Background: Clozapine remains the only effective antipsychotic drug for treatment-resistant schizophrenia (TRS), yet it continues to be markedly underused in most industrialized countries including Germany. Previous studies have identified prescriber-related factors such as concerns about adverse drug reactions, the burden of mandatory monitoring, and limited experience with clozapine use and TRS recognition as major contributors to this persistent underutilization. However, these issues have not been studied for the German healthcare system. Objectives: To investigate prescriber attitudes toward clozapine use for schizophrenia in Germany and identify related treatment barriers. Design: Cross-sectional, web-based survey study. Methods: We conducted a web-based cross-sectional survey using PsyToolkit. Our questionnaire assessed clinicians’ demographics, familiarity with relevant national guidelines, practical experience with clozapine and formalized training in its use, perceived treatment barriers, and presumptions about patients’ attitudes toward clozapine. Data were predominantly analyzed descriptively. Results: A total of 155 psychiatrists—most of them board-certified and nearly all regular clozapine prescribers for schizophrenia—completed the survey. Most participants were familiar with guideline recommendations for clozapine initiation. However, even among them, most preferred to attempt at least one trial of antipsychotic polypharmacy before starting clozapine. Formalized training had a positive impact on knowledge regarding clozapine’s effectiveness in reducing negative symptoms, aggressive behavior, and suicidality. While most participants acknowledged clozapine’s effectiveness in reducing all-cause mortality, only a small proportion of participants acknowledged its effectiveness in reducing cardiovascular mortality. Notably, three quarters of participants presumed that patients would prefer standard antipsychotics over clozapine. Monitoring requirements and concerns regarding weight gain and blood dyscrasia were ranked as the main barriers impeding clozapine use. Conclusion: We identified several modifiable prescriber-related factors limiting clozapine use for schizophrenia in Germany. Implementing mandatory targeted training programs during residency and regular use of shared decision-making to emphasize the patients’ perspective might facilitate a timelier and widespread use of clozapine.

Abstract Clozapine is the most effective and only approved drug for treatment-resistant schizophrenia (TRS). Studies based on data up to 2014 concluded that it is underutilized in most industrialized countries, including Germany. Since 2019, national guidelines have explicitly been recommending clozapine as first-line therapy in TRS. We aimed to assess whether clozapine use in Germany has increased in recent years and to examine regional variations. Using claims data covering about 20% of the German population (GePaRD), we calculated the yearly prescription prevalence and incidence of clozapine among individuals aged 0–64 years based on outpatient dispensations. For 2022, we also assessed regional variations in clozapine prescription prevalence at the district level (restricted to N = 202 districts with ≥20,000 individuals). From 2012 to 2022, the overall (age- and sex-standardized) prescription prevalence of clozapine continuously decreased by 16% (from 77.6 to 65.5 per 100,000). The relative decline was greatest in women aged 30–39 years (-51%) and in men aged 30–34 years (-57%), in urban areas (large urban cities: -23%; urban districts: -16%), and in regions with high socioeconomic status (-22%). Over the same period, the overall prescription incidence of clozapine decreased by 41%. In 2022, regional clozapine prescription prevalence differed up to 39-fold. In conclusion, clozapine prescribing in Germany did not increase from 2012 to 2022, despite new clozapine-favoring guidelines, and showed substantial regional variation. Our results suggest a persisting underutilization of clozapine in most of Germany. Further research on barriers and facilitators for clozapine use in Germany is needed.

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA's blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

BACKGROUND:Deficits in working memory (WM) and attention have a considerable functional impact on people with bipolar disorder (PBD). Understanding the neurocognitive underpinnings of these cognitive constructs might facilitate the discovery of more effective pro-cognitive interventions. Therefore, we employed a paradigm designed for jointly studying attentional control and WM encoding. METHODS:We used a visuospatial change-detection task using four Gabor Patches with differing orientations in 63 euthymic PBD and 76 healthy controls (HCS), which investigated attentional competition during WM encoding. To manipulate bottom-up attention using stimulus salience, two Gabor patches flickered, which were designated as either targets or distractors. To manipulate top-down attention, the Gabor patches were preceded by either a predictive or a non-predictive cue for the target locations. RESULTS:Across all task conditions, PBD stored significantly less information in visual WM than HCS (significant effect of group). However, we observed no significant group-by-salience or group-by-cue interactions. This indicates that impaired WM was not caused by deficits in attentional control. CONCLUSIONS:While WM was disturbed in PBD, attentional prioritization of salient targets and distractors, as well as the utilization of external top-down cues, were not compromised. Thus, the control of attentional selection appears to be intact at least for our specific manipulation of this cognitive construct. These findings provide valuable clues for models of WM dysfunction in PBD by suggesting that later stages of WM encoding, such as WM consolidation, are likely primarily impaired, while selective attention is not a main source of impairment.

