Antipsychotic medication has transformed treatment for patients with schizophrenia and related psychiatric disorders, but what is their effect on the thinking brain? Most antipsychotic medications work by acting on our brain’s dopamine D2 and D3 receptors. These receptors are found throughout the brain, concentrated in areas important for reward processing, motivation, motor control, and cognitive functioning (including our learning, working memory, and attention).
Many antipsychotics act as D2 and D3 dopamine blockers (or antagonists), reducing excess dopamine activity in the brain. Others act as ‘partial agonists’, meaning they can block dopamine when levels are high and activate D2/D3 receptors when levels are low. The challenge is that whilst antipsychotics help reduce positive (e.g., hallucinations, delusions) and negative symptoms (e.g., reduced emotional response, lack of motivation or inability to feel pleasure), cognitive impairments such as difficulty concentrating and slower thinking can persevere. Such problems can contribute to poor adherence and treatment discontinuation.
In this recent study, conducted by Dr Osugo and colleagues (published in Molecular Psychiatry), the causal role of D2/D3 dopamine activity in human cognition is investigated. To do this, they explored whether longer-term use of antipsychotic medications causes cognitive functioning changes in people without a diagnosis of schizophrenia or a related disorder. They also ask whether different types of antipsychotics have different effects on our cognitive abilities.
Antipsychotic medications effectively reduce many key symptoms of several psychiatric disorders, but cognitive impairments can often remain.
Methods
The authors used a double-blind, placebo-controlled crossover study design, meaning that neither the researchers nor the participants knew which condition they were in and that each participant became their own control comparison. They tested the effects of two commonly prescribed antipsychotics on cognitive functioning:
- Amisulpride: A traditional D2/D3 antagonist antipsychotic.
- Aripiprazole: A D2/D3 partial agonist antipsychotic.
Two separate groups of adults without a mental health diagnosis (n=25 per group) randomly received either amisulpride (400 mg daily) and placebo for seven days each or aripiprazole (10 mg daily) and placebo for seven days each. Approximately half of the participants received the drug first and then placebo, and the remainder received placebo first and then drug.
To investigate the effects of seven-day administration of the two different antipsychotics on cognitive functioning, the researchers used tasks assessing the participants working memory, attention and their ability to stop, or inhibit, responses when required.
Results
The researchers reported that both antipsychotics (amisulpride and aripiprazole) impaired cognitive performance in the working memory task when compared to the placebo drug in individuals without a diagnosis of schizophrenia or a related disorder. Specifically, the authors report that both antipsychotics impaired working memory performance in terms of how fast participants were able to recall the location of the target image in the working memory task. However, the accuracy of people’s responses was not altered following either antipsychotic in comparison to the placebo.
Interestingly, there was also no effect of either antipsychotic on attention and the participant’s ability to restrict, or inhibit, their responses. The impairments in working memory were also observed in the absence of any changes in alertness or mood reported by the participants. This suggests that the antipsychotics did not cause a general cognitive “slowing” but specifically slowed participant’s working memory capability.
The results also showed that, relative to the placebo, amisulpride and aripiprazole did not differ in their effects on working memory, suggesting that full D2/D3 antagonists were no more cognitively impairing in this study than the D2/D3 partial agonists.
Seven days of antipsychotics, amisulpride or aripiprazole, in adults without a mental health diagnosis slowed working memory speed, without affecting accuracy, attention, inhibition, mood or alertness.
Conclusions
The authors state:
This study provides causal evidence in humans of the cognitive effects of sustained antipsychotic administration, and indicates the key role of D2/D3 signalling in regulating working memory processes.
Specifically, whilst response accuracy was maintained, participants made slower responses in a working memory task following antipsychotic use. Interestingly, working memory was impaired to a similar degree for the D2/D3 dopamine receptor antagonist (amisulpride) and the D2/D3 partial agonist (aripiprazole).
These findings are not suggestive of a more general cognitive “slowing” but rather imply a key role of D2/D3 dopamine receptor signalling on working memory function in individuals without a diagnosis of schizophrenia or related psychotic disorders.
Antipsychotics may impair working memory but clear, sustained evidence of impact over time remains limited.
Strengths and limitations
This study provides novel evidence of the effects of repeated antipsychotic administration on cognitive function in a larger sample of people without a mental health diagnosis. By conducting a randomised, double-blind placebo-controlled crossover study the researchers aimed to objectively disentangle the underlying disease-state from drug-specific effects. They administered clinically relevant doses of either a D2/D3 antagonist (amisulpride) or a D2/D3 partial agonist (aripiprazole) over seven days, providing insight into more sustained antipsychotic effects. This study has clear clinical implications for larger randomised placebo-controlled clinical trials exploring the impact of sustained antipsychotic use on cognitive function in undiagnosed and clinical populations informing more targeted-treatment approaches.
