Recognizing Primary Vs Secondary Negative Symptoms and Apathy Vs Expression Domains

Brian Kirkpatrick, MD, MSPH

Department of Psychiatry and Behavioral Sciences, University of Nevada School of Medicine, Reno

Negative symptoms in schizophrenia are decreases in normal behavior or psychological functions. DSM-5 describes negative symptoms as consisting of diminished emotional expression or avolition.1 Other definitions of negative symptoms are based on rating scales, such as the SANS2 and PANSS.3 Although there is a fair amount of agreement across these scales, there is also some disagreement as to what should be considered a negative symptom. Another problem is that older rating scales do not reflect the latest research on negative symptoms, including the distinction between appetitive and consummatory pleasure (AV 1).

AV 1. Distinctions in Types of Anhedonia (00:27)


To create a consensus definition of negative symptoms, the NIMH sponsored a Consensus Development Conference where experts agreed that negative symptoms include blunted affect, alogia, asociality, anhedonia, and avolition.4 Another outcome from this conference was the development of 2 new 13-item rating scales: the CAINS5 and the BNSS,6 both of which measure the 5 agreed-upon areas of impairment.6

While rating scales are useful for identifying the presence of negative symptoms and monitoring symptom changes throughout treatment, they do not yield a diagnosis of the basis of the symptoms. Good clinical care entails distinguishing primary versus secondary negative symptoms and understanding apathy versus emotional expressivity.

Primary Versus Secondary Negative Symptoms

Primary negative symptoms, sometimes referred to as deficit symptoms, are an integral part of schizophrenia in some patients and are present during and between periods of worsening positive symptoms.7 Secondary negative symptoms are caused by factors such as positive symptoms, treatment side effects, or depression.7,8 For example, a patient’s lack of relationships could be caused by anxiety, depression, or suspiciousness. Secondary negative symptoms are usually responsive to treatment of the underlying cause.7

Unfortunately, there is currently no established treatment for primary negative symptoms.7 Current medications for schizophrenia focus on action at dopamine receptors,9 but their overall effectiveness for negative symptoms is lacking.8 When psychotic, extrapyramidal, anxiety, or depressive symptoms improve with medication, any change in negative symptoms may be due to improvement in these other symptoms.8

AV 2. Differentiating Depression From Negative Symptoms in Schizophrenia (00:37)

Based on Mulholland and Cooper10

To determine if negative symptoms are primary, clinicians should rule out 4 common causes of secondary negative symptoms: (1) depression, (2) psychotic symptoms, (3) medication side effects, and (4) substance abuse.

Depression. Depression, as characterized by low mood, psychological features, and psychomotor retardation, is common in patients with schizophrenia and can cause lethargy, lack of pleasure, and social withdrawal (AV 2).10 While depressive symptoms may resolve acutely, primary negative symptoms tend to be longstanding and not confined to a distinct episode of depression.

Psychotic symptoms. If psychotic symptoms (eg, hallucinations, delusions) are severe, negative symptoms are likely to be secondary. The atypical antipsychotics clozapine and, to a lesser degree, olanzapine and risperidone have some superiority over typical antipsychotics for improving psychotic symptoms in schizophrenia.11 Because each medication has different side effects, clinicians must individualize medication choice based on patients’ past response, tolerability, and preference.11

Side effects. Symptoms that emerge during treatment may be secondary negative symptoms caused by medication. For example, antipsychotic-induced sedation can cause what appears to be an amotivational syndrome.12 Resolving any treatment-emergent side effects through change of medication, use of anticholinergic medications, or dose adjustment should alleviate such secondary negative symptoms.

AV 3. Factor Analysis of the BNSS (00:35)

Based on Strauss et al15

Substance abuse. Substances of abuse may create symptoms that mimic negative symptoms. For example, a connection has been found between chronic cannabis abuse and an amotivational syndrome, but the causal relationship is uncertain.13 Clinicians should obtain a history of substance use as part of the evaluation.

Apathy Versus Expression Domains

Factor analytic studies14 have grouped negative symptoms into 2 domains of symptoms: apathy (anhedonia, avolition, and asociality) and diminished expression (alogia and blunted affect). The symptoms in these 2 domains have been found to cluster on rating scales such as the SANS,14 BNSS,15 CAINS,5 and SDS.16 For instance, on the BNSS, 6 of the 13 items loaded onto a diminished expression factor and 7 onto an apathy factor (AV 3).15 The clustering of symptoms into 2 groups could mean that these groups have different risk factors, course of illness, and pathophysiology, and perhaps should be considered separate treatment targets.


