Cariprazine is currently approved in four doses: 1.5, 3.0, 4.5, and 6.0 mg/day (28). According to the Summary of Product Characteristics (SmPC) the recommended starting dose for cariprazine is the lowest available dose, 1.5 mg/day (28, 29). Indeed, as summarized in Table 1, in the majority of cases cariprazine treatment was initiated with this dose. Exceptions were three patient cases where cariprazine was prescribed in the dose of 3.0 mg/day (40), as well as the Latvian observational study where 7.7% of patients received 3.0 mg/day, 3.4% 6.0 mg/day and 1.7% 4.5 mg/day as their starting dose (27). Importantly, as reported in the cases, the higher starting dose was well-tolerated and quick improvement in behavior was detected (40).

After initiation of treatment, cariprazine doses are recommended to be increased in 1.5 mg increments up to a maximum of 6.0 mg/day, if necessary (28, 29). In general, there are two main titration strategies—a fast and a slow one. Fast titration involves an increase of 1.5 mg/day each day or every second day until the target dose is achieved, as seen in the short-term clinical trials (20, 21, 23). This or similar strategy was utilized in several cases (31, 33–35, 37, 40, 41, 43), where 3.0 mg/day dose was introduced within less than a week after the beginning of the treatment. In these cases, most of the patients exhibited considerable psychotic symptoms with or without negative symptoms and weight gain problems caused by previous medication. The other—slow—titration strategy has been described in one of the long-term studies, where patients with predominant negative symptoms received cariprazine in a dose of 1.5 mg/day until week 1 and then doses were increased in 1.5 mg increments weekly up until 6.0 mg/day, if it was needed (7). It is also worth to note however, that in this study cross-titration with previous antipsychotic medication was performed in the first two weeks of treatment, whereas in the short-term studies a 7-day wash-out period before cariprazine monotherapy was introduced (20–23). Slow titration strategy was also performed in cases where patients were less psychotic (30, 39) or received cariprazine as add-on treatment (32, 36). As expected, in the Latvian observational study both strategies were present (27); in 34% of the patients, dose was increased every 3rd day, in 28% every 4th day, in 6% every 6th day and in 32% every 7th day.

In case of cariprazine, switching from another antipsychotic can be beneficial if there has been no or only partial response to positive or negative symptoms (27, 31, 32, 35, 37, 41, 43), if the patient suffers from side effects (27, 34–36, 42) that are less common with cariprazine such as weight gain, hyperprolactinemia, sexual disturbance or sedation (44) or if the patients has been prone to non-adherence or substance abuse (29, 35).

In general, there are four possible ways of switching antipsychotics; abrupt, abrupt-gradual, gradual-gradual (i.e., cross-tapering) and gradual-abrupt (12, 29). In case of abrupt switching, the previous antipsychotics medication is promptly discontinued, while the new one is immediately started (12, 29). The second option is to immediately discontinue the current medication and gradually introducing the new one (abrupt-gradual) (12, 29). In contrast to this option, gradual-abrupt switching involves the gradual dose reduction of the previous medication and the immediate start of the new one (12, 29). Finally, in cross-tapering the new antipsychotic is gradually introduced while the previous is gradually tapered down (12, 29). This can be achieved in two ways as well, either at the same time, or delayed; first, reaching a plateau where the target dose of the new antipsychotic is achieved and only then starting to decrease the dose of the previous medication (full-dose overlap) (12).

The most recommended strategy for switching to cariprazine is gradual cross-titration with different timeframes depending on the mechanism of action of the previous medication as seen in Figure 1 (29, 48). In case of antipsychotics that have a similar profile to cariprazine i.e., partial agonism at the D2 receptor with comparable histaminergic and cholinergic affinity (e.g., aripiprazole), a 1-week cross-titration is recommended where the previous drug is tapered off within 7 days while at the same time cariprazine dose is escalated to the target dose (29, 48). In contrast, about 2 weeks is necessary if switching from a second-generation antipsychotic that has D2 antagonism (e.g., risperidone) in order to avoid dopaminergic rebound causing increased psychotic symptoms, agitation and dyskinesia (29, 48). Finally, most time (3-4 weeks) should be given when switching from antipsychotics with completely different receptor profiles i.e., those with stronger antihistaminic and/or anticholinergic affinity (e.g., olanzapine, quetiapine or clozapine) so that histaminergic and cholinergic rebound is avoided hence reducing the risk of insomnia, nausea and vomiting (29, 48). At last, various panels emphasize the advantages of a full-dose overlap when switching to cariprazine regardless of the type of antipsychotic drug that has been taken by the patient (45, 46). In such case, a period of overlap for about 2 weeks is recommended before the tapering down of the previous medication hence ensuring that there will be no relapse of symptoms (45, 46).

