Key moments, in order
We do not know that our drugs address underlying causes. The serotonin deficit and dopamine excess ideas are hypothetical, and psychiatry must be honest about when it treats causes versus symptoms.
Link the mechanism to things that empower the patient, rather than an explanation that makes them depend purely on a drug to boost their serotonin.
Showing images of more neural connections after treatment can help. Then offer a menu of lifestyle interventions and have the patient pick just one, so they are not overwhelmed.
People who come off benzodiazepines tend to have more self-confidence, better concentration and less depression in observational studies, and PET scans show a healthier brain six or 12 months later.
The best evidence goes to ECT, TMS, antipsychotics (aripiprazole has the best evidence and the biggest effect size), lithium, thyroid supplement, and ketamine and esketamine. Those are the top-line interventions.
Deficit-model add-ons include folate, omega-3 fatty acids, probiotics, light therapy, vitamin D and possibly hormonal therapies, though hormones are not something psychiatrists should be doing.
Vitamin D shows a real benefit when the trials are split by whether they were correcting a deficit, rather than giving it to everyone.
One host now tests vitamin D routinely in all patients, because severe deficiency is surprisingly common in underserved community populations and primary care often does not manage it.
Testing for a deficit is not recommended. Most trials enrolled people without testing for a deficit, which is one of the holes in the deficit hypothesis.
An analogy for patients: a leather car seat left in the sun and never oiled gets crackly, crusty and broken, and that is what the brain looks like without the proper oils.
Of about 30 controlled trials of omega-3 in depression, the benefit shows up only in the ones that used high levels of EPA. Analyses now recommend at least twice as much EPA as DHA.
For depression, probiotics, omega-3 and methylfolate likely have some of the best evidence.
Zuranolone, a synthetic version of allopregnanolone, is FDA approved for postpartum depression and arose from the idea that allopregnanolone falls postpartum and disrupts GABA circuits. It is a deficit model on the pharmaceutical side with rapid benefits.
For select patients whose problem is circumscribed PMDD, the right monophasic combined oral contraceptive can make a night and day difference.
Treat it as an add-on, not a cure. Effect sizes are small: even the most potent omega-3s run about 0.3 to 0.4.
The effect is big, and it fits a deficit model: seasonal depression is a deficit of morning light. So give it in the morning, not the afternoon.
Gut dysbiosis is common in depression, so you probably do not need to test for it; assume it and give a probiotic, which has good studies in depression.
Combine light with behavioral activation: ask patients to make a goal of getting out every morning and walking around in daylight.
Lithium is one of the only psychiatric medications that regulates circadian rhythm. The closest we have come to bipolar genes are the clock genes, and lithium normalizes their expression.
One theory of thyroid augmentation is that depression is a form of thyroid resistance, so more thyroid gets into brain cells. That is why T3 (liothyronine, Cytomel) is preferred: it is more brain active.
The proper dose is 15 milligrams a day. Several products on Amazon sell it for about $5 a month, so patients can now afford it, where that used to be difficult.
Studies have found that response is more likely with a BMI over 30, or with inflammation: a high-sensitivity C-reactive protein (hs-CRP), an inexpensive test, of three or more.
Patients with inflammation are more likely to need higher doses: one study had to go up to 4,000 mg a day of EPA and DHA, where most people take 1,000 to 2,000.
It tends to deplete folate, and a study showed it works better in mania when given with folic acid, so it makes sense to give it.
Folic acid may blunt lamotrigine's antidepressant effect in some people. In one patient on valproate plus lamotrigine, adding folic acid made him feel as if he were missing the lamotrigine, and stopping it restored his mood.
Testing hs-CRP is inexpensive and gives the patient proof and motivation. If elevated, recommend Mediterranean diet, sleep hygiene, brisk walking 30 minutes every other day and stress reduction, then retest in a year, saying you will only retest if they have really done it.
Risk factors for high CRP are stress, depression, chronic medical illness, obesity, recent injury or infection and the postpartum period. Still, CRP can be normal in people who look high risk, so test rather than assume.
Ketamine has a big effect size, but the benefit does not last, so it is not something to suggest to everyone.
At the bottom of the evidence ladder sit bupropion, mirtazapine and buspirone augmentation. Taking two antidepressants rarely works better than one, yet that is what we most often do.
Estrogen-based hormone replacement improves depression when added to an antidepressant, in small trials that mostly used a patch.
Men with verified low testosterone and depression might talk with their primary care doctor about the risks and benefits of supplementing. The trials were in verified low levels, not beyond normal.
No single new medication will pull these patients out of all their problems, but a broader look at relationships, lifestyle and deficits may improve mood a bit and help them function better.
Each moment is a point made in the episode, linked to the second it was said. The topic links open everything the podcast has said on that topic.