Schizophrenia ranks among the top ten causes of disability worldwide. The provision of healthcare services requires estimates on the epidemiology of schizophrenia, but recent data for Germany are lacking. Based on a large German health claims database (GePaRD), we identified persons aged 0–64 years with treated schizophrenia, i.e., persons having at least one inpatient/outpatient ICD-10 diagnosis (F20) with at least one prescription for a schizophrenia-recommended antipsychotic in the same calendar year. For each year from 2012 (eligible persons: 9,589,084) to 2021 (eligible persons: 12,450,531), we calculated the standardized incidence proportion (SIP) and the prevalence of schizophrenia. Analyses were stratified by sex, age, and population density in the region of residence. The SIP of treated schizophrenia remained stable from 2012 to 2017 (46.0–46.5/100,000) and subsequently declined to 41.3/100,000 in 2021, with higher SIP in men (45.3/100,000) than in women (37.1/100,000). In 2021, the SIP was comparable in urban, rural, and sparsely populated rural districts (36.3–38.5/100,000) and higher in large urban cities (48.3/100,000). SIP estimates among children and adolescents (aged 0–17 years) varied between 3.5/100,000 and 4.1/100,000 over the study period. The standardized prevalence of schizophrenia declined from 366.1/100,000 in 2012 to 334.0/100,000 in 2021. Similar to other Western countries, there has been a decline in the incidence and prevalence of schizophrenia in Germany over the last few years. The higher incidence in males and those living in large urban areas highlights the health care needs of these populations.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Background People with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top-down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ encode more information in the presence of salient distractors.Methods We employed a visuospatial change-detection task using four Gabor patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two Gabor patches flickered which were designated either as targets or distractors and either a predictive or a non-predictive cue was displayed to manipulate top-down attention, resulting in four conditions.Results We observed significant effects of group, salience and cue as well as significant interactions of salience by cue, group by salience and group by cue. Across all conditions, PSZ stored significantly less information in VWM than HCS. PSZ stored significantly less non-flickering than flickering information with a non-predictive cue. However, PSZ stored significantly more flickering and non-flickering information with a predictive cue.Conclusions Our findings indicate that control of attentional selection is impaired in schizophrenia. We demonstrate that additional top-down information significantly improves performance in PSZ. The observed deficit in attentional control suggests a disturbance of GABAergic inhibition in early visual areas. Moreover, our findings are indicative of a mechanism for enhancing attentional control in PSZ, which could be utilized by pro-cognitive interventions. Thus, the current paradigm is suitable to reveal both preserved and compromised cognitive component processes in schizophrenia.

ObjectivesKynurenine, kynurenic and quinolinic acid are important metabolites in tryptophan metabolism. Due to an involvement in glutamatergic neurotransmission and immune response, previous studies have investigated this pathway in mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). Tryptophan and kynurenine have been shown to be decreased across disorders, hinting at the missing link how inflammation causes neurotoxicity and psychiatric symptoms. The main aim of our study was to investigate if individual catabolites could serve as diagnostic biomarkers for MDD, BD and SCZ.MethodsWe measured plasma levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid and ratio of quinolinic acid/kynurenic acid using mass spectrometry in n = 175 participants with acute episodes and after remission, compared with controls.ResultsDecreased levels of all tryptophan catabolites were found in the whole patient group, driven by the difference between BD and HC. Manic and mixed phase BD individuals displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between disorders. Upon reaching remission, changes in catabolite levels partially normalised.ConclusionsOur data suggests an involvement of the kynurenine pathway in mental disorders, especially BD but disqualifying those metabolites as biomarkers for differential diagnosis.

