Comment
Institute of Nursing Research, Ulster University, Jordanstown,
Newtownabbey, County Antrim BT37 0QB, UK
r.mcconkey@ulster.ac.uk
I declare no competing interests.
1 Killaspy H, Priebe S, Bremner S, et al. Quality of life, autonomy, satisfaction,
and costs associated with mental health supported accommodation
services in England: a national survey. Lancet Psychiatry 2016; published
online Oct 19. http://dx.doi.org/10.1016/S2215-0366(16)30327-3.
2 Braddock D, Emerson E, Felce D, Stancliffe R. The living circumstances of
children and adults with MR/DD in the United States, Canada, England and
Wales, and Australia. Ment Retard Dev Disabil Res Rev 2001; 7: 115–21.
Adjunctive antidepressants in bipolar depression
The never-ending debate about the use of antidepressants
in bipolar depression is now enriched by Alexander
McGirr and colleagues’ study in The Lancet Psychiatry,1
the first meta-analysis on the efficacy and safety of
modern antidepressants as adjunctive therapy for this
indication. The beauty of this study is not only that it is
totally up to date, but also that it is pragmatically focused
on adjunctive use and on modern medications. The
exclusion of tricyclics and monoamine oxidase inhibitors
in this study could better (albeit not perfectly) address
the assumption that all antidepressants are the same
than did previous meta-analyses, and the exclusion of
antidepressant monotherapy (a practice that has been
repeatedly shown as inappropiate2) also helps to tackle
the existing clinical dilemma of how to treat depression
in people with bipolar disorder. McGirr and colleagues
showed that modern antidepressants, mostly represented
in this meta-analysis by SSRIs, are superior to placebo in
the acute treatment of depression in bipolar disorder.
The effect size was small (standardised mean differences
in clinician-rated depressive symptom score 0·165,
95% CI 0·051–0·278, p=0·004), but this was affected by
a trial of agomelatine3 that had a large placebo response.
The agomelatine trial3 was also the main contributor to
another important finding related to the risk of affective
switch (ie, from depression to mania or hypomania) of
some antidepressants. The exclusion of such a trial from
the meta-analysis would result in an increased effect size
and reduced switch rates.
The relevance of McGirr and colleagues’ study1 is that
it might help to clarify the real value of antidepressants
in bipolar depression. Although these medications had
been overtly overused in bipolar depression, in the past
10 years there was a shift towards considering them
close to poison, as the potential harms were over-rated
www.thelancet.com/psychiatry Vol 3 December 2016
3 Davies HTO, Nutley SM, Mannion R. Organisational culture and quality of
health care. Qual Health Care 2000; 9: 111–19.
4 Duffy S, Waters J, Glasby J. Personalisation and adult social care: future options
for the reform of public services. Policy Politics 2010; 38: 493–508.
5 Shogren KA, Luckasson R, Schalock RL. Using context as an integrative
framework to align policy goals, supports, and outcomes in intellectual
disability. Intellect Dev Disabil 2015; 53: 367–76.
6 Black N. Patient reported outcome measures could help transform healthcare.
BMJ 2013; 346: f167.
7 Shepherd G, Boardman J, Rinaldi M, Roberts G. Supporting recovery in mental
health services: quality and outcomes. London: Centre for Mental Health and
Mental Health Network, NHS Confederation, 2014.
on the basis of scarce and contradictory data. We believe
that such a shift was also somewhat encouraged by
companies owning antipsychotics and anticonvulsants,
for which an indication in bipolar depression would
expand the market, as opposed to antidepressants,
which were already used despite the weak evidence base.
Compounds that are not classified as antidepressants,
Molekuul/Science Photo Library
such as quetiapine, lurasidone, or lamotrigine, have no
doubt proven to be effective in bipolar depression and
are legitimately acknowledged as first-line treatment in
most guidelines,4 but it is also true that their safety and
tolerability profile is less favourable than that of SSRIs. We
now know that antidepressant monotherapy should not Published Online
October 26, 2016
be used in bipolar depression. However, not only might http://dx.doi.org/10.1016/
short-term adjunctive use be reasonable but perhaps it S2215-0366(16)30347-9
should also be considered first-line treatment, according See Articles page 1138
to this landmark meta-analysis. This finding might help to
avoid excessive use of antipsychotics in bipolar disorder.
