Is depression killing your brain?

Morgan of 3QD points to a fascinating story about new discoveries that are prompting neuroscientists to rethink what depression is, and how anti-depressants actually work.

We're often told that depression is caused by neurochemical imbalances. The assumption is that Prozac and other antidepressants improve the symptoms of depression by boosting the effects of serotonin (or other key neurotransmitters, depending on the drug). Yet, if that's true, why do anti-depressants take weeks to work, despite altering neurotransmitter levels in mere hours?

More recent research suggests that depression is actually a reversible neurodegenerative disease and that antidepressants actually help the brain to heal and thrive again:

In fact, many scientists are now paying increased attention to the frequently neglected symptoms of people suffering from depression, which include problems with learning and memory and sensory deficits for smell and taste. Other researchers are studying the ways in which depression interferes with basic bodily processes, such as sleeping, sex drive, and weight control. Like the paralyzing sadness, which remains the most obvious manifestation of the mental illness, these symptoms are also byproducts of a brain that's literally withering away.

"Depression is caused by problems with the most fundamental thing the brain does, which is process information," says Eero Castren, a neuroscientist at the University of Helsinki. "It's much more than just an inability to experience pleasure."

This new scientific understanding of depression also offers a new way to think about the role of drugs in recovery. While antidepressants help brain cells recover their vigor and form new connections, Castren says that patients must still work to cement these connections in place, perhaps with therapy. He compares antidepressants with anabolic steroids, which increase muscle mass only when subjects also go to the gym.

"If you just sit on your couch, then steroids aren't going to be very effective," he says. "Antidepressants are the same way: if you want the drug to work for you, then you have to work for the drug." [Boston Globe]

I know several people who decline antidepressants because they consider the drugs to be a mere "Band-Aid solution." If this healing hypothesis of antidepressant action is correct, maybe antidepressants aren't just Band-Aids after all.

Comments

[ghostcatbce]

As a sufferer from depression who is on antidepressants, thanks very much for brining this article to my attention.

[pretzelattack]

if by therapy they mean psychotherapy, how is that supposed to "cement" the connections in place?

[swampcracker]

One should always approach a new paradigm with caution and await the outcome of clinical findings and metastudies before forming a conclusion.

The prevailing view is that depression is not just one disorder but perhaps two or more. In a percentage of cases, there is a history of emotional, physical, or sexual abuse. In theory, this form of depression is an outcome of trauma and/or humiliation. To describe this depression in context, think of a two-sided coin. On one side, there is depression; on the other side, there are repressed angers that, when “internalized” (i.e., “stuffed”), drive the depression. This type does not respond to medication alone without some form of talk therapy. Thus, the new paradigm does not contradict the prevailing view with respect to treatment modality:

Castren says that patients must still work to cement these connections in place, perhaps with therapy. He compares antidepressants with anabolic steroids, which increase muscle mass only when subjects also go to the gym.

There are also a percentage of cases wherein there is no apparent history of abuse, humiliation, or trauma. This form of depression seems to be driven by an imbalance in neurochemistry.

It is interesting to note that dissociative disorders can also driven by histories of abuse and trauma, and the symptoms are depersonalization and derealization. It would be interesting to know if there are accompanying changes in neurochemistry accompanying symptoms of dissociation.

[Lindsay Beyerstein]

I would guess that a good therapist cements these changes by providing ongoing positive interactions and teaching patients skills that will keep their brains healthy--i.e. by dealing with stress, improving interpersonal relationships, resolving emotional conflicts, etc. According to this model, a mind therapist is a lot like a physiotherapist. Medical science can splint your injury and give you medications to help it heal, but it won't get fully better without proper exercise. The brain is probably like other organs in this regard.

[Lindsay Beyerstein]

"One should always approach a new paradigm with caution and await the outcome of clinical findings and metastudies before forming a conclusion."--Definitely.

[swampcracker]

The goal of cognitive therapy is to treat the "negative messages" that reinforce depression. Messages like: “I am defective,” “stupid,” “incompetent,” “it was my fault,” “I will always be this way.” Unfortunately, there is another component to depression that is more intractable: An almost obsessive preoccupation with the original abuse that freezes the subject in time and prevents the subject from making progress.

[billofwrites]

"Yet, if that's true, why do anti-depressants take weeks to work, despite altering neurotransmitter levels in mere hours?"

lindsay...am not a neuroscientist, but i believe SRRI's work less by improving release of serotonin than by inhibiting its re-uptake.

serotonin is released by many triggers, including healthy exercise. but serotonin is experienced as such a short-term "high," if you will, because the system re-absorbs it so quickly. this inhibiting of re-absorption rates is what takes so long for SRRI's to fully take effect.

my guess is -- and it's only a guess -- evolution may have wanted us to, yes, enjoy our pleasure briefly, but then pivot quickly and return to a fierce focus on the next threat to survival -- not linger on a chemical "high" which might leave us vulnerable.

just a thought...

