Clinician Perceptions, Expectations, and Management of Negative Symptoms in Schizophrenia
Stephen R. Marder, MD
Department of Psychiatry and Behavioral Sciences, David Geffen School of Medicine; VA Desert Pacific Mental Illness Research, Education, and Clinical Center; and the Semel Institute, University of California, Los Angeles
Schizophrenia consists of psychopathology in several domains (), all of which can affect the social and occupational functioning of patients with this disorder. Negative symptoms in particular are prevalent in 50% to 90% of patients in their first episode and in 20% to 40% of patients with schizophrenia.1 Although not as prominent as the delusions and hallucinations that characterize positive symptoms, negative symptoms can hinder patients’ relationships and independence and are associated with poor functioning and poor long-term outcome.2 Negative symptoms can be defined as a loss or reduction of normal thoughts, feelings, and actions, and the most common symptoms are blunted affect, alogia, avolition/apathy, and anhedonia.
AV 1. Core Symptom Clusters of Schizophrenia (00:38)
Perceptions of Negative Symptoms
Clinicians may underestimate the presence and severity of negative symptoms for several reasons. The focus of the routine clinical assessment usually begins with positive symptoms, like delusions, hallucinations, and disorganization, because they typically cause more immediate patient suffering and also respond well to medication. In addition, patients may have learned to cope with negative symptoms and, therefore, may not spontaneously report these problems. For example, patients are not likely to complain about a lack of interest, initiative, or emotion, so clinicians may perceive these symptoms as needing little attention or intervention. Asking their family members or caregivers about these symptoms may elicit a more accurate clinical assessment.
Expectations of Negative Symptoms
Poorer outcomes are typically expected if the patient experiences multiple significant negative symptoms early in the course of illness, especially affective flattening and anhedonia.2 One hierarchical model3 suggested that the 2 main components of negative symptoms are diminished expression (or flattened affect) and social dysfunction. Patients with diminished expression do not use the gestures, facial expressions, or vocal intonations that people normally use to communicate. Social dysfunction can be shown in experiential deficits, such as anhedonia, and behavioral deficits, such as asociality. If a patient exhibits these signs, a clinician may expect that the patient is struggling with negative symptoms.
Apathy is a core experiential deficit that presents in about 50% of first-episode patients, persists in 30% of patients after 1 year, and is associated with poor functioning at 1-year follow-up.4 Because apathy affects motivation and goal-oriented behavior, it should be identified early and included in the treatment plan. Physicians may not focus on negative symptoms in the management plan because they do not expect treatment to be effective, but some options are available that may address these problems.
Management of Negative Symptoms
The first step in managing negative symptoms is to determine whether patients’ symptoms are primary or are secondary to untreated positive symptoms or comorbid disorders, such as depression or anxiety.5 For example, patients who are vaguely suspicious of others may tend to isolate themselves. While asociality is a negative symptom, if hallucinations or delusions are causing the suspicion, then the asociality is secondary. Treating positive symptoms like these with antipsychotics may improve patients’ secondary negative symptoms as well.6 Similarly, antidepressants or anxiolytics may be effective for negative symptoms associated with depression or anxiety.
Negative symptoms may also be secondary to medication side effects, such as antipsychotic-induced akinesia and parkinsonian symptoms.5 Patients with mild parkinsonian symptoms can experience apathy, mild depression, and the same lack of expressiveness seen in those with primary negative symptoms. Treating the primary movement difficulties by reducing the antipsychotic dosage or adding an antiparkinsonian agent can lead to improvement in these secondary negative symptoms.
According to the APA practice guidelines5 for treating patients with schizophrenia, persistent negative symptoms that do not respond with the treatment of positive symptoms, comorbid disorders, or medication side effects are presumed to be primary negative symptoms. Currently, no pharmacologic agents are indicated for the treatment of primary negative symptoms, although some treatment strategies are available.
With the arrival of second-generation antipsychotics in the 1990s, many clinicians thought these agents were the answer for treating negative symptoms. However, a meta-analysis7 found that only some, not all, newer antipsychotics were more effective than first-generation agents in treating negative symptoms.
Adjunctive antidepressants. Switching antipsychotics to treat negative symptoms has not proven to be clinically useful; however, antidepressants are being studied as add-on therapy to antipsychotics. A meta-analysis8 of antipsychotics (mostly first-generation) plus antidepressants found inconsistent results on specific SANS subscale scores but did report significant superiority in reducing negative symptoms as a whole with the combination treatment versus the antipsychotic alone. A more recent meta-analysis9 also found an overall significant improvement in negative symptoms with antidepressant versus placebo augmentation with antipsychotics. Before combining agents, clinicians should always consider drug interactions, additional side effects, and added costs of prescribing multiple drugs.
