
==== Front
Mol Psychiatry
Mol Psychiatry
Molecular Psychiatry
1359-4184
1476-5578
Nature Publishing Group UK London

38454078
2503
10.1038/s41380-024-02503-x
Comment
Advancing understanding of the mechanisms of antipsychotic-associated cognitive impairment to minimise harm: a call to action
Allott Kelly kelly.allott@orygen.org.au

12
http://orcid.org/0000-0003-0866-3477
Chopra Sidhant 3
Rogers Jack 4
http://orcid.org/0000-0002-2873-8512
Dauvermann Maria Regina 4
http://orcid.org/0000-0003-1640-5611
Clark Scott Richard 56
1 https://ror.org/02apyk545 grid.488501.0 Orygen, Parkville, VIC Australia
2 https://ror.org/01ej9dk98 grid.1008.9 0000 0001 2179 088X Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC Australia
3 https://ror.org/03v76x132 grid.47100.32 0000 0004 1936 8710 Department of Psychology, Yale University, New Haven, CT USA
4 https://ror.org/03angcq70 grid.6572.6 0000 0004 1936 7486 Institute for Mental Health, University of Birmingham, Birmingham, UK
5 https://ror.org/00892tw58 grid.1010.0 0000 0004 1936 7304 University of Adelaide, Discipline of Psychiatry, Adelaide, SA Australia
6 https://ror.org/008b3br98 grid.488717.5 Basil Hetzel Institute, Woodville South, SA Australia
7 3 2024
7 3 2024
2024
29 8 25712574
29 7 2023
21 2 2024
27 2 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Subject terms

Molecular biology
Schizophrenia
Biochemistry
issue-copyright-statement© Springer Nature Limited 2024
==== Body
pmcThe discovery in the 1950s that antipsychotic medication could dramatically improve the positive (and in some cases negative) symptoms of severe psychotic disorders led to antipsychotics becoming the first-line treatment for acute recovery, with maintenance for at least one to two years recommended for relapse prevention. Yet, antipsychotic medications do not usually improve the symptoms that underpin poor functional outcome, such as cognitive impairment. Clinically significant cognitive impairment is a hallmark of psychotic illness and is already present prior to the introduction of antipsychotics [1]. Whilst variable, the bulk of evidence shows that antipsychotic effects on general cognitive functioning are at best mildly positive and that these positive effects can mostly be explained by cognitive test practice effects, or atypical antipsychotics being less cognitively impairing than typical antipsychotics [2, 3]. A growing body of more recent literature suggests that antipsychotic medication may in fact worsen cognitive functioning, including specific domains such as verbal learning and memory as well as composite functioning [4, 5]. Subjective cognitive impairment, particularly cognitive slowing, is commonly reported by people taking antipsychotics. Naturalistic studies have shown higher cumulative antipsychotic exposure to be associated with poorer cognitive functioning [4], although these findings may reflect confounding by indication. Our recent triple-blind randomised controlled trial compared the effects of risperidone/paliperidone versus placebo on cognitive functioning over the first six months of treatment for first-episode psychosis [5]. A healthy control group not taking placebo or medication was also recruited. We found that in several cognitive domains the stability or improvement observed was similar across the three groups, suggesting improvements were in fact typical and not related to illness or medication [5]. However, a significant interaction was observed for verbal learning and memory, where the healthy control and placebo groups improved, but the risperidone/paliperidone group declined in performance. The effect sizes were moderate to large [5]. At the same time, there has been a rise in the number of randomised controlled trials comparing antipsychotic dose reduction with antipsychotic maintenance to evaluate their risk: benefit profile across a range of outcomes not limited to relapse. Cognition is a common outcome of these studies, where preliminary evidence suggests that medically guided dose reduction may be associated with superior cognitive outcomes, including in processing speed and global cognitive function (see Table 1).Table 1 Randomised controlled trials comparing antipsychotic dose reduction with maintenance with cognition as an outcome.

