Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment (2024)

Negative Symptom Terminology

“Negative symptoms” is a general descriptive term used without consideration of the cause, longitudinal stability, or duration of the symptoms. Although some negative symptoms are signs that can be observed by a clinician (eg, affective flattening, alogia), other aspects of behavior, such as social withdrawal or diminished engagement in productive or pleasurable activities, may or may not be associated with negative symptoms. As such, asking patients about their interests, emotions, and motivation adds great value to patient observation during negative symptom assessment. Although various more specific terms are used in the literature to describe the nature and etiology of negative symptoms (eg, deficit, predominant, prominent, persistent) as they pertain to research, there is no consensus definition for any term (Table 1). While some descriptors (eg, prominent versus predominant, enduring/persistent versus nonenduring/nonpersistent) have clinical meaning and implications for treatment, the academically appropriate term may not be as important as appropriately identifying and treating all patients in the clinic who have clinically significant negative symptoms or signs.

Differentiating primary negative symptoms (intrinsic to the underlying pathophysiology of schizophrenia) from secondary negative symptoms (related to other factors) can be challenging. Secondary symptoms, which can respond to treatment, occur in association with or result from positive symptoms, affective symptoms, medication side effects, environmental deprivation, or other treatment- or illness-related factors (Figure 1).⁷ For example, negative symptoms could be a secondary effect of primary positive symptoms in a patient who becomes socially withdrawn after experiencing delusions of persecution or paranoia; or diminished expression could be a coping strategy in a patient who is unable to process overwhelming external stimuli associated with psychotic episodes in schizophrenia.

Open in a separate window

Figure 1

Actionable factors that cause or contribute to secondary negative symptoms.

Notes: *Including Huntington’s disease, multiple sclerosis, Parkinson's disease, traumatic brain injury, chronic pain, sleep apnea, temporal lobe epilepsy.

Although several antipsychotics have demonstrated negative symptom improvement in clinical trials that were designed to study patients with acute exacerbation of schizophrenia defined by positive symptoms, treatment response should not be inferred in this context since secondary negative symptoms can improve as a consequence of improvement in other symptom domains.⁸ The most likely interpretation of these results is that when symptoms such as delusions improve, patients may become less socially withdrawn. Although any improvement in negative symptoms may represent an important advance for patients with schizophrenia, primary negative symptoms or negative symptoms that persist once a patient’s positive symptoms are effectively managed, remain a considerable clinical challenge since they generally do not respond well to currently available antipsychotic treatment with dopamine D₂ antagonists or partial D₂ agonists.

While the distinction between primary and secondary negative symptoms is important for researchers and clinical trial design, these symptoms can be difficult to differentiate. As such, the clinical focus should be on managing all negative symptoms that affect patients, do not respond to the current treatment, persist during periods of clinical stability, and interfere with normal role functions. From this viewpoint, clinicians can appreciate that any patient with a clinically significant level of negative symptoms, either alone (ie, predominant negative symptoms) or concurrently with positive symptoms (ie, prominent negative symptoms), can benefit from appropriate clinical management.

Negative Symptom Course

Negative symptoms have been reported as among the most common first symptom of schizophrenia,⁹ although they generally do not represent the reason that clinical care is initially sought for patients. Genetic contributions, prenatal events, and poor premorbid adjustment may all contribute to the development and evolution of early negative symptoms in psychotic illnesses.¹⁰

Negative symptoms commonly appear during the prodromal phase of schizophrenia and before the first acute psychotic episode (Figure 2).^2,9–11 Among patients with negative symptoms, 73% had them before the onset of positive symptoms and 20% experienced them within the same month as positive symptoms.¹¹ Prodromal onset of negative symptoms has been characterized as a risk factor for the switch to psychosis^12,13 and it is associated with negative symptoms in the first psychotic episode.¹⁴ Negative symptoms can also present during the psychotic phase of illness, so clinicians should be mindful of positive symptoms that are accompanied by decreased emotional expression, social withdrawal, and functional deterioration.¹⁰

Open in a separate window

Figure 2

See Also

Self-care and the Four R's of Resilience - Virginia Kindergarten Readiness ProgramTypes Of Stress And Their SymptomsIndicators of StressHow the Goals of Psychology Are Used to Study Behavior

Schematic course of negative symptoms in schizophrenia. Negative symptoms are present throughout the course of schizophrenia. They can occur early, persist over time, increase in severity, and remain between acute episodes of illness. Correll, C. The Prevalence of Negative Symptoms in Schizophrenia and Their Impact on Patient Functioning and Course of Illness. The Journal of Clinical Psychiatry. 74(2):e04, 2013. Copyright 2019, Physicians Postgraduate Press. Reprinted by permission.¹⁵

The long-term course of negative symptoms is unclear, with some studies reporting relative stability of symptoms over time, and others finding that negative symptoms could fluctuate or be reversible.^16–20 Similarly, the distribution of negative versus positive or mixed presentations is unclear and may differ across samples.

