Four Different Biotypes of Depression

Neuroscience research advances diagnosis and treatment.

Posted Jun 30, 2017

The impact of depression

Approximately 20 million Americans suffer from depression, and less than half of them are
receiving specialized care. According to the CDC, as of 2012, 7.6 percent of Americans
over the age of 12 had significant depression, which was higher among women, and worse
in people 40 to 59 years of age. Only 35 percent of people reporting severe depression had
met with a mental health professional within the last year. Over 40 percent with less severe
depression reported that it had caused serious difficulty with function; the number was
almost 90 percent for those with severe depression.

Over 40,000 Americans die by suicide yearly. In 2010 in the U.S. alone, depression was
estimated to have cost $210 billion due to lost productivity and clinical costs. Globally,
according to the WHO, 300 million people have depression, and close to 800,000 people
die yearly from suicide, which is the second leading cause of death in people aged 15-29.

Standard treatments such as SSRI antidepressants are only fully effective for about 30
percent of patients but are partially effective for another 30 percent (STAR-D Trial). As a
result, it often takes multiple medication trials in combination with other therapeutic
approaches such as talk therapy to achieve even a modest response, let alone a full
remission of symptoms and a full return to function.

The need for improved psychiatric care

Conventionally, as with the majority of psychiatric conditions, there are no formal

biomarkers available for diagnosis and treatment monitoring with depression. In other areas
of medicine there are many conditions for which it is routine to order diagnostic tests,
provide treatment, and monitor response. Hypothyroidism is a basic examplepatients
come with characteristic complaints, which may be due to thyroid problems but could be
related to other conditions, a panel of blood tests is ordered, and the results are generally
definitive. Treatment and monitoring is usually straightforward, and effective for most
patients.

Depression, in contrast, is diagnosed based on clinical features, and subtypes are based on
the presence of certain symptoms over others. Treatment response is tracked subjectively,
by clinical evaluation, by functional state, and sometimes using validated rating scales.
There is no biological diagnostic test available for depression, and treatment selection is
primarily based on clinical judgment and consensus guidelines.

Only recently have psychiatrists had access to patient-specific data to guide clinical
decision-making, such as from pharmacogenomic testing, which while advancing is still of
limited value. It is very difficult to predict which treatment will help which patient, leading
to a "trial-and-error" approach which can take months to work for the 1/3 of people who
don't respond at all to initial treatment.

Having robust biological markers to diagnose and treat depression (and other psychiatric
disorders), crucially is missing though progress is being made. Of course, there are many
important factors aside from diagnosis and treatment selection, personal and psychosocial
factors, the importance of wellness and resilience, and so much more for a well-lived life
than I'm focusing on right now, and I don't mean to take away from the importance of
viewing the person as a whole. Rather, I believe that having a deeper understanding of what
is really going on in the brain will enrich the experience of being human, though as with
any technological advances, caution is prudent.

The brain from a network theory perspective

The brain is a highly complex organ. It's elegant and beautiful, and key to who we are, and
of course intimately a part of the body and not just a brain in a vat. Understanding how the
brain works requires more sophisticated models which have only recently become
available. Until the last couple of decades or so (with some exceptions), basic approaches to
neuroscience were reductionisticbased on breaking things down into easier to understand
parts. Part of this is because although we could conceptualize the brain as a system, the
mathematical and computational tools have only been available recently. It's important to
recognize this shift to a complex model of the brain, because it is a game changer both
conceptually and in terms of being able to design more powerful tools based on a more
accurate understanding of how the brain actually works.

So psychiatry has tended to focus on simpler models like correcting a "chemical

imbalance"serotonin levels are low, so we'll give a medicine which increases serotonin.
This is really just a metaphor, and not an accurate one. There are many different families of
serotonin receptors all over the brain, and they are on the surface of neurons and other cells
around the body. When we prescribe a medication based on serotonin function, we don't
really understand what it is doing, both on the big picture level and on a microscopic level,
how such a medication causes changes with the cells, and moreover how these changes lead
to therapeutic benefits or adverse reactionsand whether a given medication will or won't
work for a given person.

Similarly, research has looked at what different areas of the brain do, correlating illnesses
with higher or lower activity in various brain regions. More sophisticated but still
reductionistic, we look at different "circuits" in the brain, how key areas are wired together
and how this relates to healthy function and problematic dysfunction. Sometimes this
approach works pretty wellwhen a brain region is a key hub for specific functions or a
specific circuit is closely tied to pathologybut it is more accurate and powerful to see the
brain as a system, in which different parts are interconnected to give rise to the overall
function of the brain, the mind.

The systemic perspective is powerful. From this point of view, the unit of understanding,
and the target of therapeutics, are brain networks. Different brain regions, much like the
different nodes on the Internet that dynamically form the World Wide Web, are
interconnected in complex ways in various structural and functional networks. They
provide stability over time along with the ability to rapidly adapt to changing conditions,
and when functioning smoothly maintain flowing balance to provide resilience in the face
of environmental changes.

Until recently, it was too difficult to get a deep understanding of brain networks because the
mathematics involved were not as well developed, the application to neuroscience was not
as fleshed-out, and importantly because the required computing power wasn't there yet.
Recently, due to advances in mathematics and computer technology, we can now start to
see the big picture. Because so much technical knowledge is involved, it is hard to grasp.
This widens the gap between researchers and almost everyone elsepracticing clinicians,
patients, and the lay public. Therefore, I use some technical terms while trying to avoid
unnecessary jargon.

Groundbreaking research

A major advance in the network understanding of depression was published recently in the
prestigious journal Nature Medicine by a high-powered group of researchers. In their paper,
the authors describe the findings of their elegant work, the purpose of which was to analyze
brain scans from more than 700 subjects, comparing the resting activity of depressed
patients' brains with non-depressed patients' to determine significant differences in patterns
of brain activity.

