It is possible to combine clozapione with other antipsychotics. I have expeirence with the combination whith risperidone. The indication has been refractory patients that have a partial response to clozapine.

Hello. I think that it is possible to combine clozapine with other antipsychotics (Amisulpride, Risperidone or Aripiprazole). However, in my clinical practice I have obtained low benefits with this option, and patients with refractory symptoms have not shown a significant improvement.

There is no evidence that the addition of another antipsychotic improves clozapine response. Reference: Elkis and Buckley-Psychiatric Clinics of North America 39(2016): 239-265.

According to the SmPC of clozapine combination with depot antipsychotic is contraindicated. Especially important question is how to resolve very important drug event if it has been occured, because of depot formulation. These adverse drug reactions can happen via unknown mechanism. In addition clozapine could be combined with several antipsychotics except depot formulation.

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.

 Regards,

Matej

Antipsychotic polypharmacy before clozapine use OR clozapine use before antipsychotic polypharmacy in chronic schizophrenia?. Available from: https://www.researchgate.net/post/Antipsychotic_polypharmacy_before_clozapine_use_OR_clozapine_use_before_antipsychotic_polypharmacy_in_chronic_schizophrenia/2 [accessed May 23, 2017].

Hello. I will talk about my clinical experience, not the studies. I have a good experience when clozapine is combined with aripiprazole, in one case even with aripiprazole depot (a female patient with chronic schizophrenia). However, I think that clozapine should not be combined with other antipsychotic at higher doses. The patient is given 100 mg of clozapine per day.

Polypharmacy is always fraught with serious problems and should be avoided.  There is no such thing as a refractory or treatment resistant patient.  They are called ultra-rapid, poor or non metabolisers and this can be determined in advance of treatment.

Giving multiple drugs to those who cannot properly metabolise them is potentially very harmful and of no benefit to the patient.  It is therefore not only a waste of drugs but is unethical.

Consider the genetic polymorphism and interactions before useing long trem anti-psychotics.  That would not ony save the patient from unnecessary discomfort and risk but would sve the NHS a fortune in wasted prescriptions. 

But resistance is not the only reason for polypharmacy. For example, there may be different effects on the symptoms of different antipsychotics. Or, in the case of a combination of clozapine and aripiprazole, improving the metabolic profile of patients could be one of the reasons.

Side effects are theoretical and do not occur in everyone. Therefore the prevalence is never 100% and often is less than 10%, serious side effects are rare for nearly every medication on the market.

Symptoms that are occurring have a 100% prevalence and various illnesses carry a certain risk of worsening or other symptoms occurring.

Every decision about this type of treatment is going to involve a risk benefit alternative discussion between the patient and the provider. These discussion should include the risks and benefits of no treatment (in this case not combining treatments).

I suspect this type of treatment might occur with adding clozapine to the LAI. If an LAI at a low dose is necessary to prevent life threatening decompensation, there are some people who would be willing to take that risk and others not.

Studies can only give us information to apply to a population of people but will never be able to tell us what will work for you a single individual.

Very interesting question Mr Stuhec. I run an outpatient unit with people with refractory schizophrenia. I don't remember any patient using clozapine + depot. Though I do not find it that risky in patients using clozapine for a long time, I think many other things can be tried before. The aforementioned combination with lamotrigine is very good, as well as combining it with typical antipsychotics. I have also good results with clozapine + olanzapine, and CLZ + risperidone.

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.

Dear friends on Researchgate,

Thanks for this interesting discussion. In this point of view I will summarize my opinion about this important topic:

1) Use of APP excluding depot with clozapine could be a disease related.

2) Other strategies including lamotrigine and N-acethylcisteine etc ... should be used first instead of APP (even combinations with antidepressant are safer options than APP, especially mirtazapine augmentation to clozapine, where there are no residual positive symptoms; 5-HT2C activity and 5-HT3 should be benficial as augmentation strategy).

3) Possible pharmacokinetic and/or pharmacodynamic failure could be one of the reason to use APP and theresore TDM should be used if it is available

4) In any case combination of clozapine with depot should be avoided, because serious adverse events as consequence of DDIs between clozapine and depot could occured. For example I would suggest to avoid a combination of clozapine and olanzapine (very problematic profile on H1, 5-HT2C activity, which can lead to serious metabolic problems).

5) Coping to these problems with aripiprazole seems to be a positive treatment strategy, however long term studies are needed (do not forget that aripiprazole binds to D2 and D1 receptors very strong and therefore more other antipsychotic is needed if D2 activity is desired!). Psychiatrist combine aripiprazole too often, because of its safety, although we can get lower plasma levels of activity on D2 receptors!).

6) The best way is to titrate slowly clozapine (100 mg per week) to catch appropriate concentrations. In this point of view we should wait to reach appropriate binding to receptors and receptor conformations which is very slow in the case of clozapine. It means that APP should be avoided in long term use. If we have psychotic symptoms under treatment we can use another antipsychotic in short term, however prudent titration of clozapine is necessary to avoid unnecessary APP! 

7) A combination of clozapine and another depot should not be used, because it is official contraindication in SmPC of clozapine. If it is prescribed there should be approval by patients/caregivers. Another psychopharmacological combinations should be used to prevent to be treated by this APP.

8) Amisulpride combination with clozapine and olanzapine is underconsumed, although we have many evidence that this combination works. Amisulpride as special antipsychotic is good D2 blockers (affinity is high) with high effectviness (Emax is high) and clinical effectiveness.

Regards!

Matej