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

Hi Fidel,

I support your trials, which you were attached, however i am interesting in medication combinations (e. g. two or more antipsychotics together).

Anyway, it was very helpful also for me.

Regards,

Matej

This may be of interest to those who wish to decrease irrational polypharmacy (NB: there are times when combining two or more antipsychotics may be rational--but most of the time it is a layering on of meds in treatment refractory patients who would do better with clozapine and/or clozapine + ECT):

Psychiatr Serv. 2011 Oct;62(10):1124-6. doi: 10.1176/appi.ps.62.10.1124.

Long-term impact of web-based tools, leadership feedback, and policies on inpatient antipsychotic polypharmacy.

Finnerty MT1, Kealey E, Leckman-Westin E, Gupta N, White TM, Engel GM, Opler LA.

Abstract

This column describes a series of interventions to decrease antipsychotic polypharmacy in the New York State Office of Mental Health (NYSOMH) network of psychiatric hospitals. Phase 1 consisted of implementation of the Psychiatric Services Clinical Knowledge Enhancement System (PSYCKES), a Web-based application supporting clinical decision making and quality improvement, and a policy requiring approval by NYSOMH's medical director to prescribe more than two antipsychotics per patient. In phase 2 hospital leaders received feedback from the office of the medical director identifying specific patients on polypharmacy. In phase 3, access to PSYCKES continued, but the prior-approval policy and feedback were discontinued. Polypharmacy decreased significantly during phase 1, from 16.9 to 9.7 inpatients per 1,000, and decreased further in phase 2, to 3.9 inpatients per 1,000. In phase 3 the prevalence of antipsychotic polypharmacy remained low at six-month follow-up (3.1 inpatients per 1,000), despite the ending of state-level oversight. On long-term follow-up, polypharmacy increased, eventually rising to 9.2 inpatients per 1,000 after 36 months, but remained well below baseline levels.

Treating patients with comorbid psychosis and OCD is complex! Sometimes adding aripiprazole, which is not a SDA (serotonin-dopamine antagonist) to clozapine is helpful

The use of clozapine for treatment resistant schizophrenia is quite a challenge in developing countries like Nigeria because of the need for periodic full blood count to prevent idiosyncratic agranulocytosis for the following reasons: patients with chronic schizophrenia usually belong to the low socioeconomic class, with few relations still willing to provide social support. This added to the out of pocket financing of mental health care and absolute absence of social welfare in Nigeria makes clozapine use challenging. This however does not imply we should be practicing poly pharmacy that lacks evidence base

In 1975, the Peoples' Republic of China began using clozapine as a first line drug: weekly blood draws were not required, but patients were monitored closely and if they developed any sign of infection such as sore throat, they were immediately checked for neutropenia/agranulocytosis. When I visited China in 2002, psychiatrists were puzzled re: the low utilization of clozapine + told me that deaths from agranulocytosis were extremely rare due to close monitoring.

I am not saying they were right (they have now become more like the rest of the world re:clozapine) or that they were wrong: but I am not at all convinced that the barriers that have been put up to prescribing clozapine are necessary, particularly since we have had granulocyte colony stimulating factor (GCSF; Neutropenia)  for many years--oncologists do not hesitate to prescribe anticancer drugs that sometimes lower neutrophil count and then to treat this with GCSF if necessary.

Physicians make risk/benefit decisions daily: the monitoring system for clozapine is unique.

Clozapine, like other antipsychotics, reduce seizure threshold and should be avoided in not just patients with seizure disorder but in patients having transient sharp and slow or spike and wave paroxysms. Routine EEGs should be considered after a medication failure or adverse reaction. It is very important to identify the reason for medication failure in complex refractory case. Swatzyna, Kozlowski, and Tarnow, 2014. "Pharmaco-EEG: A study of individualized medicine in clinical practice." Clinical EEG and Neuroscience, 1-5.

There may be a role for clozapine augmentation by pimavanserin....in case you don't recognize the name, that's because it is not yet FDA approved; but it is being fast tracked as its indication is "parkinson's disease psychosis" 

At the moment there are only few treatment strategy, where addition of second antipsychotic is benefitial in compare with monotherapy (e. g. aripiprazole, amisulpiride to clozapine). Those treatment have been proven in short term trial and therefore long term use is under question (e. g. QTc interval with amisulpiride augmentation) and psychoses (induced by addition of aripiprazol). Otherwise We have evidence that combination is not benefitial in many case (e. g. risperidone augmentation with clozapine (N Engl J Med. 2006 Feb 2;354(5):472-82.). According to the some reviews and trials, more than 1/3 of total patients who received antipsychotics also received its polypharmacy, which is scarce. My opinion is that in many institutions there are almost no talk about antipsychotic polypharmacy, which is non-stimulant for patients and care system. My opinion is that this is one of the most important security system in term of appropriate prescribing (how to reduce polypharmacy, which is not written according to the guidelines and EBM). When this topic is under question, wee-teached clinical pharmacist from psychiatry can be helpful (J Manag Care Pharm. 2010;16(6):393-401).

