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.

S Vincent Rajkumar

Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA

rajkumar.vincent@mayo.edu

I declare no competing interests.

1

2
3

Abola MV, Prasad V. The use of superlatives in cancer research.

JAMA Oncol 2015; published online Oct 29. DOI:10.1001/
jamaoncol.2015.3931.
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab
monotherapy in multiple myeloma. N Engl J Med 2015; 373: 120719.
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: 112228.
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib
in relapsed, refractory myeloma. N Engl J Med 2003; 348: 260917.

10

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Richardson P, Jagannath S, Hussein M, et al. Safety and ecacy of

single-agent lenalidomide in patients with relapsed and refractory multiple
myeloma. Blood 2009; 114: 77278.
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent
carlzomib (PX-171-003-A1) in patients with relapsed and refractory
multiple myeloma. Blood 2012; 120: 281725.
Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in
combination with low-dose dexamethasone in relapsed and refractory
multiple myeloma: a randomized phase 2 study. Blood 2014; 123: 182632.
Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed
or refractory multiple myeloma. N Engl J Med 2015; 373: 62131.
Moreau P, Mateos M-V, Blad J, et al. An open-label, multicenter, phase 1b
study of daratumumab in combination with backbone regimens in patients
with multiple myeloma. Blood 2014; 124: 176 (abstr).
Attal M, Lauwers-Cances V, Hulin C, et al. Autologous transplantation for
multiple myeloma in the era of new drugs: a phase III study of the
Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial).
ASH Annual Meeting Abstracts 2015; 126: A391 (abstr).
Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple
myeloma for clinical practice. Blood Cancer J 2015; 5: e365.
Rajkumar SV. Myeloma today: disease denitions and treatment advances.
Am J Hematol 2015; published online Nov 13. DOI:10.1002/ajh.24236.

Bipolar disorders: key clinical considerations

See Seminar page 1561

1492

Clinicians have two primary concerns for any illness:

accurate diagnosis and eective 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 fth (33216%) 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 cutos for bipolar II disorder are wholly arbitrary,

and criteria for duration and severity of symptoms lack
biological signicance.4
Clinically, the intricate nature of bipolar disorder also
complicates diagnosis. For instance, mild presentations
are usually dicult to distinguish from normal mood
uctuations 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 dicult, 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
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Comment

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problems, the threshold for detecting bipolar disorder

using, for example, self-report questionnaires and
structured clinical interviewsshould be fairly low.
However, this low threshold should be robustly coupled
with a very high threshold for actual assignment of
diagnosis, which should only be considered after careful
longitudinal assessment and the rigorous exclusion of all
other possibilities. This approach is especially important
in adolescence, when symptoms rst emerge. Second,
when the diagnosis is in doubt, psychoeducation and
psychological interventions should be given primacy,
and careful, prospective, clinical charting should be
instituted along with regular clinical surveillance and
review. Finally, it is important to understand that bipolar
disorder is intrinsically unpredictable and that lifelong
diagnostic and therapeutic reassessment is necessary.
Most importantly, pharmacotherapy should only be
started once the diagnosis is certain and the benets of
medication are clear cut.

Frank SitemanDoctor Stock/Science Faction/Corbis

in the USA.8 A principal reason for this startling escalation

in diagnosis was a paradigm shift instigated by key US
researchers, who proposed that children with severe
irritability and mood lability should be regarded as having
paediatric bipolar disorder, irrespective of whether or not
they manifested well-dened manic episodes.9
This broad phenotype of paediatric bipolar disorder
aimed to better dene those children who, by default,
attracted the nebulous diagnostic label of bipolar
disorder not otherwise specied (BDNOS), 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). However, in practice, the
application of the broad phenotype to dene paediatric
bipolar disorder, coupled with the view that irritability
instead of euphoria is the hallmark symptom of mania
in children,11 led to widespread misdiagnosis of children
who were probably suering from other illnesses such
as attention-decit hyperactivity disorder (ADHD),
oppositional deant disorder, and conduct disorder.
Some US experts still suggest that paediatric bipolar
disorder is best dened by chronic, non-episodic, mixed
irritable states that cycle rapidly.12
To counter the increase in diagnosis of paediatric
bipolar disorder, and perhaps defuse the attendant
concerns, DSM-5 introduced a totally new diagnosis,
namely disruptive mood dysregulation disorder
(DMDD),13 the clinical reliability of which is yet to be
established.14 This illness is classied among depressive
disorders rather than bipolar and related disorders, even
though its key features include temper outbursts and
persistent irritability. Distinction is drawn technically
between DMDD and hypomania or mania on the
basis of duration of manic symptoms (with DMDD,
these symptoms are allowed to occur for up to a day),
but in reality the clinical separation of DMDD from
broad-phenotype paediatric bipolar disorder remains
challenging.15 These diagnostic issues are of concern, not
only because they obscure the true picture of emerging
bipolar disorder but also, more importantly, because
diagnosis inevitably prompts treatment and, in the
case of paediatric bipolar disorder, entails potential
long-term exposure to neuroleptics, which can produce
deleterious brain changes.16
So what does this mean for clinical practice? First,
when assessing patients presenting with mood

