Key moments, in order
They are called antipsychotics because of a historical or FDA-approved use in psychotic disorders, but their receptor effects are so wide that the name is almost a misnomer. They are extremely effective, and a strong medication is strong in its side effects too, so use them with caution when lower-risk options exist.
Everyone is an individual: a drug that works great in 90% of people may work terribly in one, and some people gain weight on aripiprazole. Do not tell a patient starting Abilify they will not gain weight, or they will stop trusting you.
Consider metabolic side effects first, rather than just what works. Keeping a young patient on a weight-gaining antipsychotic without trying alternatives puts them on a highway to diabetes, high cholesterol, heart disease and over-sedation.
A patient who stops a medication because of weight gain is a failed medication. If GLP-1s can prevent that, they belong in the plan. We have underused metformin with antipsychotics, and now GLP-1s too.
It works really well, and it has basically no metabolic burden compared with the other first- and second-generation drugs.
The trade-off is plain: sleepy, heavier and full of metabolic syndrome on other drugs, or more tardive dyskinesia and akathisia on this one.
The HAM receptors explain much of the burden: histamine for sedation and weight gain, muscarinic for sedation and anticholinergic problems, alpha-1 for orthostatic hypotension. Many second-generation drugs block them.
Haloperidol and risperidone are one to one in chlorpromazine equivalents for D2 blockade. Nobody starts risperidone at 5 mg or takes it past 8, yet haloperidol is routinely started at 5 mg and pushed to very high doses.
The old tale that it causes depression is overblown. We have used it successfully in many patients with mood features, and their depression improved.
Like any strong dopamine blocker, it can cause neurolepsis: some apathy, emotional blunting and low motivation.
Not first line. But if a patient has failed a couple of antipsychotics, is very ill and suffering, and really does not want weight gain and sedation, try haloperidol, and treat it like risperidone.
Most patients respond below 8 mg, just like risperidone, and it is much better tolerated dosed that way. Some people do need high doses: do not be afraid of 10 to 15 mg in very rare cases.
You can use it in PTSD, anxiety and depression, but there is massive weight gain, appetite increase, diabetes risk and sedation compared with the actual antipsychotic benefit.
It is literally a different medication at different doses: 50 mg is not one eighth of 400 mg. At 50 mg and below it is a sedative, really just hitting histamine; up to about 300 mg think of it for mood symptoms; above 400 mg you start to get D2 blockade.
There is no good reason to use the XR. Sedation 24 hours a day is not a good idea, and the XR blunts the benefit of the early-night peak for sleep.
Most antipsychotics do not need twice-daily dosing, yet patients leave the hospital on BID and stay on it for years. After discharge, consolidate to once a day.
It is one of the only antipsychotics that covers the whole gamut of bipolar: the depressive episodes and the mania.
Is it better in the long run than lithium plus lamotrigine? We do not think so, though no one has studied that head to head.
The monitoring and titration requirements make clozapine extremely hard to use (who has the time to get someone stable these days?), so it self-selects for lower-acuity patients.
If the patient has been off it for more than 48 hours, restart the titration from 12.5 mg. You can probably go quicker than the first time, since you know they tolerate it. The REMS database is gone, but the monitoring is not.
The FDA took away the REMS, not the recommendation. People still get severe neutropenia, so ANC monitoring continues on the exact same schedule; you just no longer report to a central registry. Skip the classic monitoring and you are outside the standard of care, with your license on the line.
Start a bowel regimen prophylactically and ask patients if they are pooping. Docusate should be started in pretty much every patient; some guidelines start with an osmotic laxative like polyethylene glycol (MiraLAX).
It is perhaps the most effective antipsychotic of all of them in our experience. Do not be afraid to dose it lower for milder cases; it comes in a 2.5.
Time to peak is six to eight hours, against two to three for most antipsychotics, so many people do better taking it earlier in the evening.
At the other end, some patients really need very high doses: one patient who came in on 40 mg decompensated when it was moved down to 35.
Patients actually really like olanzapine. We tend to assume people will hate any drug that causes weight gain or sexual side effects, but patients report liking it.
Always ask about smoking. A patient who does not smoke on the inpatient unit and starts again after discharge can lose response, and no one knows why.
