DOI: 10.1111/bdi.
13358
EDITORIAL
“The neuroprogression hypothesis in bipolar disorders: Time
for apologies?”
​After almost 15 years since the first publications were released, the
main postulates of the neuroprogression (NP) hypothesis in bipolar
disorders (BDs) have been virtually debunked.
Over these years, NP has gained noticeable popularity and con-
sensus, thus challenging the traditional idea of general integrity of
the course of BDs and providing a new framework to comprehend
these disorders. Moreover, this hypothesis, which is in fact an up-
dated version of a similar one explored 10 years earlier in schizo-
phrenia, generated such confidence in its promoters that they also
proposed a staging system with the expectation of generating ad-
equate predictions to guide the treatment of all BD patients, inde-
pendently of their clinical-­evolutionary heterogeneity. However, the
NP hypothesis was a giant with feet of clay. Despite its potential
academic appeal at the time it was proposed, NP was grounded on a
weak evidential basis.
In early versions of this hypothesis, inflammatory markers such
as brain-­derived neurotrophic factor played a central role to the
point of being part of staging systems. However, critical weaknesses
in the data that supported these proposals have been pointed out.1
NP sustains that, as a consequence of intrinsic illness mechanisms,
an increase in the number of episodes and progressive treatment
resistance should be observed. However, systematic reviews of
previous data on the clinical evolution of BD and new longitudinal
studies, including ones with mirror-­image design and comparisons
of populations at different ages, show that in individuals with BD,
as a group, the number of episodes tends to present a static evo-
lution, not an acceleration process. Similar findings were observed
even at the level of subsyndromal symptoms and mood instabil-
ity. 2 Furthermore, these data are in line with the previously noted
evolutionary heterogeneity in BD, in which a minority group of
approximately 20% of those affected could experience a progres-
2
sive increase in their morbidity. Additionally, NP sustains that, as
a consequence of neuroinflammation due to chronicity and mood
episodes, progressive cognitive impairment leading to dementia
should happen. However, data from a significant number of longi-
tudinal studies exploring cognitive functioning in BD patients, with
follow-­up periods of up to 10 years, have, once again, consistently
found a static evolution of cognitive functioning, which is inde-
pendent of illness chronicity and the age of the subjects studied.3
Interestingly, these studies corroborated the negative correlation
between the number of manic episodes and cognitive functioning
© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Bipolar Disorders. 2023;00:1–2. 
on which NP had based its arguments. However, studies designed
with the purpose of exploring the causal relationship of this cor-
relation have not been able to demonstrate that it is the manic epi-
sodes that increase cognitive deterioration, even suggesting that the
causal direction could be the opposite.4 Finally, although the data
regarding an increased risk of dementia in people affected by BD
have been corroborated (relative risk >3), the absolute risk would be
limited to less than 10% of these people and, in addition, until now
it has not been possible to establish that this increase in risk is due
to the mechanisms proposed by the NP hypothesis or by other con-
current factors such as the increased incidence of metabolic disease
caused by the treatment of BDs.4 Finally, the NP hypothesis sustains
that neuroinflammatory processes should ultimately produce pro-
gressive pathologic changes in brain architecture. Although some
studies have found data that might show signs of chronicity-­related
neurostructural abnormalities in BD, they have run into the same
problems as those conducted in people with schizophrenia 10 years
ago, in which although chronicity correlated negatively with brain
volume, exposure to antipsychotics, and metabolic risk correlated
twice as strongly.4
All these contradictory data and conceptual problems became
rapidly available and were pointed out in both editorials and re-
views visibly published. So, why has NP spread so fast from being
a disruptive hypothesis to one that is a nearly the core concept of
BD? Maybe a point could be the attractiveness of this hypothesis:
alluring, reasonable, accessible, and combining the latest in neuro-
science, it allowed us to have the conceptual framework that we
still lack today. Indeed, we had never seen in our field graphs as
charming as those offered by NP. Furthermore, it is also evident
that the well-­earned academic position of many of the main pro-
moters of this hypothesis as well as some academic licenses that
were allowed when discussing this hypothesis was a determining
factor for its rapid and uncritical consolidation. Throughout re-
cent years, a noticeable number of nonsystematic reviews about
NP/ staging have been published, in which in almost all cases the
contradictory data and conceptual problems pointed out were sys-
tematically avoided or underestimated. This style continued and
was evident even in seminars and editorials published in the most
important medical journals. In these influential reviews, NP and
staging are assumed to be a solid part of the state of the art of BD,
not a hypothesis.
wileyonlinelibrary.com/journal/bdi | 1
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Then, does this academic behavior, although not strictly fair
play, deserve apologies? Is an apology necessary for having spent so
much money and effort on this hypothesis while we still do not know
what kind of patients will respond to lithium? The answer is no. At
the end of the day, we can all be victims of academic or “enthusiasm”
bias in a field as competitive as science and where mistakes are the
mother of many of our best advances.
However, there is a point where an apology is clearly necessary.
In the last version of the CANMAT-­ISBD guidelines for the treat-
ment of BDs, NP was incorporated as the conceptual center of these
disorders, ignoring its hypothetical nature and all the contradictory
5
data and claims that existed. Adopting the NP hypothesis, these
guidelines explain the evolutionary pattern of BD and, therefore, the
way in which we should weigh treatment decisions in our everyday
clinical practice. In fact, they are remarkably explicit in doing so by
stating that “The course of BD is heterogeneous but, on average, the risk
of recurrence increases with the number of previous episodes. In addi-
tion, data examining the effect of episodes on the course of illness shows
that the number of previous episodes is associated with increased dura-
tion and symptomatic severity of subsequent episodes. Furthermore, the
number of episodes is associated with a decreased threshold for devel-
oping further episodes and with an increased risk of dementia in the long
term.” Therefore, the message was clear: Each episode irreversibly
worsens the course and prognosis of the disorder. Then, everything
is justified with the objective of preventing episodes and, if some-
thing goes wrong, it is almost certainly the course of the illness itself.
This statement has not been free of negative consequences in
clinical terms. In recent years, we have been able to appreciate how
this concept has generated frequent and serious therapeutic prob-
lems. Why suspend an antidepressant that may be causing tachy-
phylaxis if it is the episodes themselves that cause more and more
episodes? Why think about withdrawing or reducing the dose of an
antipsychotic when a patient is apathetic and cognitively impaired if it
is precisely the manic episodes, preventable by these drugs, that pro-
duce these damages? Why make therapeutic efforts and give hope to
a person who has already suffered several episodes when their brain
should already be damaged and progressing toward dementia?
Today, it is clear that having included the NP hypothesis in clini-
cal guidelines was an error. In the same way, we cannot put in phar-
macies a medication that has not been adequately tested, we should
not have offered clinicians a concept not adequately discussed and
EDITO​RIA​L
as therapeutically relevant and determinative as NP is. At this point,
some apologies and clarifications of the case are required as this
would surely help clinicians and the people under our care to get
out of the conceptual error that has clouded both our therapeutic
paradigms and our hopes.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interest.
Sergio A. Strejilevich1
Cecilia Samamé2
Danilo Quiroz3
1
ÁREA, Assistance and Research in Affective Disorders, Buenos
Aires, Argentina
2
Catholic University of Uruguay, Montevideo, Uruguay
3
Diego Portales University, Santiago, Chile
Correspondence
Sergio A. Strejilevich, Juncal 2061 PB Dto. “C” (1116), CABA,
Buenos Aires, Argentina.
Email: sstreji@gmail.com
ORCID
Sergio A. Strejilevich https://orcid.org/0000-0001-8410-7187
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