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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.4 However, 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
Seeking new pharmacologic options
The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.
Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.
Box
Since the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations were published in 2010, many compounds have been investigated for treating negative symptoms of schizophrenia. Based on the findings of early research, further development of 5 of these has been abandoned.
Encenicline and TC-56199 were both α-7 nicotinic acetylcholine receptor agonists10; bitopertin and AMG 74711 were glycine reuptake inhibitors12; and pomaglumetad methionil13 was an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor.
Encenicline showed a treatment effect on negative symptoms in an add-on phase II study,14 but not in 2 subsequent phase III trials (NCT01716975, NCT01714661). TC-5619 showed a treatment effect in a 12-week phase II study of participants with persistent negative symptoms,15 but then failed in a subsequent study.9 Bitopertin showed a treatment effect on negative symptoms in 1 clinical trial,16 but the results were not replicated in a subsequent large multi-center trial.17 The AMG 747 development program was halted due to safety concerns.11 Finally, pomaglumetad methionil failed to meet its primary endpoint in a study of prominent negative symptoms and to show a treatment effect on psychotic symptoms in 2 pivotal phase III trials.13
Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:
- MIN-101 is a novel cyclic amide derivative.18 In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.18
- Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor19
- Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties18,20,21
- Raloxifene is a selective estrogen receptor modulator for postmenopausal women22,23
- Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.24
All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).
Continue to: Nonpharmacologic treatments
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
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.
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.4 However, 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
Seeking new pharmacologic options
The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.
Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.
Box
Since the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations were published in 2010, many compounds have been investigated for treating negative symptoms of schizophrenia. Based on the findings of early research, further development of 5 of these has been abandoned.
Encenicline and TC-56199 were both α-7 nicotinic acetylcholine receptor agonists10; bitopertin and AMG 74711 were glycine reuptake inhibitors12; and pomaglumetad methionil13 was an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor.
Encenicline showed a treatment effect on negative symptoms in an add-on phase II study,14 but not in 2 subsequent phase III trials (NCT01716975, NCT01714661). TC-5619 showed a treatment effect in a 12-week phase II study of participants with persistent negative symptoms,15 but then failed in a subsequent study.9 Bitopertin showed a treatment effect on negative symptoms in 1 clinical trial,16 but the results were not replicated in a subsequent large multi-center trial.17 The AMG 747 development program was halted due to safety concerns.11 Finally, pomaglumetad methionil failed to meet its primary endpoint in a study of prominent negative symptoms and to show a treatment effect on psychotic symptoms in 2 pivotal phase III trials.13
Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:
- MIN-101 is a novel cyclic amide derivative.18 In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.18
- Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor19
- Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties18,20,21
- Raloxifene is a selective estrogen receptor modulator for postmenopausal women22,23
- Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.24
All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).
Continue to: Nonpharmacologic treatments
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
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.4 However, 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
Seeking new pharmacologic options
The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.
Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.
Box
Since the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations were published in 2010, many compounds have been investigated for treating negative symptoms of schizophrenia. Based on the findings of early research, further development of 5 of these has been abandoned.
Encenicline and TC-56199 were both α-7 nicotinic acetylcholine receptor agonists10; bitopertin and AMG 74711 were glycine reuptake inhibitors12; and pomaglumetad methionil13 was an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor.
Encenicline showed a treatment effect on negative symptoms in an add-on phase II study,14 but not in 2 subsequent phase III trials (NCT01716975, NCT01714661). TC-5619 showed a treatment effect in a 12-week phase II study of participants with persistent negative symptoms,15 but then failed in a subsequent study.9 Bitopertin showed a treatment effect on negative symptoms in 1 clinical trial,16 but the results were not replicated in a subsequent large multi-center trial.17 The AMG 747 development program was halted due to safety concerns.11 Finally, pomaglumetad methionil failed to meet its primary endpoint in a study of prominent negative symptoms and to show a treatment effect on psychotic symptoms in 2 pivotal phase III trials.13
Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:
- MIN-101 is a novel cyclic amide derivative.18 In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.18
- Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor19
- Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties18,20,21
- Raloxifene is a selective estrogen receptor modulator for postmenopausal women22,23
- Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.24
All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).
Continue to: Nonpharmacologic treatments
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
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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
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.
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.
