Although antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.

To delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia.

Pooled data of cariprazine-treated (1.5-6mg/day) and placebo-treated patients from four short-term, randomised, double-blind trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) were analysed. Baseline characteristics (age, duration of illness) and efficacy outcome parameters (Total and Hostility Factor Score of the Positive and Negative Syndrome Scale [PANSS]) were compared in patients receiving benzodiazepines (for more ≥3 consecutive days) and not receiving benzodiazepines (<3 consecutive days).

Altogether, 36.7% and 40.7% of the CAR-treated and PBO-treated patients required BZDs. BZD-taking was associated with a higher age in both the CAR-treated (p=0.0002) and PBO-treated (p<0.0001) patients, and with longer illness-duration in both treatment groups (p<0.0001). PANSS Total Score at baseline was similar for BZD users and non-users (CAR: LS Mean=96.36 and 96.27; PBO: LS Mean=95.55 and 96.66). Change from baseline in the PANSS Total Score was greater for patients who did not use BZD vs those who did (CAR: LS Mean= -23.8 vs LS Mean 17.2, p<0.0001; PBO: LS Mean= -14.0 vs LS Mean 12.9, p=0.5776).

These findings may suggest that requiring benzodiazepines is a potential indicator of longer illness duration and poorer response in acute schizophrenia.

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The discovery of second-generation antipsychotics represented an authentic breakthrough for the management of psychotic disorders. Nevertheless, they still don’t adequately manage some aspects of these disorders, such as negative symptoms (NS), cognitive impairment, or extra-pyramidal symptoms (EPS). New-generation antipsychotics present different pharmacological mechanisms and have been reported to ameliorate these aspects. Among them, cariprazine acts as a D2/D3 partial agonist with variable affinity with serotoninergic receptors, and many studies show its efficacy for preventing and treating positive symptoms as well as for the management of NS and EPS.

To report a case of a patient diagnosed with schizophrenia with highly invalidating antipsychotic-induced EPS that remitted after switching to cariprazine, while maintaining clinical stability. To review literature about cariprazine and its relationship with NS and EPS.

We describe the case of a 66-year-old woman diagnosed with schizophrenia and under treatment with three-month injectable paliperidone 175mg. During her follow-up at outpatient clinic, she presented a progressively highly invalidating non-trembling parkinsonian syndrome attributable to medication. Paliperidone plasmatic levels were within therapeutic range. An antipsychotic switch was agreed, and cariprazine was started.

The switch from a second-generation antipsychotic to cariprazine entailed the remission of a highly invalidating EPS while improving some of the NS and maintaining psychopathological stability.

Assessing and differentiating NS and EPS is of an utmost importance during the follow-up of patients under antipsychotic treatment. Cariprazine is an interesting alternative when treating patients diagnosed with psychotic disorders that present mostly NS and antipsychotic-induced EPS.

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Affective symptoms are a common feature of schizophrenia and define bipolar disorder. Alterations in dopamine neurotransmission and activity at D3-D2 receptors is associated with depressive symptoms providing the rationale for targeting D3-D2 receptors with partial agonists.

The aim of the analysis herein is to examine and compare the efficacy of cariprazine in treating affective symptoms in both schizophrenia and bipolar depression.

Data from 3 schizophrenia [NCT00694707, NCT01104766, NCT01104779] and 3 bipolar I depression studies [NCT013896447, NCT02670538, NCT0267055] were pooled for the analyses. To investigate efficacy across individual affective symptoms, the Marder anxiety/depression and negative symptom items of the Positive and Negative Syndrome Scale (PANSS) and single items of the Montgomery-Asberg Depression Rating Scale (MADRS) were analysed. Improvement across affective symptoms was examined primarily evaluating least square mean differences (LSMDs) in comparison to placebo in mean change from baseline.

The pooled ITT population was comprised of persons with schizophrenia (placebo=442, cariprazine=1024) and bipolar disorder (placebo=460, cariprazine=923). Cariprazine resulted in a significantly greater reduction when compared to placebo in three out of the four Marder anxiety/depression items; anxiety (p<0.01), tension (p<0.001) and depression (p<0.05). Similarly, cariprazine was significantly better than placebo in 9 out of the 10 MADRS individual items; apparent sadness (p<0.001), reported sadness (p<0.001), reduced sleep (p<0.05), reduced appetite (p<0.001), concentration difficulties (p<0.001), lassitude (p<0.001), inability to feel (p<0.001), pessimistic thoughts (p<0.01) and suicidal thoughts (p<0.05).

The results herein indicate that cariprazine treatment is significantly effective at treating affective symptoms in persons with both schizophrenia and bipolar I depression.

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Chronic schizophrenia patients are experiencing persistent and severe illness for more than 15-20 years and are usually suffering from long-term negative symptoms. Cariprazine, a novel D3-D2 partial agonist has been proven to be effective in the treatment of acute schizophrenia, however its ability to treat chronic patients has not been assessed yet.

