Professor Stephan Hjorth, Professor of Pharmacology and an independent pharmacological consultant with more than 45 years of experience in preclinical neuro- and psychopharmacological research, opened the session ‘The schizophrenia polypharmacy quiz – everything you need to know about combining antipsychotics’ at the 34^th ECNP Congress and stated that he and his co-speaker Dr. Karolina Leopold,  are going to address the efficacy and safety concerns of different antipsychotic combinations from a pharmacological and clinical point of view.   

Despite antipsychotic polypharmacy (APP) is not being supported by the guidelines at all, it is more common than expected. Around 20-30% of all schizophrenia patients are using multiple drugs – started his presentation Professor Hjorth – and it is mostly used in difficult-to-treat patients with more complex symptomatology, such as negative and cognitive symptoms. 
 
He also emphasized that large, long-term, high-quality, double-blind, randomized, controlled studies investigating APP are currently missing. Another limitation – he mentioned – is the low pharmacological resolution, meaning that authors usually refer to drugs either as first-generation or second-generation antipsychotics instead of giving the names of the compounds in APPs. Most common agents in the studies are clozapine, olanzapine, risperidone and quetiapine, which are second-generation antipsychotics. And among those, the best evidence for successful combination is actually clozapine based, in particular with partial dopamine receptor agonists.

Professor Hjorth then presented the reasons for APP in schizophrenia. The first thing – he said – is that doctors want to improve the efficacy, either to enhance the efficacy in a particular domain or to broaden the efficacy of less responsive domains. In addition, physicians want to optimize dopamine D2 receptor occupancy as well as access other receptors that could be beneficial for enhancing efficacy. And overall, the intention is to adjust the doses of the components in an APP; reducing the dose while maintaining or even improving the effect and reducing the number of adverse events, thus improving tolerability and eventually increasing compliance for a better quality of life. In a nutshell, the aim of APP is to enhance & broaden efficacy, reduce side effects and promote compliance.

That being said – Professor Hjorth continued –clear pharmacological rationale is often lacking for these combinations. Target responses of antipsychotics may be both DESIRED and UNDESIRED. Professor Hjorth discussed that specific targets are mostly antagonized by antipsychotics, but that there are also agents that are partial agonists of these targets. For example, D2 partial agonists are effective on positive symptoms, which is a desired effect from an antipsychotic, but at the same time, they come with undesired effects like EPS, hyperprolactinemia, sexual and cognitive dysfunction. 5-HT1A partial agonists have beneficial anxiolytic and antidepressant effects but also undesired EPS effects. Also, there are targets that have undesired effects. 5-HT2C and H1 blockade, both have negative effects by causing metabolic dysfunction, bad appetite and weight gain, cognitive dysfunction and sedation. Alpha1 antagonistic properties are responsible for orthostatic hypotension and also sexual dysfunction. And finally, antimuscarinic properties of some of the agents cause anticholinergic side effects next to cognitive dysfunction. 

Professor Hjorth continued his speech presenting his ‘cobweb’ illustration for drug-target profile view. There are targets around the edges of the cobweb, where dots show the affinities for different targets for a certain drug. The closer the dot to the center, the higher the affinity. The profile is drawn when you join the dots by lines. An area in the middle depicts approximate free plasma exposure at clinically relevant dosing where size of area varies with dose. A very selective dopamine D2 antagonist is in the inner circle of the cobweb. 
 
He summarized that on the cobweb illustration, D2 and D3 are DESIRED targets, 5-HT1A and 5-HT2A are targets with beneficial ACCESSORY effects and 5-HT2C, H1, Alpha1 and Muscarinic targets come with UNDESIRED effects. When you plot the profile of the drug on the cobweb, you will find that drugs have distinct antipsychotic target profiles, therefore they will present distinct clinical response properties, in regards to efficacy and side effects.

Professor Hjorth then continued the second part of his speech by giving examples of APP combinations and analyzing them both from a pharmacological and clinical point of view together with Dr. Karolina Leopold, a senior physician and consultant psychiatrist at the Department of Psychiatry, Psychotherapy and Psychosomatics in Vivantes Hospital Am Urban and in Vivantes Hospital im Friedrichshain, Academic Hospital Charité-Medicine Berlin. 
 
Clozapine + aripiprazole
Prof. Hjorth explained how the profiles of clozapine and aripiprazole are plotted on the cobweb. Clozapine is rather poor at the D2 receptor but very strong at the 5-HT2A, 5-HT2C, H1, Alpha1 and muscarinic receptors. When aripiprazole is added on top of this, it brings much more D2 effect, and a bit of 5-HT1A, which changes the picture a lot. When these 2 profiles are overlapped on the cobweb, it is obvious that these 2 agents are complementary with regard to their target profiles. 

 The pros from a pharmacological perspective of the clozapine and aripiprazole combination is an improvement in antipsychotic, D2-driven effects against positive symptoms, and less metabolic and less sedative properties. On the other hand, increased akathisia may be encountered with this combination.  Professor Hjorth commented that from an overall pharmacological perspective, clozapine + aripiprazole combination is rather a recommendable combination. 
 
