Cariprazine augmentation for negative symptoms of schizophrenia: a prospective analysis and literature review

Abstract

Cariprazine is effective in a number of conditions and has shown efficacy in the treatment of negative symptoms. Data on its use as an adjunct to other antipsychotics is growing. To evaluate the effectiveness of add-on cariprazine in patients with predominant negative symptoms, we assessed a series of patients prescribed adjunctive cariprazine using the Schedule for the Assessment of Negative Symptoms (SANS). Patients had few positive symptoms, but negative symptoms were considered to have a major effect on functioning. SANS scores were calculated at baseline, 12 weeks and 24 weeks. We compared median scores using the Wilcoxon signed-rank test. Ten consecutive patients were evaluated. Median baseline SANS score was 87 (IQR 32), 66 (IQR 23) at week 12 (p = 0.002 vs baseline) and 57 (IQR 33) at week 24 (p = 0.006 vs baseline). At Week 12, 70% of the patients were still prescribed the initial starting dose of 1.5 mg daily, and at Week 24, 30% of the patients remained on the 1.5 mg/day dose. Adjunctive cariprazine was effective in the treatment of residual negative symptoms in people with minimal positive symptoms.

Keywords

cariprazine literature review negative symptoms prospective analysis treatment-resistant schizophrenia

Introduction

Negative symptoms affect up to 60% of patients with schizophrenia and can be categorised as primary negative symptoms (core feature of the disease) or secondary negative symptoms (associated with or caused by psychotic symptoms, depression or neurologic side effects related to dopaminergic blockade.¹

Importantly, negative symptoms of schizophrenia are linked to poor social and occupational functioning, but antipsychotic drugs have demonstrated limited efficacy in this domain.^2,3 Effective treatment of negative symptoms remains a major unmet need in the management of schizophrenia.

Distribution of D₃ receptors in the brain differs from that of D₁ and D₂ receptors.⁴ The former are primarily situated in the limbic areas, which control structures important for reward, motivation, and emotional processing. D₃ receptors disinhibit dopamine release in the prefrontal cortex, which, additionally, improves cognitions, mood regulation and motivation.⁴

Cariprazine is a relatively new antipsychotic being licensed for the treatment in adults in 2018.⁵ In the United States, it has been also approved for treating manic, depressive or mixed states in the context of bipolar I.⁶ It is well-tolerated with principal adverse effects being insomnia, akathisia and nausea.⁵

Cariprazine is an antipsychotic drug with a reported effect on primary negative symptoms when combined with other antipsychotics.^7
–10 It is a dopamine D₃-preferring D₃/D₂ receptor partial agonist and serotonin 5-HT_1A receptor partial agonist. Cariprazine’s therapeutic activity against negative symptoms may be related to preferential expression in the mesolimbic circuit of the dopamine D3 receptor. Partial antagonism at 5-HT1A may help to improve depressive symptoms.¹¹ Cariprazine also has antagonistic action towards 5-HT2B receptors, potentially contributing to the reduction of extrapyramidal symptoms.^11,12

Cariprazine has a long duration of action, with the parent drug having a plasma half-life of several days.⁵ Cariprazine produces two clinically active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), with a half-life of 13 days and 19 days, respectively.⁵

Reports published to date are largely limited to non-systematic evaluations of small numbers of cases of augmentation of clozapine. Here we report outcomes in ten consectutive patients receiving cariprazine in addition to a range of antipsychotics.

Methods

Approvals

This was a prospective analysis of outcomes resulting from adjunctive cariprazine use in normal clinical practice, carried out from March 2024 until December 2025. We had previously informally noted improvements in patients given cariprazine for residual negative symptoms. In this analysis, we set out to evaluate outcomes more formally and report those outcomes. The hospital location for this analysis (Sygnet Churchill Hospital, London) did not have a functioning overseeing authority or committee for research. Local management approval was sought and given. All of those whose data are reported here gave written consent relating to the use of their anonymised clinical data, and to some limited demographic data and to publication. No patient can be identified in this summary report and access to patient data was at all times restricted to those healthcare staff directly involved in each patient’s care. Patient data were anonymised at source and stored on an encrypted hard drive.

