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Cognitive impairment and negative symptoms in schizophrenia

    The ‘Cognitive impairment and negative symptoms in schizophrenia’ symposium, chaired by Professor Gabriele Sachs and Professor István Bitter, elaborated on the significance of cognitive and negative symptoms in real-life functioning and illness-related outcomes as well as on the current treatment options for these symptoms.

    Cognitive impairment and real-life functioning in schizophrenia

    Despite having effective pharmacological and psychosocial interventions, the functional outcome of patients in more advanced stages of schizophrenia is still poor, thus making it one of the leading causes of disability1 – started her presentation the first speaker of the symposium, Professor Armida Mucci, Professor of Psychiatry at the University of Campania Luigi Vanvitelli in Naples, Italy.
    Illness-related variables that are associated with functional outcomes, especially negative symptoms, neurocognitive deficits and social cognition deficits, are not addressed adequately by pharmacotherapy.1-3 In support of this statement, Professor Mucci presented the findings of the Italian Network for Research on Psychoses, according to which in clinically stable subjects with schizophrenia, antipsychotic treatment yielded only a 12% functional remission.1 Four years later, the Italian Network for Research on Psychoses conducted a follow-up study, where the same variables were assessed as in the initial study to see whether baseline values predict future outcomes at year 4.4 According to the results, variables that had the greatest impact on real-life functioning (everyday life skills, work skills and interpersonal relationships) were neurocognition and social cognition.4 Furthermore, the study also explored whether these variables had an impact on the changes occurring in the same domains of real-life functioning.4 Results revealed that indeed neurocognition explained that largest amount of variance in everyday life skills, but also in social cognition and functional capacity, whereas social cognition explained the largest amount of variance in work skills.4
    Professor Mucci concluded her talk by highlighting the findings that cognitive factors, like social cognition and neurocognition, are highly associated with real-world functioning.4
    Thus, addressing cognitive impairments experienced by schizophrenia patients is of high importance – yet, cognitive domains are neither systematically assessed, nor targeted by therapeutic interventions in community mental health services. 4
    To conclude, Professor Mucci urged health care professionals to include cognitive training interventions as well as personalised psychosocial interventions in routine mental health care.4

