Talk:Clozapine/Archive 1

Archive 1

Edit made to source 11

I have edited the text relevant to source 11, as I think it to be misleading. Clozapine is thought to have a lower ETP side effect profile compared to other drugs of the same class, but there are newer 2nd generation APs that have a lower profile still. — Preceding unsigned comment added by 148.197.98.130 (talk) 13:16, 31 October 2015 (UTC)

"Awakenings" and Tardive dyskinesia

Why no mention of "awakenings" - when patients take the drug for a prolonged period and then suddenly wake up, no voices, no fog? See this: http://www.time.com/time/magazine/article/0,9171,975910-2,00.html

Being a dopamine-antagonist, shouldn't we mention Tardive dyskinesia as a risk? —Preceding unsigned comment added by 71.249.64.128 (talk) 04:44, 8 December 2007 (UTC)

Regarding TD, guess what's so special about clozapine as an antipsychotic? Hum? Yes, got it! It doesn't cause TDs. There are some case descriptions, but to my knowledge, no grave, irreversible tardive dyskinesiae were accounted to clozapine alone (some occured in patients treated by typical or other APs prior to or after clozapine); in fact, clozapine is commonly used to (co)treat tardive dyskinesiae.--84.163.111.84 (talk) 20:39, 17 May 2008 (UTC)

No critical analysis of Clozapine

In order to have a balanced article, critics' views of the drug are needed. This would provide more information regardless of personal view. —The preceding unsigned comment was added by 66.108.112.105 (talk) 04:02, 24 April 2007 (UTC).

Clozapine for insomnia

The article mentions off label use of clozapine for treating refractory insomnia. However, this seems a bit extreme given its risk of agranulocytosis as well as how closely this medication is regulated. In addition, there are multiple alternatives (benzodiazepenes, etc.) to clozapine for treating insomnia. Is anyone familiar with this type of use? Andrew73 14:16, 27 October 2005 (UTC)

I found this indication in the standard literature Benkert/Hippius (Springer Verlag). It should be noted that Clozapine is to be considered only for the treatment of severe insomnia that proved resistant to all other means of treatment (including benzodiazepines, cyclopyrones, L-Tryptophan, antidepressants, other antipsychotics, and psychotherapy). Clozapine is not in all countries subject to restriction. Klaus, 13 November 2005, 12:07

Technical description

I saw Clozapine referred to as "a tetracyclic dibenzodiazepine antipsychotic agent"; if I knew that that meant I'd try to add it to the article somehow. 128.113.144.115 00:30, 30 September 2006 (UTC)

Clozapine is exactly as not a tetracyclic as haloperidol is not a tricyclic. In order to define "polycyclicity", you have to count the (hetero)cycles, that are condensed; by this definition, clozapine is an (atypical) tricyclic antipsychotic, because it is a derivative of dibenzodiazepine, which in turn is a tricyclic structure.--Spiperon 15:57, 1 May 2007 (UTC)

Clozapine action on D1 dopamine receptor

Quote from the article Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics: "On the other hand, there is some evidence that clozapine behaves as a D1 agonist: hypothermia produced by clozapine in rats was fully antagonized by either of the selective D1 receptor antagonists SCH23390 or NNC 01–687 (41). This aspect could be interesting given the clinical and laboratory observations implicating D1 receptor agonism in the prefrontal cortex in cognitive functions (41, 42). Finally, regardless of its agonist/antagonist action, a recent [18F]fluorodeoxyglucose PET study in patients suffering from treatment-resistant schizophrenia showed that brain metabolic and clinical responses to clozapine were related to D1 receptor genotype (43). After 5 weeks of treatment with clozapine, brain metabolic decreases were found in patients with the 2,2 but not the 1,2 D1 receptor genotype. Moreover, patients with the 2,2 D1 genotype significantly improved with clozapine, whereas those with a 1,2 D1 genotype did not (43)."

This differential reaction of people with different types of D1 seemed interesting to me. --CopperKettle 13:03, 27 November 2006 (UTC)

First paragraph

I think it's misleading to say that it "was the first of the atypical antipsychotics to be developed" and then say "It was approved by the United States Food and Drug Administration (FDA) in 1989", as if it wasn't discovered/marketed until the 1980s. I think there should be some mention of its previous use, withdrawal, and reintroduction in the opening paragraph. --Galaxiaad 09:54, 16 February 2007 (UTC)

Genetic test to predict the risk of agranulocytosis

I think the information on the link between HLA DQB1 gene and agranulocytosis and some info about the recently introduced test could be added to the article.

The PGxPredict:CLOZAPINE test makes it possible to provide patients with specific information about their probability of developing agranulocytosis in response to clozapine.

