Evidence-Based Reviews

Treating negative symptoms of schizophrenia

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

Few pharmacologic options, but evidence supports combining psychosocial interventions.

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.
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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.
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In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psychosocial treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsychotics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

Treating negative symptoms of schizophrenia

References

The limitations of antipsychotics

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