Dysfunction In Bipolar Disorder Research Articles

Cariprazine in Bipolar Disorder and Substance Use: A Dual Approach to Treatment?

Bipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression and is often complicated by comorbid substance use disorders (SUDs). Up to 60% of individuals with BD experience SUDs, which exacerbate mood instability and increase the risk of rapid cycling, suicide, and poor clinical outcomes. Current treatment strategies, including lithium and valproate, show limited efficacy in treating both BD and SUD. Psychotherapeutic approaches such as cognitive behavioral therapy (CBT) offer benefits but lack a specific focus on substances such as cannabis and cocaine. Since there is still debate on how to treat this comorbidity, there is a need to find new therapeutic options; this mini-review examines the pharmacological properties of cariprazine and its emerging role in the treatment of comorbid BD and SUD. Cariprazine, an atypical antipsychotic with partial agonism at dopamine D2 and D3 receptors, has shown promise in treating both mood symptoms and cognitive dysfunction in BD. Its unique affinity for D3 receptors, which are involved in motivation and reward processing, may offer advantages in reducing drug craving. Clinical trials indicate that cariprazine effectively treats manic, depressive, and mixed episodes in BD with a favorable side effect profile, particularly at lower doses. Preliminary results suggest its potential to reduce craving and substance use in individuals with co-occurring BD and SUD. Therefore, cariprazine, with its unique pharmacodynamic mechanism, could be further studied for the treatment of BD in comorbidity with SUD. However, evidence on the role of cariprazine in the treatment of SUDs remains limited, based primarily on case reports and animal studies. Further research, including large-scale clinical trials, is needed to determine its full efficacy in this dual diagnosis.

Evaluation and Treatment of Cognitive Dysfunctions in Schizophrenia and Bipolar Disorder

Cognitive dysfunction is the most important determinant for the recovery in schizophrenia and bipolar disorder. Cognitive dysfunction serves as an endophenotype although it may be a consequence of drug treatments. In schizophrenia starting from the first episode, pronounced cognitive defects such as cognitive flexibility, inhibition, verbal fluency, verbal memory and visual-motor processing are observable. These cognitive defects remain stable in the chronic phase of schizophrenia. On the other hand, cognitive dysfunctions in bipolar disorder patients have a heterogeneous pattern. One group of patients show no evidence of cognitive dysfunction while one group has limited dysfunction (of processing speed, attention, verbal learning and social cognition) and another one has wide spread dysfunctions as seen in schizophrenia. Despite its importance, no satisfactory results have been achieved in the treatment of cognitive dysfunctions in schizophrenia and bipolar disorder. In this article, the evaluation and treatment of the most frequent cognitive dysfunctions of schizophrenia and bipolar disorder are reviewed.

Circadian rhythm dysfunction and psychopathology in the offspring of parents with bipolar disorder: a high-risk study in the Chinese population

BackgroundUnderstanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder. Nevertheless, some of the previous studies on the...

State- and trait-related dysfunctions in bipolar disorder across different mood states: a graph theory study.

The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD. We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD. We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD. Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study. Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

Linking the gut microbiota to brain dysfunction in bipolar disorder: Evidence from neuroimaging

The gut microbiota can influence the brain function through a variety of ways, but its role in the etiology of Bipolar Disorder (BD) is yet unknown. The brain and the gut are linked through a communication pathway called the Microbiota-Gut-Brain Axis (MGBA).

Association Between the Fronto-Limbic Network and Cognitive and Emotional Functioning in Individuals With Bipolar Disorder