Study	Country6	Psychosis sample	Sample size	Dose reduction period	Primary endpoint	Cognitive outcomes	
Faber et al. [17]	Netherlands	First-episode psychosis	42	4 weeks	5 months	+ Processing speed; verbal fluency

= Attention; working memory; learning and memory; motor function

	
Hori et al. [18]	Japan	Long-term schizophrenia	39	12 weeks	5 months	+ Processing speed; attention

= Verbal memory; working memory; motor function; verbal fluency; executive function; global cognition

	
Takeuchi et al. [19]	Japan	Schizophrenia	61	24 weeks	6 months	+ Global cognition; immediate memory; language

= Visuospatial; attention; delayed memory

	
Zhou et al. [20]	China	Schizophrenia	75	12 weeks	12 months	+ Global cognition; processing speed; working memory

= Attention; learning; executive function; social cognition

	
Stürup et al. [21]	Denmark	First-episode schizophrenia	29	12 months	12 months	+ Global cognition	
+ indicates that outcomes were superior in the dose reduction group, = indicates the dose reduction and maintenance groups did not differ.

Antipsychotic medications encompass a wide variety of compounds, sharing a common mechanism - antagonism of the dopamine D2 receptor. Atypical second-generation antipsychotics additionally antagonise serotonin 5-HT2 receptors, and third generation compounds exhibit preferential binding to D3 and partial D2 receptor antagonism. It is widely accepted that the modulation of these neurotransmitter systems represents the primary mechanism behind reduction of positive symptoms, in support of the dopamine hypothesis. However, the sequalae of this modulation on cognition and variance by antipsychotic class remains understudied. Additional proposed mechanisms of antipsychotic effects on cognition include neuromodulation of excitatory (glutamatergic), inhibitory (γ-Aminobutyric acid) and anticholinergic systems, which impact on inflammatory processes and may be related to side-effects, such as anticholinergic burden, motor symptoms, and sedation. To optimise antipsychotic selection and treatment response with a view to minimising iatrogenic cognitive effects and maximising benefits and prognosis, there is a pressing need to increase our mechanistic understanding of how antipsychotics may alter cognition through systematic investigation.

Effects of dopaminergic modulation on cognitive function

Dopamine modulation subserves multiple aspects of cognition, especially through the regulation of brain circuits connecting the pre-frontal cortex and striatum via the dopaminergic mesocortical and mesolimbic pathways among others. Previous work from our group has shown that even short-term use of antipsychotics can cause prominent changes in both brain structure and function within cortico-striatal regions [6]. Positron emission tomography (PET) imaging studies demonstrate a hyperbolic association between antipsychotic dose and D2 occupancy, where increasing doses are associated with incrementally smaller impacts on D2 occupancy, yet adverse effects, including cognitive effects, appear to worsen [7]. Similarly, plasma antipsychotic concentrations corresponding to brain D2 receptor occupancy above 70% are associated with disproportionately poorer cognitive outcomes [8]. Open label studies involving antipsychotic-naïve first-episode individuals have shown risperidone (a strong dopamine antagonist) was associated with a decline in cognitive functioning over 12-weeks, with a significant negative correlation observed between extrastriatal D2/3 occupancy and cognitive performance [9]. Therefore, the effects of antipsychotics on learning, memory and other executive functions may arise due to prolonged antagonism at D2 receptors [8], with a gradual reduction in dose potentially leading to normalisation of dopamine-mediated functional brain circuits underlying higher-order cognitive processes.

Effects of anticholinergic modulation on cognitive function

While consistent evidence has implicated increased striatal presynaptic dopamine synthesis as a primary illness mechanism underlying psychosis, the neural changes associated with antipsychotic use are not exclusively localised to dopaminergic pathways, but rather may reflect widespread functional brain changes in thalamo-cortical circuits subserving higher-order cognitive processes [6]. Antipsychotic medications (and other psychotropic medications) vary in their degree of antagonism of acetylcholine receptors; a risk factor known as anticholinergic burden. The major cholinergic pathways of the brain originate in the basal forebrain, brainstem, and striatum, innervating all cortical and subcortical regions. Anticholinergic burden from psychotropic (and non-psychotropic) medication is often related to cognitive impairment, with exposure to anticholinergic drugs including antipsychotics being associated with significantly increased risk for dementia [10]. In individuals with psychosis, higher anticholinergic burden is associated with worse performance in multiple cognitive domains, including attention, verbal learning and memory, and working memory, even after accounting for confounds such as medication dose and illness severity [11]. The blockade of muscarinic cholinergic receptors by second-generation antipsychotics may contribute to this cognitive impairment. Conversely, selective muscarinic M1/M4 agonism is associated with improved negative (and potentially cognitive) symptoms in some patients [12].