Negative Symptom Prevalence

Evidence consistently supports the concept that negative symptoms constitute a distinct group of symptoms in schizophrenia that are separate from positive symptoms, depression and anxiety, and disorganized thought, speech, and behavior; higher prevalence of negative symptoms is noted among men, the unemployed, and in individuals with reduced functioning.^3,6 Although negative symptom prevalence varies according to what defining terminology is used, clinicians should be mindful that up to 60% of patients with schizophrenia have prominent or predominant negative symptoms that are clinically relevant and need treatment.^21,22

Negative symptoms are common and can occur at any point during the course of illness; for example, at least 1 negative symptom was noted in up to 90% of patients having a first psychotic episode, while 35–70% of patients continued to have clinically significant negative symptoms that persisted after treatment.^11,23 In routine clinical practice, 61% of stable outpatients with schizophrenia who were receiving antipsychotic treatment were found to have at least 1 symptom of moderate severity or worse; 5 PANSS Negative Subscale items (blunted affect, emotional withdrawal, poor rapport, social withdrawal, verbal fluency) were included in the evaluation.²¹ Social withdrawal (48%), emotional withdrawal (42%), and poor rapport (39%) were among the most common symptoms, and 19% of patients had all 5 negative symptoms. Likewise, in an analysis of 20 placebo-controlled studies of second-generation antipsychotics (n=7450), 62% of patients met the criteria for prominent negative symptoms (score of at least moderate or moderately severe on multiple PANSS Negative symptoms) and after 6 weeks of treatment, one-third of actively treated patients still had prominent negative symptoms.²² In the same analysis, 50% of patients were characterized as having predominant negative symptoms, defined as a PANSS Negative Subscale score greater than a Positive Subscale score. Further, in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (n=1442), one of the largest individual controlled studies in schizophrenia, prominent negative symptoms were also common (40%), with 19% of outpatients having prominent negative symptoms without prominent positive symptoms and 21% having both prominent positive and negative symptoms.²⁴ Collectively, studies support that negative symptoms are common in schizophrenia and can occur in every phase of the illness.

Burden of Negative Symptoms, and Functional and Cognitive Impairment

Compared with positive symptoms, which can be managed in many patients with currently available dopamine D₂ partial agonists and antagonists, negative symptoms have a higher burden of illness. This pronounced illness burden can be attributed to the limited number of effective and evidence-based treatment options, although underrecognition of these symptoms also plays a role. It is very important to assess and address negative symptoms in an effort to lessen the associated burden on patients, caregivers, and healthcare systems.²

Negative symptom severity in schizophrenia has been consistently linked to worse functional outcomes in areas such as impaired occupational and academic performance, household integration, social functioning, participation in activities, and quality of life.²⁵ Avolition has been proposed as a key negative symptom construct related to functional deterioration.⁵ Loss of motivation is thought to be associated with clinical features that are observable as changes in both individual (ie, apathy, blunted affect) and social (ie, asociality and alogia) behaviors. Although affective symptoms may appear to be anhedonic in nature, individuals with schizophrenia seem to be able to experience consummatory pleasure, with functional decline specifically related to the inability to anticipate pleasure in pursuing or achieving goal-directed behavior.²⁵ Deficits in anticipatory pleasure and reduced pleasure-seeking behavior may be related to reward processing disturbances (eg, deficits in reward learning, reward prediction, accurate and adaptive internal value representations), with subsequent impairment resulting from the inability to use reward-associated information to guide future motivated behavior.²⁵

Negative symptoms and neurocognitive dysfunction affect around 40% and 80% of individuals with schizophrenia, respectively.⁶ Although negative and cognitive symptoms are considered separate domains of psychopathology in schizophrenia, shared features suggest that symptoms from one domain may reinforce the other or that they may originate in similar neurobiological structures.^25,26 For example, impairment of executive function may contribute to avolition by interfering with the goal-directed behavior that is necessary to acquire reward.²⁷ Similarly, impairment in the ability to retrieve information from memory may underpin alogia and poor social cognition, being caused by or resulting in asociality.²⁷ Negative symptoms and cognitive deficits are closely associated with real-world functioning in schizophrenia, although adequate functioning is a complex phenomenon and several factors contribute.^28,29 Interventions for cognitive and negative symptoms partly overlap, with a combination of psychopharmacological and psychosocial interventions needed to adequately treat secondary negative symptoms that may be contributing to impairment and to address patient’s individual cognitive needs.⁶