[Lindsay Beyerstein]

Serotonin reuptake inhibitors start working at the level of the synapse soon after they are ingested, but the anti-depressant effects don't show up for weeks. If depression was just a result of insufficient NT secretion or NT insensitivity, you'd expect the symptoms of depression to start getting better immediately, but that's not what happens.

I don't think the brief pleasure hypothesis works, or if it's correct it isn't necessarily relevant to the question of how antidepressants work--because antidepressants don't confer a high or short-term hypersensitivity to pleasure.

[Crusty Dem]

Hi, I am a neuroscientist, FWIW, but not a specialist in the field of depression. It's clear that SSRIs work (assuming they do indeed work) in some sort of indirect way, since direct effects of neurotransmitter reuptake inhibitors work on the time scale of seconds or minutes to hours (other examples are cocaine and ritalin), with differences based mainly on binding kinetics. The problem with this theory (the new neurons theory) is the type and location of new neurons, there aren't any (or damn few) new ones in the parts of the brain we associate with depression. The new neurons are located in pathways we generally relate to learning and memory or epilepsy, but definitely not mood... So there's definitely an error, either the (fairly well established) theories about the pathways involved in control of mood or the new neuron model of depression is wrong. Or possibly both. At least that's my $0.02, your value may vary.

[BOMBOVA]

Good discussion; if i am soon better able to play the sax and enjoy the sax, i will soon tell you.

[TomK]

"One should always approach a new paradigm with caution and await the outcome of clinical findings and metastudies before forming a conclusion."--Definitely.

Definitely not. Do you think Galileo cautiously moved away from the dark ages paradigm and waited for meta-studies before forming a conclusion? Do you think Jonas Salk waited for metastudies to be convinced by the merits of the vaccine idea?

I'm concerned this doesn't leave room for the imaginative and artistic parts of science essential to revolutionary progress. If you are a scientist interested in revolutionizing a field, you need to give yourself space to be convinced by hypothesis that are not yet supported, and argue for them convincingly enough that people will do clinical and meta-studies.

[Lindsay Beyerstein]

Galileo wasn't a clinician.

If we're just throwing ideas around, let's be bold. Sky's the limit--especially when formulating hypotheses.

But if we're talking about choosing medical treatments, it makes sense to move more cautiously.

[TomK]

Crusty - (IANANS)

If the brain is modular, why couldn't healing pathways in learning or memory or epilepsy cure depression and the theories be right? For example, maybe increasing the neurons around learning and memory create new pathways that disrupt the engrained patterns of negative memory recall and thinking patterns, acting to treat depressions perpendicularly.

I'm a music nerd, so allow me an analogy. I hook my electric guitar up to an amp, and mic the amp so it also plays to my studio monitors. If there is feedback because the speakers are so loud that the mic picks them up, it ruins the song. I can fix this by lowering the volume on the amp, which effects the studio monitors in a secondary way to fix the song. But, it's the right fix. And it doesn't mean KRK systems theory on how their monitors work is wrong.

Given that the brain is highly modular and has feedback loops all over the place, I don't see why you would even expect a cure for depression to work primarily on the mood circuits in the brain, any more then a musician should expect to fix a feedback problem coming out of studio monitors by twiddling with the monitors. It seems quite possible that mood systems are functioning perfectly in depression (always provide the appropriate outputs to the appropriate inputs) and there in a chronic problem with the input.

Given these results, this might suggest that both therapy and antidepressants effect the way memory and learning connect with the mood centers, and that depression is primarily a problem of how memory and learning pathways connect (and what they feed into) these mood pathways (which show the effects of depression but are not the right pathways for treatment). I think you got yourself a false dichotomy on the basis of this reasoning.

[TomK]

Lindsay - I took that quote out of context and lost the medical restriction on it. Should of read it closer.

[John Callender]

Analogy-wise, I think the message is that antidepressants might _be_ Band-Aids after all--in the sense of what Band-Aids actually do (promote and accelerate the body's existing healing processes). Though I get your point. People typically disparage "Band-Aid solutions" as being things that mask the symptoms without addressing the underlying problem.

Poor Band-Aids. Always getting dissed -- and by the same people who, when they get an ouchie, reach for a Band-Aid immediately and unquestioningly.

[JohnL]

Me being a typical selfish person, the bit that I took away was this:
"They studied animals with severe cases of "lazy eye," a condition characterized by poor vision in one eye due to underdevelopment of the visual cortex. The scientists showed that fluoxetine gave brain cells the ability to take on new roles and form new connections, which erased the symptoms of the disorder."

And I have a lazy eye. Does this mean a cure is possible for us older people?

[Cass]

I've always been aware of the secondary effects of depression in myself: insomnia, a loss of taste and appetite, and an often pretty dramatic drop in my already-meager social skills. (The part of my brain responsible for small talk seems to check out entirely.) I feel less intelligent and less capable at most everything I do, and I'm pretty sure that I am.

