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Comment

ABT-199 (selective BCL-2 inhibitor), and LGH-447 (pan
PIM kinase inhibitor).13 The progress in this disease is
astonishing; there is no hype here.

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S Vincent Rajkumar

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Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
rajkumar.vincent@mayo.edu

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I declare no competing interests.
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monotherapy in multiple myeloma. N Engl J Med 2015; 373: 1207–19.
Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients
with treatment-refractory multiple myeloma (SIRIUS): an open-label,
randomised, phase 2 trial. Lancet 2016; published online Jan 6. http://dx.doi.
org/10.1016/S0140-6736(15)01120-4.
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in
survival in multiple myeloma: changes in early mortality and outcomes in
older patients. Leukemia 2014; 28: 1122–28.
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib
in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17.

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Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of
single-agent lenalidomide in patients with relapsed and refractory multiple
myeloma. Blood 2009; 114: 772–78.
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent
carfilzomib (PX-171-003-A1) in patients with relapsed and refractory
multiple myeloma. Blood 2012; 120: 2817–25.
Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in
combination with low-dose dexamethasone in relapsed and refractory
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Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed
or refractory multiple myeloma. N Engl J Med 2015; 373: 621–31.
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Bipolar disorders: key clinical considerations
See Seminar page 1561

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Clinicians have two primary concerns for any illness:
accurate diagnosis and effective treatment. With
respect to bipolar disorder, both processes can create
considerable challenges. The illness is inherently complex
and unpredictable, and diagnosis and treatment are
both compounded by the context in which the disorder
manifests. In The Lancet, Iria Grande and colleagues1
present a timely and informative overview of the many
clinical manifestations of bipolar disorder and consider,
in particular, its long-term management, highlighting
the important part that lithium still plays.
With respect to diagnosis, accurate assessment of
bipolar symptoms requires a thorough and advanced
approach that carefully integrates cross-sectional and
longitudinal clinical information.1 However, even with
skilled, structured, clinical interviewing, the diagnostic
consistency of bipolar disorder in the long term cannot
be guaranteed and, over the course of a decade, as many
as 20% of patients initially diagnosed with the illness
will acquire an alternative diagnosis.2 Conversely, up to
a fifth (3·3–21·6%) of patients in primary care diagnosed
with major depression might have undiagnosed bipolar
disorder.3 Thus, in clinical practice, the misdiagnosis of
bipolar disorder is common. One of the key reasons for
such diagnostic inconsistency is that the boundaries
of the illness are blurred. For example, the upper and

lower cutoffs for bipolar II disorder are wholly arbitrary,
and criteria for duration and severity of symptoms lack
biological significance.4
Clinically, the intricate nature of bipolar disorder also
complicates diagnosis. For instance, mild presentations
are usually difficult to distinguish from normal mood
fluctuations and features of personality, particularly
in the early stages of the illness. But even the typical
clinical picture of bipolar disorder is, for the most part,
distorted by comorbid anxiety or development of mixed
states. Mixed states are characterised by coterminous
symptoms of depression and mania, and do not
conform with present-day taxonomy.5 All these factors
make diagnosis of bipolar disorder very difficult, and the
process is even more complicated in adolescence, when
the brain is still developing.
Hence, the diagnosis of bipolar disorder has been at
the centre of recent controversy,6 particularly in children,
in whom the illness is referred to variably as paediatric
bipolar disorder, juvenile bipolar disorder, or early-onset
bipolar disorder. Part of the reason for disputation is
that, beginning in the mid 1990s, the number of children
diagnosed with paediatric bipolar disorder increased
greatly.7 Within a decade, this variant became the most
common diagnosis in children younger than 12 years
who were admitted to hospital for psychiatric disorders
www.thelancet.com Vol 387 April 9, 2016

