Science topic

Clozapine - Science topic

A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.
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While there are a few papers that use freebase Clozapine, it doesn't seem like there are any that have used the water soluble version yet. If anyone has used it successfully in rats, what dose did you use? Thanks so much!
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This Nature paper by Tan et al describes the use of clozapine dihydrochloride in vivo:
Hope this helps!
Sam
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Trace amine associated receptor agonists are going to be a good choice in the pharmacological management of Schizophrenia. There will be less side effects and better efficacy. Will these group of medicines completely replace other antipsychotics, including clozapine, in the market?
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Hi,
Schizophrenia is such a complex disorder with Neurodevelopment etiology mostly holding fort.TAAR1 agonists have to be compared with existing antipsychotics and then we can examine the evidence. Initial interest needs to be sustained
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Hi all
We are planning to use DREADD mice (hM4Di) to chronically suppress (2-6 weeks) the proprioceptive system at the level of the spinal cord and peripheral nerves, then look for our phenotype.
I would like advice regarding the ligand administration method and the type of ligand-
As I understand it, most relevant administration methods in the literature include:
1. Daily intraperitoneal injections (once a day, twice a day, more?)
2. Daily subcutaneous injections (once a day, twice a day, more?)
3. Continuous water administration
Regarding the ligand type- I understood CNO has a short half-life in its water soluble form, also it back metabolizes to clozapine, I did not find any relevant publications which used Compound 21 or Perlapine dihydrochloride or publication on any unwanted effects.
Does anyone have thoughts, recommendations or advice on the ligand type and administration methods?
With kind regards,
Eldad
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Great!
Thank you Samantha Roome , I will look into it.
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Client is a 54 years old with a bachelor degree on physics, but for him is to difficult to accept his mental condition. He attributes high value of what his voices tell him. He is able to cope with his voices. He is maintain himself functional and sociable. He is on Clozaril.
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This is a great question and also has relevance for delusions. If the patient is capable of some reality testing, you might point out that under various circumstances, virtually anyone can experience psychotic symptoms ( high fever, ingestions, temporal lobe epilepsy , etc) and that as Dr Nardi points out, these phenomena are "real" in that there is a process going on in the brain that is triggering this and it can seem very real or true. This matter-of-fact approach tends to lessen shame and may make the patient more open to questioning the psychotic symptoms.
With regard to delusions, the convention wisdom of my training was that they are unshakeable beliefs that are immune to logic. However, there is now a literature on using CBT techniques to challenge unrealistic ideas. The same techniques might be applied to voices , eg pointing out that voices of nurses making negative comments about them in the hallway was not likely to be real for a variety of reasons.
Of course, patients are more likely to listen to your counter-arguments if they have begun to experience effects from antipsychotic meds...
Michael Casher
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We are currently doing a study that assesses the knowledge, attitudes, and behaviors of psychiatrists in the MENA region towards Clozapine prescription.
What do you think about Clozapine in terms of medication? What is its current state in your country of practice?
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Thank you Rodolfo for the insightful feedback. Samer
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does anyone have experience with using clozapine-n-oxide dihydrochloride instead of clozapine n-oxide (IP) to activates DREADDs in mice?
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it should work just as well. We are moving towards using the new ultrapotent ligand "J60 - hydrochloride" which does not need to be metabolized into clozapine to work.
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i am to develop a procedure to run risperidone analysis to determine plasma concentration. i choose clozapine as internal standard. but i cant find clozapine. therefore i here ask as if i can use different IS that used in different detector (LC-MS-MS). does the detector matters the choice of IS?
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intrested
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Should clozapine be stopped if eosinophil count goes up and if clozapine is continued what are the likely adverse outcomes?
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Good morning,
I am thinking of doing my masters thesis on assessing the knowledge and attitude of nurses on clozapine medication. I am looking for preparing a questionnaire to assess the knowledge and attitude and I am looking for advice how to prepare this questionnaire or any related questionnaire available already?
thanking you in advance.
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If you are looking at knowledge on issues such as side effects you should review side effect assessments such as LUNSERS and I guess that this should also highlight issues around nursing responsibility to monitor patients receiving Clozapine. You should also check out the pharmaceutical requirements using something like the Electronic Medicines Compendium website, and best practice recommendations on antipsychotic medicines from organisations such as NICE.
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I am observing significant behavioral effects of expressing DIO Gq DREADD-mCherry when compared to control DIO mCherry, under baseline conditions without administering CNO or clozapine. I observe this with a transgenic Cre-expressing line as well as retrograde Cre-mediated DREADD expression. Does anyone have a similar experience or could point me toward relevant literature?
