Metabolomic biomarkers for (R, S)-ketamine and (S)-ketamine in treatment-resistant depression and healthy controls: A systematic review.

BACKGROUND: Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). METHODS: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. RESULTS: A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. CONCLUSIONS: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Brain-based correlates of antidepressant response to ketamine: a comprehensive systematic review of neuroimaging studies.

Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can provide predictive and mechanistic insights, but findings are limited by small sample sizes. This systematic review covers neuroimaging studies investigating baseline (pre-treatment) and longitudinal (post-treatment) biomarkers of responses to ketamine. All modalities were included. We performed searches of five electronic databases (from inception to April 26, 2022). 69 studies were included (with 1751 participants). There was substantial methodological heterogeneity and no well replicated biomarker. However, we found convergence across some significant results, particularly in longitudinal biomarkers. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions in electrophysiological studies, post-treatment increases in functional connectivity within the prefrontal cortex, and post-treatment increases in the functional activation of the striatum. Although a well replicated neuroimaging biomarker of ketamine response was not identified, there are biomarkers that warrant further investigation.

κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

BACKGROUND: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo? METHODS: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used. RESULTS: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels. CONCLUSIONS: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion. TRIAL REGISTRATION: NCT00088699 ( ClinicalTrials.gov ).

Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis.

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

Neuroimaging Correlates of Depression after Traumatic Brain Injury: A Systematic Review.

Depression is the most frequent neuropsychiatric complication after traumatic brain injury (TBI) and is associated with poorer outcomes. Neuroimaging has the potential to improve our understanding of the neural correlates of depression after TBI and may improve our capacity to accurately predict and effectively treat this condition. We conducted a systematic review of structural and functional neuroimaging studies that examined the association between depression after TBI and neuroimaging measures. Electronic searches were conducted in four databases and were complemented by manual searches. In total, 2035 citations were identified and, ultimately, 38 articles were included, totaling 1793 individuals (median [25-75%] sample size of 38.5 [21.8-54.3] individuals). The most frequently used modality was structural magnetic resonance imaging (MRI) (n = 17, 45%), followed by diffusion tensor imaging (n = 11, 29%), resting-state functional MRI (n = 10, 26%), task-based functional MRI (n = 4, 8%), and positron emission tomography (n = 2, 4%). Most studies (n = 27, 71%) were cross-sectional. Overall, depression after TBI was associated with lower gray matter measures (volume, thickness, and/or density) and greater white matter damage. However, identification of specific brain areas was somewhat inconsistent. Findings that were replicated in more than one study included reduced gray matter in the rostral anterior cingulate cortex, pre-frontal cortex, and hippocampus, and damage in five white matter tracts (cingulum, internal capsule, superior longitudinal fasciculi, and anterior and posterior corona radiata). This systematic review found that the available data did not converge on a clear neuroimaging biomarker for depression after TBI. However, there are promising targets that warrant further study.

When Mind Meets the Brain: Essentials of Well-Coordinated Management of Psychiatric Disorders in Neurological Diseases.

BACKGROUND: The management of psychiatric disorders in neurological diseases (PDND) creates special challenges that cannot be adequately addressed by either psychiatry or neurology alone. However, the literature on clinician-friendly recommendations on how to coordinate neurological and psychiatric care is limited. OBJECTIVE: This narrative review will provide practical instructions on how to efficiently integrate psychiatric and neurological care in inpatient management of PDND. METHODS: We reviewed articles published as recently as January, 2021 in five electronic databases. We included articles that assessed human care, focused on adults, and examined how to better coordinate care between different medical specialties, particularly, between psychiatry and neurology. RESULTS: Eighty-four manuscripts were included in this review, of which 23 (27%) discussed general principles of well-coordinated care of PDND in inpatient settings (first part of this review), and 61 (73%) were used to provide recommendations in specific neurological diseases (second part of this review). CONCLUSIONS: General principles of well-coordinated care of PDND include recommendations for both the primary team (usually neurology) and the consulting team (psychiatry). Primary teams should delineate a specific question, establish roles, and follow up on the recommendations of the consulting team. Consultants should do their independent assessment, be organized and specific in their recommendations, and anticipate potential problems. One of the most important aspect to develop well-coordinated care is the establishment of clear, frank and, preferably oral, communication between the teams. Practical difficulties in the management of PDND include pharmacodynamic and pharmacokinetic interactions as well as mutual dependency between psychiatry and neurology.

