Background: Long-term treatment with antipsychotic agents is indicated for patients with schizophrenia, but treatment is associated with adverse events (AEs) that contribute to medication discontinuation and nonadherence. Understanding drug safety profiles is critical to avoid unwanted side effects. Cariprazine is a potent dopamine D₃/D₂ receptor partial agonist that is approved for the treatment of adults with schizophrenia (EU, US) and acute manic/mixed and depressive episodes associated with bipolar I disorder (US). Methods: Post hoc analyses were conducted to characterize the safety profile of cariprazine within the recommended 1.5– 6 mg/d dose range for schizophrenia; data from 8 short- or long-term clinical trials were analyzed. Results: In the pooled cariprazine-treated safety population (n=2048), the rate of study completion was 52.8%, with withdrawal of consent, insufficient response, and AEs the most common reasons for premature discontinuation. The most commonly reported AEs (> 10%) in the overall cariprazine-treatment group were akathisia (14.6%), insomnia (14.0%), and headache (12.1%); most AEs were considered mild (71.0%) or moderate (26.5%). Most akathisia was mild/moderate (97.5%) and > 93% of patients remained on treatment; akathisia events were managed by rescue medications (56.3%) or dose reduction (18.3%). The metabolic profile of cariprazine was neutral in patients with short- and long-term exposure; mean weight gain was 1 kg for overall cariprazine, with an AE of weight increased reported for 5.1%. Other AEs of special interest that occurred at > 3% for overall cariprazine were extrapyramidal disorder (7.0%), sedation (3.7%), and somnolence (3.1%); prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation occurred at ≤ 1%. Conclusion: Akathisia, the most common cariprazine-related AE, was mild/moderate and resulted in few study discontinuations; symptoms were well managed and most patients remained on treatment. Results of this analysis indicated that cariprazine in the recommended dose range was safe and generally well tolerated in patients with schizophrenia. Trial Registration: Studies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012– 005485-36).

Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients’ bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients’ bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.

The aim of the chapter is to raise awareness about recent constructs of negative symptoms, their burden on patients, caregivers and society, and about their management. Schizophrenia consists of positive, negative, and cognitive symptoms. However, treating physicians are not necessarily aware about recent constructs of negative symptoms, their presence at prodromal stage, and the distinction among primary, secondary, persistent, prominent, or predominant negative symptoms. Negative symptoms have a substantial impact on the day-to-day functioning of patients with schizophrenia and contribute more to impaired quality of life and poor functioning than positive symptoms do. Additionally, they are associated with high costs for society and a substantial burden for caregivers. Negative symptoms are not adequately treated by available antipsychotic therapies. Publications have shown that no antipsychotic has a beneficial effect when compared to another. Cariprazine is the only antipsychotic that has proven superiority over another antipsychotic (risperidone) in one clinical study.

Schizophrenia is a long-term disease that needs to account for acute symptom control and long-term treatment needs such as relapse prevention, remission, and safety. The aim of the present book chapter was to summarize available literature data and guidelines on how to treat specific symptoms of schizophrenia and what aspects to consider long term. Looking at single symptoms, clozapine was better than all other antipsychotics in addressing positive and hostility symptoms of schizophrenia: however, it is not first-line treatment. Cariprazine showed superior efficacy in treating primary negative symptoms and is treatment of choice for these symptoms. Additionally, partial agonists (aripiprazole, brexpiprazole, cariprazine) were better in addressing comorbid substance use, while quetiapine, cariprazine, and olanzapine/fluoxetine showed advantages in treating mood disorders. In long term, there was no difference between antipsychotics in addressing relapse and remission; however, distinct differences in safety aspects are seen; overall, newer generation antipsychotics (aripiprazole, brexpiprazole, cariprazine, and lurasidone) are favored over other antipsychotics. In summary, careful consideration should be applied when choosing the right treatment for schizophrenia, accounting for prevalent symptoms, longitudinal aspects, psychiatric and somatic comorbidities as well as preference of patients.