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Treating Negative Symptoms of Schizophrenia

  • Negative symptoms of schizophrenia are important to treat since they affect a patient’s ability to cope with daily activities and influence quality of life.
  • Negative symptoms are recognized by the FDA and EMA as features of schizophrenia that are not adequately treated by available antipsychotic therapies.
  • Newer approved treatments or agents in development may be more effective than other second-generation antipsychotics and may better address the unmet need posed by negative symptoms in schizophrenia.

In this section

Why Should We Treat Negative Symptoms?

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 schizophrenia1–4. 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 mechanism5,6.

A Target for Drug Development

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 development8,9. 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 measure8,10,11.

Guidelines for Clinical Trials in Negative Symptoms8,9,11
Trial duration• EMA: 6 months or longer
• FDA: Minimum 3 months, Optimal 6 months or longer
Schizophrenia state• Stable
• Without exacerbation for 6 months
Negative symptoms• Stable and persistent
• 6-month minimum duration
• EMA: requires predominant negative symptoms (ie, high degree of negative symptoms and no or few positive symptoms
• FDA: requires prominent negative symptoms (ie, high degree of negative symptoms)
Symptoms in other domains• Stable and not predominant (eg, psychotic symptoms, depression, and extrapyramidal symptoms)
Trial design• In monotherapy trials, both the comparator and the trial drug would have previously demonstrated efficacy for treatment of positive symptoms
• Patients are randomly assigned to the experimental antipsychotic or the control agent
Outcomes• Negative symptom improvement is shown as the difference between baseline and endpoint on a validated scale
• Demonstration of functional improvement, e.g. improvement in functional capacity, as key secondary outcome measure is recommended
• Response rate
• Measures of potentially confounding symptoms (eg, depression, extrapyramidal symptoms, positive symptoms, side effects of medication) to rule out pseudospecific improvement

Clinical Trials in Negative Symptoms

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.

Take-Home Messages for Treating Negative Symptoms

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 failure14,23.

Treatment of Negative Symptoms Beyond Pharmacotherapy

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 symptoms16–20 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.


  1. Rabinowitz, J., Berardo, C. G., Bugarski-Kirola, D. & Marder, S. Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: A CATIE analysis. Schizophr. Res. 150, 339–342 (2013).
  2. Alonso, J. et al. Health-related quality of life (HRQL) and continuous antipsychotic treatment: 3-year results from the schizophrenia health outcomes (SOHO) study. Value Heal. 12, 536–543 (2009).
  3. Harvey, P. D. et al. Functional impairment in people with schizophrenia: Focus on employability and eligibility for disability compensation. Schizophr. Res. 140, 1–8 (2012).
  4. Rabinowitz, J. et al. Negative symptoms in schizophrenia – the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophr. Res. 150, 334–338 (2013).
  5. Galderisi, S., Mucci, A., Buchanan, R. W. & Arango, C. Negative symptoms of schizophrenia: new developments and unanswered research questions. The Lancet Psychiatry 5, 664–677 (2018).
  6. Buchanan, R. W. Persistent Negative Symptoms in Schizophrenia: An Overview. Schizophr. Bull. 33, 1013–1022 (2007).
  7. Möller, H. J. & Czobor, P. Pharmacological treatment of negative symptoms in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 265, 567–578 (2015).
  8. Laughren, T. & Levin, R. Food and Drug Administration perspective on negative symptoms in schizophrenia as a target for a drug treatment claim. Schizophr. Bull. 32, 220–222 (2005).
  9. European Medicines Agency. Guideline on clinical investigation of medicinal products, including depot preparation in the treatment of schizophrenia. (2012).
  10. Marder, S. R., Daniel, D. G., Alphs, L., Awad, A. G. & Keefe, R. S. E. Methodological issues in negative symptom trials. Schizophr. Bull. 37, 250–254 (2011).
  11. Marder, S. R. et al. Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia. Schizophr. Res. 150, 328–333 (2013).
  12. Leucht, S. et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: Systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am. J. Psychiatry 174, 927–942 (2017).
  13. Krause, M. et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 268, 625–639 (2018).
  14. Cerveri, G., Gesi, C. & Mencacci, C. Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm. Neuropsychiatr. Dis. Treat. 15, 1525–1535 (2019).
  15. Mueser, K. T., Deavers, F., Penn, D. L. & Casssisi, J. E. Psychosocial treatments for schizophrenia. Annu. Rev. Clin. Psychol. 9, 465–497 (2013).
  16. Aleman, A. et al. Treatment of negative symptoms: Where do we stand, and where do we go? Schizophr. Res. 186, 55–62 (2016).
  17. Shi, C., Yu, X., Cheung, E. F. C., Shum, D. H. K. & Chan, R. C. K. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis. Psychiatry Res. 215, 505–513 (2014).
  18. Dlabač-de Lange, J. J., Knegtering, R. & Aleman, A. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: Review and meta-analysis. J. Clin. Psychiatry 71, 411–418 (2010).
  19. Freitas, C., Fregni, F. & Pascual-Leone, A. Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophr. Res. 108, 11–24 (2009).
  20. Prikryl, R. & Kucerova, H. P. Can repetitive transcranial magnetic stimulation be considered effective treatment option for negative symptoms of schizophrenia? J. ECT 29, 67–74 (2013).
  21. Wobrock, T. et al. Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: A sham-controlled, randomized multicenter trial. Biol. Psychiatry 77, 979–988 (2015).
  22. Remington, G. et al. Treating Negative Symptoms in Schizophrenia: an Update. Curr. Treat. Options Psychiatry 3, 133–150 (2016).
  23. Reagila SmPC

Neuropsychiatric Disease and Treatment

Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm.
Cerveri G1, Gesi C2, Mencacci C2.
Neuropsychiatr Dis Treat. 2019 Jun 5; 15:1525-1535.
“Thus, we can suggest the use of cariprazine as a first-line pharmacological treatment in schizophrenia with predominant NS.”


Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.
Németh G, Laszlovszky I, Czobor P, Szalai E, Szatmári B, Harsányi J, Barabássy A, Debelle M, Durgam S, Bitter I, Marder S, Fleischhacker WW
Lancet 2017; 389(10074):1103-1113.
“Because cariprazine was superior to another second-generation antipsychotic in the treatment of predominant negative symptoms, patients who have shown improvement in positive symptoms but continue to have negative symptoms that are disabling while on an antipsychotic other than cariprazine might benefit from cariprazine treatment.”
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Cariprazine has high affinity for dopamine D3 and D2 receptors as well as serotonin 5 HT2B and 5 HT1A receptors, moderate affinity to 5 HT2A, histamine H1, and Find out more about its mechanism of action

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Negative symptoms of schizophrenia can occur as primary symptoms that are part of the underlying pathophysiology of schizophrenia or as secondary symptoms that Negative symptoms of schizophrenia can occur as primary symptoms that are part of the underlying pathophysiology of schizophrenia or as secondary symptoms that

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