Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this common causal network (CCN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis (Principal Component Analysis, PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CCN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CCN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes. This evidence further supports that treatment interventions converge on a CCN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Reviewing the neurobiology of electroconvulsive therapy on a micro- meso- and macro-level.

BACKGROUND: Electroconvulsive therapy (ECT) remains the one of the most effective of biological antidepressant interventions. However, the exact neurobiological mechanisms underlying the efficacy of ECT remain unclear. A gap in the literature is the lack of multimodal research that attempts to integrate findings at different biological levels of analysis METHODS: We searched the PubMed database for relevant studies. We review biological studies of ECT in depression on a micro- (molecular), meso- (structural) and macro- (network) level. RESULTS: ECT impacts both peripheral and central inflammatory processes, triggers neuroplastic mechanisms and modulates large scale neural network connectivity. CONCLUSIONS: Integrating this vast body of existing evidence, we are tempted to speculate that ECT may have neuroplastic effects resulting in the modulation of connectivity between and among specific large-scale networks that are altered in depression. These effects could be mediated by the immunomodulatory properties of the treatment. A better understanding of the complex interactions between the micro-, meso- and macro- level might further specify the mechanisms of action of ECT.

Contributions of age and clinical depression to metacognitive performance.

One aspect of metacognition is the ability to judge the accuracy of our own performance, even in the absence of external feedback, which is often measured using confidence ratings. Past research suggests that confidence is lower in Major Depressive Disorder (MDD). Less is known about the ability of MDD patients to discriminate correct from incorrect performance (metacognitive efficiency). The metacognitive performance of aged MDD patients (62-89y) was compared to an age-matched control group. A younger control group (21-28y) was included to also explore the relationshipbetweenageandmetacognitive performance. We found no difference in confidence bias nor metacognitive efficiency between MDD patients and age-matched controls.We found age-related differences in metacognition:normal aging was associated with higher confidencebut lower metacognitive efficiency. The overconfidence was specifically driven by overconfidence in incorrect trials. Our results point to the importance ofage while investigating the relation between MDD and metacognitive performance.

White matter changes following electroconvulsive therapy for depression: a multicenter ComBat harmonization approach.

ECT is proposed to exert a therapeutic effect on WM microstructure, but the limited power of previous studies made it difficult to highlight consistent patterns of change in diffusion metrics. We initiated a multicenter analysis and sought to address whether changes in WM microstructure occur following ECT. Diffusion tensor imaging (DTI) data (n = 58) from 4 different sites were harmonized before pooling them by using ComBat, a batch-effect correction tool that removes inter-site technical variability, preserves inter-site biological variability, and maximizes statistical power. Downstream statistical analyses aimed to quantify changes in Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD), by employing whole-brain, tract-based spatial statistics (TBSS). ECT increased FA in the right splenium of the corpus callosum and the left cortico-spinal tract. AD in the left superior longitudinal fasciculus and the right inferior fronto-occipital fasciculus was raised. Increases in MD and RD could be observed in overlapping white matter structures of both hemispheres. At baseline, responders showed significantly smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus compared with non-responders. By harmonizing multicenter data, we demonstrate that ECT modulates altered WM microstructure in important brain circuits that are implicated in the pathophysiology of depression. Furthermore, responders appear to present a more decreased WM integrity at baseline which could point toward a specific subtype of patients, characterized by a more altered neuroplasticity, who are especially sensitive to the potent neuroplastic effects of ECT.

Cognitive trajectories during and after electroconvulsive therapy in patients with MDE: Taking different perspectives.

Cognitive function during an ECT care pathway is mainly investigated at the group level by analyzing mean cognitive test scores over time. However, there are important inter-individual differences, with some patients experiencing residual invalidating cognitive deficits. This study provides a nuanced examination of cognitive functioning during and after ECT by combining three approaches for data analysis. A cognitive test battery was assessed in seventy-three ECT-treated patients with a Major Depressive Episode (MDE) at up to five time points (baseline, immediately prior to the third session and 1 week, 3 months and 6 months after completion of the index course). Group-level changes in cognitive function were investigated using linear mixed models and individual-level changes were examined using Reliable Change Indices (RCI). The presence of patient subgroups with similar cognitive trajectories was explored using Latent Class Growth Analysis (LCGA). At the group level, there was a temporary deterioration in processing speed, verbal memory and retrograde amnesia during and after index course of ECT. Individual-level analyses revealed considerable variability in cognitive effects of ECT. Three patient classes with a similar cognitive trajectory could be identified, all with a rather parallel courses over time, thus mainly differing in terms of pre-ECT cognitive functioning.