Yeah, indeed, you have raised a very pertinent issue in managing schizophrenia patients. Many authors have reviewed the literature regarding the practice of polypharmacy and have generally concluded that except in cases where an individual has failed to respond to adequate trial of monotherapies including clozapine, antipsychotic polypharmacy has little support in the medical literature. The increased risk of sudden cardiac death has long been associated with typical antipsychotics; however, a recent study ( Ray W et al, NEJM, 2009) has confirmed that this increased risk is also seen with atypical drugs. Interestingly, the risk of death increased with increasing dose of antipsychotic (whether typical or atypical). 

A frequent treatment strategy for clozapine-resistant patients with schizophrenia is the use of specific augmentors that are suitable for adjunctive therapy. Clozapine is a polyvalent drug but it lacks high-potency dopamine receptor blockade. Therefore, there has been interest in using as augmentors like substituted benzamides with highly selective dopamine receptor blocking profiles (Kerwin, 2000). Augmentation strategies incorporating sulpiride are well documented. Several groups have been interested in mimicking this study with amisulpride, a relative of sulpiride that is even more selective at the dopamine D2 receptor. A case series by Zink et al (2004) showed improvement in previously treatment-resistant symptoms following a combined treatment strategy of clozapine and amisulpride.

However, from the results of four RCTs, Paton et al. suggested that augmentation of clozapine with another antipsychotic cannot be recommended. After reviewing 19 RCTs, Correll et al. suggested that antipsychotic co-treatment may be superior to monotherapy in certain clinical situations. However, it was not possible to derive firm clinical recommendations from these results. The most commonly used antipsychotic in those trials was clozapine. 

Thus, we should remain vigilant regarding indiscriminately using multiple drugs in treating schizophrenia as in the long run the treatment may become resistant enough to seek the help of electroconvulsive therapy as treatment. 

Aripiprazole is indeed an antagonist of 5HT2a receptors serotonin. Would not add to Clozapine.

Regarding first question, I definitly would try first Clozapine as several other antypsychotics toghether. It is a wonderful drug despite hematologic side effects that should be controlled anyway.

Just one important thing regarding the withdrawal of Clozapin (for any reasons): because of its strong anticolinergic effect, patients use to develop an intense cholinergic state in the 48 -48 hours after quiting the drug. Use always bemperidene or other anticholinergic substances over 4-5 days if you want to withdrow a patient from a long time consume of clozapine.

In treatment resistent schizophrenia after all other antipsychotic drugs where tried clozapin is the one giving very good results.

Thanks to everybody, because this topic is one of the highlights in psychiatry, especially due to importance of cost-effectiveness and patients' safety. In many countries it is interesting we do not have any trial about this topic or report, which doesn't mean that there are no problems in antipsychotic polypharmacy, which does in every country exist.

After brief searching i have many conclusions:

1) Clozapine should be used before POLYPHARMACY (APP) IS APPLIED, when it is possible and there are no contraindication for its use (monitoring, DDIs, cardiovascular diseases, seizures etc ...). According to the many trials and report the use of clozapine is too low, especially in U.S.

2) BEFORE clozapine use, an antipsychotic monotherapy should be used in long duration (for example 12-16 weeks) on stable doses. This step is usually too short in real clinical practice (Stahl SM, Grady MM. Curr Med Chem. 2004 Feb;11(3):313-27. )

3) BECAUSE of too short trial with monotherapy many patients are treated with polypharmacy, which has not been proven in long term trials. It is interesting that we have trials, where efficacy is established after 6 weeks or more, but in real clinical practice we do not wait until 6-12 weeks with monotherapy.

4) IF WE USE POLYPHARMACY, then please use it in short term trial (e. g. 4-6 weeks) and after a discontinuation step is required (after 16 weeks). Especially with patients with dementia, this step should be shortened on minimum

5) IF WE COMBINE then COMBINE drugs (make APP), where an effectiveness has been proven in trials or even case series. In my short Pubmed review there are few trials to support antipsychotic polypharmacy, and what is interesting is that are many reports, case series and case reports on successful use of amisulpiride in these cases. According to these results, the prescription rate of amisulpiride in real practice is very small. So, we can combine AMISULPIRIDE with CLOZAPINE (but measure QTc please).

