Schizophrenia is a complex neuropsychiatric disorder, presenting with positive (hallucinations and delusions), negative (blunted affect, alogia, anhedonia, asociality and avolition), and cognitive (impaired retrieval of information like thinking, learning and memorizing) symptoms (1). In addition to these symptoms, patients with schizophrenia often experience affective symptoms (depression and anxiety) that is associated with increased risk of suicide and poor quality of life (2). Positive symptoms are primarily monitored to diagnose an active state of schizophrenia, but negative symptoms are significant contributors of poor psychosocial functioning and performance, impacting the patient’s quality of life (3). Identification of negative symptoms can be sometimes challenging due to their insidious onset, paucity of psychotic signs and similarity with other clinical features of schizophrenia, resulting in delayed treatment outcomes (1). The fundamental pathophysiological mechanism of negative symptoms is different from positive symptoms (3). Hyperdopaminergic state of dopamine D2 receptor in the mesolimbic area is related to positive symptom prognosis, while hypodopaminergic dysregulation of the prefrontal cortex leads to negative symptoms (1). Only a decade ago, the focus from positive symptoms has shifted to the negative symptoms. Since then, very few pharmaceutical agents have been studied that successfully met the therapeutic target of negative symptoms (4). Typical (first generation) and atypical (second and third generations) antipsychotics are primarily used to modulate the dopaminergic function (5). The mechanism of action of first generation antipsychotics (FGAs) lack preference-based blocking of dopamine pathway, resulting in extrapyramidal symptoms (dyskinesia, akathisia and tremors), hyperprolactinemia-associated sexual dysfunction and aggravation of negative symptoms (6). The second generation antipsychotics (SGAs) are combined D2 and serotonin 5-HT_2A receptor antagonists with lower risk for developing extrapyramidal symptoms (EPS) (7). Second generation antipsychotics are effective for negative symptoms, but result in several treatment-emergent side effects including diabetes, ketoacidosis, weight gain, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension and metabolic syndrome (6, 8, 9).

Negative symptoms of schizophrenia have been consistently related to poor treatment outcome. A well-tolerated and long-term effective treatment option for negative symptoms is one of the most important unmet needs that is to be addressed. Globally approved third generation antipsychotic (TGA), cariprazine is distinct from other antipsychotics and has partial agonist activity at dopamine D3/D2 and serotonin 5-HT_1A receptors (10). Because of its dopamine-dependent partial agonism to D2 and D3 receptors, cariprazine is less likely to cause weight gain, metabolic disorder and hyperprolactinemia (6). This review attempts to outline the safety and efficacy of cariprazine for the treatment of predominant negative symptoms of schizophrenia.

According to World Health Organization (2022), schizophrenia affects about 24 million people worldwide, i.e., 1 in 300 (11). It is one of the top 15 causes of global disability (12). In India, the prevalence of schizophrenia is 1.5-2.5/1000 people, with an annual rate of 0.35-0.38/1000 and 0.44/1000 people from urban and rural area, respectively (13). Many factors including migration, drug abuse, urbanicity (stress, noise and pollution), childhood traumas, psychosocial factors, infections, cannabis use, birth during winter (high chances of respiratory infections and inadequate vitamin D synthesis), and obstetric complications during fetal, childhood, adolescence and early adult life can increase the risk of developing schizophrenia (14). The onset of schizophrenia mostly occurs during late adolescence and early adulthood, and happens earlier in males (average age 18 years) than females (average age 25 years) (1). Late onset of schizophrenia (after the age of 44 years) accounts for 15-20% of all cases (15).

Prevalence of negative symptoms is 75% in patients having schizophrenia and 68% in patients with schizoaffective disorder (16). Sometimes negative symptoms appear before the onset of positive symptoms (73% prevalence) or in the same month of developing positive symptoms (20% prevalence) (17). Ninety percent patients with first psychotic episode can develop at least one negative symptom, whereas 35-70% can still suffer from negative symptoms post-treatment (17).

