C-reactive protein is associated with cognitive performance in a large cohort of euthymic patients with bipolar disorder.

Data support the notion that 40-60% of patients with bipolar disorder (BD) have neurocognitive deficits. It is increasingly accepted that functioning in BD is negatively impacted by these deficits, yet they have not been a successful target for treatment. The biomarkers that predict cognitive deficits in BD are largely unknown, however recent evidence suggests that inflammation may be associated with poorer cognitive outcomes in BD. We measured C-reactive protein (CRP), a marker of systemic inflammation and risk of inflammatory disease, in 222 euthymic BD patients and 52 healthy controls. Within the patient sample, using multivariate analyses of covariance (MANCOVA) we compared cognitive performance of those with high CRP (≥5 mg/L) versus the remaining subjects (<5 mg/L) on a battery of cognitive tests. We evaluated relationships with several other relevant clinical features. We also examined the role of CRP in cognitive decline using a proxy cognitive decline metric, defined as the difference between premorbid and current IQ estimates, in a logistic regression analysis. Approximately 80% of our sample were BD-I, and the remainder were BD-II and 42.6% of our sample had a history of psychosis. We found a statistically significant effect of CRP on cognitive performance on a broad range of tests; participants with CRP ≥ 5 mg/L had worse performance on several measures of executive functioning, MATRICS processing speed and MATRICS reasoning and problem solving relative to those with lower CRP. We also identified CRP as a significant positive predictor of proxy cognitive decline. Our results indicate that elevated CRP is associated with a broad cognitive dysfunction in affectively remitted BD patients. These results may point to a subgroup of patients who might benefit from treatments to reduce inflammation.

TNF-α and its soluble receptors mediate the relationship between prior severe mood episodes and cognitive dysfunction in euthymic bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is one of the most disabling mental health conditions in the world. Symptoms of cognitive impairment in BD contribute directly to occupational and social deficiencies and are very difficult to treat. Converging evidence suggests that BD patients have increased peripheral markers of inflammation. The hypothesis of neuroprogression in BD postulates that cognitive deficits develop over the course of the illness and are influenced by prior severe mood episodes, leading to wear-and-tear on the brain- however, there exists a paucity of data statistically testing a mediating role of immune molecules in cognitive dysfunction in BD. METHODS: This is a cross-sectional study. We measured serum levels of tumor necrosis factor alpha (TNF-α), and soluble (s) TNF receptors one and two (sTNF-R1 and sTNF-R2) in 219 euthymic BD patients and 52 Healthy Controls (HCs). Structural equation modeling (SEM) was used for the primary purpose of assessing whether TNF markers (measured by the multiple indicators TNF-α, sTNF-R1 and sTNF-R2) mediate the effect or number of prior severe mood episodes (number of prior psychiatric hospitalizations) on cognitive performance. RESULTS: BD and HC groups did not differ on circulating levels of TNF molecules in the present study. However, we found higher sTNF-R1 concentration in 'late-stage' BD illness (>1 prior psychiatric hospitalization) compared to those in early stage illness. In the subsequent SEM, we found that the model fits the data acceptably (Chi-square = 49.2, p = 0.3), and had a 'close fit' (RMSEA = 0.02, PCLOSE = 0.9). Holding covariates constant (age, sex, premorbid IQ, education, and race), we found that the standardized indirect effect was significant, p = 0.015, 90%CI [-0.07, -0.01], indicating that the estimated model was consistent with peripheral TNF markers partially mediating a causal effect of severe mood episodes on executive function. CONCLUSIONS: Our results indicate that circulating levels of TNF molecules partially mediate the relationship between prior severe mood episodes and executive function in BD. These results may implicate TNF variables in the neuroprogressive course of BD and could point to novel interventions for cognition.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Neurocognitive subtypes in patients with bipolar disorder and their unaffected siblings.

BACKGROUND: Our previous work revealed substantial heterogeneity in the cognitive profile of bipolar disorder (BD) due to the presence of three underlying cognitive subgroups characterized as: globally impaired, selectively impaired, or cognitively intact. In an effort to determine whether these subgroups are differentially related to genetic risk for the illness, we investigated whether cognitive deficits were more pronounced in unaffected siblings (UAS) of BD probands within identified clusters. METHODS: Cluster analysis was used to identify cognitive clusters in BD (N = 60). UAS (N = 49) were classified into groups according to their proband sibling's cluster assignment; comparisons were made across all clusters and healthy controls (HCs; N = 71). RESULTS: Three cognitive clusters in BD emerged: a globally impaired (36.7%), a selectively impaired (30%), and a cognitively intact cluster (33.3%). UAS showed a qualitatively similar pattern to their BD siblings; UAS of the globally impaired BD cluster showed verbal memory and general cognitive impairments relative to HCs. In contrast, UAS of the other two clusters did not differ from HCs. CONCLUSIONS: This study corroborates findings from prior work regarding the presence of cognitive heterogeneity in BD. UAS of subjects in the globally impaired BD cluster presented with a qualitatively similar cognitive profile to their siblings and performed worse than all other BD clusters and UAS groups. This suggests that inherited risk factors may be contributing to cognitive deficits more notably in one subgroup of patients with BD, pointing toward differential causes of cognitive deficits in discrete subgroups of patients with the disorder.

Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum.

BACKGROUND: Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive subgroups emerging from within each of these nosological categories uphold group-average findings. We addressed this by identifying cognitive subgroups in large samples of SZ and BD patients independently, and comparing their cognitive profiles. The utility of a cross-diagnostic clustering approach to understanding cognitive heterogeneity in these patients was also explored. METHOD: Hierarchical clustering analyses were conducted using cognitive data from 1541 participants (SZ n = 564, BD n = 402, healthy control n = 575). RESULTS: Three qualitatively and quantitatively similar clusters emerged within each clinical group: a severely impaired cluster, a mild-moderately impaired cluster and a relatively intact cognitive cluster. A cross-diagnostic clustering solution also resulted in three subgroups and was superior in reducing cognitive heterogeneity compared with disorder clustering independently. CONCLUSIONS: Quantitative SZ-BD cognitive differences commonly seen using group averages did not hold when cognitive heterogeneity was factored into our sample. Members of each corresponding subgroup, irrespective of diagnosis, might be manifesting the outcome of differences in shared cognitive risk factors.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

OBJECTIVES: Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. METHODS: Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. RESULTS: During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. CONCLUSIONS: The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications.

BACKGROUND: Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 s.d. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. METHOD: A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. RESULTS: Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. CONCLUSIONS: These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment.

Neurocognitive phenomics: examining the genetic basis of cognitive abilities.

Cognitive deficits are core to the disability associated with many psychiatric disorders. Both variation in cognition and psychiatric risk show substantial heritability, with overlapping genetic variants contributing to both. Unsurprisingly, therefore, these fields have been mutually beneficial : just as cognitive studies of psychiatric risk variants may identify genes involved in cognition, so too can genome-wide studies based on cognitive phenotypes lead to genes relevant to psychiatric aetiology. The purpose of this review is to consider the main issues involved in the phenotypic characterization of cognition, and to describe the challenges associated with the transition to genomewide approaches. We conclude by describing the approaches currently being taken by the international consortia involving many investigators in the field internationally (e.g. Cognitive Genomics Consortium; COGENT) to overcome these challenges.

Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15-year follow-up.

OBJECTIVE: Despite increasing interest in cognitive dysfunction in bipolar disorder, little is known about its impact on functional outcome relative to affective symptoms. METHOD: A total of 33 bipolar I subjects were evaluated at index hospitalization and prospectively followed up 15 years later. Affective symptoms, cognition, global functioning, work, and social adjustment were assessed at follow-up and analyzed by linear regression. RESULTS: Global functional impairment was significantly associated with poor performance on a cognitive measure of processing speed (WAIS Digit Symbol). Digit symbol performance also was the sole significant predictor of social functioning. Neither symptom severity nor course of illness features significantly contributed to global and social functioning. In contrast, verbal learning deficits, recent depression, and lifetime hospitalizations all were independently associated with work disability. CONCLUSION: Processing speed is robustly associated with social and global functioning in bipolar disorder. Poor work functioning is significantly related to subsyndromal depression, course of illness, and verbal learning deficits. Cognitive and mood symptoms warrant consideration as independent determinants of functioning in patients with bipolar disorder many years after an index manic episode.

Emotional processing subtypes in bipolar disorder: A cluster analysis.

BACKGROUND: Evidence regarding the performance of Bipolar Disorder patients (BD) on Emotional Processing (EP) is conflicting, suggesting that heterogeneity within this population may exist. It is not completely understood if this impacts on clinical presentation and functional outcomes. METHODS: A total of 212 BD patients were recruited. Patients underwent MATRICS Consensus Cognitive Battery as well as a clinical evaluation to detect premorbid traits, comorbidities and clinical features. Performance on each basic emotion on the Emotional Recognition Task (ERT) and Reading the Mind in the Eyes Test were entered into hierarchical cluster analyses in order to determine the number of clusters and to assign subjects to specific clusters. We then compared subgroups on clinical factors and real-world community functioning. RESULTS: No differences between BD patients as a group and controls were found in EP performance. Two clusters of BD patients were found, one with "intact" performance (71.2%) that performed as healthy controls (HC) and other with "impaired" performance (28.8%) performing worse than HC and schizophrenic patients on basic emotion recognition. Patients in the "impaired group" presented higher rates of childhood trauma, schizotypal traits, lower premorbid IQ and education, poor psychosocial functioning and cognitive performance. LIMITATIONS: Cross-sectional data which limits our ability to infer directionality of our findings. CONCLUSION: These results suggest the presence of two subgroups regarding EP performance with unique clinical and neurodevelopmental profiles associated. Next steps will include using these data to identify a homogeneous group of patients to target these disabling symptoms with treatment.

