Olanzapine is perhaps the most effective antipsychotic in our experience, and patients actually like it, but with clozapine it is one of the two worst for weight gain and metabolic risk. Dose it earlier in the evening, go low for milder cases, ask about smoking, and watch for new or worse OCD.
When we reach for it
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.
“It is perhaps the most effective antipsychotic out of all of these in all of my experiences. And don't be afraid, like Haldol, to dose it lower for milder cases. It comes in a 2.5”
22:01Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 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.
“patients actually really like olanzapine. I know a lot of times we think of all medications that cause weight gain or have sexual side effects as like patients are going to hate it. Patients do report liking it”
23:50Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 Not for sleep alone. Use it for sleep when the sleep problem comes with schizophrenia or schizoaffective disorder, or with refractory bipolar I after the mood stabilizers are exhausted.
“If someone is having sleep problems together with the schizophrenia or schizoaffective disorder, go ahead and use them. If someone is having them together with a refractory bipolar one and you've already exhausted the mood stabilizers, go ahead and use them”
59:23Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026
Dosing and titration
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.
“The time to peak for most of the antipsychotics is two to three hours. For olanzapine, six to eight hours. So for many people, it's better to try taking this earlier in the evening”
22:21Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 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.
“I've also had the off guy who comes in on 40 of olanzapine and I'm like, that's a lot of olanzapine. Let's see if we can go down a little bit. And I move it down five milligrams to 35 and then he decompensates”
22:57Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026
Side effects and safety
Clozapine and olanzapine are probably the two worst drugs we have for metabolic risk and weight gain, more so in non-white patients. It is very reasonable to start metformin from day one.
“clozapine and olanzapine are probably the two worst drugs we have in regards to metabolic risk in terms of weight gain. It's more significant in non-white patients. It's very reasonable to start metformin from day one”
30:03Top 10 Things to Know About ClozapineDec 2025 The pines, clozapine and olanzapine, can worsen OCD or cause new-onset OCD symptoms, and more often than you would expect.
“some of the antipsychotics can actually worsen OCD. I think clozapine and olanzapine are the most likely”
30:03Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 Also said in 1 more episode
“antipsychotics, especially the pines. So I'm talking about like clozapine, olanzapine, can exacerbate or cause new onset OCD symptoms. And I looked it up. It's much higher than I expected”
23:21Practical OCD Psychopharmacology: Evidence‑Based (& Non Evidence-Based) Medication ApproachAug 2025 It is one of the antipsychotics generally accepted in pregnancy, along with haloperidol and quetiapine.
“there's at least one study showing relative safety in pregnancy. So that's a nice thing to have with trazodone. While we're on it, I believe other ones that are generally accepted in pregnancy that you can see here on the board include Haldol, Olanzapine, and Quetiapine”
47:56Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026
Drug interactions
Smoking induces CYP1A2 and lowers olanzapine and clozapine levels. A patient who did not smoke inpatient goes home, starts again, and suddenly the medication is not working as well. Always ask about cigarettes.
“Any CYP1A2 substrates, smoking, burning leaf has the potential to induce CYP1A2. So it will decrease the levels of olanzapine and clozapine. Important to consider, patient goes inpatient, isn't smoking, then they go outpatient and all of a sudden the medication is not working as much. Always ask if they're smoking cigarettes”
24:51Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026
Compared with others
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.
“And I would put it above olanzapine, except for the fact that it is still on patent, extremely expensive. And I don't think the cost is worth the benefit because you still get plenty of weight gain on this one”
26:17Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026
It also comes up on
- AntipsychoticsThe pines (olanzapine, clozapine, quetiapine) are by far the most metabolic. The dones vary, with risperidone in the middle.
- Metabolic side effectsThe pines (olanzapine, clozapine, quetiapine) are by far the most metabolic medications we have. The dones vary more, with risperidone in the middle.
- AkathisiaThe same doctors who say never prescribe benztropine will give olanzapine and quetiapine without blinking, and those are already anticholinergic.
- AnticholinergicsThe same doctors who say never prescribe benztropine will give olanzapine and quetiapine without blinking, and those are already anticholinergic.
- BenztropineThe same doctors who say never prescribe benztropine will give olanzapine and quetiapine without blinking, and those are already anticholinergic.
- SSRIsPopulation numbers cannot tell weight gain caused directly by the drug from weight gain as a consequence of treatment. In one analysis, accounting for unhealthy eating made the SSRI weight signal mostly disappear, which is not true for heavy gainers like olanzapine.
- Weight gainIn one SSRI analysis, the weight signal mostly disappeared after accounting for unhealthy eating. That is not true of heavy gainers like olanzapine.
From these episodes
- Antipsychotic Tier List: Ranking the Best and Worst Anti-psychoticsOct 2026 · 8 points
- Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 · 1 point
- Top 10 Things to Know About ClozapineDec 2025 · 1 point
- Practical OCD Psychopharmacology: Evidence‑Based (& Non Evidence-Based) Medication ApproachAug 2025 · 1 point
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.