The Neurobiology of Negative Symptoms

Negative symptoms of schizophrenia are likely to be the result of irregularities of distributed neural networks (eg, frontocortico-temporal, cortico-striatal), as opposed to the disruption of any discrete region of the brain.²⁶ Although several hypotheses may be implicated in the pathophysiology of schizophrenia and negative symptoms, the dopamine and glutamate hypotheses are among those that are best supported by current evidence. The dopaminergic hypothesis of schizophrenia proposes that positive symptoms are the result of hyperactivity of dopaminergic neurotransmission in limbic pathways, while negative symptoms, loss of motivation, and impairment in cognition are thought to arise from hypodopaminergic functioning in the frontal lobe and additional mesolimbic structures.^30,31 However, recent imaging studies suggest that abnormal dopamine function in schizophrenia may be in the dorsal rather than in the limbic striatum.³²

Due to their localization in mesolimbic regions of the brain that control reward, emotion, and motivation, dopamine D₃ receptors may also play a role in the modulation of negative symptoms, mood, and cognition.^33–37 This hypothesis has been supported by findings from animal models, which have suggested that antagonism and partial agonism at dopamine D₃ receptors can mediate improvements in social interaction, novel object recognition, as well as displaying D₃-receptor mediated anti-anhedonic and procognitive effects in rodents.^38–40 The mechanism by which these effects may occur is not clear, although it is possible that antagonism of D₃ receptors in the midbrain (eg, ventral tegmental area) could enhance dopamine neurotransmission to the prefrontal cortex^41,42 and the nucleus accumbens,^43–45 two areas of the brain where hypodopaminergic functioning has been linked to negative symptoms and mood deficits.^46,47 This normalization of dopamine release in the prefrontal cortex could result in increased activation of D₁ receptors, which in turn could mediate improvements in cognition and negative symptoms.⁴⁷ D₃ receptors have also been associated with increased acetylcholine release in the prefrontal cortex,⁴¹ regulation of glutamatergic excitability in the prefrontal cortex,^48,49 and regulation of dopamine, CREB phosphorylation,⁵⁰ and gamma oscillations⁵¹ in the hippocampus, all mechanisms that could potentially contribute to the modulation of cognition and/or mood symptoms associated with schizophrenia. As such, D₃ antagonists and partial agonists may provide benefits in negative or cognitive symptoms.

Alternatives to the dopamine hypothesis suggest that other neurotransmitters, particularly glutamate, contribute to the development of symptoms in schizophrenia. The glutamate hypothesis is based on the clinical observation that chronic blockade of glutamate neurotransmission by antagonists at the N-methyl-D-aspartate (NMDA) receptor subtype (eg, ketamine, phencyclidine) produces a pathophysiological state resembling schizophrenia, including both positive and negative symptoms (whereas the dopamine model of amphetamine-induced psychosis only produces positive symptoms).^52,53 Although several studies have found that drugs facilitating glutamate neurotransmission by acting at the glycine accessory site of the NMDA receptor (eg, D-cycloserine) improve symptoms of schizophrenia and enhance the efficacy of antipsychotic drugs, notably against the negative symptoms of the disease,^54–56 evidence is equivocal.⁵⁷ Positive findings have led to the supposition that schizophrenia may result from glutamate deficiency, with suspected abnormalities in NMDA receptor function contributing to antipsychotic-resistant symptoms,⁵⁸ but additional studies are needed. Additional mechanisms of action, including metabotropic glutamatergic receptor (mGluR2) agonism, alpha-7 nicotinic receptor agonism, and central nervous system stimulant activity, are also targets for drug development in negative symptoms of schizophrenia.⁵⁹

Of note, however, the dopamine and glutamate hypotheses of schizophrenia are not mutually exclusive, with evidence in the literature supporting a role for both in the neurobiology of schizophrenia. Indirect clinical evidence suggests an important interaction between dopamine receptors and NMDA receptors in critical brain regions, such as the hippocampus, and between glutamatergic afferents and subcortical dopaminergic nuclei.⁵² Additionally, a link between cortical glutamate/NMDA deficiency and subcortical dopamine hyperactivity, particularly in the mesolimbic pathway, has been hypothesized in schizophrenia, with some evidence that hyperactivity produced by NMDA receptor blockade is dependent upon stimulation of the dopamine D₃ receptor subtype.⁶⁰ In any case, a better understanding of the neurobiology of negative symptoms constitutes an important step toward the identification of treatment targets and the development of novel interventions for negative symptoms that may improve treatment efficacy and outcomes overall.

Clinical Presentation, Diagnosis, and Identification of Negative Symptoms

It is generally accepted that negative symptoms include 5 key constructs,⁶¹ which can be further categorized into 2 independent factors (Figure 3).^2,62,63

Open in a separate window

Figure 3

Key negative symptom constructs. Blunted affect=decreased expression of emotion; alogia=reduction in quantity of words spoken; avolition=reduced initiation and persistence of goal-directed activity due to decreased motivation; asociality=reduced social interactions and initiative due to decreased interest in relationships with others; anhedonia=reduced experience of pleasure during an activity or in anticipation of an activity.