Individuals with bipolar disorder (BD) experience cognitive and emotional dysfunctions. Various brain circuits are implicated in BD but have not been investigated in a meta-analysis of functional magnetic resonance imaging (fMRI) studies. To investigate the brain functioning of individuals with BD compared with healthy control individuals in the domains of emotion processing, reward processing, and working memory. All fMRI experiments on BD published before March 2020, as identified in a literature search of PubMed, Embase, Web of Science, Cochrane Library, PsycInfo, Emcare, Academic Search Premier, and ScienceDirect. The literature search was conducted on February 21, 2017, and March 2, 2020, and data were analyzed from January 2021 to January 2022. fMRI experiments comparing adult individuals with BD and healthy control individuals were selected if they reported whole-brain results, including a task assessing at least 1 of the domains. In total, 2320 studies were screened, and 253 full-text articles were evaluated. A total of 49 studies were included after selection procedure. Coordinates reporting significant activation differences between individuals with BD and healthy control individuals were extracted. Differences in brain region activity were tested using the activation likelihood estimation method. A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to stimuli in 3 cognitive domains between individuals with BD and healthy control individuals were different. The study population included 999 individuals with BD (551 [55.2%] female) and 1027 healthy control individuals (532 [51.8%] female). Compared with healthy control individuals, individuals with BD showed amygdala and hippocampal hyperactivity and hypoactivation in the inferior frontal gyrus during emotion processing (20 studies; 324 individuals with BD and 369 healthy control individuals), hyperactivation in the orbitofrontal cortex during reward processing (9 studies; 195 individuals with BD and 213 healthy control individuals), and hyperactivation in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex during working memory (20 studies; 530 individuals with BD and 417 healthy control individuals). Limbic hyperactivation was only found during euthymia in the emotion and reward processing domains; abnormalities in frontal cortex activity were also found in individuals with BD with mania and depression. This systematic review and meta-analysis revealed evidence for activity disturbances in key brain areas involved in cognitive and emotion processing in individuals with BD. Most of the regions are part of the fronto-limbic network. The results suggest that aberrations in the fronto-limbic network, present in both euthymic and symptomatic individuals, may be underlying cognitive and emotional dysfunctions in BD.

Abstract 2221: An in vitro model of metabolic dysfunction in bipolar disorder

Abstract 2221: An in vitro model of metabolic dysfunction in bipolar disorder

Glial-Neuronal Interaction in Synapses: A Possible Mechanism of the Pathophysiology of Bipolar Disorder.

Bipolar disorder (BD) is a severe and chronic psychiatric disorder that affects approximately 1-4% of the world population and is characterized by recurrent episodes of mania or hypomania and depression. BD is also associated with illnesses marked by immune activation, such as metabolic syndrome, obesity, type 2 diabetes mellitus, and cardiovascular diseases. Indeed, a connection has been suggested between neuroinflammation and peripheral inflammatory markers in the pathophysiology of BD, which can be associated with the modulation of many dysfunctional processes, including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. Rising evidence suggests that synaptic dysregulations, especially glutamatergic system dysfunction, are directly involved in mood disorders. It is becoming clear that dysregulations in connection and structural changes of glial cells play a central role in the BD pathophysiology. This book chapter highlighted the latest findings that support the theory of synaptic dysfunction in BD, providing an overview of the alterations in neurotransmitters release, astrocytic uptake, and receptor signaling, as well as the role of inflammation on glial cells in mood disorders. Particular emphasis is given to the alterations in presynaptic and postsynaptic neurons and glial cells, all cellular elements of the "tripartite synapse," compromising the neurotransmitters system, excitatory-inhibitory balance, and neurotrophic states of local networks in mood disorders. Together, these studies provide a foundation of knowledge about the exact role of the glial-neuronal interaction in mood disorders.

Efficacy of automatic pupillometry as a screening technique to detect autonomic dysfunction in bipolar disorder

