Antidepressants and add-ons for major depressive disorder, mostly by what the host would pick first in real life with weight gain and side effects counted against a drug, then efficacy. From the Psychofarm podcast, May 2026: 27 ranked, each with the reason and the moment it was said.
Stimulants feel good at first but that is an intoxicant effect that wears off with tolerance, so they are not a real long-term treatment for depression. Treating depression as ADHD also lets the depression go untreated.
One host noted stimulants such as methylphenidate are commonly used for geriatric depression, so they should not be written off entirely; the other agreed there is an exception for older adults.
“Adderall immediately goes into F tier. Why are we going to do that first? Because too many psychiatrists will essentially ignore anxiety and depressive disorders and call it neurodevelopmental”
Placed in F for depression alongside Adderall, for the same reason: the lift is a drug effect that does not hold up as a treatment of the depression itself.
“F, because we're talking about depression. Okay. Is it frozen? It looks up there. We're snapping into place”
The top pick: it titrates in many steps, works well, has few drug interactions and no significant QTc prolongation. Stomach side effects tend to fade within about a week at each dose. Both hosts reach for it first.
“Yes, does have more GI side effects maybe, but those tend to dissipate at each dose after up to a week or so. Effective. Well tolerated. Great first line medication. Absolutely. S tier”
Still a great medication and a close second to sertraline, effective with few drug interactions. It has fewer titration steps and a bit more poor tolerance, and the label caps the dose in older adults.
The other host also had it in A and said he would not have fought an S placement.
“Again, Still a great medication, probably my number two, but I wouldn't put it in S tier. I would put it into A tier”
Put in S as a position statement, not as a first-line pick. Many recurrent biological depressions may sit closer to bipolar illness and respond to mood stabilization, and small studies support it as an add-on.
Both hosts said it is not first line; the placement is a deliberate statement. They also said low-dose lithium needs less lab monitoring and many clinicians are too afraid of it.
“So I'm putting it up there more as a position statement than a true. This is a first line medication for depression”
Awesome medication with a long half-life that forgives missed doses and works even at low starting doses. Held out of S for a little more sexual side effects, activation and drug interactions.
The other host placed it in B, because he is less comfortable with its dosing and finds it slightly less effective and more interaction-prone.
“Downsides, why it's not S-tier. Well, maybe a little bit more sexual side effects possibly. Maybe a little bit more activating or agitating in some”
They treat symptoms for a while and then build tolerance and habit, rather than treating the underlying depression. Other short-term options are preferred.
The other host agreed with F but defended a one-week prescription for agitated depression with severe insomnia during a crisis, calling it not useless.
“Again, similar to the stimulants, they are symptomatic treatments that create habits, build tolerance, and stop working”
Effective and works for anxiety and PTSD, but weight gain, anticholinergic effects, a short half-life and withdrawal keep it low. It is not a first-line choice.
Started as B and moved to C during the discussion.
“you know what let's put it in C you've convinced me okay it was on the edge put it in C you know bad Paxil don't give so much weight gain we can use other things”
Left ungraded in the question mark section. It is such a back-line choice, mostly used for OCD, that it cannot be fairly graded, and it has many drug interactions and insurance denials.
Not a tier; the show used a question mark section for items it would not grade.
“I think we should keep it in question mark. It's just simply such a back line choice, uh, that you pretty much only use in patients to have OCD, uh, that I don't think we can fairly grade it”
It works and tends to get a good response, but the withdrawal syndrome is the worst of the antidepressants. It could be A or even S otherwise.
The other host was cooler on it: only a small improvement over SSRIs, with blood pressure, heart rate and cardiac overdose concerns, and he would not use it first line.
“This is a B class for me. Definitely B for me. Venlafaxine. And why? Well, you know, it works”
Maybe A, based on limited experience: it may be the one true SNRI, has good titration steps, and is useful for patients with fibromyalgia.
Placed tentatively by the host with limited experience.
“I would put this one Maybe an A-Class. Whoa. Maybe, maybe, maybe. Yeah. Actually fulfilling the promise of the SNRI, you know, and... Yeah, lots of good titration steps that you can use”
Works very well and would be nearly S if not for weight gain and heavy sedation. It avoids stomach and sexual side effects.
The other host had it in S and counts it among his four usual first-line choices.
“Despite my hatred of weight gain, I must put Remeron in A class. Okay. If it was not for the weight gain and in many patients, especially Asian patients who are more sensitive to antihistamine effects, significant sedation. Oh man, it works so good”
A great medication with no weight gain or sexual side effects and a mild stimulant feel. Tolerability is hit and miss, and it can worsen anxiety, so it is not for every patient.
“Okay. Wellbutrin, great man. Hit and miss tolerability. Love to throw this on on almost everyone who doesn't respond to just one medication. A-class, certainly A-class as well”
Rated for major depression only: at the high doses needed it is not well tolerated, and it is not very effective for depression. It is better as a sleep aid.
The other host agreed with C and stressed that low-dose trazodone is not an antidepressant dose.
“I think I have to put poor old Trazodone into C-Class because we're rating it for major depressive disorder. We're not rating it for trauma disorder or insomnia”
A very good add-on at low doses, but the tardive dyskinesia risk is real, especially without schizophrenia, so they moved it down to the question mark section so viewers do not take it as an endorsement.
Moved during the episode: first S (low dose, under 5 mg), then A after pushback, then the question mark section. The show warns not to go above 5 mg for depression without psychotic features.
“You know, there's going to be a lot of lay people who are going to skip to the end of this video, so let's put it down in the question mark section, Abilify”
Ungraded on its own, but as an augmentation agent it is pretty good. Held to B by big weight gain and appetite increase. It has a lower tardive dyskinesia risk than others and is well tolerated.
Started in the question mark section, then given a B as an augmentation agent.
“But as augmentation agent, it's pretty dang good. We'll give it a B. It works right in anyone who doesn't care about weight gain and appetite increase, but it definitely causes a ton of weight gain and appetite increase”
Did not pan out on the early promises. It is expensive and not clearly more effective, but may be tolerated by people who struggle with other drugs. Worth a try, not a first reach.
“Anyway, I would put 40-oxetine and Vilazodone on the same tier B. This is expensive. It's not particularly more effective than others”
A solid B: not a first-line reach and not something to avoid. It may help a little with sexual side effects and might suit people who tolerate other drugs poorly.
“It's worth a try. Is it something you reach for first? Absolutely not. Is it something that you avoid? No, it's a solid B tier”
Works great and can be life-saving for a select group, but it has brought more drug-seeking than treatment. The effect is short and needs therapy and lifestyle change alongside it.
The other host called it C or D and agreed with that range, citing patients who seek it out instead of addressing other problems in their lives.
“Why is it in D? It's in D for me and I won't budge from that. Why? Works great in a select amount of people. Can be life-saving in a select amount of people”
Not approved for depression, but low risk, relatively well tolerated, and useful for anxiety, trauma and irritability that come with depression. Works as an add-on and may help sexual side effects.
“I would put buspirone into the B class. Okay, because it's just so low risk, and relatively well tolerated. And it is pretty efficacious for anxiety, trauma and irritability, which often can come hand in hand in your major depression patients”
These rankings are the hosts’ and guests’ opinions from one episode, for clinicians and the curious. They are education, not medical advice, and not a guide to choosing a treatment for any one person.
Educational content only. These resources are for education. They are not medical advice and not a substitute for clinical judgment, current guidelines, or individualized patient care.