goffique

None of this is medical advice. Don't ask me for medical advice. I'm not your doctor, and it's quite literally both unethical and risks my license for me to give medical advice to someone I'm not treating. I have enough patients--I'm a full-time rural family physician and my panel right now is north of 900 patients and my clinic expects me to pick up another 500.

Antidepressants work, sometimes or possibly often, but we don't know how. I'm not being facetious about that; we literally don't understand why modulating serotonin and norepinephrine neurotransmission has an effect on mood, but not for an unpredictable length of time usually in the weeks. It's been studied pretty extensively, but to the best of my knowledge, we have yet to come up with a mechanism of action that directly connects. What you get taught about how SSRIs, selective serotonin reuptake inhibitors, is mostly true. However, the step where "and then mood gets better" might as well be "and then magic."

The worse the patient's symptoms are, the more likely they are to notice a benefit with medication. This is true across a wide range of conditions. It's easier to see a big difference than a little difference.

You have as many serotonergic (serotonin producing/responsive) neurons in your gut as you do in your brain, so when you start an SSRI, you can safely expect to have some stomach upset. This typically improves over a few days. I start patients at a half-dose and have them self-titrate (adjust to effectiveness) up to a full dose once their stomach settles down. It's not dangerous, just obnoxious. There will always be a wide range of how much people feel various side effects; some people don't notice any stomach trouble (diarrhea, nausea) and other people are miserable (I laid awake all night, writhing with nausea, when I restarted citalopram--Celexa--and it didn't even fucking work for me that time).

There is a "black box" warning (which you can read as "This seems to be a thing, but we don't know why) on most antidepressants that there can be an increased risk of suicidal thoughts. We also don't know why this is. It seems to be real, and worse in young people.

There are actually several different drug classes that are considered "antidepressants." Drug classes should be understood as "drugs that look kind of alike, chemically," and often behave similarly. SSRIs are the most common antidepressant currently prescribed. The earliest ones developed, monoamine oxidase inhibitors, had more potential for serious side effects. The next class, tricyclic antidepressants, are still around, but more commonly used at lower doses for neuropathic pain/migraine/insomnia (amitriptyline, nortriptyline).

The SSRIs were a game-changer. They're extremely unlikely to kill people. There is a rare but real risk of serotonin syndrome, which involves rampant over-signalling, but I have been in medical environments for about a decade now and saw one whole case of it. That was in a patient with a severely psychotic disorder who was involuntarily hospitalized after attempting to kill a caregiver; that patient was on at least six medications that all affect serotonin. I walked into her hospital room to find her having myoclonic jerks as a med student and immediately went out to get my attending. The patient was ultimately fine. Except for lifetime involuntary institutionalization because, you know, attempted murder. (She was very clear that she had wanted and intended to kill the caregiver and was disappointed they blocked the knife.)

SNRIs, or selective norepinephrine reuptake inhibitors, are a very closely related class to SSRIs. These are both "dirty" drug classes, meaning that they aren't only targeting serotonin or norepinephrine, which you might think from the names. SNRIs have a great deal of serotonergic activity. Since we don't know how antidepressants work, we also don't know if that matters. In practice, I find them more activating than SSRIs, in general. Most antidepressants exist on a spectrum from sedating to activating. I try to tailor the antidepressant choice to the patient's symptoms--someone who can't calm down enough to sleep might benefit from a more sedating medication taken at bedtime, while someone too depressed to get out of bed might benefit from a more activating medication taken in the morning.

There was some initial data that duloxetine (Cymbalta), an SSRI, might help with neuropathic pain. Then that got walked back. I still see it prescribed for this and sometimes it helps. The reason an antidepressant helps pain isn't that it's "all in your head" in the sense that your pain is imaginary; it helps because neural processing of pain is a) extremely diffuse (so there isn't one "pain region" of the brain that you can lesion out to get rid of it) and b) not well-differentiated between emotional and physical pain. Your brain runs "ouch I got socially rejected" on the same circuitry as "ouch I touched a hot stove." This is, presumably, why people with emotional pain use painkillers to cope.

It takes at least 8 weeks on an SSRI or SNRI medication to consider it a treatment failure. Because yes, it can take that long to see results. Often people around the patient will start commenting on how they seem more energetic; that can feel like a cruel joke to the patient, who still feels like crap. However, that's a good early sign that we picked the right medication.

People who don't respond to the first anti-depressant chosen are less likely to respond to other antidepressants. We don't know why. Probably some depression comes from some sources and other depression comes from other sources, and antidepressants work on one kind but not others. However, the rate of response to a second or third antidepressant trial is still meaningfully better than zero.

There are non-MAOI, non-TCA, non-SSRI, non-SNRI antidepressants. Bupropion (Wellbutrin; all drugs have at least two names, a generic, which is generally written in lower case, and one or more brand name(s), which is written with an uppercase first letter, and in this case bupropion is the generic) is the most popular example. There's some suggestion it helps with quitting smoking, and also that it can help with ADHD, but I find it's often so activating I see worsened anxiety in my patients. It's not, like, THE WORST--Paxil, quite frankly, is the worst, because it has a high rate of side effects and takes forever to taper off--but I rarely start with it unless there's a good reason to. Wellbutrin is a weak norephinephrine/dopamine reuptake inhibitor. I'm not going into what a reuptake inhibitor is because you can definitely find about a million really good YouTube videos that will do a great job of explaining that.