Which residual symptoms predict relapse after successful electroconvulsive therapy for late-life depression?

The risk of relapse following successful acute-phase treatment of late-life depression (LLD), including electroconvulsive therapy (ECT), is substantial. In order to improve reliable prediction of individuals' risk of relapse, we assessed the association between individual residual symptoms following a successful acute course of ECT for LLD and relapse at six-month follow-up. This prospective cohort study was part of the MODECT study, which included 110 patients aged 55 years and older with major depressive disorder. Participants who showed response to the index ECT course were monitored for relapse for six months. We used multivariable stepwise logistic regression models to assess the association between the scores on the 10 individual Montgomery-Åsberg Depression Rating Scale (MADRS) items at the end of the acute ECT course and relapse at six-month follow-up. Of the 80 responders with available six-month follow-up data (58.75% of which had psychotic features at baseline), 36.25% had relapsed. Higher scores on the MADRS items 'reduced sleep' (odds ratio (OR) = 2.03, 95% confidence interval (CI) = 1.11-3.69, p = 0.0214) and 'lassitude' (OR = 1.62, 95% CI = 1.00-2.62, p = 0.0497) at the end of the acute ECT course were significantly associated with increased risk of relapse at six-month follow-up. In conclusion, some residual depressive symptoms, including sleep disturbance and lassitude, may help better identify patients vulnerable to relapse following a successful acute course of ECT for LLD. If these findings can be replicated, studies assessing interventions that target specific residual symptoms may further reduce post-ECT depressive relapse rates.

Long-term Outcome Following Electroconvulsive Therapy for Late-Life Depression: Five-Year Follow-up Data From the MODECT Study.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for late-life depression (LLD). Research addressing long-term outcome following an acute course of ECT for LLD is limited. We aimed to describe relapse, cognitive impairment and survival 5 years after a treatment with ECT for severe LLD, and assess the association of clinical characteristics with all three outcome measures. METHODS: This cohort study was part of the Mood Disorders in Elderly treated with ECT (MODECT) study, which included patients aged 55 years and older with major depressive disorder. Data regarding clinical course, cognitive impairment and mortality were collected 5 years after the index ECT course. We used multivariable Cox proportional hazards models and logistic regression models to assess the association of clinical characteristics with relapse and survival, and cognitive impairment, respectively. RESULTS: We studied 110 patients with a mean age of 72.9 years. 67.1% of patients who showed response at the end of the index ECT course relapsed, and the included clinical characteristics were not significantly associated with the risk of relapse. 38.8% of patients with available data showed cognitive impairment at five-year follow-up. 27.5% were deceased; higher age and a higher number of previous psychiatric admissions were significantly associated with increased risk of mortality. CONCLUSIONS: Five-year outcome after a course of ECT for severe LLD seems to be in line with long-term outcome following other acute treatments for severe LLD in terms of relapse, cognitive impairment and survival. Additional studies aimed at improving long-term outcome in severe LLD are warranted.

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. METHODS: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. RESULTS: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. CONCLUSIONS: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry.

Relapse after abrupt discontinuation of maintenance electroconvulsive therapy during the COVID-19 pandemic.

OBJECTIVE: Maintenance electroconvulsive therapy (M-ECT) is considered an effective relapse prevention strategy in severe mood and psychotic disorders. How long M-ECT should be continued, and what the outcome is after its discontinuation has not been adequately studied. In our tertiary psychiatric hospital, M-ECT treatments were suspended at the start of the COVID-19 pandemic. We aimed to determine the 6-month relapse rate and time to relapse after abrupt discontinuation of M-ECT and to assess the impact of patient and treatment characteristics on the risk of relapse. METHODS: Eighty-one patients whose M-ECT was discontinued abruptly were followed up prospectively for 6 months, or until relapse (i.e., hospital admission, restart of ECT, change of pharmacotherapy, or suicide (attempt)). We used multivariable Cox proportional hazards models to assess the impact of patient and treatment characteristics on the risk of relapse. RESULTS: Thirty-six patients (44.44%) relapsed within 6 months following abrupt discontinuation of M-ECT. A greater number of previous acute ECT courses, a diagnosis of psychotic disorder (compared with major depressive disorder or bipolar disorder), and a shorter interval between M-ECT treatments at the time of discontinuation were significantly associated with increased risk of relapse. CONCLUSION: Almost half of the patients relapsed, similar to the relapse rate after a successful acute course of ECT. Patients with a shorter interval between M-ECT treatments at the time of discontinuation seem to be at increased risk, as well as patients with a diagnosis of psychotic disorder, compared to patients with mood disorders.