The primary aim of the present post-hoc analysis is to assess the efficacy of cariprazine in treating patients with chronic schizophrenia (late-stage and residual schizophrenia patients).

Data from 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with more than 15 years of schizophrenia were analysed (late-stage patients). Furthermore, schizophrenia patients experiencing predominantly negative symptoms from a 26-week, randomized, double-blind, active-controlled, fixed-flexible-dose trial with an ICD-10 code of F20.5 were analysed post-hoc (residual patients).

Altogether, 414 late stage (286 cariprazine and 128 placebo) and 35 residual (23 cariprazine and 12 risperidone) patients were identified. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference in favour of cariprazine in the late stage (LSMD -6.7, p<0.01) subpopulation compared to placebo. The mean change from baseline in patients with residual schizophrenia in the cariprazine arm was -9.6 on the PANSS-FSNS scale, while -7.9 in the risperidone arm.

Based on the results, it seems that cariprazine might be a good treatment option for patients with chronic schizophrenia. Nonetheless, further studies are needed to confirm this.

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To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia.

Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance.

In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=−0.5 [P<.001]; 3 mg/d=−0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=−1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; −2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073).

These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

The aim of the post hoc analysis was to better understand the efficacy and safety of cariprazine in patients with schizophrenia for less than 5 years (early stage) and for more than 15 years (late stage).

Data from three phase II/III randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with early and late stage of schizophrenia were determined. A mixed-effects model for repeated measures approach was applied and least square (LS) mean changes from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total and factor scores were reported. Descriptive statistics were used for safety analyses including treatment emergent adverse events (TEAEs) and discontinuation rates.

Overall, 460 patients were identified as being in the early and 414 in the late stage of schizophrenia. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference between cariprazine and placebo in favor of cariprazine in both the early (LS mean difference [LSMD] −7.5 P < .001) and late stage (LSMD −6.7, P < .01) subpopulation. Early stage patients experienced similar amount of TEAEs (CAR 67.3%, PBO 54.1%) as patients in the late stage (CAR 69.6%, PBO 65.6%).

In conclusion, cariprazine, a potent D3-D2 partial agonist has been found to be safe and effective in the treatment of early and late stage schizophrenia.

The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations.

Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine–risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS.

While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and uncooperativeness in acute phase patients and hostility and delusions in patients with PNS.

This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS.

In the early stage of schizophrenia (first 5 years), the most important clinical target besides symptom control is relapse prevention as each relapse significantly decreases the possibility of preferable long-term outcomes. Early discontinuation of antipsychotic medication due to intolerable side-effects is one of the most common causes of relapse.

This poster aims to present cariprazine’s tolerability in the early stage of schizophrenia.

Data from 4 randomized, double-blind, placebo-controlled trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) with similar design (1 week of wash out period, 6 weeks of treatment and 2-4 weeks of follow-up) were pooled. For the post-hoc analysis, patients with early stage of schizophrenia (defined as having a disease duration of less than 5 years) were extracted from the whole safety population, and approved doses of cariprazine (1.5-6.0 mg/day) were combined. Treatment-emergent adverse events (TEAEs) and discontinuation rates were analysed versus placebo.

Overall, 169 placebo- (PBO) and 322 cariprazine-treated (CAR) patients were identified as having schizophrenia for less than 5 years. 67.7% cariprazine- and 56.2% placebo-treated patients reported at least one TEAE; most frequently insomnia (10.9 % CAR; 12.4% PBO), akathisia (9.6% CAR; 2.4% PBO) and extrapyramidal symptoms (9.3% CAR; 1.8% PBO). Discontinuation due to adverse events was reported in only 8.4% of cariprazine- and 14.8% of placebo-treated patients. Relapse occurred in 3.1% of cariprazine- and 5.3% of placebo-treated patients.

Cariprazine was generally well-tolerated in the early stage of schizophrenia; given the limitations of this analysis, additional research is warranted.

Studies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dombi, Acsai, Dr. Barabássy, Dr. Sebe, Dr. Laszlovszky, Dr Vass, Dr. Szatmári and Dr. Németh are employees of Gedeon Richter Plc., Dr. Earley and Dr. Patel a

Treatment-resistant schizophrenia (TRS) affects 30% of people with a diagnosis of schizophrenia, and is defined as nonresponse to at least two trials of antipsychotic medication of adequate dose and duration. Clozapine is the only evidence-based treatment for TRS. Cariprazine may be considered significantly more efficacious than risperidone in improving negative symptoms of schizophrenia.

To describe the experience of using cariprazine in combination with clozapine in patients with refractory schizophrenia and negative symptoms.

