DOSING STRATEGIES FOR THE TREATMENT OF SCHIZOPHRENIA: A FOCUS ON CARIPRAZINE
In this section
Professor Elmars Rancans, Professor of Psychiatry at Riga Stradins University in Latvia was the speaker of the Product Theatre titled ‘Cariprazine dosing recommendations for the treatment of schizophrenia’ which was organised at the 30th annual congress of the European Psychiatric Association.
Prof. Rancans began his presentation by explaining the importance of finding the optimal dosing strategy in the treatment of schizophrenia; physicians aim to have a quick and adequate treatment response as well as minimal and bearable level of side effects1. If the latter arises, it can lead to frequent switching, then non-adherence, treatment discontinuation, and at the end of the road, treatment resistance1,2. This is what should be avoided, he said.
Continuing the introduction, Prof. Rancans also talked about why it is so difficult to find an adequate dosing strategy in case of a new medication. Information regarding new medications comes primarily from clinical trials where the aim of the developer is to find the lowest effective dose against placebo so that it induces the least amount of side effects1. Therefore, the doses identified from clinical trials can be much lower than what is needed in real life1. Furthermore, he emphasised, due to the fact that patients need to meet rigorous inclusion criteria, they are likely to be different compared to what is seen by doctors in everyday practice1.
Moving on to cariprazine, Prof. Rancans explained the receptor affinities of cariprazine and how this medication is different from the other available antipsychotics. He then outlined the methodology of a recently published research paper authored by him that aimed to compare and summarise data from both clinical trials and real-world studies in terms of cariprazine dosing3. The search strategy that they used yielded 186 search results, of which 36 articles met the inclusion criteria: 6 clinical trials, 1 observational study and 29 case studies3.
Treatment initiation with cariprazine usually starts at 1.5 mg
Prof. Rancans started the discussion around cariprazine dosing strategy with treatment initiation. He explained that cariprazine is approved in 4 doses from 1.5 to 6.0 mg and in clinical trials 1.5 mg was the starting dose3. Although 1.5 mg was also predominantly used in the beginning of the treatment in real-world studies, 3.0 mg was used in some case studies and even higher doses, 4.5 mg and 6.0 mg, in the Latvian observational study3.
In the clinical trials, after cariprazine treatment started, two up-titration strategies were applied: fast titration where the dose was increased by 1.5 mg every day or every second day, and slow titration where the dose was increased weekly3. In real-world studies, fast titration was reported in 8 cases, Prof. Rancans continued, and slow titration in 4 cases3. In the observational study, there was a mix of fast and slow titration strategies3.
Gradual switching from previous antipsychotic medication is recommended with cariprazine
Prof. Rancans then addressed the topic of switching, when due to insufficient response or unbearable side effects the previous antipsychotic medication is discontinued and the new one is introduced. In general, he said there are four broad frameworks of switching which was defined in the literature: abrupt-abrupt, gradual-abrupt, gradual-gradual, and abrupt-gradual1,3. When switching to cariprazine the gradual-gradual method is recommended with various overlaps depending on the previous antipsychotic medication3. Switching to cariprazine is beneficial if the previous antipsychotic had no or only partial response to positive or negative symptoms; if certain side effects such as weight gain arose; if there was non-adherence, or substance abuse3. In terms of the different overlaps, the following rules were recommended by Prof. Rancans3:
– 1-week overlap if switching from antipsychotic that have similar receptor profile to cariprazine, such as aripiprazole
– 2-week overlap if switching from a second-generation antipsychotic that has dopamine D2 receptor antagonism, such as risperidone
– 3-week or 4-week overlap if switching from antipsychotics that have completely different receptor profile, such as clozapine.
Since in clinical trials a wash-out period was applied, data on switching is only available from real-world studies where both gradual and abrupt strategies were applied3. Before moving on to the topic of maintenance treatment, Prof. Rancans also talked about how to mitigate complications during switching e.g., in case of dopaminergic rebound, the dose of the previous antipsychotic should be increased, and he further shared some insights regarding the management of akathisia3. In terms of maintenance treatment, he showed that in the case studies and the observational study 3.0 mg, 4.5 mg and 6.0 mg were equally used as maintenance doses3.
Cariprazine and other medications
At last, Prof. Rancans talked about concomitant medications. He emphasised that although cariprazine is approved for monotherapy, polypharmacy is common in real-life practice3. Indeed, in the case studies 17.2% of doctors applied polypharmacy such as cariprazine combined with clozapine3. He also cited here an article by Hjorth and showed how the receptor profile compatibility is a highly important factor when combining antipsychotics3,4.
To conclude the lecture, Prof. Rancans summarised the most important points from his presentation. He emphasised again the importance of a good dosing strategy; confirmed that real-world data is similar to what was found in clinical trials regarding cariprazine dosing; suggested the “start low and go slow” rule for treatment initiation and titration; and finally, recommended to leave enough time before switching and to consider receptor profiles when applying polypharmacy.
- Buckley, P. F. & Correll, C. U. Strategies for dosing and switching antipsychotics for optimal clinical management. J. Clin. Psychiatry 69, 4–17 (2008).
- Fleischhacker, W. W., Oehl, M. A. & Hummer, M. Factors Influencing Compliance in Schizophrenia Patients. J. Clin. Psychiatry 64, 10–13 (2003).
- Rancans, E., Dombi, Z. B. & Barabássy, Á. Dosing cariprazine within and beyond clinical trials – recommendations for the treatment of schizophrenia. Front. Psychiatry xx, xx (2021).
- Hjorth, S. The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective. Front. Psychiatry (2021). doi:10.3389/fpsyt.2021.760181