ABSTRACT Clinical relevance Autonomic nervous system abnormalities in the pathophysiology of bipolar disorder are controversial. Pupillary features may be affected as a result of autonomic nervous system abnormalities in bipolar disorder. Small changes in pupillary responses may not be noticeable on clinical examination. Automated pupillemetries can be helpful in demonstrating these changes reliably and quantitatively. Background The aim of this study was to compare the static and dynamic pupillary responses of bipolar patients with healthy controls. In addition, pupillary response differences between mania, depression and remission stages were investigated. Methods The bipolar patient group consisted of 39 eyes of 39 patients with 13 patients in each of the stages: mania, depression and remission. The control group consisted of 39 eyes of 39 healthy volunteers. After the ophthalmic examination, static and dynamic pupillometry measurements were made. The mean pupil dilatation speed was calculated according to dynamic measurements. Static pupillometry measurements including scotopic, mesopic and photopic pupil diameters; the first dynamic measurements at 0th second and pupillary dilatation speed were used for statistical analysis. Results There was no difference static and the first dynamic pupillometry measurements between the bipolar and control groups (p > 0.05 for all parameters), but there was a significant difference in mean pupil dilatation speed (p = 0.041). No significant differences were found between the 3 groups for all static and the first dynamic pupillometry measurements and the mean pupil dilatation speed (p > 0.05). Conclusion Static and the first dynamic measurements of bipolar patients were not different from healthy controls. The mean pupil dilatation speed of bipolar patients was significantly lower, but this difference had a low effect size.

Interactive relationships of Type 2 diabetes and bipolar disorder with cognition: evidence of putative premature cognitive ageing in the UK Biobank Cohort

Type 2 diabetes (T2D) is disproportionately prevalent in bipolar disorder (BD) and is associated with cognitive deficits in psychiatrically healthy cohorts. Whether there is an interaction effect between T2D and BD on cognition remains unclear. Using the UK Biobank, we explored interactions between T2D, BD and cognition during mid and later life; and examined age-related cognitive performance effects in BD as a function of T2D. Data were available for 1511 participants with BD (85 T2D), and 81,162 psychiatrically healthy comparisons (HC) (3430 T2D). BD and T2D status were determined by validated measures created specifically for the UK Biobank. Diagnostic and age-related associations between T2D status and cognition were tested using analyses of covariance or logistic regression. There was a negative association of T2D with visuospatial memory that was specific to BD. Processing speed and prospective memory performance were negatively associated with T2D, irrespective of BD diagnosis. Cognitive deficits were evident in BD patients with T2D compared to those without, with scores either remaining the same (processing speed) or improving (visuospatial memory) as a function of participant age. In contrast, cognitive performance in BD patients without T2D was worse as participant age increased, although the age-related trajectory remained broadly equivalent to the HC group. BD and T2D associated with cognitive performance deficits across the mid-life period; indicating comorbid T2D as a potential risk factor for cognitive dysfunction in BD. In comparison to BD participants without T2D and HCs, age-independent cognitive impairments in BD participants with comorbid T2D suggest a potential premature deterioration of cognitive functioning compared to what would normally be expected.

Sexual dysfunction among males and females with bipolar disorder and healthy subjects: The burden of illness severity.

Sexual dysfunction has wide-ranging impacts on the person's functioning and quality of life, being associated with higher severity of psychiatric illnesses and poor therapeutic response. Given the paucity of data on this topic in bipolar disorder (BD), we investigated sexual functioning among males and females with BD and healthy controls (HCs) as well as whether illness severity markers and subthreshold mood symptoms were associated with sexual dysfunctions in BD patients. The study included 80 BD outpatients and 70 HCs. Sexual functioning was evaluated using the validated, gender-specific Changes in Sexual Functioning Questionnaire (CSFQ-14). BD patients had a significantly poorer sexual functioning than HCs (p< 0.00001). The odds of sexual dysfunction doubled given a one-unit increase in the number of suicide attempts (adjusted OR=2.01, 95% CI:1.23-3.55; p< 0.01) and increased by 60% for every additional hospitalization (p< 0.05). Greater illness duration was associated with arousal/orgasmic (p< 0.05) and overall sexual dysfunctions (p< 0.01). BD patients with more mixed or (hypo)manic episodes had a lower likelihood of libido loss and arousal/orgasmic disturbances (p< 0.01), respectively. Higher levels of subthreshold depressive symptoms increased by 20% the odds of sexual interest/frequency dysfunctions (p< 0.05), and up to 60% regarding orgasmic disturbances (p< 0.01). Sexual functioning may be a useful proxy of illness severity as well as a relevant dimension to more deeply characterize BD patients. Further studies are warranted to replicate our findings, to evaluate temporal associations between sexual dysfunctions and illness severity across the BD mood and treatment spectrums and to explore neurobiological underpinnings of these associations.

