Evidence-Based Reviews

Negative symptoms of schizophrenia: An update

Current Psychiatry. 2020 October;19(10):24-25,30-33,53 | doi:10.12788/cp.0049

References

1. Owen MJ, Sawa A, Mortensen PD. Schizophrenia. Lancet. 2016;388(10039):86-97.
2. Cerviri G, Gesi C, Mencacci C. Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm. Neuropsychiatr Dis Treat. 2019;15:1525-1535.
3. Mitra S, Mahintamani T, Kavoor AR, et al. Negative symptoms in schizophrenia. Ind Psychiatr J. 2016;25(2):135-144.
4. Fusa-Poli P, Papanastasiou E, Stahl D, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull. 2015;41(4):892-899.
5. Remington G, Foussias G, Fervaha G, et al. Treating negative symptoms: an update. Curr Treat Options Psych. 2016;3:133-150.
6. Harvey PD, Saoud JB, Luthringer R, et al. Effects of roluperidone (MIN-101) on two dimensions of negative symptoms factor score: reduced emotional experience and reduced emotional expression. Schizophr Res. 2020;215:352-356.
7. Dedic N, Jones PG, Hopkins SC, et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Psychopharmacol Exp Ther. 2019;371(1):1-14.
8. Bleuler E. Dementia praecox or the group of schizophrenia. New York, New York: International Universities Press; 1950.
9. Andreasen NC. The diagnosis of schizophrenia. Schizophr Bull. 1987;13(1):9-22.
10. Andreasen NC. Thought, language, and communication disorders I. Clinical assessment, definition of terms, and evaluation of their reliability. Arch Gen Psychiatry. 1979;36(12):1315-1321.
11. Crow TJ. Molecular pathology of schizophrenia: more than one disease process? Br Med J. 1980;280(6207):66-68.
12. Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry. 1982;39(7):789-794.
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17. Bobes J, Arango C, Garcia-Garcia M, et al. Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS Study. J Clin Psychiatry. 2010;71(3):280-286.
18. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013.
19. Black DW, Andreasen NC. Interviewing and assessment. In: Introductory textbook of psychiatry, 7th ed. Black DW, Andreasen NC, eds. Washington, DC: American Psychiatric Publishing; 2020:15-53.
20. Pfohl B, Winokur G. The micropsychopathology of hebephrenic/catatonic schizophrenia. J Nerv Ment Dis. 1983;171(5):296-300.
21. Hovington CL, Lepage M. Neurocognition and neuroimaging of persistent negative symptoms of schizophrenia. Expert Rev Neurother. 2012;12(1):53-69.
22. Winograd-Gurvich C, Fitzgerald PB, Georgiou-Karistianis N, et al. A review of schizophrenia, melancholic depression and Parkinson’s disease. Brain Res Bull. 2006;70(4-6):312-321.
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Treatment options

Treating negative symptoms remains challenging and there are no clear answers. When they were introduced in the 1990s, SGAs were initially thought to be superior to FGAs in targeting negative symptoms. Subsequent research, including recent reviews and meta-analyses, has shown that SGAs are not superior to FGAs in treating negative symptoms, and the effect of either medication class on negative symptoms is modest.^2-5 One exception is amisulpride (not available in the United States), which is known to antagonize D2 and D3 receptors. A meta-analysis of the efficacy of antipsychotics in schizophrenia showed that amisulpride was significantly more effective than placebo in treating negative symptoms in 590 patients who received the medication.²⁶The authors suggested that amisulpride was effective due to its binding to presynaptic receptors in the frontal cortex, thereby enhancing dopamine transmission in this region.

Cariprazine, which acts as a partial agonist at the D2 and D3 receptors, with a 10-fold affinity for the D3 receptor, also has shown promise in treating negative symptoms.² In a clinical trial of 460 patients with predominant negative symptoms, treatment with cariprazine led to a greater reduction in negative symptoms than risperidone, although the effect size was small.²⁷ In this study, cariprazine produced greater improvement in personal and social performance than risperidone. Animal data supports the possible use of cariprazine in treating negative symptoms.²⁸

Other promising agentsinclude roluperidone (MIN-101), in phase 3 of development, and SEP-363856, an investigational antipsychotic agent that is in phase 2 of development. Interestingly, roluperidone acts on serotonin 2A and sigma2 receptors and does not target dopamine receptors, whereas SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) in addition to serotonin 1A receptors.^6,7

Antidepressants also could be effective in reducing negative symptoms.³A meta-analysis of randomized controlled trials evaluating the use of antidepressants as adjuncts to antipsychotic medications showed that adding an antidepressant was effective in reducing negative symptoms.²⁹The mechanism by which an antidepressant might cause a reduction in negative symptoms is uncertain, and it is possible that the antidepressant might treat depressive symptoms that are causing or contributing to the negative symptoms.

Bottom Line

Negative symptoms in patients with schizophrenia are associated with a worse functional outcome and poorer response to antipsychotic medication than positive symptoms. First- and second-generation antipsychotics are largely ineffective in consistently treating negative symptoms. Antipsychotic medications that target the D3 receptor might be more effective. Roluperidone, which targets serotonin 2A and sigma receptors, and SEP-363856, which targets TAAR1 and serotonin 1A receptors, are being studied for their effects on negative symptoms.

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Negative symptoms of schizophrenia: An update

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Treatment options

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