Clozapine dosing

[SpinDktr]

I was just curious on how others are dosing clozapine. It has a pretty wide ranging half life, smoking can affect it, all kinds of other variables, etc. I know prescription recommendations are to dose bid, but I almost never do this. My own practice has been to start at bedtime and titrate upward only at bedtime. Rarely, if they are struggling with daytime psychosis I'll add a smaller dose in the mornings, but usually only 25 or 50 mg, with the bulk being at bedtime. When I've tried to dose twice a day, it usually is either too sedating or no more effective than once at bedtime.

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[deleted1100659]

I dose in BID due to side effects with bigger dose at night due to sedation. I worry about people getting very orthostatic and having falls with one big consolidated dose. Also i get concerned with seizures. Typically I do a 14 day titration period to get to a therapeutic dose and draw levels. I also get baseline labs such as ESR, troponin, CRP, fasting lipids, a1c, CBC w/ diff, CMP. EKG if possible as well, generally preferred. In my experience people generally tolerate BID dosing a bit better in terms of side effects, I don't want them over sedated during the day or having falls. Some people can get away with 150mg but generally more towards the 300mg as far as total dose.

Just my experience thus far.

 

[Merovinge]

Agree with BID dosing for reasons above. Peak serum levels are correlated with side-effects which can clearly be severe in clozapine. That said, don't shy away from clozapine, it remains the top agent in adult and child/adolescent schizophrenia.

 

[SpinDktr]

Interesting, thanks for that. I don't shy away from using Clozapine at all; I think in my residency there were a few attendings who pushed it, but they always dosed only at bedtime, so I've incorporated that into my own practice.

 

[hallowmann]

BID dosing. I will start similarly to what you described, low doses at bedtime, but usually will add a low daytime dose once I get past 100/150 mg at bedtime. The AM dose is always smaller than the evening dose. Titrate based on response, side effects, and levels. I don't think I've ever actually dosed as BID with two equivalent doses.

 

[Stagg737]

I'm similar to Hallowman, though I've always just done QHS dosing until around 200mg, then start adding 50mg increments in a somewhat alternating fashion unless there are side effects or other issues. Patients usually end up on 1:3 ratios of qam to qpm or something like that. I've found that doing BID dosing from the start often results in over-sedation during the day unless the patient was extremely agitated.

 

[clozareal]

I approach it similarly to Hallowman and Stagg737, but start the daytime dose a bit earlier. Half-life would suggest twice daily administration but I feel like most psychiatrists give it once at night when they reach maintenance.

 

[clausewitz2]

I approach it similarly to Hallowman and Stagg737, but start the daytime dose a bit earlier. Half-life would suggest twice daily administration but I feel like most psychiatrists give it once at night when they reach maintenance.

I think it depends on whether your implicit theory of the action of the medication for a particular patient is a function of the serum level primarily or driven mainly by downstream changes operating over longer time courses.

 

[J ROD]

I do not use it often due to all the required monitoring but I generally go 200 at bedtime, then work a daytime dose. and work towards that 1-3 model.

 

[robellis]

I think it depends on whether your implicit theory of the action of the medication for a particular patient is a function of the serum level primarily or driven mainly by downstream changes operating over longer time courses.

I mean even if it was down stream changes what does that mean exactly in terms of how often the receptors need to be occupied, does one dose cause downstream changes? Do we need 2 times a week dosing? 2 times a day? Does the receptor need to be occupied 24/7? Who knows

 

[Animal Mother]

I think once daily dosing is fine. Several RCTs have shown no difference in outcomes between once vs twice daily dosing of various antipsychotics, regardless of their supposed half-lives. I usually dose clozapine all at night. Making things simpler helps improve compliance. Not sure of a good argument against it.

 

[clozareal]

I think once daily dosing is fine. Several RCTs have shown no difference in outcomes between once vs twice daily dosing of various antipsychotics, regardless of their supposed half-lives. I usually dose clozapine all at night. Making things simpler helps improve compliance. Not sure of a good argument against it.