Inclusion criteria

The patients were identified at the point of admission to the hospital. Inclusion criteria included treatment with one antipsychotic agent, which controlled most positive symptoms of schizophrenia and the presence of negative symptoms of a moderate degree as rated with the SANS scale at baseline (see below). Patients had all been stable on their primary antipsychotic for several months before being approached. There were no observed or reported baseline extrapyramidal adverse effects during the course of the analysis. One patient was prescribed procyclidine before the commencement of the analysis, with a good effect. No patient had depressive symptoms severe enough to fulfil criteria for a depressive episode. All eligible patients were approached by one of the authors (EO-R) during the course of 32 weeks in 2023 and 2024. Two of a total of 12 patients who were approached declined to participate in the analysis. As mentioned above, all patients who agreed to be part of the analysis signed the agreement form attesting consent to the use of the Scale for the Assessment of Negative Symptoms (SANS)¹³ and the reporting of anonymised outcomes.

Exclusion criteria

Patients were excluded from the analysis if they lacked the capacity to agree to treatment with cariprazine, had a history of poor compliance with oral medication or exhibited predominantly positive symptoms of schizophrenia.

Measurements used

The SANS is a rating scale which measures negative symptoms in schizophrenia. SANS splits assessment into five domains, including affective flattening-blunting, alogia, avolition-apathy, anhedonia-asociality and attention. The symptoms of each domain are rated between (absent) and 5 (severe). The scores were assigned following agreement between the two raters. The total score below 55 indicated a mild degree of negative symptoms, above 55 – a moderate degree (the threshold in this analysis), above 70 – a marked degree, and above 85 – a severe degree.¹³

Additionally, the presence of significant depressive symptomatology was excluded at the baseline based on clinical observation and evaluation of mental state and the scores obtained on the Montgomery and Asberg Depression Rating Scale (MADRS) scale.¹⁴ The MADRS is a 10-item structured depression rating scale used for diagnostic purposes. Each item is rated on a 7-point scale based on a clinical interview. Typically, scores between 7 and 19 indicate mild depression. We did not employ a specific cut-off MADRS score but, in ensuring the absence of significant depressive co-morbidity, the authors took into account the overlapping symptomatology, mainly blunting of affect and concentration difficulties, seen in depression and schizophrenia with negative symptoms, which are both assessed by SANS and MADRS scales.

Analysis design

The SANS scores were evaluated every 12 weeks. All patients were supervised when taking medications. The initial dose of cariprazine added to the leading antipsychotic was 1.5 mg daily. The decision to increase the dose of cariprazine to 3 mg daily was made individually for each patient by one of the co-authors and was based on the clinical impression. The patients, who were prescribed clozapine, all had clozapine blood levels within the therapeutic target range. Additionally, each patient was specifically asked by a clinician about side effects during frequent one-to-one reviews and ward rounds.

The SANS scores were scored individually by one of the co-authors (EO-R) and the nurse responsible for the care of a particular patient. Disagreements were resolved by consensus.

Reporting guidelines

We followed the STROBE checklist for cohort studies in preparing this manuscript (Supplemental Material).¹⁵

Results

Demographic details and outcomes are given in Table 1. Individual patient data are provided in Table 2.

Table 1.

Group characteristics summary data.