Effects of glutamatergic modulation and neuroinflammation on cognitive function

There is emerging evidence for a complex interaction between inflammation, oxidative stress, dopamine transmission, synaptic plasticity and glutamate transmission including hypofunction of N-methyl-D-aspartate receptors (NMDAR), which lie at the core of pathology in schizophrenia [13] and associated cognitive dysfunction. For individuals with established schizophrenia, but not first-episode psychosis, risperidone appears to decrease levels of proinflammatory cytokines, such as IL-6, TNF-α, IL-2 and IL-1β, but has no significant effect on IFN-γ [14]. In contrast, for clozapine, pro-inflammatory effects can be observed early in treatment, but overall, no significant effects on IL-6 and TNF-α are found [14]. However, there are conflicting findings and further research is needed in this evolving field. Inflammation can also be linked to blood antioxidant levels (reduced) and markers of oxidative stress (increased) in those at high risk of psychosis and in untreated first-episode psychosis, but these levels normalise with long-term antipsychotic treatment [15]. Cytokines such as IFN-γ or TNF-α can also induce hypofunction in NMDAR by increasing the synthesis of kynurenic acid which blocks the NMDAR glycine binding site, but is reversible by clozapine [13]. Thus, the balance of positive and negative cognitive effects associated with antipsychotic neuromodulation must be considered. We advocate that further investigation into the complex neuroinflammatory effects of antipsychotics on cognition, which vary between drugs and across the stage and duration of illness and treatment, is imperative.

Impact of side-effects on cognitive function

The effects of antipsychotic neurotransmitter modulation on brain circuits subserving cognition, may also manifest as side-effects such as sedation, movement disorders (e.g., extrapyramidal effects), amotivation, and blurred vision, which are relatively common [16]. Side-effects can greatly influence or impair cognitive functioning or hamper performance on cognitive tasks and have further negative consequences for functional outcome, personal recovery, or quality of life. A further common consequence of antipsychotic side-effects, including cognitive effects is that people stop taking their medication without medical guidance. This potentially leads to unintended adverse outcomes, such as relapse and hospitalisation. Antipsychotic-related side-effects are rarely examined as a mechanism of cognitive impairment in psychotic disorders and require more systematic investigation so that treatment response can be optimised.

Progressing the field through mechanistic studies

We have proposed several potential mechanisms underlying the effects of antipsychotics on cognitive impairment (see Fig. 1), but the relative contributions of these mechanisms are likely to vary by antipsychotic class, dose, and duration, and require careful study to inform personalised care in the clinic. We call on the field to include more mechanistic aims and measures within dose-reduction, longitudinal, observational, and experimental studies to map and untangle the effect of these different mechanisms. These mechanistic aims should also be included in randomised controlled trials comparing antipsychotic dose reduction with maintenance. For example, including PET or Magnetic Resonance Spectroscopy measures to quantify neurotransmitter and neurometabolite levels, synthesis capacity, and receptor occupancy, or investigate associations between neuroimaging measures and normative maps of these molecular measures. Increasingly, functional neuroimaging (e.g., fMRI and EEG) is used to monitor longitudinal changes in brain connectivity and excitation/inhibition and indirectly infer balance. Similarly, including blood or saliva samples to index inflammatory response and estimated receptor occupancy markers, and the use of valid repeated anticholinergic burden and side-effect measures should be considered. Large datasets or clinical registries may also provide an avenue for understanding prescribing patterns and their association with cognitive and functional decline. Through focused investigation the field will be better able to model the precise mechanisms underlying the association between antipsychotics and cognitive function. This will advance personalised medicine and optimal treatment outcomes for people with psychosis.Fig. 1 Potential mechanisms of the effects of antipsychotics on cognitive function.

Author contributions

KA conceptualised the paper and wrote the first draft. SC reviewed and revised the draft and developed the Figure. JR, MD, and SC reviewed and revised the draft. All authors edited and approved the final version.

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions.