The open question is the long-term safety, balancing the
risk of mood destabilisation due to either prolonged use
or early discontinuation. Results from this meta-analysis
suggest that prolonged use of antidepressants might
increase the risk of switch to mania or hypomania, but
the risk of relapse into depression if antidepressants are
discontinued early remains uncertain. This issue might be
particularly important for patients with predominantly
depressive episodes.5 Unfortunately, the concept of
predominant polarity has not been introduced officially
in the classification system, and therefore it is frequently
neglected when addressing clinical questions related to
the ability of medications to protect against or induce
mood episodes of either pole. Perhaps DSM-5.1 will
address this issue.6
The results of this meta-analysis are consistent
with advice of the International Society for Bipolar
1095
 Comment
Disorders Task Force on antidepressant use in bipolar
disorder7 and with guidelines by the British Association
of Psychopharmacology,8 but inconsistent with
findings from the famous STEP-BD study,9 which
reported antidepressants to be unefficacious but safe
with regards to switch risk. Our view is that McGirr
and colleagues’ findings make more clinical sense,
because our clinical experience is that adjunctive
antidepressants work (but not always) and do cause
switch to mania or hypomania (sometimes). Adjunctive
antidepressants have a number needed to treat of 15
and number needed to harm of 19,1 meaning that the
efficacy is limited (but significant) and the tolerability
is good, even if there might be a small (but again
significant) risk of affective switch in some patients
over the long term. Our suggestion would be to provide
psychoeducation to all patients with bipolar disorder to
caution them about the risk of switch, independently
of whether it is spontaneous or drug induced. McGirr
and colleagues’ meta-analysis did not address side-
effects other than switch to mania or hypomania, and
therefore clinicians should keep in mind the overall
tolerability profile of modern antidepressants10 and
that of the alternatives when considering benefits and
risks. Another open question is whether the limited but
certain efficacy of antidepressants is affected by the
number of trials. Our clinical impression is that with
the progression of multiple episodes, the response to
antidepressants becomes less and less likely, but this
issue needs to be investigated.
In summary, we now know better what many of us
suspected for a long time—that antidepressants work
(but not very well) in bipolar depression. The precise
place of antidepressants in the treatment algorithm
C-reactive protein in bipolar disorder
Published Online Unlike most chronic diseases, the pathogenesis of bipolar
November 9, 2016
http://dx.doi.org/10.1016/
disorder is still relatively unknown. Furthermore, no
S2215-0366(16)30367-4 reliable biomarkers exist for risk of the disease, its states,
See Articles page 1147 or treatment response, and present pharmacological
therapies are often insufficient. However, in the past
decades, the immune hypothesis of psychiatric disorders
has suggested that bipolar disorder is associated with
increased immune activation,1 giving rise to the possibility
to understand at least part of the biology of this disorder.
1096
should be elucidated in head-to-head studies against
other alternatives.
*Eduard Vieta, Marina Garriga
Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic,
University of Barcelona, The August Pi i Sunyer Biomedical Research
Institute (IDIBAPS), Centro de Investigación Biomédica en Red en el
Área de Salud Mental (CIBERSAM), Barcelona 08036, Spain
evieta@clinic.ub.es
EV has received grants and served as a consultant, an advisor, or continuing
medical education speaker for AB-Biotics, Actavis, Allergan, AstraZeneca,
Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research
Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer,
Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and
Behaviour Foundation, the Spanish Ministry of Science and Innovation
(CIBERSAM), the Seventh European Framework Programme (ENBREC), and
the Stanley Medical Research Institute. MG reports honoraria from Janssen,
Lundbeck, and Ferrer, and grants from CIBERSAM.
1 McGirr A, Vöhringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy
of adjunctive second-generation antidepressant therapy with a mood
stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic
review and meta-analysis of randomised placebo-controlled trials.
Lancet Psychiatry 2016; published online Oct 26. http://dx.doi.org/10.1016/
S2215-0366(16)30264-4.
2 Vieta E. Antidepressants in bipolar I disorder: never as monotherapy.
Am J Psychiatry 2014; 171: 1023–26.
3 Yatham LN, Vieta E, Goodwin GM, et al, for the Agomelatine Study Group.
Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I
depression: randomised double-blind placebo-controlled trial. Br J Psychiatry
2016; 208: 78–86.
4 Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet 2016;
387: 1561–72.
5 Colom F, Vieta E, Suppes T. Predominant polarity in bipolar disorders: refining
or redefining diagnosis? Acta Psychiatr Scand 2015; 132: 324–26.
6 Vieta E. DSM-5.1. Acta Psychiatr Scand 2016; 134: 187–88.
7 Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for
Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar
disorders. Am J Psychiatry 2013; 170: 1249–62.
8 Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for
treating bipolar disorder: revised third edition recommendations from the
British Association for Psychopharmacology. J Psychopharmacol 2016;
30: 495–553.
9 Sachs GS, Nierenberg AA, Calabrese JR, et al.Effectiveness of adjunctive
antidepressant treatment for bipolar depression. N Engl J Med 2007;
356: 1711–22.
10 Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability
and risks associated with the use of newer generation antidepressant drugs:
a critical review of the literature. Psychother Psychosom 2016; 85: 270–88.
The systematic review and meta-analysis by Brisa S
Fernandes and colleagues2 in The Lancet Psychiatry is an
impressive contribution to this hypothesis. The authors
examined concentrations of the most commonly used
marker of inflammation, C-reactive protein (CRP),
in people with bipolar disorder and healthy controls,
and did five meta-analyses including 27 studies and
84 093 participants. The first three meta-analyses
compared CRP concentrations in patients in mania,
www.thelancet.com/psychiatry Vol 3 December 2016