Treatment of negative symptoms of schizophrenia -- eg, problems with motivation, social withdrawal, diminished affective responsiveness, speech, and movement -- is associated with a variety of improved functional outcomes and is a vital unmet clinical need.
Schizophrenia is among the top 10 disabling conditions worldwide for young adults.1,2 In the United States, the cost of treatment and loss in productivity associated with schizophrenia are estimated to be as high as $60 billion annually.3-5 More than three quarters of this amount is associated with loss in productivity.1 Patients with schizophrenia struggle with many functional impairments, including performance of independent living skills, social functioning, and occupational/educational performance and attainment.6 Most patients require some public assistance for support, and only 10% to 20% of patients are able to sustain full- or part-time competitive employment.7-9 Improving functional outcomes for these individuals is a significant mental health priority.
Research suggests that the negative symptoms of schizophrenia, including problems with motivation, social withdrawal, diminished affective responsiveness, speech, and movement, contribute more to poor functional outcomes and quality of life for individuals with schizophrenia than do positive symptoms.10-16 Moreover, caregivers of patients with negative symptoms report high levels of burden.17 Negative symptoms tend to persist longer than positive symptoms and are more difficult to treat.15,18 Research suggests that improvements in negative symptoms are associated with a variety of improved functional outcomes including independent living skills, social functioning, and role functioning.19 Targeting negative symptoms in the treatment of schizophrenia may have significant functional benefits. Treatment of negative symptoms has been identified as a vital unmet clinical need for many persons with schizophrenia.15,18
Current antipsychotic treatments primarily address the positive symptoms of the disorder.15,18,20 In brief medication visits, physicians typically assess issues related to delusions, hallucinations, disorganized and aggressive behavior, and hostility. These are common symptoms that may cause individuals to be hospitalized, go to emergency departments, seek out crisis services, or come to the attention of the criminal justice system. Physicians may not be aware of the extent of negative symptoms, may not know how to assess these symptoms, may be unclear about the impact of treatments on negative symptoms, and may be unfamiliar with treatment strategies that may favorably impact negative symptoms. In this article, we describe the nature of negative symptoms, some of the etiological factors that contribute to a negative symptom presentation, and ways of addressing negative symptoms.
What are negative symptoms?
Negative symptoms represent a reduction of emotional responsiveness, motivation, socialization, speech, and movement. Primary negative symptoms are etiologically related to the core pathophysiology of schizophrenia whereas secondary negative symptoms are derivative of other symptoms of schizophrenia, other disease processes, medications, or environment.15,21 For example, antipsychotic medications can produce akinesia or blunted affect. Depression can cause anhedonia, lack of motivation, and social withdrawal. Lack of stimulation in impoverished institutional environments can lead to complacency and problems with motivation and initiation. Negative symptoms can also be the result of psychotic processes.15,21 For example, social withdrawal can be caused by paranoia or by immersion in the psychotic process to the exclusion of real-life relationships. Primary and enduring negative symptoms are often referred to as the "deficit syndrome."22 Individuals with the deficit syndrome have been found to have greater cognitive deficits and poorer outcomes than patients who do not have this syndrome.22
The face of negative symptoms
The brief narrative presents a description of a typical day of a patient with schizophrenia. As will be apparent, the patient demonstrates several classic negative symptoms, including blunted emotional responsiveness. "Jesse" produces very little speech and needs to be repeatedly prompted by the interviewer. He spends his days without much physical activity, mostly watching television. He has no friends and is visited by his father once a week. His interests are restricted to watching television and smoking. While he states that he likes basketball, he does not play or watch basketball. Emotional responsiveness was blunted in the interview even with attempts to elicit it. Interviews with family members revealed that Jesse has exhibited these behaviors for many years. When asked, Jesse states that he wants to get a job, but he has done nothing to find a job in more than a decade.
Individuals like Jesse are often seen for brief medication visits. Because there are no obvious positive symptoms and no problems with acting out or hostility, few changes in medication may be initiated. There may be little questioning on the part of the treating physician to determine the quality of Jesse's life or manner in which he spends his time. Some of the reluctance to get into such issues has to do with the limited time public-sector physicians may be able to spend with each patient. In most clinicians' minds, patients with pressing needs, such as suicidal or aggressive behaviors or severe symptom exacerbations, need more immediate attention. Moreover, the symptoms embodied in the negative syndrome may not be considered an important domain for treatment by either the physician or the patient. Note that Jesse does not identify anything about his life as a "chief complaint." His family seems to accept these symptoms, and for the most part, society has not targeted them as an unmet health care need. There may also be a perception among physicians that little can be done for negative symptoms even if they are identified.
How to assess negative symptoms
Individuals with schizophrenia are often unaware of the extent of their negative symptoms.23 They frequently do not spontaneously report negative symptoms as problems and are less concerned about them than their relatives may be.17 Family members may complain of a lack of an emotional connection with their son or daughter and state that the individual is not involved in life, but they do not aggressively seek treatment for these symptoms. Physicians or physician extenders will usually not get information about negative symptoms unless they have time to observe and to ask about specific behaviors. Furthermore, if symptoms are identified, there are no generally recognized approaches to treatment or well-established clinical assessment tools to measure treatment progress or failure.