Although the presence of negative symptoms is not mandatory for a diagnosis of schizophrenia, negative symptoms (ie, diminished emotional expression and avolition), are 1 of the 5 symptom criteria taken into consideration in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).⁶⁴ Diminished expression, which includes reduction in the expression of facial emotions, eye contact, and speech intonation, and reduction in head, hands, and face movement that gives emotional emphasis to speech, is generally observable during a clinical interview. Avolition, indicating decrease in self-motivated and self-initiated purposeful activities, requires inquiry into patient’s behaviors outside the interview setting. A level of functioning in work, school, relationships, or self-care that is markedly below the level that has previously been achieved is also diagnostic and suggests the presence of avolition and the reduced drive to pursue goal-directed behavior.

Clinical recognition of negative symptoms is challenging because patients with schizophrenia may not be aware of the impact of negative symptoms and they rarely present with negative symptom complaints.⁶ If patients lack insight into their symptoms and corroborating information from people in the patient’s life is lacking, additional responsibility is placed on clinicians to recognize negative symptoms, which is particularly important because high negative symptom burden predicts poor treatment response and functional outcomes.⁶ Positive symptoms (eg, delusions, hallucinations) and signs of relapse, hostility, or suicidality often take clinical precedence over the less obvious and emergent negative symptoms, further complicating the identification of negative symptoms during a short clinical visit. Furthermore, while clinicians have been well trained to assess and treat positive symptoms of schizophrenia, many are unsure of the best way to identify and treat negative symptoms.²

When seeing a patient with schizophrenia, clinicians should be on the lookout for a general presentation that suggests the presence of negative symptoms, including signs such as communication difficulties, flat affect, limited emotion, social inactivity, low motivation, and retarded psychom*otor activity (Figure 4). While some of these problems are observable during clinical assessment, others need to be elicited through questions and discussions with the patient, family members, and caregivers, making informant input critical to the accurate assessment of the presence, severity, and impact of negative symptoms.

Open in a separate window

Figure 4

Clinical presentation of negative symptoms.

Negative Symptom Assessment

Treatment

Best Practices for Managing Negative Symptoms in the Clinic

Negative symptoms are common in schizophrenia and over half of patients will experience clinically relevant negative symptoms that need treatment at some point.^21,22 In addition to the limited efficacy of most available pharmacological treatments, negative symptom characteristics are a challenge in the clinic since some patients may lack insight into the extent and impact of their symptoms. Patients rarely present with negative symptom complaints and more immediately pressing positive symptoms may distract clinicians from the negative symptom burden. Given the difficulty in differentiating negative symptoms that are intrinsic to schizophrenia from negative symptoms resulting from another underlying cause, clinicians should carefully monitor and actively manage all clinically relevant negative symptoms (Table 2).

1. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067. doi: 10.1038/nrdp.2015.67 [PubMed] [CrossRef] [Google Scholar]

2. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5:664–677. doi: 10.1016/S2215-0366(18)30050-6 [PubMed] [CrossRef] [Google Scholar]

3. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr.A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry. 2001;58(2):165–171. doi: 10.1001/archpsyc.58.2.165 [PubMed] [CrossRef] [Google Scholar]

4. 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(3):495–506. doi: 10.1176/appi.ajp.162.3.495 [PubMed] [CrossRef] [Google Scholar]

5. Foussias G, Remington G. Negative symptoms in schizophrenia: avolition and Occam’s razor. Schizophr Bull. 2010;36(2):359–369. doi: 10.1093/schbul/sbn094 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

6. Carbon M, Correll CU. Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr. 2014;19 Suppl 1:38–52;quiz 35–37, 53. doi: 10.1017/S1092852914000601 [PubMed] [CrossRef] [Google Scholar]

7. Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33(4):1013–1022. doi: 10.1093/schbul/sbl057 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

8. Moller HJ, Czobor P. Pharmacological treatment of negative symptoms in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2015;265(7):567–578. doi: 10.1007/s00406-015-0596-y [PubMed] [CrossRef] [Google Scholar]

9. an der Heiden W, Hafner H. The epidemiology of onset and course of schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2000;250(6):292–303. doi: 10.1007/s004060070004 [PubMed] [CrossRef] [Google Scholar]

10. Lyne J, O’Donoghue B, Roche E, Renwick L, Cannon M, Clarke M. Negative symptoms of psychosis: a life course approach and implications for prevention and treatment. Early Interv Psychiatry. 2018;12(4):561–571. doi: 10.1111/eip.2018.12.issue-4 [PubMed] [CrossRef] [Google Scholar]

11. an der Heiden W, Leber A, Hafner H. Negative symptoms and their association with depressive symptoms in the long-term course of schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2016;266(5):387–396. doi: 10.1007/s00406-016-0697-2 [PubMed] [CrossRef] [Google Scholar]