Wozniak J. more importantly. St Leonards. 381: 1599–600.malhi@sydney. Increased rates of bipolar disorder diagnoses among US child. American Psychiatric Association. Moreno C. 48: 458–66. when assessing patients presenting with mood Gin S Malhi Academic Department of Psychiatry. Organon. Sydney Medical School—Northern. 387: 1561–72. and adult inpatients. attracted the nebulous diagnostic label of bipolar disorder not otherwise specified (BDNOS). in practice.8 A principal reason for this startling escalation in diagnosis was a paradigm shift instigated by key US researchers. Bromet EJ. Eli Lilly. Kolling Institute. am a speaker for AstraZeneca.11 led to widespread misdiagnosis of children who were probably suffering from other illnesses such as attention-deficit hyperactivity disorder (ADHD). Royal North Shore Hospital. Faraone SV. This approach is especially important in adolescence.12 To counter the increase in diagnosis of paediatric bipolar disorder. Sydney. Carlson GA. Lancet 2016. Biol Psychiatry 2007. because diagnosis inevitably prompts treatment and. when symptoms first emerge. the application of the broad phenotype to define paediatric bipolar disorder. Laje G. irrespective of whether or not they manifested well-defined manic episodes. and perhaps defuse the attendant concerns. DSM-5 introduced a totally new diagnosis. Ruggero CJ. Malhi G. not only because they obscure the true picture of emerging bipolar disorder but also.16 So what does this mean for clinical practice? First. and Servier. Birmaher B. Wozniak J. and CADE Clinic.com Vol 387 April 9.14 This illness is classified among depressive disorders rather than bipolar and related disorders. and am a consultant for AstraZeneca. it is important to understand that bipolar disorder is intrinsically unpredictable and that lifelong diagnostic and therapeutic reassessment is necessary. Aust N Z J Psychiatry 2014. Spencer T. usually because they did not meet stringent Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria10 for mania or hypomania and depression (referred to as the narrow phenotype). Second. Eli Lilly. Pfizer. Janssen-Cilag.Comment www. oppositional defiant disorder. Janssen-Cilag. Bipolar disorder. 1 2 3 4 5 6 7 8 9 10 11 Grande I. 4th edn. Vieta E. 2016 problems. Finally. 8: 78–84. Unrecognised bipolar disorder in primary care patients with depression. Malhi GS. coupled with the view that irritability instead of euphoria is the hallmark symptom of mania in children. even though its key features include temper outbursts and persistent irritability. Australia gin. this low threshold should be robustly coupled with a very high threshold for actual assignment of diagnosis.edu. non-episodic. Ranbaxy. Lundbeck. these symptoms are allowed to occur for up to a day). 1994. adolescent. Biederman J. Diagnosis of bipolar disorder: who is in a mixed state? Lancet 2013. Lundbeck. 48: 500–04. Jiang H. Eli Lilly. the threshold for detecting bipolar disorder— using. which should only be considered after careful longitudinal assessment and the rigorous exclusion of all other possibilities. by default. 199: 49–56. Berk M. Most importantly. mixed irritable states that cycle rapidly. Kelly M. NSW. Wilens TE. Berk M. Br J Psychiatry 2011. but in reality the clinical separation of DMDD from broad-phenotype paediatric bipolar disorder remains challenging. NSW 2065. Diagnosing bipolar disorder: defining thresholds and setting boundaries. Australia. psychoeducation and psychological interventions should be given primacy. self-report questionnaires and structured clinical interviews—should be fairly low. Biederman J. pharmacotherapy should only be started once the diagnosis is certain and the benefits of medication are clear cut. Some US experts still suggest that paediatric bipolar disorder is best defined by chronic. Bipolar Disord 2010. namely disruptive mood dysregulation disorder (DMDD). in the case of paediatric bipolar disorder. Blader JC. Porter R. Malhi G. St Leonards. NSW. Servier. which can produce deleterious brain changes. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. However. and Wyeth. Australia. 1493 . 12: 21–31. Pfizer. and careful. prospective. Diagnostic and Statistical Manual of Mental Disorders. J Assoc Acad Minor Phys 1997. and Wyeth. Childhood mania: insights into diagnostic and treatment issues.15 These diagnostic issues are of concern. Arch Gen Psychiatry 2007. Servier. The University of Sydney. Ten-year diagnostic consistency of bipolar disorder in a first-admission sample. entails potential long-term exposure to neuroleptics. Kotov R. and conduct disorder. et al. et al. Department of Psychiatry. Northern Sydney Local Health District.9 This broad phenotype of paediatric bipolar disorder aimed to better define those children who. who proposed that children with severe irritability and mood lability should be regarded as having paediatric bipolar disorder. clinical charting should be instituted along with regular clinical surveillance and review. Smith DJ. Mick E. Washington: American Psychiatric Association. for example. 64: 1032–39. Griffiths E. Distinction is drawn technically between DMDD and hypomania or mania on the basis of duration of manic symptoms (with DMDD. 48: 697–700. Carlson GA. 62: 107–14. However.13 the clinical reliability of which is yet to be established. Are ‘buy-polar’ forces and ‘try-polar’ thinking expanding bipolarity? Aust N Z J Psychiatry 2014. when the diagnosis is in doubt.thelancet. 1996–2004.au I have received research funding from AstraZeneca. Pediatric mania: a developmental subtype of bipolar disorder? Biol Psychiatry 2000. Frank Siteman—Doctor Stock/Science Faction/Corbis in the USA.