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Mary, this review goes into detail about constitutive activity of GPCRs, and how this could be present in DREADDs. This review was published before the Saloman et al reference and was predicting that we are bound to see ligand-independent effects of DREADDs.
One of the things they suggest to avoid constitutive activity is to lower the expression. That being said, I think information on the constitutive activity of Gq DREADD would be useful on its own.
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1. Is there a need to monitor blood levels of clozapine and it's metabolite when the doses are low and no serious adverse effects are occurring?
2. If there are consensus guidelines on TDM for clozapine I cannot find them. Please point me in the right direction.
Thanks
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A review of the clinical utility of serum clozapine and norclozapine levels
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In real clinical practice some patients are treated with combination of clozapine and another depot antipsychotic. Although we have a positive evidence of clozapine combination with some antipsychotics, clozapine should not be combined with depot antipsychotics, because of several adverse events, which can not be discontinued very easy in patients treated with depot. In clinical practice we often have problem that we have positive symptoms (residual) with only clozapine and therefore combinations could be used. In my point of view many combinations should be used first (e.g. combination with lamotrigine, combination with another antipsychotic non-depot, combination with N-acetylcysteine) before this potentially risky combination.
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Before combining with other antipsychotics, it might be helpful to control serum levels, because particularly in clozapine, non-compliance or only partial compliance is a frequent cause of treatment resistance.
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Hypotension and tachycardia are known adverse reactions to clozapine administration in treatment-resistant schizophrenia. Are there known cases where hypertension has also resulted especially in newly-diagnosed patients?
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To Beatrice and Ali, thank you so much for your help.
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Recently I learned of the potent CYP1A2 induction effects of proton-pump inhibitors (ie. omeprazole etc). These medications can significantly reduce olanzapine and clozapine concentrations. Which medications are we overlooking when it comes to CYP1A2 induction?
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Here are some drugs that induce CYP450 1A2: and that can reduce the AUC of olanzapine. The ratio of the AUC olanzapine alone and in the presence of these inductors(AUC*) is as follows :
1-Ritonavir (200-400mg/d) : AUC*/AUC = 0.89
2-Ritonavir (600-800 mg/d) : AUC*/AUC = 0.56
3-Darunavir: AUC*/AUC = 0.89
4-Lopinavir:AUC*/AUC = 0.84
5-Rifampicine (450-600 mg/d): AUC*/AUC = 0.66
6-and also Tobacco (10-20/d ) is an inducer of CYP 450 1A : AUC*/AUC = 0.78
NB: in the absence of an inducer the ratio is equal to 1.
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There are some reports about clozapine that clinical response is dependent on rise in the triglyceride levels. 
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Krishna (How are you going by the way?)
I had a quick look at our database - no evidence that fixing people's TGs changes their apparent response to orexigenic antipsychotics. If anything (remembering we use a multidimensional outcome scale) there are improvements in some dimensions probably relating to the enhancements that follow from exercise regimens. In those with severe triglyceridaemia (>8) where we would be in the statin± fenofibrate± (real) fish-oil and dancing-on-one-leg field of play, we have too few numbers to comment on changes in outcome dimensions but as these patients tend to stick in your mind, I don' t feel there were any indicators that loss of 'effectiveness' followed control of dyslipidaemia.
Tim LAmbert
Collaborative CENTRE FOR CARDIOMETABOLIC HEALTH IN PSYCHOSIS
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People with intellectual disabilities at higher risk of developing psychosis and their symptoms can be resistant to treatment. Clozapine is recommended for treatment resistant psychosis. If you have treated anyone with dual diagnosis of intellectual disabilities and psychosis please share your experience.
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Thank you Béatrice Marianne Ewalds-Kvist and Lewis Alan Opler.
Muhammad
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Psychiatric patients usually take many different medications and often they have been already treated with beta-blockers. However, there are several cases in where You should add beta-blockers, because of newly recognized heart failure or even atrial fibrillation. Often psychiatric patients take medications, which included antipsychotics or even worse an antipsychotic polypharmacy or combinations with antidepressants. According to the survival studies We know that treatment with beta-blockers in patients with stable heart failure (EF less than 35 %) is necessary for better surviving.
The third group of cases consists the consequences of psychotropic medications adverse events (e. g. arrhythmias and clozapine or olanzapine) or prolonged QTc and supraventricular arrhythmias (e. g. amisulpride with clozapine combination or ziprasidone use and escitalopram together). In these cases a trial with beta blockers is usually a first step before drug discontinuation.
From EBM we know that combination of clozapine and amisulpride is benefitial in short term trials, however long term use should lead to several complications in this field.