Qualitative design. We present a case report study of a 47-year-old male with a diagnosis of TRS, treated in our outpatient mental health clinic for twenty years. The patient experiences crystallized delusional ideas of harm, self-referential, paranoid and mystical-messianic content, phenomena of theft and thought reading, egodistonic auditory hallucinations. No substance use disorder was observed. He made several suicide attempts in the context of intense suffering and psychotic anguish. Clozapine 400mg/day was instituted after no response to treatment with amisulpride, paliperidone, olanzapine or aripiprazole. The intensity of positive symptoms was reduced (experiences of damage, commenting and insulting auditory hallucinations, self-referentiality), as well as the emotional and behavioral repercussions. Persistent negative symptoms appeared such as apathy, abulia, clinophilia, anergy, social isolation, affective flattening, impairing his functionality.

Neuroimaging and periodic blood tests results were normal. Oral cariprazine was added in ascending doses up to 4.5mg with good tolerance. The patient showed remission of apathy, enhancement of behavioral activation, socialization and motivation to perform occupational activities.

Combinations of clozapine with partial agonists may improve the quality of life in refractory schizophrenia.

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Motivation deficit is a significant aspect of lack of improvement in patients with schizophrenia especially with predominant negative symptoms (PNS). Therefore, improvement depends not only on symptoms reduction and better social functioning but also on patient engagement which is a key but less investigated aspect of successful treatment.

To investigate and compare patient engagement in PNS patients after cariprazine and risperidone treatment characterized by the 11 items of the Positive and Negative Syndrome Scale (PANSS-11).

In this phase 3 study patients suffering from PNS of schizophrenia (PANSS-FSNS≥24) were randomized to 26 weeks of treatment with either cariprazine or risperidone (target dose 4.5 and 4 mg/day, respectively). To compare the effects of the two drugs on patient engagement the PANSS-11 scale was used. Change from baseline (CfB) on the selected items and PANSS-11 total score were analyzed using mixed model of repeated measures approach without correction for multiplicity.

PANSS-11 total score mean CfB were -11.20 (SD=0.43) for cariprazine-, and -9.44 (SD=0.45) for risperidone-treated patients with a -1.79 (95% CI=-3.01, -0.56) mean difference (p=0.004) in favor of cariprazine. Most item differences were statistically significant (N1, N2, N3, N4, N5, G16) or numerically higher (N6, G7, G13) for cariprazine versus risperidone.

Cariprazine significantly improved patient engagement in patients with PNS of schizophrenia compared to risperidone based on the PANSS-11 post-hoc analysis. These results suggest that cariprazine treatment may improve not only the symptoms and everyday functioning of PNS patients but their engagement with life.

Studies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dr. Laszlovszky, Dombi, Balogh, Dr Barabassy, Dr Vass, Dr. Szatmári and Dr. Németh are employees of Gedeon Richter Plc.

Although monotherapy is preferable, in every day clinical practice polypharmacy is often unavoidable due to the need of treatment enhancement or cross-titration phases with shorter or longer overlaps of two or more drugs. However, administration of more than one drug treatment is often associated with more side effects.

The aim of the present post-hoc analysis was to examine treatment emergent adverse events (TEAEs) during co-administration of cariprazine with other antipsychotics.

Treatment emergent adverse event data (TEAE) from a randomized, double-blind, parallel-group, active-controlled study (EudraCT Number: 2012-005485-36) in adult patients with schizophrenia having predominant negative symptoms was examined in the first two weeks of the double-blind treatment period, where gradual cross-titration occurred between cariprazine (3-6 mg/day) and other antipsychotics (including amisulpride, aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, quetiapine, and sertindole). Thereafter, 24 weeks of cariprazine monotherapy followed.

During the cross-titration period, 17.83% of patients experienced at least one TEAE. The TEAEs were in line with the well-established safety data: nausea (2.61%), insomnia (2.17%), headache (2.17%), akathisia (1.74%) and restlessness (1.3%) were the most common. Most events were mild in severity (66.1% mild, 32.2% moderate, 1.7% severe (insomnia)).

While not definitive, and limited by small sample size, the co-administration of cariprazine with other antipsychotics did not show an unexpected safety profile or overlapping toxicities. This is an important finding, if intermittent or longer co-administration of other antipsychotics are unavoidable with cariprazine treatment.

Studies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dr Vass, Dr Barabássy, Dr Laszlovszky, Dr Sebe, Dombi, Dr Szatmári and Dr Németh are employees of Gedeon Richter Plc.

Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms.

Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of −2.5 (p = .0033) and −2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (−3.3; p = .0008), but not for 3 mg/day (−1.9; p = .0562).

The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.

Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.

Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).

Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P <.05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P <.01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P <.05).

Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.

This was a multicenter, open-label, flexible-dose study of cariprazine 3–9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3–9 mg/d) and 4 weeks of safety follow-up.

A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.

Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.