Depression: The Olfactory Perspective

Depressed people have worse sense of smell, and people with worse sense of smell are more likely to get depressed. Kohli 2016 tries to figure out what’s going on.

They review six studies testing how well depressed people can smell things. Most use something called “The Sniffin’ Sticks Test” (really!) where people are asked to say which of two sticks has an odor; the strength of the odorous one is then decreased until the subject can no longer consistently get it right. This determines olfactory threshold – how sensitive the subject’s smell is. Depressed subjects did marginally (but significantly) worse on this test than controls (6.31 ± 1.38 vs. 6.78 ± 0.88; P = 0.0005) – I think this corresponds to an effect size of about 0.2. They also do a couple more tests to see if depressed people are worse at identifying odors and get similarly small results. Also, some neuroimaging studies directly correlate depression and olfactory bulb volume, and find that olfactory areas of depressed people’s brains shrink.

Next they look at three studies of people who have various known respiratory diseases that impair sense of smell, and see how many of them are depressed. The answer: lots! Normosmics (people with a normal sense of smell) have an average score of 5 on the Beck Depression Inventory. Anosmics (people with no sense of smell) have an average score of 14. Hyposmics (people with weak sense of smell) are in between. This seemed true independent of respiratory disease level (ie it’s not just that having a worse respiratory disease makes your smell worse and makes you more depressed).

The two most common diseases studied were chronic rhinosinusitis and post-upper respiratory infection olfactory dysfunction. One of the studies, Jung, Lee, & Park (2014), compares them. They find that 40% of CRS patients are depressed, vs. 76% of PURIOD patients, a significant difference (also, both much higher than the ~5-10% of depressives in the general population). They note that CRS involves a gradual loss of smell, and PURIOD a sudden loss of smell, and that maybe people adjust to gradual loss better than sudden.

We can easily come up with alternative hypotheses. You can never actually control for confounders properly, and having a respiratory disease sounds depressing. Also, the sorts of people who have respiratory diseases probably differ from the rest of the population in various ways. Biologically, they might have worse immune systems, or end up with worse oxygenation and chronic infections, or just be generally sickly. Sociologically, they might be poorer, or have worse diets, or more comorbidities. Sinus problems themselves are linked to depression for a bunch of reasons, probably relating to the sinus being so closely linked to the brain that sinus inflammation screws up your brain chemistry. Also, most chronic diseases have high depression rates – sickle cell anemia (chosen kind of at random) is 44%.

There really aren’t that many causes of anosmia that are 100% exogenous and have no chance at all of contributing to depression themselves. But animal researchers can take Gandhi’s advice and become the exogenous cause they wish to see in the world. Yuan and Slotnick (2014) discuss experiments where researchers remove the olfactory bulbs of rats. These rats tend to consistently become depressed. That seems like pretty strong evidence to me.

So why would depression reduce olfactory acuity? And why would reduced olfaction cause depression?

Maybe depression reduces olfactory acuity because it reduces sensory acuity in general. We already know that depression decreases visual contrast, causing the world to literally look washed-out and gray. If I’m reading this study right, it claims depression also decreases auditory threshold – ie depressed people are less able to hear very quiet sounds. I can’t find similarly good studies on taste or touch, although they should be easy to do. If anyone knows any studies on eg two-point discrimination in depressed vs. non-depressed subjects, let me know. If not, this would be an easy project that a college psychology student could do in a few weeks, and it would add to our understanding of this subject. But right now I think the evidence is consistent with a general decline in perceptual abilities. This fits my understanding of depression as a systemic disorder – the low mood is the most noticeable symptom, but you’re also getting everything from poor digestion to worse hearing. Probably this is because whatever is affecting the emotional centers of the brain is affecting the lower parts of the brain (and nervous system?) too.

Is the opposite of this true? Does any form of decreased sensory acuity cause depression? I’m leaning toward no. This study claims to find that myopia is linked to depression, but the association is so weak that I take it as a strike against the hypothesis. These two studies find hearing loss is associated with depression, but it’s still pretty weak and it could easily be because poor hearing hurts your opportunities to socialize. I’m most struck by discussion of monochromacy, ie total colorblindness, which absolutely fail to mention depression at all. If I’m going to be splitting hairs about how depressed people see slightly duller colors, the lack of any excess depression in people without color vision seems pretty important. Blind and deaf people have pretty high rates of depression, but being blind or deaf is really hard and I don’t want to draw too many conclusions there. Overall it doesn’t seem to me like decreased sensory acuity causes depression full stop, though I could be wrong. This would mean that loss of smell is unique in its emotional effects.

The sense of smell is pretty emotionally salient. Everyone always says that “smell is the sense most linked to memory” – though I can’t figure out exactly which study discovered it and whether it considered (for example) how reliably seeing a picture of my mother reminds me of my mother. Body odor seems to be closely linked to who we’re attracted to. Smell is responsible for all taste sensation beyond sweet/salty/sour/bitter/umami, and eating food is one of life’s most visceral pleasures. From fifthsense.org.uk:

Anosmia sufferers often talk of feeling isolated and cut-off from the world around them, and experiencing a ‘blunting’ of the emotions. Smell loss can affect one’s ability to form and maintain close personal relationships and can lead to depression. An important issue here is the fact that smell loss is invisible to all but the patient; how would you know that you had met an anosmia sufferer unless they themselves told you? This is one of the reasons, alongside the general lack of understanding of the impact that smell has on our lives, why anosmia has never received much attention – you really do not know what you have got until it is gone.

But also, Yuan and Slotnick’s rat paper gives a more biological explanation. The olfactory bulb is the beginning of pathways that stimulate many other parts of the brain. When it’s removed (and presumably also when it just never gets any incoming stimuli) it stops doing that, and the downstream parts of the brain shrink. For some reason this also causes decreased brain-wide synthesis of serotonin, maybe because the olfactory bulb is a net positive stimulus on the raphe nuclei. Sure, sounds like the kind of thing that might cause depression.

What does this imply about treating depression?

SSRI antidepressants probably decrease sense of smell as an immediate side effect. Awkward. But they seem to improve sense of smell long term as part of their general treatment of depression. In studies fluoxetine (Prozac) causes nerve growth in the olfactory bulb after a few weeks. Does that suggest a story where SSRIs work by improving smell? Probably not – more likely they work by [a cascading system of effects involving] causing nerve growth more generally, and the olfactory bulb benefits along with everything else.

Could you treat depression through improving olfactory sensitivity? Maybe, but I have no idea how to do that. Yuan and Slotnick suggest directly stimulating the olfactory regions of the brain, but this is pretty invasive, and there are probably already better treatments for the small minority of patients who are going to let you directly stimulate brain regions. Maybe before we worry about this problem, we should investigate the more general question of sensory enhancement for depression. What would happen if you made people wear glasses that enhanced the color saturation of everything they saw?

Finally, what about just exposing depressed people to really strong smells? You will be excited to know that real scientists have studied this ridiculous idea, and it seems promising, at least in extremely sketchy experiments on mice (1, 2, 3). I have never seen any studies done on humans unless this is actually how “aromatherapy” works, which would be hilarious. Aromatherapy seems to get positive results for depression with the same kind of bad studies that let all quackery generate positive results for everything. I can’t say more than that and I’m pretty skeptical here.