Movement, mood and cognition: Preliminary insights into the therapeutic effects of electroconvulsive therapy for depression through a resting-state connectivity analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective treatment for depression but how it achieves its clinical effects remains unclear. METHODS: We set out to study the brain's response to ECT from a large-scale brain-network perspective. Using a voxelwise analysis, we looked at resting-state functional connectivity before and after a course of ECT at the whole-brain and the between- and within-network levels in 17 patients with a depressive episode. Using a group-independent component analysis approach, we focused on four networks known to be affected in depression: the salience network (SN), the default mode network (DMN), the cognitive executive network (CEN), and a subcortical network (SCN). Our clinical measures included mood, cognition, and psychomotor symptoms. RESULTS: We found ECT to have increased the connectivity of the left CEN with the left angular gyrus and left middle frontal gyrus as well as its within-network connectivity. Both the right CEN and the SCN showed increased connectivity with the precuneus and the anterior DMN with the left amygdala. Finally, improvement of psychomotor retardation was positively correlated with an increase of within-posterior DMN connectivity. LIMITATIONS: The limitations of our study include its small sample size and the lack of a control dataset to confirm our findings. CONCLUSION: Our voxelwise data demonstrate that ECT induces a significant increase of connectivity across the whole brain and at the within-network level. Furthermore, we provide the first evidence on the association between an increase of within-posterior DMN connectivity and an improvement of psychomotor retardation, a core symptom of depression.

Inflammatory Markers May Inform the Effects of Electroconvulsive Therapy on Cognition in Patients with Depression.

INTRODUCTION: The neurobiological mechanisms underlying the acute cognitive effects of electroconvulsive therapy (ECT) remain poorly understood. Prior research has shown that proinflammatory cytokines such as IL-6, TNF-α, IL1-ß, and IL-10 may interfere with cognitive functioning. Interestingly, immunomodulation is one of the proposed modes of action of ECT. This study investigates whether changes of peripheral levels of IL-6, TNF-α, IL1-ß, and IL-10 are related to changes in cognitive functioning following ECT. METHODS: In the week before and 1 week after an acute course of ECT, 62 patients suffering from depression underwent a neuropsychological evaluation to assess their processing speed using the Symbol Digit Substitution Test (SDST), verbal episodic memory using the Hopkins Verbal Learning Test-Revised (HVLT-R), and their retrospective autobiographic memory using the Autobiographical Memory Interview (AMI) with the peripheral inflammatory markers being measured at the same 2 time points. RESULTS: Patients improved drastically following ECT, while their main performance on both the HVLT-R and AMI declined and their SDST scores remained stable. The levels of IL-6 and IL1-ß had both decreased, where the decrease in IL-6 was related to the decrease in HVLT-R scores. Higher baseline IL-10 levels were associated with a more limited decrease of the HVLT-R scores. CONCLUSION: Our findings tentatively suggest that the effects of ECT on verbal episodic memory may be related to the treatment's immunomodulatory properties, most notably due to decreased IL-6 levels. Moreover, baseline IL-10 appears to be a potential biomarker to predict the effects of ECT on verbal episodic memory. Whilst compelling, the results of this study should be interpreted with caution as, due to its exploratory nature, no correction for multiple comparisons was made. Further, a replication in larger cohorts is warranted.

Does lithium prevent relapse following successful electroconvulsive therapy for major depression? A systematic review and meta-analysis.