Usually aripiprazole is often used in combination treatment (APP), however there are little support to do this practice. Sometimes is used, because of adverse effects of primary drug (e.g. paliperidone and prolactin), however we do not have trials to support this practice and therefore long term use in not appropriate.

However there are trials in which AAP, has not been proven, for example combination treatment of risperidone and clozapine (N Engl J Med. 2006 Feb 2;354(5):472-82.).

Usually quetiapine is added to the D-2 blockers, which are not sedative (haloperidol, risperidone ... ), however long term trials are not established and there are big methabolic probles with quetiapine even in small doses. Therefore short term use of antidepressants or even hypnotics is favourable to avoid APP.

6) COMBINATION BASED ON PHARMACOLOGICAL ACTION - VERY IMPORTANT TO UNDERSTAND

This is easy to say, hard to be proven. Usually the literature support use of D2 blockers with antipsychotics with different mode of action (e.g. clozapine and quetiapine and aripiprazole) and for ideal antipsichotic 60-70 % of D2 occupation is needed. However, some trials has not supported this use, for example combination of risperidone with clozapine (N Engl J Med. 2006 Feb 2;354(5):472-82.). On the another hand, there are many support to use clozapine and amisulpiride in short term use.

In these cases we should calculate with basic pharmacology, because there are competitions for the binding sites (e.g. receptors). Especially the drugs with high potency (small Kd) usually occupy most D2 receptors and therefore drug with higher Kd does not occupy the receptors and we do not have an additional effect, as we expect. On the other side we have many possibilities for adverse event and DDIs when polypharmacy is used (good example is APP with clozapine and risperidone).

After potency there is also efficacy which is very important for the use of antipsychotics, because we want activity or effect. In this case we have positive or negative connection between potency and efficacy, because if drug is a potent it is not neccesary to be also effective (usually is, bot not always). We know that clozapine is the most effective antipsychotic medication. IN these cases we block clozapine from being bined to D2 receptor, because of risperidone and efficacy is possible even lower than use of monotherapy.

However, an additional effect by amisulpiride is primarily based on additional D1/D3 activity, which is special for amisulpiride.

7) SUM UP

Next to this important topics we should calculate also with the symptoms. For example with patients with depression (comorbidity) the use of clozapine is usually appropriate many weeks even before APP (5HT6, 5HT7 receptors blocker). Also if we have the positive symptoms we should calculate with D2 blocker and high doses usually. If we have patient with the negative symptoms there are not support for APP use (ECNP report, 2009). Instead of APP use it is important to use another options, for example ECT or addition of glycine, lamotrigine to clozapine to improve its efficacy (better effect on glutamate system).

Next to these patients usually take many different drugs and have many different conditions and therefore the cooperation between clinical pharmacist certified for psychiatry and/or clinical pharmacologist is highly advisable and regular monitoring for the symptoms and possible or real adverse effects is needed to avoid harms with APP use.

I believe in using clozapine before polypharmacy. Thereby, the effect of clozapine is not reduced, by polypharmacy being used first; and gives clozapine a better chance to be effective.

Dear Amar,

You are right, according to the guidelines clozapine should be used in these cases, however there are many obstracles to use clozapine and consequently APP is used. For example, many weeks ago I had one example with high hypotension after exposure to clozapine etc ...

However, If you use clozapine earlier in the treatment your outcomes are better, therefore after two failures with monotherapy use of clozapine is appropriate. More You wait with different combinations of APP or even triple antipsychotics lower outcomes you get.

We know that We live in real world, where the patients usually take another medications (e. g. for hypertension, diabetes, dementia) and calculation with DDIs is necessary before prescribing of clozapine. Sometimes the patients take MTX, carbamazepine and another drugs, which can have the impact on blood sample and this can lead to avoid clozapine prescribing. In some countries monitoring of adverse effects could be a problem, because of lack of resources.

To sum up, If APP is used before clozapine, APP should be choosen according to the EBM and therefore effective combinations are appropriate, for example amisulpride or combinations with stabilizators or even antidepressants. In this term (prescribing of APP) We should imagine that monitoring is very important (follow-up) and discontinuation of second AP is suggested (after 12 weeks for example). What is seen usually in real clinical practice is that antipsychotics (add on) are not discontinued even in people with dementia and high comorbidity. What I see in my practice as psychiatric clinical pharmacist is that after long term follow up I should usually suggest discontinuation, because of serious adverse events (e. g. olanzapine and clozapine combination and hypotension and long term constipation) or inappropriate prescribing (e.g. dementia and APP).