However, several instruments have been developed to measure negative symptoms. The Table presents the domains of negative symptoms from the Negative Symptom Assessment (NSA)24 and describes the behaviors that might be observed in each domain. In addition to observation, it is important to ask questions regarding the person's daily activities and engagement with others. A very good question derived from the NSA asks, "Starting from the time you get up, could you tell me how you have spent a typical day in the past week?" From this one question, many different levels of clinical information can be gathered. Does the person generate a multifaceted answer without prompting, or as in the interview above, does the psychiatrist have to pull out every detail? Is the individual enthusiastic about specific activities? Is the individual actively engaged with hobbies, friends, and productive activity during the day? How does this individual compare with a person without schizophrenia of the same age and sex?
Options for treatment of negative symptoms
If negative symptoms are secondary to antipsychotic treatment, the symptoms can be decreased by prescribing an antipsychotic with a low likelihood of producing parkinsonian adverse effects or by reducing the dosage of the current antipsychotic to a level that does not produce extrapyramidal adverse effects. Similarly, if negative symptoms are related to depressed affect, treatments for depression could be considered. While there is no clear evidence that depression in schizophrenia responds to SSRIs, there is some evidence that SSRIs can have a positive impact on negative symptoms.25
Alternatively, if negative symptoms, such as social withdrawal, are caused by immersion in positive symptoms, increasing the dosage of antipsychotic medication or switching to a different antipsychotic may be warranted. If options for treating secondary causes of negative symptoms have failed, the options for pharmacological treatment are limited at present. Current antipsychotic treatments appear to have a modest impact at best on negative symptoms.20,26
The perceived benefits of the atypical antipsychotics on negative symptoms may result primarily from decreasing the burden of extrapyramidal adverse effects rather than better efficacy for core negative symptoms.20 However, there is some evidence that patients treated with atypical antipsychotics are more likely to participate in psychosocial treatments.27 The negative symptom benefits often attributed to atypical antipsychotics may reflect improvements because of the psychosocial interventions and not the medications per se.26 Novel compounds to specifically address negative symptoms are actively being developed,15 and there is a great deal of discussion in the literature about the best study designs to test these compounds for treatment effectiveness.28,29 Although a few studies with ampakines and more traditional broad-spectrum atypical antipsychotics are under way in patients with predominant and/or persistent negative symptoms, results for many of these trials are not yet available. Recently reported results of a trial of an ampakine were negative.30
Combining atypical antipsychotics with psychosocial interventions may have more potential to improve negative symptom outcomes than pharmacotherapy alone.31 In several randomized, rater-blind trials, we have found that environmental supports to prompt and cue adaptive behaviors led to improvement on the motivation factor of the NSA.32,33 Improvements on this factor suggest that individuals are more involved in activities, more engaged in the world around them, are performing grooming and hygiene tasks more regularly, and are more likely to pursue goals. It may be that some of this improvement has to do with decreasing the environmental impoverishment that contributes to secondary negative symptoms rather than improving primary negative signs of schizophrenia. Environmental supports may also prompt individuals to take part in activities they would otherwise not initiate, bypassing some of the apathy associated with negative symptoms. Moreover, social skills training has been found to improve social adjustment for individuals with schizophrenia.34,35 The teaching of skills needed to interact with others makes more successful attempts at initiation of conversations and maintenance of relationships likely. While more work on psychosocial treatments that specifically target negative symptoms is necessary, referral to psychosocial treatment is an important option for physicians to consider in dealing with enduring negative symptoms.
In addition, it is important to educate families about the nature of schizophrenia and negative symptoms. When the family is more aware that poor motivation, flat affect, and decreased involvement and activity reflect symptoms of schizophrenia rather than problems with the character of the individual, this can reduce the likelihood that the family will be overly critical of these behaviors.
Negative symptoms represent an important treatment target in schizophrenia. It is essential to assess for negative symptoms, treat the secondary causes of these symptoms and refer patients and families to psychosocial therapy in an attempt to improve outcomes and quality of life for these individuals. New pharmacological treatments to address negative symptoms should also be actively pursued.
References1. Jaeger J, Berns SM, Czobor P. The multidimensional scale of independent functioning: a new instrument for measuring functional disability in psychiatric populations. Schizophr Bull. 2003;29:153-168.
2. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66:1122-1129.
3. Wyatt RJ, Hentler I, Leary MC, Taylor E. An economic evaluation of schizophrenia 1991. Soc Psychiatr Psychiatr Epidemiol. 1995;30:196-205.
4. Souetre E. Economic evaluation in schizophrenia. Neuropsychobiology. 1997;35:67-69.
5. Trauer T, Duckmanton RA, Chiu E. Estimation of costs of public psychiatric treatment. Psychiatr Serv. 1998;49:440-442.