OBJECTIVE: The risk of relapse following successful antidepressant treatment, including electroconvulsive therapy (ECT), is substantial. Lithium has been suggested to effectively prevent relapse, yet data remain limited and inconclusive. We performed a systematic review and meta-analysis to examine the efficacy of continuation treatment with lithium in preventing relapse following a successful acute course of ECT in patients with major depression, in comparison to continuation treatment without lithium. We also assessed the role of several study characteristics, possibly impacting the treatment effect. METHODS: A systematic literature search, using the PubMed, Embase, Web of Science, and Cochrane Library databases (up to June 2020), was conducted for prospective and retrospective studies, including patients with unipolar or bipolar depression, that assessed the efficacy of lithium for post-ECT depressive relapse prevention. RESULTS: Of 2556 records screened, 14 articles reporting on 9748 participants who received continuation treatment either with (N = 1571) or without lithium (N = 8177) were included in the meta-analysis. Patients receiving lithium were less likely to experience depressive relapse after a successful acute course of ECT, compared to patients receiving post-ECT prophylaxis without lithium (weighted odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.34, 0.82), with a number needed to treat (NNT) of 7 (95% CI = 4, 21). We found some limited evidence that older patients may benefit more from continuation treatment with lithium, compared to younger patients. Using the GRADE criteria, the quality of evidence for our outcome measure (i.e., relapse rate) was rated as very low. CONCLUSION: Continuation treatment with lithium may have superior efficacy in reducing the risk of relapse after a successful acute ECT course for major depression, in comparison to continuation treatment without lithium. High-quality studies are needed to confirm this finding.

Improvement of psychomotor retardation after electroconvulsive therapy is related to decreased IL-6 levels.

BACKGROUND: Prior studies suggest that IL-6 may be involved in the pathophysiology of psychomotor symptoms in depression. Electroconvulsive therapy (ECT), as yet the most effective biological treatment of severe depression, is known to improve psychomotor functioning, while recent studies have shown a decrease in the elevated IL-6 levels of depressed patients following ECT. OBJECTIVES: This study investigates whether the improvement in psychomotor functions in patients with depression after ECT is related to changes in IL-6 levels. METHODS: Peripheral IL-6 was quantified and the severity of psychomotor agitation and retardation determined using the CORE assessment of psychomotor symptoms in 62 patients with a (unipolar or bipolar) depressive episode within one week before and within one week after their course of ECT. RESULTS: IL-6 levels had decreased significantly following ECT and both psychomotor retardation and agitation had improved. The decrease in IL-6 levels was related to the improvement of psychomotor retardation, with post-hoc analysis revealing that higher baseline IL-6 levels positively correlated with higher psychomotor retardation scores. CONCLUSION: With this study, we provide the first evidence that the improvement of psychomotor retardation after ECT for depression is related to the immunomodulatory properties of the treatment, most specifically the decrease in IL-6 levels.

Toward Targeted ECT: The Interdependence of Predictors of Treatment Response in Depression Further Explained.

OBJECTIVE: Several clinical variables assumed to be predictive of electroconvulsive therapy (ECT) outcome in major depressive disorder show substantial interrelations. The current study tries to disentangle this interdependence to distill the most important predictors of treatment success to help improve patient-treatment matching. METHODS: We constructed a conceptual framework of interdependence capturing age, episode duration, and treatment resistance, all variables associated with ECT outcome, and the clinical symptoms of what we coin core depression, ie, depression with psychomotor agitation, retardation, psychotic features, or a combination of the three. The model was validated in a sample of 73 patients with a major depressive episode according to DSM-5 treated twice weekly with ECT (August 2015-January 2018) using path analyses, with the size and direction of all direct and indirect paths being estimated using structural equation modeling. Reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores during treatment was the ECT outcome measure. RESULTS: The baseline presence of psychomotor agitation, retardation, and/or psychotic symptoms strongly correlated with beneficial ECT outcome (z = 0.84 [SE = 0.17]; P < .001), and the association between age and the effect of ECT appears to be mediated by their presence (z = 0.53 [SE = 0.18]; P = .004). There was no direct correlation between age and ECT response (P = .479), but there was for episode duration and ECT outcome (z = -0.38 [SE = 0.08]; P < .001). CONCLUSIONS: ECT is a very effective treatment option for severe depressive disorder, especially for patients suffering from severe depression characterized by the presence of psychomotor agitation, psychomotor retardation, psychotic symptoms, or a combination of these 3 features, with the chance of a beneficial outcome being reduced in patients with a longer episode duration. Age may heretofore have been given too much weight in ECT decision making. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02562846.