The five constructs of negative symptoms are blunted affect, alogia, anhedonia, asociality and avolition (3) that cluster into two domains: the expressive domain (blunted affect and alogia) and the experiential domain (anhedonia, asociality and avolition); latter has a larger effect on the real-world functioning (18). Moreover, negative symptoms can be primary or secondary depending on their etiology ( Figure 1 ). Primary negative symptoms for more than one year manifest deficit syndrome of schizophrenia and patients without these symptoms are considered to suffer from non-deficit schizophrenia (19). The severity of negative symptoms is also described by persistent (persisting over time, in spite of antipsychotic treatment), predominant (greater severity than co-occurring positive symptoms) and prominent (at least three moderate symptoms or two severe symptoms) negative symptoms (17, 20).

Pathology of negative symptoms includes decreased dopamine transmission in mesocortical pathways, along with decreased serotonergic, glutamatergic and noradrenergic transmission. Of note, hypodopaminergic functioning in the prefrontal lobe and additional mesolimbic structures are responsible for diminished motivation and reward-related processes, leading to negative symptoms (17, 21). Inhibition of glutamate neurotransmission after antagonizing N-methyl-D-aspartate (NMDA) receptors may results in negative symptoms of schizophrenia (17). Brain regions associated with expressive domain are rostral anterior cingulate cortex, amygdala, and ventrolateral prefrontal cortex; and with experiential domain are dorsal and ventral striatum, dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex (21, 22).

Genetic factors, prenatal complications and poor premorbid adjustments prior to development of psychotic illnesses are contributing factors for onset of negative symptoms (17). Males are more prone to develop negative symptoms, especially anhedonia and avolition (23). Negative symptoms greatly affect disease prognosis, physical and psychological health, and personal and social relationships (24–28), as reduced functioning of mental health, health utility and expert-rated quality of life were reported (29). During early phase of the syndrome, negative symptoms increase the risk of self-harm that can persist up to 7 years since first psychiatric visit, and impact different domains of real-life functioning (18). Level of negative symptoms in elderly population is equivalent to that of younger schizophrenia population (30). Anxiety and depression are the central symptoms of population with predominant negative symptoms, hence clinicians must pay attention to these symptoms too, and not only to negative symptoms (31).

Quantitative (frequency, duration and intensity) and qualitative (difference between anticipatory and consummatory aspects of anhedonia; or difference between behavioral and experiential aspects) aspects of negative symptoms is assessed using validated instruments (18). Different scales for standardized assessments of negative symptoms which are used either by professionals or by the patient (17, 20) is presented in Table 1 .

Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) are used for diagnosis of deficit schizophrenia (20). In first episode of schizophrenia, patient’s phenomenological variety of negative symptoms can be evaluated with PANSS based experiential factor (‘poor rapport’, ‘passive/apathetic social withdrawal’, ‘active social avoidance’ and ‘lack of spontaneity’) and expressive factor (‘blunted affect’, ‘emotional withdrawal’ and ‘motor retardation’) (32). Brief Negative Symptom Rating Scale (BNSS) and Clinical Assessment Interview for Negative Symptoms (CAINS) have been developed by National Institute of Mental Health (NIMH) as the ‘next generation’ scale. In the USA, 16-item Negative Symptom Assessment (NSA-16) and SANS are recommended but not PANSS negative symptoms subscale, because of its inadequate coverage; whereas, the European drug authority has endorsed the use of SANS and PANSS negative symptoms subscale in clinical studies (9). Many European countries have approved the use of Self-evaluation of Negative Symptoms (SNS) scale (18).

Treatment of negative symptoms is challenging as no particular guidelines are available related to treatment algorithms and maintenance of the treatment; patients with treatment-resistant schizophrenia usually develop prominent negative symptoms (33, 34). The European regulatory guidelines and commentary issued by the US regulators have different perspectives with respect to treatment of schizophrenia, as the former recommend splitting negative symptoms from other domain of the disease, while the latter suggested lumping all the aspects of the disease together (9). The World Federation of Societies of Biological Psychiatry guidelines recommended use of FGA for secondary but not for primary negative symptoms of schizophrenia (35). Antipsychotic treatment is recommended by the American Psychiatric Association (APA) and the British Association for Psychopharmacology (BAP) for improvement and remission of both positive and negative symptoms; National Institute for Health and Care Excellence (NICE) and Canadian Psychiatric Association (CPA) suggested this treatment approach for improving functioning and quality of life. Reduced hospitalization and mortality with antipsychotic therapy are demonstrated by APA and CPA (34). United Nations High Commissioner for Refugees (UNHCR) recommended switching from FGA to SGA in case of ineffective treatment of negative symptoms (34). Likewise, the European Psychiatric Association guidelines recommended switching to SGA in patients not responding to FGA, along with social skill training and psychosocial rehabilitation (20).

