Negative symptoms refer to a loss of patient functioning, constituted by 5 constructs, known as the 5As: alogia, blunted affect, anhedonia, avolition, and asociality.¹ Impoverished speech (alogia) makes it difficult to maintain a conversation with patients, as they tend to give very short, undetailed answers.² Patients with blunted affect display reduced facial expression (often called “wooden expression”), they speak in a monotone, engage in little eye contact and appear emotionally unresponsive.² Patients are further characterised by anhedonia, meaning they do not find pleasure or joy in activities that they have previously enjoyed and they struggle with motivation, making it difficult for them to follow through with their plans (avolition).² Patients withdraw from others, they do not find social interaction important or pleasurable anymore (asociality), leading to poor, neglected friendships.²Patients’ lack of motivation extends to everyday life and activities: they neglect personal hygiene and grooming, appear unkempt, eat an unhealthy diet, avoid physical exercise, sleep irregularly and even smoke, misuse substances and consume alcohol.²Diminished functioning usually results in deteriorated occupational and school functioning.² Patients with negative symptoms usually lack insight into their condition, and therefore do not report these symptoms to the clinician, making it the healthcare professional’s task to detect them.³ These patients are therefore more often than not outpatients, rather than hospitalised patients.

Appropriate treatment options for negative symptoms are crucial for various reasons: they are the most disabling aspect of schizophrenia and result in decreased functioning and poorer quality of life; they are harder to treat than positive symptoms; they tend to precede the onset of schizophrenia and persist long after positive symptoms diminish.⁴ The prevalence of symptoms is high not only in chronic schizophrenia, but also in early psychosis, the prodromal phase and for 2 years after first-episode psychosis.³ Finding an effective treatment for negative symptoms used to be an unmet need for patients with schizophrenia and few treatment options; however, there are now certain therapeutic methods that have the potential to fill this gap.⁵ In this subpopulation of patients, the primary aim is to treat negative symptoms and, if present, other symptom domains as well.⁵ The aim is to achieve long-term remission with increased patient functioning.⁶
Before considering treatment options, it is important to note that negative symptoms can either be primary (due to schizophrenia) or secondary (due to other factors) to schizophrenia, as treatment differs accordingly.⁵ Secondary negative symptoms can be the result of a range of different factors, such as other psychiatric disorders or symptoms (e.g. depression, positive symptoms), side effects of medication (e.g. sedation), physical illnesses (e.g. sleep apnoea) or environmental factors (e.g. stigma).⁴
One of the obstacles of treating primary negative symptoms was that current antipsychotics showed limited efficacy, and consequently adjunct treatment options were required.³ However, cariprazine, a novel D3/D2 partial agonist, was shown to be efficacious in the treatment of negative symptoms, outperforming another antipsychotic, risperidone.⁷  Patients with negative symptoms are characterised by poor social functioning, isolation, lack of social skills that need to be improved through social skill training or cognitive remediation therapy.² Overall motivation and apathy can be improved by means of CBT, which was shown to produce moderate, but positive, effects.² It is important to improve patients’ personal hygiene and educate them on a healthy lifestyle, aspects that are addressed through general behaviour interventions.² Additionally, patients need to understand their condition and their family can make a considerable contribution to helping them deal with their condition, making family therapy an important component of the treatment of negative symptoms.²

Cariprazine, a D3/D2 partial agonist with higher affinity for D3 dopamine receptors, is the only antipsychotic that proved to be superior to another second-generation antipsychotic, risperidone, in the treatment of predominant negative symptoms⁵, as shown by a 26-week, prospective, randomised, double-blind study.⁷ Cariprazine yielded significantly more robust improvements in negative symptoms compared to risperidone from week 14 onwards.⁷

Adapted from: Németh, Gy. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
 
Cariprazine produced significantly greater improvements on 5 of 7 PANSS negative symptom items.⁸

Adapted from: Fleischhacker, W. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur. Psychiatry 58, 1–9 (2019).
 
Patients with negative symptoms showed significantly greater improvements on all PANSS-derived negative symptom factors (Liemburg Expressive Deficit; Liemburg Social amotivation; Kahn Expressive deficit; Pentagonal structure model; Prosocial score) compared to risperidone.⁸

Adapted from: Fleischhacker, W. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur. Psychiatry 58, 1–9 (2019).
 
Statistically significantly more patients responded to treatment in the cariprazine group than in the risperidone group; this effect was observed in patients who responded to treatment and had an at least 20% or 30% decrease in their negative symptom scores between baseline and week 26.⁷

Adapted from: Németh, Gy. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
 
Cariprazine was shown to be effective in improving patient functionality as well: patients receiving cariprazine showed statistically significantly greater improvements in overall patient functionality (PSP) than patients receiving risperidone, which was observed from week 10 onwards.⁷

Adapted from: Németh, Gy. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
 
Statistically significant effects were observed in favour of cariprazine over risperidone in PNS patients in 3 out of 4 activities of daily living domains.⁷ This improvement can enable the rehabilitation of patients and their ability to function in the community and related psychological programmes.⁷

Adapted from: Németh, Gy. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
 
Moreover, statistically significant improvements were observed in favour of cariprazine over risperidone on the CGI-S, which measures symptom severity⁷; and significant improvements were observed in favour of cariprazine over risperidone also on the CGI-I, which addresses symptom improvement.⁷
 
 
Switching
In stable patients, slower switching strategies and gradual cross-titration may be indicated to address predominant negative symptoms.⁹ In the aforementioned study, cariprazine 1.5 mg was initiated and weekly up-titrations were performed within the dose-range 3-6 mg, mostly to the target dose of 4.5 mg.⁷ In parallel, down-titration of the previous antipsychotic was initiated⁷. 

Adapted from: Németh, Gy. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
 
Since this data was published, cariprazine has been accepted by the scientific community as one of the most appropriate medications for this patient population: a clinical algorithm recommends cariprazine be given to first-episode schizophrenia patients with predominant negative symptoms.¹⁰ Cariprazine is also a recommended treatment option for negative symptoms in acute as well as long-term settings, where it was shown to effectively treat positive symptoms and reduce the frequency of relapses.¹¹ Since schizophrenia is believed to be a life-long disorder with longer periods of remission, the treatment of negative symptoms and the tolerability of the medication becomes as important as treating positive and acute symptoms, making cariprazine one of the first-line medications.¹²

COD. 300021/R56. Submitted to AIFA on 29/11/2021