Antidepressants have never helped me, but I know they've been wonderful for others just in terms of getting a "jump start". The cruelest thing about the disease is that it takes away the very tools you need to rescue yourself: there's no question of starting a new exercise routine, or finding solace with a friend when you're truly drowning in it. With a little breathing space, however, some people can start building the structures and practices they need to keep from getting lost in the thicket all over again.

[swampcracker]

With a little breathing space, however, some people can start building the structures and practices they need to keep from getting lost in the thicket all over again.

I think this sums it up exactly. Thanks, Cass.

[Norman Costa]

TomK,

Your analogy may be more apt than you think. Let's take the example of a young child who experienced terrible abuse. Even when the psychological mechanisms have not yet developed for a 'full awareness' of the abuse, the emotional information seems to be encoded in the amygdala, a primitive brain structure. As the child grows into adulthood, a depressive reaction (and other reactions, as well) can be triggered by the primitive brain without the controlling influence of the higher cortical and cerebral structures. These structures are 'notified' by the primitive brain, but not 'consulted'.

It may be that therapy, particularly cognitive therapy, is the mechanism for gaining cortical control over primitive reflex-like functions - much like the knee jerk that doesn't even get processed by the brain.

So much of this is new, and speculative. Also, we use phrases like 'making new neural connections' that seem like common sense terms, but most of the time it's a convenient descriptor that hides the fact that we don't know what this means at the cellular or molecular level.

In my opinion, this notion of depression as "...a reversible neurodegenerative disease" and the role of therapy as a partner to medication has a lot of potential to understanding and treating some forms of depression.

[Norman Costa]

TomK,

Your analogy may be more apt than you think. Let's take the example of a young child who experienced terrible abuse. Even when the psychological mechanisms have not yet developed for a 'full awareness' of the abuse, the emotional information seems to be encoded in the amygdala, a primitive brain structure. As the child grows into adulthood, a depressive reaction (and other reactions, as well) can be triggered by the primitive brain without the controlling influence of the higher cortical and cerebral structures. These structures are 'notified' by the primitive brain, but not 'consulted'.

It may be that therapy, particularly cognitive therapy, is the mechanism for gaining cortical control over primitive reflex-like functions - much like the knee jerk that doesn't even get processed by the brain.

So much of this is new, and speculative. Also, we use phrases like 'making new neural connections' that seem like common sense terms, but most of the time it's a convenient descriptor that hides the fact that we don't know what this means at the cellular or molecular level.

In my opinion, this notion of depression as "...a reversible neurodegenerative disease" and the role of therapy as a partner to medication has a lot of potential to understanding and treating some forms of depression.

[cfrost]

One should always approach a new paradigm with caution and await the outcome of clinical findings and metastudies before forming a conclusion.

That's pretty much how it works in any field in science (and a few others, such as history). You float your new idea and invite everyone to try to blow it out of the water. If it weathers the most withering barrage that can be currently mustered, then you've got your new paradigm, which should last until a more satisfying explanation, if there is one, comes along. Any paradigm should be considered provisional in principle. If this new theory about antidepressants has merit, we'll know in a few years after the clinical findings come in and metastudies have been done.

Do you think Jonas Salk waited for metastudies to be convinced by the merits of the vaccine idea?

Salk may have been convinced, but no one was going to (or legally could) ramp up vaccine production until metastudies, etc. had settled the question of the vaccine's efficacy and safety to everyone's satisfaction.

Castren says that patients must still work to cement these connections in place . . .

I'm pretty sure work is turning my brain into cement.

[Doyle Saylor]

It seems to me that describing depression as a withering away disease misses some aspects of the 'disease'. This talk is medicalizing (making sick states of mind) cognition as opposed to a larger point of view. Everyone gets depressed. So to what level is depression a disease?

Who pays for the research? Based upon what social criteria? I mean literally what is the measure of depression that is disease?

[togolosh]

So to what level is depression a disease?

When it interferes with major life functions and does so over an extended period of time. Depression the disease isn't the same as situational depression. Depression as a disease results in significant harm to the individual (and often to the people around the person affected), and it has a proven basis in neurochemistry. Just because it looks to the uninformed outside observer as if there is a smooth continuum between being sad and being clinically depressed doesn't mean that there is no meaningful distinction. There's a major distinction between hunger and starvation, for example.

[togolosh]

So to what level is depression a disease?

When it interferes with major life functions and does so over an extended period of time. Depression the disease isn't the same as situational depression. Depression as a disease results in significant harm to the individual (and often to the people around the person affected), and it has a proven basis in neurochemistry. Just because it looks to the uninformed outside observer as if there is a smooth continuum between being sad and being clinically depressed doesn't mean that there is no meaningful distinction. There's a major distinction between hunger and starvation, for example.

[togolosh]

Or consider multiple posting as an analogy - once is a forgivable mistake. A hundred times is comment spam :-)