Mirtazapine is among the most studied antidepressants for treating negative symptoms in schizophrenia. One study10 (N=39) of patients taking first-generation antipsychotics reported significant improvement (P < .001) in PANSS negative symptom subscale scores with mirtazapine augmentation versus placebo. A clozapine augmentation study11 (N=24) found significantly reduced SANS total scores (P < .01) and significantly improved avolition/apathy and anhedonia/asociality subscale scores (P < .05) for the adjunctive mirtazapine group compared with placebo. Mirtazapine plus haloperidol has also been shown to improve negative symptoms with a 42% reduction in PANSS negative symptom scores at 6 weeks (N = 30).12 Even though these studies had small sample sizes and their effects may not be dramatic, combining antipsychotics and antidepressants for negative symptoms is a strategy worth considering.
AV 2. Effects of Adjunctive Cognitive Therapy on Avolition/Apathy (00:34)
Cognitive therapy. A recent study13 suggests that cognitive therapy with antipsychotic treatment for patients with negative symptoms may be effective. This study of low-functioning patients with chronic schizophrenia (N = 60) examined the efficacy of a recovery-oriented cognitive therapy program designed to address avolition/apathy and anhedonia/asociality as well as impaired psychosocial functioning. Those receiving standard treatment plus cognitive therapy showed significantly greater improvements in avolition/apathy (P = .01) and global functioning (P = .03) at the 18-month endpoint when compared with those receiving standard treatment only ().13 Additionally, those receiving combination therapy showed some improvement in anhedonia/asociality, although the results were not significant.
Although negative symptoms are relatively common and substantially impact patients’ functioning and recovery, they are not a common therapeutic target for clinicians. Patients often do not report negative symptoms and may not see them as particularly burdensome, so clinicians must directly inquire about cognitive functioning, lack of motivation, lack of interest, and emotional blunting to elicit an accurate clinical assessment. Asking family members and caregivers about these items can also help to get the full picture.
After determining that a patient is experiencing negative symptoms, clinicians must determine whether they are primary or secondary in nature. Secondary negative symptoms may resolve with treatment of the underlying cause, but no treatments for primary negative symptoms have been endorsed by guidelines. Clinicians can consider adding antidepressants or cognitive therapy to antipsychotic medication to alleviate negative symptoms and should keep informed of the latest research.
For Clinical Use
- Ask patients, in terms they can understand, if they are experiencing any negative symptoms
- Determine whether negative symptoms are primary, in which case they will probably persist, or secondary, in which case they should resolve with treatment for the underlying cause
- Consider augmentation strategies to antipsychotic therapy to treat primary negative symptoms
clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), mirtazapine (Remeron and others)
APA = American Psychiatric Association
PANSS = Positive and Negative Syndrome Scale
SANS = Scale for the Assessment of Negative Symptoms
Take the online posttest.
- Mäkinen J, Miettunen J, Isohanni M, et al. Negative symptoms in schizophrenia: a review. Nord J Psychiatry. 2008;62(5):334–341. PubMed
- Fenton WS, McGlashan TH. Natural history of schizophrenia subtypes, II: positive and negative symptoms and long-term course. Arch Gen Psychiatry. 1991;48(11):978–986. PubMed
- Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull. 2006;32(2):238–245. PubMed
- Faerden A, Finset A, Agartz I, et al. Apathy in first episode psychosis patients: one year follow up. Schizophr Res. 2010;116(1):20–26. PubMed
- Lehman AF, Lieberman JA, Dixon LB, et al, for the Work Group on Schizophrenia. Practice Guideline for the Treatment of Patients With Schizophrenia, Second Edition. American Psychiatric Association; Arlington, VA: 2004. http://psychiatryonline.org/content.aspx?bookid=28§ionid=1665359. Accessed September 20, 2012.
- Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33(4):1013–1022. PubMed
- Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41. PubMed
- Rummel C, Kissling W, Leucht S. Antidepressants as add-on treatment to antipsychotics for people with schizophrenia and pronounced negative symptoms: a systematic review of randomized trials. Schizophr Res. 2005;80(1):85–97. PubMed
- Singh SP, Singh V, Kar N, et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: a meta-analysis. Br J Psychiatry. 2010;197(3):174–179. PubMed
- Joffe G, Terevnikov V, Joffe M, et al. Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial. Schizophr Res. 2009; 108(1–3):245–251. PubMed
- Zoccali R, Muscatello MR, Cedro C, et al. The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2004;19(2):71–76. PubMed
- Berk M, Ichim C, Brook S. Efficacy of mirtazapine add on therapy to haloperidol in the treatment of negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol. 2001; 16(2):87–92. PubMed
- Grant PM, Huh GA, Perivoliotis D, et al. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with schizophrenia. Arch Gen Psychiatry. 2012;69(2):121–127. PubMed