Abstract Background Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine—the most effective antipsychotic—to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking. Methods Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria (‘Andreasen criteria’). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients’ and relatives’ views on treatment. Discussion This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

PURPOSE OF REVIEW:Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS). Although the evidence base for its wide-ranging, unique efficacy continues to expand, clozapine remains alarmingly underutilized in industrialized countries. Analyzing the causes and consequences of this problem is crucial for substantially improving the quality of care for TRS patients.RECENT FINDINGS:Clozapine is the most effective antipsychotic for reducing all-cause mortality in TRS. In most cases, treatment resistance emerges during the first psychotic episode. Delaying clozapine treatment has a negative impact on long-term outcome. Patients' experience with clozapine treatment is largely positive despite a comparatively high rate of side effects. Patients prefer clozapine, while psychiatrists regard it as a burden due to concerns regarding safety and side effect management. Shared decision-making (SDM), which increases the likelihood of a clozapine recommendation, is not routinely used, possibly due to stigmatization of TRS patients.SUMMARY:The mortality-reducing effects of clozapine alone warrant its regular use. Therefore, psychiatrists must not exclude patients from the decision regarding a clozapine trial by not even offering it. Rather, they have a clear obligation to align their actions more closely with the existing evidence and patients' needs and to facilitate the timely initiation of clozapine.

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Objective: Sensorimotor gating is experimentally operationalized by the prepulse inhibition (PPI) of the startle response (SR). Previous studies suggest high test-retest reliability of PPI and potential correlation with working memory (WM). Here we aimed to validate and extend the test-retest reliability of PPI in healthy humans and its correlation with working memory (WM) performance. Methods: We applied an acoustic startle PPI paradigm with four different prepulse intensities (64, 68, 72, and 76 dB) and two different WM tasks (n-back, change detection task [CDT]) in a group of 26 healthy adults (final sample size n=23). To assess test-retest reliability, we performed all tests on two separate days 28 days apart. Results: We were able to confirm high test-retest-reliability of the PPI with a mean intraclass correlation (ICC) of >0.80 and significant positive correlation of PPI with n-back but not with CDT performance. Detailed analysis showed that PPI across all prepulse intensities significantly correlated with both the 2-back and 0-back conditions, suggesting regulation by cross-conditional processes (e.g. attention). However, when removing the 0-back component from the 2-back data, we found a specific and significant correlation with WM for the 76 dB PPI condition. Conclusion: With the present study we were able to confirm the high test-retest reliability of the PPI in humans and could validate and expand on its correlation with WM performance.

Nitric oxide (NO) signalling has been implicated in the pathogenesis of several mental illnesses; however, its specific contribution remains unclear. We investigated whether peripheral NO concentration is associated with specific diagnoses, and whether there is a correlation with genetic variation in NO synthase (NOS) genes. We included 185 participants in the study; 52 healthy controls, 43 major depressive disorder (MDD) patients, 41 bipolar disorder (BPD) patients, and 49 schizophrenia (SCZ) patients. Clinical, genetic, and biochemical data were collected at admission to a psychiatric hospital and at discharge. Serum was used to quantify concentration of the stable NO metabolites nitrite and nitrate. Individuals were genotyped for the NOS1 exon 1f variable number of tandem repeats 1 (VNTR1) polymorphism, and single nucleotide polymorphisms (SNPs) in the NOS1, NOS1AP and NOS3 genes. At admission, SCZ patients were found to have significantly higher peripheral NO metabolite (NOx-) concentrations compared to healthy controls, MDD and BPD patients. NOS1 exon 1f VNTR1 short allele carriers were found to have significantly increased NOx- concentration. Moreover, this result was still significant in patients even at discharge. The data also revealed that patients who did not remit in their depressive symptoms had significantly increased NOx- concentration compared to remitters at discharge, supported by the finding of a significant positive correlation between depression symptom severity and NOx- concentration. Taken together, it is possible that elevated peripheral NOx- concentration is associated with increased severity of psychopathology, potentially due to NOS1 exon1f VNTR1 genotype. Our results further implicate NO signalling in mental illness pathogenesis, supporting its possible use as a peripheral biomarker, and imply that NOS genotype may play a significant role in regulating peripheral NOx- concentration.