If I conclude, clozapine shoud be used first If it is possible as fast is possible, otherwise after that trial with APP is recommended, although a serious monitoring and discontinuation after several weeks is recommended.

Best regards, 

Mathew

An important question is SHOULD WE USE CLOZAPINE AS A FIRST LINE TREATMENT and not require failure on 2 or more antipsychotics? My answer would be a qualified yes: patients with a history of suicidality, substance abuse (including tobacco), and violence should be started on clozapine. For other patients ONE (not two) failures with another antipsychotic should occur. I believe these changes will save lives and promote recovery.

Article Clozapine reverses cocaine craving in a treatment-resistant ...

Dear Lewis,

I agree with You. I support my approve with following statements:

Why? +

- earlier we treat better outcomes we get,

- in clinical trials with clozapine there are often TR SCH patients included, which means that clozapine is even more effective than comparator in real clinical practice if we start earlier, because after one relapse there is more chance to suffer from another relapse,

- we treat depressive symptoms together more effective (5HT6, 5HT7 mode of action).

- impact on immune system should be a highlight of future treatments for TR SCH

- there is more than 80 % chances that patient with a first episode will have TR SCH

- we reduce polypharmacy often, which minimizes risks of serious prolonged and long term side effects

Why not? -

- Drug adherence is very bad in these patients and even in clozapine there is problem in taking clozapine twice daily (it seems to be the most important negative problem in my opinion)

- DEPOT are used more often nowadays and we do not have clozapine in this formulation, which means that many patients discontinue before as it will be in DEPOT form

- Many important side effects (adverse) and DDIs

- we are afraid of concomitant treatment with DEPOT, which is very often seen in clinical practice, although it should be avoided or reserved only for special cases (case-by-case).

- Many patients with SCH are infected by serious different infections (prevalence is higher) and there are many chances that patient would be treated with ciiprofloxacin

To sum up, cooperation between different healthcare specialists is beneficial in these cases.

Regards,

Matej

Persons with schizophrenia and other serious mental illness die 25 years earlier than general population and among the main causes are:

#1-tobacco related deaths

#2-suicide

Clozapine decreases tobacco craving and suicidality.

Article The International Suicide Prevention Trial (InterSePT): Rati...

Article Effects of clozapine on smoking in schizophrenic outpatients

Dear Lewis,

I agree with you. Thanks for sharing these interesting articles!

Very important (nicotine addiction) is to understand an impact of nicotine on D2 receptors. In this point of view a use of clozapine is even more positive.

Next important issue is to combine clozapine with different psychopharmaceuticals (especially via glutamate system/glycine binding site; e.g. lamotrigine, N-acetylcysteine) to improve clozapine efficacy or better effectiveness in real clinical practice. It could be the most powerful treatment strategy as early is possible in these patients. 

Regards,

Matej

I have the following answear/question

From my experience and practice, often TRS cases are infact non-adherent patients. Using LAIs for at least 6 months will be a major change. Before polypharmacy let's try LAIs. Clozapine is ok for admitted patients. But after discharge?...

Good addition! I am sure that dr. Opler will have better answer than me, however I ll try to answer with my kowledge of psychiatric clinical pharmacy practice.

1) If you switch patient from clozapine to DEPOT at discharge from the hospital it is unethical, because you switch from the most effective medication to less effective -- (clozapine to DEPOT). Please keep in mind this important issue. When my colleague psychiatrist smth advertising this switching i do not agree (not supported by EBM)

2) DEPOT preparations have really better adherence but not drug efficacy. You are right that many patients discontinue with medications when they are discharged from the hospitals (about 50 % of patients with mood disorders within 2 months and 80 % one year). However, this is important it does not mean that each patient stable on clozapine should be switched to DEPOT.

3) If you switch from clozapine please use EBM switching, which means that you switch to olanzapine DEPOT. Olanzapine (oral form) has been shown to be effective when talking about clozapine switching to another antipsychotic.

4) In this point of view if you see that patient wont take his/her medications then switching to olanzapine would be probably the best option (depot form). In this point of view you should be very very careful about antipsychotic polypharmacy (especially connected with H1 and M1 and alpha-1 blockade). This is very important issue when switching from clozapine to olanzapine.

Regards,

Matej

Dear dr. Stuhec,

Very curious question, a very good discussion for me as a clinical pharmacologist, from which can be much useful to know any'll gladly follow!

Regards

Jasenko