First generation antipsychotics exhibits narrow efficacy spectrum in managing negative symptoms of schizophrenia (7). Second generation antipsychotics were introduced in the late 80s (24) with a promise to yield higher treatment efficacy, better receptor binding properties and lower side effects compared to FGAs (36). Significant difference in the pharmacological properties and side effect profiles exist between FGAs [fluphenazine, haloperidol, perphenazine and pimozide (D₂ antagonists) and chlorpromazine, loxapine, thioridazine and trifluoperazine (D₂ and 5-HT₂ antagonists)], SGAs [iloperidone, lurasidone, olanzapine and ziprasidone (D₂ and 5-HT₂ antagonists), asenapine, clozapine, paliperidone and risperidone (5-HT₂, D₂ and norepinephrine α₂ antagonist) and quetiapine (D₂ and 5-HT₂ antagonist and norepinephrine transporter reuptake inhibitor)], and TGAs [aripiprazole and brexpiprazole (D₂ and 5-HT_1A partial agonist and 5-HT_2A antagonists)] (37, 38). Clozapine is considered as the best evidence-based therapeutic option for treatment-resistant schizophrenia (39). Higher efficacy of clozapine than other SGAs is reported for management of schizophrenia and schizophrenia-like psychoses (40). Despite its efficacy, 40% patients with treatment-resistant schizophrenia were reported to be non-respondent to clozapine treatment (41). Nielsen et al. reported improvement in negative symptoms after treatment with aripiprazole due to its partial D2 receptor agonist effect; however, no improvement in cognitive functions was found (42). Another study on patients with schizophrenia-spectrum disorders reported lower efficacy of aripiprazole in terms of improvement in PANSS negative score and CGI-S score (43). Although brexpiprazole has shown greater efficacy in improving negative symptoms (44), but common adverse effects associated with brexpiprazole are akathisia, headache, somnolence, weight gain and altered triglyceride level. Long-term risk and benefits of brexpiprazole are also not well-established (45).

Treatment-emergent adverse events are frequent with SGAs that commonly include akathisia, EPS, weight gain, sedation, insomnia, hyperprolactinemia and metabolic changes (46). Other adverse events include periorbital edema, parotitis, (inflammation of parotid gland/s) and pseudopheochromocytoma, i.e., severe paroxysmal hypertension (39). Lobos et al. reported higher incidence of akathisia with olanzapine, elevated glucose, triglycerides and prolactin levels with olanzapine and clozapine, hypercholesterolemia and hypersalivation with clozapine and low sexual drive with clozapine and risperidone treatment (40). Clozapine is also associated with other side effects viz. EPS, agranulocytosis, drooling, sedation, headache, dizziness, tremor, tachycardia, lengthening of corrected QT (QT_C), weight gain, hypotension, visual abnormality, sweating, dry mouth, constipation, dyslipidemia and flexural intertrigo (39). Increase in prolactin level and EPS with amisulpride treatment and weight gain and elevated serum lipid and prolactin levels with amisulpride, aripiprazole, and olanzapine treatment were reported (43, 47). Additionally, evidence-based international guidelines revealed that SGAs have only moderate effect on negative symptoms; antidepressants and glutamatergic compounds are necessary to use additionally to overcome the disease burden (9). Schizophrenia patient data from 20 placebo-controlled trials reported prominent negative symptoms (8-33.1%), predominant negative symptoms (14.9%) and European Medicines Association (EMA) criteria-based negative symptoms (12.2-45.5%) even after 6 weeks of active treatment with SGA (48).

