Introduction
Obsessive–compulsive disorder (OCD) has been considered for decades a chronic, poorly responsive disorder until the introduction of serotonin reuptake inhibitors (SRIs); these medications are well established as a first-line pharmacotherapeutic treatment for OCD across consensus guidelines. However, despite the excellent safety profile and demonstrated efficacy of SRIs, a substantial proportion of individuals with OCD fails to attain sufficient benefit. Although the proportion of patients who may be considered treatment-resistant or intolerant is difficult to define, it may be approximately estimated to be between 40 and 50% after an adequate medication treatment trial.Reference Pallanti 1 In recent years, this prompted researchers to investigate possible strategies for treatment-resistant patients. One of the most studied and promising strategies, to date, is the addition of antipsychotics to SRI treatment.Reference Koran and Saxena 2 -Reference Van Roessel, Grassi and Aboujaoude 4 Several studies examining antipsychotic augmentation have demonstrated the efficacy of these agents in patients with treatment-resistant OCD: risperidone has been reported as being the most effective in treating OCD symptoms in meta-analysesReference Dold, Aigner and Lanzenberger 5 , Reference Zhou, Zhou and Li 6; aripiprazole has also been shown to be effectiveReference Pessina, Albert and Bogetto 7 , Reference Muscatello, Bruno and Pandolfo 8; quetiapine and olanzapine efficacy have been examined, although the results are inconsistent and multiple meta-analyses have been unable to demonstrate their superiority versus placeboReference Dold, Aigner and Lanzenberger 5 , Reference Bloch, Landeros-Weisenberger and Kelmendi 9 –Reference Dold, Aigner and Lanzenberger 11; paliperidone has been studied in treatment-resistant OCD patients in one randomized, placebo-controlled trial of 8 weeks showing significant baseline to post-treatment reductions in Y-BOCS, yet between group differences did not meet the threshold for significance.Reference Storch, Goddard and Grant 12 A more recent network meta-analysis investigating different pharmacological agents used in augmentation strategies for treatment-resistant OCD found that, amongst atypical antipsychotics, aripiprazole and risperidone achieved significant efficacy in Y-BOCS scores reduction.Reference Suhas, Malo and Kumar 13
Cariprazine is a partial agonist of dopamine D2/D3 receptors (with a higher affinity for D3) and serotonin 5HT1A/5HT2A receptors.Reference Stahl 14 This unique receptor profile may play a role in its efficacy and tolerability and is believed to be involved in its antipsychotic, antidepressant, antianhedonic, and pro-cognitive effects.Reference Duric, Banasr and Franklin 15 , Reference Gyertyán, Sághy and Laszy 16 FDA has approved cariprazine as an adjunctive treatment for unipolar depression (1.5–3 mg/day). However, in Europe, it has been approved only for schizophrenia. Given that cariprazine is a third-generation antipsychotic and that it has a unique pharmacologic profile involving serotoninergic activity, it might also be effective in OCD, in combination with SRIs. Up to date, there is no data regarding the use of cariprazine as an augmentation strategy in patients with OCD who failed to respond to SRI treatment.
In this retrospective observational study, we show outcomes for patients with OCD who failed to respond to SRIs and were subsequently treated with low-dose cariprazine as an add-on.
Material and methods
Clinical records of inpatients and outpatients with an OCD diagnosis according to DSM-5 criteria treated in the Mental Health Department of Alba and Bra (Italy) and the Mental Health Department of Naples (Italy) from June 2022 to April 2023 were analyzed. Patients were included in the analysis if they (i) had a Yale-Brown Obsessive-Compulsive Scale (YBOCS) total score ≥16, (ii) showed resistance to at least one adequate trial with a SRI (clomipramine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), and (iii) were subsequently treated with cariprazine as an add-on at a starting dose of 1.5 mg/day. All psychiatric diagnoses and clinical assessments were made by psychiatrists with several years of experience.
SRI resistance was defined as a failure to show an improvement ≥25% at the YBOCS total score after at least 12 weeks with an adequate dose of SRIs according to American Psychiatric Association guidelines. Written informed consent was obtained from all subjects for the potential use of their anonymized clinical data for teaching or research purposes. Written consent was also collected for off-label treatment. Socio-demographic, clinical, and safety information were collected for each subject from medical records. The primary efficacy measures were the YBOCS and the Clinical Global Impression-Severity (CGI-S) scores, which were routinely administered at each visit, approximately once every 2 weeks. Treatment response was measured by the change from baseline to week 12. The percentage of patients who responded to the augmentation with cariprazine was calculated. For the purpose of this study, we considered responders patients who had an improvement of ≥25% at the YBOCS total score with respect to the beginning of the addition phase. During each visit, the UKU Side Effect Rating Scale was used to record all adverse effects reported by patients or investigators. Paired t-tests were used to evaluate differences in YBOCS and CGI-S scores between baseline and the end of the 12-week add-on period. Significance was set at p < 0.05. The Statistical analysis was conducted using SPSS software version 19.
Results
Thirteen patients fulfilled the entry criteria and were eligible for the study. Table 1 shows the socio-demographic and clinical characteristics of the 13 patients included. A mean age of 40.9 ± 15.9 years was recorded among the patients; 7 (53.8%) were female and 6 (46.2%) were male. The majority of them were married (61.5%) and were highly educated (69.2% ≥13 years). Mean age at OCD onset was 17.2 ± 4.0 years while mean illness duration was 30.8 ± 11.4 years. None of the included subjects had psychiatric comorbidities or substance abuse.