Alexithymia predicts poorer social and everyday functioning in schizophrenia and bipolar disorder.

Alexithymia, or the inability to identify and describe one's emotions, is significantly higher in bipolar disorder (BD) and schizophrenia (SZ), compared to healthy controls (HC). Alexithymia has also been observed to predict psychosocial functioning in SZ. We investigated whether alexithymia predicted social and everyday functioning in BD, as well as transdiagnostically in HC, BD, and SZ patients. 56 BD, 45 SZ, and 50 HC were administered and compared on tests measuring neurocognition, social cognition, functioning and alexithymia. We conducted linear regressions assessing whether alexithymia predicted functional outcomes in BD. Next, we conducted hierarchical stepwise linear regressions investigating the predictive ability of neurocognition, social cognition and alexithymia on everyday and social functioning in our overall sample. BD and SZ patients were comparable on most demographics and demonstrated higher alexithymia compared to HCs. In BD, alexithymia predicted social functioning only. In the overall sample, difficulty identifying and describing feelings predicted everyday functioning; difficulty describing feelings predicted social functioning. Results suggest that aspects of alexithymia significantly predict functioning among these psychiatric groups, above and beyond the contributions of previously identified factors such as neurocognition and social cognition. Results may aid in developing proper interventions aimed at improving patients' ability to articulate their feelings.

Social cognition moderates the relationship between neurocognition and community functioning in bipolar disorder.

BACKGROUND: Schizophrenia (SZ) studies suggest that neurocognition predicts functional outcome and that social cognition mediates this relationship. Bipolar disorder (BD) patients also have cognitive, social, and functional impairments but the relationship among these factors in BD is not well established. We assessed whether social cognition modulates the influence of neurocognition on community functioning in BD, as found in SZ. METHODS: 200 BD patients and 49 healthy controls (HC) were administered and compared on a battery of tests assessing neurocognition, social cognition, and community functioning. We conducted a series of regression analyses to investigate potential mediation or moderation of social cognition on the relationship between neurocognition and community functioning. RESULTS: BD patients performed worse on neurocognitive domains of processing speed, attention, verbal learning, and global neurocognition. Also, BD patients performed worse on theory of mind, the social cognition composite score, and community functioning. Neurocognition did not significantly predict functional outcome in our BD sample. However, we found a moderating effect of social cognition: among patients with poor social cognition, better neurocognition was associated with better community functioning, a relationship not seen in BD patients with good social cognition. LIMITATIONS: The study was limited by a relatively small HC group and assessing one subtype of functioning status. CONCLUSIONS: The relationship between neurocognition and community functioning in BD may be dependent on social cognition status, implying the presence of social cognitive heterogeneity. Results may be relevant to choosing proper treatment interventions depending on the patient's social cognitive level.

Cognitive side effects of anticonvulsants.

The increasing use of anticonvulsant drugs in psychiatry has prompted greater awareness of their effects on a range of psychiatric domains, including cognition. Older versus newer antiepileptic drugs have been reported to either worsen or enhance cognitive performance in clinical populations, and the extent to which cognitive disturbances may reflect iatrogenic factors versus psychopathology is subject to debate. We review current information about the role of anticonvulsants in cognition, with particular emphasis on newer compounds (such as lamotrigine, gabapentin, and topiramate), the cognitive dimensions of affective illness, and the clinical approach to evaluating cognition in psychiatric patients taking anticonvulsant drugs over time.

Antisense mapping of opioid receptor clones: effects upon 2-deoxy-D-glucose-induced hyperphagia.

Antisense oligodeoxynucleotides (AS ODNs) directed against exons 1 and 2 of the MOR-1 clone significantly and markedly reduced (81-93%) hyperphagia induced by the anti-metabolic glucose analogue, 2-deoxy-d-glucose (2DG) across a 4 h time course. AS ODNs directed against exons 3 or 4 of the MOR-1 clone had a more limited (1-2 h) duration of action upon 2DG-induced hyperphagia. 2DG-induced hyperphagia was significantly reduced by AS ODNs directed against exon 2 (44-51%), but not exons 1 or 3 of the KOR-1 clone across a 4 h time course. Whereas an AS ODN probe directed against the KOR3/ORL-1 clone produced small (36%), but significant reductions in 2DG-induced hyperphagia, an AS ODN probe directed against the DOR-1 clone was ineffective. These data provide further converging evidence for the roles of primarily mu, but also kappa1 and kappa3 opioid receptors in mediating the hyperphagic effects of glucoprivation.