Olanzapine and samidorphan would rank above olanzapine, except that it is still on patent and extremely expensive, and you still get plenty of weight gain. The cost is not worth the benefit.
Its half-life varies between people. Our theory is that this is why some patients need it twice a day and some do not.
Risperidone is the Goldilocks antipsychotic: not too hot, not too cold, with one foot in both camps. That is why it is often the first antipsychotic chosen on inpatient algorithms.
Among second-generation antipsychotics it is the most prolactin-elevating, along with paliperidone, and the most likely to cause EPS, especially at 4 mg and above.
Keep a super low threshold for checking a prolactin level in these patients.
It is pretty decent for OCD augmentation, usually in a lower range of 2 to 3 mg.
Antipsychotics, especially clozapine and olanzapine, can worsen OCD or cause new-onset symptoms. With clozapine it is well documented and more common than we expected.
It sits in A tier with risperidone. It would be B tier otherwise, but it comes in so many forms and has so much utility.
With the three-month and six-month Invega LAIs, some people need the next dose a little early.
The liver puts a 9-hydroxy on risperidone to make paliperidone, so paliperidone is risperidone without the liver issues: it bypasses the liver and has significantly fewer drug-drug interactions.
Its schizoaffective approval has more to do with how companies go after FDA approvals. Do not think of it as a special niche, though it probably does work in schizoaffective disorder.
It is off-label for bipolar mania but has a good evidence base there. We used it all the time inpatient, especially the LAI, and saw it work really well.
Do not trust the Invega Sustenna label saying you do not need an oral bridge in the first month. The loading dose only gives a clinically significant amount of paliperidone in that first month, so you do need a bridge.
Give at least a one to two week bridge at three quarters of the oral dose, then drop it off slowly every two weeks.
Haloperidol's decanoate is one reason we love the drug: a pretty good long-acting injectable with a wide range of efficacy and doses.
We rank it B tier. We might have put it in A tier years ago, but after trying to use it a lot for its favorable side effect profile, it is simply not efficacious enough.
It is probably the number one augmenting agent for depression at a low dose: the most studied antipsychotic for MDD augmentation, added on top of another medication, with an evidence sweet spot of 2 to 5 mg. By itself it does not really help bipolar depression.
For a patient who skips several doses a week but still takes it several times a week, do not be afraid of a higher dose: if they were stable on 15 mg in the hospital, give 30 mg and they take it three or four times a week.
It has a three-day half-life. Steady state takes five half-lives, so about two weeks.
It can actually lower antipsychotic-induced prolactin, because even as a partial agonist it binds first, before the other antipsychotics.
Despite its reputation, we have all seen patients gain a ton of weight on it, and in our experience women are affected significantly worse than men. Do not tell a patient starting it that they will not gain weight because it is on the lower end: you will run into problems and they will not trust you.
We are more likely to dose it in the morning, because for a lot of patients stimulation outweighs sedation.
For psychosis or bipolar disorder, start around 15 mg and no lower than 10. Some people respond to less, but as a partial agonist it leaves about 20 percent of the dopamine receptors it binds unblocked.
Do not add it to another antipsychotic, especially haloperidol. It binds so tightly to the dopamine receptor that it counteracts the other drug, so adding low-dose aripiprazole takes antipsychotic away rather than adding more.
Brexpiprazole (Rexulti) is essentially aripiprazole, but harder to dose, in our opinion, because it comes in smaller milligram increments, and way more expensive.
It is aripiprazole with the volume turned down a little: it has a little less intrinsic activity.
We rank it B tier. Like aripiprazole, it is not very effective in the end for mania and psychosis, even if it seems to have a good effect on mood in some people.
It has two active metabolites, so it takes four to eight weeks at one dose to reach full steady state and maximum effect. It can look like it is not working if you simply start it at too low a dose.
Its D3 partial agonism might be helpful for negative symptoms.
In bipolar disorder, if we give an antipsychotic we want one that works for every phase, so we lean toward drugs with bipolar depression evidence. Cariprazine is one we think of for bipolar depression. It also has a really long half-life.
It has the highest risk of akathisia, but if it does not cause horrible akathisia, it is a great medication.