Their approach was to analyze the data for patterns that could be biomarkers for depression,
identifying different networks representing different subtypes of depression. Rather than
the conventional approachdefining different types of depression based on clinical
featurestheir approach is designed to map out differences in networks based on actual
brain activity to develop consistent biomarkers to diagnose depression. They used
complicated methodologies ("canonical correlation analysis" and "hierarchical clustering")
as well as artificial intelligence (or "machine learning") to measure connectivity and map
out networks associated with depression.

Ultimately, this information could be used to guide treatment selection by identifying

which subtypes respond to which treatments. In principle, it should then be possible to use
neuroimaging to identify which type of depression a patient has, and to guide treatment
planning.

Major findings

They found that there are four subtypes of depression, called "biotypes," illustrated below.
They are color coded to show which brain areas have the most connectivity within each
biotype. If readers are interested in learning more about the specific anatomic areas,
you may find this 3D brain tool a useful reference.
The four biotypes of depression.
Source: In Resting-state connectivity biomarkers define neurophysiological subtypes of
depression (2016)

Researchers identified two major groups of network patterns characterizing depression

involving 1) frontostriatal and orbitofrontal areas or 2) the limbic system, including areas
such as the amygdala, ventral hippocampus, ventral striatum, subgenual cingulate and
lateral prefrontal cortex.

The first group correlates with symptoms of anhedonia (difficulty experiencing pleasure)
and psychomotor retardation (difficulty initiating movement and sluggish movement) and
the second group with anxiety and insomnia. They used a clinical rating tool called the
"HAM-D" (Hamilton Depression Rating Scale) to match network analysis with
symptoms. In a basic but incomplete sense, the first group broadly has to do with top-down
control, and the second group with emotional regulation on a deep brain level.

They found that all biotypes share certain core clinical featureslow mood, anhedonia,
fatigue and lack of energyassociated with anatomic areas such as the insula, orbitofrontal
cortex, ventromedial prefrontal cortex, ventromedial prefrontal cortex, and multiple
subcortical regions.

The four biotypes vary depending on which brain regions were connected with and distinct
from one another, representing 23.6 percent, 22.7 percent, 20 percent and 33.6 percent of
the sample. They correlate with different patterns of connectivity, and moreover with
specific and distinct sets of clinical symptoms.

Here is a breakdown of which clinical symptoms go with which biotype:

Depression symptoms by biotype.
Source: In Resting-state connectivity biomarkers define neurophysiological subtypes of
depression (2016)

The clinical picture, with some overlap, is distinct for each biotype. Types 1 and 4 have
increased anxiety related to fear-based regions; types 3 and 4 show more anhedonia and
psychomotor retardation related to areas governing reward, control of movement, and
initiating actions; and types 1 and 2 have lower energy and fatigue, related to brain areas
involved with motivation and decision-making. Regardless of biotype, the overall severity
of depression was comparable among the 4 groups, though slightly less severe for type 2.
Importantly, the biotypes do not correlate well with existing clinical subtypes of
depression.

Implications for diagnosis and treatment

They found that using machine-learning, they were able to correctly identify biotypes of
depression and distinguish them from a non-depressed subjects, similar to a diagnostic test
like an MRI for a brain injury. This initial application is a possible precursor to a diagnostic
tool which could be used in regular clinical practice. They also found that the biotypes,
unlike clinical subtypes, tend to remain consistent over time, suggesting that in some
respects, biotypes may be a more reliable tool than doctor or patient assessments.

Notably, they were able to identify which biotype responded better to transcranial magnetic
stimulation (TMS), a targeted treatment for depression which is often used to activate areas
of the left frontal lobe of the brain. TMS was most effective in biotype 1, followed by
biotype 3, but was not very effective for biotypes 2 and 4. As a TMS provider, this is of
particular interest to me. A similar approach could be used to work out what other
treatments work best for different biotypes of depression, allowing for more sophisticated
personalized care.

Future directions

Because ineffective treatments are costly and time-consuming, disappointing, delay

definitive treatment, and may lead to a worsening of depression and negative outcomes,
having a way to tell what will work best would be an essential clinical tool. It will be useful
for research to identify which therapies or combination of therapies (medications, talk
therapies, and other approaches) will work best for which type of depression, and perhaps
even to design personalized treatments which will work well for specific people based on
biomarkers.

We can imagine a time in the not-so-distant future when a patient comes to the office for
psychiatric evaluation, and we order diagnostic testsfunctional brain imaging, genetic
testing, perhaps a blood test for biological response to medication treatment if appropriate,
and maybe even a computer simulation of how different treatment options would work, if
administered, or even a treatment designed for that person, as is already possible with some
cancer treatments.
In addition to clinical judgment and patient-specific factors, we would provide a
comprehensive, tailored treatment plan which could include different therapeutic
approaches. Early on, we could check to see if treatment is working, again using
biomarkers which would be earlier indicators than clinical observations, and get
information to guide changes to the treatment plan, if necessary. This sounds expensive, but
would pay for itself in quality of life and savings down the road from reduced direct and
indirect costs of treatment-resistant depression.

Depression is a difficult-to-treat condition which causes great suffering and costs

individuals, families and society more than statistics can convey. Achieving a deeper
understanding and taking a step toward refined diagnosis and treatment using empirically-
based biomarkers is a major advance, and the first chapter in a developing story.

References

Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley
B, Oathes DF, Etkin A, Shatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM,
Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ & Liston C.
(2016). Resting-state connectivity biomarkers define neurophysiological subtypes of
depression. Nature Medicine, vol. 23, no. 1, January.