However, a number of limitations should be considered. Firstly, contra to predictions and prior studies, demonstrating cognitive impairments in attention following antipsychotic use (Ramaekers et al., 1999; Beuzen et al., 1999), the authors report no effect of either antipsychotic on attention and response inhibition. The authors suggest that such previously observed deficits may be attributable differences in the measures used or, more broadly, the underlying disease process in people with schizophrenia with potential interactions between the disease process and antipsychotic treatment response (Wright et al., 2014). Given the reported findings in undiagnosed people, one suggestion would be to assess the modulation of D2/D3 antipsychotic receptor sensitivity on attention and response inhibition at the individual level, potentially informing the underlying disease process and patient stratification approaches in clinical populations.
This also speaks to a second limitation: it is unclear how far findings in undiagnosed people generalise to clinical populations, and whether cognitive deficits from repeated antipsychotic use reflect a shared or distinct underlying process in undiagnosed individuals vs people with schizophrenia. Further investigation could clarify not only the longer-term effects of antipsychotic treatment on working memory in people with schizophrenia, but also the causal role of dopamine D2/D3 receptor signalling in prefrontal (learning, memory) vs striatal reward-centred areas of the brain. It could also reveal potential differences or adaptations to D2/D3 dopamine antagonists compared to D2/D3 partial agonists over time.
This study shows how sustained antipsychotic use affects cognition in undiagnosed “healthy” adults, but it remains unclear how these findings directly apply to people with schizophrenia.
Implications for practice
Antipsychotics are prescribed for long periods of time to millions of people worldwide each year. Clarifying the cognitive impact of antipsychotics remains an important clinical question. Whilst impairments in working memory are observed in people diagnosed with schizophrenia and other neuropsychiatric disorders who are not taking antipsychotics, the results from this study suggest that taking antipsychotics that impact on D2/D3 dopamine receptors may well worsen these memory deficits albeit under experimental conditions in adults without a mental health disorder diagnosis.
Interestingly the researchers report no effect of either antipsychotic on performance in an attention-based task measuring the participant’s ability to inhibit their responses. This is contrary to previous evidence, and despite a large number of studies reporting deficits in these cognitive functions in people with schizophrenia, suggesting that these and other cognitive problems may arise from different aspects of the disease process, or even be more specific to the individual taking the antipsychotics. This finding reinforces the idea that cognitive impairments are not uniform, and that different cognitive domains may be affected by different mechanisms.
Importantly, this study was conducted in undiagnosed adults, and the findings cannot be directly generalised to people with schizophrenia or related disorders. In clinical populations, cognitive functioning is shaped by multiple factors including illness processes, long term medication exposure, comorbidities, and social context.
For practice, these results do not imply that antipsychotics should be avoided or discontinued on cognitive grounds alone. Rather, they support careful monitoring of cognitive complaints, particularly around working memory and cognitive speed, alongside symptom control, side effects, and quality of life. The absence of changes in attention, response inhibition, mood, or alertness also suggests that antipsychotic related cognitive effects may be subtle and domain specific rather than reflecting a generalised cognitive slowing. This highlights the value of targeted assessment and shared decision making when reviewing treatment over time.
Cognitive effects of antipsychotics appear subtle and domain-specific, underlining the value of personalised assessment and shared decision making.
Statement of interests
Jack Rogers acknowledges no conflicts of interest in respect to the content of this blog. AI tools assisted in initial formatting.
Editor
Edited by Éimear Foley. AI tools assisted with language refinement and formatting during the editorial phase.
Links
Primary paper
Osugo, Martin, Zahid, Uzma, Selvaggi, Pierluigi, Chilimidos, Alexandria, Finelli, Valeria, Chapman, George E., Whitehurst, Thomas, Onwordi, Ellis Chika, Murray, Robin M., Wall, Matthew B., Marques, Tiago Reis, Mehta, Mitul A., & Howes, Oliver D. (2025) Effects of antipsychotics on human cognitive function: causal evidence from healthy volunteers following sustained D2/D3 antagonism, D2/D3 partial agonism and placebo. Mol Psychiatry. 2025 Nov;30(11):5315-5325. doi: 10.1038/s41380-025-03116-8. Epub 2025 Jul 19. PMID: 40684007; PMCID: PMC12532602.
Other references
Ramaekers JG, Louwerens JW, Muntjewerff ND, Milius H, de Bie A, Rosenzweig P, et al. (1999) Psychomotor, cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (Amisulpride) and a classic (Haloperidol) antipsychotic. J Clin Psychopharmacol;19:209–21. doi: 10.1097/00004714-199906000-00003. PMID: 10350027.
Beuzen JN, Taylor N, Wesnes K, Wood A. (1999). A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers. J Psychopharmacol; 13:152–8. doi: 10.1177/026988119901300207. PMID: 10475721.
Wright L, Lipszyc J, Dupuis A, Thayapararajah SW, Schachar R. (2014) Response inhibition and psychopathology: a meta-analysis of go/no-go task performance. J Abnorm Psychol; 123:429–39. doi: 10.1037/a0036295. Epub 2014 Apr 14. PMID: 24731074.
