Discussion

Cariprazine is a dopamine D3/D2 potent partial agonist with a greater affinity for D3 than for D2 receptors and additional partial agonist activity at serotonin 5-HT1A receptors.^{Reference Nemeth, Laszlovszky, Czobor, Szalai, Szatmari and Harsanyi2,Reference Girgis, Slifstein, D'Souza, Lee, Periclou and Ghahramani6,Reference Kiss, Horvath, Nemethy, Schmidt, Laszlovszky and Bugovics7} Preclinical data suggest that antagonism at D3 receptors, preferentially expressed in the mesolimbic dopamine circuit,^{Reference Millan8} increases dopaminergic transmission in the prefrontal cortex,^{Reference Lacroix, Hows, Shah, Hagan and Heidbreder9} which could lead to an improvement in negative symptoms. Animal studies further indicate that cariprazine has anti-anhedonic and pro-cognitive effects.^{Reference Zimnisky, Chang, Gyertyan, Kiss, Adham and Schmauss10} In clinical trials, it has been reported to have significantly greater efficacy for negative symptoms than risperidone in patients with chronic but stable schizophrenia,^{Reference Nemeth, Laszlovszky, Czobor, Szalai, Szatmari and Harsanyi2} and aripiprazole in patients with an acute exacerbation of illness.^{Reference Earley, Guo, Daniel, Nasrallah, Durgam and Zhong5}

In chronic schizophrenia trials of cariprazine, the maximum effect on negative symptoms was evident after 26 weeks of treatment.^{Reference Nemeth, Laszlovszky, Czobor, Szalai, Szatmari and Harsanyi2} Here, a relatively quick time to cariprazine treatment response was observed, as is the case with other antipsychotics in FEP.^{Reference Emsley, Oosthuizen, Koen, Niehaus and Martinez11} In addition, our case series suggest that in early psychosis, lower dosages of cariprazine are required to achieve therapeutic effect than those reported in a clinical trial of patients with chronic illness (mean 4.2 mg/d),^{Reference Nemeth, Laszlovszky, Czobor, Szalai, Szatmari and Harsanyi2} similar to other antipsychotics at early stages of illness.^{Reference Salimi, Jarskog and Lieberman12} Interestingly, its concomitant use with lurasidone (see Table 1, patient 2) resulted in a much quicker response and at its lower dosage, a result which requires further evaluation in rigorous trials where cariprazine may be administered as adjunct treatment.

Although cariprazine was well-tolerated in five patients, one patient developed acute dystonic reaction (ADR). Partial dopamine agonists are associated with a low risk of extrapyramidal side-effects, as they do not completely antagonise dopaminergic activity in the nigrostriatal or tuberoinfundibular pathways.^{Reference Lieberman13} However, ADR following treatment with aripiprazole, another partial agonist, has been documented.^{Reference Desarkar, Thakur and Sinha14} Patients with FEP are more sensitive to the adverse effects of antipsychotics,^{Reference Morrison and McGuire15} and it is possible that the unexpected ADR in our patient was related to the early stages of the disorder and an observed general sensitivity to antipsychotic medication, including partial agonists.

To our knowledge, this is the first report of a case series in which cariprazine was used for the treatment of negative symptoms in FEP. Although the observations suggest that cariprazine may be useful for this indication and may alert clinicians to a novel, more effective treatment for negative symptoms, the findings are retrospective and involve a small number of patients. Large-scale, double-blind, randomised controlled trials in patients with FEP are required to formally investigate the efficacy of cariprazine in treating negative symptoms at the earliest stages of psychotic illness.