Table 1. Sociodemographic and Clinical Characteristics of the Sample
Abbreviations: CGI-S, Clinical Global Impression-Severity Scale; OCD, obsessive-compulsive disorder; SRI, serotonin re-uptake inhibitor; YBOCS, Yale-Brown Obsessive-Compulsive Scale.
All patients were still treated with cariprazine at 12 weeks. Ten out of 13 patients took the minimum dose (1.5 mg/die) of cariprazine; in 3 patients the dose had been increased to 3 mg/die. Cariprazine dosage changes were implemented according to clinical judgment (dosage variation was established in relation to efficacy and tolerability observed). The SRI dose remained unchanged during the add-on weeks for all patients.
Patients showed significant improvement over the 12-week study period (Figure 1; paired t-test for mean Y-BOCS total score at week 12 compared to baseline: t = 8.266, df = 12, p < 0.001). When examining obsessions and compulsions subscales of the YBOCS we also found a significant improvement at week 12 compared to baseline (paired t-test for mean YBOCS obsession subscale: t = 7.015, df = 12, p < 0.001; paired t-test for mean YBOCS compulsion subscale: t = 6.446, df = 12, p < 0.001). Analysis of variance revealed a significant treatment effect over the 12-week trial period for time (F = 19.682, p < 0.001); similar results emerged for the YBOCS obsession subscale (F = 14.571, p = 0.001) and the YBOCS compulsion subscale (F = 15.192, p < 0.001). Table 2 shows the YBOCS scores of the 13 OCD subjects who completed the 12-week observational period. Examining the CGI-S score we found a significant improvement at week 12 compared to baseline (paired t-test for mean CGI-S score t = 6.008, df = 12, p < 0.001); analysis of variance of CGI-S scores revealed a significant treatment effect over the 12-week trial period for time (F = 10.241, p = 0.002). At the end of the study, 8 patients (61.5%) met the response criteria of ≥25% improvement in YBOCS total score versus baseline. Overall, adverse effects were reported by 11 patients (84.6%). All the side effects reported were mild. The most common adverse event recorded was a sense of inner tension which was experienced by 3 (23.1%) patients. Table 3 summarizes all adverse events that occurred in the sample.
Figure 1. Mean reduction in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scores during the 12 week observation period.
Table 2. Efficacy Results for Patients with Obsessive-Compulsive Disorder Who Received Cariprazine as Add-On Ttherapy
Abbreviation: YBOCS, Yale-Brown Obsessive-Compulsive Scale.
Table 3. Adverse Events Reported in Patients with Obsessive-Compulsive Disorder Who Received Cariprazine as Add-On Therapy
Discussion
To the best of our knowledge, this is the first report evidencing that the addition of low doses of cariprazine to ongoing SRI treatment can improve obsessive-compulsive symptoms in patients who were resistant to SRI alone. There is only a single case report in literature describing cariprazine as an add-on to long-acting paliperidone treatment in a patient with schizophrenia who developed OCD symptoms.Reference De Berardis, Vellante and Fornaro 17 More than two-thirds of patients satisfied response criteria at the end of the 12-week study period. From a pharmacological perspective, cariprazine is a partial agonist of dopamine and serotonin receptors, and it could be through this mechanism of action that OCD symptoms improve. Although there is a recent report in the literature of cariprazine-induced OCD,Reference Pariwatcharakul and Suthisisang 18 which could be mediated by the drug interaction with D3 receptors, in our sample there was no evidence of exacerbation of OCD symptoms which could be linked to cariprazine treatment.
Due to a lack of data about cariprazine as an augmentation strategy in patients with OCD, it is not possible to compare our findings with the existing literature. However, our responder rate of 61.5% was significantly superior to that of the other antidopaminergic agents usually found to be effective in one-third of patients with treatment-resistant OCD.Reference Grassi, Cecchelli, Mazzocato and Vignozzi 19 , Reference Grassi, Cecchelli, Vignozzi and Pacini 20 Several limitations should be considered when interpreting these results: the small sample size; the retrospective nature of the data collected; and the absence of a control group.
Nevertheless, cariprazine augmentation was well tolerated. The most common adverse event was inner tension. No severe adverse events emerged during the study; no patients discontinued treatment during the 12-week period. Most notably, only one patient showed weight gain. This aspect is in line with a recent retrospective study of electronic health reports in which cariprazine treatment revealed a neutral weight and metabolic profile.Reference Masand, McIntyre and Cutler 21 This is a critical issue given the significant long-term metabolic risk of atypical antipsychotic medications and the consequent increased cardiovascular risk.
In conclusion, our preliminary results suggest that cariprazine may be a potentially effective and well-tolerated SRI augmentation strategy for treatment-resistant OCD. The results of this study need to be replicated in larger, randomized controlled trials.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/S1092852924000348
Author contributions
Data curation: D.D.B., I.P., A.M., E.P.; Formal analysis: D.D.B., V.M.; Conceptualization: I.P., A.M., E.P., V.M., C.I.C.; Methodology: F.R., C.I.C.; Supervision: F.R.
Disclosures
The authors declare no conflicts of interest.