When analyzing data from clinical cases however, the picture regarding switching strategies is much more mixed. In case of switching from risperidone, some chose abrupt switching (42), while others discontinued it over 2, 9 or 10 days period while gradually increasing the dose of cariprazine (34, 41, 43). Similarly, abrupt stop as well as cross-titration over a 3-day, 2- or 3-week period was described when switching from olanzapine to cariprazine (34, 38, 41). Interestingly, abrupt switching was frequently described in case of quetiapine (36, 41) and clozapine as well (37). In case of making the clinical decision to switch from cariprazine to another antipsychotic, the abrupt-gradual strategy is recommended due to the long half-life of cariprazine (28).

Even if carefully planned and executed however, complications throughout switching can still emerge. In case of a dopaminergic rebound, the re-initiation or dose increase of the previous antipsychotic is recommended (29). If appropriate, this strategy can also be applied to cholinergic and histaminergic rebounds, however in general, the adding of an anticholinergic (e.g., biperiden) or antihistamine (e.g., hydroxyzine) medication can also solve the complications (29). One of the most common side effects of antipsychotic medications is akathisia which can also emerge during a switching period and is recommended to be managed with beta-blockers (e.g., propranolol), benzodiazepines or anticholinergics (29).

Maintenance treatment involves the stabilization of the patient on a certain dose that has the ability to control the patient's symptoms without causing any side effects that are intolerable for the patient. Among the four available doses of cariprazine, all doses can be utilized as maintenance dose—depending on the patient's symptom and side effect profile. For instance, although the 1.5 mg/day is most often prescribed in the treatment initiation phase, 11% of the patients in the Latvian study and 4% of the reviewed cases remained on it long-term. Importantly, the rest of the doses were used as maintenance dose equally in these real-life settings; about one fourth of the patients were on 3.0 mg/day, one fourth on 4.5 mg/day and another one fourth on 6.0 mg/day. These data also shows that patients stabilizing on 6.0 mg/day are more usually psychotic and hence require higher D2 activity, while the lower doses found to be more adequate for improving negative and cognitive symptoms. If looking at the pooled data of the fixed-dose studies, based on the effect sizes for the PANSS total and positive symptom factor scores, the optimal dose for most schizophrenia patients is the 4.5 mg/day (49). Thus, prescribing this dose for an adequate time is recommended before switching from cariprazine to another antipsychotic medication due to insufficient effectiveness.

Additionally, the final dose of cariprazine is often related to the maintenance dose of the previous antipsychotic medication (29). Equivalent doses of different antipsychotics are clearly described in The Maudsley Prescribing Guidelines in Psychiatry (50) where it has been stated that 3 mg cariprazine is approximately the same dose as 3 mg risperidone, 10 mg olanzapine, 80 mg lurasidone, 2 mg brexpiprazole, 300 mg quetiapine and 400 mg amisulpride. Indeed, in the negative symptom study, patients were randomized to receive fixed doses of cariprazine (3 mg, 4.5 mg or 6 mg per day) or the equivalent in risperidone (3 mg, 4.0 mg or 6 mg per day) (7). Additionally, the same principle was applied in a case by Di Sciascio et al. that reported a successful switch and maintenance from risperidone 3 mg to cariprazine 3 mg per day (34).

Even though cariprazine is approved for mono-therapeutic use, polypharmacy—essentially the use of more medications—is quite common in real-life settings (51, 52). In fact, in 5 out of the 29 cases was cariprazine used as an add-on treatment (32, 36, 42). To give an example, De Berardis and colleagues utilized cariprazine successfully in combination with clozapine in two patients and reported the effects of cariprazine combination to be remarkable not only regarding symptom control but also concerning the management of side effects caused by clozapine (32). Moreover, in the Latvian observational study, 27% of patients were taking quetiapine, 10% olanzapine and 9% clozapine at their last visit, mostly for non-specific sedation or control of anxiety (27). Importantly, in a post-hoc analysis of the cross-titration period of the negative symptom study (7), the co-administration of cariprazine with other antipsychotic medications did not show an unexpected safety profile nor overlapping toxicities, suggesting that it is unlikely that safety will be compromised if polypharmacy with cariprazine is unavoidable (53). This shows that in certain cases patients can benefit from cariprazine combination treatment, nonetheless only if the second antipsychotic is well-chosen with careful consideration regarding the compatibility of the two medications (54).

Concomitant medications other than antipsychotics are well-described in the cariprazine literature. In the clinical trials zolpidem, zaleplon, chloral hydrate, or eszopiclone for insomnia, diphenhydramine, benztropine, or propranolol as rescue medication for extrapyramidal (EPS) symptoms, and lorazepam for agitation, restlessness, irritability, and hostility were permitted (20, 21, 23, 26). Similarly, in the Latvian observational study anti-EPS medication, benzodiazepines, mood stabilizers and antidepressants were allowed (27). Nonetheless, it is important to note that fewer patients needed concomitant medication with cariprazine compared to the antipsychotic they were previously on; 14% of the patients stopped taking anti-EPS medication, 5% antidepressants and mood stabilizers and 3% benzodiazepines (27). In the reviewed cases, most concomitant medications were benzodiazepines (alprazolam, lorazepam and diazepam) (33, 35, 38, 40) and biperiden (36, 38).