Impact of childhood maltreatment on outcomes of antidepressant medication in chronic and/or recurrent depression.

BACKGROUND: While childhood maltreatment (CMT) is associated with higher rates of chronicity and recurrence in depression, whether CMT results in poorer outcomes with antidepressant medication remains unclear. METHODS: We performed secondary analyses with data from the large, representative, multisite trial Combining Medications to Enhance Depression Outcomes (CO-MED). CO-MED was a randomized, single-blinded, placebo-controlled study with 665 individuals (663 assessed for CMT) with chronic and/or recurrent Major Depressive Disorder (MDD). CMT was determined by a brief self-reported questionnaire assessing the four types of CMT defined by the Centers for Disease Control and Prevention: sexual abuse, emotional abuse, physical abuse, and neglect. Repeated measures and logistic regression analyses were used. RESULTS: Individuals with CMT did not have a differential improvement of depressive symptoms when compared to those without CMT (adjusted p=.203 for continuous analysis; adjusted p=.320 for remission rates). Neither type of antidepressant medication (adjusted p=.302) nor the age at which CMT occurred (adjusted p=.509) affected depressive symptom outcomes. There was no difference in functional improvement between individuals with and without CMT (adjusted p=.228). A history of CMT was associated with greater antidepressant side effects (p=.009). LIMITATIONS: This study investigated treatment-seeking individuals with chronic and/or recurrent MDD. Intensity and duration of CMT were not assessed. CONCLUSION: In a sample of treatment-seeking outpatients with chronic and/or recurrent MDD, a history of CMT was not associated with differential symptomatic or functional response to pharmacological treatment. However, those with CMT reported greater antidepressant side effect burden.

Childhood maltreatment and impact on clinical features of major depression in adults.

OBJECTIVES: This study examined: 1) the prevalence of childhood maltreatment (CMT) in individuals with chronic and/or recurrent depression, 2) the association between CMT and depressive symptoms, 3) the link between CMT and worse clinical presentation of depression, 4) the effects of accumulation of different types of CMT, and 5) the relationship between the age at CMT and depression. METHODS: We analyzed the baseline data of 663 individuals from the CO-MED study. CMT was determined by a brief self-reported questionnaire assessing sexual abuse, emotional abuse, physical abuse, and neglect. Correlational analyses were conducted. RESULTS: Half of the sample (n = 331) reported CMT. Those with CMT had higher rates of panic/phobic, cognitive and anhedonic symptoms than those without CMT. All individual types of maltreatment were associated with a poorer clinical presentation including: 1) earlier MDD onset; 2) more severe MDD, 3) more suiccidality, 4) worse quality of life, and functioning, and 5) more psychiatric comorbidities. Clinical presentation was worse in participants who reported multiple types of CMT. CONCLUSIONS: In chronic and/or recurrent depression, CMT is common, usually of multiple types and is associated with a worse clinical presentation in MDD. The combination of multiple types of CMT is associated with more impairment.

Post-stroke depression: A 2020 updated review.

BACKGROUND: Post-stroke depression (PSD) is common and associated with higher mortality, poorer recovery, more pronounced cognitive deficits, and lower quality of life than is stroke without depression. This manuscript will conduct an updated, comprehensive and clinically-useful review of the risk factors, pathophysiology, assessment, prevention, and treatment of PSD. METHODS: This narrative review summarizes articles obtained on PubMed, Medline, EMBase, Google Scholar and the Cochrane Database. This review prioritized articles with a more robust level of evidence, such as original articles with longitudinal data and/or larger samples, randomized controlled trials, systematic reviews, and metaanalyses. RESULTS: One hundred twenty-four articles were reviewed, of which 44 (35%) were published before 2016 and 80 (65%) that were published since 2016. DISCUSSION: Rates of PSD range from 18 to 33%, yet it is vastly underdiagnosed and undertreated. Risk factors for PSD include female sex, history of psychiatric illness, large or multiple strokes, injuries in frontal/anterior areas or in the basal ganglia, stroke occurrence within the past year, poor social support, and pronounced disability. The pathophysiology of PSD is multifactorial and likely involves decreased levels of monoamines, abnormal neurotrophic response, increased inflammation with dysregulation of hypothalamic-pituitary-adrenal axis, and glutamate-mediated excitotoxicity. The evidence for preventive interventions for PSD is somewhat inconsistent and modest. The best treatment for PSD consists of the combination of pharmacological, psychosocial and stroke-focused interventions. CONCLUSION: PSD is a common, treatable condition that is associated with several negative outcomes. Early detection and proper management are critical to obtain better outcomes in individuals with PSD.