Demographic and outcome-related characteristics	n/SANS score
Sex, n (%)
Male	10 (100%)
Mean age, years (SD)	31.1 (7.6)
Ethnic background, n (%)
Asian	1 (10%)
Black, Caribbean or African	5 (50%)
Mixed ethnic group	0 (0%)
White British and White others	4 (40%)
Occupation, n (%)
Employed	0 (0%)
Unemployed	10 (100%)
Main diagnosis, n (%)
Schizophrenia	7 (70%)
Schizoaffective Disorder	3 (30%)
The mean course of the disease, years (SD)	11.7 (5%)
Primary antipsychotic, n (%)
Clozapine	7 (70%)
Other typical antipsychotic (zuclopenthixol decanoate)	2 (20%)
Atypical antipsychotic (paliperidone palmitate)	1 (10%)
Dose of cariprazine at 12 weeks (n %)
1.5 mg daily	7 (70%)
3 mg daily	3 (30%)
Dose of cariprazine at 24 weeks (n %)
1.5 mg daily	3 (30%)
3 mg daily	7 (70%)
Median (min, max) of MADRS ratings at the baseline	6 (1,9%)
Median (min, max) of SANS total ratings
At baseline	87 (58,112)
At 12 weeks	66 (20,110)
At 24 weeks	59 (24, 80)

Table 2.

Individual patient characteristics.

Patient	Primary diagnosis	Secondary diagnosis	Presence of positive symptoms/factors affecting the SANS score	Changes to the treatment regimen	Years of illness	Primary antipsychotic	Previously prescribed antipsychotics
1	Paranoid Schizophrenia	ASD	None	None	7 years	Zuclopenthixol decanoate 500 mg 2-weekly	Aripiprazole, olanzapine, risperidone
2	Hebephrenic Schizophrenia	–	Chronic auditory hallucinations, Positive for THC at Week 10	Promethazine 25 mg was added at Week 16.	13 years	Clozapine 575 mg/24 h	Risperidone, olanzapine, olanzapine pamoate, amisulpride, flupentixol decanoate, chlorpromazine, haloperidol, haloperidol decanoate
3	Paranoid Schizophrenia	–	Chronic auditory hallucinations, Positive for THC at Week 16	None	6 years	Clozapine 300 mg/24 h	Aripiprazole, olanzapine, haloperidol, lurasidone
4	Paranoid Schizophrenia	–	Chronic, mild paranoid delusions	None	24 years	Paliperidone palmitate 100 mg monthly	Aripiprazole, risperidone, amisulpride, flupentixol decanoate, zuclopenthixol decanoate,
5	Paranoid Schizophrenia	–	Residual auditory hallucinations	None	10 years	Clozapine 600 mg/24 h	Olanzapine, quetiapine, risperidone, paliperidone palmitate, zuclopenthixol decanoate, flupentixol decanoate
6	Paranoid Schizophrenia	–	Chronic grandiose beliefs	Zuclopenthixol 25 mg for positive symptoms at Week 20	16 years	Zuclopenthixol decanoate IM depot 600mg 2-weekly	Aripiprazole, olanzapine, risperidone, risperidone long-acting injection
7	Paranoid Schizophrenia	–	None	None	6 years	Clozapine 600 mg /24 h	Olanzapine, risperidone, paliperidone palmitate
8	Paranoid Schizophrenia	C-PTSD	Mood fluctuation and pseudo-hallucinations	None	8 years	Clozapine 500 mg/24 h	Aripiprazole, olanzapine, risperidone, flupentixol decanoate
9	Schizoaffective Disorder	C-PTSD	Positive for cocaine + THC at Week 22	None	10 years	Clozapine 525 mg/24 h	Aripiprazole olanzapine, zuclopenthixol decanoate, haloperidol, haloperidol decanoate
10	Schizoaffective Disorder		Residual auditory hallucinations, Positive for THC at Day 3 and at Week 11	None	12 years	Clozapine 400 mg/24 h	Aripiprazole, olanzapine, quetiapine, risperidone, paliperidone palmitate, haloperidol, haloperidol decanoate, zuclopenthixol decanoate

Group characteristics

A total of ten male patients with the diagnosis of paranoid schizophrenia and schizoaffective disorder per ICD-11 (WHO, 2018), were identified between 2020 and 2023. All patients were classified as treatment-resistant. All male patients were former inpatients admitted to the male rehabilitation high-dependency ward. Alongside psychiatric intervention, they underwent psychological and occupational therapy interventions with a fluctuating level of r attendance. The average length of stay in the unit was 3 years.