    Negative symptoms and treatment outcomes in schizophrenia

    There are various definitions of negative symptoms in schizophrenia, and depending on how we define them, the efficacy of the same treatment varies – introduced the focus of his presentation Professor István Bitter, Professor at the Department of Psychiatry and Psychotherapy at the Semmelweis University in Budapest, Hungary.
    In studies investing the treatment of general negative symptoms, data is lumped together on both primary and secondary negative symptoms, and sometimes even cognitive symptoms are considered part of the negative symptom domain – explained Professor Bitter. Thus, the major challenge posed by research is to differentiate between primary and secondary negative symptoms, with the former being rather difficult to treat5.
    Treatment of general negative symptoms
    Professor Bitter started his lecture by presenting data on the treatment of general negative symptoms; a large meta-analysis by Fusar-Poli et al. looked at negative symptom alleviation as measured on the Clinical Global Impression Severity Scale.6 Results revealed that most treatments did not reach clinical significance in the reduction of negative symptoms.6 However, Professor Bitter highlighted that clinicians should especially refrain from using first-generation antipsychotics, as they can even induce secondary negative symptoms.
    Treatment of secondary negative symptoms
    Next, Professor Bitter introduced the definition of secondary negative symptoms, whereby such symptoms are not intrinsic to schizophrenia, rather they are caused by factors like positive symptoms, depression/depressive symptoms or side-effects of pharmacological treatment (e.g. neurological or extrapyramidal symptoms, sedation).7 To date, data is lacking on the identification and treatment of secondary negative symptoms, so treatment is focusing on the assumed causal syndrome, i.e. positive or depressive symptoms etc. – said Professor Bitter.
    When discussing negative symptoms secondary to positive symptoms, two types of interactions between positive and negative symptoms can be observed – continued Professor Bitter – “relatively synchronised” trajectory, where positive and negative increase together, while in the “relatively desynchronised” trajectory, where negative symptoms might emerge due to positive symptoms, and even though positive symptoms do not increase further, negative symptoms do.7 If negative symptoms are assumed to be secondary to positive symptoms, there is no need to treat negative symptoms separately, as they would improve with an “optimal” antipsychotic medication, one that is not associated with extrapyramidal symptoms – suggested Professor Bitter.
    The lack of specific studies examining secondary negative symptoms due to depression warrants the need to look at studies on depression in schizophrenia – said Professor Bitter. A systematic review and meta-analysis colluded 19 studies, most of which used selective serotonin reuptake inhibitors and tricyclic antidepressants.8 The findings suggest that antidepressants may be effective in the treatment of depression in schizophrenia, however, results are mixed.8
    Lastly, Professor Bitter discussed negative symptoms secondary to side-effects of medication – similarly, he said, no specific studies are available, so the review of pharmacological treatments is suggested. When aiming to treat secondary negative symptoms due to side-effects, the following aspects should be considered: lowering the dose or the number of antipsychotics used, or changing the antipsychotic or other medication.9
    Treatment of persistent and/or predominant negative symptoms
    Finally, Professor Bitter presented the conclusions of a systematic review and meta-analysis by Krause and colleagues10, where they highlighted the potential of cariprazine, as it outperformed risperidone in the treatment of primary negative symptoms in a study that was well-controlled for secondary negative symptoms – although the study was sponsored by its manufacturer.10
    Professor Bitter then went onto presenting a proposal of a clinical algorithm looking at the treatment of persistent and/or predominant negative symptoms.11 According to the algorithm, firstly, the first-generation antipsychotic should be evaluated and changed to a second-generation antipsychotic, if deemed necessary; in case of inadequate improvement, Cariprazine 3-6mg/day should be taken.11 If there is poor efficacy or side-effect arise, Amisulpride 50-300mg/day is advised; in case of poor efficacy or side-effects, quetiapine or olanzapine is recommended, although evidence is getting weaker and weaker.11 So, if quetiapine/olanzapine proves to be ineffective or side-effects are present, antidepressants should be considered as an add-on treatment.11 From these suggestions, Professor Bitter concluded that only antipsychotics and antidepressants have any reasonable evidence for the treatment of persistent and predominantly negative symptoms.
    To conclude his presentation, Professor Bitter summarised a few key-points regarding the pharmacological treatment of negative symptoms in schizophrenia, as well as highlighted that the development of better research designs for negative symptom studies is highly anticipated, with closer collaboration between academia, industry, and regulatory agencies.

    Therapeutic interventions for cognitive impairment in schizophrenia

    Therapeutic interventions for cognitive impairment in schizophrenia include pharmacological treatments, cognitive enhancers – although they are not yet available in clinical practice –, as well as cognitive remediation – started her presentation Professor Gabriele Sachs, Department of Psychiatry and Psychotherapy at the Medical University of Vienna.
    An optimal pharmacological treatment for achieving cognitive function should have low anticholinergic potential, low extrapyramidal symptoms, low sedation potential, minimal effective dose, as well as they should have high 5-HT2A receptor affinity and dopaminergic activity in the prefrontal cortex.
    Professor Sachs then presented studies investigating the effectiveness of first- versus second-generation antipsychotics on cognitive functioning. The findings of the NeSSy trial showed beneficial effects of second-generation antipsychotics during the initial 6-week treatment on verbal fluency and executive functions and at week 24, on executive functions and verbal memory.12 In contrast, the first-generation antipsychotic group showed improvements on executive functions, but at week 6, a decline in verbal fluency and at week 24 a significant decline in executive functions, verbal memory and verbal fluency was detected.12 Thus, these findings support the advantage of SGA over FGA for the improvement of cognition functions during prolonged treatment.
    Professor Sachs proceeded to discuss the potential of novel antipsychotics – brexpiprazole, cariprazine, lumateperone and lurasidone – highlighting the pro-cognitive effects of cariprazine.13 Cariprazine is a dopamine D2 and D3 partial agonist, with preferential binding to D3 receptors.14 In a post-hoc analysis, a significant improvement was found in the cariprazine group on the Meltzer cognitive subscale, the Marder disorganised thought domain and in the prosocial functioning scale compared to the risperidone group.15
    What about cognitive enhancers as an add-on therapy to antipsychotics? – continued Professor Sachs. Potential pharmacotherapeutic targets include the dopaminergic, glutamatergic and cholinergic systems.16 A large meta-analysis investigated the effect of cognitive enhancers on different neurotransmitter systems, showing a significant, albeit small positive effect on cognition.17 However, conclusive evidence cannot be drawn from these findings, due to the lack of studies, especially on the dopaminergic system.17 
    In the last part of her presentation, Professor Sachs presented findings on the effect of cognitive remediation, showing durable effects on cognition and functioning18, as well as presented the 4 core aspects of cognitive remediation, as defined by an expert working group; having a highly trained cognitive remediation therapist, sessions should include cognitive exercise, and it should include procedures to develop problem-solving strategies as well as procedures to facilitate transfer to real-world functioning.19
    Professor Sachs ended her lecture with highlighting the most important take-away messages from her talk: atypical antipsychotics might have an advantage over typical antipsychotics in the enhancement of cognitive functioning, cognitive remediation was shown to be effective in improving cognition, especially when combining with atypical antipsychotics, and finally, further research is warranted on the effectiveness of cognitive enhancers.