--CopperKettle 11:43, 16 February 2007 (UTC)

Added the information; gave two references - to the company site and to the Forbes press-release; Found only one (PMID 11281944) PubMed paper linking HLA-DQB1 to the agranulocytosis risk, but abstained from adding it, cause this particular paper may be not related. --CopperKettle 02:58, 9 March 2007 (UTC) I've placed it into "Side effects" section, but it could be moved into "Monitoring"; I chose not to cause the test is not widely used as of now. --CopperKettle 09:41, 9 March 2007 (UTC)

Edited for junk

Removed the line "Treatment of But Rape" from the list of possible additional uses. Clearly junk.

24.113.82.222 01:34, 9 March 2007 (UTC)

Clozapine developement

Clozapine was not developed by Sandoz. In fact, it was created first in the late 1950s in laboratories of Wander AG, which was merged with Sandoz in 1967. The brand-mark Leponex (Europe) and Clozaril (US) were brought by the Sandoz in 1969-1971, I think.--84.163.106.158 20:59, 12 May 2007 (UTC)

Further, clozapine was not withdrawn in all lands after the drug-related death cases due to agranulocytosis in the early 1970s; in most countries, yes, but e.g. in Germany, it was soon re-introduced and in Czechoslovakia it wasn't withdrawn at all, the prescription was only restricted and strict therapeutic monitoring was made compulsory.--84.163.123.104 10:41, 13 May 2007 (UTC)

Dosage information

Would anyone object to removal of the dosage section? It is currently completely unreferenced and very prescriptive. Also, WP:MEDMOS specifically discourages the addition of such information to articles, as it is easily subject to vandalism and uninformed good-faith edits. Fvasconcellos (t·c) 02:09, 18 June 2007 (UTC)

Umm..normally yes but clozapine is a special case as it has a very strict commencement criteria as written here. I will try to get a ref. Another approach maybe to write "Due to risk of serious side effects, clozapine is commenced at a very low dose (25mg daily) and increased slowly until a therapeutic dose of 300-600 mg daily is reached" cheers, Casliber (talk · contribs) 13:34, 21 June 2007 (UTC)

That's perfectly fine by me, I've reworded accordingly and hopefully not detracted from the clarity of your draft. I'd still like this article to be very closely watched to prevent these figures being vandalized, though—would you like to help me on this one? :) Fvasconcellos (t·c) 00:01, 22 June 2007 (UTC)

P.S.: Text as it was for easy reference:

Start with 12.5 mg bedtime dose (6.25 mg in outpatients). The dose might then by increased cautiously by 25mg daily. The usual effective dose is 150 mg to 600 mg. In severely ill and/or younger patients up to 900 mg may be needed. In the elderly much lower doses may be sufficient (25 to 100 mg). The greater part or all of the daily dose may be given at bedtime, once maintenance dose has been determined, in order to minimize daytime sedation and orthostatic problems.

Yep added a bit -bd dosing sucks for long term compliance. All antispychotic effects are long term so bd dosing generally makes no sense once a person is stabilised. cheers, Casliber (talk · contribs) 02:18, 22 June 2007 (UTC)

Is it possible to give a reference and provide more details on the following: "In the elderly, much lower doses may be sufficient (25 to 100 mg)". My wife is only 38, she has been on 100 mg for 4 years. Currently she is on 75 mg and Clozaril still works for her. I am interested in studies on even lower dosage.

Citing the article

I didn't really wanna mess up the whole article with a bunch of cite needed tags, but I'll work on them this week -much easier to get refs at work. cheers, Casliber (talk · contribs) 14:51, 24 June 2007 (UTC)

Good luck :) The article's coming along very well. BTW, if you'd like to add to the history section, PMID 17580753 seems very interesting (I don't have access, though, so I can't speak to its accuracy). Fvasconcellos (t·c) 15:00, 24 June 2007 (UTC)

Thanks for the tip - will check that one at work.cheers, Casliber (talk · contribs) 15:09, 24 June 2007 (UTC)

One more article which may be interesting: PMID 11900316, free on Medscape. Fvasconcellos (t·c) 14:37, 2 July 2007 (UTC)

Some thoughts

For your consideration :)

• Might it be a good idea to separate agranulocytosis and cardiac side effects as subheadings of Adverse effects? That could help to keep things organized, e.g. keep the pharmacogenetic test bit together with the introduction on agranulocytosis, and perhaps expand a bit on cardiomyopathy/myocarditis?

agree. These are the two biggies.

• Goodman & Gilman's mentions ileus as a particular concern of clozapine use—worth mentioning?

? - never heard of or seen that one...maybe mention as a one off if at all.