Demographically, all patients except one were in their twenties or early thirties (the age distribution was from 23 to 52), and all held no employment at the point of admission. Half of the patients were of Black ethnic background, one of Asian background, and four patients were of White ethnic background.

Seven patients were diagnosed with paranoid schizophrenia and three with schizoaffective disorder. The average duration of illness was over 11 years and varied from 6 to 24 years. Half of the patients presented with severe negative symptoms at the baseline, two with marked negative symptoms, and three with moderate negative symptoms.

In relation to the primary antipsychotic, in seven cases, the primary antipsychotic was clozapine, in two cases, zuclopenthixol decanoate depot and in one case, paliperidone depot.

None of the patients reported emergent adverse effects when taking cariprazine, and none discontinued cariprazine due to poor tolerability. No patient needed to be prescribed an additional short-term course of benzodiazepine for agitation or akathisia. Compliance was monitored daily and within a 24-week period, there was no record of non-compliance. All patients underwent regular blood tests and ECG monitoring, including QTc intervals (no QTc prolongation was reported). No substantial oversedation or drowsiness was observed or reported during the analysis period.

At Week 12, 70% of the patients were prescribed the dose of 1.5 mg daily, and at Week 24, 30% of the patients remained on the 1.5 mg dose. Median baseline SANS score was 87 (IQR 32) at baseline, 66 (IQR 23) at week 12 (p = 0.002) and 57 (IQR 33) at week 24 (p = 0.006).

A Shapiro-Wilk test showed that the data were not normally distributed (p = 0.28). A Wilcoxon signed-rank test for non-parametric data was conducted to compare SANS scores at weeks 0–12, 0–24 and 12–24.

Median SANS scores fell by 21 points in weeks 0–12 (z = −3.0973, p = 0.002) and by 30 points in weeks 0–24 (z = −2.6132, p = 0.006). The reduction in SANS score between weeks 12 and 24 was 9 points (z = −1.886, p = 0.059; Tables 3 and 4 and Figure 1).

Table 3.

SANS score and cariprazine dose at baseline, week 12, and week 24.

Patient	SANS baseline	SANS, week 12	SANS, week 24
1* SA/O	94	82 (1.5 mg)	35 (1.5 mg)
2** SA	98	88 (1.5 mg)	80 (1.5 mg)
3* SA	112	76 (1.5 mg)	58 (1.5 mg)
4*	107	100 (1.5 mg)	66 (4.5 mg)
5* SA	84	70 (1.5 mg)	75 (3 mg)
6* SA	70	61 (1.5 mg)	70 (3 mg)
7* SA	66	57 (3 mg)	37 (3 mg)
8* SA/O	62	62 (1.5 mg)	56 (1.5 mg)
9** SA/O	58	20 (1.5 mg)	24 (3 mg)
10** SA	90	59 (3 mg)	52 (3 mg)

O: other diagnoses; SA: history of illicit substance misuse; X: discharged.

Paranoid schizophrenia.

Schizoaffective disorder.

SANS, schedule for the assessment of negative symptoms.

Table 4.

Median and IQR scores at baseline, Week 12, and Week 24.

SANS	Median	IQR
SANS Baseline	87	32
SANS Week 12	66	23
SANS Week 24	57	33

IQR, interquartile range; SANS, schedule for the assessment of negative symptoms.

Figure 1.

SANS score over 24 weeks.

