Evidence-Based Reviews

Treating negative symptoms of schizophrenia

Current Psychiatry. 2018 December;17(12):19-23

References

1. Rabinowitz J, Werbeloff N, Caers I, et al. Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophr Res. 2013;150(2-3):334-338.
2. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The schizophrenia patient outcomes research team (PORT): updated treatment recommendations 2009. Schizophrenia bulletin. 2010;36(1):94-103.
3. Veerman SRT, Schulte PFJ, de Haan L. Treatment for negative symptoms in schizophrenia: a comprehensive review. Drugs. 2017.
4. Aleman A, Lincoln TM, Bruggeman R, et al. Treatment of negative symptoms: Where do we stand, and where do we go? Schizophr Res. 2017;186:55-62.
5. Awad AG. Subjective tolerability of antipsychotic medications and the emerging science of subjective tolerability disorders. Expert Rev Pharmacoecon Outcomes Res. 2010;10(1):1-4.
6. Kirkpatrick B. Recognizing primary vs secondary negative symptoms and apathy vs expression domains. J Clin Psychiatry. 2014;75(4):e09.
7. Artaloytia JF, Arango C, Lahti A, et al. Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers. Am J Psychiatry. 2006;163(3):488-493.
8. Fervaha G, Takeuchi H, Lee J, et al. Antipsychotics and amotivation. Neuropsychopharmacology. 2015;40(6):1539-1548.
9. Walling D, Marder SR, Kane J, et al. Phase 2 Trial of an alpha-7 nicotinic receptor agonist (TC-5619) in negative and cognitive symptoms of schizophrenia. Schizophr Bull. 2016;42(2):335-343.
10. Haig GM, Bain EE, Robieson WZ, et al. A randomized trial to assess the efficacy and safety of ABT-126, a selective alpha7 nicotinic acetylcholine receptor agonist, in the treatment of cognitive impairment in schizophrenia. Am J Psychiatry. 2016;173(8):827-835.
11. U.S. National Library of Medicing. ClinicalTrials.gov. 20110165: Study to evaluate the effect of AMG 747 on schizophrenia negative symptoms (study 165). https://clinicaltrials.gov/ct2/show/NCT01568229. Accessed July 1, 2017.
12. Bugarski-Kirola D, Blaettler T, Arango C, et al. Bitopertin in negative symptoms of schizophrenia-results from the phase III FlashLyte and DayLyte studies. Biol Psychiatry. 2017;82(1):8-16.
13. Stauffer VL, Millen BA, Andersen S, et al. Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo. Schizophr Res. 2013;150(2-3):434-441.
14. Keefe RS, Meltzer HA, Dgetluck N, et al. Randomized, double-blind, placebo-controlled study of encenicline, an alpha7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia. Neuropsychopharmacology. 2015;40(13):3053-3060.
15. Lieberman JA, Dunbar G, Segreti AC, et al. A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. Neuropsychopharmacology. 2013;38(6):968-975.
16. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014;71(6):637-646.
17. Kingwell K. Schizophrenia drug gets negative results for negative symptoms. Nat Rev Drug Discov. 2014;13(4):244-245.
18. Davidson M, Saoud J, Staner C, et al. Efficacy and safety of MIN-101: a 12-week randomized, double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017;172(12):1195-1202.
19. Nemeth G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389(10074):1103-1113.
20. Levkovitz Y, Mendlovich S, Riwkes S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71(2):138-149.
21. Chaudhry IB, Hallak J, Husain N, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacology. 2012;26(9):1185-1193.
22. Usall J, Huerta-Ramos E, Labad J, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial. Schizophr Bull. 2016;42(2):309-317.
23. Usall J, Huerta-Ramos E, Iniesta R, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557.
24. Acadia Pharmaceuticals. Pimavanserin - schizophrenia negative symptoms. http://www.acadia-pharm.com/pipeline/pimavanserin-schizophrenia-negative-symptoms/. Accessed July 23, 2017.
25. Elis O, Caponigro JM, Kring AM. Psychosocial treatments for negative symptoms in schizophrenia: current practices and future directions. Clin Psychol Rev. 2013;33(8):914-928.
26. Turner DT, van der Gaag M, Karyotaki E, et al. Psychological interventions for psychosis: a meta-analysis of comparative outcome studies. Am J Psychiatry. 2014;171(5):523-538.
27. Velligan DI, Roberts D, Mintz J, et al. A randomized pilot study of MOtiVation and Enhancement (MOVE) Training for negative symptoms in schizophrenia. Schizophr Res. 2015;165(2-3):175-180.

28. U.S. National Library of Medicing. ClinicalTrials.gov. Treatment Development Targeting Severe and Persistent Negative Symptoms (MOVE). https://clinicaltrials.gov/ct2/show/NCT01550666. Accessed July 20, 2017.
29. Rabany L, Deutsch L, Levkovitz Y. Double-blind, randomized sham controlled study of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia. J Psychopharmacology. 2014;28(7):686-690.
30. Bation R, Brunelin J, Saoud M, et al. Intermittent theta burst stimulation of the left dorsolateral prefrontal cortex for the treatment of persistent negative symptoms in schizophrenia. European Neuropsychopharmacology. 2015;25:S329-S30.
31. Li Z, Yin M, Lyu XL, et al. Delayed effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia: findings from a randomized controlled trial. Psychiatry Res. 2016;240:333-335.
32. Wobrock T, Guse B, Cordes J, 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. 2015;77(11):979-988.
33. U.S. National Library of Medicing. ClinicalTrials.gov. Repetitive transcranial magnetic stimulation and intermittent theta burst (iTBS) in schizophrenia phase 2. https://clinicaltrials.gov/ct2/show/NCT01315587. Accessed July 18, 2017.
34. Treatment of Negative Symptoms and Schizophrenia (STICCS) Phase 1/2. https://clinicaltrials.gov/ct2/show/NCT02204787. Accessed July 15, 2017.
35. U.S. National Library of Medicing. ClinicalTrials.gov. Schizophrenia TreAtment With electRic Transcranial Stimulation (STARTS). https://clinicaltrials.gov/ct2/show/NCT02535676. Accessed July 10, 2017.
36. Bellack AS, Mueser KT, Gingerich S, Agresta J. Social skills training for schizophrenia. A step-by-step guide. New York, NY: Guilford Press; 1997:20-30.
37. Hogarty GE, Anderson CM, Reiss DJ, et al. Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. I. one-year effects of a controlled study on relapse and expressed emotion. Arch Gen Psychiatry. 1986;43(7):633-642.

Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psychosocial approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

References

The daunting challenge of schizophrenia: Hundreds of biotypes and dozens of theories

Treating negative symptoms of schizophrenia

References

Nonpharmacologic treatments

Social skills training and combined interventions

Bottom Line

Related Resource

Drug Brand Names

Pages

Next Article: