For bipolar depression we lean on second-generation antipsychotics with proven efficacy for that phase, used temporarily, plus lamotrigine, which in our experience works better than the studies suggest. Aripiprazole alone does little here, lumateperone can cause agitation and cycling in true bipolar patients, and bupropion's reputation as a safe antidepressant in bipolar disorder is a myth. Profound leaden fatigue tilts the odds toward bipolar over unipolar depression, a little.
How we diagnose it
Of the atypical features, leaden paralysis (a profound lack of energy) raises the probability that a depression is bipolar rather than unipolar a little. The overlap is too big for it to be very precise. Rejection hypersensitivity overlaps too much with borderline personality to be worth sorting out.
“It is more likely that when someone shows up with this profound lack of energy, that that's a bipolar depression as opposed to unipolar. It raises that probability a little bit. The overlap is too big for it to be very precise”
52:43How to Diagnose Bipolar Disorder with Dr. Phelps: Hypomania, Mixed States & the Clues DSM MissesSep 2026Guest episode Also said in 1 more episode
“Lead in energy, lead in paralysis, that was the third of those atypical features. And then the last one was rejection hypersensitivity, which is way too overlapping with borderlimity. I don't think really you'd spend too much time trying to sort that one out”
53:21How to Diagnose Bipolar Disorder with Dr. Phelps: Hypomania, Mixed States & the Clues DSM MissesSep 2026Guest episode
When we reach for it
For a bipolar depressive episode, the best thing to do is go temporarily to the second-generation antipsychotics with proven efficacy for bipolar depression. We like those the most.
“Then really, unfortunately, the best thing that you can do is go temporarily again to those second generation antipsychotics that have some kind of proven efficacy for bipolar depression. I like those the most for the use”
49:46The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025 If you are giving an antipsychotic, you want one that works for every phase of bipolar disorder, which naturally points to lurasidone. Unfortunately it probably carries the most akathisia risk of any antipsychotic.
“if I'm going to give you an antipsychotic, I want it to work for every phase of the bipolar disorder. So naturally, that's Latuda. Unfortunately, Latuda has The most akathisia risk, that's the restlessness of every antipsychotic, probably”
37:01The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025 Cariprazine is one we think of for bipolar depression, with a really long half-life. It can have a good effect on mood in some people but is not very effective in the end for mania and psychosis.
“but it is one of the ones that I consider, that I think of when I think of bipolar depression. Similar to the other ABCs that we talked about, really long half-life, as you mentioned”
44:20Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 Also said in 1 more episode
“Just like Abilify, not very effective in the end for mania and psychosis, even if it seems to have some good effect in some people on mood”
42:45Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 Lamotrigine's anti-manic effect is not great, but its antidepressant effect in bipolar depression is relatively robust. The studies say it does not treat acute depression; our clinical experience contradicts that.
“its anti-manic efficacy is not fantastic, but its relatively robust antidepressant effect for bipolar depression, pretty great. I know the studies show that it's not effective for treating acute depression. I'm going to say my clinical experience contradicts that”
43:07Mood Stabilizers for Bipolar Disorder: Lithium, Lamotrigine, Depakote & MoreJul 2026 Beyond medication, TMS seems to help while the mood is stabilized, and esketamine can be considered for some patients.
“wanted to mention also for the depression component beyond that, TMS, I am seeing some pretty good effect while your mood stabilized seems to be helpful. And you can consider esketamine for some patients”
51:20The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025 Physical activity is a great tool for targeting depression in bipolar disorder without running the risk of inducing mixed states, more cycling or mania.
“Mood, trying to target depression, particularly in bipolar, in doing so, In a way that does not run the risk of inducing mixed states and more recycling and mania. Physical activity is just a great tool”
1:13:51How to Stabilize Mood without Medications: Social Rhythm Therapy Anyone Can Use with Dr. Jim PhelpsNov 2026Guest episode
How long to treat
In depression we usually wait at least six months of remission before changing medications. In bipolar disorder we are willing to move a little earlier.
“I think if someone's generally in remission from depression, my practice is actually to go minimum six months of remission before I move the medications. But in bipolar disorder, I'm willing to go probably a little bit earlier”
52:42The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025
Pitfalls and myths
Aripiprazole is probably the number one low-dose augmenting agent for unipolar depression, but by itself it does not really help bipolar depression.
“It is probably the number one augmenting agent at a low dose for depression, proper depression when added to an antidepressant, but by itself doesn't really help in bipolar depression”
35:41Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 Lumateperone is basically a serotonin reuptake inhibitor combined with an antipsychotic. Clever pharmacology, but in our view it causes too much agitation and cycling in true bipolar patients.
“Okay, so it's basically an SRI that's been combined with an antipsychotic. Very clever, you know, pharmacologically, but in my opinion, causes too much agitation and cycling in true bipolars”
58:30Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 The community idea that bupropion is the safer antidepressant in bipolar disorder is a myth; we do not think there are data to show it.
“What are the antidepressants that I find a little safer? Not Wellbutrin, not Bupropion. That's what kind of is out there in the community. Kind of myth, if you ask me. I don't think we have any data to demonstrate that”
50:12The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025 A full-on light box at 18 inches can induce a manic episode. It is an antidepressant, and light is a powerful tool.
“A full-on light box at 18 inches is Can induce a manic episode. It's just, it's an antidepressant. So light is a powerful tool”
58:19How to Stabilize Mood without Medications: Social Rhythm Therapy Anyone Can Use with Dr. Jim PhelpsNov 2026Guest episode
It also comes up on
- LurasidoneIt is a really great medication, especially in bipolar. It was only studied in bipolar depression and never tested in acute mania, likely because it was sold as the bipolar depression drug; given how it acts, it makes no sense that it would work in acute schizophrenia but not acute mania.
- MindfulnessIt will not treat mania or bipolar depression, but it is still worth teaching to people with bipolar disorder or schizophrenia. Like exercise, it helps in every patient's life, in a dose that fits that person.
- QuetiapineIt is approved and effective for bipolar depression. We do not use it much because of the side effect profile, but if someone does not gain weight and is not oversedated on it, it is a good choice.
- AntipsychoticsIf you see what looks like major depression with psychotic features alongside PTSD, consider the agents with bipolar depression efficacy.
- Bipolar disorderMindfulness will not treat mania or bipolar depression, but it is still worth teaching.
- ManiaLurasidone is a really great medication in bipolar disorder; it was just never tested in acute mania. It makes no sense, given its action, that it would work in acute schizophrenia but not acute mania. It was only studied in bipolar depression.
- PTSDAntipsychotics help most when the PTSD is severe and comes with a real comorbid major depressive or bipolar-type mood disorder. If it looks like depression with psychotic features alongside PTSD, consider the agents with bipolar depression efficacy.
- PsychosisIf major depression with psychotic features appears alongside PTSD, consider the agents with bipolar depression efficacy.
From these episodes
- How to Stabilize Mood without Medications: Social Rhythm Therapy Anyone Can Use with Dr. Jim PhelpsNov 2026 · 2 points
- Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 · 4 points
- How to Diagnose Bipolar Disorder with Dr. Phelps: Hypomania, Mixed States & the Clues DSM MissesSep 2026 · 2 points
- Mood Stabilizers for Bipolar Disorder: Lithium, Lamotrigine, Depakote & MoreJul 2026 · 1 point
- The Best Bipolar Medication Review From The Best Bipolar ExpertJan 2025 · 5 points
Every point above is something said on the Psychofarm podcast, with the words as spoken and a link to the moment in the episode. It is education, not medical advice, and an episode reflects what we thought when we recorded it.