Discussion

Cariprazine was effective in improving negative symptoms in all patients evaluated. These therapeutic effects of cariprazine may be associated with its partial D3 receptor activity – cariprazine has the highest affinity for D3 receptors among all antipsychotics.^16,17

Cariprazine has also been shown to improve negative symptoms as monotherapy in a randomised controlled trial¹⁸ and in post hoc analyses of controlled trials.^19,20 Several other case studies report the benefits of adding cariprazine to other antipsychotic agents, predominantly clozapine. Karoline and colleagues²¹ reported in a single case study of a male with treatment-resistant schizophrenia. Cariprazine at 3 mg daily was added as an augmentation to clozapine. Within 4 weeks, an improvement in negative symptoms was noted. Siwek and co-workers,⁷ in a retrospective chart review study on 12 patients, described an improvement of the Clinical Global Impression-Improvement scores following clozapine augmentation with cariprazine. Treatment led to a reduction in positive, negative, affective, and anxiety symptom severity, as well as an improvement in patients' global functioning. The median time to see improvement was 6 weeks. One patient discontinued the treatment due to akathisia. Pappa and colleagues¹⁰ presented a pilot case study of 10 patients of clozapine augmentation with cariprazine. There was a statistically significant reduction in total PANSS score from baseline at 3 months, and in the positive PANSS score, and negative PANSS score. Two of ten patients discontinued cariprazine within the first 6 weeks, one due to restlessness and one due to poor response. Boydstun and colleagues¹⁶ described two patients with treatment-resistant schizophrenia and an extensive hospitalisation history related to aggression and hostility, managed initially only on long-acting injectable antipsychotics. Following augmentation with cariprazine, both patients’ hostility and cognition improved. Lastly, Viegas and co-workers,²² described one case of a patient where adding 3 mg of cariprazine to clozapine caused an improvement in the psychomotor drive and mood in the first 30 days, and after 3 months, an improvement in communication and sociability. The same team described two other clinical cases of patients, who benefitted from switching clozapine and paliperidone to cariprazine in terms of better motivation, sociability and communication, improvement in the metabolic parameters as well as the absence of delusions.

In the present analysis, a real-world, 24-week prospective analysis, cariprazine added to the primary antipsychotic significantly and substantially improved refractory negative symptoms, both at Week 12 and Week 24. Several of the patients included had a duration of illness of over 20 years. Additionally, three patients (those on depot medication) had a history of non-compliance with oral medication and two of them presented a significant risk of harm to others when unwell. All seemed to adhere to cariprazine. The results additionally suggest that cariprazine is safe and well-tolerated in improving negative symptoms in those with minimal positive symptoms.

Limitations

There are limitations to this prospective analysis, the most important being the small sample size and the absence of any a priori sample size calculation. Participant numbers were limited by the availability of patients with predominantly negative symptoms. The patient group was also heterogeneous with regard to duration of illness and the number of previous treatment trials. SANS scores were assessed and calculated by professionals directly involved in patients’ care, which opens up the possibility of measurement bias. Further, some improvements in negative symptoms may have been secondary to psycho-social interventions, which were provided alongside pharmacological treatment. In addition to this, cariprazine doses were not definitively optimised. The dose was dictated by individual clinical response and observed functional improvement. In each case, the dose of cariprazine was collaboratively agreed upon with each patient, following the assessment of their capacity, with the hope that cariprazine would be willingly continued following their discharge. We also aimed to constrain the combined antipsychotic dose to 150% of the total maximum licensed dose of the primary antipsychotic and cariprazine combined

Conclusion

This prospective analysis demonstrated a statistically and clinically significant beneficial effect of adjunctive cariprazine on negative symptoms in treatment-resistant schizophrenia in patients with few residual positive symptoms. These outcomes support observations of previous studies showing the beneficial effect of cariprazine as an adjunct antipsychotic in the improvement of the negative symptoms of schizophrenia. Randomised controlled studies are needed to confirm this beneficial effect.

Supplemental Material

sj-docx-1-tpp-10.1177_20451253261456389 – Supplemental material for Cariprazine augmentation for negative symptoms of schizophrenia: a prospective analysis and literature review

Supplemental material, sj-docx-1-tpp-10.1177_20451253261456389 for Cariprazine augmentation for negative symptoms of schizophrenia: a prospective analysis and literature review by Ewa Okon-Rocha and David Taylor in Therapeutic Advances in Psychopharmacology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

David Taylor

Supplemental material

Supplemental material for this article is available online.