What can lifestyle factors tell us about cognitive dysfunction in bipolar disorder?

Affective disorders represent psychopathological entities lying on a continuum, characterized by high prevalence and functional impairment. A delay in treatment initiation might increase the burden associated with affective spectrum disorders. The present study was aimed at analyzing the correlates of a long duration of untreated illness (DUI) in these conditions. We recruited subjects diagnosed with affective disorders, both in- and outpatients, and collected information concerning socio-demographic, clinical, and psychopathological characteristics. Long DUI was defined according to previous research criteria as >2 years for Bipolar Disorders or >1 year for Depressive Disorders. Bivariate analyses were performed to compare subjects with a long and short DUI (p<0.05). A logistic regression was operated to evaluate the correlates of long DUI. In the present sample (n=135), 34.1% (n=46) subjects showed a long DUI. This subgroup presented with more physical comorbidities (p=0.003), higher body mass index (BMI) (p<0.001), more frequent anxiety onset (p=0.018), younger onset age (p=0.042), and more severe depressive symptoms (Hamilton Depression Rating Scale item 1-depressed mood (p=0.032) and item 2-guilt feelings (p=0.018)). At the logistic regression, higher severity of depressed mood (OR 1.568), higher BMI (OR 1.264), and younger age at onset (OR 0.935) were associated with long DUI. The present study confirmed a possible role of DUI as a construct underpinning higher clinical severity in affective spectrum disorders, possibly linked to worse illness course and unfavorable outcomes. Intervention strategies targeting physical comorbidities and depressive symptoms severity may decrease disease burden in subjects with a long DUI.

Altered activity in functional brain networks involved in lexical decision making in bipolar disorder: An fMRI case-control study

BackgroundBrain networks involved in language, attentional and response processes are detectable by fMRI during lexical decision (LD). Here, we investigated possible abnormalities in the functional networks involved in LD in patients with bipolar disorder (BD). MethodsfMRI and behavioural data were compared between BD (n = 25) and control (n = 21), with groups matched for age and sex. The functional brain networks involved in LD were extracted by manipulating the “word-likeness” of LD stimuli and using a multidimensional analysis method. ResultsAttentional, response and language processes were captured in separate function-specific brain networks (default mode network, response network, linguistic processing network, respectively) in the BD and control groups, replicating the results of our previous study in an independent group of healthy adults. Behaviourally, the BD group showed higher performance than the control group in the LD task. Activity in the default mode network (DMN) and the linguistic processing network (LPN) did not differ between the groups, but the BD group had higher activation than the control group in the response network (RESP). LimitationsDue to the small sample, the study is underpowered, capable of only detecting large effects. ConclusionsThe results suggest that BD may be associated with sustained activity in the RESP network, which might contribute to psychomotor dysfunction in BD. Future studies should investigate the possible link between altered RESP activation and psychomotor disturbances in BD, as well as the basis for altered RESP activity in BD.

Bipolar‐associated miR‐499‐5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2

Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR‐499‐5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR‐499‐5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR‐499‐5p impairs dendritogenesis and reduces surface expression and activity of the L‐type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory β‐subunit of Cav1.2, as a direct functional target of miR‐499‐5p in neurons. miR‐499‐5p overexpression in the hippocampus in vivo induces short‐term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR‐499‐5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress‐induced miR‐499‐5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD.