The CATIE looked at several different dosing strategies for antipsychotics and most concluded that once a day was better tolerated, had lower doses, and were re-hospitalized less for schizophrenia. The one I see most commonly used BID where once daily is the same and tends to be at lower doses when hitting max efficacy is risperidone.

this study tries to argue for divided dosing for clozapine but isn't a clinical trial:

Clozapine administered once versus twice daily: does it make a difference? - PubMed

Clozapine, generally considered to be the most effective antipsychotic, is the gold standard for treatment-resistant schizophrenia. With a relatively short half-life of 12h and a very quick dissociation rate from the dopamine D2 receptor, pharmacokinetic and pharmacodynamics principles would...

pubmed.ncbi.nlm.nih.gov

The product monographs recommends that clozapine be administered more than once daily if the dose exceeds 200 mg/day in Canada.

Whereas this cross-sectional study looked at patterns of once vs twice daily dosing:

Clozapine administration in clinical practice: once-daily versus divided dosing - PubMed

Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

pubmed.ncbi.nlm.nih.gov

There's one clinical trial that was trying to look at this in a double-blind RCT. Not sure what the status of that study is though.

 

[J ROD]

The CATIE looked at several different dosing strategies for antipsychotics and most concluded that once a day was better tolerated, had lower doses, and were re-hospitalized less for schizophrenia. The one I see most commonly used BID where once daily is the same and tends to be at lower doses when hitting max efficacy is risperidone.

this study tries to argue for divided dosing for clozapine but isn't a clinical trial:

Clozapine administered once versus twice daily: does it make a difference? - PubMed

Clozapine, generally considered to be the most effective antipsychotic, is the gold standard for treatment-resistant schizophrenia. With a relatively short half-life of 12h and a very quick dissociation rate from the dopamine D2 receptor, pharmacokinetic and pharmacodynamics principles would...

pubmed.ncbi.nlm.nih.gov

The product monographs recommends that clozapine be administered more than once daily if the dose exceeds 200 mg/day in Canada.

Whereas this cross-sectional study looked at patterns of once vs twice daily dosing:

Clozapine administration in clinical practice: once-daily versus divided dosing - PubMed

Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

pubmed.ncbi.nlm.nih.gov

There's one clinical trial that was trying to look at this in a double-blind RCT. Not sure what the status of that study is though.

getting all scientific! lol

 

[Dr.MONO]

I like to dose Clozapine once at night. I started it BID but then gradually switch to once QHS dosing. Clozapine is a strong sedative and patients do not like feeling that groggy in the daytime

 

[Evidence Based]

This is an interesting conversation, I usually default to dosing once at night for the reasons mentioned above (adherence). For clozapine especially, peak efficacy seem to be reached after about 6 months, which argues more for downstream effects of the medication vs needing to hit some sort of peak concentration for efficacy.
One thing I haven't seen mentioned is the role of serum monitoring- our clozapine clinic targets a trough level of 350 if patient tolerates rather than a specific dose per se.
My overall thinking is that clozapine is massively underutilized, has the potentially to truly change patient's lives, and whatever we can do to make it more accessible to patients we should be doing (which I would argue once daily dosing is given the known drop offs across drug classes in adherence once you hit BID or greater dosing). The monitoring is a pain (don't get me started on the clinical utility of monthly ANC monitoring forever in a patient w/ no history of neutropenia), but patients who have failed 2 antipsychotics deserve a clozapine trial given the large upside.

 

[deleted1100659]

Speaking of the monitoring I know were going to the new REMS system but I was confused when I was reading about it, will we still be able to report ANC on the website or will we have to do it only via the form? It was worded in a confusing way when i read it.

 

[Old&InTheWay]

How quickly are you all uptitrating? (As in, milligram increase per how many days)

 

[deleted1100659]

around 25mg increments generally

 

[robellis]

25-50 per day

 

[SpinDktr]

Speaking of the monitoring I know were going to the new REMS system but I was confused when I was reading about it, will we still be able to report ANC on the website or will we have to do it only via the form? It was worded in a confusing way when i read it.

I was confused as well, so called them up. For now, we are supposed to update ANC's on the old website. When the new site is fully updated on November 15th, then we can update ANC's there.

 

[NickNaylor]

I use clozapine not infrequently and will typically try to dose as much as possible at bedtime and avoid BID dosing, if possible. Morning dosing can contribute substantially to daytime somnolence, which can be a problem for some folks. I find that people tend to have trouble with all bedtime dosing once you start to get to 200-300 mg. For patients with significant anxiety/agitation during the day, a smaller dose in the morning may not be a bad idea.

I titrate by 25 mg/day.