References

Correll

Schooler

NR.

Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat 2020; 16: 519–534.

Keefe

Bilder

Davis

, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64(6): 633–647.

Nasrallah

Tandon

Keshavan

Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment. Epidemiol Psychiatr Sci 2011; 20(4): 317–327.

Kiss

Laszlovszky

Krámos

, et al. Neuronal dopamine D3 receptors: translational implications for preclinical research and CNS disorders. Biomolecules 2021; 11(1): 104.

Recordati Pharmaceuticals Limited. Summary of Product Characteristics. Reagila (cariprazine hydrochloride) hard capsules, https://www.medicines.org.uk/emc/product/9401/smpc (2024, accessed 6 January 2025).

U.S. Food and Drug Administration. Highlights of prescribing information VRAYLAR® (cariprazine) capsules, for oral use, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204370s009lbl.pdf (2022, accessed 6 January 2025).

Siwek

Chrobak

Gorostowicz

, et al. Cariprazine augmentation of clozapine in schizophrenia-a retrospective chart review. Front Pharmacol 2024; 14: 1321112.

Oloyede

Clark

Mace

, et al. Clozapine augmentation with cariprazine for negative symptoms: a case series and literature review. Ther Adv Psychopharmacol 2022; 12: 20451253211066642.

Ivanov

Smulevich

Voronova

, et al. Early clinical effects of novel partial D3/D2 agonist cariprazine in schizophrenia patients with predominantly negative symptoms (open-label, non-controlled study). Front Psychiatry 2021; 12: 770592.

10.

Pappa

Kalniunas

Sharma

Raza-Syed

Kamal

Larkin

Efficacy and safety of cariprazine augmentation in patients treated with clozapine: a pilot study. Ther Adv Psychopharmacol. 2022;12:20451253221132087.

11.

Fountoulakis

Ioannou

Tohen

, et al. Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties: a hypothesis based on data. Eur Neuropsychopharmacol 2023; 72: 30–39.

12.

Selvan

Devkare

Shetty

, et al. A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia. Front Psychiatry 2024; 15: 1385925.

13.

Andreasen

Scale for the assessment of negative symptoms (SANS). Br J Psychiatry 1989; 155(Suppl. 7): 49–58.

14.

Montgomery

Asberg

A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.

15.

Equator Network. The strengthening the reporting of observational studies in epidemiology (STROBE)statement: guidelines for reporting observational studies, https://www.equator-network.org/reporting-guidelines/strobe/ (accessed 1 April 2026).

16.

Boydstun

Lynch

DiGenova

Cariprazine: an augmentation strategy for treatment-resistant schizophrenia with pro-cognitive and anti-hostility effects. Int Clin Psychopharmacol 2023; 38(5): 361–366.

17.

Stahl

SM.

Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr 2017; 22(5): 375–384.

18.

Németh

Laszlovszky

Czobor

, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 2017; 389(10074): 1103–1113.

19.

Leucht

Dombi

Szabó

, et al. Single trajectory treatment response for predominant negative symptoms: post-hoc analysis of a clinical trial with cariprazine and risperidone. Schizophr Res 2023; 261: 24–30.

20.

Fleischhacker

Galderisi

Laszlovszky

, et al. The efficacy of cariprazine in negative symptoms of schizophrenia: post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry 2019; 58: 1–9.

21.

Karoline

Sekar

Charitha

, et al. Cariprazine augmentation in a patient with clozapine-resistant schizophrenia. Ind Psychiatry J 2023; 32(Suppl. 1): S279–S280.

22.

Viegas

Ferreira

Campos

Using cariprazine to ameliorate negative symptoms and metabolic side effects of clozapine and paliperidone – clinical cases. Neuropsychiatr Dis Treat 2022; 18: 1145–1149.

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