• Mention possibility of relapse with abrupt withdrawal? (Unnecessary?)

Sort of unnecessary-self explanatory I'd have thought.

• I can't find a specific source for the sexual dysfunction paragraph with regard to clozapine in particular. Should it be commented out?

It is known and there should be a ref for it somewhere...

• As for cites, this nice article from MedSafe (NZ pharm regulatory authority) may provide some sources, at least for the Adverse effects section.

Brilliant. Was nosing round work and there were bugger all refs in all the cloazpine blurbs. Not gone online yet.

Best, Fvasconcellos (t·c) 02:21, 26 June 2007 (UTC)

Ditto cheers, Casliber (talk · contribs) 06:18, 26 June 2007 (UTC)

Argh Current Opinion - totally forgot about that mag -always a goodie for thistype of thing....cheers, Casliber (talk · contribs) 19:59, 2 July 2007 (UTC)

Access to Full CBC

Methinks this is not correct. The only two things that are measured and entered in the subject registry are WBC and ANC. (And ANC, if not measured, can be calculated from WBC and other data.) Source: firsthand experience. elpincha 12:50, 12 November 2007 (UTC)

What is ANC? neutrophil count? You are correct in that only white cells and neutrophils need be measured, for practical purposes this means a full blood count. Cheers, Casliber (talk · contribs) 21:47, 17 May 2008 (UTC)

ANC is the Absolute Neutrophil Count (bands+segs). — Preceding unsigned comment added by 198.49.6.225 (talk) 02:44, 1 June 2015 (UTC)

OK - game plan

Since last I looked at this, we now have two relatively recent medication articles Featured. Looking at sertraline, it seems prudent to make this one like that one.

• Given that wikipedia is not a 'how-to' manual, I have revised my opinion of a year ago WRT dosing section and monitoring. I think the monitoring material on CBC etc can go under/into Agranulocytosis subsection as the two are obviously intimately linked. Ditto material on when echocardiograms are done, under Cardiac toxicity. The note on gradual dosing and increasing slowly can go into adverse effects.

What do we think? Cheers, Casliber (talk · contribs) 13:40, 3 July 2008 (UTC)

We think it's an excellent idea. Fvasconcellos (t·c) 13:55, 3 July 2008 (UTC)

Ok then...hehehe Cheers, Casliber (talk · contribs) 13:57, 3 July 2008 (UTC)

Clozapine & Negative Symptoms of Schizophrenia

Wikipedia says very clearly in the third paragraph of this section:

Clozapine works well against positive (e.g. delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no dyscognitive effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation.

However, this article (Molecular Psychiatry (2007) 12, 904–922; doi:10.1038/sj.mp.4002062; published online 31 July 2007) says much to the contrary:

Whether clozapine has any significant beneficial effect on negative symptoms and cognition is unclear.

and

The documented superiority of clozapine over other antipsychotic drugs has led to an intense effort over the past 15–20 years to develop clozapine-like atypical antipsychotics that are safer and better tolerated than clozapine. As such, multiple atypical and pseudo-atypical antipsychotic drugs, including risperidone, olanzapine, quetiapine and ziprasidone have been developed. Expectations that these agents comprised a breakthrough in the treatment of schizophrenia, especially with regards to improvements in negative symptoms and cognition were initially high. These expectations, however, have not been realized. While there is evidence that most of the new medications offer, at best, modest advantages over the typical antipsychotic drugs with regard to improvement in negative symptoms, cognitive impairment and functional capacity, the improvements are not consistent among studies.

These sections indicate to me that Wikipedia is overstating clozapine's effectiveness in treating the negative symptoms of schizophrenia.

However, it is a possibility that the author is being overly pessimistic about clozapine's effectiveness for the sake of making the point that research on new drugs for treating schizophrenia still has a ways to go. Wallers (talk) 15:26, 19 February 2009 (UTC)

Yeah. Difficult area and opinions vary. In my experience most still favour the benefits case, but there are some conflicting reports (eg I recall somewhere the rate of unemployment is still unchanged from typicals (interesting given suposed benefit vs neg symptoms). At some stage I was going to give this a good going-over and collect all the review articles and consensus statements so we could get a more accurate position overall. Casliber (talk · contribs) 19:12, 19 February 2009 (UTC)

Several researchers (Javitt, Coyle.. ) proposed some time ago that Clozapine's action at NMDAr's glycine site could be partially linked to its unique profile. They tried to give high doses of glycine to patients; the preliminary results were encouraging, but the multicenter study showed no effect, sadly. --CopperKettle 19:29, 19 February 2009 (UTC)

anticholinergic antipsychotics

My brother has been on a antipsychotic medication [clozapine/Leponex (Clozaril in the US) and quetiapine/Seroquel] for many years. He has developed a serious urine retention problem which is a result of the weakening of the bladder muscle caused by the drugs. We therefore need to replace those drugs with others that have a comparably lower anti-cholinergic effect. I've read that Olanzapine/Zyprexa could be a solution. Is that accurate? What other drugs could help us avoid further bladder muscle damage? Many thanks