Depressive Disorders in HIV/AIDS: A Clinically Focused Narrative Review.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Assess strategies for diagnosing depressive disorders in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)• Identify factors that contribute to the development of depressive disorders in HIV/AIDS• Evaluate strategies for managing depressive disorders in HIV/AIDS ABSTRACT: Depressive disorders and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) are associated with major socioeconomic burdens. The negative impact of depressive disorders on HIV/AIDS is well known, including on treatment outcomes. Unfortunately, depressive disorders are underdiagnosed and undertreated in seropositive persons. This review summarizes clinically useful information on depressive disorders in HIV/AIDS. More specifically, we address assessment, differential diagnosis, contributing factors, management, and common challenges in the treatment of depressive disorders in seropositive individuals. Assessment and diagnosis of depression may be challenging in seropositive persons because of several biopsychosocial particularities associated with HIV/AIDS. One of the difficulties is the overlap between depression and HIV/AIDS symptoms, particularly in individuals with advanced AIDS, requiring consideration of a broad differential diagnosis. Several factors related to HIV/AIDS status contribute to the higher rates of depressive disorders, including infectious-immunological, psychosocial, and exogenous factors. The treatment of depressive disorders in HIV/AIDS involves three groups of interventions: (1) pharmacological interventions, (2) psychotherapeutic interventions, and (3) management of other contributing factors. Challenges in management include poor adherence to treatment and the risk of suicide. We provide evidence-based recommendations to improve assessment and management of depressive disorders in seropositive persons.

Positive and negative valence systems in major depression have distinct clinical features, response to antidepressants, and relationships with immunomarkers.

BACKGROUND: Heterogeneity in major depressive disorder (MDD) is well recognized but not well understood. Core depressive features are reward and emotional symptoms, which reflect dysfunctions in the positive valence (PV) and negative valence (NV) systems, respectively. This study assessed whether PV and NV systems (based on selected symptoms) were associated with different clinical features, antidepressant response, and levels of immunomarkers in adults with MDD. METHODS: These analyses used data from combining medications to enhance depression outcomes study (N = 665; n = 166 for immunomarkers). PV and NV symptom scores were extracted from the clinician-rated 30-item Inventory of Depressive Symptomatology. Correlational analyses were conducted. RESULTS: PV and NV symptom scores were substantially associated with different clinical features. PV symptoms (impaired motivation, impaired energy, and anhedonia) were independently associated with female gender (p < .001), older age (p = .012), and higher cognitive and physical impairment (p < .001) according to the 7-item Cognitive and Physical Functioning Questionnaire. Conversely, NV symptoms (anxiety and interpersonal sensitivity) were independently associated with younger age (p = .013), more anxious comorbidities (p = .001 for generalized anxiety disorder and p = .002 for social phobia) and other commonly associated noncriterion symptoms (p < .001). Overall, PV symptoms were more responsive to antidepressants than NV symptoms (p < .0001; Cohen's d = .455). A PV symptom score was positively correlated with the concentration of three proinflammatory and one anti-inflammatory factor. In contrast, an NV symptom score was negatively associated with only one proinflammatory immunomarker. CONCLUSIONS: PV and NV system functions appear to be reflected in selected clinical symptoms that differentially relate to other clinical features, treatment outcomes, and immunological function.