12. Piskulic D, Addington J, Cadenhead KS, et al. Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry Res. 2012;196(2–3):220–224. doi: 10.1016/j.psychres.2012.02.018 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Velthorst E, Nieman DH, Becker HE, et al. Baseline differences in clinical symptomatology between ultra high risk subjects with and without a transition to psychosis. Schizophr Res. 2009;109(1–3):60–65. doi: 10.1016/j.schres.2009.02.002 [PubMed] [CrossRef] [Google Scholar]

14. Lyne J, Renwick L, Madigan K, et al. Do psychosis prodrome onset negative symptoms predict first presentation negative symptoms?Eur Psychiatry. 2014;29(3):153–159. doi: 10.1016/j.eurpsy.2013.02.003 [PubMed] [CrossRef] [Google Scholar]

15. Correll C.The prevalence of negative symptoms in schizophrenia and their impact on patient functioning and course of illness. J Clin Psychiatry. 2013;74(2):e04. [Google Scholar]

16. Austin SF, Mors O, Budtz-Jorgensen E, et al. Long-term trajectories of positive and negative symptoms in first episode psychosis: a 10year follow-up study in the OPUS cohort. Schizophr Res. 2015;168(1–2):84–91. doi: 10.1016/j.schres.2015.07.021 [PubMed] [CrossRef] [Google Scholar]

17. Kulhara P, Chandiramani K. Positive and negative subtypes of schizophrenia. A follow-up study from India. Schizophr Res. 1990;3(2):107–116. doi: 10.1016/0920-9964(90)90043-7 [PubMed] [CrossRef] [Google Scholar]

18. Lindenmayer J-P, Kay SR, Friedman C. Negative and positive schizophrenic syndromes after the acute phase: a prospective follow-up. Compr Psychiatry. 1986;27(4):276–286. doi: 10.1016/0010-440X(86)90003-9 [PubMed] [CrossRef] [Google Scholar]

19. Pogue-Geile MF, Harrow M. Negative symptoms in schizophrenia: their longitudinal course and prognostic importance. Schizophr Bull. 1985;11(3):427–439. doi: 10.1093/schbul/11.3.427 [PubMed] [CrossRef] [Google Scholar]

20. Thara R, Henrietta M, Joseph A, Rajkumar S, Eaton WW. Ten-year course of schizophrenia–the Madras longitudinal study. Acta Psychiatr Scand. 1994;90(5):329–336. doi: 10.1111/j.1600-0447.1994.tb01602.x [PubMed] [CrossRef] [Google Scholar]

21. Bobes J, Arango C, Garcia-Garcia M, Rejas J, CLAMORS Study Collaborative Group. Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study. J Clin Psychiatry. 2010;71(3):280–286. doi: 10.4088/JCP.08m04250yel [PubMed] [CrossRef] [Google Scholar]

22. 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. doi: 10.1016/j.schres.2013.06.023 [PubMed] [CrossRef] [Google Scholar]

23. Makinen J, Miettunen J, Isohanni M, Koponen H. Negative symptoms in schizophrenia: a review. Nord J Psychiatry. 2008;62(5):334–341. doi: 10.1080/08039480801959307 [PubMed] [CrossRef] [Google Scholar]

24. Rabinowitz J, Berardo CG, Bugarski-Kirola D, Marder S. Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: a CATIE analysis. Schizophr Res. 2013;150(2–3):339–342. doi: 10.1016/j.schres.2013.07.014 [PubMed] [CrossRef] [Google Scholar]

25. Foussias G, Agid O, Fervaha G, Remington G. Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders. Eur Neuropsychopharmacol. 2014;24(5):693–709. doi: 10.1016/j.euroneuro.2013.10.017 [PubMed] [CrossRef] [Google Scholar]

26. Millan MJ, Fone K, Steckler T, Horan WP. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol. 2014;24(5):645–692. doi: 10.1016/j.euroneuro.2014.03.008 [PubMed] [CrossRef] [Google Scholar]

27. Marder SR, Galderisi S. The current conceptualization of negative symptoms in schizophrenia. World Psychiatry. 2017;16(1):14–24. doi: 10.1002/wps.20385 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Harvey PD, Strassnig M. Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms, and health status. World Psychiatry. 2012;11(2):73–79. doi: 10.1016/j.wpsyc.2012.05.004 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

29. Malaspina D, Walsh-Messinger J, Gaebel W, et al. Negative symptoms, past and present: a historical perspective and moving to DSM-5. Eur Neuropsychopharmacol. 2014;24(5):710–724. doi: 10.1016/j.euroneuro.2013.10.018 [PubMed] [CrossRef] [Google Scholar]

30. Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring new evidence. Int J Neuropsychopharmacol. 2004;7(Supplement 1):S1–S5. doi: 10.1017/S1461145704004110 [PubMed] [CrossRef] [Google Scholar]

31. Stahl S. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed. Cambridge; New York: Cambridge University Press; 2013. [Google Scholar]

32. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci. 2019;42(3):205–220. doi: 10.1016/j.tins.2018.12.004 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