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Fatouros-Bergman H Cervenka S Flyckt L Edman G Farde L Meta-analysis of cognitive performance in drug-naive patients with schizophrenia Schizophrenia Res 2014 158 156 62 10.1016/j.schres.2014.06.034
Fatouros-Bergman H, Cervenka S, Flyckt L, Edman G, Farde L. Meta-analysis of cognitive performance in drug-naive patients with schizophrenia. Schizophrenia Res. 2014;158:156–62.
2. Goldberg TE Goldman RS Burdick KE Malhotra AK Lencz T Patel RC Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia. Is it a practice effect? Arch Gen Psychiatry 2007 64 1115 22 10.1001/archpsyc.64.10.1115 17909123
Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia. Is it a practice effect? Arch Gen Psychiatry. 2007;64:1115–22.17909123
3. Keefe RSE Bilder RM Davis SM Harvey PD Palmer BW Gold JM Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial Arch Gen Psychiatry 2007 64 633 47 10.1001/archpsyc.64.6.633 17548746
Keefe RSE, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry. 2007;64:633–47.17548746
4. Husa AP Rannikko I Moilanen J Haapea M Murray GK Barnett J Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia - An observational 9-year follow-up study Schizophrenia Res 2014 158 134 41 10.1016/j.schres.2014.06.035
Husa AP, Rannikko I, Moilanen J, Haapea M, Murray GK, Barnett J, et al. Lifetime use of antipsychotic medication and its relation to change of verbal learning and memory in midlife schizophrenia - An observational 9-year follow-up study. Schizophrenia Res. 2014;158:134–41.
5. Allott K Yuen HP Baldwin L O’Donoghue B Fornito A Chopra S Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial Transl Psychiatry 2023 13 199 10.1038/s41398-023-02501-7 37301832
Allott K, Yuen HP, Baldwin L, O’Donoghue B, Fornito A, Chopra S, et al. Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial. Transl Psychiatry. 2023;13:199.37301832
6. Chopra S Francey S O’Donoghue B Sabaroedin K Arnatkeviciute A Cropley V Functional connectivity in antipsychotic-treated and antipsychotic-naive patients with first-episode psychosis and low risk of self-harm or aggression: Secondary analysis of a randomized clinical trial JAMA Psychiatry 2021 78 994 1004 10.1001/jamapsychiatry.2021.1422 34160595
Chopra S, Francey S, O’Donoghue B, Sabaroedin K, Arnatkeviciute A, Cropley V, et al. Functional connectivity in antipsychotic-treated and antipsychotic-naive patients with first-episode psychosis and low risk of self-harm or aggression: Secondary analysis of a randomized clinical trial. JAMA Psychiatry. 2021;78:994–1004.34160595
7. de Haan L Lavalaye J Linszen D Dingemans PM Booij J Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone Am J Psychiatry 2000 157 1019 20 10.1176/appi.ajp.157.6.1019 10831489
de Haan L, Lavalaye J, Linszen D, Dingemans PM, Booij J. Subjective experience and striatal dopamine D(2) receptor occupancy in patients with schizophrenia stabilized by olanzapine or risperidone. Am J Psychiatry. 2000;157:1019–20.10831489
8. Sakurai H Bies RR Stroup ST Keefe RS Rajji TK Suzuki T Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data Schizophrenia Bull 2013 39 564 74 10.1093/schbul/sbr189
Sakurai H, Bies RR, Stroup ST, Keefe RS, Rajji TK, Suzuki T, et al. Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data. Schizophrenia Bull. 2013;39:564–74.
9. Nørbak-Emig H Ebdrup B Fagerlund B Svarer C Rasmussen H Friberg L Frontal D2/3 receptor availability in schizophrenia patients before and after their first antipsychotic treatment: Relation to cognitive functions and psychopathology Int J Neuropsychopharmacol 2016 19 006 10.1093/ijnp/pyw006
Nørbak-Emig H, Ebdrup B, Fagerlund B, Svarer C, Rasmussen H, Friberg L, et al. Frontal D2/3 receptor availability in schizophrenia patients before and after their first antipsychotic treatment: Relation to cognitive functions and psychopathology. Int J Neuropsychopharmacol. 2016;19:006.
10. Coupland CAC Hill T Dening T Morriss R Moore M Hippisley-Cox J Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study JAMA Intern Med 2019 179 1084 93 10.1001/jamainternmed.2019.0677 31233095
Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. 2019;179:1084–93.31233095
11. Joshi YB Thomas ML Braff DL Green MF Gur RC Gur RE Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia Am J Psychiatry 2021 178 838 47 10.1176/appi.ajp.2020.20081212 33985348
Joshi YB, Thomas ML, Braff DL, Green MF, Gur RC, Gur RE, et al. Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia. Am J Psychiatry. 2021;178:838–47.33985348
12. Brannan SK Sawchak S Miller AC Lieberman JA Paul SM Breier A Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia N. Engl J Med 2021 384 717 26 10.1056/NEJMoa2017015 33626254
Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N. Engl J Med. 2021;384:717–26.33626254
13. de Bartolomeis A Barone A Vellucci L Mazza B Austin MC Iasevoli F Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review Mol Neurobiol 2022 59 6460 501 10.1007/s12035-022-02976-3 35963926
de Bartolomeis A, Barone A, Vellucci L, Mazza B, Austin MC, Iasevoli F, et al. Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review. Mol Neurobiol. 2022;59:6460–501.35963926
14. Patlola SR Donohoe G McKernan DP Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis J Psychiatr Res 2023 160 126 36 10.1016/j.jpsychires.2023.01.042 36804109
Patlola SR, Donohoe G, McKernan DP. Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis. J Psychiatr Res. 2023;160:126–36.36804109
15. Rambaud V Marzo A Chaumette B Oxidative Stress and Emergence of Psychosis Antioxidants 2022 11 1870 10.3390/antiox11101870 36290593
Rambaud V, Marzo A, Chaumette B. Oxidative Stress and Emergence of Psychosis. Antioxidants. 2022;11:1870.36290593
16. Read J Williams J Positive and Negative Effects of Antipsychotic Medication: An International Online Survey of 832 Recipients Curr Drug Saf 2019 14 173 81 10.2174/1574886314666190301152734 30827259
Read J, Williams J. Positive and Negative Effects of Antipsychotic Medication: An International Online Survey of 832 Recipients. Curr Drug Saf. 2019;14:173–81.30827259
17. Faber Smid Van Gool Wiersma Van den Bosch The effects of guided discontinuation of antipsychotics on neurocognition in first onset psychosis Eur Psychiatry 2012 27 275 80 10.1016/j.eurpsy.2011.02.003 21561741
Faber Smid, Van Gool, Wiersma, Van den Bosch. The effects of guided discontinuation of antipsychotics on neurocognition in first onset psychosis. Eur Psychiatry. 2012;27:275–80.21561741
18. Hori Yoshimura Katsuki Sugita Atake Nakamura Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients J Psychiatr Res 2013 47 1843 8 10.1016/j.jpsychires.2013.08.024 24054464
Hori, Yoshimura, Katsuki, Sugita, Atake, Nakamura. Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients. J Psychiatr Res. 2013;47:1843–8.24054464
19. Takeuchi Suzuki Remington Bies Abe Graff-Guerrero Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study Schizophrenia Bull 2013 39 993 8 10.1093/schbul/sbt090
Takeuchi, Suzuki, Remington, Bies, Abe, Graff-Guerrero, et al. Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. Schizophrenia Bull. 2013;39:993–8.
20. Zhou Li Li Cui Ning Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: A single-blinded, 52-week, randomized controlled study J Psychopharmacol 2018 32 524 32 10.1177/0269881118756062 29493377
Zhou, Li, Li, Cui, Ning. Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: A single-blinded, 52-week, randomized controlled study. J Psychopharmacol. 2018;32:524–32.29493377
21. Stürup AE Hjorthøj C Albert N Dolmer S Birk M Ebdrup BH Tapered discontinuation vs. maintenance therapy of antipsychotic medication in patients with first-episode schizophrenia: Obstacles, findings, and lessons learned in the terminated randomized clinical trial TAILOR Front Psychiatry 2022 13 910703 10.3389/fpsyt.2022.910703 35935409
Stürup AE, Hjorthøj C, Albert N, Dolmer S, Birk M, Ebdrup BH, et al. Tapered discontinuation vs. maintenance therapy of antipsychotic medication in patients with first-episode schizophrenia: Obstacles, findings, and lessons learned in the terminated randomized clinical trial TAILOR. Front Psychiatry. 2022;13:910703.35935409