Aggression directed towards others vs. aggression directed towards the self: clinical differences between intermittent explosive disorder and nonsuicidal self-injury

Objective: To investigate the clinical differences between intermittent explosive disorder (IED) (disorder of aggression primarily directed towards others) and nonsuicidal self-injury (NSSI) (disorder of aggression predominantly directed towards the self) in order to better understand the different clinical subtypes of aggression. Methods: We used treatment-seeking samples to compare demographic and clinical correlates between 82 participants with IED and 55 participants with NSSI. Results: The IED group was older, more likely to be male, in a relationship, and employed than the NSSI group. With respect to clinical variables, the NSSI group had more severe depressive symptoms and more social adjustment difficulties. Regarding psychiatric co-morbidities, the IED group had higher rates of generalized anxiety disorder. On the other hand, the NSSI group had higher rates of major depressive disorder, agoraphobia, substance use disorder, and bulimia nervosa. Conclusions: Individuals with NSSI may benefit from better management of psychiatric comorbidities, specifically depressive symptoms and social adjustment difficulties. Conversely, the treatment of individuals with IED may be improved by targeting comorbid generalized anxiety disorder. Our results provide important insight for the development of tailored interventions for specific subtypes of aggression.

Aggression directed towards others vs. aggression directed towards the self: clinical differences between intermittent explosive disorder and nonsuicidal self-injury.

OBJECTIVE: To investigate the clinical differences between intermittent explosive disorder (IED) (disorder of aggression primarily directed towards others) and nonsuicidal self-injury (NSSI) (disorder of aggression predominantly directed towards the self) in order to better understand the different clinical subtypes of aggression. METHODS: We used treatment-seeking samples to compare demographic and clinical correlates between 82 participants with IED and 55 participants with NSSI. RESULTS: The IED group was older, more likely to be male, in a relationship, and employed than the NSSI group. With respect to clinical variables, the NSSI group had more severe depressive symptoms and more social adjustment difficulties. Regarding psychiatric co-morbidities, the IED group had higher rates of generalized anxiety disorder. On the other hand, the NSSI group had higher rates of major depressive disorder, agoraphobia, substance use disorder, and bulimia nervosa. CONCLUSIONS: Individuals with NSSI may benefit from better management of psychiatric comorbidities, specifically depressive symptoms and social adjustment difficulties. Conversely, the treatment of individuals with IED may be improved by targeting comorbid generalized anxiety disorder. Our results provide important insight for the development of tailored interventions for specific subtypes of aggression.

Cognitive-behavioral group therapy for intermittent explosive disorder: description and preliminary analysis

Objectives: To evaluate the efficacy of a group therapy based on cognitive-behavioral techniques customized for intermittent explosive disorder (IED). The current report presents the preliminary results of a clinical trial comparing pre- and post-intervention scores in different anger dimensions. Methods: The studied sample consisted of 84 treatment-seeking subjects. The mean (standard deviation) age was 43.0 (11.9) years, and 78% were male. The therapeutic group program consisted of 15 weekly sessions plus three maintenance sessions. The sessions lasted approximately 90 minutes each. Results: No differences were found in demographic profile and pre-treatment status between subjects who completed treatment (n=59) and dropouts (n=25). Comparison of State-Trait Anger Expression Scale (STAXI) scores pre- and post-treatment showed statistically significant changes in all anger scales and subscales of the questionnaire. Conclusion: This preliminary report is a significant addition to currently scarce clinical data. Our findings provide further evidence that structured cognitive-behavioral group therapy, with a focus on anger management and cognitive coping, may be a promising approach to the treatment of IED.

Gambling disorder and obsessive-compulsive personality disorder: A frequent but understudied comorbidity.

Background and aims Epidemiological data have suggested that the prevalence of co-occurring personality disorders is particularly high in people with gambling disorder (GD). Among the personality disorders, obsessive-compulsive personality disorder (OCPD) appears to be the most common problem. The objective of this study was to investigate the clinical presentation of GD with and without co-occurring OCPD. Methods We studied 25 subjects with current GD and lifetime diagnosis of OCPD. They were matched for age and gender with 25 individuals with current GD but no lifetime diagnosis of any personality disorder. Results Subjects with GD and OCPD demonstrated (a) lower severity of gambling symptoms, (b) slower progression from recreational gambling to full-blown GD, (c) preferred individual forms of betting, (d) identified more triggers to gambling (specially the availability of money and stress); and (e) reported less negative impact on relational problems due to GD. Conclusions Our research provides further insight on GD co-occurring with OCPD, such as increasing social support and improvement of coping skills, especially to deal with financial difficulties and stress. Our findings may lead to more customized and effective therapeutic approaches to this frequent comorbidity.