6. Sharma T, Antonova L. Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr Clin North Am. 2003;26:25-40.
7. Anthony WA, Blanch A. Supported employment for persons who are psychiatrically disabled: an historical and conceptual perspective. Psychosoc Rehabil J. 1987;11:5-23.
8. Mueser KT, Becker DR, Wolfe R. Supported employment, job preferences, and job tenure and satisfaction. J Ment Health. 2001;10:411-417.
9. McGurk SR, Mueser KT. Cognitive functioning, symptoms, and work in supported employment: a review and heuristic model. Schizophr Res. 2004;70: 147-173.
10. Velligan DI, Mahurin RK, Diamond PL, et al. The functional significance of symptomatology and cognitive function in schizophrenia. Schizophr Res. 1997; 25:21-31.
11. Lysaker PH, Lancaster RS, Nees MA, Davis LW. Attributional style and symptoms as predictors of social function in schizophrenia. J Rehabil Res Dev. 2004; 41:225-232.
12. Lysaker PH, Davis LW. Social function in schizophrenia and schizoaffective disorder: associations with personality, symptoms, and neurocognition. Health Qual Life Outcomes. 2005;2:15.
13. Norman RM, Malla AK, McLean T, et al. The relationship of symptoms and level of functioning in schizophrenia to general well-being and the Quality of Life Scale. Acta Psychiatr Scand. 2000;102:303-309.
14. Milev P, Ho BC, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162:495-506.
15. Kirkpatrick B, Fischer B. Subdomains within the negative symptoms of schizophrenia: commentary. Schizoph Bull. 2006;32:246-249.
16. Kurtz MM. Symptoms versus neurocognitive skills as correlates of everyday functioning in severe mental illness. Expert Rev Neurother. 2005;6:47-56.
17. Provencher HL, Mueser KT. Positive and negative symptom behaviors and caregiver burden in the relatives of persons with schizophrenia. Schizophr Res. 1997;26:71-80.
18. Alphs L. An industry perspective on the NIMH consensus statement on negative symptoms. Schizophr Bull. 2006;32:225-230.
19. Leeuwenkamp O, Velligan DI, Wang M, et al. Association between changes on the negative symptom assessment scale and measures of functional outcome in schizophrenia. Schizophr Bull. 2007;33:594-595.
20. Erhart SM, Marder SR, Carpenter WT. Treatment of schizophrenia negative symptoms: future prospects. Schizophr Bull. 2006;32:234-237.
21. Tarrier N. Negative symptoms in schizophrenia: comments from a clinical psychology perspective. Schizophr Bull. 2006;32:231-233.
22. Carpenter WT, Arango C, Buchanan RW, Kirkpatrick B. Deficit psychopathology and a paradigm shift in schizophrenia research. Biol Psychiatry. 1999; 46:352-360.
23. Selten JP, Wiersma D, van den Bosch RJ. Discrepancy between subjective and objective ratings for negative symptoms. J Psychiatr Res. 2000;34:11-13.
24. Alphs L, Summerfelt A, Lann H, Muller RJ. The Negative Symptom Assessment: a new instrument to assess negative symptoms of schizophrenia. Psychopharmacol Bull. 1989;25:159-163.
25. Jockers-Scherubl MC, Bauer A, Godemann F, et al. Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: a double-blind placebo-controlled study. Int Clin Psycho- pharmacol. 2005;20:27-31.
26. Buckley PF, Stahl SM. Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatr Scand. 2007;115:93-100.
27. Marder SR. Lessons from each drug trial. Am J Psychiatry. 2007;164:375-376.
28. Alphs L, Panagides J, Lancaster S. Asenapine in the treatment of negative symptoms of schizophrenia: clinical trial design and rationale. Psychopharmacol Bull. 2007;40:41-53.
29. Laughren T, Levin R. Food and Drug Administration perspective on negative symptoms in schizophrenia as a target for a drug treatment claim. Schizophr Bull. 2006;32:220-222.
30. Goff DC, Lamberti JS, Leon AC, et al. A placebo-controlled add-on trial of the ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology. 2007 May 9; [Epub ahead of print].
31. Marder SR. Integrating pharmacological and psychosocial treatments for schizophrenia. Acta Psychiatr Scand. 2000;102:87-90.
32. Velligan DI, Bow-Thomas CC, Huntzinger CD, et al. Randomized controlled trial of the use of compensatory strategies to enhance adaptive functioning in outpatients with schizophrenia. Am J Psychiatry. 2000; 157:1317-1323.
33. Velligan DI, Prihoda TJ, Ritch JL, et al. A randomized single-blind pilot study of compensatory strategies in schizophrenia outpatients. Schizophr Bull. 2002;28:283-292.
34. Glynn SM, Marder SR, Liberman RP, et al. Supplementing clinic-based skills training with manual-based community support sessions: effects on social adjustment of patients with schizophrenia. Am J Psychiatry. 2002;159:829-837.
35. Granholm E, McQuaid JR, McClure FS, et al. Randomized controlled trial of cognitive behavioral social skills training for older people with schizophrenia: 12-month follow-up. J Clin Psychiatry. 2007;68:730-737.