To sum up, DDIs with psychotropics and beta-blockers should be calculated before prescribing beta-blockers. For example, atenolol is not appropriate with several antipsychotics and antidepressants (QTc prolongation). Also story with metoprolol is more or less the same, however metoprolol is very selective for B1 receptors, however there are cases of induced delirium with propranolol. Smart use included pindolol, especially in patients on antidepressants, because of add on efficacy, however we do not have long term trials.  At the end I think cooperation between clinical pharmacist and psychiatrist and cardiologist is the best approach to deal with these patients.
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I prescribe Inderal (propranolol) in consultation with internists/cardiologists for treatment of lithium tremor and occasionally performance anxiety. Others (e.g., Yudosky and Silver) have published extensively on using high dose propranolol for rage attacks in persons with TBI.  Other than that, I do not prescribe beta blockers.
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Antipsychotic polypharmacy refers to the co-prescription of more than one antipsychotic drug for an individual patient. According to the many studies consumption of clozapine in patients with chronic schizophrenia is still low (about 25 %) and antipsychotic polypharmacy prevalence before clozapine use is very high, although the evidence usually does not support its use. How to manage patients with chronic schizophrenia with higher clozapine consumption?
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Hi Matec,
Polypharmacy in psychosis is ill-adviced. It is associated with high rates of morbidity and increase in mortality. Clozapine mono therapy should probably be used more often. Also, note a recent study on the American Journal of Psychiatry by Petrifies et al. regarding the concurrent use of clozapine and electroconvulsive therapy for clozapine-resistant schizophrenia where excellent results were found (Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, Kane JM,
Sanghani S, Goldberg TE, John M, Mendelowitz A. Electroconvulsive therapy
augmentation in clozapine-resistant schizophrenia: a prospective, randomized
study. Am J Psychiatry. 2015 Jan;172(1):52-8. doi:
10.1176/appi.ajp.2014.13060787. Epub 2014 Oct 31. PubMed PMID: 25157964)
Best regards,
Fidel
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Sialorrhea is the fancy term for hypersalivation.
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Yes, It does not cross the blood–brain barrier and consequently has no to few central effects as Trospium chloride. We do not have glycopyrrolate in most European countries and Butylscopolamine is very similar. Trospium chloride is not ideal because it can produce delirium and hallucinations (effect because of croossing of BB barrier).
Yes i also think mirtazapine is much better than TCAs. No important interactions with clozapine in normal dose and minimum probability of serious adverse events (careful on weight gain). 
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The patient has responded to several APs regarding positive features but the negative features are quite treatment resistant to risperidone, olanzapine, amisulpride, ziprasidone, and aripiprazole.  Thanks.
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Consider to add mirtazapine as a coadjuvant therapy for antipsychotic treatment (e.g., aripiprazole). There is several clinical trials supporting the usefulness of mirtazapine for treating negative symptomatology when a given antipsychotic alone is unable to do it. See for instance: 
- Caforio et al. Mirtazapine add-on improves olanzapine effect on negative symptoms of schizophrenia. J Clin Psychopharmacol. 2013 Dec;33(6):810-2.
- Terevnikov et al. Add-on mirtazapine improves depressive symptoms in schizophrenia: a double-blind randomized placebo-controlled study with an open-label extension phase. Hum Psychopharmacol. 2011 Apr;26(3):188-93.
- Stenberg et al. More evidence on proneurocognitive effects of add-on mirtazapine in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):1080-6.
- Cho et al. Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: a randomized controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):208-11.
- Terevnikov et al. More evidence on additive antipsychotic effect of adjunctive mirtazapine in schizophrenia: an extension phase of a randomized controlled trial. Hum Psychopharmacol. 2010 Aug;25(6):431-8.
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A patient suffering from psychotic disorder treated with low dose clozapine (150mg/day) experienced a very high, asymptomatic raises of serum CPK (up to 40 000). No symptoms of neuroleptic malignant syndrome. Any suggestions?
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Thanks for the paper abstract. That is really interesting. And quite possible with our patient :-) He is a devoted user of a stationary bike.
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Does anyone use PANSS as an assessment before augmenting and do you look at the overall total score or separate the scores for negative and positive symptoms? If you separate the scores what are the minimum and maximum you are looking for before augmenting?
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Another way to use the PANSS - it can be used to MEASURE SYMPTOMS OF REMISSION in clinical as well as research settings by using 8 items as recommended by Andreasen et al (2006) - in this landmark paper Andreasen et al spell out how to operationalize remission utilizing either the PANSS or the SANS-SAPS or the BPRS: Mark G Opler and colleagues at ProPhase have developed a scale and interview for reliably assessing the 8 PANSS items and validation studies are both published and in process and planned