Reducing global diabetes burden by implementing solutions and identifying gaps: a Lancet Commission Diabetes is a silent killer that affects men and women. might be fuelling new cases of premature cardiovascular-renal disease. 2013. Smieskova R. Arch Gen Psychiatry 2008. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Child bipolar I disorder: prospective continuity with adult bipolar I disorder. political. rigorous epidemiological data on diabetesrelated morbidity and cost are limited to only about a dozen countries. one in 11 adults has diabetes worldwide. Despite the www. Differentiating bipolar disorder–not otherwise specified and severe mood dysregulation. and US$1 in $9 of health-care expenditure is spent on diabetes and its complications. 5th edn. 2016 .1 In many of these places.4 With increased life expectancy and a decline in the prevalence of cardiovascular disease. Bufferd SJ. According to the International Diabetes Federation. such as renal disease. characteristics of second and third episodes.3 Between 1990 and 2000. partly driven by gestational diabetes and childhood obesity. such as myocardial infarction. especially among Published Online April 6. one person dies with diabetes every 6 s.6 In both type 15 and type 2 diabetes. Bolhofner K.Comment 12 13 14 Geller B. DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children Psychol Med 2014. American Psychiatric Association. Ho BC. and most of them have type 2 diabetes. Andreasen NC.doi. Borgwardt S. These benefits can potentially be translated into long-term reduction in microvascular and macrovascular complications and all-cause death.3 Although most people with diabetes live in low-income and middle-income countries. and hyperglycaemia crisis. Tillman R. 44: 2339–50. amputation. stroke.4. Diagnostic and Statistical Manual of Mental Disorders. Birmaher B. 52: 466–81. Axelson D. Further. there is a dearth of data from these areas which makes it challenging to define needs and prioritise decisions. J Am Acad Child Adolesc Psychiatry 2013. rich and poor.1016/ S0140-6736(16)30165-9 Astier/BSIP/Science Photo Library See Editorial page 1483 1494 individuals with genetic predisposition and underserved communities. predictors of 8-year outcome. is a growing concern. Smith VC. behavioural. 37: 1680–91.5 However. marked reduction in all clinical endpoints can be expected.com Vol 387 April 9. end-stage renal disease. Zimerman B. randomised clinical trials have now confirmed that structured lifestyle modification can prevent diabetes in people with impaired glucose tolerance.8 intensive glycaemic control reduces diabetes-related complications and death.9 The complexity of diabetes transcends biomedical. leaving the true worldwide impact unclear. and dementia. Washington: American Psychiatric Association. 65: 1125–33. frailty. Together with control of other risk factors. in 2016. Fusar-Poli P. 15 16 Towbin K. Kempton MJ. However. Neurosci Biobehav Rev 2013.1 More than 80% of people with diabetes live in lowincome and middle-income countries. declined in the USA.thelancet. the burden of other comorbidities. psychological. the high burden of diabetes among adolescents and young adults in low-income and middleincome countries. the rising prevalence in both type 12 and type 2 diabetes highlights the potential effects of rapid urbanisation on health and disease development.org/10. and technological domains. socioeconomical. Dougherty LR. Leibenluft E. cancer. such as high blood pressure and lipids. young and old. 2016 http://dx. cognitive. the rates of diabetes-related comorbidities. et al.