Gin S Malhi
Academic Department of Psychiatry, Kolling Institute, St Leonards,
NSW, Australia; Sydney Medical SchoolNorthern, The University
of Sydney, Sydney, NSW, Australia; and CADE Clinic, Department of
Psychiatry, Royal North Shore Hospital, Northern Sydney Local
Health District, St Leonards, NSW 2065, Australia
gin.malhi@sydney.edu.au
I have received research funding from AstraZeneca, Eli Lilly, Organon, Pzer,
Servier, and Wyeth; am a speaker for AstraZeneca, Eli Lilly, Janssen-Cilag,
Lundbeck, Pzer, Ranbaxy, Servier, and Wyeth; and am a consultant for
AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, and Servier.
1
2

3
4
5
6
7

10

11

Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet 2016;

387: 156172.
Ruggero CJ, Carlson GA, Kotov R, Bromet EJ. Ten-year diagnostic
consistency of bipolar disorder in a rst-admission sample. Bipolar Disord
2010; 12: 2131.
Smith DJ, Griths E, Kelly M, et al. Unrecognised bipolar disorder in primary
care patients with depression. Br J Psychiatry 2011; 199: 4956.
Malhi G, Berk M. Diagnosing bipolar disorder: dening thresholds and
setting boundaries. Aust N Z J Psychiatry 2014; 48: 50004.
Malhi GS. Diagnosis of bipolar disorder: who is in a mixed state? Lancet
2013; 381: 1599600.
Malhi G, Porter R. Are buy-polar forces and try-polar thinking expanding
bipolarity? Aust N Z J Psychiatry 2014; 48: 697700.
Moreno C, Jiang H, Laje G, et al. National trends in the outpatient diagnosis
and treatment of bipolar disorder in youth. Arch Gen Psychiatry 2007;
64: 103239.
Blader JC, Carlson GA. Increased rates of bipolar disorder diagnoses among
US child, adolescent, and adult inpatients, 19962004. Biol Psychiatry
2007; 62: 10714.
Biederman J, Mick E, Faraone SV, Spencer T, Wilens TE, Wozniak J.
Pediatric mania: a developmental subtype of bipolar disorder?
Biol Psychiatry 2000; 48: 45866.
American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, 4th edn. Washington: American Psychiatric
Association, 1994.
Wozniak J, Biederman J. Childhood mania: insights into diagnostic and
treatment issues. J Assoc Acad Minor Phys 1997; 8: 7884.

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12

13

14

Geller B, Tillman R, Bolhofner K, Zimerman B. Child bipolar I disorder:

prospective continuity with adult bipolar I disorder; characteristics of
second and third episodes; predictors of 8-year outcome.
Arch Gen Psychiatry 2008; 65: 112533.
American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, 5th edn. Washington: American Psychiatric
Association, 2013.
Dougherty LR, Smith VC, Buerd SJ, et al. DSM-5 disruptive mood
dysregulation disorder: correlates and predictors in young children
Psychol Med 2014; 44: 233950.

15

16

Towbin K, Axelson D, Leibenluft E, Birmaher B. Dierentiating bipolar

disordernot otherwise specied and severe mood dysregulation.
J Am Acad Child Adolesc Psychiatry 2013; 52: 46681.
Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC,
Borgwardt S. Progressive brain changes in schizophrenia related to
antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
Neurosci Biobehav Rev 2013; 37: 168091.

Reducing global diabetes burden by implementing solutions

and identifying gaps: a Lancet Commission
Diabetes is a silent killer that aects men and women,
young and old, rich and poor. According to the
International Diabetes Federation, in 2016, one in
11 adults has diabetes worldwide, one person dies
with diabetes every 6 s, and US$1 in $9 of health-care
expenditure is spent on diabetes and its complications.1
More than 80% of people with diabetes live in lowincome and middle-income countries, and most of
them have type 2 diabetes.1 In many of these places,
the rising prevalence in both type 12 and type 2 diabetes
highlights the potential eects of rapid urbanisation
on health and disease development, especially among

Published Online
April 6, 2016
http://dx.doi.org/10.1016/
S0140-6736(16)30165-9

Astier/BSIP/Science Photo Library

See Editorial page 1483

1494

individuals with genetic predisposition and underserved

communities.3
Between 1990 and 2000, the rates of diabetes-related
comorbidities, such as myocardial infarction, stroke,
amputation, end-stage renal disease, and hyperglycaemia
crisis, declined in the USA.4 With increased life expectancy
and a decline in the prevalence of cardiovascular disease,
the burden of other comorbidities, such as renal disease,
cancer, frailty, and dementia, is a growing concern.4,5
However, rigorous epidemiological data on diabetesrelated morbidity and cost are limited to only about
a dozen countries, leaving the true worldwide impact
unclear. Further, the high burden of diabetes among
adolescents and young adults in low-income and middleincome countries, partly driven by gestational diabetes
and childhood obesity, might be fuelling new cases of
premature cardiovascular-renal disease.3
Although most people with diabetes live in low-income
and middle-income countries, there is a dearth of data
from these areas which makes it challenging to dene
needs and prioritise decisions. However, randomised
clinical trials have now conrmed that structured lifestyle
modication can prevent diabetes in people with
impaired glucose tolerance. These benets can potentially
be translated into long-term reduction in microvascular
and macrovascular complications and all-cause death.6
In both type 15 and type 2 diabetes,8 intensive glycaemic
control reduces diabetes-related complications and
death. Together with control of other risk factors, such
as high blood pressure and lipids, marked reduction in all
clinical endpoints can be expected.9
The complexity of diabetes transcends biomedical,
socioeconomical, cognitive, psychological, behavioural,
political, and technological domains. Despite the
www.thelancet.com Vol 387 April 9, 2016