Inflammation, Hippocampal Volume, and Therapeutic Outcome following Electroconvulsive Therapy in Depressive Patients: A Pilot Study.

INTRODUCTION: Electroconvulsive therapy (ECT) influences the concentration of peripheral inflammatory markers, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In which way this immune effect contributes to the impact of ECT on the central nervous system in depression remains unknown. OBJECTIVE: The aim of this study was to examine whether the hippocampal volumetric increase in depressed patients treated with ECT is related to changes in peripheral IL-6 and TNF-α levels. METHODS: IL-6 and TNF-α plasma levels were measured in 62 patients 1 week before and after an acute course of ECT. Hippocampal volumes were analyzed in a magnetic resonance imaging (MRI) subsample of 13 patients at the same time points. RESULTS: A significant decrease in IL-6 levels was observed in the total sample and a significant increase in hippocampal volume in the MRI subsample. The reduction of peripheral IL-6 correlated with an increase in total hippocampal volume. A more limited decrease of TNF-α correlated with a more limited increase of both the total and left hippocampus volumes. CONCLUSION: This pilot study is the first to highlight the link between peripheral immune changes and hippocampal volume increase following ECT. Further research is required to conclude whether ECT indeed exerts its central effect on the brain via changes of peripheral inflammatory markers.

The basal ganglia: A central hub for the psychomotor effects of electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective biological treatment for depression. Aside the well-known therapeutic effect on mood symptoms, it has also a unique positive impact on psychomotor agitation and retardation, which are core symptoms of depression. The neurobiology behind these effects, however, remains unclear. The basal ganglia are proposed to be important regions in the pathogenesis of psychomotor symptoms in depression. Since ECT can trigger neuroplasticity in these subcortical nuclei, we speculate that ECT-induced volumetric changes of the basal ganglia will positively influence psychomotor symptoms. METHODS: Psychomotor symptoms were analyzed in 17 patients with severe depression before and after an acute ECT course using a CORE assessment of the retardation, agitation, and non-interaction domains. The volumes of the caudate, putamen, pallidum, and accumbens regions were determined using magnetic resonance imaging one week before and after ECT. RESULTS: Psychomotor functions had improved significantly after ECT and significant volume increases were found for the accumbens region, the putamen, and pallidum. The volume increase of the nucleus accumbens correlated with an improvement of psychomotor retardation, while the volume increase of the pallidum correlated negatively with an improvement of the agitation subscore. CONCLUSION: Our findings support the notion of an association between the impact of ECT on depression-related psychomotor symptoms and volume increases of the accumbens region and pallidum, pointing to the importance of the basal ganglia in the therapeutic effect of ECT on psychomotor functioning.

DSM-5 Assessments of the Level of Personality Functioning: Intrapersonal and Interpersonal Functioning.

Objective: In DSM-5, Section III, the Level of Personality Functioning (LPF) was proposed as a severity index of personality disorders (PDs), but as it reflects both trait-like (availability) and state-like (accessibility) features, of which, moreover, the relationship with the experience of patients is unclear, we critically examined LPF in patients with general psychopathology. Method: This study compared the validity of the direct Inventory of Personality Organization (IPO), and the indirect Differentiation-Relatedness Scale (DRS) LPF-measure, in relation to measures of intrapersonal and interpersonal functioning. The sample consisted of 70 inpatients with general psychopathology and no primary PDs. Associations of both measures with DSM-PDs were examined, with and without controlling for clinical distress. Results: The IPO was significantly related to age and clinical distress. When controlling for clinical distress, the IPO was still associated with cluster A (odd) and B (erratic) PD features, high levels of self-criticism, conflict in relationships and low levels of adaptive coping strategies. The DRS was only related to the schizotypical PD. Conclusions: In patients with general psychopathology, both the IPO and the DRS, appear to have limitations in measuring LPF. The IPO seems to be prone to state effects, although correlations with PDs remained significant when controlling for clinical distress. The DRS seemed to be more independent from clinical distress but was unexpectedly unrelated to features of personality pathology. DRS reflects availability, while IPO also reflects different degrees of accessibility of LPF in PDs.