Dr. Leopold explained how this combination looks from a clinical perspective. In most cases – she commented, when aripiprazole is added to clozapine, a positive effect is observed on the symptoms. The most important of all is, when you add aripiprazole, you can reduce the clozapine dose in most patients so that you can achieve less sedation with more active patients with better daily functioning and weight loss. 
 
Clozapine + cariprazine
Next, Professor Hjorth plotted the clozapine profile on the cobweb and added cariprazine profile on top of it. Cariprazine, similar to aripiprazole, has strong D2 receptor partiality but even higher D3 receptor partiality, both of which are clearly lacking in clozapine. These two agents seem to be very complementary to each other, with beneficial effects from the D2 and D3, in regards to positive and negative symptoms. This combination ends up with less metabolic side effects and less sedation. Similar to previous combination, increased akathisia may be encountered, but mild and transient in nature. Therefore, from a pharmacological perspective, clozapine + cariprazine combination is a beneficial combination – commented Professor Hjorth and asked Dr. Leopold her clinical interpretation. 
 
Lots of patients really have a good effect by this combination – commented Dr. Leopold. In clinical practice, patients who have monotherapy with clozapine and who still have negative symptoms have an improvement with the addition of cariprazine. This combination enables patients to have a higher psychosocial functioning, a better life quality and a healthier lifestyle. Patients’ energy levels and activity increase, they are more social. 
 
Similar to clozapine + aripiprazole combination, – continued Dr. Leopold – you can lower the dose of clozapine when combined with cariprazine, without losing the efficacy on positive symptoms. Also, this combination provides better efficacy on negative symptoms by less sedation and more activity. She concluded by mentioning her positive experience in clinical practice regarding this combination.
 
Olanzapine + risperidone
The profile of olanzapine is not very different from clozapine on the cobweb – explained Professor Hjorth. Dopamine D2 receptor affinity seems to be a bit higher than clozapine as well as H1 receptor affinity, which may not always be very good. When risperidone is added, they overlap quite a lot, and there seems to be no complementary effect. With both agents there is an increase in D2 receptor occupancy, which helps with positive symptoms. On the other hand, by adding risperidone to olanzapine, most side effects that are already there are increased. Increase in the risk of EPS, hyperprolactinemia and sexual side effects, orthostatic hypotension, increase in sedation, and increase in overall metabolic side effects are the cons of this combination. From a pharmacological point of view, – commented Professor Hjorth – it is not a recommendable, but rather a questionable choice of combination. 
 
Dr. Leopold agreed Professor Hjorth from a clinical point of view. Though the combination may enhance efficacy on positive symptoms, – she added – but the side effects coming from both agents are bothersome for most patients. One exception for use of this combination could be patients that long-acting injectables are needed, in which case tolerability should be monitored closely. 
 
Olanzapine + cariprazine
When you overlap the profiles of two medications on the cobweb, you get a picture which is similar to the combination of cariprazine with clozapine – explained Professor Hjorth – so you have a complementary effect. With this combination, the antipsychotic effect that emanates from D2 and D3 regarding positive and negative symptomatology might be improved. In addition, this combination might also encounter metabolic and sedative side effects derived from olanzapine, and increased akathisia as an undesired effect. 
 
This combination looks like recommendable, even preferable, – concluded Professor Hjorth and passed on to Dr. Leopold to learn about her clinical perspective. Dr. Leopold commented that treatment goals are important when recommending a combination like this. If there is no control of positive symptoms even with a high dose of olanzapine, she would prefer this combination. But when the patient has low or no positive symptoms, but rather negative symptoms that interfere with the functioning and the quality of life, then adding cariprazine is a good idea. Thus, the patient has increased physical activity, weight loss, social interaction and eventually a healthier lifestyle and a better quality of life.
 
Clozapine + quetiapine
The last example Professor Hjorth gave is the combination of clozapine and quetiapine. When both profiles are plotted, there is an overlap. He commented that there are no benefits from D2 or D3 side. But, antihistaminergic effects of both compounds could be a very good way to bringing an agitated patient down, where I guess there are better ways of doing that – he explained. This combination comes with cardiovascular problems, QTc prolongation risk and sedation as well. He added that this would never be an option from his perspective, and passed on to Dr. Leopold to see if she agrees. 
 
This combination is a bad idea – said Dr. Leopold. Combination of clozapine + olanzapine or clozapine + quetiapine is highly sedative. Patients sleep up to 18 hours a day, they also have orthostatic dysregulation, risk of sudden death and weight gain. I would neither recommend nor use this combination for my patients – she concluded.
 
At the end of the session, Professor Hjorthemphasized that monotherapy is always preferred for several reasons, but if it doesn’t seem to work out after at least two sequential monotherapies, in line with most of the guidelines, then it is time to go for antipsychotic polypharmacy but with a good pharmacological rationale.
 
Professor Hjorthconcluded the session suggesting that before using a combination the best thing is to go back and check the very first diagnosis, and he left the audience by asking the most crucial and basic questions: ‘Is the diagnosis really what you thought from the beginning?’ ‘Is the patient taking his or her pill?’ ‘Do you have compliance?’ ‘Can you check that with therapeutic drug monitoring?’ ‘And is there comorbidity, particularly when it comes to drugs of abuse?’ 
 
If you are interested in learning more, check out all the contents at https://www.ecnp.eu – they are available until 13 January 2022 for registered members.