Understanding the relationship between a symptom from a specific domain in schizophrenia and clinical outcomes is important because interventions that just focus on psychotic symptoms often fail to improve functioning and quality of life. Negative symptom severity, which impinges on a patient’s ability to live independently, perform daily activities, be socially active, have personal relationships, and work and study, has been consistently linked to worse functional outcomes in schizophrenia^1–4. Although the introduction of second-generation antipsychotics was expected to lead to a breakthrough in the treatment of negative symptoms, accumulating evidence suggests that they are primarily effective against positive symptoms of schizophrenia, with only a limited impact on negative symptoms¹.

Treatment of all negative symptoms is crucial. Primary and secondary negative symptoms should be differentiated if possible since secondary negative symptoms often respond to treatment of the underlying cause (eg, depression, positive symptoms, extrapyramidal symptoms), while primary negative symptoms may require different treatment options due to their different pathophysiological mechanism^5,6.

Given their high prevalence, persistence, relationship to functional impairment, and current treatment challenges, negative symptoms are a key area of interest for current and future drug development⁷. Regulatory officials in both Europe and the United States (European Medicines Agency [EMA] and the Food and Drug Administration [FDA]) have endorsed negative symptoms as a legitimate target for drug development^8,9. In close alignment, international officials agree that a claim for negative symptom efficacy should be made only if specially designed studies are conducted. Functional improvement should also be shown as the secondary outcome measure^8,10,11.

Although clinical trials in patients with acute exacerbation of schizophrenia have reported improvement in negative symptoms with antipsychotic treatment versus placebo, improvements typically occurred in the early stages of treatment in conjunction with improvement of psychotic symptoms. As such, these improvements in negative symptoms are difficult to interpret since they could have occurred secondarily to improvements in positive, depressive or extrapyramidal symptoms¹⁴. Newer approved treatments for schizophrenia may be more effective than other second-generation antipsychotics in addressing the unmet need posed by primary negative symptoms in schizophrenia.

A recent systematic review and pair-wise meta-analysis was conducted to evaluate the effects of 34 antipsychotic drugs in patients with negative symptoms¹³. All studies had a priori negative symptom inclusion/exclusion criteria and the primary outcome was mean change from baseline to endpoint in negative symptoms of schizophrenia as measured by a validated negative symptom rating scale.

Twenty-one randomized controlled trials (n=3451) were included in analyses and few positive results were reported. In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials, however results were confounded by parallel improvement in positive symptoms and depression was not accounted for.

In patients with predominant negative symptoms, amisulpride was superior to placebo in 4 trials (n=590), olanzapine was superior to haloperidol in 1 small trial (n=35), and cariprazine was superior to risperidone in one large, well-designed trial (n=456)²³. Of note, amisulpride, which is approved to treat negative symptoms in several European countries, was also significantly different than placebo on depressive symptoms, which makes it difficult to say whether the treatment effect was due to improvement in primary negative symptoms or only the result of changes in another symptom domain (pseudospecific improvement). In the cariprazine study, there was a run-in phase confirming that negative symptoms were stable and depressive and positive symptoms were minimal; outcomes demonstrated greater improvement in negative symptoms for cariprazine versus risperidone, with no effects on depressive symptoms or positive symptoms and no differential between-treatment effects on extrapyramidal side-effects²³.

Overall, the authors conclude that studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms and that predominantly negative symptom trials are better to assess efficacy on primary negative symptoms¹³.

A significant difference in negative symptom improvement in favor of cariprazine over risperidone in stable patients with predominant negative symptoms accompanied by no effect on depressive or positive symptoms, and no differential effects on extrapyramidal side-effects, suggests that negative symptom improvement was a genuine effect of treatment with cariprazine and not secondary to improvements in other symptoms domains²³. In contrast, with amisulpride there was a parallel reduction of depression. Therefore, a recent publication by Cerveri et al proposes as a clinical algorithm for the treatment of negative symptoms cariprazine as first-line treatment and amisulpride as an alternative in cases of cariprazine failure^14,23.

Given the high impact of negative symptoms on functioning, both cross-sectionally and longitudinally¹⁴, it is important that clinicians are aware about the scope of psychosocial interventions that should be used in conjunction with antipsychotics for a comprehensive treatment plan. General healthy lifestyle interventions, including a focus on exercise, sleep, diet, smoking cessation, appropriate alcohol consumption, and social participation, should always be suggested. The main psychosocial approaches to treatment are skill-based (eg, social skills training), psychological (eg, cognitive behavioral therapy), and family interventions (eg, education, crisis management)¹⁵.

Additionally, repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation tool with good tolerability and safety, has shown equivocal efficacy in treating negative symptoms of schizophrenia. While earlier meta-analyses supported the efficacy of rTMS in negative symptoms^16–20 the largest trial to date failed to find benefits for active versus sham rTMS²¹. Despite these confounded results, investigation of rTMS and newer techniques of brain stimulation (eg, transdirect current stimulation, deep rTMS) is likely to continue given the need for effective treatment options for negative symptoms²².