Poor outcomes with FGAs, and major side effects and inadequate response to SGAs leave a gap regarding the most appropriate treatment of negative symptoms, which is a long-standing challenge for schizophrenia management. Recently, a review on mental health care in central and eastern Europe suggested that many countries across the Europe have incorporated cariprazine as the first-line treatment for negative symptoms (49). Both the EMA and the US Food and Drug Administration (FDA) have approved cariprazine for schizophrenia management (50). The position statement of Polish Psychiatric Association on the use of D2/D3 receptor partial agonists highlighted the benefits of cariprazine in the management of predominant and persistent negative symptoms (51).

Cariprazine was approved in 2015 by the US FDA and later in 2018 in the UK (5, 7). The antipsychotic is approved in the US for treatment of schizophrenia, mania or mixed episodes, and depressive episodes related to bipolar I disorder and as adjunctive therapy to anti-depressants for the treatment of major depressive disorders, whereas in Europe it is approved for treatment of schizophrenia (26). Midlands and Lancashire Commissioning Support Unit 2019 has also recommended cariprazine for the treatment of predominant negative symptoms of schizophrenia (52). In 2021, India’s national regulatory body for cosmetics, pharmaceuticals and medical devices, Central Drugs Standard Control Organization (CDSCO) approved cariprazine for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder (53).

Cariprazine is available in capsule form with doses of 1.5, 3, 4.5, or 6 mg for schizophrenia treatment (6). At clinically relevant doses, cariprazine appeared to have higher occupancies of D2 and D3 receptors (54). Cariprazine dose of 1.5 mg/day results in 69% occupancy of both D2 and D3 receptors, and 3 mg/day for 14 days leads to 90% occupancy, suggesting adequate efficacy (6). Efficacy, tolerability and safety of cariprazine in patients having acute exacerbation of schizophrenia is established at a daily dose of 3 or 6 mg (55). More rapid onset of action (by 1 to 2 weeks) is achieved at a daily cariprazine dose of ≥3 mg than 1.5 mg; however, efficacy of cariprazine at 6^th week remains same with both higher and lower doses (56). Improvement in PANSS total score and CGI-S with cariprazine was reported at a dose of 1.5, 3 and 4.5 mg/day in one study (57), and at 3-6 or 6-9 mg/day in another study (58). Cariprazine dose of 4.5–6 mg/day improves negative symptoms (26); 3-6 or 6-9 mg/day improves PANSS and CAINS negative symptom scores (54) and 3, 6 or 9 mg/day lowers the chances of relapse (59). Cariprazine is also effective for patients with schizophrenia and concomitant substance use disorder, as it appeared to reduce cravings of illicit drugs/alcohol in such patients (60).

This review article provides new insights on the possible use of cariprazine for negative symptom management ( Figure 2 ). In a nutshell, negative symptoms of schizophrenia hinder patient’s quality of life and treatment options are limited. Antipsychotic management of negative symptoms is recommended by various international guidelines. However, FGAs are ineffective for treatment of negative symptoms when they are secondary to positive symptoms, and SGAs have partial benefits on negative symptoms due to frequent incidence of treatment-related side effects. Cariprazine, a recently approved antipsychotic, has high affinity and occupancy for D2/D3 receptors, partial agonism to 5-HT_1A and antagonism to 5-HT_2B receptors, and longer half-life which is efficacious in management of patients with negative symptoms of schizophrenia. The drug appears to be superior to available SGAs with lower incidence of metabolic disorders and relapse. Therefore, cariprazine can be used as a viable alternative to other antipsychotics for predominant negative symptom treatment. More clinical trials need to be conducted to confirm the beneficial effect of cariprazine for treatment of negative symptoms over other antipsychotics.

PS: Validation, Writing – review & editing. PD: Data curation, Investigation, Writing – original draft. AS: Data curation, Investigation, Writing – original draft. SD: Data curation, Investigation, Writing – original draft. CK: Data curation, Investigation, Writing – original draft. AM: Validation, Writing – review & editing. SM: Validation, Writing – review & editing. CA: Supervision, Validation, Writing – review & editing.