It is a no-go for anyone whose appetite fluctuates with their mood disorder or psychosis: they will intermittently decompensate whenever they start eating less dinner.
It 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.
Food, food, food, and dinnertime. It does not absorb without at least 350 calories, or the patient gets half the dose, and it seems better tolerated once at night. You do need to talk to patients about this.
It is metabolically pretty clean: minimal weight gain, minimal QTc prolongation and low prolactin. Along with ziprasidone, it is probably the best second-generation choice for avoiding weight gain.
It seems to cause less of the cognitive dulling we see with a lot of other antipsychotics.
Antipsychotics generally accepted in pregnancy include haloperidol, olanzapine and quetiapine.
C tier. Quite flattening, lots of dopamine blockade and not much help for mood, but not a bad choice. The QTc prolongation should not scare you: it is basically clinically insignificant.
You really need to take it with food: the main drawback is the 500 calorie absorption requirement, which not everyone can meet routinely. The antipsychotics that need food tend to end in "-done".
There are studies showing IM ziprasidone works for acute agitation, and some say it is underused there. It seems to calm the patient without flattening them.
The main effect of a PRN for agitation is the social component and the sedation, not the antipsychotic.
It is quite a good augmenting agent in schizophrenia spectrum and bipolar disorders for people who tolerate it. We will go up to about 90 mg, watching for sedation and orthostasis.
Adding buspirone to a D2 blocker builds a synthetic second-generation receptor profile. Push the dose and it is almost a second antipsychotic.
B tier, though its actual efficacy might even reach the A class, or at least sit somewhere between B and A.
It is the only sublingually absorbed antipsychotic we have. Orally dissolving tablets and films are not sublingual: they turn into liquid in the mouth and still have to be swallowed. If asenapine is swallowed, you get none of it.
It does not come in enough doses: the thinking was that there is one dose and it works, and life does not work that way.
It is basically an SRI combined with an antipsychotic. Very clever pharmacologically, but in our opinion it causes too much agitation and cycling in true bipolar patients.
Once it is off patent, we might reach for it for patients with schizoaffective disorder, depressive type, who only want to take one medication.
Iloperidone is the alpha-1 antipsychotic, with strong alpha-1 blockade and orthostatic hypotension.
Pimavanserin gets D tier: a niche drug for patients who cannot tolerate D2 blockade, with no full remission seen in psychosis from neurocognitive disorder.
A lot of people are trying it as a second antipsychotic because its mechanism is totally different. When it is tolerated, we do not see it making much of a dent, and when it does make a minor dent, it is completely intolerable.
It is a muscarinic agonist: xanomeline activates M1 and M4 receptors. Trospium is not there for the symptoms; it just blocks the peripheral muscarinic effects so that, in theory, there are fewer problems.
In schizophrenia spectrum disorders with any hint of mood problems on either pole, add a mood stabilizer (A tier): Depakote first for agitation and impulsivity, otherwise lithium. Do it probably even before a second antipsychotic.
It is genuinely an awful medication in terms of side effects, and you do not get much D2 blockade until higher doses, where the side effects are intolerable. Having been tested in children is no reason to be comfortable giving it to them.
We cannot recall keeping anyone on it as an outpatient, or any patient keeping themselves on it. It is just so poorly tolerated.
It hits the HAM receptors, so it brings histamine, alpha-1 and muscarinic problems. It counts as first generation because it also causes EPS, and it carries a high risk of tardive dyskinesia.
Schizophrenia has its own rate of movement disorders. Pre-antipsychotic studies show patients developing tardive dyskinesia anyway.
Second-generation drugs may seem to cause less TD for two reasons: we use them at lower doses, and patients have been on them for less time than first-generation drugs.
Loxapine is C tier: roughly 60 percent of clozapine's efficacy without blood draws, but with urinary incontinence and retention.
Fluphenazine is not really any better, and its long-acting injectable lasts only one to two weeks, so it is harder to dose and give than haloperidol's.
B tier, because we kind of think it should be used a little more: it is more atypical than you think.
Compared with haloperidol or fluphenazine, the high-potency first-generation drugs, you get less EPS and akathisia, though still a moderate EPS risk. It is a little cleaner metabolically with minimal weight gain, and surprisingly decent for negative symptoms.
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.