The ultimate goal in schizophrenia treatment is recovery, which encompasses symptom remission in addition to adequate self-care, improved social and vocational functioning, maintenance of treatment effects, and relapse prevention¹. To achieve treatment success, an antipsychotic must reduce acute symptoms, and achieve response and remission with minimal and tolerable side effects so patients can adhere to their treatment regimen². The decision to switch to another antipsychotic usually involves symptom-related issues or tolerability problems for stable patients. For example, residual symptoms, agitation, mood symptoms, continuing negative symptoms and cognitive dysfunction, lack of psychosocial or functional improvement, or impending relapse could precipitate a medication switch. In patients with stable disease, bothersome side effects such as weight gain, nausea, somnolence, or metabolic issues may warrant a switch to a different antipsychotic³.

Clinicians may choose to switch from another antipsychotic to cariprazine¹⁵. Patients with persistent negative symptoms may be particularly good candidates since cariprazine has proven greater improvement in this symptom domain^4,5 compared with other antipsychotics^4,6,15.

Although different strategies can be employed when switching to cariprazine, a gradual cross-titration has been shown to be safe and effective in the cariprazine negative symptom study^4,15. In this study, the patient’s current antipsychotic treatment remained unchanged in a 4-week prospective lead-in period. During the first part of double-blind treatment, a concurrent up-titration of cariprazine and down-titration of the prior antipsychotic occurred¹⁵. For this cross-titration, cariprazine was initiated at 1.5 mg/d for 6 days, followed by an increase to 3 mg/d on days 7 to 13, and then an increase to cariprazine 4.5 mg/d on day 14¹⁵. The prior antipsychotic, which was concurrently down-titrated to mirror the up-titration of cariprazine, was discontinued on day 14¹⁵. The down-titration process could be delayed for a maximum duration of 4 weeks if a risk of psychotic deterioration or withdrawal symptoms was anticipated⁴.

Although the safe and effective use of a slow up-titration strategy has been demonstrated in a population of patients with stable symptoms of schizophrenia in the negative symptom study⁴, other strategies for switching to cariprazine may be more appropriate in other situations^3,15. For example, in patients with acute symptoms or patients receiving high doses of previous antipsychotics, a faster titration with daily 1.5 mg dose increases may be preferable^7-10. Likewise, the optimal speed of down-titration of the previous antipsychotic may vary based on its half-life and anticipated risk of effects from dopamine receptor hypersensitivity or anticholinergic withdrawal syndrome^3,10.

Reference: Adapted from Stahl, S. M. Stahl ’ s Essential Psychopharmacology: Prescriber’s Guide. Cambridge University Press. (2017)¹⁰

When switching to cariprazine, the receptor profile of the antipsychotic you are switching from may influence the down-titration schedule¹⁵. Depending on the circumstances, various strategies may be appropriate, although knowledge of the pharmacokinetic/ pharmacodynamic principles of the drugs involved and expert clinical management are key³.

For switching to cariprazine, recommendations and guidance based on clinical data for switching from a currently administered antipsychotic to aripiprazole, a dopamine D₂/D₃ receptor partial agonist with relatively similar pharmacological characteristics to cariprazine, may provide supportive information¹⁵. A search of the literature was performed to identify recommendations and guidelines for switching to aripiprazole in the attempt to give a prototype example for cariprazine¹⁵.

Two consensus papers were recently published that add valuable information to the literature about switching to aripiprazole. Panels of experts in psychiatry from Turkey (2018)¹¹ and Italy (2015)¹² each recommended up-titration of aripiprazole, a period of overlap with the previous antipsychotic for about 2 weeks, followed by de-escalation of the previous antipsychotic dose (5%-20% every 15 days depending on the previous antipsychotic). This full-dose overlap strategy is consistent with a strategy recommended by a 2007 multidisciplinary UK panel of experts¹³.

Reference: Adapted from Veznedaroglu, B., Dilbaz, N., Uzun, O. & Isik, E. TARC: Turkish aripiprazole consensus report- Aripiprazole use and switching from other antipsychotics to aripiprazole- consensus recommendations by a Turkish multidisciplinary panel. Ther. Adv. Psychopharmacol. 8, 271–285 (2018)¹¹

Sometimes switching to cariprazine may be complicated by the receptor profile of the antipsychotic that is being discontinued¹⁵. Awareness that switching from certain drugs may cause symptoms or side effects is important. Clinicians should use cross-titration strategies to minimize problems related to the drug that is being discontinued and give patients ample time to adjust to the drug that is being initiated³.

For example, if a patient is switching from a medication with strong antihistaminergic or anticholinergic properties (eg, clozapine, olanzapine or quetiapine), there is a possibility that upregulated and/or sensitized receptors could promote histaminergic or cholinergic activity¹⁰. In such cases, slower down-titration may reduce the risk of rebound symptoms (eg, agitation, insomnia, anxiety, restlessness, EPS, akathisia)^3,10. Similarly, switching from a strong antidopaminergic medication, such as risperidone, haloperidol, or paliperidone, to a partial D₂ agonist may result in psychosis or agitation, possibly due to hypersensitized and/or upregulated D₂ receptors¹⁴. In cases like these, slower down-titration should also be considered. Further, discontinuing an agent with central muscarinic blockade may cause agitation, confusion, psychosis, insomnia, anxiety, and EPS/akathisia, while removal of serotonin receptor blockade may result in anxiety, EPS/akathisia and possibly psychosis and decreased appetite¹⁴.

Given all the relevant factors when switching from one antipsychotic to another, any overlap and tapering strategy should be personalized and adjusted to the individual patient and the individual antipsychotic agents involved³. Patient response and clinical history, including disease state, symptom severity, the receptor profile of previous agent, and the duration of treatment with the previous antipsychotic should all be considered³.
 
A gradual cross-titration strategy has been shown to be safe and effective for switching from another antipsychotic to cariprazine in a clinical trial in stable patients^4,15. Similar to what has been recommended by expert consensus panels, however, a full-dose overlap period of a few weeks before dose de-escalation of the discontinued antipsychotic may also be appropriate when switching to a partial agonist like cariprazine^11-13,15.