent in the DSM‑5 (REF. 169), might also help to design tailored treat‑ ment regimens. Over the coming decades, more atten‑ tion will be given to the complications of bipolar illness, including comorbidities (diabetes mellitus, osteoporosis, metabolic syndrome and hypertension), suicide and cog‑ nitive impairment. New treatments based on chemical, physical and psychological paradigms may be designed to tackle specific dimensions of the disease. ‘Big’ and ‘thick’ ‘data will be equally important for that endeavour. Large observational studies and large, goodquality patient registries might be particularly important to increase the external validity of the data gathered from controlled studies, as treatment guidelines are based on trials that are conducted in cohorts that represent <5% of the true population with bipolar disorders (such as patients with no comorbidities, those with no risk of suicide, those using contraceptive measures and those who are willing to participate in trials, among others)90,91.

Of the drugs in the current pipeline, 50% are derived from currently available therapies that are based on traditional targets, such as dopamine and serotonin receptor antago‑ nists or inhibition of monoamine transport, among others89. Longacting formulations of currently available drugs are currently underused in bipolar I disorder with manic predominant polarity. However, some innovative approaches are ongoing, such as drugs acting through glutamatergic pathways, such as ketamine, esketamine and rapastinel, some of which are in laterstage clinical trials, for the treatment of bipolar depression. These drugs might provide rapid relief to bipolar depression and suicidality and could ultimately change our approach to the treatment of bipolar depression, although the risks of dependency, other adverse effects and long term effectivness remain to be established170. Lastly, new brain stimulation techniques that could improve the treatment of difficult cases are also under study171. Finally, the prevention of bipolar disorders will become paramount, including primary prevention by promoting healthy physical and emotional habits, increasing cog‑ nitive reserve, stress management and new substance use policies. In parallel, improved understanding of the mechanisms underlying the regulation of emotions, maturation and brain function in healthy individuals will help to identify specific circuits and pathways as targets for novel therapeutic approaches.

새로운 치료법과 개인 맞춤형 치료

양극성 장애의 병태생리에 대한 이해가 향상되면 보다 정확한 진단과 개선된 치료법으로 이어질 수 있을 것으로 기대됩니다. 정밀 정신의학으로 나아가기 위해서는 기존의 무작위 위약 대조 임상시험에 도전할 필요가 있습니다166,167. 이러한 진전을 위해서는 분자 정신병리학168 및 특정 바이오마커를 통해 상태를 정의하는 능력을 향상시켜야 하는데, 현재 이용 가능한 대부분의 바이오마커는 전신 스트레스 또는 만성 뇌 손상과 대략적인 상관관계가 있는 것입니다54. DSM-5(참고 169)에 없는 다른 지정자(예: 우성 극성 또는 조기 발병)를 사용하여 환자를 계층화하는 것도 맞춤형 치료 요법을 설계하는 데 도움이 될 수 있습니다. 향후 수십 년 동안 동반 질환(당뇨병, 골다공증, 대사 증후군, 고혈압), 자살, 인지 장애 등 양극성 장애의 합병증에 더 많은 관심을 기울일 것입니다. 화학적, 물리적, 심리적 패러다임에 기반한 새로운 치료법은 질병의 특정 차원을 해결하기 위해 고안될 수 있습니다. 이러한 노력에는 '큰' 데이터와 '두꺼운' 데이터가 똑같이 중요할 것입니다. 치료 가이드라인은 실제 양극성 장애 인구의 5% 미만을 대표하는 코호트(동반 질환이 없는 환자, 자살 위험이 없는 환자, 피임 조치를 사용하는 환자, 임상시험에 참여할 의사가 있는 환자 등)90,91에서 수행된 임상시험을 기반으로 하기 때문에 대규모 관찰 연구와 양질의 대규모 환자 레지스트리는 대조 연구에서 수집한 데이터의 외부 타당성을 높이는 데 특히 중요할 수 있습니다.

현재 파이프라인에 있는 약물 중 50%는 도파민 및 세로토닌 수용체 길항제 또는 모노아민 수송 억제와 같은 전통적인 표적에 기반한 현재 사용 가능한 치료법에서 파생된 약물입니다89. 현재 사용 가능한 약물의 장기 지속형 제형은 조증 우위 극성을 가진 양극성 장애에서 현재 잘 사용되지 않고 있습니다. 그러나 케타민, 에스케타민, 라파스티넬과 같은 글루탐산염 경로를 통해 작용하는 약물과 같은 일부 혁신적인 접근 방식이 양극성 우울증 치료를 위해 진행 중이며, 그중 일부는 후기 임상 시험 단계에 있습니다. 이러한 약물은 양극성 우울증과 자살 충동을 빠르게 완화하고 궁극적으로 양극성 우울증 치료에 대한 접근 방식을 바꿀 수 있지만, 의존성, 기타 부작용 및 장기적인 효과에 대한 위험성은 아직 밝혀지지 않았습니다170. 마지막으로, 어려운 사례의 치료를 개선할 수 있는 새로운 뇌 자극 기술도 연구 중입니다171. 마지막으로, 건강한 신체적, 정서적 습관을 장려하고, 신체적, 정서적 예비력을 높이고, 스트레스 관리 및 새로운 약물 사용 정책을 통해 양극성 장애를 예방하는 것이 가장 중요해질 것입니다. 이와 동시에 건강한 개인의 감정, 성숙 및 뇌 기능 조절의 기초가 되는 메커니즘에 대한 이해가 향상되면 새로운 치료 접근법의 표적으로서 특정 회로와 경로를 식별하는 데 도움이 될 것입니다.