Machine learning algorithms revealed distorted retinal vascular branching in individuals with bipolar disorder

BackgroundConverging evidence designate vascular vulnerability in bipolar disorder. The predisposition progresses into distortion in time, thus detection of the vascular susceptibility may help reducing morbidity and mortality. It was aimed to assess retinal fundus vasculature in cardiovascular risk-free patients with bipolar disorder. MethodsTotal of 68 individuals (38 patients with bipolar disorder, 30 healthy controls) were enrolled. In order to avoid from degenerative processes, participants were between 18 and 45 years of age, vascular risk factors were eliminated. Microscopic retinal fundus images were processed with machine learning algorithms (multilayer perceptron and support vector machine) and artificial neural network approaches. ResultsIn comparison to the healthy control group, the bipolar disorder group had lower number of breaking points (P < 0.001), lower number of curved vessel segments (P < 0.001). Total length of smooth vessels was longer (P = 0.040), and total length of curved vessel segments was significantly shorter (P < 0.001) than the control group. Vascular endothelial growth factor levels and gender were the confounders. There were significant correlations between vascular measures and serum lipid levels. LimitationsSample size was small and patients were on various medications. ConclusionsThese results indicate distortion in retinal vascular branching in bipolar disorder. Disrupted branching may reflect disturbed prosperity of retinal vascular plexus in patients with bipolar disorder. Alterations in the retinal vessels might be indicators of disruption in cerebral vascular system efficiency and thus neurovascular unit dysfunction in bipolar disorder.

Investigation of blood-brain barrier disruption in an animal model of mania induced by D-amphetamine

• Inflammation and oxidative stress are linked to mood symptoms and cognitive dysfunction in BD. • BBB disruption has been proposed as a key mechanism of BD pathophysiology. • This study evaluated BBB disruption in a rat model of mania induced by AMPH. • AMPH and lithium did not affect BBB integrity given by brain levels of claudin-5. • TNFα and TBARS levels in specific brain regions did not differ between groups. High levels of inflammation and oxidative stress are observed in bipolar disorder (BD) being further associated with mood symptoms and cognitive dysfunction. Due to the crosstalk between the periphery and central nervous system, the blood-brain barrier (BBB) disruption has been considered a key mechanism of the BD pathophysiology. This study aimed to evaluate claudin-5 expression in the brain of a model of mania induced by D -amphetamine (AMPH). Wistar rats were injected with AMPH (2 mg/kg i.p.) and treated with lithium (47.5 mg/kg i.p.). Locomotor behavior was assessed, followed by euthanasia, blood collection, and brain removal. Tumor necrosis factor (TNF) α and thiobarbituric acid reactive substances (TBARS) were quantified in the serum and brain tissue, and claudin-5 was quantified in the brain. AMPH-injected animals exhibited increased locomotor activity. In the serum, TBARS levels were augmented in lithium-treated groups, while TNFα was not detected. In the brain, TBARS and TNFα did not differ between groups but were positively andstrongly correlated in the striatum of AMPH-injected rats. Contrary to our hypothesis, AMPH and lithium injections did not affect claudin-5 levels in the brain. The main limitations include the lack of a dynamic marker of BBB integrity and limited number of biomarkers analyzed. This is one of the first attempts to investigate the effects of AMPH on BBB integrity, and no disruption was observed. Still, we provide rationale for future research to elucidate the importance of BBB disruption in BD, recently proposed as a marker of illness progression.

Gut Microbial Dysbiosis and Cognitive Impairment in Bipolar Disorder: Current Evidence.

Recent studies have reported that the gut microbiota influences mood and cognitive function through the gut-brain axis, which is involved in the pathophysiology of neurocognitive and mental disorders, including Parkinson’s disease, Alzheimer’s disease, and schizophrenia. These disorders have similar pathophysiology to that of cognitive dysfunction in bipolar disorder (BD), including neuroinflammation and dysregulation of various neurotransmitters (i.e., serotonin and dopamine). There is also emerging evidence of alterations in the gut microbial composition of patients with BD, suggesting that gut microbial dysbiosis contributes to disease progression and cognitive impairment in BD. Therefore, microbiota-centered treatment might be an effective adjuvant therapy for BD-related cognitive impairment. Given that studies focusing on connections between the gut microbiota and BD-related cognitive impairment are lagging behind those on other neurocognitive disorders, this review sought to explore the potential mechanisms of how gut microbial dysbiosis affects cognitive function in BD and identify potential microbiota-centered treatment.