33. Gyertyán I, Saghy K, Laszy J, et al. Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. Behavioural characterisation of RG-15. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(5):529–539. doi: 10.1007/s00210-008-0311-x [PubMed] [CrossRef] [Google Scholar]

34. Joyce JN, Millan MJ. Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today. 2005;10(13):917–925. doi: 10.1016/S1359-6446(05)03491-4 [PubMed] [CrossRef] [Google Scholar]

35. Kiss B, Laszlovszky I, Horvath A, et al. Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: I. Neurochemical characterisation of RG-15. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(5):515–528. doi: 10.1007/s00210-008-0308-5 [PubMed] [CrossRef] [Google Scholar]

36. Laszy J, Laszlovszky I, Gyertyán I. Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005;179(3):567–575. doi: 10.1007/s00213-004-2096-z [PubMed] [CrossRef] [Google Scholar]

37. Leggio GM, Salomone S, Bucolo C, et al. Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol. 2013;719(1–3):25–33. doi: 10.1016/j.ejphar.2013.07.022 [PubMed] [CrossRef] [Google Scholar]

38. Duric V, Banasr M, Franklin T, et al. Cariprazine exhibits anxiolytic and dopamine d3 receptor-dependent antidepressant effects in the chronic stress model. Int J Neuropsychopharmacol. 2017;20(10):788–796. doi: 10.1093/ijnp/pyx038 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

39. Watson DJ, Loiseau F, Ingallinesi M, Millan MJ, Marsden CA, Fone KC. Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology. 2012;37(3):770–786. doi: 10.1038/npp.2011.254 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40. Zimnisky R, Chang G, Gyertyán I, Kiss B, Adham N, Schmauss C. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013;226(1):91–100. doi: 10.1007/s00213-012-2896-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

41. Lacroix LP, Hows ME, Shah AJ, Hagan JJ, Heidbreder CA. Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex. Neuropsychopharmacology. 2003;28(5):839–849. doi: 10.1038/sj.npp.1300114 [PubMed] [CrossRef] [Google Scholar]

42. Sokoloff P, Le Foll B. The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2017;45(1):2–19. doi: 10.1111/ejn.13390 [PubMed] [CrossRef] [Google Scholar]

43. Joseph JD, Wang YM, Miles PR, et al. Dopamine autoreceptor regulation of release and uptake in mouse brain slices in the absence of D(3) receptors. Neuroscience. 2002;112(1):39–49. doi: 10.1016/S0306-4522(02)00067-2 [PubMed] [CrossRef] [Google Scholar]

44. Koeltzow TE, Xu M, Cooper DC, et al. Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice. J Neurosci. 1998;18(6):2231–2238. doi: 10.1523/JNEUROSCI.18-06-02231.1998 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Le Foll B, Diaz J, Sokoloff P. Neuroadaptations to hyperdopaminergia in dopamine D3 receptor-deficient mice. Life Sci. 2005;76:1281–1296. doi: 10.1016/j.lfs.2004.09.018 [PubMed] [CrossRef] [Google Scholar]

46. Gorwood P. Neurobiological mechanisms of anhedonia. Dialogues Clin Neurosci. 2008;10(3):291–299. [PMC free article] [PubMed] [Google Scholar]

47. Stahl SM. Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr. 2017;22(5):375–384. doi: 10.1017/S1092852917000608 [PubMed] [CrossRef] [Google Scholar]

48. Clarkson RL, Liptak AT, Gee SM, Sohal VS, Bender KJ. D3 receptors regulate excitability in a unique class of prefrontal pyramidal cells. J Neurosci. 2017;37(24):5846–5860. doi: 10.1523/JNEUROSCI.0310-17.2017 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49. Yang S, Ben-Shalom R, Ahn M, et al. beta-arrestin-dependent dopaminergic regulation of calcium channel activity in the axon initial segment. Cell Rep. 2016;16(6):1518–1526. doi: 10.1016/j.celrep.2016.06.098 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

50. D’Amico AG, Scuderi S, Leggio GM, Castorina A, Drago F, D’Agata V. Increased hippocampal CREB phosphorylation in dopamine D3 receptor knockout mice following passive avoidance conditioning. Neurochem Res. 2013;38(12):2516–2523. doi: 10.1007/s11064-013-1164-3 [PubMed] [CrossRef] [Google Scholar]

51. Lemercier CE, Schulz SB, Heidmann KE, Kovacs R, Gerevich Z. Dopamine D3 receptors inhibit hippocampal gamma oscillations by disturbing CA3 pyramidal cell firing synchrony. Front Pharmacol. 2015;6:297. [PMC free article] [PubMed] [Google Scholar]

52. Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull. 2012;38(5):920–926. doi: 10.1093/schbul/sbs076 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Domino EF, Mirzoyan D, Tsukada H. N-methyl-D-aspartate antagonists as drug models of schizophrenia: a surprising link to tobacco smoking. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(5):801–811. doi: 10.1016/j.pnpbp.2004.05.024 [PubMed] [CrossRef] [Google Scholar]

54. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158(9):1367–1377. doi: 10.1176/appi.ajp.158.9.1367 [PubMed] [CrossRef] [Google Scholar]

55. Heresco-Levy U, Javitt DC. Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res. 2004;66(2–3):89–96. doi: 10.1016/S0920-9964(03)00129-4 [PubMed] [CrossRef] [Google Scholar]

56. Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry. 1994;151(8):1234–1236. [PubMed] [Google Scholar]

57. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007;164(10):1593–1602. doi: 10.1176/appi.ajp.2007.06081358 [PubMed] [CrossRef] [Google Scholar]

58. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26(4–6):365–384. doi: 10.1007/s10571-006-9062-8 [PubMed] [CrossRef] [Google Scholar]

59. Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options. Neuropsychiatr Dis Treat. 2014;10:777–789. doi: 10.2147/NDT [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Leriche L, Diaz J, Sokoloff P. Dopamine and glutamate dysfunctions in schizophrenia: role of the dopamine D3 receptor. Neurotox Res. 2004;6(1):63–71. doi: 10.1007/BF03033298 [PubMed] [CrossRef] [Google Scholar]

61. Kirkpatrick B, Fenton WS, Carpenter WT Jr., Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32(2):214–219. doi: 10.1093/schbul/sbj053 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

62. Kirkpatrick B, Fischer B. Subdomains within the negative symptoms of schizophrenia: commentary. Schizophr Bull. 2006;32(2):246–249. doi: 10.1093/schbul/sbj054 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Messinger JW, Tremeau F, Antonius D, et al. Avolition and expressive deficits capture negative symptom phenomenology: implications for DSM-5 and schizophrenia research. Clin Psychol Rev. 2011;31(1):161–168. doi: 10.1016/j.cpr.2010.09.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

64. APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. [Google Scholar]

65. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261 [PubMed] [CrossRef] [Google Scholar]

66. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989;155(7):49–58. doi: 10.1192/S0007125000291496 [PubMed] [CrossRef] [Google Scholar]

67. Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item Negative Symptom Assessment. J Psychiatr Res. 1993;27(3):253–258. doi: 10.1016/0022-3956(93)90036-2 [PubMed] [CrossRef] [Google Scholar]

68. Kring AM, Gur RE, Blanchard JJ, Horan WP, Reise SP. The Clinical Assessment Interview for Negative Symptoms (CAINS): final development and validation. Am J Psychiatry. 2013;170(2):165–172. doi: 10.1176/appi.ajp.2012.12010109 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Kirkpatrick B, Strauss GP, Nguyen L, et al. The brief negative symptom scale: psychometric properties. Schizophr Bull. 2011;37(2):300–305. doi: 10.1093/schbul/sbq059 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

70. Daniel DG. Issues in selection of instruments to measure negative symptoms. Schizophr Res. 2013;150(2–3):343–345. doi: 10.1016/j.schres.2013.07.005 [PubMed] [CrossRef] [Google Scholar]

71. Alphs L, Morlock R, Coon C, van Willigenburg A, Panagides J. The 4-item Negative Symptom Assessment (NSA-4) instrument: a simple tool for evaluating negative symptoms in schizophrenia following brief training. Psychiatry (Edgmont). 2010;7(7):26–32. [PMC free article] [PubMed] [Google Scholar]

72. Velligan DI, Lopez L, Castillo DA, Manaugh B, Milam AC, Miller AL. Interrater reliability of using brief standardized outcome measures in a community mental health setting. Psychiatr Serv. 2011;62(5):558–560. doi: 10.1176/ps.62.5.pss6205_0558 [PubMed] [CrossRef] [Google Scholar]

73. Firth J, Torous J. Smartphone apps for schizophrenia: a systematic review. JMIR Mhealth Uhealth. 2015;3(4):e102. doi: 10.2196/mhealth.4930 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

74. Haddad PM, Correll CU. The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol. 2018;8(11):303–318. doi: 10.1177/2045125318781475 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

75. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Davis JM. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2012;(5):CD008016. [PubMed] [Google Scholar]

76. 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. doi: 10.1016/j.schres.2016.05.015 [PubMed] [CrossRef] [Google Scholar]

77. Barnes TR, Schizophrenia Consensus Group of British Association for P. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2011;25(5):567–620. doi: 10.1177/0269881110391123 [PubMed] [CrossRef] [Google Scholar]

78. Fusar-Poli P, Papanastasiou E, Stahl D, et al. Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophr Bull. 2015;41(4):892–899. doi: 10.1093/schbul/sbu170 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

79. Leucht S, Leucht C, Huhn M, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry. 2017;174(10):927–942. doi: 10.1176/appi.ajp.2017.16121358 [PubMed] [CrossRef] [Google Scholar]

80. Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry. 2009;14(4):429–447. doi: 10.1038/sj.mp.4002136 [PubMed] [CrossRef] [Google Scholar]

81. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41. doi: 10.1016/S0140-6736(08)61764-X [PubMed] [CrossRef] [Google Scholar]

82. Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2018;268:625–639. doi: 10.1007/s00406-018-0869-3 [PubMed] [CrossRef] [Google Scholar]

83. Németh 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. doi: 10.1016/S0140-6736(17)30060-0 [PubMed] [CrossRef] [Google Scholar]

84. Cho DI, Zheng M, Kim KM. Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors. Arch Pharm Res. 2010;33(10):1521–1538. doi: 10.1007/s12272-010-1005-8 [PubMed] [CrossRef] [Google Scholar]

85. Guy W. Clinical global impressions In: Guy W, editor. ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Rockville, MD: National Institute of Mental Health, Psychopharmacology Research Branch; 1976:217–222. [Google Scholar]

86. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–329. [PubMed] [Google Scholar]

87. Arango C, Garibaldi G, Marder SR. Pharmacological approaches to treating negative symptoms: a review of clinical trials. Schizophr Res. 2013;150(2–3):346–352. doi: 10.1016/j.schres.2013.07.026 [PubMed] [CrossRef] [Google Scholar]

88. Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry. 2017;74(7):675–684. doi: 10.1001/jamapsychiatry.2017.0624 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

89. Galling B, Vernon JA, Pagsberg AK, et al. Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia. Acta Psychiatr Scand. 2018;137(3):187–205. doi: 10.1111/acps.2018.137.issue-3 [PubMed] [CrossRef] [Google Scholar]

90. Helfer B, Samara MT, Huhn M, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry. 2016;173(9):876–886. doi: 10.1176/appi.ajp.2016.15081035 [PubMed] [CrossRef] [Google Scholar]

91. Torrey EF, Davis JM. Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas. Clin Schizophr Relat Psychoses. 2012;5(4):208–216. doi: 10.3371/CSRP.5.4.5 [PubMed] [CrossRef] [Google Scholar]

92. 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;174(12):1195–1202. doi: 10.1176/appi.ajp.2017.17010122 [PubMed] [CrossRef] [Google Scholar]

93. Micoulaud Franchi JA, Quiles C, Belzeaux R, Adida M, Azorin JM. Negative symptoms of schizophrenia: from electrophysiology to electrotherapy. Encephale. 2015;41(6Suppl 1):6S50–S56. doi: 10.1016/S0013-7006(16)30011-2 [PubMed] [CrossRef] [Google Scholar]

94. Krogmann A, Peters L, von Hardenberg L, Bödeker K, Nöhles VB, Correll CU. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr. 2019;24(S1):38–69. doi: 10.1017/S109285291900124X [PubMed] [CrossRef] [Google Scholar]

95. Beck AT, Grant PM, Huh GA, Perivoliotis D, Chang NA. Dysfunctional attitudes and expectancies in deficit syndrome schizophrenia. Schizophr Bull. 2013;39(1):43–51. doi: 10.1093/schbul/sbr040 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

96. Chacon F, Mora F, Gervas-Rios A, Gilaberte I. Efficacy of lifestyle interventions in physical health management of patients with severe mental illness. Ann Gen Psychiatry. 2011;10:22. doi: 10.1186/1744-859X-10-22 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

97. Turner DT, van der Gaag M, Karyotaki E, Cuijpers P. Psychological interventions for psychosis: a meta-analysis of comparative outcome studies. Am J Psychiatry. 2014;171(5):523–538. doi: 10.1176/appi.ajp.2013.13081159 [PubMed] [CrossRef] [Google Scholar]

98. 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. doi: 10.1016/j.cpr.2013.07.001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

99. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011;168(5):472–485. doi: 10.1176/appi.ajp.2010.10060855 [PubMed] [CrossRef] [Google Scholar]

100. Jauhar S, McKenna PJ, Radua J, Fung E, Salvador R, Laws KR. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry. 2014;204(1):20–29. doi: 10.1192/bjp.bp.112.116285 [PubMed] [CrossRef] [Google Scholar]

101. Klingberg S, Wolwer W, Engel C, et al. Negative symptoms of schizophrenia as primary target of cognitive behavioral therapy: results of the randomized clinical TONES study. Schizophr Bull. 2011;37(Suppl 2):S98–110. doi: 10.1093/schbul/sbr073 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

102. Velligan D, Maples N, Roberts DL, Medellin EM. Integrated psychosocial treatment for negative symptoms. Am J Psychiatric Rehab. 2014;17(1):1–19. doi: 10.1080/15487768.2013.873370 [CrossRef] [Google Scholar]

103. 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. doi: 10.1016/j.schres.2015.04.008 [PMC free article] [PubMed] [CrossRef] [Google Scholar]