    Cod: 300021/R63. Submitted to AIFA on 03/12/2021

    References title

    1. Galderisi, S. et al. The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia. World Psychiatry 13, 275–287 (2014).
    2. Green, M. F., Hellemann, G., Horan, W. P., Lee, J. & Wynn, J. K. From perception to functional outcome in schizophrenia: Modeling the role of ability and motivation. Arch. Gen. Psychiatry 69, 1216–1224 (2012).
    3. Galderisi, S. et al. The interplay among psychopathology, personal resources, context-related factors and real-life functioning in schizophrenia: stability in relationships after 4 years and differences in network structure between recovered and non-recovered patients. World Psychiatry 19, 81–91 (2020).
    4. Mucci, A. et al. Factors Associated with Real-Life Functioning in Persons with Schizophrenia in a 4-Year Follow-up Study of the Italian Network for Research on Psychoses. JAMA Psychiatry 78, 550–559 (2021).
    5. Galderisi, S., Mucci, A., Buchanan, R. W. & Arango, C. Negative symptoms of schizophrenia: new developments and unanswered research questions. The Lancet Psychiatry 5, 664–677 (2018).
    6. Fusar-Poli, P. et al. Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr. Bull. 41, 892–899 (2015).
    7. Bitter, I. Definitions and measurement of negative symptoms in schizophrenia. in Managing Negative Symptoms of Schizophrenia 1–18 (2020). doi:10.1093/med/9780198840121.003.0001
    8. Gregory, A., Mallikarjun, P. & Upthegrove, R. Treatment of depression in schizophrenia: systematic review and meta-analysis. Br. J. Psychiatry 211, 198–204 (2017).
    9. Kirschner, M., Aleman, A. & Kaiser, S. Secondary negative symptoms — A review of mechanisms, assessment and treatment. Schizophrenia Research (2017). doi:10.1016/j.schres.2016.05.003
    10. Krause, 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. 268, 625–639 (2018).
    11. Cerveri, G., Gesi, C. & Mencacci, C. Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm. Neuropsychiatr. Dis. Treat. 15, 1525–1535 (2019).
    12. Veselinović, T. et al. Disparate effects of first and second generation antipsychotics on cognition in schizophrenia – Findings from the randomized NeSSy trial. Eur. Neuropsychopharmacol. 29, 720–739 (2019).
    13. Corponi, F. et al. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur. Neuropsychopharmacol. 29, 971–985 (2019).
    14. Stahl, S. M. Mechanism of action of cariprazine. CNS Spectr. 21, 123–127 (2016).
    15. Fleischhacker, W. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur. Psychiatry 58, 1–9 (2019).
    16. Tamminga, C. A. The neurobiology of cognition in schizophrenia. J. Clin. Psychiatry 67, 9–13 (2006).
    17. Sinkeviciute, I. et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. npj Schizophr. 4, (2018).
    18. Wykes, T., Huddy, V., Cellard, C., McGurk, S. R. & Czobor, P. A Meta-Analysis of Cognitive Remediation for Schizophrenia: Methodology and Effect Sizes. Am. J. Psychiatry 168, 472–485 (2011).
    19. Bowie, C. R. et al. Cognitive Remediation for Schizophrenia: An Expert Working Group White Paper on Core Techniques. Schizophr. Res. 215, 49–53 (2020).

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    This article by Correll et al. aims to provide useful information for physicians about treating negative symptoms in schizophrenia.

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    Negative symptoms refer to a loss of patient functioning, constituted by 5 constructs, known as the 5As: alogia, blunted affect, anhedonia, avolition, and asoci

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