Study Suggests Cariprazine May Have Direct Effects on Negative Symptoms

A recently completed clinical study of 460 patients has provided the most compelling evidence to date that the atypical antipsychotic cariprazine may lead to improvements in schizophrenia patients with predominant negative symptoms.

While most current antipsychotics are effective at treating the positive symptoms of the disorder, treating negative symptoms such as anhedonia and cognitive challenges associated with the disease has proven more difficult. Some research suggests antidepressants may reduce negative symptoms if given as an adjunct therapy, but the evidence is limited.

Cariprazine—a dopamine D3 and D2 receptor partial agonist that was approved by the Food and Drug Administration in 2015 to treat adults with schizophrenia and manic/mixed episodes of bipolar disorder—generated some excitement early on after trials suggested the medication led to improvements in positive and negative symptoms. But, these trials were unable to determine whether the improvements in negative symptoms were directly from the medication or secondary to improvements in positive symptoms or comorbid depression (Psychiatric News, October 16, 2015).

The current study was carried out across 11 health centers across Europe. Researchers sought to tease apart these two possibilities by assessing only patients with predominantly negative symptoms. All enrollees had stable schizophrenia (six months or more without a psychotic exacerbation or a psychiatric hospitalization) and positive symptoms were well-controlled by their current medication.

The patients were weaned off their current medication and then randomly assigned to once-daily cariprazine (3 to 6 mg/day) or risperidone (3 to 6 mg/day) for 26 weeks. Risperidone, an atypical antipsychotic, was chosen as the comparator since it is widely used and has a history of not exacerbating negative symptoms. (Patients who had previously taken risperidone were excluded from the trial.)

There was no clinical difference early on, but after 14 weeks patients taking cariprazine began to show greater improvements in both negative symptoms (measured with the Positive and Negative Syndrome Scale, PANSS) and psychosocial functioning (measured using the Personal and Social Performance Scale, PSP) compared with patients on risperidone.

After 26 weeks, the cariprazine group experienced an average decline of 8.90 points in PANSS negative scores compared with a decline of 7.44 points in the risperidone group. For PSP, cariprazine patients saw a 14.30-point improvement compared with 9.66-point improvement for risperidone.

“The effect sizes were modest, but the study identified consistent advantages for cariprazine for a variety of measures,” said John Kane, M.D., the chair of psychiatry at the Zucker Hillside Hospital in Glen Oaks, N.Y., and the Dr. E. Richard Feinberg Chair in Schizophrenia Research at the Albert Einstein College of Medicine.

Kane, who has carried out clinical trials with cariprazine previously but was not involved with the current study, noted that the authors estimated a number needed to treat (NNT) of nine for cariprazine—for every nine patients treated with cariprazine, one would be expected to experience improvements in negative symptoms of schizophrenia beyond what is commonly experienced on other antipsychotics. Generally, NNTs of 10 or less are considered clinically valuable, he said.

Given the lack of options for patients with elevated negative symptoms, “this was exactly the kind of study needed to advance the field of schizophrenia therapy,” Kane told Psychiatric News.

Study author Stephen Marder, M.D., a professor of psychiatry and biobehavioral sciences at UCLA’s David Geffen School of Medicine, agreed that the findings are an important step forward, but cautioned multiple factors must be considered when prescribing to schizophrenia patients.

“If a new patient comes to a clinic for schizophrenia treatment, I think it’s still critical to treat their psychosis first using the best option based on their positive symptom profile,” he said. “Once the patient has stabilized, one should assess the patient and ensure that persisting negative symptoms are not secondary to depression or to extrapyramidal side effects. If they are not, a trial of cariprazine may be considered.” Even then, it may take months after initiating cariprazine therapy to see clinical improvement.

Marder also emphasized that cariprazine should not be considered a standalone treatment for schizophrenia. Behavioral therapies to increase interest and motivation are also paramount to fully rehabilitate patients that have likely experienced a period of social withdrawal.

This study, published February 6 in Lancet, was funded by Gedeon Richter Plc, the makers of Vraylar (cariprazine). Marder contributed to the study as a scientific and clinical trial expert and did not receive any personal fees from the funding agency. ■