Another one I often reach for is mirtazapine (Remeron). We think it increases release of serotonin and norephinephrine. You remember I mentioned tricyclics? Well, this one is a tetracyclic. It's off in its own corner. I like it for the elderly, because it makes people sleepy and hungry, and a lot of my frail elderly patients don't eat enough and can't sleep.

You know how you have a "fight or flight" system? The opposite is "rest and digest," so a lot of medications that help with anxiety also make you sleepy and hungry. See: weed.

The leading killer of people with bipolar disorder is heart disease, because most of our good mood stabilizers also seem to greatly increase the risk of metabolic syndrome. I tell patients "Better fat than dead" all the time and nag them about taking their statins (protective against heart attack and stroke but can also cause dysregulated blood sugar and diabetes so you still gotta watch the labs) and getting exercise. Just something to keep in mind next time you feel like talking shit about someone's weight. Actually, next time you feel like that, just kick yourself right in the tits.

Back when I was in grad school, we were hoping aripiprazole (Abilify) was going to be the best antidepressant to ever hit the market. Sadly, it isn't. Technically, it's a second-generation antipsychotic. Even more technically, it's a dopaminergic modulator--it increases dopamine activity when concentrations are low, and decreases it when concentrations are high. Psychosis is understood neurochemically as excessive dopaminergic activity. The brain is a great recycler, so unfortunately, medications to help tamp that excessive activity down also affect the reward circuitry, so people often find antipsychotics make it very difficult for them to feel joy. Understandably, they then go off their meds to feel something good again; then, if they're one of the unlucky folks who get repeated psychotic breaks, they break from reality and often feel pretty crappy. But what aripiprazole can do for depression is augment (boost the effectiveness of) antidepressants. If someone is on a reasonable treatment dose of an SSRI or SNRI and their mood is still depressed, I'll offer starting at a low dose (often 2.5mg, since most insurances will cover a 5mg tab but not a 2mg tab, don't ask me why, insurance is the devil) of Abilify and seeing if that can boost the effectiveness. If they feel better but not enough, I'll try going up to 5mg. I rarely find we need more than 5mg to augment an SSRI, but for people with comorbid (co-occurring) psychosis, they may well need more like 15mg. I have one poor sweetheart who's on 30mg right now because of abruptly worsening hallucinations and delusions of persecution. When the activity goes through the roof, you have to increase treatment aggressively to control it, but when they start feeling better, you can try tapering back to their usual levels. Same goes for mania. Antipsychotics are effective at suppressing manic episodes, which is important, because mania can ruin lives in a matter of hours. This isn't an antipsychotics post. Let me know if you'd like one.

Seroquel--shoot, I just said this wasn't an antipsychotics post, but quetiapine (Seroquel) is another second-generation antipsychotic. It's a partial agonist at multiple serotonin receptors. At lower doses (like 50mg) it's an antipsychotic; at much higher doses, it's an antidepressant (like 300mg). It's also popular among the meth users community, as it helps mitigate feeling crappy with the come-down. I once had a man throw things in a small enclosed space while I was a med student because the attending psychiatrist I was with wouldn't order Seroquel for him to come down off a multi-day meth binge. I was very frightened, and I was glad, despite the fact that I'd specifically requested a high-intensity inpatient psychiatric training experience, that I was only there for one night. There is a black market for it at the jail where I also work part-time as my side hustle. I was taught that it doesn't get you high, but some of my Juvie patients snort it, which means either it might or they're just idiots, because many kids are idiots who will snort whatever their friend dares them to. Many adults, too. Seroquel is not typically a first-line antidepressant, because it has some potentially nasty side effects, but it's an option for some patients and it's saved some of my patients' lives.

Antidepressants aren't one size fits all. We're bad at predicting which meds will work for which patients. I play the numbers game, I try to pick something with a decent shot of helping someone without making them worse, and I prescribe it. I've been on a couple myself now, and the difference it makes to not be constantly thinking "I want to die, I want to die" is unbelievable. It gives me my time back. I hate the side effects; I hate that my libido gets flattened into oblivion, when I was on duloxetine I hated the night sweats, but I've been on Lexapro for a year and a half now, tried to taper down twice, and ended up going back up both times because my brain just doesn't want to work without it. I didn't try any medication for this until I was 27, and if I could go back in time, I would kick my own ass for waiting so long. I just started a patient in her 70s on Lexapro recently and she said to me, "My daughter is on Lexapro" (why I picked that for her in the first place; genetics aren't everything, but they matter) "and she's been telling me to try this for years. I can't believe the difference it makes. I can't believe I waited so long." She's angry, she's grieving the lost time.

I have vague thoughts about the energy balance/stress response connection from the neuroendocrine side of things, especially harping on glucocorticoids which are often mischaracterized by folks on my side of the fence as "stress hormones". In fact as you probably know as well or better than I do, the same glucocorticoids are also intimately involved in energy balance metabolism.

On the other end of the fence, I worked with leptin for my dissertation which was supposed to be the "satiety hormone" that made you feel full and stop eating, except that adding leptin didn't do anything above a certain threshold. It turns out that leptin levels can mediate the strength of an immune response or the amount of energy that an individual invests in social behavior well over the threshold values that control satiety; your body is trying to understand how many resources are available to it when it works out how to correctly prepare itself for the challenges of life.