NEGATIVE SYMPTOMS OF SCHIZOPHRENIA PLUS

The review summarizes the main issues regarding negative symptom management and the role of cariprazine treatment. Cariprazine was approved in 2015 by US FDA for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar I disorder, and in 2017 by EMA for the same indications. Cariprazine is a novel second-generation antipsychotic that specifically targets the D3 receptor that is involved in the pathophysiology of negative symptoms of schizophrenia and represents a novel therapeutic opportunity to treat this subpopulation of patients. Both the diagnosis and management of negative symptoms are still challenging. Primary and enduring negative symptoms are a core feature of schizophrenia, and patients presenting with negative symptoms account for a distinct clinical subpopulation. The role of DA in schizophrenia is dual: on the one side, dopaminergic hyperactivity, traditionally located in the mesolimbic regions, seems to cause emergence of psychotic symptoms, although more recent data implicate hyperdopaminergia in the dorsal striatum on the other side, dopaminergic hypoactivity in cortical regions underlies the negative symptoms and cognitive deficits. Alterations in dopaminergic function represent a hallmark in numerous mental diseases, including schizophrenia. There are no medium or long term data.Dopamine (DA) is a key brain neurotransmitter that contributes to control of different functions, such as cognition, motivation and rewards, as well as locomotion. There are no data at all on outcomes such as compliance, cost, social and cognitive functioning, relapse, recurrence of negative symptoms, rehospitalisation or quality of life. For movement disorders and other adverse effects, no statistically significant differences were found in any of the studies that provided usable data on these outcomes. No statistically significant difference was found between treatment groups in regards to the outcome 'at least one adverse event' (n=84, 2 RCTs, RR 1.80 CI 0.66 to 4.90).

Significant differences in favour of the combination therapy were seen in different aspects of negative symptoms: 'affective flattening' (n=30, 1 RCT, WMD -7.0 CI -10.37 to -3.63), 'alogia' (n=26, 1 RCT, WMD -3.00 CI -5.14 to -0.86) and 'avolition' (n=30, 1 RCT, WMD -3.0 CI -5.04 to -0.96).

More people allocated to combination therapy had a clinically significant improvement in negative symptoms compared with those given antipsychotics and placebo (n=60, 2 RCTs, RR 0.56 CI 0.32 to 0.97, NNT 3 CI 3 to 34).

NEGATIVE SYMPTOMS OF SCHIZOPHRENIA PLUS

In terms of clinical response, participants treated with the antipsychotic plus antidepressant medications showed a statistically significant greater improvement (n=30, 1 RCT, WMD -1.0 CI -1.61 to -0.39) and showed a significantly lower severity at endpoint (n=30, 1 RCT, WMD -0.9 CI -1.55 to -0.25) on the Clinical Global Impression Scale than those treated with antipsychotics alone. Leaving early due to adverse events (n=64, 2 RCTs, RR 5.0 CI 0.26 to 97.0) and leaving the study early due to inefficacy (n=34, 1 RCT, RR 3.0 CI 0.13 to 68.84) also showed no significant difference between the two treatment groups. We found no significant difference for 'leaving the study early for any reason' between the antipsychotic plus antidepressant combination and the control group (n=90, 3 RCTs, RR 3.0 CI 0.35 to 26.04). We included five studies (all short-term, total N=190).

Negative symptoms of schizophrenia