Abstract Background Previous studies have linked disturbances in the kynurenine pathway, responsible for the main catabolism of tryptophan and a key regulator of the immune system, to mental disorders such as major depressive disorder (MDD), bipolar disorder (BD) or schizophrenia (SCZ). However, the relationship between tryptophan catabolism and the presentation of psychiatric disorders seems to be rather complex, as up to now results have mostly been inconsistent or even contradictory. In this study, we measured plasma levels of tryptophan catabolites (TRYCATs: tryptophan, kynurenine, kynurenic acid and quinolinic acid) in a sample of in total 175 participants consisting of individuals suffering from an acute disease episode seeking inpatient treatment as well as healthy controls (HC) to investigate whether individual metabolites could serve as a biomarker for differential diagnosis. Results Significantly decreased levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid were found in the patient group as a whole. This was mainly driven by the difference between BD patients and HC. Specifically, the manic symptom domain in manic and mixed phase BD patients displayed significantly lower kynurenine and kynurenic acid levels. We could not find significant differences between the psychiatric disorders disqualifying TRYCATs as biomarkers for differential diagnosis. None of the assessed potential demographic or pharmaceutical confounding factors revealed a significant correlation to TRYCAT concentrations. Upon reaching (partial) remission, the changes in TRYCAT levels partially normalized in the patient group. Conclusions Our data suggests an involvement of the kynurenine pathway in mental disorders, especially BD. Although we cannot prove a causal relationship, underlying mechanisms might include pro-inflammatory states in the central nervous system and/or increased neurotoxicity contributing to the immune assault. Also considering the manifold, but inconsistent previous analyses regarding TRYCAT concentrations in psychiatric disease, larger, cross-sectional and longitudinal studies will be needed for detangling the mystery about the role the tryptophan catabolism plays in the pathophysiology of mental disorders and for answering the burning question if it might constitute a possible therapeutic target in the future.

Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.

Introduction Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. Method Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). Finding We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. Conclusion Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.

Schizophrene Psychosen sind durch einen hohen Grad an durch Behinderung beeinträchtigter Lebensjahre aber auch deutlich beeinträchtigter Lebensqualität ge-kennzeichnet. Bei ca. 30 % der Patienten zeigt sich im Krankheitsverlauf eine The-rapieresistenz, d.h., eine unzureichende Response auf mehrere lege artis durchge-führte antipsychotische Standardtherapieversuche. Bei therapieresistenter Schizo-phrenie (TRS) ist Clozapin noch immer die einzige wirksame medikamentöse Be-handlungsoption. Hierbei ist Clozapin durch eine gute Wirksamkeit in verschiede-nen Symptomdimensionen charakterisiert. Neben der überlegenen Wirksamkeit bei Positivsymptomatik bestehen positive Effekte auf Negativsymptomatik. Weiterhin senkt Clozapin das Risiko für Suizidversuche und aggressives Verhalten stärker als andere Antipsychotika, gleiches gilt auch für komorbiden Substanzkonsum. Zudem weist Clozapin die stärkste Mortalitätsreduktion aller Antipsychotika auf. Von hoher Relevanz für eine optimale Wirksamkeit ist hierbei der frühzeitige Einsatz von Clo-zapin nach Feststellung einer Therapieresistenz. Trotz der nachgewiesenen Effekte wird Clozapin bei TRS weiterhin zu selten und meist Jahre zu spät verordnet. Haupthinderungsrund ist hierbei wahrscheinlich neben der unzureichenden An-wendung der Therapieresistenzkriterien und der damit verbundenen Leitlinienemp-fehlungen die noch immer weiter verbreitete Furcht vor Nebenwirkungen wie Agra-nulozytose und Myokarditis. Das Ziel dieser Übersichtsarbeit ist es, der ungerecht-fertigten Zurückhaltung beim Einsatz von Clozapin entgegen zu wirken, indem ak-tuelle Erkenntnisse zu den umfassenden positiven Effekten von Clozapin und evi-denzbasierte Handlungsempfehlungen für ein optimales Nebenwirkungsmanage-ments dargestellt werden. Weiterhin werden evidenzbasierte Augmentationsstrate-gien für den Fall einer unzureichenden Therapieresponse unter Clozapin darge-legt.

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.