Sorry, we can't give medical advice here. He really needs to talk to his treating psychiatrist. Sorry, Casliber (talk · contribs) 22:17, 19 March 2009 (UTC)

Casliber, thank you for your msg. I wish his psychiatrist would help me on this. You see there is a general concensus that people with mental disorders are "expendable" and thus not worth worrying too much about. I am just asking if anyone knows, based on the information that the various drug manufacturers publish, whether Zyprexa (or some other drug) has got a comparably lower anticholinergic effect on the bladder. Again, thank you for your attention —Preceding unsigned comment added by 94.68.180.231 (talk) 07:44, 20 March 2009 (UTC)

i'm a practicing clinical pharmacist and worked in psychiatric pharmacy for years, too. this isn't medical advice, but drug information: lurasidone has the least effect on histamine (the prime culprit in eliciting anticholinergic effects among antipsychotics), but there are several factors that need to be weighed before choosing an option. iloperidone and haloperidol have less antihistaminic effects than do most other antipsychotics. olanzapine has relatively potent anticholinergic effects. your brother's psychiatrist should be able to work through options with him and hopefully, find some improvement.

Drugbox width

I noticed that the Drugbox is so wide that it interferes with the readability of the first few paragraphs at relatively common browser window widths. 66.11.179.30 (talk) 07:04, 6 December 2011 (UTC)

Clozapine drug safety program back in 1990's

It might be good to mention that Clozapine was one of the first drugs to have a real Drug Safety Program attached to it (the "no blood, no drug" mantra/program). This was WAY before the FDAAA of 2007, and the REMS programs of today. If anyone has a good grasp of this history, it would probably be good to add it to the History section of the article. --159.178.233.211 (talk) 17:04, 5 March 2012 (UTC)

Clozapine withdrawal from the market in the 1970s

Currently, the article states following:

"...In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.[55] Clozapine fell out of favor for more than a decade. ..."

This might be true for many countries around the wqorld, however not for Germany and Czechoslovakia, for example. After the reports of fataly ending agranulocytosis emerged, Sandoz reached an agreement with the german authorities (the IfA at BGA) allowing continued marketing of clozapine (Leponex Tablets and Injections) under stringent restrictions (i.e. regular WBC and frequent assesment of the patient by his psychiatrist, along keeping records for futher risk/benefit analysis) as the neuroleptic of the last resort in patients with refractory schizophrenia. Similar clinical programme was estabilished in the Czechoslovakia and possibly elsewhere (I only know for sure about Germany and the CSSR). These national programmes provided necessary risk assesment data for later re-registration, along with obligatory close pharmacovigilance. Think about it, if clozapine would be withdrawn in 1975 all over the world, there would be far too little clinical data for it to be re-registered pretty much everywhere around 1990; it would most likely become one of those obscure, early drugs with some interesting initial clinical experience but deemed too toxic for any kind of clinical use. Cheers,--149.172.140.151 (talk) 01:57, 18 June 2013 (UTC)

unreferenced material :(

I have removed a large accretion of unreferenced content. Continued vigilance will be necessary to prevent the article from degenerating again. DavidLeighEllis (talk) 18:23, 28 July 2013 (UTC)

Borderline Personality Disorder?

I am on this med for BPD. Apparently there have been positive studies in using it for BPD. Is there anything online that could be added? — Preceding unsigned comment added by 109.204.111.61 (talk) 16:11, 15 September 2014 (UTC)

I found this: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805385/ — Preceding unsigned comment added by 109.204.111.61 (talk) 22:33, 29 September 2014 (UTC)

Your link led me on to find this. I haven't read either, but reviews are generally better sources than individual papers. Keep WP:MEDRS and WP:SECONDARY in mind. Tomásdearg92 (talk) 23:36, 29 September 2014 (UTC)

3-D model of molecule

The 3-D (tinkertoy) model of the molecule has a minor error -- the structural drawing is correct. In the 3-D model, in the seven-member ring, the double-bonded nitrogen has a hydrogen attached (which it shouldn't), and the single-bonded nitrogen has no hydrogen, but should. 121.99.52.172 (talk) 23:35, 17 October 2014 (UTC)Phil Petit

It does appear to be wrong, so I have removed it. Thanks for catching the error and reporting it here. -- Ed (Edgar181) 11:53, 18 October 2014 (UTC)