Rethinking “aggression” and impulsivity in bipolar disorder: Risk, clinical and brain circuitry features

BackgroundElevated aggression and impulsivity are implicated in Bipolar Disorder (BD); however, relationships between these behavioral constructs have not been clarified, which can lead to misconceptions with negative consequences including stigma and adverse outcomes including suicide. The study aimed to clarify brain-based distinctions between the two constructs and their associations to risk factors, symptoms and suicide thoughts and behaviors. MethodsSelf-rated Brown-Goodwin Aggression (BGA) and Barratt Impulsiveness Scale (BIS) scores were compared between adults with BD (n = 38, 74% female) and healthy controls (HC, n = 29, 64% female). Relationships were examined between BGA and BIS with childhood trauma questionnaire (CTQ), mood, comorbidities, and magnetic resonance imaging gray matter volume (GMV) assessments. ResultsIn BD, BGA and BIS total scores were both elevated and associated with childhood maltreatment (CM), particularly emotional CM, depression, substance use disorders (SUDs) and suicide attempts (SAs). BGA scores were increased by items corresponding to dysregulation of emotional and social behavior and associated with elevated mood states and suicide ideation and GMV decreases in bilateral orbitofrontal cortex and left posterior insula brain regions, previously associated with these behaviors and clinical features. BIS motor impulsiveness scores were associated with GMV decreases in anterior cingulate cortex implicated in mood and behavioral dyscontrol. Limitationsmodest sample size, self-reports ConclusionsThe findings suggest separable brain-based domains of dysfunction in BD of motor impulsiveness versus emotionally dysregulated feelings that are primarily self-directed. Both domains are associated with suicide behavior and modifiable risk factors of CM, depression and SUDs that could be targeted for prevention.

Metabolomics analysis of cerebrospinal fluid suggests citric acid cycle aberrations in bipolar disorder

Mounting evidence indicates mitochondrial dysfunction in bipolar disorder pathophysiology. Here, we employed Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of cerebrospinal fluid (CSF) samples from well-characterized bipolar disorder patients (n ​= ​67) and healthy controls (n ​= ​55) in order to measure absolute concentrations of multiple metabolites. Focusing on four citric acid cycle metabolites — citrate, glucose, lactate, and pyruvate — we found higher concentrations of both citrate and glucose in patients compared with controls after correcting for age, sex and body mass index, but only the difference in CSF citrate survived correction for multiple comparisons. Within the patient group, CSF citrate concentrations were higher among lithium users than non-users. In conclusion, this report adds further evidence for a mitochondrial dysfunction in bipolar disorder.

The Role of Kynurenines in Cognitive Dysfunction in Bipolar Disorder

Introduction: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway metabolites are key inflammatory mediators, studies investigating the association between KYN metabolism and cognition in BD are scarce. We aimed to explore the relationship between KYN metabolism and cognitive functioning across different mood states in BD. Methods: Sixty-seven patients with BD (35 depressed and 32 [hypo] manic) and 29 healthy controls were included. Cognitive functioning was assessed at 3 time intervals (baseline, 4, and 8 months) assessing processing speed, sustained attention, verbal memory, working memory, and response inhibition. Plasma samples for quantification of 3-hydroxykynurenine, quinolinic acid, and kynurenic acid (KYNA) were concurrently provided. Linear mixed models were used for statistical analysis. Results: The manic group showed deficits in all assessed cognitive domains with the exception of verbal memory at all test moments. The bipolar depression group showed deficits in the processing speed at all test moments. Throughout the whole follow-up period, KYNA was significantly lower in both patient groups than in controls. Only in the bipolar depression group, low KYNA was associated with worse global cognitive functioning (B = 0.114, p = 0.02) and slower processing speed in particular (B = 0.139, p = 0.03). Conclusion: Only in the bipolar depression group, lower KYNA was associated with worse cognitive functioning. Future large-scale longitudinal studies are warranted to confirm the role of KYN metabolites in cognitive impairment in patients with BD and the possible therapeutic implications of this relationship.