The number of trials is small, but there are suggestions from these trials that these 2 negative symptom factors may have a differential response to treatment. For example, adjunctive galantamine, an acetylcholinesterase inhibitor, improved symptoms measured by the SANS alogia subscale, although the drug and placebo groups did not significantly differ on SANS total scores.17 In contrast, the partial α7-nicotinic agonist 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), 150 mg, demonstrated significant improvement on SANS total scores compared with placebo and improved negative symptoms on both the alogia and anhedonia SANS subscales in a phase 2 trial.18 Another phase 2 study19 compared response to placebo versus 3 doses (10 mg, 30 mg, 60 mg) of adjunctive bitopertin (a selective glycine reuptake inhibitor) in patients with schizophrenia using 2 PANSS factors: avolition and diminished expression. The 10-mg and 30-mg dose groups showed greater reduction in negative symptoms than the 60-mg dose and placebo groups. Bitopertin had a greater effect on apathy and social withdrawal than on expressive deficits.19 The results of these trials, although interesting, do not yet provide enough information to conclude whether or not the 2 negative symptom factors will have different responses to treatment. In addition to the need for replication, the use of different rating scales across some of the studies raises some uncertainty.


Negative symptoms include blunted affect, alogia, asociality, anhedonia, and avolition. Rating scales are helpful for documenting the presence of and tracking change in these symptoms, but clinicians need to determine the cause of the symptoms as well. Secondary negative symptoms can be caused by depression, psychotic symptoms, medication side effects, and substance abuse. Clinicians should assess these possible causes to ascertain if and when patients have primary negative symptoms. Secondary negative symptoms usually improve with treatment of the underlying cause. The 2 symptom domains that emerge in most factor analysis studies of negative symptom rating scales are apathy and diminished expression; a 2-factor model which may help clarify new approaches to treatment. However, the need remains for effective treatments of primary negative symptoms, either through psychosocial treatments or through agents with mechanisms of action different than current antipsychotic agents.

Drug Names

clozapine (Clozaril, FazaClo, and others), galantamine (Razadyne and others), olanzapine (Zyprexa), risperidone (Risperdal and others)


BNSS = Brief Negative Symptom Scale; CAINS = Clinical Assessment Interview for Negative Symptoms; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; NIMH = National Institute of Mental Health; PANSS = Positive and Negative Syndrome Scale; SANS = Scale for the Assessment of Negative Symptoms; SDS = Schedule for the Deficit Syndrome

Clinical Points

  • Distinguish between primary and secondary negative symptoms by assessing for underlying causes such as depression, psychotic symptoms, medication side effects, or substance abuse
  • Treat the causes of secondary negative symptoms
  • Watch for new negative symptoms treatments that incorporate improved study designs and rating scales


  1. 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
  2. 2. Andreasen NC. Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry. 1982;39(7):784–788. PubMed
  3. 3. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. PubMed
  4. 4. Kirkpatrick B, Fenton WS, Carpenter WT, et al. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32(2):214–219. PubMed
  5. 5. Kring AM, Gur RE, Blanchard JJ, et al. The Clinical Assessment Interview for Negative Symptoms (CAINS): final development and validation. Am J Psychiatry. 2013;170(2):165–172. PubMed
  6. 6. Kirkpatrick B, Strauss GP, Nguyen L, et al. The Brief Negative Symptom Scale: psychometric properties. Schizophr Bull. 2011;37(2):300–305. PubMed
  7. 7. Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33(4):1013–1022. PubMed
  8. 8. Tandon R, Jibson M. Negative symptoms of schizophrenia: how to treat them most effectively. Curr Psychiatry. 2002;1(9):36–42.
  9. 9. Howes OD, Kambeitz J, Kim E, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69(8):776–786. PubMed
  10. 10. Mulholland C, Cooper S. The symptom of depression in schizophrenia and its management. Adv Psychiatr Treat. 2000;6(3):169–177. Full Text
  11. 11. Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother. 2012;13(11):1545–1573. PubMed
  12. 12. Miller DD. Atypical antipsychotics: sleep, sedation, and efficacy. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 2):3–7. PubMed
  13. 13. Schmits E, Quertemont E. So called “soft” drugs: cannabis and the amotivational syndrome [French]. Rev Med Liege. 2013;68(5–6):281–286. PubMed
  14. 14. Blanchard JJ, Cohen AS. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr Bull. 2006;32(2):238–245. PubMed
  15. 15. Strauss GP, Hong LE, Gold JM, et al. Factor structure of the Brief Negative Symptom Scale. Schizophr Res. 2012;142(1–3):96–98. PubMed
  16. 16. Nakaya M, Ohmori K. A two-factor structure for the Schedule for the Deficit Syndrome in schizophrenia. Psychiatry Res. 2008;158(2):256–259. PubMed
  17. 17. Buchanan RW, Conley RR, Dickinson D, et al. Galantamine for the treatment of cognitive impairments in people with schizophrenia. Am J Psychiatry. 2008;165(1):82–89. PubMed
  18. 18. Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008;165(8):1040–1047. PubMed
  19. 19. Umbricht D, Lentz E, Santarelli L, et al. A post-hoc analysis of the negative symptom factor score in a proof-of-concept study of glycine reuptake inhibitor bitopertin in schizophrenia. Papers of the 25th ECNP Congress. Vienna, Austria; October 13–17, 2012. Eur Neuropsychopharmacol. 2012;22(suppl 2):SB11.