Cognitive-behavioral group therapy for intermittent explosive disorder: description and preliminary analysis.

OBJECTIVES: To evaluate the efficacy of a group therapy based on cognitive-behavioral techniques customized for intermittent explosive disorder (IED). The current report presents the preliminary results of a clinical trial comparing pre- and post-intervention scores in different anger dimensions. METHODS: The studied sample consisted of 84 treatment-seeking subjects. The mean (standard deviation) age was 43.0 (11.9) years, and 78% were male. The therapeutic group program consisted of 15 weekly sessions plus three maintenance sessions. The sessions lasted approximately 90 minutes each. RESULTS: No differences were found in demographic profile and pre-treatment status between subjects who completed treatment (n=59) and dropouts (n=25). Comparison of State-Trait Anger Expression Scale (STAXI) scores pre- and post-treatment showed statistically significant changes in all anger scales and subscales of the questionnaire. CONCLUSION: This preliminary report is a significant addition to currently scarce clinical data. Our findings provide further evidence that structured cognitive-behavioral group therapy, with a focus on anger management and cognitive coping, may be a promising approach to the treatment of IED.

Major depressive disorder and depressive symptoms in intermittent explosive disorder.

It is estimated that between 1.7 and 2.6 million people have had intermittent explosive disorder (IED) during their life in the United States alone. Co-occurring psychiatric disorders are very common in IED, being major depressive disorder arguably the most common. The objective of this study was to examine the clinical correlates of IED and depressive manifestations in 74 treatment-seeking subjects. After controlling for confounders, there were associations between major depressive disorder and severity of depressive symptoms, and (a) higher assault scores, (b) more severe hostile behavior and (c) worse social adjustment. Management of depressive symptoms may be an important for IED treatment.

Bipolar disorder and tobacco smoking: Categorical and dimensional clinical correlates in subjects from the Brazilian bipolar research network.

BACKGROUND: People with bipolar disorder (BD) have high rates of smoking. However, the scientific literature examining the association between clinical outcomes in BD and tobacco smoking is still limited and there are conflicting results. The objective of the current study was to comprehensively investigate associations between BD and tobacco smoking in a large Brazilian sample. METHODS: This study evaluated 336 outpatients from the Brazilian Bipolar Research Network, which is a collaboration between three large academic centers in Brazil. MAIN FINDINGS: Regarding the categorical analysis (i.e. current smokers versus non-smokers), tobacco smokers showed: 1) a higher percentage of individuals identifying as Non-Caucasians; 2) a longer duration of illness; 3) a longer duration of untreated illness; 4) more severe manic symptoms; 4) a stronger family history of mood disorder; and 6) a higher current prevalence of alcohol/substance use disorder. The dimensional analysis in smokers (i.e. number of cigarettes per day versus clinical variables) found a positive correlation between number of cigarettes per day and a) age, b) age at onset of BD, c) duration of illness, and d) current diagnosis of panic disorder. CONCLUSION: This study found important clinical correlates of tobacco smoking in BD subjects. We observed that the variables associated with current smoker status (categorical approach) are not necessarily correlated with number of cigarettes per day (dimensional approach). Duration of illness appears to be a particularly relevant clinical variable in the association between BD and tobacco smoking.

How to measure monetary losses in gambling disorder? An evidence-based refinement.

Diverse monetary measures have been utilized across different studies in gambling disorder (GD). However, there are limited evidence-based proposals regarding the best way to assess financial losses. We investigated how different variables of monetary losses correlate with validated assessments of gambling severity and overall functioning in a large sample of subjects with GD (n = 436). We found that relative monetary variables (i.e. when financial losses were evaluated in relation to personal income) showed the most robust correlations with gambling severity and overall psychosocial functioning. Percentage of monthly income lost from gambling was the variable with the best performance.